MRD’s Role in AML Continues to Develop

Naval Daver, MD

Although currently minimal residual disease (MRD) offers little that can be utilized in clinical practice, it still demonstrates prognostic potential, explained Naval Daver, MD, in a presentation during the 39th Annual CFS®: Innovative Cancer Therapy for Tomorrow, a program by Physicians’ Education Resource (PER®), LLC. Moreover, newer modalities are seeking to pinpoint the extent to which MRD negativity in acute myeloid leukemia (AML) can inform prognoses and help shape treatment decisions.

“At this time, there is really no clear way to direct or eradicate MRD in patients with AML,” said Daver, who is director of the Leukemia Research Alliance Program, and an associate professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center.

“Although MRD is prognostic, it really is not definitive. If you have a patient who becomes MRD negative and you still believe they have high-risk baseline features, [we still] use baseline molecular cytogenetic features to decide [whether to go to] transplant—because we know that even in those who become MRD negative, there can be a 30% relapse risk and vice versa.”

Two methods of detecting MRD involve multiparametric flow cytometry, which has been most used, and real-time quantitative polymerase chain reaction (PCR) in the form of next-generation sequencing (NGS) and digital droplet sequencing, among others. Although the PCR approach is becoming a more preferred method, it has proven to be both expensive and time consuming, Daver noted, who was also awarded PER®’s 2021 Educator of the Year during this year’s conference.

Utilizing MRD as a Prognostic Tool in AML Outcomes

Flow Cytometry

MRD assessed by flow cytometry also has been shown to be highly prognostic in young patients with AML. For example, a study of 280 younger patients with AML were treated with intermediate-dose cytarabine and idarubicin-based induction chemotherapy and achieved remission; 186 patients were assessed for MRD via an 8-color multiparameter flow cytometry panel with a sensitivity rate of at least 0.1%.²

In the 166 patients with available samples 1 to 2 months after induction at the time of complete remission (CR), 79% were MRD negative; MRD-negative status was linked with an improvement in relapse-free survival (RFS; P = .0002), as well as overall survival (OS; P = .0002). During consolidation, 116 patients were evaluated for MRD status, and in turn, 86% were MRD negative; MRD negativity was also associated with a significant improvement in RFS (P < .0001) and OS (P < .0001).

Upon treatment completion, 69 patients were evaluated for their MRD status, and 84% were MRD negative with negative status associated with an RFS improvement (P < .0001) and OS improvement (P < .0001). A multivariate analysis, which included age, cytogenetics, response, and MRD showed that MRD-negative status was the most significant independent predictor of RFS and OS at response (P = .008 and P = .0008, respectively), during consolidation (P < .0001 for both), and at therapy completion (P < .0001 and P = .002, respectively).

“The key is to achieve MRD negativity, and more and more, we’re starting to realize…that MRD is really a marker of sensitivity of the cancer to the chemotherapy being used,” Daver said. “Basically, for those who achieve MRD negativity, whether it is early or late, the cancer is sensitive to that particular therapy and that is being shown here with the achievement of MRD negativity.”

Daver added that in most cases in clinical practice, transplant is considered if patients do not achieve MRD negativity following 3 or 4 treatment cycles of intensive chemotherapy.

MRD can also be utilized as a tool to predict relapse in patients with AML following receipt of hypomethylating agents (HMAs). In a 9-color flow cytometry–based study of older patients with AML who were treated HMAs, MRD negativity was not found to have a significant impact on OS (median 12.9 months for MRD-negative patients vs 11.6 months for MRD-positive patients at 3-months post remission; P = .81).³ However, MRD negativity was strongly linked with RFS (10.94 months for MRD-negative patients vs 4.74 months for MRD-positive patients, both 3 months post remission; P = 0.21).

Molecular-Based MRD Testing

The use of PCR is likely to have an uptick in AML practice in the next 5 to 10 years, according to Daver, which will “hopefully” allow researchers to have more consistent large-scale randomized clinical trial data sets to establish it as a clinical and regulatory marker.

Researchers in a European study conducted NGS in patients with newly diagnosed AML at diagnosis and following CR with induction therapy. A total 89.2% of patients had at least 1 detected mutation; of these patients, 51.4% had mutations that persisted during CR and were present at various allele frequencies.⁴

Once persistent DTA mutations were excluded, detection of molecular MRD was linked with a significantly higher relapse rate vs no detection, at 55.4% vs 31.9%, respectively (HR, 2.14; P <.001). The RFS rates were 36.6% and 58.1%, respectively (HR, 1.92; P <.001) and OS rates were 41.9% and 66.1%, respectively (HR, 2.06; P <.001).

However, it was noted in a multivariate analysis that detection of non-DTA persistent mutations often linked with clonal hematopoiesis in CR had independent predictive value. This was shown in rates of relapse (HR, 1.89; P <.001), RFS (HR, 1.64; P = .001), and OS (HR, 1.64; P = .003).

“NGS-based MRD tracking of AML mutations could be used for long-term survival,” Daver said. Combining NGS and flow cytometry could increase the strength of predicting relapse in patients with AML, he added; this showed a concordance rate 69.1%.

A large-cohort meta-analysis of 81 studies comprising 11,151 patients with AML also showcased the impact that MRD negativity has on OS (HR, 0.36; 95% CI, 0.33-0.39) and disease-free survival (DFS; HR, 0.37; 95% CI, 0.34-0.40).⁵ The 5-year OS and DFS rates for MRD-negative patients were 68% and 64%, respectively, compared with 34% and 25%, respectively, for MRD-positive patients.

“If I see MRD negativity, I feel more confident to tell my patients, especially with this very large data set, that the chance of long-term survival is much better, and getting to the 65% to 75% range,” Daver noted. “If they are MRD positive, of course, we are thinking of transplant and interventions, but even with those transplant and interventions, we are still going to expect a lower long-term survival at this time. Maybe with posttransplant maintenance approaches, this could improve over time.”

Defining the Role of Transplant in an MRD-Filled Era

Even upon remission, patients with AML continue to be at risk for disease relapse following allogeneic hematopoietic stem cell transplantation (HSCT). However, in an analysis of a phase 3 trial, researchers set out to determine whether modulating the intensity of transplant conditioning regimens in MRD-positive patients with AML could prevent relapse and improve OS.⁶ Patients who were in morphologic CR had been randomized to receive myeloablative conditioning (MAC) or reduced-intensity conditioning (RIC). Ultra-deep error-corrected sequencing was performed for 13 commonly mutated genes.

Data showed that in patients with a detectable mutation—deemed NGS-positive— the 3-year cumulative incidence of relapse was 19% vs 67% for those who received MAC vs RIC, respectively (P <.001). The 3-year OS rates were 61% vs 43%, respectively (P = .02). Furthermore, when adjusting for disease risk and donor group in multivariable analysis of these patients, increased relapse (HR, 6.38; 95% CI, 3.37-4.69; P <.001), decreased RFS (HR, 2.94; 95% CI, 1.84-4.69; P <.001), and decreased OS (HR, 1.97; 95% CI, 1.17-3.30; P = .01) were all observed with RIC compared with those on MAC.

“One of the key messages from this paper, that we use in clinical practice, is that if there is an MRD-positive [result], whether it’s by NGS and I would say by flow cytometry, one would lean more toward using a myeloablative conditioning in this population [rather] than a RIC-based approach,” Daver said.

In a second analysis, the impact of transplant was also evaluated in both MRD-negative and -positive patients with AML who were in first CR.⁷ The primary end point was 1-year relapse incidence following transplant. Data showed that patients with MRD-positive disease had a higher incidence of relapse at 32.6% vs 14.4% for those with MRD-negative disease (P = .002), and inferior rates of leukemia-free survival, at 43.6% vs 64.0% (P = .007), respectively, and OS at 48.8% vs 66.9% (P = .008), respectively.

“Our approach at MD Anderson has been to take patients to transplant who we would have taken to transplant based on the baseline [European Leukemia Net] risk factor. [As such,] the patients who have high-risk molecular cytogenetic abnormalities, FLT3 positivity, RUNX1, TP53, we will take to transplant even if they are MRD positive,” Daver explained. “Our opinion is that transplant can still help mitigate the risk [in MRD-positive patients], and they will do less poorly than they would have without a stem cell transplant.”

For example, in an analysis of patients with AML who were in morphological CR and underwent a first stem cell transplant, a subset with MRD-positive disease who were stratified into an intermediate-risk group were found to have “reasonably well” outcomes to stem cell transplant, with a 1-year relapse incidence rate of 29% and a 1-year OS rate of 61%.⁸

Next Steps: Examining Posttransplant Settings and Novel Drugs With Potential

There have been many approaches of interest to modulate MRD, including maintenance strategies, modulating donor lymphocyte infusions, incorporating oral CC-486 and FLT3 inhibitors in different settings, and exploring the use of early intervention with HMAs based on the loss of donor chimerism.

The latter approach was tested in the phase 2 RELAZA2 trial (NCT01462578), which included patients aged 18 years or older with advanced myelodysplastic syndrome or AML who had achieved CR following conventional chemotherapy or allogeneic HSCT.⁹ At a median follow-up of 13 months (IQR 8.5-22.8) following the start of MRD-guided therapy, the 1-year RFS rate was 46% (95% CI, 32%-59%) in MRD-positive patients who were treated with azacitidine compared with 88% (95% CI, 82%-94%) in MRD-negative patients (HR, 6.6; 95% CI, 3.7-11.8; P <.0001).

“Using preemptive therapy with azacitidine based on the donor chimerism could be a good way to use early intervention without waiting for a full MRD-based relapse,” Daver said. “[Researchers] were able to show that using this approach of early HMA intervention based on loss of chimerism, even before true detectable flow [cytometry] or molecular MRD, was useful.”

Additionally, the use of FLT3 inhibitors is being investigated in the posttransplant setting, most recently in the ongoing BMT-CTN 1506/Morpho trial (NCT02997202), which is randomizing 346 posttransplant patients with FLT3-ITD–mutated AML 1:1 to receive either gilteritinib (Xospata) or placebo.10 Investigators are seeking to answer whether there is a benefit to FLT3 inhibition posttransplant; whether the detection of a FLT3-ITD mutation by a validated, sensitive MRD assay predicts relapse; and whether a potent FLT3 inhibitor prevents relapse when a MRD assay detects a FLT3-ITD mutation.

Ongoing research is focused on uncovering MRD-converting drugs, and with current investigations on bispecific antibodies, cellular therapies with both natural killer and CAR T cells and potentially CD47, “then we will have a really important path forward to use these MRD erasers in the future,” Daver concluded.

References
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9. Platzbecker U, Middeke JM, Sockel K, et al. Measurable residual disease-guided treatment with azacitidine to prevent haematological relapse in patients with myelodysplastic syndrome and acute myeloid leukaemia (RELAZA2): an open-label, multicentre, phase 2 trial. Lancet Oncol. 2018;19(12):1668-1679. doi:10.1016/S1470-2045(18)30580-1
10. A trial of the FMS-like Tyrosine Kinase 3 (FLT3) Inhibitor gilteritinib administered as maintenance therapy following allogeneic transplant for patients with FLT3/internal tandem duplication (ITD) acute myeloid leukemia (AML). ClinicalTrials.gov. Updated October 8, 2021. Accessed November 3, 2021. https://www.clinicaltrials.gov/ct2/show/NCT02997202