A Phase II Prospective Feasibility Study of Clofarabine Cytoreduction Prior to Allogeneic Hematopoietic Cell Transplantation (HCT) for Patients with Relapsed or Refractory Acute Leukemias and Advanced Myelodysplastic Syndromes
Authors: Agarwal Rajiv , Locke Frederick L , Kunnavakkam Rangesh , van Besien Koen , Larson Richard A. , Odenike Olatoyosi , Godley Lucy , Liu Hongtao , Le Beau Michelle M. , Gurbuxani Sandeep , Thirman Michael J , Sipkins Dorothy A. , White Carol , Artz Andrew , Stock Wendy 
Published: October 2019

Abstract
Abstract 496
HCT may provide long-term disease control for patients (pts) with relapsed and/or refractory acute leukemias (AL) and advanced myelodysplastic syndromes (MDS). Active disease burden at HCT is associated with high relapse rates and poor long-term outcomes. We hypothesized tolerable intensification would be achieved safely by clofarabine cytoreduction followed by HCT conditioning at the nadir and would result in improved outcomes. We performed a prospective study (3/08 – 9/10) to examine the feasibility and efficacy of clofarabine (Clo) cytoreduction prior to HCT for relapsed or refractory AL and MDS with > 5% marrow blasts. Clo was administered at 30mg/m2/day IV over 2 hours for 5 consecutive days. On Day 12 post Clo initiation, a bone marrow (BM) biopsy determined cytoreduction, followed by HCT conditioning by day 21 post-Clo. Our primary endpoint was to assess the proportion of pts who achieved effective cytoreduction, defined as BM cellularity <20% and BM blasts<10% on Day 12 post Clo initiation. Our secondary endpoints included (a) the proportion of pts able to proceed to HCT within 21 days of initiating Clo bridge, (b) Clo-related toxicities, and (c) disease free (DFS) and overall survival (OS) on Day 100 post HCT. 29 pts were enrolled and evaluable; 11 AML, 7 MDS, 3 t-MN, 4 secondary AML, 2 CML, 2 ALL; median age was 51 years (range 23–69); sex: 16 M, 13 F. 16 pts had high risk and 13 had intermediate risk cytogenetic profiles. 3 of 12 pts evaluated showed a FLT3 ITD mutation. 18 of 23 evaluable pts had high C-reactive protein levels at study entry (>5mg/L). All pts had ECOG performance status of 0 to 1. The median Charlson co-morbidity index was 1 (range 0–8). Effective cytoreduction was achieved in 15/29 pts (52%). Clo bridge therapy was well tolerated with mild toxicities (CTCAE v.3) prior to HCT as follows: 7% with grade (gr.) 1 creatinine elevation; 46% gr.1–2 and 7% gr.3 bilirubin elevation; 50% gr.1–2 and 25% gr.3 SGOT elevation, which were reversible. There were no hand-foot syndrome, cardiac, or CNS toxicities. All 29 pts (100%) successfully proceeded to HCT conditioning after clofarabine bridge – one pt with refractory AML, who achieved cytoreduction and conditioning, died one day before HCT due to sepsis. Median time from Clo initiation to HCT was 21 days (range 18–77). Two pts were delayed due to infection and/or failure to cytoreduce; both received second bridge with HiDAC mitoxantrone and achieved cytoreduction followed by HCT. 25 of 29 underwent reduced intensity conditioning (flu-mel-campath-17, clo-mel-campath 3, flu-mel-atg 5) and 26 of 28 received T-cell depletion (campath 22, ATG 5). Among the 28 transplanted pts, graft sources included: 23 PBSC (11 matched related, 12 matched unrelated), and 5 haploidentical PBSC plus a cord blood unit. With a median follow up 343 days after HCT, the median PFS = 353 days (95% CI 229–573) and the median OS = 381 days (95% CI 229–649). One year PFS is 65% by Kaplan-Meier estimate for cytoreduced pts compared to 33% in non-cytoreduced pts. Of the 28 pts who received transplant, 3 pts died before Day 100 – one due to sepsis before Day 28 post HCT, and two due to disease progression. At Day 28 post HCT, 26/27 pts (96%) had BM biopsies showing no evidence of residual disease – one pt had residual AML. The cumulative incidence of gr.2–3 acute GVHD by Day 100 was 9/27 pts, and 2/25 pts developed mild or moderate chronic GVHD within the first year. The Kaplan Meier estimate for one year survival is 65% (95% CI 35–84%) for the cytoreduced pt group and 41% (95% CI 16–65%) for the non-cytoreduced pt group. In summary, clofarabine bridge achieved cytoreduction in 52% of very high risk pts with advanced hematologic malignancies with low toxicity. Cytoreduction was associated with prolonged PFS, but late relapse remains problematic. Despite RIC and T-cell depletion, most pts achieved remission post-HCT with low rates of acute and chronic GVHD. This bridging approach provides a platform for testing novel post-transplant interventions.

Disclosures:
Off Label Use: Clofarabine is being used for treatment of advanced leukemia for cytoreduction prior to HCT. Locke:Genzyme: Honoraria. van Besien:Genzyme: Research Funding. Odenike:Genzyme: Membership on an entity's Board of Directors or advisory committees, Research Funding. Stock:Genzyme: Research Funding.