Selection and Efficacy of Cytoreductive Agents in Patients with Mastocytosis Included in the Registry of the European Competence Network on Mastocytosis (ECNM)

Mastocytosis is a heterogeneous group of clonal hematopoietic disorders characterized by uncontrolled expansion and accumulation of mast cells in the bone marrow and other tissues. While in indolent forms anti-mediator therapy is safe and effective, cytoreductive treatment is required for disease control in advanced mastocytosis. In addition to traditional agents, such as alpha-interferon (IFN-A) or hydroxyurea (HU), cladribine (2-CdA) and midostaurin have demonstrated efficacy in these patients.

The aim of this study was to analyze the determinants and the efficacy of various cytoreductive treatments in mastocytosis in the "real-life" clinical practice, based on the dataset of the ECNM Registry.

As of March 2017, 2,115 adult patients (median age 48; range 18-91 years; M/F ratio 930/1185) from 11 countries were enrolled in the ECNM registry. Of these patients, 200 (9.5%) had cutaneous mastocytosis (CM), 266 (12.6%) mastocytosis in the skin (MIS), 1026 (48.5%) indolent systemic mastocytosis (ISM), 260 (12.3%) bone marrow mastocytosis (BMM, a provisional sub-category of ISM), 56 (2.5%) smoldering SM (SSM), 71 (3.4%) aggressive SM (ASM), 27 (1.3%) mast cell leukemia (MCL), 207 (9.8%) SM with associated hematologic neoplasm (SM-AHN), and 2 (0.1%) mast cell sarcoma (MCS). Overall, 386 patients (18.2%) received cytoreductive treatment. As expected, the proportion of treated patients was significantly different in disease categories (CM 2%, BMM/ISM 9.1%, SSM 45.5%, ASM-MCL-MCS 73.9%, SM-AHN 74.4%, P<.001). The fraction of treated patients was similar across countries in SSM and advanced SM , whereas a significant difference was observed in CM and ISM (P=.033 and P<.001, respectively), as well as in SM-AHN (P=.006). Median time from diagnosis to treatment was 12 and 19 months in ISM and SSM respectively, whereas it decreased to 1 month in ASM-MCL and SM-AHN. When focusing on the determinants of cytotoxic therapeutic intervention in indolent forms, the presence of skin involvement, flushing, pruritus, headache, bone pain, gastrointestinal symptoms, malabsorption, splenomegaly and high level of tryptase and alkaline phosphatase were significantly associated with the introduction of cytoreductive treatment (P<.01), while c-KIT mutational status was not. Median number of treatments per individual patient was higher in advanced than in indolent SM (median 2 vs 1, range 1-7), 41% of patients requiring two or more lines of therapy. When focusing on first-line treatment, in advanced SM the most frequently used agents were tyrosine-kinase inhibitors (TKIs) (32/79, 41%) (midostaurin 47%, imatinib 34%; others 19%) followed by IFN-A (22/79, 28%) and 2-CdA (17/79, 22%). Overall response rates (ORR) were 73%, 30% and 82% in midostaurin, IFN-A and 2-CdA, respectively. In BMM and ISM, 46/116 patients (40%) were treated with TKIs (midostaurin 37%, imatinib 28%, others 35%), 39% with IFN-A, and 14% with 2-CdA, with ORR of 63%, 40% and 60% in midostaurin, IFN-A and 2-CdA, respectively. HU and polychemotherapy were less frequently used (6.6% in ASM and 2.7% in ISM). In multivariate analyses, the choice of first-line therapy was significantly influenced by the year of therapy (i.e. before or after 2000 and 2005) (P<.001), TKIs being the most frequently used in the last decade, and by country of origin in both patients with advanced and indolent SM (P=.026 and P=.003, respectively). In SM-AHN, therapeutic intervention was mainly triggered by the type of AHN.

After a median follow-up of 3.1 years (0-31.4 years), a 10-year probability of overall survival (OS) of 81% was observed in the whole cohort, with a significant difference among disease categories (ranging from 93% in ISM to 14% in SM-AHN, P<.001). In multivariate analyses in both patients with aggressive and indolent SM, a significant effect of receiving any cytotoxic therapy was observed on OS (P<.001), while no significant effect of the type of therapy was noticed (P values .45 and .19).

In conclusion, this study shows that only a minority of patients with mastocytosis requires cytoreductive therapy, mostly indolent forms refractory to anti-mediator therapy and advanced SM. The selection of treatment was significantly influenced by country and year of treatment, 2-CdA and midostaurin becoming the most widely used drugs, associated with high overall response rates.