Multicenter Phase 2 Trial of G-CSF Priming, Clofarabine, and High Dose Cytarabine (GCLAC) for Newly Diagnosed Acute Myeloid Leukemia, Advanced Myelodysplastic Syndrome or Advanced Myeloproliferative Neoplasm

Several regimens composed of clofarabine and cytarabine have exhibited efficacy for both newly diagnosed and relapsed/refractory acute myeloid leukemia (AML) (Faderl et al Blood 2005, 2006, 2008). Clofarabine's ability to increase araCTP formation and inhibit ribonucleotide reductase confer potent anti-leukemic effect. We previously reported the results of an induction regimen consisting of G-CSF priming, clofarabine, and high dose cytarabine for relapsed/refractory AML (GCLAC) (Becker et al Br J Haematol 2011), which resulted in a complete remission (CR) rate of 46% overall, and a CR rate of 50% in patients with poor risk cytogenetics. Furthermore, we demonstrated that GCLAC is superior to fludarabine/cytarabine combinations in the relapsed/refractory setting (retrospective comparison; Becker et al Haematologica Epub ahead of print, 2012). Because of its activity as a salvage regimen, we examined the response rate and toxicity of GCLAC in the upfront setting.

A multicenter clinical trial (NCT01101880) of G-CSF priming, clofarabine, and high dose cytarabine enrolled newly diagnosed patients < 65 years old with acute myeloid leukemia (AML), advanced myelodysplastic syndrome (MDS) or advanced myeloproliferative neoplasm (MPN) from September 2010 through May 2012. The GCLAC regimen consists of G-CSF 5 mcg/kg/day by subcutaneous injection beginning the day prior to chemotherapy until neutrophil recovery, clofarabine 30 mg/m²/day × 5, and cytarabine 2 gm/m²/day × 5. A second induction with the same regimen was permissible if marrow blasts over 5% persisted on day 21 or thereafter. Consolidation courses were administered for up to 3 cycles, with clofarabine 25 mg/m²/day days 1–4, cytarabine 2 gm/m²/day days 1–4, and G-CSF days 0–4.

Fifty patients with non-APL AML, RAEB2, or myelofibrosis with >10% blasts were treated. The median age was 53, range 22–64. Twenty-one of the patients (42%) had antecedent hematologic disorders or proliferative/dysplastic disorders with ≥10% blasts or secondary leukemia. Twelve patients (24%) had unfavorable, 32 patients (64%) intermediate, and 4 (8%) favorable cytogenetics. Overall, 37 patients (74%) achieved complete remission (CR; 95% CI 62–86%), 40 (80%) CR + CRp (CR with incomplete platelet recovery). Of these remissions, 5CRs and 1 CRp had been attained after a second induction course in 11 patients. Thirty-four patients received one, 20 two, and 11 three cycles of consolidation treatment. The CR rate was 83% for patients without antecedent hematological disorder (AHD), and 57% for those with AHD. The CR rate was 100% for patients with favorable risk, 84% for those with intermediate risk, and 46% for those with unfavorable risk cytogenetics. The median time to neutrophil recovery (>500/μl) was 19 days (13–35 range) and to platelet recovery >100,000/μl 24 days (16–63 range) after induction. The most significant grade 4 toxicity occurring in 3 patients, was a constellation of pulmonary infiltrates, hypoxia, and diffuse alveolar hemorrhage that responded to steroids, and was rarely seen when patients were premedicated with steroids. Out of the 125 cycles of chemotherapy administered, the most frequent grade 3 adverse events (AEs) were pulmonary (11), bacteremia (22), and transaminase elevation (10). There were 11 grade 4 AEs including pulmonary (5), hyperglycemia (2), transaminase elevation (1), acute cholecystits (1), and septic shock (2). The 30 day mortality was 0%.

GCLAC is a well tolerated induction regimen and a comparison with 7+3 is in progress, using data from Southwest Oncology Group (SWOG) and the Fred Hutchinson Cancer Research Center (FHCRC).

Becker:Sanofi: Research Funding. Off Label Use: Clofarabine is indicated for the treatment of pediatric patients with relapsed or refractory acute lymphoblastic leukemia.