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

Abstract

PURPOSE On the basis of data from the German Registry on Disorders of Eosinophils and Mast Cells, we compared the efficacy of midostaurin and cladribine in patients with advanced systemic mastocytosis (AdvSM). PATIENTS AND METHODS Patients with AdvSM (n = 139) were treated with midostaurin only (n = 63, 45%), cladribine only (n = 23, 17%), or sequentially (midostaurin-cladribine, n = 30, 57%; cladribine-midostaurin, n = 23, 43%). Prognosis was assessed through the Mutation-Adjusted Risk Score (MARS). Besides the comparison of efficacy between midostaurin and cladribine on response (eg, organ dysfunction, bone marrow mast cell [MC] infiltration, and tryptase), overall survival (OS), and leukemia-free survival, we focused on the impact of treatment on involved non-MC lineages, for example, monocytes or eosinophils, and the KIT D816V expressed allele burden. RESULTS Midostaurin only was superior to cladribine only with effects from responses on MC and non-MC lineages conferring on a significantly improved OS (median 4.2 v 1.9 years, P = .033) and leukemia-free survival (2.7 v 1.3 years, P = .044) on the basis of a propensity score–weighted analysis of parameters included in MARS. Midostaurin compensated the inferior efficacy of cladribine in first- and second-line treatment. On midostaurin in any line, response of eosinophilia did not improve its baseline adverse prognostic impact, whereas response of monocytosis proved to be a positive on-treatment parameter. Multivariable analysis allowed to establish three risk categories (low/intermediate/high) through the combination of MARS and the reduction of the KIT D816V expressed allele burden of ≥ 25% at month 6 (median OS not reached v 3.0 years v 1.0 year; P < .001). CONCLUSION In this registry-based analysis, midostaurin revealed superior efficacy over cladribine in patients with AdvSM. In midostaurin-treated patients, the combination of baseline MARS and molecular response provided a compelling three-tier risk categorization (MARSv2.0) for OS.

Efficacy of avapritinib versus best available therapy in the treatment of advanced systemic mastocytosis

“…Outcomes observed for the BAT cohort in this study are consistent with prior studies of therapies for AdvSM. In a registrybased analysis, Lübke et al reported an OS from initiation of 1L treatment with midostaurin of 3.1 years (37 months) and OS from initiation of 1L treatment with cladribine of 1.6 years (18 months) [13]. In this study, the most commonly observed 1L therapies in the BAT cohort were midostaurin (54.2%) and cladribine (18.7%), and the mean OS from initiation of 1L treatment for the BAT cohort was 27 months, consistent with findings of Lübke et al [9].…”

“…As the majority (>90%) of patients with AdvSM carry a KIT D816V mutation [11], recent therapeutic advances have focused on KIT inhibitors [12]. Treatment options for patients with AdvSM include the multikinase KIT inhibitor midostaurin, for which efficacy and safety has been reported in several clinical trials and observational studies [9,[13][14][15][16][17][18]. In addition, imatinib is a treatment option for the limited indication of ASM patients who are KIT D816V-negative or with unknown KIT mutation status [19].…”

“…In addition, imatinib is a treatment option for the limited indication of ASM patients who are KIT D816V-negative or with unknown KIT mutation status [19]. Commonly used off-label cytoreductive therapies include cladribine [13,[20][21][22][23] and interferon alfa [22,24]. For treatmentresistant patients and those with rapidly progressive disease after tyrosine kinase inhibitor (TKI) treatment, multiagent chemotherapy and subsequent allogenic hematopoietic stem cell transplantation (HSCT) are considerations [25].…”

Systemic Mastocytosis and Other Entities Involving Mast Cells: A Practical Review and Update

“…Given that most patients are included in the MARS low-risk cohort, midostaurin may be the preferable treatment for these patients [ 89 ]. Another registry-based data analysis of patients with advanced SM, based on the MARS parameters and KIT D618V VAF, demonstrated the superiority of midostaurin versus cladribine regarding OS and leukemia-free survival [ 92 ]. Other studies showed that cytoreduction with cladribine successfully reduced the bone marrow mast cell burden and serum tryptase levels [ 93 , 94 , 95 , 96 , 97 , 98 ], particularly in patients with KIT D816V.…”

Target Therapies for Systemic Mastocytosis: An Update

“…The use of midostaurin in any line compensated for the inferior efficacy of cladribine. The combination of MARS score and the reduction of KITD816V allele burden at month 6 allowed us to distinguish three risk categories with a significantly different OS [65].…”