The promise of minimal residual disease (MRD) detection for assessing chemoimmunotherapy efficacy and predicting patient outcomes in chronic lymphocytic leukemia (CLL) has been well recognized for several years.1-4 More recently, evidence has accumulated that the same is true for patients treated with venetoclax-based regimens.1,2
A recent retrospective study of 62 patients with relapsed or refractory (R/R) CLL who were treated with venetoclax found that those with undetectable MRD in peripheral blood samples saw progression-free duration and overall survival outcomes “at least as favorable” as those with undetectable bone marrow MRD.1 Ninety percent of undetectable peripheral blood MRD (uMRD) was achieved by 24 months of treatment.1
“There was no new PB [peripheral blood] uMRD attainment after 24 months without treatment intensification,” the Australian research team noted.1 “The dominant association with earlier attainment of uMRD was concurrent rituximab. Complex karyotype was associated with inferior uMRD attainment after 12 months of therapy, and patients attaining uMRD whose disease harbored TP53 abnormalities demonstrated a trend toward earlier recrudescence (P = .089).”
Approximately 27% of patients (4 of 15 individuals) receiving venetoclax dose escalations achieved improved responses. And while concurrent rituximab administration appeared to influence uMRD, dose escalation and treatment beyond the standard 24 months “infrequently” deepened responses, the authors concluded. They also reported that in the absence of venetoclax escalations, additional duration of venetoclax therapy beyond 24 months was not associated with additional MRD benefit.
“This is an important paper. The authors attempted to demonstrate that the rate of conversion to undetectable MRD plateaus at approximately 24 months, which is the prescribed fixed-duration schedule of venetoclax plus rituximab. It seems that all of the undetectable MRD, if it’s going to happen, happens by month 24. What it doesn’t address is whether the extent of patients with undetectable MRD will deepen with further venetoclax exposure,” commented hematologic oncologist Anthony Mato, MD, MSCE, director of the CLL Program at Memorial Sloan Kettering Cancer Center in New York City.
That supports the hypothesis that 24 months is the appropriate time for combination therapy with venetoclax and rituximab. The idea is that a fixed-duration schedule can achieve all or most of the possible MRD benefit, Dr Mato said.
But therapy usually stops at month 24, he cautioned — so these findings do not necessarily preclude the possibility that longer treatments could offer additional benefit.
“I don’t think anyone can say with absolute certainty that there wouldn’t be any additional undetectable disease, but it does seem that there is somewhat of a plateau at this time point,” he said.