Adverse Prognostic Impact of the KIT D816V Transcriptional Activity in Advanced Systemic Mastocytosis

Abstract

In systemic mastocytosis (SM), qualitative and serial quantitative assessment of the KIT D816V mutation is of diagnostic and prognostic relevance. We investigated peripheral blood and bone marrow samples of 161 patients (indolent SM (ISM), n = 40; advanced SM, AdvSM, n = 121) at referral and during follow-up for the KIT D816V variant allele frequency (VAF) at the DNA-level and the KIT D816V expressed allele burden (EAB) at the RNA-level. A round robin test with four participating laboratories revealed an excellent correlation (r > 0.99, R2 > 0.98) between three different DNA-assays. VAF and EAB strongly correlated in ISM (r = 0.91, coefficient of determination, R2 = 0.84) but only to a lesser extent in AdvSM (r = 0.71; R2 = 0.5). However, as compared to an EAB/VAF ratio ≤2 (cohort A, 77/121 patients, 64%) receiver operating characteristic (ROC) analysis identified an EAB/VAF ratio of >2 (cohort B, 44/121 patients, 36%) as predictive for an advanced phenotype and a significantly inferior median survival (3.3 vs. 11.7 years; p = 0.005). In terms of overall survival, Cox-regression analysis was only significant for the EAB/VAF ratio >2 (p = 0.006) but not for VAF or EAB individually. This study demonstrates for the first time that the transcriptional activity of KIT D816V may play an important role in the pathophysiology of SM.

Superior Efficacy of Midostaurin Over Cladribine in Advanced Systemic Mastocytosis: A Registry-Based Analysis

“…The reliability and validity of our registry data has been demonstrated individually 6,7,9,21-25,27,37-39 and also in relation to several projects of the ECNM. 5,6,40-45 For the current analyses, salient strengths include (1) a comprehensive data set of clinical and molecular parameters from baseline and on-treatment from a high number of patients of whom > 70% were repeatedly seen at the same institution, (2) evaluation of almost all BM biopsies by ECNM reference pathologists, 9,30 and (3) the use of widely acknowledged statistical methodologies through propensity score analyses as an optimal approach for comparing outcomes across cohorts with balanced distributions and the best possible approximation of a randomized trial.…”

“…17-20 KIT D816V independent somatic mutations, for example, in SRSF2 , ASXL1 , and RUNX1 ( S/A/R gene panel), and cytogenetic aberrations are frequently identified in AdvSM and confer an inferior response to treatment, more rapid disease progression, for example, into secondary MCL or secondary AML, and reduced overall survival (OS). 6,21-27…”

“…[17][18][19][20] KIT D816V independent somatic mutations, for example, in SRSF2, ASXL1, and RUNX1 (S/A/R gene panel), and cytogenetic aberrations are frequently identified in AdvSM and confer an inferior response to treatment, more rapid disease progression, for example, into secondary MCL or secondary AML, and reduced overall survival (OS). 6,[21][22][23][24][25][26][27] Established response criteria are predominantly anchored to SM-related parameters (BM MC burden and serum tryptase levels) and improvement or normalization of organ damage (C-findings). 15,22,28 A more granular response assessment also taking into account the AHN compartment, for example, monocytosis and eosinophilia, has not yet been established.…”

Role and Significance of c-KIT Receptor Tyrosine Kinase in Cancer: A Review

“…Systemic mastocytosis is a rare myeloproliferative neoplasm in which malignant mast cells infiltrate bone marrow and other extracutaneous tissues such as liver, spleen, and peripheral blood. More than 90% of adult patients with this disease present a gain-of-function mutation in exon 17 within the c- kit gene, particularly KIT D816V, a missense mutation in which aspartic acid is substituted by valine in codon 816 [ 13 , 91 ]. Through kinase assays, it has been shown that the D816V mutant can autoactivate 586-fold faster than native c-KIT [ 79 ], which explains the adverse prognostic impact of the c- kit mutation in this hot spot in patients with systemic mastocytosis [ 91 ].…”

“…More than 90% of adult patients with this disease present a gain-of-function mutation in exon 17 within the c- kit gene, particularly KIT D816V, a missense mutation in which aspartic acid is substituted by valine in codon 816 [ 13 , 91 ]. Through kinase assays, it has been shown that the D816V mutant can autoactivate 586-fold faster than native c-KIT [ 79 ], which explains the adverse prognostic impact of the c- kit mutation in this hot spot in patients with systemic mastocytosis [ 91 ]. The D816V mutation is also present in children with systemic mastocytosis but with a lower frequency (42%).…”