www.oncotarget.com Oncotarget, 2018, Vol. 9, (No. 93), pp: 36603-36612 Research Paper Clofarabine/busulfan-based reduced intensity conditioning regimens provides very good survivals in acute myeloid leukemia patients in complete remission at transplant: a retrospective study on behalf of the SFGM-TC Amandine Le Bourgeois1, Myriam Labopin2, Mathieu Leclerc3, Régis Peffault de Latour4, Jean-Henri Bourhis5, Patrice Ceballos6, Corentin Orvain7, Hélène Labussière Wallet8, Karin Bilger9, Didier Blaise10, Marie-Thérese Rubio11, Thierry Guillaume1, Mohamad Mohty2, Patrice Chevallier1 and on behalf of Société Francophone de Greffe de Moelle et de Thérapie Cellulaire 1Department of Hematology, CHU Hôtel Dieu, Nantes, France 2Department of Hematology, Hôpital Saint Antoine, Paris, France 3Department of Hematology, Hôpital Henri Mondor, Créteil, France 4Department of Hematology, Hôpital Saint Louis, Université Paris 7, Denis Diderot, Paris, France 5Department of Hematology, Hôpital Gustave Roussy, Paris, France 6Department of Hematology, CHU de Montpellier, Montpellier, France 7Department of Hematology, CHU d’Angers, Angers, France 8Department of Hematology, Centre Hospitalier Lyon Sud, Lyon, France 9Department of Hematology, CHU Strasbourg, Strasbourg, France 10Department of Hematology, Centre de Recherche en Cancérologie de Marseille, Institut Paoli Calmettes, Marseille, France 11Department of Hematology, CHU Nancy, Nancy, France Correspondence to: Amandine Le Bourgeois, email: [email protected] Patrice Chevallier, email: [email protected] Keywords: allogeneic stem cell transplantation; clofarabine; busulfan; reduced intensity conditioning regimen; acute myeloid leukemia Received: August 24, 2018 Accepted: November 01, 2018 Published: November 27, 2018 Copyright: Bourgeois et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Background: Clofarabine has been proved to have higher anti-leukemic myeloid activity compared to fludarabine, a drug extensively used as part of reduced intensity conditioning (RIC) for allogeneic stem cell transplantation (allo-SCT). Results: Eighty-four patients were included. The majority of patients had acute myeloid leukemia (AML, n = 63). Sixty-one patients were in complete remission (AML n = 55). With a median follow up of 31 months (range: 5.7–74.1), 2-year overall (OS) and disease-free (DFS) survivals, relapse incidence (RI), non-relapse mortality (NRM) and graft-versus-host disease (GVHD)/relapse free survival (GRFS) were 64.5% (53.8–75.2); 57.2% (46.2–68.2); 27.7% (18.2–37.9); 15.1% (8.2–23.9) and 43.6% (32.5–54.7), respectively. Considering AML in remission, 2-year OS, DFS, RI, NRM and GRFS were 74.2% (62–86.5); 66.8% (53.6–79.9); 23.4% (12.7–36); 9.8% (3.5–19.9) and 50.9% (36.9–64.9), respectively. Two-year outcomes were similar between CloB2A1 and CloB2A2 sub-groups. In multivariate analysis, active disease at transplant was the only factor adversely impacting 2 years outcomes. Conclusions: CloB2A2/A1 RIC regimen provides very good results for AML patients allografted in CR and could be retained as a new RIC platform for these patients. www.oncotarget.com 36603 Oncotarget Materials and Methods: This was a retrospective study including all patients who received a clofarabine/busulfan based RIC allo-SCT for myeloid malignancies and reported within the SFGM-TC registry. RIC regimen consisted of clofarabine 30 mg/ m²/day 4 to 5 days (Clo), busulfan 3.2 mg/kg/day 2 days (B2) and 2.5 mg/kg/day of rabbit anti-thymocyte globulin 1 or 2 days (A1 or A2). The primary objective of the study was to report the main outcomes of the whole cohort at 2 years. INTRODUCTION (CloB2A1) after 2014 with the aim to decrease relapse, [4] we also assessed the effect of this lower dose on outcomes. Reduced-intensity conditioning regimens (RIC) were successfully introduced twenty years ago to RESULTS decrease the toxicity of myeloablative allogeneic stem cell transplantation (allo-SCT). This resulted in the doubling of Characteristics of patients (Table 1) the number of allo-SCT performed each year, because older patients and those with comorbidities could tolerate such Between January 2008 and December 2016, 84 a procedure [1–7]. The FB2A2 regimen (fludarabine 30 patients (males n = 47, median age: 61.6 years) met the mg/kg/day for 5 days, busulfan 3.2 mg/kg/d iv for 2 days, inclusion criteria. The outcomes of some patients have and rabbit anti-thymocyte globulin (ATG) 2.5 mg/kg/d already been reported [16, 18]. The majority of patients for 2 days) was rapidly established as one of the standards had AML (n = 63), including 43 cases in CR1, 12 in CR2 of care for RIC regimen in Europe, especially in France and 8 with active disease at transplant. According to ELN- [4–9]. risk classification [21], 7 AML cases were classified as As relapse remains as one of the main causes of favorable, 24 as intermediate-1, 8 as intermediate-2 and 6 morbidity and mortality after allo-SCT, strategies to as unfavorable (unknown n = 18). There were 21 patients improve outcomes of patients were developed thereafter, with MDS (n = 18) or MPS (n = 3), including 6 in CR1 including modification of the conditioning regimen (all MDS) and 15 with active disease at transplant. All using the same drugs at higher dose (reduced-toxicity patients but one (bone marrow graft) received peripheral myeloablative conditioning regimen, FB3/FB4) [10–12] or blood stem cell as graft source. All patients received cells other drugs with higher anti-leukemic activity. For the latter, from matched donors (sibling n = 34; unrelated n = 50). clofarabine, a second-generation purine analogue, has been There were no significant differences in terms of proven to have both anti-myeloid [13–15] and anti-lymphoid characteristics between CloB2A2 (n = 43, median follow- activity [16, 17]. Recently, clofarabine (Clo) has been up 39 months) and CloB2A1 (n = 41, median follow-up 21 used as part of fludarabine-busulfan-based conditioning months) patients, except for the median age of the cohort regimen instead of fludarabine, showing encouraging (65 vs 61 years, p = 0.02), the dose of clofarabine (≥150 results. Thus, the CloB2A2 RIC regimen (clofarabine mg/m2: 97.5% vs 49% of the patients, p < 0.001), which 30 mg/kg/day for 5 days, busulfan 3.2 mg/kg/day were higher in the latter group and, as expected, the median iv for 2 days, ATG 2.5 mg/kg/day for 2 days) has been year of transplant (2013 vs 2015, p < 0.001) (Table 1). All validated in a prospective phase II study including 14 patients engrafted except one CLOB2A1 case. patients with acute lymphoblastic leukemia (ALL), 11 with acute myeloid leukemia (AML) and 5 with Outcomes myelodysplastic syndrome (MDS). At one year, the overall survival (OS) and leukemia free survival (LFS) With a median follow up of 31 months (range: were of 63% and 57%, respectively, and the non-relapse 5.7–74.1) for patients alive, the 2-year OS, LFS, RI, and mortality (NRM) only of 3.3%, suggesting a very good NRM were 64.5% (53.8–75.2), 57.2% (46.2–68.2), 27.7% safety profile of the RIC regimen [18]. More intensive (18.2–37.9) and 15.1% (8.2–23.9), respectively. The CI of clofarabine/busulfan RIC regimens (CloB4) have also 100-day acute GVHD grade II-IV and III-IV were 20.2% shown good safety profile after transplant for ALL (12.4–29.4) and 7.1% (2.9–14), respectively. The 2-year [19]. Our group retrospectively compared the CloB2A2 CI of extensive chronic GVHD was 9.6% (4.1–17.8%). (n = 39) versus FB2A2 (n = 316) RIC regimens in a cohort The 2-year GRFS was 43.6% (32.5–54.7). The median of patients with myeloid disease, and showed a significant time to relapse/progression from the transplant was OS benefit for the former in multivariate analysis [20]. 5.6 months (range: 0.59–31.5). At last follow-up, 32 patients The aim of the present study was to confirm the had died, mainly due to relapse (n = 17), then to GVHD favorable impact of the CloB2A2 RIC regimen in a (n = 6), infection (n = 6), hemorrhage n = 1; larger cohort of patients with myeloid malignancies. microangiopathy n = 1, and non-identified transplant- Also, because some centers decreased the dose of ATG related n = 1. www.oncotarget.com 36604 Oncotarget Table 1: Patients’ characteristics Whole cohort CloB2A1 CloB2A2 p-value N = 84 n = 41 n = 43 Median follow-up: months (range) 30.9 (5.7–74.1) 20.7 (5.7–34.3) 38.9 (20.5–74.1) Median year of transplant 2014 (09–16) 2015 (14–16) 2013 (09–16) <0.001 Gender: males 47 (56%) 25 (61%) 22 (51%) 0.36 Median age at transplant: years 61.6 (20.6–73.9) 65 (24.6–73.9) 60.8 (20.6–71.1) 0.028 (range) Diagnosis: 0.9 AML 63 (75%) 31 (75.6%) 32 (74.4%) MDS/MPS 21 (25%) 10 (24.4%) 11 (25.6%) Status at transplant: 0.39 CR1 49 (58.3%) 27 (65.8%) 22 (51.2%) CR2 12 (14.3%) 5 (12.2%) 7 (16.3%) Active disease 23 (27.4%) 9 (22%) 14 (32.5%) Recipient CMV status: + 40 (48%) 23 (56%) 17 (39.5%) 0.12 Type of donor: Gender: males 52 (62%° 27 (66%) 25 (58%) 0.46 Sibling 34 (40.5%) 19 (46.3%) 15 (34.9%) 0.285 MUD 50 (59.5%) 22 (53.7%) 28 (65.1%) CMV status: + 24 (29%) 9 (22%) 15 (35%) 0.19 Sex matching 0.47 Female → Male 13 (15.5%) 5 (12.2%) 8 (18.6%) Others 71 (84.5%) 36 (87.8%) 35 (81.4%) Stem-cell source 0.33 Bone Marrow 1 (1.2%) 0 (0%) 1 (2.3%) PBSC 83 (98.8%) 41 (100%) 42 (97.7%) Previous transplant: 0.19 No 75 (89.3%) 39 (95.1%) 36