Risk of tumor lysis syndrome in patients with acute myeloid leukemia treated with venetoclax-containing regimens without dose ramp-up.
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ABSTRACT:
SUBMITTER: Shahswar R
PROVIDER: S-EPMC7817590 | biostudies-literature | 2021 Feb
REPOSITORIES: biostudies-literature
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Risk of tumor lysis syndrome in patients with acute myeloid leukemia treated with venetoclax-containing regimens without dose ramp-up.
Shahswar Rabia R Beutel Gernot G Gabdoulline Razif R Koenecke Christian C Markel Dominik D Eder Matthias M Stadler Michael M Gohring Gudrun G Schlegelberger Brigitte B Trummer Arne A Krauter Juergen J Thol Felicitas F Heuser Michael M
Annals of hematology 20200723 2
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Project description:Venetoclax in combination with hypomethylating agents (HMAs) or low-dose cytarabine (LDAC) has demonstrated exceptional activity in elderly and unfit patients with newly diagnosed acute myeloid leukemia (AML). Notably, the safety profile of venetoclax-based induction regimens was favorable, with a low rate of early treatment-related mortality, even in frail study participants. Thus, the introduction of venetoclax has transformed the landscape of AML therapy in elderly patients. Given these promising results, venetoclax in combination with other agents is now being studied as a frontline therapy in younger patients with AML, as well as in relapsed/refractory AML patients. Here, we review clinical data for venetoclax-based therapy in AML, both from prospective as well as retrospective studies, and highlight ongoing novel studies of venetoclax-containing regimens and discuss future research directions.
| S-EPMC7882757 | biostudies-literature
Project description:AbstractVenetoclax has transformed the therapeutic landscape of acute myeloid leukemia (AML). Hypomethylating agents with venetoclax (HMA-VEN) have significantly improved outcomes and have become the standard therapy for older/unfit patients with newly diagnosed AML and are comparable to intensive chemotherapy in salvage setting. Venetoclax with intensive chemotherapy have shown high response rates in both frontline and salvage setting in younger patients, and triplet combinations with HMA-VEN and FLT3 inhibitors have shown encouraging results in FLT3mut AML. While patients with NPM1mut, IDH1/2mut experience favorable outcomes, those with TP53mut and secondary AML may experience minimal benefit from the addition of venetoclax. Despite improved outcomes, severe cytopenias and infectious complications are common with venetoclax-based regimens. Early response evaluation, dose reductions, venetoclax interruptions, use of growth factors, and prophylactic antimicrobials may minimize such myelosuppression and risk of infections. Outcomes after failure of frontline HMA-VEN are dismal, and novel approaches are needed to abrogate primary and acquired resistance.
| S-EPMC8785772 | biostudies-literature
Project description:AbstractVenetoclax is a B-cell lymphoma 2 inhibitor used in chronic lymphocytic leukemia (CLL), which can cause tumor lysis syndrome (TLS). We aimed to determine the incidence of, and risk factors for, TLS among patients with CLL/small lymphocytic lymphoma who received treatment with venetoclax at our institution from 1 January 2016 to 31 December 2020. We included 616 venetoclax escalations among 136 patients with CLL. Overall, 74 patients (54%) underwent escalation exclusively outpatient, 35 (26%) had at least 1 planned hospitalization, and 27 (20%) were escalated exclusively inpatient. During venetoclax initiation, 86% of patients received allopurinol, 71% intravenous hydration, 18% phosphate binders, and 10% prophylactic rasburicase. Among the entire cohort, 7 patients (5.1%) developed laboratory TLS by modified Cairo Bishop criteria and none developed clinical TLS. Incidence of laboratory TLS was 15% for those escalated exclusively inpatient, 2.9% for those with any prophylactic hospitalization, and 2.7% for those escalated exclusively outpatient. Those who developed TLS were more likely to have higher TLS risk, and no additional risk factors were identified. In this single institution retrospective cohort study, laboratory TLS was observed, although clinical TLS was not. Prophylactic measures, including use of IV hydration, may have contributed to low rates of observed TLS in the outpatient setting.
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Project description:Venetoclax is a potent oral, highly selective small-molecule inhibitor of the antiapoptotic B-cell lymphoma 2 protein approved for chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma in treatment-naive patients (in combination with obinutuzumab) or for patients with relapsed/refractory CLL (in combination with rituximab). Venetoclax, in combination with azacitidine, decitabine, or low-dose cytarabine, is also approved in the United States for the treatment of newly diagnosed acute myeloid leukemia (AML) in adults who are ≥ 75 years or have comorbidities that preclude use of intensive induction chemotherapy. Clinical studies of patients with CLL or AML report both hematologic (e.g., neutropenia) and nonhematologic (e.g., gastrointestinal disorders and tumor lysis syndrome) adverse events associated with administration of venetoclax. It is therefore essential to provide information on the appropriate management of venetoclax-associated side effects. This article discusses the efficacy and safety of venetoclax administration and presents strategies specifically for the management of neutropenia and certain nonhematologic adverse events in patients receiving venetoclax for the treatment of AML and CLL.
| S-EPMC9214960 | biostudies-literature
Project description: Not available
| S-EPMC10641872 | biostudies-literature
Project description:PurposeClinical trials of venetoclax reported negligible rates of clinical tumor lysis syndrome (TLS) in patients with chronic lymphocytic leukemia (CLL) when using an extended dose escalation schedule. We aimed to understand TLS prophylaxis, rates of select adverse events (AE), and impact of dosing modifications in routine clinical practice.Experimental designThis retrospective cohort study included 297 CLL venetoclax-treated patients outside of clinical trials in academic and community centers. Demographics, baseline disease characteristics, venetoclax dosing, TLS risk and prophylaxis, and AEs were collected.ResultsThe group was 69% male, 96% had relapsed/refractory CLL, 45% had deletion chromosome 17p, 84% had unmutated IGHV, 80% received venetoclax monotherapy, and median age was 67. TLS risk was categorized as low (40%), intermediate (32%), or high (28%), and 62% had imaging prior to venetoclax initiation. Clinical TLS occurred in 2.7% of patients and laboratory TLS occurred in 5.7%. Pre-venetoclax TLS risk group and creatinine clearance independently predict TLS development in multivariable analysis. Grade 3/4 AEs included neutropenia (39.6%), thrombocytopenia (29.2%), infection (25%), neutropenic fever (7.9%), and diarrhea (6.9%). Twenty-two patients (7.4%) discontinued venetoclax due to an AE. Progression-free survival was similar regardless of number of dose interruptions, length of dose interruption, and stable venetoclax dose.ConclusionsThese data provide insights into current use of venetoclax in clinical practice, including TLS rates observed in clinical practice. We identified opportunities for improved adherence to TLS risk stratification and prophylaxis, which may improve safety.
| S-EPMC8020996 | biostudies-literature
Project description:Venetoclax is a BH3-mimetics agent interacting with the anti-apoptotic protein BCL2, facilitating cytochrome c release from mitochondria, subsequent caspases activation, and cell death. Venetoclax combined with azacitidine (VEN-AZA) has become a new standard treatment for AML patients unfit for intensive chemotherapy. In the phase III VIALE-A study, VEN-AZA showed a 65% overall response rate and 14.7 months overall survival in comparison with 22% and 8 months in the azacitidine monotherapy control arm. Despite these promising results, relapses and primary resistance to venetoclax are frequent and remain an unmet clinical need. Clinical and preclinical studies have been conducted to identify factors driving resistance. Among them, the most documented are molecular alterations including IDH, FLT3, TP53, and the newly described BAX mutations. Several non-genetic factors are also described such as metabolic plasticity, changes in anti-apoptotic protein expression, and dependencies, as well as monocytic differentiation status. Strategies to overcome venetoclax resistance are being developed in clinical trials, including triplet therapies with targeted agents targeting IDH, FLT3, as well as the recently developed menin inhibitors or immunotherapies such as antibody-drug conjugated or monoclonal antibodies. A better understanding of the molecular factors driving venetoclax resistance by single-cell analyses will help the discovery of new therapeutic strategies in the future.
| S-EPMC10969100 | biostudies-literature
Project description: Not available
| S-EPMC10423012 | biostudies-literature
Project description:There is a deficiency of real-world data on the impact of combining venetoclax (VEN) with hypomethylating agents (HMAs) in newly diagnosed acute myeloid leukemia (AML) patients. We conducted a single-center, propensity-adjusted retrospective cohort study to compare composite complete remission (CCR) rates, median overall survival (m-OS) and median event-free survival (m-EFS). A total of 170 adult AML patients were treated with first-line azacitidine (AZA) or decitabine (DEC) +/- VEN. Median age was 71 years and 99 (58%) were male. Median follow-up in HMA and HMA-VEN groups was 79 and 21 months. Treatments included AZA alone (n=35, 21%), DEC alone (n=84, 49%), AZA-VEN (n=24, 14%) and DEC-VEN (n=27, 16%). VEN improved CCR rates to HMAs overall (52% vs. 27%, P<0.05) and to AZA (54% vs. 10%, P<0.05), but not to DEC (43% vs. 32%, P=0.35); it did not improve OS, and only improved EFS for AZA (10.5 vs. 3.8 months, P<0.05). CCR rates were lower with AZA than with DEC (13% vs. 33%, P<0.05), but OS and EFS were not different statistically. CCR rates did not differ for AZA-VEN vs. DEC-VEN (CCR: 58% vs. 52%, P=0.66), but OS and EFS were longer for AZA-VEN (m-OS: 12.3 vs. 2.2 months, P<0.05; m-EFS: 9.2 vs. 2.1 months, P<0.05). Our analysis showed that combining VEN with AZA in newly diagnosed AML patients improved outcomes, but combining VEN with DEC did not. AZA-VEN was associated with improved outcomes compared to DEC-VEN. Further studies are needed to test the benefit of combining VEN with DEC.
| S-EPMC9008336 | biostudies-literature