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<p>The Philadelphia positive acute lymphoblastic leukemia (ALL BCR::ABL1 positive) is characterized by the presence of&#xa0;the t(9;22)(q34;q11) resulting in the formation of the BCR::ABL1 fusion, constant high cellular BCR-ABL1 tyrosine&#xa0;kinase activity, abnormal lymphoid cell proliferation and genetic instability of leukemic cells. Recently, great&#xa0;progress has been made due to the incorporation of tyrosine kinase inhibitors (TKI’s) into the treatment algorithms.&#xa0;Despite this, a significant number of patients experienced therapy resistance mainly due to disease evolution and/or&#xa0;acquisition of TKI resistant BCR::ABL1 mutation(s). Herein, we report the therapy outcome in a 65 year old woman&#xa0;with high-risk BCR::ABL1 positive ALL treated with the PALG ALL7 (including imatinib, IM) protocol, who obtained&#xa0;complete hematologic remission (CHR) and complete molecular remission (CMR) after treatment with induction,consolidation I and II. Despite the fully matched donor identification, the patient refused to continue with intensive&#xa0;chemotherapy. Therefore, only IM therapy was continued, with periodic drug dose reduction due to hematological&#xa0;toxicity. CHR loss with the absence of BCR::ABL1 KD mutation was noticed 10 months later. The treatment with&#xa0;dasatinib (DAS) 140mg/d and dexamethasone resulted in a second CMR. Due to gastrointestinal toxicity, the DAS&#xa0;dose was reduced to 100mg/d. The second disease relapse was diagnosed 3 months later. BCR::ABL1 KD mutation&#xa0;screening showed the Lys404Glu (K404E) substitution. The 3-week long treatment with ponatinib in the dose of&#xa0;45mg/d resulted in disease progression. The reinduction therapy with anti-CD22 MoAb (Inotuzumab ozogamycin) led&#xa0;to the 3rd CMR (duration time 9 months).&#xa0;According to our knowledge, it is the first report on the emergence of a BCR::ABL1 Lys404Glu mutation in an ALL&#xa0;patient receiving TKI treatment. Due to the mutation emergence on DAS, and disease progression on subsequent&#xa0;ponatinib treatment, the impact of the mutation acquisition on the 3D structure of ABL1 molecule and the process of&#xa0;TKI’s binding to ATP-binding site were additionally studied. The results of the study indicate that the TKI resistance&#xa0;observed in the presented case is probably the result of the impossibility of the formation of stable complexes&#xa0;between ATP-competitive inhibitors and mutant Lys404Glu BCR-ABL1 tyrosine kinase due to conformational molecule&#xa0;changes.</p>

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Inotuzumab therapy resulted in molecular remission of relapsed/resistant B-cell acute lymphoblastic leukemia with BCR::ABL1 Lys404Glu mutation

  • 期刊论文

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  • 发表日期：

    2025年5月16日

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  • Krzysztof Lewandowski,
  • Maciej Janicki,
  • Marta Barańska,
  • Zuzanna Kanduła,
  • Katarzyna Godziewska,
  • Jolanta Kiernicka-Parulska,
  • Agnieszka Ludwików,
  • Joanna I. Loch

摘要

The Philadelphia positive acute lymphoblastic leukemia (ALL BCR::ABL1 positive) is characterized by the presence of the t(9;22)(q34;q11) resulting in the formation of the BCR::ABL1 fusion, constant high cellular BCR-ABL1 tyrosine kinase activity, abnormal lymphoid cell proliferation and genetic instability of leukemic cells. Recently, great progress has been made due to the incorporation of tyrosine kinase inhibitors (TKI’s) into the treatment algorithms. Despite this, a significant number of patients experienced therapy resistance mainly due to disease evolution and/or acquisition of TKI resistant BCR::ABL1 mutation(s). Herein, we report the therapy outcome in a 65 year old woman with high-risk BCR::ABL1 positive ALL treated with the PALG ALL7 (including imatinib, IM) protocol, who obtained complete hematologic remission (CHR) and complete molecular remission (CMR) after treatment with induction,consolidation I and II. Despite the fully matched donor identification, the patient refused to continue with intensive chemotherapy. Therefore, only IM therapy was continued, with periodic drug dose reduction due to hematological toxicity. CHR loss with the absence of BCR::ABL1 KD mutation was noticed 10 months later. The treatment with dasatinib (DAS) 140mg/d and dexamethasone resulted in a second CMR. Due to gastrointestinal toxicity, the DAS dose was reduced to 100mg/d. The second disease relapse was diagnosed 3 months later. BCR::ABL1 KD mutation screening showed the Lys404Glu (K404E) substitution. The 3-week long treatment with ponatinib in the dose of 45mg/d resulted in disease progression. The reinduction therapy with anti-CD22 MoAb (Inotuzumab ozogamycin) led to the 3rd CMR (duration time 9 months). According to our knowledge, it is the first report on the emergence of a BCR::ABL1 Lys404Glu mutation in an ALL patient receiving TKI treatment. Due to the mutation emergence on DAS, and disease progression on subsequent ponatinib treatment, the impact of the mutation acquisition on the 3D structure of ABL1 molecule and the process of TKI’s binding to ATP-binding site were additionally studied. The results of the study indicate that the TKI resistance observed in the presented case is probably the result of the impossibility of the formation of stable complexes between ATP-competitive inhibitors and mutant Lys404Glu BCR-ABL1 tyrosine kinase due to conformational molecule changes.