Burden of Morbidities Associated with Splenomegaly and From Existing Treatments In Patients with Myelofibrosis
Authors: Harrison Claire N. , Elkins Benjamin R. , Yee Kimberly , Nellesen Dave , Pulgar Sonia 
Published: October 2019

Abstract 5059

Background:

Myelofibrosis (MF) is a Philadelphia chromosome-negative myeloproliferative neoplasm (MPN) that often presents with moderate to massive splenomegaly secondary to extramedullary hematopoiesis. Symptoms such as cachexia and fatigue can occur as a consequence of anemia, splenomegaly, and potentially also due to the effects of circulating cytokines. MF may present de novo as primary (P)MF or following essential thrombocythemia or polycythemia vera (post ET/PV MF). Although there are no approved therapies for MF, treatments currently used in clinical practice include cytoreductive medications, splenectomy, and splenic irradiation as well as supportive care for disease related anemia and symptoms. As the burden of splenomegaly in MF has not been well documented, a critical review of the literature was conducted to describe associated morbidities and existing treatments for splenomegaly in patients with MF.

Methods:

A comprehensive search of Medline, EMBASE, Cochrane Library, and ASH, ASCO, and EHA abstracts was conducted to identify studies that included PMF and post ET/PV MF patients with splenomegaly. Only primary reports of investigational or observational studies conducted among humans were retained. Studies that did not identify MF as a primary baseline condition or did not identify patients as having splenomegaly were excluded. Aggregate data on prevalence of splenomegaly, severity of splenomegaly (including assessment method), morbidities, and therapies investigated for treatment of splenomegaly were systematically extracted from included studies. Additional hand-searching was done to identify other potentially relevant publications.

Results:

The search yielded 688 studies, of which 100 were retained after applying inclusion and exclusion criteria. Retained studies varied in study type, including 1 pooled analysis, 29 clinical trials, 11 prospective studies, 18 retrospective studies, and 41 case reports, and included data on 3,402 patients. Among these patients, 50 unique baseline morbidities were identified; 66% (2,248) had splenomegaly. Other morbidities reported in ≥5% of patients included: anemia (25%), thrombocytopenia (14%), transfusion dependence (11%), and hepatomegaly (9%). Other less commonly reported but severe morbidities included cachexia, fecal incontinence, splenic infarction, and portal hypertension. Health-related quality of life (HRQoL) studies of MF and other MPN also described a substantial burden due to pain, fatigue and weight loss, which may be in part due to splenomegaly.

Of the 33 different therapies with an expected or observed effect on splenomegaly, the most commonly investigated therapies (≥5 studies) were alpha2 interferon (5 studies; 40 patients), thalidomide (8 studies; 345 patients), and splenectomy (18 studies; 540 patients). Thirty-nine unique grade 3/4 treatment-emergent adverse events (TEAEs) were reported across the 33 investigated treatments. Treatment-related death was reported in 10 studies, occurring in 48 out of 490 treated patients (9.8%). The most commonly reported (≥6 studies) grade 3/4 TEAEs were fatigue, thrombocytopenia, neutropenia, bleeding or hemorrhage, and rash or dry skin. Eight of the 18 studies (44%) investigating splenectomy reported at least one treatment-related death, with a total of 35 deaths among 427 patients (8.2%). The largest included study of splenectomized MF patients (n=314) reported a surgery-related mortality rate of 6.7% (Mesa et al., Cancer 2006). Substantial inconsistencies in the measurement of splenomegaly and in the reporting of morbidities limited analysis of results.

Conclusions:

MF patients with splenomegaly experience a wide range of function-limiting and, in some cases, life-threatening morbidities. Numerous morbidities were reported in the literature, including anemia, transfusion dependence, cachexia, pain, portal hypertension, bleeding and hemorrhage, and fecal incontinence. Treatment options are limited and bear significant risks, including mortality risk and severe hematologic adverse events associated with medical therapies. Future investigations could significantly improve the body of evidence through standardization in the assessment of splenomegaly and associated morbidities and systematic measurement of HRQoL in the context of prospective studies.

Disclosures:

Harrison: Incyte: Honoraria; Novartis: Honoraria.