Targeted resequencing analysis of 31 genes commonly mutated in myeloid disorders in serial samples from myelodysplastic syndrome patients showing disease progression

Pellagatti, Andrea; Roy, S.; Genua, Cristina Di; Burns, Adam; McGraw, Kathy L.; Valletta, Simona; Larrayoz, M.J.; Fernández-Mercado, Marta; Mason, Joanne; Killick, Sally; Mecucci, Cristina; Calasanz, Marı́a José; List, Alan F.; Schuh, Anna; Boultwood, Jacqueline

doi:10.1038/leu.2015.129

Cited by 52 publications

(52 citation statements)

References 15 publications

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“…These results are in agreement with recent studies of myelodysplastic syndromes 12 and AML patients. 13 In two recent NGS studies of 197 MPNs in chronic phase 6 and 33 post-MPN AMLs…”

Section: Letters To the Editorsupporting

confidence: 83%

Genomic analysis of myeloproliferative neoplasms in chronic and acute phases

et al. 2016

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“…These results are in agreement with recent studies of myelodysplastic syndromes 12 and AML patients. 13 In two recent NGS studies of 197 MPNs in chronic phase 6 and 33 post-MPN AMLs…”

Section: Letters To the Editorsupporting

confidence: 83%

Genomic analysis of myeloproliferative neoplasms in chronic and acute phases

et al. 2016

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“…In addition to functional significance, recent sequencing technology also uncovered clonal dynamics based on detailed information of mutated clone size. In particular, multiple samples tested at serial time points in each case can conclude acquisition timing of each mutation, clonal architecture, and intratumor heterogeneity in myelodysplasia [4,[17][18][19][20].…”

Section: Introductionmentioning

confidence: 99%

Somatic SETBP1 mutations in myeloid neoplasms

Makishima

2017

Int J Hematol

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“…27 The data are also reminiscent to other myeloid neoplasms and their clonal diversity, in which mutations in RUNX1, N/KRAS or IDH2 were also identified as late events and drivers for disease progression. 19,[28][29][30][31] Of interest, no significant increase in clone size was observed for mutations in TET2 or SRSF2, although they represent early mutations in the multistep pathogenesis of SM, 8 chronic myelomonocytic leukemia, 32 or MDS. 19 These results suggest that the extensive clinical heterogeneity of advSM is most likely because of the presence and dynamic evolution of several molecularly disparate subclones, which have a variable impact on clinical characteristics and response to treatment.…”

Section: Discussionmentioning

confidence: 99%

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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Targeted resequencing analysis of 31 genes commonly mutated in myeloid disorders in serial samples from myelodysplastic syndrome patients showing disease progression

Cited by 52 publications

References 15 publications

Genomic analysis of myeloproliferative neoplasms in chronic and acute phases

Genomic analysis of myeloproliferative neoplasms in chronic and acute phases

Somatic SETBP1 mutations in myeloid neoplasms

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

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