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Phase II Trial of Low Dose, Subcutaneous Decitabine in Myelofibrosis

2008; Elsevier BV; Volume: 112; Issue: 11 Linguagem: Inglês

10.1182/blood.v112.11.2809.2809

1528-0020

Olatoyosi Odenike, John E. Godwin, Koen van Besien, Dezheng Huo, Dorie Sher, Patrick W. Burke, Scott E. Smith, Margaret Green, Julia Melnick, James L. Wade, Eric P. Lester, Rebecca B. Klisovic, Maria R. Baer, Richard A. Larson, Wendy Stock,

Eosinophilic Disorders and Syndromes

Abstract DNA hypermethylation of promoter-specific CpG islands has been implicated in the pathogenesis and progression of myelofibrosis (MF). We have evaluated Decitabine, a DNA methyltransferase inhibitor in patients (pts) with MF, including primary MF (PMF), and MF arising after polycythemia vera or essential thrombocythemia (post-PV or post-ET MF). This was a multicenter, single stage Phase II trial, with a planned accrual of 20 patients. The regimen would be deemed worthy of further investigation if ≥ 5 pts responded. Eligibility criteria included myelofibrosis associated with anemia (hemoglobin <11g/dL) and/or palpable splenomegaly. Decitabine was administered subcutaneously (SQ) at a dose of 0.3mg/kg/d on days 1–5 and days 8–12; cycles were repeated every 6 weeks, in the absence of dose limiting toxicities. Response was determined every 12 weeks as an improvement in cytopenias and/or splenomegaly. A maximum of 9 cycles was allowed; pts who had a complete remission (CR) had treatment discontinued provided they had received at least 4 cycles of therapy. Peripheral blood obtained at baseline and on days 5 and day 12 of the first 2 cycles of therapy was analyzed for potential biomarkers predictive of response to decitabine. Biomarkers evaluated included CD34+ cells measured by flow cytometry, as elevated CD34+ counts have been associated with advanced stage and evolution to blast phase in MF. CXCR4 gene expression levels were measured by REAL-time RT-PCR; reduced expression of CXCR4 on CD34+ cells has been linked to the abnormal stem cell trafficking in this disease, and decitabine has been shown to upregulate CXCR4 levels in primary MF cells in vitro. Hemoglobin F levels were evaluated by HPLC as induction of hemoglobin F levels has been demonstrated with decitabine therapy in primates and in patients with sickle hemoglobinopathy. Twenty-one pts were enrolled on the study. Pt characteristics: M/F:12/9, median age 67 years (range 42–89), median absolute CD34+ cell count 350 × 106/L (1.2–4959), Dupriez score of 2, 1 and 0 in 24%, 57% and 19% respectively, PMF= 76%, post PV-MF=19%; post ET MF=5%; 4 pts had blast phase disease (blast phase- MF) and 12 pts (57%) had transfusion dependent anemia and/or thrombocytopenia. Eight pts (38%) were previously untreated and 38% had abnormal bone marrow karyotype at baseline. Median number of cycles administered was 4 (range 1–9) and four pts remain on treatment. Grade 3/4 neutropenia (ANC) and grade3/4 thrombocytopenia occurred in 95% and 52% of pts respectively. Nine pts have developed febrile neutropenia. Two pts have died of sepsis-related complications while on study, both pts had significant impairment of hematopoiesis at baseline: 1 had blast phase-MF, the other had advanced PMF with a baseline ANC of 50/μL. Drug related non-hematologic toxicities have been infrequent and include gradeI/II fatigue and liver function abnormalities. 19 pts are evaluable for response: A total of 7 pts (37%) have responded, including 2 with blast phase-MF. CR=1 (normalization of counts and transfusion-independence), PR=2 (hemoglobin increase to normal levels, multilineage improvement including ANC and/or platelets). Hematologic improvement in erythroid lineage n=2: (both of these patients achieved red cell transfusion- independence) and platelets n=2: (>50% increase in platelet levels) have also been observed. Median time to response was 2 cycles (range 1–6); median duration of response was 5 months (range 2–15). Two pts are maintaining their responses at 2 and 14 months. All responders who developed disease progression did so while off therapy. Analysis of the effects of decitabine on CD34+ cells revealed a 61% reduction (p<0.001) in mean levels between cycles 1 and 2 of therapy in responders (n=7), in contrast to non-responders (n=12), in whom there was no change (p=0.45). There was no statistically significant change in CXCR4 or hemoglobin F levels over time, but responders to decitabine had higher levels of hemoglobin F (>1%) than non-responders at baseline and post-therapy (p<0.01) Conclusions: Low dose SQ decitabine is feasible, has clinical activity and deserves further investigation in myelofibrosis. Myelosuppression is common and requires close monitoring. A decline in circulating CD34+ progenitor cells that persists into cycle 2 of therapy may serve as a novel biomarker that predicts response to decitabine in myelofibrosis.