The Role of Minimal Residual Disease (MRD) in Acute Lymphoblastic Leukemia

Minimal residual disease (MRD) is a key predictor of outcomes in patients with B-cell acute lymphoblastic leukemia (ALL). This test refers to the small number of cancer cells that may remain in the body after treatment, which are undetectable by standard diagnostic methods but could lead to relapse. Detecting MRD helps assess how well a treatment is working and guides further therapy decisions.

In clinical trials, there are different tests that assess MRD, for example, flow cytometry which detects abnormal leukemia cells based on surface markers. And Next-Generation Sequencing (NGS) that analyzes unique genetic mutations or immune receptor rearrangements in leukemia cells, providing ultra-sensitive detection.

However, it is unclear whether achieving extremely low levels of MRD improves the outlook for patients with high-risk genetic or molecular features. 

At the 66th annual American Society of Hematology (ASH) conference, Dr. Walid Macaron presented a study that explored whether achieving deep MRD negativity could overcome the poor prognosis typically associated with high-risk disease.

What Are the Study Details? 

This study did a retrospective analysis of 161 patients with ALL who received frontline therapy. It included patients in complete remission (CR) or complete remission with incomplete blood count recovery who had at least one MRD assessment within the first six months of treatment. 

The MRD assessments were performed using the clonoSEQ test, a highly sensitive Next Generation Sequencing-based method capable of detecting MRD at levels as low as 1 in a million cells, similar to finding a needle in a haystack.

What Are the Study’s Key Findings?

One of the main findings is that MRD negativity increased over time, meaning that if a patient doesn’t reach MRD negativity immediately after treatment, it’s likely that they can achieve it even after 6 months of receiving therapy, based on the analysis:

• At 1.5 months, 35% of patients were MRD-negative.
• At 3 months, 68% were MRD-negative.
• At 6 months, 85% were MRD-negative.

No difference between high-risk and non-high-risk patients

• Among patients with Philadelphia chromosome-negative (Ph-) ALL, those with high-risk features achieved MRD negativity at similar rates as those without high-risk features.
• By six months, 72% of high-risk and 71% of non-high-risk patients had become MRD-negative.

MRD negativity was linked to better survival

• Achieving MRD-negativity at 1.5, 3, and 6 months, kept the two-year relapse-free survival over 80%. 
• Among patients with Philadelphia negative ALL who achieved early MRD negativity, none relapsed.

Early MRD response is a critical factor for predicting relapse risk 

Although achieving MRD negativity improves survival, the likelihood of remaining relapse-free increases the earlier MRD negativity is attained.

In high-risk Philadelphia negative ALL, achieving early MRD negativity was crucial. The study analysis found that 100% of patients who became MRD-negative within 1.5 months were relapse-free after two years. Patients who became MRD-negative later (within six months) had a two-year relapse-free survival of 34%.

What’s the Role of Stem Cell Transplant in MRD Negativity for ALL?

Stem cell transplantation (SCT) didn’t impact survival for high-risk Philadelphia negative ALL patients who achieved MRD negativity within the first three to six months of therapy. However, SCT benefited high-risk patients who remained MRD-positive at six months. The two-year relapse-free survival was 100% for those who underwent SCT compared to only 20% for those who did not.

Conclusions

• Achieving MRD negativity early in treatment is a strong predictor of long-term survival in B-cell ALL patients, particularly in people with high-risk features. 
• MRD should be considered as a risk predictor for relapse-free survival. 
• For high-risk Philadelphia negative ALL patients who achieve early MRD negativity, SCT may not provide additional survival benefits, but it appears beneficial for those with poor MRD responses.

What This Means for Patients and Caregivers

For patients with B-cell ALL, monitoring MRD levels with highly sensitive techniques like NGS can provide valuable insights into treatment response and prognosis. 

Achieving early MRD negativity can significantly improve survival chances, and in some cases, may reduce the need for SCT. These findings reinforce the importance of MRD testing in guiding treatment decisions and risk stratification for ALL patients.

Next Steps 

For patients with B-cell ALL, the next step is to discuss MRD testing with their physician, as it plays a crucial role in determining treatment response and long-term outcomes. Since MRD assessment is a personalized process that requires careful medical evaluation and interpretation, patients should seek professional guidance to understand their results and how they might impact their treatment plan. Regular monitoring and discussions with your healthcare team can help ensure the most effective approach for each individual case.

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Source: 

• Early Achievement of Deep Measurable Residual Disease (MRD) Negativity Identifies Patients with B-Cell Acute Lymphoblastic Leukemia (ALL) Who Have Excellent Long-Term Outcomes and Do Not Benefit from Allogeneic Stem Cell Transplant, Irrespective of Baseline High-Risk Cytomolecular Features