MRD in Venetoclax-Based Treatment for AML: Does it Really Matter?

Abstract

The prognosis of newly diagnosed patients with acute myeloid leukemia is still unfavorable in the majority of cases within the intermediate and mainly adverse genetic risk group but also in a considerable fraction of favorable-risk patients, mainly due to recurrence of disease after complete remission achievement or, less frequently, primary refractoriness. Besides genetic classification at diagnosis, post-treatment prognostic factors include measurable residual disease evaluation in patients in complete remission and in most cases measurable residual disease (MRD) positivity predicts hematologic relapse potentially allowing early therapeutic intervention. Currently, the most commonly used methods for detection of minimal residual disease are multiparameter flow cytometry and quantitative PCR, applicable to around 90% and 50% of patients, respectively. In addition, in > 90% of acute myeloid leukemia (AML) patients, molecular aberrations can be identified by next-generation sequencing, a technology that is widely used in clinical practice for the initial mutational screening at the time of diagnosis but more often, for MRD detection because its flexibility allows almost every mutated gene to be used as an MRD marker. Threshold levels of residual disease and correlation with outcome have been thoroughly studied and established in younger patients treated with intensive induction and consolidation chemotherapy as well as after allogeneic transplantation. Yet, experience on MRD monitoring and interpretation in patients treated with low-intensity regimens, including new agents, is still limited. The updated armamentarium of anti-leukemic agents includes the BCL-2 inhibitor venetoclax, which demonstrated good tolerability, high response rates, and prolonged overall survival when combined with hypomethylating agents or low dose cytarabine in patients considered elderly/”unfit” to tolerate intensive regimens. Although remissions with negative minimal residual disease clearly translated into improved outcomes after intensive treatments, data supporting the same evidence in patients receiving low-intensity venetoclax-based treatments are not still consolidated. We here review and discuss more recent data on the minimal residual disease interpretation and role in AML patients treated with venetoclax-based combinations.

Measurable Residual Disease Detection in Acute Myeloid Leukemia: Current Challenges and Future Directions

“…As described above, the prognostic significance of achieving MRD negativity following intensive chemotherapy or alloSCT has been thoroughly analyzed [ 119 ]. However, as lower intensity regimens with promising response rates, such as the combination of the BCL-2 inhibitor, venetoclax (VEN), and hypomethylating agents (HMA) are increasingly administered in elderly or unfit patients, the role of the MRD status in these populations has become of growing interest [ 119 , 120 , 121 , 122 ]. In comparison to intensive treatment, data from the assessment of MRD in patients treated with low-intensity approaches are still limited (see Table 3 ).…”

“…This limitation likely stems from the initial expectation that most unfit patients would not achieve deep remissions with the available low-intensity treatments. With the addition of VEN to HMAs such as azacitidine (AZA) and decitabine (DEC), a significant improvement in response rates and longer overall survival could be reached, raising the question of whether the achievement of MRD negativity might also be a treatment goal in this patient population [ 122 ].…”

“…Further randomized prospective trials are needed to implement MRD detection in non-intensive regimens into clinical decision making. By collecting prospective data, MRD monitoring may contribute to clinical decisions of therapy deintensification or discontinuation in an MRD-negative AML subgroup in the future [ 122 ].…”

“…For non-intensive treatment strategies including venetoclax + HMA, MRD analysis in CR can be informative, as MRD remains an important prognostic factor for OS in these patients as well [ 121 , 122 , 123 , 124 , 125 , 126 ]. However, with current knowledge, treatment discontinuation is not advised in MRD-negative patients as further prospective data on therapy de-intensification in this patient subgroup are clearly needed [ 127 ].…”

Modern Risk Stratification of Acute Myeloid Leukemia in 2023: Integrating Established and Emerging Prognostic Factors

“…While the prognostic role of MRD is established in young and fit patients receiving intensive chemotherapy, there is limited evidence for its clinical significance in patients treated with low-intensity prolonged regimens, probably reflecting the low chances of deep and prolonged remissions. Recently, the introduction of venetoclax-based combinations led to increased CR rates and response durations, prompting researchers to evaluate MRD impact in this setting as well [ 149 ].…”