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

Background: Children, adolescents, and young adults (CAYA) with Acute Leukemia in third complete remission (CR3), induction failure (IF) or refractory relapse (RR) have a poor prognosis. (Gaynon, BJH 2005, Wells, JCO 2003, Hochster/Cairo, BJH 2013) Clofarabine (CLO), a purine anti-metabolite, has been shown to have synergy with cytarabine (Faderl, Blood 2005) and induce lasting remissions following CLO and busulfan-based conditioning and allogeneic hematopoietic cell transplantation (AlloHCT) in poor-risk AML. (Magneau, Blood 2011)

Objectives: This study seeks to determine the safety, day-100 treatment-related mortality (TRM), and relapse rate associated with a conditioning regimen of CLO, cytarabine, and Total Body Irradiation (TBI) followed by AlloHCT in CAYA with poor-risk ALL or AML.

 Methods: This is a multi-center Phase I/II trial of a novel conditioning regiment of CLO (maximal dose 52mg/m²/d achieved without dose limiting toxicity) x5d, cytarabine 1000 mg/m² x6d 4 hours post-CLO, and TBI (1200cGy) followed by AlloHCT from matched related or unrelated donors in CAYA with ALL or AML in CR3, RR or IF. GVHD prophylaxis consisted of tacrolimus and MMF. (Oswunko/Cairo, BBMT 2004, Bhatia/Cairo, BBMT 2010) Supportive care consisted of growth factor support, and CMV and fungal prophylaxis as previously described. (Waxman/Cairo, Ped. Transplantation 2009, Shereck/Cairo, Ped. Blood Cancer 2007, Roman/Cairo, Ped. Blood Cancer 2008) Donor chimerism was assessed by semi-quantitative PCR-based methods as previously described.  (Geyer/Cairo, BJH 2011) The Kaplan-Meier method was used to determine the probabilities of engraftment, GVHD, TRM, and overall survival (OS).

 Results: 30 patients, median age: 11.9 yrs (range 1.5 – 21.8); M:F 21:9, ALL:AML 27:3 (10 CR3, 3RR, 17 IF), 11 related donors, 19 unrelated donors (11 BM/PBSCs, 8 UCB). Median TNC and CD34 dose was 4.49x10⁸/kg and 4.2x10⁶/kg for BM/PBSCs and 4.8x10⁷/kg and 3.4x10⁵/kg for UCB. Probabilities of neutrophil, platelet engraftment, grade II-IV aGVHD and chronic GVHD were 100%, 93%, 47%, and 35% respectively. Median Day 100, 180, and 365 whole blood chimerisms were all 100%. Day 100 TRM was only 6.7%. The probabilities of relapse, 1-yr progression-free survival and OS were 27% (CI₉₅: 13-52%), 40% (CI₉₅: 23-57%), and 47% (CI₉₅: 28-63%) respectively in this poor-risk population.

 Conclusions: These preliminary results suggest that this novel conditioning regimen including CLO dose 52 mg/m² with Ara-C and TBI followed by AlloHCT is safe and  tolerated in CAYA with poor-risk ALL or AML. Our results are promising with respect to a low risk of day 100 TRM and relapse rate in this poor risk population. This approach should be considered in better risk CAYA patients with ALL/AML who require AlloHCT.