KIT D816 Mutated / CBF-Negative Acute Myeloid Leukemia (AML): A New Poor-Risk Subtype Associated with Systemic Mastocytosis (SM-AML)

Systemic mastocytosis with an associated hematologic neoplasm (SM-AHN) is the most common subtype of advanced SM (advSM), diagnosed in up to 80% of patients. The AHN is most frequently diagnosed as a myeloid neoplasm, e.g., SM-MDS/MPNu or SM-CMML. Acquired mutations in KIT (usually KIT D816, KIT D816^mut) are detectable in >90% of patients. The basis for the SM-AHN phenotype is usually the multi-lineage involvement, e.g. monocytes, eosinophils and other non-mast cell lineages, of KIT mutations. Core binding factor (CBF) positive AML (CBF^pos AML) represents a distinct subtype and is identified in 5-8% of all AMLs. KIT mutations, most frequently KITD816^mut, are detectable in up to 45% of CBF^pos AML patients and are associated with an adverse prognosis. There is, however, only little information on KIT D816^mut/CBF^neg AML. We therefore evaluated a) clinical and molecular characteristics, b) response to treatment and, c) survival and prognostic factors in 40 KIT D816^mut/CBF^neg patients with histologically proven SM and associated AML (SM-AML), collected at 4 centers of the European Competence Network on Mastocytosis (ECNM). Molecular analyses (n=32) revealed at least one additional somatic mutation (median, n=3) apart from KIT D816, most frequently SRSF2 (n=12, 38%), RUNX1 (n=11, 34%), TET2 (n=11, 34%), ASXL1 (n=10, 31%), or NPM1 (n=7, 22%). At least one mutation in SRSF2, ASXL1 or, RUNX1 (S/A/R^pos) was identified in 21/32 (66%) patients. At diagnosis of SM-AML 21/40 (52%) patients had an aberrant karyotype. Secondary AML evolved in 29/40 (73%) patients from SM ± associated myeloid neoplasm and longitudinal molecular analyses revealed acquisition of new somatic mutations (TP53, n=2; NPM1, n=1; RUNX1, n=1, ASXL1, n=1; BCOR, n=1; IDH1/2, n=1) and/or karyotype evolution in 15/16 (94%) patients at the time of SM-AML. Thirty-one of 40 (78%) patients were treated with intensive chemotherapy (ICT) with a complete response (CR) rate of 40%. Allogeneic stem cell transplantation (SCT) was performed in 12/40 (30%) patients with durable CR in 6/12 (50%) patients. S/A/R^pos and/or the presence of a poor-risk karyotype were adverse predictive markers for response to treatment. To further investigate whether KITD816^mut/CBF^neg AMLdefines a distinct AML subtype associated with SM, two independent AML databases (AML^databases) were retrospectively screened and 69 KIT D816^mut/CBF^neg AML patients identified. The comparison between KIT D816^mut/CBF^neg SM-AML from ECNM (n=40) centers with KIT D816^mut/CBF^neg AML^databases(n=69) revealed remarkable similarities: a) a high KIT D816 variant allele frequency (VAF) (median 34% vs. 29%), b) with the exception of SRSF2 (38 vs. 18%), a highly similar mutation landscape, rather comparable to that of advSM (Jawhar et al., Blood 2017) than to that of de novo AML, c) in contrast to de novo AML, a low frequency of FLT3 mutations (3 vs. 7%), and d) a high frequency of an aberrant karyotype (52 vs. 42%). The median overall survival (OS) of 40 KIT D816^mut/CBF^neg SM-AML and 17 evaluable KIT D816^mut/CBF^neg AML^databases was 5.4 (95% confidence interval, CI [1.7-9.1]) and 26.4 (95% CI [0-61.0]) (P=0.015) months, respectively (Figure 1). However, if only the patients with ICT ± allogeneic SCT were compared, median OS between the two groupswas not different (16.7 vs. 26.4 months, P=0.4). In multivariate analyses, S/A/R^pos and a poor-risk karyotype remained the only independent poor-risk factors with regard to OS. These results were independent of treatment modalities. We conclude that KIT D816^mut/CBF^neg AML is a new poor-risk subtype associated with SM (SM-AML). The remarkable clinical, genetic and prognostic similarities between SM-AML and AML^databases suggest that a significant proportion of the AML^databases patients may in fact have SM-AML. We therefore strongly recommend to determine serum tryptase and KIT D816 mutation status in all AML patients, and to perform bone marrow histology in KIT D816^mut patients. These simple diagnostic measures would allow reclassification to SM-AML and inclusion of KIT inhibitors in established treatment modalities of AML.

View largeDownload slide

View largeDownload slide

Close modal