Salvage-free, transplantation-free survival (STFS) in AML: Proposition for a novel clinical endpoint to better assess the efficacy of novel drugs in combination with intensive chemotherapy. a dataml registry study.

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Abstract IntroductionResults from pivotal clinical trials evaluating the combination of intensive chemotherapy (IC) with inhibitors of IDH1, IDH2, menin, FLT3 and BCL2 are expected in the coming years. These results could transform the therapeutic landscape for AML patients (pts) fit for IC. However, although some of these studies are placebo-controlled, interpreting phase 3 results in the field of AML is often tricky since consolidation treatments may include allo-HSCT, which has a very different mechanism of action, highly effective in preventing relapse, but also potentially toxic. Furthermore, salvage treatments including targeted agents and/or allo-HSCT for induction failure or relapse may also be curative. Traditional evaluation criteria such as OS, EFS, and RFS, are therefore potentially influenced by both therapeutic interventions. We postulate that any new molecules added to IC must be effective enough to significantly increase the proportion of patients who are cured after first-line treatment without the need for allo-HSCT in first CR or additional salvage therapy. Therefore, we propose to define a composite endpoint to analyze the specific impact of new drugs in the frontline treatment of AML: the salvage-free, transplantation-free survival (STFS). In this study, we evaluated this endpoint in a cohort of pts treated with IC with a special focus on subgroups for which significant progress is expected soon.MethodsInclusion criteria for the AML cohort: ND AML between 01/2010 and 12/2022, ≥18y, treated with IC. Exclusion criteria: pts treated in clinical trial assessing novel drugs. Inclusion criteria for the APL cohort (used as control): ≥18y, between 01/2010 and 12/2022, first-line treatment including arsenic trioxide (ATO) and ATRA. EFS, RFS and OS were calculated according to ELN 2017 definition. STFS was measured from day 1 of induction chemotherapy to the date of induction failure after 1 or 2 cycles, salvage therapy, morphologic or molecular relapse, allo-HSCT, or death from any cause, whichever occurs first (or the date of last contact if no event).Results1966 AML pts were included: median age, 62y; female sex (n=897, 46%), secondary AML (n=428, 22%), PS 0-1 (n=1549, 81%), median WBC (8.6 G/L), cytogenetic risk: favorable (n=174, 9%), intermediate (n=1322, 67%), adverse (n=470, 24%), ELN 2017: favorable (n=195, 20%), intermediate (n=163, 16%), adverse (n=629, 64%); mutations: NPM1 (n=530, 31%), FLT3-ITD (n=338, 20%), FLT3-TKD (n=94, 7%), IDH1 (n=116, 9%), IDH2 (n=126, 10%), KMT2Ar (n=57, 3%). CR/CRi rate was 83% after 1 or 2 IC cycles. Day-30 and -60 death rates were 6 and 8%. Allo-HSCT was performed in 561 pts (35%) during CR1 and in 244 pts (27%) after relapse. The APL cohort included 100 pts: age 53y, WBC ≥ 10 G/L: 16%, CR rate 93% after ATO/ATRA based-therapy, d30 and d60 death: 6% and 8%, 3 relapses, 0 HSCT.The median FU was 91 months. For the whole AML cohort, median OS, EFS, RFS and STFS were 31, 15, 22 and 6 months. In CBF-AML, median OS, EFS, RFS and STFS were not reached (NR, 74% at 5y), NR (57% at 5y), NR (58% at 5y) and 12 months (35% at 5y). In the NPM1mut without FLT3-ITD subgroup, OS, EFS, RFS and STFS were 109 (60% at 5y), 49 (46% at 5y), 69 (52% at 5y) and 22 months (37% at 5y). In pts with FLT3-ITD, median OS, EFS, RFS and STFS were 25, 12, 16 and 5 months. In pts with IDH1 mutation and wild type FLT3, median OS, EFS, RFS and STFS were 54, 16, 20 and 7 months. In pts with IDH2 mutation and wild type FLT3, median OS, EFS, RFS and STFS were 48, 17, 17 and 8 months. In pts with KMT2Ar, median OS, EFS, RFS and STFS were 23, 13, 14 and 4 months.In the APL cohort, 5y-OS, EFS, RFS and STFS were 86%, 85%, 91% and 84%.ConclusionThis study shows that there is considerable room for improvement in the outcome of AML patients, even in the favorable subgroups, who often require additional therapy to achieve a cure. The impact of truly effective first-line treatment is illustrated in APL patients, who previously had a similar prognosis to other AML patients before the era of PML-RARA directed therapies. Improving STFS should become a key objective in clinical trials assessing new targeted agents in combination with IC in AML.

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