Low Day 100 Transplant-Related Mortality (TRM) and Relapse Rate Following Clofarabine in Combination with Cytarabine, Total Body Irradiation and Allogeneic Stem Cell Transplantation in Children, Adolescents and Young Adults with Poor-Risk Acute Leukemia

Background: Acute leukemias (ALL or AML) in third complete remission (CR3), refractory relapse (RR) or induction failure (IF) have an extremely poor prognosis, with <20% event free survival (EFS) (Gaynon, BJH, 2005; Wells, JCO, 2003). CLO, an inhibitor of DNA polymerase and ribonucleotide reductase, has been shown to be safe and induce durable remissions, both in conjunction with busulfan in poor-risk AML (Magenau et al., Blood, 2011) and with Melphalan in poor-risk hematologic malignancies in adults (van Besien et al, BBMT, 2012).  Clo has also been found to have significant activity in relapsed ALL and AML (Jeha, JCO 2006, 2009) and synergy with cytarabine (Faderl, Blood, 2005). We therefore  sought to determine safety, day-100 TRM, and overall survival (OS) associated with CLO, cytarabine and TBI followed by AlloSCT in CAYA with poor-risk ALL or AML.

Methods: This is a multi-center phase I/II trial of a novel conditioning regimen of CLO (dose escalation; maximal dose of 52mg/m²/d achieved without dose limiting toxicity) x5d, sequential (4 hrs later) cytarabine 1000 mg/m² x6d and TBI (1200cGy) followed by AlloSCT from matched related or unrelated donors in CAYA with ALL or AML in CR3, RR or IF. Patients with unrelated donors received R-ATG. GVHD prophylaxis consisted of tacrolimus and MMF (Bhatia/Cairo, BBMT, 2009). Kaplan-Meier method was used to determine the probabilities of engraftment, GVHD, TRM and OS.

Results: 29 pts, median age: 11.8 yrs (1.5-21); M:F: 20:9, ALL/AML: 26:3 (10 CR3, 3 RR, 16 IF), 10 related donors, 19 unrelated donors (11 BM/PBSCs, 8 UCB).  Median TNC and CD34 dose was 4.51x10⁸/kg and 4.8 x10⁶/kg for BM/PBSCs and 4.24x10⁷/kg and 3.4x10⁵/kg for UCB, respectively. Probabilities of neutrophil, platelet engraftment, grade II-IV aGVHD and chronic GVHD were 100%, 93%, 45%, and 35%, respectively. Probability of Day 100 TRM was only 7.6%. The probability of relapse was 27% (CI₉₅: 4-59%). Probability of 1-yr PFS and OS were 52% (CI₉₅: 30-70%), and 46% (CI₉₅: 26-64%) respectively.

Conclusions: These updated results suggest that this novel conditioning regimen followed by AlloSCT is safe and well tolerated in CAYA with very poor-risk ALL or AML with CLO dose 52 mg/m². Our results also continue to be encouraging with respect to a low risk of day 100 TRM and leukemic relapse rate associated with this conditioning regimen in this poor-risk population. This approach should be considered in better risk patients with ALL/AML who require AlloSCT.