MRD-Guided CLL Treatment Duration: Personalization or Malpractice?

One expert called it the “biology-driven” approach; the other called it “malpractice.” After a spirited debate at the European Hematology Association (EHA) 2026 Congress, the arguments of one seemed to change the minds of the session’s attendees who had congregated in the hall and spilled into overflow areas to hear the rationale for stopping first-line chronic lymphocytic leukemia (CLL) at a predefined time point vs choosing individualized duration based on measurable residual disease (MRD).

Moderating the debate was Krzysztof Giannopoulos, MD, PhD, DSc, of the Medical University of Lublin in Poland, who noted that guidelines published by the EHA on June 10 call for time-limited therapy for first-line CLL as determined by TP53 mutation and IGHV status.¹ These guidelines were based on findings from the CLL17 study finding that fixed-duration targeted treatment was noninferior to continuous ibrutinib,² but Giannopoulos also cited the findings of the FLAIR trial that “MRD functions as a treatment-guiding tool to individualize therapy duration.”³

An initial poll of the debate audience revealed that a slim majority (57.3%) agreed that MRD status should be used to guide treatment duration in first-line CLL, whereas the remainder (42.6%) disagreed.

The Evidence for Fixed-Duration Therapy

Arguing the position that CLL therapy should last for a fixed duration, Stephan Stilgenbauer, MD, of University Hospital Ulm in Germany, noted that the question pertains to routine clinical practice, not clinical trials. MRD is the presence of a single CLL cell among hundreds or thousands of normal cells: a “sophisticated laboratory finding,” not a disease.

Phase 2 trials evaluating MRD-guided treatment have provided promising results but no direct evidence of comparison, Stilgenbauer said, and the phase 3 FLAIR trial also lacked a standard fixed-duration arm.³ Delving further into FLAIR, he emphasized that the design of the trial allowed patients who became MRD-positive to restart treatment without it being considered progression, meaning they could receive several lines of treatment before registering a progression-free survival (PFS) event and explaining the encouraging PFS results of that study.

In the GLOW trial, the MRD depth patterns and dynamics with ibrutinib and venetoclax diverged sharply by IGHV mutation status,⁴ as rates of undetectable MRD less than 10⁴ were 31.3% in those with mutated IGHV and just 20.9% in those with unmutated IGHV. Stilgenbauer called this a “disconnect” supporting his position that MRD relevance differs in biological subgroups. In clinical trials, MRD is a very valuable research tool, he said, but in general practice, there’s no role for MRD-guided treatment, and “rightly so,” as no guidelines recommend MRD testing in general practice and no regulatory bodies have approved it for determining treatment duration.

The Argument for MRD-Guided Therapy Duration

Arguing for the use of MRD to select the optimal duration was the lead investigator on FLAIR, Talha Munir, MBChB, PhD, of University of Leeds/Leeds Teaching Hospital NHS Trust. He called the fixed-duration approach “arbitrary,” noting that it can be 12 months in trials of venetoclax-obinutuzumab but 15 months for ibrutinib-venetoclax. Considering all the factors that affect outcomes—genomic aberrations of IGHV or TP53, the tolerability and toxicity of treatment—he positioned MRD-guided duration as the more individualized approach.

“If you choose the right therapy up front, we might be able to functionally cure some of our patients,” Munir noted, and stopping treatment too soon risks missing out on achieving a potential cure. Based on the FLAIR results,³ MRD-driven ibrutinib-venetoclax should be standard of care because it provokes better responses than continuous therapy, and up to 40% of patients could be suboptimally treated with fixed-duration therapy.

While there are toxicity concerns with longer combination treatment, MRD status offers a risk-adapted approach to maximize outcomes while reducing toxicity, and it puts the goal of functional cure within reach, with more than 70% of patients with unmutated IGHV still having undetectable MRD at 6 years of follow-up. The MRD-guided approach offers a prolonged treatment-free interval, Munir said, which aligns with patient preferences and is more cost-effective for the health care system.

Taking a cue from the excitement surrounding the FIFA World Cup, Munir drew upon a football metaphor: “Be confident with your MRD strike—don’t do an own goal.”

The Experts Debate and the Audience Reacts

Stilgenbauer rebutted with the argument that treatment decisions must be based on evidence, not concepts, and there are no data directly showing the superiority of an MRD-guided approach. A single CLL cell is a “phenomenon” that does not harm anyone, but patients do die from overtreatment, he said, noting that many of the deaths in the CLL17 trial resulted from infections. “We must not overtreat because we aim for this miraculous MRD negativity,” Stilgenbauer cautioned.

On the contrary, Munir felt the evidence is lacking to support 15 months of therapy as being sufficient for all patients. “We can use MRD to help us identify the right fixed-duration therapy for our patient, which we are not doing at this time,” he argued.

In response to a moderator question about standardization of MRD measurement, Munir agreed that laboratories must be accredited and use the same techniques to give productive answers. Stilgenbauer noted that not all institutions follow the ERIC guidelines,⁵ and repeated testing for MRD status takes a real toll on patient anxiety.

A second poll of the audience revealed their positions had flipped: now, 53.7% agreed that MRD should not be used to guide treatment duration in first-line CLL, aligning with Stilgenbauer’s position. Munir maintained that there is “good evidence behind it” and the new EHA guidelines praise the findings of “excellent outcomes using MRD-driven guidance,”¹ but Stilgenbauer delivered the final word: “MRD-guided treatment in general practice is malpractice.”

References

1. Eichhorst B, Ghia P, Bosch F, et al. EHA guidelines on management of chronic lymphocytic leukemia and Richter transformation. HemaSphere. 2026;10(6):e70403. doi:10.1002/hem3.70403

2. Al-Sawaf O, Stumpf J, Zhang C, et al. Fixed-duration versus continuous treatment for chronic lymphocytic leukemia. N Engl J Med. 2026;394(11):1084-1096. doi:10.1056/NEJMoa2515458

3. Munir T, Girvan S, Cairns DA, et al. Measurable residual disease-guided therapy for chronic lymphocytic leukemia. N Engl J Med. 2025;393(12):1177-1190. doi:10.1056/NEJMoa2504341

4. Moreno C, Munir T, Owen C, et al. First-line fixed-duration ibrutinib plus venetoclax (Ibr+Ven) versus chlorambucil plus obinutuzumab (Clb+O): 55-month follow-up from the Glow study. Blood. 2023;142(suppl 1):634. doi:10.1182/blood-2023-177713

5. Javidi-Sharifi N, Brown JR. MRD-driven treatment strategies in CLL: Current practice, limitations, and emerging paradigms. Semin Hematol. 2025;62(5):418-430. doi:10.1053/j.seminhematol.2026.03.010