In April 2017, the U.S. Food and Drug Administration approved the multitargeted KIT inhibitor for the treatment of adult patients with FLT3-positive, newly diagnosed acute myeloid leukemia and adults with aggressive systemic mastocytosis (SM), SM with associated hematologic neoplasm, or mast cell leukemia. The approval for SM was based on results from a clinical trial in which patients with advanced SM demonstrated an overall response rate (ORR) of 60 percent when treated with the drug.
More than 80 percent of patients with SM have the somatic KIT D816V mutation. While research has suggested that several other mutations acquired prior to KIT D816V play a role in the pathogenesis of advanced SM, there is little information about biomarkers of response to midostaurin.
In a paper published in Blood, Mohamad Jawhar, MD, from Heidelberg University in Mannheim, Germany, and colleagues measured clinical parameters and molecular markers to identify factors predictive of response and prognosis in midostaurin-treated patients with advanced SM. They found that the absence of mutations in the SRSF2/ASXL1/RUNX1 (S/A/R) gene panel at baseline and a reduction in KIT D816V allele burden are associated with improved survival.
The study population included 38 patients with advanced SM (median age = 67 years; range = 48-76 years) who were treated with midostaurin at University Medical Centre Mannheim at Heidelberg University.
Fifteen patients (43%) received ≥1 prior therapy (median = 1 therapy; range = 1-4 therapies). Most patients (n=35; 92%) had the KIT D816V mutation, one patient had the KIT D816Y mutation, and two patients were KIT D816-negative.
Patients were initially treated with midostaurin 100 mg twice daily. Three patients (8%) stopped midostaurin within the first 4 months of treatment because of intolerance (nausea and vomiting), leaving 35 patients who completed the study.
Of the remaining patients, the median duration of midostaurin treatment was 13 months (range = 1-88 months). At 6-month follow-up (n=29) or at the end of treatment because of progression or death prior to month six (n=6), the ORR was 51 percent (n=18), including 12 major responses (MR; 34%) and six partial responses (PR; 17%). Eight patients (23%) had stable disease and nine had progressive disease (26%).
Median overall survival (OS) was 30 months (95% CI 6-54), and 20 patients (57%) died during treatment, including six patients within the first 6 months from early disease progression.
The 12 patients who were S/A/Rneg had a higher ORR, compared with the 23 patients who were S/A/Rpos (75% vs. 39%; p=0.04). The median OS was also longer for S/A/Rneg patients (not reached vs. 27 months; 95% CI 16-38; p=0.01), with long-term survival (>5 years) observed in five S/A/Rneg patients but no S/A/Rpos patients.
The investigators also assessed the expressed allele burden (EAB) of KIT D816V at baseline and at least every 3 months in the 28 KIT D816V-positive patients, finding that the best median response in all patients was a 29 percent decrease in EAB (range = –100-71%). Nineteen (68%) and 13 patients (46%) had a relative KIT D816V EAB reduction of ≥25 percent or ≥50 percent, respectively, independent of baseline EAB.
Those who had a KIT D816V EAB reduction ≥25 percent by 6 months were classified as KIT responders (n=17), and these patients had a significantly higher ORR and longer median duration of treatment compared with KIT non-responders (76% vs. 18% [p=0.006] and 25 months vs. 9 months [p=0.01], respectively).
KIT responders also had mutation profiles that included S/A/Rpos (n=9), TET2/CBL/JAK2 (n=1), TET2/JAK2 (n=1), and TET2 (n=1), but four responders had no mutations.
Univariate analyses of clinical parameters and molecular markers revealed that the following factors were associated with favorable prognosis and OS:
- reduction of serum tryptase levels (p=0.03; hazard ratio [HR] = 4.8)
- reduction of alkaline phosphatase levels (p=0.04; HR=3.2)
- reduction of KIT D816V EAB <25% (p=0.0004; HR=7.6)
- clinical response (MR or PR; p=0.01; HR=3.6)
In multivariate analyses, only a reduction in KIT D816V EAB <25 percent remained an independent risk factor for poor OS (p=0.004; HR=6.8). Notably, this was an even stronger predictor of survival than clinical response.
Dr. Jawhar and researchers also conducted serial next-generation sequencing of 28 genes in a cohort of 16 patients with multiple mutations and determined that newly acquired mutations and changes in variant allele frequency of the following genes were associated with disease progression in seven patients: K/NRAS, RUNX1, IDH2, and NPM1.
The results of the analysis suggest that “regular measurements of the KIT D816V allele burden should be performed in the routine follow-up for residual disease on or after potentially effective treatment regimens, including midostaurin, chemotherapy, and/or allogeneic hematopoietic cell transplantation,” the authors wrote.
The study’s findings are limited by its small patient population and single-center design. This study also was not designed to answer questions about the mechanisms behind these associations, but Dr. Jawhar and colleagues noted that “progression may be caused by expansion of subclones exhibiting new mutations in critical target genes independent of KIT D816V.”
Jawhar M, Schwaab J, Naumann N, et al. Response and progression on midostaurin in advanced systemic mastocytosis: KIT D816V