The study authors found that the efficacy and safety of the combination therapy were similar to those of other treatment regimens commonly tested in clinical trials.

They concluded that their findings support treatment for patients who are ineligible for clinical trials, and they suggested that current eligibility criteria for Phase 1/2 clinical trials be reexamined.

Dr. Guillermo Garcia-Manero of the MD Anderson Cancer Center in Houston presented these findings at the 2011 American Society of Hematology (ASH) conference in San Diego earlier this month.

In order for a patient to be eligible to participate in most clinical trials for myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML), the patient must display acceptable overall health, kidney function, and liver function. Patients also cannot have any other co-existing diseases.

Researchers at the MD Anderson Cancer Center found that MDS and AML patients who are not eligible for clinical trials have a median survival of less than 60 days if they do not receive treatment.

In the present study, the researchers aimed to evaluate the influence of therapy on survival outcomes for MDS and AML patients who do not qualify to participate in clinical trials. All 30 patients in the study were treated with Vidaza (azacitidine) and Zolinza (vorinostat) for a median of 3.5 cycles. The researchers chose this combination therapy because they consider it to be safe and it has shown significant activity in both MDS and AML patients.

Vidaza is approved by the U.S. Food and Drug Administration (FDA) as a treatment for patients with MDS. Zolinza also is approved by the FDA, but as a treatment for specific kind of lymphoma. It can be prescribed, however, by a physician as a treatment for other conditions – such as MDS – if the physician feels there is sufficient evidence to justify such use of the drug.

The median patient age in the MD Anderson study of the Vidaza-Zolinza combination treatment was 74 years, and 53 percent of the patients had MDS. In addition, 53 percent had another type of cancer. The remaining patients had another co-existing disease, including chronic liver disease, liver failure, heart dysfunction, chronic bronchitis and emphysema, or poor overall health.

The overall response rate was 30 percent, with 27 percent achieving a complete response. Half of the patients who did not register a response to the treatment regimen nevertheless had stable disease for more than eight weeks.

The median survival was seven months, and 80 percent of patients survived longer than 60 days.

Thirty percent of the patients are still alive as of the date the trial data were analyzed in preparation for the ASH meeting. All of the deaths during the study were due to progression of the patient’s primary disease.

The researchers pointed out that the therapy was well tolerated since only one patient (3 percent) developed a serious, non-blood-related side effect (nausea and vomiting).

For more information, please see abstract 608 at the ASH 2011 meeting website.

Dr. Andrea Kuendgen of the Heinrich-Heine-Universitaet in Duesseldorf, Germany, presented the findings at the 2011 American Society of Hema­tology (ASH) conference in San Diego last week.

Revlimid (lenalidomide) is approved by the U.S. Food and Drug Admin­istration as a treatment for the subgroup of lower-risk myelodys­plastic syndromes (MDS) patients who are dependent on blood transfusions and have a deletion of the long arm in chromosome 5 (“del5q”).

The drug, which is a close chemical cousin of thalidomide, was approved by the FDA based on data showing that patients treated with it are able to become transfusion independent.

Two large multi-center clinical trials, MDS-003 and MDS-004, have looked at the impact of Revlimid treatment on MDS patients.

All patients in the MDS-003 trial received Revlimid, whereas patients in the MDS-004 trial were randomized to receive Revlimid or a placebo.  However, patients in the placebo arm of the MDS-004 trial were allowed to crossover to the Revlimid arm early on in the study.

As a result, researchers were unable to assess the impact of Revlimid on overall survival and progression to leukemia.

In the present study, researchers retrospectively compared data from 295 patients from the MDS-003 and MDS-004 trials with those of 125 untreated MDS patients with del5q from a large patient registry. Patients in the control group also had lower-risk MDS and were transfusion-dependent.

At two years, 7 percent of the Revlimid-treated patients progressed to leukemia, compared to 12 percent of the untreated, control-group patients.

At five years, 23 percent of the Revlimid-treated patients and 20 percent of the untreated patients progressed to leukemia.

These differences in time to progression to leukemia were not, however, statistically significant.

In regard to survival, the overall survival rate was higher for the Revlimid-treated group than the untreated group at two years (90 percent versus 74 percent) and at five years (54 percent versus 41 percent).

Also, patients who were treated with Revlimid lived longer than patients who did not receive treatment (a median of 5.2 years versus a median of 3.8 years).

Once again, however, the differences between the two patient groups were not statistically significant.

The authors therefore used statistical modeling techniques to determine more clearly which factors affect an MDS patient’s risk of progressing to leukemia and a patient’s risk of death.

This modeling showed that treatment with Revlimid leads to a reduced risk of death that is both clinically and statistically significant.

The modeling also showed that Revlimid does not increase the risk of MDS patients progressing to leukemia.  This result is important in part because there have been concerns that patients treated with Revlimid might be at an increased risk of developing so-called “secondary” cancers (see related Beacon news).

The modeling likewise confirmed the importance of several factors that have been shown in earlier research to increase the risk of an MDS patient progressing to leukemia.  These factors include having more than one additional chromosomal abnormality besides del5q, 5 percent to 10 percent of immature blood cells (blasts), and higher transfusion needs.

For more information, please see abstract 119 at the ASH 2011 meeting website.

So what is the etymology (word history) of “myelodysplastic syndromes?”

To begin with, “myelo-“ has as its origin the Greek word μυελός, meaning “marrow.”  Interestingly, there are also a number of terms related to the spinal cord that use the myelo- prefix.  For example, there is “myelitis,” an inflammatory condition of the spinal cord, and there is a type of congenital malformation of the spinal column that is confusingly called “myelodys­plasia.”

That is because some of the early Greek anatomists more than 2000 years ago believed (incorrectly) that the spinal cord – part of the central nervous system – was just a peculiar type of bone marrow, since it is encased in bone just like other marrow. They didn’t really understand the nature of blood as a liquid tissue full of cells and certainly did not know anything about the role of the bone marrow in producing in blood cells.

“-dys-,“ from the Greek δυσ, refers to anything that is bad, difficult, or (dis)ordered.  We see this dys- root in many English terms: dysfunctional, dysphoric, or dyslexic (i.e., difficulty reading). When used to describe MDS, the “dys” means failure to produce normal healthy blood cells.

“-plastic,” in turn, comes from πλαστική – another Greek root – and carries a sense of the process of formation or molding.

Although for most of us the word “plastic” suggests the plastic materials used for making automobile parts or inexpensive children’s toys, which were famously discussed as the “wave of the future” during a poolside scene in the 1968 Dustin Hoffman film “The Graduate,” the term plastic has a much broader meaning.  “Plastic surgery,” for example, is molding of the human flesh; the plastic materials used to make Fisher-Price telephones or Chevrolet taillights are not used to perform tummy-tucks, chin lifts, or breast augmentation.

Putting myelo-, -dys-, and –plastic together as “myelodysplastic” means that when looking at the bone marrow under the microscope, the marrow appears abnormal, and that abnormal-appearing marrow also forms abnormal cells. This is an accurate description of our current understanding of MDS.

Finally, we can briefly consider what the term “syndrome” adds (the recent trend is to use “syndromes” to refer to MDS instead of “syndrome” to reflect the diversity of these conditions).  Here we find yet two more Greek roots.

First, “syn-“ comes from the Greek σύν, meaning “together” or “with.”  The same root is used in many “togetherness” terms like synesthesis, synagogue, symphony, and sympathy.

“-drome,” in turn, comes from δρόμος and means “course,” “road,” or “walking.” A “syn-drome,” then, is several things that walk or move together, or are found together.

In the medical sense, a syndrome is collection of several clinically recognizable disease features that are often found together in the same patient at the same time, including symptoms reported by patients (e.g., fatigue), physical signs observed by physician during examination of the body (e.g., paleness or racing heart), and results of laboratory tests (e.g., low hemoglobin level, meaning anemia.).

Syndromes often lack a clear cause, which certainly describes most cases of myelodysplastic syndromes, where the origin is not yet known.

Many syndromes are named either after the first patient described with the disorder or the physician who first described it. Examples include Down Syndrome, caused by an extra copy of chromosome 21 and named after physician John Langdon Down, and Edwards Syndrome (Edwards Syndrome does not refer to cheating on your wife during a Presidential political campaign, but instead to having an extra copy of chromosome 18).

The term syndrome is also often used facetiously to describe things that are not medical disorders at all, such as Depleted Mother Syndrome, Black Friday Shopping Syndrome, or Political Misery Syndrome.

The term “myelodysplastic syndromes” has evolved through a century of observations of blood and bone marrow and it describes a group of disorders in which the bone marrow fails to produce an adequate number of healthy blood cells, of unclear cause.

This is a pretty good description, and although the term may sound excessively technical to some, it conveys a lot of information to those who are aware of the word origin or its component parts.

Dr. David Steensma is a physician at the Dana-Farber Cancer Institute in Boston and an Associate Professor in the Department of Medicine at Harvard Medical School. His primary area of research focuses on myelodysplastic syndromes and related conditions.

However, she herself became the patient in May 2005 when she was diagnosed with myelodysplastic syndromes (MDS) at the age of 50.

That May, O’Neill began having hot flashes, flu-like symptoms, and fatigue.  She attributed the symptoms to menopause and went to see her doctor in October 2005 for blood tests and to discuss starting hormone replacement therapy.

About a week later, her doctor called her back in for more blood tests after noticing her white blood cell counts were low.  O’Neill was referred to a specialist at the Adelaide and Meath Hospital in Dublin.

“I think if I had not started menopause when I did, I would not have found out about my illness,” said O’Neill.  “I was told they caught me at an early stage.”

When she arrived at the hospital for the additional blood tests, she noticed it was a cancer ward.  “I was very shocked!” she described.

A few days later, O’Neill was asked to return to the hospital for a bone marrow test.  When the test results returned, she was told she had MDS.

“I was told it was a ‘wait and see illness’ and it mostly occurs in elderly people,” O’Neill said.  “None of my family have this cancer but [they do have] cancer of different types.”

A nuclear power plant is located across the Irish Sea in Sellafield, England. “I believe Sellafield has a lot to do with all the cancers on the east coast of Ireland,” said O’Neill.

The plant has “been blamed for a lot of cancers on the east coast, and a lot of children have been born with Down syndrome,” she continued

After her diagnosis, O’Neill made weekly trips to the hospital for blood tests. 

However, O’Neill had already planned a vacation to Greece in September and a trip to New York in November to celebrate her 50^th birthday.

“I don’t think the doctor thought I was well enough to go New York,” recalled O’Neill.

Despite her doctor’s advice against traveling to the United States, O’Neill visited New York for four days.

“I was okay until the last day,” recalled O’Neill.  “I got pains in my legs and was very tired.  Two days after I got back to Ireland, I was out of breath if I walked anywhere.”

O’Neill’s doctor immediately sent her to the hospital where she stayed for two days and received four blood transfusions to increase her blood counts.

O’Neill is currently treated with NeoRecormon (epoetin beta) to help with her fatigue.

“I was feeling tired and going to bed earlier – I just put it down to it being winter,” recalled O’Neill.

As her blood counts have increased, her NeoRecormon dosage has decreased and O’Neill has learned how to administer her own injections.

“I still can’t believe how sick I was,” reflected O’Neill.  “I just put up with it.”

Up until November, O’Neill went to the hospital every four months to monitor her blood counts.

However, at her last hospital visit in early November, her blood tests showed that her hemoglobin (a red blood cell protein) had fallen.

“I’ll be back in six weeks to keep an eye on it,” explained O’Neill.  “If the blood count stays down, they are going to increase the NeoRecormon dose.”

O’Neill is currently looking for a matched stem cell donor on the Irish Unrelated Bone Marrow Registry after finding out her two younger sisters are not matches.  Her doctors plan for her to receive a stem cell transplant when her condition worsens.

“Hopefully a transplant will be a good while away yet,” said O’Neill.

In the meantime, O’Neill has learned to be more in tune with her body.  “I have loads of energy, but sometimes I might get tired.  I listen to my body and have a nap,” she said.

Although every English-speaking adult has heard the word “leukemia” and most people have at least some sense what sort of disease leukemia represents, the term “myelodysplastic syndromes” (MDS) is not widely recognized by the general public.

Given how commonly MDS is diagnosed – several times more frequently than all forms of acute leukemia combined, with tens of thousands of new patients in the United States each year (the exact number is disputed) – this ignorance may at first seem surprising.

Yet that tongue-twisting six-syllable first component of MDS, “myelodysplastic,” may not convey much information to people without formal medical training or a working knowledge of Classical Greek.

As a result, each time that a celebrity or famous person is diagnosed with MDS — for example, the physicist and astronomer Carl Sagan, Congressman Bob Matsui of California, writer Roald Dahl, 1992 U.S. presi­dential candidate Paul Tsongas, or literary critic Susan Sontag — the newspaper stories reporting their diagnosis or cause of death inevitably describe MDS as “a rare bone marrow condition” or “an unusual blood disorder, similar to leukemia.”

And sometimes the newspapers spell it wrong.

But if one understands the history of how MDS was first described, as well as the meaning of the three parts of the term “myelodysplastic”, the mystery disappears.

Before World War II – “Di Guglielmo Syndrome” And “Refractory Anemia”

Bone marrow biopsies were not regularly performed on living patients until after the 1920s, so although anemia had been recognized since the 1820s, it wasn’t until the first half of the 20^th century that specific marrow conditions such as MDS could be defined.

In 1923, Giovanni Di Guglielmo, a physician in Naples, Italy, described a group of bone marrow disorders associated with bizarrely-shaped red blood cells that resulted in anemia and other low blood counts, which in some cases ultimately proved fatal.

For a long time, all of the bone marrow disorders associated with anemia and abnormal-appearing cells were collectively called “Di Guglielmo Syndrome” by doctors – a term that is still used occasionally for a specific type of leukemia, erythroleukemia (AML M6). Some cases of what was once called “Di Guglielmo Syndrome” would now be called MDS.

During the same decade that Di Guglielmo published his famous paper, George Whipple in California and George Minot and William Murphy in Boston figured out how to treat patients with a condition called pernicious anemia (now known to be due to vitamin B12 deficiency) with extracts of raw liver, a substance rich in vitamin B12. This event is often considered the beginning of the modern age of the science of hematology.

Over the course of the 1930s, patients who were anemic and did not have a good response to liver therapy were labeled as having “refractory” (meaning “resistant to treatment”) anemia.

In 1938, C.P. Rhoads and W. Halsey Barker in New York City reported a series of about 100 patients with refractory anemia, distinguishing cases that arose without any obvious predisposition from other cases in which the patient had been previously exposed to a recognized bone marrow toxin such as benzene.

Rhoads and Barker used the term “refractory anemia” for their series. Just as for Di Guglielmo Syndrome, many of the patients described by Rhoads and Barker would have been classified as MDS today.

Since World War II – From “Pre-Leukemic Anemia” To MDS

Then, in 1949, a London pathologist, J.L. Hamilton-Paterson, published a paper in which he noted that some cases of refractory anemia had a tendency to develop leukemia; he called this condition “pre-leukemic anemia.” Several French investigators came to similar conclusions that refractory anemia could evolve into leukemia.

In 1953, three physicians from my alma mater, the University of Chicago’s Medical School, published a prominent paper in the Journal of the American Medical Association describing 12 patients with “pre-leukemic acute human leukemia,” which greatly increased awareness of this condition among physicians in the United States.

In the 1960s and the 1970s, what we now know as MDS was widely known as “preleukemia.”

By 1976, however, Dr. John Bennett from Rochester, New York, and a group of six other pathologists from France, the United States of America, and Great Britain – the so-called “French American British (FAB) Co-Operative Group” – had noticed that most patients with preleukemia never actually went on to develop leukemia.

Clinicians who told their patients they had preleukemia found that while the patients were often most anxious about developing leukemia – leukemia can be a scary word – many instead died from complications of the low blood counts without ever developing leukemia, so all the worry was misdirected.

“Preleukemia” fell out of favor as a diagnosis after investigators published studies indicating that only about 20 percent to 25 percent of patients with MDS ever developed acute leukemia.

In 1976, the FAB group proposed the term “dysmyelopoietic syndrome” as an alternative to preleukemia.  A few years later, “dysmyelopoietic syndrome” was revised to become the “myelodysplastic syndrome(s)” still used today.

The latest classification of MDS used by doctors worldwide is the one published by the World Health Organization (WHO) in 2008.  Among the 11 types of MDS defined by the WHO (see table below), four still include the term “refractory anemia,” which shows that terminology used more than 70 years ago is still alive.

Ironically, although “refractory” anemia as defined by Rhoads and Barker in 1938 was any form of anemia that didn’t respond to treatment with liver extract or to other hematinics (vitamins or other substances known to improve blood counts, such as folic acid and iron), today many cases of “refractory” anemia are not actually refractory to treatment anymore.

Anemia associated with MDS can be successfully treated with Vidaza (azacitidine), Dacogen (decitabine), Revlimid (lenalidomide), Procrit (epoetin), Aranesp (darbepoetin alfa), allogeneic stem cell transplantation, and other therapies.

The 11 Types Of Pure (Not Overlapping) MDS
(as defined by the World Health Organization in 2008)

* These three can be considered subtypes of a larger category,
“refractory cytopenias(s) with unilineage dysplasia”

Dr. David Steensma is a physician at the Dana-Farber Cancer Institute in Boston and an Associate Professor in the Department of Medicine at Harvard Medical School. His primary area of research focuses on myelodysplastic syndromes and related conditions.

The German regimen involves four days of treatment with fludarabine, amsacrine, and high-dose cytarabine followed, several days later, by a single high dose of melphalan.

The researchers investigating this regimen found that 97 percent of the patients who received it achieved complete remission within one month following their stem cell transplant.

Stem cell transplantation is currently the only potentially curative treatment available to patients with myelodysplastic syndromes (MDS).

In this procedure, patients first receive one or more drugs intended to either treat their MDS or kill off their existing stem cells, after which donor stem cells are transplanted into the patient.

Some patients also receive radiation therapy prior to transplant to help kill their existing stem cells.

There are differences of opinion, however, when it comes to what kind of preparative treatment should be used in MDS patients prior to stem cell transplantation.

In Europe, it is common for preparative treatment to include two types of therapies.

Initially, patients receive one or more rounds of “induction therapy,” which is intended to treat the patient’s MDS.  This therapy is continued until a patient’s MDS is in full or partial remission.

At that point, patients receive ”conditioning therapy,” which aims to kill off a patient’s existing stem cells.

In the U.S., physicians often skip induction therapy and instead go straight to conditioning therapy.  This approach shortens the time between diagnosis and transplant, which is considered important.

Previous research has shown that patients with higher-risk MDS experience the longest overall survival when transplants are performed soon after diagnosis.

In addition, higher-risk MDS patients often do not respond well to induction therapy, and they often get infections during induction therapy that can make them ineligible for a stem cell transplant.

An alternative approach to preparative therapy that is being explored is one that combines a brief round of induction therapy followed quickly by conditioning therapy and stem cell transplant.

One such approach that has been tried is a short induction regimen of fludarabine (Fludara), amsacrine (Amsidine), and high-dose cytarabine (Cytosar-U), followed by a conditioning regimen of low-dose total body irradiation and cyclophosphamide (Cytoxan) or busulfan (Busulfex).

According to the German authors of the current study, this quick sequential approach has shown promising results.

In the present study, the German researchers evaluated a modified version of the sequential regimen just described.  In their study, 30 previously untreated higher-risk MDS patients first received a four-day induction regimen of fludarabine, amsacrine, and high-dose cytarabine.

Then, to avoid the toxicity often seen with irradiation and cyclophosphamide or busulfan, the researchers used only high-dose melphalan (Alkeran), with or without thiotepa, as a conditioning regimen.

Following transplant, patients in the German study received granulocyte colony stimulating factor to stimulate the production of white blood cell counts. They also received Prograf (tacrolimus) and mycophenolate mofetil (Cellcept) to prevent graft-versus-host disease, a common transplant-related complication in which the donor stem cells recognize the patient’s immune system as foreign and attack it.

In addition, most of the 30 patients in the study received anti-thymocyte globulin (ATG)  for several days between induction and conditioning therapy to help prevent graft-versus-host-disease.

Patients received their transplants within a median of 134 days after diagnosis.

The German researchers found that all but one of the patients experienced improved blood cell counts after transplant. The median time for white blood cell and platelet recovery were 13 days and 17 days, respectively.

At 28 days after transplant, 97 percent of the patients were in complete remission.

At a median follow-up time of 28 months, 70 percent of patients were alive and disease-free.  Among those patients who received only melphalan during their conditioning regimen — as opposed to melphalan and thiotepa — 79 percent were alive and disease-free.

Thirteen percent of patients relapsed, but after receiving treatment with Vidaza (azacitidine) and white blood cell infusions, these patients are alive and disease-free.

Of the 30 patients included in the study, 73 percent experienced acute graft-versus-host disease, which develops within the first 100 days after the transplant; 63 percent of patients experienced chronic graft-versus-host disease, which occurs 100 days or longer after the transplant.

The most common severe, treatment-related complications were infections (53 percent), mouth ulcers (50 percent), and acute graft-versus-host disease (20 percent).

Thirty percent of patients died due to treatment-related complications. The researchers found that the risk of treatment-related death was related to the development of severe acute graft-versus-host disease.

Since the share of patients who died was particularly high among patients who received melphalan with thiotepa (67 percent), the study authors decided to remove thiotepa from the protocol early on in the trial.

For more information, please refer to the article in Biology of Blood and Marrow Transplantation (abstract).

“Those patients who have an early platelet response will do very well, and these patients should be encouraged to continue Vidaza,” said the study’s lead author, Dr. Gerwin Huls of the University Medical Centre Groningen in the Netherlands.

“However, it should be noted that the lack of a platelet response does not mean that a patient will not benefit from Vidaza treatment. Indeed, the general rule to give at least six cycles of chemotherapy still is valuable,” he added.

Dr. Huls and his co-authors pointed out that, due to a relatively short follow-up period, further studies are needed to confirm their findings.

Vidaza (azacitidine) has been approved for the treatment of myelodysplastic syndromes (MDS) in the United States since 2004. The European Medicines Agency (EMA) approved Vidaza in 2008 for higher-risk MDS, but it was available prior to the EMA approval through a compassionate use program to patients with higher-risk MDS and certain types of leukemia. The program allows physicians to prescribe non-approved drugs for the treatment of patients with serious or life-threatening illnesses when all approved therapies have failed.

According to the study authors, the effectiveness of Vidaza is often not apparent until the completion of several treatment cycles. However, it would be useful to know early in the treatment process which patients are likely to benefit from Vidaza treatment.

In the current study, the Dutch researchers retrospectively analyzed data from 90 patients treated with Vidaza in the Netherlands under the compassionate use program to assess the patients’ response rates and to identify early predictors for response. The median patient age was 71 years, and 52 percent of patients had MDS (8 percent low-risk, 44 percent high-risk).

Patients received daily Vidaza injections (75 mg/m²) for seven days in a 28-day cycle. They received a median of five treatment cycles.

After a median follow-up of eight months, 48 percent of patients responded to treatment, including 14 percent who achieved a complete response. Patients with low-risk MDS had the highest response rate of the patient subgroups at 57 percent. Patients with acute myeloid leukemia had the lowest response rate at 39 percent. The median time to response was two months.

The median overall survival was 13 months. Patients who responded to Vidaza treatment experienced longer overall survival (16 months) compared to non-responders (6 months).

The study authors also found that patients whose platelet counts at least doubled after the first treatment cycle had significantly longer overall survival times (median not yet reached), compared to patients whose platelet count did not increase as much (13 months).

Other factors that served as predictors for overall survival included the presence of circulating immature blood cells and a poor-risk chromosomal profile.

About one-fourth of patients discontinued treatment prior to receiving three Vidaza cycles due to early death (12 percent), rapid disease progression (6 percent), severe side effects (6 percent), stem cell transplantation (2 percent), stroke (1 percent), and consent withdrawal (1 percent). In addition, 23 percent required dosing reductions or dosing schedule changes.

For more information, please refer to the study in the British Journal of Haematology (abstract).

Thalassemia is a genetic condition that causes anemia.

The FDA approval of Ferriprox (deferiprone), which will be marketed by the Canadian company ApoPharma, is in line with the recommendation the agency received from its Oncology Drug Advisory Committee, which met last month to review the drug (see related Beacon news).

At that meeting, the advisory committee voted 10-2 to recommend that the FDA approve Ferriprox. 

There was concern during the meeting, however, about the safety of Ferriprox if it were to be used in myelodysplastic syndromes (MDS) patients.  Not many MDS patients were included in Ferriprox’s clinical trials.  In addition, the FDA explicitly recommends against the use of Exjade (deferasirox), a drug similar to Ferriprox, in high-risk MDS patients because Exjade may cause potentially life-threatening side effects in those patients (see related Beacon news). 

In response to these concerns, ApoPharma made clear that it was only seeking approval for Ferriprox in thalassemia patients, and only if patients have failed another iron overload therapy.  

This was the use that eventually was approved by the FDA last Friday.

Ferriprox’s FDA-approved use is more limited than the approved uses of Desferal (deferoxamine) and Exjade, the two other drugs commonly used in the U.S. to treat iron overload.

Desferal is approved generally for the treatment of ”chronic iron overload due to transfusion-dependent anemias.”  Likewise, Exjade is approved “for the treatment of chronic iron overload due to blood transfusions.”  Neither of these drugs is limited to patients with a specific disease, as is the case with Ferriprox.  Nor are the other two drugs limited to patients who have failed other iron overload treatments.

Like Exjade, Ferriprox can be taken orally, whereas Desferal is typically administered by injection or infusion.

Although Ferriprox’s officially approved use is limited to thalassemia patients who have failed another iron overload treatment, U.S. physicians are permitted to prescribe Ferriprox for other patients if they believe there is sufficient justification for such use.  It is not clear, however, whether such “off label” use of Ferriprox will be reimbursed by insurance companies or Medicare.

Ferriprox’s approval by the FDA was based on a retrospective analysis of data from twelve clinical trials. Half of the participants in those trials showed at least a 20 percent decrease in ferritin levels, a protein that stores iron in the blood, with Ferriprox treatment. All study participants had previously received iron overload therapy.

Ferriprox was first approved in Europe in 1999 and is currently being used in 61 countries worldwide.

Due to safety concerns that arose after Ferriprox’s initial approval in Europe, ApoPharma launched a program there that requires physicians and patients taking Ferriprox to track patient blood cell counts. The company has indicated that it will launch a similar program in the United States.

For more information, please see the FDA press release.

“My doctor noticed that my blood counts were low,” explained Jack.  “He decided we needed to see a specialist in Medford, Oregon.”

The specialist performed a bone marrow biopsy right away and informed Jack that he had myelodysplastic syndromes (MDS) with refractory anemia (low red blood cell counts that do not respond to treatment) and excess blasts (immature bone marrow cells).  The blast count was 10 percent at the time, and Jack was on his way to developing acute myeloid leukemia.

When the doctor informed the Grubbs that Jack’s diagnosis was MDS, neither he nor BJ had heard of the disease.

“It was a shock to both of us,” recalled Jack.  “We’re healthy people. We eat right, and we exercise; we don’t smoke or consume alcohol. We basically have no significant bad habits that should affect our general health.”

However, they knew about leukemia and realized MDS was serious and not something one would simply recover from.

They also realized that Jack had a projected life span of a couple of years if they chose to do nothing.  They learned that day that the only known cure for MDS is a donor (allogeneic) stem cell transplant. They decided then and there that Jack would have a transplant as soon as he was determined to be a viable candidate.

Immediately after diagnosis, Jack began treatment with Vidaza (azacitidine), which he received seven consecutive days every month for close to a year.  The goal was to decrease his blast count as low as possible in preparation for the stem cell transplant.

He responded positively to the Vidaza; his blast counts decreased to just below 5 percent. However, Jack’s oncologist did not see the results she had hoped for.

In the fall of 2010, she switched him to Dacogen (decitabine) infusions for five consecutive days every month, which led to a more rapid reduction in the blast count.

“The most recent bone marrow biopsy [after switching to Dacogen] showed that my blast count was down below 2 percent, and we were all really excited,” explained Jack.

Jack has been treated with Dacogen for most of this year, and the treatment continues to be successful. However, he and BJ are focusing their efforts on getting Jack a donor stem cell transplant as soon as a donor can be located.

They found out in June that Jack’s transplant coordinator at Oregon Health & Science University had found a donor for him in May. However, the transplant coordinator informed them that the donor would not be available until October of next year.

Jack and BJ were disappointed after hearing the news, but they remain positive. “We’re not in a panic mode right now because my body is responding so well to Dacogen. However, as infusions are a very temporary fix, it’s nice to know there’s somebody out there who is a match in case things go wrong,” said Jack.

In the meantime, Jack’s transplant team continues to search for other donors.

“It’s very possible we’ll find another donor sooner than a year,” continued BJ.  “But if not and we can hang on until October [of next year], we’ll jump right on it.”

As part of the preparation for a stem cell transplant, Jack’s doctor recommended pulling some of Jack’s teeth to avoid transplant-related complications.

“My teeth were fairly good, but they had real loose roots on them,” said Jack.  “They were afraid that bacteria could get down in there and cause a problem.”

Jack has also been advised by medical staff to avoid store-bought, fresh produce because of the possibility of exposure to pesticides, contaminants, and bacteria from improper handling. BJ grows a vegetable garden that provides wholesome, fresh, organic food. That way, Jack and BJ rest assured there is nothing more on Jack’s veggies than dust from the country roads.

Since his diagnosis, Jack has learned enough about MDS that he knows, “The transplant is going to beat you up, and you want to be ready for it.”

Jack, therefore, works diligently to take care of himself to stay healthy. He stays clear of sick people, washes his hands religiously, and avoids crowded places.  He is more careful about conserving his energy than pre-diagnosis, which means that he takes a break when he starts feeling tired.

He also discovered that there is a lot of research available on the Internet about nutritional tips and vitamin/food supplements. He since has developed his own personal health smoothie, which he consumes every morning.

While waiting for a donor and Jack’s stem cell transplant, the Grubbs became involved with Be the Match, the national bone marrow registry, by raising awareness and funds for the organization.

“BJ and I and a friend of mine, the three of us raised $760 in donations from friends and family for the Be the One Run in Portland, Oregon, in July,” said Jack.  “That all went to Be the Match for research and to make people aware of becoming a stem cell donor.”

Additionally, the Grubbs stay informed about new developments in MDS by attending conferences, patient seminars, and support group meetings. They have started their own small local support group with three couples, in which each of the husbands has a form of MDS or leukemia.

Jack and BJ were also proactive in lobbying Medicare to authorize payments for stem cell transplants for elderly MDS patients.  “The rules stipulated that they would pay for a transplant once my condition became full-blown leukemia, and my chances of survival at that point were predictably poor,” explained Jack.

The Grubbs organized a benefit in their small rural town to encourage people to contact their local Congressional representatives to pass legislation to allow Medicare to pay for elderly MDS patients to receive stem cell transplants.

“Our Congressman ended up with about 200 letters on his desk,” said Jack.  “We worked really hard to try to change the way [Medicare] was doing this.”

“In August 2010, we heard that Medicare had responded favorably to the public and would begin authorizing coverage for transplants in January 2011, on a case-by-case basis. We were ecstatic,” he added.

Based on their own experiences, the Grubbs advise other MDS patients to ask lots of questions, become as informed as possible, and be proactive.  They also encourage other patients to keep positive thoughts and do whatever fits their lifestyles to achieve peace within.

“Just jump in and do the most that you can for yourself,” recommended BJ.  “Ultimately, you are doing the most that you can for everybody.”

Given the frequency of sexual dysfunction in these patients, the researchers concluded that there is a strong need for treatment studies in this area.

“Sexuality and sexual function is a quality of life variable that is in particular need of further research and attention in the clinical setting,” said Dr. Kristina Thygesen of Rigshospitalet University in Copenhagen, Denmark. “Hopefully, this will lead to preventive interventions that may improve quality of life in [stem cell transplant] patients,” she added.

Stem cells have the unique ability of developing into many different types of cells with specific functions within the body, such as a blood cell. In myelodysplastic syndromes (MDS) and many other blood cancers, the development from stem cells to mature, specialized cells is no longer regulated.

As a result, many patients undergo stem cell transplantation, a procedure in which the patients receive healthy stem cells, either from a donor or their own cells that were harvested prior to chemotherapy. In MDS, stem cell transplantation with donated stem cells remains the only curative treatment available.

Researchers have previously determined that patients may experience sexual dysfunction after radiation treatment or chemotherapy. However, according to the Danish researchers, there has so far been little discussion about the impact of stem cell transplantation on sexuality.

The Danish researchers therefore conducted a systematic literature review on the topic and identified 14 studies relating stem cell transplantation and sexuality. In five of the studies, patients received stem cells from a donor; patients received their own stem cells in two studies; and in the remaining seven studies, patients received either their own cells or cells from a donor.

The researchers found that following transplantation, 48 percent of patients reported dissatisfaction with their quality of sexual life, which extended up to six months after transplantation.

Patients who underwent stem cell transplantation experienced significantly lower sexual functioning, compared to patients treated with chemotherapy only. After stem cell transplantation, patients reported decreases in the following aspects of sexual functioning: sexual activity (38 percent), ability to have sex (36 percent), pleasure from sex (31 percent), and interest in sex (28 percent).

Both female and male patients experienced specific sexual problems after transplantation, including vaginal dryness, painful sexual intercourse, and erectile dysfunction.

In one study, 38 percent of men experienced a delay or absence of orgasm and ejaculation more frequently than prior to transplantation. In addition, 74 percent experienced erectile dysfunction more often following transplantation, including 25 percent who always or often experienced this side effect.

The researchers compared the sexual activity of patients who underwent transplantation with that of healthy people. They found that male patients who survived five years after transplantation had significantly lower sexual activity than the healthy men. In females, 40 percent of the surviving patients were not sexually active up to five years after transplantation, compared to 21 percent of healthy women.

The researchers also found several gender-related differences in sexuality. Female patients reported significantly more problems over time, whereas male patients maintained a consistent level of problems. Female patients also reported a higher number of problems and lower rates of sexual activity than male patients at all of the follow-up periods after transplantation.

At one year after transplantation, male patients had problems with physical appearance and obtaining an erection, ejaculation, and orgasm. Female patients had problems with lack of sexual interest, appearance, vaginal dryness, and painful intercourse.

At three years after transplantation, 80 percent of female patients reported sexual problems, compared to 29 percent of male patients.

In one study, patients who received stem cells from a donor (which is commonly used for MDS transplants) reported more changes in sexual function and experienced more hormonal disorders, compared to patients who received their own harvested stem cells. However, two other studies found no difference in the ability to have sex between these two treatment groups.

Another study found that patients who received stem cells from a donor also experienced more difficulties related to erectile dysfunction, compared to patients who received maintenance chemotherapy.

Several of the studies included in the review showed conflicting data on the relationship between sexual dysfunction and graft-versus-host disease, a common transplant-related complication in which the newly infused stem cells view the patient’s cells as foreign and attack them.

In one study, the researchers found no significant association between graft-versus-host-disease and reduced sexual function. However, a greater percentage of patients who experienced sexual dysfunction also had graft-versus-host-disease. According to the authors of the review, this finding indicates that graft-versus-host-disease increases sexual dissatisfaction.

“There was no significant correlation between sexual dysfunction and graft-versus-host-disease, even though graft-versus-host-disease can manifest in the genital area. Therefore, future research needs to investigate this [topic],” said Dr. Thygesen.

Two studies found a significant association in patients who received donated stem cells between chronic graft-versus-host-disease and lower emotional well-being, less sexual satisfaction, and arousal/orgasm problems.

Patients who experienced reduced sexual function also reported increased fatigue and lower quality of life. Patients who received stem cells from a donor reported poorer quality of life than patients who received their own stem cells.

For more information, please refer to the article in Bone Marrow Transplantation (abstract).