Adverse Immunologic, Cytogenetic, and Molecular Features of AML in Elderly Patients Could Be Overcome by Allogeneic Hematopoietic Cell Transplantation Following Reduced Intensity Conditioning
Authors: Al-Ali Haifa Kathrin , Jaekel Nadja , Krahl Rainer , Nehring Claudia , Becker Cornelia , Braunert Leanthe , Leiblein Sabine , Edelmann Jeanett , Franke Georg , Poenisch Wolfram , Lange Thoralf , Niederwieser Dietger 
Published: October 2019

Abstract
Abstract 3065
Allogeneic hematopoietic cell transplantation (HCT) following reduced-intensity-conditioning (RIC) is a curative therapeutic option in elderly patients with AML. Yet, hematological relapse (HR) and non-relapse mortality (NRM) remain major issues. The impact of AML characteristics, post-induction consolidation chemotherapy (PCC) in patients with complete remission (CR), type of donor [unrelated (UD) vs. related (RD)], graft cell count, and Donor-cell-chimerism (DCC) on long-term outcome and management of relapse after HCT following 200 cGy TBI + fludarabine 30 mg/m2 for 3 days followed by mycophenolate mofetil and cyclosporine were analysed in 245 consecutive patients with AML [132 male/113 female; median age 62 years] transplanted at the University of Leipzig. De novo and secondary AML were diagnosed in 151 (62%) and 94 (38%) patients respectively. A positive leukemic CD34-phenotype > 15% was present in 60%.Cytogenetics were high and intermediate (IR)-risk in 64 (26.7%) and 166 (69%) patients respectively. FLT3 -mutations (FLT3 mut) were present in 32 (28%) of the 115 patients with known FLT3 status. CR at HCT was present in 85% (CR1, n=155; CR2, n=53). The number of PCC applied was 0 in 88 (42%), 1 in 93 (45%), and 2 in 25 (12%). Donors were UD in 197 (80%) and RD in 48 (20%) patients. DCC in flow-sorted CD34+-marrow cells at days 28, 56, 84, and at 3 months interval thereafter was monitored by PCR of polymorphic micro satellite regions. After a median follow-up of 3.6 years, survival (OS), leukemia-free-survival (DFS), NRM, and Relapse (RI) at 5-years were 39%, 34%, 32% and 51% respectively. Engraftment was 95.5%. Incidence of acute GvHD > grade 3, limited and chronic GvHD was 22.5%, 20%, and 44.6% respectively. In multivariate analysis, type of AML, cytogenetics, CD34+-phenotype, and graft cell counts (CD3+, CD34+- and natural killer-cells) had no impact on outcome. Irrespective of the number of PCC applied, outcome was similar for CR1 and CR2. For the entire cohort and also for patients with IR-cytogenetics in CR, FLT3 mut did not adversely affect OS or RI. The lower RI after UD-HCT (39%) compared to RD-HCT (63%) (p=0.04) was opposed by a higher NRM after UD-HCT (36%) vs. 13% for RD-HCT (p=0.05) so that long-term OS and LFS were similar for both donor types. Chronic GvHD was associated with a superior OS, LFS and lower RI compared to patients without GvHD or with acute GvHD only (p<0.0005). Irrespective of leukemic CD34+-phenotype, CD34+-DCC day28 <90% was highly predictive of inferior OS (12%) and higher RI (95%) vs. OS of 50% and RI of 39% if CD34+-DCC day28 was > 90% (p<0.0001). In multivariate analysis, UD (p=0.007), female donor/male patient (p=0.02), and a higher CD34+- (p=0.01) but not CD3+-cells in the graft correlated with CD34+-DCC day28 was > 90%. HR and CD34+-DCC <90% without HR were managed by immunomodulation + chemotherapy. Overall, CR was achieved in 29% of HR and 36.4% of CD34+-DCC <90%. Relapse beyond day 100, a declining CD34+-DCC rather than a HR, and induction of GvHD correlated with a superior response and OS after relapse. Donor cells rather than the usual AML prognostic features predict long-term survival and relapse after RIC-HCT. In particular, CD34+-DCC is very effective in predicting outcome and identifying patients at risk of relapse thereby allowing early immunomodulation to enhance the graft-versus-leukemia effect. Yet, research is needed to further optimize the graft-versus-leukemia effect without the injurious effects of GvHD.

Disclosures:
No relevant conflicts of interest to declare.