Advanced Systemic Mastocytosis Patients Research Articles

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.

EPH107 Treatment Landscape for Patients With Advanced Systemic Mastocytosis in Germany in 2015 to 2020 Based on Claims Data Analysis

Advanced systemic mastocytosis (AdvSM) is a group of rare disorders characterized by abnormal growth and accumulation of mast cells in one or several organs which lead to mediator release and/or organ dysfunction/damage with therefore reduced life expectancy. The study objective was to describe the distribution of systemic therapy prescriptions and prevalence of adult AdvSM patients in Germany based on claims data from 2015 to 2020. Avapritinib received EMA approval in March 2022 and was therefore not included in the analysis.

The Use of Avapritinib in Advanced Systemic Mastocytosis: Report of an Open-Label Compassionate Use Program in the United Kingdom

Background: Advanced systemic mastocytosis (AdvSM) is a rare haematological neoplasm occurring due to clonal proliferation of mast cells in extracutaneous organs. In up to 95% of cases, the driver mutation is KIT D816V. AdvSM encompasses aggressive SM (ASM), mast cell leukaemia and SM with an associated haematological neoplasm (SM-AHN). In this latter, the AHN component often dictates the clinical course, being most frequently associated with chronic myelomonocytic leukaemia (CMML). Treatment for AdvSM has evolved recently with the introduction of targetted tyrosine kinase inhibitors (TKI). Avapritinib, a highly selective inhibitor for KIT and PDGFRA, produced robust responses in measures of mast cell/disease burden in the PATHFINDER trial, leading to approval in USA and Europe. We report the clinical experience of AdvSM patients who have received avapritinib at 11 centers in the United Kingdom via an open-label compassionate use program. Methods: Avapritinib was commenced in AdvSM patients with progressive disease-related symptoms and end-organ damage. The initial dose was adjusted according to tolerability and kept continuously until disease progression or unmanageable toxicity. Results: In a cohort of 13 patients, with an age average of 68.8 years (range 57-76), 11 patients (84.6%) were diagnosed with SM-AHN; 81.8% with a concomitant diagnosis of CMML. 2 patients (15.4%) were diagnosed with ASM. All patients harbored the D816V mutation and 8 patients (61.5%) presented with additional mutations; 5 with SRSF2 and 1 with ASXL1. On application of prognostic scores; International Prognostic Scoring system for Mastocytosis (IPSM) 10 patients (76.9%) were classified as AdvSM-3/4 and Mutation-Adjusted Risk Score for Advanced Systemic Mastocytosis (MARS) 7 patients (53.8%) were stratified as high risk. Treatment: 10 patients (76.9%) received avapritinib as a first-line regime, and 9 patients (69.2%) started at a dose of 200 mg od. Three patients were previously treated with other regimes - one patient with midostaurin, one with cladribine and one with azacytidine. Response: Median duration of treatment was 503.7 days (range 75 - 1168 days). Baseline median blood parameters for this cohort were tryptase level of 168 ng/mL (range 91-811), alkaline phosphatase (ALP) of 437 IU/L (range 127-1235), albumin of 34.5 g/L (range 24-48) and a spleen size of 16.4 cm (range 12-26), measured by radiologically. At response evaluation, 9 patients (69.2%) had a tryptase level <20 ng/mL and 11 patients (84.6%) had normalised their ALP and albumin levels. None of the patients had a clinically enlarged spleen, with 9 patients (69.2%) having a normal spleen size on abdominal ultrasound. 8 patients had a complete pathological remission. The overall response rate (using the modified IWG-ECNM-MRT criteria) was 76.9% with a complete response (CR) or CR with partial haematologic recovery in 53.8% of patients. At the last follow-up, 3 patients (23.1%) died; 1 from SM progression, 1 from haematemesis and 1 due to progression of the AHN component but had a partial response of the SM with avapritinib. Toxicities:10 patients (76.9%) had haematological toxicities. Bleeding was reported in 4 patients (30.8%); 3 patients with grade 1/2 (1 mucocutaneous and 2 mild gastrointestinal bleeds), and 1 fatal gastrointestinal bleed. No intracranial bleeds were reported. Fluid retention was noted in 3 patients (23.1%). Less frequent side effects noted were nausea/vomiting (2 patients) and skin/hair discoloration (1 patient). 11 patients (84.6%) needed dose reduction of avapritinib due to haematological toxicity with 8 patients (72.7%) remaining at 100 mg od. 4 patients (36.4%) had to intermittently stop treatment until haematological recovery. Avapritinib was stopped in 2 patients (15.4%) due to disease progression or unmanageable toxicity. Conclusion: This small cohort of patients reflects the clinical heterogeneity of AdvSM and mirrors the PATHFINDER trial outcomes in 'real world 'experience in the UK. Avapritinib as 1st line was tolerated, producing sustained clinical and pathological responses in the majority of this group of non-selected patients with AdvSM with high risk disease. Dose adjustments due to anticipated myelosuppression were made, with 72.2% of patients maintained on 100mg Avapritinib od. 2 patients with SM-AHN are referred for HSCT as a curative treatment as a result of achieving a CR with Avapritinib.

Response and Resistance to Cladribine in Patients with Advanced Systemic Mastocytosis: A Registry-Based Analysis

For nearly two decades, the off-label treatment with the purine analogue cladribine was considered as the standard-of-care for patients with advanced systemic mastocytosis (AdvSM), which is driven by the KIT D816V mutation in >90% of patients. High response rates and improved progression-free- and overall survival (OS) have favored the use of the multikinase inhibitor midostaurin and the specific KIT D816V inhibitor avapritinib, but cladribine remains a relevant treatment option beyond first-line (1L) treatment due to intolerance, resistance and progression on KIT inhibitors. Based on data from the 'German Registry on Disorders of Eosinophils and Mast Cells (GREM)', we therefore sought to evaluate response and resistance to cladribine in both 1L- and second-line (2L) in 79 AdvSM patients. Prior treatment included midostaurin while subsequent treatment approaches included individually or sequentially midostaurin, avapritinib, acute myeloid leukemia-like intensive chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT). Treatment options with a low disease-modifying impact (e.g. interferon-alpha) or solely directed towards the associated hematologic neoplasm (e.g. hydroxyurea, azacytidine) were not considered as 1L- or 2L-treatment. This study is an updated and more detailed analysis of a recently published comparative study between midostaurin and cladribine (Lübke et al., J Clin Oncol 2022). Cladribine was used at a dose of 0.14 mg/kg/day subcutaneously or intravenously on days 1-5 of a 28-day course. For 1L- (n=48, 61%) and 2L-treatment (n=31, 39%), a median number of 3 cycles was applied over a median of 3.3 (range 0.1-16.0) and 3.0 (range 0.1-28.5) months, respectively (P=0.612). Three or more cycles were applied in 32/79 (41%) patients (1L, n=21, 66%; 2L, n=11, 34%). The main reason for dose reduction, e.g. application only on days 1-3 or extension of intervals, was prolonged myelosuppression (15/79, 19%). Separating 1L- and 2L-treatment, the overall response rate (ORR), according to modified Valent criteria (46 evaluable patients), was 41% (12/29) and 35% (6/17, P=0.690), and median OS (all patients evaluable) was 1.9 years (48/79), and 1.2 years (31/79), respectively (P=0.311). Independent of the treatment line, application of ≥3 vs. <3 cycles (median OS 2.8 vs. 1.2 years, P=0.038) and response vs. no response after at least 1 cycle (median OS 3.4 vs. 1.5 years, P=0.002) correlated with improved OS. After minimizing confounding effects through treatment with midostaurin, avapritinib, intensive chemotherapy or allogeneic HSCT, multivariable analyses revealed leukocytosis ≥16 x 109/L (hazard ratio [HR] 5.0, 95% confidence interval [CI 1.2-21.0], P=0.026) and eosinophilia ≥1.5 x 109/L (HR 3.0 [CI 1.0-8.8], P=0.048) as independent adverse prognostic markers for OS. There was no impact of other laboratory (anemia, thrombocytopenia, serum tryptase; P>0.517) or genetic markers (mutations in SRSF2, ASXL1 or RUNX1; P=0.412), on OS. Due to an excess mortality of low- and intermediate-risk patients, none of the recently established prognostic scoring systems (MARS, IPSM, MAPS or GPSM) were predictive for OS. In conclusion, cladribine is effective in 1L- and 2L-treatment of AdvSM. The presence of leukocytosis or eosinophilia, application of <3 cycles and a lack of response according to modified Valent criteria are adverse prognostic markers. The various prognostic models for AdvSM are of limited value because of high mortality in low- and intermediate-risk patients. Overall, cladribine remains a relevant sequential treatment option for patients with AdvSM. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

MPN-453 Clinical Presentation and Diagnosis of Advanced Systemic Mastocytosis (AdvSM) in a Community Oncology Setting.

Advanced systemic mastocytosis (AdvSM) is a rare hematologic neoplasm with poor overall survival that is characterized by an accumulation of neoplastic mast cells in various tissues and organs. Although driven by KIT D816V in 95% of cases, the heterogeneous symptom presentation of AdvSM patients may contribute to a lengthy diagnostic journey. To characterize the symptomology of AdvSM patients reported by oncologists at the initial patient encounter in a community-based setting. This was a cross-sectional survey study conducted from August-November 2021. Community oncologists affiliated with Integra Connect were asked to complete a structured eCRF on referral patterns, patient signs and symptoms at initial visit, approach to diagnosis, and ongoing disease management for patients they diagnosed or treated with AdvSM in the prior 24 months. Community oncology practices affiliated with Integra Connect. Twenty-eight community oncologists provided data on 55 AdvSM patients. Twenty-one had managed 2 or more AdvSM patients in the previous 3 years. Mean patient age was 56 years; 55% were female. Comorbid conditions included cardiovascular disease (38%), diabetes (38%), GERD (29%), and COPD/asthma (25%). AdvSM patients were referred to participating oncologists by primary care physicians (33%), immunologists (28%), dermatologists (11%), another oncologist (11%), rheumatologists (7%), and other specialists (9%). 93% of oncologists reported bone marrow biopsy as critical in making an AdvSM diagnosis and indicated that elevated serum tryptase (64%) and detection of KIT D816V (56%) were also important factors in making the AdvSM diagnosis. Cutaneous, gastrointestinal (GI), neuropsychiatric, and musculoskeletal signs and symptoms were common. The most common symptoms reported were pruritis (65%), maculopapular cutaneous mastocytosis (62%), flushing (60%), nausea (58%), and bloating and diarrhea (52%). Allergic reactions (40%), anaphylaxis (24%), dyspnea (35%), anxiety (49%), and fatigue (62%) were also frequently reported at the initial visit. This study shows that AdvSM patients receiving care in a community-based oncology setting are referred to oncologists from a variety of different specialties with a range of disease-related symptoms and multitude of comorbid conditions. Improving awareness of the clinical presentation and diagnostic strategies for AdvSM patients may expedite disease recognition, diagnosis, and treatment initiation.

Clinical Outcomes of Adults with Systemic Mastocytosis: A 15-Year Multidisciplinary Experience.

Simple SummaryThe term mastocytosis denotes a heterogeneous group of rare disorders characterized by abnormal accumulation and activation of mast cells in various organs. Based on the WHO classification, mastocytosis can essentially be split into indolent and advanced systemic disease. Indolent mastocytosis is the most prevalent variant in adults. In our retrospective study, we aimed to analyze the clinical outcomes of patients with mastocytosis attending our center over the last 15 years. We found that most patients in our cohort suffered from the indolent variant of mastocytosis. Furthermore, we determined the overall prevalence of mastocytosis in our region to be one case per 10,000 adults. In addition, overall survival was significantly better in indolent mastocytosis patients compared to patients with advanced disease. Therefore, awareness of differences in the prognoses of patients with indolent and advanced mastocytosis is important.Systemic mastocytosis (SM) is a rare, clonal, clinically heterogeneous disorder of the mast cells (MCs), and mainly affects adults. The present study aims to describe the clinical and laboratory features as well as the outcomes of SM. A 15-year retrospective study was conducted on 195 consecutive SM patients (aged ≥ 18 years) diagnosed in 2006–2020 at the Multidisciplinary Mastocytosis Center at Karolinska University Hospital. Patients with indolent SM (ISM) represented the most common SM variant (88.2%). Furthermore, the frequencies of aggressive SM and SM with associated non-mast-cell hematological neoplasm were 4.1% and 7.7%, respectively. The prevalence of SM in the adult population of the Stockholm region was estimated to be 10.6/100,000 inhabitants, and the mean incidence of SM cases in the Stockholm region was 0.77/100,000 people per year. In this series, tryptase levels were below 20 ng/mL in 51 patients (26%). Osteoporosis was present in 21.9% of all cases. Interestingly, there was no progression from ISM to advanced SM variants in our study. Furthermore, overall survival was significantly better in ISM patients compared to advanced SM patients (p < 0.0001). Our data suggest that the early recognition and correct diagnosis of SM has prognostic significance.

P1013: OVERALL SURVIVAL IN PATIENTS WITH SYSTEMIC MASTOCYTOSIS WITH ASSOCIATED HEMATOLOGIC NEOPLASM TREATED WITH AVAPRITINIB VERSUS BEST AVAILABLE THERAPY

Background: Avapritinib, a selective inhibitor of KIT D816V, was approved in the United States (US) for treatment of adults with advanced systemic mastocytosis (AdvSM), a rare myeloid neoplasm with poor overall survival (OS), based on data from the Phase 1 EXPLORER (NCT02561988) and Phase 2 PATHFINDER (NCT03580655) single-arm trials. Systemic mastocytosis with an associated hematologic neoplasm (SM-AHN) is both the most common and most heterogenous subtype of AdvSM. No randomized control trial (RCT) has been conducted comparing efficacy of avapritinib with best available therapy (BAT) in SM-AHN. Aims: This study (NCT04695431) compared OS between SM-AHN patients treated with avapritinib in the EXPLORER and PATHFINDER trials versus SM-AHN patients treated with BAT in standard clinical practice. Methods: A multi-center, global, observational, retrospective chart review study was conducted at 6 study sites (4 European, 2 US) to identify and collect data from AdvSM patients who received BAT. SM-AHN patients were identified using inclusion/exclusion criteria similar to the EXPLORER and PATHFINDER trials. Patients receiving BAT could contribute data on multiple lines of therapy (LOTs) to the analysis; these data were compared with patient-level data from the EXPLORER and PATHFINDER trials. OS was defined as the time from avapritinib or BAT initiation to death from any cause; patients were censored at date of last follow-up if alive. Kaplan-Meier analysis was used to assess OS. Inverse probability of treatment weighting (IPTW) was used to adjust for differences in key variables between the treatment cohorts, including age, sex, region, anemia, thrombocytopenia, leukocyte count, skin involvement, number and type of prior treatments, performance status, serum tryptase level, and presence of SRSF2/ASXL1/RUNX1 mutations. An IPTW-weighted Cox proportional hazards model, adjusted for variables that remained unbalanced after weighting, was used to compare OS between treatment groups. Results: This analysis included 119 avapritinib patients and 83 BAT patients with SM-AHN (the latter contributed data on 121 LOTs). Median (range) age of the avapritinib and BAT cohorts was 70 (45−88) and 71 (38−88) years, and 61% vs. 76% of patients were male, respectively. Prior systemic therapy was received by 58% of avapritinib and 44% of BAT patients. In the avapritinib cohort, 76% of patients from both trials were dosed at ≤200mg and 24% of patients, all from EXPLORER, were dosed at ≥300mg. BAT patients were most frequently treated with tyrosine kinase inhibitors (73 out of 121 LOTs, 60%) or cytoreductive therapies (46 out of 121 LOTs, 38%). Mean durations of follow-up were 17.6 and 18.1 months, with 29 (24%) and 56 (68%) deaths in avapritinib and BAT cohorts, respectively. Median OS for avapritinib was 46.9 months (95% CI: 44.9, not estimable) and 18.0 months (95% CI: 13.0, 26.8) for BAT (Figure 1). IPTW-adjusted median OS was 46.9 months (95% CI: 21.4, 49.0) for avapritinib and 19.5 months (95% CI: 13.0, 32.2) for BAT. Weighted Cox analysis showed that OS was significantly improved for avapritinib versus BAT (hazard ratio [95% CI]: 0.42 [0.24, 0.74]; P<0.001), even with further adjustment for unbalanced variables. Image:Summary/Conclusion: The results of this analysis indicate that patients with SM-AHN treated with avapritinib in clinical trials had significantly longer OS compared to patients treated with BAT. With no RCTs, these data offer crucial insights into the survival benefit of SM-AHN patients treated with avapritinib compared to other treatments for AdvSM.

P1014: OVERALL SURVIVAL IN PATIENTS WITH ADVANCED SYSTEMIC MASTOCYTOSIS RECEIVING AVAPRITINIB VERSUS MIDOSTAURIN OR CLADRIBINE

Background: Avapritinib, a selective KIT D816V inhibitor, was approved for the treatment of adults with advanced systemic mastocytosis (AdvSM) in the United States (US), based on two single-arm trials: Phase 1 EXPLORER (NCT02561988) and Phase 2 PATHFINDER (NCT03580655). No randomized controlled trial (RCT) has been conducted comparing efficacy of avapritinib versus alternative therapies for AdvSM. Aims: This study (NCT04695431) compared overall survival (OS) between AdvSM patients treated with avapritinib in the EXPLORER and PATHFINDER trials and those treated with midostaurin or cladribine in real-world clinical practice. Methods: Pooled data from the EXPLORER and PATHFINDER trials were compared with data for patients with AdvSM obtained through a multi-center, global, observational, retrospective chart review study conducted at 6 study sites (4 European, 2 US). Patients treated with midostaurin or cladribine were identified using inclusion/exclusion criteria similar to the trials and could contribute multiple lines of therapy (LOTs) to the analysis. OS, assessed using Kaplan-Meier analysis, was defined as time from initiation of avapritinib, midostaurin, or cladribine to death from any cause; patients were censored at date of last follow-up if alive. Inverse probability of treatment weighting (IPTW) was used to adjust for differences in key variables between treatment cohorts, including age, sex, AdvSM subtype, anemia, thrombocytopenia, leukocyte count, skin involvement, number and type of prior treatments, performance status, serum tryptase level, and presence of SRSF2/ASXL1/RUNX1 mutations. IPTW-weighted Cox proportional hazards models, adjusted for variables that remained unbalanced after weighting, were used to compare OS between cohorts. Results: This analysis included 176 patients treated with avapritinib, 94 treated with midostaurin (LOT, n=99), and 44 treated with cladribine (LOT, n=49). Median (range) age was 68 (31−88) for avapritinib, 69 (26−87) for midostaurin, and 66 (45−88) years for cladribine patients. 103 (59%) avapritinib patients were male, versus 64 (68%) in the midostaurin and 27 (61%) in the cladribine cohort. In the avapritinib cohort, 136 (77%) patients from both trials were dosed at ≤200mg and 40 (23%) patients, all from EXPLORER, were dosed at ≥300mg. In unweighted analysis of avapritinib versus midostaurin, mean follow-up durations were 17.9 and 27.9 months, respectively, during which 34 (19%) avapritinib patients and 56 (60%) midostaurin patients died. Median OS was not reached (NR) (95% CI: 46.9, not estimable) in the avapritinib cohort and was 28.6 months (95% CI: 18.2, 44.6) in the midostaurin cohort (Figure 1). In weighted Cox analysis, OS was significantly improved in the avapritinib versus midostaurin cohort (hazard ratio [HR] [95% CI]: 0.59 [0.36, 0.97]; P<0.001). The mean-follow-up duration for the cladribine cohort was 24.2 months, during which 29 (66%) patients died. The median OS in the cladribine cohort was 23.4 months (95% CI: 14.8, 40.6). Weighted Cox analysis showed that OS was significantly improved in the avapritinib versus cladribine cohort (HR [95% CI]: 0.32 [0.15, 0.67]; P=0.003). Image:Summary/Conclusion: The results from this study indicate that AdvSM patients treated with avapritinib in clinical trials experienced significantly improved survival compared with patients treated with midostaurin or cladribine in the real world. Given the lack of RCTs, these data offer essential insights into the improved survival of patients treated with avapritinib compared to alternative therapies for AdvSM.

Healthcare Resource Utilization and Costs of Advanced Systemic Mastocytosis Among Medicare Fee for Service Beneficiaries

Healthcare Resource Utilization and Costs of Advanced Systemic Mastocytosis Among Medicare Fee for Service Beneficiaries

‘Application of Prognostic Scoring in Systemic Mastocytosis Patients within a UK Centre of Excellence: Guys and St Thomas’ NHS Foundation Trust.‘

‘Application of Prognostic Scoring in Systemic Mastocytosis Patients within a UK Centre of Excellence: Guys and St Thomas’ NHS Foundation Trust.‘

Organ Damage at Initial Presentation across the Spectrum of Advanced Systemic Mastocytosis Variants

Organ Damage at Initial Presentation across the Spectrum of Advanced Systemic Mastocytosis Variants

MPN-395: Efficacy and Safety of ≤200 mg Avapritinib in Patients with Advanced Systemic Mastocytosis: Pooled Results from the Phase 1 EXPLORER and Interim Phase 2 PATHFINDER Studies

<h3>Introduction</h3> Systemic mastocytosis (SM), a clonal neoplasm driven by <i>KIT</i> D816V mutation in ~95% of cases, has limited treatment options. We evaluated pooled efficacy and safety of avapritinib, a selective inhibitor of D816V-mutant <i>KIT,</i> in patients with advanced SM (AdvSM) from the phase I/II EXPLORER (NCT02561988) and from interim analysis of the phase II PATHFINDER (NCT03580655) studies. <h3>Methods</h3> Patients included in this <i>post hoc</i> pooled analysis were ≥18 years of age with centrally confirmed diagnosis of AdvSM and treated with once-daily avapritinib at starting doses up to 200 mg. Overall response rate (ORR), defined as complete remission with full (CR) or partial hematologic recovery (CRh), partial remission (PR), or clinical improvement, was evaluated per modified IWG-MRT-ECNM criteria. Other analyses included overall survival (OS), changes from baseline in mast cell disease burden, and safety. <h3>Results</h3> Efficacy of avapritinib was analyzed in 53 ORR-evaluable patients; median age was 67 years (range, 37–85), 32% had an ECOG PS of 2–3, 66% had prior anti-neoplastic therapy, 47% received prior midostaurin, and 94% had a D816V mutation. Responses occurred in 72% (95% CI, 58–83) of patients, with 57% achieving a PR or better (95% CI, 42–70) and 28% with a CR/CRh. Median duration of response was 38.3 months (95% CI, 21.7–NE), and median time to response was 1.9 months (range, 0.3–26.7), with responses deepening over time. Median estimated 12-month OS rate was 84%. Patients achieved ≥50% reductions from baseline in serum tryptase (49/53, 92.5%), marrow mast cell aggregates (46 of 52 evaluable, 88.5%), and blood KIT D816V allele fraction (37 of 52 evaluable, 71.2%). In all AdvSM patients (safety population) receiving the starting avapritinib dose of 200 mg (n=80), common AEs were edema (79%), diarrhea (28%), nausea (24%), and fatigue/asthenia (23%). Decreased platelets (64%), hemoglobin (55%), and neutrophils (54%) from baseline were the most common laboratory abnormalities. Overall, 4 (5%) patients discontinued treatment due to drug-related AEs and 6 (8%) from disease progression. Of 2 (3%) AE-related deaths, neither were treatment-related. <h3>Conclusions</h3> Pooled study results showed ≤200 mg avapritinib induced rapid and deepening clinical responses and had a manageable safety profile.

Pure Pathologic Response Is Associated with Improved Overall Survival in Patients with Advanced Systemic Mastocytosis Receiving Avapritinib in the Phase I EXPLORER Study

Pure Pathologic Response Is Associated with Improved Overall Survival in Patients with Advanced Systemic Mastocytosis Receiving Avapritinib in the Phase I EXPLORER Study

Comparison of RNA-Based Versus DNA-Based Quantitative KIT D816V Mutation Analysis Reveals Significant Disparity in Patients with Advanced Systemic Mastocytosis

Systemic mastocytosis (SM) is characterized by activating mutations in KIT, usually KIT D816V in &gt;90% of patients. According to the WHO classification, detection of KIT D816V is a minor diagnostic criterion. Moreover, a reduction of the RNA-based KIT D816V expressed allele burden (EAB) of ≥25% at month 6 is a favorable marker for improved survival in midostaurin-treated advanced SM (AdvSM) patients. However, only limited data exist upon the comparison between RNA-based and DNA-based quantitative KIT D816V mutation analyses. We therefore collected peripheral blood samples from 161 SM patients (indolent SM [ISM], n=40; AdvSM, n=121) at time of referral. We applied a real time reverse-transcriptase polymerase chain reaction (qRT-PCR) assay for assessment of the KIT D816V EAB and a chip-based digital PCR (dPCR) for the quantification of the DNA-based KIT D816V variant allele frequency (VAF, QuantStudio 3D dPCR System, ThermoFisher Scientific, Massachusetts, USA). The limit of detection (LOD) was assessed through serial dilution experiments with DNA from healthy individuals and DNA from a SM patient with a KIT D816V VAF of approximately 50%. All samples were analyzed in two independent dPCR runs. In an inital round-robin test for an inter-laboratory (n=4) comparison on 30 DNA samples (ISM, n=7; AdvSM, n=19), we found a very good correlation between 3 different chip-based digital PCR systems (dPCR; droplet-based dPCR, ddPCR, BioRad Laboratories, California, USA; quantitative real-time PCR, qPCR, California, USA; dPCR vs. ddPCR r=0.99, R2=0.99; dPCR vs. qPCR r=0.99, R2=0.98). In ISM patients, the comparison between EAB and VAF revealed a strong linear relationship with a correlation (r) of 0.91 and a coefficient of determination (R2) of 0.84, which was significantly inferior (r=0.71; R2=0.5) in AdvSM patients. In 45/121 (37%) and 76/121 (63%) of AdvSM patients, the EAB/VAF ratio was ≤2 (cohort A) or &gt;2 (cohort B). To confirm the significant disparity between EAB and VAF in individual patients, serial analyses of at least 3 samples in 12 patients revealed a stable EAB/VAF ratio during follow-up. The comparison between cohort A and cohort B revealed significant differences in terms of a higher median hemoglobin level (p=0.006), a lower percentage of patients with hemoglobin &lt;10g/dL (p=0.02), a lower median monocyte level (p=0.01), a lower median alkaline phosphatase level (p=0.03), and a lower number of patients with a high risk molecular profile (at least one gene mutation in SRSF2, ASXL1, and/or RUNX1, S/A/R, p=0.02) in cohort A. Moreover, patients of cohort A had a significantly better overall survival (OS) (median OS 12.9 versus 3.3 years; hazard ratio 2.1; 95% confidence interval 1.2-3.5; p=0.005; Figure). We conclude that a) KIT D816V EAB and VAF are significantly different in AdvSM patients but not in ISM and b) AdvSM patients with an EAB/VAF ratio &gt;2 present with an aggressive phenotype and adverse prognosis as compared to patients with EAB/VAF ratio ≤2. We therefore recommend to routinely determine KIT D816V EAB and VAF in AdvSM patients. Disclosures Fabarius: Novartis: Research Funding. Reiter:Blueprint: Consultancy, Honoraria, Other: Travel reimbursement; Deciphera: Consultancy, Honoraria, Other: Travel reimbursement; Novartis: Consultancy, Honoraria, Other: Travel reimbursement, Research Funding.

An Increased Bone Mineral Density As an Adverse Prognostic Factor in Patients with Systemic Mastocytosis

Systemic mastocytosis (SM) is characterized by expansion of clonal mast cells that infiltrate various organ systems. The extent of organ infiltration and subsequent organ damage distinguishes between indolent SM (ISM) and advanced SM (AdvSM). ISM patients usually present with a low mast cell burden and have a nearly normal life expectancy while AdvSM patients have a high disease burden, multiple organ damage and poor prognosis. In ISM patients, measurement of the bone mineral density (BMD) frequently reveals osteopenia and osteoporosis (lumbar spine BMD T-score of ≤ −2.5 standard deviation [SD]). In contrast, the association between increased BMD and osteosclerosis, respectively, and the various SM subtypes is unclear. We therefore sought to evaluate the BMD in 61 patients (ISM, n = 29, 48%; AdvSM, n = 32, 52%) and correlated the prevalence of osteoporosis, increased BMD and osteosclerosis with clinical parameters and prognosis. All patients were scanned on the same 16 row CT Scanner (SOMATOM Emotion 16, Siemens Healthcare Sector, Forchheim, Germany). The results were expressed as T-score (SD below the mean of young healthy adults) and as Z-score (SD below the age- and gender-matched mean reference value). According to established WHO criteria, osteoporosis was defined as a lumbar spine BMD T-score of ≤ −2.5 SD. Increased BMD and osteosclerosis were defined as Z-score &gt; 1 SD and &gt; 2 SD, respectively. Osteoporosis was detected in 11/29 (38%) patients with ISM and 2/32 (6%) patients with AdvSM (p = 0.004). Bone marrow mast cell infiltration (median 10% versus 20%, p=0.035) and serum tryptase levels (median 31 µg/L versus 58 µg/L, p = 0.047) were significantly lower in ISM patients with osteoporosis as compared to those without osteoporosis (n=18, 62%). No significant differences were seen regarding age, gender, blood counts, and overall survival. An elevated BMD was detected in 1/29 (3%) patient with ISM and 24/32 (75%) patients with AdvSM (p &lt; 0.001) while osteosclerosis was only detected in AdvSM patients (16/32, 50%). AdvSM patients with increased BMD were older (median 77 years versus 68 years, p = 0.0043), had lower platelet counts (median 111 x 109/L versus 238 x 109/L, p = 0.041) and higher levels of bone marrow mast cell infiltration (50% versus 10%, p=0.002), serum tryptase (median 262 µg/L versus 62 µg/L, p = 0.003) and alkaline phosphatase (238 U/L versus 74 U/L, p &lt; 0.0001). In consequence, prognosis of AdvSM patients with increased BMD was significantly inferior as compared to those without increased BMD (median overall survival 3.6 years versus not reached, p = 0.031). In conclusion, i) osteoporosis is a common feature in ISM but not in AdvSM patients, ii) an increased BMD is frequent in AdvSM but not in ISM patients, iii) osteosclerosis is restricted to AdvSM patients, and iv) an elevated BMD is associated with a more aggressive phenotype and inferior survival (Figure A-B). Disclosures Fabarius: Novartis: Research Funding. Reiter:Novartis: Consultancy, Honoraria, Other: Travel reimbursement, Research Funding; Blueprint: Consultancy, Honoraria, Other: Travel reimbursement; Deciphera: Consultancy, Honoraria, Other: Travel reimbursement.

UK Single Institution Experience of Mastocytosis: Guy's and St Thomas' NHS Foundation Trust

Introduction: Systemic mastocytosis (SM) is a heterogeneous disorder of neoplastic mast cells ranging from an indolent to aggressive multi-system disease. We registered our UK Mastocytosis Centre of Excellence with the European Competence Network of Mastocytosis (ECNM) in 2005. Our multidisciplinary team (MDT) includes haematologists, haematopathologists, dermatologist, immunologist and molecular diagnosticians. Over 500 patients have been reviewed in our quarterly SM-MDT. We present a large single centre experience of a rare disorder. Method: We have reviewed prospective and retrospectively collected clinical data for 125 adult patients from 2009. The data captures clinical, laboratory, diagnostic results and management. Local patients with a tryptase level of &gt;20ug/L are offered haematology review and bone marrow investigation with KIT D816V mutation analysis using digital PCR. Patients seen for a second opinion have their diagnostic material reviewed. Since 2018, next generation sequencing (NGS) based myeloid gene panels are carried out on patients with advanced SM (AdvSM). Results: Classification of mastocytosis patients: In 125 patients no gender bias was seen: 56 (44.8%) were male and 69 (55.2%) female. Median age of patients with indolent SM (ISM) was 49 years (range 22-78); and for AdvSM: (aggressive SM, SM with an associated haematological neoplasm and mast cell leukaemia) was 64years (range 5-77). The median serum tryptase level was 48.9ug/L for ISM patients (range 4-682) and 120ug/L for AdvSM patients (range 24-854). 112/125 patients had a bone marrow biopsy. 13 patients chose not to have a biopsy. 88% (110/125) of patients had a mast cell disorder. 4% (5/125) had no marrow involvement. 84% (105/125) met WHO criteria for a diagnosis of SM - Figure 1.These were sub-classified: 71/105 (67%) ISM; 2/105 (2%) smouldering SM (SSM); 3/105 (3%) aggressive SM (ASM); 2/105 (2%) mast cell leukaemia (MCL) and 27/105 (26%) SM with an associated hematologic neoplasm (SM-AHN). The most frequent associated haematological neoplasms were MPN and CMML. Lymphomas (n=3) and plasma cell dyscrasias (n=1) were seen patients. In 10/27 (37%) cases of SM-AHN the SM was the initial diagnosis with subsequent development of an AHN. In 5/27(19%) cases the AHN component preceded the SM and in 12/27 (44%) cases the 2 components were co-diagnosed. Mutation status : 24/32 patients with AdvSM were noted to be positive for an activating KIT mutation (D816V, n=23; D816L, n=1). 15/32 AdvSM patients had NGS myeloid gene panel analysis for the SAR panel (SRSF2, ASXL1 and RUNX1) which confers poor prognosis. 4 of the15 patients harboured at least 2 out of 3 SAR mutations. JAK2 V617F mutation was detected in 7 of 8 classical MPN patients and in 1 of 4 patients with MPNu/MDS overlap. 4 patients had a TET2 mutation. 1 patient with mast cell leukaemia had a GATA2 mutation in addition to all 3 in the SAR panel. Cutaneous involvement: 70% (88/125) of patients had skin involvement: 62% (78/125) urticaria pigments, 3% (4/125) telangiectasia macularis eruptiva perstans and 5% (6/125) having non-specific involvement. Skin involvement was more common in ISM (78%) than AdvSM (54% in SM-AHN, none in the 2 patients with MCL). Management : Treatments in ISM are usually for symptom control. Antihistamines, anti-inflammatory agents, anti-leukotriene agents, mast cell stabilising agents, bisphosphonates, proton-pump inhibitors, PUVA and steroids are used. Various cytoreductive therapies have been used in AdvSM (hydroxycarbamide, pegylated interferon-α, cladrabine, cytarabine, azacitadine alone/combination with midostaurin). Patients with SM-AHN have tailored management depending on the disease component that requires treatment. Access to targeted therapies for AdvSM patients in a trial or compassionate use programme has been successful: 7/32 patients with advanced SM have been enrolled into trials (midostaurin 1; avapritinib 6). Conclusions: Our data reflects the heterogeneous nature of the SM classification spectrum clinically and diagnostically. An experienced MDT provides holistic high standard of care within a comprehensive centre for good patient outcomes (Figure 2). Development of a portfolio of novel therapeutic options in multi-centred, international collaborative trials is beneficial to patients and pivotal for research in this rare disorder. Disclosures Cross: Novartis: Consultancy, Research Funding; Incyte: Consultancy. McLornan:Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Novartis: Honoraria. Radia:Blueprint Medicines: Consultancy; Novartis: Consultancy, Speakers Bureau. OffLabel Disclosure: There are very few medications available in mastocytosis and various off label medications have been used including pegylated interferon alpha.

Novel approaches to treating advanced systemic mastocytosis.

Mastocytosis is a myeloproliferative neoplasm characterized by expansion of abnormal mast cells (MCs) in various tissues, including skin, bone marrow, gastrointestinal tract, liver, spleen, or lymph nodes. Subtypes include indolent systemic mastocytosis, smoldering systemic mastocytosis and advanced systemic mastocytosis (AdvSM), a term collectively used for the three most aggressive forms of the disease: aggressive systemic mastocytosis, mast cell leukemia, and systemic mastocytosis with an associated clonal hematological non-mast cell disease (SM-AHNMD). MC activation and proliferation is physiologically controlled in part through stem cell factor (SCF) binding to its cognate receptor, KIT. Gain-of-function KIT mutations that lead to ligand-independent kinase activation are found in most SM subtypes, and the overwhelming majority of AdvSM patients harbor the KITD816V mutation. Several approved tyrosine kinase inhibitors (TKIs), such as imatinib and nilotinib, have activity against wild-type KIT but lack activity against KITD816V. Midostaurin, a broad spectrum TKI with activity against KITD816V, has a 60% clinical response rate, and is currently the only drug specifically approved for AdvSM. While this agent improves the prognosis of AdvSM patients and provides proof of principle for targeting KITD816V as a driver mutation, most responses are partial and/or not sustained, indicating that more potent and/or specific inhibitors are required. Avapritinib, a KIT and PDGFRα inhibitor, was specifically designed to inhibit KITD816V. Early results from a Phase 1 trial suggest that avapritinib has potent antineoplastic activity in AdvSM, extending to patients who failed midostaurin. Patients exhibited a rapid reduction in both symptoms as well as reductions of bone marrow MCs, serum tryptase, and KITD816V mutant allele burden. Adverse effects include expected toxicities such as myelosuppression and periorbital edema, but also cognitive impairment in some patients. Although considerable excitement about avapritinib exists, more data are needed to assess long-term responses and adverse effects of this novel TKI.

Comprehensive Cytokine Profiling of Patients with Advanced Systemic Mastocytosis Treated with Midostaurin

Background: Advanced systemic mastocytosis (AdvSM) comprises a group of hematologic neoplasms primarily driven by the oncogenic KIT D816V mutation. Morbidity and mortality relate to organ damage caused by neoplastic mast cell infiltration and mast cell mediator symptoms. Midostaurin, an oral multikinase/KIT inhibitor, produced reversion of organ damage in 60-70% of AdvSM patients (Gotlib et al, NEJM, 2016; DeAngelo et al, Leukemia, 2018), which was associated with decreases in bone marrow mast cell burden, serum tryptase levels, and splenomegaly in the majority of patients. Similar to myelofibrosis (MF) patients treated with JAK inhibitors, midostaurin improves disease symptoms and quality of life (Gotlib et al, NEJM, 2016). We conducted a cytokine profiling study to better understand the biologic effects of midostaurin in this patient population.Methods: Plasma cytokine levels were analyzed in 19 patients with AdvSM (2 aggressive SM, 10 SM with an associated hematologic neoplasm, and 7 with mast cell leukemia) treated with midostaurin 100 mg twice daily. Seventeen patients were treated on the phase II investigator-initiated trial (DeAngelo et al,Leukemia, 2018), and two were treated on a compassionate-use basis. Cytokine levels were compared to 10 patients with MF (primary MF [n=4]; post PV/ET MF [n=6]), treated with JAK inhibitors (ruxolitinib, fedratinib, or momelotinib) and 10 healthy patients whose age range matched the SM group. Plasma samples were obtained pretreatment, and after 4-8 weeks of therapy. Each patient sample was evaluated for 62 cytokines using a Luminex assay (eBioscience) performed at the Stanford Human Immune Monitoring Center. Sparse partial least squares discriminant analysis (SPLS-DA) was used to identify the most predictive cytokines from the expression data that help classify patient samples based on disease states, and SPLS regression was used to identify cytokines correlated with survival (Rohart et al, mixOmics. R package version 6.3.2). Overall survival was calculated from the time of initiation of midostaurin to time of death.Results: Plasma levels of several cytokines were higher at baseline in AdvSM and MF patients compared to healthy controls (Fig 1A-B). In patients with AdvSM and MF, pretreatment levels of leptin (false discovery rate (FDR) < 0.002), epidermal growth factor (EGF; FDR < 2e-5), and brain-derived neurotrophic factor (BDNF; FDR < 3.5e-7) were lower than healthy controls. Using SPLS-DA, we identified a distinct baseline cytokine expression profile that could classify patient samples as either AdvSM, MF, or healthy with an error rate of less than 0.10 (Fig 1C). The six most predictive cytokines were nerve growth factor, EGF, BDNF, interferon alpha, intercellular adhesion molecule-1 (ICAM1), and leukemia inhibitory factor. Corroborating prior data (Verstovsek et al, NEJM 2010), we found that several plasma cytokine levels significantly decreased in MF patients after 1-2 cycles of JAK inhibition (Fig 1B). Although we observed similar decreases in plasma cytokine levels for AdvSM patients on midostaurin (Fig 1A), the results were more variable and did not reach statistical significance. AdvSM patients that responded to midostaurin (major or partial response per Valent criteria) expressed a different baseline cytokine expression profile when compared to non-responders. SPLS-DA was able to distinguish these two classes of patients with an error rate of 0.35 (Fig 1D). SPLS regression identified baseline levels of interleukin-7 (IL7), ICAM1, interleukin 12 subunit p40 (IL12p40), EGF, and platelet-derived growth factor BB (PDGFBB) as potential predictors of survival for patients with AdvSM treated with midostaurin. High pretreatment levels of IL7 (109 months (m) vs. 33 m; p=0.01), EGF (92 m vs. 34 m; p=0.04), and PDGFBB (80 m vs. 37 m; p=0.09) and low pretreatment levels of ICAM1 (91 m vs. 19 m; p=0.02) and IL12p40 (91 m vs. 19 m; p=0.03) were associated with increased survival.Conclusions: Cytokine expression profiling can distinguish patients with AdvSM or MF from healthy controls. Compared to the use of JAK inhibitors in MF, midostaurin's activity in AdvSM appears less related to reversion of pro-inflammatory cytokines. Investigation of a larger cohort of patients is needed to determine whether such analyses of plasma cytokines will provide added value to new scoring prognostic systems of AdvSM that incorporate clinical and molecular data. [Display omitted] DisclosuresDeAngelo:Glycomimetics: Research Funding; Amgen: Consultancy; ARIAD: Consultancy, Research Funding; Takeda: Honoraria; BMS: Consultancy; Incyte: Consultancy, Honoraria; BMS: Consultancy; ARIAD: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria; Shire: Honoraria; Amgen: Consultancy; Pfizer Inc: Consultancy, Honoraria; Blueprint Medicines: Honoraria, Research Funding. George:Blueprint Medicines: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Gotlib:Deciphera: Consultancy, Honoraria, Research Funding; Kartos: Consultancy; Promedior: Research Funding; Gilead: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Blueprint Medicines: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding.

SETD2 and histone H3 lysine 36 methylation deficiency in advanced systemic mastocytosis

The molecular basis of advanced systemic mastocytosis (SM) is not fully understood and despite novel therapies the prognosis remains dismal. Exome sequencing of an index-patient with mast cell leukemia (MCL) uncovered biallelic loss-of-function mutations in the SETD2 histone methyltransferase gene. Copy-neutral loss-of-heterozygosity at 3p21.3 (where SETD2 maps) was subsequently found in SM patients and prompted us to undertake an in-depth analysis of SETD2 copy number, mutation status, transcript expression and methylation levels, as well as functional studies in the HMC-1 cell line and in a validation cohort of 57 additional cases with SM, including MCL, aggressive SM and indolent SM. Reduced or no SETD2 protein expression—and consequently, H3K36 trimethylation—was found in all cases and inversely correlated with disease aggressiveness. Proteasome inhibition rescued SETD2 expression and H3K36 trimethylation and resulted in marked accumulation of ubiquitinated SETD2 in SETD2-deficient patients but not in patients with near-normal SETD2 expression. Bortezomib and, to a lesser extent, AZD1775 alone or in combination with midostaurin induced apoptosis and reduced clonogenic growth of HMC-1 cells and of neoplastic mast cells from advanced SM patients. Our findings may have implications for prognostication of SM patients and for the development of improved treatment approaches in advanced SM.

Next-generation sequencing in systemic mastocytosis: Derivation of a mutation-augmented clinical prognostic model for survival.

In routine practice, the World Health Organization classification of systemic mastocytosis (SM) is also the de facto prognostic system; a core value is distinguishing indolent (ISM) from advanced SM (includes aggressive SM [ASM], SM with associated hematological neoplasm [SM-AHN] and mast cell leukemia [MCL]). We sequenced 27 genes in 150 SM patients to identify mutations that could be integrated into a clinical-molecular prognostic model for survival. Forty four patients (29%) had ISM, 25 (17%) ASM, 80 (53%) SM-AHN and 1 (0.7%) MCL; overall KITD816V prevalence was 75%. In 87 patients, 148 non-KIT mutations were detected; the most frequently mutated genes were TET2 (29%), ASXL1 (17%), and CBL (11%), with significantly higher mutation frequency in SM-AHN > ASM > ISM (P < 0.0001). In advanced SM, ASXL1 and RUNX1 mutations were associated with inferior survival. In multivariate analysis, age > 60 years (HR = 2.4), hemoglobin < 10 g/dL or transfusion-dependence (HR = 1.7), platelet count < 150 × 10(9) /L (HR = 3.2), serum albumin < 3.5 g/dL (HR = 2.6), and ASXL1 mutation (HR = 2.3) were associated with inferior survival. A mutation-augmented prognostic scoring system (MAPSS) based on these parameters stratified advanced SM patients into high-, intermediate-, and low-risk groups with median survival of 5, 21 and 86 months, respectively (P < 0.0001). These data should optimize risk-stratification and treatment selection for advanced SM patients. Am. J. Hematol. 91:888-893, 2016. © 2016 Wiley Periodicals, Inc.