Prognostic impact of RAS-pathway mutations in patients with myelofibrosis

Santos, Fábio Pires de Souza; Getta, Bartlomiej; Masárová, Lucia; Famulare, Christopher; Schulman, Jessica; Datoguia, Tarcila Santos; Puga, Renato D; Paiva, Raquel de Melo Alves; Arcila, Maria E.; Hamerschlak, Nelson; Kantarjian, Hagop M.; Levine, Ross L.; Campregher, Paulo Vidal; Rampal, Raajit K.; Verstovšek, Srđan

doi:10.1038/s41375-019-0603-9

Cited by 63 publications

(74 citation statements)

References 46 publications

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“…The four‐tiered GIPSS risk categories included low (zero points), intermediate‐1 (one point), intermediate‐2 (two points), and high (≥3 points), with corresponding median survivals of 26.4 years, 8.0 years, 4.2 years, and 2 years (Table 5). Most recently, RAS / CBL mutations in PMF were associated with poor response to ruxolitinib therapy, poor prognostic features, and inferior survival; in the latter regard, however, incorporation of such information to MIPSS v2 did not show additional value 36,37 …”

Section: Risk Stratificationmentioning

confidence: 99%

Primary myelofibrosis: 2021 update on diagnosis, risk‐stratification and management

2020

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Disease Overview: Primary myelofibrosis (PMF) is a myeloproliferative neoplasm (MPN) characterized by stem cell-derived clonal myeloproliferation that is often but not always accompanied by JAK2, CALR, or MPL mutations. Additional disease features include bone marrow reticulin/collagen fibrosis, aberrant inflammatory cytokine expression, anemia, hepatosplenomegaly, extramedullary hematopoiesis (EMH), constitutional symptoms, cachexia, leukemic progression, and shortened survival. Diagnosis: Bone marrow morphology is the primary basis for diagnosis. Presence of JAK2, CALR, or MPL mutation, expected in around 90% of the patients, is supportive but not essential for diagnosis; these mutations are also prevalent in the closely related MPNs, namely polycythemia vera (PV) and essential thrombocythemia (ET). The 2016 World Health Organization classification system distinguishes "prefibrotic" from "overtly fibrotic" PMF; the former might mimic ET in its presentation. Furthermore, approximately 15% of patients with ET or PV might progress into a PMF-like phenotype (post-ET/PV MF) during their clinical course. Adverse Mutations: SRSF2, ASXL1, and U2AF1-Q157 mutations predict inferior survival in PMF, independent of each other and other risk factors. RAS/CBL mutations predicted resistance to ruxolitinib therapy. Adverse Karyotype: Very high risk abnormalities include −7, inv (3), i(17q), +21, +19, 12p-, and 11q-. Risk Stratification: Two new prognostic systems for PMF have recently been introduced: GIPSS (genetically-inspired prognostic scoring system) and MIPSS70+ version 2.0 (MIPSSv2; mutation-and karyotype-enhanced international prognostic scoring system). GIPSS is based exclusively on mutations and karyotype. MIPSSv2 includes, in addition, clinical risk factors. GIPSS features four and MIPSSv2 five risk categories. Risk-adapted Therapy: Observation alone is advised for MIPSSv2 "low" and "very low" risk disease (estimated 10-year survival 56%-92%); allogeneic hematopoietic stem cell transplant (AHSCT) is the preferred treatment for "very high" and "high" risk disease (estimated 10-year survival 0%-13%); treatment-requiring patients with intermediate-risk disease (estimated 10-year survival 30%) are best served by participating in clinical trials. In non-transplant candidates, conventional treatment for anemia includes androgens, prednisone, thalidomide, and danazol; for symptomatic

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Section: Risk Stratificationmentioning

confidence: 99%

Primary myelofibrosis: 2021 update on diagnosis, risk‐stratification and management

2020

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“…Mutations in ASXL1 , EZH2 , IDH1/2 , and, SRSF2, called “high molecular risk, HMR” [ 26 ] or “molecular high risk, MHR” [ 27 ] mutations, have been associated with worse prognosis in PMF patients. There is a clear statistical significant association of the presence of one or more mutation of this type with fibrotic progress also in our cohort: 7 out of 16 (44%) with fibrotic progress versus 1 out of 20 (5%) with stable disease, Chi 2 -test, p = 0.0065.…”

Section: Resultsmentioning

confidence: 99%

Genome-wide DNA methylation profiling is able to identify prefibrotic PMF cases at risk for progression to myelofibrosis

et al. 2021

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Background Patients suffering from the BCR-ABL1-negative myeloproliferative disease prefibrotic primary myelofibrosis (pre-PMF) have a certain risk for progression to myelofibrosis. Accurate risk estimation for this fibrotic progression is of prognostic importance and clinically relevant. Commonly applied risk scores are based on clinical, cytogenetic, and genetic data but do not include epigenetic modifications. Therefore, we evaluated the assessment of genome-wide DNA methylation patterns for their ability to predict fibrotic progression in PMF patients. Results For this purpose, the DNA methylation profile was analyzed genome-wide in a training set of 22 bone marrow trephines from patients with either fibrotic progression (n = 12) or stable disease over several years (n = 10) using the 850 k EPIC array from Illumina. The DNA methylation classifier constructed from this data set was validated in an independently measured test set of additional 11 bone marrow trephines (7 with stable disease, 4 with fibrotic progress). Hierarchical clustering of methylation β-values and linear discriminant classification yielded very good discrimination between both patient groups. By gene ontology analysis, the most differentially methylated CpG sites are primarily associated with genes involved in cell–cell and cell–matrix interactions. Conclusions In conclusion, we could show that genome-wide DNA methylation profiling of bone marrow trephines is feasible under routine diagnostic conditions and, more importantly, is able to predict fibrotic progression in pre-fibrotic primary myelofibrosis with high accuracy.

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“…Clonal dynamics play a role as well, with higher JAK2 mutant allele fractions and lower number of mutations predicting favorable responses [ 22 , 23 ]. In addition, RAS pathway mutations have recently been associated with resistance to JAK inhibitors and poor outcomes [ 24 , 25 , 26 ]. Durability of spleen response to ruxolitinib treatment is associated with improved overall survival, while thrombocytopenia and clonal evolution correlate with inferior outcomes [ 27 , 28 ].…”

Section: Rationale For Combination Therapymentioning

confidence: 99%

“…Other combinations that are supported by preclinical data and have yet to reach, or just recently entered, clinical testing are worth noting. Recent reports have suggested that disease progression in MF patients treated with ruxolitinib is associated with activation of receptor tyrosine kinase and RAS pathway mutations, and RAS pathway mutations, including PTPN11 (which encodes the SHP2 phosphatase), confer poor prognosis [ 24 , 25 ]. Notably, inhibition of MEK, a mediator of MAP kinase signaling, has been shown to be effective in murine models as a single agent as well as in combination with ruxolitinib [ 175 ].…”

Section: Novel Combinations Pending Clinical Experiencementioning

confidence: 99%

Finding a Jill for JAK: Assessing Past, Present, and Future JAK Inhibitor Combination Approaches in Myelofibrosis

Kuykendall

Horvat

Pandey

et al. 2020

Cancers

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Myelofibrosis (MF) is a myeloproliferative neoplasm hallmarked by the upregulation of the Janus kinase (JAK)—signal transducer and activator of transcription (STAT) pathway with associated extramedullary hematopoiesis and a high burden of disease-related symptoms. While JAK inhibitor therapy is central to the management of MF, it is not without limitations. In an effort to improve treatment for MF patients, there have been significant efforts to identify combination strategies that build upon the substantial benefits of JAK inhibition. Early efforts to combine agents with additive therapeutic profiles have given way to rationally designed combinations hoping to demonstrate clinical synergism and modify the underlying disease. In this article, we review the preclinical basis and existing clinical data for JAK inhibitor combination strategies while highlighting emerging strategies of particular interest.

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Prognostic impact of RAS-pathway mutations in patients with myelofibrosis

Cited by 63 publications

References 46 publications

Primary myelofibrosis: 2021 update on diagnosis, risk‐stratification and management

Primary myelofibrosis: 2021 update on diagnosis, risk‐stratification and management

Genome-wide DNA methylation profiling is able to identify prefibrotic PMF cases at risk for progression to myelofibrosis

Finding a Jill for JAK: Assessing Past, Present, and Future JAK Inhibitor Combination Approaches in Myelofibrosis

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