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

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.