Short title / Key scientific finding Sorafenib Short title / Key scientific finding Sorafenib as maintenance therapy post alloHSCT for FLT3-ITD positive AML: results from the randomized, double-blind, placebo- controlled multicentre Sormain trial There was 31.7% difference found in RFS between sorafenib (85%) and placebo (53.3%) Results of 2-year relapse and non relapse mortality showed no significant difference (p=0.011 and p=0.981, respectively) in sorafenib and placebo At 30 months (end of the study), OS was not significantly different between the groups [HR=0.447 (95% CI: 0.20, 0.97), p=0.03 Overall 24.1% patients received sorafenib, 22.9% patient received chemotherapy and 8.4% patients received second alloSCT treatment after relapse Most common grade 3/4 AEs in sorafenib vs placebo were infections (26.2% vs 23.1%), GvHD (76.8%; placebo, 59.8%), skin toxicity (11.9% vs 2.6%) Post-transplant sorafenib improves OS in FLT3 mutated AML: A report from the EBMT ALWP (Retrospective registry; N=462) The 2-year LFS, OS, and GRFS were reported to be 51%, 59%, and 38% respectively Multivariate analysis showed that maintenance with sorafenib in NPM1pos significantly improved RI (p=0.001), LFS (p=0.01), OS (p=0.03), GRFS (p=0.002) In sorafenib post-transplant, multivariate analysis showed significance in RI (p=0.05), LFS (p=0.01), OS (p=0.03) and GRFS (p=0.02) Matched-pair analysis was performed in the sorafenib vs no sorafenib (n=26 each) - The 2-year LFS for the sorafenib vs no sorafenib was 79% vs 54% (p=0.02) - The 2-year OS for the sorafenib was 83% vs 62% in the no sorafenib (p=0.007) - The 2-year GFRS for the sorafenib vs control was 68% vs 38% Overall 158 pts relapsed, 39% of pts achieved CR in sorafenib compared to 38% in no sorafenib group In pts that relapsed after alloHCT treatment significantly improved OS after sorafenib treatment as compared to no sorafenib (p=0.002) In pts with FLT3mut AML post alloHCT sorafenib either as prophylactic or preemptive therapy or as treatment for relapse, significantly improved OS, LFS, GRFS and may be considered as a SoC Burchert Abstract # 661 Bazarbachi Abstract # 708 AEs, adverse events; alloSCT, allogeneic stem cell transplantation; ALWP, acute leukemia working party; AML, acute myeloid leukemia; ITD, internal tandem duplication; GvHD, graft-versus-host-disease; GRFS, GVHD relapse free survival; mos, months; OS, overall survival; LFS, leukemia free survival; pts, patients; RFS, relapse-free survival; SoC, standard of care AIHAMLppt/ONCO/1101206 /XX/JAN/2019

Sorafenib as maintenance therapy post alloSCT for FLT3-ITDpos AML: results from the randomized, double-blind, placebo-controlled multicenter SORMAIN trial Burchert (Abstract # 661) Objectives To assess whether prophylactic FLT3-ITD inhibition with sorafenib can prevent AML relapse & improve outcome of pts in CHR after alloSCT Methods SORMAIN Trial (EudraCT 2010-018539-16; DRKS00000591) was done at 15 centers in Germany & Austria (primary endpoint analysis date was July 2018) Results Results of 2-year relapse and non relapse mortality showed no significant difference (p=0.011 and p=0.981, respectively) in sorafenib and placebo At 30 months (end of the study), OS was not significantly different between the groups [HR=0.447 (95% CI: 0.20, 0.97), p=0.03 Overall 24.1% patients received sorafenib, 22.9% patient received chemotherapy and 8.4% patients received second alloSCT treatment after relapse Most common grade 3/4 AEs in sorafenib vs placebo were infections (26.2% vs 23.1%), GvHD (76.8%; placebo, 59.8%), skin toxicity (11.9% vs 2.6%) Authors Conclusions Sorafenib was well-tolerated and post-alloSCT maintenance with sorafenib significantly reduces the risk of relapse/death resulting in an improved survival. 2 year extension of sorafenib maintenance after allo-SCT might be helpful AML, acute myeloid leukemia; AEs, adverse events; allo-SCT, allogenic stem cell transplantation; CHR, complete hematological remission; d, day; GVHD, graft- versus host disease; HLA, human leukocyte antigen; ITD, internal tandem duplication; mos, months; OS, overall survival; pts, patients; qd, once a day; RFS, relapse-free survival; tbl, tablet; yrs, years. AIHAMLppt/ONCO/1101206 /XX/JAN/2019

Autologous CAR-T cells CAR-T depletion EGFRt/iCasp9 FLT3 inhibitor treatment increases FLT3 expression that exposes FLT3-ITD+ AML blasts to elimination by FLT3 CAR-T Cells Jetani (Abstract # 903) Objectives This in vitro and in vivo study determined the antileukemic efficacy of combination treatment with FLT3 inhibitors and FLT3 CAR T cells. Methods IC50 dosage of FLT3 inhibitors (midostaurin, quizartinib and crenolanib) were administered in FLT3 mutant AML cell lines MOLM-13 (ITD+/-) and MV4-11 (+/+). THP-1 (wt) was used for WT AML cell line MOLM-13 engrafted NSG mice were treated with 5x106 CAR T cells alone or in combination with the FLT3 inhibitors Results In vitro Increase in FLT3 expression was observed in FLT3-ITD+ AML cells after treatment with FLT3 inhibitors (quizartinib > crenolanib > midostaurin) FLT3 CAR-T demonstrated superior lysis of FLT3-inhibitor treated AML cells Crenolanin/quizartinib had the strongest synergy with FLT3 CAR-T cells In vivo FLT3 inhibitors induced higher FLT3 expression Fastest and deepest leukemic remission was demonstrated for FLT3 CAR-T + crenolanib FLT3 CAR-T cells recognize normal hematopoietic stem cell and interferes with hematopoiesis Proposed clinical implication strategy: T-cells from patient Autologous CAR-T cells (Therapeutic window) Pre-transplant: CR/MRDNeg induction CAR-T depletion EGFRt/iCasp9 Donor alloHSCT Post transplant GvL Authors Conclusions FLT3 CAR-T cells both in vitro and in vivo demonstrated potent reactivity. FLT3 inhibitors also enhance surface expression of FLT3 on ITD+ AML cells increase the anti-leukemic efficacy of FLT3-CAR T cells Small molecule inhibitors and CAR T cell can be used synergistically. The concept is applicable with any FLT3 inhibitor with increased efficacy, lowered toxicity and risk of antigen escape is mitigated AML, acute myeloid leukemia; alloHSCT, allogeneic hematopoietic stem cell transplantation; CAR, chimeric antigen receptor; CR, complete remission; GvL, graft versus leukemia; ITD, internal tandem duplication; MRD, minimal residual disease; Neg, negative; NSG, NOD scid gamma AIHAMLppt/ONCO/1101206 /XX/JAN/2019