Dose Escalation of Clofarabine 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

Despite dramatic improvements in cure rates for pediatric ALL and AML, the prognosis remains poor for pediatric patients with ALL or AML in third complete remission (CR3) or with relapsed or refractory disease (10-20% EFS). Single-agent clofarabine has demonstrated activity in CAYA with relapsed or refractory ALL and AML (Jeha et al., Blood, 2004, JCO, 2006 and JCO, 2009). Clofarabine is a potent inhibitor of DNA polymerase and ribonucleotide reductase; biochemical and clinical studies suggest synergy with cytarabine (Faderl et al., Blood 2005). Clofarabine in combination with cytarabine has been studied in adults with AML and MDS and results in greater rates of CR than clofarabine alone (Faderl et al., Blood, 2006 and Blood, 2008). The combination of clofarabine and cytarabine in CAYA with relapsed acute leukemia appears to be safe and well-tolerated (Cooper et al., ASH, 2009).

To determine the maximum tolerated dose (MTD) of clofarabine in combination with cytarabine and TBI followed by AlloSCT and to assess the safety, progression-free survival (PFS) and overall survival (OS) associated with this regimen in CAYA with poor-risk acute leukemia.

We instituted a multi-center phase I/II study of a novel conditioning regimen consisting of clofarabine, cytarabine and TBI prior to AlloSCT in CAYA with ALL or AML in CR3, relapse, or induction failure (IF). Herein we report results from the phase I portion of the study. Eligible patients received 5 days (day-9 to day-5) of clofarabine (dose escalation with 40 mg/m² [n=3], 46 mg/m² [n=3], 52 mg/m² [n=6]) and sequential cytarabine 1000 mg/m² (day-10 to day-5) and TBI (1200cGy) followed by AlloSCT from matched related or unrelated donors. Unrelated donor AlloSCT recipients also received R-ATG 2 mg/kg (day-4 to -2). GVHD prophylaxis consisted of tacrolimus and MMF as we have recently described (Bhatia/Cairo et al., BBMT, 2009). Probabilities of engraftment, acute and chronic GVHD, PFS and OS were computed using the Kaplan-Meier method.

Twelve patients enrolled, median age 11 years (range 5–18), 10/2 M/F, 9 ALL (6 CR3, 2 refractory relapse, 1 CR2 with history of IF), 3 AML (2 primary IF, 1 treatment-related AML in CR3), 6 with history of IF, 6 related donors (5 bone marrow [BM], 1 PBSCs), 6 unrelated donors (3 BM, 2 umbilical cord blood [UCB], 1 PBSCs). HLA matching was 5/6 (n=4) or 6/6 (n=4) at HLA-A, B and DRB1 for related donors and unrelated UCB donors and 9/10 (n=1) or 10/10 (n=3) at HLA-A, B, C, DRB1 and DQB1 for unrelated BM or PBSC donors. Median total nucleated cell dose (TNC) was 4.76×10⁸/kg (2.30-14.56) and CD34 dose 5.04×10⁶/kg (2.41-10.10) for patients receiving BM or PBSCs and 4.78×10⁷/kg (4.00-5.55) and 4.04×10⁵/kg (1.41-6.66), respectively, for patients receiving UCB grafts. An MTD of clofarabine was not exceeded at 52mg/m²/dose. No serious adverse events related to clofarabine were observed. One patient developed grade III hearing loss in the setting of atypical PRES, unlikely related to clofarabine, with normal cochlear function and abnormal auditory brainstem response.

All engrafted neutrophils at median day 14 (12-29) and 90% of evaluable patients engrafted platelets at median day 36 (16-97). All achieved 100% whole blood donor chimerism by day +30. Day 100 transplant related mortality is 0%. The probability of grade II-IV acute GVHD was 43% (CI₉₅: 13–71%); no patients developed chronic GVHD. Two patients died days +137 and +182 from multi-organ failure in the setting of infection and acute GVHD. Two experienced progressive disease on days +87 and +126 and received further therapy off study; one remains alive and stable. Eight are alive in continuous CR at a median of 209 days (40-770). Probabilities of PFS and OS are 53.3% (CI₉₅: 18–80%) and 61.0% (CI₉₅: 20–86%), respectively.

Myeloablative conditioning with clofarabine, cytarabine and TBI followed by AlloSCT from related or unrelated donors is well tolerated in CAYA with poor-risk ALL and AML. Clofarabine 52 mg/m²/day × 5 days in combination with cytarabine and TBI can safely be used in the phase II study. Preliminary results from the phase I cohort are encouraging with respect to the risk of early relapse, despite poor-risk underlying disease. Efficacy data and measurements of change in minimal residual disease in the phase II study will provide a broader experience at the MTD to assess the role of this conditioning regimen in CAYA with poor-risk acute leukemia.

Talano:Genzyme: Membership on an entity's Board of Directors or advisory committees. Cairo:Genzyme: Research Funding, Speakers Bureau.