Phase 2 Trial of G-CSF Priming, Clofarabine, and High Dose Cytarabine (GCLAC) for the Treatment of Newly Diagnosed Acute Myeloid Leukemia (AML) or Advanced Myelodysplastic Syndrome or Advanced Myeloproliferative Neoplasm,
Authors: Becker Pamela S , Medeiros Bruno C. , Appelbaum Frederick R. , Scott Bart Lee , Hendrie Paul C. , Storer Barry , Pierce Sherry , Petersdorf Stephen H. , Estey Elihu H. 
Published: October 2019

Abstract
Abstract 3617
Clofarabine and cytarabine combinations have been effective in the treatment of adult acute myeloid leukemia (AML) in both the relapsed/refractory and upfront settings. Based on our results with GCLAC (G-CSF priming, clofarabine, and high dose cytarabine) in a trial for relapsed/refractory AML (Becker et al. Br J Haematol in press), we are currently testing this regimen in newly diagnosed patients age < 65. The G-CSF dose is 5 mcg/kg/day by subcutaneous injection beginning the day prior to chemotherapy, clofarabine 30 mg/m2/day × 5 and cytarabine 2 gm/m2/day × 5. 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 at a dose of 25 mg/m2/day × 4 days and cytarabine 2 gm/m2/day × 4 days. The primary objectives of this trial are to estimate rates of CR (complete remission) and EFS (event free survival). A stopping rule would be imposed if there was reasonable evidence that the CR rate was inferior to that obtained with standard induction 7+3, 70% (Fernandez et al. NEJM 2009; 361:1249–59). Absent early stopping, 50 patients will be treated. Twenty-five patients with non-APL AML, RAEB2, CMML2, or myelofibrosis with >10% blasts have been treated thus far; their median age is 52, range 22–63. Eleven patients had antecedent hematologic disorders(AHD). Four patients had poor risk cytogenetics, four patients had normal cytogenetics with Flt3+, and 5 patients had good risk cytogenetics. The most significant grade 3/4 toxicity occurring in 2 patients, was a constellation of pulmonary infiltrates, hypoxia, and diffuse alveolar hemorrhage that responded to steroids. This incidence is not dissimilar to the pulmonary toxicity described with single-agent high-dose cytarabine (Andersson et al. Cancer 1990; 65:1079–84). Pulmonary toxicity has not occurred in 8 subsequent patients given steroid premedication. The other grade 3 adverse events (AEs) included pneumonia (8), viral respiratory infection (6), abscess (4), bacteremia (13), and one additional grade 4 AE was septic shock. There has been no treatment related mortality. Fifteen of 17 currently evaluable patients have achieved CR, all but one with a single course, and 1 additional patient attained CRp (complete remission with incomplete platelet recovery). Using a model that accounts for cytogenetics, age, AHD, and organ function, the observed CR rate of 88% (95% CI 64%to 95%) exceeds the expected rate of 61% had the same patients received other high-dose cytarabine containing regimens but without clofarabine. Given the recent shortage of daunorubicin and the lack of assurance that an idarubicin dose (18mg/m2) that would be the nominal equivalent of 90mg/m2 daunorubicin is safe (Garcia-Manero et al. Haematologica 2002; 87:804–7), GCLAC may be a suitable alternative induction regimen for newly diagnosed AML and advanced myelodysplastic syndrome or myeloproliferative neoplasm.

Disclosures:
Becker: Sanofi-Oncology: Research Funding. Off Label Use: Clofarabine is FDA approved for treatment of relapsed pediatric acute lymphoblastic leukemia.