Clinical challenges: use of MRD in the management of chronic lymphocytic leukemia

For patients with chronic lymphocytic leukemia (CLL), minimal residual disease (MRD) has become a very sensitive indicator of the disease burden during and at the end of treatment, and has been correlated with the time to onset of the disease. ‘event. The use of MRD has shown promise in guiding the duration of treatment for patients with CLL on time-limited treatment.

Undetectable MRD (uMRD) – defined as less than 1 LLC cell in 10,000 leukocytes (10-4 ) in peripheral blood and bone marrow at the end of treatment – is assessed by multi-color flow cytometry, real-time quantitative polymerase chain reaction and high-throughput sequencing. A recent and more sensitive analysis may detect MRD at thresholds of 10-5 and even 10-6.

MRM has been correlated with favorable progression-free survival (PFS) and overall survival (OS) after chemoimmunotherapy. Given the utility of assessing depth of response, determination of uMRD status becomes an outcome goal in CLL trials, particularly on fixed-course therapy.

Recently updated results from the CLL14 trial showed that treatment-naïve patients receiving venetoclax (Venclexta) and obinutuzumab (Gazyva) had detectable MRD at a later time than those receiving chlorambucil plus l ‘obinutuzumab, with only 7.9% in the venetoclax arm requiring a next line of treatment more than 3 years after stopping treatment. The estimated PFS and OS at 4 years were also higher in the venetoclax arm.

Significantly, regular MRD evaluations over time demonstrated a profound clearance of CLL cells from the peripheral blood of venetoclax-obinutuzumab recipients, indicating its potential as an end-of-treatment prognostic parameter. MRD in this study was detected at a sensitivity level of 10-6.

“Measuring DRM is not necessarily the standard of care at this time, but it will continue to emerge as an important goal of treatment in fixed-term CLL regimes,” said Catherine Coombs, MD, of the University of North Carolina School of Medicine at Chapel. Hill. “Studies of treatment with venetoclax have shown that achieving negative MRD levels is the prognosis for favorable outcomes with better PFS and better OS.”

Daniel Persky, MD, of the University of Arizona College of Medicine in Tucson, agreed:

“The assessment of MRD is emerging as an important and actionable test in the care of patients with CLL. We use it to make decisions about stopping treatment for CLL. The data show that patients in MRD-negative complete remission may consider discontinuing certain treatments for CLL. “

So how far do uMRD levels have to go to predict a good outcome?

“Classically, we took 10-4, but now we have the ability to detect levels of 10-6, and a lower tier is probably better, ”Coombs said.

For patients on continuous treatment with Bruton’s tyrosine kinase (BTK) inhibitors, however, MRD does not exclude prolonged PFS. For example, earlier this year, a study on Blood reported that MRM was not associated with improvement in PFS in patients receiving indefinite treatment with ibrutinib (Imbruvica). PFS, however, was significantly longer in patients with undetectable MRM who received six cycles of fludarabine, cyclophosphamide, and rituximab (Rituxan).

As to whether MRD levels are ready to guide clinical decision making, Coombs was cautious:

“I don’t think we’re there yet. It’s still up for debate, and the big question is whether the results of MRD are actionable. It’s pretty clear that patients with undetectable MRD are doing better, and I think measuring the MRD will be the way of the future. “

The speed at which uMRD is achieved can be an important factor, according to Jacob Soumerai, MD, of Massachusetts General Hospital Cancer Center in Boston, and Andrew Zelenetz, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York City.

At last year’s American Society of Hematology (ASH) Virtual Annual Meeting, their group presented a study on time-limited MRD therapy with zanubrutinib (Brukinsa), obinutuzumab, and venetoclax. in previously untreated LLC.

The combination achieved frequent and lasting uMRD responses, with 89% of patients achieving uMRD in both peripheral blood and bone marrow; treatment was stopped after a median of 10 months.

“It is important to note that the data on the kinetics of MRD that we presented to ASH suggests that it is not just a question of whether or not you achieve uMRD, but rather your kinetics of. Early response to MRD could predict MRD outcomes and define biological differences, ”Soumerai said. MedPage today.

In the study, 60% of patients had rapid MRD response kinetics (ΔMRD400 performing) and these patients had rapid bone marrow uMRD (100% within 8 months) and longer lasting uMRD -5. In contrast, 40% of patients did not reach ΔMRD400. These had later bone marrow uMRD and early detectable MRD 10-5, despite longer treatment times due to the length of the trial’s MRD treatment.

“These data suggest that assessment of the early dynamic response of MRM is a prognostic biomarker of MRM outcome and should be explored as a predictive biomarker to guide treatment,” Zelenetz said.

So how often should MRD be measured?

“This is an important question,” Soumerai said. “I assess MRD at the end of treatment, usually using the approved clonoSEQ test, but I do not use MRD as a monitoring tool after stopping treatment. “

For a patient who develops a detectable recurrent MRM without clinical sign of disease, this currently has no impact on the management. “I continue to monitor this patient at the same time interval and only initiate treatment if the patient develops an indication for treatment,” Soumerai said.

Lymphocytosis or recurrent lymphadenopathy is usually detected in asymptomatic patients by physical examination and routine labs.

“The question is whether some patients might benefit from early treatment for relapsed / refractory, but this should only be done in a clinical trial,” Zelenetz said.

The kinetics of MRD appear to identify two groups of patients, Soumerai said: “Patients who reach ΔMRD400 achieve early uMRD, which appears to be durable. Patients with slower responses are at risk for early recurrence of MRD and should probably have a longer treatment duration. “

Regarding the role of MRD in other treatments for CLL such as the inhibitors of BTK and PI3Kdelta, “since these regimens rarely reach uMRD and are administered continuously regardless of the depth of the response. , I do not systematically assess MRD for patients undergoing these therapies, ”noted Soumerai.

Coombs said that while MRD levels are not yet routinely used nationwide to alter the duration of treatment with fixed-duration venetoclax regimens, “I think further trials will involve therapy. adaptive to MRD and will modify treatment duration depending on MRD response, but this needs to be chopped in future studies. “

Persky foresees a time when MRD will systematically guide decisions about the duration of treatment and may become a new goal of treatment.

“It could also potentially be used to restart treatment for a person whose CLL has changed from MRD-negative to MRD-positive status,” he said.

But as MRD tests become increasingly sensitive and able to detect ever smaller amounts of residual disease, “before we agree that uMRD becomes a new target, we must agree on a standard way to measure it, “he added.

  • Diana Swift is a Toronto-based freelance medical journalist.