Pediatric patients with ALL who have multiple relapses show a declining reinduction rate with each successive relapse. Chessels et al reported the results in 235 pediatric patients with ALL in CR3 treated between 1972 and 1998. Only 18 of the 235 patients remained alive, with multiple early treatment failures implying significant instability of the third remission state. Factors that were found to be of significant influence on survival for these patients in CR3 were length of CR2, type of second event, immunophenotype, type of third treatment, type of first relapse, presenting leukocyte count, and length of CR1. The 3-year leukemia-free survival for patients with ALL in CR3 treated with hematopoietic progenitor cell transplantation (HPCT) was reported as 20% in a single-institution report on patients transplanted with unrelated donors between 1987 and 1999. This report found a 20% relapse rate in ALL patients in CR3 and reported that patients transplanted after 1992 had a higher rate of relapse, implying that as improved chemotherapy regimens become more successful in curing patients, those who develop relapse may have disease more resistant to treatment. Clofarabine (\[2-chloro-9-(2-deoxy-2-fluoro-D-arabinofuranosyl)adenine\]; Cl-F-ara-A; CAFdA) is a rationally designed, second-generation purine nucleoside antimetabolite. Clofarabine was designed as a hybrid molecule to overcome the limitations and incorporate the best qualities of fludarabine (F-ara-A) and cladribine (2-CdA, CdA), all three molecules are currently approved by the FDA for treatment of hematologic malignancies. In an open-label Phase II, pediatric patients with refractory or relapsed ALL received clofarabine 52 mg/m2 by IVI over 2 hours for 5 consecutive days repeated every 2 to 6 weeks depending on toxicity and response. Among the 49 patients evaluated for efficacy, the overall remission rate was 20%. The median duration of remission could not be calculated for the 6 patients who achieved a CR because 3 patients were still in remission at the time of data cutoff. The median duration for the 4 patients who achieved a CRp was 20 weeks (Range: 4.6 to 28.6 weeks). Eight (16%) patients went on to receive a transplant with 7 (14%) experiencing clinical benefit. In an open-label Phase II study, pediatric patients with refractory or relapsed AML received clofarabine 52 mg/m2 by IVI over 2 hours for 5 consecutive days repeated every 2 to 6 weeks depending on toxicity and response. The overall remission rate (CR + CRp) was 3%; 23% of patients achieved a PR. The median duration of remission for patients who achieved at least a PR was 16.2 weeks. Twelve (34%) patients went on to receive a transplant, 7 of whom were still alive at the time of data cutoff with survival ranging from 16.4 weeks to 93.6 weeks.

Patients enrolling must have undergone an extensive pre-transplant evaluation to assess remission status, assure adequate organ system function, and document freedom from active viral, bacterial, and fungal infection. Patients should proceed to transplant as soon as possible following their reinduction chemotherapy. Patients with delays in therapy due to toxicity or donor procurement delays should receive maintenance chemotherapy if possible. Patients must be scheduled to begin their preparative regimen within 10 days of enrolling on the study. This will be a 2 part study. Part A will be the dose escalation phase. Once the MTD and/or safe/tolerated dose of clofarabine has been established, Part B will accrue patients to further define the event free, disease free and overall survival at the MTD or safe/tolerated dose of clofarabine. At study entry during Part A, a clofarabine dose level will be assigned to each patient. During Part B, the established MTD or safe/tolerated dose of clofarabine will be used.

In Part A this study will enroll patients with ALL and ANLL in relapse, induction failure, CR3 or CR3P and without prior AlloSCT. These patients will receive a conditioning regimen of clofarabine, ARA-C and TBI followed by AlloSCT. Patients will start their pre-conditioning regimen on Day -10. Patients will receive ARA-C (3000 mg/m2 \[total ARA-C dose of 18g/m2\]) daily on Days -10, -9, -8, -7, -6, and -5 and clofarabine (Dose assigned at enrollment, see section 8.2.2 for dose escalation table for Part A) on Days -9, -8, -7, -6, and -5. On days when clofarabine and ARA-C are both given, clofarabine will be given as a 2 hr infusion followed by 4 hr rest and then ARA-C given as a 3 hr infusion. Fractionated TBI (200 cGy) will be administered twice daily for 3 days on Day -4, -3 and -2. The AlloSCT will be performed on Day 0. GVHD prophylaxis will consist of tacrolimus and MMF. In Part B, this study will enroll patients with ALL or ANLL in CR3 or CR3P and without prior AlloSCT. The pre-conditioning regimen will be the same as in Part A EXCEPT the established MTD or safe/tolerated dose of clofarabine from Part A will be utilized.