Combination Regimen’s Timing Studied for Patients With CLL/SLL

A phase 3 trial is investigating the benefits of early intervention compared with delayed therapy for a combination treatment in certain patients with chronic lymphocytic leukemia (CLL). The study examining venetoclax (Venclexta; Abbvie and Genentech) and obinutuzumab (Gazyva; Genetech) is in progress and currently recruiting patients who are newly diagnosed with asymptomatic, high-risk CLL for a 12-month period of study.

Sponsored by the US National Institutes of Health, the EVOLVE CLL study (NCT04269902) was described in a presentation during the virtual 2021 American Society of Clinical Oncology (ASCO) Annual Conference.

According to lead author and presenter Deborah M. Stephens, DO, from the Huntsman Cancer Institute at the University of Utah in Salt Lake City, current recommendations for patients with asymptomatic CLL include a “watch and wait” approach. She said this approach is used because prior studies with standard chemotherapy, such as chlorambucil (Leukeran; Aspen Global) and fludarabine (Fludara; Genzyme and Sanofi), have failed to show an overall survival benefit with early intervention

“Now we have some really nice prognostic factors that can help us to determine which patients are at risk for short survival, or a short time until first treatment,” Stephens said.

One modern tool for predicting survival is the CLL International Prognostic Index (IPI). According to Stephens, this scoring tool incorporates clinical and molecular risk factors that include deletion 17p (TP53 mutation), serum beta-2 microglobulin, unmutated IgHV status, Rai stage, and an age of 65 years or older.

IPI scores of 4 or greater indicate high risk disease, and patients in this group have a 5-year overall survival (OS) rate of approximately 50%. Patients with scores of 7 or greater are considered very high risk, with a 19% OS rate, and a 50% treatment-free rate at 5 years.

“[Patients with scores of 7 or higher] is really a group of interest for early intervention,” Stephens said.

As frontline CLL treatments shift from chemotherapy toward targeted therapy, venetoclax and obinutuzumab are under close examination. The study’s goal is to answer the question of whether the combination can prolong survival in patients with high-risk CLL.

According to Stephens, patients participating in the study are being divided between predicted high-risk and very high-risk disease, and randomized, 2-to-1 to receive early versus delayed venetoclax and obinutuzumab therapy. The study currently has 2 randomized patients, she said, and 247 patients are needed.

Patients eligible for the study must be asymptomatic and with no cytopenias, and must have received no prior CLL directed therapy. Additionally, these patients must have a CLL IPI score of 4 or higher or complex cytogenetics, a good performance status of 0 to 2 on the ECOG scale, and no gastrointestinal malabsorption problems.

The primary endpoint of the study is OS; secondary endpoints include safety, overall response, duration of response, progression-free survival, time to next treatment, minimal residual disease (MRD) status, and quality of life; and translational endpoints include MRD status and its effects on resistance and outcomes, according to Stephens.

Individuals seeking information about the trial should contact investigators by email at S1925@Utah.edu.

REFERENCE

Stephens D. Randomized, phase III study of early intervention with venetoclax and obinutuzumab versus delayed therapy with venetoclax and obinutuzumab in newly diagnosed asymptomatic high-risk patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): EVOLVE CLL/SLL study. Presented at: 2021 American Society of Clinical Oncology Annual Conference; June 4-8, 2021.