A Multidisciplinary Diagnostic Approach Reveals a Higher Prevalence of Indolent Systemic Mastocytosis: 15-Years’ Experience of the GISM Network

Systemic mastocytosis (SM) and other adult clonal mast cell disorders (CMD) are often underestimated, and their epidemiology data are scarce. We aimed at evaluating the impact of the activity of the Interdisciplinary Group for Study of Mastocytosis (GISM) of Verona on the prevalence and incidence of CMD. We examined the data of 502 adult patients diagnosed with CMD and residing in the Veneto Region, consecutively referred to GISM between 2006 and 2020. SM was diagnosed in 431 cases, while 71 patients had cutaneous mastocytosis or other CMD. Indolent SM represented the most frequent SM variant (91.0%), mainly with the characteristics of bone marrow mastocytosis (54.8%). The prevalence of SM in the adult population of the Veneto region and of the Verona province was 10.2 and 17.2/100,000 inhabitants, respectively. The mean incidence of new SM cases in Verona was 1.09/100,000 inhabitants/year. Hymenoptera venom allergy was the main reason (50%) leading to the CMD diagnosis. Osteoporosis, often complicated by fragility fractures, was present in 35% of cases, even in young patients, especially males. Our data show a higher prevalence and incidence of SM than previously reported, confirming that reference centers with multidisciplinary approach are essential for the recognition and early diagnosis of CMD.

A rare case of asymptomatic solitary cutaneous mastocytoma in a child

Mastocytosis is a rare group of disorders occurring when mast cells diffusely infiltrate the skin or internal organs. It has two forms: Cutaneous and systemic mastocytosis. We present a case of a 12-year-old male child presenting with a reddish-brown cutaneous nodule on the anterior chest wall for 1 month. No other similar lesions were noted elsewhere. Routine hematological and radiological investigations did not reveal any abnormality. The lesion was excised, and a diagnosis of solitary cutaneous mastocytoma was made based on the clinical, histopathological, and immunohistochemical features. This case highlights the importance of diagnosing this rare tumor which can present as an asymptomatic cutaneous lesion in a young child.

Mast cells and tryptase. Modern aspects

The present review considers the role of mast cells (MC) and tryptase levels in various pathological conditions in children and adults. The main causes of hypertryptasemia are presented, as well as a list of the most important stimuli that can cause activation of MC. Cliical allergologists should focus their clinical practice on the patients with anaphylaxia and suspected MC activation syndromes. Moreover, hypertryptasemia (> 20 ng/ml) is considered an additional diagnostic criterion for systemic mastocytosis, according to the WHO recommendations. As a rule, the level of tryptase is constantly elevated in most patients with systemic mastocytosis, whereas it is undergo changes in acute IgE-mediated hypersensitivity reactions. In cases of anaphylaxia, tryptase concentration should be determined in the patients during the first hours following onset of acute allergic reaction, and 24-48 hours later. Recommendations are given for determining tryptase levels in blood serum of the patients (basal and peak values), and algorithms are provided for usage of these indexes in various diseases. The article also provides the assessed threshold values of tryptase when diagnosing anaphylaxia, MC activation syndromes, and a novel disorder – alpha-tryptasemia. In the diagnosis of hereditary alpha-tryptasemia, as well as MC activation syndromes (primary and secondary), clinical manifestations in the patient and time dynamics of tryptase levels should be taken into account. The accumulated experience allowed to consider, first of all, frequency of severe allergic reactions (most often as anaphylaxia) in the patients with suspected MC activation syndromes. The syndrome of MC activation is characterized by excessive release of their granule contents without signs of clonal proliferation, which in many cases may be due to gene allele duplication, especially, TPSAB1 α-tryptase gene. For patients with hereditary alpha-tryptasemia, the most characteristic manifestations are represented by vegetative-vascular dystonia (orthostatic tachycardia), joint hypermobility, etc. Hence, determination of tryptase level (especially in time course) should be given more attention in the practice of clinicians. Difficulties with interpretation of the results arise in cases when tryptase concentration remains within normal range (up to 11.4 ng/ml), and the patient has clinically evident mastocytosis, or MC activation syndromes. If the patient has a history of anaphylaxia, especially after bites of hymenoptera insects, the TC activation syndromes should be excluded.

Newly Developed Psoriasis in a Patient with Telangiectasia Macularis Eruptiva Perstans and Systemic Mastocytosis Treated with Interferon

The authors present a rare case of a patient with telangiectasia macular eruptiva perstans, with confirmed D816V mutation which later progressed to systemic mastocytosis confirmed by trepanobiopsy. First-line treatment – phototherapy – had to be stopped, and systemic treatment with interferon alpha-2a was initiated. The treatment was successful with regression of skin lesions as well as mast cell infiltrates in the bone marrow. However, the treatment was complicated by the onset of psoriasis lesions.

Safety and efficacy of avapritinib in advanced systemic mastocytosis: the phase 1 EXPLORER trial

Advanced systemic mastocytosis (AdvSM) is a rare hematologic neoplasm driven by the KIT D816V mutation and associated with poor survival. This phase 1 study (NCT02561988) evaluated avapritinib (BLU-285), a selective KIT D816V inhibitor, in patients with AdvSM. The primary endpoints were the maximum tolerated dose, recommended phase 2 dose and safety of avapritinib. Secondary endpoints included overall response rate and changes in measures of mast cell burden. Avapritinib was evaluated at doses of 30–400 mg once daily in 86 patients, 69 with centrally confirmed AdvSM. Maximum tolerated dose was not reached, and 200 mg and 300 mg daily were studied in dose-expansion cohorts. The most frequent adverse events observed were periorbital edema (69%), anemia (55%), diarrhea (45%), thrombocytopenia (44%) and nausea (44%). Intracranial bleeding occurred in 13% overall, but in only 1% of patients without severe thrombocytopenia (platelets <50 × 109/l). In 53 response-evaluable patients, the overall response rate was 75%. The complete remission rate was 36%. Avapritinib elicited ≥50% reductions in marrow mast cells and serum tryptase in 92% and 99% of patients, respectively. Avapritinib induced deep and durable responses, including molecular remission of KIT D816V in patients with AdvSM, and was well tolerated at the recommended phase 2 dose of 200 mg daily.

Efficacy and safety of avapritinib in advanced systemic mastocytosis: interim analysis of the phase 2 PATHFINDER trial

Advanced systemic mastocytosis (AdvSM) is a rare, KIT D816V-driven hematologic neoplasm characterized by mast cell infiltration and shortened survival. We report the results of a prespecified interim analysis of an ongoing pivotal single-arm phase 2 trial (no. NCT03580655) of avapritinib, a potent, selective KIT D816V inhibitor administered primarily at a once-daily starting dose of 200 mg in patients with AdvSM (n = 62). The primary endpoint was overall response rate (ORR). Secondary endpoints included mean baseline change in AdvSM–Symptom Assessment Form Total Symptom Score and quality of life, time to response, duration of response, progression-free survival, overall survival, changes in measures of disease burden and safety. The primary endpoint was successfully met (P = 1.6 × 10-9), with an ORR of 75% (95% confidence interval 57–89) in 32 response-evaluable patients with AdvSM who had sufficient follow-up for response assessment, including 19% with complete remission with full or partial hematologic recovery. Reductions of ≥50% from baseline in serum tryptase (93%), bone marrow mast cells (88%) and KIT D816V variant allele fraction (60%) were observed. The most frequent grade ≥3 adverse events were neutropenia (24%), thrombocytopenia (16%) and anemia (16%). Avapritinib demonstrated a high rate of clinical, morphological and molecular responses and was generally well tolerated in patients with AdvSM.