CMV Status Predicts Survival in Refractory/Relapsed Myeloid Patients after a Clofarabine-Based Sequential Regimen: A Retrospective Study on Behalf of the SFGM-TC

Abstract

Background: Recently, we have published the prospective results of a sequential regimen using a clofarabine (clo), cytosine arabinoside and reduced-intensity conditioning (RIC) regimen in 24 cases with primary refractory acute myeloid leukemia (AML) showing encouraging results with a very low non relapse mortality (Mohty, 2017). Here we report the outcomes after such sequential regimen in a larger cohort of patients.Methods: This was a retrospective study including all patients reported within the SFGM-TC registry having received a clo-based sequential conditioning regimen before allotransplant for active myeloid disease. Data were obtained through PROMISE, an internet-based system shared by all European transplantation centers. All patients gave informed consent allowing to collect their personal data from this data base.The sequential regimen consisted of clo (30 mg/m2/day) and cytosine arabinoside (1 g/m2/day) for 5 days, followed, after a 3-day rest, by RIC combining cyclophosphamide (60 mg/kg), iv busulfan (3.2 mg/kg/day) for 2 days and anti-thymocyte globulin (2.5 mg/kg/day) for 2 days.The primary objective of the study was to report the main outcomes at 1 year: overall survival (OS), disease free survival (DFS), relapse incidence (RI), NRM and GVHD Relapse free survival (GRFS). Secondary objectives were to identify prognostic factors for patient's survival.Results: Between January 2007 and December 2016, 131 patients (males n=75, median age: 52.6 years, range: 18-71) met the inclusion criteria. There were 111 AML patients, including 9 secondary AML, and 20 cases with myelodysplastic or myeloproliferative syndrome. Status at transplant was as follows: primary refractory n=81, relapse 1 or 2 n=46, missing n=4. The majority of patients received peripheral blood stem cell as source of graft (n=127, bone marrow n=4). All patients received a graft from a matched donor (sibling n=64, unrelated n=67). Donor (D)/recipient (R) CMV status was as follows: D-/R-: n=55, D+/R-: n=14, D-/R+: 24, D+/R+: 38.Engraftment was observed in 105/122 assessable cases (86%) and patients achieving complete remission (CR) after transplant were 63% (n=72/114 evaluable cases). With a median follow-up of 12 months (range: 2.7-74.3) for alive patients, 1-year OS, DFS, RI, NRM and GRFS were 39.2% [30.2-48.2], 28.1% [19.8-36.5], 41% [32.1-49.8], 30.8% [22.7-39.3], and 22.2% [14.3-30], respectively.In univariate analysis, the only factor associated with lower survivals and GRFS and higher RI was unexpectedly a D-/R- CMV status at transplant: 1-year OS: 30% vs others status: 46.1%, =0.009; 1-year DFS: 18.1% vs 35.7%, p=0.015; 1-year GRFS: 11.9% vs 29.9%, p=0.009; 1-year RI: 53.2% vs 31.9%, p=0.004. In multivariate analysis, D/R CMV negative status remained independently associated with lower OS (HR: 1.74, 95%CI: 1.10-2.76, p=0.016), DFS (HR: 1.70; 95%CI: 1.09-2.66, p=0.018) and GRFS (HR: 1.76; 95%CI: 1.15-2.71, p=0.009) and higher RI (HR: 2.48; 95%CI: 1.37-4.50, p=0.002). D/R CMV status was not associated with NRM.Conclusion: Despite high CR achievement, this large cohort of patients confirmed the relatively poor outcome of patients with active myeloid disease at transplant and receiving a clofarabine-based sequential regimen. Post-transplant strategies should be proposed early to improve results and decrease incidence of relapse. The favorable impact on survivals of positive D or R CMV status may be related to a potential graft-vs-leukemia effect of CMV reactivation (thanks to NK or T cells stimulation) after transplant. The validation of this hypothesis is on-going. DisclosuresPeffault De Latour:Novartis: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding. Mohty:Sanofi: Honoraria, Speakers Bureau.