Outcomes of Newly Diagnosed Acute Myeloid Leukemia Patients Treated With Hypomethylating Agents With or Without Venetoclax: A Propensity Score-Adjusted Cohort Study

Ali, Muhamad; Corley, Elizabeth M.; Alharthy, Hanan; Kline, Kathryn A. F.; Law, Jennie Y.; Lee, Seung Tae; Niyongere, Sandrine; Duong, Vu H.; Emadi, Ashkan

doi:10.3389/fonc.2022.858202

Cited by 14 publications

(11 citation statements)

References 26 publications

(28 reference statements)

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“…While we observed that some characteristics such as gender, age, and karyotype were reasonably similar in the considered real-world studies and in the RCT of DiNardo et al, we were not able to evaluate the prevalence of other important prognostic factors (e.g., ECOG performance status scale, baseline cytopenia grade, pre-treatment laboratory values, such as potassium, phosphate, uric acid, calcium, and creatinine) [43]. A possible heterogeneity of the clinical features among patients included in the different studies conducted in this setting was Matthews et al [27], Mustafa et al [38], and Winters et al [42] were considered in this analysis.…”

Section: Discussionmentioning

confidence: 90%

“…Indeed, although the trial of DiNardo et al reported a median overall survival of 14.7 months (95% CI 11.9-18.7), real-world studies showed substantially lower survival. With the only exception of Cherry et al and Mirgh et al, which reported a median survival of more than 15 months, the other authors showed an overall survival ranging between 4 and 13 months [21,24,[26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42]. As a consequence, the pooled median survival in our meta-analysis was 9.37 months (95% CI 8.81-10.5), significantly lower than that reported by DiNardo et al This difference was also confirmed in the secondary analyses that we performed, in particular after we excluded studies enrolling subjects with worse prognoses (i.e., secondary, therapy-related, and TP53mutated AML).…”

Section: Discussionmentioning

confidence: 97%

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Venetoclax with Hypomethylating Agents in Newly Diagnosed Acute Myeloid Leukemia: A Systematic Review and Meta-Analysis of Survival Data from Real-World Studies

Ucciero,

Pagnoni,

Scotti

et al. 2023

Cancers

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In recent years, the association of venetoclax (VEN) with hypomethylating agents (HMAs) significantly improved the outcome of patients with newly diagnosed acute myeloid leukemia (AML) who were unfit for intensive chemotherapy and became the standard of care after the publication of the pivotal RCT VIALE-A. However, it is still not clear to what extent the results observed in the VIALE-A apply to a real-world setting. For this reason, we carried out a systematic review and meta-analysis of real-world studies on newly diagnosed patients with AML, ineligible for intensive induction chemotherapy, receiving first-line VEN+HMA. We then compared their results in term of survival with those from the VIALE-A. Kaplan-Meier curves were extracted from all included studies and individual survival data was reconstructed. We then estimated a pooled survival curve and compared it with the results of the VIALE-A using the log-rank test. We also conducted a secondary analysis including only studies considering VEN plus azacytidine (AZA) as treatment, as this was the schedule originally used in the VIALE-A. Nineteen real-world studies met the inclusion criteria and were included in the systematic review. Most of them reported a worse survival than the VIALE-A. The pooled survival curve was similar to that reported in the VIALE-A during the first three months of treatment but diverged thereafter (p-value = 0.0001). The pooled median survival among the real-world studies was 9.37 months (95%CI 8.81–10.5), substantially lower than that reported in the VIALE-A (14.7 months; 95%CI 11.9–18.7). Results slightly increased when the analysis was restricted to the studies using VEN+AZA as treatment (median survival: 11.5 months; 95%CI 10.2–14.8). Survival of newly diagnosed AML patients treated with VEN+HMAs in a real-world setting seems to be lower than previously reported in the VIALE-A, while the effect of VEN+AZA is more in line with expected results. Future studies are needed to evaluate whether this apparent discrepancy is due to the different characteristics of enrolled patients or to a non-optimal adherence to therapy, and whether alternative regimens can provide better results in terms of safety and effectiveness.

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 97%

Venetoclax with Hypomethylating Agents in Newly Diagnosed Acute Myeloid Leukemia: A Systematic Review and Meta-Analysis of Survival Data from Real-World Studies

Ucciero,

Pagnoni,

Scotti

et al. 2023

Cancers

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“…Retrospective analyses are conflicting, with no definitive differences in response rates between azacitidine‐venetoclax and decitabine‐venetoclax in the first‐line setting [ 16 ]. In one retrospective study, the median overall survival significantly favored the azacitidine‐venetoclax group at 12.3 months compared to 2.8 months with decitabine‐venetoclax [ 17 ]. In contrast, other retrospective analyses showed a non‐significant survival benefit favoring decitabine‐venetoclax over azacitidine‐venetoclax [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

Venetoclax with decitabine or azacitidine in the first‐line treatment of acute myeloid leukemia

Bouligny

Murray

Doyel

et al. 2023

eJHaem

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Treatment paradigms for acute myeloid leukemia (AML) have evolved at a rapid pace in recent years. The combination of venetoclax with a hypomethylating agent prolonged survival in clinical trials when compared to hypomethylating agent monotherapy. However, little is known about the performance of venetoclax‐based regimens outside of clinical trials, given conflicting safety and efficacy data. Even less is known about the impact of the hypomethylating agent backbone. In this study, we demonstrate that decitabine‐venetoclax is associated with a significantly higher rate of grade three or higher thrombocytopenia, but lower rates of lymphocytopenia compared to azacitidine‐venetoclax. There was no difference in response or survival across ELN 2017 cytogenetic risk categories in the overall cohort. Significantly more patients succumb to relapsed or refractory disease than death from any other cause. We demonstrated that a Charlson comorbidity index score threshold of seven identifies exceptionally high‐risk patients, providing evidence for clinical use to reduce the risk of early treatment‐related mortality. Lastly, we provide evidence that measurable residual disease negativity and an IDH mutation predict a significant survival benefit outside clinical trials. Taken together, these data illuminate the real‐world performance of venetoclax and decitabine or azacitidine in the treatment of AML.

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“…Hypomethylating agents, such as azacytidine and decitabine, have become a milestone in treatment of older AML and high-risk MDS patients with good efficacy and safety profile ( Serio B et al, 2022 ). In 2018, the Bcl-2 inhibitor venetoclax has been added to hypomethylating agents or low-dose cytarabine for treatment of newly diagnosed AML patients aged 75 or older not eligible for high-dose standard chemotherapy based on phase III clinical trial results ( DiNardo CD et al, 2020 ; Stein EM et al, 2020 ; Pollyea DA et al, 2021 ; Labrador J et al, 2022 ; Mustafa Ali MK et al, 2022 ; Wolach O et al, 2022 ). However, real-world data are still few.…”

Section: Discussionmentioning

confidence: 99%

Clinical efficacy of azacytidine and venetoclax and prognostic impact of Tim-3 and galectin-9 in acute myeloid leukemia and high-risk myelodysplastic syndromes: A single-center real-life experience

et al. 2022

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Treatment of acute myeloid leukemia (AML) and high-risk myelodysplastic syndromes (MDS) is difficult in older patients with comorbidities and high-risk disease factors. Venetoclax, the first-in-class Bcl-2 inhibitor, has proven efficacy and safety in combination with azacytidine for treatment of high-risk myeloid diseases. In this single-center real-life retrospective study, a total of 27 consecutive patients treated with azacytidine plus venetoclax were included, and clinical outcomes, hematological improvements, and biomarkers of responsiveness to therapy were compared to those observed in an historical cohort of 95 consecutive patients treated with azacytidine as single agent. Azacytidine plus venetoclax was effective and safe in older and frail AML and high-risk MDS patients, with median overall survival of 22.3 months, higher than that reported in phase III trial (14.7 months), and higher than that of historical cohort (5.94 months). Progression-free survival was higher in patients treated with the drug combination compared to those treated with azacytidine as single agent (p = 0.0065). Clinical benefits might increase when azacytidine and venetoclax are administered as upfront therapy (p = 0.0500). We showed that Tim-3 expression could be a promising therapeutic target in refractory/relapsed patients, and galectin-9 a biomarker of responsiveness to therapy. Moreover, patients treated with azacytidine and venetoclax displayed a higher overall survival regardless the presence of negative prognostic markers at diagnosis (e.g., increased WT1 copies and/or normalized blast count). These encouraging results in a real-world setting supported efficacy and safety of azacytidine plus venetoclax as upfront therapy in AML and high-risk MDS, with clinical outcomes comparable to those of clinical trials when an appropriate venetoclax management with bone marrow assessment at every first, second, fourth, and eighth cycle, and dose adjustments for toxicities are performed.

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Outcomes of Newly Diagnosed Acute Myeloid Leukemia Patients Treated With Hypomethylating Agents With or Without Venetoclax: A Propensity Score-Adjusted Cohort Study

Cited by 14 publications

References 26 publications

Venetoclax with Hypomethylating Agents in Newly Diagnosed Acute Myeloid Leukemia: A Systematic Review and Meta-Analysis of Survival Data from Real-World Studies

Venetoclax with Hypomethylating Agents in Newly Diagnosed Acute Myeloid Leukemia: A Systematic Review and Meta-Analysis of Survival Data from Real-World Studies

Venetoclax with decitabine or azacitidine in the first‐line treatment of acute myeloid leukemia

Clinical efficacy of azacytidine and venetoclax and prognostic impact of Tim-3 and galectin-9 in acute myeloid leukemia and high-risk myelodysplastic syndromes: A single-center real-life experience

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