Pattern and Outcomes of Synchronous Neoplasms in Patients with Philadelphia Chromosome Negative Myeloproliferative Neoplasm (MPN): A SEER Database Analysis

Introduction: MPNs, including essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF), survivors are reported to have a higher frequency of subsequent malignancies. However, patterns of synchronous neoplasm (SN), defined as primary neoplasms diagnosed within six months of each other [Moertel et al., Cancer. 1961], is not well described for MPNs. Telomere biology, particularly long telomere length [DeBoy et al., NEJM, 2023] and other biological factors may predispose patients (pts) to a higher risk of SN. Identification of patterns of SN in MPN pts will inform further investigations into the predisposition of two distinct, yet co-existing, malignancies. Methods: We interrogated NCI's Surveillance, Epidemiology and End Result (SEER)-17 registries to analyze adult pts diagnosed with MPN [ICD-O-3 codes: PV 9950/3, ET 9962/3, and PMF 9961/3] during the years 2000 to 2021, and another non-myeloid SN. The neoplasms were identified using ICD-O-3/WHO-2008 site codes. Pts with a diagnosis of second myeloid neoplasm were excluded. SNs were categorized as solid and lymphoid (lymphoma, lymphocytic leukemia, and myeloma). Demographic data were extracted using SEER-Stat v8.4.3 software's MP-SIR session. We also retrieved data for pts with diagnosis of only MPN during this period. Descriptive statistics, chi-squared test (to calculate difference between categorical variables), and Kaplan-Meier survival analysis were performed using R(v4.2.2)-software. Results: A total of 52,187 pts with MPN diagnosis (aged ≥15 years) during 2000-2021 were analyzed. There were 10.3% (n= 5355/52187) pts with a second non-myeloid neoplasm, including SN within 6 months in 1.6% (n=851). Majority of pts diagnosed with SN were men 57.7% (n= 491/851), with white race 85.7% (n= 729/851), and had median (IQR) age of 70 (62-77) years at diagnosis. We next retrieved data for pts with a diagnosis of MPN without other neoplasm and survival beyond ≥6 months (N= 34,373, henceforth, ‘pts without SN‘). This cohort comprised predominantly women (52.7%), white race (80.1%), and had a median age of 64 (52-74) years at diagnosis. Among MPN pts with SN (n=851), index diagnosis of ET, PV, and PMF was noted in 43.9% (n=374), 42.8% (n=364), and 13.3% (n=113). Lymphoid and solid SN constituted 23% (n=196/851) and 77% (n=655/851), respectively. There was greater proportion of lymphoid malignancies as SN in pts with PMF (34%, n= 39/113), compared to PV (20%, n=73/364) and ET (22.5%, n= 84/374). When subcategorizing lymphoid SN, there was higher proportion of synchronous lymphoma in pts with PMF (21%, n=24/113), compared to PV (8%, n=30/364) and ET (12%, n=44/374). Distribution of synchronous acute or chronic lymphocytic leukemia and myeloma did not differ significantly among pts with PV, PMF and ET. Solid SN were more frequent in PV (80 %, n= 291/364) and ET (77.5%, n=290/374) than PMF (65.5%, n=74/113). The four most common solid synchronous cancers [lung and bronchus (20.1%, n=132/655), prostate (12.9%, n=85), breast (11%, n=73), and colorectal cancer (10.7%, n=70)] comprised 54.5% of all solid SN. These were followed by approximately 7% each of kidney (n=51) and skin (n=42) cancers. When stratified by age at MPN diagnosis (18-50, 50-65, 65+ years), a greater proportion of pts with SN were 65+ years at diagnosis vs pts without SN (65.4% vs 46.2%, χ2 test P<0.0001). When comparing pts with solid vs lymphoid SN, proportion of pts in these age groups, particularly 50-65 (29.3% vs 19.9%) and 65+ years (63.5% vs 71.4%), was significantly different (P=0.033). Median survival (OS) was significantly lower in MPN pts with SN compared to without SN [median OS (95% CI): 65 (56-74) months vs 165 (161-169), log rank test P< 0.0001]. Conclusion: In this cohort of over 50000 pts with MPN diagnosis between 2000-2021, 10% had a second non-myeloid neoplasm, including 1.6% with a SN within six months of MPN. Patients with SN had a significantly lower OS. The screenable solid SN (breast, colorectal, lung and prostate cancers) were the most commonly occurring SN, highlighting the importance of implementation of existing screening guidelines. Lymphoid neoplasms were the next most common, noted in one-third of PMF pts with SN. These co-existing unrelated neoplasms, diagnosed particularly at older age, necessitate future studies to elucidate molecular and mechanistic explanations of the evolution of distinct malignant clones in pts with MPN.