MRD, Clinical Outcomes Linked in Chronic Leukemia

Measurable residual disease (MRD) and progression-free survival (PFS) are likely related, according to the results of the first study in the targeted therapy era to assess the association between MRD and clinical outcomes in chronic lymphocytic leukemia (CLL).

Details of the study, a large systematic review and meta-analysis involving more than 2700 patients, appear in JAMA Oncology.¹

Assessing MRD status as an end point in clinical trials and utilizing it as a PFS surrogate may improve trial design and efficiency and allow accelerated drug registration, the authors stated. The team found that the MRD/PFS association was especially strong in the first-line treatment setting and with time-limited therapy. Overall, they said, the substantial magnitude of benefit associated with undetectable MRD corresponded to a 72% reduction in the risk of death or progression for patients who achieved it. Undetectable MRD was defined as the presence of disease at levels so low that it cannot be detected by conventional pathologic analysis.

During their research, the present study authors observed potential links between undetectable MRD with PFS in subgroup analyses in the first-line treatment setting, trials using time-limited therapy, and in the relapsed or refractory disease setting | Image Credit: sdecoret-stock.adobe.com

Study Methods

The authors assessed the association between MRD and PFS in CLL using data from prospective, single-arm, and randomized clinical trials published through July 31, 2023, that studied treatments based on targeted agents (eg, venetoclax or Bruton tyrosine kinase [BTK] inhibitors [ibrutinib, acalabrutinib, zanubrutinib]) or obinutuzumab and reported PFS by MRD status, if they had sufficient description of MRD information.

From each study, they extracted its sample size, median patient age, median follow-up time, line of treatment, MRD detection method and time points, and survival outcomes. Meta-analyses were performed using a random-effects model.

An Impressive Link

Eleven prospective clinical trials (9 randomized and 2 nonrandomized) that included 2765 patients were analyzed. Achieving undetectable MRD at 0.01% was associated with an HR of 0.28 (P < .001) for PFS, the authors said. Although median PFS was not reached in either the overall undetectable MRD or MRD group, the estimated 24-month PFS was better in the uMRD group (91.9% vs 75.3%; P < .001). This outcome reflects “that the incorporation of novel agents has substantially transformed and improved the management of CLL.”²

The authors said theirs was the first meta-analysis in this area to be done in the targeted therapy era, to their knowledge. A previous meta-analysis included 11 studies in which all patients were treated with chemoimmunotherapy and none with venetoclax and/or BTK inhibitors, they noted. In that work, the estimated 3-year PFS for patients with undetectable MRD was 86% vs 32% in those with MRD.

In their meta-analysis, the researchers observed the association of undetectable MRD with PFS in subgroup analyses in the first-line treatment setting (HR, 0.24), trials using time-limited therapy (HR, 0.28), and in the relapsed or refractory disease setting (HR, 0.34). In most subgroup analysis, they noted, the association between MRD and PFS held regardless of treatment used, duration of therapy, MRD testing method, cytogenetic risk, and enrolled patient population.

They added that although ibrutinib therapy is rarely associated with complete response or undetectable MRD in CLL, the association of undetectable MRD with PFS persisted with ibrutinib therapy. The association thus seems agnostic of choice of therapy, they concluded.

Given the study’s outcomes, the researchers believe that “timing and frequency of assessment, tissue tested, and technique used to assess MRD should be standardized [so that] more homogeneous evidence” is collected to support the MRD/PFS association. Their colleagues, they said, should continue to consider MRD as a surrogate end point of PFS, potentially incorporating it into trials to guide fixed-duration treatment discontinuation or intensification according to MRD status.

References

1. Rios-Olais FA, McGary AK, Tsang M, et al. Measurable residual disease and clinical outcomes in chronic lymphocytic leukemia: a systematic review and meta-analysis.JAMA Oncol. Published online July 11, 2024. doi:10.1001/jamaoncol.2024.2122

2. Molica S, Giannarelli D, Montserrat E. Minimal residual disease and survival outcomes in patients with chronic lymphocytic leukemia: a systematic review and meta-analysis. Clin Lymphoma Myeloma Leuk. 2019;19(7):423-430. doi:10.1016/j.clml.2019.03.014