KIT D816V Research Articles

Predictive Value of Elevated Tryptase and Mediator Symptoms in Systemic Mastocytosis - a Single Center Experience

Background: Systemic mastocytosis (SM) is a rare clonal hematologic disorder primarily driven by the KIT D816V mutation in almost all (95%) patients. These patients most often have elevated serum tryptase levels and can present with a wide spectrum of symptoms caused by mediator release from clonal mast cell degranulation (e.g., skin rash, anaphylaxis, diarrhea, and neurocognitive symptoms). However, these symptoms are similar in other non-clonal mast cell disorders such as idiopathic mast cell activation syndrome (MCAS) and hereditary alpha-tryptasemia (HaT). As such, many patients are referred to hematology for SM work-up based on elevated serum tryptase and mediator release symptoms. We evaluated a real-world single-center experience determining whether elevated serum tryptase, mediator release symptoms, and/or a history of anaphylaxis correlated with a diagnosis of SM. Methods: We conducted a retrospective chart review of patients referred to the Mastocytosis Clinic at Huntsman Cancer Institute at the University of Utah for a year between August 2022 and July 2023. Data were collected by chart review and analyzed for disease characteristics, laboratory values, and diagnostic outcomes. Findings/Results: There were a total of 37 patients referred to us during the designated time period with either a tryptase value greater than 10.9 ug/L or abnormal mast cells found on tissue biopsy (e.g., skin, colon, etc) with or without systemic mediator release symptoms. Patients did not have to have a history of anaphylaxis to be seen. Of these, 7 patients already had a known diagnosis of SM and had bone marrow biopsy at an outside institution. Of the 30 remaining patients, 19 (63%) patients reported a history of at least one mediator release symptom, defined as pruritus, flushing, syncope, bloating, nausea, vomiting, or diarrhea. The median serum tryptase level was 17.4 ug/L. (Range 2 - 317 ug/L). KIT D816V mutation was detected in the peripheral blood by digital droplet PCR in 7 (23.3%) patients. Diagnostic bone marrow was done in 19 patients wherein 6 (31.5%) of them met the WHO diagnostic criteria for SM. Of these patients, 5 patients tested positive for KIT D816V mutation on peripheral blood and 1 patient had KIT wild type. Two patients with KIT D816V mutations did not receive bone marrow biopsy as they had no mediator release symptoms. The remaining 13 patients had a bone marrow biopsy but did not have a diagnosis consistent with SM, although some had rare scattered mast cells identified in the marrow. They were all KIT D816V mutation negative and serum tryptase ranged from 2.7 - 43 ug/L. As of the date of data analysis, 4 (30.7%) patients tested positive for HaT; serum tryptase ranged from 20 - 26 ug/L in this cohort. Conclusion: While SM can have a variety of clinical manifestations, including elevated tryptase level and mediator release symptoms, the presence of KIT D816V in the peripheral blood is a strong predictor of SM diagnosis. Persistently elevated serum tryptase without the KIT D816V mutation may suggest the likelihood of HaT, while only mediator release symptoms with normal serum tryptase and without the KIT mutation is a strong negative predictor of SM and HaT.

Molecular and Cytogenetic Evaluation in Systemic Mastocytosis

Systemic mastocytosis (SM) is a rare hematological neoplasm characterized by pleomorphic symptoms, related to mediators release from pathological mast cells. Tissue infiltration of liver, spleen, gastro-intestinal (GI) tract and osteolysis are present in aggressive disease. As KIT D816V mutation can be found in approximately 80% of patients, several additional somatic mutations of prognostic significance have been detected in a subset of patients. We report on clinical, cytogenetic and molecular characteristic of 160 patients with SM diagnosed in the last 15 years at our center. Fourteen (8.9%) patients had cutaneous mastocytosis, 85 (53.5%) had indolent SM (ISM), 12 (7.5%) had smoldering SM (SSM), 27 (17%) had aggressive SM (ASM), 17 (10.5%) had SM with an associated hematological neoplasm (AHN-SM) and 1 (0.6%) had mast cell leukemia. Symptoms were mostly related to mediators release: itching and blistering (69, 43%), anaphylaxis (49, 30%), diarrhea/bloating (19, 12%), osteoporosis/bone fracture (10, 6%), constitutional symptoms (8, 5%), bone pain and myalgia (16, 10%), anaphylaxis from Hymenoptera venom (24, 15%). While SM patients were mostly treated with antihistamines and membrane stabilizers, 29 patients needed a disease modifying therapy. Four patients with ISM were treated with Interferon (IFN) for bone lytic alterations, while 1 patient with ISM started midostaurin for uncontrolled symptoms. Other 11 patients with ASM were treated with midostaurin: 4 responded, while 7 needed multiple lines of therapy including allogeneic transplant in 4 cases. Eleven patients with ASM were treated with tyrosin kinase inhibitors (TKI) before midostaurin became available, while 2 elderly patients were treated with low dose cytarabine and TKI for concomitant acute leukemia. KIT D816V mutation was found in 111 of 131 (85%) evaluable patients with SM. Cytogenetics was normal in all but 2 patients with AHN-SM in which a chromosomal gain was reported. Among 6 patients with ISM, KIT mutation was found in only 2 cases. One patient had isolated KIT mutation and was treated with IFN for skin symptoms and bone fracture, and another patient had a DNMT3A associated mutation and was treated with imatinib. Moreover, 1 patient presented both DNMT3A and TET2 mutations and was treated with IFN for bone fracture. Among 12 ASM patients, 1 was negative for significant mutations: no disease control was achieved after target therapy, and bone marrow function slowly recovered after allogeneic transplant. The most frequently recorded mutations were SRSF2 and TET2: they were present in 4 patients each and recorded together in 3 cases. Two patients with SRSF2 and TET2 mutations died after multiple lines of therapy: 1 patient for infection and graft versus host disease after allogeneic transplant and 1 for progressive disease. Moreover, the latter had additional RUNX1 mutation. Two patients with concomitant SRSF2 and IDH1 mutations and TET2 mutation respectively responded to midostaurin, while 1 with DNMT3A mutation received multiple lines of therapy and died for pneumonia. One patient with ASXL1 mutation responded to chemotherapy after 2 previous lines of treatment. Among 4 patients with isolated KIT mutation, 2 responded to midostaurin, 1 obtained a partial control of symptoms after 4 lines of treatment and 1 suddenly died after achieving stable disease after 2 lines of therapy. Among 3 patients with SM associated to myelodyplastic syndrome, 1 was negative for KIT but positive for TP53 mutations and died for natural event after symptoms directed therapy and continuing recombinant erythropoietin. The other 2 KIT positive patients presented multiple concomitant mutations. Additional TET2 and SRSF2 mutations were recorded in a patient who died few weeks after diagnosis, while additional TET2, SRSF2, RUNX1 and KRAS mutations were recorded in a patient treated with midostaurine and 2CDA before successful allogeneic transplant. Molecular characterization of SM has uncovered a complex landscape of somatic mutations other than KIT D816V. Although the prognostic significance of some recurrent mutations has been reported, prospective correlation with clinical response may highlighted their role in the pathogenesis of disease and possibly elucidate mechanism of resistance to treatment. On the other hand, cytogenetics might no be considered mandatory except for AHN-SM

Predicting the Clinical Course of Treatment with Midostaurin in Patients with Advanced Systemic Mastocytosis

Introduction: Advanced systemic mastocytosis (AdvSM) is characterized by presence of the KIT D816V mutation and variably other somatic mutations in the mast cell but also non-mast cell lineages, e.g. monocytes or eosinophils, in ≥80-90% of patients. Midostaurin is an approved multikinase/KIT inhibitor for treatment of AdvSM. The intricate landscape in assessment of response, resistance or progression, the occurrence of adverse events with its impact on dose modification and the recent approval of the specific KIT D816V inhibitor avapritinib contribute to complex decision-making. We here sought to characterize the most valuable baseline and on-treatment parameters for prediction of response and survival in midostaurin-treated patients with AdvSM. Methods: On basis of the ´German Registry on Disorders of Eosinophils and Mast Cells' (GREM), this retrospective-prospective analysis included 79 patients with AdvSM. Treatment was initiated between 2009 and 2022 accumulating into a 239 patient-years overall follow-up period. In addition to common serological, morphological, and molecular response parameters, we specifically examined the recurrent observation of an early flare-up in alkaline phosphatase (AP) levels, which was defined as a ≥25% AP increase within three months after treatment initiation, followed by a subsequent decline below baseline within six months. Results: Midostaurin was used in first-line (1L) or second and further lines (2L+; median 1 prior treatment line, range 0-4) in 63 (80%) and 16 (20%) patients, respectively. In 1L/2L+, median overall survival (OS) was 2.6/2.4 years. At baseline, the presence of additional somatic mutations in SRSF2 (n=36, 46%, HR 2.0 [1.2-3.6], P=0.014), ASXL1 (n=15, 19%, HR 2.0 [1.0-3.9], P=0.043), and EZH2 (n=6, 8%, HR 4.3 [1.7-11.3], P=0.003) significantly stratified patients according to their hazard ratio-weighted risk (median OS, 5.8 vs. 2.9 vs. 1.0 years; P<0.001). In 25 evaluable patients, the variant allele frequency in 72 additional somatic mutations remained stable (mean change 8%, absolute change >5% in 16/72 (22%) mutations). New mutations were identified in 9/25 (36%) patients during follow-up (Figure). Durable responses (complete, partial, clinical improvement) according to modified Valent criteria, IWG-MRT-ECNM criteria or Pure Pathological Response (PPR) criteria over a median duration between 12 and 24 months were achieved in 60%, 29% and 13% of patients, respectively. Within the first 12 months, duration of response was associated with an OS benefit ( P<0.001). An AP flare-up was observed in 22/79 (28%) patients, was paralleled by contemporaneous decrease of serum tryptase (median -35%, range -82 - 191%) and resulted into improved OS (median 5.8 vs. 2.2 years, P=0.007). Multivariable analysis identified the AP flare-up ( P=0.029), a ≥25% reduction of bone marrow (BM) mast cell (MC) infiltration ( P=0.046) and a ≥25% reduction of the KIT D816V expressed allele burden (EAB; P=0.034) at any time within the first 6 months as independent markers for improved OS (Table). Dynamic risk assessment of the independent parameters during follow-up allowed to abrogate a negative baseline risk-categorization. The initial dose was 200 mg/d (100 mg BID, including patients with a prespecified rapid dose escalation), 150 mg/d or 100 mg/d in 63/79 (80%), 2/79 (3%) and 14/79 (18%) patients, respectively. In the combined 150 mg and 100 mg cohorts, a dose increase to 200 mg/day was achieved in 9/16 (56%) patients. The 200 mg could be maintained at month 3, 6, 12, 24, and 36 in 50/63 (79%), 30/48 (63%), 23/34 (68%), 15/22 (68%) and 9/9 (100%) patients, respectively. Overall, 96 adverse events (AE) led to dose-adjustment (including temporary or permanent discontinuation). Hematologic and nonhematologic toxicities accounted for 24 (25%) and 36 (38%) of AEs with neutropenia (n=8, 8%) and nausea/emesis (n=22, 22%) being the most common AEs leading to dose-adjustment. Of note, the various dose levels had no impact on response or survival. Conclusions: Baseline mutations in SRSF2, ASXL1 and EZH2 conferred resistance to midostaurin. The various dose levels had no impact on response or survival. The on-treatment parameters AP flare-up, and a ≥25% reduction of BM MC infiltration and of KIT D816V EAB abrogated a negative baseline risk-categorization. No new safety signals occurred.

A Phase 1 Study of Avapritinib in Combination with Decitabine in Patients with Systemic Mastocytosis with an Associated Hematologic Neoplasm

Background and Rationale: Systemic mastocytosis (SM) is a clonal hematologic neoplasm characterized by abnormal accumulation of mast cells which can lead to symptoms related to mast cell degranulation and/or, in the case of advanced systemic mastocytosis (AdvSM), organ dysfunction due to mast cell infiltration. AdvSM is a category of SM comprised of aggressive systemic mastocytosis (ASM), mast cell leukemia (MCL), and SM with an associated hematologic neoplasm (SM-AHN). Among these, SM-AHN is the most common subtype, accounting for approximately 70% of AdvSM. A KIT D816V mutation found in up to 95% of SM cases is the primary oncogenic driver, making it a key therapeutic target. Avapritinib, a highly potent and selective inhibitor of D816V mutant KIT, has demonstrated high rates of rapid, deep, and durable responses in all AdvSM subtypes, including SM-AHN. However, a recent analysis of the EXPLORER study showed that avapritinib-treated patients were still at risk for progression of the AHN component, despite continued control of mast cell disease burden, indicating that combination therapy is likely to be required for optimal control of SM-AHN due to its inherent molecular complexity. Hypomethylating agents (HMA) form the backbone of therapy for advanced myelodysplastic syndrome (MDS) and myelodysplastic/myeloproliferative neoplasm (MDS/MPN), hematologic neoplasms most likely to co-occur with SM in patients (pts) with SM-AHN. To date, the combination of HMA and KIT inhibitors has not been clinically evaluated. In this study, we aim to assess the safety and tolerability of the combination of avapritinib and decitabine in patients with SM-AHN. Study design: The primary objective of the study is to establish the recommended dose (RP2D) of avapritinib in combination with decitabine based on dose-limiting toxicity, overall safety, and clinical activity data. A dose evaluation steering committee (DESC) comprised of participating investigators will review the totality of safety and efficacy data to determine RP2D. Secondary endpoints include SM overall response rate by the end of 6 cycles by the m-IWG consensus criteria and proposed ECNM-AIM criteria ( Gotlib et al., J Allergy Clin Immunol Pract, 2022), as well as incidence and frequency of adverse events. Exploratory endpoints will consist of patient reported outcomes, progression free survival, overall survival, and correlative biomarkers linked to mast cell disease or AHN. Adult pts with a diagnosis of SM-AHN by the WHO 2022 classification criteria will be eligible for inclusion. Eligible pts must have any of the following myeloid AHN per WHO 2022 criteria: MDS, chronic myelomonocytic leukemia, MDS/MPN with neutrophilia, MDS/MPN with SF3B1 mutation and thrombocytosis, or MDS/MPN- not otherwise specified. Patients with MDS must have intermediate, high- or very-high risk by IPSS-R. Patients with very-low or low-risk MDS by IPSS-R must be intolerant/refractory to ESA or have serum EPO > 200 U/L. A baseline platelet count of ≥ 75 x 10 9/L and ≥ 25 x 10 9/L will be required for inclusion in the dose-finding and the dose-expansion phases, respectively (Figure). Key exclusion criteria include a diagnosis of acute myeloid leukemia, history of intracranial hemorrhage or risk of major hemorrhage, prior treatment with avapritinib or decitabine with documented progression in SM or AHN component, respectively, or history of treatment with alternative KIT inhibitor or azacitidine within 4 weeks of study treatment initiation. In the dose finding part of the study, a Bayesian adaptive design will be employed to assess different doses of avapritinib (50 to 200 mg PO daily) in combination with fixed doses of decitabine (oral decitabine/cedazuridine: 35/100 mg/day or intravenous decitabine: 20 mg/m 2/day on days 1-5) in a 28-day treatment cycle. Close attention will be paid to treatment-emergent thrombocytopenia with protocol-driven treatment holds and dose modification strategies employed when platelet count drops below 50 x 10 9/L. After RP2D is determined, an additional 10 patients will be enrolled in the dose expansion phase. Patients with platelet count ≥ 25 x 10 9/L and < 75 x 10 9/L, will receive lead-in dosing with decitabine or decitabine/cedazuridine with the ability to add avapritinib if sufficient platelet thresholds are achieved. This study will open at 7 sites in the United States and is anticipated to open in January 2024.

Prognostic Characterization of Advanced Mastocytosis Patients Treated with Midostaurin According to Diagnosis and Mutation-Adjusted Risk Score: A Nation-Wide Ceremast Study of 170 Patients

Introduction: Mastocytosis is a spectrum of diseases characterized by the accumulation of atypical mast cells (MC) in tissues. The most frequent form in adult patients is systemic mastocytosis (SM) including indolent SM, bone marrow mastocytosis, smoldering SM and advanced SM (adv-SM). Adv-SM encompasses aggressive SM (ASM), MC leukemia (MCL), SM associated with hematological neoplasms (SM-AHN) and is associated with a poor outcome. Prior the use of tyrosine kinase inhibitors (TKIs), therapeutic options were limited in adv-SM patients. The first TKI developed for adv-SM with KIT D816V mutation was midostaurin, which greatly improved outcomes for patients. However, most patients are primary refractory or relapse early (<12 months) after midostaurin onset. To identify high risk adv-SM patients, a prognostic score the so-called Mutation-Adjusted Risk Score (MARS) have been developed. However, given the heterogeneity of outcomes according to subtype of adv-SM, the identification of high-risk patients within each subtype is critical to optimize therapy. To address this question, we investigated predictive value on outcome of MARS score risk in midostaurin treated Adv-SM patients in a larger group of patients, according to each subtype of adv-SM. Methods: We conducted a nationwide retrospective study of all patients with Adv-SM patients included in the French national mastocytosis reference center registry (CEREMAST). Main inclusion criteria were: (i) adults patients treated with midostaurin in France since 2009 (ii) diagnosis of adv-SM according to WHO 2016 classification (iii) presence of C findings. Patients that have received combination therapy (i.e. azacytidine) or with chronic type of MCL without C finding or lymphoid neoplasm AHN or AML prior midostaurin onset were excluded. Response to midostaurin was assessed according to Valent criteria and MARS score was used to stratify patients into 3 risk groups (high risk, intermediate and low). Results: Overall, 170 patients treated with midostaurin were identified, including 46 ASM patients, 11 MCL patients and 113 SM-AHN patients. Among SM-AHN patients, chronic myelomonocytic leukemia was the most frequent neoplasm (52%). Response to midostaurin was significantly different regarding subtype of adv-SM (73% in ASM vs 27% in MCL vs 50% in SM-AHN, p=0.006). With a median follow-up of 19 months since midostaurin start, median overall survival (OS) was 69, 9.9 and 32 months (p=0.0013) and time to treatment failure (TTF) was 30, and 3.6 and 9 months in ASM, MCL and SM-AHN (p<0.0001), respectively. MARS risk group distribution was heterogeneous between ASM, MCL and SM-AHN (p=0.026). In MARS low risk group, median OS was not reached (NR) and 58 months in ASM and SM-AHN respectively (p=0.034, Figure 1). Median OS for both low risk ASM and low risk SM-AHN were significantly different compared with intermediate/high-risk (int/high-risk) groups (NR vs 33 months for ASM, p=0.003 and 58 months vs 24 months, p=0.017). Int/high-risk SM-AHN was the only group with a median OS not significantly different compared with MCL (24 months vs 9 months p=0.266) Median TTF was 60 months for low risk ASM, 26 months for low risk SM-AHN and only 6.7 months for high/int-risk ASM, 8.4 months for high/int-risk SM-AHN and 3.6 months for MCL. For the 19 patients who underwent hematopoietic stem cell transplantation (HSCT), median OS was 88 months but did not reach statistical significance compared to non-transplanted patients (47 months, p=0.15). In multivariate analysis, MARS and WHO mastocytosis subtype were the only variables independently associated with OS ( figure 2). MARS and midostaurin response were not predictive for both AHN progression and AML transformation in SM-AHN, which occurred in 31% and, 22% of patients respectively. In contrast, presence of portal hypertension/ascites (68% vs 29%, p<0.001) and abnormal karyotype (40 vs 11%, p=0.007) were predictive of AML transformation. Conclusions: We report herein the largest cohort of adv-SM patients treated with midostaurin. We identified portal hypertension/ascites and karyotype abnormalities as risk factors predictive of AML evolution. Subtype of adv-SM are heterogeneous and, together with MARS, are predictive for both OS and TTF. According to these variables, 5 sub-groups of adv-SM have been identified with different outcomes prompting for specific management.

A Model of Cumulative Risk of Disease Progression Among Patients with Indolent Systemic Mastocytosis

Introduction Indolent systemic mastocytosis (ISM), a clonal mast cell disease driven by the KIT D816V mutation in ~95% of cases, can cause lifelong debilitating cutaneous, gastrointestinal, and neurocognitive symptoms with some cases progressing to advanced systemic mastocytosis (AdvSM). While several studies have quantified variable rates of disease progression from ISM to AdvSM based on the absolute frequency of these events, these studies were limited by short median follow-up time considering the long clinical course of this condition sometimes in decades, thereby leading to underestimation of the cumulate rates of progression from ISM to AdvSM. We conducted a Markov analysis using population level data in the US to estimate the lifetime risk of progression for ISM patients. Methods We modeled the total course of SM as a discrete-time Markov chain, enabling us to estimate cumulative rates of disease progression based on fixed-interval empirical observations from the literature and, where there is no literature available, expert opinion. The Markov model assumes that patients enter the model as at-risk ISM, not-at-risk ISM, or de novo AdvSM, based on the assumed relative incidence of each subtype. Not-at-risk patients will then move to death after a period of time, with an annualized risk of death from disease. At-risk patients with ISM will remain in that state, progress to AdvSM (which may be tyrosine kinase inhibitor treated or not) or die. Finally, those who progress to AdvSM will either remain in their state or die. See Figure1 for details, where each model parameter is reflected as a line between states and modeled based on an annualized rate of state transition. See Figure 2 for a full list of model parameters. Two hundred trials were performed, in which the model parameters were statistically sampled from a range of likely values, based on a triangular distribution between minimum, mode, and maximum. For each trial, the disease course for 5000 patients with SM was then simulated from initial SM diagnosis until death. Results Based on the rates of disease incidence, progression, treatment, and survival documented within various studies, we estimate the cumulative risk (± standard deviation) of disease progression from ISM to AdvSM to be 18.0% ± 3.1%, based on a probabilistic sampling of the underlying assumptions. Conclusions This study suggests that the cumulative rate of disease progression among patients with ISM may be higher than previously recognized. In our earlier work, we showed a higher rate of disease progression in ISM patients with high symptom burden (Mukherjee S, et al. ASH 2022). These data highlight the importance of close monitoring for signs of progression and warrant further research to identify subsets of ISM patients who may have a higher underlying risk of progression.

A Snapshot Audit of Symptom Burden in Patients with Indolent Systemic Mastocytosis Utilising the ISM-SAF © within a UK Centre of Excellence: Guy's and St Thomas' NHS Foundation Trust

Background: Indolent systemic mastocytosis (ISM) is a rare, clonal haematological neoplasm driven by the KIT D816V mutation in up to 95% of cases. It is characterized by a debilitating, heterogenous and unpredictable symptom burden due to mast cell mediator release among patients. Treatment is limited to symptom management with no approved targeted therapies in the UK. The Indolent Systemic Mastocytosis Symptom Assessment Form (ISM-SAF ©) (Taylor et al. [2021]) is a validated symptom-assessment tool developed specifically for ISM patients focusing on 11 symptoms over a 24-hour recall period: bone pain, abdominal pain, nausea, skin spots, itch, flushing, fatigue, dizziness, brain fog, headache and diarrhoea. Each symptom is scored on a scale from 0-10. To date, there has not been any published UK data examining symptom burden in ISM patients. Subsequently we assessed symptom burden utilising the ISM-SAF © in our patient cohort at Guy's and St Thomas' Hospital. Method: All adult ISM patients who had a routine outpatient appointment between May 2022 and May 2023 were identified retrospectively. Over a four-week period, patients were invited to complete the ISM-SAF © by telephone or in person. Additionally we collected demographic data, clinical data, anti-mediator therapy, anaphylaxis history and the impact of SM on their work and quality of life. All consultations were conducted by a clinical member of the mastocytosis team. Results: 95 adult patients with ISM were identified within our database, of which 76 consented to take part in this study. There was a slight female predominance (41% male; 59% female) and the median age at diagnosis was 46 years (range 21 - 78). Median time to ISM diagnosis was 4.6 years (range 0.5-18.5). Median serum tryptase was 35 mcg/L (range 9-632). 66 patients (88%) were noted to have the KIT D816V mutation (6% D816V-negative, 6% not available). The median Total Symptom Score (TSS) was 24 (range 0-110). The highest scoring symptoms were fatigue (mean score 4.66), skin spots (3.97), brain fog (3.43) and itch (2.83). 33 patients (43%) had a TSS ≥28 which is the threshold determined by psychometric analysis to identify patients with moderate to severe symptoms, and is used for screening in clinical trials (Shields et al. [2023]). 46 patients (61%) were prescribed ≥2 anti-mediator therapies; at the time of the study, current therapies included H1 antihistamines (n=64), H2 antihistamines (n=28), proton pump inhibitors (n=20), sodium cromoglycate (n=18), montelukast (n=12), corticosteroid (n=5) and omalizumab (n=1). 12 patients (16%) were on a bisphosphonate. The number of patients with both a TSS ≥28 and on ≥2 anti-mediator therapies was 27 (36%). 30 patients (39%) reported a history of anaphylaxis at least once in their lifetime while 12% (n=9) reported using an adrenaline autoinjector within the last 12 months. There was no statistically significant correlation between TSS and serum tryptase (Pearson correlation coefficient r= -0.08, p=0.48). Some patients reported having to reduce their working hours, needing adjustments or retiring early due to symptoms attributed to their ISM diagnosis. Conclusions: Our data demonstrate a significant real-world symptom burden among the ISM patient cohort within the UK Mastocytosis Centre of Excellence and reflect the findings of other centres, in particular fatigue being the most severe symptom (van Anrooij et al. [2016]; Mesa et al. [2022]). The ISM-SAF © is an effective tool for capturing a snapshot of symptom severity and has utility in the outpatient setting. Importantly, we found over one third of patients in our centre had a TSS ≥28 and were on ≥2 anti-mediator therapies, meaning they could potentially be eligible to access tyrosine kinase inhibitors within the clinical trial setting.

Initial Results from Summit: An Ongoing, 3-Part, Multi-Center, Randomized, Double-Blind, Placebo-Controlled Phase 2 Clinical Study of Bezuclastinib in Adult Patients with Nonadvanced Systemic Mastocytosis (NonAdvSM)

Background: Systemic mastocytosis (SM) is a rare disease characterized by neoplastic mast cell infiltration of extracutaneous tissues and encompasses a spectrum of subtypes that can range from non-advanced to advanced disease. Nonadvanced SM (NonAdvSM) includes two variants of SM: indolent systemic mastocytosis (ISM) and smoldering systemic mastocytosis (SSM). NonAdvSM is often associated with debilitating symptoms which may significantly reduce health-related quality of life (HRQoL). In up to 95% of patients, SM is driven by the somatic KIT D816V gain of function mutation located in exon 17. Bezuclastinib (CGT9486) is an oral, potent, and selective type 1 tyrosine kinase inhibitor (TKI) with activity against KIT D816V. Preclinical studies demonstrate bezuclastinib inhibits KIT D816V with minimal brain penetration. Early results from Part 1 of a Phase 2 trial of patients with AdvSM demonstrate that bezuclastinib is well-tolerated and is associated with encouraging clinical activity. Bezuclastinib resulted in meaningful reductions in markers of disease burden including serum tryptase, bone marrow mast cell burden, and KIT D816V variant allele fraction (DeAngelo et al. [abstract] In: Blood (ASH) 2022; 140 (Supplement 1): 1512-13). These results support the investigation of bezuclastinib as a potential therapy in NonAdvSM. Study Design and Methods: Summit (NCT05186753) is a multi-center, Phase 2, randomized, double-blind, placebo-controlled, 3-part clinical trial of bezuclastinib in patients with NonAdvSM, including ISM and SSM, who have inadequate control of symptoms despite treatment with best supportive care (BSC). Patient-reported outcome measures (PROMs), including mastocytosis activity score (MAS) and mastocytosis quality of life (MC-QoL), are being used to assess treatment impact on symptoms and HRQoL. Approximately 48 patients will be enrolled in Part 1 of the trial with 1:1:1 randomization to one of two doses of bezuclastinib (100 or 200 mg QD for Part 1a; 100 or 150 mg QD for Part 1b) or placebo. Here we report initial data from Part 1a of the Summit trial. Results: Part 1a of Summit enrolled 20 patients; 18 patients had ISM and 2 patients had SSM. In Part 1a, a majority of patients were female (75%) and had an Eastern Cooperative Oncology Group Performance Status of 0-1 (90%) or 2 (10%). Mean age was 54. Patients utilized a median (range) of 3 (2 to 7) BSC medications, with 100% using H1 blockers, 95% using H2 blockers and 40% using leukotriene receptor antagonists. Enrolled patients had a median (range) serum tryptase of 74 (10 to 592) ng/mL and 85% of patients had a serum tryptase ≥20 ng/mL. 75% of patients were KIT D816V positive and median (range) KIT D816V variant allele fraction in whole blood was 0.5% (0 to 32). Median (range) percent bone marrow mast cell burden was 23% (1 to 80%). Utilizing MAS to assess baseline disease severity, a majority of patients self-reported severe disease with a median score of 43 (range 22-79). Patients also self-reported a mean score of 56+/- 19 on the MC-QOL, indicating moderate impact to their HRQoL. Conclusions: The Summit trial evaluating safety and efficacy of bezuclastinib enrolled 20 patients in Part 1a. The patients enrolled in Part 1a of the Summit trial are generally representative of the population of patients with moderate to severe nonadvanced systemic mastocytosis based on number of supportive care medications, symptom severity, and disease impact on HRQoL. Initial safety and efficacy results from Part 1a of the 3-part, randomized, double-blind, placebo-controlled Summit trial will be presented.

Elenestinib, an Investigational, Next Generation KIT D816V Inhibitor, Reduces Mast Cell Burden, Improves Symptoms, and Has a Favorable Safety Profile in Patients with Indolent Systemic Mastocytosis: Analysis of the Harbor Trial

Introduction Indolent systemic mastocytosis (ISM) is a rare clonal mast cell disease driven by the KIT D816V mutation in nearly all patients. Patients with ISM can present with debilitating acute and chronic cutaneous, gastrointestinal, neurocognitive, and systemic symptoms caused by the release of inflammatory mediators from abnormal mast cells. In some patients, symptoms are not adequately controlled with best supportive care (BSC) medications. Elenestinib (BLU-263) is a novel, investigational, oral, next-generation tyrosine kinase inhibitor that potently and selectively inhibits KIT D816V with limited central nervous system penetration and pharmacokinetics (PK) that support once daily dosing. HARBOR (NCT04910685) is a randomized, double-blind, placebo-controlled, phase 2/3 study assessing efficacy and safety of elenestinib in patients with ISM. Methods Eligible adult patients with ISM, confirmed following central review of bone marrow (BM) pathology, clinical, and laboratory findings per World Health Organization criteria and a moderate-to-severe symptom score based on minimum mean total symptom score (TSS) of the ISM-Symptom Assessment Form (ISM-SAF©2018), were stratified by baseline serum tryptase (<20 ng/mL vs ≥20 ng/mL) and randomly assigned 3:1 to elenestinib 25 mg, 50 mg, or 100 mg once daily + BSC (“elenestinib”) or placebo + BSC (“placebo”). The primary objective of Part 1 was to determine the recommended dose based on safety, PK, and pharmacodynamics. Secondary endpoints included changes in biomarkers of disease burden (serum tryptase, KIT D816V variant allele fraction [VAF], and BM mast cells) and ISM-SAF TSS. Three additional open-label PK groups enrolled patients at 50 mg, 75 mg, and 100 mg to further characterize PK and safety. Results As of data cutoff on July 3, 2023, a total of 122 patients with ISM have received their assigned treatment in Part 1 of the study; 39 were blinded and randomized to elenestinib or placebo, and 83 were treated with open-label elenestinib in the PK groups (21 patients at 50 mg, 34 patients at 75 mg, and 28 patients at 100 mg). Baseline demographics were similar to those reported for the general ISM population. After 12 weeks of therapy, symptom improvement was observed for all dose cohorts, and symptom reduction by TSS was greater for patients on elenestinib versus placebo in the blinded portion of Part 1. Patients receiving elenestinib at 25 mg, 50 mg, and 100 mg doses showed reduction (mean percent) from baseline for tryptase (-15.4%, -50.9%, and -68.4% vs 3.3%, respectively) and KIT D816VVAF (-37.5%, -70.3%, and -77.0% vs -2.5%, respectively) as compared to placebo. Similar reductions in TSS and disease-related biomarkers were observed in the open-label PK cohorts. After a median treatment duration of 35.3 weeks, elenestinib was well-tolerated at all dose levels. There were no treatment-related serious adverse events and no treatment-related adverse events that led to drug discontinuation. Conclusion Elenestinib at all tested doses demonstrated beneficial effects on disease-related symptoms and biomarkers of mast cell burden in this large and maturing cohort of patients with ISM with a moderate-to-severe symptom burden. Elenestinib was well tolerated across all dose levels with a promising early benefit-risk profile in ISM. These preliminary findings will inform dosing for the planned Part 2 of HARBOR, which will examine elenestinib versus placebo in a randomized, blinded, placebo-controlled setting.

Multicenter Retrospective Analysis of Eosinophilic Myeloid Neoplasms

Background. Some patients who present with clinical features consistent with idiopathic hypereosinophilic syndrome (HES; absolute eosinophil count (AEC) ≥1.5 x 10 9/L with related end organ damage) are ultimately diagnosed with a myeloid neoplasm. Although FIP1L1::PDGFRA is the most common molecular abnormality in this setting, many other fusion genes, point mutations and cytogenetic abnormalities have been implicated in driving primary (neoplastic) eosinophilia. Given the poor prognosis of these disorders in the absence of treatment and the availability of targeted therapies for many of the driver mutations, it is becoming increasingly important to rapidly identify the underlying genetic alteration. In this regard, the expense and variable sensitivity of molecular diagnostic tests remains problematic. Although clinical features have been reported to distinguish between PDGFRA-associated myeloid neoplasms and D816V KIT-positive systemic mastocytosis with hypereosinophilia, little is known about the clinical phenotypes of other subsets of patients. This multicenter retrospective study aimed to assemble a large cohort of patients with HES secondary to a myeloid neoplasm to explore the utility of clinical and laboratory features in predicting the underlying molecular abnormality. Methods. Retrospective, de-identified data from 16 centers were collected via an online Research Electronic Data Capture repository. Patients and associated data were obtained from in-house research databases and/or electronic medical record searches at each site. Clinical and laboratory data were entered in accordance with local Institutional Review Boards. Inclusion criteria were peripheral blood hypereosinophilia (AEC >1.5 x 10 9/L) on at least two occasions and one of the following: ≥1 confirmed genetic abnormality recurrently associated with primary myeloid neoplasms, other evidence of clonal eosinophilia, or increased blasts (≥2% in the blood or >5% but <20% in the marrow). Patients with acute myeloid leukemia were excluded. Results. A total of 277 patients followed between 1990 and 2022 were included in the analysis. Median length of follow up was 31 months (range <1-356), and 217/277 (78%) were alive at last follow up. The most common genetic abnormality was FIP1L1::PDGFRA (n=131) followed by D816V KIT mutations (n=39) and alterations involving JAK2 (n=22) (Figure 1). Five patients had genetic abnormalities involving two distinct genes recurrently associated with eosinophilic myeloid neoplasms. The overall median age at diagnosis was 55 years (range 12-89) and 79% of the patients were male. When patients with abnormalities involving PDGFRA and PDGFRB were excluded from the analysis, the male predominance was significantly lower at 62% (p<0.001, Fisher's exact test as compared to the data set as a whole). The overall pattern of organ system involvement was similar irrespective of the underlying genetic abnormality with a few notable exceptions. Cardiac involvement was most common in patients with FIP1L1:: PDGFRA, abnormalities involving JAK2 or without pathologic alterations identified (reported in 22%, 32% and 30%, respectively); whereas skin and gastrointestinal involvement, lymphadenopathy and splenomegaly were most frequent in patients with KIT D816V. Laboratory abnormalities also differed between groups. Whereas anemia was the most common blood abnormality (reported in >50% of patients), erythrocytosis was noted primarily in patients with abnormalities involving JAK2. In contrast, circulating blasts were identified in 70% of patient with BCR::ABL1 and 29% of patients with chromosomal abnormalities or KIT D816V, but in <15% of patients in any of the other groups. Whereas peak AEC alone did not discriminate between the different patient groups, the AEC/tryptase ratio was increased in patients with PDGFRA-associated myeloid neoplasms, molecular abnormalities involving JAK2, or chromosomal abnormalities as compared to those with KIT mutations (Figure 2). Conclusions. Despite the limitations of retrospective data analysis, the data from this large multicenter cohort of patients with HES due to a chronic myeloid neoplasm suggest that routine demographic, clinical and laboratory features vary depending on the underlying molecular abnormality. This approach could ultimately help guide empiric therapy when molecular studies are negative or unavailable.

Safety and Efficacy of Bezuclastinib (CGT9486), a Novel, Highly Selective, Potent KIT D816V Tyrosine Kinase Inhibitor, in Patients with Advanced Systemic Mastocytosis (AdvSM): Results from Part 1 of the Phase 2 Apex Trial

Background: Systemic mastocytosis (SM) is a rare disease characterized by the aberrant proliferation of mast cells (MC). In about 95% of adult patients, SM is driven by a gain-of-function mutation (D816V) in exon 17 of KIT. Advanced SM (AdvSM) is a life-threatening form of SM and includes three subtypes: aggressive SM (ASM), SM with an associated hematologic neoplasm (SM-AHN), and Mast Cell leukemia (MCL). Bezuclastinib is an oral, potent, and selective tyrosine kinase inhibitor (TKI) with activity against KIT D816V. Preliminary results from the on-going Apex study in patients with AdvSM (NCT04996875) were presented previously (DeAngelo et al. [abstract] In: Blood (ASH) 2022; 140 (Supplement 1): 1512-13). Methods: Apex is a randomized Phase 2, open-label, multicenter trial in adult patients diagnosed with AdvSM per 2022 WHO criteria with a baseline serum tryptase of ≥20 ng/mL. In Part 1, patients were randomized 1:1:1:1 to bezuclastinib 50mg BID, 100mg BID, 200mg BID, or 400mg QD. Patients with a history of prior TKI therapy (e.g., avapritinib, midostaurin) are permitted in the trial. Data from Part 1 informed dose selection for Part 2 of the trial. The primary efficacy endpoint for this trial is overall response rate (complete response [CR], CR with incomplete hematologic recovery [CRh], partial response [PR] and clinical improvement [CI]) as assessed by a central review committee based on mIWG-MRT-ECNM response criteria. Results: As of April 2023, Part 1 was fully enrolled with 33 AdvSM patients. Patients were randomized to 50mg BID (n=8), 100mg BID (n=8), 200mg BID (n=8), or 400mg QD (n=9). Disease subtypes included ASM (n=7), MCL (n=2), and SM-AHN (n=24); AHN subtypes included CMML (n=18), MDS (n=3), MPN (n=1), and MDS/MPN-U (n=2). The majority of patients were male (64%), ECOG PS 0-1 (82%) and KITD816V positive at baseline (91%). At baseline, 67% of patients were TKI-naïve; 33% had prior midostaurin, and 15% had prior avapritinib. Median (range) BM MC burden, serum tryptase, and KIT D816V VAF at baseline were 30% (5-90), 163 ng/mL (35-1578), and 7% (0-47), respectively. Of the 33 patients enrolled, 25 patients (76%) had C-findings evaluable per mIWG-MRT-ECNM criteria; 20 patients (61%) were positive for SRSF2/ASXL1/RUNX1 mutation which are associated with poor survival in SM. Conclusion: Enrollment in Part 1 of the Apex trial is complete. Patients enrolled in Part 1 of the Apex trial are generally representative of the population of patients with AdvSM based on patient characteristics and markers of disease. Part 1 includes a small subset of patients with prior use of TKIs. Safety, clinical activity, and clinical objective response for all patients in Part 1 will be presented.

Involvement of the JAK-STAT Pathway in the Molecular Landscape of Fusion-Free Myeloid Neoplasms with Eosinophilia

Introduction. Gene fusions leading to the constitutive activation of tyrosine kinases (TK) such as PDGFRA, PDGFRB or FGFR1 have been the first recurrent genetic defects involved in myeloid hypereosinophilic syndromes (HES). Although activation of the Janus kinase (JAK)/Signal Transducer and Activator of Transcription(STAT) pathway is critical for eosinophil production and survival, genes involved in the JAK/STAT pathway are not included in most next-generation sequencing (NGS) panels used for the etiological workup of hypereosinophilia (HE). Methods. A custom 149-gene NGS panel including subunits of the IL3/IL5/GM-CSF receptors, TK ( PDGFRA/B, FGFR1, ABL1, FLT3, KIT), intracellular proteins of the JAK-STAT and RAS-MAPK pathways was performed in 64 consecutive adult patients (experimental group) referred between March 2012 to June 2023 to the French Reference Center for Hypereosinophilic Syndromes (CEREO) for HE/HES displaying at least one clinic-biological feature suggestive of myeloid neoplasm ( i.e. splenomegaly, other unexplained CBC abnormality besides HE, increased serum tryptase and/or vitamin B12 levels, corticosteroid-refractory HE and/or sensitivity to either TK inhibitors or JAK inhibitors). All of them were negative by PCR and/or FISH analyses for gene rearrangements involving PDGFRA, PDGFRB or FGFR1. Patients with lymphocytic HES (n=7), idiopathic HES (n=26) and HE of undetermined significance (n=11) were used as controls (total, n=44). Results. Concordant with the latest recommendations of the international cooperative working group on eosinophil-associated disorders, at least one mutation was reported in 50/64 (78%) patients of the experimental group versus 8/44 (18%) patients in the control group (p<0.001) when applying a threshold of at least 3% of variant allele frequency (VAF). Mutations in the control group implied genes involved in age-related clonal hematopoiesis ( e.g. DNMT3A, TET2), with low VAF in almost all cases. All 35 patients with at least one mutation involving the JAK/STAT pathway belonged to the experimental group, among whom all 22 patients treated with steroids were refractory to therapy. Eighteen patients had STAT5B mutations, including 13 (72%) with the somatic N642H mutational hotspot. Two patients harbored JAK2Ex13InDel mutations, including one with eosinophilia and erythrocytosis. Previously unreported molecular alterations were also evidenced, including seven patients with JAK1 mutations and three STAT5A-mutated patients who shared common features i.e. the co-occurrence of BCOR mutations, high hemoglobin levels and eosinophil hyperplasia. Of note, the latter mutations were not reported both in a public database (GnomAD) as well as in a second cohort of 613 samples referred for suspicion of myeloid malignancies (yet without HE) studied with the same NGS workflow, thereby strongly supporting their association with myeloid HES. Deciphering the data from bulk sequencing also suggests that JAK-STAT mutations were frequently preceded by (or associated with) myelodysplasia-related gene mutations, with SF3B1 (12/36) and ASXL1 (10/36) mutations being the most common. Overall, both KIT D816V (n=2) and RAS/MAPK pathway activation mutations (n=3) were rare. No mutation of either PDGFRA/B, FGFR1 or IL3/IL5/GM-CSF-receptor genes was evidenced.In the experimental group, 17/18 (94%) patients (including 12 with JAK-STAT mutations) treated with ruxolitinib and with > 3 months of follow-up responded to treatment (12 complete and 5 partial hematological responses). Discussion. These dataemphasize the usefulness of NGS in daily practice for the workup of fusion-free HES patients harboring features suggestive of myeloid neoplasms. In such patients, druggable mutations involving the JAK-STAT pathway (including yet unidentified STAT5A mutations) are frequent. Most JAK/STAT mutations occur in the setting of a preexisting myelodysplastic or myelodysplastic/myeloproliferative disease harboring mutations in RNA-splicing genes or chromatin modifiers. These findings provide a rationale for refining treatment algorithms in fusion-free myeloid HES patients, supporting the use of JAK inhibitors as frontline therapy. More data are warranted to assess whether JAK inhibition enables sustained molecular remission in all disease subtypes.

Diagnosis and Outcome of Patients with Idiopathic Hypereosinophilic Syndrome and Cardiac Involvement

Introduction: Diagnostic criteria of idiopathic hypereosinophilic syndrome (iHES) comprise persisting reactive/non-clonal eosinophilia ≥1.5 G/l and associated organ infiltration/dysfunction. The pattern and extent of organ involvement is most relevant for symptoms, quality of life, complications, response to treatment and prognosis. Of note, the potentially life-threatening cardiac involvement (CI) is frequently underrecognized. Patients and Methods: Based on the ´German Registry on Disorders of Eosinophils and Mast Cells (GREM)', we sought to investigate CI in 62 patients (pts) with iHES and predominantly multifocal organ involvement (sinus [n=26], lungs [n=36, including asthma, n=23], abdominal organs [n=15], skin [n=15] and lymph nodes [n=9]) by cardiac magnetic resonance imaging (MRI, 62/62 pts), echocardiography (30/62 pts), myocardial biopsy (10/62 pts) and the cardiac biomarkers troponin I (TNI, 49/62 pts) and N-terminal prohormone B-type natriuretic peptide (NT-proBNP, 38/62 pts). Clonal eosinophilia, e.g. FIP1L1::PDGFRA, alternative tyrosine kinase fusion genes and point mutations, e.g. KIT D816V, was excluded by the combination of cytogenetic/molecular analyses, bone marrow histology and immunohistochemistry. Myeloid peroxidase (MPO)-ANCA antibodies as characteristic marker of eosinophilic granulomatosis with polyangiitis (EGPA) were absent in all 62/62 (100%) pts and no evaluable patient had histologic evidence of vasculitis. Results: Cardiac MRI was pathologic in 34/62 (55%) pts with overlapping presence of late gadolinium enhancement (LGE, 31/34, 91%), pericardial effusion (11/34, 32%), involvement of heart valves/conduction system (9/34, 26%), impaired left-ventricular ejection fraction (LVEF <50%, 9/34, 26%) and presence of intracavitary thrombus (6/34, 18%). Concomitant echocardiography revealed pathological findings only in 10/24 (42%) pts with a pathologic MRI. Myocardial biopsy unveiled fibrosis (4/10, 40%) or eosinophilic infiltration (2/10, 20%) but was also non-informative (4/10, 40%). CI was rather associated with involvement of lungs (24/34, 71%) and sinus (23/34, 68%) than of abdominal organs (8/34, 24%) and skin (5/34, 15%). The combination of CI and asthma, potentially suggestive of ANCA-negative EGPA, was observed in 16/34 (47%) pts, but an indistinguishable pattern of multifocal organ involvement was also present in 18/34 (53%) pts with CI and absence of asthma. All 10/49 (20%) pts with an elevated vs. 0/49 (0%) pts with a normal troponin I (<0.045µg/l) and 20/38 (53%) pts with an elevated vs. 7/38 (18%) pts with a normal NT-proBNP (<125ng/l) revealed a pathologic cardiac MRI (Table). During a median follow-up of 108 months (range 3-470), the occurrence of cardiac events (n=15; death, n=3; cerebral embolism, n=4; worsening of LVEF, n=2; arrhythmias, n=2; valve surgery, n=2; pericardial effusion, n=1; coronary artery aneurysm, n=1) was strongly associated with a pathologic cardiac MRI in 15/15 (100%) pts (prior to MRI, n=6; after MRI, n=9) and an elevated troponin I and/or elevated NT-proBNP in 14/15 (93%) or 12/15 (80%) pts, respectively. During a median follow-up of 7.6 years (range 0.3-29.2), glucocorticoid-based immunosuppressive treatment resulted in improved MRI findings in 9/20 (45%) pts (improved LGE, n=7; regression of thrombus, n=1; improved LVEF, n=1) and a median NT-proBNP decrease of 48%. In pts with a pathologic MRI and elevated biomarkers, 9/13 (69%) and 5/19 (26%) pts, respectively, had a normalization of troponin I or NT-proBNP. Conclusions: In pts with iHES, i) the incidence of CI is high, particularly in pts with multifocal organ involvement, ii) it is questionable whether absence or presence of asthma in pts with multiple organ involvement is qualified for the challenging differentiation between iHES and ANCA-negative EGPA, iii) CI should be assessed by troponin I/NT-proBNP and cardiac MRI as they are superior to echocardiography, iv) the combination of elevated troponin I and to a lesser extent also elevated NT-proBNP with a pathologic cardiac MRI is associated with retrospective and subsequent, potentially life threatening cardiac events, and v) cardiac biomarkers and cardiac MRI are useful for monitoring response to treatment.

Allogeneic Hematopoietic Stem Cell Transplantation in Advanced Systemic Mastocytosis

Purpose Advanced systemic mastocytosis (AdvSM) is driven by the KIT D816V mutation in >90% of patients (pts.). Depending on subtype, median survival is between 1.5 and 4 years. Despite recent advances on responses and survival due to the availability of effective KIT inhibitors, allogeneic hematopoietic stem cell transplantation (alloHSCT) remains the only curative treatment option. Data on optimal timing, conditioning regimens, and pre- as well as post-alloHSCT treatments for maintenance or relapse are however scarce. Current recommendations mainly refer to a retrospective analysis published almost 10 years ago (Ustun et al., JCO 32, 2014). With the advent of new therapies and improved transplant procedures, more recently collected data on alloHSCT in AdvSM are needed for actual assessment of optimal treatment strategies. Patients & Methods This retrospective analysis identified 71 pts. with AdvSM who underwent alloHSCT at 20 German centers between 1999 and 2021. Data were collected via the 'German Stem Cell Transplantation Registry (DRST)' and the 'German Registry on Disorders of Eosinophils and Mast Cells (GREM)'. Additional baseline characteristics and response status prior to, during and post alloHSCT were provided by the participating centers. Results At time of alloHSCT, median age was 59 years (range 21-84); 55/71 (77%) pts. were male. Median time between diagnosis of AdvSM and alloHSCT was 1.2 years (range 0.1-16.7). Pts. were grouped into (i) aggressive systemic mastocytosis (ASM, n=6) and SM with an associated hematological neoplasm (SM-AHN, n=24), totaling 30/71 (42%) ASM/SM-AHN pts., (ii) SM with an associated acute myeloid leukemia (SM-AML; 28/71, 39%) and (iii) mast cell leukemia ± AHN (MCL±AHN; 13/71, 18%). The median follow-up time after alloHSCT was 1.4 years (range 0-20.4). PFS and OS were 52% (SD ± 6.1%) and 62% (SD ± 5.9%) at 1 year, and 39% (SD ± 6.3%) and 50% (SD ± 6.2%) at 3 years. Discrimination between the three cohorts allowed a three-tier risk stratification (median PFS, 4.5 vs. 0.7 vs. 0.3 years, P<0.001; median OS, 9.0 vs. 3.3 vs. 0.9 years, P=0.007, Figure 1). Overall non-relapse mortality rate was 30% (21/71) including infectious complications in 8/21 (38%), GvHD in 1/21 (5%), cardiotoxicity in 1/21 (5%) and ‘combinations/not further specified’ in 11/21 (52%) pts. The 100-day non-relapse mortality was 8% (6/71; ASM/SM-AHN, 0/30; SM-AML, 4/28, 14%; MCL±AHN, 2/13, 15%). OS was associated with response status of SM (17/41, 41%; median OS 4.6 vs. 1.1 years, P=0.029) or AHN (26/43, 60%, median OS not reached vs. 0.4 years, P=0.003) prior to alloHSCT ( Figure 2). Univariable analyses revealed absence of a KIT D816V mutation (HR 2.9 [1.2-6.5], P<0.001) and a complex karyotype (HR 4.2 [1.8-10.0], P=0.016) as adverse prognostic factors regarding OS. PFS was significantly impacted by diagnosis of MCL±AHN (HR 3.5 [1.7-7.5], P<0.001), absence of a KIT D816V mutation (HR 2.5 [1.2-5.4], presence of a complex karyotype (HR 4.2 [1.8-10.0], P=0.016), P=0.021) and absence of the use of tyrosine kinase inhibitors prior to alloHSCT (HR 0.461 [0.249-0.854], P=0.014). In contrast, HLA match (complete vs. incomplete), type of conditioning (myeloablative vs. dose-reduced intensity), use of total body irradiation (≥8 Gy yes vs. no) or the transplantation at high volume centers (≥7 patients yes vs. no) were not associated with significant differences in PFS or OS. During or after alloHSCT, 30/71 (42%) pts. showed either refractory (9/71, 13%) or relapsed (21/71, 29%) disease (R/R), being highest among MCL±AHN pts. (11/13, 85%; ASM/SM-AHN, 9/30, 30%; SM-AML, 10/28, 36%; P=0.002). R/R SM was predominantly observed in MCL±AHN (10/11, 91%) while R/R AHN was higher in SM-AML patients (6/10, 60%) and ASM/SM-AHN (5/9, 56%). The median time to relapse was 0.6 years (range 0.1-4.5). Post alloHSCT, a response to various treatment regimens was achieved in 13/30 (43%) pts. (ASM/SM-AHN, 3/9, 33%; SM-AML, 5/10, 50%; MCL±AHN, 5/11, 45%) with highest response rates in 9 pts. receiving midostaurin and/or avapritinib (7/9, 78%). Conclusions In pts. with AdvSM eligible for alloHSCT, i) baseline characteristics affect outcome of alloHSCT more than specific transplant procedures, ii) alloHSCT should not be performed in pts. without response prior to alloHSCT and iii) post-alloHSCT strategies such as preemptive or residual disease guided maintenance therapy should be considered to improve post-alloHSCT outcome.

The diagnostic workup for systemic mastocytosis differs from consensus recommendations: Results of a worldwide survey

ObjectiveMastocytosis is a complex disorder affecting various organs. The diagnostic workup can be challenging and requires a multidisciplinary approach including the use of uncommon tests. To assess mastocytosis management around the globe, we conducted the first worldwide online survey for physicians. MethodsA 21-item questionnaire was sent out to the members of the World Allergy Organization (WAO), the Global Allergy and Asthma European Network (GA2LEN), the Urticaria (UCARE) and Angioedema (ACARE) Centers of Reference and Excellence, the German Society of Allergology and Clinical Immunology (DGAKI), and the European Mast Cell and Basophil Research Network (EMBRN) in April–June 2021. ResultsAcross 628 respondents from 79 countries 87.7% and 9.7% of physicians were allergists/clinical immunologists and/or dermatologists. Participating physicians were from all regions of the world (Europe, EU: 41.6%; North America, NA: 24.8%; Latin America, LA: 14.5%; Asia-Pacific, AP: 12.6%; and Africa/Middle East, AME: 6.5%). Only 2.2% of respondents worked at Specialized Mastocytosis Centers (SMCs) in North America or European Union. Physicians reported caring for 4 patients with mastocytosis per year, with higher numbers in European Union and Asia Pacific (5/year) compared to Latin America (2/year). Dermatologists and physicians who work at SMCs reported higher patient numbers (15/year and 80/year, respectively). Suspicion of mastocytosis in the allergology and dermatology community is commonly driven by anaphylaxis (82.9%), mastocytosis skin lesions (82.1%), or elevated tryptase levels (76.6%). Osteoporosis and gastrointestinal symptoms less often prompted suspicion of mastocytosis (21.4% and 49.9%, respectively). World Health Organisation (WHO)-diagnostic criteria and classification, regardless of the region, are only used by about 50% of physicians, with higher rates for SMCs (83.3%). Serum tryptase, bone marrow biopsy, and KIT D816V mutation analysis are included in the diagnostic workup by 90.9%, 61.5%, and 58.4% of physicians, respectively. The biggest challenges for the management of mastocytosis are the lack of more effective treatment options (51.1%), missing multidisciplinary networks (47.1%), and the lack of experience of specialists from other disciplines (39.0%). ConclusionsThe diagnostic workup for mastocytosis differs from consensus recommendations and varies between regions. This may be improved by establishing active multidisciplinary networks, increasing access to diagnostic procedures, consistently applying WHO criteria, and developing new Mastocytosis Centers of Reference and Excellence.

Antibody-Based and Cell Therapies for Advanced Mastocytosis: Established and Novel Concepts.

Advanced systemic mastocytosis (SM) is a heterogeneous group of myeloid neoplasms characterized by an uncontrolled expansion of mast cells (MC) in one or more internal organs, SM-induced tissue damage, and poor prognosis. Advanced SM can be categorized into aggressive SM (ASM), MC leukemia (MCL), and SM with an associated hematologic neoplasm (SM-AHN). In a vast majority of all patients, neoplastic cells display a KIT mutation, mostly D816V and rarely other KIT variants. Additional mutations in other target genes, such as SRSF2, ASXL1, or RUNX1, may also be identified, especially when an AHN is present. During the past 10 years, improved treatment approaches have led to a better quality of life and survival in patients with advanced SM. However, despite the availability of novel potent inhibitors of KIT D816V, not all patients enter remission and others relapse, often with a multi-mutated and sometimes KIT D816V-negative disease exhibiting multi-drug resistance. For these patients, (poly)chemotherapy, antibody-based therapies, and allogeneic hematopoietic stem cell transplantation may be viable treatment alternatives. In this article, we discuss treatment options for patients with drug-resistant advanced SM, including novel KIT-targeting drugs, antibody-based drugs, and stem cell-eradicating therapies.

Increased TIM-3 and galectin-9 serum levels in patients with advanced systemic mastocytosis

Systemic mastocytosis is characterized by expansion of clonal mast cells in various tissues. Several biomarkers with diagnostic and therapeutic potential have recently been characterized in mastocytosis, such as the serum marker tryptase and the immune checkpoint molecule PD-L1. We aimed to investigate whether serum levels of other checkpoint molecules are altered in systemic mastocytosis and whether these proteins are expressed in mastocytosis infiltrates in the bone marrow. Levels of different checkpoint molecules were analyzed in serum of patients with different categories of systemic mastocytosis and healthy controls and correlated to disease severity. Bone marrow biopsies from patients with systemic mastocytosis were stained to confirm expression. Serum levels of TIM-3 and galectin-9 were increased in systemic mastocytosis, particularly in advanced subtypes, compared with healthy controls. TIM-3 and galectin-9 levels were also found to correlate with other biomarkers of systemic mastocytosis, such as serum tryptase and KIT D816V variant allele frequency in the peripheral blood. Moreover, we observed expression of TIM-3 and galectin-9 in mastocytosis infiltrates in bone marrow. Together, our results demonstrate for the first time that serum levels of TIM-3 and galectin-9 are increased in advanced systemic mastocytosis. Moreover, TIM-3 and galectin-9 are expressed in bone marrow infiltrates in mastocytosis. These findings provide a rationale for exploring TIM-3 and galectin-9 as diagnostic markers and eventually therapeutic targets in systemic mastocytosis, particularly in advanced forms.

Avapritinib versus Placebo in Indolent Systemic Mastocytosis

BackgroundIndolent systemic mastocytosis (ISM) is a clonal mast-cell disease driven by the KIT D816V mutation. We assessed the efficacy and safety of avapritinib versus placebo, both with best supportive care, in patients with ISM.MethodsWe randomized patients with moderate to severe ISM (total symptom score [TSS] of ≥28; scores range from 0 to 110, with higher numbers indicating more severe symptoms) two to one to avapritinib 25 mg once daily (n=141) or placebo (n=71). The primary end point was mean change in TSS based on the 14-day average of patient-reported severity of 11 symptoms. Secondary end points included reductions in serum tryptase and blood KIT D816V variant allele fraction (≥50%), reductions in TSS (≥50% and ≥30%), reduction in bone marrow mast cells (≥50%), and quality of life measures.ResultsFrom baseline to week 24, avapritinib-treated patients had a decrease of 15.6 points (95% CI, −18.6 to −12.6) in TSS compared to a decrease of 9.2 points (−13.1 to −5.2) in the placebo group; P<0.003. From baseline to Week 24, 76/141 patients (54%; 45% to 62%) in the avapritinib group compared to 0/71 patients in the placebo group achieved a ≥50% reduction in serum tryptase level; P<0.001. Edema and increases in alkaline phosphatase were more common with avapritinib than placebo; there were few treatment discontinuations because of adverse events.ConclusionsIn this trial, avapritinib was superior to placebo in reducing uncontrolled symptoms and mast-cell burden in patients with ISM. The long-term safety and efficacy of this approach for patients with ISM remain the focus of the ongoing trial. (Funded by Blueprint Medicines Corporation; ClinicalTrials.gov number, NCT03731260.)

Recent advances in diagnosis and therapy in systemic mastocytosis.

Mastocytosis is a heterogeneous neoplasm characterized by accumulation of neoplastic mast cells in various organs. There are three main types: cutaneous mastocytosis (CM), systemic mastocytosis (SM), and mast cell sarcoma. CM mainly affects children and is confined to the skin, whereas SM affects adults and is characterized by extracutaneous involvement, with or without cutaneous involvement. Most cases of SM have an indolent clinical course; however, some types of SM have aggressive behavior and a poor prognosis. Recent advances in the understanding of the molecular changes in SM have changed the diagnosis and treatment of aggressive and advanced SM subtypes. The International Consensus Classification and World Health Organization refined the diagnostic criteria and classification of SM as a result of accumulation of clinical experience and advances in molecular diagnostics. Somatic mutations in the KIT gene, most frequently KIT D816V, are detected in 90% of patients with SM. Expression of CD30 and any KIT mutation were introduced as minor diagnostic criteria after the introduction of highly sensitive screening methods. SM has a wide spectrum of clinical features, and only a few drugs are effective at treating advanced SM. Currently, the mainstay of SM treatment is limited to the management of chronic symptoms related to release of mast cell mediators. Small-molecule kinase inhibitors targeting the KIT-downstream and KIT-independent pathways were recently approved for treating advanced SM. I describe recent advances in diagnosis of SM, and review the currently available and emerging therapeutic options for SM management.

Mast cell leukemia: clinical and molecular features and survival outcomes of patients in the ECNM Registry.

Mast cell leukemia (MCL) is a rare subtype of systemic mastocytosis defined by ≥20% mast cells (MC) on a bone marrow aspirate. We evaluated 92 patients with MCL from the European Competence Network on Mastocytosis registry. Thirty-one (34%) patients had a diagnosis of MCL with an associated hematologic neoplasm (MCL-AHN). Chronic MCL (lack of C-findings) comprised 14% of patients, and only 4.5% had "leukemic MCL" (≥10% circulating MCs). KIT D816V was found in 62/85 (73%) evaluable patients; 9 (11%) individuals exhibited alternative KIT mutations, and no KIT variants were detected in 14 (17%) subjects. Ten evaluable patients (17%) had an abnormal karyotype and the poor-risk SRSF2, ASXL1, and RUNX1 (S/A/R) mutations were identified in 16/36 (44%) patients who underwent next-generation sequencing. Midostaurin was the most common therapy administered to 65% of patients and 45% as first-line therapy. The median overall survival (OS) was 1.6 years. In multivariate analysis (S/A/R mutations excluded owing to low event rates), a diagnosis of MCL-AHN (hazard ratio [HR], 4.7; 95% confidence interval [CI], 1.7-13.0; P= .001) and abnormal karyotype (HR, 5.6; 95% CI, 1.4-13.3; P= .02) were associated with inferior OS; KIT D816V positivity (HR, 0.33; 95% CI, 0.11-0.98; P= .04) and midostaurin treatment (HR, 0.32; 95% CI, 0.08-0.72; P= .008) were associated with superior OS. These data provide the most comprehensive snapshot of the clinicopathologic, molecular, and treatment landscape of MCL to date, and should help further inform subtyping and prognostication of MCL.