Concomitant L248V with E225V mutation in BCR-ABL gene associated with rapid CML lymphoid blast crisis

Concomitant L248V with E225V mutation in BCR-ABL gene associated with rapid CML lymphoid blast crisis | 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 Concomitant L248V with E225V mutation in BCR-ABL gene associated with rapid CML lymphoid blast crisis Songphol Tungjitviboonkun, Pawitthorn Wachirapornpruet, Sorrawit Unsuwan This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4148236/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm characterized by the presence of the Philadelphia chromosome (Ph), resulting from the t(9;22)(q34;q11.2) translocation. Imatinib, a tyrosine kinase inhibitor, has revolutionized the treatment of CML. However, despite the initial response, some patients may progress to an advanced stage, such as a blast crisis. Case Presentation: We report a 40-year-old female who presented with CML chronic phase taking imatinib 400 mg/day and achieved a complete hematological response (CHR) after one month of treatment. She achieved suboptimal response in the third month (BCR-ABL positive 10.29% IS). However, five months into therapy, she developed a sudden lymphoid blast crisis with chromosomal aberrations involving chromosome 10 and 12. Molecular analysis detected concomitant L248V with partial exon 4 deletion and E225V mutations within the BCR-ABL1 fusion gene. The patient received intensive chemotherapy and dasatinib. Conclusion We report the first case of concomitant mutation of L248V with partial exon 4 deletion and E255V on BCR-ABL1 gene mutation which contributes to a sudden precursor B-cell lymphoid blast crisis. Hematology Chronic Myeloid Leukemia Imatinib Blast Crisis BCR-ABL Mutation Figures Figure 1 Figure 2 Introduction Chronic Myeloid Leukemia (CML) is a clonal myeloproliferative disorder characterized by the unregulated proliferation of myeloid precursor cells within the bone marrow. This leads to the accumulation of abnormal white blood cells, primarily granulocytes, in the peripheral blood and bone marrow. The disease is driven by the BCR-ABL1 chimeric gene product, that codes for a constitutively active tyrosine kinase, resulting from a reciprocal balanced translocation between the long arms of chromosomes 9 and 22, t(9;22)(q34.1;q11.2), known as the Philadelphia chromosome (Ph) 1 . CML accounts for 15–20% of adult leukemia cases. The worldwide incidence is approximately 0.6 to 2.0 cases per 100,000 persons, which are more common in males than females, with ratios ranging between 1.3 and 1.8. 2 According to European LeukemiaNet (ELN) definition 3 , CML is categorized into different stages based on the progression of the disease, comprising the chronic phase, accelerated phase, and blast phase. (Table 1 ) The chronic phase usually lasts several years. The accelerated phase lasts 4 to 6 months. The blast phase, terminal phase of CML, lasts only a few months. 4,5 The majority of CML cases (> 90%) are diagnosed in chronic phase, while a minority (2.2%) may present with de novo blast crisis. 6 Patient with blast transformation from chronic phase or accelerated phase can either be myeloid or lymphoid blast crisis. Lymphoid blast crisis accounts for around 30% of CML blast crisis cases. 7 Table 1 CML categories base on European LeukemiaNet (ELN) definition Chronic phase Accelerated phase Blast phase • Blast cells: <15% of total in blood • Blast cells: ≥15% of total in blood or bone marrow • Blast cells: ≥30% of total in blood or bone marrow • Blast cells and promyelocytes: <30% of total in blood and bone marrow • Blast cells and promyelocytes: ≥30% of total in blood or bone marrow • Extramedullary disease with immature blast cells • Basophils: 100 × 10 9 cells per L • Persistent thrombocytopenia (< 100 × 10 9 platelets per L) unrelated to therapy • No additional chromosomal abnormalities at the time of diagnosis • Clonal chromosomal abnormalities in Philadelphia chromosome-positive cells, major route, on treatment The first-line treatment is a Tyrosine-kinase inhibitor (TKI). A short course of hydroxyurea may be given in symptomatic patients with high white blood cell or platelet counts while molecular and cytogenetic confirmation of the CML diagnosis is pending. Currently, four FDA-approved TKIs that are commercially available to use as a first-line treatment for chronic phase CML are first-generation imatinib and second-generation dasatinib, nilotinib, and bosutinib. It is essential to regularly monitor the patient's response to TKI drug therapy in CML to assess the response. (Table 2 ) Table 2 Response definition Response Definition Complete hematologic response (CHR) Leukocyte count < 10 x 10 9 /L; platelet count 95% Ph positive cells Minimal cytogenetic response 66–95% Ph positive cells Minor cytogenetic response 36–65% Ph positive cells Major cytogenetic response Complete and Partial cytogenetic responses - Partial cytogenetic response (PCyR) 1–35% Ph positive cells - Complete cytogenetic response (CCyR) 0% Ph positive cells Major molecular response (MMR) BCR-ABL1 IS ≤ 0.1% - MR4.0 BCR-ABL1 IS ≤ 0.01% - MR4.5 BCR-ABL1 IS ≤ 0.0032% Complete molecular response (CMR) Undetectable BCR-ABL1 The European LeukemiaNet (ELN) has defined a treatment milestones base on quantity of BCR-ABL1 during treatment. 3 (Table 3) Table 3 Treatment milestones base on European LeukemiaNet (ELN) definition Optimal response Warning or subopotimal response Intolerance or resistance Baseline Not applicable High-risk ACA, high-risk ELTS score Not applicable 3 months BCR-ABL1 ≤10% BCR-ABL1 >10% BCR-ABL1 >10% confirmed within 1–3 months 6 months BCR-ABL1 ≤1% BCR-ABL1 >1–10% BCR-ABL1 >10% 12 months BCR-ABL1 ≤0.1% BCR-ABL1 >0.1–1.0% BCR-ABL1 >1% Any time after 12 months BCR-ABL1 ≤0.1% BCR-ABL1 >0.1% to 1·0% and loss of major molecular response BCR-ABL1 >1%; emergence of resistance mutations; high-risk ACA Following imatinib treatment, early molecular response rates at 3 months (BCR-ABL1 ≤ 10% IS) range between 60 and 80%. At one and 5 years, MMR rates range between 20–59% and 60–80%, respectively. 8–10 Sudden blast crisis (SBC) is categorized as a rapid onset of blast crisis after a documented optimal response to TKI and within 3 months of a normal complete blood count. Incidence was 0.7% of CML chronic phase patients who were treated with imatinib. 11 Though SBC is rare during the TKI therapy era, it was reported in a patient who, previously achieved MMR, discontinue TKI due to restricted access to health services during COVID-19 pandemic. 12 Although persistent expression of BCR-ABL leads to genomic instability, there is a report that deletions of the derivative chromosome 9 in CML can lead to rapid progression to blast crisis by loss of one or more tumor suppressor genes(TSG). 13 Chromosomal abnormalities involving chromosome 8,17,19 and 22 were reported, whether they were associated with genomic stability or not, with duplication of the Ph chromosome or trisomy 8 being the most frequent in CML blast crisis. 14 There are two reports of L248V BCR-ABL mutation in imatinib-resistant CML patients. 15 Both cases developed disease progression between 15 to 17 months. While the E255V mutation reported in Korea was a relatively more aggressive clinical course in just three months, the patient developed to an accelerated phase, not a blast crisis. 16 This report presents an adult woman with CML sudden lymphoid blast crisis from concomitant L248V with partial exon deletion and E255V mutation developed in a patient who previously responded to imatinib and had good compliance with medication. Case Report A 40-year-old female with no known underlying diseases presented to the hospital with a two-day history of high-grade fever. Upon examination, her temperature was 36.6 C, her blood pressure measured 130/80 mmHg, and her respiratory rate was 20/min. General examination revealed no pallor. Abdominal examination indicated mild hepatomegaly and splenomegaly 4 FB BLCM. Initial investigations revealed Hb 11.3 g/dL, WBC 92790 cells/mm 3 , Neutrophils 67% Lymphocytes 14%, Monocyte 3%, Eosinophil 3%, Basophil 3%, Band form 2%, Blast 1%, Metamyelocyte 3%, Promyelocyte 3%, Platelet count 737000/mm 3 . BCR-ABL by reverse transcription PCR (RT-PCR) from blood was positive > 55% IS. Bone marrow biopsy showed 95% cellularity, marked myeloid predominance, and increased megakaryocytes. Bone marrow aspiration revealed markedly hypercellular marrow, M:E ratio of 10:1, and myeloblast 2%. Chromosome study showed 46, XX,t(9;22)(q34;q11.2)[ 20 ]. She was diagnosed with the CML chronic phase, intermediate risk Sokal score. Imatinib 400 mg oral per day was started in December 2023. Management and outcome One month after starting imatinib, the patient achieved CHR, which Hb 10.0 g/dL, WBC 2760/mm 3 with normal differential counts and platelet count 288,000/mm 3 . Physical examination showed no hepatomegaly and no splenomegaly. She reported good compliance with imatinib. Three months after starting imatinib, CBC was normal. Hb 10.7, WBC 7370, N66%, L28%, Eo1%, Monocyte3%, platelet 268000. BCR-ABL was positive 10.29% IS, compatible with suboptimal response, according to ELN definition. After discussing it with the patient, she decided to continue with imatinib 400 mg/day. Five months after starting imatinib, the patient developed fatigue, dyspnea, and gum bleeding. Physical examination was body temperature 36.5 C, blood pressure 167/94 mmHg, pulse rate 97/min, respiratory rate 20/min, mild hepatomegaly, splenomegaly 2 FB BLCM. Her CBC revealed Hb 10.2, Hct 31.6%, WBC 269490/mm 3 with 94% of lymphoblast and platelet count of 52,000/mm 3 . Peripheral blood smear showed markedly increase lymphoblasts. (Figs. 1 and 2) Bone marrow biopsy showed small foci of atypical large cells with blastic nuclear appearance infiltration. Bone marrow aspiration revealed markedly hypercellular marrow, 90% lymphoblast. Flow cytometry showed CD10+, CD19+, CD34+, HLA-DR+, TdT + blasts with aberrant CD33 expression compatible with precursor B acute lymphoblastic leukemia (ALL). Chromosome study was 46,XX,t(9;22)(q34;q11.2),del(12)(q22q24.1)[ 8 ]/ 46,XX,t(9;22)(q34;q11.2),ins(10;12)(q22;q22q24.1)[ 3 ]. BCR-ABL1 protein p210 (b2a2) was positive, p190 was negative. BCR-ABL mutation gene assay with peripheral blood sample (by RT-polymerase chain reaction) detected L248V with partial exon 4 deletion and E225V mutation. She was diagnosed with CML with lymphoid blast crisis. The patient received Pediatric-adapted Ph-positive-ALL treatment protocol due to age 40 years old. She received vincristine [2 mg/week intravenously for 4 doses], doxorubicin [30 mg/m 2 weekly for 3 doses], prednisolone [60 mg/m 2 for 28 days], and asparaginase [5,000 U/m 2 for 10 days], together with switching the TKI from imatinib to dasatinib 140 mg/day. Due to intensive chemotherapy, she developed two episodes of Candida tropicalis septicemia and Stenotrophomonas septicemia. She died from septic shock nonresponsive to multiple antibiotics 7 months after the initial CML diagnosis. Discussion Imatinib is one FDA-approved, first-line treatment for chronic phase CML. Although the patient has responded to imatinib by achieving CHR before, mutations within the tyrosine kinase domain of the ABL gene are a significant contributor to resistance against tyrosine kinase inhibitors in individuals with chronic myelogenous leukemia (CML). These mutations are observed in a substantial portion of CML patients who experience resistance, with prevalence ranging from 30–90%, depending on the studies 17,18 . These mutations encompass over 40 distinct amino acid changes, each imparting varying degrees of resistance to imatinib, a commonly used TKI 17 . Based on current knowledge, it is not advisable to routinely conduct mutation screening unless there are specific reasons to do so, such as a loss of treatment effectiveness 19 . Identifying mutations in the ABL gene during the chronic phase (CP) of CML treatment may potentially improve treatment outcomes. Nevertheless, it's important to note that regular ABL mutation screening is not generally recommended for CML patients 20 . In this study, we found a concomitant mutation of L248V with partial exon 4 deletion and E255V on the BCR-ABL1 gene mutation and chromosomal aberrations involving chromosome 10 and 12 which contributes to not only resistance to tyrosine kinase inhibitors but also a sudden lymphoid blast crisis. Conclusion This case describes mutations in the BCR-ABL1 gene, specifically the L248V with partial exon 4 deletion and E255V variants, and chromosomal aberrations involving chromosome 10 and 12 which impact the response to imatinib treatment and a sudden lymphoid blast crisis in a patient who previously responded to imatinib. Declarations ST wrote the first draft of the manuscript. PW researched literature and revised the manuscript. SU participated in data collection and analysis. All authors reviewed and edited the manuscript and approved the final version of the manuscript. Informed Consent The patient and her family were informed about this publication and consent form was signed. References Rowley JD. Letter: A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature 1973;243:290-3. Rohrbacher M, Hasford J. Epidemiology of chronic myeloid leukaemia (CML). Best Pract Res Clin Haematol 2009;22:295-302. Hochhaus A, Baccarani M, Silver RT, et al. European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia. Leukemia 2020;34:966-84. Kantarjian HM, Keating MJ, Talpaz M, et al. Chronic myelogenous leukemia in blast crisis. Analysis of 242 patients. Am J Med 1987;83:445-54. Spiers AS. The clinical features of chronic granulocytic leukaemia. Clin Haematol 1977;6:77-95. Hoffmann VS, Baccarani M, Hasford J, et al. The EUTOS population-based registry: incidence and clinical characteristics of 2904 CML patients in 20 European Countries. Leukemia 2015;29:1336-43. Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood 2016;127:2375-90. Cortes JE, Saglio G, Kantarjian HM, et al. Final 5-Year Study Results of DASISION: The Dasatinib Versus Imatinib Study in Treatment-Naive Chronic Myeloid Leukemia Patients Trial. J Clin Oncol 2016;34:2333-40. Hochhaus A, Saglio G, Hughes TP, et al. Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial. Leukemia 2016;30:1044-54. Brummendorf TH, Cortes JE, de Souza CA, et al. Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukaemia: results from the 24-month follow-up of the BELA trial. Br J Haematol 2015;168:69-81. Jabbour E, Kantarjian H, O'Brien S, et al. Sudden blastic transformation in patients with chronic myeloid leukemia treated with imatinib mesylate. Blood 2006;107:480-2. Avenoso D, Milojkovic D, Clark J, et al. Lymphoid blast crisis after prolonged treatment-free remission in chronic myeloid leukaemia after tyrosine kinase inhibitor de-escalation during the COVID-19 pandemic. EJHaem 2022;3:215-7. Huntly BJ, Bench A, Green AR. Double jeopardy from a single translocation: deletions of the derivative chromosome 9 in chronic myeloid leukemia. Blood 2003;102:1160-8. Johansson B, Fioretos T, Mitelman F. Cytogenetic and molecular genetic evolution of chronic myeloid leukemia. Acta Haematol 2002;107:76-94. Gruber FX, Hjorth-Hansen H, Mikkola I, Stenke L, Johansen T. A novel Bcr-Abl splice isoform is associated with the L248V mutation in CML patients with acquired resistance to imatinib. Leukemia 2006;20:2057-60. Park TS, Cheong JW, Kim SJ, et al. Concomitant t(3;3)(q21;q26), trisomy 19, and E255V mutation associated with imatinib mesylate resistance in chronic myelogenous leukemia. Cancer Genet Cytogenet 2009;190:46-8. Cortes J, Jabbour E, Kantarjian H, et al. Dynamics of BCR-ABL kinase domain mutations in chronic myeloid leukemia after sequential treatment with multiple tyrosine kinase inhibitors. Blood 2007;110:4005-11. Ray A, Cowan-Jacob SW, Manley PW, Mestan J, Griffin JD. Identification of BCR-ABL point mutations conferring resistance to the Abl kinase inhibitor AMN107 (nilotinib) by a random mutagenesis study. Blood 2007;109:5011-5. An X, Tiwari AK, Sun Y, Ding PR, Ashby CR, Jr., Chen ZS. BCR-ABL tyrosine kinase inhibitors in the treatment of Philadelphia chromosome positive chronic myeloid leukemia: a review. Leuk Res 2010;34:1255-68. Awidi A, Ababneh N, Magablah A, et al. ABL kinase domain mutations in patients with chronic myeloid leukemia in Jordan. Genet Test Mol Biomarkers 2012;16:1317-21. Additional Declarations The authors declare no competing interests. Cite Share Download PDF Status: Posted Version 1 posted 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. 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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-4148236","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":282587209,"identity":"64fb232b-3038-418c-ae19-a1594908b135","order_by":0,"name":"Songphol Tungjitviboonkun","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA6ElEQVRIiWNgGAWjYLACxgYGGTb58x8fANk8fMRq4eGTYDA2AGlhI1qLnASDmQSIQ1CLfHvv4deFO2x42KQb0iq/5tjJsDEwP3x0A48WgzPn0qxnnknjYZM5cOy27LZkoMPYjI1z8GmRyDEz5m07DFSZ2HZbchszkAG0EZ8W+RlwLclsxZLb6glrYbiRY/wYrEUijY3x47bDhLUYnDljxjyzDegXnjPM0ozbjvOwMRPwi3x7j/HnwjYbOSCD8ePPbdX2/OzNDx/jdRgwIqRhLGYeMIlfOVjJZxiL8Qdh1aNgFIyCUTACAQBGOD/VCIbVegAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0009-0001-9910-6563","institution":"Sirindhorn hospital","correspondingAuthor":true,"prefix":"","firstName":"Songphol","middleName":"","lastName":"Tungjitviboonkun","suffix":""},{"id":282587210,"identity":"7ff3da65-b754-4928-b737-532dc36ca054","order_by":1,"name":"Pawitthorn Wachirapornpruet","email":"","orcid":"","institution":"Sirindhorn hospital","correspondingAuthor":false,"prefix":"","firstName":"Pawitthorn","middleName":"","lastName":"Wachirapornpruet","suffix":""},{"id":282587571,"identity":"cfb35760-1783-4744-8a11-4e6690be23b3","order_by":2,"name":"Sorrawit Unsuwan","email":"","orcid":"","institution":"Chulalongkorn university","correspondingAuthor":false,"prefix":"","firstName":"Sorrawit","middleName":"","lastName":"Unsuwan","suffix":""}],"badges":[],"createdAt":"2024-03-22 08:33:17","currentVersionCode":1,"declarations":{"humanSubjects":true,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":true,"humanSubjectConsent":true,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":true,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-4148236/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4148236/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":53508051,"identity":"3505c76f-f583-4698-a662-409fd171ec6b","added_by":"auto","created_at":"2024-03-26 20:50:19","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":354313,"visible":true,"origin":"","legend":"\u003cp\u003eperipheral blood smear\u003c/p\u003e","description":"","filename":"PBS1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4148236/v1/762841922a2bdd98bb2928b0.jpg"},{"id":53508059,"identity":"afc3e0bb-80af-4274-94eb-5238fc5f8788","added_by":"auto","created_at":"2024-03-26 20:50:21","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":331068,"visible":true,"origin":"","legend":"\u003cp\u003eperipheral blood smear\u003c/p\u003e","description":"","filename":"PBS3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4148236/v1/d321d07ca1b51dc0f70db8db.jpg"},{"id":53508076,"identity":"7c6a1394-a0e2-478a-adfc-22ba77fd4525","added_by":"auto","created_at":"2024-03-26 20:50:28","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":448499,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4148236/v1/c2dc4b5a-ec6f-4c2d-8651-930f1d05db60.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eConcomitant L248V with E225V mutation in BCR-ABL gene associated with rapid CML lymphoid blast crisis\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eChronic Myeloid Leukemia (CML) is a clonal myeloproliferative disorder characterized by the unregulated proliferation of myeloid precursor cells within the bone marrow. This leads to the accumulation of abnormal white blood cells, primarily granulocytes, in the peripheral blood and bone marrow. The disease is driven by the \u003cem\u003eBCR-ABL1\u003c/em\u003e chimeric gene product, that codes for a constitutively active tyrosine kinase, resulting from a reciprocal balanced translocation between the long arms of chromosomes 9 and 22, t(9;22)(q34.1;q11.2), known as the Philadelphia chromosome (Ph)\u003csup\u003e1\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eCML accounts for 15\u0026ndash;20% of adult leukemia cases. The worldwide incidence is approximately 0.6 to 2.0 cases per 100,000 persons, which are more common in males than females, with ratios ranging between 1.3 and 1.8.\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eAccording to European LeukemiaNet (ELN) definition \u003csup\u003e3\u003c/sup\u003e, CML is categorized into different stages based on the progression of the disease, comprising the chronic phase, accelerated phase, and blast phase. (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e) The chronic phase usually lasts several years. The accelerated phase lasts 4 to 6 months. The blast phase, terminal phase of CML, lasts only a few months.\u003csup\u003e4,5\u003c/sup\u003e The majority of CML cases (\u0026gt;\u0026thinsp;90%) are diagnosed in chronic phase, while a minority (2.2%) may present with \u003cem\u003ede novo\u003c/em\u003e blast crisis.\u003csup\u003e6\u003c/sup\u003e Patient with blast transformation from chronic phase or accelerated phase can either be myeloid or lymphoid blast crisis. Lymphoid blast crisis accounts for around 30% of CML blast crisis cases.\u003csup\u003e7\u003c/sup\u003e\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eCML categories base on European LeukemiaNet (ELN) definition\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eChronic phase\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eAccelerated phase\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eBlast phase\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026bull; Blast cells: \u0026lt;15% of total in blood\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026bull; Blast cells: \u0026ge;15% of total in blood or bone marrow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026bull; Blast cells: \u0026ge;30% of total in blood or bone marrow\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026bull; Blast cells and promyelocytes: \u0026lt;30% of total in blood and bone marrow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026bull; Blast cells and promyelocytes: \u0026ge;30% of total in blood or bone marrow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026bull; Extramedullary disease with immature blast cells\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026bull; Basophils: \u0026lt;20% of total in blood and bone marrow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026bull; Basophils: \u0026ge;20% of total in blood or bone marrow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026bull; Platelets: \u0026gt;100\u0026thinsp;\u0026times;\u0026thinsp;10\u003csup\u003e9\u003c/sup\u003e\u0026nbsp;cells per L\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026bull; Persistent thrombocytopenia (\u0026lt;\u0026thinsp;100\u0026thinsp;\u0026times;\u0026thinsp;10\u003csup\u003e9\u003c/sup\u003e\u0026nbsp;platelets per L) unrelated to therapy\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026bull; No additional chromosomal abnormalities at the time of diagnosis\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026bull; Clonal chromosomal abnormalities in Philadelphia chromosome-positive cells, major route, on treatment\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eThe first-line treatment is a Tyrosine-kinase inhibitor (TKI). A short course of hydroxyurea may be given in symptomatic patients with high white blood cell or platelet counts while molecular and cytogenetic confirmation of the CML diagnosis is pending. Currently, four FDA-approved TKIs that are commercially available to use as a first-line treatment for chronic phase CML are first-generation imatinib and second-generation dasatinib, nilotinib, and bosutinib.\u003c/p\u003e\n\u003cp\u003eIt is essential to regularly monitor the patient's response to TKI drug therapy in CML to assess the response. (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab2\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eResponse definition\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eResponse\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eDefinition\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eComplete hematologic response (CHR)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLeukocyte count\u0026thinsp;\u0026lt;\u0026thinsp;10 x 10\u003csup\u003e9\u003c/sup\u003e/L; platelet count\u0026thinsp;\u0026lt;\u0026thinsp;450 x 10\u003csup\u003e9\u003c/sup\u003e/L; normal differential with no early forms; no splenomegaly\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNo cytogenetic response\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026gt;\u0026thinsp;95% Ph positive cells\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMinimal cytogenetic response\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e66\u0026ndash;95% Ph positive cells\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMinor cytogenetic response\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e36\u0026ndash;65% Ph positive cells\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMajor cytogenetic response\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eComplete and Partial cytogenetic responses\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e- Partial cytogenetic response (PCyR)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u0026ndash;35% Ph positive cells\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e- Complete cytogenetic response (CCyR)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0% Ph positive cells\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMajor molecular response (MMR)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBCR-ABL1 IS\u0026thinsp;\u0026le;\u0026thinsp;0.1%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e- MR4.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBCR-ABL1 IS\u0026thinsp;\u0026le;\u0026thinsp;0.01%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e- MR4.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBCR-ABL1 IS\u0026thinsp;\u0026le;\u0026thinsp;0.0032%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eComplete molecular response (CMR)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUndetectable BCR-ABL1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eThe European LeukemiaNet (ELN) has defined a treatment milestones base on quantity of BCR-ABL1 during treatment.\u003csup\u003e3\u003c/sup\u003e (Table 3)\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab3\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eTreatment milestones base on European LeukemiaNet (ELN) definition\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eOptimal response\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eWarning or subopotimal response\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eIntolerance or resistance\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBaseline\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHigh-risk ACA, high-risk ELTS score\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBCR-ABL1\u0026nbsp;\u0026le;10%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBCR-ABL1\u0026nbsp;\u0026gt;10%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBCR-ABL1\u0026nbsp;\u0026gt;10% confirmed within 1\u0026ndash;3 months\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBCR-ABL1\u0026nbsp;\u0026le;1%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBCR-ABL1\u0026nbsp;\u0026gt;1\u0026ndash;10%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBCR-ABL1\u0026nbsp;\u0026gt;10%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e12 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBCR-ABL1\u0026nbsp;\u0026le;0.1%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBCR-ABL1\u0026nbsp;\u0026gt;0.1\u0026ndash;1.0%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBCR-ABL1\u0026nbsp;\u0026gt;1%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAny time after 12 months\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBCR-ABL1\u0026nbsp;\u0026le;0.1%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBCR-ABL1\u0026nbsp;\u0026gt;0.1% to 1\u0026middot;0% and loss of major molecular response\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBCR-ABL1\u0026nbsp;\u0026gt;1%; emergence of resistance mutations; high-risk ACA\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eFollowing imatinib treatment, early molecular response rates at 3 months (BCR-ABL1\u0026thinsp;\u0026le;\u0026thinsp;10% IS) range between 60 and 80%. At one and 5 years, MMR rates range between 20\u0026ndash;59% and 60\u0026ndash;80%, respectively.\u003csup\u003e8\u0026ndash;10\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eSudden blast crisis (SBC) is categorized as a rapid onset of blast crisis after a documented optimal response to TKI and within 3 months of a normal complete blood count. Incidence was 0.7% of CML chronic phase patients who were treated with imatinib.\u003csup\u003e11\u003c/sup\u003e Though SBC is rare during the TKI therapy era, it was reported in a patient who, previously achieved MMR, discontinue TKI due to restricted access to health services during COVID-19 pandemic.\u003csup\u003e12\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eAlthough persistent expression of BCR-ABL leads to genomic instability, there is a report that deletions of the derivative chromosome 9 in CML can lead to rapid progression to blast crisis by loss of one or more tumor suppressor genes(TSG).\u003csup\u003e13\u003c/sup\u003e Chromosomal abnormalities involving chromosome 8,17,19 and 22 were reported, whether they were associated with genomic stability or not, with duplication of the Ph chromosome or trisomy 8 being the most frequent in CML blast crisis.\u003csup\u003e14\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eThere are two reports of L248V BCR-ABL mutation in imatinib-resistant CML patients.\u003csup\u003e15\u003c/sup\u003e Both cases developed disease progression between 15 to 17 months. While the E255V mutation reported in Korea was a relatively more aggressive clinical course in just three months, the patient developed to an accelerated phase, not a blast crisis.\u003csup\u003e16\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eThis report presents an adult woman with CML sudden lymphoid blast crisis from concomitant L248V with partial exon deletion and E255V mutation developed in a patient who previously responded to imatinib and had good compliance with medication.\u003c/p\u003e"},{"header":"Case Report","content":"\u003cp\u003eA 40-year-old female with no known underlying diseases presented to the hospital with a two-day history of high-grade fever. Upon examination, her temperature was 36.6 C, her blood pressure measured 130/80 mmHg, and her respiratory rate was 20/min. General examination revealed no pallor. Abdominal examination indicated mild hepatomegaly and splenomegaly 4 FB BLCM.\u003c/p\u003e\n\u003cp\u003eInitial investigations revealed Hb 11.3 g/dL, WBC 92790 cells/mm\u003csup\u003e3\u003c/sup\u003e, Neutrophils 67% Lymphocytes 14%, Monocyte 3%, Eosinophil 3%, Basophil 3%, Band form 2%, Blast 1%, Metamyelocyte 3%, Promyelocyte 3%, Platelet count 737000/mm\u003csup\u003e3\u003c/sup\u003e. BCR-ABL by reverse transcription PCR (RT-PCR) from blood was positive\u0026thinsp;\u0026gt;\u0026thinsp;55% IS. Bone marrow biopsy showed 95% cellularity, marked myeloid predominance, and increased megakaryocytes. Bone marrow aspiration revealed markedly hypercellular marrow, M:E ratio of 10:1, and myeloblast 2%. Chromosome study showed 46, XX,t(9;22)(q34;q11.2)[\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e]. She was diagnosed with the CML chronic phase, intermediate risk Sokal score. Imatinib 400 mg oral per day was started in December 2023.\u003c/p\u003e\n\u003ch3\u003eManagement and outcome\u003c/h3\u003e\n\u003cp\u003eOne month after starting imatinib, the patient achieved CHR, which Hb 10.0 g/dL, WBC 2760/mm\u003csup\u003e3\u003c/sup\u003e with normal differential counts and platelet count 288,000/mm\u003csup\u003e3\u003c/sup\u003e. Physical examination showed no hepatomegaly and no splenomegaly. She reported good compliance with imatinib.\u003c/p\u003e\n\u003cp\u003eThree months after starting imatinib, CBC was normal. Hb 10.7, WBC 7370, N66%, L28%, Eo1%, Monocyte3%, platelet 268000. BCR-ABL was positive 10.29% IS, compatible with suboptimal response, according to ELN definition. After discussing it with the patient, she decided to continue with imatinib 400 mg/day.\u003c/p\u003e\n\u003cp\u003eFive months after starting imatinib, the patient developed fatigue, dyspnea, and gum bleeding. Physical examination was body temperature 36.5 C, blood pressure 167/94 mmHg, pulse rate 97/min, respiratory rate 20/min, mild hepatomegaly, splenomegaly 2 FB BLCM. Her CBC revealed Hb 10.2, Hct 31.6%, WBC 269490/mm\u003csup\u003e3\u003c/sup\u003e with 94% of lymphoblast and platelet count of 52,000/mm\u003csup\u003e3\u003c/sup\u003e. Peripheral blood smear showed markedly increase lymphoblasts. (Figs.\u0026nbsp;1 and 2) Bone marrow biopsy showed small foci of atypical large cells with blastic nuclear appearance infiltration. Bone marrow aspiration revealed markedly hypercellular marrow, 90% lymphoblast. Flow cytometry showed CD10+, CD19+, CD34+, HLA-DR+, TdT\u0026thinsp;+\u0026thinsp;blasts with aberrant CD33 expression compatible with precursor B acute lymphoblastic leukemia (ALL). Chromosome study was 46,XX,t(9;22)(q34;q11.2),del(12)(q22q24.1)[\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e]/ 46,XX,t(9;22)(q34;q11.2),ins(10;12)(q22;q22q24.1)[\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e]. BCR-ABL1 protein p210 (b2a2) was positive, p190 was negative. BCR-ABL mutation gene assay with peripheral blood sample (by RT-polymerase chain reaction) detected \u003cstrong\u003eL248V with partial exon 4 deletion and E225V mutation.\u003c/strong\u003e She was diagnosed with CML with lymphoid blast crisis.\u003c/p\u003e\n\u003cp\u003eThe patient received Pediatric-adapted Ph-positive-ALL treatment protocol due to age 40 years old. She received vincristine [2 mg/week intravenously for 4 doses], doxorubicin [30 mg/m\u003csup\u003e2\u003c/sup\u003e weekly for 3 doses], prednisolone [60 mg/m\u003csup\u003e2\u003c/sup\u003e for 28 days], and asparaginase [5,000 U/m\u003csup\u003e2\u003c/sup\u003e for 10 days], together with switching the TKI from imatinib to dasatinib 140 mg/day. Due to intensive chemotherapy, she developed two episodes of \u003cem\u003eCandida tropicalis\u003c/em\u003e septicemia and Stenotrophomonas septicemia. She died from septic shock nonresponsive to multiple antibiotics 7 months after the initial CML diagnosis.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eImatinib is one FDA-approved, first-line treatment for chronic phase CML. Although the patient has responded to imatinib by achieving CHR before, mutations within the tyrosine kinase domain of the ABL gene are a significant contributor to resistance against tyrosine kinase inhibitors in individuals with chronic myelogenous leukemia (CML). These mutations are observed in a substantial portion of CML patients who experience resistance, with prevalence ranging from 30\u0026ndash;90%, depending on the studies \u003csup\u003e17,18\u003c/sup\u003e. These mutations encompass over 40 distinct amino acid changes, each imparting varying degrees of resistance to imatinib, a commonly used TKI \u003csup\u003e17\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eBased on current knowledge, it is not advisable to routinely conduct mutation screening unless there are specific reasons to do so, such as a loss of treatment effectiveness \u003csup\u003e19\u003c/sup\u003e. Identifying mutations in the ABL gene during the chronic phase (CP) of CML treatment may potentially improve treatment outcomes. Nevertheless, it's important to note that regular ABL mutation screening is not generally recommended for CML patients \u003csup\u003e20\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn this study, we found a concomitant mutation of L248V with partial exon 4 deletion and E255V on the BCR-ABL1 gene mutation and chromosomal aberrations involving chromosome 10 and 12 which contributes to not only resistance to tyrosine kinase inhibitors but also a sudden lymphoid blast crisis.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis case describes mutations in the BCR-ABL1 gene, specifically the L248V with partial exon 4 deletion and E255V variants, and chromosomal aberrations involving chromosome 10 and 12 which impact the response to imatinib treatment and a sudden lymphoid blast crisis in a patient who previously responded to imatinib.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eST wrote the first draft of the manuscript. PW researched literature and revised the manuscript. SU participated in data collection and analysis. All authors reviewed and edited the manuscript and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003eInformed Consent\u003c/p\u003e\n\u003cp\u003eThe patient and her family were informed about this publication and consent form was signed.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eRowley JD. Letter: A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature 1973;243:290-3.\u003c/li\u003e\n\u003cli\u003eRohrbacher M, Hasford J. Epidemiology of chronic myeloid leukaemia (CML). Best Pract Res Clin Haematol 2009;22:295-302.\u003c/li\u003e\n\u003cli\u003eHochhaus A, Baccarani M, Silver RT, et al. European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia. 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J Clin Oncol 2016;34:2333-40.\u003c/li\u003e\n\u003cli\u003eHochhaus A, Saglio G, Hughes TP, et al. Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial. Leukemia 2016;30:1044-54.\u003c/li\u003e\n\u003cli\u003eBrummendorf TH, Cortes JE, de Souza CA, et al. Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukaemia: results from the 24-month follow-up of the BELA trial. Br J Haematol 2015;168:69-81.\u003c/li\u003e\n\u003cli\u003eJabbour E, Kantarjian H, O\u0026apos;Brien S, et al. Sudden blastic transformation in patients with chronic myeloid leukemia treated with imatinib mesylate. Blood 2006;107:480-2.\u003c/li\u003e\n\u003cli\u003eAvenoso D, Milojkovic D, Clark J, et al. Lymphoid blast crisis after prolonged treatment-free remission in chronic myeloid leukaemia after tyrosine kinase inhibitor de-escalation during the COVID-19 pandemic. EJHaem 2022;3:215-7.\u003c/li\u003e\n\u003cli\u003eHuntly BJ, Bench A, Green AR. Double jeopardy from a single translocation: deletions of the derivative chromosome 9 in chronic myeloid leukemia. Blood 2003;102:1160-8.\u003c/li\u003e\n\u003cli\u003eJohansson B, Fioretos T, Mitelman F. Cytogenetic and molecular genetic evolution of chronic myeloid leukemia. Acta Haematol 2002;107:76-94.\u003c/li\u003e\n\u003cli\u003eGruber FX, Hjorth-Hansen H, Mikkola I, Stenke L, Johansen T. A novel Bcr-Abl splice isoform is associated with the L248V mutation in CML patients with acquired resistance to imatinib. Leukemia 2006;20:2057-60.\u003c/li\u003e\n\u003cli\u003ePark TS, Cheong JW, Kim SJ, et al. Concomitant t(3;3)(q21;q26), trisomy 19, and E255V mutation associated with imatinib mesylate resistance in chronic myelogenous leukemia. Cancer Genet Cytogenet 2009;190:46-8.\u003c/li\u003e\n\u003cli\u003eCortes J, Jabbour E, Kantarjian H, et al. 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Genet Test Mol Biomarkers 2012;16:1317-21.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"sirindhorn hospital","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Chronic Myeloid Leukemia, Imatinib, Blast Crisis, BCR-ABL Mutation","lastPublishedDoi":"10.21203/rs.3.rs-4148236/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4148236/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eChronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm characterized by the presence of the Philadelphia chromosome (Ph), resulting from the t(9;22)(q34;q11.2) translocation. Imatinib, a tyrosine kinase inhibitor, has revolutionized the treatment of CML. However, despite the initial response, some patients may progress to an advanced stage, such as a blast crisis.\u003c/p\u003e\u003ch2\u003eCase Presentation:\u003c/h2\u003e \u003cp\u003eWe report a 40-year-old female who presented with CML chronic phase taking imatinib 400 mg/day and achieved a complete hematological response (CHR) after one month of treatment. She achieved suboptimal response in the third month (BCR-ABL positive 10.29% IS). However, five months into therapy, she developed a sudden lymphoid blast crisis with chromosomal aberrations involving chromosome 10 and 12. Molecular analysis detected concomitant L248V with partial exon 4 deletion and E225V mutations within the BCR-ABL1 fusion gene. The patient received intensive chemotherapy and dasatinib.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eWe report the first case of concomitant mutation of L248V with partial exon 4 deletion and E255V on BCR-ABL1 gene mutation which contributes to a sudden precursor B-cell lymphoid blast crisis.\u003c/p\u003e","manuscriptTitle":"Concomitant L248V with E225V mutation in BCR-ABL gene associated with rapid CML lymphoid blast crisis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-26 20:50:13","doi":"10.21203/rs.3.rs-4148236/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"50ccc1dc-8ef8-46f7-a922-fd99da285630","owner":[],"postedDate":"March 26th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":29753847,"name":"Hematology"}],"tags":[],"updatedAt":"2024-03-26T20:50:13+00:00","versionOfRecord":[],"versionCreatedAt":"2024-03-26 20:50:13","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4148236","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4148236","identity":"rs-4148236","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}