Advances in the Treatment of Myelodysplastic Syndromes

Advances in the Treatment of Myelodysplastic Syndromes: A Report from the 2008 American Society of Hematology MeetingDean Buckner, MD, Medical Editor, Cancer Consultants, Inc


The myelodysplastic syndromes (MDS) are a collection of clonally-derived hematopoietic disorders typified by peripheral blood cytopenias, transfusion-dependency, and in a subset of patients, increased likelihood of transformation to acute myeloid leukemia (AML). There has been significant progress over the past decade in the treatment of patients with MDS. Today, there are an expanding number of treatment options for patients with MDS. These include: 1) growth factors with erythropoietins such as Aranesp® (darbepoetin alfa) and granulocyte-growth factors such as Neulasta® (pegfilgrastim); 2) immunotherapy with ATG, cyclosporine, and steroids; 3) hypomethylating agents such as Dacogen® (decitabine) and Vidaza® (azacitidine); 4) Revlimid® (lenalidomide) for low-risk MDS, red cell transfusion dependence with 5q abnormalities; 5) Gleevec® (imatinib) for cytogenetic translocations involving 5q33; 6) intensive chemotherapy and allogeneic stem cell transplant for younger eligible patients and reduced-intensity transplants for older patients; and 7) oral chelation agents to avoid iron overload. The 2008 meeting of the American Society of Hematology (ASH) was notable for updates on the use of hypomethylating agents, Revlimid, and the introduction of Nplate® (Romiplostim) for the treatment of thrombocytopenia.

Economic Impact of MDS in the US

The estimated incidence of MDS in the US is about 14,650 cases per year. The incidence of MDS is five times higher in patients age 80 years or older compared to patients age 60 to 69 (36.3 versus 7.4 cases/100,000). With a median survival of about three years, the prevalence of MDS would be about 40,000 to 50,000 patients in the U.S. At ASH 2008, researchers from the John Theurer Cancer Center in New Jersey reported that MDS represents a significant US health concern among Medicare patients. These researchers used the Medicare Standard Analytic File 5% (SAF5%) claims database to identify 705 patients with MDS; the patients were followed from 2003 until 2005 or death. Seventy-two percent were 70 years of age or older. Seventy-four percent of patients suffered a cardiac event, 46% received blood transfusions, 43% had diabetes and 51% had dyspnea. Deaths occurred in 39% during the study period with the highest rate in patients with therapy-induced MDS. The median Medicare payment in 2003 was $17,556. The median payment for therapy-induced MDS was $34,271. The median Medicare payments were $11,775 in 2004 and $9,840 for 2005. These authors suggest that chronic anemia contributes to cardiac dysfunction due to iron overload. They suggested that strategies to improve anemia and treatment of iron overload were important for improving outcomes of patients with MDS.

Prognostic Models for MDS

For the past decade the International Prognostic Scoring System (IPSS) has been used to classify newly diagnosed patients with MDS. The IPSS provides an algorithm that classifies patients into low, intermediate 1, intermediate 2 and high risk groups with median survivals of 5.7, 3.5, 1.2 and 0.4 years, respectively (Tables 1 and 2)
Table 1: International Prognostic Scoring System (IPSS) for MDS

* Good, Normal, -Y, del(5q), del(20q); Poor, complex (> 3 abnormalities) or chromosome 7 anomalies; Intermediate, other abnormalities.

  • Definitions of cytopenias: hemoglobin < 10 g/dl, granulocytes < 1.5 x 109/L, platelets < 100 x 109/L
    Table 2: International Prognostic Scoring System Classification

At ASH 2008, researchers from several US institutions proposed a new prognostic model for MDS which includes additional variables and was validated for patients who were not newly diagnosed. This model was developed in 1,915 patients treated between 1993 and 2005. Table 3 summarizes the prognostic factors in this model and the points given for each factor.
Table 3: New Prognostic Model for MDS; Prognostic Factors:

Table 4 shows the outcome of patients by the new prognostic model:
Table 4: Outcome by risk group

This model had predictive ability when categories were further broken down to CMML, MDS with prior therapy, secondary MDS and patients treated on a Dacogen trial. These authors suggest that this model, in contrast to the IPSS which is only applicable to newly diagnosed patients, is applicable to all patients with MDS or CMML regardless of prior history. This model also was predictive in patients receiving Dacogen.

Hypomethylating Agents

Vidaza® (azacitidine) and Dacogen® (decitabine) are hypomethylating agents approved by the US Food and Drug Administration (FDA) for the treatment of patients with MDS. Approval of both agents was based primarily on treatment of better-risk patients but more recent results suggest a significant impact for both agents in higher-risk MDS patients. At ASH 2008, researchers from Germany presented data that suggested a substantial benefit of either Vidaza or Dacogen compared to low-dose cytarabine or best supportive care for higher-risk patients. They compared the outcomes of 40 patients treated with Dacogen or Vidaza with 140 patients receiving low-dose cytarabine or best supportive care. The median survival for patients receiving Dacogen or Vidaza was 28 months compared to 10 months in the control group.

Researchers from the MD Anderson Cancer Center also presented data which documented the superiority of Dacogen or Vidaza compared to conventional chemotherapy in patients with MDS or AML with chromosome 5 and 7 abnormalities. The complete remission rate in patients receiving Dacogen or Vidaza was 41% compared to 35% for patients receiving chemotherapy. The median duration of remission was 45 weeks for patients receiving hypomethylating agents versus 23 weeks for the chemotherapy group.

Vidaza® (Azacitidine)

The randomized controlled trial of Vidaza versus supportive care carried out in 191 patients by researchers affiliated with Cancer and Leukemia Group B led to approval of Vidaza by the US FDA. Responses were reported in 60% of patients receiving Vidaza, with 7% being complete, 16% being partial and 37% “improved”. Only 5% of control patients showed improvement, and the median time to leukemic transformation or death was 21 months in the Vidaza arm versus 13 months in the supportive care arm. This was a crossover study, with approximately 55% of those randomized to supportive care ultimately receiving Vidaza treatment. The crossover group had a 12.8% complete or partial response. A landmark analysis suggested a 7-month improvement in survival for those randomized to receive Vidaza initially. There was also an improvement in quality-of-life parameters in patients receiving Vidaza compared to those receiving supportive care.

At ASH 2008, researchers presented the outcomes of a randomized trial of Vidaza versus conventional care regimens in 358 patients with high risk MDS. This study evaluated the impact of continuing Vidaza until disease progression or unacceptable toxicity. In this study, 51% achieved a complete response, a partial response, or had hematologic improvement. Patients were treated with up to 11 cycles of therapy. This study showed that 40% of responders later achieved an improved response after nine cycles of therapy. This suggests that Vidaza therapy should be continued indefinitely.

Vidaza Maintenance Therapy for MDS and MDS-AML in Remission:

At ASH 2008, researchers from Scandinavia reported outcomes of 23 patients with MDS or MDS transformed to AML who were in complete remission after induction therapy with daunorubicin and cytarabine. Patients in this study received low-dose Vidaza subcutaneously until relapse. The median duration of remission was 13.5 months (2-49+months). Four patients had remission exceeding two years.

Dacogen® (Decitabine)

Dacogen has been shown to be effective treatment for patients with high-risk MDS and chronic myelomonocytic leukemia. Dacogen was approved in 2006 by the US FDA for treatment of MDS. At ASH 2008, researchers affiliated with the EORTC and the German MDS Study Group presented data on a randomized trial of low-dose Dacogen versus supportive care in 233 patients older than age 60 years with MDS or CMML. The results of this trial are shown in Table 5.

Table 5: Low-dose Dacogen versus supportive care for MDS

These data show that Dacogen is safe and effective in elderly patients with MDS.

At ASH 2008, researchers from the M. D. Anderson Cancer Center reported that the addition of valproic acid to Dacogen did not improve the outcomes of patients with MDS and AML compared to Dacogen alone. Valproic acid is a histone deacetylase inhibitor which has little activity as a single agent, and the combination of Vidaza, valproic acid and ATRA has been previously reported to be effective treatment for patients with AML and MDS. The complete response rate in this study was 34% and there was no improvement with added valproic acid. The median survival was 14.9 months for all patients with MDS with no difference between Dacogen alone or Dacogen plus valproic acid.

Revlimid® (Lenalidomide)

Revlimid is an immunomodulatory drug that is a derivative of thalidomide with fewer associated toxicities. Revlimid has anti-angiogeneic properties as well as numerous possible immune and biologic properties. Revlimid is approved by the FDA for the treatment of both MDS and multiple myeloma. Results from a multi-center Phase II study indicate that Revlimid is highly effective in the treatment of transfusion-dependent MDS associated with chromosome 5q31 deletion (the most common cytogenetic abnormality in transfusion-dependent MDS). At ASH 2008, researchers presented the results of a Phase I study combing Revlimid with Vidaza in patients with high-risk MDS. This study established the optimal dose of Vidaza at 75 mg/m2 sc on days 1-5 and Revlimid at 10 mg orally on days 21 of each cycle of therapy. There are also plans for evaluating sequential treatment. This study also suggested higher activity for the combination than for single agent therapy.

Clolar® (Clofarabine)

Clolar® is a purine nucleoside antimetabolite that is in Phase II testing for acute leukemia. It is approved by the US FDA for the treatment of pediatric patients with acute lymphoblastic leukemia (ALL) who have failed at least two prior treatment regimens. Clolar also has orphan drug status for other uses. Recent studies have focused on evaluating it as a less toxic drug for remission induction in elderly patients with AML. Previous studies from the M.D. Anderson Cancer Center showed that the combination of Clolar plus low-dose cytarabine was more effective than Clolar alone for the treatment of patients 50 years of age or older with AML. At ASH 2008, researchers from the M. D. Anderson Cancer Center treated 60 patients with high-risk MDS with oral or intravenous Clolar. Patients were treated at two different dose levels for both the oral and the intravenous route. The complete response rate was 25-35%, the CR rate without platelet recovery was 8-15%. Responses were observed at lower dose levels. Six patients died on study of infectious complications and all had received IV Clolar. These authors suggested that Clolar had significant activity in MDS but that the optimal dose and route of administration remained undetermined.

The Use of Growth Factors

Aranesp® (darbepoetin) has become standard therapy for patients with anemia associated with MDS. For maximum effectiveness Neupogen® (filgrastim) or Neulasta® (pegfilgrastim) is often added to Aranesp initially or subsequently.

Researchers from France have previously reported that Aranesp produces an erythroid response in approximately 70% of patients with lower-risk MDS. This study, performed by the Groupe Francais des Myelodysplasies (GFM), involved the treatment of 62 anemic patients with “low-risk” MDS. All patients had endogenous EPO levels less than 500 mU/ml, and were low and intermediate-1 risk by IPSS. Neupogen (filgrastim) 150 mcg TIW was added after four months, for another four months, if no response to Aranesp was observed. Overall, 44 of 62 patients (71%) had an erythroid response, which was major in 34 patients and minor in 10 patients. Eight of 13 patients who had previously failed epoetin alfa responded to Aranesp. Two of 10 patients responded after the addition of Neupogen. After a median of 40 weeks 36 of 46 total responders continued to respond to Aranesp.

Several Italian studies have also shown that Aranesp is effective for treating anemia associated with MDS. One study evaluated a single weekly dose of Aranesp for at least 12 weeks in 37 patients with low- or intermediate-risk MDS. Thirteen patients achieved a major rise in hemoglobin and two had minor improvements. Thirteen responders are continuing treatment for 7-22 months. The investigators did not observe any adverse side effects. They also reported that patients with a low level of endogenous erythropoietin were more likely to respond, as were patients with no blasts in the bone marrow and/or with cellular bone marrow. These authors concluded that Aranesp was effective in a significant proportion of patients with MDS. In another study, researchers demonstrated that Aranesp was as effective as Procrit® (epoetin alfa) for the treatment of patients with low- and intermediate-risk MDS. This study included 53 patients who received treatment for approximately six months. They observed a correction of anemia in 45% of patients. At a follow-up of 9.4 months, 17 patients have maintained their responses. There were no relevant side effects associated with Aranesp. They also reported that increases in red blood cells were associated with an improved quality of life.

Researchers affiliated with the Nordic Myelodysplastic Syndrome Group have reported that approximately 40% of patients with MDS treated with Procrit® and Neupogen have partial or complete correction of anemia without an increase in the incidence of leukemic transformation or a decrease in survival.

At ASH 2008, researchers from Spain have reported that Aranesp with or without Neupogen is effective treatment for anemia associated with low and intermediate-1 risk MDS. Patients received Neupogen at eight weeks if there was no response to Aranesp alone. Seventy-three percent of patients in this study were transfusion independent and the median hemoglobin level was 9.2 g/dL. Approximately 70% of patients who were transfusion dependent or transfusion independent had a major hemoglobin response. The only predictive factor for response was the serum erythropoietin level.

Platelet Stimulating Agents

Nplate® (Romiplostim)

Researchers involved in a US multicenter trial reported that the combination of Nplate® (romiplostim) and Vidaza® (azacitidine) is effective and well tolerated in patients with low- and intermediate-risk MDS. Nplate is the first thrombopoietin receptor agonist approved by the US FDA for treatment of immune thrombocytopenic purpura (ITP). A member of the TPO mimetic class, Nplate is an Fc-peptide fusion protein (peptibody) that activates intracellular transcriptional pathways leading to increased platelet production via the TPO receptor (also known as cMpl). The peptide portion of Nplate has no amino acid sequence homology to endogenous TPO, mitigating the risk for development of anti-Nplate antibodies that cross-react with endogenous TPO. Nplate is approved for the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura (ITP) who have had an insufficient response to corticosteroids, immunoglobulins or splenectomy. Nplate should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increases the risk for bleeding. Nplate should not be used in an attempt to normalize platelet counts.

The study presented at ASH 2008 included 40 patients with low- or intermediate-risk MDS with thrombocytopenia who were randomly allocated to one of three groups:

  • Vidaza plus placebo (n=13)
  • Vidaza plus Nplate at 500 micrograms (n=13)
  • Vidaza plus Nplate at 750 micrograms (n=14)

The platelet nadir was 14,000 for the placebo group compared to 33,000 and 32,000 for the two groups treated with Nplate, respectively. Patients receiving Nplate had fewer episodes of significant bleeding and received fewer platelet transfusions. There were two deaths in the placebo group and none in the Nplate groups. These authors concluded that Nplate reduced the incidence of clinically significant thrombocytopenic events and platelet transfusions, and improved platelet nadirs

Oral Iron Chelation

Parenteral chelation with desferoximine is effective therapy for iron overload due to transfusions. However, the logistics and compliance with parenteral chelation has led to the development of Exjade® (deferasirox), an oral chelating agent. Exjade has a long half-life and is given once daily. Exjade is approved by the US FDA for the treatment of iron overload. The longest follow-up for patients treated with Exjade is approximately four years. At ASH 2008, researchers from the US affiliated with the USO3 trial reported that Exjade was well tolerated in patients with MDS with iron overload. This trial currently included 176 patients with low- or intermediate-risk MDS with iron overload defined as serum ferritin >1000 microg/kg/L who had received >20 transfusions. Over 12 months the median dose of Exjade was 21 mg/kg/day and the mean transfusion rate was 3.4 units per month. The following changes in serum ferritin levels were observed:

  • Baseline Ferritin = 3397
  • 3 Month Ferritin = 3057
  • 6 Month Ferritin = 2802
  • 12 Month Ferritin = 2635

Patients with elevated labile plasma iron had stabilization by three months. The discontinuation rate was 13% with the most common side effects being diarrhea and rash. These patients will be followed for evaluation of long-term toxicities.

Researchers affiliated with the EPIC trial reported that Exjade provided significant reduction in serum ferritin levels over one year of therapy. There were 341 patients in this study who were treated for at least one year. The following changes in serum ferritin levels were observed:

  • Baseline Ferritin = 2729
  • 3 Month Ferritin = 2358
  • 6 Month Ferritin = 2209
  • 9 Month Ferritin = 2076
  • 12 Month Ferritin = 1903

The discontinuation rate in this study was 49% including 8% who died. Only 25 patients discontinued for drug-related toxicities. These authors are still evaluating the reasons for this high discontinuation rate.

Allogeneic Stem Cell Transplantation

The only known cure for patients with MDS is allogeneic stem cell transplants. The results of allogeneic stem cell transplants using myelo-ablative regimens depend on the age of the patient and stage of the disease at the time of transplant. Transplant-related mortality increases with age and relapses increase with advanced stage of MDS. Transplant-related mortality is also related to the intensity of the regimen used to eradicate the disease and the immune system. Over the past several years researchers have developed engraftment strategies that are associated with less toxicity. The primary focus has been to administer more immunosuppressive therapy with reduced-intensity transplant regimens. The idea is to establish the graft and allow the graft-versus leukemia effect to eradicate disease.

Researchers from Italy reported that the combination of thiotepa and fludarabine was an effective reduced-intensity transplant regimen for patients with MDS and MDS-AML in complete remission. There were 50 patients in this study and the median age was 54 years with the oldest patient being 71 years old. Sixteen patients had low/intermediate-1 score, 16 had intermediate-2/high IPSS and 18 had MDS-AML. The overall five-year survival of this group of patients was 50%. Failures were equally caused by relapse and transplant-related mortality. The five-year survival was 73% and 28%, respectively, for low- and high-risk patients. These authors concluded that thiotepa and fludarabine was effective and well tolerated in patients who were not candidates for myeloablative transplant regimens.

Researchers from Germany reported outcomes of 172 patients with AML and MDS with adverse cytogenetics receiving a reduced-intensity transplant regimen. Seventeen of these patients had MDS treated with chemotherapy followed by an up-front allogeneic stem cell transplant. The overall survival of this group was 80% compared to 28% for patients who received a transplant after transformation to AML. These authors suggested that allogeneic stem cell transplant should be performed before transformation to AML.

Researchers from the M. D. Anderson Cancer Center reported the outcomes of 89 patients with MDS receiving busulfan based transplant regimens. These regimens are categorized as myeloblative but less toxic than previous regimens. The median age was 54 years with the oldest patient being 67 years of age. Overall survival was 80% for patients with intermediate or low risk MDS versus 28% for those with categorized as high or very high risk. These researchers concluded that cytogenetics and prognostic scores based on cytogenetics predict outcomes in this study.

Researchers from the M. D. Anderson Cancer Center also reported that allogeneic stem cell transplantation of patients with AML and high-risk MDS in complete remission was more effective than continued chemotherapy. Using a case-control method these authors reported that relapse-free survival was over 50% for patients transplanted in first complete remission compared to 25% for patients receiving continued chemotherapy.

Effects of Age on Outcome of Allogeneic Stem Cell Transplants

Myelodysplastic syndromes occur predominantly in older individuals. For allogeneic stem cell transplantation to have a major impact on MDS the procedure must be applicable to older patients. Reduced-intensity allogeneic stem cell transplants have offered a way to extend this technique to older individuals.

At ASH 2008, researchers affiliated the Center for International Blood and Marrow Transplant Research (CIBMTR) reported outcomes of 565 patients with AML and 551 patients with MDS who had received reduced-intensity allogeneic stem cell transplants. The patients were divided into four groups by age: 40-54, 55-59, 60-64, and 65 and older. These researchers evaluated transplant-related mortality, engraftment, incidence of acute and chronic graft-versus-host disease, leukemia-free survival, and overall survival in each group.

The results of the analysis indicated that across all age groups there was no statistically significant difference in transplant-related mortality (TRM), acute or chronic graft-versus-host disease, relapse (Rel) rates, leukemia-free survival (LFS), or overall survival (OS). Table 6 summarizes the main findings in patients with MDS:

Table 6: Results of Reduced-Intensity Allogeneic Stem Cell Transplants in Patients with MDS.

These researchers concluded that outcomes for older individuals undergoing allogeneic stem cell transplantation for AML or MDS were not significantly different from those for younger patients, regardless of risk factors. They suggest that age alone should not be the limiting factor for allogeneic stem cell transplantation in older individuals with AML or MDS.

Vidaza Maintenance after Allogeneic Stem Cell Transplantation

Researchers from the M. D. Anderson Cancer Center have reported that Vidaza is safe and effective maintenance therapy for patients with relapsed or refractory AML or MDS who have received an allogeneic stem cell transplant. Patients receiving reduced-intensity transplants for refractory AML and MDS have a high rate of relapse or remission failure. This study was carried out to determine the dose and schedule of post-transplant Vidaza that was safe and would possibly prevent relapses in high-risk patients with MDS or AML who had successful engraftment. 40 patients in this study were in complete remission on day 30 after allogeneic stem cell transplant. Ten patients have relapsed so far. These researchers will now perform a randomized trial to determine if Vidaza maintenance is effective in preventing relapses after allogeneic stem cell transplantation.

Post-Transplant Immunotherapy

Researchers from the Dana Farber Cancer Center have reported that GVAX, a cancer vaccine composed of autologous leukemia cells genetically modified to secrete granulocyte macrophage-colony stimulating factor (GM-CSF), may have anti-leukemic effects when administered after a reduced-intensity allogeneic stem cell transplant in patients with advanced myeloid malignancies. GVAX is an investigative vaccine that utilizes a technology platform in which non patient-specific or patient-specific whole tumor cells are lethally irradiated, and genetically modified to secrete GM-CSF. GVAX is administered intradermally on an outpatient basis and is intended to be marketed for “off the shelf” pharmaceutical use. GVAX is currently in ongoing clinical trials evaluating its efficacy in various types of cancers including prostate cancer and chronic myeloid leukemia (see related news).

In the current study patient-specific leukemia cells were used to make the vaccine. Vaccine was successfully made in 24 patients in this study. Sixteen patients had AML, six had MDS and one had CML in blast crisis. Fifteen of these patients underwent reduced-intensity allogeneic stem cell transplantation and 10 completed all six vaccinations. Relapse-free and overall survival for these 15 patients was 45% and 56%, respectively, at two years. Matched control patients without vaccination with GVAX had a two-year relapse-free survival of 12% and an overall survival of 16%. Nine of the 10 patients who received all six post-transplant vaccinations remain alive and in remission with a median follow-up of 23 months. These authors suggested that GVAX had significant anti-leukemic effects. These are very interesting data which strongly suggest activity for GVAX as post-transplant immunotherapy in patients with myeloid malignancies.

Umbilical Cord Blood Transplantation for MDS in Children

Researchers affiliated with the European Working Group of MDS in Childhood, the Center for International Blood and Marrow Transplant Research and the Eurocord-European Blood and Marrow Transplant Group reported that umbilical cord blood transplantation is an acceptable alternative in children with MDS without a related or unrelated source of stem cells. There were 70 children in this study with a variety of types of MDS. The three-year probability of survival for all patients was 39% but this increased to 50% in patients transplanted after 2001. Adverse risk factors included transplantation before 2001, cytogenetic abnormalities other than monosomy 7. Patients with monosomy 7 had a disease-free survival of 61%.


There appears to be continued progress in the treatment of patients with MDS. One of the most important new studies was the demonstration that Nplate improved platelet counts in patients being treated with Vidaza. The documentation that both Vidaza and Dacogen are effective long-term therapies for MDS was encouraging. Another important advance was the demonstration that the oral chelating agent, Exjade, was effective in patients with MDS is very important since another study presented at ASH 2008 demonstrated that iron overload causes significant morbidity and mortality in MDS patients. Finally, there appears to be continued improvement in allogeneic stem cell transplants for the treatment of MDS. The donor problem appears to predominantly be solved with improvements in finding unrelated donors and in the use of cord blood as a source of stem cells. Reduced-intensity treatment regimens have also allowed this technique to be extended to older patients with significant co-morbidities. However, several studies again demonstrated the importance of transplanting patients with MDS early in the disease course for optimal effects.


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