Splicing Gene Mutations Do Not Affect Outcomes in Newly Diagnosed Patients with Acute Myeloid Leukemia

Background: Recent studies have shown that splicing factor (SF) gene mutations in AML implicate a negative prognostic significance associated with secondary AML and are now included as adverse in the 2022 ELN guidelines (Dohner et.al., Blood 2022). However, the contribution of these mutations to the prognosis of patients (pts) with AML, relative to their age, prior history of myeloid disorders, cytogenetics (CTG), concurrent mutations and frontline (FL) therapy requires further characterization.

Methods: We retrospectively analyzed all pts with newly diagnosed (ND) AML treated at our center over the last 5 years (yrs) and compared outcomes for patients with and without SF mutations (S^mut= SF3B1, SRSF2, U2AF1 and ZRSR2). FL therapy was classified as intensive (INT) and low intensity (L-I), with/without venetoclax (VEN). Relapse free survival (RFS) was calculated from the time of response to relapse or death and overall survival (OS) was calculated from the time of therapy initiation to death; both were censored at last follow up (F/U)

Results: From January 2017 to April 2022, 994 ND pts with AML were reviewed; 266 (27%) had S^mut in ≥ 1 of the SF genes while the rest were wild type (S^WT). The most common S^mut was SRSF2 (53%). Only 3% pts had >1 S^mut (Table 1). The median age of S^mut group was 72 yrs compared to 65 yrs in the S^WT group, and significantly more pts in the former had secondary/therapy related AML (s/t AML) (51% vs 41%). The S^mut group had less complex karyotype (CK), non CK adverse risk CTG and did not include any pts with core-binding factor (CBF) leukemias. Fewer pts in the S^mut had a pathogenic TP53^mut but had higher frequencies of RUNX1 and ASXL1 mutations. Overall, 71% S^mut pts were classified as ELN 2017 adverse risk compared to 54% S^WT pts (p<0.0001). 20% pts in the S^mut group vs. 44% S^WT pts received INT therapy (p<0.0001). Of the S^mut pts who received L-I therapy, 62% received a hypomethylating agent (HMA) and 66% received a VEN- based combination, frequencies similar to the S^WT group. At a median F/U of 26 months (mos), the median RFS and OS was 9.6 vs. 12.4 and 13.1 vs 13.3 mos for the S^mut and S^WT groups respectively. Given the significant age heterogeneity between the 2 groups we analyzed by young (<60 yrs) and older (≥60 yrs) pts with non-CBF AML and compared survival outcomes (Fig.1). Both S^mut and S^WT pts had similar RFS and OS in their respective age groups. In a small subgroup of older pts with de novo AML with CK treated with L-I regimens, the RFS and OS were especially dismal for those with S^mut (RFS= 1.5 vs 5.7 mos, p=0.14 and OS= 2.6 vs 9.3 mos, p=0.003). For other subgroups (stratified based on ELN risk stratification, de novo or s/t AML, CK, TP53^mut) outcomes of S^mut and S^WT were similar in both young and older pt groups treated with INT or L-I therapies. S^mut pts who received VEN in the L-I arm had better RFS and OS, especially if they had denovo AML (RFS= 19 vs 5.5 mos and OS 25 vs 4 mos).

On univariate (UV) analysis using age, CTG [adverse risk (AR) /intermediate risk (IR)], therapy arm (INT/L-I), S^mut/S^WT status and concurrent mutations (TP53, ASXL1, RAS, RUNX1, NPM1, FLT3-ITD) as covariates for overall response (OR= CR/CRi/MLFS): lower age, IR-CTG, TP53^wt, RAS^wt ,FLT3^mut, NPM1^mut and use of INT therapy were favorable while all the factors other than FLT3^mut , age and therapy arm remained significant on the multivariate (MV) model. Within the S^mut cohort, the presence of SF3B1^mut alone negatively affected the odds of OR (0.65, 95%CI=0.3-0.98) on UV but not on MV analysis. Cox regression analysis demonstrated adverse risk CTG, TP53^mut and s/t AML had higher hazards of relapse, while the above factors along with the presence of RAS^mut increased the hazards of death. On stratifying by specific S^mut, no individual mutation impacted OS. Cox regression analysis of the above covariates affecting RFS and OS in S^mut pts who received L-I therapy showed VEN based combinations significantly reduced the hazards for relapse (0.5, 95% CI=0.3-0.8) and death (0.5, 95%CI=0.3-0.7). Overall, the presence of S^mut did not affect response rates to therapy, RFS or OS in both young and older pts treated with L-I (majority VEN based) or intensive therapy.

Conclusion: S^mut are more common in elderly pts with AML and in s/t AML. S^mut does not necessarily affect response rates and survival outcomes compared to S^WT pts when controlled for these covariates, and with current therapeutic options including HMA + VEN based regimens.

Short:Takeda Oncology: Consultancy, Research Funding; Astellas: Research Funding; AstraZeneca: Consultancy; Novartis: Consultancy; Stemline Therapeutics: Research Funding; Amgen: Consultancy, Honoraria; Pfizer: Consultancy. Daver:Agios, Celgene, SOBI and STAR Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kartos and Jazz Pharmaceuticals: Other: Data monitoring committee member; Karyopham Therapeutics and Newave Pharmaceutical: Research Funding; Astellas, AbbVie, Genentech, Daiichi-Sankyo, Novartis, Jazz, Amgen, Servier, Karyopharm, Trovagene, Trillium, Syndax, Gilead, Pfizer, Bristol Myers Squibb, Kite, Actinium, Arog, Immunogen, Arcellx, and Shattuck: Consultancy, Other: Advisory Role; Astellas, AbbVie, Genentech, Daiichi-Sankyo, Gilead, Immunogen, Pfizer, Bristol Myers Squibb, Trovagene, Servier, Novimmune, Incyte, Hanmi, Fate, Amgen, Kite, Novartis, Astex, KAHR, Shattuck, Sobi, Glycomimetics, Trillium: Research Funding. Pemmaraju:stemline: Consultancy; abbvie: Consultancy; immunogen: Consultancy; mustangbio: Research Funding; incyte: Consultancy; novartis: Research Funding; pacylex: Consultancy, Research Funding; samus: Research Funding; daiichi sankyo: Research Funding; cellectis: Research Funding; cellularity: Research Funding. Sasaki:Pfizer: Membership on an entity's Board of Directors or advisory committees; Otsuka Pharmaceuticals: Honoraria; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Borthakur:Astex Pharmaceuticals, Ryvu, PTC Therapeutics: Research Funding; Pacylex, Novartis, Cytomx, Bio Ascend: Membership on an entity's Board of Directors or advisory committees; Catamaran Bio, Abbvie, PPD Development, Protagonist Therapeutics, Janssen: Consultancy. Ravandi:Novartis: Consultancy; Syos: Consultancy, Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy; Amgen: Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Biomea Fusion, Inc.: Research Funding; Xencor: Research Funding; Prelude: Research Funding; Astex/Taiho: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Research Funding. Kantarjian:Amgen: Honoraria, Research Funding; Ipsen Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; ImmunoGen: Research Funding; KAHR Medical Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees; NOVA Research: Honoraria; Novartis: Honoraria, Research Funding; Jazz Pharmaceuticals: Research Funding; Pfizer: Honoraria, Research Funding; Daiichi-Sankyo: Consultancy, Research Funding; AbbVie: Honoraria, Research Funding; Ascentage: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas Health: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria. DiNardo:Cleave: Research Funding; Novartis: Honoraria; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Forma: Research Funding; GenMab: Membership on an entity's Board of Directors or advisory committees; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding; Servier: Consultancy, Honoraria, Research Funding; Astellas: Honoraria; Bluebird Bio: Honoraria; Foghorn: Honoraria, Research Funding; ImmuneOnc: Honoraria, Research Funding; Takeda: Honoraria; LOXO: Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Astex: Research Funding; Kura: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; Jazz: Honoraria.