Defining the Goals of Venetoclax Treatment in Relapsed/Refractory CLL

Achieving undetectable measurable residual disease (MRD) predicts a better clinical outcome in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) who are treated with venetoclax, but questions remain about the optimal method of MRD assessment and whether venetoclax escalation can deepen long-term response.

In a new study published in Blood Advances, Thomas E. Lew, from The Royal Melbourne Hospital and Peter MacCallum Cancer Centre in Australia, and co-authors attempted to define the most informative methods for measuring MRD through a retrospective review of data from 3 trials of venetoclax in the CLL population.

The present analysis included 62 patients with CLL who had objective responses to venetoclax – either as monotherapy or in combination with rituximab. In the entire population, patients had received a median of 3 prior therapies, with 2 patients having no history of treatment. All participants had received venetoclax at doses ranging from 150 mg to 600 mg daily until either disease progression or treatment discontinuation.

While none of the studies required MRD assessment, patients were serially monitored for MRD in both peripheral blood and blood marrow at the clinician’s discretion. The following MRD statuses were defined and recorded:

  • undetectable MRD: <1 CLL cell detectable per 10,000 leukocytes (0.01%) in peripheral blood or bone marrow
  • MRD positivity: burden of MRD in all peripheral blood and bone marrow assessments was ≥0.01%; no MRD assessment due to early progression
  • MRD indeterminate: no detectable CLL observed on flow cytometric assays (but sensitivity inferior to <0.01%)

Most patients (95%) had MRD assessed at least once. Over a total observation period of 186 person-years, the number of MRD assays in peripheral blood and bone marrow were:

  • peripheral blood: 684 MRD assays (3.7 per person-year)
  • bone marrow: 199 (1 per person-year)

Across all studies, patients were followed for a median of 62 months (range = 41-81+).
Overall, 26 patients (42%) had confirmed undetectable MRD in the peripheral blood, bone marrow, or both: 19 in the peripheral blood (31%) and 21 in the bone marrow (34%).

In terms of timing of MRD assessment, the researchers found that deep responses, defined as either MRD indeterminate or confirmed undetectable MRD, were achieved between 9 and 18 months of venetoclax initiation. The median times to undetectable MRD on peripheral blood and bone marrow assessments were similar, at 18 months, with 90% and 94% of patients, respectively, achieving this level of response within 24 months.

Response appeared to plateau after 24 months, the investigators reported. Among the 30 patients with MRD assessments after 24 months, 10 (33%) experienced no change in the MRD burden and 18 (60%) had rising MRD, while 2 (7%) had reductions in MRD. Notably, “there was no new peripheral blood undetectable MRD attainment after 24 months without treatment intensification,” the authors reported.

“These data suggest that the majority of patients who ultimately achieve undetectable MRD with venetoclax therapy do so within 24 months.”

—Thomas E. Lew

Of the 15 patients who received escalating doses of venetoclax (to a maximum of 600 mg/day), 4 patients had rising MRD, while 1 had deepening of response from stable disease to partial response. “These data suggest that the majority of patients who ultimately achieve undetectable MRD with venetoclax therapy do so within 24 months and ongoing unaltered therapy beyond this time rarely eradicates persistent MRD,” the researchers wrote.

The researchers also found that achieving undetectable MRD – in either the blood or marrow compartment – was associated with improved long-term outcomes, compared with those who did not achieve MRD-negativity, including:

  • longer time to progression (peripheral blood: not reached vs. 55 months [p=0.0043]; bone marrow: not reached vs. 58 months [p=0.032])
  • longer median overall survival (peripheral blood: not reached vs. 82 months [p=0.033]; bone marrow: not reached vs. 82 months [p=0.107])

When the researchers reviewed patient and disease characteristics associated with achieving undetectable MRD, concomitant rituximab was the most significant factor that influenced the likelihood of attaining undetectable MRD at 24 months (64% with rituximab vs. 23% without rituximab; hazard ratio =2.86; 95% CI 1.22-6.69; p=0.012). In addition, patients with complex karyotype appeared to have inferior rates of undetectable MRD with ongoing venetoclax therapy vs. those without (37% vs. 27%; p=0.015). Presence of a TP53 or del17p mutation also appeared to confer a worse prognosis, the investigators reported, with a trend toward earlier MRD recrudescence vs. their absence (37 vs. 45 months; p=0.089).

The authors concluded that these findings potentially support MRD monitoring in peripheral blood as sufficient for use in clinical practice, within 24 months of venetoclax initiation. However, the study is limited by its retrospective nature, the reliance on clinician-directed MRD assessment, and the inclusion of a small number of patients in the final dataset.

Study authors report relationships with AbbVie and Genentech, which sponsored the included trials.

Reference

Lew TE, Anderson MA, Lin VS, et al. Undetectable peripheral blood MRD should be the goal of venetoclax in CLL, but attainment plateaus after 24 months. Blood Adv. 2020;4:165-173.