Abstract
Background:Pts with post‐MPN AML have a dismal prognosis and new therapies are needed. Dac is widely used in pts with accelerated and blast phase MPN. We previously published single‐agent activity of rux in pts with post‐MPN AML (Eghtedar, Blood 2012). Rux and dac synergize in xenograft models of JAK2 V617F‐driven AML (Rampal, PNAS USA 2014).Aims:To evaluate the efficacy and safety of combined rux and dac in pts with post‐MPN AML.Methods:The phase 1 portion of this ongoing, open‐label, single‐institution, investigator‐initiated, phase 1/2 trial employed a “3+3” dose escalation strategy and established 50 mg twice daily of rux and 20 mg/m2/d of dac on days 1–5 every 28 days as the recommended phase 2 dose of the combination (Bose, ASH 2016). No dose‐limiting toxicity (DLT) was observed. Pts must have post‐MPN AML or MDS/MPN in blast phase to be eligible for the phase 2 portion (10 of 12 DLT‐evaluable pts in phase 1 also had post‐MPN AML). Prior rux for the treatment of MPN is allowed. Prior hypomethylating agent therapy is not permitted.Results:Of 31 pts enrolled (14 in phase 1 and 17 in phase 2), 1 did not begin study treatment and 1 came off‐study early, being found ineligible. Of the rest (n = 29), 62% were male and the median age was 69 (range, 32–92)). Diagnoses preceding AML included PV in 3, ET in 8, PMF in 7, post‐PV MF in 3, post‐ET MF in 2, atypical CML, BCR‐ABL negative in 2, and MDS in 1 (phase 1 pt). An additional phase 1 pt had refractory AML. Two other pts had AML apparently arising from PMF and MDS/MPN. Medians (ranges) for WBC count, platelet count, Hgb level, absolute neutrophil count and bone marrow blasts at baseline (n = 29) were 5 (0.4–24.8), 45 (7–319), 9 (7.4–10.7), 2.19 (0.05–13.14) and 30% (1–74%), respectively. Only 5 pts had a diploid karyotype. JAK2 was mutated in 40%, TP53 in 26%, ASXL1 in 14%, IDH2 in 10%, and NRAS and KRAS in 5% each.Eighteen pts received rux at a dose of 50 mg twice daily, 9 of whom required dose reduction, mainly due to cytopenias.All pts are currently off‐study. Reasons for discontinuation include disease progression in 15 pts, relapse in 5, stem cell transplant in 4, and loss to follow‐up, early death from intracranial bleeding, death from lung infection in CRp, new diagnosis of lung cancer and patient/physician decision in 1 pt each.Median follow‐up was 6.1 (2.3–32.2) months. One pt was lost to follow‐up before completing cycle 1 and is not response‐evaluable. The overall response rate (n = 28) was 46%, with 2 pts (7%) attaining complete remission (CR), 1 (4%) CR with incomplete neutrophil recovery (CRn), 3 (11%) CR with incomplete platelet recovery (CRp), 6 (21%) morphologic leukemia‐free state (MLFS), and 1 (4%) partial remission (PR). At the data cut‐off, 22 pts had died. Median survival was 6.3 (0.4–32.2) months (Figure). The median duration of CR was 1.7 (0.9–30.8) months.Four pts underwent SCT, 2 in CR (alive at 8 and 31 months), 1 in PR (achieved CRp after SCT but died in CRp at 15 months) and 1 in MLFS (alive in CRp at 10 months).Rux plus dac was well tolerated. No grade 3/4 adverse events attributable to the study drugs occurred. Grade 1/2 fatigue (n = 3), pruritus (n = 2), diarrhea (n = 2), nausea (n = 1) and dizziness (n = 1) were observed.Summary/Conclusion:Rux plus dac is modestly active in post‐MPN AML, with some pts able to achieve remission and proceed to SCT, required for long‐term survival with chemotherapy (Kennedy, Blood 2013). However, survival remains poor and is not substantially different than that reported with alternative dosing schedules (Rampal, ASH 2018).image
Published Version
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