In MDS, the bone marrow produces reduced amounts of mature blood cells of all types, including red blood cells, so people with MDS are especially at risk for anemia.

Red blood cells are often the first to be affected by MDS. At the time of their diagnosis, more than half of people with MDS have anemia that requires blood transfusions. Others “go several years” before they develop anemia, wrote Dr. Steensma.

Overall, “about 90 percent of patients will have anemia during the course of disease and most will require [blood] transfusions at some point,” wrote Dr. Esther Oliva, who has published research on MDS in Leukemia & Lymphoma and other journals, in an e-mail to the Beacon.

Symptoms

Anemia can lead to symptoms that can have a major impact on MDS patients’ daily lives. People with MDS and anemia often experience chronic tiredness, chest pain, headaches, problems concentrating, shortness of breath, fast or irregular heartbeat, pale skin, chilled sensations, cold hands and feet, and dizziness. Patients may feel the effects of anemia intensify when standing or after exercise.

The tiredness may be especially troublesome. “Patients with MDS often experience profound fatigue.  Anemia exacerbates that fatigue, though the fatigue can be quite problematic even in people with only mild anemia,” wrote Dr. Steensma.

“Low energy levels and frequent hospital visits can even impair patients’ social lives,” added Dr. Oliva.

Untreated, anemia may lead to nerve damage and decreased mental capacity. The heart may also become overworked as it rapidly pumps blood to compensate for the lack of sufficient oxygen-carrying red blood cells, which may cause heart problems or heart failure. Severe cases of anemia can lead to death.

Risk Factors

MDS patients who are most at risk for anemia have certain other conditions, including inflammatory disorders, kidney impairment, or vitamin B12 and folate deficiency. Certain medications, including aspirin, ibuprofen, anticonvulsant drugs, and certain drugs used to treat HIV or hypertension, can also increase the risk for anemia.

People with higher-risk MDS are more likely to need blood transfusions for their anemia than people with lower-risk MDS. About 40 percent of people with low-risk MDS receive blood transfusions for anemia, while 80 percent of people with high-risk MDS do. People who have had MDS for longer may also be more likely to need transfusions.

Diagnosis

To diagnose anemia, doctors take patients’ medical histories, perform a physical exam, and draw blood samples to perform a complete blood count. A complete blood count measures the levels of red blood cells and hemoglobin, the oxygen-carrying protein found in red blood cells. Doctors examine the shape, size, and color of the red blood cells, to determine the underlying cause of the anemia.

A doctor may also find a patient’s anemia from the bone marrow exam used to diagnose MDS.

When found, anemia is classified as mild, moderate, or severe, depending on how much hemoglobin there is in the patient’s blood. People with mild anemia may not feel any symptoms. People with moderate anemia feel symptoms, and people with severe anemia are treated right away, as severe anemia can be lethal.

Treatment

Severe anemia in MDS patients is most commonly treated with red blood cell transfusions, which are done in a hospital or clinic. During a transfusion, the patient receives donated red blood cells through a tube connected to a needle inserted in the patient’s vein. A transfusion takes two to three hours per unit of blood, according to the National Marrow Donor Program. Transfusions provide relief from anemia symptoms within 24 hours, but the effects are short-lived, sometimes lasting less than a week.

Treatments for MDS can also help with anemia by stimulating blood cells to mature. Studies show the drug Vidaza (azacitidine) decreases the need for blood transfusions, and Revlimid (lenalidomide) can eliminate the need for transfusions in people with MDS. Melphalan and Ara-C (cytosine arabinoside) eliminate abnormal, immature red blood cells. However, Dacogen (decitabine) has been shown to decrease red blood cell counts.

For less severe anemia or to prevent the condition altogether, people with MDS often take drugs called erythropoietin (EPO) and granulocyte colony-stimulating factor (G-CSF). EPO and G-CSF increase blood cell production. EPO usually provides relief within six to eight weeks and works best for people who do not require frequent transfusions or do not require transfusions at all. With G-CSF, “the earlier the treatment is initiated, the faster the response,” wrote Dr. Oliva.

Complications of Treatment

Frequent red blood cell transfusions may cause the body to store excess iron from hemoglobin. Excess iron is often treated with chelation therapy drugs, which bind and remove iron from the body. Treatment for excess iron is not standardized, however.  “There is controversy among MDS experts about just how common or important iron overload is, and about which patients might benefit from chelation therapy,” Dr. Steensma wrote.

For more information on excess iron in MDS, please see the related Beacon resource article.

Prognosis

Research has consistently shown that MDS patients who are not dependent on red blood cell transfusion have longer overall survival than those who need regular transfusions.  One of the factors that contribute to decreased overall survival in patients who receive repeated transfusions is excess iron build-up that can reach potentially toxic levels.

Take-Home Strategies

“There is little that patients can do at home,” said Dr. Steensma. Dr. Oliva wrote patients “must follow a balanced diet, take vitamins and have iron storage evaluation monitored.”

Anemia is a major and often disruptive facet of MDS. However, doctors have several different ways of fighting the “almost universal” anemia in people with MDS, with different options available for patients’ specific conditions.

“Patients with MDS are at increased risk of developing heart disease, diabetes, and infections, compared to their age matched peers.  Thus the total financial cost of caring for patients with MDS is more than the average Medicare patient,” said Dr. Stuart Goldberg, chief of the Division of Leukemia at the John Theurer Cancer Center, in an email to The MDS Beacon.

In their study, researchers analyzed files for more than 1 million Medicare recipients older than 65 years from both hospitals and private practices. They identified 45,000 new cases of MDS in 2003. This approximation is almost five times higher than the National Cancer Institute’s previous estimates of 10,300.

Researchers found that MDS patients had considerably higher rates of heart problems (73.2 percent), diabetes (40 percent), blood infection (22.5 percent), and shortness of breath (49.4 percent) compared to the rest of the Medicare population during a three-year follow-up period. 

The three-year overall survival was also lower for MDS patients (60 percent) compared to their peers (84.7 percent).

MDS patients who received regular red blood cell transfusions had higher rates of complications, increased rates of progression to acute myeloid leukemia, and lower overall survival than transfusion-independent MDS patients.

The study also showed that MDS is costly, as the 2003 median Medicare payment for MDS patients was $16,181, compared to $1,575 for the general Medicare population.

Although the research may be slightly overestimated due to coding errors in the Medicare system, researchers concluded that MDS is more common than previously estimated.

“Since MDS is more common and expensive than previously realized, I hope our trial will encourage the National Institutes of Health, National Institute of Corrections and other research funders to pay attention to this disease,” said Dr. Goldberg. “Specifically I would like to find out if the adoption of treatment has decreased the complication rates of MDS and/or lengthened survival.”

For more information, see the Journal of Clinical Oncology (abstract).

For patients who are considering participating in a clinical trial, it is important to be entirely comfortable with the decision. This article will provide resources for finding a clinical trial as well as explain details of participating in them.

Where can I find a clinical trial that is right for me?

MDS patients can actively seek clinical trials that best fit them through several methods.

Patients can first ask their doctors if they know of currently recruiting clinical trials that may be appropriate for them.

In addition, the clinical trial registry of the United States National Institutes of Health allows patients to search for MDS-specific studies conducted in the U.S. and worldwide.  Similar lists can also be found at eCancerTrials.com, CenterWatch.com, ClinicalTrialsSearch.org, and the National Cancer Institute website.

Organizations like the Leukemia & Lymphoma Society (LLS) and Aplastic Anemia & MDS International Foundation (AA&MDSIF) have also compiled their own lists of studies for MDS patients.

Finally, patients may want to look for studies by location, such as those being conducted at specific hospitals or clinical trial centers.  Examples of hospital-based clinical trials for MDS can be found for City of Hope, Memorial Sloan-Kettering Cancer Center, Mayo Clinic, and the Fred Hutchinson Cancer Research Center.

What should I do after I find a clinical trial?

It is important for patients to learn as much as possible about the clinical trial before deciding to participate.

First, patients should ask their doctors about the clinical trial.  Physicians who know the possible risks and benefits of the treatment under investigation can offer individualized insight for their patients, ensuring that it is appropriate for them.

Patients should then meet with the study’s research coordinator, who is responsible for clearly explaining what participation will entail.  Patients are welcome to bring a family member or friend to the meeting for support.

At the meeting, patients should learn details of the study that will help them decide if they want to participate.  Meeting with the research coordinator does not mean that a patient is eligible for the trial or that they have agreed to participate.  In addition, they are not required to make a decision at the meeting.

Patients should come with questions and not be timid about asking for any clarification.  It is recommended that patients take notes or ask the research team for permission to record the meeting for later reference.  Possible questions to ask may include:

• What is the purpose and phase of this study?
  • What is the treatment?
• Why do you believe the treatment being tested is effective?
• Has it been tested before?
  • If so, what were the results?
  • Who can participate in this study?
  • How long will this study last?
  • How will the treatment be administered?
  • How much will I be given, and how often?
  • What are the potential risks and benefits of this treatment?
    • Are there any potential side effects?
  • What are the potential short- and long-term effects?
  • Am I required to undergo lab tests?
    • If so, which ones?
  • Who will oversee my treatment, my local physician or the study’s investigator?
  • What are the expected effects on daily living?
  • How will you measure if the treatment is successful?
  • What happens if the treatment is ineffective or harmful?

Other important questions that may not be associated with the actual treatment include:

• Will I be informed about the results of the study?
• Does participation require time commitments, such as extra travel, doctors’ visits, or hospitalization?
• Who will pay for the treatment?
  • Will I be compensated for travel and/or meal costs?

Patients should also consider what will happen after the study is completed:

• Will the treatment still be available to me after the specified length of the trial?
• Are you planning to do long-term follow-up after completing the study?

How much will it cost to participate in a clinical trial?

The research organization that sponsors the clinical trial usually pays for expenses related to conducting the trial, including the treatment, personnel, and analysis of results.

Other costs related to patient care may or may not be covered by a patient’s insurance. Patients should ask their doctor about coverage.  Routine care costs that relate to doctors’ visits, hospital stays, lab tests, and x-rays are usually covered regardless of trial participation.  However, extra costs related to tests that are not part of standard care may not be included.

Patients should also consider travel and food expenses that accompany extra doctors’ visits and tests.  These costs are sometimes covered by trial sponsors. Organizations such as the AA&MDSIF may offer to financially reimburse participants for travel costs.

What happens after the clinical trial ends?

The research team may follow participants for a time specified in their protocol after the treatment period ends to monitor any short and long-term side effects.  Patient results will usually be categorized as having no response, partial response, or complete response leading to disease-free or progression-free survival.

Depending on the level of response, patients may choose to remain on the treatment by enrolling in the extension arm of the study, which is sometimes made available by the sponsoring organization.  Patients who participate in the extension arm continue to receive treatment at no cost.

If this option is unavailable, patients may also choose to purchase the drug, if it has been approved by the FDA by that time.  Insurance coverage and payment methods may vary by treatment type.

Finally, if patients are unresponsive, they can choose to return to their previous treatment or try another treatment after talking with their doctor.  Patients may also be eligible for other clinical trials investigating different therapies; however, they must usually wait a specified amount of time before enrollment.

What if I am currently ineligible for ongoing clinical trials?

Patients who do not meet the criteria to participate in clinical trials may consider expanded access protocols.  In these studies, the FDA allows manufacturers to distribute experimental treatments to patients who may benefit from the treatment but are ineligible for ongoing clinical trials.

However, there must be existing evidence that the treatment is potentially effective for patients. Evidence can be provided through ongoing or completed clinical trials.  Patients may consider participating in expanded access studies if there are no good treatment alternatives available and their disease is life-threatening.

Results from expanded access studies can contribute more information about the safety of the investigational treatment.  However, because expanded access protocols are not under the same strict guidelines as clinical trials, patients may be at risk for unforeseen safety issues.  Expanded access studies can be found at the clinical trial registry of the U.S. National Institutes of Health.

Who will benefit from my participation?

It is often difficult to envision the names and faces of future MDS patients who will be treated or cured through participation in a clinical trial.  However, it is important to remember that every MDS patient who currently receives treatment or has been cured is indebted to years of research in the past.

Hopeful reminders for MDS patients can be found through stories of survival and cure, such as those on the AA&MDSIF or Fred Hutchinson Cancer Research Center websites.  Individualized resources, such as the LLS-based My Personal MDS Journey, may help patients know that they are not alone.

Participating in clinical trials is just one way that patients can partner with the medical community to take small steps toward preventing, treating, and curing diseases like MDS.

For more information about clinical trials for MDS patients, please see Part 1: Learning About Clinical Trials and Part 2: Benefits Ands Risks Of Clinical Trials.

For the majority of low- or intermediate-1 risk MDS patients, anemia, or low red blood cell count, is the most common cause of symptoms that significantly alters their quality of life.  Although regular red blood cell transfusions can relieve symptoms and keep the body adequately supplied with blood, transfusions are associated with certain side effects, such as excess iron (see related Beacon article). Previous research has shown that MDS patients who are dependent on transfusions typically have significantly lower overall survival than those who do not require regular transfusions. 

Aranesp is a growth factor that stimulates red blood cell development.  As a type of supportive care, it does not stop or reverse MDS progression, but it is still an important treatment option. 

The study’s results showed that the majority of MDS patients had improved red blood cell development after receiving Aranesp.  In addition, their short-term quality of life improved, with better physical function, increased emotional well-being, and decreased fatigue.

In the study, 40 low-risk MDS patients received 150 µg Aranesp by subcutaneous injection once a week for 24 weeks.  Throughout the study period, the dose was increased to 300 µg for transfusion-independent patients who did not respond after four weeks or transfusion-dependent patients who did not improve after eight weeks.  After three months, 80 percent of MDS patients received the 300 µg dose.

Seventy-three percent of all patients responded to Aranesp during the 24 weeks, with the most significant responses occurring by 8 weeks of treatment.

Fifty-six percent of transfusion-independent MDS patients responded to the treatment for an average of 22 weeks.  Sixty-five percent responded after a median of six weeks.

Fifty-nine percent of patients receiving regular blood transfusions responded to Aranesp.  Transfusion dependence was defined as requiring at least two red blood cell transfusions every 16 weeks.  Although their response was shorter (average duration of 15.1 weeks), 82 percent achieved a response after a median of 8.4 weeks.  Almost 24 percent became transfusion-independent during the study period.

As there was no observed disease progression through the 24-week period, study authors concluded that Aranesp did not decrease survival.

Patients did not experience any significant side effects, such as blood clotting, after receiving Aranesp, wrote Dr. Esther Oliva, lead scientist in the study, in an e-mail to the MDS Beacon.  A few patients reported pain at the injection site.

In addition to measuring responses, researchers evaluated changes in patients’ quality of life.  The MDS patients experienced improved physical function, emotional well-being, and decreased fatigue as a result of anemia symptom relief.  Most improvements were observed in the first eight weeks of the study.

Quality of life increased more significantly for transfusion-independent patients than transfusion-dependent patients. Researchers speculated that this was likely due to the inferior prognosis for patients who require regular transfusions. 

In addition, transfusion-dependent patients needed to travel regularly to the treatment center to receive transfusions which may have produced a poorer perception of their illness. These study participants “may have been disturbed by dependence on hospital and staff and by the ‘waste’ of personal time,” added Dr. Oliva.

Improved quality of life was only sustained as long as improved blood cell production was observed.  The study authors speculated this was due to the study protocol requiring reduced Aranesp doses after patients reached the target goal of 12 g/dL hemoglobin.

The researchers recommend further studies investigate what doses and dosing schedules of Aranesp can produce sustained improvement for MDS patients with anemia, as well as how to treat higher-risk patients.

For more information, please see Leukemia & Lymphoma (abstract).

Myelodysplastic Syndromes: An Update On Diagnosis And Treatment - The Leukemia & Lymphoma Society (LLS) will hold a free telephone/webcast education program on May 18, from noon to 1 p.m. EST for MDS patients.  Dr. Stephen D. Nimer, MDS expert and chair of hematology services at Memorial Sloan-Kettering Cancer Center, will talk about current diagnostic tools and treatments for MDS.  A Q&A session is included in the event.  For more information, see the LLS website.

Living With Myelodysplastic Syndromes: A One-Day Conference For MDS Patients And Their Families – The Aplastic Anemia & MDS International Foundation will be holding a free one-day conference in collaboration with the M.D. Anderson Cancer Center for MDS patients and their families on May 18, from 8 a.m. to 3:45 p.m. in Houston, TX.  The meeting will give patients an opportunity to hear from experts about diagnosis tests and procedures, current treatments, and how to optimize physical and emotional health throughout all stages of MDS.  Breakfast and lunch will be provided.  The registration deadline is May 14.  For more information, see the Aplastic Anemia & MDS International Foundation website.

For a more detailed listing of MDS-related events, please check the MDS Beacon Events Calendar.

The authors of the analysis suggest that treating physicians should be aware of potential treatment-associated side effects and measures how to manage them to ensure long-term Vidaza treatment and maximize treatment benefits.

Vidaza is a DNA demethylating agent approved for the treatment of MDS.  Two recent clinical trials have shown that Vidaza prolongs the time to acute myeloid leukemia progression, decreases red blood cell transfusion-dependence and improves blood cell development. One of the trials also showed that Vidaza extended overall survival in higher-risk MDS compared to conventional care.

The results of the two trials also showed that it took some time before patients began to show improvements from Vidaza treatments. In one study, patients experienced the most positive survival results after a median of nine Vidaza treatment cycles.  

The authors of the report were concerned that patients may end Vidaza treatment prematurely before reaching the complete benefit due to treatment-related side effects.

The researchers therefore analyzed previously unpublished side effect data from the two clinical trials to provide more details on treatment-related side effects.

Patients in both trials received 75 mg/m² Vidaza daily for seven consecutive days every 28 days. 

Researchers found the most common side effects associated with Vidaza therapy to be low blood counts, fatigue, fever, injection site reactions, nausea, and constipation.

Researchers also found that side effects of Vidaza tended to be temporary and that the drug did not cause a long-term toxic response.

Most of the side effects occurred during the first two cycles, decreasing in frequency with subsequent cycles. Nausea, vomiting, constipation, and injection-site reactions were most commonly seen during the first week of treatment for each cycle. 

Researchers found strategies such as delaying the next dosing cycle, dose reduction, and administering blood transfusions worked best to minimize side effects. Patients in the study were also prescribed medications for their digestive problems. 

Researchers concluded that raising awareness among treating physicians about treatment-related side effects and how to manage them can ensure patients do not prematurely discontinue therapy before experiencing its full effects. They added that it may also make patients more willing to continue treatment for the required length of time, improving overall survival. 

For more information, see the analysis in the European Journal of Haematology (abstract).

St. Anthony’s Triathlon – Join the Leukemia & Lymphoma Society (LLS) on Sunday, April 25 to raise funds for blood cancer research at the St. Anthony’s Triathlon. The 0.9 mile swim, 24.8 mile bike, and 6.2 mile run, which starts in St. Petersburg, FL, will cover scenic waterfronts and will kick off the North American triathlon season. For more information, please see the LLS website.

Living With A Blood Disease Symposium – The Mayo Clinic will be holding a symposium about blood diseases for patients and their families on May 8 and 9 in Rochester, MN. Physicians from the Mayo Clinic and other medical experts will talk about the latest research and new therapies as well as more personal issues, such as financial planning, spirituality, and intimacy. The experts will also answer questions from the audience. Registration is required, and the fee for the event is $175 per person. For more information, see the Mayo Clinic website.

For a more detailed listing of MDS-related events, please check the MDS Beacon Events Calendar.

Eosinophils and basophils are two types of white blood cells that develop and mature in the bone marrow.  Eosinophils normally make up about 1 to 6 percent of white blood cells, and basophils compose less than 1 percent of white blood cells. They have important functions in the immune system. Their levels increase when the immune system mounts a response to infections, parasites, and allergies. 

It is currently not clear if eosinophil and basophil levels have any prognostic value in MDS.  Prognosis for MDS patients is usually determined by the International Prognostic Scoring System (IPSS), which bases its low-, intermediate-1, intermediate-2, and high-risk categories on low blood cell counts, bone marrow blast percentages, and the presence of abnormal genetic material.

To shed some light on the issue, the researchers examined eosinophil and basophil levels in 1008 primary MDS patients over a median of 13 months.  Primary MDS, which is not linked to exposure to certain chemicals or chemotherapy, accounts for 70 to 80 percent of MDS diagnoses.  

Most patients were receiving supportive care, such as red blood cell and platelet transfusions, throughout the observation period.  For follow-up, the researchers re-examined patients’ bone marrow for possible disease progression.

Abnormally high levels of eosinophils (eosinophilia) and basophils (basophilia) were defined as having more than 350 eosinophils/µL and more than 250 basophils/µL respetively.  Eosinophilia and basophilia often accompany bone marrow cancers. 

Results showed that patients with both eosinophilia and basophilia had significantly lower overall survival compared to patients who had neither.  The researchers also found that having both eosinophilia and basophilia was significantly more predictive of lower survival than having only one of the conditions.

Over 40 percent of MDS patients with eosinophilia and basophilia had high-risk MDS, compared to 25 percent of patients who had low-risk MDS.

Among the patients who were eosinophilia- and basophilia-free, 32.9 percent were patients were low-risk, compared to 7.7 percent who were classified as high-risk.

The researchers were not able to demonstrate that eosinophilia or basophilia could predict progression to acute myeloid leukemia, a type of blood cancer.

The study authors concluded that eosinophil and basophil counts may be used as an additional tool to assess prognosis for MDS patients, especially for those with intermediate-2 risk MDS.

For more information, see the study in the journal Cancer (abstract).

Italian researchers found that patients who developed misshapen chromosomes after diagnosis in a process called cytogenetic evolution had a 7 times higher risk of shorter survival and a 36 times higher risk of progressing to acute myeloid leukemia (AML) than chromosomally stable patients.

The study revealed that 30.7 percent of MDS patients undergo cytogenetic evolution and that this process is more prevalent in patients with advanced MDS than patients with early or low-risk MDS. These results were independent of pre-existing chromosomal abnormalities discovered at diagnosis. 

The study provided more scientific evidence that MDS progression is accompanied by a steady decrease in genetic stability.

Previous to this study, specific genetic developments had not been clinically and biologically linked with the progression of MDS. 

The researchers analyzed chromosomal profiles of 153 MDS patients at diagnosis, and followed them for a median of 45.2 months. Eighty-four percent of patients were receiving red blood cell transfusions or growth factors, while the remaining 16 percent received immunosuppressive therapy, chemotherapy, or blood cell development-inducing treatments. 

At the end of follow-up, 42.4 percent of patients had experienced worsening of disease after a median 65.2-month period of progression-free survival. A total of 30.7 percent of patients acquired chromosomal defects during follow-up. Twenty-six percent of the patients developed chromosomal abnormalities before their MDS progressed toward more advanced stages or AML. 

Analysis showed MDS patients who did not undergo cytogenetic evolution had significantly longer two- and five-year survival rates (93 percent and 70 percent) compared to patients who developed chromosomal abnormalities (40 percent and 10 percent).

Low-risk MDS patients tended to acquire chromosome 5 and 11 irregularities, while patients with advanced MDS developed abnormalities on chromosomes 7 and 17.  Trisomy 8 occurred equally for low and high-risk patients. The chromosomal abnormality del(7)(q31q34) was the defect that significantly affected the risk of progressing to advanced MDS or AML. 

Researchers concluded MDS patients who developed chromosomal abnormalities during follow-up had an increased risk of shorter survival and progressing to AML by 7 and 36 times, respectively.

For more information, please see the study in the Annals of Hematology (abstract).

The main goals when treating high-risk MDS patients are to increase overall survival and delay progression to acute myeloid leukemia (AML). Researchers also strive to improve quality of life through supportive care, achieve independence from red blood cell transfusions, and decrease symptoms.

Options for high-risk MDS patients are divided into high-intensity therapies, including stem cell transplantation and standard chemotherapy, and low-intensity treatments, such as reduced-intensity chemotherapy and drug therapies such as Vidaza (azacitidine) and Dacogen (decitabine). 

In the U.S., 29 percent of MDS cases are classified as high-risk disease at diagnosis according to the International Prognostic Scoring System (IPSS). 

The IPSS score predicts median survival and expected progress to AML if patients do not receive treatment.  It is determined by evaluating the percent of immature blood stem cells, blood cell counts, and genetic structure at the time of diagnosis. The World Prognostic Scoring System (WPSS) also predicts prognoses, but evaluates patients as their disease progresses.

This article describes the different levels of treatment as evaluated by the authors of the review.

High-Intensity Therapies

Stem cell transplantation is the only curative option for high-risk MDS patients. In this treatment, the bone marrow of a patient is initially destroyed by high-dose chemotherapy or radiation, and then replaced with bone marrow from a matched donor. Although not guaranteed to produce a full recovery, stem cell transplants give the patient new bone marrow to produce normal blood cells. 

Studies have shown that stem cell transplantation soon after diagnosis maximizes the average survival for high-risk patients. In addition, age alone is no longer a deterrent for transplantation.

Other studies have shown that although increasing age, longer duration of disease, mismatched donor, and being male significantly increase non-relapse mortality after stem cell transplantation, they do not affect disease-free survival in MDS patients.

The authors of the review point out that research has not yet shown if previous treatment before transplantation with DNA demethylating agents, such as Vidaza or Dacogen, or remission-inducing chemotherapy improves transplantation success.

Reduced-Intensity Therapies

MDS patients who are older, have higher-risk disease, or have other concurrent health conditions and therefore would not be candidates for stem cell transplantation can choose to have reduced-intensity chemotherapy before stem cell transplantation. Reduced-intensity chemotherapy would allow them to have stem cell transplantation because it is associated with fewer complications and side effects.

Although patients receiving reduced-intensity therapy before stem cell transplantation have increased relapse rates after transplant, they tend to have decreased mortality if relapse does not occur. In addition, overall survival and progression-free survival is similar to patients receiving standard, high-intensity chemotherapy. 

The authors of the review point out that optimal timing and overall effectiveness of reduced-intensity therapy has not yet been established.

Low-Intensity Therapies

Vidaza and Dacogen are considered low-intensity therapies for high-risk MDS patients. Both drugs are DNA demethylating agents that remove methyl groups bound to the DNA in the bone marrow in order to allow the DNA to regulate normal cell growth.

Vidaza is one commonly used drug therapy for high-risk MDS patients. It has been shown to significantly increase survival time, slow progression to AML, produce red blood cell transfusion independence, and improve blood counts and quality of life compared to conventional care and chemotherapy. 

Although Vidaza does not guarantee complete response, the significantly higher survival rates show that complete response to therapies is not necessarily required to increase patient survival time. 

High-risk MDS patients receiving Dacogen also have significantly higher rates of complete response, partial response, and blood counts than those receiving best supportive care. They also have longer periods of survival that are free of disease progression to AML.

However, median survival and overall progression to AML is similar between the patients receiving Dacogen or supportive care.

The authors of the review point out that high-risk patients who do not respond to any of the existing therapies can choose to participate in clinical trials that investigate new treatment options. 

For more information, please see the article in the supplement of Cancer Control (pdf).

The study authors pointed out that although the risk of AML transformation was higher for patients with skin lesions, it was not a significant vulnerability. They suggested dermatologists work closely with hematologists to assess skin conditions in patients with MDS. 

Skin lesions differ by diagnosis but are usually characterized by red bumps.  Depending on the diagnosis, they may grow in size or become clusters that are inflamed or develop painful blisters. 

The study by the French researchers was the second to investigate the role of skin lesions in MDS patients.  It was the first to analyze demographic, genetic, and prognostic finding in MDS patients with skin conditions. 

The researchers recorded the progression of disease in 157 primary MDS patients for a median of 44 months.  Primary MDS, which is not linked to exposure to certain chemicals or chemotherapy, accounts for 70 to 80 percent of MDS diagnoses.  

All skin conditions were diagnosed and classified by a microscopic examination, and lesions were examined by a dermatologist every six months. 

Almost 10 percent of patients showed skin lesions associated with MDS, including neutrophilic dermatosis (4.5 percent), specific lesions (3.2 percent), cutaneous vasculitis (1.3 percent) and Behçet disease (0.6 percent).

Most patients (88.4 percent) received treatment throughout the follow-up period. 

During follow-up, a total of approximately 30 percent of patients experienced transformation to AML, and 45 percent of patients died. Fourtyseven percent of patients who had skin lesions progressed to AML, compared to 28 percent of patients who did not have skin conditions. Researchers did not find any difference in survival between patients with or without skin lesions.

Resesarchers also did not find any significant differences between patients with our without lesions in terms of gender, disease sub-type, prognosis, or genetic abnormality.  However, patients with skin lesions were younger than those without skin lesions. 

For more information, please see the Journal of the European Academy of Dermatology and Venereology (abstract).

Lymphocytes are a type of white blood cell that defend the body against infections and play a vital role in the body’s immune response. Lymphocyte count is a frequently used prognostic indicator in lymphoid cancers.

Previous research has shown that immune system may be linked to the development of MDS (see related Beacon article).

Currently, prognoses for MDS are determined using the International Prognostic Scoring System (IPSS) and the World Health Organization classification-based Prognostic Scoring System (WPSS).  Disease progression and survival is predicted in IPSS and WPSS by blood counts, transfusion-dependence, genetic structures, and percentage of blasts in the bone marrow. 

Researchers had previously shown that low lymphocyte count predicts poor prognoses in MDS patients with the chromosomal abnormality del-5q.

In this study, they investigated if lymphocyte count could also be used to predict outcome in MDS patients without the chromosomal abnormality.

The researchers evaluated records of 503 untreated MDS patient who were diagnosed between 1996 and 2007 at the Mayo Clinic.   The study analyzed the relationship between the initial lymphocyte count taken at diagnosis and overall survival time.  Patients were grouped as having lymphocyte levels greater or less than 1.2 x 10⁹/L, the group’s median count. 

At median follow-up of 15.5 months, 41 percent of the patients who had a lymphocyte count greater than 1.2 x 10⁹/L were still living, compared to 29 percent of patients with counts lower than 1.2 x 10⁹/L.  Researchers concluded that patients with the higher lymphocyte counts at diagnosis had longer overall survival. 

The researchers pointed out that this was the first time that a lymphocyte count at diagnosis had been determined as a reliable predictor for survival in patients without the del-5q mutation.  . 

The researchers suggested lymphocyte count be used as a complementary prognosis tool to IPSS and WPSS.  A complete blood count, which includes a lymphocyte count, is part of normal diagnosis and is an inexpensive and universally available test. “The absolute lymphocyte count is an easily obtained blood parameter that may offer some additional prognostic information that is independent of the IPSS”, said Dr. David Steensma, one of the study authors.

The researchers recommended further studies investigate the specific role of the immune system in MDS, as well as the effects of available treatments on patient immune systems.  “If there were a way of re-awakening the immune system to attack malignant cells it could have quite a profound effect on how we treat MDS,” said Dr. David Steensma.

Studies have yet to find the exact reason why individuals have lower levels of lymphocytes than others.  The main potential reasons include stem cell defects that disrupt normal blood cell development or other immune system abnormalities.

According to Dr. Shernan Holtan, one of the study authors, the biological importance of lymphocytes and the immune system in the development of MDS will continue to be a research topic of great interest. 

“Cancer research has, in general, predominantly focused on the tumor.  I believe that understanding the [patient] response to cancer is every bit as valuable.  Research into factors [within the patient] responsible for disease progression and survival is really an unmet need in myeloid malignancies,” said Dr. Holtan.

For more information, please see  the study in the American Journal of Hematology (abstract).

Patients on the new regimen receive 20 mg/m² of Dacogen by intravenous infusion over one hour for five consecutive days, every four weeks. The new regimen decreases the infusion time compared to the current dosing schedule.

Under the current dosing schedule, patients receive 15 mg/m² of Dacogen by intravenous infusion for three hours, every eight hours.  This regimen lasts three consecutive days requiring patients to stay at the hospital for two nights. The regimen is repeated every six weeks. 

Research showed that patients receiving Dacogen on the new schedule responded at a rate comparable to the current dose.  Of the 99 MDS patients, 16 percent responded to the outpatient dosing schedule after a median of 162 days.  The median duration of response was 443 days.

Side effects remained similar to the old Dacogen schedule.  Patients experienced low white blood cell count (37 percent), low red blood cell count (22 percent), and low platelet count (24 percent).  Fever, red and itchy skin, and abnormally high blood sugar may also occur.

Dacogen is approved to treat all sub-types of MDS.  The drug removes methyl groups that are bound to the DNA of rapidly dividing mis-shapen and immature blood cells (dysplastic cells) in the bone marrow, which block the regulation of cellular growth.  As a DNA demethylating agent, Dacogen removes these methyl groups and allows the DNA sequences to function normally.

Complete blood counts should be performed while taking Dacogen to monitor response and side effects because treatment is often associated with low white blood cell counts and low platelet counts. 

Please see the Esai’s press release for more information.

Exjade is an iron chelating agent that works to remove excess iron, which may have built up in the heart, liver, and endocrine cells due to repeated blood transfusions.  The drug binds free iron in the blood and prevents the metal from forming toxic deposits. 

Novartis released the revised prescribing information for Exjade on February 17, stating that the kidney and liver damage or gastrointestinal bleeding could be fatal, especially for elderly patients or those with high-risk MDS.  Patients with underlying liver or kidney conditions or platelet counts less than 50×10⁹/L were also cautioned about the side effects.  The black box warning is the strictest type of warning required by the FDA.

The FDA first began investigating the safety of Exjade in September 2009 (see related Beacon article), due to previous analyses that showed MDS patients taking Exjade had a greater risk of serious side effects than patients without MDS. 

Although doctors are still free to prescribe the iron chelating agent, the new black box warning will, according to Novartis, “enhance the ability of physicians to appropriately treat patients who are prescribed or taking Exjade to manage transfusional iron overload.”

An alternative iron chelating agent available to MDS patients in the U.S. is deferoxamine (Desferal). The FDA also is reviewing Ferriprox (deferiprone) for approval in the U.S.  It is currently available in a number of countries outside of the U. S.  In addition, there is evidence that wheat grass juice may be a natural option for reducing excess iron.

For more information about the FDA’s announcement about Exjade’s safety, please see the FDA Web site. For more information about excess iron and chelation therapy in MDS patients, please see the related MDS Beacon resource article.

Recombinant erythropoietin alpha is an erythroid stimulating agent that stimulates red blood cell production. It is beneficial for MDS patients with anemia (low red blood cell count) and can reduce transfusion-dependence and improve quality of life. Recombinant means that the erythropoietin originates from an external organism and not from the patients’ own bodies.

Past studies reported patients benefited from r-EPO administered in combination with G-CSF. G-CSF is a growth factor that stimulates the production of white blood cells and red blood cell-producing stem cells. The analysis showed that r-EPO is effective when used without G-CSF.

Researchers analyzed the responses and survival times of 192 transfusion-dependent MDS patients.  Eighty-three patients received r-EPO in doses of either 10,000 units three times per week or 40,000 units once a week for at least 12 weeks, while the other 109 patients were not treated with r-EPO.  All patients were followed for at least five years after diagnosis, or until death.

The median length of treatment was 19 months for responders, compared to 14 months for patients who received r-EPO but did not respond.

Researchers found that median overall survival was not statistically different between patients who had received r-EPO (36 months) and those who had not received the treatment (38 months).

However, researchers observed differences in survival among the patients who had received r-EPO. Patients who responded to r-EPO had significantly longer survival times (52 months) than non-responders (31 months). The survival time of non-responders was similar to patients who never received r-EPO, according to researchers.

In addition, 28.9 percent of patients who received r-EPO experienced improved red blood cell production for a median of 17 months. 

Some patients had long-lasting responses that continued even after r-EPO treatment was stopped, evidence that r-EPO can produce a prolonged improvement in red blood cell production in some patients. 

The study suggests there are certain MDS patients who respond to r-EPO treatment while otherwise similar patients do not. This analysis did not specify if the responsive MDS patients had a naturally better prognosis which led to their response, or if r-EPO modified their disease, producing a response.

The authors are currently conducting further related research using r-EPO and another erythroid stimulating agent called darbepoetin.  They are observing long-term effects on recently diagnosed MDS patients who are being treated with high doses of both drugs.

For more information, please see the study in the journal Leukemia Research (abstract).

Allogeneic stem cell transplantation, or allotransplantation, involves destroying patient bone marrow by chemotherapy or radiation and replacing it with healthy bone marrow from a matched donor.  Although this process is the only cure for MDS, it does not guarantee full recovery.

Transplants were previously not an option for older patients because of the increased risk for graft vs. host disease.  Graft vs. host disease is a potential threat for transplant patients where functional immune cells in the healthy transplanted marrow identify the recipient’s cells as foreign and attack them.

However, recent studies have shown that patients over 55 can successfully tolerate transplantation (see related Beacon article). 

The process has also become more feasible with the development of lower doses of pre-transplant chemotherapy and radiation, donor-matching technology, and supportive care (see related Beacon article). 

In this study, researchers analyzed the records of 1,333 MDS patients in the European Group for Blood and Marrow Transplantation registry who had received a bone or blood marrow transplant between January 1998 and October 2006.  The median age of the patients was 56, and all patients were over 50.

Forty two percent of patients had-early stage MDS, 52 percent had advanced stage MDS, and 6 percent of patients did not have blast percentage recorded.  Early-stage MDS was defined as having less than 5 percent blasts in the bone marrow, while advanced-stage patients had greater than 5 percent blasts. 

Records showed 38 percent of patients received the standard dose of chemotherapy in preparation for their transplants, while 62 percent received reduced-intensity conditioning.

The study compared the effects of patient age, stage of MDS, intensity of treatment, and relation of donor on rate of relapse and non-relapse mortality.  

Researchers found that patients in the 50 to 60 age group had higher relapse but similar non-relapse mortality rates as patients over the age of 60.

Patients who underwent transplantation in the advanced stage of MDS had significantly higher rates of both relapse and non-relapse mortality than patients with early-stage MDS. 

Patients on the low-intensity chemotherapy had a higher relapse but lower non-relapse mortality rate than patients on standard chemotherapy.

The researchers found that non-relapse mortality rates decreased significantly if older patients received bone marrow from a related donor.  However, transplants from both related and unrelated donors can be beneficial for patients over 60.

Upon further analysis of the study data, the researchers found that advanced disease stage at transplantation and low-intensity chemotherapy were associated with an increased relapse rate. They also found that advanced disease stage at transplantation and the use of unrelated donor were associated with non-relapse mortality. Advanced disease stage at transplantation was also associated with an inferior 4-year overall survival.

They concluded that disease stage at the time of transplantation was the single most important prognostic variable for the outcome of allogeneic stem cell transplantation.

The authors recommended considering alternative or novel treatment options for elderly patients with advanced disease at transplantation, including agents that modify MDS or interact with the immune system. 

In addition, they suggested future studies should try to find treatments that can prevent relapse, maintaining the post-transplant cure.

For more information, please see the American Journal of Clinical Oncology (abstract).

The findings are from a Phase 2 study conducted by researchers at the M.D. Anderson Cancer Center in Houston and were presented at the 51st annual American Society of Hematology (ASH) meeting and exposition held in New Orleans in December.

Valproic acid activates the production of protein based on a person’s genes by inhibiting an enzyme called histone deacetylase. Valproic acid is most commonly used to treat seizures, bipolar disorder, and migraine headaches, but recent studies have shown that it may be effective against a wide range of cancers. 

Previous studies have shown that valproic acid has the potential to suppress MDS and other blood- or bone-related cancers when given in combination with hypomethylating agents such as Dacogen and Vidaza (azacitidine), which regulate cell division (see related Beacon news). 

However, interim results from the M.D. Anderson Cancer Center study showed similar response and survival rates for patients receiving either Dacogen alone or Dacogen in combination with valproic acid. MDS patients in both treatment groups responded better (64 percent overall response, 39 percent complete response) than patients with acute myeloid leukemia (46 percent overall response, complete response 25 percent).

To better understand the results, the researchers further investigated the effect of the two different treatment regimens on certain genes involved in the development of MDS.

They found that the addition of valproic acid to Dacogen effectively increased the production of key proteins. However, researchers also discovered that valproic acid reduced Dacogen’s efficacy. These two opposing trends may be the reason why the response rates were similar with and without the addition of valproic acid to Dacogen.

The researchers suggested a stronger histone deacetylase inhibitor administered on different days than Dacogen may be necessary to improve the efficacy of Dacogen for the treatment of MDS. 

For more information, please see abstract 3808 on the 2009 ASH meeting Web site.

However, the study authors point out that the improved responses were improved marrow responses rather than improvements in blood cell development.

Vidaza, approved by the US Food and Drug Administration in 2004, is a widely used therapy for MDS. However, many MDS patients either do not respond or only have limited or brief responses, leading researchers to investigate potential combination treatments with other drugs (see related Beacon news).

Enbrel, a drug already approved for rheumatoid arthritis and other autoimmune diseases, is currently investigated for the treatment of MDS. Response rates to Enbrel treatment as a single agent have been low.

For their study, researchers recruited 32 MDS and chronic myelomonocytic leukemia (CMML) patients. The patients received 75 mg/m2 Vidaza by intravenous or subcutaneous injection for seven consecutive days every four weeks in combination with 25 mg Enbrel by subcutaneous injection on days 8, 11, 15, and 18. Treatments were continued unless patients progressed toward acute myeloid leukemia, a more severe type of blood cancer.

At three months, 23 patients (72 percent) responded to the combination therapy, nine of whom achieved a complete response. Ten patients (31 percent) showed a bone marrow response. Bone marrow response is defined as having less than 5 percent blasts in the bone marrow.

The response rates observed in this study were higher than a 2006 Phase 3 collaborative clinical trial investigating the impact of Vidaza alone on MDS patients. In that study, researchers reported an overall response rate of 33-53 percent with 10-17 percent of patients achieving complete response.

The median duration of response had not been reached at the time of the data analysis. However, 12 patients showed bone marrow responses lasting more than one year, 92 percent of whom experienced more than two years of sustained improvement.

Twenty nine patients required dose reductions of Vidaza during the first three months of treatment because they experienced low white blood cell and platelet counts which were the most common severe side effects. However, the authors suggest that the combination therapy is still tolerable because 30 patients, or 94 percent, completed at least three cycles of treatment.

The researchers concluded that the Vidaza and Enbrel combination therapy should be investigated further in Phase 3 clinical trials.

For more information, please see the study in the British Journal of Haemotology (abstract).

Company Developing Sapacitabine For Treatment Of Myelodysplastic Syndromes To Raise Millions In Direct Offerings — Cyclacel Pharmaceuticals, Inc. announced plans on January 21 to raise up to $7.9 million in capital through registered direct offerings to its investors. The company is currently testing sapacitabine for the treatment of myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and several other cancers. Interim results of an ongoing Phase 2 clinical trial in MDS were presented at the recent American Society of Hematology annual meeting (see related Beacon news). For more information, please see the Cyclacel press release.

Understanding Clinical Trials For Blood Cancers Like Myelodysplastic Syndromes, LLS Web Seminar — The Leukemia and Lymphoma Society (LLS) is sponsoring an online seminar (webinar) titled “Understanding Clinical Trials For Blood Cancers” on Thursday, January 28, from 7 p.m. to 8 p.m. EST. Dr. Karen Yee will explain clinical trials in detail, including how they are organized, safety concerns, and how myelodysplastic syndromes patients can participate. Registration is required.  For more information, please visit the LLS Web site.

For a more detailed listing of MDS-related events, please check the MDS Beacon Events Calendar.

The findings were presented as a poster at the American Society of Hematology meeting and exposition in December 2009.

The Australian study followed results published in 2008 which showed that treating MDS and AML patients with Vidaza and thalidomide was as effective as treating high-risk patients with Vidaza alone (see related Beacon news). 

The Australian researchers stated that since there had been limited experience with this combination treatment so far, they investigated the combination treatment further to see if side effects impacted its tolerability.

For their study, the researchers enrolled a total of 80 MDS patients. Fourty one of these patients received treatment between July 2008 and July 2009 and have been evaluated for results.  Participants were required to be first-time recipients of thalidomide or any of its derivatives and Vidaza or any other demethylating agents. 

Of the 41 MDS patients evaluated, 12 percent were identified as low-risk, 37 percent as intermediate-1, 34 percent as intermediate-2, and 12 percent as high-risk.

Each patient received 50 mg thalidomide daily for four weeks at which point the dose was increased to 100 mg per day, and administered continuously for a maximum of 12 months. In addition, patients received 75mg/m² Vidaza per day for seven consecutive days every four weeks.  Treatment was stopped or reduced if patients experienced disease progression or excessive side effects due to toxicity. 

Fourteen patients, or 34 percent, remained on the thalidomide and Vidaza throughout the entire treatment period. These patients experienced median exposure times of 209 days to thalidomide and seven cycles of Vidaza.

Sixty six percent of patients discontinued thalidomide during treatment after a median of 49 days, while 59 percent discontinued Vidaza after a median of two cycles. 

During the first treatment cycle, 13 patients experienced severe side effects, most of which were infection-related. The risk of developing infections was increased in patients older than 65 years, patients with low white blood cell counts, and patients with restricted physical activity.

Researchers did not observe severe peripheral neuropathy (nerve damage in the limbs), a common side effect of thalidomide, in any of the 41 patients.

The study authors concluded that the combination therapy of Vidaza and thalidomide can be used to treat MDS without unexpected side effects altough infections were common in the first cycle of combination therapy. The study authors pointed out that infections are a recognized risk associated with MDS and Vidaza as a single-agent treatment and were therefore not unexpected. 

For more information, see abstract 1749 on the 2009 ASH meeting Web site.

Vidaza has been one of the main therapies for MDS since it was approved by the US Food and Drug Administration in 2004.  In August 2009, the National Comprehensive Cancer Network recommended Vidaza as the preferred drug for “treating MDS patients with progressing or relatively high-risk disease,” which includes patients most likely to progress to acute myeloid leukemia (see related Beacon news).

However, many MDS patients either do not respond or only have limited or brief responses to single-agent therapy like Vidaza. Researchers are therefore exploring potential combination therapies for the treatment of MDS.

Thalidomide is currently being investigated as a potential treatment for MDS patients due to evidence that it stabilizes blood cells by improving the bone marrow environment where blood cell development occurs (see related Beacon news). 

In this study, researchers tested Vidaza therapy in combination with thalidomide in 24 MDS and 16 acute myeloid leukemia (AML) patients. They received 75 mg/m² Vidaza subcutaneously for five days every four weeks and 50 mg thalidomide per day, which was increased to 100 mg daily on day 8.  Of the 40 patients, 36 were evaluable for results.

Results showed that 58 percent of patients responded to the combination treatment. Seventeen percent of the patients achieved a complete remission (2 MDS and 4 AML patients).  Forty two percent experienced disease progression or did not show any improvements.

The median survival of the MDS patients was 18.5 months, compared to 13.2 months for AML patients.  Overall median survival of all evaluated patients was 17.8 months. 

The results also revealed that patients who did not improve through combination therapy possibly had genetic sequences that distinguished them from respondents. 

Side effects were mostly mild to moderate and consistent with the known side effects associated with the two drugs.

The study authors concluded that treating the MDS and AML patients with Vidaza and thalidomide was well tolerated and at least as effective as Vidaza alone. 

For more information, please see the related article in Cancer (full text).

The MDS Beacon will continue to follow research about Vidaza and thalidomide combination therapy from the recent 51st Annual American Society of Hematology Meeting and Exposition that took place in early December.  Other research and news articles about Vidaza and thalidomide can also be found on the Beacon.

The del-5q mutation is a chromosomal abnormality which is characterized by a missing ‘q’ arm of chromosome 5. Although the del-5q sub-type was identified as a specific MDS diagnosis in 2001, few studies have examined the progression of this disease sub-type to AML.  

This study tracked 303 low or intermediate-1 patients with del-5q mutation. The median age of the study participants was 65 years. Patients were identified through MDS registries and followed from diagnosis. The median follow-up time was three years. During the study period, all patients were treated with supportive care. Researchers recorded any changes regarding blood cell count, dependence on red blood cell transfusions, and general disease progression, with progression to AML defined as producing more than 20 percent blasts in the bone marrow. 

Results of the study showed a median survival of nearly six years (71.5 months).  Based on the WPSS score, the median patient survival times were 107 months for very low-risk MDS, 73 months for low-risk MDS, 56 months for intermediate-risk MDS, and 37 months for high-risk MDS.

Del-5q patients with only one chromosomal abnormality achieved median 73 month survival, compared to median survival of 19.3 months for those with more than one chromosomal abnormality. 

The study also revealed that transfusion-independent patients had a significantly higher median survival time (97 months) than transfusion-dependent patients (37 months).

Out of the 303 patients, 44 (15 percent) progressed to AML. Researchers found that patients with intermediate 1 IPSS and high-risk WPSS scores had an increased risk of AML transformation.

In addition, risk for disease progression increased with greater than 5 percent blasts in the bone marrow and red blood-cell transfusion dependence. 

Researchers concluded that the survival of del-5q patients is high.  When compared to other MDS sub-types or diagnoses, del-5q patients were found to have a risk for AML progression comparable with patients who have refractory cytopenia with multilineage dysplasia without the del-5q mutation.

Researchers recommended that further studies be conducted to better identify MDS patients at greatest risk for AML progression.

For more information, see abstract 945 on the 2009 ASH meeting Web site.

Sapacitabine is an orally-administered drug that mimics naturally-occurring chemical structures in the body and helps stop abnormal cell division that is characteristic of MDS or acute myeloid leukemia (AML). It is currently being investigated for the treatment of MDS and AML.

The primary goal of the ongoing Phase 2 trial is to evaluate the one-year survival rate in MDS patients. Researchers also have designed the trial to test different dosing schedules of sapacitabine. In case participants respond to all dosing schedules, researchers want to determine which one produces the best one-year survival rate.

The study participants were required to be more than 60 years old with intermediate-2 or high-risk MDS subtypes, and they must already have been treated with – and no longer be responding to – either Dacogen (decitabine) or Vidaza (azacitidine).

The participants have been divided into three groups receiving three different doses of sapacitabine.  The first group has received 200 mg sapacitabine twice a day for seven consecutive days every three to four weeks. The second group has received 300 mg twice a day for seven consecutive days every three to four weeks.  The third group has received 400 mg twice a day for three days per week for two weeks, within an overall three- to four-week cycle.  There is no maximum limit of cycles, but treatment with sapacitabine is halted if a patient shows signs of excessive toxicity.

Across all three groups, sapacitabine thus far has had an overall response rate of 23 percent.  The 23 percent overall response rate consists of one patient (2.6 percent) who achieved a complete response, and eight patients (20.5 percent) who registered major hematological improvements.

The second group of patients had the highest overall response rate (38 percent), compared to the first group (23 percent) and the third group (8 percent).  The median time to response was one to two cycles.

Common side effects included fatigue, nausea, diarrhea, and constipation.  Patients also experienced varying degrees of low white blood cell or red blood cell counts.  One patient died due to causes unrelated to treatment with sapacitabine.

Researchers concluded that all three dosing regimens of sapacitabine are safe for treating MDS.  Based on the preliminary results, they believe the second group’s dose (300 mg for seven consecutive days every three to four weeks) is the most effective regimen.

Cyclacel, the manufacturer of sapacitabine, is currently still recruiting MDS patients for the above trial to further evaluate the efficacy, safety, and optimal dosing of sapacitabine.

For more information, please see abstract 1758 at the American Society of Hematology Web site or Cyclacel’s related press release.

U.S. MDS Patient And Family Forum —The MDS Foundation is sponsoring a free educational forum for MDS patients and their families on December 18 in Lake Success, NY. The main speaker will be Dr. Steven Allen of the North Shore University Hospital.  The event is free, but registration is required.  For more information about registering, please see The MDS Foundation Web site.

For a more detailed listing of MDS-related events, please check the MDS Beacon Events Calendar.

In MDS, developing blood cells fail to properly mature, resulting in a lower than normal number of healthy blood cells (a condition known as cytopenia).

Immunosuppressive agents like ATG and cyclosporine can increase the number of healthy blood cells in some MDS patients. However, the continued use of ATG in combination with cyclosporine has been associated with increased kidney damage.

Campath is another immunosuppressive agent that is currently used to treat B-cell chronic lymphocytic leukemia.

In their study, the researchers tested Campath in 22 Intermediate-1 and Intermediate-2 risk MDS patients. The patients received 10 mg of Campath by intravenous infusion for 10 days. Median follow-up was 11 months.

Results showed that 93 percent of Intermediate-1 and 40 percent of Intermediate-2 risk patients showed at least a partial response three months after starting the infusion. All patients who responded to Campath were no longer dependent on blood transfusions.

After nine months, 55 percent of patients had normal blood counts.

In addition, five of seven patients who initially showed cytogenetic, or chromosomal, abnormalities achieved complete response. One patient with monosomy 7 benefited from Campath with 3.8 years of continuous remission.

The share of patients who survived without relapsing was comparable to those in previous studies receiving ATG, or ATG and cyclosporine combination therapy. Relapse was defined as requiring additional treatment to Campath, including cyclosporine.

Two of the patients experienced decreased blood counts during therapy, though not below pre-treatment levels.  Two other patients progressed to leukemia, while another two patients developed other diseases.  One Intermediate-1 risk patient died due to disease progression.

The study authors concluded that Campath effectively produces long-lasting improved blood production in some Intermediate-1 MDS patients.

Although previous studies have shown that MDS patients who are most responsive to such treatment are younger in age, the authors point out that more research is necessary to identify how immunosuppressive treatments can be used appropriately for all MDS patients.

For more information, see abstract 116 on the 2009 ASH meeting Web site.

Revlimid has already been used with Low- or Intermediate-1 risk MDS subtypes, especially those who require red blood cell transfusions or have del-5q, as it produces a high rate of transfusion independence and improved chromosomal abnormalities.

Patients with del-5q are missing the ‘q’ arm of chromosome 5.

Although the exact mechanism of Revlimid has yet to be fully characterized, it relieves symptoms of MDS by stimulating the immune system, causing cell death, and inhibiting new blood vessel growth.

Twenty High-risk MDS and acute myeloid leukemia (AML) patients, the majority of whom had del-5q, received varying doses of Revlimid over a median of 13 weeks. Doses varied incrementally from 10 mg to 30 mg, and maximum doses were administered for 8 weeks.

Patients’ chromosomal responses were evaluated 8 and 16 weeks after beginning treatments, while bone marrow responses were assessed every four weeks.

Although only seven patients were able to complete the entire 16 weeks of treatment, six achieved greater than 50 percent reduction of chromosomal abnormalities and one patient’s blast count decreased from 9.5 percent to less than 5 percent.

Thirteen patients did not complete the study; ten experienced severe side effects, including hospitalization due to infection or low white blood count, while three encountered disease progression.

Results showed 30 percent of the participating MDS or AML patients achieved at least partial chromosomal response, while 67 percent also reported improvement in blood cell development.

In addition, 15 patients experienced serious adverse events that led to inpatient hospitalization. Although six patients died from these events, cause of death was determined to be unrelated to Revlimid.

These results are similar to a previous study in the journal Blood, which reported 10 mg Revlimid per day for 21 consecutive days every four weeks improved blood cell development in High-risk MDS patients with del-5q.

This Phase 2 study was conducted with 47 patients, 27 percent of whom achieved at least partial response. Seven patients experienced complete remission, and overall median survival was 272 days.

Patients in this study did experience side effects such as low white blood cell or platelet counts; however, researchers were unable to find a correlation to the treatment, due to the high number of patients who presented such symptoms before receiving Revlimid.

In conclusion, Revlimid is promising treatment for High-risk MDS patients with del-5q, despite the frequency of side effects and infection.

Future clinical trials will likely test Revlimid in combination with other agents, including cytostatic or hypomethylating agents, to further improve patient responses.

For more information, please see abstract 115 at the ASH Meeting Web site.

Medicare coverage of bone marrow transplants, the only known curative treatment for MDS, is important because 80 percent of MDS patients are 65 or older. MDS patients typically respond best to allogeneic stem cell transplantation, where the bone marrow of a patient is initially destroyed by chemotherapy or radiation and then replaced with donated bone marrow that is able to produce normal blood cells.

“Without coverage for allogeneic transplant, many patients with MDS are simply forced to wait until they become even more ill before qualifying for a transplant after being diagnosed with acute leukemia,” said Mike Boo, chief strategy officer of the National Marrow Donor Program (NMDP).

The NMDP is one of many organizations encouraging the public to voice their support by submitting comments and personal stories to CMS.

The strongest evidence in support of national coverage for Medicare-aged MDS patients comes from studies that show five-year survival rates after allogeneic stem cell transplants are significantly longer than supportive care methods. Of these non-curative treatments, chemotherapy has presented the best five-year survival rate at 8 percent, while transplants result in approximately 20 to 30 percent survival.

According to Boo, the largest age group of patients receiving transplants through NMDP is over 50 years. Last year, 36 percent of transplants from unrelated donors were to patients over 50, while 7 percent of unrelated transplants were for patients 65 and older.

Previously, the risks associated with stem cell transplantation were considered too dangerous for older patients. However, new technology and reduced-intensity chemotherapy regimens have increased the number of elderly patients who are offered this curative option (see related Beacon news).

CMS has given the public the opportunity to submit comments and stories as the center prepares to review evidence surrounding the use of allogeneic bone marrow transplantation for MDS patients in the coming year. They are specifically looking for scientific observations and recent clinical trials that demonstrate that allogeneic transplants are safe and effective in MDS patients 65 years and older.

“Patients who have been told that they are good candidates for transplantation but who are unable to undergo the process due to a lack of Medicare coverage have important stories to share,” said Boo. “Additionally, patients or families of patients that had MDS and, because of the coverage limitations, were unable to receive a transplant until their condition worsened, are also very important.”

Efforts to include national coverage of bone marrow transplants for MDS patients was initiated in September 2009 by a coalition of blood cancer and bone marrow foundations. It is projected that CMS will make their decision to include or exclude the expanded coverage by August 2010.

For more information, please see the CMS Web site, including the National Coverage Determination Request (pdf), which is a letter to CMS that documents supporting evidence and new data and formally requests consideration of this issue.

Public comments in support of Medicare coverage of transplants for MDS patients can be viewed on the CMS Web site. Additional submissions may be made through December 10. [Several of the CMS pages are loading slowly due to the volume of people trying to access them.  According to CMS, there is no other way to submit comments.  Please allow the site plenty of time to load or try again later in the day.]

The four-day exposition is an opportunity for blood disease specialists to share new research, network, and discuss the “next 50 years” of hematology.  A variety of presentations and posters will detail the latest advances in blood disease prevention, care, treatment, and survival.

There are many MDS seminars planned for the 2009 ASH meeting. The MDS Beacon will be covering the event, so readers can expect many articles in the upcoming weeks about the key MDS findings from the meeting. 

Saturday, December 5, will include several sessions about the biology of MDS and specific factors that may predict response to the disease and specific treatments. 

An MDS Education Program is scheduled for Saturday, December 5. Dr. David Steensma will present issues surrounding the classification of MDS subtypes in a seminar titled, “The Changing Classification of MDS: What’s in a Name?”  Dr. Heather Leitch will discuss iron chelation in “Chelation Therapy and Supportive Care in MDS: Are We Saving Lives, or Just Lowering Iron?” 

Also on Saturday, Dr. Peter Greenberg will discuss health care policy in a seminar titled, “Myelodysplastic Syndromes: An Illustration of the Impact of Treatment Drug Costs On Patients.”

In Sunday’s session about treatments and clinical observations, researchers will share information about new drugs that may be used to treat MDS, such as Campath (alemtuzumab) and Clolar (clofarabine). 

Mutations will be the focus of Monday’s session, where researchers will share their findings about the effects of specific genetic abnormalities.

A special session on Monday, December 7 will highlight pediatric MDS in a presentation titled, “Spotlight on Myelodysplastic Syndrome in Children: Biology and Treatment.”  As MDS is rare at a young age, clinical specialists will discuss the unique development of MDS and treatment options for children.

Three additional seminars about more general MDS topics will be held on December 7 and 8.  The disease will also be discussed with regard to transplantation, health services, and education in other informational presentations.

Over 100 abstracts specific to MDS research will be displayed in three separate poster sessions at the ASH meeting.

Posters on Saturday will highlight several potential new treatments, including sapacitabine, romiplostin, and combination therapies with Vidaza (azacitidine).  Posters on Sunday will cover a variety of topics, including Revlimid (lenalidomide), Dacogen (decitabine), and gene expression.  Posters on Monday will include additional research on the genetic component of MDS, agent Exjade (deferasirox), and prognoses.

Further information about the ASH meeting, including registration forms, meeting abstracts, and symposia information, can be found at the ASH Web site. For similar coverage of the EHA 2009 meeting (European Hematology Association) and ASCO 2009 meeting (American Society of Clinical Oncology), please see the related articles here at the Beacon.

The most common form of bone marrow transplantation for MDS patients is allogeneic stem cell transplantation, also called allotransplantation. This procedure involves destroying patient bone marrow by chemotherapy or radiation, then replacing it with bone marrow from a matched donor. It is the only curative treatment currently available, but it does not guarantee full recovery.

Until recently, the risks of allogeneic stem cell transplants were considered too high for patients older than 50 years of age. Concerns about the inability of elderly transplant recipients to effectively fight graft vs. host disease resulted in limited recommendations for elderly MDS patients. Graft vs. host disease is a post-transplant threat caused by functional immune cells in the transplanted marrow. These immune cells view the recipient’s cells as foreign and attack them.

Due to the association between older age and a higher risk for graft vs. host disease, transplants have been largely recommended for younger patients only.

However, changes in transplantation technology are leading to better overall survival rates for elderly patients following stem cell transplantation.

Dr. Giralt states that reduced-intensity treatments involving lower doses of pre-transplant chemotherapy and radiation are improving survival rates in the elderly population. In addition, donor matching technology and supportive care have been developed to prevent a life-threatening immune response and delay relapse.

As a result, the number of older patients considered or recommended for transplants is increasing. From 1995 to 1997, only 23 percent of patients who reported to bone marrow transplant registries were older than 50 years of age. The number of patients who were reported to be over 50 increased to 35 percent from 2000 to 2006.

Dr. Giralt reviewed nine different studies investigating the survival and non-relapse mortality rates of elderly MDS patients who received reduced-intensity drug regimens before bone marrow transplants. The patients’ median age ranged from 52 to 60 years.

The results of these studies show that a large percentage of older patients survive or do not worsen when evaluated three years after treatment..

The average three-year survival rates ranged from 30 to 50 percent, while two to three-year mortality rates spanned from 10 to 30 percent.

Patients who received allogeneic stem cell transplants in first remission had even higher survival rates. At the three-year mark, these patients showed a 60 percent survival rate. Less than 15 percent had died from causes not related to relapse.

Though chemotherapy dose intensity varied significantly in the clinical trials he reviewed, Dr. Giralt did not make conclusions about an optimal dose. However, the dose is important for post-transplant disease control. A study reporting the transplant outcomes of 722 patients gives supporting evidence for the benefit of treating elderly MDS and acute myelogenous leukemia (AML) patients with reduced-intensity chemotherapy. While the mortality rate for patients who received normal-dose treatments was 32 percent, the proportion decreased to 18 percent for patients who underwent reduced-intensity treatments.

Dr. Giralt concludes that elderly patients should be offered transplantation options soon after diagnosis, based on the high risk of the disease getting worse quickly or progressing to AML and given the improved two or three-year survival rates for older patients.

He states that overcoming disease resistance and long-term administration of reduced-intensity follow-up regimens are important priorities in stem cell transplants for MDS patients. He adds that future clinical trials will investigate combination therapies and further develop transplant technologies to extend lives.

For more information, please see the article in Clinical Lymphoma, Myeloma & Leukemia (pdf).

Acute pulmonary failure is a rare but serious complication of chemotherapy.  The condition is characterized by lung injury and respiratory distress, and it is unrelated to heart failure.

MDS patients receive chemotherapy drugs to kill cancerous cells, help bone marrow to produce healthy blood cells, and prepare for bone marrow transplantation.  Intensive treatments usually range from six to nine months, and bring short-term reduction of symptoms for as high as 60 percent of MDS patients.

Researchers reviewed 1541 newly diagnosed AML and High-risk MDS patients undergoing intensive chemotherapy.  High-risk MDS patients had greater than 10 percent blasts, which are mass groupings of cells. AML patients showed greater than 20 percent blasts.

Patients requiring mechanical ventilatory support in the intensive care unit within two weeks of the initiation of chemotherapy regimen were categorized as having acute pulmonary failure.

The study did not distinguish AML from MDS patients.  Results showed that 8 percent developed acute pulmonary failure, 30 percent did not respond to treatment, and 14 percent died within six weeks of beginning chemotherapy.  These effects were similar for AML and High-risk MDS patients.

Fifty-five percent achieved complete response, as defined by the 2000 International Working Group criteria as having a blood count of more than 1,000 neutrophil per mL (type of white blood cell) and more than 100,000 platelets per mL (growth cells).

The median duration of complete response for all patients after starting chemotherapy was eight months.  Patients who developed acute pulmonary failure survived a median of three weeks, while those who did not experience lung failure survived for a median of 15 months.

There are no definite factors for predicting acute pulmonary failure; course and prognosis of the condition are not well understood.  In addition, it is often difficult to discern the most important cause when there are multiple contributing factors.

This study revealed pre-existing conditions that may predispose AML and High-risk MDS patients for lung failure.  These include being male, having acute promyelocytic leukemia, not responding well to chemotherapy, and the presence of lung infiltrate at diagnosis.

Although the causes of acute pulmonary failure cannot be identified and prevented completely, MDS patients can be monitored for signs of predisposing factors.  The authors suggest supportive care is important, such as platelet support for High-risk patients, restriction of fluids, and other methods to reduce the probability of unnecessary bleeding.

Such strategies can increase the tolerance of high-intensity chemotherapy and ultimately increase long-term outcomes of High-risk MDS patients.

For more information, please see the journal Cancer (full text).

Revlimid has been used to treat Low- or Intermediate-1 risk MDS subtypes, especially those who require red blood cell transfusions or have del-5q.  The del-5q mutation is a chromosomal abnormality which is characterized by a missing ‘q’ arm of chromosome 5.  Many del-5q MDS patients experience temporarily lowered white blood cell (neutropenia) and platelet (thrombocytopenia) counts. 

Clinical trials have shown that patients taking Revlimid consistently become independent of blood transfusions and show a complete cytogenetic, or chromosomal, response.  A complete cytogenetic response is defined by no abnormal cells present in a specific stage of cell division. 

Although the exact mechanism of Revlimid has yet to be fully characterized, it relieves symptoms of MDS by stimulating the immune system, causing cell death, and inhibiting new blood vessel growth.

The researchers performed a long-term follow-up analysis of 42 Low or Intermediate-1 risk patients with del-5q receiving Revlimid therapy.  Patients received either 10 mg daily or 10 mg for 21 in 28 days.  They were treated until the disease progressed or they relapsed.  

At a median follow-up of 40 months, 58 percent of patients had improved red blood cell production and 48 percent showed a full or partial chromosomal response. 

Thirty-six percent of patients had progressed to AML, and 87 percent of these patients had developed other chromosomal abnormalities in addition to del-5q. 

Results showed del-5q patients who responded to Revlimid treatment with a cytogenetic response had fewer incidents of AML progression.  Three and five years after study entry, 10 and 21 percent of patients who showed a cytogenetic response to Revlimid had progressed to AML, respectively.  In contrast, 46 and 60 percent of patients without cytogenetic response had progressed to AML at three and five year follow-up, respectively.

The study authors conclude that cytogenetic response after Revlimid treatment may be an indicator for a decreased risk of AML progression.  Patients without a cytogenetic response to Revlimid are more likely to progress to AML than those who do show a cytogenetic response.

However, the authors feel their research cannot answer the question of whether or not Revlimid increases the risk of AML transformation.

Dr. Brigitte Schlegelberger, one of the study authors, said in an email to the MDS Beacon “A definite answer cannot be given, since it cannot be excluded that a subpopulation containing genetic lesions that trigger the transformation was present before treatment.” She added, however,”a leukemic transformation rate of more than 60 percent seems quite high.”

The authors suggest regularly monitoring del-5q patients taking Revlimid in order to identity patients who may be at an increased risk for AML progression..

For more information, please see the Annals of Hematology (abstract).

5th International Congress On Myeloproliferative Diseases And Myelodysplastic Syndromes — On November 5 through 7, the 5th International Congress on Myeloproliferative Diseases and Myelodysplastic Syndromes will be held in New York City. The conference is geared toward medical professionals and will feature updates and discussions about blood cancer research. To register, or for more information, please see the Congress Web site.

The Unknown Side Effects Of Cancer — The Leukemia & Lymphoma Society (LLS) is sponsoring an educational program that will help cancer patients confront the psychological and emotional difficulties that often accompany cancer. The event will be held on Thursday, November 12, from 11:30 a.m. to 2:30 p.m. in Rockford, IL. For more information, please see the LLS Web site.

For a more detailed listing of MDS-related events, please check the MDS Beacon Events Calendar.

The researchers, based at Washington University in St. Louis, find that a five-day IV regimen yielded response rates and response durations similar to those reported for the standard seven-day subcutaneous Vidaza dosing regimen. At the same time, overall survival times for the five-day regimen were lower than observed in studies using the standard regimen.

Vidaza is typically administered by two or three subcutaneous injections each day over the course of seven consecutive days. The drug’s overall treatment cycle is 28 days — seven days of injections, and 21 days without injections. This regimen matches the one in two key clinical trials that established the efficacy of Vidaza. However, the regimen often results in pain and bruising around injection sites, and the need for weekend injections is inconvenient for some patients.

Vidaza also can be administered by IV infusion, but the efficacy and safety of this approach is not clearly established because clinical trials have not tested it in comparison to subcutaneous injection.

This Washington University study was carried out to determine if a five-day course of IV infusions could have outcomes similar to those of the standard seven-day subcutaneous regimen, while also offering greater convenience and fewer injection site side effects.

During the Washington University study, 22 patients with primarily intermediate- to high-risk MDS received one 20-minute IV infusion of Vidaza daily for five consecutive days. Patients received a median of 4.5 treatment cycles.

Six of the 22 patients in the study, or 27 percent, achieved complete or partial remission. Another nine patients, or 41 percent, showed no signs of disease progression.

The patients who achieved a complete or partial remission responded to treatment after a median of 108 days, and the median duration of their response was 15 months.

Across all patients in the study, median overall survival was just short of 15 months.

Side effects with the five-day regimen included those usually associated with Vidaza. Patients reported reduced red and white blood cell counts, and they also experienced fatigue, fever, low platelet counts, nausea, and cardiac events due to infection.

Nausea, however, was unusually common among the patients in the Washington University study. Fully 100 percent of the patients required anti-nausea medication by the third 28-day treatment cycle in the study. The authors note that, among patients treated with Vidaza according to the standard seven-day regimen, the incidence of nausea is about five percent.

In the discussion of their results, the study authors note that the response rates observed with the five-day IV Vidaza regimen are similar to those seen in the two major clinical trials that tested the now-standard seven-day subcutaneous Vidaza regimen.

Overall survival time, however, was noticeably lower among the patients in the Washington University study — 15 months, as opposed to 21 and 24 months in the two major trials that used the seven-day subcutaneous regimen.

The difference in survival time would seem to be a clear strike against the five-day IV regimen.

Yet the researchers are not so certain. They note that the patients in their study had noticeably weaker immune systems – based on their absolute neutrophil counts – compared to patients in the two major trials that used the seven-day subcutaneous Vidaza regimen.

And, in fact, a key difference in the survival of the patients in the different studies is that almost one quarter of the Washington University study patients died – primarily due to infections – within two months of starting their Vidaza therapy. In comparison, there were very few early deaths in the two seven-day regimen trials.

Thus, the researchers believe the five-day IV Vidaza regimen still merits further investigation. They note that the sample size of their study was rather small, and many of the key questions raised by their results could be addressed in a larger trial explicitly comparing the two dosing regimens.

In an email exchange with The MDS Beacon, Dr. Ravi Vij, one of the Washington University researchers, said “One cannot make any firm conclusions from a small set of patients. However, the abbreviated five-day regimen seems to have a shorter survival rate than the seven-day regimen. [Our] study was meant to provide justification for conducting a larger multi-center trial. It met its efficacy end-point in that regard.”

A representative of Celgene, the pharmaceutical company that markets Vidaza, told the Beacon that the firm is not currently planning any clinical trials to further investigate the five-day IV regimen.

For more information about the Washington University study, please see the American Journal of Hematology (abstract).

Additional Notes: (1) The daily Vidaza dose given to the patients in the Washington University study was the same (75 mg/m²) as the daily dose typically administered to patients treated with Vidaza in the standard seven-day subcutaneous regimen. The dose was increased, however, by a third for those patients in the study who failed to respond after two 28-day cycles of therapy. (2) The Washington University study defined “complete remission” based on the modified International Working Group (2006) criteria, which require blood counts of more than 1,000 neutrophils per µL and more than 100,000 platelets per µL. MDS patients in complete remission are not necessarily fully cured or free of cancer cells, but they are considered free of any symptoms of MDS.

Vidaza is one of several new FDA-approved drugs for the treatment of myelodysplastic syndromes (MDS).  Clinical trial data indicate that Vidaza typically delays progression of MDS to acute myeloid leukemia and improves overall survival among MDS patients.

Vidaza is administered either via infusion or a subcutaneous injection.  When administered as an injection, the drug often causes painful, but otherwise harmless, inflammation at the injection site.

At the recommendation of an MDS patient who had successfully used evening primrose oil for injection site irritation, German researchers tested the oil’s effectiveness in ten patients who had experienced skin reactions during previous Vidaza treatment cycles.

Six of the ten patients experienced a significant reduction in injection site redness and inflammation after applying the oil.

The authors attribute the anti-inflammatory effects of evening primrose oil to gamma-linoleic acid, which is an unsaturated fatty acid. The oil is extracted from evening primrose seeds and sold as capsules for oral consumption or as topical oil.

The German researchers used the liquid form and applied the oil directly to the skin after injection.

The oil of the evening primrose (Oenothera biennis) is used as a complementary or alternative treatment for skin conditions characterized by red, flaky skin that may be inflamed or sensitive. It has also been used for allergies, arthritis, menopausal symptoms, and breast pain.

Clinical studies supporting medical use of the oil are still lacking, but it has been observed to be well-tolerated with mild side effects, such as headache or gastrointestinal upset.

Evening primrose oil for topical application is sold over-the-counter, and is available at pharmacies and health food stores. Patients should consult their physicians before applying the oil, especially if they are being treated with other medications.

While the authors recognize that their observations require further testing, they believe evening primrose oil can be an inexpensive and safe way to reduce the skin irritation caused by Vidaza injections.

For more details, see the German researchers’ report at the Annals of Hematology.

FDA Advisory Committee Set to Review Ferriprox - (See important update immediately below) On October 6, the U.S. Food and Drug Administration (FDA) Oncology Drugs Advisory Committee (ODAC) will review the iron chelating agent Ferriprox (deferiprone) for possible marketing approval in the U.S.  Ferriprox is approved for sale in a number of countries outside of the U.S., and is used to treat iron overload in patients who require frequent blood transfusions.  The meeting will include presentations by Ferriprox manufacturer ApoPharma Inc. and the FDA staff as well as questions from the public.  The FDA usually follows the advice it receives from its advisory committees, but it is not required by law to do so.  For more information, please see the meeting’s draft agenda and the Ferriprox Web site (intended for non-U.S. visitors).

Update: The FDA has announced that the Ferrirprox review meeting has been cancelled “to allow time for the FDA to review and resolve several outstanding issues.”  The agency says that it intends to continue evaluating Ferriprox, and it will reschedule the ODAC meeting “as needed.”

Living With Myelodysplastic Syndromes One-Day Conference – The Moffitt Cancer Center  and the Aplastic Anemia & MDS International Foundation (AA&MDSIF) are sponsoring a free opportunity to learn about the latest MDS diagnostic and treatment information, and ask questions of leading MDS researchers.  This one-day conference will be on Saturday, October 10, at the Moffitt Cancer Center in Tampa, Florida, from 9 a.m. to 4 p.m.  Breakfast and lunch are provided.  Space is limited, so please register by October 2.  For more information, please visit the AA&MDSIF Web site.

MDS Patient & Family Forum – Participate in a forum organized by the Myelodysplastic Syndromes Foundation on Tuesday, October 6, in Ontario, Canada.  Dr. Karen Yee from Princess Margaret Hospital will be providing information pertinent to MDS patients and their families.  Individuals must register by calling 1-800-MDS-0839 or emailing dmurray@mds-foundation.org.  For a listing of other upcoming U.S. and international forums, please see the MDS Foundation Web site.

For a more detailed listing of MDS-related events, please check the MDS Beacon Events Calendar.

Selected results from the new study, by a team from Tel Aviv University in Israel, were presented this summer at the European Hematology Association 14th Congress in Berlin, and were briefly discussed in a previous MDS Beacon news article.

After reviewing a large number of studies for potential inclusion in their analysis, the Israeli researchers found four relevant randomized controlled trials.  The four trials involved 952 predominantly high-risk MDS patients who received either Vidaza, Dacogen, or conventional treatment.

Vidaza and Dacogen are two examples of hypomethylating (or demethylating) agents that help decrease uncontrollable cell division, a characteristic of MDS that can be caused by methyl groups that are bound to DNA sequences, blocking the regulation of cellular growth.  The drugs remove the problematic methyl groups and allow the DNA sequences to function normally.

There were three types of conventional treatment included in the studies analyzed by the Israeli team: supportive care, low-dose chemotherapy, and intensive chemotherapy.

Supportive care is used to treat symptoms of MDS caused by low blood cell counts, but it does not cure MDS or prevent progression to acute myeloid leukemia (AML).  Stem cell transplantation is currently the only therapy able to generate complete recovery from MDS.  Supportive care includes blood transfusions and treatment with growth factors.

The low-dose chemotherapy in the studies was low-dose cytarabine (Cytosar-U).  The intensive chemotherapy was the “7+3” regimen involving standard dose cytarabine plus daunorubicin (Cerubidine).

The study evaluated overall survival, length of time to AML or death, complete or partial response, and severity of side effects.  A complete response, as measured by the 2000 International Working Group (IWG) criteria, is defined as having a blood count of more than 1,000 neutrophils per µL and more than 100,000 platelets per µL.

Results from the Israeli team’s systematic review indicate that hypomethylating agents as a group prolong overall survival and slow progression to AML compared to conventional care.  Patients receiving hypomethylating agents also were more than seven times likelier to achieve a complete response, and more than six times likelier to achieve a partial response, regardless of which drug was administered.  At the same time, although Vidaza and Dacogen increased blood counts (as reflected in the better response rates for the agents), they did not as a group decrease dependence on red blood cell transfusions.

Moreover, patients receiving hypomethylating agents had a 20 percent greater chance of serious side effects such as lowered white blood cell counts (neutropenia) and platelet counts (thrombocytopenia).  They also had a higher rate of treatment-related mortality than those receiving conventional care.

The study also examined whether the hypomethylating agents have better overall survival than each of the three specific kinds of conventional care covered by the analysis. The study finds such a benefit versus supportive care and low-dose chemotherapy, but not versus intensive chemotherapy.  The authors note, though, that the hypomethylating agents may still be a better option for patients due to their ease of administration and the adverse events common with intensive chemotherapy.

The Israeli researchers also compared the overall survival benefit of the individual hypomethylating agents versus conventional care.  This analysis favors Vidaza, finding evidence of a survival benefit for Vidaza but not for Dacogen.  Similarly, the study finds Vidaza more effective than Dacogen in lengthening the time to death or AML.

Despite the review’s findings, the authors note that the small number of clinical trials limits the emphasis that should be placed on the Dacogen vs. Vidaza comparisons.

Neither Celgene Corporation, the company that markets Vidaza, nor Eisai Inc., the company that markets Dacogen, responded to requests from The MDS Beacon for comment on the article by the Israeli researchers.  Eisai announced late last year that it will be sponsoring the first clinical trial to directly compare Vidaza against Dacogen.  The main goal of the study will be to compare the complete response rates of the two drugs.

Overall, the Israeli team concludes that hypomethylating agents should “have a major role in the treatment of [high risk] MDS.”

In comments to the MDS Beacon about the Israeli team’s article, Dr. Emmanuel Besa of Thomas Jefferson University in Philadelphia said he is uncertain whether the article really adds much beyond what is already available in the four individual studies analyzed in the paper.  Dr. Besa, an MDS specialist, took issue with the authors’ grouping of supportive care, low-dose chemotherapy, and intensive therapy into a single “conventional care” category of treatment, noting that the three treatments are very different from one another.

Likewise, Dr. Besa pointed out that both of the Dacogen clinical trials surveyed by the paper were halted before significant survival data could be collected.  In addition, one of the two Vidaza trials in the paper included a large number of patients who were treated with both Vidaza and supportive care.

For more information about the Israeli team’s study, please see the journal Haematologica (abstract; full article also available at no cost).

Exjade is an iron chelating agent, a type of drug used to bind free iron in the blood and prevent it from forming deposits in organs.  It also works to remove excess iron that may have already built up in the heart, liver, and endocrine cells, and thus decreases the possibility of toxic effects.  Exjade is often prescribed to MDS patients who have excess iron, a condition often seen after repeated red blood cell transfusions.

The FDA data analysis showed that, compared to patients with other conditions, MDS patients were at higher risk for experiencing kidney failure, gastrointestinal bleeding, and death after taking Exjade.  However, the FDA has not yet made a conclusion about the drug’s safety because the adverse events may be  linked to several factors that often specifically characterize MDS patients, such as advanced age, the need for blood transfusions, and other medical complications.  The data analysis also suggested that  serious or fatal side effects were fewer in younger patients with conditions other than MDS that require blood transfusions. 

Novartis, the pharmaceutical company that markets Exjade, released the following statement in regard to the FDA investigation:

Patient safety is the highest priority at Novartis. As part of ongoing pharmacovigilance discussions with the FDA, we recently submitted a comprehensive safety analysis of various data sources regarding the use of Exjade for the treatment of transfusional iron overload in patients with myelodysplastic syndromes (MDS).  We have also shared this information with other regulatory authorities worldwide.

We are working with the FDA to further review and clarify the population of MDS patients most appropriate for treatment with Exjade and will update the label accordingly.  We take our obligations to patients and healthcare providers seriously and will work to ensure our label reflects the most up-to-date information to help physicians make optimal prescribing decisions.

Exjade continues to offer an important treatment option for appropriate patients with sickle cell disease, thalassemia, MDS and other rare anemias who are at risk for transfusional iron overload. Exjade has been used by more than 70,000 people worldwide.

While it reviews  Exjade’s safety, the FDA recommends patients speak to their own physicians for personalized treatment advice.  Physicians are still free to prescribe the drug to reduce excess iron in MDS patients.

Dr. Bart Scott, an MDS specialist at the University of Washington and Fred Hutchinson Cancer Research Center in Seattle, told the MDS Beacon that this new information about Exjade may slow its adoption among MDS patients.  He does not expect, however, the news to lead to a near-term drop in the number of MDS patients taking Exjade. 

Dr. Scott said that he personally would only use Exjade in patients who are transfusion dependent with ferritin levels greater than 1,000 and with a life expectancy greater than one year.

Deferoxamine (Desferal) is an alternative iron chelating drug available to MDS patients in the U.S.  The FDA also is currently reviewing an application by ApoPharma to market the iron chelation drug Ferriprox (deferiprone) in the U.S.  In addition, there is evidence that wheat grass juice may be a natural option for reducing excess iron.

For more information about the FDA’s announcement about Exjade’s safety, please see the FDA Web site.  The MDS Beacon also has a resource article with information about excess iron and chelation therapy in MDS patients.

The review, carried out by researchers from the University of Pittsburgh, Amgen, the Cleveland Clinic, and SUNY Downstate, is a meta-analysis of data from ten independent studies carried out in Japan, Europe, and the United States.  The authors of the new review statistically combine the data from the ten previous studies to discern trends difficult to see in the small sample sizes of the previous studies.

The previous studies included male and female patients at least 18 years old.

All ten earlier studies examined the risk of smoking, and included a total of 1,839 people with MDS as well as 2,831 people without MDS (as controls).  In order to assess the link between smoking and developing MDS, the studies grouped ex-smokers and current smokers together in one group, and all others in a “non-smoking” group.

Based on their review, the authors of the new study estimate that smokers have a 45 percent higher likelihood of developing MDS than non-smokers.

This result “makes biological sense,” the authors write in their review.  Cigarettes are a common source of exposure to benzene, a hydrocarbon known to cause MDS.  In addition, tobacco products may cause chromosomal abnormalities, such as missing, extra, and malformed structures, or interchanged chromosome segments.  Genetic irregularities, such as deletions on chromosome 5 and 7, have already been established as risk factors for MDS.

The new study did not estimate a minimum smoking dose associated with MDS because not all of the independent studies reviewed in the study reported this factor.

Though the role of smoking in MDS is moderate compared to its association with other conditions such as lung cancer, the authors believe the risk is still important when considering the overall implications of smoking for public health.  Smoking has already been linked to MDS in separate studies, such as one conducted by the Yale School of Public Health and discussed in a previous MDS Beacon news article.

The authors of the new review also examined data from five of the ten previous studies, with a total of 745 patients and 1,642 controls, that examined the possible role of alcohol consumption in causing MDS.  Each study varied in how it grouped people for the purpose of comparing drinkers versus non-drinkers.

The review of the data from the five previous studies does not find support for a link between alcohol consumption and MDS.  The analysis shows a somewhat positive association between alcohol consumption and developing MDS, but the association is not strong enough to be statistically significant.

The authors note that previous research suggests that alcohol could be protective against MDS due to the antioxidant content of some alcoholic beverages, particularly red wine.  The new review, though, does not find support for such a link, but the authors acknowledge that more studies are needed to settle the role of alcohol consumption in MDS.

The authors also note that past research has established that major risk factors for MDS include age, male gender, exposure to hydrocarbons and other specific chemicals, and radiation.  However, they believe that further investigation of other possible causes, such as genetics, race, ethnicity, and lifestyle behaviors, is needed.

Similarly, the authors feel that further studies are needed to clarify to what extent the interaction of individual factors, such as smoking and alcohol consumption, may increase the risk of MDS.

The new study will be published in an upcoming issue of Leukemia Research (abstract).

Emerging Therapies In Blood Cancer Educational Program – The Leukemia & Lymphoma Society (LLS) will host a free educational program on emerging therapies in blood cancers, including myelodysplastic syndromes, at the John Jones Cancer Center in Morgantown, WV .  Participants are encouraged to bring any questions about clinical trials and advances in the field of blood cancer treatment, and participate in a group discussion.  The event will be held at the John Jones Cancer Center at the West Virginia University Hospital on Tuesday, September 29, from 6:30 p.m. to 8:30 p.m.  For more information, please visit the LLS Web site or register online. 

Light the Night Walk – Join The Leukemia & Lymphoma Society on this special walk to raise funds for blood cancers.  Participants can literally light the night by carrying illuminated balloons, as part of a community that is bringing hope to the fight against blood cancers.  Participate on September 30 in Waterford, CT or October 1 in Dayton, OH.

For a more detailed listing of MDS-related events, please check the MDS Beacon Events Calendar.

Although the drug was initially perceived to be equally effective across all risk categories and for all deletion 5q patients, recent research has shown that the baseline prognosis of various chromosome 5 abnormalities is different.  This is expected to affect the way Revlimid is prescribed for these conditions, including deletion 5q and monosomy 5.

Patients with deletion 5q syndrome have a significant deletion in the long arm of chromosome 5. This condition most frequently occurs in young female Low-risk MDS patients who need red blood cell transfusions, have anemia (low red blood cells counts), and have normal or average platelet counts. In the condition known as monosomy 5, patients lack one entire chromosome 5. Abnormalities on chromosome 5 are found in 20 percent of all MDS patients.

Revlimid, a structurally similar analog of thalidomide, was first approved by the U.S. Food and Drug Administration after a study showed that MDS patients responded positively.  Although the exact mechanism of Revlimid has yet to be fully characterized, it is believed to affect the genes that direct the cell’s growth and activity, particularly those associated with cytokines, cell death, and metabolism.

Results showed that 66 percent of Revlimid-treated patients became independent of red blood cell transfusions, while 44 percent of patients in the study showed a complete response.  Complete response is defined by the International Working Group as having a blood count of more than 1,000 neutrophils per µL and more than 100,000 platelets per µL.  Patients had a median remission length of 116 weeks.  The drug has been determined as non-curative, but is used to delay or prevent progression to acute myeloid leukemia (AML), a type of blood cancer.

Since the drug was first approved for treating MDS, the potential benefits or effects on the specific subgroups of MDS patients with chromosome 5 abnormalities has not been studied until recently.

Researchers from the M.D. Anderson Cancer Center in Houston investigated the baseline prognoses of MDS patients without Revlimid treatment.  They demonstrated that there are different prognoses even among patients who have abnormalities on chromosome 5.  In addition, results showed that median survival progressively worsened with increased numbers of additional chromosomal abnormalities.

Researchers concluded that those with deletion 5q generally had lower-risk MDS than those with monosomy 5, and that they should not be treated as one group.  This may help oncologists offer Revlimid to patients whose prognoses predict improvement, rather than to those who may not benefit from the treatment.

For more details about the study, please see the related MDS Beacon article or the study in the journal Cancer (abstract).

Results showed that Chinese patients tended to develop MDS a median of 15 years earlier than Western patients. In addition, the disease presented different symptoms when caused by benzene exposure, compared to other causes.

These differences suggest Chinese and Western patients need to be diagnosed and treated according to these variations.

The finding came from the Shanghai Health Study, evaluating 649 new cases of MDS in Shanghai over four years, focusing specifically on the role of benzene exposure as a source of secondary MDS.

The study was a collaborative effort between Cinpathogen, Fudan University, the University of Colorado, the Shanghai Hematology Society, and the Shanghai Pathology Society. Cinpathogen is a leading biomedical research and consulting firm based in Shanghai, China.

For more information, please see the Cinpathogen press release or the related MDS Beacon research summary about MDS differences in Chinese, Romanian, and Western patients.

Transfusions are usually used to reduce symptoms of anemia (low red blood cell count), a common characteristic of MDS. Red blood cells are responsible for distributing oxygen throughout the body, and insufficient levels can cause symptoms such as fatigue, infection, shortness of breath, pale skin, and chilled sensations.

During a transfusion, a patient’s blood is replaced with healthy blood from a blood bank. Approximately 80 percent of MDS patients require red blood cell transfusions during their treatment. Reduced dependence on transfusions has been associated with a longer survival time, and some treatments have already been developed to lower the need for transfusions

The study included 47 patients with a median age of 67 years. These patients had been diagnosed with MDS for an average of five years. Eighty-seven percent had previously received a blood transfusion, and 49 percent had received one transfusion within the three months prior to participation in the study.

Patients were asked to give their opinion about specific aspects of transfusions that affected their health-related quality of life. Patients evaluated issues such as

• Reliance on blood transfusions and health care facilities
• Inconvenience of arranging their lives around medical appointments
• Fatigue and tiredness that limited routine physical activities
• Interference of disease with social and family lives
• Worrying about the future
• Discomfort associated with MDS and treatments
• Being at risk of infection
• Relying on others for care
• Feeling burdensome to their families
• Feelings of sadness, hopelessness, and helplessness.

Patients were also asked time trade-off questions that assessed their preference for living with MDS for five years compared to being without disease for a shorter period of time.

Results showed that patients reported some troubles with pain and discomfort (47 percent), moving around (45 percent), routine activities (40 percent), and anxiety or depression (34 percent). The health-quality tests and interviews showed that patients valued transfusion-independence to both reduced transfusions and transfusion-dependence. A few patients even valued transfusion-dependence as worse than being dead (6 percent).

Researchers produced a summary evaluation of patients’ key concerns and the value placed on reduced transfusions or transfusion-independence compared to potentially longer life with transfusions. They concluded that transfusion-independence was associated with a higher quality of life and statistically preferred by patients. This suggests that producing future MDS treatments that aim to reduce transfusion-dependence may become a priority.

For more information, please see the related article in Health and Quality of Life Outcomes (pdf).

Chromosomal abnormalities, which can include missing, extra, and malformed structures, or interchanged segments, are often correlated with MDS diagnoses. However, abnormalities on the same chromosome can result in different prognoses. Having a predicted prognosis for specific conditions can help physicians prescribe effective treatments accordingly.

Deletion 5q and monosomy 5 are two specific abnormalities on chromosome 5. Patients with deletion 5q syndrome have a significant deletion in the long arm of chromosome 5. This condition most frequently occurs in young female Low-risk MDS patients who need red blood cell transfusions, have anemia (low red blood cells counts), and have normal or average platelet counts. In the condition known as monosomy 5, patients lack one entire chromosome 5. Abnormalities are found on chromosome 5 in 20 percent of all MDS patients.

This study evaluated the records of 2,743 patients diagnosed with MDS and referred to the M.D. Anderson Cancer Center records from 1966 to 2009. Eighteen percent of all patients had some type of chromosomal abnormality, while 10 percent had deletion 5q syndrome and 8 percent had monosomy 5. Regardless of previous treatment, survival was measured from the time patients were referred to the cancer center.

Table 1. Median Survival Times for Different Combinations of Chromosome 5 Abnormalities

This study demonstrated that there are different prognoses even among patients who have abnormalities on chromosome 5. In addition, results showed that median survival progressively worsened with increased numbers of additional chromosomal abnormalities (Table 1).

Researchers concluded that those with deletion 5q generally had lower-risk MDS than those with monosomy 5, and that they should not be treated as one group.

For more information, please see the related article in the journal Cancer (abstract).

Rock ‘n’ Roll Half Marathon — SunTrust presents the ninth annual Rock ‘n’ Roll Half Marathon on September 6, 2009. Over 20 local bands will provide live entertainment ranging from classic rock, R&B, and reggae as runners race for 13.1 miles along Virginia Beach. The race starts for women at 6:45 a.m. and for men at 7 a.m. More information can be found on the Rock ‘n’ Roll Half Marathon Web site.

For a more detailed listing of MDS-related events, please check the MDS Beacon Events Calendar.

Eighty to 90 percent of MDS patients receive transfusions to treat symptoms of anemia, which is a decrease in the number of red blood cells. Symptoms commonly include chronic tiredness or fatigue, shortness of breath, heart palpitations, and chilled sensations.

Transfusions help anemic patients by supplementing the insufficient levels of red blood cells. However, transfusions also introduce approximately 200 to 250 mg of iron to the body without providing a means of removing excess iron. Proteins that normally bind iron and prevent it from reacting destructively with other cells in the body can become overloaded. This causes iron deposits that can cause cell death, tissue damage, and reduced life expectancy, especially in the heart, liver, and endocrine system.

Patients who continually receive at least two red blood cell transfusions each month are at risk of iron overload and its associated clinical complications. Iron overload is the most significant negative effect of transfusions. Iron chelation therapy, the use of molecules that bind heavy metals and remove them from the body, is needed to get rid of excess iron and keep the levels from becoming toxic.

The Czech study analyzed variables affecting the overall survival time of 137 patients in the early stages of MDS. With a median age of 49 years, the group was younger than the typical MDS patient, probably because many younger patients were referred to the study as good transplant candidates.

All patients had primary MDS without excess blasts, which are the characteristic immature blood cells that die prematurely in the bone marrow. Patients were diagnosed with one of the following: Refractory Anemia (RA), Refractory Anemia with Ringed Sideroblasts (RARS), Refractory Cytopenia with Multilineage Dysplasia (RCMD), Refractory Cytopenia with Multilineage Dysplasia and Ringed Sideroblasts (RCMD-RS), or 5q-syndrome. RA, RARS, and 5q-syndrome are caused by abnormal levels of red blood cells, while RCMD and RCMD-RS are caused by insufficient levels of more than one blood cell type.

Researchers observed length of overall survival, progression-free survival, and the percentage of patients living three, five, and 10 years after diagnosis. In this study, 87 percent of patients received at least one red blood cell transfusion during the course of the disease, with a median of two transfusions each month.

Results showed that median overall survival was decreased from 65 months to 35 months in patients who required more than two red blood cell transfusions per month. Additionally, patients with RCMD or RCMD-RS had median overall survival of 22 months, which is significantly shorter compared to patients with RA, RARS, or 5q-syndrome, who survived a median of 48 months.

Researchers acknowledged that the most important variable affecting survival throughout the experiment, regardless of dependency on transfusions, was disease progression to more advanced stages of MDS or acute myeloid leukemia (AML). Patients with RCMD, RCMD-RS, or abnormal chromosomes who experienced disease progression had significantly decreased survival.  In RA, RARS, and 5q-syndrome patients who did not  receive a transplant and who did not progress towards AML, frequent red blood cell transfusions were the only factor that negatively impacted their survival.

The study concluded that transfusion dependency has a significant negative impact on survival, most likely due to iron buildup. The authors suggest that patients with RA, RARS, or 5q-syndrome should be the main target group for iron chelation therapy, since their survival is longer and they are likely to receive more transfusions during that time.

Similar studies have shown that iron levels significantly affect survival time and support the use of iron chelation therapy to remove excess deposits.

For more information, please see the related article in Leukemia Research (abstract) and the Beacon resource article about excess iron in MDS patients.

The NCCN Guidelines provide recommendations to physicians for managing most types of cancers. The guidelines include a “decision pathway” that outlines recommended care for MDS patients.

The NCCN upgraded Vidaza’s status to Category 1, or “preferred” therapy, for high-risk MDS patients, who are most likely to progress to acute myeloid leukemia (AML). This recommendation is based on preliminary data from a large international Phase 3 clinical trial presented at the 50th Annual Meeting of the American Society of Hematology. Results showed the drug significantly increased survival rates of high-risk MDS patients.

The study enrolled 358 high-risk MDS patients, 113 of whom had already progressed to AML. Patients who received Vidaza were given 75 mg/m² by subcutaneous injection for seven days during each 28 day cycle. Others received either intensive chemotherapy, low doses of the chemotherapy drug cytarabine, or best supportive care.

The study’s overall results showed those who received Vidaza survived a median of 25 months after treatment, and 51 percent of patients were still living after two years. Those receiving conventional care survived a median of 15 months, with only 26 percent still living after the two year follow-up.

In the AML patient subset, median overall survival for patients who received Vidaza was 25 months, compared to 16 months with conventional care. In addition, 50 percent of AML patients who received Vidaza were still living two years after treatment, compared to 16 percent of patients who were given conventional care.

Vidaza has been shown to have the unprecedented ability to delay AML progression and improve survival in patients already diagnosed with AML. Its potential for helping all high-risk MDS patients is reflected in the NCCN recommendation.

In addition to Vidaza, the NCCN guidelines also mention encouraging results for studies involving Dacogen (decitabine) and Revlimid (lenalidomide), two other drugs approved by the U.S. Food and Drug Administration for treating MDS.

For more information, please see The MDS Foundation press release (pdf) or the NCCN Clinical Guidelines for MDS (pdf).

Iron is an essential element to all living organisms, as it is an important aspect of health and disease. Iron is essential to red blood cells since they house most of the body’s iron content. Iron is normally bound by different proteins which prevent it from reacting destructively with other cells in the body. However, excess iron can overload these proteins, leading to free iron circulating and accumulating in the body due to the lack of an active mechanism to excrete iron. Iron deposits, especially in the heart, liver, and the endocrine system, can cause cell death, tissue damage, and reduced life expectancy.

Ferritin, one iron-storage protein, is measured as an indicator of iron levels because it correlates to the body’s regulation of the metal. Ferritin levels normally range from 12 to 300 ng/mL in healthy adult males and 12 to 150 ng/mL in females, but they increase dramatically when too much iron is present in the body.

Symptoms of excess iron are often non-specific, such as abdominal discomfort and fatigue. Complications caused by excess iron include cardiac failure, pancreatic impairment leading to diabetes, muscle cramps, bronzed pigmentation of fair skin, and a weakened immune system.

Why do MDS patients suffer from excess iron?

Excess iron is a concern for myelodysplastic syndromes (MDS) patients who have repeated red blood cell transfusions. Eighty to 90 percent of MDS patients receive transfusions to treat symptoms of low blood cell levels, such as fatigue, heart palpitations, and shortness of breath. However, transfusions also introduce iron to the body without providing a means of removing excess deposits.

Some MDS patients have iron build-up without ever having received transfusions, such as those with sideroblastic anemia or the specific gene sequence HFE, because these diseases involve an inherent defect in processing iron.

Iron chelation therapy

The term chelation therapy refers to the administration of organic compounds, known as chelating agents, that bind and remove unwanted metals from the body. The goal of iron chelation therapy is to bind free iron in the blood and prevent it from forming deposits in organs. It also removes excess iron that may have already built up in the heart, liver, and endocrine cells, and thus decreases the possibility of toxic effects.

The two iron chelators currently available in the United States are Desferal (deferoxamine), which requires injection, and Exjade (deferasirox), which is taken orally. Ferriprox (deferiprone) is another oral iron chelator that is available outside of the U.S.  The U.S. Food and Drug Administration for FDA is currently reviewing an application by Ferriprox’s manufacturer, ApoPharma, to market the drug in the U.S.

Additional ways to regulate iron levels

Patients who are genetically predisposed to form iron deposits without having received blood transfusions may also be treated by phlebotomy. Phlebotomy is a procedure that removes blood from the body thereby reducing the number of iron-rich red blood cells in the body.

Regulation of dietary intake can also help decrease iron levels. Foods that contain large amounts of iron or increase iron absorption, such as red meat, alcohol, and Vitamin C, should be avoided.

Difficulty surrounding iron chelation therapy

Iron overload remains difficult to treat due to the disagreement among clinicians regarding its seriousness. There are no specific guidelines that define iron overload, and the threshold level of ferritin, an iron-storage protein, that requires iron chelation varies by physician. In addition, there are many differences regarding the optimal levels of red blood cell transfusions, type of iron chelator, and dose that should be administered.

Measurement of ferritin levels also introduces problems, as levels vary by the type of testing used. Directly testing the liver gives the most accurate measurements of body iron, but there is a high risk for infection and bleeding, due to the low blood cell counts that often accompany MDS. Accurate non-invasive measures also exist, but they are few in number and inaccessible to most patients. Magnetic resonance imaging techniques for the liver and heart have been utilized, but discrepancies have been observed.

Iron chelation is also expensive and logistically difficult to obtain. For example, Exjade costs about $5,000 per month for the average U.S. patient. In addition, iron chelators are sometimes only available by mail order, and insurance authorization can be difficult.

Side effects, such as skin, digestive, hearing, and visual abnormalities, also obscure the guarantee of iron chelation therapy as a satisfactory option. Patients who are permanently dependent on blood transfusions are also at risk for blood disease, kidney failure, and liver failure.

Some researchers believe that MDS patients who have excess iron without having ever received transfusions are good candidates for iron chelation therapy because their life expectancies are longer than those of other diagnoses. However, the disagreements among physicians about the importance of iron chelation in treating MDS remain a source of controversy.

To better understand the role of iron chelation therapy in treating MDS patients with excess iron, large, multi-year studies are needed, due to the rapid progression of MDS and the slow effects of excess iron.

Wisconsin Boy Scout To Hold Blood And Marrow Donor Awareness Drive – In partnership with the American Red Cross, boy scout Micah Topel of Evansville, WI will host “Micah’s Drive for Life” – a combination blood drive, bone marrow donor drive, and organ/tissue donor sign up – on Thursday, August 6 at the UAW Local 95 Hall. The drive will raise awareness about blood, bone marrow, and organ donations and raise money for the Restoring Hope Transplant House where families can stay while patients are receiving treatment at University of Wisconsin-Madison Hospital. For more information, see the Janesville Gazette article.

Chinese MDS Patients Have Different Genetic Abnormalities Than Western Patients – A study reported that 68 percent of Chinese patients with MDS showed genetic mutations, but at different types and rates than those observed in western patients. The observed chromosomal abnormalities included varying numbers of copies, structural irregularities, and translocations, in which different sections of chromosomes were switched.  Twelve translocations in this study had never been reported before.  Researchers hypothesize that eastern and western patients develop MDS through different abnormalities due to environmental factors and exposure to different chemicals and infectious agents. More information can be found in Leukemia Research.

For a more detailed listing of MDS-related events, please check the MDS Beacon Events Calendar.

The sixty year old patient received Dacogen (20 mg/m² per day) for five days by intravenous injection. Following the therapy, the patient reported a skin rash, slow marrow recovery, and fatigue. She was admitted to the hospital one month post treatment due to neutropenic fever, a fever accompanied by other signs of infection due to an abnormally low white blood cell count. An x-ray confirmed fluid in her lugs and area surrounding the heart.

The fluid build up disappeared 14 weeks after the end of treatment with Dacogen.

Dacogen is approved for treating patients with intermediate or high-risk MDS. Previously reported side effects include liver dysfunction, aching bones, and decreased production of blood cells and platelets.

For more information, see the related letter in Leukemia Research, and be sure to check back for updated coverage as we gain further information about this story.

While the rATG therapy induced a favorable response in patients as a first-choice therapy, AA patients had a higher response rate (92 percent) compared to MDS patients (33 percent).

Immunosuppressive treatments are being studied for AA and MDS because research suggests that these diseases may be caused by immune cells that destroy developing blood cells. Anti-thymocyte globulin therapies have been shown to regulate the immune system, and therefore hold promise for treating AA and MDS.

rATG was administered in combination with the immunosuppressant cyclosporine as well as granulocyte colony-stimulating factor (G-CSF) to stimulate the bone marrow.

Twelve low-risk MDS patients and 13 AA patients received rATG (3.5 mg/kg) daily for five days, although MDS patients older than 55 years received 2.5 mg/kg per day. All patients also took cyclosporine (5 mg/kg) orally every day for a minimum of six months, and G-CSF (5 µg/kg) by subcutaneous injection for up to three months. AA patients were evaluated a median of 12.2 months after starting treatment, while MDS patients were evaluated a median of 12.4 months after starting treatment.

Of the 12 MDS patients, 8 percent achieved complete remission, while 25 percent achieved a partial response. Complete remission for MDS is defined by the International Working Group as having a blood count of more than 1,000 neutrophils per µL and more than 100,000 platelets per µL. This does not necessarily mean that MDS is fully cured or that there are no cancer cells in the body, although there are no evident symptoms of the disease. MDS patients responded to treatment after a median of 111 days.

Of the 13 AA patients, 38 percent achieved complete remission, and 54 percent achieved a partial response. AA patients responded after a median of 93 days.

The main side effects of the treatment included low blood counts, fever, kidney failure, and electrolyte deficiency, but they were determined to be reversible and not significantly harmful.

Currently, severe AA patients who are not candidates for stem cell transplants are typically treated with horse anti-thymocyte globulin (hATG) in combination with cyclosporine. Previous to this study, rATG was usually administered to AA patients only after they relapsed after hATG treatment.

Researchers determined the rATG-cyclosporine-G-CSF regimen to be safe for both AA and MDS patients based on the study results. Future studies will likely investigate predictive factors for a positive response to this therapy in both AA and MDS patients, and whether rATG or hATG is superior as a first-line therapy for AA.

For more information, please see the related research article in Leukemia (abstract).

The study followed 26 patients who were diagnosed as having Intermediate-1, Intermediate-2, or high risk MDS. They were treated with Vidaza from 2002 to 2008 and received a median of two cycles.

At the end of the study, seven of the 26 patients were ineligible for evaluation. Ten (53 percent) of the remaining 19 patients responded positively to the treatment, four of whom reached complete remission, which is defined by the International Working Group as having a blood count of more than 1,000 neutrophils per µL and more than 100,000 platelets per µL. Patients that achieve complete remission often show no symptoms even after a thorough examination. However, the diagnosis does not necessarily mean that MDS is fully cured or that there are no cancer cells in the body. Two of the ten patients who responded positively reached partial remission, while four minimally improved their blood cell counts. Nine of the remaining 19 patients (47 percent) did not show any response to treatment.

The patients who reached remission had significantly higher numbers of thrombocytes, received more cycles of treatment, and had lower serum ferritin levels than patients who did not respond to Vidaza. Ferritin, an iron-storage protein that prevents iron from forming free radicals, corresponds to blood iron levels. MDS patients who undergo repeated transfusions are at risk for high serum ferritin and often take iron chelators to remove excess iron from the body.

Responses largely varied on whether patients were given Vidaza as the first choice of therapy. From patients who received Vidaza as a front-line treatment, 71 percent of patients showed a significant response, while 29 percent of patients did not. Characteristics that did not affect patient responses included age, sex, and pre-treatment leukocyte, hemoglobin, and neutrophil counts.

Researchers concluded that response to Vidaza depended most significantly on whether patients had previously received a different treatment, what their initial thrombocyte count and serum ferritin levels were, and the number of cycles that were administered.

For more information, please see abstract e18003 at the 2009 ASCO meeting Web site.

Cytopenia is a condition characterized by unusually low blood cell counts and is routinely identified by blood tests. Bone marrow examinations are usually required to determine whether MDS is the cause of the cytopenia. However, some patients have inconclusive bone marrow examinations and require more sensitive tests, such as flow cytometry, to establish or exclude a diagnosis of MDS.

A flow cytometry test requires collecting a sample of bone marrow cells from the patient. The sample is treated with antibodies that are marked with fluorescent dyes. These antibodies bind to cells that contain specific cellular markers. A laser is then used to detect and count the cells that give off light, indicating the presence of these markers. Because normal development of blood cells produces known levels of specific cellular markers, samples that have abnormal amounts will give off light at different intensities. In this study, dye intensities resulting from more than five abnormalities were assigned a positive flow cytometry score. An intermediate score indicated three or four abnormal markers, while two or fewer irregularities were given a negative score.

The study tested 102 cytopenic patients whose bone marrow examinations did not show clear signs of MDS, such as abnormally shaped and defective blood cells or immature cells that accumulate in the bone marrow.

A positive flow cytometry value was found in 21.6 percent of patients, a negative value in 67.6 percent, while the remaining 10.8 percent had an intermediate flow cytometry value. During the median 11 month follow-up period, cytopenia was attributed to MDS or another bone marrow disease in 11.8 percent of patients, a different medical condition in 59.8 percent, and was indeterminate in 28.4 percent.

Results showed a high correlation between flow cytometry score, an indication of the severity of irregular blood cell development, and the cause of cytopenia. Specifically, 41 percent of patients with a positive flow cytometry result were later diagnosed with MDS or a related bone marrow disease, and another 41 percent remained undiagnosed. Furthermore, 97 percent of patients with negative scores, indicating few developmental abnormalities, were able to attribute their cytopenia to another condition or remained undiagnosed.

Researchers concluded that flow cytometry may become more useful in diagnosing MDS in cytopenic patients who have initially inconclusive bone marrow examinations.

For more information, please see the related research article in Leukemia Research (abstract).

A HSCT is often necessary for CML or MDS patients whose bone marrow is unable to make sufficient amounts of normal blood cells during hematopoiesis, the process of blood cell production. The bone marrow of the patient is initially destroyed by chemotherapy or radiation, and then replaced with donated healthy bone marrow. HSCT is the only possible curative therapy for either disease, but concern about cognitive side effects, such as decreased memory or attention span, can influence treatment decisions.

This study investigated the effects of different treatments on the cognitive function of CML and MDS patients. Researchers made a general assessment of the 91 CML and 15 MDS patients who participated in the study by interviewing them regarding their education, occupation, past medical and psychiatric history, medication history, intelligence quotient, as well as physical and mental health. They also measured their cognitive functions through a series of tests incorporating attention, memory, and motor speed. The first assessment was made a median of 5.6 months before patients underwent any treatment. Patients were re-evaluated after 12 months, and again after 18 months.

Forty-seven percent of CML patients and 20 percent of MDS patients received HCST. The remaining 53 percent of CML patients received Gleevec (imatinib mesylate), hydroxyurea, or interferon, while 80 percent of MDS patients received hydroxyurea, supportive care, erythropoietin, or Vidaza (azacitidine).

Results showed that the improvement of cognitive function differed according to the length of time from treatment, the disease, and the type of treatment. All patients showed significant improvement in memory in the assessments after 12 and 18 months. In general, CML patients performed in the tests better than MDS patients in all neurocognitive measures. In addition, HSCT recipients improved in almost every cognitive function relative to patients with other treatments, except for physical function or motor speed. The comparatively poor physical performance may have been caused by the effects of total body irradiation and chemotherapy, graft-versus-host disease (a condition that occurs when the body’s immune system begins to attack transplanted stem cells), or medications for the treatment of graft-versus-host disease.

The study indicates that undergoing a transplant leads to the least amount of cognitive difficulty compared to other available treatment options, which is reassuring to potential HSCT recipients. However, researchers also caution that treatment side effects differ according to patient diagnosis and timing of evaluation. This is especially important because perceived mental status side effects may have been present before beginning treatment.

For more information, please see the study in the journal Cancer (abstract).

Vidaza and Dacogen are hypomethylating, or demethylating, agents that allow DNA sequences to function normally. They remove methyl groups that are bound to DNA sequences, allowing the sequences to regulate cellular growth and control cell division.

In this trial, decreased kidney function was defined as having greater than 1.5 mg/dL creatinine in the blood. Creatinine is normally filtered from the blood by the kidneys. Prior to this study, such patients were normally not treated with hypomethylating agents.

The study examined the responses of 42 patients with either MDS, chronic myelomonocytic leukemia, or acute myeloid leukemia (AML) to standard doses of Vidaza and Dacogen. Thirty-three percent of patients received Vidaza, which is normally administered by subcutaneous injection or intravenous infusion for seven consecutive days every 28 days. The remaining 67 percent received Dacogen through intravenous infusion for three consecutive days every six weeks.

Results showed that nine percent of patients achieved a complete response. According to the International Working Group, a complete response is defined as having a blood count of more than 1,000 neutrophil per µL of blood and more than 100,000 platelets per µL of blood. Although there are no longer observable symptoms of disease, this does not necessarily mean that MDS is fully cured or that there are no cancer cells still in the body. Sixty-two percent of patients had an observable, though not complete, response.

During the course of the trial, 21 percent of patients needed to delay or stop treatment with the hypomethylating agents, while 28 percent received a dose that was lower than the standard. Specifically, 58 percent of patients with more than 2 mg/dL of creatinine in their blood experienced problems with kidney and bone marrow function during the trial and were required to decrease the treatment dose. Some patients experienced therapy-related complications, including infections (36 percent) and bleeding (17 percent).

Researchers concluded hypomethylating agents such as Vidaza and Dacogen can be used in patients with MDS and AML with greater than 1.5 mg/dL of creatinine in the blood if their response rate was comparable to patients with normal kidney function. They also recognized the need for dose adjustment in some patients.

For more information, see abstract 7089 on the 2009 ASCO meeting Web site.

Thrombocytopenia is a common symptom of MDS, and the only current treatment option is a platelet transfusion. Platelets are responsible for blood clotting, and low levels can cause nosebleeds, bleeding gums, rashes of small red dots, and flat, pinpoint bruises. These symptoms are normally treated by platelet transfusions. Nplate is a protein that stimulates platelet production, decreasing the need for transfusions.

The trial included 28 patients with low or intermediate-1 risk MDS with a low platelet count. The average patient was 71 years old, and 68 percent had received platelet transfusions in the year prior to participating in the study. Patients received 750 µg Nplate weekly or biweekly by subcutaneous injection or bi-weekly by intravenous infusion. The average length of treatment was 12 weeks; treatments ranged from four weeks of weekly subcutaneous injection to 20 weeks of biweekly subcutaneous injection.

Sixty-five percent of patients who completed eight weeks of treatment, regardless of schedule, achieved a platelet response, which is defined by the International Working Group criteria as a minimum of 100,000 platelets per µL of blood or an increase of at least 30,000 platelets per µL during treatment. Sixty-one percent of patients completing eight weeks of treatment did not require any platelet transfusions during the therapy. Patients experienced fatigue (18 percent) and headaches (18 percent), and two patients progressed to acute myeloid leukemia.

The small number of study participants limited the ability to compare treatment schedules. However, researchers concluded Nplate is effective in raising platelet counts and decreases the need for transfusions for low and intermediate-1 risk MDS patients. They recommend future studies use 750 µg Nplate administered weekly or bi-weekly by subcutaneous injection.

For more information, please visit abstract 7009 on the 2009 ASCO meeting Web site.

Leukemia Cup Regatta – The Leukemia & Lymphoma Society (LLS) will hold its 11th Annual Southern Chesapeake Leukemia Cup Regatta at the Fishing Bay Yacht Club & Stingray Harbour Yacht Club in Deltaville, VA on July 10 through 12. The Leukemia Cup Regatta is an annual series of sailing races across the United States to raise money to fight leukemia, lymphoma, and myeloma. The weekend will include auctions and chances to win prizes while the participating sailors race in honor of a community member who has blood cancer. For details, please visit the LLS Web site.

19th Annual Bobby Mitchell Toyota Hall of Fame Golf Classic – On July 12, more than 45 NFL and NBA Hall of Famers will play in the Leukemia & Lymphoma Society’s (LLS) annual golf tournament weekend at the Lansdowne Resort in Lansdowne, VA. Bobby Mitchell, who was diagnosed with leukemia shortly before beginning his professional football career, founded the tournament to raise money for leukemia research. The tournament begins at 8:30 a.m. and ends at 2:00 p.m. Through $5 donations to the cause, the public can watch the tournament and participate in a putting contest to win a trip to the Hall of Fame. Children under 12 are admitted free. For further details, please visit the LLS Web site.

Funding Gives Go-Ahead To Phase 3 Tosedostat Trial – UK-based Chroma Therapeutics received £15 million through private funding, which will allow a Phase 3 registration trial of tosedostat (CHR-2797) to proceed. Tosedostat treats myelodysplastic syndromes by inhibiting proteins that promote cellular growth. For more information, please see the related Chroma Therapeutics press release (pdf).

Researchers collaborated with the National Institutes of Health American Association of Retired Persons (AARP) Diet and Health Study, an organization that involves more than 560,000 men and women across the United States. Members between 50 and 71 years of age residing in six states (California, Florida, Louisiana, New Jersey, North Carolina, and Pennsylvania) and two metropolitan areas (Atlanta and Detroit) were mailed questionnaires asking about demographics, dietary intake, and health-related behavior. The study tracked participants from 1995 or 1996 until either their date of death, diagnosis of MDS, relocation out of the registry area, or December 31, 2003 – whichever was earliest.

A total of 471,799 AARP members participated in the study. Researchers examined self-reported weight, height, smoking, physical activity, alcohol consumption, and diet, as well as demographic variables such as age, sex, race or ethnicity, and education. They analyzed these factors as potential variables and causes of MDS.

Results showed obese participants (body mass index (BMI) >30) were more than twice as likely to develop MDS as overweight (BMI 25 to <30) or normal weight (BMI 18.5 to <25) participants. Among participants, 35 percent were of normal weight, 43 percent were overweight, and 22 percent were obese. In addition, participants who reported being physically active a minimum of 20 minutes three times a week reduced their risk of MDS by 32 percent, compared to people who were active less than three times a month.

Researchers recommend more studies be conducted to specify the mechanism through which obesity may cause MDS. One potential pathway involves insulin resistance as a result of obesity. Insulin may promote excess division of blood cells and eventually lead to MDS. Leptin, which normally suppresses appetite, increases the rate of metabolism, and plays a role in the division of blood cells, also possibly links obesity and MDS. Blood precursor cells may develop abnormally over time if the body absorbs irregular levels of leptin.

In addition, both former and current cigarette smokers had higher risks of MDS compared to participants who had never smoked. Current smokers who smoke more than one pack a day increase their risk by more than four-fold. This is because cigarettes are a common source of exposure to benzene, a hydrocarbon which can cause secondary MDS.

Results showed that alcohol consumption, fruit and vegetable intake, and total meat intake were not associated with MDS.

An overall analysis showed MDS highly correlated with obesity, regardless of gender, smoking, and physical activity. Obese participants were more likely to be male, less educated, physically inactive, non- smokers, and have high energy and meat intakes with lower alcohol consumption.

More studies are needed to determine the risks of obesity and smoking to MDS in people under 50 years.

For more information, please see the study in the American Journal of Epidemiology (abstract).

Allogeneic HCT, the replacement of abnormal patient bone marrow with healthy donor stem cells, is the only therapy known to cure MDS. However, the possibility of graft versus host disease, in which donated stem cells react against the patient’s tissue, and other complications, limit the number of MDS patients who undergo HCT. Though studies have shown allogeneic HCT to extend survival time for MDS patients below the age of 60 years, the procedure has been considered too risky for most patients over 60 years due to significant transplant-associated mortality rates of 10 to 30 percent.

This study investigated the advantage of allogeneic HCT for the survival of elderly patients. Eighty-nine patients, ranging from age 60 to 71 and diagnosed with primary MDS unrelated to prior chemotherapy or heavy exposure to chemicals, received chemotherapy and radiation in preparation for the transplant. Thirty patients received standard-intensity treatment while 59 patients received a reduced dose.

Three years after transplantation, 40 percent of patients were still alive, demonstrating the effectiveness of allogeneic HCT for MDS patients older than 60 years. However, the results depended on marrow blast percentages before the transplant; only 29 percent of patients with more than 20 percent blasts survived after three years, compared to 44 percent of patients with less than 20 percent blasts. Furthermore, it was observed that the presence of additional diseases decreased overall survival rates.

The study concluded that time between diagnosis and treatment, the presence of additional diseases, and intensity of chemotherapy and radiation conditioning affected overall survival rates. However, age, donor relation, and presence of chromosomal abnormalities did not affect transplantation success.

Researchers recognized that allogeneic HCT should not be recommended for all elderly patients. Careful selection of patients is important to minimize allogeneic HCT-related mortality. In the future, studies will examine the role of HCT for patients with advanced MDS.

For more information, see abstract 0489 from the “Myelodysplastic syndromes” session of the 14th Congress of the European Hematology Association.

Red blood cell (RBC) or platelet transfusions are types of conventional supportive care that are necessary for patients whose bone marrow is unable to make sufficient amounts of healthy cells. These courses of therapy, however, only treat symptoms caused by low blood cell counts, and do not cure MDS or prevent acute myeloid leukemia (AML) transformation.

The study monitored 179 high-risk MDS patients with refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-t), chronic myelomonocytic leukemia (CMML), and Intermediate-2 or High-risk MDS. Each patient received Vidaza (75 mg/m²) subcutaneously for daily for seven days without additional red blood cell production stimulants. The treatment cycle was repeated after 28 days.

Transfusion dependence at the beginning of the treatment and transfusion independence measured patients’ responses to Vidaza. These were defined as requiring more than one transfusion during the 28 days prior to receiving Vidaza, and maintaining a transfusion-free status for 56 days or longer, respectively.

Patients initially RBC transfusion-dependent who achieved transfusion independence during treatment received a median of 14 cycles, while those who continued to need RBC transfusions throughout the study received four cycles. Likewise, platelet transfusion-dependent patients who became transfusion independent received 11 cycles, compared to a median of three cycles for continually platelet-dependent patients.

Results showed all patients who achieved transfusion independence at some point during treatment received Vidaza for a longer period of time and had longer overall survival than patients who did not. Forty-five percent (50 out of 111) of patients who were RBC transfusion-dependent prior to treatment achieved transfusion independence, while 42 percent (16 out of 38) of patients needing platelet transfusions prior to treatment became transfusion independent. Transfusion-dependence reflects overall survival; thus, the median length of overall survival was extended for patients who received more Vidaza treatment cycles.

The study concluded patients who received Vidaza for a longer period of time had longer median overall survival and were more likely to become or remain independent of RBC or platelet transfusions.

For more information, see abstract 0813 from the “Myelodysplastic syndromes” session of the 14^th Congress of the EHA.

The Road to Discovery: Emerging Therapies in Blood Cancers – On June 25, the Leukemia & Lymphoma Society (LLS) is sponsoring an educational program at Pappadeaux Seafood Kitchen in Duncanville, TX from 6 p.m. to 8 p.m. Topics include the development of new cancer treatments, how to distinguish myths from facts about clinical trials, and how to talk to your doctor about clinical trials as a possible treatment option. The event is free with pre-registration for patients, caregivers, nurses, and social workers. A complimentary dinner will begin at 5:30 p.m. More information can be found at the LLS Web site.

Lintuzumab Phase 1  Clinical Trial Results – Seattle Genetics reported results from a recent lintuzumab (SGN-33) Phase 1 clinical trial. The results showed that 17 percent of acute myeloid leukemia patients responded to lintuzumab, and 65 percent of patients with myelodysplastic syndromes (MDS) or other myeloproliferative diseases achieved stable disease in response to the therapy. Lintuzumab is an antibody that binds to a specific substance that normally causes an immune system response. It is also being studied in combination with Revlimid (lenalidomide) and Vidaza (azacitidine) for the treatment of MDS. For more information on the study, please visit the Seattle Genetics press release.

TET2 is located on chromosome 4q24 and codes for proteins of unknown function. This study suggests their possible role in cell transformation, specifically in the early development of stem cells that become different blood types in a process called hematopoiesis.

In this study, researchers hypothesized that mutations in early hematopoietic stem cells were a common denominator to MDS, myeloproliferative disorders, and Acute Myeloid Leukemia (AML), a type of blood cancer. One third of MDS cases progress to AML, while defective development of white blood cells in the bone marrow cause myeloproliferative diseases.

The study found deletions and mutations in the TET2 gene sequence in approximately 15 percent of the study’s participants. This included 15 out of 81 patients with MDS (19 percent), 24 out of 198 with myeloproliferative disorders (24 percent), five out 21 with chronic myelomonocytic leukemia (12 percent), and two out of nine with AML (24 percent). These mutations are predicted to shorten the length of the encoded protein, causing partial or total loss of its yet unknown function.

Dr. Olivier Bernard, a senior author of the study, said, “Until now, very little was known regarding the molecular bases of some of [the myeloid malignancies in humans], such as myelodysplastic syndrome, and this study has shown that there are common genetic abnormalities among these malignant disorders.”

Myeloproliferative disorders have already been associated with a mutation in the gene sequence JAK2 V617F, which causes uncontrollable production of a certain protein. Analyses revealed that TET2 mutations occur independently of JAK2 V617F mutations.

In addition, study of the different MDS subtypes suggested that early cells retain the mutation as the disease progresses. TET2 mutations were observed to be more prevalent in developed, mature cells than in cells that still have the capability of becoming many different cell types. This is evidence that the mutation is important in early stages of hematopoiesis and affects future development.

The discovery of a specific gene sequence abnormality highly correlated with myeloid diseases is significant for earlier prediction and diagnoses.

More research will be done to specify mechanisms that influence the blood-related stem cells, as well as establish biological and clinical phenotypes that characterize the TET2 defects.

For more information, see the full text of the article at the New England Journal of Medicine.

Though the exact association of Sweet syndrome with bone-marrow-related diseases is unknown, researchers concluded the changing composition of skin biopsy samples was able to predict the onset of MDS, thus heightening the correlation between the two conditions.

Sweet syndrome, also known as acute febrile neutrophilic dermatosis, is a skin condition characterized by series of small bumps that appear predominantly on the face, neck, back, and upper limbs. These characteristic bumps can grow in size and spread in small clusters, becoming tender lesions.

Though the exact cause is unknown, patients usually have an initially high lymphocyte count (number of specific white blood cells in the immune system), which progresses to higher neutrophil counts (another type of white blood cell) in later stages.

Researchers established this association after analyzing the biopsy results of nine patients. Patients were all male, of median age 65, and had Sweet syndrome. For each patient, bumps healed without treatment and later returned. After relapsing several times, patients gradually developed lower levels of red blood cells and lymphocytes. While lymphocyte levels decreased, neutrophils increased in the body. All patients were eventually diagnosed with MDS a median of 3.5 years after their first skin symptoms.

The follow-up, which ranged from three to ten years, showed that MDS could be controlled by blood transfusions or erythropoietin therapy, which is the addition of a substance naturally produced by the kidneys that stimulates the bone marrow to make red blood cells. Treatments also prevented progression to acute myeloid leukemia in all nine patients. Eight of the nine patients died after being diagnosed with MDS from various causes, a median of 5.5 years after developing Sweet syndrome. These cases demonstrated that a poor prognosis for Sweet syndrome may be associated with MDS.

Twenty percent of Sweet syndrome cases are associated with MDS or other blood development conditions. Patients who have both conditions often show signs of premature death of living tissue as well as immature bone marrow cells.

Though researchers have not yet determined why the skin disease appears years before MDS is identified, the presence of Sweet syndrome may help in the early diagnosis and treatment of MDS.

More information can be found in the Archives of Dermatology.

Methyl groups that are bound to DNA sequences cause problems by preventing the regulation of cellular growth and causing uncontrollable cell division. Hypomethylating or demethylating agents, like Vidaza or Dacogen, allow the DNA sequences to function normally by removing these problematic methyl groups.

Researchers found four relevant randomized controlled trials, but only evaluated three, which compared 952 patients who received either hypomethylating agents or supportive care. Supportive care, such as blood transfusions and antibiotics, does not cure MDS or prevent acute myeloid leukemia (AML) transformation, but treats symptoms caused by low blood cell counts known as cytopenias. Stem cell transplantation is currently the only therapy able to generate complete recovery from MDS. This study evaluated Vidaza and Dacogen with respect to non-curative treatments.

The study evaluated overall survival, length of time to AML or death, complete or partial response, and severity of side effects. A complete response, as measured by the 2000 International Working Group (IWG) criteria, is defined by having a blood count of more than 1,000 neutrophil per µL and more than 100,000 platelets per µL. Evaluation of two of the four studies consisting of 549 patients showed treatment with Vidaza resulted in longer overall survival time than treatment with supportive care. However, one of the trials with 233 patients taking Dacogen did not show this same overall survival advantage.

An overview of all three evaluated studies and a fourth study abstract concluded that hypomethylating agents significantly lengthened the progression time to AML or death, improved the number of complete or partial responses, and resulted in few side effects.

For more information, see abstract 0261 from the “Myelodysplastic syndromes I” session of the 14th Congress of the EHA.

Her presentation on May 7, called “Controlling the ‘Fate’ of T-Cells in MDS,” focused on natural killer T-cells, white blood cells that are the immune system’s first non-specific defense against foreign pathogens and defective cells. Natural killer cells are normally functional in low-risk MDS patients, but they may become exhausted with time and lose their ability to suppress cancer cells. As a result, numbers of abnormal leukemic cells may increase, allowing MDS to progress to Acute Myeloid Leukemia (AML). Her talk highlighted research about why T-cells lose their ability to suppress cancer cells, and increasing evidence that receptors that activate them may play a role in their fate. The immune system seems to be linked to MDS through this research, as reduced natural killer function is associated with higher-risk MDS.

Dr. Burnette’s team is also exploring other aspects of immunology that are important in MDS, such as specific gene sequences that have been found to be linked to patient responses to treatments. Corresponding gene markers are being developed to predict responses and possible underlying autoimmune disorders. Such markers can become an important part of distinguishing MDS from other possible diseases and ensuring that patients receive the most appropriate therapy as soon as possible. Studies have shown that MDS patients with autoimmune diagnoses have better responses to immunosuppressive drugs than only MDS-specific therapies. To date, the National Heart Blood and Lung Institute (NHLBI) at the National Institutes of Health (NIH) has shown that younger patients with lower-risk MDS and the HLA-DR15 gene sequence (genotype) respond most favorably to immunosuppressive drugs.

Patients who need to address compound autoimmune-MDS disorders will benefit from establishment of gene biomarkers. Identification of genotypes, such as HLA-DR15, can increase the rate of successful MDS treatments by specifying patients who will have good responses to immunosuppressive therapy.

“If these markers are confirmed to be predictive for response to immunosuppressive therapy in an independent study, then patients with the biomarkers will be placed on immunosuppressive drugs as a first line of therapy,” says Epling-Burnette.

As research in immunopathology clarifies the relationship between autoimmune disorders and MDS, combination therapies can become more individualized.

“We are working on better predictive biomarkers to indicate which patients have autoimmunity so that immunosuppressive therapy can be given to the right patient,” says Epling-Burnette. “Since the currently available immunosuppressive therapies work non-specifically, we hope to develop novel treatment modalities based on specific immune abnormalities in MDS.”

A video of her interview following her presentation can be viewed at the MDS Foundation International Symposium Web site.

Contreras came from a family with a clean medical history, free of cancer and high blood pressure. It came as a surprise, then, that a rare disease like MDS would choose Roger, who, at the time, “was building hospitals, not going to them.” Yet within the year of his diagnosis, his Web site, IHaveMDS.com, and its corresponding blog have reached out to support many other MDS patients, friends, and family.

In an interview with The MDS Beacon, he tells of how he wrote online journal entries as he began months of hospital visits and blood transfusions. He was lonely, without information, and in need of support.

“There was no one to talk to, there were no answers – I couldn’t find any answers,” says Contreras.

His blog served as an outlet for the thoughts, emotions, and daily lifestyle of a man decades younger than the average MDS patient. At the same time, he gathered information for his own reference and decided to share it with the public on his Web site. His online sources eventually attracted others who were scouring the Web for MDS, all confused by the foreign medical terms and looking to hear it firsthand from others going through it. Comments left by subscribers illustrate how encouraging his blogging honesty has been.

Contreras’ own support system has been his family, who he says has been there from the beginning. In March 2009 when he was eligible for a bone marrow transplant, the only curative treatment for MDS currently available, his sister volunteered to be his donor. In addition, his family was able to sit in the hospital room with him during the procedure.

Although he has a catheter in his chest, no hair due to chemotherapy, and still needs daily transfusions to ensure a healthy blood count and no neurological complications, Roger Contreras is well on his way to recovery. His voice was strong, matter-of-fact, yet urgent during the interview as he spoke of how the transplant changed the focus of his blog and Web site.

“Up until transplant time, it was all about me and what I was going through,” remembers Contreras. “But now it’s more about trying to get information out, trying to reach people, and looking for donors.”

His main concern is awareness. Not only had he never heard of MDS before his diagnosis, but blood donation was also a foreign concept. He sees importance in getting more minorities involved because a transplant becomes much more difficult and time-consuming when the availability of matching donors is limited. Contreras wants to reach out to communities, especially to men like himself, who would not hesitate to donate if they knew about its need or importance in saving lives. He has already organized a local blood drive for this October and is considering coordinating a July event as well.

His Web site and blog are not only records of his MDS journey, but also forums to help others. There are requests for prayers, blood donations, and support for Tami, a 44-year-old mother diagnosed with MDS, and Grant, a three-year-old boy recently diagnosed with acute lymphoblastic leukemia.

Contreras knows how easy it is to get blind-sided and lost by all the medical terms when a disease with a name like “myelodysplastic syndrome” comes knocking. However, as a fighting survivor, he wants to give hope to anybody who will be following in his footsteps.

His words are comforting and truthful: “You’re not alone; there are other people out there. The more knowledge you have, the less fear you’ll have going into it. Fear of the unknown is the greatest thing. The more answers you have, the better it is.”

This study showed the triple combination to be safe, as patients did not experience any severe or life-threatening side effects.

There were 22 patients enrolled in the study; of these, three relapsed/refractory AML patients of the 22 initially underwent a pre-clinical trial testing the safety of the combination therapy. Two achieved complete response achieved complete response as measured by the 2000 International Working Group (IWG) criteria. A complete response is defined by the IWG as having a blood count of more than 1,000 neutrophil per µL and more than 100,000 platelets per µL. Patients also have no observable symptoms after a thorough examination, though the diagnosis does not necessarily mean that MDS is fully cured or that there are no cancer cells in the body. One patient showed minimal symptoms of MDS, though not to the extent as complete response patients.

Seventeen patients, median age 49, then underwent the Phase 2 trial. The median white blood cell count was 12.75 × 109/L at the beginning of the trial, while examination of DNA showed abnormalities in 71 percent of participants. In addition, 47 percent of participants had a secondary disease.

The untreated intermediate-2 or high-risk MDS or AML patients with adequate renal and liver functions were given 500 mg of Zolinza for three days, then both idarubicin (12 mg/m2) and cytarabine (1.5 g/m2) on the fourth. Five cycles of 500 mg of Zolinza with 8 mg/m2 of idarubicin and 0.75 g/m2 of cytarabine over 24 hours was then administered to patients with a complete response. This was followed by one year of maintenance with Zolinza.

Results showed 82 percent of patients achieved complete response, which was associated with decreased chromosomal abnormalities. However, two patients died during induction and two relapsed within four to five months. A median progression-free survival rate has not yet been observed.

Histone deacetylase inhibitors like Zolinza have been shown to work cooperatively with anthrayclines like idarubicin in therapies for MDS. Cytarabine is a chemotherapy agent that keeps the body from producing excess DNA.

Researchers plan to compare the results of this study with a parallel cytarabine study also being conducted at the M.D. Anderson Cancer Center to see how it enhances MDS treatments. Further studies are also investigating DNA damage and repair pathways.

For more information, please see abstract 7004 on the 2009 ASCO meeting Web site.

The Phase 3 trial participants (D-0007 and EORTC-06011) were given 15 mg/m2 intravenously over three hours every eight hours for three days every six weeks with supportive care. Phase 2 trial participants (DACO-020 and ID03-0180) were given 20 mg/m2 intravenously over one hour once daily for five consecutive days every four weeks without supportive care.

In the three-day regimen Phase 3 trials, a median of three Dacogen treatment cycles were administered to the D-0007 group, while the EORTC-06011 patients were given four cycles. Thirteen percent of patients who received four cycles achieved complete response as measured by the 2000 International Working Group (IWG) criteria, compared to only nine percent of the group given three cycles. A complete response is defined by the IWG as having a blood count of more than 1,000 neutrophil per µL and more than 100,000 platelets per µL. Patients also have no observable symptoms after a thorough examination, though the diagnosis does not necessarily mean that MDS is fully cured or that there are no cancer cells in the body.

In addition, the one-cycle difference showed an overall improvement increase of four percent (30 percent for three cycles, 34 percent for four cycles). Dependence on blood transfusions during the clinical trial also decreased for nine percent of participants with the extra Dacogen treatment, from 32 to 23 percent. However, progression to Acute Myeloid Leukemia (AML) or death decreased from 10 to 8.8 months for the four-treatment-cycle group, as did progression-free survival and overall survival (7.3 to 6.6 months and 12.8 to 10.1 months, respectively).

Groups DACO-020 and ID03-0180 received either five or seven cycles, respectively, within a five-day regimen. Phase 2 studies showed improvement in nearly every category. The two-cycle median increase improved complete response from 15 to 37 percent and overall improvement from 43 to 65 percent. In addition, time to AML progression or death was lengthened from 12.1 to 15.2 months, and progression-free and overall survival also increased from 8.1 to 9.2 months and 17.8 to 20.3 months, respectively.

The duration of improvement ranged between 9.2 and 11.3 months in all four trials.

Researchers correlate the 30 percent overall improvement rate by IWG criteria to the increased number of Dacogen treatment cycles.

For more information, please see abstract 7011 on the 2009 ASCO meeting Web site.

Patients with MDS or other transfusion-dependent diseases are at risk for toxic iron build-up in cells, and possible organ damage. Iron chelators bind to excess iron for removal from the body.

The study included 20 transfusion-dependent MDS patients between the ages of 42 of 72 years (median 55 years). The participants drank 30 mL of fresh wheat grass juice daily for six months. Blood ferritin levels were, on average, reduced from 2,250 to 950 ng/mL. Ferritin, an iron-storage protein that prevents iron from forming free radicals, corresponds to blood iron levels and ranges from 12 to 300 ng/mL in healthy adult males and 12 to 150 ng/mL in females.

In addition, blood transfusion intervals lengthened and performance status of patients increased from 60 to 80 percent.

This trial followed a study with 200 intermediate thalassemia, or major chronic anemia, patients in which 80 percent who drank wheat grass juice became transfusion-independent.

In a dose-dependent comparison with deferoxamine (Desferal), a standard iron chelator, soluble wheat grass extract, collected from five to seven day old leaves, showed more effective iron chelating ability. In addition, analysis by a separation technique showed the crude extract to be rich in oxalic and malic acid, which possibly function in the dietary absorption of iron from the intestine.

Researchers encourage the use of wheat grass juice for patients requiring repeated blood transfusions.

For more information, please see abstract 7012 at the 2009 ASCO meeting Web site.

MDS is characterized by overactive bone marrow that produces too many stem cells; however, many of these cells are defective (called “dysplastic”) and immature (called “blasts”). While dysplastic cells are abnormal in shape and unable to function properly, blasts die prematurely, due to unknown cancer-related mutations. Blasts also reproduce rapidly and accumulate in the bone marrow.

The severity of MDS is based on the percentage of blasts within the patient’s bone marrow. Patients with over 5 percent blasts are considered to have “high-risk” MDS, whereas patients with over 20 to 30 percent blasts are considered to have acute myelogenous leukemia (AML), a form of cancer.

Who is at Risk? »

MDS can be characterized in two ways, depending on the cause.

Primary, or “de novo” MDS, accounts for 70-80 percent of MDS diagnoses. The exact cause of primary MDS is unknown, however certain risk factors – such as age, gender, ethnicity, and genetics – can be contributors.

• Aging increases an individual’s risk for developing MDS. MDS can occur at any age, but 80-90 percent of diagnosed patients are over 60 years old. Also, the median age for patients is 65.
• Men have a higher risk of developing MDS than women. The risk of developing MDS is 1.75 times higher for men than it is for women.
• Caucasians are at a higher risk of developing MDS. Considering both ethnicity and gender, caucasian males have the highest risk of developing MDS.
• Genetic causes for MDS have yet to be found. However, there is a slightly higher risk of developing MDS in families with a history of Sideroblastic or Fanconi’s anemia.
• Pediatric MDS may be due to certain rare congenital bone marrow disorders. Children with Down syndrome are also more susceptible to MDS.

Secondary, or treatment-related MDS, makes up 20-30 percent of MDS diagnoses. It can be caused by either prior chemotherapy treatment or heavy exposure to certain chemicals. Treatment-related MDS poses a risk for up to 10 years following chemotherapy and radiation treatment. Examples of harmful chemicals include melphalan (Alkeran), nitrogen mustard, cyclophosphamide (Cytoxan), busulfan (Myleran), and chlorambucil (Leukeran).

In general, heavy exposure to solvents, pesticides, heavy metals, and hydrocarbons (like benzene) may contribute to secondary MDS. Cigarettes are a common source of exposure to benzene. Additionally, people who work in certain industrial settings may come into contact with many types of hydrocarbons. Vietnam veterans, who were exposed to Agent Orange, may also be at risk.

Radiation therapy, chemotherapy, toxic chemicals, or environments have not been found as common causes for MDS in young children.

Signs and Symptoms »

Anemia, or low red blood cell count, cause the most common symptoms because red blood cells are responsible for distributing oxygen throughout the body. In MDS, the percentage of healthy red blood cells is below normal; therefore, the body does not receive adequate oxygen.

Signs of anemia include:

• Chronic tiredness or fatigue
• Shortness of breath
• Heart palpitations
• Pale skin
• Chilled sensations
• Cardiovascular symptoms, such as chest pain (older patients)

Neutropenia, or a low white blood cell count, is another symptom of MDS. A shortage of white blood cells, which are responsible for fighting infections, increases the likelihood of acquiring an infection or fever. Of the various types of white blood cells, most people with MDS lack neutrophils, rather than lymphocytes, making them more susceptible to bacterial than viral infections. It is possible to have a defective immune system despite normal neutrophil counts.

The common infections associated with neutropenia include:

• Skin infection
• Sinus infection accompanied by nasal congestion
• Lung infection accompanied by shortness of breath or a cough
• Urinary tract infection accompanied by frequent and painful urination.

Thrombocytopenia, or low platelet count, is also a symptom of MDS. Platelets are responsible for blood clotting.

People with MDS have a greater frequency of the following symptoms:

• Nosebleeds (epistaxis)
• Bleeding gums
• Flat, pinpoint bruises
• Rashes of small red dots(petachiae).

Less common signs of MDS include:

• Enlarged spleen (splenomegaly)
• Enlarged liver (hepatomegaly)
• Abnormal shape or size of cells
• Chromosomal abnormalities.

Diagnosis »

MDS is difficult to diagnose, because symptoms are commonly shared with other diseases. MDS can only be confirmed after other causes are ruled out. In the sections below, a few of the tests used to help diagnose MDS are described.

Blood Tests

The first step in diagnosing MDS is a complete blood count (CBC). Red blood cells, white blood cells, and platelets are counted by an automatic cell counter. Abnormal cell counts may lead to manual inspection of the blood cells. In addition, cell shapes and sizes are noted. Both low blood cell counts (cytopenia) and abnormally shaped cells (dysplasia) are distinctive features of MDS.

Additional blood tests are done to rule out other causes of low red blood cell count (anemia), such as abnormal thyroid function, kidney failure, heart failure, HIV, lupus, hepatitis, and other cancers. All of these conditions commonly cause chronic tiredness or fatigue, shortness of breath, heart palpitations, pale skin, and chilled sensations. Nutrient, iron, and vitamin deficiencies must also be eliminated as sources of anemic symptoms. Last, blood tests help rule out myelodysplastic/myeloproliferative diseases, which cause similar symptoms as MDS by a higher than normal number of blasts that develop into blood cells. MDS is caused by a shortage of such cells.

Hemoglobin, an oxygen-carrying protein, and erythropoietin (EPO), a protein that stimulates red blood cell production, are also measured because low levels of either protein also cause anemic symptoms.

Bone Marrow Sample

As blood test results may be inconclusive, bone marrow tests can also be performed. Bone marrow analyses can help diagnose MDS by calculating a percentage of immature blood cells (blasts) and confirming defective blood cell formation (hematopoiesis).

There are two methods to obtain bone marrow samples – bone marrow trephine biopsy and bone marrow aspiration. In a bone marrow trephine biopsy, a thick needle is used to withdraw a sample of bony tissue from the bone marrow. In bone marrow aspiration, a thin needle is used to take a sample of bone marrow fluid. In both tests, local anesthesia is applied.

Bone marrow examinations usually do not require staying in a hospital overnight. The actual procedure takes less than an hour. After each procedure, the patient is asked to lie flat for 10 to 15 minutes, applying pressure to the wound. If there is no bleeding, normal activities may be resumed, though it is advised not to wash the area for 24 hours. Mild soreness is expected for two to three days. Worsening pain, redness, fever, or swelling may suggest a complication.

Bone marrow trephine biopsy and bone marrow aspiration samples provide different types of information, and sometimes both procedures are performed. With these samples, several laboratory tests can be performed.

Bone Marrow Laboratory Tests

Cytochemistry: Cells from the bone marrow sample are placed on glass microscope slides and exposed to dyes, which are attracted to specific chemicals. This causes a color change only in cells containing these chemicals.

Immunocytochemistry: Similar to cytochemistry, bone marrow cells are exposed to antibodies, which cause color change in cells that possess specific corresponding foreign substances (antigens), to which the antibodies bind. This test is helpful in diagnosing MDS by excluding other possible diseases and distinguishing the different types of MDS.

Cytogenetic Analysis: Cells from bone marrow aspirate are grown in laboratory dishes and the gene-containing structures (chromosomes) then viewed under a microscope. Cytogenetic tests examine these chromosomes for abnormalities, including missing, extra, and malformed structures, or interchanged (translocated) segments. Sixty percent of MDS cases have observable chromosomal irregularities. In MDS, the most common cytogenetic abnormalities include the complete loss of chromosome 5 or 7, an extra copy of chromosome 8, and deletion in the long arm of chromosomes 5, 7, or 20. Deletion of chromosome 5 has a better prognosis than deletion of chromosome 7.

Flow Cytometry: A sample of cells from bone marrow (or blood) is treated with antibodies and passed in front of a laser beam. Antibodies bind to cells that contain specific substances (antigens) whose presence indicates different stages of MDS. These cells give off light and are detected and counted by a computer. This test classifies MDS very accurately but is not required for all MDS patients.

Fluorescent In-Situ Hybridization (FISH): Abnormalities are located in chromosome segments with specific gene sequences. Fluorescent dyes that bind specifically to these sequences cause the areas to glow. FISH is not required for all patients, but is more sensitive than cytogenetic analysis and is helpful in giving an accurate prognosis.

Conclusion

If both blood tests and bone marrow tests reveal only mild dysplasia, i.e. less than five percent blasts and no cytogenetic abnormalities, then there is insufficient evidence to diagnose MDS. Patients are then monitored regularly with non-invasive procedures. In addition, genetic tests and immune cell examinations may be performed until the clinical criteria are met to diagnose MDS.

Patients diagnosed with MDS will be classified under the IPSS, WHO, and/or FAB system according to percentage of blasts in the blood, blood cell counts and morphology, and genetic findings. A patient’s individual health condition and specific classification are taken into account before proceeding with treatment.

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Prognosis »

Supportive Care

Supportive care is not a cure, but the management of symptoms caused by low blood cell counts (cytopenias). To counteract the shortage of red blood cells (anemia) and platelets, a patient’s abnormal blood cells are often replaced with healthy blood from a matching donor, a procedure called a blood transfusion. To reduce the need of transfusions, patients often receive growth factors – such as erythropoietin (EPO) and granulocyte-colony stimulating factor (G-CSF) – that simulate more blood cell development. To counteract low white blood cells (neutropenia) and a weak immune system, patients typically receive antibiotics.

Drug Therapy

In the US, three drugs have been approved for MDS treatment. Each of these drugs was approved for use individually, and not in combination with the other two drugs.

• Vidaza (azacitidine) kills rapidly dividing cells in bone marrow and removes methyl groups from DNA (demethylation). Methyl groups that bind to DNA sequences prevent the regulation of cellular growth, causing uncontrollable cell division. Demethylating agents, such as Vidaza, allow the DNA sequences to function normally by removing these methyl groups. It is approved for all MDS subtypes and is administered by subcutaneous injection or intravenous infusion for seven days every 28 days.
• Revlimid (lenalidomide) inhibits new blood vessel growth while stimulating both cell death and the immune system. It is effective for treating Low- or Intermediate-1 risk MDS, specifically those who require red blood cell transfusions or have 5q-syndrome. It is taken orally as a capsule once a day for as long as the treatment lasts.
• Dacogen (decitabine) is a DNA demethylating agent and is approved for all MDS sub-types. It is administered through intravenous infusion for three consecutive days every six weeks, requiring a hospital stay.

Chemotherapy

Chemotherapy is the use of drugs to kill cancerous cells, while also helping bone marrow to produce healthy blood cells. Unlike radiation or surgery, chemotherapy is not localized to one area of the body and can affect every cell. Intensive chemotherapy treatment runs between six to nine months and may bring short-term reduction of symptoms for as high as 60 percent of MDS patients. Chemotherapy may help MDS patients more permanently if bone marrow transplantation is an option.

Drugs used commonly in chemotherapy for MDS include:

• Cytarabine (Cytosar-U)
• Idarubicin (Idamycin)
• Daunorubicin (Cerubidine)
• Mitoxantrone (Novantrone)

Bone Marrow Transplantation

Bone marrow transplantation is the only curative treatment currently available. The bone marrow of a patient is initially destroyed by chemotherapy or radiation, and then replaced with donated bone marrow. The risks of the procedure may be aggravated by age, and a transplant does not guarantee full recovery.

• Allogeneic stem cell transplant (Allotransplantation) patients receive bone marrow from a matched donor. Graft vs. host disease is a possible risk, as functional immune cells in the transplanted marrow may discriminate the recipient body as foreign and attack it.
• Reduced-intensity / Non-myeloablative allogeneic stem cell transplantation is a lower-risk procedure for older patients and involves lower doses of chemotherapy and radiation in preparation for the transplant, supplemented by immunosuppressive drugs that prevent the body from rejecting the foreign transplanted marrow.
• Autologous stem cell transplant patients receive their own stem cells after the bone marrow is destroyed. However, this type of transplant is not a standard treatment for patients with MDS because their bone marrow contains abnormal stem cells.

Future Treatments

Clinical trials are currently being held to test and approve new treatments for MDS, especially combination treatments of FDA-approved drugs and chemotherapy. All trials are focused on developing methods to improve patient quality of life, effectiveness of treatments, and survival rates for MDS patients.

Current investigational studies are targeting cancer cells through many different mechanisms. New treatments may be able to reduce the number of blasts, while producing less-toxic side effects of standard treatments.

In addition, antithymocyte globulin (ATG), thalidomide (Thalomid), and anticancer agents called histone deacetylase inhibitors are being investigated for their role in stopping cellular proliferation and causing differentiation or death of tumor cells. Differentiation therapy aims to restrain growth of malignant cells by forcing immature tumor cells to resume the process of maturation and eventually differentiate into mature cells.

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By contrast, indicators of poor MDS prognosis include a severe lack of white blood cells or platelets, blast percentages between 20 to 29 percent, and the presence of blasts in the blood (Auer rods).

Karyotypes, which are organized profiles of an individual’s chromosomes arranged by size and type, are also used to give prognoses. An abnormal karyotype that shows complex bone marrow chromosome abnormalities is an indicator of a poor prognosis.

Chromosomal aberrations are also good predictors of an MDS patient’s prognosis. Patients with an extra copy of chromosome 8, a missing Y chromosome, or a missing part of chromosome 5 (the ‘q’ arm) are more likely to have a better prognosis than patients with other abnormalities.

Patients with chromosome 7 anomalies, or more than three chromosomal abnormalities, are more likely to have a poorer prognosis.

MDS patients with over 20 to 30 percent of immature stem cells (blasts) are considered to have acute myelogenous leukemia (AML), a form of cancer.

Approximately one-third of MDS patients progress to AML. The risk of MDS transforming into AML increases with prior exposure to chemotherapy and radiation treatment.  It also is higher among older MDS patients than among younger MDS patients.

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