Mutations in MPNs: prognostic implications, window to biology, and impact on treatment decisions

Abstract

The last decade has witnessed tremendous scientific advances, ushered in by the JAK2 V617F discovery, contributing to enhanced diagnostic capability and understanding of the biology of myeloproliferative neoplasms (MPNs). Discovery of the calreticulin mutations filled a diagnostic gap; more recent work sheds light on its contribution to disease pathogenesis, and prognosis. Recent studies have also identified novel JAK2 and MPL mutations in patients with essential thrombocythemia and myelofibrosis (MF). Especially in MF, the driver mutational profile has prognostic implications, with additive contributions from the acquisition of additional somatic mutations. The hope is that sophisticated molecular profiling will not only aid in prognostication, but also guide selection of therapy for patients with MPNs.

Conflict of interest statement

Conflict-of-interest disclosure: J.M.S. has received research funding, consulted for, received honorarium from, and has been affiliated with the Speakers Bureau for Alexion, Incyte, Novartis, and Celgene. B.L.S. has consulted for Incyte.

© 2016 by The American Society of Hematology. All rights reserved.

Figures

Figure 1.

(A) How we approach the management of ET and PV. (B) How we approach nontransplant management of MF. CV, cardiovascular; Epo, erythropoietin; ESA, erythropoiesis-stimulating agent; Hct, hematocrit; HU, hydroxyurea; PBT, phlebotomy; Plts, platelets; symptoms (bone pain, fever, night sweats, and weight loss).

Figure 2.

(A) Evolution in prognostic assessment: ET. Constructed prior to CALR discovery (*). CALR co-segregates with younger age and absent thrombosis risk, and therefore, does not modify IPSET score (**). Unable to predict MF or AML risk (***). (B) Evolution in prognostic assessment: PV. (C) Evolution in prognostic assessment: MF. The latest proposed MF scoring systems incorporate molecular and genetic information in the assessment (*). The GPSS identified very high (3 points) and high-risk karyotypes (2 points), TN status (2 points), JAK2/MPL-mutated (2 points), type-2/type-2–like CALR-mutated (2 points), ASXL1-mutated (1 point), and SRSF2-mutated (1 point), as independent predictors of shortened survival; these variables were included in this score, along with age >60 years. Another system, the Mutation-enhanced IPSS (MIPSS), analyzed 986 PMF patients, identifying age >60, constitutional symptoms, Hb <10 g/dL, platelets <200 × 109/L, TN status (1.5 points), JAK2-mutated or MPL-mutated (0.5 points), ASXL1-mutated (0.5 points), and SRSF2-mutated (0.5 points) status as significant, adverse indicators. CV, cardiovascular; DIPSS, dynamic IPSS; GPSS, genetics-based Prognostic Scoring System; pts, patients.