Enhanced Remission and Survival Outcomes with Decitabine Plus Venetoclax in Additional Sex Comb Like 1 Mutated Acute Myeloid Leukemia

Summary

Decitabine combined with Venetoclax shows improved response rates and favourable survival signals compared with decitabine alone in elderly patients with additional sex comb-like 1-mutated adult acute myeloid leukemia who are unfit for intensive chemotherapy. However, early mortality differences were limited, and prospective validation is required.

Abstract

Decitabine (DEC) and Venetoclax (VEN) are approved for elderly adult acute myeloid leukemia (AML) patients with an additional sex comb-like 1 (ASXL1) mutation who cannot tolerate intensive chemotherapy. However, direct comparative data in this population remain limited. A systematic review and meta-analysis were conducted to assess the indirect efficacy of DEC alone and VEN in older AML patients with ASXL1 mutations. A matched cohort was created by comparing outcomes of consecutive adults with AML who received DEC or DEC with VEN after propensity score matching using the nearest-neighbor methodology. The DEC + VEN cohort had a lower early mortality rate than the DEC cohort (30-day mortality: 2.7%-5% vs. 9.7%, p = 0.01; RR = 0.90, 95% CI 0.83-0.97 versus RR = 0.97, 95% CI 0.92-1.02). However, the 30-day and 60-day mortality rates were similar between groups (9.5% vs. 2.7%, p = 0.17; 18.9% vs. 9.5%, p = 0.16). Overall survival (OS) was measured at 7.9-25.1 months. The DEC + VEN cohort had significantly higher response rates than the decitabine cohort. According to the 2017 EL N Genetic Risk classification, people with a favorable moderate risk had a higher rate of complete response or complete response with incomplete hematologic recovery than those with high risk (65% vs. 34%). The use of DEC for 5 or 10 days as the hypomethylating agents combination with VEN did not affect the CR/Cri rate. In conclusion, DEC plus VEN was associated with improved clinical responses and survival signals in ASXL1-mutated AML, warranting prospective confirmation.

Introduction

Adult acute myeloid leukemia (AML) has the highest incidence and fatality rates of any kind of leukemia. It is projected that in 2024, there will be more than 62,000 new patients in the United States alone, the majority of whom will be AML. AML is more common in North America, Europe, and Oceania than it is in Asia and Africa. The incidence of AML varies by geography^1,2,3. Recent epidemiologic analyses indicate that the global incidence of AML has increased markedly over the past decades, particularly among older adults, while overall leukemia incidence has remained stable or declined in some regions⁴. For example, global burden of disease data demonstrates an approximately 80% increase in incident AML cases between 1990 and 2021^4,5. The mortality rate for this type of leukemia is very high, at 60%, and the prognosis is particularly poor in elderly patients, with just 30% of them expected to survive at one year intervals^5,6,7.

An important problem in treating AML in elderly patients is the substantial risk of treatment-related death associated with intensive chemotherapy. Consequently, there is a rising inclination toward less intensive treatment plans, such as the use of hypomethylating drugs in conjunction with venetoclax (VEN). Azacitidine (AZA) plus VEN (AZA+VEN) is now the recommended course of treatment for elderly or frail patients, according to recent trials that demonstrate its superiority over azacitidine alone. Nonetheless, there is ongoing discussion about the effectiveness of VEN and hypomethylating drug combinations in AML, especially concerning the inclusion of "unfit" patients in clinical trials and the reliability of early VEN trials for expedited U.S Food and Drug Administration (FDA) approval^5,6,7,8,9,10.

The possible advantages of intense chemotherapy over VEN-based regimens are also taken into consideration, along with the effect of these regimens on outcomes for patients who are not suited for intensive chemotherapy, in situations in which older patients may still meet clinical eligibility criteria for intensive chemotherapy despite advanced age. In clinical practice, the two most commonly utilized hypomethylating drugs are AZA and decitabine (DEC). AZA or DEC monotherapy has limitations concerning response rates, time to maximal response, and overall survival. As a result, older AML patients urgently require targeted therapies with enhanced tolerability, the capacity to quickly elicit clinical responses, and long-lasting benefits¹¹,¹².

Additional Sex Comb-like 1 (ASXL1) mutations represent one of the most clinically relevant molecular alterations in AML, occurring in approximately 10%-20% of cases and conferring adverse prognosis and poor chemotherapy responsiveness. Despite this, the therapeutic implications of ASXL1 mutations in the context of hypomethylating agents and VEN remain insufficiently defined. One gene that is involved in controlling gene silencing and activation is Additional Sex Comb-like 1 (ASXL1). Many myeloid malignancies, including AML, have been linked to somatic mutations in the ASXL1 gene¹³. These mutations cause loss of a specific protein domain and truncation in exon 12 of the gene¹⁴. The American Journal of Hematology stated that ASXL1 mutations have been linked to improved response and survival in patients with myelodysplastic syndromes (MDS) with excess blasts (EB) after VEN and hypomethylating agent (HMA) therapy. The ASXL1 mutation may function as a potential marker for a favorable response to this combo treatment, while additional validation is required^13,15. In particular, it is thought that ASXL1 plays a role in attracting the Polycomb Repressive Complex 2 (PRC2) to particular loci, such as the HOXA cluster. PRC2 keeps genes in a repressed state by altering chromatin epigenetically. Thus, decreased PRC2 activity following an inactivating ASXL1 mutation causes abnormal gene activation¹⁵.

This PRC2 dysregulation has been associated with altered DNA methylation patterns, upregulation of BCL2, and increased susceptibility to VEN-based therapy, providing a biologic rationale for evaluating VEN-containing regimens specifically in ASXL1-mutated disease. These findings show that AZA sensitivity is linked to ASXL1 mutant cells that display extensive changes in DNA methylation, mostly in gene bodies. Collectively, these findings suggest a potential mechanistic link between ASXL1 mutations, epigenetic dysregulation, and increased sensitivity to VEN- and AZA-based therapy, although further experimental validation is required^16,17,18,19. The frequency and predictive value of ASXL1 mutations in acute myeloid leukemia have not been thoroughly elucidated. The 2022 European LeukemiaNet guidelines have enhanced the molecular classification system for AML patients, leading to better prognoses for patients receiving aggressive chemotherapy. Nevertheless, additional investigation is required to better understand the outcomes associated with less intense treatment approaches involving VEN^20,21. Critically, no randomized trials have directly compared DEC with DEC plus VEN (DEC+VEN) in ASXL1-mutated AML, leaving uncertainty regarding optimal therapy for this high-risk subgroup.

Based on the findings of the VIALE-A trial, the suggested course of treatment for elderly or frail people involves utilizing a hypomethylating agent such as AZA or DEC in conjunction with the oral BCL2 inhibitor VEN. In a randomized phase III clinical study that included participants diagnosed with AML and deemed unfit for intensive treatment, they were given the option to receive either AZA+VEN or a combination of AZA with a placebo^22,23. However, there is a scarcity of real-world studies that evaluate the effectiveness of DEC+VEN in comparison to DEC monotherapy in ASXL1 mutant patients. To address this critical gap, the present study undertook a systematic review and meta-analysis to evaluate the safety and efficacy of DEC-VEN versus DEC alone, specifically in elderly AML patients harboring ASXL1 mutations. By synthesizing available clinical and observational data, this analysis aims to clarify treatment outcomes in this genomically defined subgroup and provide evidence to guide clinical decision-making.

Protocol

Since this research was conducted through a review and analysis of already published data, it did not require ethical approval. All the data utilized in this study were obtained from previously published research, and no information regarding individual patients was accessed. The systematic review was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines (Figure 1). The databases considered are listed in the Table of Materials.

1. Information sources and search strategy

1. Conduct a detailed exploration of pertinent published papers using databases such as PubMed (via NCBI), Web of Science Core Collection, Embase (Elsevier), and the Cochrane Library. Manually search pertinent reference lists to identify any additional relevant trials.
2. Base the search strategy on the following combination of MeSH and keyword terms: ("Decitabine" OR "5-aza-2′-deoxycytidine" OR "Dacogen"), ("Venetoclax" OR "ABT-199" OR "Venclexta"), ("acute myeloid leukemia" OR "AML"), ("older" OR "elderly"), and ("ASXL1 mutations" OR "Somatic mutations in the additional sex comb-like 1").
3. Impose limitations on the population (AML patients aged over 65 years) and on the publishing language (English only).
4. Undertake a comprehensive review of existing literature pertaining to the management of AML. Apply inclusion criteria encompassing double-blind, placebo-controlled, phase II, III, or IV randomized controlled trials of any duration, as well as published systematic reviews, meta-analyses, and randomized controlled trials involving adults aged ≥ 18 years.
   NOTE: Do not impose limits on the publication year, and update the search through March 2024. Acknowledge that the protocol was not registered in PROSPERO as a methodological limitation.

2. Study selection and data management

1. Import all retrieved citations into EndNote X9 to manage references and remove duplicate records. Transfer de-duplicated records to Microsoft Excel for title and abstract screening and subsequent full-text review. Screen each identified article rigorously to assess adherence to predefined inclusion criteria.
2. Use a standardized checklist and a structured Excel form. Screen all citations initially by title and abstract, and conduct a full-text review for eligible records.
   1. Perform article evaluations by a team of three reviewers during both the primary and secondary assessments. Cross-check a random sample of 10% of the screened articles by an independent reviewer to ensure consistency. Apply a positive exclusion approach, excluding only publications that fail to meet one or more inclusion criteria.
3. Consider the following Inclusion and exclusion criteria:
   1. Apply the following criteria to publications eligible for inclusion in this meta-analysis. Confirm adult AML (age ≥18 years). Confirm that decitabine monotherapy was administered to elderly, treatment-naïve AML patients. Confirm that at least one target outcome (CR, ORR, or OS) is reported. Confirm a minimum sample size of 10 participants.
   2. Exclude a study if any of the following conditions apply. Exclude studies that include acute promyelocytic leukemia. Exclude studies that fail to report any target outcomes. Exclude studies that report insufficient data for extraction.
      1. Exclude studies that include fewer than 10 participants. Address potential biases within retrospective studies by applying standardized risk-of-bias assessment tools, performing duplicate screening, and cross-verifying extracted data. Perform sensitivity analyses by excluding high-risk studies when applicable.

3. Data extraction

1. Perform data extraction independently by two reviewers based on predefined eligibility criteria using a standardized Microsoft Excel-based data extraction template developed prior to study selection.
   1. Extract the following data from each included publication: study characteristics, participant characteristics, intervention details, outcome measures, data extraction methods, quality assessment results, and adjusted effect estimates (OR, RR, or HR) with corresponding 95% confidence intervals for patients with acute myeloid leukemia.
2. Identify the following outcomes of interest: quality of life; morphologic complete remission; recurrence rates; severe toxicity (grade ≥3); mortality rates; and burden on caregivers. Also assess measurements related to caregiver burden. Exclude studies involving participants with acute promyelocytic leukemia.

4. Type of interventions

1. Initiate venetoclax at the commencement of treatment and sustain the regimen for the complete 28-day cycle or for a modified shorter period to accommodate toxicity or drug-drug interactions.
2. Administer venetoclax at 20 mg (early escalation cohorts) or 100 mg, and escalate to a target daily dose of 400 mg, 800 mg, or 1200 mg. Within 28-day cycles, combine venetoclax with either azacitidine at 75 mg/m² or decitabine at 20 mg/m² for five or ten days.
3. Administer the decitabine-venetoclax regimen in consecutive 28-day cycles until intolerability, disease progression, or death. Permit cycle delays and dose modifications in response to adverse events or marrow recovery.

5. Definition of outcomes

1. Define complete remission (CR) as bone marrow blasts of less than 5%, peripheral blood neutrophils exceeding 1.0 × 10⁹/L, platelets exceeding 100 × 10⁹/L, and the absence of extramedullary leukemia.
2. Define the overall response rate (ORR) as the combination of partial response, complete remission with incomplete leukocyte or platelet recovery (CRi), and complete remission. Measure overall survival (OS) from study entry until death from any cause or censoring at the last follow-up.

6. Quality assessment

1. Evaluate the certainty of evidence using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach. Assess each outcome across key domains, including risk of bias, inconsistency, indirectness, imprecision, and publication bias, to determine the overall strength of evidence.
   1. Categorize the evidence into four levels of certainty: high, moderate, low, or very low. Downgrade evidence from studies that are otherwise methodologically robust if important limitations are identified within any GRADE domain.

7. Data synthesis and statistical analysis

1. Conduct all meta-analyses using GraphPad Prism software. Express effect sizes as relative risk (RR) or hazard ratio (HR) with corresponding 95% confidence intervals. Apply both fixed- and random-effects models, and select random-effects models when statistical heterogeneity exceeds I² > 50% or when τ² indicates between-study variability.
2. Quantify heterogeneity using the I² statistic and χ² tests. Refrain from formally assessing publication bias (e.g., funnel plots or Harbord/Egger tests) when fewer than ten studies are available.
3. Synthesize treatment effects descriptively across included retrospective studies in the absence of direct head-to-head randomized comparisons, and do not perform adjusted indirect or network comparisons. Limit all analyses to aggregate data reported within each study, and do not perform propensity-matched or additional comparative cohort analyses.

Results

A total of 875 potentially relevant reports (95 from Medline and 780 from Embase) were identified using the approach search strategy. Following the removal of 234 duplicate reports, the relevancy of the 641 remaining reports was assessed by an examination of the abstract and title. A total of 626 studies were excluded based on the following criteria: (1) articles not written in English; (2) reviews, meta-analyses, commentary, editorials, or conference abstracts; (3) reports not relevant to AML with ASXL1 mutation; (4) re...

Discussion

This study characterizes the largest retrospective analysis thus far associating the consequences of combining HMA with VEN versus using HMA alone in AML patients unsuitable for aggressive chemotherapy. The results indicate a survival benefit associated with the combination therapy in a real-world setting, which remained statistically significant after adjustment for baseline prognostic factors. While the interpretational constraints of response data in the study are acknowledged, it is evident that response rates were c...

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
Embase	Elsevier	https://www.elsevier.com/products/embase	Biomedical and pharmacologic database used for systematic search.
GRADEpro GDT	McMaster University / Evidence Prime	https://www.gradepro.org/	Used to generate GRADE certainty profiles and summary tables.
GraphPad Prism (Version 9)	GraphPad Software, LLC	https://www.graphpad.com/features	Software used for data synthesis, forest plots, and statistical modeling.
Medline (via PubMed)	U.S. National Library of Medicine	https://pubmed.ncbi.nlm.nih.gov/	Primary biomedical literature database used for systematic search.
Microsoft Excel (Office 365)	Microsoft	https://www.microsoft.com/en-us/microsoft-365	Used for screening logs, data extraction tables, and study characteristics.
PDF Reader (Adobe Acrobat or equivalent)	Adobe Inc.	https://get.adobe.com/reader/	Used for full-text article review and annotation.
PRISMA 2020 Checklist	EQUATOR Network	https://www.prisma-statement.org/	Reporting guideline used for systematic review compliance.
PRISMA Flow Diagram Tool	PRISMA / University of Oxford	https://www.prisma-statement.org/PRISMAStatement/FlowDiagram	Used to construct the study selection flowchart.
Rayyan (Web-based Screening Tool)	Qatar Computing Research Institute	https://www.rayyan.ai/	Used for blinded title/abstract screening and conflict resolution.
Zotero (Reference Manager)	Corporation for Digital Scholarship	https://www.zotero.org/download/	Used to manage citations and remove duplicate records.