Myeloproliferative neoplasms: A decade of discoveries and treatment advances

Abstract

Myeloproliferative neoplasms (MPN) are clonal stem cell diseases, first conceptualized in 1951 by William Dameshek, and historically included chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). In 1960, Nowell and Hungerford discovered an invariable association between the Philadelphia chromosome (subsequently shown to harbor the causal BCR‐ABL1 mutation) and CML; accordingly, the term MPN is primarily reserved for PV, ET, and PMF, although it includes other related clinicopathologic entities, according to the World Health Organization (WHO) classification system. In 2005, William Vainchenker and others described a Janus kinase 2 mutation (JAK2V617F) in MPN and this was followed by a series of additional descriptions of mutations that directly or indirectly activate JAK‐STAT: JAK2 exon 12, myeloproliferative leukemia virus oncogene (MPL) and calreticulin (CALR) mutations. The discovery of these, mostly mutually exclusive, “driver” mutations has contributed to revisions of the WHO diagnostic criteria and risk stratification in MPN. Mutations other than JAK2, CALR and MPL have also been described in MPN and shown to provide additional prognostic information. From the standpoint of treatment, over the last 50 years, Louis Wasserman from the Unites States and Tiziano Barbui from Italy had skillfully organized and led a number of important clinical trials, whose results form the basis for current treatment strategies in MPN. More recently, allogeneic stem cell transplant, as a potentially curative treatment modality, and JAK inhibitors, as palliative drugs, have been added to the overall therapeutic armamentarium in myelofibrosis. In the current review, I will summarize the important advances made in the last 10 years regarding the science and practice of MPN. Am. J. Hematol. 91:50–58, 2016. © 2015 Wiley Periodicals, Inc.

Calreticulin variant stratified driver mutational status and prognosis in essential thrombocythemia

“…These so-called "driver" mutations [5] include Janus kinase 2 (JAK2), calreticulin (CALR), and myeloproliferative leukemia virus oncogene (MPL) and are present in about 85% of patients with ET with respective frequencies of 58, 23, and 4% [6]; the remaining cases constituting 15% are wild-type for all three mutations and are operationally referred to as being "triple negative" [6,7]. More than 80% of CALR mutated ET patients harbor one of only two mutation variants: type 1, a 52-bp deletion (p.L367fs*46) and type 2, a 5-bp TTGTC insertion (p.K385fs*47) [7] with a frequency of 46 and 38%, respectively [8]; the rest of the CALR mutations are classified as type 1-like and type 2-like, based on their structural similarities to type 1 and type 2 CALR variants, respectively [9,10].…”

“…More than 80% of CALR mutated ET patients harbor one of only two mutation variants: type 1, a 52-bp deletion (p.L367fs*46) and type 2, a 5-bp TTGTC insertion (p.K385fs*47) [7] with a frequency of 46 and 38%, respectively [8]; the rest of the CALR mutations are classified as type 1-like and type 2-like, based on their structural similarities to type 1 and type 2 CALR variants, respectively [9,10]. Specific driver mutations in ET have been associated with characteristic phenotypes [5][6][7][8][11][12][13] and the risk of thrombosis has been shown to be higher in patients with JAK2 or MPL mutations [12].…”

Prevalence of the Janus kinase 2 V617F mutation in Philadelphia-negative myeloproliferative neoplasms in a Portuguese population

“…The identification of JAK2/MPL mutations in the majority of patients led to the development of JAK kinase inhibitors. Although ruxolitinib was recently approved for use in hydroxyurea-resistant PV, its role in routine clinical practice remains controversial (6,(46)(47)(48)(49). For myelofibrosis patients, stem cell transplant is the current treatment of choice for genetically or clinically high-risk disease.…”

NCCN Guidelines Insights: Myeloproliferative Neoplasms, Version 2.2018

“…3,4 However, certain aspects of clinical management regarding the diagnosis, assessment of symptom burden, and selection of appropriate symptom-directed therapies continue to present challenges for hematologists and oncologists. 5 The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for MPNs provide recommendations for the diagnostic workup, risk stratification, treatment, and supportive care strategies for disease management in adults.…”

“…However, the presence of additional mutations (TET2, ASXL1, IDH2, and TP53) was associated with poorer molecular response. 37 In a phase II trial that included 40 patients with ET, peginterferon alfa-2a induced a CHR rate of 77% and a CMR rate of 17% after a median follow-up of 42 NCCN Guidelines Insights 4 If any of the following factors are present then the pregnancy should be considered at high risk: • Previous microcirculatory disturbances or presence of two or more hereditary thrombophilic factors.…”