The findings were presented at the 2011 American Society of Hematology (ASH) meeting held in December.

The results need to be considered carefully, however, because the analysis compares the rate of second cancers among Revlimid-treated MDS patients in clinical trials with the rate of cancer in the general public.

A more relevant comparison would be to look only at patients within the same controlled clinical trials, and compare cancer rates for patients treated with Revlimid with rates for patients not treated with Revlimid.

Similar to the current MDS study, an analysis involving multiple myeloma patients showed that cancer rates among patients treated with Revlimid were much the same as those in the general public (see related Myeloma Beacon news).

However, other studies showed that myeloma patients treated for long periods with Revlimid in controlled clinical trials were at significantly higher risk of developing a second cancer compared to myeloma patients in the same trials who were not treated with Revlimid (see additional Myeloma Beacon news).

Revlimid (lenalidomide) is approved by the U.S. Food and Drug Administration (FDA) for the treatment of lower-risk myelodysplastic syndromes (MDS) patients who have the deletion 5q chromosomal abnormality and are dependent on red blood cell transfusions.

In April 2011, the FDA began investigating the possibility that Revlimid may cause additional, or secondary, cancers  (see related Beacon news).  The investigation was started based on the results from clinical trials in patients with the blood cancer multiple myeloma.

The trial results suggested that Revlimid may increase the risk of developing new types of cancers in patients taking the drug for extended periods of time.  However, despite its investigation, the FDA advised patients currently taking Revlimid to continue treatment.

In the current study, European and American researchers retrospectively analyzed five clinical trials involving lower-risk MDS patients to determine if Revlimid use was associated with an increased risk of additional cancers in MDS patients.

The analysis included data from 557 lower-risk MDS patients who had received Revlimid treatment. The median patient age was 71 years; 72 percent of patients were 65 years or older.

Of the 557 patients included in the analysis, 16 percent had previously had cancer including skin, brain, breast, and lung cancer.

The researchers found that 5 percent of patients developed at least one secondary cancer after a median of 13.5 months of therapy; of these patients, 18 percent had a prior history of cancer.

The researchers also determined that 2.6 percent of patients developed a secondary cancer each year.

They then compared this rate of cancer development to the rate of new cancer cases in the general public, which are reported to the Surveillance, Epidemiology, and End Results cancer registry, to determine if Revlimid-treated MDS patients were more likely to develop secondary cancers.

The cancer registry shows that 2.1 percent of people who are at least 65 years old develop cancer every year.

For more information, please see abstract 1704 at the ASH 2011 meeting website.

Treatment with a combination of Vidaza (azacitidine) and Revlimid (lenalidomide) has previously been shown to be effective in higher-risk myelodysplastic syndromes (MDS) patients with or without chromosomal abnormalities.

The two new studies on the combined use of Vidaza and Revlimid were presented at the 2011 American Society of Hematology (ASH) meeting last month.

Phase 2 Trial: Simultaneous Treatment With Vidaza And Revlimid

Dr. Mikkael Sekeres of the Cleveland Clinic presented results from a Phase 2 trial showing high efficacy of the Vidaza-Revlimid combination therapy in higher-risk MDS patients who had not been previously treated with either drug.

The study included 36 patients with a median age of 68 years. They had been diagnosed a median of eight weeks before signing up for the trial.

The patients were treated with 75 mg/m² of Vidaza daily for the first five days of a 28-day treatment cycle.  They also received 10 mg of Revlimid daily for the first 21 days of the treatment cycle.

Patients could receive a maximum of seven cycles of combination therapy, after which they could choose to continue treatment with Vidaza alone.  The study participants received a median of five treatment cycles.

Overall, 72 percent of patients responded to the Vidaza-Revlimid combination treatment after a median of three months: 42 percent of patients achieved a complete response lasting for a median of 16 months, plus 28 percent of patients showed improved blood cell counts.

The patients who experienced a complete response had a median overall survival of 27 months; 50 percent of these patients progressed to acute myeloid leukemia at a median of 20 months.

The most common severe side effects included low white blood cell counts with fever (31 percent), heart problems (11 percent), lung problems (11 percent), infections (8 percent), blood clots (6 percent), and central nervous system bleeding (6 percent).

Three patients (8 percent) died during the trial.

Phase 1 Trial: Vidaza Treatment Immediately Followed By Revlimid Treatment

Results of a recent Phase 1 study of Vidza followed by high-dose Revlimid were summarized in a poster presentation. The results show that the combination may be effective and safe in certain higher-risk MDS patients.

This study included 28 patients with MDS, chronic myelomonocytic leukemia, or acute myeloid leukemia.

Study participants could be any age if they were unresponsive to their previous treatment (22 patients).  Patients were also accepted if they were older than 60 years and had not received prior treatment for their condition (six patients).  The median age of the study participants was 65 years.

The patients received 75 mg/m² Vidaza intravenously (in the vein) for the first five days of a 28-day treatment cycle.

They then received 10 mg to 75 mg of Revlimid starting on the sixth day of the treatment cycle for five consecutive days or 75 mg of Revlimid for ten consecutive days

The study participants completed a median of 1.5 treatment cycles.

The researchers were able to evaluate five of the six patients who had not received prior treatment; 60 percent of these patients achieved a complete response.  They were treated with 25 mg or 50 mg of Revlimid for five consecutive days following Vidaza treatment.

None of the previously treated patients responded to the sequential treatment; 47 percent maintained stable disease.

The most common side effects included fatigue, loss of appetite, constipation, rash, fever, and weight loss.

No dose-limiting side effects were observed, so the maximum tolerable Revlimid dose was not determined.

One of the patients who received 75 mg of Revlimid for ten days after Vidaza treatment died.  The remaining six patients in this treatment group continued treatment without any severe side effects.

A Phase 2 trial is currently under way to study the effects of 50 mg of Revlimid for ten consecutive days after Vidaza treatment in 40 newly diagnosed patients.

For more information, please see abstract 607 and abstract 2613 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.

Day 1

Saturday started off with an education session on myelodysplastic syndromes (MDS) that consisted of three talks. The program was repeated in the afternoon.  

The day ended with a large poster session, during which study results from hundreds of blood disorder-related studies were displayed on big posters attached to boards throughout the exhibition hall. Many posters were accompanied by a presenter or printouts of the poster for attendees to take with them.

There were a number of posters about current MDS treatments as well as new drugs that are under development. Some of the highlights are described below.

French researchers conducted a small study to see if home administration of Vidaza (azacitidine) is possible. They argued that home administration would significantly improve the quality of life of MDS patients. They found that home administration was safe and feasible. A similar median number of cycles and treatment delays were observed between patients who received Vidaza at the hospital and those who received Vidaza at home. Side effect levels and rates of hospitalization were also similar between the two groups (abstract).

Preliminary results from a Phase 1/2 study suggest that the HDAC inhibitor panobinostat, which is being developed by Novartis, is well tolerated and shows some clinical activity in combination with Vidaza in previously untreated MDS patients. The maximum tolerated dose was 30 mg of panobinostat in combination with a 5-day Vidaza schedule of 75 mg/m² daily (abstract).

Results of an analysis of five trials involving Revlimid (lenalidomide) for the treatment of MDS did not show any clear evidence that Revlimid is associated with an increased risk of secondary cancers in patients with lower-risk MDS with or without del(5q). According to the study authors, the rate of invasive secondary cancers among patients treated with Revlimid was what would be expected among persons in this age group (abstract). Concerns about an increased risk of secondary cancers were first raised at last year’s ASH meeting when study results showed an increased rate of secondary cancers in multiple myeloma patients who had received Revlimid as maintenance therapy (see related news).

Results of a small French study showed that Nplate (romiplostim), which is currently approved to increase platelet levels in patients with chronic immune thrombocytopenia, may be a treatment option for patients who experience low platelet counts after donor stem cell transplantation. Low platelet counts increased in all seven study participants who received Nplate therapy (abstract).

Results from a Korean analysis showed that for patients who receive Vidaza or Dacogen (decitabine) before donor stem cell transplantation, outcomes after stem cell transplantation were better for patients who started the transplant process while still responding to Vidaza or Dacogen than for patients who had progressed. These findings suggest that stem cell transplantation should be initiated while the patient is still responding to Vidaza or Dacogen therapy (abstract).

Treatment with Vidaza or Dacogen may also be a good treatment alternative for patients who are older or cannot tolerate donor stem cell transplantation. When researchers from the MD Anderson Cancer Center in Texas retrospectively compared outcomes for patients who received treatment with Vidaza or Dacogen to patients with similar characteristics who had received a stem cell transplant, they found that the median survival was 26 months for patients receiving a stem cell transplant and 25 months for patients treated with Vidaza or Dacogen. The eight-year overall survival rates were 24 percent and 23 percent, respectively (abstract).

Another analysis from the National Institutes of Health looked at the role of immunosuppressive therapy in MDS. In some types of MDS, the immune system attacks the bone marrow and prevents it from making healthy blood cells. As a result, scientists have recently proposed immunosuppressive therapy as a possible treatment for MDS. This therapy employs drugs that reduce the immune system’s response, thereby allowing the bone marrow to produce more blood cells. The analysis showed that the overall response rate to immunosuppressive therapy was 41 percent. Response rates were higher in patients younger than 60 years old and patients with lower-risk MDS.  The number of immature blood cells and the duration of transfusion dependence did not affect response (abstract).

Day 2

Yesterday was the second full day of the ASH annual meeting. The MDS sessions included a series of talks in the afternoon and a poster session in the evening.

The talks in the afternoon focused on treatment options for MDS patients.

Results of a Phase 1/2 extension study showed that Nplate improved platelet counts in 37 percent of lower-risk MDS patients. However, Nplate also led to an increase in immature blood cell counts and increased risk of progression to acute myeloid leukemia (AML), so the study was discontinued earlier this year (abstract).

After that, results results from a Phase 1 trial were presented showing that the investigational drug ARRY-614 has clinical activity in lower-risk, relapsed/refractory MDS patients. The goal of the study was to determine the maximum tolerated dose of ARRY-614. At the highest dose tested, 38 percent of patients showed blood cell count improvements. The most common side effects were rash and diarrhea (abstract).

In addition, results from a retrospective analysis were presented showing that Revlimid extends overall survival and is not associated with an increased risk of progression to AML in lower-risk, transfusion-dependent MDS patients with the chromosomal abnormality del(5q). The two- and five-year rates of AML progression were 7 percent and 23 percent for patients who received Revlimid, compared to 12 percent and 20 percent for patients who did not receive Revlimid. Median time to AML progression has not been reached for this patient group. The two- and five-year overall survival rates were 90 percent and 54 percent for patients who received Revlimid, compared to 74 percent and 41 percent for patients who did not receive Revlimid. Median overall survival was 5.2 years for patients who received Revlimid, compared to 3.8 years for patients who did not receive Revlimid (abstract).

The evening once again featured a poster session that included additional results from many MDS-related clinical trials. Some of the results are highlighted below.

In one study, researchers tested the combination of the HDAC inhibitor belinostat, which is being developed by the pharmaceutical company Spectrum Pharmaceuticals, in combination with Velcade (bortezomib) in patients with AML and MDS. They found that the combination was tolerated and showed modest activity. The maximum tolerated dose has not been reached yet (abstract).

In another study, researchers investigated the efficacy of Vidaza in MDS patients with the chromosomal abnormality del(5q) who had previously failed Revlimid treatment. They found that the response rates were similar to those reported in patients without the chromosomal abnormality, which led the researchers to conclude that Vidaza may be an effective salvage treatment for this patient population (abstract).

In a Phase 1 study, researchers evaluated Telintra (ezatiostat hydrochloride) in combination with Revlimid in lower-risk MDS patients with the chromosomal abnormality del(5q). Forty-three percent of patients responded at the highest dose recommended for further testing. According to the researchers, Telintra may enhance Revlimid’s efficacy and the combination was well tolerated (abstract).

In another Phase 1 trial, researchers tested quick, sequential administration of Vidaza and Revlimid because they hypothesized that this approach may be particularly useful for patients with high-risk MDS and AML. Patients received 75 mg/m² Vidaza on days 1 to 5, followed by Revlimid starting on day 6 for five to ten days of a 28-day treatment cycle. Different Revlimid doses were tested, but the maximum tolerated dose has not been reached yet. So far, 60 percent of previously untreated patients have achieved a complete response (abstract).

Transfusion dependency may be an important factor for the prognosis of MDS patients. When European researchers retrospectively analyzed data from an MDS and AML registry, they found that patients who required more than 20 units of transfusions had the highest death rate (30 percent), compared to patients who did not need transfusions (5 percent) (abstract).

When French researchers investigated the impact of incorporating the immunosuppressive therapy agent antithymocyte globulin (ATG) into the preparative treatment for donor stem cell transplantation, they found that ATG resulted in a lower rate of acute graft-versus-host disease, a common transplant-related complication. At the same time, ATG did not negatively affect relapse rates nor survival (abstract).

The most common side effects were low blood cell counts, which required close monitoring. However, the study authors concluded from these results that the side effects were acceptable when compared to conventional chemotherapy, which is often ineffective and intolerable in high-risk patients.

Previous research has shown that the combination therapy of Vidaza (azacitidine) and Revlimid (lenalidomide) is effective and safe in patients with higher-risk myelodysplastic syndromes (MDS) (see related Beacon news).

Vidaza destroys rapidly dividing cells by removing methyl groups from DNA. Revlimid promotes cell death by preventing the growth of new blood vessels needed for tumor survival.

Researchers have recently proposed that the complementary mechanisms of Vidaza and Revlimid may produce additional benefits not seen in single-agent therapy.

In the present study, French researchers report their experience with Vidaza and Revlimid as a first-line therapy in eight patients with high-risk MDS or acute myeloid leukemia (AML) with chromosomal abnormalities. All of the patients had three or more abnormalities in their chromosomes, which is called a complex karyotype. The median patient age was 66.5 years.

The median time from diagnosis to the start of treatment was 3.5 months.

Five patients received 75 mg/m² of Vidaza on days 1 through 5, and three patients received 75 mg/m² on days 1 through 7 of a 28-day cycle. In addition, the patients received 10 mg of Revlimid on days 1 through 21. One patient received 5 mg of Revlimid.

Six of the eight patients responded to treatment: three with a complete response and three with a partial response. The two remaining patients experienced disease progression during treatment.

The initial response occurred at a median of 10 weeks after the treatment started. Four of the six responders relapsed at a median of 12 weeks after their initial response. The other two responding patients are still alive and in complete remission. Both patients received a donor stem cell transplant.

The median overall-survival and progression-free survival were 15 months and 9.5 months, respectively.

The major observed side effects were low blood cell counts. Seven of the eight patients experienced severe to life-threatening low platelet counts. Five patients developed severe to life-threatening low white blood cell counts, which often resulted in blood poisoning and, in two cases, hospitalization in the intensive care unit.

Five of the eight patients died. Two patients died because their disease was resistant to treatment. After initially responding to treatment, three patients died from disease progression.

For more information, please refer to the article in Leukemia (abstract).

The study’s authors found that a lower dosage given for an additional week during each treatment cycle improved red blood cell counts for a longer time and caused fewer side effects.

“Telintra is the first oral GST P1-inhibitor that has been shown to reduce or eliminate the need for red blood cell transfusions, which potentially would be a significant clinical benefit for myelodysplastic syndromes (MDS) patients,” said the study’s lead author, Dr. Azra Raza of Columbia University.

“Lower-risk MDS patients suffer from the consequences of progressive bone marrow failure, requiring red blood cell transfusion support, and patients may be at risk for infections and bleeding. An oral therapy that can treat the consequences of low blood counts, improve symptoms, and eliminate the need for transfusions will satisfy an unmet medical need and improve the quality of patients’ lives,” Dr. Raza added.

Interim results from this study were presented by Dr. Raza in December at the American Society of Hematology annual meeting (see related Beacon news).

Telintra (ezatiostat hydrochloride) is currently being developed by the California-based biopharmaceutical company Telik as an oral drug for the treatment of MDS. It promotes the growth and maturation of stem cells while also killing off blood cells that do not mature properly (blasts).

In the present study, researchers evaluated two extended dosing schedules of Telintra in 89 lower-risk MDS patients.

The first 14 patients enrolled in the study received 4,500 mg of Telintra daily for either two weeks or three weeks followed by a week off before the start of the next cycle of treatment.  To reduce side effects and the number of pills taken each day, all patients enrolled thereafter received lower doses of Telintra.  Specifically, half of the patients received 3,000 mg daily for two weeks followed by a week off (dosing schedule 1), and the other half received 2,000 mg daily for three weeks followed by a week off (dosing schedule 2).

The researchers were able to evaluate 30 patients from dosing schedule 1 (3,000 mg for two weeks) for treatment efficacy. They found that 24 percent had improved red blood cell counts, 10 percent had improved white blood cell counts, and 7 percent had improved platelet counts. Seventeen percent experienced improvements in all three counts.

For dosing schedule 2 (2,000 mg for three weeks), the researchers were able to evaluate 31 patients for treatment efficacy. They found that 19 percent had improved red blood cell counts, 27 percent had improved white blood cell counts, and 0 percent had improved platelet counts. No patients had improvements in all three blood cell counts.

“Since MDS patients also may have low white blood cell and platelet levels, Telintra’s ability to improve white blood cell and platelet [counts] could provide a therapeutic advantage over available agents,” said Dr. Raza.

The researchers observed that duration of response for red blood cell counts depended on time of exposure to Telintra. In dosing schedule 1, which had a higher dose but shorter exposure time, the median response duration was 18 weeks. In dosing schedule 2, the exposure time was extended by a week for each treatment cycle, and the median response duration was 46 weeks.

In addition to analyzing the efficacy of the two dosing schedules, the researchers also evaluated patients’ responses based on what therapies they had previously received.

Among patients who had not previously received Revlimid (lenalidomide), Dacogen (decitabine), or Vidaza (azacitidine), 28 percent achieved improved red blood cell counts after Telintra therapy, and 50 percent had reduced needs for transfusions.

In comparison, among patients who were previously treated with Revlimid, 31 percent achieved improved red blood cell counts, 39 percent had reduced needs for transfusions, and 22 percent achieved transfusion independence.

Telintra was not as effective in patients previously treated with Dacogen or Vidaza.  Among these patients, 7 percent achieved improved red blood cell counts and 11 percent had reduced needs for transfusions.  In addition, previous treatment with Dacogen or Vidaza significantly reduced patients’ duration of response to Telintra (median of 34 weeks versus 46 weeks).

The researchers stated that Telintra was well tolerated with 3 percent of treatment cycles requiring dose reductions, mostly due to nausea, diarrhea, vomiting, and fatigue.  In addition, 20 percent of patients experienced abnormal skin odor.

Side effects were more common with higher doses of Telintra.  Additionally, prior treatment with Dacogen or Vidaza increased the risk and severity of side effects.

“We believe that dose schedule 2 is the best dose and dose schedule for this investigational drug, and we will be conducting two new studies with dose schedule 2,” concluded Dr. Raza.

The first new study will be for lower-risk MDS patients with the deletion 5q abnormality who have previously failed prior Revlimid therapy.  The second new study will be for lower-risk MDS patients without the deletion 5q chromosomal abnormality, for whom Revlimid is not approved.

For more information, please refer to the article in the journal Cancer (abstract).

He recommended that patients with low red blood cell counts (anemia) be treated with red blood cell-stimulating agents, which produced response rates of 40 percent in these patients.

For patients who do not respond to this treatment or have other low blood cell counts, he recommended treatment with Revlimid, Vidaza, Dacogen, and Anti-Thymocyte Globulin, which produced response rates of up to 67 percent.

Upon diagnosis, physicians categorize myelodysplastic syndromes (MDS) patients based on the severity of their disease. Nearly 75 percent of patients fall into the lower-risk disease category, which is defined by a score of 1.0 or less in the International Prognostic Scoring System (IPSS) or by less than 5 percent blasts (immature stem cells).

When To Start Treatment

According to Dr. Sekeres, patients with lower-risk MDS do not necessarily need to start treatment immediately after diagnosis.

One very important factor to consider in the decision process is how MDS-related symptoms impact the patient’s quality of life. Dr. Sekeres found that patients with lower-risk MDS reported an average of six days per month where their physical health is “not good.” In addition, MDS-related symptoms prevent them from completing their normal routine for an average of four days per month.

Dr. Sekeres determined that treatment should only be initiated if the patient’s MDS-related symptoms are more severe than the potential side effects of the treatment.

He also pointed out that physicians need to keep in mind, when discussing potential treatment options with patients, that the patients may not be aware of the severity of their disease.

Results of previous studies showed that the majority of patients had their disease described to them as a ‘bone marrow disorder’ (80 percent) or ‘anemia’ (56 percent). In addition, Dr. Sekeres found that 55 percent of patients do not know their IPSS risk level, and 42 percent do not know the percent of blasts in their bone marrow, which makes it more difficult for the treating physician to explain potential treatment options that are associated with severe side effects.

Treatment For Low Red Blood Cell Counts

Dr. Sekeres recommended that lower-risk MDS patients with low red blood cell counts receive drugs that stimulate red blood cell production. Results from previous clinical trials showed that approximately 40 percent of lower-risk MDS patients responded to this form of treatment. The median duration of response is about two years.

Although several studies pointed to a negative association between the use of red blood cell-stimulating agents and survival outcomes in patients with solid tumors, Dr. Sekeres noted that no MDS patients were included in these trials. Additionally, three retrospective studies found that MDS patients treated with these drugs experienced improved survival outcomes compared to patients receiving supportive care or MDS-modifying treatments.

In order to determine which patients will most likely benefit from this treatment, physicians should identify the patient’s transfusion dependence and the level of erythropoietin, a hormone that controls red blood cell production, in the blood. Previous research found that patients with low transfusion dependence and low erythropoietin levels in the blood had a 74 percent chance of response. A statistical model found that these patients should be initially treated with drugs that stimulate red blood cell production.

By contrast, patients with high transfusion needs and high erythropoietin levels had a 7 percent chance of response. According to the same statistical model, these patients should be treated initially with MDS-modifying therapies.

If treatment with red blood cell stimulating agents is unsuccessful, Dr. Sekeres recommended treatment with Revlimid (lenalidomide) for patients with lower-risk MDS, particularly those with abnormalities in chromosome 5.

He pointed to several recent clinical trials to demonstrate the effectiveness of Revlimid in lower-risk MDS patients with abnormalities in chromosome 5.

In a Phase 2 clinical trial, 67 percent of patients treated with Revlimid reached transfusion independence, and the median duration of transfusion independence was 2.2 years.

In a Phase 3 clinical trial, 43 percent to 52 percent of MDS patients achieved and maintained transfusion independence for at least six months, compared to 6 percent of patients treated with supportive care. The three-year risk of progression to acute myeloid leukemia (AML) was 25 percent.

Although Revlimid is only approved for patients with abnormalities in chromosome 5, it is frequently used for patients without this abnormality.

In a Phase 2 clinical trial for patients without the chromosome 5 abnormalities, 26 percent reached transfusion independence, with a median duration of about 0.8 years.

Dr. Sekeres identified the following patient characteristics that predicted transfusion independence after Revlimid treatment: younger age, shorter time since diagnosis, reduced transfusion needs, and treatment-related low platelet counts. He found that patients were significantly more likely to reach transfusion independence if they experienced reductions in platelet counts by at least 50 percent within the first eight weeks of treatment.

Treatment For Other Low Blood Cell Counts

If lower-risk MDS patients experience low platelet counts (thrombocytopenia) that require platelet transfusions or cause bleeding, the available treatment options are limited, according to Dr. Sekeres.

One potential treatment option may be the drug Nplate (romiplostim), a platelet growth factor that is approved for treatment of low platelet levels in patients with chronic immune thrombocytopenia.

Clinical trials are currently being conducted to assess Nplate’s efficacy and safety in MDS.

In a recent Phase 1/2 clinical trial involving lower-risk MDS patients, 46 percent of patients treated with Nplate experienced improved platelet counts. In addition, 93 percent of the trial participants continued weekly injections of the drug in the extension phase of the study. However, Dr. Sekeres cautioned that two patients progressed to AML and four others had increased blast counts after treatment with Nplate.

For patients with low counts of all cell types, Dr. Sekeres recommended considering treatment with anti-thymocyte globulin, Vidaza (azacitidine), or Dacogen (decitabine).

Treatment with anti-thymocyte globulin produces response rates of 30 percent in lower-risk MDS patients. Response rates are higher in patients who are younger and have a shorter duration of transfusion dependence. This treatment also requires inpatient administration of the drug to monitor treatment-related side effects.

Treatment with Vidaza and Dacogen produces response rates comparable to those achieved with Revlimid in patients without abnormalities in chromosome 5. In order to justify treatment with these drugs, which are often accompanied by severe side effects, Dr. Sekeres advised that patients must have severely low cell counts or quality of life.

Treatment With Iron Chelation

According to Dr. Sekeres, consensus guidelines currently support the use of iron chelation therapy for MDS patients with increased transfusion needs or high levels of ferritin, a protein that stores iron, in the blood. Iron chelation drugs remove excess iron that accumulates in the body as a result of frequent blood transfusions. The United States Food and Drug Administration has so far approved the iron chelators oral Exjade (deferasirox) and intravenous Desferal (deferoxamine).

However, Dr. Sekeres cautioned that iron chelation therapy was approved in the United States with limited MDS data, and it has never demonstrated an impact on survival in MDS patients. He advised that iron chelation therapy should be limited to lower-risk patients because in his opinion, higher-risk patients may not live long enough to experience the benefits of treatment.

For more information, please refer to the article in Leukemia (abstract).

Modified Versions Of Ecstasy May Possess Anti-Cancer Activity – Researchers have made modified forms of the illegal drug ecstasy (MDMA) that kill white blood cell cancers 100 times more effectively than ecstasy itself.  Ecstasy has been known to kill cancers involving white blood cells, such as multiple myeloma, leukemia, and lymphoma.  However, the doses of ecstasy necessary to treat cancer would be lethal to the patient.  The new, more potent forms have the potential to be safe at therapeutic doses.  For more information, see the study in the journal Investigational New Drugs (abstract).

Webinar On Making Treatment Decisions In MDS – On September 1, the Aplastic Anemia & MDS International Foundation (AA&MDSIF) is hosting a webinar on making treatment decisions in MDS. Dr. Mikkael Sekeres of the Cleveland Clinic will lead the webinar, which starts at 1 p.m. EST. Dr. Sekeres will first review the diagnostic and prognostic criteria used for MDS and the available treatment options. He will then present a simulated patient journey to discuss his treatment decisions, starting at diagnosis. At the end of the webinar, there will be time for questions. For more information or to register, please see the AA&MDSIF website.

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

They found that having higher platelet counts at the beginning of Revlimid (lenalidomide) treatment and achieving red blood cell transfusion independence for at least 26 weeks were associated with increased overall survival.

Having high transfusion needs at the beginning of treatment and having additional chromosomal abnormalities were associated with an increased risk of progressing to acute myeloid leukemia (AML).

The researchers presented their findings on June 11 at the 2011 congress of the European Hematology Association (EHA) in London.

According to the researchers, most prior studies that have evaluated the prognoses of myelodysplastic syndromes (MDS) patients have focused on untreated patients with all types of MDS. They pointed out that there is little data available on prognostic factors for specific subgroups of patients.

The researchers therefore analyzed data from a previous Phase 2 and a previous Phase 3 trial to identify factors predictive of overall survival and disease progression that are specific to red blood cell transfusion-dependent, lower-risk MDS patients with the chromosomal abnormality deletion 5q who were treated with Revlimid.

Deletion 5q is a chromosomal abnormality in which part of chromosome 5 is missing. Deletion 5q tends to affect more women than men.

Among the 286 patients included in the analysis, the median age was 69 years, 70 percent were female, 73 percent had lower-risk MDS, and 26 percent had other chromosomal abnormalities in addition to deletion 5q.

The patients were treated with one of three dosing schedules: 5 mg Revlimid every day for 28 days, 10 mg Revlimid daily on days 1 through 21 of a 28-day treatment cycle, or 10 mg Revlimid every day for 28 days.

The median follow-up time was 38.4 months in the Phase 2 study and 36.1 months in the Phase 3 study.

The researchers found that patients who achieved red blood cell transfusion independence for at least 26 weeks had a decreased risk of death (64 percent decrease).  Patients who had high platelet counts at the beginning of treatment also had a decreased risk of death (13 percent decrease for each additional 100×10⁹ platelets/L).

The authors indicated that these results are consistent with findings from previous, smaller-scale studies.

On the other hand, patients had a significantly increased risk of death if they had MDS with refractory anemia and excess immature blood cells or chronic myelomonocytic leukemia (63 percent increase), an increasing need for red blood cell transfusions (6 percent increase per unit of blood per eight weeks), or older age (5 percent increase per year.)

Patients who had high red blood cell transfusion needs at the beginning of treatment and those who had other chromosomal abnormalities in addition to deletion 5q had an increased risk of progressing to AML.

For more information, please see abstract 481 at the EHA 2011 meeting website.

The findings were presented during a poster session last Friday at the American Society of Clinical Oncology (ASCO) annual meeting in Chicago.

MDS patients frequently have low red blood cell counts, which can cause symptoms such as fatigue, infection, shortness of breath, pale skin, and chills. As a result, patients frequently receive red blood cell transfusions to replenish their blood with red blood cells. Because transfusion independence is associated with a longer survival time and a higher quality of life, researchers are currently developing treatments to reduce dependence on transfusions.

Revlimid (lenalidomide) is currently approved for patients with myelodysplastic syndromes (MDS) with a deletion in chromosome 5 who are dependent on red blood cell transfusions.

In the current study, researchers evaluated predictive factors for the achievement of transfusion independence at 26 weeks with Revlimid treatment by analyzing data from two previous trials. In these trials, patients had received 5 mg of Revlimid on 28 days, 10 mg of Revlimd on 21 days, or 10 mg of Revlimid on 28 days in 28-day treatment cycles.  The median follow-up times in the two trials were 166 weeks and 156 weeks, respectively.

The researchers found that the most significant predictive factors for the achievement of red blood cell transfusion independence at 26 weeks were higher platelet counts at the beginning of treatment and a higher total Revlimid dose during the first treatment cycle. Higher transfusion burden at the beginning of treatment and chromosomal abnormalities (in addition to the chromosome 5 deletion) had a negative impact on achieving red blood cell transfusion independence.

In addition, they found that the total Revlimid dose during the first treatment cycle was associated with the achievement of a cellular response, which means that the number of cells with chromosomal abnormalities has been reduced.

They also found that patients who achieved a cellular response sustained longer independence from red blood cell transfusions than patients who did not respond to Revlimid.

For more information on the results, please see abstract 6522 on the ASCO Meeting website.