Work

Preliminary Results of Phase I/II Study of Clofarabine (CLO) in Combination With Cytarabine and Total Body Irradiation (TBI) Followed by Allogeneic Stem Cell Transplantation (AlloSCT) in Children, Adolescents and Young Adults (CAYA) With Poor-Risk Acute Leukemia

Year: 2011

Type: article

Abstract: CAYA with ALL or AML in third complete remission (CR3), refractory relapse (RR) or induction failure (IF) continue to have extremely poor prognosis, < 20% EFS (Gaynon, BJH, 2005, Wells et al, JCO, 2003). CLO is an inhibitor of DNA polymerase and ribonucleotide reductase and has demonstrated activity in CAYA with relapsed ALL/AML (Jeha et al., JCO, 2006, 2009). Studies suggest synergy with cytarabine (Faderl et al, Blood, 2005). CLO with cytarabine has shown greater rates of CR than CLO alone in adults with AML and in CAYA with relapsed ALL/ AML (Faderl et al, Blood, 2006, 2008; Cooper et al, ASH, 2009). We sought to determine maximum tolerated dose (MTD) or tolerable dose of CLO and assess the safety, progression-free survival (PFS) and overall survival (OS) of CLO, cytarabine and TBI followed by AlloSCT in CAYA with poor-risk ALL/ AML. This is a multi-center phase I/II trial of novel conditioning regimen of CLO (dose escalation: 40mg/m2 [n = 3], 46 mg/m2 [n = 3], 52 mg/m2 [n = 8]) 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/AML in CR3, RR or IF. Pts with unrelated grafts received R-ATG. GVHD prophylaxis consisted of tacrolimus and MMF (Bhatia/Cairo et al., BBMT, 2009). Kaplan-Meier method was used to determine the probabilities of engraftment, GVHD, PFS and OS. 14 pts, median age: 10.6 yrs (5-18); M:F: 10:4, ALL/AML: 11:3 (9 CR3, 2 RR, 3 IF), 6 related donors, 8 unrelated donors (5 BM/PBSCs, 3 UCB). Median TNC and CD34 dose was 5.04x108/kg and 5.04x106/kg for BM/PBSCs and 4.0x107/kg and 1.8x105/kg for UCB. Probabilities of neutrophil and platelet engraftment and grade II-IV aGVHD were 100%, 91.7% and 51.8%, respectively. All achieved 100% whole blood donor chimerism by day 30. Day 100 TRM was 0%. CLO dose was tolerable at 52mg/m2/d x5d and is being used in the phase II setting. No serious adverse events related to CLO were observed. 2 pts experienced progressive disease at days 90 and 126. 10 pts are alive in continuous CR at median 171 days (42-834). Probabilities of 1-yr PFS and OS are 60.2% (CI95: 24-83%) and 54.0% (CI95: 18-80%), respectively. Preliminary results suggest this regimen followed by AlloSCT is safe and well tolerated in CAYA with poor-risk ALL/ AML with CLO dose of 52 mg/m2. Very early results are encouraging with respect to low risk of early leukemic relapse with this conditioning regimen.

Source: Transplantation and Cellular Therapy

DOI: 10.1016/j.bbmt.2010.12.101