Achieving complete morphological remission has been considered a first step in achieving a cure in patients with acute myeloid leukemia (AML).¹ One of the tools used to detect leukemic cells is measurable residual disease (MRD), formerly referred to as minimal residual disease. MRD in AML as an independent postdiagnosis prognosticator has grown in importance. Its role in risk stratification and treatment planning also contributes to its impact.

For example, a meta-analysis of 81 publications reporting on 11,151 patients with AML determined that the disease-free survival was 64% for patients without MRD and 25% for patients with MRD. The analysis further demonstrated that overall survival (OS) was 68% for patients without MRD and 34% for those with MRD.²

During a presentation at the 2023 American Association for Cancer Research Special Conference: Acute Myeloid Leukemia and Myelodysplastic Syndrome, Farhad Ravandi-Kashani, MD, addressed the use of MRD in the setting of lower- intensity therapy in AML.³

“Traditionally, studies have been conducted in patients treated with intensive cytotoxic chemotherapy,” Ravandi-Kashani said. “There have been very little data concerning lower-intensity therapy because it is a fairly new concept in therapy.” Ravandi-Kashani is the Janiece and Stephen A. Lasher Professor of Medicine and chief of developmental therapeutics in the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston.

The addition of venetoclax (Venclexta) to hypomethylating agents such as azacitidine and decitabine has resulted in positive responses. Maiti A et al⁴ assessed MRD after venetoclax-based lower-intensity regimens were administered to older, unfit patients with AML in a phase 2 trial (NCT03404193). The investigators found that 83 patients achieved either a complete remission (CR) or a CR with incomplete hematologic recovery (CRi) and 52 patients became MRD negative.⁴

Median time to becoming MRD negative was 2.0 months (IQR, 0.9-3.1 months). Patients becoming MRD negative by 2 months had longer relapse-free survival (RFS) compared with those remaining MRD positive (median RFS, not reached vs 5.2 months, respectively; HR, 0.31; 95% CI, 0.12-0.78; P = .004). MRD-negative status also resulted in longer event-free survival (EFS) (median EFS, not reached vs 5.8 months; HR, 0.25; 95% CI, 0.12-0.55; P < .001) and longer OS (median OS, 25.1 vs 7.1 months; HR, 0.23; 95% CI, 0.11-0.51; P < .001).⁴

In the same study, mutational subgroups such as NPM1, FLT3, IDH1/2, TP53, and others were evaluated. The investigators reported a high response rate in these subsets of patients with high levels of MRD negativity recorded by multiparameter flow cytometry. Roughly 2 months after starting therapy, which equates to 2 cycles of treatment, patients who became MRD negative had a significantly better RFS and OS compared with patients who were MRD positive.⁴

“I think this tells us that for these newer, more effective lower-intensity regimens, MRD assessment is relevant and important,” Ravandi-Kashani said. The Viale-A study (NCT02993523) evaluated outcomes of patients treated with venetoclax plus azacitidine who achieved composite CR (cCR) and MRD status less than 10^-3. Among evaluable patients (n = 164), 41% achieved MRD less than 10^-3 and 59% had MRD of 10^-3 or greater. The median duration of response, EFS, and OS were not reached in patients with cCR and MRD less than 10^-3.⁵

At 12 months, duration of response, EFS, and OS were 81.2%, 83.2%, and 94.0%, respectively. Pratz et al reported that multivariate analysis showed that cCR with MRD less than 10^-3 was a strong predictor of OS (adjusted HR, 0.285; 95% CI, 0.1590.510; P < .001).⁵

Timing of MRD Assessment

Ravandi-Kashani raised a question about the timing of conducting the MRD assessment. He noted that in patients who received intensive treatment, MRD is assessed after 1 or 2 cycles of induction and usually at the end of consolidation therapy. But in the lower-intensity therapy setting, the best time to assess MRD has yet to be determined.

He noted that Pratz et al evaluated MRD status after cycle 1, 4, 7, and beyond 7. The investigators reported that approximately the same proportion of patients became MRD negative at these time points.⁵ “When they looked at patients who were negative after just 1 cycle and compared that [with] anyone who became negative beyond the first cycle, they showed that in terms of survival, these findings were super imposable,” Ravandi-Kashani said. “[The investigators] said that when you’re using these lower-intensity regimens, you can actually have a delay in terms of the final time that you become MRD negative and that probably still leads to a better survival [FIGURE⁵].”

Other studies also addressed the issue of timing of MRD assessment, Ravandi- Kashani said. Cicconi et al,⁶ for example, showed that after induction, the reduction of promyelocytic leukemia–retinoic acid receptor α transcripts was greater in patients treated with arsenic trioxide and all-trans retinoic acid compared with standard alltrans retinoic acid and chemotherapy in newly diagnosed, low-intermediate–risk acute promyelocytic leukemia. “This could also apply to other differentiating low-intensity regimens,” Ravandi-Kashani said.

Achieving MRD Negativity Is the Goal

“In these retrospective analyses, it appears achieving MRD negativity or achieving CR with MRD negative should be the goal of therapy,” Ravandi-Kashani said. “The form of therapy is not going to be as important.” Ravandi-Kashani did, however, caution that more research is still needed to establish the low-intensity regimen.

REFERENCES

1. Stein EM, Tallman MS. Remission induction in acute myeloid leukemia. Int J Hematol. 2012;96(2):164-170. doi:10.1007/s12185-012-1121-y

2. Short NJ, Zhou S, Fu C, et al. Association of measurable residual disease with survival outcomes in patients with acute myeloid leukemia: a systematic review and meta-analysis. JAMA Oncol. 2020;6(12):1890-1899. doi:10.1001/jamaoncol.2020.4600

3. Ravandi F. Measurable residual disease assessment in lower-intensity therapy in AML. Presented at: 2023 American Association for Cancer Research Special Conference: Acute Myeloid Leukemia and Myelodysplastic Syndrome; January 23-25, 2023; Austin, Texas. Accessed February 8, 2023. https://bit.ly/40UoRZV

4. Maiti A, DiNardo CD, Wang SA, et al. Prognostic value of measurable residual disease after venetoclax and decitabine in acute myeloid leukemia. Blood Adv. 2021;5(7):1876–1883. doi:10.1182/bloodadvances.2020003717

5. Pratz KW, Jonas BA, Pullarkat V, et al. Measurable residual disease response and prognosis in treatment-naïve acute myeloid leukemia with venetoclax and azacitidine. J Clin Oncol. 2022;40(8):855-865. doi:10.1200/JCO.21.01546

6. Cicconi L, Divona M, Ciardi C, et al. PML-RARα kinetics and impact of FLT3-ITD mutations in newly diagnosed acute promyelocytic leukaemia treated with ATRA and ATO or ATRA and chemotherapy. Leukemia. 2016;30(10):1987-1992. doi:10.1038/leu.2016.122