Singh, Amritpal

Background An increased risk of second cancers (SC), in patients with myeloproliferative neoplasms (MPN), has been suggested by a number of population-based and cancer registry studies (Blood 2011;118:6515). Such studies often included patients belonging to a broad category of MPN entities and did not always account for history of cancer prior to the diagnosis of MPN, associated comorbidities, mutations, or treatments received, in assessing risk association and prediction (Leukemia 2019;33:1996). The current study seeks to fill knowledge gaps, in this regard, in the context of a biologically more homogeneous MPN setting, vis-ẚ-vis polycythemia vera (PV) and essential thrombocythemia (ET). Methods The present study was conducted under an institutional review board approved minimum risk protocol that allowed retrospective collection and analysis of data from Mayo Clinic patient records. Diagnostic criteria were according to the International Consensus Classification (Blood 2022; 140:1200). Documented primary cancers were annotated in 17 categories, not including pre-cancerous conditions or MPN progressions. SC was defined as any cancer that developed after 3 months from the initial diagnosis of MPN. Cox proportional hazard regression model was used for univariable and multivariable analysis. Kaplan-Meier plots were used for time-to-event assessment (considering the first in case of multiple events). Results The study population included 1,968 consecutive patients (median age 60 years; 56% females) with PV (N=1,001) or ET (N=967), seen at the Mayo Clinic between 1970 and 2024. Median follow-up was 8.6 years. The incidences of arterial/venous thrombosis were14%/12% at diagnosis and 12%/10% after diagnosis. Co-morbid conditions included diabetes (12%), hypertension (52%), tobacco use (16%), and history of autoimmune/inflammatory disease (AID; 6%); hyperlipidemia was annotated in PV cases only (51%). Non-driver mutation information was available in 620 patients: TET2 (13%), ASXL1 (7%), DNMT3A (5%), SRSF2 (3%), SF3B1 (3%) and TP53 (2%). A history of another cancer was documented in 598 (30%) patients and included cancers documented before/at (N=291; 15%) or after (N=404; 20%) the diagnosis of MPN, with only the latter being referred to as “SC”. Most frequent cancer type was non-melanoma skin cancer (NMSC), accounting for 28% of cancers diagnosed before/at MPN, and 47% of SC; other SC types included lymphoid neoplasms (10%), melanoma (10%), prostate cancer (9%), and trachea/lung/bronchial cancer (8%), as the most frequent. On multivariable analysis, cancer history, before/at or after MPN diagnosis, clustered with age >60 years (OR 2.7), male sex (OR 1.5), and history of AID (OR 1.7). History of cancer prior to MPN diagnosis, NMSC or otherwise, was associated with inferior overall survival (p<0.01); by contrast, neither myelofibrosis-free (p=0.5) nor leukemia-free (p=0.8) survival was affected. Median time from MPN diagnosis to SC was 5.7 years. In multivariable analysis including all cancers, SC-free survival was adversely affected by age>60 years (HR 2.5; p<0.01), male sex (HR 1.7; p<0.01), history of previous cancer (HR 2.5, p<0.01), and AID history (HR 1.6; p<0.01); all these 4 risk factors remained significant after excluding NMSC. Interestingly, among informative cases, SRSF2 mutation also predicted SC (HR 2.6; p=0.02), even after NMSC cases were excluded (HR 3.4; p=0.02). Pre-MPN history of cancer did not affect either arterial (p=0.9) or venous thrombosis-free survival (p=0.7), in age- and sex-adjusted analysis. Conversely, after excluding post-SC thrombotic events, venous (p=0.02) but not arterial (p=0.1) events, occurring after MPN diagnosis, were predictive of SC. This association remained significant in multivariable analysis that included age, sex, and venous thrombosis history (p=0.03). Additional observations from this study, include an independent association between SC and hyperlipidemia in PV (p<0.01) and ruxolitinib monotherapy with NMSC (HR 9; p<0.01). Conclusions The risk of SC in patients with MPN is significantly higher in older patients, men, and in the presence of pre-MPN cancer history and AID. Incidental venous, but not arterial, thrombosis was associated with subsequent SC, not NMSC. The observed association of SC with SRSF2 mutations and hyperlipidemia is noted but requires further validation.

AbstractTwo‐hundred pregnancies involving 100 women with essential thrombocythemia (ET) were accessed from Mayo Clinic databases (1990–2023). Median platelet count displayed a decline during pregnancy, nadiring at 48% of baseline, in the third trimester: 704–369 × 109/L. Live birth rate was 72%. Of 53 (27%) unintentional pregnancy losses, 48 (24%) occurred in the first trimester. Other fetal complications included preterm birth 3%, intrauterine growth retardation 3%, and stillbirth 1%. Maternal complications included major hemorrhage (7%), preeclampsia (6%), thrombosis (1%), and placental abruption (0.5%). Antepartum management included no specific therapy in 52 (26%), aspirin alone in 112 (56%), aspirin combined with cytoreductive drugs or systemic anticoagulants in 23 (12%), and other permutations in the remaining. Postpartum systemic anticoagulation was documented in 29 (15%) pregnancies. Unintentional first‐trimester loss was predicted by prior fetal loss (43% vs. 18%; p < .01), diabetes mellitus (DM; 67% vs. 23%; p = .02), and absence of aspirin therapy (45% vs. 14%; p < .01); the salutary effect of aspirin therapy was independent of the other two risk factors and apparent in both high (presence of ≥1 risk factor; 33% vs. 61%; p = .07) and low (absence of both risk factors; 10% vs. 34%; p < .01) risk scenarios. The benefit of aspirin therapy, in preventing first‐trimester loss, was significant in both JAK2‐mutated (18% vs. 50%; p < .01) and CALR‐mutated (8% vs. 43%; p < .01) cases. Aspirin use was also associated with a lower risk of venous thrombosis (0% vs. 3%; p = .03). By contrast, the use of systemic anticoagulation, antepartum or postpartum, did not influence fetal or maternal complication rates. CALR mutation and DM predicted maternal hemorrhage (13% vs. 4%; p = .05) and preeclampsia (33% vs. 5%; p = .03), respectively. The current study demonstrates the protective role of aspirin in preventing first‐trimester loss in ET, independent of driver mutation status or other risk factors.

AbstractWe retrospectively examined our experience with midostaurin therapy in 33 consecutive patients (median age 68 years; 58% females) with advanced systemic mastocytosis (adv‐SM): aggressive SM (ASM; n = 17), SM associated with another hematologic neoplasm (SM‐AHN; n = 14) and mast cell leukemia (MCL; n = 2). KITD816V mutation was detected in 84% of the patients and C findings in 91%. Eleven (33%) patients were previously treated with other cytoreductive drugs, including cladribine (n = 4) and imatinib (n = 3). Median time from diagnosis to initiation of midostaurin therapy was 2.2 months (range 0.3–41). Using modified valent criteria, overall response was 42% (53% ASM, 29% SM‐AHN, 50% MCL; p = .22), all classified as being major. Responses included ≥50% reduction in bone marrow mast cells in 40% and normalization of serum tryptase in 29%, of evaluated cases. After a median follow‐up of 14.6 months from initiation of midostaurin therapy, 7 (21%) deaths, 1 (3%) leukemic progression, and 18 (55%) treatment discontinuations were documented; median duration of midostaurin treatment was 7.9 months (range 0.5–123) and response duration 21.5 months (range 2.9–123). Most frequent side effect was gastrointestinal (51%) while grade 3/4 neutropenia or thrombocytopenia occurred in 12% of patients. Response to treatment was not predicted by KIT mutation (p = .67) or exposure to prior cytoreductive therapy (p = .44). Median survival was longer in midostaurin responders but not significantly (median 26.5 vs. 16 months; p = .15). Findings from the current study are broadly consistent with previously published clinical trial observations.