A panel of international experts has proposed dropping the term ‘minimal’ residual disease alongside other recommendations to standardise nomenclature and assessment of measurable residual disease (MRD) as an indicator of disease burden in chronic lymphocytic leukaemia (CLL), in light of emerging treatments able to achieve deep remission.

In an article published in Leukaemia, a research group has outlined key consensus recommendations made by a multidisciplinary, 174-member panel on MRD, including aspects such as MRD determination, assay requirements, timing and frequency.

With regard to MRD nomenclature, the panel agreed that, going forward, only the term ‘measurable’ rather than ‘minimal’ should be used, as ‘minimal’ is subjective while ‘measurable’ is unambiguous when a detection limit is specified. Also, ‘undetectable-MRD’ (U-MRD) is preferable to ‘MRD-‘ or ‘MRD negative’ as a general term to describe the inability to detect measurable disease at a specified threshold.

Elsewhere, the panel advised that only validated assays – such as ERIC-compliant flow cytometry and EuroMRD-compliant real-time PCR tests – are used to quantify MRD, but also stressed that choice of assay should depend on the rationale for MRD determination. “The minimum sensitivity required for regulatory approval is MRD4 (10−4), whereas evaluating curative approaches may require the most sensitive method available, based on local availability and/or economic restrictions,” the authors noted.

On timing and frequency of MRD assessment, new recommendations are that for fixed-duration therapies, MRD testing “should be aligned with response assessment, at least two months after completion of the last treatment”, while for continuous treatment status should be assessed when best clinical response has been achieved.

Also, the panel advised that MRD should be assessed in patients who achieve a partial response (PR) to treatment as well as those with a complete response (CR), as those with a PR may also achieve U-MRD. According to the authors: “In first-line CIT [chemoimmunotherapy treatment] of CLL, MRD status was independently associated with extended treatment-free survival, progression-free survival, and overall survival. U-MRD is more accurately associated with survival than conventional responses after first-line CIT. In this setting, patients achieving U-MRD and PR may have a prognosis superior to that of MRD-positive patients achieving CR.”

However, they also pointed out that there could be other factors involved in the relationship between end-of-treatment MRD status and progression free survival/overall survival and, as such, emphasised the need for further studies to determine potential effects of prior treatment, prior response, IGHV mutational status, del(17p)/mutated TP53 status, cytogenetic abnormalities and other variables.

With regard to the optimal method for assessing response in CLL, this will in clinical practice depend on patient status, treatment type and treatment goal. “At a minimum, response assessment should include full blood count and clinical examination,” and bone marrow and CT scan may also be included, the authors advised. “MRD assessment is recommended to inform prognosis and quality of response, and to potentially identify candidates for MRD-driven changes in treatment duration,” they stressed.

On treatment, it was noted that while the most active CIT regimen – fludarabine, cyclophosphamide and rituximab (FCR) – achieved CR in the majority of people with CLL, with U-MRD in around one-half of those receiving first-line treatment, the regimen is limited to younger, fitter patients. Venetoclax-based treatment however, “not only achieves a higher rate of U-MRD in first-line and relapsed CLL than CIT does, but it also is well-tolerated, including in older patients, making deep remission and U-MRD with fixed-duration treatment a realistic goal”.

The panel stressed that currently “there is no clear role for MRD status determination in routine CLL clinical practice.” As such, it has “strongly recommended” that trials of fixed-duration treatments with the goal of achieving deepest remission “evaluate MRD status in PB [peripheral blood] at a sensitivity of at least 10−4 to correlate with time-to-event outcomes”.

“Adoption of these recommendations will work toward standardising data acquisition and interpretation in future studies with new treatments with the ultimate objective of improving outcomes and curing chronic lymphocytic leukaemia,” the authors concluded.

Read the recommendations in full here