ALBERT

Description: The murine non-myeloablative regimen of total lymphoid irradiation (TLI) and anti-thymocyte serum (ATS) was recently translated into a transplantation strategy for human hematolymphoid malignancies, preventing recipients from acute graft-versus-host disease (GVHD) without tumor relapses (Lowsky et al, NEJM, 2005). To investigate GVHD protection, we transplanted 50 x 106 bone marrow cells and 60 x 106 splenocytes (BMT) from wild-type, CD4−/−, IL-4−/, or IL-10−/− C57BL/6 (H-2b) donor mice into wild-type or natural killer (NK) T cell deficient Jα18−/− BALB/c (H-2d) hosts following non-myeloablative host conditioning with TLI/ATS. Control wild-type BALB/c hosts received a conventional regimen, either 800cGy (lethal) or 450 cGy (sublethal) total body irradiation (TBI) and ATS with BMT from wild-type C57BL/6 donors. TLI/ATS-conditioned wild-type hosts given BMT from wild-type donors survived 100 days without evidence of GVHD. TBI/ATS-conditioned wild-type hosts given BMT from wild-type donors and TLI/ATS conditioned wild-type hosts given BMT from CD4−/−, IL-4−/−, or IL-10−/− donors succumbed to GVHD, with marked donor CD8+ T cell accumulation demonstrated in liver, mesenteric lymph nodes (MLN), and colon at day 6. Given the dependence of GVHD protection on donor CD4+ cells and the donor cytokines IL-4 and IL-10, we investigated the role of donor CD4+CD25+Foxp3+regulatory T cells (CD4+Tregs) in GVHD protection after TLI/ATS and BMT. Wild-type TLI/ATS conditioned hosts given BMT from wild-type donors demonstrated a significant (p〈 0.01) ten-fold increase in both the percentage and absolute number of donor CD4+CD25+Foxp3+Tregs present in the host spleen at day 6. These donor CD4+CD25+Foxp3+cells demonstrated typical IL-4 and IL-10 dominant cytokine secretion profiles on PMA/ionomycin stimulation and were functional both in vitro in donor-host MLR suppression and in vivo in secondary GVHD suppression assays. Using congenic markers (CD45.1/CD45.2), we demonstrate that these donor CD4+ Tregs are derived from splenic (peripheral) T cells within the donor cell inoculum. When wild-type donor bone marrow and spleen cells were rigorously CD25-depleted using magnetic bead selection prior to BMT into wild-type TLI/ATS treated hosts, donor CD4+CD25+Foxp3+ Tregs were not present in the host spleen at day 6, and all hosts demonstrated markedly increased donor CD8+ T cell accumulation in the liver, MLN, and colon at day 6 accompanied by GVHD after BMT. TLI/ATS-conditioned Jα18−/− hosts given BMT from wild-type donors demonstrated low numbers of donor CD4+CD25+Foxp3+ Tregs in host spleen and GVHD similar to TBI/ATS controls. When wild-type host NK T cells were adoptively transferred before BMT into TLI/ATS-conditioned Jα18−/− hosts, the use of non-CD25-depleted donor cells resulted in increased numbers of donor CD4+ Tregs and markedly reduced donor CD8+ T cell accumulation in the host liver, MLN, and colon at day 6, whereas CD25 depletion of donor cells resulted in loss of donor CD4+CD25+Foxp3+ Tregs in the host spleen and significantly increased donor CD8+ T cell accumulation. Our previous studies demonstrated that host invariant NK T cells are critical for GVHD protection after TLI/ATS host conditioning. The present studies show that host regulatory NK T cells can facilitate the expansion of donor CD4+CD25+Foxp3+ Tregs, and that this expansion plays a pivotal role in protecting TLI/ATS treated hosts from lethal GVHD after allogeneic BMT.

Description: Sinus histiocytosis with massive lymphadenopathy (SHML or Rosai-Dorfman disease) is a rare histiocytic proliferation of unknown etiology. There is a known association between SHML and immune disorders. Recently, histologic changes of SHML have been found in lymph nodes of patients with autoimmune lymphoproliferative syndrome (ALPS), a disorder most commonly associated with mutations in the TNFRSF6 gene that encodes the Fas antigen. We retrospectively analyzed tissue from 22 patients with SHML for TNFRSF6 gene mutations using isolated genomic DNA from paraffin-embedded tissue followed by screening of PCR products for the promoter regions and all exons (1–9) of the gene for possible mutation by high performance liquid chromatography. Mutations were confirmed by direct sequencing. We identified six patients (27%) with SHML and mutations of the TNFRSF6 gene as listed below, including three cases (14%) with potentially significant mutations (*) involving promotor and splice donor regions, and frameshift mutations. The samples with mutations had a 4:2 male:female ratio with a mean/median age of 39/43 years (range 7–68 years) compared to a 9:7 male:female ratio, mean/median age of 42/43 years (range 12–76 years) for the non-mutated samples. No differences in site of disease were identified in the mutated versus non-mutated groups. None of the samples had morphologic features to suggest ALPS. These results suggest that at least a subset of cases of SHML are associated with disruption of the Fas apoptotic pathway. Additional study of other components of the apoptotic pathway may be warranted in this disease. Cases with TNFRSF6 mutations. Case No. Nucleotide Change Localization Codon Amino acid change **Numbering for the promoter sequence, according to www.mutationdiscovery.com. All other numbering according to GeneBank accession number M67454. 1 c217+34A〉G Intron 7 c217+40A〉G Intron 7 2 T779C Exon 7 195 Val --〉 Ala 3 c217+1G〉A Intron 7 Splice defect* T763C Exon 7 190 Val --〉 Ala c217+182A〉G Intron 7 c217+183A〉G Intron 7 C1425T Exon 9II 3′UTR * 4 597del T Exon 4 135 Frameshift* 5 T/C 4656** Promoter * c189+4A〉T Intron 6 5′ consensus splice donor site* C729T Exon 6 179 Leu --〉 Phe 6 c218-84A〉G Intron 7

Description: Abstract 4044 Background: Conventionally, multiple myeloma is believed to coexist in approximately 10% of AL amyloidosis patients. However, it is unclear whether this figure is too low based on current World Health Organization criteria. These criteria, mainly created to differentiate myeloma from monoclonal gammopathy of undetermined significance, include the presence of ≥ 10% plasma cells on a bone marrow biopsy or aspirate as being diagnostic of myeloma. Aims: To define the frequency and relevance of a concomitant diagnosis of myeloma in patients with AL amyloidosis. Methods: Records from consecutive patients with biopsy-proven AL amyloidosis treated at the Stanford University Amyloid Center were reviewed. Plasma cell percentages were determined by manual counts from bone marrow aspirate smears and by CD138 immunohistochemistry (IHC) performed on bone marrow core biopsies. Results: A total of 41 patients (median age 61 years, 32% female) were evaluated. The median number of organs involved with amyloidosis was 2 (range 1–4), with 28 patients (68%) having cardiac involvement, 22 patients (54%) having renal involvement, 15 patients (37%) having gastrointestinal involvement, 12 patients (29%) having soft tissue involvement, and 10 patients (24%) having nervous system involvement. All patients had bone marrow biopsies and aspirates performed at the time of amyloid diagnosis, with most undergoing both manual counts of plasma cells from aspirates and IHC from core biopsies. Based on conventional criteria, manual aspirate counts defined 15/28 (54%) patients as having myeloma, and IHC defined 26/31 (84%) patients as having myeloma (p=0.01). Only nine patients had a detectable serum paraprotein on immunofixation (median 1.1 g/dl, range 0.4–2.6). 81% of patients had an elevated serum free light chain (85% lambda), with a median level of 37.3 mg/dl (range 8.6–256 mg/dl). Compared to the frequency of elevated plasma cells, the prevalence of anemia (29%), hypercalcemia (14%), impaired kidney function (21%), and lytic lesions (7%) was low. After a median follow-up of 13 months (range 1–127 months), the one-year overall survival (74% vs. 58%) and three-year overall survival (50% vs. 50%) was not significantly different between patients with ≥10% plasma cells and patients with

Description: Background: Systemic mastocytosis (SM) is a rare mast cell disorder associated with a range of debilitating symptoms and a shortage of effective treatment options. Little is known about the impact of the disease from the patients' perspective. Systematically characterizing the natural history of SM and its impact on patients will facilitate the development of new therapies. Registries that engage patients have proven valuable in other rare diseases by expanding knowledge of current treatment approaches, evaluating disease burden and accelerating clinical trials. Methods: Mast Cell Connect (NCT02620254, www.mastcellconnect.org) is an observational database that captures demographic, socioeconomic and disease information from patients with mastocytosis. It is the first patient-reported registry for mastocytosis to our knowledge. Key objectives are to improve collective understanding of the disease burden on patients and to facilitate development of new therapies by increasing participation in clinical trials. Enrollment is "site-agnostic" as participants register and take surveys on a secure online portal. Since many US patients are seen outside large clinical centers, this enables broader participation and collection of real-world data. Inclusion criteria are a diagnosis of SM or cutaneous mastocytosis (CM). Diagnoses are self-reported and participants are asked to provide medical reports that will be used to confirm diagnoses in the future. Informed consent is required to join this IRB-approved study. Results: Mast Cell Connect opened on December 1, 2015. As of May 31, 2016, 166 participants had registered, of whom 157 had responded to the online survey. Of the 153 participants who reported their diagnosis, 107 had SM and 38 had CM. Those who reported a diagnosis of SM were categorized as SM participants if they also reported other diagnoses. The current analyses are based on data provided by the 107 SM participants. Of the 107 SM participants, 60 (56%) had Indolent SM (ISM), 8 (7%) had Smoldering SM (SSM), 10 (9%) had Advanced SM (AdvSM, defined as aggressive SM, SM with an associated hematological neoplasm, and Mast Cell Leukemia) and 29 (27%) did not know their subtype. Median age was 50 years (range 4-77). More females participated (74%) than males (26%). Median time from symptom-onset to diagnosis was 7 years. Participants saw a median of 3 specialists prior to diagnosis, most frequently dermatology (67%), allergy/immunology (67%), hematology/oncology (63%) and general practitioner/internal medicine (63%). Specialists diagnosing SM most often included dermatology (36%), allergy/immunology (25%) and hematology/oncology (23%). AdvSM participants were typically diagnosed by hematology/oncology (70%). The medications taken most often at the time of survey were anti-histamines (85% H1 blockers, 72% H2 blockers), leukotriene inhibitors (38%) and cromolyn sodium (33%). Agents to reduce mast cell burden were taken less often (imatinib: 7%, interferon-α: 2%, hydroxyurea: 1% and investigational agents: 1%). Symptoms reported as moderately to severely bothersome included: fatigue (69%), difficulty concentrating (63%), abdominal pain (55%), pain in other locations (53%), difficulty sleeping (53%), itching (46%), diarrhea (45%), bloating (43%), nausea (42%), headache (40%), skin changes (40%), anxiety (39%) and flushing (37%). Participants reported being limited in work or other daily activities "quite a bit" to "very much" in 47% of ISM, 43% of SSM, and 70% of AdvSM cases. Participants' physical condition or medical treatment interfered with their family life "quite a bit" or "very much" in 59% of ISM, 43% of SSM, and 80% of AdvSM cases. Conclusions: Over 160 participants joined Mast Cell Connect in the first 6 months, indicating the mastocytosis community, including The Mastocytosis Society, is highly motivated to participate in research. SM participants reported a diagnostic odyssey, seeing multiple specialists over a median of 7 years prior to diagnosis. Despite frequent use of symptom-directed medications, symptom burden remains substantial and considerably impacts quality of life. Novel therapies targeting the underlying disease are needed. Establishing US centers of excellence may hasten the time to diagnosis. Continued collaboration between researchers, patient advocates and industry is needed to advance the care of patients with SM. Disclosures Lee: Blueprint Medicines: Employment, Equity Ownership. George:Allakos: Research Funding; Novartis: Consultancy; Blueprint Medicines: Consultancy; Allakos: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Consultancy, Research Funding; Incyte: Consultancy; GLG: Consultancy; Wiley Blackwell: Consultancy; American Registry of Pathology: Patents & Royalties; Wolters Kluwer: Patents & Royalties; UpToDate: Patents & Royalties. Shi:Blueprint Medicines: Employment, Equity Ownership. Evans:Blueprint Medicines: Employment, Equity Ownership. Singh:Blueprint Medicines: Employment, Equity Ownership. Boral:Blueprint Medicines: Employment, Equity Ownership. Rangel Miller:PatientCrossroads: Employment, Equity Ownership.

Description: 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. Disclosures DeAngelo: 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.

Description: Although CD4+CD25+ T cells (T regulatory cells [Tregs]) and natural killer T cells (NKT cells) each protect against graft-versus-host disease (GVHD), interactions between these 2 regulatory cell populations after allogeneic bone marrow transplantation (BMT) have not been studied. We show that host NKT cells can induce an in vivo expansion of donor Tregs that prevents lethal GVHD in mice after conditioning with fractionated lymphoid irradiation (TLI) and anti–T-cell antibodies, a regimen that models human GVHD-protective nonmyeloablative protocols using TLI and antithymocyte globulin (ATG), followed by allogeneic hematopoietic cell transplantation (HCT). GVHD protection was lost in NKT-cell–deficient Jα18−/− hosts and interleukin-4 (IL-4)−/− hosts, or when the donor transplant was Treg depleted. Add-back of donor Tregs or wild-type host NKT cells restored GVHD protection. Donor Treg proliferation was lost in IL-4−/− hosts or when IL-4−/− mice were used as the source of NKT cells for adoptive transfer, indicating that host NKT cell augmentation of donor Treg proliferation after TLI/antithymocyte serum is IL-4 dependent. Our results demonstrate that host NKT cells and donor Tregs can act synergistically after BMT, and provide a mechanism by which strategies designed to preserve host regulatory cells can augment in vivo donor Treg expansion to regulate GVHD after allogeneic HCT.

Description: Abstract 799 Background: Aggressive systemic mastocytosis (ASM) and mast cell leukemia (MCL) with or without an associated clonal hematologic non-mast cell lineage disease (AHNMD) are myeloproliferative neoplasms (MPN) with inadequate treatment options. The activating KIT D816V mutation occurs in ≈80% of patients (pts) with these advanced forms of SM and is central to disease pathogenesis. Midostaurin is an oral inhibitor of multiple tyrosine kinases, including wild-type and D816-mutated KIT. Promising results of an investigator-initiated trial (Gotlib et al. Blood. 2010;116:316) led to initiation of this multicenter phase 2 study (NCT00782067) of midostaurin in pts with advanced SM. Here, we report the efficacy and preliminary safety results of stage 1 of this trial. Methods: Midostaurin (100 mg BID) was administered continuously in 28-d cycles until progression or intolerable toxicity. Enrollment into an extension phase was permitted if the null hypothesis of an overall response rate (ORR) ≤ 30% was rejected per Fleming 2-stage design. Pts were required to have ≥ 1 measurable C-finding(s) (CF; eg, cytopenias, liver dysfunction) considered related to SM. The primary endpoint was ORR (major response [MR] + partial response [PR] according to Valent criteria) occurring in the first 6 cycles and maintained for ≥ 8 weeks (wk). International Working Group criteria for myelodysplastic syndrome (MDS; with slight modifications) were used to evaluate changes in transfusion dependence. Results: 62 pts were enrolled in stage 1, of whom 40 (65%) were eligible for efficacy evaluation. Reasons for ineligibility included absence of measurable CF (n = 11) or CF considered unrelated to SM (n = 11). Median age of eligible pts (25 males, 63%) was 64.5 y (range: 48–80 y). 33 (83%) pts had ASM (27 with an AHNMD) and 7 (18%) had MCL (3 with an AHNMD). AHNMDs (n=30) included 10 chronic myelomonocytic leukemia (CMML), 10 MDS/MPN-unclassified (MDS/MPN-u), 4 hypereosinophilic syndrome/chronic eosinophilic leukemia (HES/CEL), and 6 other subtypes. 22 (55%) pts received at least 1 prior therapy (median: 1.5; range: 1–4). 28 (70%) pts were KIT D816V/Y–positive, 3 (8%) were KIT D816V/Y–negative, and 9 (23%) were not evaluable for mutation status. The ORR was 60% (24/40), and most responses were MRs (21/24; Table). With a median follow-up of 27 months (mo), the median duration of response and median overall survival (OS) have not been reached. Of the 7 pts with MCL, 4 (57%) achieved an MR, including 3 ongoing incomplete remissions (IR) (19+ mo in 2 pts and 32+ mo in 1 pt). The OS in MCL pts was 22.6 mo. Additionally, 3 of 4 responding ASM/MCL-HES/CEL pts exhibited resolution of blood eosinophilia (mean baseline % and absolute eosinophils: 64% and 15.6 × 109/L). Median change in serum tryptase level among the 40 pts was −61% (range: −97% to 16%), with 16 (40%) pts exhibiting a ' 50% reduction lasting ≥ 8 wk. Median change in marrow mast cell (MC) burden in 32 evaluable pts was −41% (range: −92% to 83%), with 15/32 (47%) pts exhibiting a ≥ 50% reduction. All 62 pts received at least 1 dose of midostaurin and were included in the safety analysis. Grade 3/4 hematologic adverse events (AEs) considered drug-related were neutropenia (11%), anemia (3%), and thrombocytopenia (3%). The most common grade 3/4 drug-related non-hematologic AEs were fatigue (6%), nausea (6%), vomiting (5%), diarrhea (5%), and increased lipase (5%). As of March 15, 2012, therapy was discontinued in 26/40 pts: 7 for AEs (5 drug-related), 12 for disease progression, and 7 for other reasons. 3 of 30 pts with an AHNMD (2 CMML and 1 MDS/MPN-u) developed AML. Conclusion: In advanced SM pts, midostaurin was well tolerated and demonstrated a high rate of durable responses, including in MCL, which historically has a dire prognosis. The drug can produce significant reductions in MC burden, indicating the potential for disease modification. The stage 1 ORR was sufficient to reject the null hypothesis and permitted enrollment in the extension phase, where full accrual of 116 pts has been completed. Disclosures: Gotlib: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. George:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Akin:Novartis: Consultancy. Sotlar:Novartis: Consultancy. Awan:Allos Therapeutics: Speakers Bureau. Morariu:Novartis: Employment. Squier:Novartis: Employment. Villeneuve:Novartis: Employment. Emery-Salbert:Novartis: Employment. Horny:Novartis: Consultancy. Valent:Novartis: Consultancy, Honoraria. Reiter:Novartis: Consultancy, Honoraria.

Description: Systemic mastocytosis (SM) has greatly benefited from the broad application of precision medicine techniques to hematolymphoid neoplasms. Sensitive detection of the recurrent KIT D816V mutation and use of next-generation sequencing (NGS) panels to profile the genetic landscape of SM variants have been critical adjuncts to the diagnosis and subclassification of SM, and development of clinical-molecular prognostic scoring systems. Multilineage KIT involvement and multimutated clones are characteristic of advanced SM (advSM), especially SM with an associated hematologic neoplasm (AHN). A major challenge is how to integrate conventional markers of mast cell disease burden (percentage of bone marrow mast cell infiltration and serum tryptase levels) with molecular data (serial monitoring of both KIT D816V variant allele frequency and NGS panels) to lend more diagnostic and prognostic clarity to the heterogeneous clinical presentations and natural histories of advSM. The approval of the multikinase/KIT inhibitor midostaurin has validated the paradigm of KIT inhibition in advSM, and the efficacy and safety of second-generation agents, such as the switch-control inhibitor ripretinib (DCC-2618) and the D816V-selective inhibitor avapritinib (BLU-285) are being further defined in ongoing clinical trials. Looking forward, perhaps the most fruitful marriage of the advances in molecular genetics and treatment will be the design of adaptive basket trials that combine histopathology and genetic profiling to individualize treatment approaches for patients with diverse AHNs and relapsed/refractory SM.