Correlation of mutation profile and response in patients with myelofibrosis treated with ruxolitinib

Patel, Keyur P.; Newberry, Kate J.; Luthra, Rajyalakshmi; Jabbour, Elias; Pierce, Sherry; Cortes, Jorge; Singh, Rajesh R.; Mehrotra, Meenakshi; Routbort, Mark J.; Luthra, Madan G.; Manshouri, Taghi; Santos, Fábio Pires de Souza; Kantarjian, Hagop M.; Verstovšek, Srđan

doi:10.1182/blood-2015-03-633404

Cited by 171 publications

(152 citation statements)

References 37 publications

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“…However, in the same patient cohort as in the Newberry et al report, it was shown by using an enlarged mutation panel that those patients with 3 or more mutations at study entry were more likely to discontinue treatment early and had lower odds of achieving spleen response. 8 These latter findings suggest that patients with higher mutation complexity are less likely to obtain sustained responses to ruxolitinib, in line with findings that the number of mutations is independently associated with shorter survival and increased risk of leukemic transformation. 9,10 When deciding on initial treatment using ruxolitinib, the above molecular information represents green and yellow lights for starting the treatment (see figure).…”

Section: Alessandro M Vannucchi and Paola Guglielmelli University Ofsupporting

confidence: 69%

Traffic lights for ruxolitinib

Vannucchi

Guglielmelli

2017

Blood

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Section: Alessandro M Vannucchi and Paola Guglielmelli University Ofsupporting

confidence: 69%

Traffic lights for ruxolitinib

Vannucchi

Guglielmelli

2017

Blood

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“…35 In the present study, we observed a poorer MR rate on CALR mutant clones in patients harboring additional mutations, suggesting that molecular alterations in pathways such as epigenetics may hamper the efficacy of IFNa therapy. The presence of additional mutations such as ASXL1 has been reported to hinder the clinical response to ruxolitinib in MF patients, 36 an effect not observed in our cohort of ET patients treated with IFNa.…”

Section: Discussionmentioning

confidence: 49%

Clinical and molecular response to interferon-α therapy in essential thrombocythemia patients with CALR mutations

Verger

Cassinat

Chauveau

et al. 2015

Blood

139

108

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“…These data are reminiscent of the treatment of myelofibrosis (MF) with ruxolitinib for which the presence of mutations in ASXL1 or SRSF2 was also inversely correlated with spleen response, time to treatment discontinuation and shortened OS. 26 We found no evidence for additional KIT mutations that might be conferring resistance to midostaurin (data not shown).…”

Section: Discussionmentioning

confidence: 67%

Response and progression on midostaurin in advanced systemic mastocytosis: KIT D816V and other molecular markers

Jawhar

Schwaab

Naumann

et al. 2017

Blood

102

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Key Points• The complexity and dynamics of mutations significantly impact on response, progression, and prognosis in midostaurintreated advSM patients.In advanced systemic mastocytosis (advSM), disease evolution is often triggered by KIT mutations (D816V in >80% of cases) and by additional mutations (eg, in SRSF2, ASXL1, and/or RUNX1 [S/A/R pos in >60% of cases]). In a recently reported phase 2 study, midostaurin, a multikinase/KIT inhibitor, demonstrated an overall response rate (ORR) of 60% in advSM but biomarkers predictive of response are lacking. We evaluated the impact of molecular markers at baseline and during follow-up in 38 midostaurin-treated advSM patients. The median overall survival (OS) was 30 months (95% confidence interval, 6-54) from start of midostaurin. ORR and OS were significantly different between S/A/R neg (n 5 12) and S/A/R pos (n 5 23) patients (ORR: 75% vs 39%, P 5 .04; OS: P 5 .01, HR 4.5 [1.3-16.2]). Depending on the relative reduction of the KIT D816V expressed allele burden (EAB) at month 6, patients were classified as KIT responders ( ‡25%, n 5 17) or KIT nonresponders (<25%, n 5 11). In univariate analyses at month 6, reduction of KIT D816V EAB ‡25%, tryptase ‡50%, and alkaline phosphatase ‡50% were significantly associated with improved OS. In multivariate analysis, only KIT D816V EAB reduction ‡25% remained an independent on-treatment marker for improved OS (P 5 .004,). Serial next-generation sequencing analysis of 28 genes in 16 patients revealed acquisition of additional mutations or increasing variant allele frequency in K/NRAS, RUNX1, IDH2, or NPM1 associated with progression in 7 patients. In midostaurin-treated advSM patients, the complexity and dynamics of mutational profiles significantly affect response, progression, and prognosis. (Blood. 2017;130(2):137-145)

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Correlation of mutation profile and response in patients with myelofibrosis treated with ruxolitinib

Abstract: Key Points In patients treated with ruxolitinib, harboring ≥3 mutations was inversely correlated with spleen response and time to treatment discontinuation. Multigene profiling may be useful for therapeutic planning.

Cited by 171 publications

References 37 publications

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Traffic lights for ruxolitinib

Clinical and molecular response to interferon-α therapy in essential thrombocythemia patients with CALR mutations

Response and progression on midostaurin in advanced systemic mastocytosis: KIT D816V and other molecular markers

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