Abstract
Acute myeloid leukemia (AML) carries a dismal prognosis in older patients, with median survival 8-12 months and especially poor outcomes in patients with unfavorable cytogenetics and/or poor performance status. Decitabine (5-aza-2’-deoxycytidine) has single-agent efficacy in older AML patients, with 40-50% CR (Blum et al, Proc Natl Acad Sci,107(16):7473-8,2010; Ritchie et al Leuk Lymphoma, 2013). AML originates from a rare population of leukemia stem cells (LSCs) that are capable of self-renewal, proliferation and differentiation into malignant blasts. LSCs may persist after treatment and contribute to disease relapse. Drugs that release LSCs from their protective microenvironment may leave them more vulnerable to therapy, as they are strongly dependent on the niche for proliferation and survival. Plerixafor blocks SDF1-mediated CXCR4 signaling and significantly decreases the survival of AML cells in vitro. The objective of this study was to investigate the safety and efficacy of decitabine combined with plerixafor in newly diagnosed older patients with AML and to evaluate the clinical and biological effects of plerixafor on LCSs.
Patients were treated with repeated monthly cycles of decitabine 20 mg/m2 days 1-10 combined with escalating doses of plerixafor (320-810 μg/kg) days 1-5. Plerixafor was administered every other cycle so patients could serve as their own control when assessing the effects of CXCR4 blockade. Two cohorts of patients were treated at each dose level: cohort A received plerixafor only during even-numbered cycles and cohort B received plerixafor only during odd-numbered cycles. Patients achieving a clinical response received ongoing monthly maintenance cycles with 5 days of decitabine and plerixafor during alternate cycles.
Sixty-nine patients were treated. Baseline patient characteristics were 55% male with a median age of 73 (56-87) yrs; ECOG 0 17%, 1 64%, 2 19%; cytogenetics intermediate 57%, adverse 44%; antecedent hematologic disorder 44%; secondary AML 45%; prior hypomethylating agent treatment (HMA) 20%. The overall response rate was 43% (36% CR, 7% CRi), with median time to response 1.9 mos (2 cycles) and median response duration 4.5 mos. Adverse karyotype did not predict overall response (P=0.31) and 53% of patients with adverse cytogenetics responded to treatment (43% CR, 7% CRi). Median overall survival (OS) for responders was significantly longer (18 mos) than for nonresponders (5 mos, P<0.0001). Prior HMA treatment was the strongest independent predictor of OS (HR=3.1; 95% CI 1.3-7.3; P=0.008). Whereas 52% of HMA treatment naive patients achieved CR (46%/6% CR/CRi), only 14% of patients previously treated with an HMA achieved response (0% CR, 14% CRi, P=0.002). Accordingly, the median survival of patients with prior HMA was much shorter (2.5 mos) than for HMA-naive patients (12.6 mos, P=0.001). We observed no significant differences in ORR or OS linked to plerixafor dose or treatment cohort (A vs B), but the study was not powered for these comparisons.
Toxicities were predictable and typical of older AML patients. Cytopenias and infections were the most common adverse events. There was no clinically significant hyperleukocytosis with plerixafor. Fourteen (56%) patients treated with 810 ug/kg plerixafor experienced reversible, treatment-associated insomnia.
Immunophenotypically-defined leukemia stem and progenitor cells (LSPCs) were mobilized in a subset of patients as a consequence of CXCR4 blockade. Importantly, increased proliferation of LSPCs was also observed by Ki-67 staining. Decitabine-induced hypomethylation of AML-specific DNA methylation biomarker regions was observed in LSPCs of responders, but not in non-responders. Interestingly, this biochemical response preceded clinical response by at least one month in the subset of 7 patients analyzed to date.
The combination of decitabine and plerixafor resulted in a high response rate with a favorable toxicity profile in poor-prognosis elderly AML patients. The MTD of plerixafor was 810 ug/kg and results from ongoing translational studies suggest that measures to optimize the regimen based on LSPC mobilization and DNA methylation may be feasible.
Disclosures:
Off Label Use: decitabine for AML.
Multiple myeloma patients experience high response rate with new three-drug combination
