Clofarabine and Clofarabine Plus Low-Dose Cytarabine (ara-C) as Induction Therapy for Patients (pts) ≥ 60 Years with Newly Diagnosed Acute Myeloid Leukemia (AML).

Optimal induction therapy for pts ≥ 60 years (yrs) with AML remains undefined. Clofarabine is a purine deoxyadenosine analog with single agent activity in AML. Due to its metabolic and pharmacokinetic properties it is also an ideal agent for biochemical modulation strategies with other nucleoside analogs such as ara-C. In previous trials we reported our experience with clofarabine + intermediate doses of ara-C for salvage and frontline AML pts. To further explore clofarabine in AML, we investigated a lower dose schedule of clofarabine +/− low-dose ara-C (LDAC) in pts ≥ 60 yrs and previously untreated AML. Pts were adaptively randomized (based on history of response in each arm) to receive either clofarabine (C) at 30mg/m²/d i.v. daily d1-5 or clofarabine at 30mg/m²/d i.v. daily d1-5 + LDAC at 20mg/m²/d s.c. daily d1-14. Pts in remission received consolidation therapy q4-7 wks with clofarabine daily on d1-3 +/− LDAC daily on d1-7. Pts with ECOG PS ≥ 3 and/or a history of NYHA ≥ grade 3 heart disease were not eligible. Pts were admitted to a laminar airflow room (“protective environment”) for the duration of the induction. All pts received antibiotic prophylaxis consisting of levaquin, valacyclovir, and itraconazole (or equivalents). No antifungal prophylaxis was given during the days of the clofarabine infusions. Fifty-four pts have been enrolled (C 14; C+LDAC 40). Median age: 71 yrs (range 60–83). An antecedent hematologic disorder (MDS, CMML, NHL) or other malignancy was present in 28 pts (52%). Twenty-four pts (44%) had abnormal cytogenetics of whom 11 (20%) had −5, −7, or 11q23 abnormalities. Flt3 ITD/mutations were found in 7 pts (14%). Forty-four pts are evaluable for response (C 12; C+LDAC 32). Twenty-four pts (55%) achieved CR and 1 (2%) CRp for an overall response rate (ORR) of 57%. Median time to CR: 34 days (25–78). Response by treatment arm: 1) C (n=12): 5 (42%) CR; 2) C+LDAC (n=32): 19 (59%) CR, 1 (3%) CRp, ORR 62% (p=NS for CR rate). Most toxicities were ≤ grade 2 and included nausea/vomiting, diarrhea, fatigue, skin rashes and temporary elevations of transaminases and serum bilirubin. Myelosuppression was ubiquitous and myelosuppression-associated infectious complications were frequent. Nine pts (17%) died during induction (6/40 on C; 3/14 on C+LDAC), of whom 2 died early (≤ 14 days of treatment start): 71 yo female with E. coli sepsis on d12 (C); 83 yo male with pulmonary hemorrhage and pneumonia d14 (C+LDAC). In summary, clofarabine and clofarabine + LDAC show activity in older pts with AML. Its role in elderly AML induction needs to be evaluated further. Myelosuppression-associated complications remain frequent. An update of responses and time-to-event parameters will be presented.