Phase 2 Results of Clofarabine In Combination with Etoposide and Cyclophosphamide In Pediatric Patients with Refractory or Relapsed Acute Lymphoblastic Leukemia

Dramatic improvements have been made in treating children with newly diagnosed acute lymphoblastic leukemia (ALL). However, poor outcomes are still observed in patients who are either refractory to or who have relapsed after conventional chemotherapy. Salvage therapy options are urgently needed for this patient population. Clofarabine is approved as a single agent for treatment of pediatric ALL in second relapse. Previously we reported the safety profile and response rates from the phase 1 study assessing clofarabine in combination with etoposide and cyclophosphamide in pediatric patients with refractory/relapsed acute leukemia (Hijiya, Leukemia, 2009). Here we report the phase 2 results.

Patients (pts) aged 1–21 years with refractory/relapsed ALL were treated at the recommended phase 2 dose of clofarabine 40 mg/m²/day, cyclophosphamide 440 mg/m²/day, and etoposide 100 mg/m²/day. All 3 agents were given IV daily for 5 consecutive days in induction and 4 consecutive days in consolidation. Patients could receive up to 2 induction cycles, followed by consolidation (max 8 cycles including induction). The primary endpoint was overall remission rate (ORR: complete remission [CR] and CR without platelet recovery [CRp]). Secondary endpoints were safety and tolerability, rate of partial remission (PR), duration of remission (DOR), event-free survival (EFS), 4-month EFS, and overall survival (OS). Minimal residual disease (MRD) by flow cytometry was evaluated as an exploratory endpoint.

Phase 2 comprised 25 pts (median follow-up 10.7 weeks [wks]): 16 males and 9 females with a median age of 14.0 years. Twenty-one pts had pre-B cell ALL, 1 pt had T cell ALL and 3 pts had an unknown immunophenotype. Fourteen pts had 2 prior induction regimens, 7 pts had 3 prior induction regimens and 4 pts had 1 prior induction regimen. Fifteen pts (60%) were refractory to their immediately preceding regimen. Four pts had received a prior hematopoietic stem cell transplant (HSCT). The investigator-assessed ORR was 44%; 7 CR (28%) and 4 CRp (16%). Additionally, 3 pts (12%) achieved PR. Eight pts were evaluable for MRD after induction, 5 were MRD negative (defined as <0.01%) and 3 were positive. Overall, 10 pts proceeded to HSCT, including 7 of 11 responders (CR + CRp). The median DOR at the last known follow-up (not censored for alternative therapy) was 15.9 wks (range: 2.9–109.6+) for pts with CR, but was not estimable for pts with CRp (range: 30.1+-67.7+). Median DOR for responders censored at alternative therapy/HSCT was not estimable as most pts received alternate therapy or transplant prior to event occurrence (range: 0.1+-10.9+ wks). Median OS censored at the last known follow-up was 10.7 wks for all patients (range: 1.0–113.1+) and 80.9 wks for responders (range: 8.1–113.1+). The median EFS for responders was 73.9 wks and 44% of all 25 pts were free of events at 4 months. The median cumulative number of clofarabine cycles received was 1 (range: 1–3), with most pts (10 of 11 responders) achieving best response after 1 cycle. The treatment-related non-hematologic adverse events (AEs) occurring in ≥25% of phase 2 pts were vomiting (88%); nausea (72%); febrile neutropenia (60%), pyrexia (52%); decreased appetite (44%); ALT increased, AST increased, hypokalemia, and hypotension (36% each), diarrhea and hyperbilirubinemia (28% each). One pt discontinued study treatment due to treatment-related fungal sinusitis which occurred 17 days after the last dose of study drug. Serious treatment-related AEs, were reported in 84% of pts. Six pts (24%) died within 30 days of receiving last dose of study treatment. Deaths were due to hepatic veno-occlusive disease (2 pts), septic shock (2 pts), pulmonary edema (1 pt) and infection (1 pt). As reported previously, after 4 of the initial 8 pts developed severe hepatotoxicity, the protocol was amended to exclude pts with prior HSCT, viral hepatitis cirrhosis, or elevated conjugated bilirubin levels at study entry (Hijiya, ASH 2008). There were no additional events of severe hepatotoxicity observed in the remaining 17 pts.

Combination treatment with clofarabine, etoposide and cyclophosphamide in pediatric pts with refractory or relapsed ALL resulted in an ORR of 44% and negative MRD in heavily treated pts. Ten pts including 7 of 11 responders proceeded to HSCT. The safety profile is acceptable in this relapsed/refractory population.

Hijiya:Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Clofarabine (Clolar) is approved by the US FDA for the treatment of pediatric patients 1 to 21 years old with relapsed or refractory acute lymphoblastic leukemia after at least two prior regimens. This trial examines the use of clofarabine in combination with etoposide and cyclophosphamide. Paul:Genzyme: Employment, Equity Ownership. Borowitz:genzyme: Research Funding; becton-dickinson: Research Funding; Alexion: Consultancy; beckman-coulter: Research Funding. Isakoff:Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Silverman:Genzyme: Research Funding; Enzon : Honoraria, Membership on an entity's Board of Directors or advisory committees; EUSA: Honoraria, Membership on an entity's Board of Directors or advisory committees. Steinherz:Genzyme: Research Funding. Kadota:Genzyme: Employment, Equity Ownership. Pressey:Genzyme: Research Funding. Shen:Genzyme: Research Funding. Chu:Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cooper:Genzyme: Research Funding. Jeha:Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Razzouk:Genzyme: Research Funding. Rytting:Genzyme: Research Funding. Barry:Genzyme: Employment, Equity Ownership. Carroll:Genzyme: Research Funding. Gaynon:Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.