Immunomodulation with Azacytidine and Donor Lymphocyte Infusion Following Sequential Conditioning Allogenic Stem Cell Transplantation Improves Outcome of Unfavorable AML

Abstract

Background : Patients with acute myeloid leukemia in relapse or refractory to induction therapy have dismal prognosis. Response rates to common salvage regimens are low and allogenic hematopoietic stem cell transplantation is the only curative option. Several studies have demonstrated that salvage chemotherapy with sequential conditioning could reduce leukemia relapse risk with an acceptable toxicity profile for unfavorable acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). [1] Therefore, we decided to assess this procedure in our center at Amiens University Hospital. Methods We conducted a monocentric retrospective study, including 53 patients aged over 18 years undergoing a hematopoietic stem cell transplant (HSCT) with sequential conditioning between January 2012 and December 2018, for relapse/refractory AML or high risk MDS. 44 (83%) patients received sequential conditioning containing clofarabine (SET-RIC) or Amsacrine (FLAMSA) and 9 (17%) thiotepa based (TEC-RIC) with post-transplant cyclophosphamide for mismatched donors. Patients who were GVHD free after immunosuppressors withdrawal received immunomodulation as relapse prevention with azacytidine 37.5mg/m²/day 5 days every 4 weeks for 12 cycles with 3 donor lymphocyte infusions (DLI) alterned between azacytidine cycles. Results The median age was 52 years (range 18-70). Before conditioning, 48 patients had unfavorable AML with ELN intermediate score refractory to at least one course of induction therapy or in relapse, or unfavorable ELN score; 5 patients had high risk MDS with complex karyotype. 32 patients (60,5%) had active disease and 21 (39,5%) were in complete remission (CR) including 12 with positive MRD. 13 (24,5%) patients had HLA-identical sibling donors, 27 (51%) match unrelated donors (MUD), 4 (7,5%) mismatch unrelated donors (MMD) and 9 (17%) haploidentical donors. Majority of patients (90,5%) received peripheral blood stem cell (PBSC) PBSC with median CD34+ count of 7,94.106/kg (1,84-8,44). Acute GvHD prophylaxis with Ciclosporin A, in combination with Mycophenolate mofetil for MUD/MMR/Haplo, was withdrawal with a median time of 90 days. With a median follow-up of 40 months, overall survival (OS) at 1 and 2 years was 68% and 52%. Median OS was 18,7 months (0-72,4 months) and median disease free survival (DFS) was 14,9 months (0-72,4 months). 17 patients (32%) experienced relapse after HSCT with a median time from HSCT to relapse of 6 months (1-35 months). 22 (41,5%) of patients presented with grade I-II acute graft versus host disease (GVHD) and 6 (11,3%) with grade III IV aGVHD . GVHD free relapse free survival (GRFS) at 1 and 2 years was 53% and 34,2%. One-year cumulative incidence of disease related death and non-relapse mortality was 12,6% and 17% respectively. 19 patients received immunomodulation with 5 Azacitidine and DLI if no GVHD occurred within day 120. OS was 79 % in the 19 patients receiving DLI. In univariate analysis immunomodulation post HSCT (Figure 1) was significantly associated with overall survival and leukemia free survival (p=0,0164 and p=0,0359 respectively) but not the disease status before HSCT (p=0,7). Immunomodulation administration with azacytidine and DLI was not significantly associated with cGVHD occurrence (p=0.31). Benefit of immunomodulation OS persisted in multivariate analysis (p=0.0284). Conclusion: Sequential conditioning regimen on refractory AML with secondary immunomodulation with azacytidine and DLI shows very good results with an acceptable toxicity profile in unfavorable AML. We achieve very good OS and DFS whatever disease status before HSCT. GRFS is also encouraging comparing to previously report datas [1]. Reference: [1] Similar outcome of allogeneic stem cell transplantation after myeloablative and sequential conditioning regimen in patients with refractory or relapsed acute myeloid leukemia: A study from the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire. Decroocq et al. Am J Hematol 2018 ;93 :416-423. Figure 1 Disclosures No relevant conflicts of interest to declare.

Maintenance With Hypomethylating Agents After Allogeneic Stem Cell Transplantation in Acute Myeloid Leukemia and Myelodysplastic Syndrome: A Systematic Review and Meta-Analysis

“…Two HMAs were used in this meta-analysis: azacitidine and decitabine. The OS, RFS and NRM outcomes of the azacitidine group were significantly better than those of the observation group ( Figures 2 , 3 ) ( 14 , 16 – 20 , 22 , 28 ). Likewise, the decitabine arm had superior OS, RFS and CIR outcomes to those of the observation arm ( Figures 2 , 3 ) ( 21 , 24 , 29 ).…”

“…The work by Guillaume et al, Joris et al, and Booth et al compared HMAs in combination with DLI and observation arms. Although the OS and RFS outcomes tended to be better for HMAs combined with DLI, only RFS rates were statistically significant (pooled RR, 1.20; 95% CI, 0.86–1.67; I 2 , 37%; and pooled RR, 1.33; 95% CI, 1.09–1.62; I 2 , 0%; Figure 6 ) ( 19 , 20 , 27 ).…”

“…Decitabine was administered at 5–20 mg/m 2 on Day 1 to Day 5 every 6–12 weeks for 1–22 cycles. Some patients received prophylactic DLI in addition to HMA maintenance in five studies ( 14 , 18 – 20 , 22 , 27 ).…”

Commentary: Maintenance with hypomethylating agents after allogeneic stem cell transplantation in acute myeloid leukemia and myelodysplastic syndrome: A systematic review and meta-analysis

“…In reviewing the other studies included in the metaanalysis, some had not accounted the immortal time bias (7)(8)(9)(10)(11). All patients were included at time of transplantation leading to an overestimation of the efficacy of HMA.…”

“…In addition, some studies used prophylactic donor lymphocytes infusion (7,12) or gemtuzumab ozaogamicin (8), which may further overestimate the effect of HMA. Finally, data recovery was probably an issue because some of studies were not published as regular article but as a letter or as a poster at conference (7)…”