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Treatment and monitoring of Philadelphia chromosome-positive leukemia patients: recent advances and remaining challenges.

ABSTRACT: The Philadelphia (Ph) chromosome, resulting from the t(9;22)(q34;q11) translocation, can be found in chronic myeloid leukemia (CML) as well as in a subset of acute lymphoblastic leukemias (ALL). The deregulated BCR-ABL1 tyrosine kinase encoded by the fusion gene resulting from the translocation is considered the pathogenetic driver and can be therapeutically targeted. In both CML and Ph-positive (Ph+) ALL, tyrosine kinase inhibitors (TKIs) have significantly improved outcomes. In the TKI era, testing for BCR-ABL1 transcript levels by real-time quantitative polymerase chain reaction (RQ-PCR) has become the gold standard to monitor patient response, anticipate relapse, and guide therapeutic decisions. In CML, key molecular response milestones have been defined that draw the ideal trajectory towards optimal long-term outcomes. Treatment discontinuation (treatment-free remission, TFR) has proven feasible in a proportion of patients, and clinical efforts are now focused on how to increase this proportion and how to best select TFR candidates. In Ph+ ALL, results of trials with second- and third-generation TKIs are challenging the role of intensive chemotherapy and even that of allogeneic stem cell transplantation. Additional weapons are offered by the recently introduced monoclonal antibodies. In patients harboring mutations in the BCR-ABL1 kinase domain, prompt therapeutic reassessment and individualization based on mutation status are important to regain response and prevent disease progression. Next-generation sequencing is likely to become a precious tool for mutation testing because of the greater sensitivity and the possibility to discriminate between compound and polyclonal mutations. In this review, we discuss the latest advances in treatment and monitoring of CML and Ph+ ALL and the issues that still need to be addressed to make the best use of the therapeutic armamentarium and molecular testing technologies currently at our disposal.

SUBMITTER: Soverini S

PROVIDER: S-EPMC6480772 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Treatment and monitoring of Philadelphia chromosome-positive leukemia patients: recent advances and remaining challenges.

Soverini Simona S Bassan Renato R Lion Thomas T

Journal of hematology & oncology 20190423 1

The Philadelphia (Ph) chromosome, resulting from the t(9;22)(q34;q11) translocation, can be found in chronic myeloid leukemia (CML) as well as in a subset of acute lymphoblastic leukemias (ALL). The deregulated BCR-ABL1 tyrosine kinase encoded by the fusion gene resulting from the translocation is considered the pathogenetic driver and can be therapeutically targeted. In both CML and Ph-positive (Ph+) ALL, tyrosine kinase inhibitors (TKIs) have significantly improved outcomes. In the TKI era, te ...[more]

PMID: 31014376

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Project description:Abstract Tyrosine kinase inhibitors (TKIs) have significantly changed the treatment of chronic myeloid leukemia (CML) and improved outcomes for patients with CML in chronic phase (CML-CP) and accelerated phase (AP). Now armed with numerous effective therapeutic options, clinicians must consider various patient- and disease-specific factors when selecting the most appropriate TKI across lines of therapy. While most patients with CML expected to have a near-normal life expectancy due to the success of TKIs, emphasis has expanded beyond response and survival to include factors like quality of life, tolerability, and long-term toxicity management. Importantly, a subset of patients can achieve sustained deep molecular response and can attain treatment-free remission. Despite these successes, unmet needs remain related to CML treatment, including the persistent challenge of treatment resistance and intolerance, broadening treatment options for patients with resistance mutations or serious comorbidities, and focus on specific populations such as children and young adults. In particular, the only previously available treatments for patients with CML-CP with the T315I mutation were ponatinib, olverembatinib (exclusively approved for use in China at the time of this writing), omacetaxine, and hematopoietic stem cell transplantation. Asciminib has entered the CML treatment landscape as a new option for adult patients with CML-CP who have received ≥2 prior TKIs or those with the T315I mutation. Asciminib’s unique mechanism of action, Specifically Targeting the ABL Myristoyl Pocket, sets it apart from traditional adenosine triphosphate-competitive TKIs. While asciminib may overcome unmet needs for patients with CML-CP and continues to be studied in other novel settings, guidance on how to integrate asciminib in treatment algorithms is needed. This review focuses on clinical data and how asciminib can overcome current unmet needs, discusses how to individualize patient selection, and highlights future directions to investigate asciminib in earlier lines of therapy and in children and adolescents.

Dataset Information

Treatment and monitoring of Philadelphia chromosome-positive leukemia patients: recent advances and remaining challenges.

Publications

Treatment and monitoring of Philadelphia chromosome-positive leukemia patients: recent advances and remaining challenges.

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