More potent strategies are needed to induce minimal residual disease (MRD) in acute myeloid leukemia (AML) patients before they proceed to transplant.
The majority of patients with AML achieve complete remission (CR) after induction therapy. Despite intensive consolidation regimens, less than one-third of adult patients with AML are cured, mainly because of a high incidence of relapse. Allogeneic hematopoietic stem cell transplantation (alloSCT) benefits many patients with AML in first remission.
At the 2021 Great Debates & Updates in Hematologic Malignancies virtual meeting, Farhad Ravandi, MD, Chief of the Section of Acute Myeloid Leukemia in the Department of Leukemia at the University of Texas MD Anderson Cancer Center, outlined the available assays to detect MRD and strategies to deal with MRD in AML patients.
Multiple assays are available with different sensitivities, strengths, and weaknesses to detect how much leukemia is left after initial treatment. Persistent cytogenetically abnormal cells at CR predict a significantly shorter relapse-free survival (RFS) and overall survival (OS) in AML patients.
Real time-PCR can be used to detect MRD for leukemia-specific targets according to age. "For patients over age 60, detection of mutations and aberrations tend to be less common. A significant proportion of the younger population has mutations that can be detected by PCR assays," said Ravandi. "PCR negative fusion transcripts are also beneficial for outcome."
If patients achieve PCR-negativity, their risk of relapse is less. "Preemptive therapy leads to significant reduction in the risk of relapse," said Ravandi. Co-binding factor leukemia fusion transcripts can be evaluated in peripheral blood and bone marrow to predict relapse.
NPM1 mutation is common and found 30 percent overall in AML patients. NPM1 in peripheral blood after the second cycle of chemotherapy is an important predictor of clinical outcomes.
"If MRD is positive after 2 cycles of initial chemotherapy, patients are more likely to relapse compared to patients who clear the mutation," said Ravandi. "Flow cytometry is also able to detect MRD to predict which patients will do worse."
Treatment Strategies
A variety of strategies are available to deal with MRD, including alloSCT, antibodies, and targeted agents.
Maintenance treatment with hypomethylating agents for patients with AML in first or subsequent CR is safe and feasible. "Patients on decitabine with positive MRD by flow cytometry have significantly worse RFS and OS. Positive flow cytometry is a high predictor," said Ravandi.
Younger patients under age 60 who receive high-dose cytarabine and are MRD-negative on flow cytometry have better RFS and OS. "Flow cytometry MRD-positive patients in CR are as bad as patients in partial response. CR MRD-negative patients have the best outcome," said Ravandi.
Next-generation sequencing shows patients with persistent mutations at CR do better than those who have cleared mutations by the time of CR. The detection of persistent leukemia-associated mutations in at least 5 percent of bone marrow cells in day 30 remission samples has been associated with a significantly increased risk of relapse and reduced OS, suggesting that this genomic approach may improve risk stratification for patients with AML.
"Patients with persistent mutations at CR tend to be more likely to relapse and have worse RFS and OS," noted Ravandi. He suggested that patients with persistent mutations undergo both next-generation sequencing and flow cytometry. "Incorporate both assays together to get more definitive data."
A recent systematic review and meta-analysis of 81 publications reporting on 11,151 AML patients found the estimated 5-year disease-free survival was 64 percent for patients without MRD and 25 percent for those with MRD (JAMA Oncol 2020;6(12):1890-1899). The estimated OS was 68 percent for patients without MRD and 34 percent for those with MRD. The findings suggest that "achievement of MRD-negativity is important. We need to eradicate MRD. At the moment, we only have potential agents to eradicate MRD," said Ravandi.
If flow cytometry shows MRD-positivity prior to allotransplant, RFS and OS are worse, and there is a higher relapse rate post-transplant. "Positive MRD is worse than no MRD at all, mainly due to the higher likelihood of relapse," he noted.
If patients need to be in MRD-negativity prior to transplant, would a transplant be beneficial? he asked. "Molecular clearance of MRD shows those who receive myeloablative regimens do better. For young patients who are MRD-positive, the use of myeloablative conditioning may be beneficial," Ravandi explained.
Other targeting agents can eradicate MRD, including hypomethylating agents. "Azacitidine converts positive to negative MRD. The benefits are shown in MRD responders," he stated.
The phase III, randomized, double-blind, placebo-controlled QUAZAR AML-001 trial showed the benefits of the oral azacitidine CC-486 in both MRD-positive and MRD-negative patients (N Engl J Med 2020; 383:2526-2537). Maintenance therapy was associated with significantly longer OS and RFS than placebo in these older patients with AML who were in remission after chemotherapy.
"Patient benefits included improvement of survival, although this was more statistically significant in cytogenetic MRD-positive patients," said Ravandi. "Perhaps we can convert patients from MRD-positive to MRD-negative with oral CC-486 and improve OS."
Bispecific T-cell engager (BiTE) antibodies have shown promising early results in acute lymphoblastic leukemia with the CD19-directed BiTE antibody blinatumomab. BiTEs could be MRD eradicators, and studies are looking at these agents in AML, he said.
In conclusion, Ravandi stated, "we have improved assessment of residual disease and better definitions for response are likely to evolve. We also have increasingly complex MRD assessments. Standardization of techniques is crucial, and MRD monitoring in CR is increasingly important.
"We need more potent strategies to eradicate MRD. MRD eradication is important prior to transplant, if we have the ability. A number of agents, including hypomethylating agents, appear promising. We will be able to convert patients to MRD-negative prior to transplant."
Mark L. Fuerst is a contributing writer.