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Promising genes and variants to reduce chemotherapy adverse effects in acute lymphoblastic leukemia.

ABSTRACT: Almost two decades ago, the sequencing of the human genome and high throughput technologies came to revolutionize the clinical and therapeutic approaches of patients with complex human diseases. In acute lymphoblastic leukemia (ALL), the most frequent childhood malignancy, these technologies have enabled to characterize the genomic landscape of the disease and have significantly improved the survival rates of ALL patients. Despite this, adverse reactions from treatment such as toxicity, drug resistance and secondary tumors formation are still serious consequences of chemotherapy, and the main obstacles to reduce ALL-related mortality. It is well known that germline variants and somatic mutations in genes involved in drug metabolism impact the efficacy of drugs used in oncohematological diseases therapy. So far, a broader spectrum of clinically actionable alterations that seems to be crucial for the progression and treatment response have been identified. Although these results are promising, it is necessary to put this knowledge into the clinics to help physician make medical decisions and generate an impact in patients' health. This review summarizes the gene variants and clinically actionable mutations that modify the efficacy of antileukemic drugs. Therefore, knowing their genetic status before treatment is critical to reduce severe adverse effects, toxicities and life-threatening consequences in ALL patients.

SUBMITTER: Barcenas-Lopez DA

PROVIDER: S-EPMC7720095 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Promising genes and variants to reduce chemotherapy adverse effects in acute lymphoblastic leukemia.

Bárcenas-López Diego Alberto DA Mendiola-Soto Diana Karen DK Núñez-Enríquez Juan Carlos JC Mejía-Aranguré Juan Manuel JM Hidalgo-Miranda Alfredo A Jiménez-Morales Silvia S

Translational oncology 20201205 1

Almost two decades ago, the sequencing of the human genome and high throughput technologies came to revolutionize the clinical and therapeutic approaches of patients with complex human diseases. In acute lymphoblastic leukemia (ALL), the most frequent childhood malignancy, these technologies have enabled to characterize the genomic landscape of the disease and have significantly improved the survival rates of ALL patients. Despite this, adverse reactions from treatment such as toxicity, drug res ...[more]

PMID: 33290991

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Project description:BackgroundBlinatumomab, a bispecific monoclonal antibody construct that enables CD3-positive T cells to recognize and eliminate CD19-positive acute lymphoblastic leukemia (ALL) blasts, was approved for use in patients with relapsed or refractory B-cell precursor ALL on the basis of single-group trials that showed efficacy and manageable toxic effects.MethodsIn this multi-institutional phase 3 trial, we randomly assigned adults with heavily pretreated B-cell precursor ALL, in a 2:1 ratio, to receive either blinatumomab or standard-of-care chemotherapy. The primary end point was overall survival.ResultsOf the 405 patients who were randomly assigned to receive blinatumomab (271 patients) or chemotherapy (134 patients), 376 patients received at least one dose. Overall survival was significantly longer in the blinatumomab group than in the chemotherapy group. The median overall survival was 7.7 months in the blinatumomab group and 4.0 months in the chemotherapy group (hazard ratio for death with blinatumomab vs. chemotherapy, 0.71; 95% confidence interval [CI], 0.55 to 0.93; P=0.01). Remission rates within 12 weeks after treatment initiation were significantly higher in the blinatumomab group than in the chemotherapy group, both with respect to complete remission with full hematologic recovery (34% vs. 16%, P<0.001) and with respect to complete remission with full, partial, or incomplete hematologic recovery (44% vs. 25%, P<0.001). Treatment with blinatumomab resulted in a higher rate of event-free survival than that with chemotherapy (6-month estimates, 31% vs. 12%; hazard ratio for an event of relapse after achieving a complete remission with full, partial, or incomplete hematologic recovery, or death, 0.55; 95% CI, 0.43 to 0.71; P<0.001), as well as a longer median duration of remission (7.3 vs. 4.6 months). A total of 24% of the patients in each treatment group underwent allogeneic stem-cell transplantation. Adverse events of grade 3 or higher were reported in 87% of the patients in the blinatumomab group and in 92% of the patients in the chemotherapy group.ConclusionsTreatment with blinatumomab resulted in significantly longer overall survival than chemotherapy among adult patients with relapsed or refractory B-cell precursor ALL. (Funded by Amgen; TOWER ClinicalTrials.gov number, NCT02013167 .).

Project description:During the last few decades, pediatric acute lymphoblastic leukemia (ALL) cure rates have improved significantly with rates exceeding 90%. Parallel to this remarkable improvement, there has been mounting interest in the long-term health of the survivors. Consequently, modified treatment protocols have been developed and resulted in the reduction of many adverse long-term consequences. Nevertheless, these are still substantial concerns that warrant further mitigation efforts. In the current review, pediatric-ALL survivors' late adverse events, including secondary malignant neoplasms (SMNs), cardiac toxicity, neurotoxicity, bone toxicity, hepatic dysfunction, visual changes, obesity, impact on fertility, and neurocognitive effects have been evaluated. Throughout this review, we attempted to answer a fundamental question: can the recent molecular findings mitigate pediatric-ALL chemotherapy's long-term sequelae on adult survivors? For SMNs, few genetic predisposition factors have been identified including TP53 and POT1 variants. Other treatment-related risk factors have been identified such as anthracyclines' possible association with breast cancer in female survivors. Cardiotoxicity is another significant and common adverse event with some germline variants been found, albeit with conflicting evidence, to increase the risk of cardiac toxicity. For peripheral neurotoxicity, vincristine is the primary neurotoxic agent in ALL regimens. Some germline genetic variants were found to be associated with the vincristine neurotoxic effect's vulnerability. However, these were mainly detected with acute neuropathy. Moreover, the high steroid doses and prolonged use increase bone toxicity and obesity risk with some pharmacogenetic biomarkers were associated with increased steroid sensitivity. Therefore, the role of these biomarkers in tailoring steroid choice and dose is a promising research area. Future directions in pediatric ALL treatment should consider the various opportunities provided by genomic medicine. Understanding the molecular bases underlying toxicities will classify patients into risk groups and implement a closer follow-up to those at higher risk. Pharmacogenetic-guided dosing and selecting between alternative agents have proven their efficacy in the short-term management of childhood ALL. It is the right time to think about a similar approach for the life-long consequences on survivors.

Project description:BackgroundThe rat sarcoma virus (RAS) pathway controls cell proliferation, differentiation, and apoptosis, which have been implicated in the pathogenesis of various hematological malignancies. Prognostic importance of RAS gene mutation, relatively frequently in childhood acute lymphoblastic leukemia (ALL), has been debated. We aimed to study RAS gene mutation profile and prognosis in 93 children with newly diagnosed ALL.MethodsWe retrospectively analyzed clinical characteristics, treatment, and outcomes of 93 ALL children during first induction chemotherapy in Anhui Provincial Children's Hospital under the Chinese Children's Leukemia Group-acute lymphoblastic leukemia 2018 (CCLG-ALL-2018). All genomic DNA samples were obtained from bone marrow mononuclear cells upon new diagnosis. RAS gene mutation was performed by polymerase chain reaction (PCR). All children were stratified into standard-, medium-, and high-risk groups, and then treated with risk-based regimens according to CCLG-ALL-2018 protocol.ResultsOf 93 ALL children, 26 (27.9%) were positive for RAS mutation, among whom 19 had N-RAS mutation, 8 had K-RAS mutation, and 1 had a double mutation. The ETV6/RUNX1 fusion gene was the most common genetic alteration (n=16, 17.2%). The most common adverse events during first induction chemotherapy were coagulation abnormalities (n=76, 81.7%), followed by fever (n=71, 76.3%) and alanine transaminase (ALT) elevation (n=34, 36.6%). Compared with negative RAS mutation group, the risk of hyperbilirubinemia was significantly reduced in RAS mutation group (P=0.018), and there was no significant difference in any other adverse events. The average duration of agranulocytosis during first induction chemotherapy was 6 days, and the average duration of agranulocytosis in RAS mutation group and RAS negative group was 6 and 5 days, with no significant difference. Multivariate linear regression analysis showed that in RAS mutation group, when body mass index (BMI) exceeded the median value of this ALL population (BMI >15.38), the risk of agranulocytosis was significantly increased (P=0.003).ConclusionsNewly diagnosed ALL in children with RAS mutation is less likely to be associated with fusion gene expression. RAS mutation increases the risk of agranulocytosis duration during first induction chemotherapy, lowers BMI and reduces the risk of hyperbilirubinemia in ALL children.

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Promising genes and variants to reduce chemotherapy adverse effects in acute lymphoblastic leukemia.

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Promising genes and variants to reduce chemotherapy adverse effects in acute lymphoblastic leukemia.

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