Progress in Disease Detection Sets the Stage for MRD’s Role in AML

For patients with acute myeloid leukemia (AML) advances in targeting minimal residual disease (MRD) represents the next wave of advances in the field and is necessary to cure AML, according to Farhad Ravandi-Kashani, MD.

“We have known for a long time that achieving complete morphological remission is the first step toward achieving a long-term, better outcomes or cure in patients with AML,” Ravandi-Kashani said in a presentation during the 27th Annual International Congress on Hematologic Malignancies^®: Focus on Leukemias, Lymphomas, and Myeloma. “We have better technologies for detecting any residual disease and, essentially, the [we can apply] these newer and sophisticated technologies to detect any residual leukemia after your initial induction or consolidation therapy.” Ravandi-Kashani is the Janiece and Stephen A. Lasher Professor of Medicine and chief of section of developmental therapeutics in the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston.

MRD detection in AML leverages cutoff points garnered from various detection methods include flow cytometry or real-time quantitative polymerase chain reaction (pCR).^1,2 Real-time pCR, which has sensitivity of 10^–4 to 10^–6 with a turnaround time of 2 to 5 days. Other detection methods in 8 to 16 color flow cytometry have reported detection up to 10^–4 with a turnaround time of 1 to 2 days.¹ “We have been relying on just morphology and this is not very sensitive, looking at only about 500 cells usually,” Ravandi-Kashani said. “Then we had, more recently, more sensitive assays such as multiparameter, flow cytometry, as well as molecular assays for the aberrations that can be detected molecularly with much more sensitivity, going down to 10^–4 or even higher.” Ravandi-Kashani added that even more sensitive assays are on the horizon with digital pCR and next-generation sequencing (NGS) improvements being added to development.

Using NGS to detect MRD showed promise in the 2018 study from Jongen-Lavrencic et al, which reported that the detection of persistent DTA mutations such as DNMT3A, TET2, and ASXL1 were not association with an increased relapse rate. However, the detection of molecular MRD was associated with a significantly higher rate of relapse vs no detection of MRD (HR, 2.14). Ravandi-Kashani noted that this assay was not highly sensitive, but subsequent NGS assays, including the one used in the QuANTUM-First trial (NCT02668653), were better able to detect MRD at sensitivity of 10^–4, a key secondary end point of the study.³

“In the overall population of patients who became MRD negative by this assay, which is down to the 10^–4 or even lower, patients did better if they became negative, or if the FLT3-ITD mutations became negative,” Ravandi-Kashani said. In the study 539 patients with FLT3-ITD–positive AML were randomly assigned to quizartinib (n = 268) or placebo (n=271). Treatment with quizartinib was noted to result in a 3-fold lower level of FLT3­-ITD MRD among patients who achieved composite complete remission (CRc) vs placebo (P = .017).³

For patients with detectable MRD treated with quizartinib (n = 85) or placebo (n = 98) who had MRD the CRc rates were 24.6% 21.4%, respectively (P = .385). Among those with MRD negativity, the CRc rate with quizartinib (n = 77) was 13.8% vs 7.4% with placebo using a cutoff of 10^–5 or less (P = .017). The Median OS among those who had MRD-negative disease was not reached compared with 29.4 months for those with MRD-positive disease (HR, 0.56; 95% CI, 0.38-0.79).³

In addition to the specific analyses, Ravandi-Kashani cited findings from a meta-analysis of over 80 publications and over 11,000 patients.⁴ “These publications over the years using various assays for detecting MRD, including flow and molecular assays have clearly shown that if you become MRD-negative in AML, you do better in terms of disease-free [survival] and OS.” However, these studies have limitations in terms of applicability as they were all conducted among patients who had received high-intensity induction and consolidation therapy with cytarabine- and anthracycline-based regimens.

“We have now begun to rely more and more on lower-intensity [regimens] including venetoclax [Venclexta]-based regimens, particularly [when treating] older patients with AML,” Ravandi-Kashani said. “The question is: Is MRD clearance also relevant in the patients who are treated with these lower intensity regimens?”

Early studies prior to venetoclax showed that among patients who received a single-agent hypomethylating agent such as decitabine, who became MRD-negative had better relapse rates; however, this did not translate to better outcomes, according to Ravandi-Kashani. “Perhaps because single-agent hypomethylating agents, as you all know, are not highly effective strategies for treating AML. Of course, you will know that venetoclax has really changed the landscape of therapy in AML, particularly for the older patients. I’m sure you all have been using hypomethylating agents plus venetoclax to treat your older patients.”

Combinations such as venetoclax and azacitidine (Vidaza) in the VIALE-A study (NCT02993523) showed high response rates among subsets of patients with AML, including those with NPM1-mutant disease.⁵ “When we assess these [patients] for MRD by flow cytometry, you can you see that a significant proportion of patients become MRD negative,” Ravandi-Kashani said.

MRD negativity in the study was defined as less than 10–3 or 0.01% via multiparametric flow cytometry. Among 164 patients who achieved CRc, 41% were MRD negative. The median duration of remission (DOR), event-free survival (EFS), and OS were not reached in this cohort compared with 9.7 months, 10.6 months, and 18.7 months for those who were positive for MRD. The 12-month DOR for the MRD-negative and MRD-positive groups was 81.2% vs 46.6%, respectively, and the and 18-month DORs were 69.6% vs 33.5%, respectively.⁵

“And this was true across the board in all the subsets that were evaluated,” he said. “In terms of OS, the patients who were less than 10^–3 by flow cytometry did significantly better compared with those who remain MRD persistent. A multivariate analysis [showed that] achieving an MRD negative status, as well as the cytogenetic risk, intermediate or adverse, were the only 2 factors that were associated with OS.”

Ravandi-Kashani cited another trial assessing molecular MRD in venetoclax-based, lower-intensity regimens, which showed that MRD was highly predictive of remission among patients with NPM1-mutated disease.⁶ For all patients, the 18-month OS rate was 61% and those with the deepest MRD response within the first 6 months was associated with better OS; the 18-month OS rate for those with MRD negativity was 95%.⁶

“I think this is very important because we have to think about how we are going to analyze MRD in our lower intensity regimens, and particularly, the time points of assessment,” Ravandi-Kashani said.

A study published during the ASH meeting also pointed to how MRD can supersede treatment intensity in predicting outcomes for patients with AML in a single-center study at MD Anderson. The retrospective study assessed patients with AML who achieved a CR, CR with incomplete count recovery, or morphologic leukemia-free state, treated at MD Anderson from 2010-2021. Patients were split into high-intensity (n = 385) and low-intensity (n = 250) cohorts and the key outcomes measures were OS and cumulative incidence of relapse (CRI). The median ages were reflective of the regimens used at 52 years and 71 years, respectively.

For patients who achieved MRD-negativity the median OS in the high-intensity group was 51 months (95% CI, 27.7-83.5) vs 24.6 months (95% CI, 14.5-43.7) in the low-intensity group (P = .002). In those who were MRD-positive, the median OS was 15.1 months (95% CI, 10.2-20.2) vs 9.9 (95% CI, 7.6-11.7), respectively (P = .035). The 2-year CRI rates were 41.1% vs 33.5% with high- and low-intensity regimens in the MRD-negative group. These rates were 62.2% vs 59.9% in the MRD-positive group.⁷

“When we do a multivariate analysis, the intensity of therapy disappears in terms of being important,” Ravandi-Kashani said. “So the only factors that remain relevant are again, age, CR vs lessor responses, MRD clearance, and cytogenetic risk group—it doesn’t matter whether [the regimen was] intensive or low plus venetoclax. And this is also true for patients over the age of 60 [years].”

Ravandi-Kashani cautioned that due to low numbers (n = 11) for patients under the age of 60 in the low-intensity cohort, the conclusions from this study are limited to older patients.

With ongoing efforts across the field, Ravandi-Kashani said: “We hope to be able to uncover mechanisms of MRD resistance in patients by comparing the transcriptional and genomic profile of patients at the time of diagnosis, as well as after treatment in the MRD setting…I think it’s a good idea to try to develop MRD-eradicating strategies. I think it’s not a dream, because we have seen this already in acute lymphoblastic leukemia with blinatumomab [Blincyto]… So hopefully, we will have strategies to be able to eradicate MRD in patients with AML.”

References

1. Ravandi-Kashani F. Assessment of MRD in AML— applications to intensive and low-intensity regimens. Presented at: 27th Annual International Congress on Hematologic Malignancies^®: Focus on Leukemias, Lymphomas, and Myeloma; February 23-26, 2023; Miami, FL.
2. Schuurhuis GJ, Heuser M, Freeman S, et al. Minimal/measurable residual disease in AML: a consensus document from the European LeukemiaNet MRD Working Party. Blood. 2018;131(12):1275-1291. doi:10.1182/blood-2017-09-801498
3. Levis MJ, Erba HP, Montesionos P, et al. Quantum-First trial: FLT3-ITD–specific MRD clearance is associated with improved overall survival. Blood. 140(suppl 1):546-548. doi:10.1182/blood-2022-162739
4. 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
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. Othman J, Tiong IS, Mokretar K, et al. Molecular MRD assessment is strongly prognostic in patients with NPM1 mutated AML receiving venetoclax based non-intensive therapy. Blood. 2022;140(suppl 1):2033-2035. doi:10.1182/blood-2022-159467
7. Bazinet A, Kadio TM, Short N, et al. Achievement of measurable residual disease (MRD) negativity supersedes treatment intensity in predicting the outcome of patients with acute myeloid leukemia. Blood. 2022;140(suppl 1):2267-2269. doi:10.1182/blood-2022-162892