The Role of Chemoimmunotherapy Dwindles Among New Regimens in Frontline CLL

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Although frontline chemoimmunotherapy regimens have been the gold standard for patients with chronic lymphocytic leukemia 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.

Matthew S. Davids, MD, MMSc

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.

This regimen should be considered up front for patients with CLL, and in particular, those with higher-risk disease who may not tolerate chemotherapy, explained Davids.

Although the field appears to lean toward frontline BTK inhibitors versus venetoclax/obinutuzumab, there are factors to weigh in treatment selection, Davids said.

Namely, BTK inhibitor therapy is supplemented by long-term efficacy data, as well as other data testing ibrutinib against FCR and BR. BTK inhibitors are also potentially more convenient and do not require infusions or tumor lysis syndrome monitoring. Additionally, more data are available regarding the efficacy of venetoclax in patients who progress on ibrutinib.

In favor of venetoclax/obinutuzumab, there is the potential to provide patients 1 year of time-limited therapy that does not have known cardiac or bleeding risk. Additionally, the short-term treatment duration may provide better long-term adherence to treatment, said Davids. Finally, if 1 year of therapy with venetoclax/obinutuzumab provides durable responses, the regimen may provide cost-saving potential to the health care field as a whole.

The Future of Frontline CLL Management

Choosing between regimens may not be a challenge in the future as there are ongoing studies evaluating combination regimens with newer agents.

For example, frontline ibrutinib plus venetoclax demonstrated rapid and deep responses among patients with previously untreated CLL in the phase 2 CAPTIVATE trial.6 Moreover, most of the 155 patients treated with the combination achieved undetectable minimal residual disease (MRD).

Additionally, frontline acalabrutinib in combination with venetoclax and obinutuzumab (AVO) demonstrated activity in a phase 2 trial.7 After a median follow-up of 11 cycles, the objective response rate was 97.3% after cycle 4, and 100% after cycle 8 and cycle 16. Additionally, after cycle 8, 16.7% of patients achieved a complete response with undetectable MRD in the bone marrow.

Moreover, the safety profile with the combination was favorable and the rate of infusion-related reactions was significantly lower with AVO versus historical data with obinutuzumab with or without chemotherapy.

Additionally, multiple phase 3 trials are currently underway evaluating various formulations of treatment in the frontline setting for patients with CLL.

For example, the CLL13/GAIA trial is testing FCR/BR versus venetoclax/rituximab versus venetoclax/obinutuzumab versus ibrutinib/venetoclax/obinutuzumab. The trial is enrolling 920 patients.

Other studies, namely the Alliance A041702 and ECOG EA9161 trials, are evaluating the up-front role of venetoclax in older and younger patients with CLL, respectively.

Novel Agents Demonstrate Activity in Relapsed/Refractory CLL

In addition to being highly efficacious in the frontline setting, acalabrutinib has shown significant activity in the relapsed/refractory space.

The randomized phase 3 ASCEND trial showed that acalabrutinib significantly improved PFS compared with investigator’s choice of idelalisib (Zydelig)/rituximab or BR in patients with relapsed/refractory CLL who had received a median of 2 prior lines of therapy.8 After a median follow-up of 16.1 months, the PFS was not reached with acalabrutinib monotherapy versus 16.5 months with chemoimmunotherapy (HR, 0.31; 95% CI, 0.20-0.49; P < .0001). The estimated 12-month PFS rates were 88% and 68%, respectively.

Additionally, updated results from the phase 3 MURANO trial showed that at a median follow-up of 48 months, the estimated PFS rate was 57.3% with venetoclax/rituximab versus 4.6% with BR. Additionally, at 4 years, the OS rates were sustained with venetoclax/rituximab versus BR. The OS rates were 85.3% and 66.8%, respectively (HR, 0.41; 95% CI, 0.26-0.65; P < .0001).9

“I think [the data from the MURANO trial] is really the ‘nail-in-the-coffin’ for [not] using chemoimmunotherapy in the relapsed/refractory setting of CLL. Based on this data set and for any patient who is a candidate for venetoclax, we can’t justify using BR based on this overall survival benefit,” concluded Davids.


1. Thompson PA, Tam CS, O’Brien SM, et al. Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia. Blood. 2016;127(3):303-309. doi:10.1182/blood-2015-09-667675

2. Fischer K, Bahlo J, Fink AM, et al. Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood. 2016;127(2):208-215. doi:10.1182/blood-2015-06-651125

3. Shanafelt TD, Wang XV, Kay NE, et al. Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Eng J Med. 2019;381(5):432-443. doi:10.1056/NEJMoa1817073

4. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzumab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet. 2020;395(10232):1278-1291. doi:10.1016/S0140-6736(20)30262-2

5. Al-Sawaf O, Zhang C, Tandon M, et al. Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (CLL14): follow-up results from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2020;21(9):1188-1200. doi:10.1016/S1470-2045(20)30443-5

6. Tam CS, Siddiqi T, Allan JN, et al. Ibrutinib (Ibr) plus venetoclax (Ven) for first-line treatment of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): results from the MRD cohort of the phase 2 CAPTIVATE study. Blood. 2019;134(suppl 1):35. doi:10.1182/blood-2019-121424

7. Lampson BL, Tyekucheva S, Crombie JL, et al. Preliminary safety and efficacy results from a phase 2 study of acalabrutinib, venetoclax and obinutuzumab in patients with previously untreated chronic lymphocytic leukemia (CLL). Blood. 2019;134(suppl 1):32. doi:10.1182/blood-2019-127506

8. Ghia P, Pluta A, Wach M, et al. ASCEND: Phase III, randomized trial of acalabrutinib versus idelalisib plus rituximab or bendamustine plus rituximab in relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol. 2020;38(25):2849-2861. doi:10.1200/JCO.19.03355.

9. Seymour JF, Kipps TJ, Eichhorst BF, et al. Four-year analysis of Murano study confirms sustained benefit of time-limited venetoclax-rituximab (VenR) in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Blood. 2019;134(suppl 1):355. doi:10.1182/blood-2019-123930

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