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).1,2 This past decade has brought increased attention to MDS with the approval by the U.S. Food and Drug Administration of three MDS therapies, and a more complete understanding of these diseases on a molecular level. This year at the American Society of Hematology (ASH) 2007 annual meeting, presentations focused on the implications and management of MDS- and treatment-related cytopenias; results of clinical trials of hypomethylating agents, including the first prospectively-acquired survival data; and extension of the potential applicability of immunomodulatory drugs.
Cytopenias – The Double-Edged Sword
Cytopenias are a sine qua non of MDS. They result from ineffective hematopoeisis deriving from the dysplastic cells themselves; from premature apoptosis in normal stem cells resulting from the effects of pro-inflammatory cytokines produced by the dysplastic cells; from excessive proliferation of immature myeloblasts in a confined compartment; or a combination of the three. Though anemia is the most common cytopenia, any cell line can be affected, depending on where the dysplasia is predominating. One approach to treating MDS is to maximize production of the remaining intact hematopoietic elements through stimulation with growth factors.
An international, multicenter Phase I/II study led by Kantarjian followed a dose-escalation strategy of administering the novel thrombopoiesis-stimulating peptibody romiplostim (AMG 531) to low-risk (International Prognostic Scoring System [IPSS} score <1.0) MDS patients with thrombocytopenia.3 Patients with a mean baseline platelet count of 50,000/L or lower were enrolled in sequential cohorts of 300, 700, 1000, and 1500µg weekly, and after four weeks of therapy entered an extension phase to the study. Of 44 patients enrolled on the study, 41 entered the treatment extension, and 35 of these completed >4 weeks of treatment extension. Response was assessed using 2006 International Working Group criteria, and had to be maintained for 8 weeks or greater. The median age of patients was 74 years, with a median baseline platelet count of 25,700/L. Treatment-related adverse events included mild-moderate headache, dizziness, and flu-like illness; serious osteonecrosis, febrile neutropenia, and thrombocytopenia (one patient each); and transient increase in blast percentage in 6 patients (resolving after cessation of romiplostim therapy), with transformation to frank AML occurring in 1 patient. Of the 35 patients on therapy for 12 weeks or more, 19 (54%) achieved a hematologic improvement along platelet lines, with equal percentages achieving this mark among those with baseline platelet counts < or > 20,000/L. The median time to response was 3 weeks, and median response duration was 19 weeks. Not surprisingly, achievement of a platelet response was associated with fewer transfusions and bleeding events.
Cytopenias often result from the MDS treatment itself. It has long been hypothesized that, similar to successful therapies for AML, some degree of treatment-related bone marrow aplasia may be requisite for demonstration of activity. The Cleveland group, in collaboration with others, analyzed data from the two Phase II studies of lenalidomide in low-risk MDS (MDS-003, in transfusion-dependent low-risk MDS patients with the del(5q) abnormality, and MDS-002, in transfusion-dependent low-risk MDS patients without the del(5q) abnormality),4,5 to determine whether lenalidomide-induced cytopenias predicted red blood cell transfusion independence response.6 Focusing first on the MDS-002 study in del(5q) patients, treatment-related cytopenias were given functional definitions, with treatment-related neutropenia defined as a >75% decline in absolute neutrophil count (ANC), and treatment-related thrombocytopenia as a >50% decline in platelet count, both during the first 8 weeks of therapy. The investigators found that patients experiencing treatment-related thrombocytopenia, regardless of baseline platelet counts, were more likely to achieve red blood cell transfusion independence (75% vs. 47% for those without baseline thrombocytopenia, and 58% vs. 33% for those with baseline thrombocytopenia, p<0.01). For those without baseline neutropenia, those with treatment-related neutropenia were more likely to respond to therapy (82% vs. 51%, p=0.02), though for those with baseline neutropenia, treatment-related neutropenia was not predictive of red blood cell transfusion independence (p=0.79). Results were similar in multivariate analyses, and treatment-related cytopenias correlated with cytogenetic responses. In the MDS-002 study, for patients without the del(5q) abnormality, however, neither treatment-related thrombocytopenia, nor neutropenia, correlated with red blood cell transfusion independence response (p=0.3 and 0.3, respectively). The authors concluded that these findings support a direct cytotoxic effect of lenalidomide on the del (5q) clone that may be obligate for transfusion independence response, and that the mechanism leading to response in non-del (5q) MDS patients may be due to the drug's effects on the bone marrow microenvironment.
Hypomethylating Agents – Living the Good Life
One of the more anticipated MDS presentations at ASH 2007 was the Phase III study of patients randomized to azacitidine (AZA) or conventional care regimens (CCR) by Fenaux and colleagues (AZA-001).7 A total of 358 higher-risk MDS patients (IPSS Int-2 or High, or those with French-American-British [FAB] classifications of refractory anemia with excess blasts (RAEB), RAEB in transformation, or chronic myelomonocytic leukemia with 10-29% blasts) were enrolled and received either AZA (n=179, 75mg/m2 daily x 7 days repeated every 28 days) or CCR (n=179), which included low-dose cytarabine (n=49, 20mg/m2 daily x 14 days, repeated every 28 days), standard AML-style remission induction therapy with cytarabine and an anthracycline (n=25), or best supportive care(n=105). The median age of patients was 69 years, and they received a median of 9 cycles of AZA and 4.5 cycles of low-dose cytarabine; approximately one-third (34%) had RAEB-t (considered AML by the World Health Organization classification system). At a median follow-up of 21 months, patients randomized to AZA had a significantly prolonged overall survival (24.4 months vs. 15 months, p=0.0001) and two-year survival (
50.8% vs. 26.2%, p<0.0001) compared to CCR. The median time to AML transformation or death was 13 months vs. 7.6 months for CCR, and the complete + partial remission rate was 29% for AZA vs. 12% for CCR, with higher CR rates for patients treated with intensive chemotherapy (40%) and low-dose cytarabine (12%). Interestingly, when overall survival was compared for AZA vs each of the CCR arms individually, it was only significantly different when compared to best supportive care, though the study probably was not powered to find differences between AZA and individual CCR subgroups. Also of note was the survival advantage in patients with abnormalities in chromosome 7, which may have a predilection for responsiveness to hypomethylating agents. This was the first study to demonstrate a survival advantage prospectively in MDS patients treated with a non-transplant approach.
One challenge to administering both FDA-approved hypomethylating agents is in keeping to the approved schedule, which for decitabine (DAC) necessitates hospitalization every 6 weeks, and for AZA requires weekend administration.8,9 Two presentations focused on alternative dosing strategies for these agents. The first, by Kantarjian and colleagues, updates previously published data in which patients were randomized (using an adaptive or Bayesian approach) to receive DAC with one of three dosing schemes, including 20mg/m2 intravenously daily for 5 days, repeated every 28 days.8,10,11 Of 93 patients enrolled on this schedule, 39 were not categorized by the IPSS due to secondary disease, and 74% of the remaining patients had higher-risk disease. The median age was 65 years, and median duration of MDS was 2.5 months at the time of study entry, though more than half of patients (56%) had received prior therapy, the majority of which was growth factors. Results did not change substantially from the initial publication: 36 patients (39%) achieved a complete remission in a median of 2.3 months, and for a median duration of 14 months. The median overall survival was 20 months, with 1- and 2-year survival rates of 61% and 41%, respectively. The improved response rates compared to the registration trail for DAC are likely due to the more appropriate, higher-risk population being treated, and to the greater number of cycles (a median of 8+) administered to patients.
AZA was also studied using alternative dosing schedules including 75mg/m2 daily subcutaneously for 5 days (n=50), repeated every 28 days; the same dose given for 5 days, with a weekend off, and continued for 2 days the following week (5-2-2, n=50)); or 50mg/m2 daily for 5 days, followed by 2 days off, followed by an additional 5 days of treatment (5-2-5, n=51).12 In this Phase II, multicenter study, patients were randomized to one of these treatment arms and treated for 6 cycles, with the option afterwards to enroll on a 12-month maintenance schedule of the 5-day regimen. Most patients (approximately two-thirds) had lower-risk disease, and of the 151 patients on-study, 66 (44%) were transfusion-dependent, with approximate equal numbers in each treatment arm. Response was assessed using 2000 International Working Group response criteria.13 In the 5-day treatment arm, 57% of patient experienced either a major or minor hematologic improvement response, similar to the 52% of patients in the 5-2-5 arm and 44% of patients in the 5-2-2 arm. Similar percentages of transfusion-dependent patients on each arm achieved transfusion-independence. These data appear to indicate, in a preliminary fashion, that similar responses can be achieved in MDS patients with a variety of AZA dosing schedules. Many aspects of this study have yet to be defined, including how response was assessed; prior therapies received; criteria for initiating therapy, duration of MDS at baseline; and more complete demographic data.
Immunomodulatory Agents Extend Their Applicability
Lenalidomide, approved by the U.S. FDA for the treatment of transfusion-dependent, low-risk MDS patients with a del (5q) abnormality, appears to have specific activity on the del (5q) clone, separate from any effects it may have on the bone marrow microenvironment. Low-risk MDS patients with this abnormality, treated with lenalidomide, achieve transfusion independence approximately two-thirds of the time, and cytogenetic remissions almost half the time. It has yet to be determined whether lenalidomide exerts similar effects on patients with the del (5q) abnormality and more advanced disease.
Burcheri et al. from France reported a Phase I/II study of lenalidomide (dosed at 10mg daily for 21 of 28 days, with dose escalation to 15mg daily after 2 cycles in the absence of response) in patients with higher-risk (IPSS Int-2 and high) MDS.14 A total of 49 patients have been enrolled, with 29 evaluable. Median age was 68 years, and 22 patients had RAEB-2 or RAEB-t, with 19 having an IPSS risk category of high. Four patients had isolated del (5q), 8 patients had del (5q) + 1 other abnormality, and the reminder had del (5q) with 2 or more abnormalities. Patients received a median of 34 days of therapy, and 12 patients required dose reduction. A total of 5 patients achieved a complete remission (4 with RAEB, 1 with RAEB-t), with 40% of patients with an isolated del (5q) achieving CR. Significant myelosuppression was seen, with hospitalization necessitated in almost all patients. The authors concluded that lenalidomide demonstrated efficacy in higher-risk MDS patients with del (5q), though it was associated with significant myelosuppression.
Another study took lenalidomide to the next step, of treating older adults with AML, regardless of cytogenetics status.15 High-dose lenalidomide (50mg daily) was given for 14 or 21 days, with 30 days of rest in-between, followed by a maintenance schedule of 10mg daily. Of the first 15 patients enrolled, median age was 71 years, one-third had antecedent MDS and 9 patients had normal cytogenetics. Nine of 12 patients had significant reductions in blast percentage, demonstrating at least a modicum of activity in this non-selective population. The use of high-dose lenalidomide in AML patients with the del (5q) abnormality is being explored in the Southwest Oncology Group (study S0605).
The first study combining lenalidomide with a hypomethylating agent (AZA) in patients with higher-risk MDS also had preliminary results presented.16 In this Phase I, dose escalating trial of the Rare Diseases Network: Bone Marrow failure consortium, lenalidomide was dose escalated from 5mg daily for 14 days, to 5mg daily for 21 days, up to 10mg daily for 21 days. Meanwhile, AZA was also dose-escalated from the 5-day schedule to the 5-2-5 schedule. As of October, 2007, 12 patients had been enrolled (through dosing cohort 4, lenalidomide at 5mg daily for 14 days, AZA at the 5-2-5 schedule) without a dose-limiting toxicity. Of the first 7 patients, the median age was 64 years, and all had RAEB-2. Of the first 6 evaluable patients, 3 achieved a complete remission, 2 a hematologic response, and 1 progressive disease. No patient had the del (5q) abnormality. There was 1 episode of febrile neutropenia. The combination was tho
ught to be well-tolerated, with early results suggesting efficacy in patients with high-risk MDS.
Therapies for MDS have evolved considerably over the past few years. Following the availability of the first non-growth factor therapies for this collection of diseases, treatment has become more refined, with a focus on combining available therapies and targeting specific abnormalities. At ASH 2007, we saw a report on the first treatment directed towards thrombocytopenia; the response predictive capacity of treatment-related cytopenias; the first prospectively-acquired survival data and alternative dosing schemas of the hypomethylating agents; and the expanded therapeutic capacity of lenalidomide. The next year will see further combination trials and maturation of results from existing studies, as well as preliminary results from novel approaches.
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2 Vardiman JW, Harris NL, Brunning RD. Organization (WHO) classification of the myeloid neoplasms 10.1182/blood-2002-04-1199. Blood. 2002;100:2292-2302.
3 Kantarjian H, Fenaux P, Sekeres MA, et al. Phase 1/2 Study of AMG 531 in Thrombocytopenic Patients (pts) with Low-Risk Myelodysplastic Syndrome (MDS): Update Including Extended Treatment. ASH Annual Meeting Abstracts. 2007;110:250.
4 List A, Dewald G, Bennett J, et al. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med. 2006;355:1456-1465.
5 Raza A, Reeves JE, Feldman EJ, et al. Long-Term Clinical Benefit of Lenalidomide (Revlimid) Treatment in Patients with Myelodysplastic Syndrome without Del 5q Cytogenetic Abnormalities. ASH Annual Meeting Abstracts. 2006;108:250.
6 Sekeres M, Maciejewski J, Giagounidis A, et al. Lenalidomide-induced Cytopenias: Relationship to Hematologic Improvement in Patients with Myelodysplastic Syndromes (MDS). Blood. 2007;110:Abstract 821.
7 Fenaux P, Mufti GJ, Santini V, et al. Azacitidine (AZA) Treatment Prolongs Overall Survival (OS) in Higher-Risk MDS Patients Compared with Conventional Care Regimens (CCR): Results of the AZA-001 Phase III Study. ASH Annual Meeting Abstracts. 2007;110:817.
8 Kantarjian H, Issa JP, Rosenfeld CS, et al. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer. 2006;106:1794-1803.
9 Silverman LR, Demakos EP, Peterson BL, et al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol. 2002;20:2429-2440.
10 Kantarjian H, Oki Y, Garcia-Manero G, et al. Results of a randomized study of three schedules of low-dose decitabine in higher risk myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood. 2007;109:52-57.
11 Kantarjian H, Garcia-Manero G, O'Brien S, et al. Survival and Efficacy of Decitabine in Myelodysplastic Syndromes (MDS), Analysis of the 5-Day IV Dosing Regimen. ASH Annual Meeting Abstracts. 2007;110:115.
12 Lyons RM, Cosgriff T, Modi S, et al. Results of the Initial Treatment Phase of a Study of Three Alternative Dosing Schedules of Azacitidine (Vidaza(R)) in Patients with Myelodysplastic Syndromes (MDS). ASH Annual Meeting Abstracts. 2007;110:819.
13 Cheson BD, Bennett JM, Kantarjian H, et al. Myelodysplastic syndromes standardized response criteria: further definition. Blood. 2001;98:1985.
14 Burcheri S, Prebet T, Beyne-Rauzy O, et al. Lenalidomide (LEN) in INT 2 and High Risk MDS with DEL 5q. Interim Results of a Phase II Trial by the GFM. ASH Annual Meeting Abstracts. 2007;110:820.
15 Fehniger TA, Nelson A, Trinkaus K, et al. Phase II Study of High Dose Lenalidomide as Initial Treatment for Older Acute Myeloid Leukemia Patients: Early Results Show a Significant Reduction of Bone Marrow Blasts after 14 Days of Therapy. ASH Annual Meeting Abstracts. 2007;110:916.
16 Sekeres MA, List A, Cuthbertson D, Paquette R, Loughran T, Maciejewski JP. Preliminary Results from a Phase I Study of Revlimid(R) (Lenalidomide) in Combination with Vidaza(R) (Azacitidine) in Patients with Advanced Myelodysplastic Syndromes (MDS). ASH Annual Meeting Abstracts. 2007;110:1458.