BACKGROUND: Hypomethylating drugs are useful in the management of myelodysplastic syndrome (MDS). Two of these drugs, azacitidine and decitabine, have received FDA approval for the treatment of MDS and chronic myelomonocytic leukemia (CMML). However, phase 2 and 3 studies that assessed these agents in MDS included only a small number of patients with CMML. The objective of this study was to evaluate the efficacy and safety of azacitidine in the treatment of CMML. METHODS: The records of thirty-eight patients diagnosed with CMML and treated with azacitidine at our institution were reviewed. Azacitidine was administered at 75 mg/m 2 /day for 7 days or 100 mg/m 2 /day for 5 days every 4 weeks. Patients who received at least 1 cycle of the drug were considered evaluable for response. RESULTS: Response was assessed by the modified International Working Group (IWG) criteria. The overall response rate was 39% (14 of 36); complete response (CR) rate was 11% (4 of 36); partial response (PR) rate was 3% (1 of 36); hematologic improvement (HI) was 25% (9 of 36). The median overall survival was 12 months. There was a statistically significant overall survival advantage in responders compared with nonresponders: 15.5 months versus 9 months, respectively (P ¼ .04). Treatment was generally well tolerated. One of 2 patients had complete resolution of a skin rash that was due to monocytic infiltration. CONCLUSIONS: Azacitidine is active in the treatment of CMML. The therapy-associated toxicity is acceptable. Our results support further investigation of azacitidine in CMML, particularly in combination with other agents.

BACKGROUNDPatients older than 55 years of age with acute myelogenous leukemia (AML) are less likely to achieve complete remission and more likely to experience toxicity with conventional induction chemotherapy than younger patients. Azacitidine administered in the outpatient setting is well tolerated and can induce complete hematological remission in patients with myelodysplastic syndromes (MDS). At higher doses, azacitidine has activity in AML.METHODSTwenty patients were retrospectively identified who had been treated with azacitidine with bone marrow blast counts between 21 and 38%. Patients with blast counts up to 29% were initially treated as MDS, but by WHO now meet criteria for AML. Patients with blast counts over 29% were treated with azacitidine after being deemed poor candidates for induction chemotherapy. Azacitidine 75 mg/m2/day was administered subcutaneously for 7 days every 4 weeks, which was defined as 1 cycle.RESULTSThe overall response rate was 60% (12/20): complete response (CR; n = 4; 20%); partial response (PR; n = 5; 25%); hematologic improvement (HI; n = 3; 15%). The median survival of responders was 15+ months compared with 2.5 months for nonresponders (P = .009). During therapy, responders had an Eastern Cooperative Oncology Group (ECOG) performance status of 1 or 0. The most common toxic event was infection (n = 8). Four patients were hospitalized during the first cycle of treatment.CONCLUSIONSAzacitidine administered in the outpatient setting can induce remission in AML. The therapy is well tolerated and might be an alternative for patients unlikely to tolerate standard induction chemotherapy. Cancer 2006. © 2006 American Cancer Society.

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Rationale: Myelodysplastic syndrome (MDS) is characterized by peripheral blood cytopenia, a major cause of morbidity and mortality. Two current treatments that may ameliorate cytopenia in MDS are azacitidine (aza) and hematopoietic growth factors. When used alone in MDS, erythropoietin (epo) and G-CSF are reported to increase the hemoglobin level and the neutrophil count, respectively. Additionally, epo and G-CSF may work synergistically to improve anemia and neutropenia. This study examined whether the combination of growth factors and aza would be more effective than aza alone for the treatment of MDS. Methods: We identified 86 MDS patients treated at our institution who received an average of 10.8 cycles of aza. Forty-nine (49) of these patients also received either epo, G-CSF or both during the course of their aza treatment, while 37 did not receive hematopoietic growth factors. These 2 groups did not differ significantly either in number of cycles of aza received (p=0.34) or FAB MDS subtype (p=0.50). Hematological responses were tabulated by International Working Group criteria and compared using chi-square statistics. Results: Patients treated with aza alone had a 51% (19/37) overall hematological response rate (OHR). Patients who received aza + epo (A + E) had a 50% (6/12) OHR and when compared to aza alone (A), was not statistically different (p=0.9). Patients who received aza + G-CSF +/− epo (A + G +/− E) had an 84% (31/37) OHR versus 51% (25/49) in patients who did not receive G-CSF (A +/− E) (p=0.003). When the group A + G +/− E was compared to A +/− E there was a statistically significant difference in favor of A + G +/− E in erythroid (77% vs. 37%; p=0.001) and platelet (72% vs. 47%; p=0.04) response, but no difference in neutrophil response (71% vs. 67%; p=0.9). Conclusion: In patients with MDS treated with aza the addition of G-CSF improved OHR, erythroid and platelet response. Surprisingly, neutrophil response was not improved. The biological basis for these observations suggests an effect upon erythroid and megakaryocytic lineages. We postulate that G-CSF may have an anti-apoptotic effect as has been previously demonstrated when used in combination with epo.

16532 Background: Azacitidine (AZA) is a DNA methyltransferase inhibitor with activity in patients with myelodysplastic syndrome (MDS). The current approved schedule of AZA is 75 mg/m2/d for 7 days every 28 days. This schedule is inconvenient for patients and providers because of the need for weekend administration. Methods: The records of 9 patients who received AZA 100 mg/m2/d for 5 days with an anticipated 28 day cycle between 10/04 to 1/06 were reviewed to determine response, duration of response and tolerability. A minimum of two cycles were required for response evaluation (n = 8). All patients were assessed for tolerability. The International Working Group response criteria for MDS was utilized for evaluation. Results: Patients had secondary MDS (n = 4), chronic myelomonocytic leukemia (n = 2), refractory anemia (n = 2) and refractory anemia with ringed sideroblasts (n = 1). Of the 8 patients who received at least 2 cycles of therapy, 5 responded: 1 achieved partial response, 3 achieved hematologic improvement in at least one cell line and 1 remained in a stable disease state. The overall response rate was 63%. Average response duration was 6.2 months. The longest response duration was 10 months. Myelosuppression was seen in 2 of the 9 patients treated, one of whom continued treatment with growth factor support; therapy is currently on hold for the other patient. Injection site reaction was seen in 2 patients, resulting in discontinuation of treatment in one. One patient experienced severe malaise after 2 cycles and was given the standard dose for further therapy with a major hematologic improvement. Other isolated events included mouth ulcers, mild nausea and flare of erythema nodosum. Of the 5 responders, 1 later died of disease progression (after 7 cycles), 1 died of a complication of comorbidity (after 5 cycles), 1 is alive with disease progression (after 10 cycles) and 2 are continuing therapy with AZA (after 4 and 5 cycles, respectively). Conclusions: AZA 100 mg/m2/day for 5 days every 28 days seems to be tolerated as well as the 7-day treatment schedule. It also appears to have efficacy similar to the standard dose and schedule. If larger studies are confirmatory, this 5-day schedule may be more convenient for patients and providers. [Table: see text]