Clofarabine (Clo) and Busulfan (Bu) as a Novel Reduced Toxicity Conditioning Regimen for Allogeneic Hematopoietic Cell Transplantation (HCT) In Patients (pts) with Acute Lymphoblastic Leukemia (ALL).

Clo 40 mg/m² followed by Bu 130 mg/m² were infused daily for 4 days followed by hematopoietic cell infusion 2 days later. Bu was infused either as a fixed dose per BSA, or to target an average daily AUC of 5,500 microMol-min for pts up to 60 years of age or 4000 microMol-min for pts greater than 60 years, determined by a test dose of Bu at 32 mg/m² given 48 hours prior to the high dose regimen. Dilantin was given for seizure prophylaxis. GVHD prophylaxis was based on tacrolimus and mini-MTX, with the addition of rabbit anti-thymocyte globulin (4 mg/kg total dose) for unrelated donor transplants. The presence of minimal residual disease (MRD) was determined by multiparameter flow cytometry.

14 pts (12 B-lineage, 2 T-lineage) with median age 29 years (range 21–64) received an allogeneic matched sibling (n=8) or matched unrelated donor (n=6) HCT in CR1 (n=7, 3 MRD positive), CR2 (n=6, 3 MRD positive), or refractory relapse (n=1). Nine pts had high-risk cytogenetic profiles as defined by the presence of t(9;22), t(4;11), or complex cytogenetics. The median time from diagnosis to HCT was 8.5 months (range 2–115) with a median 2 lines of chemotherapy received (range 1–3). Median days to ANC > 0.5 × 10⁹/L and platelet count > 20 × 10⁹/L were 12 (range 10–14) and 16 (13-23), respectively. The most common toxicity was mucositis (8 grade II, 2 grade III). Grade 3 reversible elevation of liver function tests was noted in 3 pts. No VOD or renal toxicity was noted. One pt with a prior history of stenotrophomas and fungal pneumonia died of pneumonia complications 18 days after HCT. Eleven pts are evaluable for response. All evaluable pts achieved CR clearing MRD by day +30 after HCT. Five pts achieved full donor chimerism at 30 days following HCT, 4 pts remain with mixed chimerism at 60 day assessment following HCT, and 1 pt progressed early. The incidence of grades II-IV acute GVHD is 40% (n=3 grade II GI, n=1 steroid refractory liver); chronic GVHD was not assessed due to short follow-up. With a median follow-up of 3 months among surviving patients (0.4-8), overall and disease-free survival is 92% at 3 months. Two pts in CR2 with persistent MRD at time of HCT progressed at a median 5 months following HCT. Two pts older than 60 years were treated on the reduced Bu dose arm, and both remain in continued remission.

The CloBu combination is well-tolerated in this small cohort of patients with high-risk ALL who received a median of 8.5 months of intensive (mainly HCVAD-based) chemotherapy prior to receiving transplant. The clearing of MRD encourages further investigation of this regimen. Longer follow-up is needed to more completely assess disease control.

Kebriaei:Otsuka Pharmaceuticals: Research Funding. Off Label Use: Busulfan and Clofarabine for trasplant conditioning. De Lima:Otsuka: Membership on an entity's Board of Directors or advisory committees. Champlin:Otsuka: Research Funding; Genzyme: Consultancy. Andersson:Otsuka: Consultancy.