TITLE: PROGNOSTIC IMPACT OF MRD NEGATIVITY IN AML PATIENTS TREATED WITH VENETOCLAX BASED THERAPY: A SYSTEMATIC REVIEW AND META ANALYSIS Background: Minimal Residual Disease (MRD) has become an important marker for predicting outcomes in acute myeloid leukemia (AML). There is substantial data demonstrating improved survival and overall prognosis in patients achieving MRD negativity with high intensity induction chemotherapy. However, data available on the clinical utility of monitoring measurable residual disease (MRD) in patients with acute myeloid leukemia treated with venetoclax and hypomethylating agents remains limited. MRD negativity has been associated with improved clinical outcomes; however, the strength and consistency of this prognostic relationship, specifically in venetoclax treated AML populations, remain incompletely defined. To better quantify the survival advantage conferred by MRD negativity in this therapeutic context, we conducted a meta analysis to assess the significance of MRD status in AML patients receiving venetoclax and HMA therapy.

Methods: A systematic review was conducted across PubMed, Embase, and the Cochrane Central Register of Controlled Trials to identify studies published between 2018 and 2025 that met predefined inclusion criteria. Of the 51 articles reviewed, 6 met the eligibility criteria and were included in the final analysis.

Inclusion criteria: (1) adult patients (≥18 years) with newly diagnosed or relapsed/refractory AML, (2) treatment including venetoclax plus HMA, (3) MRD assessment was performed using defined thresholds, with MRD negativity defined as <1 residual blast per 1,000 leukocytes (<10⁻³ or <0.1%), and (4) studies could be observational or interventional, with availability of hazard ratios for survival outcomes stratified based on MRD status.

Exclusion criteria: (1) studies not involving venetoclax/HMA based treatment, (2) studies reporting only response rates without survival outcomes, (3) pediatric AML cohorts, (4) case reports or series with fewer than 10 patients, and (5) duplicate analyses from overlapping patient populations without additional outcome data.

Data from six studies comprising a total of 562 patients were independently abstracted by two reviewers. Pooled hazard ratios for Overall Survival (OS), Event Free Survival (EFS), and Relapse/Progression Free Survival (RFS/PFS) were calculated using a Hartung Knapp Sidik Jonkman random effects model. Between study heterogeneity was assessed using the I² statistic, with values >50% indicating moderate to high variability.

Results: MRD negativity was consistently linked to better survival. The pooled HRs favored MRD negative patients for all outcomes:

• OS: HR 0.31 (95% CI: 0.19, 0.50), with low variability (I² = 31.4%)

• EFS: HR 0.29 (95% CI: 0.11, 0.80), with moderate variability (I² = 64.0%)

• RFS/PFS: HR 0.15 (95% CI: 0.05, 0.48), with low variability (I² = 41.3%)

The strongest relative benefit was seen in RFS/PFS, highlighting the relevance of MRD negativity early for disease control and relapse prevention. Sensitivity analyses excluding individual studies did not significantly alter the pooled estimates, supporting the broader applicability of the observed associations.

Conclusions: This is the first meta analysis to measure the prognostic effect of MRD status in AML patients treated with low intensity treatment regimens. MRD negativity was strongly linked to better outcomes. Even with some variation in effect estimates, the findings were consistent, supporting the use of MRD as a valuable tool for risk assessment in venetoclax based AML therapy. These findings support the integration of MRD status as a meaningful prognostic biomarker in the management of AML treated with lower intensity regimens. MRD may serve not only as an endpoint in clinical trials but also as a valuable tool for guiding post remission strategies, risk adapted therapy, and treatment discontinuation decisions. Future prospective studies can standardize MRD assessment techniques and timing, and validate MRD driven clinical algorithms in venetoclax based AML therapy.

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2025
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