Clofarabine/Cyclophosphamide (ClofCy) for Debulking refractory Acute Leukemias Prior to Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Rabitsch Werner , Boehm Alexandra , Schellongowski Peter , Kalhs Peter , Valent Peter , Sperr Wolfgang R 
Published: October 2019

Abstract
Abstract 4504
Patients (pts) with acute leukemias i.e. acute myeloid leukemia (AML) and acute lymphocytic leukemia (ALL) suffering form primary refractory disease or refractory relapse have a very poor prognosis. Allogeneic hematopoietic stem cell transplantation (alloHSCT) is the only potential curative treatment option for such pts. However, disease-control prior to HSCT is essential for long term CR. In the present study we have retrospectively analyzed the outcome of pts who received clofarabine (10 mg/m2, d 1–4) and cyclophosphamide (200 mg/m2, d 1–4; ClofCy) to reduce the burden of leukemic cells prior to alloHSCT. A total number of 18 pts (females, n= 11; males, n= 7; median age; 37.5 years, range 21–64 years) with refractory leukaemias (AML, n=14; ALL, n=4) received ClofCy between December 2008 and January 2012 (1 cycle: 7 pts; 2 cycles: 3 pts; 3 cycles: 7 pts; 4 cycles: 1 patient). In all pts a marked decrease in leukemic cells was observed after a median of 2 cycles (range 1–4 cycles). Side effects included infections (n=7), moderate skin rush (n=4), transient increase in ALT and AST (n=2) and diarrhoea (n=1). AlloHSCT was performed in 13/18 pts. Five pts were not eligible for alloHSCT because of severe systemic fungal infections in 3 pts, clinical deterioration in 1 patient, or CNS relapse of leukemia in 1 patient. Myeloablative conditioning (cyclophosphamide/TBI) was administered in 9 pts, and dose-reduced conditioning (FLAMSA n=2; Fludarabin/Melphalan/Carmustin/ATG n=2) in 4 pts. Following stem cell infusion (median number of CD34+ cells/kg: 7.22×106) from a related (n=4) or unrelated (n=9) donor all pts showed rapid haematologic engraftment and full donor chimerism (median time to ANC > 0.5 G/l: 16 days; range: 12–25 days; median time to platelet >20G/l without substitution: 17 days; range: 13–32 days). As evidenced by bone marrow biopsy on day +28, all pts achieved CR following alloHSCT. After a median observation time of 262 days (range: 33–1496 days) 7 pts are alive. One patient died because of acute steroid-refractory graft-versus-host disease (day +48) and one from a systemic fungal infection (day +56). Four pts died after following reoccurrence of leukemia. Three pts had a hematologic relapse (days +383, +275, +141, respectively) and 1 patient developed a myelosarcoma on day +934. Of the 7 patients alive 5 are in continuous CR (691, 673, 555, 533 and 170 days post TX), two patients had a relapse and achieved a CR after DLI or a second HSCT, respectively. Together, we demonstrate that cytoreduction with ClofCy is a novel reasonable treatment approach for pts with refractory acute leukemias prior to alloHSCT. The regimen is relatively well-tolerated and resulted in a high response rate. Whether this novel debulking protocol will lead to improved long term outcome in pts with refractory leukemias remains to be determined in forthcoming studies with larger patient samples and longer observation periods.

Disclosures:
Valent: Phadia: Research Funding. Sperr:Genzyme: Speakers Bureau.