Pharmacotherapy and cardiovascular challenges: a case report of olverembatinib-induced myocardial infarction with non-obstructive coronary arteries.

The anticancer drug of tyrosine kinase-inhibitors (TKIs) has significantly improved the prognosis of patients with specific leukemia but has also increased the risk of organ adverse reactions. Herein, we present a case of a patient diagnosed with myeloproliferative neoplasms who experienced recurrent chest pain after receiving treatment with Olverembatinib. Electrocardiography and coronary angiography confirmed the diagnosis of myocardial infarction with non-obstructive coronary arteries. This case serves as a reminder for clinicians to pay more attention and actively prevent the cardiac adverse reactions of TKIs when using such medications.

Olverembatinib combined with blinatumomab in treating T315I-mutated Philadelphia chromosome-positive acute lymphoblastic leukemia: two-case report.

ABL tyrosine kinase inhibitors (TKIs) act an irreplaceable role in the management of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). The treatment of these diseases has been revolutionized by the application of immunotherapeutic modalities. However, diseases with ABL kinase domain mutation T315I are resistant to the majority of TKIs, which is responsible for treatment failure. Olverembatinib is a third-generation TKI that has been approved for the treatment of T315I-mutated chronic myeloid leukemia (CML) in China; its usage in Ph+ ALL needs further exploration. Here, we present two cases with relapsed T315I mutation Ph+ ALL who received the combination regimen of blinatumomab and olverembatinib. This regimen, which has not been reported yet, was safe and effective as the patients achieved minimal residual disease (MRD) negative after 1 cycle of therapy. The management of these cases provides evidence of this new chemo-free regimen as an efficient approach for relapsed or refractory(R/R)Ph+ ALL.

Case report: Olverembatinib monotherapy: the chemotherapy-free regimen for an elderly patient with relapsed Ph-positive acute lymphoblastic leukemia.

Background: The advent of first- and second-generation BCR/ABL1 tyrosine kinase inhibitors (TKIs), such as imatinib and dasatinib, has markedly improved the clinical outcomes of patients with philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+-ALL). However, due to acquired drug resistance, most Ph+-ALL patients experience relapse. Thus, third-generation BCR/ABL1 TKIs, including ponatinib and olverembatinib, have been developed with the aim of overcoming drug resistance. Case report: A 79-year-old woman presented with intermittent fever and fatigue for 4 days. After comprehensive cytogenetic examination, the patient was diagnosed with Ph+-B-ALL. Starting on 22 September 2021, a combined regimen of flumatinib and vincristine/prednisone (VP) was administered for seven cycles, followed by flumatinib maintenance therapy. The patient remained in first complete molecular remission (1st CMR) for 19 months. On 12 March 2023, she again complained of fatigue and loss of appetite for nearly a month. A comprehensive examination showed Ph+-B-ALL relapse with additional E255V mutation, although T315I mutation was negative. In view of her frail physical condition, she received olverembatinib monotherapy and achieved second CMR (second CMR). No severe toxicities were recorded except for mild fatigue. At present, she has been in second CMR for over 6 months. Conclusion: For elderly patients with relapsed Ph+-ALL, olverembatinib monotherapy may offer a novel option with a good safety profile, suggesting the feasibility of a chemo-free regimen.

Determination of olverembatinib in human plasma and cerebrospinal fluid by an LC-MS/MS method: Validation and clinical application.

A sensitive and robust LC-MS/MS method has been developed and validated for olverembatinib quantification in human plasma and cerebrospinal fluid (CSF). The method involved liquid-liquid extraction with methyl tertiary butyl ether for plasma pretreatment and precipitation enrichment with methanol for CSF pretreatment. Separation was achieved on the C18 column with gradient elutions of 10 mM ammonium formate in water and methanol-acetonitrile (50:50,v/v). Analyte detection was conducted by electrospray ionization (ESI) in a positive ion mode using multiple reaction monitoring (MRM). The m/z transitions were 533.4→433.2 for olverembatinib and m/z 502.4→394.2 for the internal standard (IS, Imatinib-d8). Calibration curves ranged from 0.500 to 50.0 ng/mL for plasma and from 0.0100 to 1.00 ng/mL for CSF. The intra- and inter-day precision and accuracy were < 15% for both plasma and CSF with four different quality control concentrations. The relative matrix effect was < 10% in plasma and artificial CSF. This method was successfully utilized for the measurement of olverembatinib concentrations in plasma and CSF from chronic myeloid leukemia patients.

Transcriptome- and metabolome-based candidate mechanism of BCR-ABL-independent resistance to olverembatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia.

Olverembatinib represents the third-generation breakpoint cluster region protein-Abelson-murine leukemia 1 (BCR-ABL1) tyrosine kinase inhibitor with oral bioavailability, which can be used to overcome the T315I mutation in Philadelphia chromosome-positive (Ph +) leukemia. BCR-ABL-independent resistance to olverembatinib has been reported among patients in various clinical cases. However, the mechanism of olverembatinib resistance has rarely been reported. This study has illustrated bone marrow cell transcriptome and metabolome profiles among Ph + acute lymphoblastic leukemias (ALL) cases pre- and post-olverembatinib resistance. The transcriptome studies demonstrated that PI3K/AKT, purine metabolism, and other signaling pathways could play a vital role in olverembatinib resistance. As suggested by metabolomics, olverembatinib resistance in Ph + ALL was associated with purine metabolism alterations. Subsequently, high-performance liquid chromatography along with real-time quantitative PCR was utilized to measure purine metabolism-related mRNA levels and metabolism expression levels between olverembatinib resistance and sensitive cell lines. Our results elucidate the mechanism of olverembatinib resistance in Ph + ALL at transcriptome and metabolome levels, which facilitate a better understanding of olverembatinib resistance and hence may prove crucial in identifying novel drugs to tackle this conundrum.

A review of the therapeutic role of the new third-generation TKI olverembatinib in chronic myeloid leukemia.

Several tyrosine kinase inhibitors (TKIs) have been developed as targeted therapies to inhibit the oncogenic activity of several tyrosine kinases in chronic myeloid leukemia (CML), acute lymphoid leukemia (ALL), gastrointestinal stromal tumor (GIST), and other diseases. TKIs have significantly improved the overall survival of these patients and changed the treatment strategy in the clinic. However, approximately 50% of patients develop resistance or intolerance to imatinib. For second-generation TKIs, approximately 30%-40% of patients need to change therapy by 5 years when they are used as first-line treatment. Clinical study analysis showed that the T315I mutation is highly associated with TKI resistance. Developing new drugs that target the T315I mutation will address the dilemma of treatment failure. Olverembatinib, as a third-generation TKI designed for the T315I mutation, is being researched in China. Preliminary clinical data show the safety and efficacy in treating CML patients harboring the T315I mutation or who are resistant to first- or second-line TKI treatment. Herein, we review the characteristics and clinical trials of olverembatinib. We also discuss its role in the management of CML patients.

Olverembatinib in chronic myeloid leukemia.

The introduction of tyrosine kinase inhibitors (TKIs) represents a new era in the management of chronic myeloid leukemia (CML). Despite their long clinical success, point mutations emerging before or during TKI treatment remain an obstacle for several cases. T315I is one of these point mutations in the tyrosine kinase domain of BCR::ABL1. It is a major cause of resistance against first- and second-generation TKIs and therefore lowers survival rates of a small group of patients. Olverembatinib (HQP-1351, formerly GZD-824) is a novel, orally active TKI, which acts through targeting the ATP-binding site of the BCR::ABL1 tyrosine kinase. In recent studies, olverembatinib appears to be an effective and safe treatment option for CML patients harboring T315I mutation. This article mainly focuses on the efficacy and safety data of olverembatinib along with other clinically available and potentially active drugs against T315I-mutated CML.

Olverembatinib inhibits SARS-CoV-2-Omicron variant-mediated cytokine release in human peripheral blood mononuclear cells.

The N-terminus domain (NTD) of the SARS-CoV-2 Omicron variant spike protien strongly induces multiple inflammatory molecules in human peripheral blood mononuclear cells, unaffected by the mutations observed in the NTD. Olverembatinib, a clinical-stage multi-kinase inhibitor, potently inhibits Omicron NTD-mediated cytokine release.