Efficacy and safety of mammalian target of rapamycin inhibitors in systemic mastocytosis: A nationwide French pilot study.

Systemic mastocytosis (SM) corresponds to a rare and heterogeneous spectrum of diseases characterized by the accumulation of atypical mast cells (MCs). Advanced mastocytosis (Adv-SM) is associated with poor survival; in contrast, patients with non-advanced SM (non-Adv-SM) usually have a normal life expectancy but may experience poor quality of life. Despite recent therapeutic progress including tyrosine kinase inhibitors, new treatment options are needed for refractory and/or intolerant patients with both severely symptomatic and Adv-SM. In vitro, the mTOR pathway is activated in MCs from patients bearing the KIT D816V mutation. Furthermore, rapamycin induces the apoptosis of KIT D816V MCs selectively. In this nationwide study, we report the outcomes of patients diagnosed with SM and treated with a mammalian target of rapamycin inhibitor (imTOR) within the French National Reference Center for mastocytosis (CEREMAST). All patients registered were relapsing, treatment-refractory, or ineligible for other cytoreductive therapy. Non-Adv-SM patients received imTOR as a monotherapy (rapamycin/everolimus), and Adv-SM patients received imTOR as a monotherapy or in combination with cytarabine. The objective response rate (ORR) in non-Adv-SM was 60% (partial response in 40% and major response in 20%), including reductions in skin involvement, mediator release symptoms, and serum tryptase. In the Adv-SM group, the ORR was 20% (including one major response and one partial response, both in patients with a KIT D816V mutation), which enabled a successful bridge to allogeneic stem cell transplantation in one patient. Our results suggest that imTOR treatment has potential benefits in patients with SM harboring a KIT D816V mutation.

Allogeneic haematopoietic cell transplantation for advanced systemic mastocytosis: Best practice recommendations on behalf of the EBMT Practice Harmonisation and Guidelines Committee.

Systemic Mastocytosis (SM) is a multifaceted clinically heterogeneous disease. Advanced SM (AdvSM) comprises three entities: aggressive SM (ASM), mast cell leukaemia (MCL) and SM with an associated hematologic neoplasm (SM-AHN), the latter accounting for 60-70% of all AdvSM cases. Detection of a disease-triggering mutation in the KIT gene (esp. KIT D816V) in >90% of the patients with ASM or SM-AHN has led to a significant improvement in therapeutic options by the implementation of two KIT-targeting kinase inhibitors: midostaurin and avapritinib. Although complete remissions have been reported, neither of these targeted agents is 'curative' in all patients and the duration of responses varies. The median overall survival, depending on the WHO subtype and scoring result, is approximately 1 to 4 years. Although the European Competence Network on Mastocytosis (ECNM) and American Initiative in Mast Cell Diseases (AIM) consensus groups recommend allogeneic haematopoietic cell transplantation (allo-HCT) in drug-resistant and other high-risk patients, there is a relative lack of information to guide clinicians on which patients with AdvSM should be considered for transplant, and how KIT inhibitors may fit into the transplant algorithm, including their use pre- and post-transplant to optimise outcomes. Following the generation of an expert panel with a specialist interest in allo-HCT and mastocytosis, these best practice recommendations were generated according to the European Society for Blood and Marrow Transplantation (EBMT) Practice Harmonisation and guidelines and ECNM methodology. We aim to provide a practical, clinically relevant and up-to-date framework to guide allo-HCT in AdvsM in 2024 and beyond.

Allogeneic Hematopoietic Cell Transplantation in Advanced Systemic Mastocytosis: A retrospective analysis of the DRST and GREM registries.

We identified 71 patients with AdvSM (aggressive SM [ASM], SM with an associated hematologic neoplasm [SM-AHN, e.g., acute myeloid leukemia, SM-AML], mast cell leukemia [MCL]) in two national registries (DRST/GREM) who received an allogeneic hematopoietic cell transplantation (alloHCT) performed in Germany from 1999-2021. Median overall survival (OS) of ASM/SM-AHN (n = 30, 45%), SM-AML (n = 28, 39%) and MCL ± AHN (n = 13, 19%) was 9.0, 3.3 and 0.9 years (P = 0.007). Improved median OS was associated with response of SM (17/41, 41%; HR 0.4 [0.2-0.9], P = 0.035) and/or of AHN (26/43, 60%, HR 0.3 [0.1-0.7], P = 0.004) prior to alloHCT. Adverse predictors for OS included absence of KIT D816V (10/61, 16%, HR 2.9 [1.2-6.5], P < 0.001) and a complex karyotype (9/60, 15%, HR 4.2 [1.8-10.0], P = 0.016). HLA-match, conditioning type or transplantation at centers reporting above-average alloHCTs (≥7) had no impact on OS. Taking into account competing events at years 1, 3 and 5, relapse-related mortality and non-relapse mortality rate were 15%/23%, 20%/30% and 23%/35%, respectively. Irrespective of subtype, subsequent treatment response was achieved in 13/30 (43%) patients and was highest on midostaurin/avapritinib (7/9, 78%). We conclude that outcome of alloHCT in AdvSM is more affected by disease phenotype and treatment response prior to transplant than by transplant characteristics.

The Prevalence Of Osteoporosis Is Low in Adult Cutaneous Mastocytosis Patients.

BACKGROUND: Systemic mastocytosis (SM) is a clonal disorder of mast cells (MCs) frequently associated with vertebral osteoporosis (OP) and subsequent vertebral fractures (VFs). The natural history of this OP remains unclear. Importantly, we do not know whether OP represents an early event triggered alongside MC abnormalities, and whether MC clonality is sufficient to trigger osteoporosis. OBJECTIVE: To describe OP in patients with medullar clonality in cutaneous mastocytosis (CM) and monoclonal mast cell activation syndrome (MMAS) and to compare their osteoporosis characteristics with those of nonadvanced SM patients (bone marrow mastocytosis and indolent systemic mastocytosis). METHODS: We retrospectively analyzed clinical, biological, and densitometric data of 27 CM, 13 MMAS, and 135 SM patients from the Mastocytosis Expert Center (CEREMAST) in Toulouse, France. RESULTS: The OP (respectively 3.7, 30.8, and 34.1%) and VFs (0.0%, 15.4%, and 20%) were less frequent in CM than in MMAS and SM, despite the presence of clonal MCs in the bone marrow. Most patients with OP and VFs in the non-SM groups had the usual risk factors for OP. Interestingly, the only non-SM patient with a typical SM-like OP had high bone marrow tryptase, developed bone marrow KIT mutation during follow-up, and had a family history of SM. Our data show that OP is not a common clinical finding in CM but is frequent in MMAS. When OP and VFs occur in CM and MMAS patients, they differ from the usual phenotype of SM bone fragility. CONCLUSIONS: Our findings suggest that, in most CM patients, the meaning and management of OP differs from that of OP in MMAS and nonadvanced SM. Prospective longitudinal studies and the validation of predictors are needed to identify CM and MMAS patients developing SM-related OP.

Epidemiology of mastocytosis: a population-based study (Sweden).

BACKGROUND: Mastocytosis is a disease characterized by accumulation of aberrant mast cells and mediator-related symptoms and is divided into systemic mastocytosis (SM) and cutaneous mastocytosis (CM). The epidemiology of mastocytosis remains incompletely understood. OBJECTIVE: To estimate the incidence, prevalence, overall survival (OS) and burden of comorbidities in adult mastocytosis patients identified in Swedish population-based registries. METHODS: Individuals (≥ 20 years of age) with a mastocytosis diagnosis in the National Patient Register (NPR) and/or the Swedish Cancer Register (SCR) between 2001 and 2018, were identified. In a matched cohort design, for each case five randomly selected mastocytosis-free comparators matched on age, sex, and county of residence were chosen from the Population Register. The Kaplan-Meier method was used to compare OS between individuals with mastocytosis and comparators. Information on concomitant disease at baseline was assessed by use of the Charlson Comorbidity Index (CCI). RESULTS: We identified 2,040 adults with a mastocytosis diagnosis yielding an annual incidence of 1.56 per 100,000 (95% CI 1.29-1.87) and a prevalence of 23.9 per 100,000 (95% CI 22.8-25.0). The comorbidity burden was higher, and the OS lower, in patients with mastocytosis compared to comparators. INTERPRETATION: We found a higher incidence and prevalence of mastocytosis compared to assessments in other settings and confirmed that the prognosis generally is favorable. Of special note was evidence of a higher comorbidity burden in mastocytosis patients compared to the background population. LIMITATIONS: Underreporting and inconsistencies in the use of diagnostic codes.

Mast Cell-Targeting Therapies in Mast Cell Activation Syndromes.

PURPOSE OF REVIEW: Provide an overview of the expanding landscape of mast cell (MC)-targeting treatments in mast cell activation syndromes (MCAS). RECENT FINDINGS: Tyrosine-kinase inhibitors (TKIs) targeting wild-type and mutated KIT can efficiently induce MC depletion. Avapritinib and midostaurin can also temper IgE-mediated degranulation. Avapritinib has been recently approved by the FDA for the treatment of indolent systemic mastocytosis (ISM). Targeting activation pathways and inhibitory receptors is a promising therapeutic frontier. Recently, the anti Siglec-8 antibody lirentelimab showed promising results in ISM. MCAS is a heterogeneous disorder demanding a personalized therapeutic approach and, especially when presenting as anaphylaxis, has not been formally captured as outcome in prospective clinical trials with TKI. Long-term safety of TKI needs to be addressed. New drugs under investigation in diseases in which non-neoplastic MCs play a pivotal role can provide important inputs to identify new efficient and safe treatments for MCAS.

Mastocytosis in the skin in dogs: A multicentric case series.

Canine cutaneous mastocytosis (CM) is rare in contrast to canine mast cell tumours. In humans, CM commonly affects children and is usually indolent with possible spontaneous resolution. Systemic mastocytosis (SM) with bone marrow involvement typically affects adults, can have a poor outcome, and often includes skin lesions. 'Mastocytosis in the skin' (MIS) is the preferred term of skin lesions, if bone marrow evaluations are not available, which is often the cases in dogs. In human SM and CM, KIT mutations are often detected. The veterinary literature suggests clinical resemblances between human and canine MIS, but data is limited, and KIT mutations are rarely assessed. This retrospective study describes clinicopathological findings, treatment and outcome of 11 dogs with suspected MIS. Dogs with multiple mast cell tumours were excluded. Histopathology reports (n = 5) or slides (n = 6) were reviewed. KIT mutation analysis including exons 8, 9, 11, 14 and 17 were analysed in eight dogs. Median age at diagnosis was 4 years (range, 1-12). Typical clinical signs included multifocal to generalised nodules and papules. Histologically, skin lesions were characterised by dermal infiltration of well-differentiated mast cells. KIT mutations were detected in 3/8 dogs (exon 9: n = 2; exon 11: n = 1). One dog had mastocytaemia suggesting possible SM. Glucocorticoids were mostly successful with lesion improvement in all treated dogs (n = 8). This cohort highlights resemblances between human and canine MIS. Further studies are required to confirm these findings and establish diagnostic criteria for CM and MIS associated with SM in dogs.

A clinical, morphological and molecular study of 70 patients with gastrointestinal involvement in systemic mastocytosis.

In 70 patients with KIT D816V positive systemic mastocytosis (SM) including 36 patients with advanced SM (AdvSM), we correlated the extent of reported mucosal mast cell ([m]MC) infiltration of the upper and/or lower gastrointestinal tract (UGIT, n = 63; LGIT, n = 64; both, n = 57) with symptoms and markers of MC burden/subtype. GI symptoms were reported by all patients (mean 2.1 number of symptoms). A strong mMC infiltration was identified in 24 patients (UGIT, 17/63, 27%; LGIT, 19/64, 30%). Concurrent involvement of UGIT and LGIT (n = 12) correlated with female gender (75%) and a higher symptom burden (mean 2.7) but not with MC burden or subtype. Significant differences between non-AdvSM and AdvSM were reported regarding food intolerance (54% vs. 17%), cramping (54% vs. 22%) and weight loss (0% vs. 64%). KIT D816V was identified in 54/56 (96%) available biopsies. In 46 patients, digital PCR revealed a correlation with low albumin levels (r = - 0.270, P = 0.069) and the KIT D816V VAF in peripheral blood (r = 0.317, P = 0.036) but not with the extent of mMC infiltration or markers of MC burden/subtype. Although MC mediator triggered GI symptoms have a substantial impact on the quality of life, correlation to objective disease parameters is lacking thus making its systematic assessment challenging.

Granularity in disease classification impacts survival prediction in advanced systemic mastocytosis: A single institution study of 329 informative cases.

The World Health Organization (WHO) classification system categorizes advanced systemic mastocytosis (SM-Adv) into aggressive SM (ASM), mast cell leukemia (MCL), and SM with associated hematological neoplasm (SM-AHN). By contrast, the International Consensus Classification (ICC) requires "immature" MC cytomorphology for the diagnosis of MCL and limits SM-AHN to myeloid neoplasms (SM-AMN). The current study includes 329 patients with SM-Adv (median age 65 years, range 18-88; males 58%): WHO subcategories SM-AHN (N = 212; 64%), ASM (N = 99; 30%), and MCL (N = 18; 6%); ICC subcategories SM-AMN (N = 190; 64%), ASM (N = 99; 33%), and MCL (N = 9; 3%); WHO-defined MCL with "mature" MC cytomorphology and SM-AHN associated with lymphoid neoplasms were operationally labeled as "MCL-mature" (N = 9) and SM-ALN (N = 22), respectively, and distinguished from ICC-defined MCL and SM-AMN. Multivariable analysis that included the Mayo alliance risk factors for survival in SM (age >60 years, anemia, thrombocytopenia, increased alkaline phosphatase) revealed more accurate survival prediction with the ICC versus WHO classification order: (i) survival was significantly worse with MCL-immature versus MCL-mature (hazard ratio [HR] 15; p < .01), (ii) prognostic distinction between MCL and SM-AHN/AMN was confirmed in the context of ICC (HR 9.3; p < .01) but not WHO classification order (p = .99), (iii) survival was similar between MCL-mature and SM-AMN (p = .18), and (iv) SM-AMN (HR 1.7; p < .01) but not SM-ALN (p = .37) was prognostically distinct from ASM. The current study provides evidence for the independent prognostic contribution of both the ICC system for SM-Adv and the Mayo alliance risk factors for survival in SM.

Pathophysiologic implications of elevated prevalence of hereditary alpha-tryptasemia in all mastocytosis subtypes.

BACKGROUND: Mastocytosis and monoclonal mast cell (MC) activation syndrome (MMAS) are heterogeneous conditions characterized by the accumulation of atypical MCs. Despite the recurrent involvement of KIT mutations, the pathophysiologic origin of mastocytosis and MMAS is unclear. Although hereditary α-tryptasemia (HαT, related to TPSAB1 gene duplication) is abnormally frequent in these diseases, it is not known whether the association is coincidental or causal. OBJECTIVE: We evaluated the prevalence of HαT in all mastocytosis subtypes and MMAS and assessed the pathophysiologic association with HαT. METHODS: Clinical data, laboratory data, KIT mutations, TPSAB1 duplication (assessed by droplet digital PCR), and HαT prevalence were retrospectively recorded for all patients with mastocytosis and MMAS registered in the French national referral center database and compared to a control cohort. To increase the power of our analysis for advanced systemic mastocytosis (advSM), we pooled our cohort with literature cases. RESULTS: We included 583 patients (27 with MMAS and 556 with mastocytosis). The prevalence of HαT in mastocytosis was 12.6%, significantly higher than in the general population (5.7%, P = .002) and lower than in MMAS (33.3%, P = .02). HαT+ patients were more likely to have anaphylactic reactions and less likely to have cutaneous lesions than HαT- patients (43.0% vs 24.4%, P = .006; 57.7% vs 75.6%, respectively, P = .006). In the pooled analysis, the prevalence of HαT was higher in advSM (11.5%) than in control cohorts (5.2%, P = .01). CONCLUSION: Here we confirm the increase incidence of anaphylaxis in HαT+ mastocytosis patients. The increased prevalence of HαT in all subtypes of systemic mastocytosis (including advSM) is suggestive of pathophysiologic involvement.

Advanced systemic mastocytosis-Revised classification, new drugs and how we treat.

Mastocytosis constitutes the neoplastic proliferation of mast cells and is broadly classified into systemic mastocytosis (SM), cutaneous mastocytosis and mast cell sarcoma. SM is further partitioned into advanced (AdvSM) and non-advanced (SM-non-Adv) subcategories. AdvSM includes aggressive SM (ASM), SM with an associated haematological neoplasm (SM-AHN) and mast cell leukaemia (MCL). In 2022, two separate expert committees representing the 5th edition of the World Health Organization (WHO5) and the International Consensus (ICC) classification systems submitted revised classification criteria for SM, highlighted by the ICC-proposed incorporation of mast cell cytomorphology in the diagnostic criteria for MCL and myeloid-lineage restriction for the AHN component in SM-AHN. Recent developments in SM also include the introduction of KIT-targeting tyrosine kinase inhibitors (KITi), including midostaurin and avapritinib, both drugs have shown potent activity in reducing mast cell and mutant KIT burden and alleviating mast cell-associated organopathy and mediator symptoms; however, their overall impact on survival or superiority over pre-KITi era treatment options (e.g. cladribine) has not been studied in a controlled setting. In the current review, we provide a summary of recent changes in disease classification and an analysis of recent clinical trials and their impact on our current treatment approach in AdvSM.