1. 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/ /XX/JAN/2019

2. 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 ; DRKS ) 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/ /XX/JAN/2019

3. 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/ /XX/JAN/2019