RAS/CBL mutations predict resistance to JAK inhibitors in myelofibrosis and are associated with poor prognostic features

Abstract

The dysregulation of the JAK/STAT pathway drives the pathogenesis of myelofibrosis (MF). Recently, several JAK inhibitors (JAKis) have been developed for treating MF. Select mutations (MTs) have been associated with impaired outcomes and are currently incorporated in molecularly annotated prognostic models. Mutations of RAS/MAPK pathway genes are frequently reported in cancer and at low frequencies in MF. In this study, we investigated the phenotypic, prognostic, and therapeutic implications of NRASMTs, KRASMTs, and CBLMTs (RAS/CBLMTs) in 464 consecutive MF patients. A total of 59 (12.7%) patients had RAS/CBLMTs: NRASMTs, n = 25 (5.4%); KRASMTs, n = 13 (2.8%); and CBLMTs, n = 26 (5.6%). Patients with RAS/CBLMTs were more likely to present with high-risk clinical and molecular features. RAS/CBLMTs were associated with inferior overall survival compared with patients without MTs and retained significance in a multivariate model, including the Mutation-Enhanced International Prognostic Score System (MIPSS70) risk factors and cytogenetics; however, inclusion of RAS/CBLMTs in molecularly annotated prognostic models did not improve the predictive power of the latter. The 5-year cumulative incidence of leukemic transformation was notably higher in the RAS/CBLMT cohort. Among 61 patients treated with JAKis and observed for a median time of 30 months, the rate of symptoms and spleen response at 6 months was significantly lower in the RAS/CBLMT cohort. Logistic regression analysis disclosed a significant inverse correlation between RAS/CBLMTs and the probability of achieving a symptom or spleen response that was retained in multivariate analysis. In summary, our study showed that RAS/CBLMTs are associated with adverse phenotypic features and survival outcomes and, more important, may predict reduced response to JAKis.

Venetoclax with azacitidine or decitabine in blast‐phase myeloproliferative neoplasm: A multicenter series of 32 consecutive cases

“…In the current study, we identified RAS mutations and complex karyotype as independent predictors of poor response to Ven + HMA while no associations with IDH1/2 mutations were apparent; incidentally, the association between poor response and preleukemic PV phenotype was explained by the latter clustering with complex karyotype. Interestingly, we have recently identified RAS / CBL mutations as predictors of poor treatment response to ruxolitinib, in patients with myelofibrosis 23 . In a previous study of relapsed/refractory AML in older patients, IDH2 and NPM1 mutations were associated with higher response rates and durable remissions while an association with IDH1 was less certain 24 .…”

Molecular pathogenesis of the myeloproliferative neoplasms

“…There is evidence to support alternative heterodimer formation between JAK2 and JAK1 or TYK1 in MPN cell line models persistently exposed to ruxolitinib and evidence to support recruitment of alternative MAPK signalling bypassing the JAK/STAT pathway as mechanistic explanations of this resistance [ 150 ]. The complexity of the genetic changes within the MPN clone may also determine the responsiveness of the cell to ruxolitinib, whilst new somatic mutations driving clonal evolution on therapy and subsequent expansion of new clones has been clearly documented [ 151 , 152 ].…”

<p>Impact of Mutational Profile on the Management of Myeloproliferative Neoplasms: A Short Review of the Emerging Data</p>

“… [ 54 , 60 , 108 , 119–121 ] CBL Mutations lead to increased STAT5 phosphorylation, cytokine hypersensitivity and cell proliferation; mostly homozygous missense substitutions. <1 0–2 0–6 4 Reduced overall survival in MF, resistance to JAKi [ 60 , 108 , 122 , 123 ] NRAS/KRAS Heterozygous missense mutations, particularly in codons 12, 13 and 61 led to a constitutive activation of growth signalling. <1 <1 3–4 7–15 Reduced overall survival in MF, resistance to JAKi [ 60 , 108 , 123 , 124 ] PTPN11 Missense mutations in Src-homology 2 (N-SH2) and phosphotyrosine phosphatase (PTP) domains <1 <1 1 2–5 Reduced overall survival in BP [ 108 ] Transcription factors RUNX1 Element of core bonding factor (CBF) heterodimer.…”