Avapritinib monotherapy induces rapid and deep remission of heavily treated, KIT D816H-mutated t(8;21) acute myeloid leukemia

Avapritinib monotherapy induces rapid and deep remission of heavily treated, KIT D816H-mutated t(8;21) acute myeloid leukemia | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Avapritinib monotherapy induces rapid and deep remission of heavily treated, KIT D816H-mutated t(8;21) acute myeloid leukemia Ted M. Getz, Kamila Bakirhan, Stuart Seropian, Rory M. Shallis This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5932205/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 27 Jun, 2025 Read the published version in Annals of Hematology → Version 1 posted 7 You are reading this latest preprint version Abstract Acute myeloid leukemia (AML) with t(8;21) is a subset of core binding factor AML and is considered to be favorable risk disease in patients receiving intensive cytarabine based chemotherapy. However, relapse remains a significant clinical challenge. Mutations in KIT , which frequently co-occur in t(8;21) AML, have been associated with worse relapse free and overall survival. Avapritinib is a novel tyrosine kinase inhibitor targeting KIT mutations that is currently approved for systemic mastocytosis but doesn’t currently have an established role in the treatment of AML. Here we report the case of a patient with heavily treated KIT D816H-mutated t(8;21) AML that relapsed following allogeneic hematopoietic stem cell transplant who received avapritinib monotherapy with rapid induction of a deep remission. This case highlights the potential role of avapritinib as a targeted therapy for relapsed t(8;21) AML with KIT mutations, warranting further clinical investigation. Acute Myeloid Leukemia KIT mutations t(8 21) Avapritinib Figures Figure 1 Introduction Approximately 7% of acute myeloid leukemia (AML) harbors t(8;21), a core binding factor (CBF) lesion that leads to the RUNX1/RUNX1T1 (AML1/ETO) fusion gene and consequently the translation of an abnormal transcription factor that induces leukemogenesis [1]. Although AML with t(8;21) is over-represented in younger patients with AML and is associated with excellent response to cytarabine based chemotherapy and a favorable prognosis, 40–50% of patients will relapse with chemotherapy alone [2]. Furthermore, AML with t(8;21) frequently harbors mutations in KIT that lead to constitutive KIT activation, mediate activation of downstream signaling pathways involved in cell proliferation, differentiation, and survival, including the PI3K, JAK/STAT, MAPK, and Src kinase pathways, ultimately associating in some studies with inferior relapse free survival and overall survival (OS) [3–5]. KIT inhibitors have been studied in AML, namely the non-selective KIT inhibitor dasatinib in combination with standard intensive induction therapy for KIT- mutated CBF-AML and has yielded encouraging results [6, 7]. However, robust data for the use of gemtuzumab ozogamicin for CBF-AML and the lack of randomized data in support of a true benefit for KIT inhibition has limited broad uptake of this approach. More selective and potent KIT inhibitors are now available, including avapritinib, which is currently approved for the treatment of advanced systemic mastocytosis based on the results of the PATHFINDER and EXPLORER trials [8, 9]. These data provide the rationale for the use of avapritinib for use in the management of KIT -mutated AML. Here we describe the case of a 31-year-old female with AML harboring t(8;21) and a KIT D816H mutation that relapsed following allogeneic hematopoietic stem cell transplant (alloHSCT) and was successfully treated with avapritinib monotherapy. Patient Presentation A 31-year-old woman presented with cough, fever, weakness, and menorrhagia. She was found to have a white blood cell (WBC) count of 23k/uL with 67% circulating blasts, anemia (hemoglobin 2.7 g/dL), and thrombocytopenia (platelet 37k/uL). A bone marrow evaluation revealed a hypercellular marrow (90%) with 69% blasts that were CD33+. Fluorescence in situ hybridization (FISH) revealed t(8;21) and 4 copies of KMT2A in 12% of cells. Polymerase chain reaction (PCR) for AML-ETO was not sent at this time. Next generation sequencing (NGS) revealed a KIT D816H mutation with a variant allele frequency (VAF) of 44%. The patient was induced with 7 + 3 with gemtuzumab ozogamicin and achieved a complete remission (CR) with FISH negative for t(8;21), although PCR still positive for AML-ETO transcripts (Fig. 1 ). After 2 cycles of high dose cytarabine (HiDAC) consolidation peripheral blood was negative for AML-ETO by PCR and KIT by NGS. However, AML-ETO was re-detected by PCR after second cycle of HiDAC and she ultimately underwent a matched related donor alloHSCT from her sister with myeloablative conditioning with busulfan and fludarabine. Bone marrow evaluations on day + 30, +90, and + 180 showed continued remission with t(8;21) negative by FISH as well as AML-ETO negative by PCR and KIT negative by PCR and NGS. However, on day + 193 post-alloHSCT, 2% blasts were detectable in peripheral blood with t(8;21) and KIT D816H (VAF of 21%) also re-detected by NGS. A bone marrow evaluation was deferred as peripheral blood blasts rapidly increased to 60%. Relapsed/refractory therapy was initially deferred for infection(s), but on day + 263 she eventually started azacitidine and venetoclax. A post-cycle 1 marrow revealed a hypercellular marrow (40–50% cellular) with 10% blasts on an aspirate cell count. Persistent AML was likewise revealed after a cycle 2 marrow aspirate with 7–10% blasts and was considered for 3rd line therapy. Avapritinib 100 mg daily was started a and bone marrow biopsy 30 days later revealed CR without measurable residual disease by flow, PCR for AML-ETO and NGS for KIT. This favorable response allowed a second alloHSCT from a matched unrelated donor after fludarabine and melphalan with post-transplant cyclophosphamide. She continues to do relatively well 100 days after second alloHSCT with stage 2 grade 1 cutaneous and suspected mild liver graft- versus -host disease improving on only low-dose tacrolimus, but with most recent marrow evaluation confirming continued CR with FISH and molecular MRD-negativity as well as 100% donor chimerism. Discussion/Literature Review KIT mutations are present in 20–45% of patients with CBF-AML, including nearly half of patients with AML with t(8;21) and represents a promising target in AML [10]. Based on the activity of avapritinib for KIT D816V-mutated advanced systemic mastocytosis and case reports of efficacy in hematologic malignancies, the patient was treated with avapritinib [11, 12]. This led to a molecular-MRD-negative CR and the ability to proceed to a curative intent second alloHSCT. On review of the literature, we were able to find four additional case reports or case series of patients with AML with t(8;21) and KIT mutation who were treated with avapritinib, although the largest (n = 20) was restricted to use as a post-alloHSCT MRD-directed therapy, a minority (n = 3) of patients for whom avapritinib was used in overt relapse, and none of which received avapritinib monotherapy (Table 1 ) [12–14]. Our patient is the only one in the available literature that has achieved an MRD-negative CR with avapritinib monotherapy in the relapsed/refractory setting, including after venetoclax exposure/failure, a situation notorious for lack of efficacy with subsequent therapy. Table 1 Case Reports of Avapritinib Used in Patients with AML Population KIT Mutation Sex Age Range Number of Patients Therapy Response Reference MRD positive AML with t(8;21) and KIT mutation after AlloHSCT 50% D816, 20% N822, 10% D816 + N822, and 20% other 15 men and 5 women 4 to 41 Years (2 ≤ 18 years and 18 ≥ 18 years) 20 Avapritinib 100mg daily if weight ≥ 50kg and 50mg daily if weight < 50kg 20% became MRD negative; 25% with ≥ 2 log reduction in t(3;21) transcript; 60% with ≥ 1 log reduction in t(3;21) transcript. Kong et al. 2023 1 AML with t(8;21) and KIT mutation relapsed after AlloHSCT D816I Women 8 years old 1 Avapritinib 200mg daily t(8;21) negativity achieved 42 days after starting treatment. Xue et al. 2022 2 Relapsed/Refractory AML with t(8;21) and KIT mutation previously treated with intensive chemotherapy 50% D816V and 50% D816Y 3 men and 1 women 19 to 52 years old 4 Avapritinib 100mg daily + Venetoclax; Avapritinib 15mg daily + Azacitidine + Venetoclax; Avapritinib 200mg in 2 patients 2 MRD negative complete remission and 2 MRD positive complete remissions Yin et al. 2022 3 AML with t(8;21) and KIT mutation after AlloHSCT MRD positive or MRD negative 33% N822I, 17% D816Y, 50% exon 17 5 men and 1 women 4 to 12 years old 6; 4 MRD positive and 2 MRD negative Avapritinib 25-100mg daily 3 of 4 patients who were MRD positive converted to MRD negative. 2 RMD negative patients remained MRD negative Wang et al. 2023 4 Avapritinib appears to be a promising agent for the treatment of KIT -mutated CBF-AML with a well-studied and favorable safety profile. The response in this case clearly illustrates a need for further study. There are two ongoing phase II clinical trials in China evaluating avapritinib in relapsed/refractory KIT -mutated AML (NCT05821738 and NCT05821738), although there are no trials open with in the United States (US). We hope this informative case, believed to be the first of reported use of avapritinib for AML in the US, empowers providers to consider its use for similar patients who have no true standard of care in the relapsed/refractory setting that often requires the administration of therapies with less attractive risk:benefit profiles. Declarations Competing Interest Statement RMS had a consultancy with Bristol Myers Squibb, Curio Science, Gilead Sciences, Kura Oncology, Servier, and Rigel and served in Steering Committees for Servier Ethics and Consent to Publish Declarations : No funding was received for conducting this study. RMS had a consultancy with Bristol Myers Squibb, Curio Science, Gilead Sciences, Kura Oncology, Servier, and Rigel and served in Steering Committees for Servier. TMG, KB, and SS have no relevant financial or non-financial interests to disclose. The participant has consented to the submission of the case report to the journal. This case report adheres to the ethical standards set by Yale New Haven Hospital. Author Contribution TMG and RMS conceptualized this article, wrote the original draft, and prepared the figures. KB, SS, and RMS were involved in reviewing and editing. References Borthakur G, Kantarjian H (2021) Core binding factor acute myelogenous leukemia-2021 treatment algorithm. Blood Cancer J 11:114. https://doi.org/10.1038/S41408-021-00503-6 Grimwade D, Hills RK, Moorman A V., et al (2010) Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood 116:354–365. https://doi.org/10.1182/BLOOD-2009-11-254441 Ishikawa Y, Group for the JALS, Kawashima N, et al (2020) Prospective evaluation of prognostic impact of KIT mutations on acute myeloid leukemia with RUNX1-RUNX1T1 and CBFB-MYH11. Blood Adv 4:66–75. https://doi.org/10.1182/BLOODADVANCES.2019000709 Christen F, Hoyer K, Yoshida K, et al (2019) Genomic landscape and clonal evolution of acute myeloid leukemia with t(8;21): an international study on 331 patients. Blood 133:1140–1151. https://doi.org/10.1182/BLOOD-2018-05-852822 Katagiri S, Chi S, Minami Y, et al (2022) Mutated KIT Tyrosine Kinase as a Novel Molecular Target in Acute Myeloid Leukemia. Int J Mol Sci 23:. https://doi.org/10.3390/IJMS23094694/S1 Paschka P, Schlenk RF, Weber D, et al (2018) Adding dasatinib to intensive treatment in core-binding factor acute myeloid leukemia—results of the AMLSG 11 − 08 trial. Leukemia 2018 32:7 32:1621–1630. https://doi.org/10.1038/s41375-018-0129-6 Marcucci G, Geyer S, Laumann K, et al (2020) Combination of dasatinib with chemotherapy in previously untreated core binding factor acute myeloid leukemia: CALGB 10801. Blood Adv 4:696–705. https://doi.org/10.1182/BLOODADVANCES.2019000492 DeAngelo DJ, Radia DH, George TI, et al (2021) Safety and efficacy of avapritinib in advanced systemic mastocytosis: the phase 1 EXPLORER trial. Nature Medicine 2021 27:12 27:2183–2191. https://doi.org/10.1038/s41591-021-01538-9 Gotlib J, Reiter A, Radia DH, et al (2021) Efficacy and safety of avapritinib in advanced systemic mastocytosis: interim analysis of the phase 2 PATHFINDER trial. Nature Medicine 2021 27:12 27:2192–2199. https://doi.org/10.1038/s41591-021-01539-8 Shafik NF, Ibraheem D, Selim MM, et al (2022) The Prognostic Significance of c-KIT Mutations in Core Binding Factor Acute Myeloid Leukemia. Clin Lymphoma Myeloma Leuk 22:e363–e375. https://doi.org/10.1016/J.CLML.2021.11.015 Sandow L, Heinrich M (2023) Avapritinib treatment of KIT D816V-mutant atypical chronic myeloid leukemia. Leuk Res Rep 19:100371. https://doi.org/10.1016/J.LRR.2023.100371 Yin J, Zhu F, Zhang ZB, et al (2022) Rapid and deep response to avapritinib in heavily treated acute myeloid leukemia with t (8;21) and KIT mutation. Ann Hematol 101:. https://doi.org/10.1007/S00277-022-04897-6 Kong J, Zheng FM, Wang ZD, et al (2023) Avapritinib is effective for treatment of minimal residual disease in acute myeloid leukemia with t (8;21) and kit mutation failing to immunotherapy after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 58:777–783. https://doi.org/10.1038/S41409-023-01973-X Xue S, Huang W, Liu F, et al (2022) Rapid response to avapritinib of acute myeloid leukemia with t(8;21) and KIT mutation relapse post allo-HSCT. Leuk Lymphoma 63:2247–2250. https://doi.org/10.1080/10428194.2022.2064994 Additional Declarations Competing interest reported. RMS had a consultancy with Bristol Myers Squibb, Curio Science, Gilead Sciences, Kura Oncology, Servier, and Rigel and served in Steering Committees for Servier Cite Share Download PDF Status: Published Journal Publication published 27 Jun, 2025 Read the published version in Annals of Hematology → Version 1 posted Editorial decision: Revision requested 09 Mar, 2025 Reviews received at journal 24 Feb, 2025 Reviewers agreed at journal 20 Feb, 2025 Reviewers invited by journal 20 Feb, 2025 Editor assigned by journal 12 Feb, 2025 Submission checks completed at journal 12 Feb, 2025 First submitted to journal 30 Jan, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5932205","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":414774547,"identity":"4b78f9ee-a978-444c-bb15-f35c6942c9ed","order_by":0,"name":"Ted M. 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Shallis","email":"","orcid":"","institution":"Yale Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Rory","middleName":"M.","lastName":"Shallis","suffix":""}],"badges":[],"createdAt":"2025-01-30 18:53:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5932205/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5932205/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00277-025-06388-w","type":"published","date":"2025-06-27T15:57:12+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":76297660,"identity":"4f4e902b-6d6b-4707-a1ae-bf960537ee99","added_by":"auto","created_at":"2025-02-14 13:29:27","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":161963,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003e(A)\u003c/strong\u003e Percent of cells with t(8;21) by PCR over time and \u003cstrong\u003e(B)\u003c/strong\u003e Variant alle frequency of KIT over time\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-5932205/v1/15f42ce1c1ff15ffb92c6035.jpeg"},{"id":85686110,"identity":"68d52fdd-b0a5-4874-9641-93882b13ecce","added_by":"auto","created_at":"2025-06-30 16:03:29","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":537420,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5932205/v1/e1697a96-5766-47fd-af6d-4c10d63b2d0b.pdf"}],"financialInterests":"Competing interest reported. RMS had a consultancy with Bristol Myers Squibb, Curio Science, Gilead Sciences, Kura Oncology, Servier, and Rigel and served in Steering Committees for Servier","formattedTitle":"Avapritinib monotherapy induces rapid and deep remission of heavily treated, KIT D816H-mutated t(8;21) acute myeloid leukemia","fulltext":[{"header":"Introduction","content":"\u003cp\u003eApproximately 7% of acute myeloid leukemia (AML) harbors t(8;21), a core binding factor (CBF) lesion that leads to the RUNX1/RUNX1T1 (AML1/ETO) fusion gene and consequently the translation of an abnormal transcription factor that induces leukemogenesis [1]. Although AML with t(8;21) is over-represented in younger patients with AML and is associated with excellent response to cytarabine based chemotherapy and a favorable prognosis, 40\u0026ndash;50% of patients will relapse with chemotherapy alone [2]. Furthermore, AML with t(8;21) frequently harbors mutations in \u003cem\u003eKIT\u003c/em\u003e that lead to constitutive KIT activation, mediate activation of downstream signaling pathways involved in cell proliferation, differentiation, and survival, including the PI3K, JAK/STAT, MAPK, and Src kinase pathways, ultimately associating in some studies with inferior relapse free survival and overall survival (OS) [3\u0026ndash;5].\u003c/p\u003e \u003cp\u003eKIT inhibitors have been studied in AML, namely the non-selective KIT inhibitor dasatinib in combination with standard intensive induction therapy for \u003cem\u003eKIT-\u003c/em\u003emutated CBF-AML and has yielded encouraging results [6, 7]. However, robust data for the use of gemtuzumab ozogamicin for CBF-AML and the lack of randomized data in support of a true benefit for KIT inhibition has limited broad uptake of this approach. More selective and potent KIT inhibitors are now available, including avapritinib, which is currently approved for the treatment of advanced systemic mastocytosis based on the results of the PATHFINDER and EXPLORER trials [8, 9]. These data provide the rationale for the use of avapritinib for use in the management of \u003cem\u003eKIT\u003c/em\u003e-mutated AML. Here we describe the case of a 31-year-old female with AML harboring t(8;21) and a \u003cem\u003eKIT\u003c/em\u003e D816H mutation that relapsed following allogeneic hematopoietic stem cell transplant (alloHSCT) and was successfully treated with avapritinib monotherapy.\u003c/p\u003e"},{"header":"Patient Presentation","content":"\u003cp\u003eA 31-year-old woman presented with cough, fever, weakness, and menorrhagia. She was found to have a white blood cell (WBC) count of 23k/uL with 67% circulating blasts, anemia (hemoglobin 2.7 g/dL), and thrombocytopenia (platelet 37k/uL). A bone marrow evaluation revealed a hypercellular marrow (90%) with 69% blasts that were CD33+. Fluorescence \u003cem\u003ein situ\u003c/em\u003e hybridization (FISH) revealed t(8;21) and 4 copies of \u003cem\u003eKMT2A\u003c/em\u003e in 12% of cells. Polymerase chain reaction (PCR) for AML-ETO was not sent at this time. Next generation sequencing (NGS) revealed a \u003cem\u003eKIT\u003c/em\u003e D816H mutation with a variant allele frequency (VAF) of 44%.\u003c/p\u003e \u003cp\u003eThe patient was induced with 7 + 3 with gemtuzumab ozogamicin and achieved a complete remission (CR) with FISH negative for t(8;21), although PCR still positive for AML-ETO transcripts (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). After 2 cycles of high dose cytarabine (HiDAC) consolidation peripheral blood was negative for AML-ETO by PCR and \u003cem\u003eKIT\u003c/em\u003e by NGS. However, AML-ETO was re-detected by PCR after second cycle of HiDAC and she ultimately underwent a matched related donor alloHSCT from her sister with myeloablative conditioning with busulfan and fludarabine. Bone marrow evaluations on day + 30, +90, and + 180 showed continued remission with t(8;21) negative by FISH as well as AML-ETO negative by PCR and \u003cem\u003eKIT\u003c/em\u003e negative by PCR and NGS.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eHowever, on day + 193 post-alloHSCT, 2% blasts were detectable in peripheral blood with t(8;21) and \u003cem\u003eKIT\u003c/em\u003e D816H (VAF of 21%) also re-detected by NGS. A bone marrow evaluation was deferred as peripheral blood blasts rapidly increased to 60%. Relapsed/refractory therapy was initially deferred for infection(s), but on day + 263 she eventually started azacitidine and venetoclax. A post-cycle 1 marrow revealed a hypercellular marrow (40–50% cellular) with 10% blasts on an aspirate cell count. Persistent AML was likewise revealed after a cycle 2 marrow aspirate with 7–10% blasts and was considered for 3rd line therapy.\u003c/p\u003e \u003cp\u003eAvapritinib 100 mg daily was started a and bone marrow biopsy 30 days later revealed CR without measurable residual disease by flow, PCR for AML-ETO and NGS for \u003cem\u003eKIT.\u003c/em\u003e This favorable response allowed a second alloHSCT from a matched unrelated donor after fludarabine and melphalan with post-transplant cyclophosphamide. She continues to do relatively well 100 days after second alloHSCT with stage 2 grade 1 cutaneous and suspected mild liver graft-\u003cem\u003eversus\u003c/em\u003e-host disease improving on only low-dose tacrolimus, but with most recent marrow evaluation confirming continued CR with FISH and molecular MRD-negativity as well as 100% donor chimerism.\u003c/p\u003e "},{"header":"Discussion/Literature Review","content":"\u003cp\u003e \u003cem\u003eKIT\u003c/em\u003e mutations are present in 20–45% of patients with CBF-AML, including nearly half of patients with AML with t(8;21) and represents a promising target in AML [10]. Based on the activity of avapritinib for \u003cem\u003eKIT\u003c/em\u003e D816V-mutated advanced systemic mastocytosis and case reports of efficacy in hematologic malignancies, the patient was treated with avapritinib [11, 12]. This led to a molecular-MRD-negative CR and the ability to proceed to a curative intent second alloHSCT.\u003c/p\u003e\u003cp\u003eOn review of the literature, we were able to find four additional case reports or case series of patients with AML with t(8;21) and \u003cem\u003eKIT\u003c/em\u003e mutation who were treated with avapritinib, although the largest (n = 20) was restricted to use as a post-alloHSCT MRD-directed therapy, a minority (n = 3) of patients for whom avapritinib was used in overt relapse, and none of which received avapritinib monotherapy (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) [12–14]. Our patient is the only one in the available literature that has achieved an MRD-negative CR with avapritinib monotherapy in the relapsed/refractory setting, including after venetoclax exposure/failure, a situation notorious for lack of efficacy with subsequent therapy.\u003c/p\u003e\u003cp\u003e \u003c/p\u003e\u003cdiv class=\"gridtable\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCase Reports of Avapritinib Used in Patients with AML\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e\u003ccolgroup cols=\"8\"\u003e\u003c/colgroup\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePopulation\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eKIT Mutation\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAge Range\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNumber of Patients\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eTherapy\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eResponse\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMRD positive AML with t(8;21) and KIT mutation after AlloHSCT\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e50% D816, 20% N822, 10% D816 + N822, and 20% other\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 men and 5 women\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 to 41 Years (2 ≤ 18 years and 18 ≥ 18 years)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAvapritinib 100mg daily if weight ≥ 50kg and 50mg daily if weight \u0026lt; 50kg\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e20% became MRD negative; 25% with ≥ 2 log reduction in t(3;21) transcript; 60% with ≥ 1 log reduction in t(3;21) transcript.\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eKong et al. 2023\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAML with t(8;21) and KIT mutation relapsed after AlloHSCT\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eD816I\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eWomen\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 years old\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAvapritinib 200mg daily\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003et(8;21) negativity achieved 42 days after starting treatment.\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eXue et al. 2022\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRelapsed/Refractory AML with t(8;21) and KIT mutation previously treated with intensive chemotherapy\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e50% D816V and 50% D816Y\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 men and 1 women\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e19 to 52 years old\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAvapritinib 100mg daily + Venetoclax; Avapritinib 15mg daily + Azacitidine + Venetoclax; Avapritinib 200mg in 2 patients\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2 MRD negative complete remission and 2 MRD positive complete remissions\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eYin et al. 2022\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAML with t(8;21) and KIT mutation after AlloHSCT MRD positive or MRD negative\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33% N822I, 17% D816Y, 50% exon 17\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 men and 1 women\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 to 12 years old\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6; 4 MRD positive and 2 MRD negative\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAvapritinib 25-100mg daily\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3 of 4 patients who were MRD positive converted to MRD negative. 2 RMD negative patients remained MRD negative\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eWang et al. 2023\u003csup\u003e4\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/table\u003e\u003c/div\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eAvapritinib appears to be a promising agent for the treatment of \u003cem\u003eKIT\u003c/em\u003e-mutated CBF-AML with a well-studied and favorable safety profile. The response in this case clearly illustrates a need for further study. There are two ongoing phase II clinical trials in China evaluating avapritinib in relapsed/refractory \u003cem\u003eKIT\u003c/em\u003e-mutated AML (NCT05821738 and NCT05821738), although there are no trials open with in the United States (US). We hope this informative case, believed to be the first of reported use of avapritinib for AML in the US, empowers providers to consider its use for similar patients who have no true standard of care in the relapsed/refractory setting that often requires the administration of therapies with less attractive risk:benefit profiles.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eCompeting Interest Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRMS had a consultancy with Bristol Myers Squibb, Curio Science, Gilead Sciences, Kura Oncology, Servier, and Rigel and served in Steering Committees for Servier\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics and Consent to Publish Declarations\u003c/strong\u003e:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNo funding was received for conducting this study.\u003c/p\u003e\n\u003cp\u003eRMS had a consultancy with Bristol Myers Squibb, Curio Science, Gilead Sciences, Kura Oncology, Servier, and Rigel and served in Steering Committees for Servier. TMG, KB, and SS have no relevant financial or non-financial interests to disclose. The participant has consented to the submission of the case report to the journal. \u0026nbsp;This case report adheres to the ethical standards set by Yale New Haven Hospital.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eTMG and RMS conceptualized this article, wrote the original draft, and prepared the figures. KB, SS, and RMS were involved in reviewing and editing.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBorthakur G, Kantarjian H (2021) Core binding factor acute myelogenous leukemia-2021 treatment algorithm. Blood Cancer J 11:114. https://doi.org/10.1038/S41408-021-00503-6\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGrimwade D, Hills RK, Moorman A V., et al (2010) Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood 116:354\u0026ndash;365. https://doi.org/10.1182/BLOOD-2009-11-254441\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIshikawa Y, Group for the JALS, Kawashima N, et al (2020) Prospective evaluation of prognostic impact of KIT mutations on acute myeloid leukemia with RUNX1-RUNX1T1 and CBFB-MYH11. Blood Adv 4:66\u0026ndash;75. https://doi.org/10.1182/BLOODADVANCES.2019000709\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChristen F, Hoyer K, Yoshida K, et al (2019) Genomic landscape and clonal evolution of acute myeloid leukemia with t(8;21): an international study on 331 patients. Blood 133:1140\u0026ndash;1151. https://doi.org/10.1182/BLOOD-2018-05-852822\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKatagiri S, Chi S, Minami Y, et al (2022) Mutated KIT Tyrosine Kinase as a Novel Molecular Target in Acute Myeloid Leukemia. Int J Mol Sci 23:. https://doi.org/10.3390/IJMS23094694/S1\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePaschka P, Schlenk RF, Weber D, et al (2018) Adding dasatinib to intensive treatment in core-binding factor acute myeloid leukemia\u0026mdash;results of the AMLSG 11\u0026thinsp;\u0026minus;\u0026thinsp;08 trial. Leukemia 2018 32:7 32:1621\u0026ndash;1630. https://doi.org/10.1038/s41375-018-0129-6\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMarcucci G, Geyer S, Laumann K, et al (2020) Combination of dasatinib with chemotherapy in previously untreated core binding factor acute myeloid leukemia: CALGB 10801. Blood Adv 4:696\u0026ndash;705. https://doi.org/10.1182/BLOODADVANCES.2019000492\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDeAngelo DJ, Radia DH, George TI, et al (2021) Safety and efficacy of avapritinib in advanced systemic mastocytosis: the phase 1 EXPLORER trial. Nature Medicine 2021 27:12 27:2183\u0026ndash;2191. https://doi.org/10.1038/s41591-021-01538-9\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGotlib J, Reiter A, Radia DH, et al (2021) Efficacy and safety of avapritinib in advanced systemic mastocytosis: interim analysis of the phase 2 PATHFINDER trial. Nature Medicine 2021 27:12 27:2192\u0026ndash;2199. https://doi.org/10.1038/s41591-021-01539-8\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShafik NF, Ibraheem D, Selim MM, et al (2022) The Prognostic Significance of c-KIT Mutations in Core Binding Factor Acute Myeloid Leukemia. Clin Lymphoma Myeloma Leuk 22:e363\u0026ndash;e375. https://doi.org/10.1016/J.CLML.2021.11.015\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSandow L, Heinrich M (2023) Avapritinib treatment of KIT D816V-mutant atypical chronic myeloid leukemia. Leuk Res Rep 19:100371. https://doi.org/10.1016/J.LRR.2023.100371\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYin J, Zhu F, Zhang ZB, et al (2022) Rapid and deep response to avapritinib in heavily treated acute myeloid leukemia with t (8;21) and KIT mutation. Ann Hematol 101:. https://doi.org/10.1007/S00277-022-04897-6\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKong J, Zheng FM, Wang ZD, et al (2023) Avapritinib is effective for treatment of minimal residual disease in acute myeloid leukemia with t (8;21) and kit mutation failing to immunotherapy after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 58:777\u0026ndash;783. https://doi.org/10.1038/S41409-023-01973-X\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXue S, Huang W, Liu F, et al (2022) Rapid response to avapritinib of acute myeloid leukemia with t(8;21) and KIT mutation relapse post allo-HSCT. Leuk Lymphoma 63:2247\u0026ndash;2250. https://doi.org/10.1080/10428194.2022.2064994\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"annals-of-hematology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"aohe","sideBox":"Learn more about [Annals of Hematology](http://link.springer.com/journal/277)","snPcode":"277","submissionUrl":"https://submission.nature.com/new-submission/277/3","title":"Annals of Hematology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Acute Myeloid Leukemia, KIT mutations, t(8, 21), Avapritinib","lastPublishedDoi":"10.21203/rs.3.rs-5932205/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5932205/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eAcute myeloid leukemia (AML) with t(8;21) is a subset of core binding factor AML and is considered to be favorable risk disease in patients receiving intensive cytarabine based chemotherapy. However, relapse remains a significant clinical challenge. Mutations in \u003cem\u003eKIT\u003c/em\u003e, which frequently co-occur in t(8;21) AML, have been associated with worse relapse free and overall survival. Avapritinib is a novel tyrosine kinase inhibitor targeting KIT mutations that is currently approved for systemic mastocytosis but doesn\u0026rsquo;t currently have an established role in the treatment of AML. Here we report the case of a patient with heavily treated \u003cem\u003eKIT\u003c/em\u003e D816H-mutated t(8;21) AML that relapsed following allogeneic hematopoietic stem cell transplant who received avapritinib monotherapy with rapid induction of a deep remission. This case highlights the potential role of avapritinib as a targeted therapy for relapsed t(8;21) AML with KIT mutations, warranting further clinical investigation.\u003c/p\u003e","manuscriptTitle":"Avapritinib monotherapy induces rapid and deep remission of heavily treated, KIT D816H-mutated t(8;21) acute myeloid leukemia","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-02-14 13:29:22","doi":"10.21203/rs.3.rs-5932205/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-03-09T14:15:33+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-02-24T17:50:57+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"268984167920328824803964146834780610642","date":"2025-02-20T18:39:44+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-02-20T14:35:25+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-02-12T11:43:02+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-02-12T11:39:44+00:00","index":"","fulltext":""},{"type":"submitted","content":"Annals of Hematology","date":"2025-01-30T18:50:04+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"annals-of-hematology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"aohe","sideBox":"Learn more about [Annals of Hematology](http://link.springer.com/journal/277)","snPcode":"277","submissionUrl":"https://submission.nature.com/new-submission/277/3","title":"Annals of Hematology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"6bc06cf2-1528-45e9-9fb0-854b296b2965","owner":[],"postedDate":"February 14th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-06-30T15:59:30+00:00","versionOfRecord":{"articleIdentity":"rs-5932205","link":"https://doi.org/10.1007/s00277-025-06388-w","journal":{"identity":"annals-of-hematology","isVorOnly":false,"title":"Annals of Hematology"},"publishedOn":"2025-06-27 15:57:12","publishedOnDateReadable":"June 27th, 2025"},"versionCreatedAt":"2025-02-14 13:29:22","video":"","vorDoi":"10.1007/s00277-025-06388-w","vorDoiUrl":"https://doi.org/10.1007/s00277-025-06388-w","workflowStages":[]},"version":"v1","identity":"rs-5932205","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5932205","identity":"rs-5932205","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}