Phase I Study of Clofarabine with Standard-Dose Infusional Cytarabine (Ara-C) as Intensive Induction Therapy for Newly-Diagnosed De Novo Acute Myeloid Leukemia in Older Adults Age ≥60 Years.

Background The median age of AML is approximately 70 years, and the survival of older adults age ≥60 years remains poor with standard therapy. Clofarabine (CLO) has significant single agent activity in AML, and in vitro studies demonstrate synergy with Ara-C. We therefore performed a phase I study to determine the maximum tolerated dose (MTD) of CLO with standard dose Ara-C (100mg/m2/day D1-7 by 24hr continuous infusion) as AML induction therapy. CLO was administered daily × 5 days beginning D2 to allow for pharmacokinetic (PK) & pharmacodynamic (PD) studies. Methods Enrollment was restricted to newly-diagnosed de novo AML patients age ≥60 years considered candidates for intensive therapy; those with prior MDS or hypoplastic AML ( 1 pt per cohort. The CLO starting dose was 30mg/m2/day ×5 (dose level 1), with the intention to increase to CLO 40mg/m2 if tolerated. However, CLO dose reductions of 25% (CLO 22.5 mg/m2/day × 5, dose level -1) & 50% (CLO 15mg/m2/day ×5, dose level -2) were allowed in the event of dose-limiting toxicity (DLT). Pts achieving complete remission (CR) received 2 cycles consolidation with CLO ×5 & Ara-C 100mg/m2 × 5. Results A total of 13 pts (median age 69 yrs, range 61–77; 10 male) have been treated. DLT was observed at dose level 1 (Table 1), and the protocol was amended to mandate additional hydration with CLO, and antibiotic/antifungal prophylaxis. At dose level -1, 1 pt died from PE on D27 after hematologic recovery, considered treatment-related per protocol, mandating dose de-escalation to dose level -2. Pt 13 is in active induction therapy, and not yet evaluable for response, although DLT has not been encountered. Febrile neutropenia occurred in 11/13 pts. The MTD in this study is CLO 15mg/m2/day × 5 with standard infusional Ara-C (dose level -2). Significant clinical activity was observed, particularly at higher CLO doses, including CR in 2 pts with complex karyotype. In contrast, only 1/5 evaluable pts at dose level-2 achieved CR. PK & PD studies are in progress. Conclusions In contrast to prior reports using intermediate dose bolus Ara-C (1g/m2), the MTD of CLO combined with standard dose infusional Ara-C in older adults with AML is lower, and the toxicity profile appears different. Significant clinical activity was noted at higher CLO dose levels & with complex karyotype. Based on this observation an escalation to CLO 20mg/m2 is now planned. | Patient | CLO Dose Level | Age | Cytogenetics | Response (CR Duration) | DLT | |:---------------------------- | -------------- | --- | ------------ | ---------------------- | ------------------------- | | Fail - failure to achieve CR | | 1 | 1 (30mg) | 66 | −7 | Death | Infection/Renal | | 2 | 1 | 61 | −7, complex | CR (15 mths) | none | | 3 | 1 | 69 | intermediate | CR (2 mths) | none | | 4 | 1 | 77 | 5q-, complex | Death | Infection/Renal/Vasc Leak | | 5 | −1 (22.5mg) | 75 | +8 | Death | Pneumonia | | 6 | −1 | 67 | diploid | CR (5 mths) | none | | 7 | −1 | 71 | 9q- | Death | Pulm Embolism Day 27 | | 8 | −2 (15mg) | 74 | 5q-, complex | Fail | none | | 9 | −2 | 64 | diploid | Fail | none | | 10 | −2 | 63 | diploid | Fail | none | | 11 | −2 | 73 | complex | CR (5 mths) | none | | 12 | −2 | 72 | diploid | Fail | none | | 13 | −2 | 63 | diploid | - | - | CLO & Standard Dose Infusional Ara-C: Toxicity & Efficacy