Abstract
Background: Primary myelofibrosis (PMF) is a myeloproliferative neoplasm that is marked by bone marrow fibrosis, cytopenias, extramedullary hematopoiesis, and a increased risk of acute leukemia. Leukocytosis is frequently seen and a white blood cell count (WBC) > 25,000/uL has been shown to convey an inferior prognosis. Rarely, patients develop severe leukocytosis (defined as WBC > 50,000/uL) either at presentation or during the course of their disease. Genomic characterization, management, and outcomes of these patients are not well defined. In this study, we aimed to further characterize PMF patients with severe leukocytosis and assess their clinical outcomes.
Methods: We retrospectively reviewed PMF patients who presented to our institution between 2001 and 2018. We included patients who developed a WBC count > 50K at any time during their clinical course. Patients who developed acute myelogenous leukemia (AML) were censored at the time of disease diagnosis. Overall survival (OS) defined from first date that WBC documented as > 50K.
Results: Among 493 PMF patients treated at our institution, 71 (14.4%) developed severe leukocytosis during the course of their disease. Ten (14%) had severe leukocytosis at the time of diagnosis and 30 (42%) developed it within 1 year of diagnosis and 40 (56%) developed it more than 1 year after diagnosis. Eight (11.3%) patients demonstrated peripheral blast percentage > 10% blasts at the time severe leukocytosis first documented.
Compared to patients who did not develop severe leukocytosis, those with severe leukocytosis had an increased frequency of EZH2 (p < 0.001), RAS (p < 0.001), and KIT (p = 0.04) mutations. ASXL1 mutations were seen in a similar proportion of patients (p = 0.41). A similar proportion of patients were high risk by GIPSS (26% v 24%) prognostic model.
From the time development of severe leukocytosis, the median overall survival (mOS) was 13.3 months. Median OS from diagnosis was significantly shorter for patients who developed severe leukocytosis (35.4 mo v 63.5 mo; p = 0.02) compared to those that did not. Eleven (15%) patients with severe leukocytosis developed AML compared to 38 (9%) patients who did not develop severe leukocytosis (p = 0.13). Median time to development of AML was 13.3 months from time of severe leukocytosis.
At development of severe leukocytosis, 12 patients (17%) received hydrea (mOS 14.0 months) and 9 patients (13%) received ruxolitinib (mOS 21.2 months). The remaining cohort which either received no documented treatment, an alternative treatment or unknown treatment had a mOS of 5.3 months. This was not statistically significant. Ten patients (14%) ultimately underwent allogeneic stem cell transplantation after the development of hyperleukocytosis.
Conclusion: Severe leukocytosis occurs rarely in primary myelofibrosis. RAS, KIT, and EZH2 mutations are enriched in these patients. Management strategies in these patients is varied and outcomes are poor. Further studies assessing the benefit of cytoreductive therapies in this population should be performed.
Sallman:Celgene: Research Funding, Speakers Bureau. Sweet:BMS: Honoraria; Astellas: Consultancy; Jazz: Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Jazz: Speakers Bureau; Phizer: Consultancy; BMS: Honoraria; Celgene: Honoraria, Speakers Bureau; Astellas: Consultancy; Agios: Consultancy; Phizer: Consultancy; Celgene: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Agios: Consultancy. List:Celgene: Research Funding. Komrokji:Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Kuykendall:Janssen: Consultancy; Celgene: Honoraria.
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