Decitabine (DAC) in Combination with Donor Lymphocyte Infusions (DLIs) Can Induce Remissions of Overt Aml Relapses after Allogeneic Transplantation

Background: Treatment with the DNA hypomethylating agents (HMAs) 5-azacytidine (AZA) or DAC has become a well-established option for elderly MDS and AML patients (pts). Regarding their mechanism of action, HMAs not only reactivate tumor suppressor genes, but also lead to an immune activation response, by expression of Cancer/testis antigens (Almstedt et al., Leuk. Res. 2010; Goodyear et al., Blood 2010) and endogenous retroviruses (Chiappinelli et al., Cell 2015; Roulois et al., Cell 2015). Hypothesizing that HMA-mediated immune activation may sensitize blasts to subsequent DLIs, we and others showed that AZA combined with DLIs can induce long-term remissions in pts with relapsed MDS/AML after allogeneic transplantation, particularly with a low leukemic burden, and after failure to respond to DLIs alone (Steinmann et al., BMT 2015, Schroeder et al., BBMT 2015). As DAC is considered useful also in pts with higher WBC and higher blast counts, we now treated 18 pts (most of them with more aggressive hematologic relapse) with DAC+DLIs.

Patients and Methods: Between 10/06 and 03/16, 18 pts (median age 63 years, range 29-76, 10 males) with hematological relapse after allogeneic transplantation were treated with DAC and (where feasible) DLIs. Thirteen pts had AML (genetic risk by ELN: 3x int-1, 4x int-2, 6x adverse (4 MK+), 3 had MDS, 1 had polycythemia vera, 1 had atypical CML. Sixteen and 2 pts had received reduced-toxicity conditioning (mostly FBM) and myeloablative conditioning, respectively. Donors: matched unrelated in 8 pts, matched sibling in 4, mismatched in 6. DLIs at relapse after 1st/2nd transplant in 15/3 pts (1st/2nd/3rd/4th relapse in 11/5/1/1 pts). Median duration from transplant to hematologic relapse was 306 days (range, 56-4943). Median % blasts before DAC was 4% in peripheral blood (pb, range, 0-40%), 30 % in bone marrow (range, 7-60%), the median WBC was 4,770/µl (range, 430-30,800). DAC (20 mg/m² per day) was administered either as a standard 5-day (15 pts) or a 10-day course (3 pts). DLIs were to be given 7 days after the last HMA dose. Prior AZA as relapse treatment was allowed.

Results: Of 18 pts with myeloid neoplasias (mostly AML) with hematologic relapse after allografting, 15 received DAC+DLIs (for 8 of them after previous DLI-only, for 3 after previous AZA+DLI), 3 pts only received DAC (median number of DAC cycles: 2, range 1-8, median number of DLIs: 2, range 1-10). Two AML pts (aged 64 and 76 yr, no previous AZA, 7 and 4% pb blasts, respectively) attained a complete hematologic and molecular remission after 5-day DAC+DLI, with a duration of 250+ and 391 days, respectively. One of them is still in CR with no signs of GvHD, the other died in CR because of liver GvHD and hemosiderosis. A third AML pt attained complete donor chimerism following DAC+DLI but died at day 35 because of a fungal pneumonia (concurrent Sorafenib). Eleven additional pts achieved a temporary disease control (median duration 93 days, range 34-212), 5 of them were subsequently re-transplanted. Four pts showed no response to DAC+DLI, 3 developed GvHD. Seven pts died of PD, 6 pts of infections, 1 pt of intracranial hemorrhage, 1 pt of GvHD.

Conclusions: DAC in combination with DLIs showed good feasibility in pts with relapsed AML/MDS after allogeneic transplantation. Despite overall higher median WBC and blast expansion than a large previous cohort treated with AZA+DLI, clinical activity was comparable, and in 2/18 pts (11%) a complete hematologic and molecular remission was achieved (despite the presence of peripheral blood blasts). This approach is investigated prospectively within the RELDAC substudy of the EORTC trial AML21 of older AML patients (inDACtion vs. induction, NCT02172872).