Search

Systemic mastocytosis (SM) is a rare disease with a range of clinical presentations, and the vast majority of patients have a KIT D816V mutation that results in a gain of function. The multikinase/KIT inhibitor midostaurin inhibits the D816V mutant and has a well-established role in treating advanced SM. Even if considered the standard of therapy, some open questions remain on optimizing midostaurin management in daily practice. The current review presents the opinions of a group of experts who met to discuss routine practice using midostaurin in patients with advanced SM. The efficacy and safety of midostaurin in Phase 2 trials are overviewed, followed by practical guidance for optimal therapy management and adverse events during therapy with midostaurin. Specific guidance is given for initiating therapy and evaluating response with midostaurin as general assessment and laboratory, instrumental, pathological, and molecular exams. Special consideration is given to dose interruption, reduction, and discontinuation of therapy, as well as adverse event management and supportive therapy. Patients should be informed about possible side effects and receive practical advice to avoid or limit them and antiemetic prophylaxis so that therapy with midostaurin can continue as long as clinical benefit is observed or until unacceptable toxicity occurs. Lastly, considerations on the use of midostaurin during the ongoing Covid-19 pandemic are made. The overall scope is to provide guidance that can be useful in daily practice for clinicians using midostaurin to treat patients with advanced SM., Competing Interests: Competing interests: The authors declare no conflict of Interest. Conflicts of Interest. CP reports to have participated in Advisory Boards for Novartis and AbbVie, outside the submitted work. LF has nothing to disclose. VF reports to have participated in an Advisory Board for Amgen, outside the submitted work. FIG has nothing to disclose. NP has nothing to disclose. PP reports payment or honoraria as a speaker and for Advisory Boards from Novartis Italia, outside the submitted work. AR reports consulting fees from Novartis and to have participated on a Data Safety Monitoring Board/Advisory Board for Novartis, outside the submitted work.

Systemic mastocytosis (SM) results from a clonal proliferation of abnormal mast cells (MCs) in extra-cutaneous organs. It could be divided into indolent SM, smoldering SM, SM with an associated hematologic (non-MC lineage) neoplasm, aggressive SM, and mast cell leukemia. SM is generally associated with the presence of a gain-of-function somatic mutation in KIT at codon 816. Clinical features could be related to MC mediator release or to uncontrolled infiltration of MCs in different organs. Whereas indolent forms have a near-normal life expectancy, advanced diseases have a poor prognosis with short survival times. Indolent forms should be considered for symptom-directed therapy, while cytoreductive therapy represents the first-line treatment for advanced diseases. Since the emergence of tyrosine kinase inhibitors (TKIs), KIT inhibition has been an attractive approach. Initial reports showed that only the rare KITD816V negative cases were responsive to first-line TKI imatinib. The development of new TKIs with activity against the KITD816V mutation, such as midostaurin or avapritinib, has changed the management of this disease. This review aims to focus on the available clinical data of therapies for SM and provide insights into possible future therapeutic targets.

Reduced bone mass with or without fragility fractures is a common feature of mastocytosis, particularly in adult males. However, bone mineral density does not account for all the fragility fractures, being a part of them attributable to impairment in bone quality. Aim of this study is to assess the usefulness of DXA-derived geometry and structural indexes in the assessment of bone status in mastocytosis. Ninety-six consecutive patients (46 women and 50 men) affected by cutaneous (CM) or systemic (SM) mastocytosis were studied. Mean age (± SD) was 53.3 ± 14.23. Spine lateral X-rays for Genant's scale, DXA for lumbar (L) and femoral (F) bone mineral density (BMD), bone strain index (BSI), lumbar trabecular bone score (TBS), and hip structural analysis (HSA) were performed. Among the laboratory variables, data of serum tryptase were reported. Tryptase was higher in SM (p = 0.035), inversely correlated with LBMD (r =  - 0.232; p = 0.022) and TBS (r =  - 0.280; p = 0.005), and directly with L-BSI (r = 0.276; p = 0.006). L-BSI remained statistically significant (p = 0.006; adjusted R 2  = 0.101) together with mastocytosis (SM or CM: p = 0.034) in the multivariate regression model with tryptase as dependent variable, being LBMD and TBS not statistically significant (p = 0.887, and p = 0.245, respectively). Tryptase increased about 22 units for each unit increase of L-BSI and about 18 units for SM against CM. L-BSI was lower (p = 0.012), while FN-BSI and FT-BSI were higher in women (p < 0.001) than in men. HSA indexes were significantly higher in men, particularly with SM. SM is a risk factor for reduced bone mass, texture and strength. Since mean L-BSI and Z-modulus of all the femoral sites are statistically higher in men than in female, it could be argued that men have a better femoral bone resistance to bending forces than women, but a worse lumbar bone resistance to compressive loads. DXA indexes of bone quality are useful in mastocytosis' bone assessment and its clinical management.

Available studies on metabolic syndrome (MS) after hematopoietic stem cell transplantation (HSCT) are retrospective with heterogeneous inclusion criteria, and little is known about the early post-transplant phase. In our prospective study, clinical and laboratory data were collected in 100 HSCT recipients, 48 allogeneic and 52 autologous, at baseline, at + 30, + 100 and + 360 days. At baseline, MS was observed in 24 patients, significantly associated with insulin resistance and leptin on multivariate analysis. At + 30, the diagnosis of MS was confirmed in 43 patients, significantly related to insulin resistance and allogeneic transplants. If the whole series was considered, patients with MS had significantly higher mortality from any cause. The baseline presence of any MS feature was a predictor of + 30 MS. Isolated occurrences of MS features were related to hyperleptinemia and hyperinsulinemia, except in the case of low HDL cholesterol, linked to adiponectin and resistin. Our data confirm that patients undergoing HSCT have a high prevalence of MS, with hyperleptinemia playing a major role. The early peak of new MS cases is primarily attributable to insulin resistance, notably but not exclusively immunosuppression-induced; the subsequent long-term increase in MS cases may be an effect of persistent adipokine imbalance.

Systemic mastocytosis is a rare heterogeneous myeloproliferative neoplasm characterized by abnormal proliferation and activation of mast cells. We describe a large multicentre series of 460 adult patients with systemic mastocytosis, with a diagnosis based on WHO 2008 criteria, in a "real-life" setting of ten Italian centers with dedicated multidisciplinary programs. We included indolent forms with (n = 255) and without (n = 165) skin lesions, smouldering (n = 20), aggressive (n = 28), associated with other hematological diseases mastocytosis (n = 21) and mast cell leukemia (n = 1). This series was uniquely characterized by a substantial proportion of patients with low burden of neoplastic mast cells; notably, 38% of cases were diagnosed using only minor diagnostic criteria according to WHO 2008 classification, underlying the feasibility of early diagnosis where all diagnostic approaches are made available. This has particular clinical relevance for prevention of anaphylaxis manifestations, that were typically associated with indolent forms. In multivariate analysis, the most important features associated with shortened overall survival were disease subtype and age at diagnosis >60 years. Disease progression was correlated with mastocytosis subtype and thrombocytopenia. As many as 32% of patients with aggressive mastocytosis suffered from early evolution into acute leukemia. Overall, this study provides novel information about diagnostic approaches and current presentation of patients with SM and underlines the importance of networks and specialized centers to facilitate early diagnosis and prevent disease-associated manifestations. Am. J. Hematol. 91:692-699, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)