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Activity of decitabine, a hypomethylating agent, in chronic myelomonocytic leukemia
Version of Record online: 11 JAN 2007
Copyright © 2006 American Cancer Society
Volume 109, Issue 4, pages 713–717, 15 February 2007
How to Cite
Aribi, A., Borthakur, G., Ravandi, F., Shan, J., Davisson, J., Cortes, J. and Kantarjian, H. (2007), Activity of decitabine, a hypomethylating agent, in chronic myelomonocytic leukemia. Cancer, 109: 713–717. doi: 10.1002/cncr.22457
- Issue online: 2 FEB 2007
- Version of Record online: 11 JAN 2007
- Manuscript Accepted: 15 NOV 2006
- Manuscript Revised: 14 NOV 2006
- Manuscript Received: 11 OCT 2006
- chronic myelomonocytic leukemia;
- hypomethylating agent
Hypomethylating agents have activity in myelodysplastic syndrome (MDS) and have received approval for the treatment of both MDS and chronic myelomonocytic leukemia (CMML). The specific efficacy in CMML has not been detailed in a large number of patients. The aim of the study was to evaluate the activity and safety of decitabine in CMML.
Nineteen adults with a diagnosis of CMML treated on decitabine studies were analyzed. Decitabine was given at 100 mg/m2 per course every 4 weeks. The median number of courses given was 9 (range, 1–18).
Overall, 11 patients (58%) achieved complete response (CR) and 2 (11%) had hematologic improvement (HI), for an overall response rate of 69% according to the modified International Working Group (IWG) criteria. Median survival was 19 months. Severe (grade 3–4) extramedullary side effects were rare.
Decitabine is active in CMML. Studies of combinations of decitabine with topoisomerase I inhibitors or other active anti-CMML agents are indicated. Cancer 2007. © 2007 American Cancer Society.
Chronic myelomonocytic leukemia (CMML) is a hybrid disorder characterized by proliferation of the myeloid series and dysplasia of the erythroid-megakaryocytic series.1 CMML is now categorized as a separate entity from myelodysplastic syndrome (MDS).2 It is often considered as an overlap between MDS and myeloproliferative disorders, and can be divided into low- and high-grade subtypes, based essentially on the percent of marrow blasts and the degree of anemia and thrombocytopenia.1 CMML affects older individuals (median age, 60–65 years), predominantly men. Presenting features include fatigue and anemia, neutropenia, thrombocytopenia and bleeding, and splenomegaly. The median survival in CMML is 18 to 20 months. Commonly used approaches to treat CMML include supportive care, growth factors, hydroxyurea, topotecan and cytarabine or intensive acute myeloid leukemia (AML)-type therapies, splenectomy (refractory splenomegaly and hypersplenism/cytopenias), and allogeneic stem cell transplantation (SCT).3–5 The only approved therapies for CMML are 5-azacitidine and decitabine, the approval by the US Food and Drug Administration being part of the blanket approval for MDS, rather than an expanded specific study in CMML. The approval was for MDS based on the French-American-British (FAB) classification, which included CMML. CMML is now considered separate by the World Health Organization (WHO) classification.2 Fewer than 10 patients with CMML were treated in each of the 2 pivotal studies.6, 7
A subset (1%–2%) of patients with MDS or CMML have chromosomal abnormalities involving translocations between chromosome 5q33 and other chromosomes, eg, t(5;12)(q33;p12-13). They respond well to imatinib mesylate therapy, which has been recently approved by the Food and Drug Administration for this uncommon disorder.
In this analysis, we review our experience with decitabine therapy in CMML.
MATERIALS AND METHODS
Adults with a diagnosis of CMML treated on decitabine studies were analyzed. Informed consent was obtained according to institutional guidelines. Eligibility criteria required an age ≥16 years old, adequate performance status of 0 to 2 (ECOG scale), and adequate liver (bilirubin ≤1.5 mg/dL) and renal functions (creatinine ≤1.5 mg/dL). Patients were required not to have received more than 1 prior regimen or biological therapy, prior high doses of cytarabine (≥1 g/m2 daily), or chemotherapy for at least 2 weeks before receiving decitabine, and to have recovered from the side effects of prior therapy. Nursing females were excluded and patients of child-bearing potential were required to practice effective birth control measures.
The diagnosis of CMML included patients with confirmed morphologic disease with monocytosis of 8% or more in the blood and marrow, as well as an absolute monocyte count of 109/L or above, regardless of the white blood cell (WBC) cutoff of 12 × 109/L.3–5,8
Patients received decitabine in a Bayesian randomized design detailed elsewhere,9 in 1 of 3 schedules: 1) 20 mg/m2 intravenously (i.v.) over 1 hour daily × 5; 2) 20 mg/m2 daily × 5, given in 2 subcutaneous (s.c.) doses daily; or 3) 10 mg/m2 i.v. over 1 hour daily × 10. All patients received the same decitabine total dose per course, 100 mg/m2. The final results and outcomes by schedule were previously detailed.9 Courses of decitabine were given every 4 weeks, at least in the first 3 courses, regardless of the counts, as long as there were no significant myelosuppressive life-threatening complications with a particular course, such as pneumonia, severe infection or bleeding, or severe organ damage; and there was evidence of persistent disease. Timely and repeated courses of decitabine every 4 weeks (rather than 6–8 weeks as in previous studies) for a minimum of at least 3 courses was important for the decitabine dose-schedule delivery.
No dose escalations were considered. Dose reductions by 25% to 30%, rounded to 15, 10, 7.5, and 5 mg/m2, were allowed for grade 3–4 nonmyelosuppressive toxicities, for severe myelosuppression-associated complications (infections, bleeding), or for prolonged myelosuppression defined as a hypocellular marrow (5% or less cellularity) without evidence of disease for 6 weeks or more after the start of a course of therapy. Other dose modifications, eg, 50% dose reductions, were occasionally considered for severe complications, if judged in the best safety interest of the patient. Use of erythropoietin and G-CSF were allowed as indicated by the clinical condition. Antibiotic prophylaxis and therapy for fever of infections was according to institutional guidelines.9
Patient responses were evaluated by the new proposed International Working Group (IWG) criteria.10 Toxicity was graded according to the NCI Common Toxicity Criteria v. 2.0. Transient cytopenias due to drug-related myelosuppression, infections, or other factors known to cause myelosuppression did not interrupt evaluation of response duration. Response criteria of the IWG for complete response (CR) and partial response (PR) were similar to the ones used for acute myeloid leukemia (AML), but required response durability for at least 4 weeks and improvement of hemoglobin to 11 g/dL or above. A CR required normalization of the bone marrow and peripheral counts with 5% or less marrow blasts, a granulocyte count 109/L or above, hemoglobin level 11 g/dL or above, and a platelet count 100 × 109/L or above, lasting for at least 4 weeks. A PR was similar to CR except for persistent marrow blasts above 5%, but which were reduced by 50% or more. A marrow CR referred to reduction of marrow blasts to 5% or less without normalization of peripheral counts. In addition, a CR required disappearance of palpable splenomegaly if present and a PR required reduction of palpable splenomegaly by at least 50%. A complete cytogenetic response referred to disappearance of the cytogenetic abnormality; partial cytogenetic response referred to 50% or more reduction of the cytogenetic abnormality.10
Hematologic improvements (HIs) were coded by the IWG criteria: HI-E referred to a hemoglobin increase by at least 1.5 g/dL or transfusion independence; HI-P referred to an absolute increase of platelet counts from less than 20 to more than 20 × 109/L and by at least 100%, or if more than 20 × 109/L, by an absolute increase of at least 30 × 109/L; HI-N referred to a granulocyte increase by at least 100% and by an absolute increase of at least 0.5 × 109/L. HIs were required to last for at least 8 weeks. Persistence of dysplastic changes in CR were allowed.
Survival was dated from the start of therapy. Survival curve was according to the Kaplan-Meier method.
A total of 19 patients with CMML were treated from February, 2004, to October, 2005. Their median age was 66 years (range, 44–82 years); 5 (26%) patients were females. The characteristics of the study group are detailed in Table 1. Splenomegaly was present in 22%, anemia in 53%, thrombocytopenia in 63%, and chromosomal abnormalities in 31%. Secondary MDS was present in 16% of patients (Table 1). The number of patients treated on each schedule was: 1) i.v. daily × 5, 16 patients; 2) s.c. daily × 5, 1 patient; 3) i.v. daily × 10, 2 patients.
|Age, y||≥60||14 (74)|
|Splenomegaly, n = 18*||Yes||4 (22)|
|Hemoglobin, g/dL||<10||10 (53)|
|Platelets, ×109/L||<50||8 (42)|
|WBC, × 109/L||>12||13 (68)|
|% marrow blasts||6–10||5 (26)|
|Chromosomal abnormalities||None||13 (68)|
|Chromosome 5 or 7||1 (5)|
|Duration of disease, mo||< 6||11 (58)|
|Prior therapy for CMML||None||10 (53)|
|Chemotherapy and other||3 (16)|
|Secondary CMML||Yes||3 (16)|
Overall, 11 patients achieved CR (58%), and 2 (11%) had hematologic improvement (1 HI erythroid + platelet, 1 HI platelet), for an overall response rate of 68%. Splenomegaly was reduced by more than 50% in 3 of the 4 patients with initial palpable splenomegaly (1 CR, 2 HIs). The response data are detailed in Tables 2 and 3. The CR rate by schedule was: 1) i.v. daily × 5, 10 CR/16 = 62%; 2) s.c. daily × 5, 0 CR/1 = 0%; 3) i.v. daily × 10, 1 CR/2 = 50%. In the overall study evaluation the i.v. daily × 5 schedule was selected as the one associated with the highest CR rate, as detailed in a previous report.9
|Response||No. response (%)|
|Complete response||11 (58)|
|Hematologic improvement||2 (11)|
|Patient||Age, y||Karyotype/Response||Prior therapy for MDS Yes/No||Response/Duration, mo||% Marrow blasts Pre/Post||WBC, ×109/L Pre/Post||Platelets, ×109/L Pre/Post||% Monocytes Pre/Post|
|13||76||Monosomy 7/ NR||Yes||NR||8/9||62/39||162/133||40/22|
|14||66||Deletion 12q/ CG PR||No||CR/3||3/1||75.5/8.8||55/147||4/3|
|15||82||Trisomy 8/ CG CR||No||CR/9||18/1||9.3/4.9||21/281||30/8|
|19||76||Trisomy 8/ CG CR||No||CR/8+||8/0||45/2.7||37/275||30/6|
The median number of courses given was 9 (range, 1–18). The median number of courses to achieve CR was 3 (range, 1–6). The 2-year survival rate was 48% (Fig. 1).
Nonhematologic side effects were minimal (Table 4). Myelosuppression-associated complications occurred in 8% of courses. Drug-related myelosuppression requiring dose reductions was noted in 17% of courses. There were no deaths associated with adverse events.
|Grade 1–2||Grade 3–4|
|A. Nonhematologic toxicities (19 patients)|
|Bone aches||0||2 (11)|
|Liver dysfunction||2 (11)||1 (5)|
|Nausea, vomiting||2 (11)||0|
|B. Myelosuppression-related toxicities (174 courses)|
|Fever of unknown origin||6 (3.5)|
|Documented bacterial infections|
|Sepsis alone||5 (3)|
|Minor infections||4 (2)|
|Pneumonias ± other infections||2 (1)|
|With other infections||0|
|Bleeding||10 (6)||1 (0.5)|
|Hospitalization (All)||23 (13)|
|Patients never hospitalized 5/19 = 26%|
Studies of the efficacy of novel therapies for CMML are scarce. Most such studies combine MDS with CMML, and very few evaluate the benefits of such regimens selectively in CMML. Whereas decitabine and 5-azacitidine have received approval for the treatment of CMML, very few patients with CMML had in fact been treated with either agent.6, 7 This is the first study to report on a relatively sizable number of patients with CMML treated with a specific therapy, decitabine in this case.
In this study decitabine showed positive activity in CMML. The response rate with decitabine was 68% (CR rate 58%). Nonhematologic side effects were minimal and myelosuppression-associated complications acceptable. There were no drug-related mortalities. Seventeen (89%) patients received at least 3 courses. Thus, the profiles of efficacy and side effects of decitabine appear favorable and suggest the need to pursue the activity of decitabine in CMML, a disease with few treatment options.
Topotecan, and other topoisomerase I inhibitors, have demonstrated activity in MDS and CMML.3, 11 As a single agent, topotecan induced complete remissions in 28% of patients with CMML.3 These results were with a continuous administration schedule of topotecan. In a Phase I study of oral topotecan for patients with MDS, CMML, or AML, responses were observed in 42% of patients, including CR in 17%.12 Future studies may consider combining decitabine and topotecan for the treatment of CMML.
The criteria for initiation of therapy in CMML are not clearly defined and are often based on the patient symptoms, involvement of organs by CMML (eg, skin disease, renal dysfunction, leukostasis), and the physician's experience. In general, therapy is initiated for: 1) increased signs or symptoms of CMML such as fever, weight loss, symptomatic splenomegaly, hyperleukocytosis; 2) worsening cytopenias (anemia, thrombocytopenia, need for transfusions); 3) CMML organ involvement (skin, renal dysfunction, pulmonary symptoms); or 4) increasing blasts (usually to more than 5% to 10%).
Allogeneic stem cell transplant (SCT) is the only curative modality for CMML but is risky. A search for a donor should be initiated at the time of diagnosis of CMML. The timing of allogeneic SCT is based on patient age, donor source (related vs unrelated) and degree of matching, and expected prognosis. It should be performed under optimal conditions of minimal CMML disease (possibly optimized safely with pre-SCT use of hypomethylation strategies) and when the patient is still in a good health status (good performance status and organ functions, no infections).
In summary, decitabine has shown encouraging activity in the specific subset of CMML, and should be further investigated in combination therapies.