Sustained Effect of First Line Sequential Therapy with Intensive Consolidation Chemotherapy and Allogeneic Hematopoietic Stem Cell Transplantation (ASCT) after Reduced Intensity Conditioning (RIC) for Patients with Acute Myeloblastic Leukemia (AML) in First Complete Remission (CR1).
Authors: Blaise Didier , Tabrizi R. , Faucher C. , Mohty Mohamad , Bay J.O. , Boiron J.M. , Marit G. , Furst S. , Stoppa A.M. , Charbonnier A. , Prebet T. , Chabannon C. , Vey N. 
Published: October 2019

Abstract
We recently reported our experience using RIC prior to ASCT in pts with AML in CR1 (Blaise, Cancer, 2005). We have shown that RIC-based ASCT can be safely used in this setting after intensive consolidation chemotherapy. With a median follow-up of 18 months, disease control was high and was not related to a selection bias (Mohty, Leukemia, 2005). In the present analysis, we investigated if this control was maintained after a longer follow-up. Thirty-seven pts (age: 51 (range, 26–60)) with high risk clinical characteristics (n=26; 70%) (Age ≥ 50 (N=22, 59%); Associated severe comorbidity (N=10; 30%)) and/or poor risk leukemic features (n=24; 65%) (Poor Cytogenetics (N=13, 35%); failure of first induction course (N= 10, 27%); secondary leukemia (N= 4; 11%), High white blood cell counts(N= 5; 14%) or partial remission (N=1, 3%)) were included in this analysis. After CR1, all pts received a low dose cytarabine consolidation chemotherapy followed one month later by one course of high dose cytarabine (24 g/m²) and anthracycline (HIDAC). Pts were then scheduled to receive ASCT prepared with RIC (fludarabine (180 mg/m²), busulfan (8 mg/kg), Thymoglobulin (2.5 to 10 mg/kg)) followed with BMT (N=10 (28%) or PBSC (N=26 (72%)). However after treating the first pts, it becomes evident that this schedule was not associated prohibitory toxicity. All following pts were, thus, proposed to receive one month after HIDAC, one course of melphalan (140 mg/m²) (HDMEL) with auto-SCT followed after recovery by the allo-SCT. Overall, 21 pts received HIDAC only and 16 HIDAC and HDMEL. Median follow-up at time of abstract is 3 years (16 months–70 months). 15 pts experienced aGVHD (Grade 1: 7; Grade 2: 4; Grade 3–4: 4). The cumulative incidence of grade 2–4 aGVHD was 22% (9–35). 33 pts (90%) were evaluable for cGVHD: 10 and 14 pts presented a limited and extensive form respectively. The cumulative incidence of cGVHD was 65 % (50–80). Three deaths were attributed to non-relapse causes (AGVHD: 1; CGVHD: 2° (cumulative incidence of non-relapse death (NRD): 8% (95% CI: 0–17). In all, 8 pts relapsed at 5 months (2–19) (cumulative incidence: 22% (95% CI, 9–35). Relapse was clearly associated with the absence of cGVHD (cGVHD: 4 (4–12), no cGVHD 44% (12–76), p=.02) and at a lesser extent with the intensity of consolidation chemotherapy (HIDAC: 33% (13–53); HIDAC + AUTO; 6% (0–19%), p=.06). Twenty-six pts are still alive in CR1 for overall survival and leukemia-free survival (LFS) probability estimates at 4 years of 67 % (95%CI, 49–81%) and 68% (95%CI, 50–81%) respectively. When restricting the analysis to the 33 pts evaluable for cGVHD, cGVHD remained the only independent risk factor positively influencing LFS (cGVHD: 83% (59–74); no cGVHD (56% (27–81), p=.03). We conclude that RIC Allo-SCT preceded by adequate prior intensive chemotherapy might offer a relatively low NRD while exerting a sustained leukemia control even in high risk pts. The intensity of intensive chemotherapy needed for optimal will be assessed prospectively.