MRD-Triggered Anti-CD20 Therapy Effective in High-Risk CLL

Minimal residual disease (MRD)-guided retreatment with anti-CD20 antibodies could significantly improve outcomes in patients with high-risk, relapsed chronic lymphocytic leukemia (CLL), according to a new report.

The authors of the report, which is based on a retrospective case-series analysis, say their findings suggest proactive retreatment before clinical relapse could make a major impact on survival outcomes. The findings were published in Blood Advances.¹

Patients with aggressive forms of CLL benefit from targeted therapies like Bruton tyrosine kinase (BTK) inhibitors and BCL-2 inhibitors, the authors explained.

“Nevertheless, optimal timing for retreatment is unclear, and strategies to achieve long-term control of high-risk CLL need to be defined,” they said.

MRD is commonly used in clinical trials to assess treatment responses. In such settings, patients who achieve undetectable MRD (uMRD) have been shown to have superior progression-free survival (PFS) and overall survival (OS), the authors noted.² Yet, MRD guidance is not a routine part of clinical practice, the authors noted.¹ They therefore decided to test whether monitoring MRD and initiating retreatment when certain thresholds were met might improve patient outcomes. The authors focused on retreatment with anti-CD20 therapy, hoping that a proactive, pre-relapse approach to therapy might improve long-term outcomes.

The authors studied a series of 12 patients with high-risk CLL, which they defined as having complex karyotype abnormalities, TP53 abnormalities, and/or early relapse within 2 years of induction therapy. The patients ranged in age from 52 to 92 years old.

The investigators defined MRD relapse as detectable MRD (the presence of at least 1 CLL cell in 10,000 leukocytes) after previous treatment.

Patients who met the MRD-relapse threshold were given either obinutuzumab (Gazyva; Genentech) or rituximab (Rituxan; Genentech and Biogen). The choice between the 2 therapies was based on the patient’s prior exposure and tolerability to the therapies, the authors said.

The 12 patients had previously been treated with a variety of therapies, including chemoimmunotherapy, venetoclax (Venclexta; Abbvie and Genentech) with or without obinutuzumab, ibrutinib, or a combination of those drugs.

The investigators found that MRD-triggered anti-CD20 therapy was highly effective at controlling the disease. All of the patients experienced a reduction of MRD levels below 1% of leukocytes, and the median duration of uMRD ranged from 2.5 months to 8.8 years, they said. At a median follow-up of 14 years, just 2 patients had died due to disease progression.

In terms of safety, 7 treatment-related adverse events were reported in 3 patients, of which 5 were grade 3 or above. Twenty-one serious adverse events were reported in 8 patients, though only 2 were believed to be treatment-related.

The authors said their data show that their strategy is viable and effective.

“We demonstrate that patients with high-risk CLL features, including TP53 abnormalities, complex karyotype, and early relapse, could benefit from MRD-triggered intervention,” they said.

The authors said intervention prior to clinical relapse creates the possibility of deep remission, rather than continuous treatment until progression. Such an approach would also have benefits in terms of long-term toxicity, they said.

The authors said it was particularly notable that some patients survived almost 9 years.

“This suggests that MRD-driven anti-CD20 therapy may not only delay the need for subsequent treatments, but also offer the potential for long-term disease control, if not cure, in some high-risk CLL patients,” they wrote.

Still, the authors said their sample size was small and the patients’ MRD assessment time points varied. In addition, since there was no control group, they said it may be possible that some of the patients in the case series might have remained clinically stable even without further intervention.

Overall, though, the authors said their data make a clear case that more research into this treatment strategy is warranted.

References

1. Goergen E, Robrecht S, Ligtvoet R, et al. Efficacy of MRD-triggered anti-CD20 retreatment in patients with high-risk chronic lymphocytic leukemia: a case series. Blood Adv. Published online September 9, 2025. doi:10.1182/bloodadvances.2025017109
2. Böttcher S, Ritgen M, Fischer K, et al. Minimal residual disease quantification is an independent predictor of progression-free and overall survival in chronic lymphocytic leukemia: a multivariate analysis from the randomized GCLLSG CLL8 trial. J Clin Oncol. 2012;30(9):980-988. doi:10.1200/JCO.2011.36.9348