Impact of mutational status on outcomes in myelofibrosis patients treated with ruxolitinib in the COMFORT-II study

Guglielmelli, Paola; Biamonte, Flavia; Rotunno, Giada; Artusi, Valentina; Artuso, Lucia; Bernardis, Isabella; Tenedini, Elena; Pieri, Lisa; Paoli, Chiara; Mannarelli, Carmela; Fjerza, Rajmonda; Rumi, Elisa; Stalbovskaya, Viktoriya; Squires, Matthew; Cazzola, Mario; Manfredini, Rossella; Harrison, Claire; Tagliafico, Enrico; Vannucchi, Alessandro M.

doi:10.1182/blood-2013-11-536557

Cited by 116 publications

(83 citation statements)

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“…Patients with PMF who have the CALR type 1/type 1-like mutation constitute a group with a more favorable disease compared with those who are CALR type 2/type 2-like, JAK2V617F or MPLW515x mutated [14][15][16], and patients who result negative for the 3 driver mutations mentioned above (so called "triple negative" patients) are at even greater risk of earlier death [11]. Furthermore, a category of "High Molecular Risk" (HMR) patients was defined to include those patients who harbor any mutation in ASXL1, EZH2, SRSF2, IDH1, and IDH2; HMR patients have significantly shorter overall survival and enhanced risk of transformation to acute leukemia [12,17] compared with those who lack prognostically detrimental mutations. In addition, the number of HMR mutations, and widely the number of subclonal mutations, represents a strong negative predictor of survival for patients with PMF [18,19].…”

Section: Introductionmentioning

confidence: 99%

Epidemiology and clinical relevance of mutations in postpolycythemia vera and postessential thrombocythemia myelofibrosis: A study on 359 patients of the AGIMM group

et al. 2016

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Transformation to secondary myelofibrosis (MF) occurs as part of the natural history of polycythemia vera (PPV-MF) and essential thrombocythemia (PET-MF). Although primary (PMF) and secondary MF are considered similar diseases and managed similarly, there are few studies specifically focused on the latter. The aim of this study was to characterize the mutation landscape, and describe the main clinical correlates and prognostic implications of mutations, in a series of 359 patients with PPV-MF and PET-MF. Compared with PV and ET, the JAK2V617F and CALR mutated allele burden was significantly higher in PPV-MF and/or PET-MF, indicating a role for accumulation of mutated alleles in the process of transformation to MF. However, neither the allele burden nor the type of driver mutation influenced overall survival (OS), while absence of any driver mutation (triple negativity) was associated with significant reduction of OS in PET-MF, similar to PMF. Of the five interrogated subclonal mutations (ASXL1, EZH2, SRSF2, IDH1, and IDH2), that comprise a prognostically detrimental high molecular risk (HMR) category in PMF, only SRSF2 mutations were associated with reduced survival in PET-MF, and no additional mutation profile with prognostic relevance was highlighted. Overall, these data indicate that the molecular landscape of secondary forms of MF is different from PMF, suggesting that unknown mutational events might contribute to the progression from chronic phase disease to myelofibrosis. These findings also support more extended genotyping approaches aimed at identifying novel molecular abnormalities with prognostic relevance for patients with PPV-MF and PET-MF. Am. J. Hematol. 91:681–686, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc

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Section: Introductionmentioning

confidence: 99%

Epidemiology and clinical relevance of mutations in postpolycythemia vera and postessential thrombocythemia myelofibrosis: A study on 359 patients of the AGIMM group

et al. 2016

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“…78 Guglielmelli et al recently evaluated the impact of molecular abnormalities in a subset of the COMFORT-II cohort (166 of the 219 total patients were evaluated) by genotyping 14 MF-associated prognostically significant mutations, but did not identify any molecular predictors of response to ruxolitinib. 81 In aggregate, these results indicate that any survival benefit of ruxolitinib in patients with intermediate-or advanced-phase MF is not occurring as a result of selectively targeting the malignant hematopoietic clone. It is plausible that increased dietary intake and enhanced performance status as a result of improved constitutional symptoms and reduced splenomegaly could contribute to the improved Kaplan-Meier survival estimates for patients treated with ruxolitinib.…”

Section: Inhibiting Jak2 Kinase Activitymentioning

confidence: 83%

How does JAK2V617F contribute to the pathogenesis of myeloproliferative neoplasms?

Chen

Mullally

2014

Hematology

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A decade on from the discovery of the JAK2V617F mutation in the majority of patients with myeloproliferative neoplasms (MPNs), JAK2V617F is now firmly installed in the hematology curriculum of medical students and the diagnostic-testing algorithm of clinicians. Furthermore, the oral JAK1/JAK2 inhibitor ruxolitinib, rationally designed to target activated JAK2 signaling in MPN, has been approved by the Food and Drug Administration (FDA) of the United States for the past 3 years for the treatment of intermediate-and advanced-phase myelofibrosis. Notwithstanding this, JAK2V617F continues to stimulate the MPN research community and novel insights into understanding the mechanisms by which JAK2V617F contributes to the pathogenesis of MPN are continually emerging. In this chapter, we focus on recent advances in 4 main areas: (1) the molecular processes coopted by JAK2V617F to induce MPN, (2) the role that JAK2V617F plays in phenotypic diversity in MPN, (3) the functional impact of JAK2V617F on hematopoietic stem cells, and (4) therapeutic strategies to target JAK2V617F. Although great strides have been made, significant deficits still exist in our understanding of the precise mechanisms by which JAK2V617F-mutant hematopoietic stem cells emerge and persist to engender clonal hematopoiesis in MPN and in developing strategies to preferentially target the JAK2V617F-mutant clone therapeutically. Critically, although myelofibrosis remains arguably the greatest clinical challenge in JAK2V617F-mediated MPN, the current understanding of myelofibrosis-specific disease biology remains quite rudimentary. Therefore, many important biological questions pertaining to JAK2V617F will continue to engage and challenge the MPN research community in the coming decade. Learning Objective• To understand the role played by the JAK2V617F mutation in the development of MPNs: specifically, to outline its role in perturbing signal transduction, engendering distinct clinical disease phenotypes, altering hematopoietic stem cell function, and serving as a rational therapeutic target in MPN

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“…84 Analysis of the prospective COMFORT-II cohort, which compared ruxolitinib with best available therapy in patients with MF, showed that ruxolitinib improved survival for such HMR patients, which is the first indication that treatment choices may influence the natural history of MF with HMR mutations. 85 Similar studies in PV and ET are awaited. Clinical studies of retrospective cohorts have shown that CALR mutations are associated with a better prognosis and survival in MF and reduced thrombosis in ET, 10,11,35 and this may be relevant for future risk stratification of patients.…”

Section: Clinical Importance Of the Mutational Landscape In Mpnsmentioning

confidence: 98%

The evolving genomic landscape of myeloproliferative neoplasms

Nangalia

Green

2014

Hematology

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Our understanding of the genetic basis of the Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) has moved forward at a staggering pace over the last decade. With the discoveries of underlying mutations in JAK2, MPL, and, most recently, calreticulin (CALR), that together account for ∼90% of patients with MPNs, these conditions are now among the best characterized of hematological malignancies. While JAK-STAT pathway activation has been shown to be central to the pathogenesis of the MPN phenotype, the mechanism by which mutant CALR alters cellular function to result in myeloid proliferation remains unclear. Other mutations in several epigenetic modifiers, such as ASXL1, DNMT3a, TET2, EZH2, IDH1, and IDH2, as well as in genes involved in mRNA splicing, such as SF3B1 and U2AF2, have also been described in recent years in patients with MPNs, and evidence is emerging as to how these may be contributing to disease biology. From a therapeutic perspective, the discovery of aberrations in JAK2 has rapidly translated into the successful clinical use of JAK inhibitors in MPNs. Mutant calreticulin has the potential to be a tumor-specific therapeutic target because the mutations generate a novel protein C-terminus. In this chapter, we detail the genomic alterations that underlie MPNs, with a focus on the recent discovery of mutations in CALR, and explore the clinical and biological relevance of the altered genomic landscape in MPNs.

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Impact of mutational status on outcomes in myelofibrosis patients treated with ruxolitinib in the COMFORT-II study

Abstract: Key Points Improvements in splenomegaly and symptoms in patients receiving ruxolitinib occurred regardless of the mutations that were present. Ruxolitinib relieved the negative impact of prognostically detrimental mutations in myelofibrosis patients from the COMFORT-II study.

Cited by 116 publications

References 22 publications

Epidemiology and clinical relevance of mutations in postpolycythemia vera and postessential thrombocythemia myelofibrosis: A study on 359 patients of the AGIMM group

Epidemiology and clinical relevance of mutations in postpolycythemia vera and postessential thrombocythemia myelofibrosis: A study on 359 patients of the AGIMM group

How does JAK2V617F contribute to the pathogenesis of myeloproliferative neoplasms?

The evolving genomic landscape of myeloproliferative neoplasms

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