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Undetectable Measurable Residual Disease in CLL / SLL

In science and medicine, information is constantly changing and may become out-of-date as new data emerge. All articles and interviews are informational only, should never be considered medical advice, and should never be acted on without review with your health care team.

Authored by Brian Koffman, MDCM (retired), MSed

The Bottom Line:

Undetectable measurable (minimal) residual disease (uMRD) has strong prognostic significance in CLL and may, in the future, guide the duration of therapy and serve as an endpoint in trials for drug approval. Recent research shows a good correlation between MRD status and progression-free survival (PFS).

Who Performed the Research and Where Was it Published:

Dr. Tilal Hilal of Mayo Clinic, Phoenix, Arizona, was one of the researchers publishing Measurable Residual Disease and Clinical Outcomes in Chronic Lymphocytic Leukemia: A Systematic Review and Meta-Analysis in JAMA Oncology in 2024.

Background:

For years, a complete response (CR) was considered the best possible outcome in chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL), but testing has become more sophisticated. While a skilled pathologist using a microscope can find as few as one CLL cell in a hundred by their appearance or morphology, automated flow cytometry that looks at the cell’s surface “fingerprint” can find one in 10,000 (uMRD-4) or even one in a 100,000 (uMRD-5) and next generation sequencing (NGS), can find one in a million cells (uMRD-6).

Research:

Large data sets are needed to answer questions as to whether measurable residual disease (sometimes called minimal residual disease) or MRD can accurately predict PFS.

  • Researchers pooled eleven trials (two single-arm with 204 patients and nine randomized studies with 2,561 patients).
  • Seven of the studies reported on first-line treatment.
  • Undetectable MRD (uMRD) was defined as less than 0.01% or one in 10,000 cells. Anything higher was labeled MRD positive or detectable measurable residual disease.
  • The uMRD group had an estimated two-year PFS of 91.9% compared to 75.3% of the MRD-positive group. This was a statistically significant difference.
  • uMRD is much more helpful in patients using limited-duration therapy than those using continuous BTKi therapies, where disease control can be very durable, but uMRD is rarely achieved.

Discussion and Conclusions:

It is becoming increasingly clear that in multiple different types of time-limited therapy (but not with continuous therapy), measuring MRD is more important prognostically than achieving a complete remission. This is important because while continuous therapies are still the best choice for many, the trend is towards more limited-duration options.

While this is not yet happening often in clinical practice outside of the research setting, it is now frequently designed into clinical trials because of the use of MRD status to guide when to stop therapy and when to continue or even intensify it.

What is also not happening yet, though it has been adopted in multiple myeloma research, is MRD status’ recognition as a surrogate endpoint for progression-free survival in registration trials for drug approval. That change by the FDA could help get drugs to patients much more quickly and could lower the cost of drug development. Dr. Hilal’s research and many other studies, including the German study group’s End Point Surrogacy in First-Line Chronic Lymphocytic Leukemia referenced in the interview, help move us closer to that goal.

Links:

Watch CLL Society’s interview with Dr. Hilal, which digs deeper into the topic of undetectable measurable (minimal) residual disease:

Undetectable Measurable Residual Disease in CLL / SLL – Dr. Tilal Hilal

The original research abstract can be accessed at: Measurable Residual Disease and Clinical Outcomes in Chronic Lymphocytic Leukemia. For a library of information on MRD, CLL Society provides several articles and webinars, basic and advanced, on our MRD landing page. To help understand how researchers and clinicians traditionally measure responses to therapy, scroll down to the last half of this clinical trials article.