Myelodysplastic Syndrome: An Update from ASCO 2007

Myelodysplastic Syndrome: An Update from ASCO 2007

Introduction

Ten years ago there was very little to offer patients with a diagnosis of myelodysplastic syndrome (MDS) outside the context of observation, supportive care, and transfusions. Today, we have an expanding armentarium of treatment options for MDS. These include: 1) growth factors with erythropoietins (darbepoetin alfa and epoetin alfa) and G-CSF (filgrastim and pegfilgrastim); 2) immunotherapy with ATG, cyclosporine, and steroids; 3) hypomethylating agents like decitabine or azacitidine; 4) lenalidomide for low-risk MDS, red cell transfusion dependence with 5q abnormalities; 5) imatinib for cytogenetic translocations involving 5q33; 6) intensive chemotherapy and allogeneic stem cell transplant for younger eligible patients; and 7) oral chelation agents to avoid iron overload. The 2006 meeting of the American Society of Hematology (ASH) was notable for updates on the use of growth factors in MDS, lenalidomide in low-risk MDS with or without 5q abnormalities, and on the role of hypomethylating agents in MDS.

At the 2007 American Society of Clinical Oncology (ASCO) meeting there were several interesting studies reported concerning supportive care issues in MDS, hypomethylating agents, growth factors, iron overload and prognostic factors.

Thrombocytopenia in MDS

Thrombocytopenia is a serious complication of MDS, resulting in severe bleeding events in 15% to 40% of patients and in hemorrhagic deaths in 10% to 25% of patients. A Phase I study of AMG531 in patients with low-risk MDS and life threatening thrombocytopenia was reported at ASCO.[1] AMG531 is a thrombomimetic agent which has shown activity in immune-mediated thrombocytopenia (ITP) with improvements in platelet counts in 50% to 80% of patients.[2] In this Phase I study, 28 patients have so far been treated. AMG531 was given subcutaneously weekly with a starting dose of 300mcg and dose escalations to 700, 1000, and 1500. Seventeen patients continue on treatment. Dose-limiting toxicity was, as expected, thrombocytosis more than 600 x 109/L in two cases. Seventeen patients (60%) achieved a platelet response. The median platelet count in responders increased from a baseline of 25 to 130 x 109/L. Among 18 patients completing 12 weeks of treatment, 11 (48%) achieved durable platelet responses of at least two months (by IWG criteria). This study suggests a potential role of AMG531 and other thrombomimetic agents in the treatment of life-threatening thrombocytopenia in MDS, and perhaps in other hematological malignancies.

Hypomethylating Agents in MDS

Two studies of interest were reported at ASCO 20007 concerning hypomethylating agents in MDS. The first study by Lyons et al evaluated 3 different schedules of azacitidine in MDS:

  1. The classical schedule of azacitidine, 75 mg/m2 subcutaneously (SQ) daily x 7 (5 on 2 off 2 on);

  2. Azacitidine 50 mg/m2 SQ daily x 10 (5 on 2 off 5 on); and

  3. Azacitidine 75 mg/m2 SQ daily x 5.

    [The overall response rate was similar with the three schedules.]

The authors concluded that, with the current follow up, the three dose schedules of azacitidine appear safe and demonstrate similar efficacy.[3]

The second study reported on an oral dosage formulation of azacitidine. This study by Ward et al evaluated the absorption of oral azacitidine in dogs, demonstrating rapid absorption and an absolute bioavailability of 67% compared to 71% following subcutaneous dosing. At the ASCO meeting, the investigators presented preliminary data with single daily dose oral azacitidine given in a Phase I study (1 individual at each dose level) demonstrating good oral absorption and adequate levels. These data need to be confirmed in larger studies, to show consistent reasonable absorption at therapeutic dosages similar to what can be delivered in SQ schedules with acceptable toxicity and similar efficacy. This will then offer patients with MDS an important alternative and easier route of treatment delivery.[4]

Growth Factors in MDS

Recent studies of erythropoietin (EPO) in patients with solid tumors have suggested an unfavorable outcome with worse mortality (reviewed by F. Khouri).[5] This may not be the case in hematologic malignancies like AML or MDS, where studies so far have shown that EPO (darbepoetin alfa and epoetin alfa) has been associated with responses rates of 40 – 60%, which were durable for a median of 2-2.5 years, and were associated with decreased transfusion requirements and better quality of life.[6],[7] Studies have also demonstrated that increased red cell transfusion needs in MDS and iron overload are independently associated with worse survival, as well as with increased mortality, due to organ failures from iron overload.

A recent study using historical comparisons suggested that using EPO in low-risk MDS with low transfusion requirement (less than 2 units per month) was associated with improved survival.8 At this ASCO meeting, two studies by Gabrilove, et al. and Moyo, et al. updated the results of EPO therapy in MDS with anemia, again confirming the beneficial effect.[8],[9] In the study of Moyo et al, a review of the existing literature from 1990-2006 identified 39 studies of which 19 were selected for a meta-analysis based on availability of response data. The authors reported that comparable erythroid response rates were noted when using EPO alone or EPO plus filgrastim (response rate 49% versus 51%), but that higher EPO dose schedules were associated with higher response rates than standard EPO dose schedules (p < 0.001). The authors concluded that increasing EPO dose may have a greater impact on erythroid response than the addition of G/GM-CSF.

Prognostic Factors in MDS

Several studies of prognostic factors in MDS reported at ASCO 2007 were of interest. Shan et al evaluated 898 patients with low or intermediate-1 risk disease by IPSS referred to MD Anderson Cancer Center from 1976 to 2005. The aim of this study was to identify within this MDS group, usually considered to have a benign course, factors that identify poor prognosis and mandate treatment intervention rather than observation. They identified by multivariate analysis several characteristics associated with worse survival (low platelets, anemia, older age, increased percent of marrow blasts, and poor risk cytogenetics > 3 abnormalities). They could divide patients into 3 categories: 1) 22% favorable with a median survival of 69 months; 2) 40% intermediate with a median survival of 25 months; and 3) 38% unfavorable with a median survival of 17 months. The latter two categories of patients, referred to tertiary cancer centers because of clinical reasons of deterioration while remaining in IPSS favorable low or intermediate-1 risk disease, would be candidates for investigational therapeutic interventions.[10]

Kuddus et al reported their experience in 1,424 patients with MDS. Their median survival was 2.9 years. Median survival by IPSS was: low-risk 7.5 years; intermediate-1 risk 3.6 years; intermediate-2 or high risk, 1.2 and 1.1 years, respectively. The percent of marrow blasts was also very important. The median survival was 5.3 years for blasts < 5 % versus 1.7 years for blasts 5-10%. Interestingly, the median survival with blasts 11-20% or more than 20% was not that different, 1.2 and 1.3 years, respectively. Patients with cytopenias involving 0, 1, 2, or 3 lineages had respective median survivals of 6.4, 4.4, 2.6, and 1.8 years (p < 0.0001). Complex karyotypes (3 or more abnormalities) had a median survival of 0.8 years. This study confirms many of the literature findings.[11]

In a separate study from the same institution, Galili investigated the significance of thrombocytopenia in patients with chromosome 5 abnormalities. A review of 189 patients with deletion 5q were included. Seventy patients had isolated 5q abnormality and 119 had additional abnormalities. The median survival was significantly better if isolated deletion 5q was noted (median survivals 2.45 versus 0.63 years for complex abnormalities; p=0.001). Taking the median platelet cut-off of 115 x 109/L, the investigators demonstrated that survival was significantly worse with lower versus higher platelets (median survivals 0.54 versus 2.6 years; p=0.0001). Patients with low-risk MDS and deletion 5q who had low platelet counts had a poor survival (median 0.84 years). Those with deletion 5q and < 5% blasts also had a poor survival (median 0.68 years). Isolated deletion 5q and low platelets also had a short median survival of 0.74 years. These poor risk groups may benefit from lenalidomide therapy, although the studies with lenalidomide have all been conducted in patients with platelets > 50 x 109/L. Thus, we should be cautious about extrapolating the favorable results of lenalidomide in low-risk MDS with deletion 5q to patients who start with low platelet counts. This should be a subject of a separate prospective trial.[12]

MDS Patients with Low-Risk, Chromosome 5 Abnormalities

The results of lenalidomide in patients with low-risk MDS and chromosome 5 abnormalities (erythroid response rate 66%, complete cytogenetic response rate 44%, median response duration two years) encouraged its use in MDS. To clarify the outcome of MDS and chromosome 5q abnormality, Holtan et al reviewed the Mayo clinic experience in 175 consecutive patients with a diagnosis of MDS and 5q 31 deletions (1996-2005) referred to their institution. Their median age was 73 years. A true 5q syndrome was identified of the 38 cases, 5q deletion was present as the sole abnormality in 30%, with one other abnormality in 10%, and part of a complex karyotype in 59%. The median survival from referral to Mayo Clinic was surprisingly very low, 7.2 months. Patients with 5q syndrome had a median survival of 1.8 years (p = 0.001). Patients with noncomplex cytogenetics had a median survival of 1.44 years versus 0.41 years for others (p < 0.001). Worse survival was observed in patients with prior chemotherapy. The authors concluded that the classic 5q syndrome, as defined by WHO, is present in only a minority of patients with MDS and 5q deletions. The surprising short survival is likely due to a referral bias, although it could also be an indication of a less benign course than previously reported.[13]

Summary

The study of AMG531 may herald new developments in second generation TPO like agents which may lead to success analogous to EPO and G-CSF. Studies presented at ASCO 2007 also confirmed the effectiveness of EPO in low to intermediate risk patients with MDS. The effectives of lenalidomide, decitabine and azacitidine for treatment of MDS were also confirmed and the development of an oral azacitidine is of interest. Thus, there appears to be continued progress in the development of new therapies for patients with MDS.

References:

[1] Kantarjian HM, Giles FJ, Fenaux P, et al. The AMG 531 in Myelodysplastic Syndrome Study Group. Evaluating safety and efficacy of AMG 531 for the treatment of thrombocytopenic patients with myelodysplastic syndrome (MDS): Preliminary results of a phase 1/2 study. Proceeding from the American Society of Clinical Oncology Conference. Chicago, IL. 2007. Abstract # 7032.

[2] Bussel JB, Kuter DJ, Phil D, et al. AMG 531, a Thrombopoiesis-Stimulating Protein, for Chronic ITP. New England Journal of Medicine 2006; 355:1672-1681.

[3] Lyons RM, Cosgriff T, Modi S, McIntyre H, Beach CL, Backstrom JT. Tolerability and hematologic improvement assessed using three alternative dosing schedules of azacitidine in patients with myelodysplastic syndromes. Proceeding from the American Society of Clinical Oncology Conference. Chicago, IL. 2007. Abstract # 7083.

[4] Ward MR, Stoltz ML, Etter JB, Patton LM, Garcia-Manero G, Sharma S. An oral dosage formulation of azacitidine: A pilot pharmacokinetic study. Proceeding from the American Society of Clinical Oncology Conference. Chicago, IL. 2007. Abstract # 7084.

[5] Khuri FR. Weighing the hazards of erythropoiesis stimulation in patients with cancer. New England Journal of Medicine. 2007; 356:2445-2448.

[6] Mundle S, Lefebvre P, Duh M, Bourezak A, Yektashenas B, and Moyo V. Erythroid response (ER) rates in myelodysplastic syndromes (MDS) patients treated with epoetin alfa (EPO) or darbepoetin alfa (DARB) using International Working Group Response Criteria (IWGc): Comparative meta-analysis. Proceedings from the The American Society of Hematology

Annual Conference. 2006. Orlando, FL. Abstract # 2672.

[7] Jädersten M, Malcovati L, Dybedal I, Della Porta M, Invernizzi R, Montgomery S, Pascutto C, Porwit-MacDonald A, Cazzola M, and Hellström-Lindberg E. Treatment with erythropoietin and G-CSF improves survival in MDS patients with low transfusion need. Proceedings from the The American Society of Hematology Annual Conference. 2006. Orlando, FL. Abstract # 521.

[8] Gabrilove J, Paquette R, Lyons R, Mushtaq C, Sekeres M, Tomita D, Lillie T. Baseline predictors of response to treatment with darbepoetin-alpha (DA) in anemic patients with low-risk myelodysplastic syndrome (MDS). Proceeding from the American Society of Clinical Oncology Conference. Chicago, IL. 2007. Abstract # 7081.

[9] Moyo VM, Lefebvre P, Duh M, Yektashenas B, Mundle S. Treating the anemia of MDS with erythropoietin: Impact of higher dose compared to combination with G/GM-CSF. Proceeding from the American Society of Clinical Oncology Conference. Chicago, IL. 2007. Abstract # 7082.

[10] Sugarbaker D, Richards WG, Alsup CA, Jaklitsch MT, Corson JM, Godleski JJ, Chirieac LR, Bueno R, Zellos L. Impact of pathological staging on survival in patients with epithelial mesothelioma treated with extrapleural pneumonectomy. Proceeding from the American Society of Clinical Oncology Conference. Chicago, IL. 2007. Abstract # 7706.

[11] Quddus F, Ahmed A, Naqvi S, Hasan K, Mumtaz M, Galili N, Raza A. Validation of IPSS criteria in more than 1,600 MDS patients. Proceeding from the American Society of Clinical Oncology Conference. Chicago, IL. 2007. Abstract # 7079.

[12] Galili N, Ahmed A, Quddus F, Jandani S, Gul Z, Siddiqui A, Mumtaz M, Mehdi M, Devuni D, Raza A. Prognostic value of low platelets in MDS patients with del(5q). Proceeding from the American Society of Clinical Oncology Conference. Chicago, IL. 2007. Abstract # 7078.

[13] Holtan SG, Santana-Davila R, Dewald G, Ketterling R, Tefferi A, Steensma DP. Natural history of patients with myelodysplastic syndromes (MDS) with interstitial deletions of chromosome 5q detected on G-banded karyotyping. Proceeding from the American Society of Clinical Oncology Conference. Chicago, IL. 2007. Abstract # 7078.

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