Measurable Residual Disease in CLL: What the Test Means

Chronic lymphocytic leukaemia (CLL) is often indolent, and modern treatment can drive the disease to a level where no leukaemic cells can be detected by standard tests. Measurable residual disease — MRD, historically called minimal residual disease — is the measurement of what remains below that threshold. It has emerged as one of the strongest prognostic markers in CLL: patients who achieve undetectable MRD at the end of treatment have longer progression-free and overall survival. The 2021 international consensus recommendations standardise how it is measured and how it should be used.

How MRD is measured

Two main approaches exist. Flow cytometry detects leukaemic cells by their surface marker pattern and can detect one CLL cell among ten thousand white cells with standard methods, and — with highly sensitive, validated protocols — down to one in a million. PCR-based methods track the specific immunoglobulin gene rearrangement or, increasingly, use next-generation sequencing to identify and follow the clone's unique sequence. The consensus emphasises that sensitivity must be standardised: a result of "MRD negative" is meaningless without knowing the sensitivity of the assay used, because one in ten thousand and one in a million are very different depths. Sampling from blood is standard; bone marrow adds sensitivity in some settings but is more invasive.

Where MRD is assessed

MRD is measured at defined points — at the end of treatment, and in trials at intermediate time points — in peripheral blood, and increasingly in bone marrow for patients treated with fixed-duration regimens, since marrow clearance lags behind blood clearance. Its main validated role is as a prognostic marker: undetectable MRD at the end of treatment independently predicts longer progression-free and overall survival, and the depth and duration of that remission matter — patients whose MRD stays undetectable for years do particularly well.

How it is being used in treatment decisions

The most active area is response-adapted therapy: in clinical trials, treatment is stopped early or extended according to MRD results, with the aim of shortening exposure for patients who have already achieved deep remission and intensifying for those who have not. Time-limited combination regimens — venetoclax with an anti-CD20 antibody, for example — rely heavily on MRD to decide duration. Outside of trials, the consensus is more cautious: MRD is well established for prognosis and is increasingly used to guide treatment duration in approved fixed-duration regimens, but routine MRD-driven escalation — treating an asymptomatic patient purely because MRD has reappeared — is not standard practice, because disease progression, not MRD alone, has been the accepted trigger for starting treatment.

What MRD does not tell you

MRD negativity is not the same as cure, and MRD positivity does not mean you are about to feel ill. A rising MRD level over consecutive measurements is more meaningful than a single value, and reappearance of MRD after a period of negativity — MRD recurrence — usually precedes clinical relapse by months to years. Results are interpreted alongside blood counts, symptoms, lymph node examination and treatment history.

Practical advice

Ask three questions: what assay and sensitivity was used, was it blood or bone marrow, and does this result change my treatment plan? If you are on a fixed-duration regimen, ask whether MRD will be used to decide the duration. If you are in watch-and-wait, understand that MRD testing is not usually the trigger to start treatment — symptoms, falling blood counts and progressive disease are.