A Single Center Experience of Cladribine, Cytarabine, Filgrastim and Mitoxantrone (CLAG-M regimen) in High-Risk or Relapsed/Refractory, Acute Myeloid Leukemia (AML)

Background: High-risk (HR) AML including secondary AML (sAML) or therapy-related (tAML) are associated with significantly lower complete remission (CR) rates and poor outcome, after upfront "3+7" and post-remission chemotherapy. No standard intensive treatment approach for relapsed/refractory AML is well established, even more so, in older patients, but "bridging" such patients in CR to allogeneic stem-cell transplantation (HSCT), whenever feasible, remain the only curative strategy, as in younger patients. Addition of cladribine, a purine analog, to cytarabine is an available option. Significant clinical activity of CLAG (-M) regimens is now well established, with a response rate (RR) of 60% in relapsed/refractory AML or AML patients who failed hypomethylating agents. A prospective frontline study of an intensified CLAG-M regimen has recently confirmed its association to a high response rate, that may particularly benefit HR-AML patients, as a bridge to HSCT. As other reports in the literature remain sparse, we report here our current experience with CLAG-M in relapsed/refractory and sAML patients. Methods: From January 2015 to July 2018, 20 consecutive patients with HR-AML, were treated in our center, with one course of CLAG-M (cladribine 5 mg/m2 /day (days 2-6), cytarabine 2g/m2/day (days 2-6) and reduced to 1g/m2/day for patients 65y+, filgrastim 300mcg/daily (days 1-6), and mitoxantrone 10mg/m2/day (days 2-4)). If eligible for HSCT, a second CLAG course was to be administered to patients in CR. Extended myeloid mutation analysis was performed, using a 37-gene NGS panel. Such patients were classified according to Lindsley et al.,Blood 2015. Results: Median age was 63.5 years (33-79) with a 3:1 M/F ratio. Four sAML patients and 4 tAML patients were treated upfront (5 CR, 1 early death (ED) and 2 treatment failures). ELN cytogenetics was adverse (n=5), intermediate (n=1) or failed (n=4). Twelve patients were all treated after frontline 7+3 and intensive consolidation courses (n=10) or azacytidine (n=2). Three patients were refractory to prior intensive chemotherapy or AZA and 9 were in first or subsequent relapse, at time of CLAG-M administration. Median time from first treatment for MDS/AML to CLAG-M onset was 17 mos (3-29). Initial/relapse ELN cytogenetics was adverse (n=5), intermediate (n=5) and failed (n=2). Of these 12 patients, 7 obtained a response (6 CR, one CRi), 3 failed to obtain a response and 2 early died from sepsis. Seventeen patients could be classified, according to Lindsley et al. The 3 patients with missing NGS data, all had adverse ELN cytogenetics (inv3q/MECOM1, MLLr by FISH analysis or monosomy 7, associated with an IDH2 mutation). After one course, 5/7 patients, classified as secondary AML, obtained a CR, including one CRi, 3/4 patients classified as pan AML obtained a CR, while only 2/6 patients with mutated TP53 alleles obtained a CR (3 failed to respond). Overall, 12 of the 20 patients obtained a complete response (11 CR and 1 CRi), despite adverse genetical characteristics and 12 of them being administered CLAG-M, during the late evolution of their disease. Three patients early died due to undocumented pneumonitis (n=2) or bacterial sepsis (n=1). Otherwise, observed treatment toxicities were mild, with no unusual infections seen after CLAG-M. Median duration of neutropenia ( Disclosures Peffault De Latour:Amgen Inc.: Research Funding; Pfizer Inc.: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Braun:CELLIPSE: Research Funding.