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Pharmacist Updates on a Rare Disease: Case Studies in the Management of Myelofibrosis

OVERVIEW

With advances in identifying molecular features and strides in next generation sequencing, our understanding of myeloid blood disorders has evolved rapidly. This evolution has allowed researchers and clinicians to better classify disorders arising from the myeloid blood line, leading to better diagnosis, prognosis, and ultimately treatment. The most recent classification system is the 2016 World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia.¹ Within this, primary myelofibrosis (PMF) is 1 of a number of myeloproliferative neoplasms (MPN). However, because of the genetic nature of PMF, it is frequently thought of together with 2 other MPNs, polycythemia vera (PV) and essential thrombocythemia (ET). Because of the genetic similarity of these three MPNs, PV and ET can morph into a myelofibrosis (MF)-like disease called post-PV or post-ET MF, which has similar outcomes and treatment to PMF.^2,3 Lastly, PMF is sub-divided into pre-fibrotic and overtly-fibrotic stages to further differentiate it from other MPNs.

MF is a rare disease that affects older adults with a median age of diagnosis of 67 years. The disease course can be aggressive with 10-year leukemic transformation risk occurring in nearly 20% of patients. This also accounts for the most common cause of MF-related death. Other causes of mortality include infections and bleeding events.⁴

Over 90% of MF cases result from 3 driver mutations: JAK2, CALR, and MPL. The most frequent mutation of the 3, JAK2 V617F mutation, leads to abnormal myeloproliferation by increasing cell signaling of the JAK-STAT pathway. Researchers more recently discovered CALR and MPL mutations, which also drive the disease phenotype.^5,6 If none of these mutations are present, the disease is considered “triple negative”. Triple negative disease is associated with the worst prognosis, whereas the presence of CALR is a positive factor that produces the best outcomes. Other mutations that are found in MF include ASXL1, SRSF2, and U2AF1Q157 at varying frequencies, and they have ramifications in MF disease prognostics.^7-9 These mutations have been implemented in an aggressive disease course and risk of leukemic progression.

Patients most frequently present with severe fatigue and anemia, occurring in 50% to 70% of patients with MF.¹⁰ Constitutional symptoms of early satiety, fever, and night sweats are often present. Other symptoms include bone pain, pruritis, thrombotic events, and bleeding. Marked hepatosplenomegaly is a hallmark sign and any findings of this on physical exam should warrant further evaluation and a full workup of hematologic laboratory values. Patients with circulating blasts of 3% or greater or platelet counts of less than 100 x 10⁹/L at diagnosis are at highest risk for leukemic transformation.¹¹ In addition, clinicians suspecting MF should perform a bone marrow biopsy to diagnose the disease. The diagnosis of MF is based on the WHO diagnostic criteria consisting of 3 major and 5 minor criterions (Table 1). Patients must meet all 3 major criteria and at least 1 minor criterion to establish an MF diagnosis.

RISK STRATIFICATION

Risk stratification for MF was initially performed via the International Prognostic Scoring System (IPSS) which evaluated the presence of 5 clinical factors.¹² Clinicians use this system at the time of diagnosis to evaluate survival. Expanding on this base, development of the Dynamic International Prognostic Scoring System (DIPSS) allowed clinicians to score survival at any time throughout the disease course.¹³ Improvement of that system was seen with the advent of the DIPPS+ prognostic model, which took into consideration the addition of platelet count, red blood cell (RBC) transfusions, and karyotype for a total of 8 risk factors.¹⁴ The DIPSS and DIPSS+ systems are acceptable to use if molecular analysis is not available.

Experts devised the Mutation-Enhanced International Prognostic Scoring System (MIPSS70) to take into account mutational information and a younger population of those younger than 70 years of age. This specifically addressed those who are most likely eligible for curative therapy with bone marrow transplantation. At the same time, MIPSS70+ added karyotype information.¹⁵

Currently, however, the most preferred and complete system is version 2 of the MIPSS70+ (MIPSS70+v2). This is a 5-tiered system consisting of molecular, karyotype, and clinical variables. The tiers are very low, low, intermediate, high, and very high risks.¹⁶ The system assigns each variable 1 to 4 points dependent on its effect on survival (Table 2). The addition of the points determines in which risk tier the patient falls. The genetic factors are the presence of very high risk (VHR) karyotype, an unfavorable karyotype, 2 or more high molecular risk (HMR) mutations (Table 3), 1 HMR mutation, and the absence of a type 1/like CALR mutation. The presence of type 1/like CALR is considered a favorable mutation. The clinical factors are severe anemia, moderate anemia, 2% or less circulating blasts, and the presence of constitutional symptoms. Severe anemia is defined as a hemoglobin (Hgb) less than 8 g/dL in women and less than 9 g/dL in men. Moderate anemia is defined as a Hgb of 8 to 9.9 g/dL in women and 9 to 10.9 g/dL in men. Median survival based on risk tier ranges from 1.8 years with those with very high-risk disease to 16.4 years with low-risk disease. Median survival for those with very low-risk disease was not reached in the study.

Capitalizing on recent advances in molecular profiling, the Genetically Inspired Prognostic Scoring System (GIPSS) is a 4-tiered system (i.e., low, intermediate-1, intermediate-2, and high risks) that is solely based on karyotype and genetic variables.¹⁷ The variables include a VHR karyotype, an unfavorable karyotype, the absence of a type 1/like CALR mutation, and the presence of ASXL, SRSF2, and U2AF1Q157 mutations. Its strength as a simpler tool to use may be offset by the fact that it requires molecular profiling for use. Also, the intermediate tiers are not very specific for prognostic value and perhaps a more clinical picture is needed for accuracy. Knowing this, clinicians can gain more insight to prognosis by applying the MIPSS70+v2 system to the GIPSS.

For MF arising post-PV or post-ET, the Myelofibrosis Secondary to PV and ET-Prognostic Model (MYSEC-PM) stratification system is used.¹⁸

Though the multiple tiers of the MIPSS70+v2 system make it a good tool for predicting survival, in terms of MF management, consensus guidelines consolidate into 2 levels, lower risk and higher risk.¹⁹ A MIPSS70+v2 score of 0 to 3 is considered lower risk whereas higher risk is a MIPSS70+v2 score of 4 to 9. Treatment within these levels consist of observation, pharmacotherapy to alleviate symptom burden, and curative intent with allogeneic bone marrow transplantation.

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