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.

Keywords: MRD - measurable residual disease; acute myeloid leukemia; low-intensity; treatment; venetoclax.

Figure 1

The concept of MRD. Hypothetical scenarios of leukemia cell burden changes in response to therapy (8). Figure from Buckley SA, et al. BMT 2013 (8).

Figure 2

Prognostic value of measurable residual disease after venetoclax and decitabine in acute myeloid leukemia (10). Figure from Maiti A, et al. Blood Adv 2021 (10). HR, hazard ratio; NR, not reached.

Figure 3

Measurable residual disease response and prognosis in treatment-naıve acute myeloid leukemia with venetoclax and azacytidine. (A) DoR among patients with composite complete remission. (B) Forest plot for DoR in subgroups (20). Figure from Pratz KW, et al. JCO 2021 (20). CR, complete remissions; CRi, complete remission with incomplete hematologic recovery; DoR duration of remission; MRD, measurable residual disease; NR, not reached.