The role of E255K/V-inclusive mutations in a Philadelphia-positive acute lymphoblastic leukemia with mutation evolution during sequential TKIs therapies: A case report.

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Tytuł:: The role of E255K/V-inclusive mutations in a Philadelphia-positive acute lymphoblastic leukemia with mutation evolution during sequential TKIs therapies: A case report.
Autorzy:: Zhao M; Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan.
Gui X; Department of Hematology, People's Hospital of Hanchuan, Wuhan University, Hanchuan, Hubei, China.
Wu Q; Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan.
Xia L; Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan.
Wang Y; Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan.
Źródło:: Medicine [Medicine (Baltimore)] 2021 May 07; Vol. 100 (18), pp. e25579.
Typ publikacji:: Case Reports; Journal Article
Język:: English
Imprint Name(s):: Original Publication: Hagerstown, Md : Lippincott Williams & Wilkins
MeSH Terms:: Mutation Rate*
Antineoplastic Combined Chemotherapy Protocols/*pharmacology
Drug Resistance, Neoplasm/*genetics
Neoplasm Recurrence, Local/*genetics
Precursor Cell Lymphoblastic Leukemia-Lymphoma/*drug therapy
Protein Kinase Inhibitors/*pharmacology
Aged ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; DNA Mutational Analysis ; Fatal Outcome ; Female ; Fusion Proteins, bcr-abl/genetics ; Humans ; Imidazoles/pharmacology ; Imidazoles/therapeutic use ; Karyotyping ; Philadelphia Chromosome ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/diagnosis ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics ; Protein Kinase Inhibitors/therapeutic use ; Pyridazines/pharmacology ; Pyridazines/therapeutic use
References:: Soverini S, Bassan R, Lion T. Treatment and monitoring of Philadelphia chromosome-positive leukemia patients: recent advances and remaining challenges. J Hematol Oncol 2019;12:39.
Ottmann O, Pfeifer H, Cayuela J-M, et al. Nilotinib (Tasigna®) and low intensity chemotherapy for first-line treatment of elderly patients with BCR-ABL1-positive acute lymphoblastic leukemia: final results of a prospective multicenter trial (EWALL-PH02). Blood 2018;132: (Suppl 1): 31.
Shah NP, Skaggs BJ, Branford S, et al. Sequential ABL kinase inhibitor therapy selects for compound drug-resistant BCR-ABL mutations with altered oncogenic potency. J Clin Invest 2007;117:2562–9.
Brown PA, Wieduwilt M, Logan A, et al. Guidelines insights: acute lymphoblastic leukemia, Version 1.2019. J Natl Compr Canc Netw 2019;17:414–23.
Cortes JE, Kim DW, Pinilla-Ibarz J, et al. A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med 2013;369:1783–96.
O’Hare T, Shakespeare WC, Zhu X, et al. AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell 2009;16:401–12.
Redaelli S, Mologni L, Rostagno R, et al. Three novel patient-derived BCR/ABL mutants show different sensitivity to second and third generation tyrosine kinase inhibitors. Am J Hematol 2012;87:E125–128.
Khoury HJ, Cortes JE, Kantarjian HM, et al. Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure. Blood 2012;119:3403–12.
Gambacorti-Passerini C, Kantarjian HM, Kim DW, et al. Long-term efficacy and safety of bosutinib in patients with advanced leukemia following resistance/intolerance to imatinib and other tyrosine kinase inhibitors. Am J Hematol 2015;90:755–68.
Zabriskie MS, Eide CA, Tantravahi SK, et al. BCR-ABL1 compound mutations combining key kinase domain positions confer clinical resistance to ponatinib in Ph chromosome-positive leukemia. Cancer Cell 2014;26:428–42.
Rafei H, Kantarjian HM, Jabbour EJ. Targeted therapy paves the way for the cure of acute lymphoblastic leukaemia. Br J Haematol 2019;207–23.
Wei G, Wang J, Huang H, et al. Novel immunotherapies for adult patients with B-lineage acute lymphoblastic leukemia. J Hematol Oncol 2017;10:150.
Topp MS, Gokbuget N, Stein AS, et al. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicenter, single-arm, phase 2 study. Lancet Oncol 2015;16:57–66.
Eide CA, Zabriskie MS, Savage Stevens SL, et al. Combining the allosteric inhibitor asciminib with ponatinib suppresses emergence of and restores efficacy against highly resistant BCR-ABL1 mutants. Cancer Cell 2019;36:431–43. e435.
Grant Information:: 81201866 the Natural Science Foundation of China
Substance Nomenclature:: 0 (Imidazoles)
0 (Protein Kinase Inhibitors)
0 (Pyridazines)
0 (abl-bcr fusion protein, human)
4340891KFS (ponatinib)
EC 2.7.10.2 (Fusion Proteins, bcr-abl)
Entry Date(s):: Date Created: 20210505 Date Completed: 20210512 Latest Revision: 20230103
Update Code:: 20240104
PubMed Central ID:: PMC8104221
DOI:: 10.1097/MD.0000000000025579
PMID:: 33950935
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Rationale: Until recently, the survival rate in patients with Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) was approximately 30%. Tyrosine kinase inhibitors (TKIs), which are a new class of drugs that target BCR-ABL fusion protein, have shown to be effective in treating Ph+ ALL in adults. However, the resistance mechanisms that promote the disease recurrence have altered the initial success of these revolutionary agents.
Patient Concerns: A 71-year-old Chinese female patient who suffered from severe shoulder and back pain for 1 week.
Diagnosis: The patient was diagnosed with Ph+ ALL (B-cell) because of the following items. Complete blood count showed extremely abnormal white blood cell count (26.26×109/l), hemoglobin concentration (65 g/l) and platelet count (14×109/l). And because that Bone marrow aspirate showed 72.5% lymphoblasts and 59.30% lymphoblasts were confirmed by flow cytometry (FCM). At mean time, Real-time fluorescent quantitative PCR analysis confirmed that the P190 BCR/ABL fusion gene expression was 5.9%. Karyotype analysis indicated the following: 45, XX, -7, t (922) (q34; q11) [cp3].
Interventions: The patient was treated with chemotherapy and different TKIs including imatinib, dasatinib, ponatinib, and bosutinib.
Outcomes: The patient achieved complete remissions with different TKIs after diagnose but relapsed afterward and died of infection.
Lessons: Multidrug-resistant mutations within the BCR-ABL1 kinase domain are an emerging clinical problem for patients receiving sequential TKIs therapy. Acquisition of E255K/V-inclusive mutations is usually associated with ponatinib resistance, thus it is necessary to screen out new real pan-inhibitor compounds for all BCR/ABL mutations and figure out the potential efficacy of asciminib-based drug combinations in the future.
Competing Interests: The authors have no conflicts of interest to disclose.
(Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

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