Venetoclax Shows Good Results Even in Short-Telomere Patients With CLL

A pair of studies examining the role of venetoclax (Venclexta) in treating chronic lymphocytic leukemia (CLL) were presented at the 2024 American Society of Hematology (ASH) Annual Meeting & Exposition.

The first study dealt with the impact of venetoclax on telomere length as a prognostic factor; the second related to venetoclax in combination with duvelisib in patients with relapsed or refractory (R/R) CLL or Richter syndrome (RS). Lukas Peter Frenzel, MD, of the University of Cologne, and colleagues outlined research suggesting treatment with venetoclax may “neutralize” the apparent association between telomere length and prognosis among people with CLL.¹

Previous research has shown that telomere length is associated with outcomes in patients treated with chemotherapy. Similarly, evidence suggests telomere length has prognostic value in younger, fit patients with CLL. However, as treatment for CLL has evolved, Frenzel and colleagues said it is important to see whether telomere length holds the same prognostic value when patients are treated with newer therapies.

These investigators used data from the CLL14 trial of venetoclax to see whether telomere length was associated with outcomes in a previously untreated population with coexisting conditions.² They randomly chose 210 patients from the trial, 93 of whom had received chemotherapy with chlorambucil (Leukeran) and obinutuzumab (Gazyva; combination Clb-Obi) and 107 of whom received venetoclax and obinutuzumab (Ven-Obi).¹

One study looked at the impact of venetoclax on telomere length as a prognostic factor. | Image credit: peterschreiber.media – stock.adobe.com

At baseline, the 2 arms had statistically similar telomere lengths. The median telomere length in the Clb-Obi arm was 4.653 kB; in the Ven-Obi group it was 4.824 kB. The investigators defined “short” telomeres as those less than 6.293 kB, and 71.9% of patients overall fit that category. Those patients with short telomeres were also more likely to have other high-risk characteristics, the investigators found.

In the overall cohort, short telomere length was associated with a shorter progression-free survival (PFS; median 48.4 vs 62.2 months; HR, 1.709; 95% CI, 1.130-2.584, P = .011). Those with short telomeres also had an overall survival advantage.

Yet, when the investigators looked at outcomes by treatment group, they found a disparity. Patients in the Clb-Obi arm tended to have worse outcomes if they were in the short-telomere group (median PFS 28.3 vs 47.6 months; HR, 2.165; 95% CI, 1.249-3.754, P = .006). Yet, the same was not true in the Ven-Obi arm (median PFS 64.7 months vs not reached; HR, 1.590; 95% CI, 0.843-2.997, P = .152).

When they compared patients with short telomeres in the Clb-Obi group with those in the Ven-Obi arm, the latter had a PFS advantage (HR, 0.344; 95% CI, 0.230-0.513, P < .001), though no similar effect was seen among long-telomere patients. Frenzel and colleagues said they plan to run similar analyses of data from trials of other targeted therapies to better understand the apparent link between therapy type and the impact of telomere length on outcomes.

Also presented at ASH was new data from a phase 2 study of venetoclax and duvelisib (Copiktra) in people with R/R CLL or RS.³ Corresponding author Jennifer L. Crombie, MD, physician at Dana-Farber Cancer Institute and assistant professor of medicine at Harvard Medical School, and colleagues noted that despite the efficacy of the venetoclax plus rituximab (Rituxan) regimen, the length of treatment time and the need for 6 months of infusions can be a drawback for some patients. In the new trial, investigators looked at combining venetoclax and duvelisib, an oral PI3K-δ/γ inhibitor that has already been approved in patients with R/R CLL who have undergone 2 prior lines of therapy.

The new trial included 38 patients (29 with CLL; 9 with RS) with a median age of 69 years, 70% of whom were male. Among the CLL cohort, the best overall response rate (ORR) was 97% and the complete response/complete response with incomplete count recovery (CR/CRi) rate was 62%. After 12 cycles of therapy, the ORR was 72% (44% CR/CRi), the authors reported. In TP53-aberrant patients, the CR/CRi rate was 64%, and in patients who had previously been treated with a BTKi, it was 46%.

The investigators observed toxicities such as grade 5 hepatic failure related to progressive RS and COVID-19 pneumonia—each in 1 patient—but the authors said toxicities were manageable in most patients. They said their findings support larger studies of venetoclax plus duvelisib.

References

1. Frenzel PL, Beckmann L, Robrecht S, et al. Venetoclax may overcome the prognostic disadvantage of short telomeres regarding progression free survival in previously untreated CLL patients with coexisting conditions: a study by the German CLL Study Group. Presented at: 66th ASH Annual Meeting & Exposition; December 7-10, 2024; San Diego, CA. Abstract 3250.
2. Al-Sawaf O, Robrecht S, Zhang C, et al. Venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia: 6-year results of the randomized phase 3 CLL14 study. Blood. 2024;144(18):1924-1935. doi:10.1182/blood.2024024631
3. Crombie JL, Ryan CE, Ren Y, et al. A phase 2 study of duvelisib and venetoclax in patients with relapse or refractory (R/R) chronic lymphocytic leukemia (CLL) or Richter’s syndrome (RS). Presented at: 66th ASH Annual Meeting & Exposition; December 7-10, 2024; San Diego, CA. Abstract 4628.