How Does MRD in ALL Management Measure Up?

By Leah Lawrence - Last Updated: February 2, 2023

Decades in the making, information on measurable residual disease can greatly affect therapeutic decision making.

Measurement of measurable residual disease (MRD) in acute lymphoblastic leukemia (ALL) has been a component of risk stratification in the disease for more than a decade, but within the past few years, MRD has entered new territory: therapeutic decision-making.

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However, as Lori Muffly, MD, MS, Assistant Professor of Blood and Marrow Transplantation and Cellular Therapy at Stanford University in California, told Blood Cancers Today, certain subspecialists were ahead of the curve.

“Before my time, pediatricians were using MRD in all risk-stratified protocols for ALL,” Dr. Muffly said. “Many years ago, they already understood that MRD was a very important prognostic feature.”

In fact, studies in adult and pediatric ALL have shown strong associations between MRD positivity—commonly defined as at least 1 leukemia cell in 10,000 normal cells (expressed as 10-4)—and risk for relapse.

A meta-analysis evaluating MRD in ALL showed that pediatric patients achieving MRD negativity were more than twice as likely to be disease-free at 10 years (77% vs. 32%) and much more likely to be alive at 10 years (84% vs. 55%) compared with those who were MRD-positive. In adults, MRD-negative patients were 3 times more likely to be disease-free and 4 times more likely to be alive at 10 years compared with those who were MRD-positive.1

In pediatric ALL, MRD informs risk-directed therapy and is built into treatment algorithms, according to Ching-Hon Pui, MD, Chair of the Department of Oncology at St. Jude Children’s Research Hospital in Memphis, Tennessee.

In contrast, in ALL and other hematologic malignancies, the clinical utility of MRD testing for adults has been historically questioned because the results rarely changed patient management, Dr. Muffly explained.

That all changed in 2018, when the Food and Drug Administration (FDA) approved the bispecific monoclonal antibody blinatumomab for the treatment of B-cell precursor ALL in first or second complete remission with MRD greater than or equal to 0.1%.2

“That was an enormous breakthrough,” Dr. Muffly said. “It led to the incorporation of MRD as standard of care across all types of ALL.”

Taking Measure

ALL is not one of the more common leukemias in the United States, accounting for less than half of 1% of all cancers. Most cases of ALL occur in children (6 out of 10 cases), but most deaths from ALL occur in adults (about 4 out of every 5).3

“ALL is heterogeneous in terms of outcomes between pediatric populations and adults,” said Nicholas J. Short, MD, Assistant Professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston. “But, even in adults, outcomes for ALL have improved significantly in recent years.”

Dr. Short noted that “part of that disparity is due to modification of chemotherapy and better treatment options, and part is due to the fine-tuning of risk-stratification, where MRD can be used to identify which patients should be considered for alternative, MRD-directed therapies.”

Evaluation of MRD is now a standard component of the management of patients with ALL. For example, the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines recommend that all patients suspected of having ALL should undergo baseline flow cytometric and/or molecular characterization of leukemic clone to facilitate subsequent MRD testing.4

There are multiple methods for MRD assessment, Dr. Short said. These include multiparameter flow cytometry, quantitative polymerase chain reaction (PCR), and next-generation sequencing (NGS; Figure 1). No matter the method, any MRD assessment should be performed by high-volume laboratories that use standardized, validated MRD assays, he noted.

 

In the United States, multiparameter flow cytometry is the most common method for measuring MRD, and the only approach that provides information on leukemia antigen expression.

“It is important to have that information, particularly in the age of targeted therapies, where we can target antigens with chimeric antigen receptor (CAR) T-cell therapy and other agents,” Dr. Muffly said.

Flow cytometry also has a fast turnaround time and provides a sensitivity of about 10-4 in the bone marrow.

Quantitative PCR is predominantly used in Europe. This method is a bit more labor-intensive but is also more sensitive than flow cytometry, with a sensitivity threshold of about 10-5. In the United States, use of quantitative PCR generally is limited to detection of BCR-ABL1 in patients with Philadelphia chromosome-positive ALL.

NGS is the newest option, frequently performed with the clonoSEQ Assay.

“This method gives a sensitivity of 10-6, meaning it can detect 1 abnormal cell out of 1 million cells,” Dr. Short said. “This is 1 to 2 logs more sensitive than flow or PCR assays, which detect 1 leukemia cell out of 10,000 or 100,000 cells at best.”

MRD assessment with NGS has the longest turnaround time of these options, returning results in about 1 week. In addition, Dr. Muffly said that this method also requires a diagnostic leukemia sample to enable clonal tracking, which will not be available for every patient.

“NGS is approved by the FDA, but we don’t have as much clinical correlation data about what to do with these tiny amounts of MRD,” Dr. Short said. “We don’t have those answers yet.”

The currently accepted threshold for defining MRD negativity is 0.01%, according to Dr. Pui.

“In the future though, as NGS MRD becomes more widely available, things might change,” Dr. Pui said. “For example, in the transplantation setting, patients with MRD levels less than 0.0001% before transplant have superb outcomes. If they stay at that level after transplant, they rarely relapse.”

Using the threshold of 10-6 may identify patients with disease that is “highly curable,” Dr. Pui said.

When to Test

For patients with ALL, NCCN Guidelines recommend MRD assessment after completion of initial induction therapy and then periodically based on the regimen and the patient’s response.

Dr. Pui said that most pediatric centers will assess MRD after induction and after consolidation, with some centers choosing to add more assessments for research purposes. For example, at St. Jude, Dr. Pui said clinicians perform an MRD assessment in the middle of induction therapy.

“We use these levels to direct treatment,” Dr. Pui said. “If the patient has poor response, we can intensify induction and post-remission treatment.”

Specifically, they measure MRD after day 8 of induction, after 1 week of treatment. If the patient has good MRD response, they will skip the use of anthracyclines and the patient will receive more mild therapy. If a patient still has an MRD level of 1% or more by 2 weeks into induction, clinicians will administer extra treatment and intensified treatment thereafter. However, the exact timing of assessment in pediatrics is often dependent on ALL lineage.

Dr. Muffly said that MRD assessment should be performed following induction therapy and early consolidation or within 3 months of the start of treatment. MRD should also be assessed prior to the administration of any cellular therapy and before proceeding with transplant. Generally, assessments are recommended every 3 to 6 months.

She added that her institution is beginning to perform ongoing MRD monitoring throughout maintenance, potentially using peripheral blood, which is much easier and more convenient for the patient.

“In my practice, which is a bone marrow transplant/CAR T-cell therapy practice, we do one bone marrow assessment post-transplant to assess disease response. After that, we use blood,” Dr. Muffly explained. “We have shown that blood and bone marrow correlate very closely in a population of transplant patients.”

Dr. Short said that his institution assesses MRD at every bone marrow aspirate, but the decision of how often to assess MRD in patients who are MRD-negative is less clear.

“We are not going to know if someone converts from MRD-negative to MRD-positive if we do not test for it,” he said. “In patients who were MRD-negative and become MRD-positive, the likelihood of relapse is extremely high. Furthermore, these patients are candidates for MRD-directed therapies, such as the bispecific antibody blinatumomab.”

MRD Erasers

Blinatumomab is known as an “MRD eraser,” which can be employed if a patient who achieved MRD negativity becomes MRD-positive. The FDA’s March 2018 approval of blinatumomab was based on results from the single-arm BLAST trial. The trial included 86 patients who had received at least 3 chemotherapy blocks of standard ALL therapy and were in complete remission and had MRD level of 0.1% or greater using a minimum sensitivity of 0.01% (10-4).2

Undetectable MRD was achieved by 85% of patients in first complete remission (CR) and 72% of patients in second CR. After treatment, 74% of patients in first CR and 56% of patients in second CR underwent hematopoietic stem cell transplantation in continuous hematologic complete remission.

At the 2021 Society of Hematologic Oncology (SOHO) Annual Meeting, Rachel E. Rau, MD, Assistant Professor in the Department of Pediatrics at Baylor College of Medicine and physician at Texas Children’s Hospital in Houston, discussed the use of blinatumomab in the ALL setting in more detail. She acknowledged that several questions still surround its use, including if blinatumomab is best used in the setting of relapsed disease or as front-line treatment, and when it should be used rather than CAR T-cell therapy.

Additionally, blinatumomab is still being evaluated in combination with chemotherapy in pediatric patients with B-cell ALL in the AALL1731 study.

“Blinatumomab is clearly a highly active agent for B-cell malignancies,” Dr. Rau said during her presentation. “Its activity is likely greatest in MRD-positive settings and, although we know it is highly effective for [patients with] relapsed or refractory [disease], we would postulate that perhaps it is best used in the upfront setting.”

Dr. Short said that blinatumomab is likely the most clinically relevant breakthrough related to MRD in the past decade.

“We can now convert someone who was historically considered high-risk into someone in whom there is an open question about whether they need to be transplanted if they have a good response to blinatumomab,” Dr. Short said.

Another potential MRD eraser is CAR T-cell therapy with CD19-directed tisagenlecleucel. CAR T-cell therapy has also been shown to be very good at eradicating MRD but is only approved in the pediatric relapsed/refractory setting, Dr. Short said.

ELIANA was the pivotal trial of tisagenlecleucel in pediatric B-cell ALL. In this study, the complete response rate was 81%, with a 1-year event-free survival rate of 50%.5 Durability of remission left room for improvement, according to Rebecca A. Gardner, MD, Associate Professor in the Department of Pediatrics and Division of Hematology/Oncology at Seattle Children’s. Dr. Gardner also presented at the 2021 SOHO Annual Meeting.

Dr. Pui agreed with Dr. Gardner’s assessment.

“Initially, everybody was very excited about CD19-targeting CAR T-cell therapy, but CAR T cells appeared to have limited persistence,” Dr. Pui said. “Many of these patients’ disease relapses and it seems more like CAR T-cell therapy is serving as a bridge to transplant.”

The story may change as more cellular therapies are developed, he noted.

In adults, Dr. Muffly said that CAR T-cell therapy as its own curative modality is not quite ready for routine clinical use, but more will be learned now that there are commercial products for use in adults.

In comparing the options for patients with MRD positivity, Dr. Rau pointed to the fact that
blinatumomab is immediately available to patients with no need for apheresis and manufacturing. Side effects are also more manageable, she said.

Some potential pitfalls of blinatumomab, though, are the fact that it is given as a continuous infusion and that it is short-lived compared with CAR T-cell therapy, which has shown evidence of persistence. There are also data to suggest that blinatumomab, when administered prior to CAR T-cell therapy, could be associated with increased post-CD19 CAR relapse and decreased event-free survival.6

This possibility emphasizes ongoing questions about how to sequence these available treatments, Dr. Short said.

“How do we sequence these agents with monoclonal antibodies, and how do we use CAR T-cell therapy in relationship to transplant?” Dr. Short questioned. “There is a lot we don’t know yet.”

MRD Endpoint

Ongoing advances in the use of MRD in ALL have also led to inevitable questions about the use of MRD negativity as a surrogate clinical endpoint.

In January 2020, the FDA released guidance for industry on the use of MRD in development of drug products for hematologic malignances, with evidence to support its clinical validity varying across cancer types and patient populations.7

The FDA also cosponsored public workshops on MRD in ALL and other areas. In its guidance, the agency stated that “MRD has emerged as one of the most significant prognostic factors in ALL, independent of patient age, B- or T-cell origin, or genetic subtype.”

For new drugs that have demonstrated durable CR in patients with relapsed or refractory ALL, the FDA has accepted MRD levels of less than 0.01% as evidence of efficacy. Currently, ALL is the only disease in which MRD has been used as a surrogate endpoint supporting drug approval.

“The FDA has specific criteria to define what counts as surrogacy for clinical trials,” Dr. Short said. “I agree with the FDA that we have robust data in ALL supporting MRD negativity’s association with better outcomes and MRD positivity’s association with risk of relapse. Thus, the rate of MRD negativity with a new drug or regimen can be used to evaluate new therapies without needing to wait for 3 or more years to collect enough survival data to determine efficacy.”

Dr. Pui said that, moving forward, he questions if MRD alone will be a good enough endpoint. To make solid decisions for precision treatment, clinicians will have to know the MRD level at a specific timepoint, what kind of genotype the patient has, and what type of induction treatment the patient received. That is because, in pediatric populations, studies have shown that MRD distributions vary with distinct disease subtypes. Patients with low-risk cytogenetics may clear disease faster than those with high-risk cytogenetics.8

Dr. Muffly said that leukemia-free survival and overall survival endpoints still trump MRD, which alone may not be enough. Instead, she hopes to see more clinical trials in ALL use MRD positivity as inclusion for research.

“We have more than enough data showing that these patients have worse outcomes in a multitude of settings,” Dr. Muffly said. “We as a community need to include MRD in research. I very much hope to see more of that, especially in the CAR T-cell space and with other novel therapeutics.”

Leah Lawrence is a freelance health writer and editor based in Delaware.

References

  1. Berry DA, Zhou S, Higley H, et al. Association of minimal residual disease with clinical outcome in pediatric and adult acute lymphoblastic leukemia. A meta-analysis. JAMA Oncol. 2017;3(7):e170580.
  2. U.S. Food and Drug Administration. FDA granted accelerated approval to blinatumumab (Blincyto, Amgen Inc.) for the treatment of adult and pediatric patients with B-cell precursor acute lymphoblastic leukemia. March 29, 2018. Accessed December 8, 2021. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-granted-accelerated-approval-blinatumomab-blincyto-amgen-inc-treatment-adult-and-pediatric.
  3. American Cancer Society. Key Statistics for Acute Lymphocytic Leukemia (ALL). Accessed December 8, 2021. https://www.cancer.org/cancer/acute-lymphocytic-leukemia/about/key-statistics.html.
  4. Brown PA, Shah B, Advani A, et al. Acute Lymphoblastic Leukemia, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2021;19(9):1079-1109.
  5. Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378:439-448.
  6. Taraseviciute A, Steinberg SM, Myers RM, et al. Pre-CAR blinatumomab is associated with increased post-CD19 CAR relapse and decreased event free survival. Blood. 2020;136(suppl 1):13-14.
  7. U.S. Department of Health and Human Services. Hematologic Malignancies: Regulatory Considerations for Use of Minimal Residual Disease in Development of Drug and Biological Products for Treatment Guidance for Industry. January 2020. Accessed December 16, 2021. https://www.fda.gov/media/134605/download.
  8. O’Connor D, Enshaei A, Bartram J, et al. Genotype-specific minimal residual disease interpretation improves stratification in pediatric acute lymphoblastic leukemia. J Clin Oncol. 2018;36(1):34-43.
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