Efficacy of the combination of venetoclax and hypomethylating agents in relapsed/refractory acute myeloid leukemia.
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ABSTRACT:
SUBMITTER: Aldoss I
PROVIDER: S-EPMC6119155 | biostudies-literature | 2018 Sep
REPOSITORIES: biostudies-literature
Publications
Efficacy of the combination of venetoclax and hypomethylating agents in relapsed/refractory acute myeloid leukemia.
Aldoss Ibrahim I Yang Dongyun D Aribi Ahmed A Ali Haris H Sandhu Karamjeet K Al Malki Monzr M MM Mei Matthew M Salhotra Amandeep A Khaled Samer S Nakamura Ryotaro R Snyder David D O'Donnell Margaret M Stein Anthony S AS Forman Stephen J SJ Marcucci Guido G Pullarkat Vinod V
Haematologica 20180315 9
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| S-EPMC8855495 | biostudies-literature
Project description:Off-label hypomethylating agents and venetoclax (HMA/VEN) are often used for relapsed and refractory (R/R) AML patients. However, predictors of outcome are elusive. The objective of the current retrospective observational multicenter study of 240 adult patients (median age 68.6 years) with R/R AML was to establish a prognostic risk score. Overall response was documented in 106 (44%) patients. With a median follow-up of 31.5 months, 179 deaths were recorded. Median overall survival (mOS) was 7.9 months. In multivariate analysis of the subgroup with molecular information (n = 174), risk factors for inferior survival included the presence of extramedullary disease, HMA pretreatment and mutations in NF1, PTPN11, FLT3, and TP53, whereas mutated SF3B1 was identified as favorable risk factor. These risk factors were subsequently applied to construct an HR-weighted risk model that allocated patients to one of three risk groups with significantly different survival outcomes: favorable (n = 46; mOS 21.4 months), intermediate (n = 75; mOS 7.5 months), and adverse (n = 53; mOS 4.6 months; p < 0.001). The model was validated in 189 AML patients treated with HMA/VEN in first line. This clinical-molecular, 3-tiered venetoclax prognostic risk score (VEN-PRS) for HMA/VEN treatment outcomes in R/R AML patients will support the selection of appropriate treatment options in this high-risk population.
| S-EPMC11879869 | biostudies-literature
Project description: Not available
| S-EPMC7927994 | biostudies-literature
Project description:Relapsed/refractory acute myeloid leukemia (AML) is a devastating disease with a poor prognosis and represents a major unmet medical need. We report on a real-world academic center experience of treating 25 patients with relapsed/refractory AML using venetoclax in combination with decitabine or azacitidine, which is not otherwise widely evaluated in the current literature. Our patients come from a large, socioeconomically and geographically diverse area including the majority of Northern California. Most had ELN Adverse Risk (52%) or Intermediate Risk (44%) AML, and most had an ECOG Performance Status of 1 (64%). Over half (52%) had prior hypomethylating agent exposure, and 40% had Secondary AML. We observed an overall response rate of 52%, with eight patients (32%) achieving composite complete remission. Median overall survival was 5.5 months, and for patients achieving composite complete remission this was 21.6 months. One-year estimated overall survival was 38%. Three patients were able to proceed directly to stem cell transplant for consolidation, and all three were alive at last follow-up, ranging 13.8-24.0 months. We found venetoclax in combination with hypomethylating agents to be well tolerated and potentially efficacious in securing long-term remissions for patients with relapsed/refractory AML.
| S-EPMC7991747 | biostudies-literature
Project description:Recently, the combination of VEN-HMA has been shown to achieve durable responses in patients with both newly diagnosed (ND) and R/R-AML. We retrospectively evaluated the post-allo-HCT outcomes of 50 patients who received VEN-HMA therapy. In total, 10 were ND and 40 were R/R and, at the time of HCT, the median age was 53 years. In the ND- and R/R-AML groups, the percentage of patients who achieved CR/CRi or MLFS was 90% and 92.5%, respectively. In all, after a median follow-up of 13.7 months, the probabilities of overall survival (OS), relapse-free survival (RFS), cumulative incidence of relapse (CIR), and nonrelapse mortality (NRM) at 1 year were 63.7%, 59.3%, 28.5%, and 12.2%, respectively. In addition, the cumulative incidences of grade II-IV acute graft-versus-host disease (GVHD) and moderate-severe chronic GVHD at 1 year were 28.4% and 37.4%, respectively. In multivariate analysis, the factors associated with a statistically significant impact on OS were VEN-HMA cycle (p = 0.021), ELN risk group (p = 0.041), and the response to VEN-HMA therapy before allo-HCT (p = 0.003). Although 80% of our patients had R/R-AML and 30% underwent a second allo-HCT, our data still suggest that allo-HCT following VEN-HMA therapy is a safe and effective treatment option.
| S-EPMC10046472 | biostudies-literature
Project description:Hypomethylating agents (HMAs) in combination with venetoclax have been widely adopted as the standard of care for patients who cannot tolerate induction chemotherapy and for patients who have relapsed/refractory (R/R) acute myeloid leukemia (AML). This study retrospectively analyzed the outcomes of all patients with AML (n = 65) or myelodysplastic syndrome (n = 7) who received the combination of HMA and venetoclax at our institution. Outcomes measured included complete remission (CR) and CR with incomplete hematologic recovery (CRi) rates, duration of response (DOR), and overall survival (OS). Patient mutational profiles and transfusion requirements were also assessed. Of 26 newly diagnosed AML patients, the CR/CRi rate was 53.8%. The median DOR and OS were 6.9 months and not reached, respectively. Of 39 R/R AML patients, the CR/CRi rate was 38.5%. The median DOR and OS were both 8.1 months. Responders to HMA and venetoclax were enriched for TET2, IDH1, and IDH2 mutations, while nonresponders were associated with FLT3 and RAS mutations. Adaptive resistance was observed through various mechanisms including acquired RAS pathway mutations. Of transfusion-dependent patients, 12.2% and 15.2% achieved red blood cell (RBC) and platelet transfusion independence, respectively, while 44.8% and 35.1% of RBC and platelet transfusion independent patients, respectively, became transfusion dependent. In total 59.1% of patients developed a ≥grade 3 infection and 46.5% neutropenic fever. HMA + venetoclax can lead to impressive response rates with moderately durable remissions and survival. However, the benefits of this combination are diminished by the significant toxicities from infection, persistent cytopenias, and transfusion requirements.
| S-EPMC7951133 | biostudies-literature
Project description:BackgroundAs we delve into the intricate world of venetoclax combination therapy in relapsed or refractory acute myeloid leukemia (AML), our exploration not only aims to contribute to the current body of knowledge but also strives to inform future research directions, clinical decision-making, and the ongoing evolution of therapeutic strategies in the relentless pursuit of improved outcomes for patients facing this formidable hematologic malignancy.MethodsWe systematically searched PubMed, Embase, and Cochrane databases from inception to November 2023 for English-language studies on venetoclax combination therapy in relapsed/refractory AML. We excluded duplicate published studies, incomplete studies, those with incomplete data, animal experiments, literature reviews, and systematic studies. Meta-analysis was performed using STATA 15.1.ResultsOut of 58 identified articles, seven were included in the meta-analysis. The pooled complete remission (CR) rate was 15.4%, and the composite complete remission (CRc) rate was 35.7%. The partial remission (PR) rate was 2.6%, while the non-remission (NR) rate was 24.4%. The minimal residual disease status in CRc patients (MRD-CRc) rate was 39.4%, and the morphologic leukemia-free state (MLFS) rate was 10.3%. Incidence of adverse events included diarrhea (10.0%), nausea (4.3%), vomiting (2.6%), hypokalemia (16.4%), hypomagnesemia (0.8%), decreased appetite (4.2%), fatigue (9.1%), febrile neutropenia (39.6%), and thrombocytopenia (28.4%). Subgroup analysis based on combined drugs revealed varying CR and CRc rates. the combination of venetoclax and azacitidine + demonstrates superior outcomes, displaying the highest rates of CR at 31.3% and CRc at 62.7%. In contrast, venetoclax and idasanutlin exhibits a moderate CR rate of 6.1% and a CRc rate of 26.5%, while venetoclax and mivebresib shows the lowest CR rate at 3.3% and a moderate CRc rate of 8.0%.ConclusionIn conclusion, while venetoclax combination therapies, particularly with azacitidine + , show promise in achieving favorable treatment responses in relapsed/refractory AML patients, a comprehensive evaluation of safety profiles is essential. Nevertheless, it is essential to underscore the markedly increased incidence rates of febrile neutropenia and thrombocytopenia observed among adverse events.
| S-EPMC11472599 | biostudies-literature
Project description:IntroductionCurrently, there are only a few avaailable treatment options for patients with relapsed and refractory acute myeloid leukemia (R/R AML).MethodsWe conducted a single-center, phase 1 prospective study (ChiCTR2200065634) to evaluate the efficacy and safety of chidamide, demethylating drugs (azacitidine), cytarabine, aclacinomycin, and G-CSF plus venetoclax (CDCAG-VEN) in patients with R/R AML. The previous CDCAG regimen was used as a historical control to compare its efficacy and safety. Thirty and 22 patients received one course of CDCAG with or without a 14-day course of venetoclax, respectively.ResultsThe overall response rate (ORR) was significantly higher in the CDCAG-VEN group than in the CDCAG-treated group (78.6% vs. 45.5%; p = 0.015), and the CDCAG-VEN group achieved a better trend of measurable residual disease-negative response (61.1% vs. 22.2%, p = 0.134). Compared with the CDCAG group, the CDCAG-VEN group exhibited significantly better 1-year overall survival (63.3% vs. 35.1%, p = 0.005) and progression-free survival (76.7% vs. 36.0%, p = 0.022). The duration of response was notably better in the CDCAG-VEN group than in the CDCAG group (71.2% vs. 34.3%, p = 0.021) and had a lower cumulative incidence of relapse (22.2% vs. 48.9%, p = 0.095). The neutrophil and platelet recovery times were similar between the CDCAG-VEN and CDCAG groups (neutrophil: 18 days vs. 19 days, p = 0.293; platelet: 18 days vs. 19 days, p = 0.311). The frequencies of adverse events were comparable between both groups, except for a lower incidence of thrombosis in the CDCAG-VEN group (0% vs. 22.7%, p = 0.006).DiscussionIn conclusion, venetoclax in combination with CDCAG is an effective and safe treatment regimen for R/R AML, thereby rapidly identifying chemosensitive patients and inducing measurable residual disease-negative remission in a high proportion of patients with R/R AML.
| S-EPMC11891779 | biostudies-literature
Project description:Despite the progress in the development of new therapeutic strategies, relapsed/refractory (R/R) acute myeloid leukemia (AML) still represents a high unmet medical need. Treatment options in this setting include enrollment into clinical trials, allogeneic stem cell transplantation and/or targeted therapy. Nevertheless, it is associated with poor outcomes. Thus, the development of new treatments, which could ameliorate the prognosis of these patients with a good safety profile are highly demanded. Recently, venetoclax (VEN) has been approved for naïve AML patients unfit for intensive chemotherapy. In this regard, regimens including VEN could represent a valuable treatment option even in those with R/R disease and several studies have been conducted to demonstrate its role in this clinical setting. This review aims to summarize the current evidence on the use of VEN regimens in the treatment of R/R AML.
| S-EPMC8750253 | biostudies-literature
Project description:Acute myeloid leukemia (AML) is the most common acute leukemia in adults. While induction chemotherapy leads to remission in most patients, a significant number will experience relapse. Therefore, there is a need for novel therapies that can improve remission rates in patients with relapsed and refractory AML. CD70 is the natural ligand for CD27 (a member of the TNF superfamily) and appears to be a promising therapeutic target. Consequently, there is considerable interest in developing chimeric antigen receptor (CAR) T-cell therapy products that can specifically target CD70 in various neoplasms, including AML. In this study, we employed routine diagnostic techniques, such as immunohistochemistry and flow cytometry, to investigate the expression of CD70 in bone marrow samples from treatment-naïve and relapsed AML patients after hypomethylating agents (HMA). Also, we evaluated the impact of HMA on CD70 expression and examined CD70 expression in various leukemic cell subsets and normal hematopoietic progenitors.
| S-EPMC11564407 | biostudies-literature