Acute myolysis in patients on tyrosine kinase inhibitor therapy for chronic myeloid leukemia.

HJKC3-007: Outcomes of Patients with Chronic Myeloid Leukemia in Chronic Phase Treated with Asciminib and Other Tyrosine Kinase Inhibitors in Routine Clinical Practice

Chronic myeloid leukemia (CML) was considered for a long time one of the most hostile leukemia that was incurable for most of the patients, predominantly due to the extreme resistance to chemotherapy. Part of the resistance to cell death (apoptosis) is the result of increased levels of anti-apoptotic and decreased levels of pro-apoptotic member of the BCL-2 family induced by the BCR-ABL1 oncoprotein. BCR-ABL1 is a constitutively active tyrosine kinase responsible for initiating multiple and oncogenic signaling pathways. With the development of specific BCR-ABL1 tyrosine kinase inhibitors (TKIs) CML became a much more tractable disease. Nevertheless, TKIs do not cure CML patients and a substantial number of them develop intolerance or become resistant to the treatment. Therefore, novel anti-cancer strategies must be developed to treat CML patients independently or in combination with TKIs. Here, we will discuss the mechanisms of BCR-ABL1-dependent and -independent resistance to TKIs and the use of BH3-mimetics as a potential tool to fight CML.

Dasatinib promotes apoptosis of cutaneous squamous carcinoma cells by regulating activation of ERK1/2.

Inhibition of the BCR-ABL tyrosine kinase activity by the specific tyrosine kinase inhibitors (TKI) imatinib, nilotinib and dasatinib leads to complete remission of the disease in most patients with chronic myeloid leukemia (CML). Cessation of CML treatment or the occurrence of resistance mediating bcr/abl gene mutations leads to relapse of the disease, initiated by a small fraction of cells that persisted during CML therapy. Those cells are CD34 positive leukemic progenitor cells with the phenotype of the "side population" and show high expression of the intracellular ABC transporter A3 (ABCA3) at the lysosomal membranes. The majority (>75 %) of imatinib in these cells was sequestrated in the lysosomal compartment. The aims of this work were the examination of the ABCA3 expression regulation and of the mechanism leading to ABCA3 mediated cellular export of TKI in leukemic cells. Overexpression and shRNA mediated suppression of ABCA3 showed that this transporter protects leukemic cells from the cytotoxic effects of imatinib, dasatinib and nilotinib. In those cells surviving the exposition to TKI, the expression of ABCA3 was highly increased in vivo and in vitro, associated with a strong increase of the transcription factor SALL4 that is able to bind to the ABCA3 promoter. Inhibition of ABCA3 or SALL4 by genetic manipulation or inhibiting substances indomethacin or rapamycin, but not gamma interferon disrupted the SALL4-dependent regulation of ABCA3 expression and restored the susceptibility of the leukemic cells towards TKI treatment. Further analysis showed that imatinib accumulated in microvesicles after lysosomal sequestration and was exported out of the cells. The results of this work may lead to the development of strategies to increase the amount of intracellular active TKI and thereby improve the treatment of CML patients.

Patients' and Physicians' Concerns about Tyrosine Kinase-Inhibitor Therapy in Chronic Myeloid Leukemia

Author response: Predictive nonlinear modeling of malignant myelopoiesis and tyrosine kinase inhibitor therapy

Dynamics of Methylation Profiling in Response to Tyrosine Kinase Inhibitor Therapy in Chronic Myeloid Leukemia

Decision letter: Predictive nonlinear modeling of malignant myelopoiesis and tyrosine kinase inhibitor therapy

7548 Background: NCCN CML practice guidelines were updated in 11/2016 and in 9/2019 to include considerations for discontinuation of TKI therapy in patients (pts) with CML-CP. This study characterized TKI discontinuation practices in the US after these updates and drew parallels with a similar study conducted prior to these guideline updates (Ritchie et al. Leuk Lymphoma. 2019). Methods: Pt charts of adult CML-CP pts with TKI discontinuation (1/2017-12/2018) outside a clinical trial after achieving an adequate response were abstracted (11/2019-12/2019) via an online case report form by US oncologists/hematologists. Physicians’ assessment of adequate response (TKI duration, molecular response [MR], MR duration) and relapse were described. Results: 61 physicians (academic: 43%; community-based practices: 57%) contributed 153 pt charts. Most physicians were from large practices (57%), had > 10 years (y) experience since completing subspecialty training (59%), and treated a median of 30 CML pts in the last 2y; 56% did not have access to precise molecular response monitoring for BCR-ABL of ≥4.5 log when attempting TKI discontinuation. Pts with TKI discontinuation had mean age 56 years, were mostly male (60%), white (69%), and had TKI discontinued in first-line (96%). Most common reasons for TKI discontinuation were pt request (54%) and adverse events (18%), besides achieving an adequate response. Physicians’ assessment of adequate response for TKI discontinuation are reported in the Table. 21% of pts (academic: 12%; community: 30%) relapsed after TKI discontinuation (treatment-free remission [TFR] failure; 66% relapsed within 1y). Conclusions: Although NCCN CML practice guidelines provide guidance for discontinuation of TKI therapy, there remains heterogeneity in US practice and TKI discontinuation is predominantly attempted in first-line (similar to Ritchie et al. 2019). TKI discontinuation is being practiced without adequate sensitive tools mandated by practice guidelines to monitor response. Broader application of practice guidelines for optimal TKI therapy discontinuation in CML-CP pts is needed, particularly in community-based practices, to improve long-term TFR rates. [Table: see text]

Clinical Significance of Deeper Molecular Responses with Four Modalities of Tyrosine Kinase Inhibitors As Frontline Therapy for Chronic Myeloid Leukemia

Imatinib mesylate (Gleevec/Glivec, Novartis, Basel, Switzerland), formerly called STI571, is a specific and potent inhibitor of the BCR-ABL tyrosine kinase, the molecular hallmark of chronic myeloid leukaemia. Several clinical trials have demonstrated the efficacy of imatinib in different phases of this disease. On the other hand, imatinib is also active against other tyrosine kinases, such as ABL, the stem cell factor receptor (c-kit) and the platelet-derived growth factor receptor, whose inhibition might have potential implications for the treatment of several malignancies. In this regard, imatinib has already shown a remarkable activity in patients with hypereosinophilic syndrome and gastrointestinal stromal tumours. Imatinib is an example of how a better understanding of the pathogenetic mechanisms of a neoplastic disease can lead to the development of a molecular-targeted therapy.

Imatinib co-loaded targeted realgar nanocrystal for synergistic therapy of chronic myeloid leukemia

Introductions: Dasatinib is indicated as a first line, second line and third line tyrosine kinase inhibitor (TKI) in chronic myeloid leukemia (CML). In our center it is used as a second line or third line therapy in BCR-ABL gene positive CML.
 Methods: It is a retrospective observational therapy done from June 2015 to May 2018. The purpose of the study is to see the response rates using the second line and third line dasatinib after failing or not tolerating imatinib alone or following a sequential therapy with imatinib and nilotinib.
 Results: A total of 31 (male 56.3%) patients were included in our study. In eighteen patients it was used as a second line TKI and in 13 a third line TKI. Complete Hematologic Response (CHR) was achieved in 93.55%. Best optimal responses were 46.66% and 61.53% in second and third line dasatinib respectively. Major Molecular Response (MMR) was achieved in 35.71% (26.66% and 46.14% in second line and third line dasatinib respectively). For both the groups, the overall survival was 92% and 94 % at 20 months and the event free survival was 70% at 10 months.
 Conclusions: Dasatinib is effective in achieving MMR and inducing survival benefit in the patients who failed imatinib alone and imatinib and nilotinib.

Chronic myeloid leukemia (CML) is driven by the BCR::ABL1 fusion gene, and the introduction of tyrosine kinase inhibitors (TKIs) has dramatically improved long-term survival. In Japan, five agents-imatinib (Glivec®), dasatinib (Sprycel®), nilotinib (Tasigna®), bosutinib (Bosulif®), and STAMP inhibitor asciminib (Scemblix®)-are currently approved for first-line therapy. Each has distinct efficacy and toxicity profiles, requiring individualized treatment decisions based on age, comorbidities, cardiovascular risk, fertility, adherence, and financial factors. Recent advances have shifted treatment goals from disease control to treatment-free remission (TFR), with imatinib, dasatinib, and nilotinib supported by robust clinical trial data. Emerging strategies, such as low-dose regimens and step-up dosing of TKI, highlight the importance of balancing efficacy with tolerability and quality of life. Looking forward, immunologic determinants of TFR and novel therapeutic approaches, including targeting CML stem cells with agents such as asciminib or demethylating drugs, may offer prospects for cure. This review summarizes the current evidence and practical considerations in selecting first-line therapy for chronic-phase CML, with a focus on optimizing long-term outcomes and advancing toward individualized and potentially curative strategies.

Somatic Mutations in Myeloid Transcription Factors and in Activated Signaling Pathway, but Not in Epigenetic Modifier Pathway, Predict the Risk of Treatment Failure and Progression to Advanced Phase in Chronic Myeloid Leukemia