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BIOMARKER:

KIT D816V

i
Other names: KIT, C-Kit, CD117, PBT, SCFR, Stem Cell Factor Receptor, V-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog
Entrez ID:
10d
Capitalizing on paradoxical activation of the MAPK pathway for treatment of Imatinib-resistant mast cell leukemia. (PubMed, Hematol Oncol)
We observed that low concentrations of the TKIs Nilotinib and Ponatinib resulted in enhanced proliferation, suggesting paradoxical activation of the MAPK pathway...The combination of Ponatinib with the MEK inhibitor Trametinib, at nanomolar concentrations, effectively suppressed HMC-1.2 proliferation, metabolic activity, and induced apoptotic cell death...Effectiveness of this drug combination was recapitulated in the human KIT D816V MC line ROSA and in KIT D816V hematopoietic progenitors obtained from patient-derived induced pluripotent stem cells (iPS cells) and systemic mastocytosis patient samples. In conclusion, mutated KIT-driven Imatinib resistance and possible TKI-induced paradoxical activation can be efficiently overcome by a low concentration Ponatinib and Trametinib co-treatment, potentially reducing the negative side effects associated with MCL therapy.
Journal
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BRAF (B-raf proto-oncogene) • KIT (KIT proto-oncogene, receptor tyrosine kinase)
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KIT D816V • KIT V560G
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Mekinist (trametinib) • imatinib • Iclusig (ponatinib) • Tasigna (nilotinib)
25d
Summit: A 3-Part, Phase 2 Study of Bezuclastinib (CGT9486), an Oral, Selective, and Potent KIT D816V Inhibitor, in Adult Patients with Nonadvanced Systemic Mastocytosis (NonAdvSM) (ASH 2022)
There are currently no approved therapies for patients with NonAdvSM. Data from the Summit study will support further development of bezuclastinib in SM.
Clinical • P2 data • Tumor Mutational Burden
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TMB (Tumor Mutational Burden) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • KDR (Kinase insert domain receptor) • PDGFRB (Platelet Derived Growth Factor Receptor Beta) • CSF1R (Colony stimulating factor 1 receptor)
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KIT mutation • KIT D816V • KIT exon 17 mutation
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bezuclastinib (PLX9486)
25d
Preliminary Safety and Efficacy from Apex, a Phase 2 Study of Bezuclastinib (CGT9486), a Novel, Highly Selective, Potent KIT D816V Tyrosine Kinase Inhibitor, in Adults with Advanced Systemic Mastocytosis (AdvSM) (ASH 2022)
Patients with a history of prior TKI therapy (e.g., avapritinib, midostaurin) are permitted in the study. Early data suggest that bezuclastinib is well-tolerated and is associated with encouraging early signs of clinical activity as demonstrated by meaningful reductions in serum tryptase, MC burden, and KIT D816V VAF. Enrollment is currently ongoing. Updated safety and clinical activity as well as initial clinical objective response data will be presented.
Clinical • P2 data
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KIT (KIT proto-oncogene, receptor tyrosine kinase) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • PDGFRB (Platelet Derived Growth Factor Receptor Beta) • CSF1R (Colony stimulating factor 1 receptor)
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KIT mutation • KIT exon 11 mutation • KIT exon 9 mutation • KIT D816V • KIT exon 17 mutation • KIT positive
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Rydapt (midostaurin) • Ayvakit (avapritinib) • bezuclastinib (PLX9486)
25d
Response and Resistance to Cladribine in Patients with Advanced Systemic Mastocytosis: A Registry-Based Analysis (ASH 2022)
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...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.
Clinical
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ASXL1 (ASXL Transcriptional Regulator 1) • RUNX1 (RUNX Family Transcription Factor 1) • SRSF2 (Serine and arginine rich splicing factor 2)
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KIT mutation • ASXL1 mutation • SRSF2 mutation • KIT D816V
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azacitidine • Rydapt (midostaurin) • cladribine • Ayvakit (avapritinib) • hydroxyurea
25d
The Use of Avapritinib in Advanced Systemic Mastocytosis: Report of an Open-Label Compassionate Use Program in the United Kingdom (ASH 2022)
Three patients were previously treated with other regimes - one patient with midostaurin, one with cladribine and one with azacytidine. 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.
Clinical
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PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • ASXL1 (ASXL Transcriptional Regulator 1) • SRSF2 (Serine and arginine rich splicing factor 2)
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KIT mutation • SRSF2 mutation • KIT D816V
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azacitidine • Rydapt (midostaurin) • cladribine • Ayvakit (avapritinib)
25d
NGS Testing Practices and Molecular Profile Landscape of the KIT Gene in Systemic Mastocytosis: Real-World Insights from Selected European Countries (ASH 2022)
This study provides new insights into the occurrence of KIT alterations and concurrent presence of co-mutations in systemic mastocytosis patients, and how specific somatic NGS applications, namely HemOnc panels, are used across France, Italy, Germany, and Spain. The comprehensive characterization of the molecular epidemiology of KIT variants and co-mutations is crucial to better define SM prognosis and treatment strategies. More research is needed to determine the implications of these findings.
Clinical • Real-world evidence • Next-generation sequencing
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KIT (KIT proto-oncogene, receptor tyrosine kinase) • ASXL1 (ASXL Transcriptional Regulator 1) • RUNX1 (RUNX Family Transcription Factor 1) • TET2 (Tet Methylcytosine Dioxygenase 2) • SRSF2 (Serine and arginine rich splicing factor 2)
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KIT mutation • RUNX1 mutation • ASXL1 mutation • SRSF2 mutation • KIT D816V
1m
Mastocytosis and related entities: a practical roadmap. (PubMed, Acta Clin Belg)
There is emerging evidence suggesting there might be a link between HaT and due to the increased prevalence of HaT in patients with SM. The aim of this review is to provide a practical roadmap for diagnosis and management of mastocytosis and its associated entities, since there are still many misconceptions about these topics.Abbreviations: AdvSM: Advanced systemic mastocytosis; ASM: Aggressive systemic mastocytosis; aST: acute serum tryptase; BM: Bone marrow; BMM: Bone marrow mastocytosis; bST: baseline serum tryptase; CM: Cutaneous mastocytosis; DCM: Diffuse cutaneous mastocytosis; HVA: Hymenoptera venom allergy; HaT: Hereditary alpha tryptasemia; ISM: Indolent systemic mastocytosis; MC: Mast cell; MCA: Mast cell activation; MCAS: Mast cell activation syndrome; MCL: Mast cell leukemia; MIS: Mastocytosis in the skin; MMAS: Monoclonal mast cell activation syndrome; MPCM: Maculopapular cutaneous mastocytosis; SM: Systemic mastocytosis; SM-AHN: Systemic mastocytosis with associated hematological neoplasm; SSM: Smouldering systemic mastocytosis; VIT: Venom immunotherapy.
Journal • IO biomarker
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KIT (KIT proto-oncogene, receptor tyrosine kinase) • TPSAB1 (Tryptase Alpha/Beta 1)
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KIT mutation • KIT D816V
2ms
MPN-352 Clinicopathologic and Molecular Correlates of Organ Damage Across the Spectrum of Advanced Systemic Mastocytosis. (PubMed, Clin Lymphoma Myeloma Leuk)
In AdvSM, patterns of organ damage reflect disease subtype, prior therapy, and mutation profile. These data can help inform enrollment of AdvSM pts into clinical trials that currently require ≥1 organ damage findings. Grant Acknowledgments: ASH HONORS Award, NIH grant P30CA124435.
Observational data • Journal
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ASXL1 (ASXL Transcriptional Regulator 1) • RUNX1 (RUNX Family Transcription Factor 1) • SRSF2 (Serine and arginine rich splicing factor 2)
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RUNX1 mutation • ASXL1 mutation • SRSF2 mutation • KIT D816V
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Rydapt (midostaurin) • Ayvakit (avapritinib)
2ms
Clinicopathologic and Molecular Correlates of Organ Damage Across the Spectrum of Advanced Systemic Mastocytosis (SOHO 2022)
Patients or Other Participants: Our cohort included 240 AdvSM pts: 66 from the Stanford MPN registry and 174 from the phase I EXPLORER and phase II PATHFINDER studies of avapritinib in AdvSM...Compared to midostaurin-naïve pts, those who had received midostaurin had a greater bone marrow mast cell burden (P=0.06) but less frequently met WHO liver (P<0.001) and WHO malabsorption (P<0.001) criteria... In AdvSM, patterns of organ damage refl ect disease subtype, prior therapy, and mutation profi le. These data can help inform enrollment of AdvSM pts into clinical trials that currently require 1 organ damage fi ndings.
Clinical
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ASXL1 (ASXL Transcriptional Regulator 1) • RUNX1 (RUNX Family Transcription Factor 1) • SRSF2 (Serine and arginine rich splicing factor 2)
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RUNX1 mutation • ASXL1 mutation • SRSF2 mutation • KIT D816V
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Rydapt (midostaurin) • Ayvakit (avapritinib)
3ms
Mast Cell Leukemia: Clinical and Molecular Features and Survival Outcomes of Patients in the ECNM Registry. (PubMed, Blood Adv)
In multivariate analysis (S/A/R mutations excluded due to low event rates), a diagnosis of MCL-AHN (HR 4.7, 95% CI 1.7 - 13.0, p = 0.001) and abnormal karyotype (HR 5.6, 95% CI 1.4 - 13.3, p = 0.02) were associated with inferior OS; KIT D816V positivity (HR 0.33, 95% CI 0.11 - 0.98, p = 0.04) and midostaurin treatment (HR 0.32, 95% CI 0.08 - 0.72, p = 0.008) 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.
Journal
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KIT (KIT proto-oncogene, receptor tyrosine kinase) • ASXL1 (ASXL Transcriptional Regulator 1) • RUNX1 (RUNX Family Transcription Factor 1) • SRSF2 (Serine and arginine rich splicing factor 2)
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RUNX1 mutation • ASXL1 mutation • SRSF2 mutation • KIT D816V
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Rydapt (midostaurin)
3ms
Chlorpromazine cooperatively induces apoptosis with tyrosine kinase inhibitors in EGFR-mutated lung cancer cell lines and restores the sensitivity to gefitinib in T790M-harboring resistant cells. (PubMed, Biochem Biophys Res Commun)
When utilized in combination with trametinib (a MEK inhibitor), dabrafenib (an RAF inhibitor), and everolimus (an mTOR inhibitor), CPZ suppressed the growth of PC9ZD cells cooperatively with everolimus but not with trametinib or dabrafenib. However, after CPZ treatment, EGFR was unevenly distributed in the cells, and colocalization with the early endosome marker Rab5 and EEA1 became more apparent, indicating that CPZ disrupted the intracellular transport of EGFR. These results suggest that CPZ has therapeutic potential for NSCLC with mutated EGFR by a novel mechanism different from conventional TKIs alone or in combination with other agents.
Preclinical • Journal
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EGFR (Epidermal growth factor receptor) • FLT3 (Fms-related tyrosine kinase 3) • MET (MET proto-oncogene, receptor tyrosine kinase) • KIT (KIT proto-oncogene, receptor tyrosine kinase) • RAB5A (Ras-related protein Rab-5A)
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EGFR mutation • FLT3-ITD mutation • EGFR exon 19 deletion • EGFR T790M • MET amplification • KIT D816V
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Mekinist (trametinib) • Tafinlar (dabrafenib) • gefitinib • everolimus • chlorpromazine
3ms
Atypical Mast Cells With KIT Mutation May Be Overshadowed by Enteropathy-Associated T-Cell Lymphoma (CAP 2022)
EATL usually carries an aggressive course and a poor prognosis; how mastocytosis/c-Kit mutation affects the course and prognosis of EATL needs close follow-up. The mechanism of the occurrence of EATL and mastocytosis is unknown and needs further study.
IO biomarker
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KIT (KIT proto-oncogene, receptor tyrosine kinase) • CD20 (Membrane Spanning 4-Domains A1) • TNFRSF8 (TNF Receptor Superfamily Member 8) • IL2RA (Interleukin 2 receptor, alpha) • ALK1 (Activin A Receptor Like Type 1) • CD5 (CD5 Molecule) • NCAM1 (Neural cell adhesion molecule 1) • CD7 (CD7 Molecule) • ITGAE (Integrin Subunit Alpha E) • CD2 (CD2 Molecule)
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KIT mutation • KIT D816V
3ms
Atypical Mast Cells With KIT Mutation May Be Overshadowed by Enteropathy-Associated T-Cell Lymphoma (CAP 2022)
EATL usually carries an aggressive course and a poor prognosis; how mastocytosis/c-Kit mutation affects the course and prognosis of EATL needs close follow-up. The mechanism of the occurrence of EATL and mastocytosis is unknown and needs further study.
IO biomarker
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KIT (KIT proto-oncogene, receptor tyrosine kinase) • CD20 (Membrane Spanning 4-Domains A1) • TNFRSF8 (TNF Receptor Superfamily Member 8) • IL2RA (Interleukin 2 receptor, alpha) • ALK1 (Activin A Receptor Like Type 1) • CD5 (CD5 Molecule) • NCAM1 (Neural cell adhesion molecule 1) • CD7 (CD7 Molecule) • ITGAE (Integrin Subunit Alpha E) • CD2 (CD2 Molecule)
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KIT mutation • KIT D816V
5ms
Immunohistochemical Staining to Identify Concomitant Systemic Mastocytosis in Acute Myeloid Leukemia with RUNX1::RUNX1T1. (PubMed, Ann Lab Med)
Concomitant SM-AHN was not infrequent in AML patients with RUNX1::RUNX1T1. This study showed the importance of CD117 and CD25 IHC staining after induction chemotherapy for SM-AHN screening, especially in patients with KIT variants.
Journal
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KIT (KIT proto-oncogene, receptor tyrosine kinase) • RUNX1 (RUNX Family Transcription Factor 1) • RUNX1T1 (RUNX1 Partner Transcriptional Co-Repressor 1) • IL2RA (Interleukin 2 receptor, alpha)
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KIT D816V
5ms
Clinical • P2 data • Tumor Mutational Burden
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TMB (Tumor Mutational Burden)
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KIT mutation • KIT D816V • KIT exon 17 mutation
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bezuclastinib (PLX9486)
6ms
Clinical Impact and Proposed Application of Molecular Markers, Genetic Variants and Cytogenetic Analysis in Mast Cell Neoplasms: Status 2022. (PubMed, J Allergy Clin Immunol)
Moreover, HαT more frequent in SM patients with Hymenoptera venom allergy and severe mediator-related symptoms than in SM patients without symptoms. Based on this knowledge, we propose a diagnostic algorithm in which genetic markers are applied together with clinical and histopathological criteria to establish the diagnosis and prognosis in SM.
Journal
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KIT (KIT proto-oncogene, receptor tyrosine kinase) • JAK2 (Janus kinase 2) • ASXL1 (ASXL Transcriptional Regulator 1) • RUNX1 (RUNX Family Transcription Factor 1) • SRSF2 (Serine and arginine rich splicing factor 2)
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SRSF2 mutation • KIT D816V
7ms
Mast cell neoplasm: a challenging pathological diagnosis. (PubMed, Hum Pathol)
Despite limited resources, basically morphology and a restricted immunohistochemical panel, it is possible to diagnose mast cell neoplasm. Of note, pathologist should recognize the different morphological variants of the disease and include the adequate markers when requesting immunohistochemical studies.
Journal
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KIT (KIT proto-oncogene, receptor tyrosine kinase)
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KIT mutation • KIT D816V • Chr t(15;17)
7ms
RESPONSES TO AVAPRITINIB IN PATIENTS WITH ADVANCED SYSTEMIC MASTOCYTOSIS: HISTOPATHOLOGIC ANALYSES FROM EXPLORER AND PATHFINDER CLINICAL STUDIES (EHA 2022)
This was accompanied by an improvement of fibrosis and a decrease in circulating MCs . These improvements in disease histopathology provide further support that treatment with this highly selective and potent KIT D816V inhibitor i s disease modifying in AdvSM .
Clinical
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TNFRSF8 (TNF Receptor Superfamily Member 8) • IL2RA (Interleukin 2 receptor, alpha)
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KIT mutation • KIT D816V
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Ayvakit (avapritinib)
7ms
A PHASE 2 STUDY OF BEZUCLASTINIB (CGT9486), A NOVEL, HIGHLY SELECTIVE, POTENT KIT D816V INHIBITOR, IN ADULTS WITH ADVANCED SYSTEMIC MASTOCYTOSIS (APEX): METHODS, BASELINE DATA, AND EARLY INSIGHTS (EHA 2022)
Part 1 of the Apex study aims to determine the optimal dose to further evaluate in Part 2. Early insights into the safety and tolerability profile and biomarker data will further inform clinical development of bezuclastinib in AdvSM.
Clinical • P2 data • Tumor Mutational Burden
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TMB (Tumor Mutational Burden) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • PDGFRB (Platelet Derived Growth Factor Receptor Beta) • CSF1R (Colony stimulating factor 1 receptor)
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KIT mutation • KIT D816V • KIT exon 17 mutation
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bezuclastinib (PLX9486)
7ms
CLINICOPATHOLOGIC AND MOLECULAR CORRELATES OF ORGAN DAMAGE ACROSS THE SPECTRUM OF ADVANCED SYSTEMIC MASTOCYTOSIS (EHA 2022)
Methods Our cohort included 244 AdvSM pts: 68 pts from our Stanford IRB-approved MPN registry and 176 pts from the phase I EXPLORER (NCT02561988) and phase II PATHFINDER (NCT03580655) studies of avapritinib in AdvSM...The median number of prior anti-neoplastic therapies was 1 (range, 0-6), with 87 pts (36%) previously treated with midostaurin...Conclusion In AdvSM, patterns of organ damage reflect disease subtype, prior therapy, and mutation profile beyond KIT D816V ( Figure ). These data can help inform the clinical heterogeneity of AdvSM patients who are being evaluated for clinical trials which currently require 1 or more organ damage findings defined by the WHO or (m)IWG criteria.
Clinical
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ASXL1 (ASXL Transcriptional Regulator 1) • RUNX1 (RUNX Family Transcription Factor 1) • SRSF2 (Serine and arginine rich splicing factor 2)
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KIT mutation • RUNX1 mutation • ASXL1 mutation • SRSF2 mutation • KIT D816V
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Rydapt (midostaurin) • Ayvakit (avapritinib)
7ms
DURATION OF TREATMENT AND REDUCTION IN SERUM TRYPTASE LEVELS IN PATIENTS WITH ADVANCED SYSTEMIC MASTOCYTOSIS TREATED WITH AVAPRITINIB VERSUS BEST AVAILABLE THERAPY (EHA 2022)
Among 188 BAT LOTs with agent-level data available, most common treatments were midostaurin (53%) and cladribine (24%). Conclusion AdvSM patients treated with avapritinib experienced significantly longer DOT and greater reduction in serum tryptase levels compared to patients treated with BAT. In the absence of RCTs, these data offer important and meaningful insight into the improved effectiveness of avapritinib compared to alternative therapies for AdvSM.
Clinical
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ASXL1 (ASXL Transcriptional Regulator 1) • RUNX1 (RUNX Family Transcription Factor 1) • SRSF2 (Serine and arginine rich splicing factor 2)
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RUNX1 mutation • ASXL1 mutation • SRSF2 mutation • KIT D816V
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Rydapt (midostaurin) • cladribine • Ayvakit (avapritinib)
7ms
SUCCESSFUL OUTCOME OF A PATIENT WITH ADVANCED SYSTEMIC MASTOCYTOSIS TREATED WITH AZACYTIDINE AND AVAPRITINIB: A CASE REPORT (EHA 2022)
The patient can be considered for an allogeniec bone marrow transplant as a curative treatment. International trials with sequential/combination therapy for patients with AdvSM in the new era of targeted C-KIT inhibitors will inform better treatment decisions for patients with SM-AHN.
Clinical
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JAK2 (Janus kinase 2) • TET2 (Tet Methylcytosine Dioxygenase 2) • SRSF2 (Serine and arginine rich splicing factor 2) • IL2RA (Interleukin 2 receptor, alpha) • CD34 (CD34 molecule) • CD14
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KIT mutation • TET2 mutation • SRSF2 mutation • JAK2 V617F • KIT D816V
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azacitidine • Ayvakit (avapritinib)
8ms
Midostaurin therapy for advanced systemic mastocytosis: Mayo Clinic experience in 33 consecutive cases. (PubMed, Am J Hematol)
Eleven (33%) patients were previously treated with other cytoreductive drugs, including cladribine (n = 4) and imatinib (n = 3). Median survival was longer in midostaurin responders but not significantly (median 26.5 vs 16?months; p = 0.15). Findings from the current study are broadly consistent with previously published clinical trial observations.
Retrospective data • Journal
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KIT (KIT proto-oncogene, receptor tyrosine kinase)
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KIT mutation • KIT D816V
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imatinib • Rydapt (midostaurin) • cladribine
8ms
(EXPLORER) Study of BLU-285 in Patients With Advanced Systemic Mastocytosis (AdvSM) and Relapsed or Refractory Myeloid Malignancies (clinicaltrials.gov)
P1, N=80, Active, not recruiting, Blueprint Medicines Corporation | Trial completion date: Dec 2021 --> Oct 2022 | Trial primary completion date: Nov 2021 --> Sep 2022
Trial completion date • Trial primary completion date
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KIT (KIT proto-oncogene, receptor tyrosine kinase)
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KIT D816V
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Ayvakit (avapritinib)
8ms
(PATHFINDER) Study to Evaluate Efficacy and Safety of Avapritinib (BLU-285), A Selective KIT Mutation-targeted Tyrosine Kinase Inhibitor, in Patients With Advanced Systemic Mastocytosis (clinicaltrials.gov)
P2, N=103, Active, not recruiting, Blueprint Medicines Corporation | Trial completion date: May 2022 --> Jan 2026 | Trial primary completion date: May 2022 --> Jan 2026
Trial completion date • Trial primary completion date
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TMB (Tumor Mutational Burden) • KIT (KIT proto-oncogene, receptor tyrosine kinase)
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KIT mutation • KIT D816V
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Ayvakit (avapritinib)
9ms
Bezuclastinib is a differentiated KIT inhibitor that exhibits unique selectivity to KIT A-loop mutations, minimal brain penetration, and favorable pharmacokinetic properties in preclinical models (AACR 2022)
Second-line sunitinib is active against exon 13/14 mutations but not A-loop mutations and identifying inhibitors that target the spectrum of possible mutations without incurring off-target toxicities related to broad-spectrum kinase inhibition has been challenging. This attractive selectivity and nonclinical safety profile, combined with early clinical data in advanced solid tumors, supports the potential for a best-in-class KIT inhibitor. Bezuclastinib is currently under clinical investigation in advanced SM (Phase 2, Apex NCT04996875), non-advanced SM (Phase 2, Summit), and imatinib-resistant GIST (Phase 3, Peak).
PK/PD data • Preclinical
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PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • KDR (Kinase insert domain receptor) • PDGFRB (Platelet Derived Growth Factor Receptor Beta) • CSF1R (Colony stimulating factor 1 receptor)
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KIT mutation • KIT D816V
|
imatinib • Sutent (sunitinib) • bezuclastinib (PLX9486)
10ms
Mast cell sarcoma: clinicopathologic and molecular analysis of 10 new cases and review of literature. (PubMed, Mod Pathol)
Taken together, there are no standardized therapeutic regimens available for MCS at this time, and the prognosis is dismal. Therefore, it is critical to further investigate and characterize this rare entity, with the hope of improving diagnostic accuracy and providing more effective, targeted therapies.
Review • Journal
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KIT (KIT proto-oncogene, receptor tyrosine kinase) • TNFRSF8 (TNF Receptor Superfamily Member 8) • IL2RA (Interleukin 2 receptor, alpha) • CD33 (CD33 Molecule) • CD68 (CD68 Molecule) • CD2 (CD2 Molecule) • SPN (Sialophorin)
|
KIT mutation • KIT D816V
11ms
The Prognostic Significance of c-KIT Mutations in Core Binding Factor Acute Myeloid Leukemia. (PubMed, Clin Lymphoma Myeloma Leuk)
According to our study, the results may suggest c-KIT mutation as a poor risk factor in pediatric CBF-AML.
Journal
|
KIT (KIT proto-oncogene, receptor tyrosine kinase)
|
KIT mutation • KIT D816V • KIT exon 17 mutation • KIT exon 8 mutation
12ms
Precision Medicine in Systemic Mastocytosis. (PubMed, Medicina (Kaunas))
Allogeneic stem cell transplant (SCT) may be considered in selected SM cases. Here, we review the clinical, diagnostic, and therapeutic issues of SM, with special emphasis on the translational implications of SM genetics for a precision medicine approach in clinical practice.
Review • Journal
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IL2RA (Interleukin 2 receptor, alpha)
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KIT mutation • KIT D816V • IL2RA expression
1year
Genomic Analysis Focusing on RUNX1-RUNX1T1 in Japanese Patients with AML: HM-Screen-Japan 01 (ASH 2021)
AML with RUNX1-RUNX1T1 fusion gene is currently not indicated for transplantation in the first remission. Previous studies have demonstrated that approximately 30% of patients with CBF-AML harbored the KIT mutations at diagnosis, which might be an indicator of poor prognosis. In our study, the KIT mutations were detected much more frequently than in previously studies of newly-diagnosed CBF-AML.
Clinical
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FLT3 (Fms-related tyrosine kinase 3) • JAK2 (Janus kinase 2) • RUNX1 (RUNX Family Transcription Factor 1) • RUNX1T1 (RUNX1 Partner Transcriptional Co-Repressor 1)
|
FLT3 mutation • FLT3 D835Y • FLT3 D835 • KIT N822K • JAK2 V617F • KIT D816V • JAK2 mutation • RUNX1-RUNX1T1 fusion
|
FoundationOne® Heme CDx
1year
Possible Early Clinical Management of Systemic Mastocytosis Patients with Recently FDA Approved Drug Avapritinib By Molecular Diagnosis Using a Highly Sensitive KIT D816 Mutation Assay (ASH 2021)
It is important to have a highly sensitive KIT D816 mutation analysis assay to detect low levels of KIT D816 allele burden that may be present in blood or bone marrow especially at early stage disease. Our highly sensitive laboratory developed KIT D816 assay based on allele specific PCR with a limit of detection of 0.25% could help physicians identify SM patients and clinically manage the disease.
Clinical • FDA event
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KIT (KIT proto-oncogene, receptor tyrosine kinase)
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KIT mutation • KIT D816V
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Ayvakit (avapritinib)
1year
Preclinical Data with KIT D816V Inhibitor Bezuclastinib (CGT9486) Demonstrates High Selectivity and Minimal Brain Penetrance (ASH 2021)
This attractive selectivity and nonclinical safety profile, combined with early clinical data in advanced solid tumors (Trent et al, 2020), supports the potential for a best-in-class KIT inhibitor. Bezuclastinib is currently under clinical investigation in advanced SM with additional clinical studies planned in non-advanced SM and imatinib-resistant GIST.
Preclinical
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PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • KDR (Kinase insert domain receptor) • PDGFRB (Platelet Derived Growth Factor Receptor Beta) • CSF1R (Colony stimulating factor 1 receptor)
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KIT mutation • KIT D816V
|
imatinib • bezuclastinib (PLX9486)
1year
A Phase 2 Study of Bezuclastinib (CGT9486), an Oral, Selective, and Potent KIT D816V Inhibitor, in Adult Patients with Advanced Systemic Mastocytosis (AdvSM) (ASH 2021)
Data from this study will support continued development of bezuclastinib in SM including Non-Advanced SM. This study opened in June 2021.
Clinical • P2 data • Tumor Mutational Burden
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TMB (Tumor Mutational Burden) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • KDR (Kinase insert domain receptor) • PDGFRB (Platelet Derived Growth Factor Receptor Beta) • CSF1R (Colony stimulating factor 1 receptor)
|
KIT mutation • KIT D816V • KIT exon 17 mutation
|
bezuclastinib (PLX9486)
1year
‘Application of Prognostic Scoring in Systemic Mastocytosis Patients within a UK Centre of Excellence: Guys and St Thomas’ NHS Foundation Trust.’ (ASH 2021)
Both are alive to date having received the KIT inhibitor avapritinib, with one continuing on this treatment... Application of the IPSM and MARS prognostic scores to our data reflects findings of other groups with better outcomes seen in non-AdvSM compared to AdvSM patients. Furthermore, although our AdvSM cohort is small, the presence of adverse risk factors could be overcome through recent advances in treatments and consolidation with stem cell transplant. Hence, identification of high-risk patients using these prognostic scores can direct targeted first-line therapy and improve outcomes.
Clinical
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ASXL1 (ASXL Transcriptional Regulator 1) • RUNX1 (RUNX Family Transcription Factor 1) • SRSF2 (Serine and arginine rich splicing factor 2)
|
KIT mutation • SRSF2 mutation • KIT D816V
|
Ayvakit (avapritinib)
1year
Cladribine Therapy for Advanced and Indolent Systemic Mastocytosis: Mayo Clinic Experience in 42 Consecutive Cases (ASH 2021)
Current drug therapy for SM is primarily directed at reversing C findings or alleviating symptoms/UP, and includes cladribine, midostaurin, and avapritinib. Conclusions : The current study confirms the favorable side effect profile and long-term safety of cladribine as a first-line drug of choice for both indolent and advanced SM. Response to cladribine therapy was evident in all aspects of the disease, including MC-associated organopathy, UP, MC-MSs, serum tryptase level and bone marrow MC burden.
Clinical
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KIT (KIT proto-oncogene, receptor tyrosine kinase) • TPSAB1 (Tryptase Alpha/Beta 1)
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KIT mutation • KIT D816V
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Rydapt (midostaurin) • cladribine • Ayvakit (avapritinib)
1year
A 3-Part, Phase 2 Study of Bezuclastinib (CGT9486), an Oral, Selective, and Potent KIT D816V Inhibitor, in Adult Patients with Nonadvanced Systemic Mastocytosis (NonAdvSM) (ASH 2021)
The study will enroll approximately 138 subjects. Data from this study will support further development of bezuclastinib in SM.
Clinical • P2 data • Tumor Mutational Burden
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TMB (Tumor Mutational Burden) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • KDR (Kinase insert domain receptor) • PDGFRB (Platelet Derived Growth Factor Receptor Beta) • CSF1R (Colony stimulating factor 1 receptor)
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KIT mutation • KIT D816V • KIT exon 17 mutation
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bezuclastinib (PLX9486)