Randomized Trial of GM-CSF and G-CSF Following High-Dose Cytarabine and Mitoxantrone Chemotherapy for Relapsed and Refractory Acute Leukemia.
Authors: Baer Maria R. , Ford Laurie A. , Bundy Brian N. , Tighe Sheila M. , O’Loughlin Kieran L. , Slack James L. , Wetzler Meir , Wallace Paul K. 
Published: April 2020

Abstract
Patients with acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) refractory to or in relapse following induction chemotherapy have a poor prognosis, and inducing an immune response to autologous AML or ALL cells following chemotherapy is an attractive approach to improving outcome. Immune responses to autologous leukemia cells may be stimulated by dendritic cell presentation of leukemia cell antigens, dendritic cells may be deficient in acute leukemia, and administration of the recombinant hematopoietic growth factors granulocyte-monocyte colony-stimulating factor (GM-CSF) or granulocyte colony-stimulating factor (G-CSF) following chemotherapy may increase dendritic cell numbers. We compared the effects of GM-CSF and G-CSF administered following high-dose chemotherapy. Adult relapsed and refractory AML and ALL patients received salvage chemotherapy consisting of high-dose cytarabine 3 g/m2 (1.5 g/m2 for age ≥50 years) over one hour every 12 hours × 12 doses and mitoxantrone 12 mg/m2 daily × 3 (HiDAC/Mx), and at completion of chemotherapy were randomized to receive GM-CSF 250 mcg/m2 or G-CSF 5 mcg/kg daily beginning 12 hours after the last chemotherapy dose, until absolute neutrophil count ≥5 × 109〈1 year) and late (≥1 year) first and subsequent relapse. Peripheral blood was collected when ANC reached 5 × 109/L for measurement of myeloid dendritic cell (lineage-negative, HLADr+, CD11c+) percentages by flow cytometry. Sixty patients were enrolled, ages 18 to 82 (median 66) years, 41 male and 19 female, 47 with AML and 13 with ALL, and 15 with primary refractory disease, 27 in early and 17 in late first relapse and one in subsequent relapse; 6 had relapsed following allogeneic transplantation. Overall, 22 of 60 patients (37%) achieved CR and 4 (7%) CR with incomplete count recovery (CRi), while 23 (38%) had resistant disease and 11 (18%) died. The regimen was generally well tolerated, the most frequent grade ≥4 toxicities pulmonary, infectious and cardiac, in 8, 7 and 6 patients, respectively, and 13 patients subsequently received transplant-based therapies (9 allogeneic, 4 autologous). 56 patients were randomized, as 4 died or stopped therapy before randomization, and randomization was to GM-CSF in 29 patients and G-CSF in 27. CR and CRi were achieved by 13 and 1 patients of 29 patients receiving GM-CSF and 9 and 3 of 27 receiving G-CSF (p NS, Fisher’s Exact Text). ANC ≥0.5 was achieved at 22 to 98 days (median 27) from start of chemotherapy in 25 GM-CSF patients and at 18 to 65 days (median 25) in 20 G-CSF patients (p=0.08, Wilcoxon Rank Sum Test). Toxicities did not differ significantly on the two arms. Only 17 patients (G-CSF: 7 and GM-CSF: 10) had blood samples submitted and successfully studied for myeloid dendritic cell percentages. Myeloid dendritic cell percentages were 0 to 40 (median 22), and the comparison by treatment group showed no evidence of a difference. In summary, HiDAC/Mx is an effective salvage regimen in this high-risk population and may serve as a bridge to transplant-based therapies or, possibly, a backbone for targeted therapies, myeloid dendritic cells are present at count recovery in patients receiving GM-CSF or G-CSF following HiDAC/Mx, and treatment outcome, toxicities, count recovery and myeloid dendritic cell percentages did not differ in patients receiving GM-CSF or G-CSF following HiDAC/Mx.