This article was originally published by OncLive

Although frontline chemoimmunotherapy regimens have been the gold standard for patients with chronic lymphocytic leukemia (CLL) for many years, the advent of BTK inhibitors and other novel drugs has moved the field toward adopting chemotherapy-free options for patients in this setting.

“For 50 years or so, there weren’t too many major developments in this field,” said Matthew S. Davids, MD, MMSc, director of clinical research and the lymphoma program at Dana-Farber Cancer Institute. “We had some improvements in the intensity of chemoimmunotherapy regimens, but in the last 10 years, we have had some really remarkable developments where the whole field was transformed.”

In an virtual presentation during the 2nd Annual Precision Medicine Symposium, a program developed by Physicians’ Education Resource® LLC, Davids, who is also an associate professor of medicine at Harvard Medical School, discussed the switch to chemotherapy-free regimens and whether chemoimmunotherapy combinations will retain a role in the frontline treatment of patients with CLL.

Novel Therapies Challenge Standard Frontline Chemoimmunotherapy Regimens

Upfront fludarabine, cyclophosphamide, and rituximab (Rituxan; FCR) chemoimmunotherapy was considered the gold standard for patients with CLL. Moreover, studies such as the FCR 300 and CLL8 trials showed that time-limited FCR can provide functional cure in patients with IGHV-mutant CLL.^1,2

“This does highlight the important role of IGHV mutation status when we are thinking about using chemoimmunotherapy,” explained Davids. “IGHV-unmutated patients tend to have steady disease progression over time and do not enjoy the potential functional cure [that IGHV-mutated patients may derive].”

Other chemoimmunotherapy regimens such as bendamustine and rituximab (BR), which is widely used in the community setting, according to Davids, and obinutuzumab (Gazyva) plus chlorambucil, are also active in the frontline CLL space.

However, in recent years, studies have demonstrated superiority with novel regimens compared with chemoimmunotherapy.

“Much of [the advancements made in CLL] are due to the investment in basic science that was done in the late 1990s and early 2000s that allowed us to understand the role of the microenvironment in CLL and how that can be leveraged to treat the disease,” said Davids.

For example, in the phase 3 ECOG 1912 trial, the combination of the BTK inhibitor ibrutinib (Imbruvica) and rituximab, followed by ibrutinib maintenance therapy, demonstrated favorable progression-free survival (PFS) compared with FCR chemoimmunotherapy in patients 70 years or younger with previously untreated CLL.³

At a median follow-up of 33.6 months, the PFS rate was 89.4% with the ibrutinib/rituximab regimen versus 72.9% with chemoimmunotherapy (HR, 0.35; 95% CI, 0.22-0.56; P < .001). Moreover, overall survival (OS) also favored the chemotherapy-free regimen at 98.8% versus 91.5% with chemoimmunotherapy (HR, 0.17; 95% CI, 0.05-0.54; P < .001).

However, at 3 years, the PFS rate in patients with IGHV-mutant disease was 87.7% with ibrutinib/rituximab versus 88% with FCR (HR, 0.44; 95% CI, 0.14-1.36).

Although these chemotherapy-free options have been revolutionary in the frontline treatment of patients with CLL, chemoimmunotherapy may still be considered in this particular subgroup of IGHV-mutant patients, according to Davids.

“For my young fit patients with IGHV-mutant disease, FCR is certainly still part of the conversation,” Davids explained, adding that data suggest BR and obinutuzumab/chlorambucil are also options for these patients. In particular, BR should be considered for older, frail, IGHV-mutant patients who have cardiovascular comorbidities since giving BTK inhibitor therapy could increase the risk of cardiovascular events.

Similarly, results from the randomized phase 3 ELEVATE-TN trial demonstrated that acalabrutinib (Calquence) with or without obinutuzumab significantly improved PFS over obinutuzumab/chlorambucil chemoimmunotherapy.⁴ The median PFS at 28.3 months of follow-up was not reached with acalabrutinib as monotherapy or in combination with obinutuzumab versus 22.6 months with chemoimmunotherapy (HR, 0.1; 95% CI, 0.06-0.17; P < .0001; HR 0.20; 95% CI, 0.13-0.30; P < .0001).

Moreover, Davids added, chemoimmunotherapy may be selected in patients who prefer a time-limited therapy versus continuous treatment with a newer regimen.

“We can give 6 months of FCR and know that we have a good chance of very long-term remission,” said Davids. “We do have to counsel patients about cytopenias, infection risk, and secondary myeloid neoplasms. [These] are slightly more common in patients with CLL treated with FCR, but the rates are low.”

CLL14 Trial Aims to Eliminate the Need for Chemotherapy Altogether

The extended follow-up from the phase 3 CLL14 trial showed that the estimated 24-month PFS rate was 88.2% with the combination of venetoclax (Venclexta) and obinutuzumab versus 64.1% with obinutuzumab/chlorambucil.⁵ Although there was no statistically significant difference in OS between arms, venetoclax/obinutuzumab was associated with a low incidence of high-grade adverse effects in patients with relevant comorbidities.

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