Adolescents and Young Adults (AYA) with Myeloproliferative Neoplasms (MPNs): Analysis of Patient Outcomes and Impact of High-Molecular Risk Mutations

Introduction: Despite the median age of classical MPN being 65 years (yrs) old, an increasingly recognized group is comprised of AYA patients (pts) aged 15-39 yrs. The impact of high-molecular risk mutations (HMR) have begun to be evaluated in MPN AYA (England Leuk 2024; Boddu Ann Hematol 2018), however comprehensive data are lacking in this area. We sought to analyze our large cohort of MPN AYA pts, highlighting their unique clinical characteristics with a focus on evaluating the impact of HMR mutations on transformation/survival outcomes.

Methods: Pts with ET, PV, or MF were included in either AYA (15-39 yrs) or non-AYA (>40 yrs) per age at diagnosis. Overall survival (OS), transformation-free survival ([TFS]; development of post-MPN blast phase [BP]), myelofibrosis-free survival (MFS), and event-free survival (EFS; development of either post MPN-BP or post-ET/PV-MF) were determined from time of diagnosis. We evaluated the impact of HMR mutations (presence of >1 mutation in ASXL1, EZH2, IDH1/2, SRSF2, TP53, or U2AF1 Q157) on EFS and OS in AYA pts.

Results:

3,765 pts with MPN were included, of which 454 (12%) were AYA. Median age of AYA was 33 yrs [15 - 39 yrs] vs 62 yrs [40-95 yrs] in non-AYA. AYA were mostly female (63%) vs non-AYA (46%). The most common AYA MPN was ET (n = 238, 53%), followed by PV (n = 118, 26%), and MF (n = 98, 22%), vs mostly MF seen in non-AYA (n = 2034, 61%), followed by PV (n = 662, 20%), and ET (n = 615, 19%). 56 (12%) AYA (ET = 25, PV = 21, MF = 10) had prior thromboses (including 17 hepato/splenic/portal) vs 483 (15%) thromboses in non-AYA, p 0.18. More AYA (n = 32, 7%) experienced prior bleeding vs non-AYA (n = 163, 5%), p 0.04. AYA had less splenomegaly vs non-AYA (20% vs 39%, p < 0.001), as well as less frequent cytogenetic abnormalities (7% vs 29%, p < 0.001). Thrombotic events during follow-up did not differ between AYA vs non-AYA (1.5% vs 1%, p 0.73), however there were fewer bleeding events in AYA vs non-AYA (2% vs 4%, p 0.04).

Median JAK2 VAF was lower in AYA vs non-AYA (32.2% vs 49%, p 0.002). Baseline Hb (g/dL) did not differ between AYA and non-AYA (median 14.4 vs 14.2, p 0.53), however there was a trend towards lower WBC count (K/uL) in AYA vs non-AYA (9.2 vs 10.5, p 0.05). There was a higher incidence of splenomegaly in AYA vs non-AYA (24% vs 2%, p < 0.001).

In AYA, the majority were JAK2 (54%), followed by CALR (29%) and MPL (1%). The incidence of CALR was similar between AYA vs non-AYA (29% vs 21% p 0.12). 25 AYA (11%) were IPSET high risk due to prior thrombotic event. Median platelet (plt) counts (K/uL) were higher for AYA vs non-AYA (669 vs 585, p < 0.001). No significant difference in BM blast %, WBC, or splenomegaly were seen in AYA vs non-AYA.

More AYA were CALR vs non-AYA (43% vs 22% p < 0.001). AYA were mostly DIPSS-plus intermediate-1 vs non-AYA who were mostly DIPSS-plus intermediate-2. Median Hb (g/dL) was higher in AYA vs non-AYA (11.8 vs 10.4, p < 0.001); the same was observed with plt (K/uL) (274 vs 212, p < 0.001). Baseline WBC did not differ between AYA and non-AYA. While there was no difference between median BM blast % in AYA vs non-AYA, fewer AYA had peripheral blasts >1% (34% vs 46% p < 0.001).

Median follow-up was 7 yrs [0.1 - 42 yrs] in AYA vs 6.8 yrs in non-AYA [0.1 - 36.3 yrs], p 0.008. 15-year OS was 92% vs 41% for all AYA MPN vs all non-AYA MPN, p < 0.001. 15-year EFS was 98% vs 85% in AYA vs non-AYA, p < 0.001. 10 AYA (2%) progressed to post-ET/PV MF, vs 50 non-AYA (4%), p 0.28; median MFS was not reached (NR) in both AYA and non-AYA. For ET, 15-yr MFS was 99% vs 93% in AYA vs non-AYA, p 0.01, however, 15-yr MFS was no different among AYA vs non AYA in PV. 10 AYA pts (2%) developed post-MPN BP vs 178 pts (5%) in non-AYA, p 0.003; median TFS was NR in both AYA and non-AYA.15-year TFS was 99% vs 89% in AYA vs non-AYA, p < 0.001.

20/232 (9%) AYA with available NGS had a HMR (ASXL1 = 13, IDH1 = 0, IDH2 = 2, EZH2 = 1, TP53 = 4, SRSF2 = 0, U2AF1 = 0). AYA with > 1 HMR vs no HMR had 15-yr OS of 81% vs 98%, p 0.04 and a 15-yr EFS of 90% vs 99%, p < 0.001.

Conclusions: MPN AYA pts experienced superior OS, TFS, and EFS vs non-AYA. Among AYA, the incidence of HMR approached 10%, and the presence of >1 HMR negatively impacted both OS and EFS. These data significantly underscore the importance of performing NGS in all pts with MPN, including AYA, as although their survival is superior, they remain at risk for transformation to more aggressive disease states. Obtaining these data carries prognostic significance and may inform risk stratification.

Kantarjian:AbbVie, Amgen, Ascentage, Ipsen Biopharmaceuticals, KAHR Medical, Novartis, Pfizer, Shenzhen Target Rx, Stemline,Takeda: Consultancy, Honoraria. Masarova:GSK: Consultancy, Other: Travel support; Cogent: Other: Advisory Board Participant; MorphoSys: Other: Advisory Board Participant; PharmaEssentia: Other: Advisory Board Participant. Daver:Genentech: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; FATE Therapeutics: Other: Consulting Fees, Research Funding; Gilead: Consultancy, Research Funding; Servier: Consultancy, Research Funding; Jazz: Consultancy; Glycomimetics: Research Funding; Hanmi: Research Funding; Novartis: Consultancy; Novimmune: Research Funding; Arog: Consultancy; Shattuck Labs: Consultancy; Trovagene: Research Funding; Daiichi-Sankyo: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; KITE: Research Funding; Celgene: Consultancy; Syndax: Consultancy; Agios: Consultancy; Menarini Group: Consultancy; Pfizer: Consultancy, Research Funding. Jabbour:AbbVie, Adaptive Biotechnologies, Amgen, Astellas Pharma, BMS, Genentech, Incyte, Pfizer, Takeda: Consultancy; AbbVie, Adaptive Biotechnologies, Amgen, Ascentage Pharma Group, Pfizer, Takeda: Research Funding. 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Garcia-Manero:Curis: Research Funding; Helsinn: Research Funding; Merck: Research Funding; Bristol Myers Squibb: Other: Personal fees, Research Funding; Astex: Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Helsinn: Other: Personal fees; Aprea: Research Funding; Janssen: Research Funding; Forty Seven: Research Funding; Genentech: Research Funding; Amphivena: Research Funding; Astex: Other: Personal fees; AbbVie: Research Funding; Novartis: Research Funding; Genentech: Other: Personal fees. Ravandi:Prelude: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Astyex/Taiho: Research Funding; Amgen: Research Funding; Syros: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria; Xencor: Research Funding; Abbvie: Consultancy, Honoraria. 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