“Unfavorable Genetics” Negatively Impacted MRD in Some Patients With R/R CLL

Favorable genetic characteristics may be able to predict which patients with relapsed/refractory chronic lymphocytic leukemia (R/R CLL) who were treated with venetoclax-rituximab will attain undetectable minimal residual disease (MRD).

Favorable genetic characteristics may be able to predict which patients will attain undetectable minimal residual disease (uMRD), according to a study of patients with relapsed/refractory chronic lymphocytic leukemia (R/R CLL) who were retreated with venetoclax-rituximab (VenR).

The poster, presented at the European Hematology Association 2021 Virtual Congress, included data on a substudy of the phase 3 MURANO trial. In the substudy, patients with R/R CLL were included who had progressed after completing their initial treatment of either VenR or bendamustine-rituximab (BR). The patients in the substudy either were retreated with VenR (n = 25) or crossed over from BR to receive VenR (n = 9).

The poster specifically reported on the 25 patients who progressed after their initial treatment and were retreated with VenR. The researchers evaluated molecular profile changes from the main study baseline (BL-1) to the retreatment baseline (BL-2).

The median follow-up for the 25 patients retreated with VenR was 12.1 months and they had a median treatment-free interval of 28.3 months. “Unfavorable genetic characteristics were enriched among the retreatment cohort,” the researchers wrote.

The median progression-free survival was 45.7 months for the patients who were retreated compared with 53.6 months for the overall population of the MURANO trial. The unfavorable key genetic characteristics of patients who were retreated included complex (high) genomic complexity and abnormal del(17p) and/or TP53 mutation.

Approximately two-thirds (65%) of the evaluable patients (n = 20) had del(17p) at BL-2. Among these patients were 3 with newly acquired del(17p) and 4 who shifted from low to high clone. The researchers also noted there was “evidence of clonal evolution” in the retreatment group and that the “prevalence of TP53 mutation increased more than 2-fold, with higher clonal size in some patients.”

Despite the “unfavorable” genetics, the researchers reported that 29% of retreated patients with a valid MRD assessment (17/25) achieved uMRD. Both increased del(17p) clone status and genomic complexity were associated with a negative impact on MRD. There were 10 patients with del(17p) at BL-2 and they were all MRD positive: 4 of the 10 either had new del(17p) or had evolved from low clone to high clone from BL-1.

In addition, of the 10 patients with genomic complexity at BL-2, 8 were MRD positive: 5 of the 10 had new or increased genomic complexity from BL-1.

“Deep initial response, with favorable BL-2 characteristics, may predict uMRD attainment with VenR retreatment,” the researchers concluded. “Further investigation into these findings is required due to the small sample size presented here.”

Reference

Qun Wu J, Seymour JF, Eichhorst B, et al. Impact of unfavorable genetics on minimal residual disease (MRD) response to venetoclax+rituximab retreatment in relapsed or refractory chronic lymphocytic leukemia (R/R CLL): phase 3 MURANO substudy. Presented at: EHA2021 Virtual Congress; June 9-12, 2021. Poster EP599.