TKIs in CML

BCR::ABL1-independent pathways contribute to primary resistance to tyrosine kinase inhibitor (TKI) treatment in chronic myeloid leukemia (CML) and play a role in leukemic stem cell persistence. Here, we perform ex vivo drug screening of CML CD34+ leukemic stem/progenitor cells using 100 single drugs and TKI-drug combinations and identify sensitivities to Wee1, MDM2, and BCL2 inhibitors. These agents effectively inhibit primitive CD34+ CD38- CML cells and demonstrate potent synergies when combined with TKIs...

Tyrosine kinase inhibitors (TKIs) have significantly improved the survival of patients with chronic myeloid leukemia (CML), however, older patients are often underrepresented in pivotal trials. Approximately 20% of older adults never start treatment and face significant barriers to accomplish favorable outcomes. The treatment goal is to improve survival, prevent progression, and preserve quality of life. This is achieved through optimizing TKI doses and employing discontinuation strategies to attain treatment-free remission (TFR), a goal increasingly pursued by older patients...

The use of tyrosine kinase inhibitors (TKIs) has become the mainstay of treatment in patients suffering from chronic myeloid leukemia (CML), an adult leukemia caused by a reciprocal translocation between chromosomes 9 and 22, which creates an oncogene resulting in a myeloproliferative neoplasm. These drugs function by inhibiting the ATP-binding site on the fusion oncoprotein and subsequently halting proliferative activity. The goal of this work is to investigate the current state of research into genetic factors that influence the efficacy of four FDA-approved TKIs used to treat CML...

OBJECTIVE: Mutational analysis of BCR::ABL1 kinase domain (KD) is a crucial component of clinical decision algorithms for chronic myeloid leukemia (CML) patients with failure or warning responses to tyrosine kinase inhibitor (TKI) therapy. This study aimed to detect BCR::ABL1 KD mutations in CML patients with treatment resistance and assess the concordance between NGS (next generation sequencing) and Sanger sequencing (SS) in detecting these mutations. RESULTS: In total, 12 different BCR::ABL1 KD mutations were identified by SS in 22...

The management of chronic myelogenous leukemia (CML) has seen significant progress with the introduction of tyrosine kinase inhibitors (TKIs), particularly Imatinib. However, a notable proportion of CML patients develop resistance to Imatinib, often due to the persistence of leukemia stem cells and resistance mechanisms independent of BCR::ABL1 This study investigates the roles of IL6R, IL7R, and MYC in Imatinib resistance by employing CRISPR/Cas9 for gene editing and the Non-Invasive Apoptosis Detection Sensor version 2 (NIADS v2) for apoptosis assessment...

Chronic myeloid leukaemia (CML) is caused by BCR::ABL1. Tyrosine kinase-inhibitors (TKIs) are the initial therapy. Several organizations have reported milestones to evaluate response to initial TKI-therapy and suggest when a change of TKI should be considered. Achieving treatment-free remission (TFR) is increasingly recognized as the optimal therapy goal. Which TKI is the best initial therapy for which persons and what depth and duration of molecular remission is needed to achieve TFR are controversial. In this review we discuss these issues and suggest future research directions...

This study investigated changes in treatment modalities and outcomes of chronic myeloid leukemia in the chronic phase (CP-CML) after the approval of second-generation tyrosine kinase inhibitors (2G-TKIs) for first-line therapy. Patients were grouped into those who underwent TKI therapy up to December 2010 (imatinib era group, n = 185) and after January 2011 (2G-TKI era group, n = 425). All patients in the imatinib era group were initially treated with imatinib, whereas patients in the 2G-TKI era group were mostly treated with dasatinib (55%) or nilotinib (36%)...

Chronic myeloid leukemia (CML) is a clonal hematopoietic stem cell disorder resulting from a balanced translocation leading to BCR::ABL1 oncogene with increased tyrosine kinase activity. Despite the advancements in the development of tyrosine kinase inhibitors (TKIs), the T315I gatekeeper point mutation in the BCR::ABL1 gene remains a challenge. We have previously reported in a Drosophila CML model an increased hemocyte count and disruption in sessile hemocyte patterns upon expression of BCR::ABL1 p210 and BCR::ABL1 T315I in the hemolymph...

Chronic myeloid leukemia (CML) is a clonal myeloproliferative hematological disease characterized by the chimeric breakpoint-cluster region/Abelson kinase1 (BCR::ABL1) oncoprotein; playing a pivotal role in CML molecular pathology, diagnosis, treatment, and possible resistance arising from the success and tolerance of tyrosine kinase inhibitor (TKI)-based therapy. The transcription factor STAT5 constitutive signaling, which is influenced by the cytokine signaling network, triggers BCR::ABL1-based CML pathogenesis and is also relevant to acquired TKI resistance...

Lifelong immunosuppression, cytotoxic effects of some immunosuppressive drugs, and opportunistic oncogenic viruses increase malignancy risks in solid-organ recipients. The risk of myeloid neoplasms including chronic myeloid leukemia (CML) is also increased in this patient population. Tyrosine kinase inhibitors (TKIs), the key element of CML therapy should be used cautiously in transplantation patients as they may interact with calcineurin inhibitors. With this report, a 63-year-old female kidney transplant recipient who developed CML 9 years after kidney transplantation is presented...

INTRODUCTION: Tyrosine kinase inhibitors (TKIs) revolutionized the treatment of chronic myeloid leukemia (CML) but are endowed with negative effects on endothelial function. OBJECTIVES: To characterize endothelial function in patients with CML treated with various TKIs. PATIENTS AND METHODS: Forty-eight patients diagnosed with chronic phase CML treated with TKIs, such as imatinib, bosutinib, nilotinib, ponatinib, and asciminib were included...

A 3-year-old boy was referred to our hospital with splenomegaly. Blood tests revealed hyperleukocytosis and bone marrow examination showed major BCR::ABL1 fusion, leading to the diagnosis of chronic myelogenous leukemia (CML). Due to intolerance, the tyrosine kinase inhibitor (TKI) was changed from imatinib to dasatinib to nilotinib. The patient achieved molecular remission but became markedly short in stature, measuring 129.3 cm (height standard deviation score [SDS] -3.3) at the age of 12. TKI therapy was discontinued at age 12 years and 10 months, which was 9 years and 8 months after the start of TKI and 1 year and 6 months after achievement of MR4...

Chronic myeloid leukemia is a type of blood cancer that affects the bone marrow and results in an overproduction of immature WBCs. The genetic mutation that causes CML is the BCR-ABL fusion gene. Adolescents are rarely affected. The case study aims to discuss a rare case of chronic myeloid leukemia causing bilateral hearing impairment, tinnitus, and vertigo. A 30-year-old female presented to the hospital in November, 2021, with sudden hearing impairment and other symptoms, leading to a CML diagnosis. Blood tests revealed hyperleukocytosis with marked neutrophilia, mild basophilia, and eosinophilia, and a BCR-ABL quantitation of 85%...

Nilotinib, a second-generation tyrosine kinase inhibitor for the treatment of chronic myelogenous leukemia (CML), inhibits Bcr-Abl tyrosine kinase activity and proliferation of Bcr-Abl-expressing cells, as well as other malignancies. In the present study, new nilotinib analogues were synthesized and fully characterized. A platelet aggregation assay was performed, and the expression of P-selectin and PAC-1, as well as the effect on the proliferation of healthy endothelial cells, were evaluated. The expression and antimetastatic effects of E-cadherin and N-cadherin were assessed...

Chronic myeloid leukemia is a multistep, multi-lineage myeloproliferative disease that originates from a translocation event between chromosome 9 and chromosome 22 within the hematopoietic stem cell compartment. The resultant fusion protein BCR::ABL1 is a constitutively active tyrosine kinase that can phosphorylate multiple downstream signaling molecules to promote cellular survival and inhibit apoptosis. Currently, tyrosine kinase inhibitors (TKIs), which impair ABL1 kinase activity by preventing ATP entry, are widely used as a successful therapeutic in CML treatment...

BACKGROUND: Second- and third-generation tyrosine kinase inhibitors (TKIs) are now available to treat chronic-phase chronic myeloid leukemia (CP-CML) in the first and second line. However, vascular adverse events (VAEs) have been reported for patients with CML treated with some TKIs. METHODS: We retrospectively evaluated the cumulative incidence (CI) and cardiovascular risk for 210 patients included in the Canarian Registry of CML. RESULT: With a mean follow up of 6 years, 19/210 (9...

Tyrosine kinase inhibitors (TKIs) have revolutionized therapy for patients with chronic myeloid leukemia (CML) over the last two decades. However, some patients still do not achieve an adequate response to these drugs, and hematopoietic stem cell transplantation (HSCT) is indicated in this scenario. We present the results of a 20-year follow-up study of 70 patients who underwent transplantation after TKI failure. The primary objective of the study was to evaluate overall survival (OS) and the secondary objective was to evaluate the outcomes of relapse-free survival (RFS), GVHD-free, relapse-free survival (GFRS) and the incidences of relapse (RI), non-relapse mortality (NRM), acute and chronic GVHD...

INTRODUCTION: Despite the notable success of tyrosine kinase inhibitors (TKIs) in treating chronic myeloid leukemia (CML), a subset of patients experiences resistance, or relapse after discontinuation. This challenge is attributed to the Ph+ leukemia stem cells (LSCs) pool not fully involved in the inhibition process due to the current therapeutic approach. AREAS COVERED: Current pharmacological advancements in CML therapy focus on targeting LSCs, intervening in self-renewal pathways, and exploiting biological vulnerabilities...

Breakpoint cluster region-Abelson ( BCR::ABL1 ) gene fusion is an essential oncogene in both chronic myeloid leukemia (CML) and Philadelphia-positive (Ph+ ) B-cell acute lymphoblastic leukemia (B-ALL). While tyrosine kinase inhibitors (TKIs) are effective in up to 95% of CML patients, 50% of Ph+ B-ALL cases do not respond to treatment or relapse. This calls for new therapeutic approaches for Ph+ B-ALL. Previous studies have shown that inhibitors of the thioredoxin (TXN) system exert antileukemic activity against B-ALL cells, particularly in combination with other drugs...

The BYOND study evaluated the efficacy and safety of bosutinib 500 mg once daily in patients with chronic myeloid leukemia (CML) resistant/intolerant to prior tyrosine kinase inhibitors (TKIs). These post-hoc analyses assessed the efficacy and safety of bosutinib by resistance or intolerance to prior TKIs (imatinib-resistant vs dasatinib/nilotinib-resistant vs TKI-intolerant), and cross-intolerance between bosutinib and prior TKIs (imatinib, dasatinib, nilotinib), in patients with Philadelphia chromosome-positive chronic phase CML...