Venclexta Added to Novel Combination Therapy Elicits High Responses in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia

Data presented at the 2020 American Society of Hematology Annual Meeting showed that adding Venclexta (venetoclax) to the combination of TGR-1202 (umbralisib) and TGTX-1101 (ublituximab) demonstrated encouraging rate of efficacy in patients with relapsed/refractory chronic lymphocytic leukemia (CLL), including patients whose disease was resistant to previous Bruton tyrosine kinase (BTK) inhibitor treatment.

“Given the growing use of BTK inhibitors in the first-line setting, we aimed to develop an effective (Venclexta)-containing regimen of limited duration for our relapsed/refractory patients,” said lead investigator Dr. Paul M. Barr during a virtual presentation of the data.

Barr, medical director of the Clinical Trial Office and professor of Medicine at the James P. Wilmot Cancer Institute of the University of Rochester Medical Center in New York, and his colleagues conducted the phase 1/2 study to evaluate the safety and efficacy of adding Venclexta to the novel combination. The phase 1 portion of the trial, which study results were presented during the 2019 Annual Meeting, identified the recommended dose of TGR-1202 and TGTX-1101 to be administered with the standard five-week ramp up dose of Venclexta in the phase 2 portion of the trial.

Assessing the safety of the triplet therapy was the main goal of the study with additional goals including complete response rates, progression-free survival (PFS), and undetectable minimal residual disease (MRD).

All patients on the study received three cycles of the novel combination followed by the standard Venclexta ramp up, which was continued for nine cycles. Patients underwent a full response assessment following completion of the 12-cycle treatment plan. To date, 43 patients (median age, 64 years; range, 43 to 83) have been enrolled and are evaluable for safety, and 39 patients have completed the first three cycles of treatment and are evaluable for efficacy.

Patients had received a median of two prior lines of therapy, with 33% being resistant to their first previous therapy. Overall, 74% of patients had prior anti-CD20 therapy, 70% had prior chemoimmunotherapy, 58% had prior BTK inhibitor therapy, 5% had a prior PI3K inhibitor, and 2% had received prior Venclexta. Among those who received a BTK inhibitor (25 patients), either Imbruvica (ibrutinib) or Calquence (acalabrutinib), 52% were refractory to the therapy, with seven of eight tested patients having a BTK or PLCy mutation detected.

Seventy-nine percent of patients had at least one high-risk feature, including 11q deletion (30%), 17p deletion (26%), TP53 mutation (18%), NOTCH1 mutation (27%), or SF3B1 mutation (15%); 74% of patients were IGHV unmutated.

The objective response rate (the proportion of patients who had a complete or partial response to treatment) after three cycles of induction therapy with the novel combination was 77%, composed exclusively of partial responses, with 23% of patients having stable disease. The objective response rate among patients who received seven cycles of treatment (31 patients) was 100%, with all patients achieving a partial response. Among patients who completed all 12 cycles (27 patients) of the triplet therapy, the objective response rate was 100%, with 41% of patients achieving a complete response and the rest achieving a partial response.

At the third cycle, the objective response rate was 64% among the BTK-refractory population and 74% among those who received a prior BTK inhibitor.

Overall, 96% of patients had undetectable minimal residual disease in the peripheral blood and 77% in the bone marrow.

The median progression-free survival, or the time from the start of treatment until disease worsened, was 15.6 months. One patient progressed 10 months after reaching undetectable minimal residual disease in the peripheral blood and bone marrow and discontinued therapy.

All-cause adverse events (AEs) of any severity occurring in at least 20% of patients included infusion reactions (60%), anemia (56%), thrombocytopenia (53%), neutropenia (51%), creatine decrease (49%), leukopenia (47%), fatigue (42%), and diarrhea (40%). The most common grade 3 or 4 (more serious or severe) AEs included neutropenia (21%), leukopenia (12%), infusion reaction (7%), anemia (5%), and diarrhea (5%).

“Three cycles of (the novel combination) induction appeared effective at reducing the tumor lysis risk. Six and 21 patients, respectively, had high and medium (tumor lysis syndrome) risk and most were relegated to having low (tumor lysis syndrome) risk after the induction. This represented an 81% relative reduction in tumor lysis risk after the three (novel combination) cycles,” concluded Barr. “Following three cycles of (the novel combination), no patients had developed clinical or laboratory (tumor lysis syndrome) during the (Venetoclax) ramp up.”