Clinical features and outcomes of myeloproliferative neoplasm patients with MPL mutations and concurrent JAK2/calr mutations Free

Backgroud Myeloproliferative neoplasms (MPNs) are a group of hematologic malignancies characterized by constitutive activation of the JAK-STAT signaling pathway, typically driven by mutations in JAK2, CALR, or MPL. Among these, JAK2 mutations are the most frequently observed, while MPL mutations are relatively rare. These driver mutations are generally mutually exclusive, and reports of concurrent MPL mutations with JAK2 or CALR are limited. Our study aims to characterize the clinical presentation of patients with MPNs who have MPL mutations with concurrent JAK2 or CALR mutations.

Method This retrospective case series was conducted at Massachusetts General Hospital (MGH) and Moffitt Cancer Center (MCC) between 2010-2022. At MGH, 33 patients with MPL mutations and a diagnosis of essential thrombocythemia (ET), myelofibrosis (MF), or unclassified MPN were identified through next-generation sequencing. At MCC, 54 patients with MF and MPL mutations were identified. All patients had minimum follow-up of six months. The final study cohort comprised 11 patients with concurrent MPL and either JAK2 or CALR mutations. Data collected included demographics, disease characteristics, molecular profiles, and treatment history. Prognostic risk scores (R-IPSET and MIPSS70v2) were manually calculated. Clinical outcomes included disease progression to post-ET MF or acute leukemia. Descriptive statistical methods were used to summarize patient characteristics and clinical outcomes.

Results 11 patients with concurrent mutations were identified from the 87 patients with MPL mutations identified at both sites. Of these, 4 were diagnosed with ET, including 2 who progressed to post-ET MF. 6 patients were diagnosed with primary MF, and 1 with unclassified MPN. 9 patients had concurrent MPL and JAK2mutations, while two had concurrent MPL and CALR mutations. MPL variants included W515L (n=7), W515R (n=1), P440L (n=1), R592Q (n=1), and Y519D (n=1). Of 9 patients with concurrent MPL and JAK2 mutations, 8 had V617F and one had T875N. Notably, the patients with concurrent MPL and CALR mutations had the MPL R592Q and P440L variants, which are less commonly reported. High molecular risk (HMR) mutations were identified in six patients: 5 had ASXL1, 1 had SRSF2, and 1 had ASXL1 and EZH2. Other mutations were also noted in multiple patients, including SH2B3 (LNK) in 4 patients, SF3B1, NOTCH1 and TET2 in 2 patients. 2 ET patients were noted only to have MPL and JAK2 without other mutations, and neither progressed to MF. The median age at diagnosis was 74 years (range 46–86), with a median follow-up duration of 33 months (range 14–182). 8 patients were white, 2 were black, and 1 was Hispanic. Median white counts, hemoglobin, and platelet counts at ET diagnosis were 9.4 × 10³/μL, 11.2 g/dL, and 513.0 × 10³/μL; corresponding values at MF or MPN unclassified diagnosis were 9.4 × 10³/μL, 11.2 g/dL, and 347 × 10³/μL. ET treatments included hydroxyurea and off-label Ropeginterferon alfa-2b. Among those with MF, 7 patients received ruxolitinib, 2 required anemia-related therapies, including darbepoetin alfa and Luspatercept. None of the patients received bone marrow transplant, and none progressed to acute myeloid leukemia. At the last follow-up, 5 out of 12 patients have died. Thromboembolic and bleeding events following diagnosis occurred in 2 out of 5 MGH patients; both after they were diagnosed with post-ET MF.

Conclusions This study demonstrates that phenotypic driver mutations co-occur in MPN patients. We identified 87 patients with MPL mutations and 11 patients demonstrated co-occurring mutations, suggesting that dual mutations occur more frequently than previously reported. Moreover, several patients exhibited rare MPLpathogenic variants, raising the possibility that rarer driver mutations impact JAK-STAT signaling differently, allowing additional driver mutations to co-occur. However, further work is required to investigate this hypothesis. Limited follow-up and the predominance of White populations in our cohort underscore the need for studies involving larger and more diverse populations with extended longitudinal data to better understand the prognostic significance and therapeutic implications of the co-mutations.