Balancing Speed and Stamina in CLL Treatment

In the near future, treatment of chronic lymphocytic leukemia (CLL) will be a choice between infinite therapy or time-defined therapy, according to Ryan W. Jacobs, MD, clinical director of the Lymphoma Division and an associate professor of medicine at Atrium Health Levine Cancer, Wake Forest University School of Medicine.¹

“Historically, we only had chemoimmunotherapy. There was no discussion of indefinite versus time-defined therapy. The chemotherapy was too toxic to give indefinitely, so we were only talking about fixed-duration therapy then,” said Dr. Jacobs in a presentation during the CLL session at The HemOnc Pulse Live, which took place May 2-3, 2025, in Austin Texas.

New Contenders

In recent years, the introduction of Bruton’s tyrosine kinase (BTK) monotherapy revolutionized practice for hematologists-oncologists treating CLL in the upfront setting. It is the most used treatment approach, according to Jacobs. With ongoing clinical trials, options exist beyond BTK inhibitor monotherapy, including fixed-duration BCL2/BTK inhibitor doublets and triplets.

Based on the outcomes seen with novel combinations, clinicians can help their patients with first-line CLL win the race against their disease. The unanswered question, according to Jacobs, is whether the race will be a marathon or a sprint.

Shorter Strides, Stronger Results

According to Jacobs, one trial that demonstrates how time-defined therapy offers stability during the race is the phase 3 CLL14 study. Jacobs shared, “We have this time-defined option with really excellent outcomes… At 6 years, roughly 66% are still free of progression—and I honestly think that just talking about time to next treatment might be underselling [the] venetoclax benefit quite a bit.”

Because CLL is an indolent disease, it is not necessary to treat the disease at progression, Jacobs explained. Therefore, time to next therapy (TTNT) is the key end point to look at when making the case for time-defined therapy.¹

The CLL14 study randomized 432 patients 1:1 to either venetoclax plus obinutuzumab or obinutuzumab plus chlorambucil. Patients received 12 cycles of treatment. After 6 years of follow-up, results showed a median TTNT of not reached in the venetoclax-containing arm compared with 52.9 months with obinutuzumab/chlorambucil. The 6-year TTNT rate observed with venetoclax/obinutuzumab was 65.2% versus 37.1% with obinutuzumab/chlorambucil.^1,2

Another study, the phase 3 AMPLIFY trial, showed that acalabrutinib in combination with venetoclax with or without obinutuzumab extended progression-free survival (PFS) compared with chemoimmunotherapy in fit patients with first-line CLL.³

Patients in the AMPLIFY trial (n=867) were randomized 1:1:1 to acalabrutinb/venetoclax, acalabrutinb/venetoclax/ obinutuzumab, or chemoimmunotherapy consisting of either fludarabine/cyclophosphamide/rituximab or bendamustine/rituximab. The 36-month PFS rates were 76.5% with the doublet, 83.1% with the triplet, and 66.5% with chemoimmunotherapy (hazard ratio [HR], 0.65; 95% CI, 0.49-0.87; P=0.004).³

Aside from the efficacy end points, the true benefits of time-defined therapy include the amount of time off therapy, cost-effectiveness, and lower toxicity, Jacobs explained. Whereas with the alternative, Jacobs concluded “indefinite therapy is more like a marathon… it’ll take its toll.”¹

References:

1. Jacobs R. The HemOnc Pulse Live.
2. Fischer K, et al. Blood. 2024;144(18):1924-1935.doi:10.1182/blood.2024024631
3. Brown J, et al. N Engl J Med. 2025;392(8):748-762. doi:10.1056/NEJMoa2409804