Debating the Role of Chemoimmunotherapy in the First-Line Setting of CLL

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The advent of new targeted agents for chronic lymphocytic leukemia (CLL) has ushered in a golden age of treatment, leading to longer, more durable periods of disease control. Not all oncologists are convinced, however, that improvements in progression-free survival alone warrant dispensing with chemoimmunotherapy, which has long been the mainstay of induction therapy. At the National Comprehensive Cancer Network (NCCN) 2019 Annual Congress: Hematologic MalignanciesTM, William G. Wierda, MD, PhD, and Jennifer R. Brown, MD, PhD, debated the role of chemoimmunotherapy in the first-line setting of CLL.1

Dr. Wierda: No Role for Chemoimmunotherapy in CLL

According to Dr. Wierda, Professor of Medicine at The University of Texas MD Anderson Cancer Center, Houston, small-molecule inhibitors such as ibrutinib and venetoclax offer a better approach to treating CLL than exposing patients to genotoxic chemotherapy. With ibrutinib, a Bruton’s tyrosine kinase inhibitor, patients can achieve a sustained and durable period of disease control, said Dr. Wierda, albeit through continuous therapy. Venetoclax, a selective inhibitor of B-cell lymphoma 2, on the other hand, offers deep remissions with fixed-duration treatment.

"Small-molecule inhibitors such as ibrutinib and venetoclax offer a better approach to treating CLL than exposing patients to genotoxic chemotherapy."
— William G. Wierda, MD, PhD

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As Dr. Wierda reported, the effectiveness of ibrutinib-based front-line therapy for CLL has been demonstrated with the results of several phase III randomized clinical trials: RESONATE-2, which randomly assigned patients to either ibrutinib or chlorambucil monotherapy2; iLLUMINATE, which compared ibrutinib plus obinutuzumab with chlorambucil plus obinutuzumab3; the three-arm Alliance trial, which randomly assigned patients to ibrutinib monotherapy, ibrutinib plus rituximab, or bendamustine/rituximab4; and the ECOG E1912 trial, which compared ibrutinib plus rituximab with fludarabine, cyclophosphamide, and rituximab (FCR).5

“All of these trials were positive in showing longer progression-free survival for the ibrutinib-based arm compared with chemoimmunotherapy, and the ECOG E1912 trial demonstrated a survival difference with a larger number of events in the FCR arm,” said Dr. Wierda. He noted that differences in overall survival may emerge in other trials with longer follow-up.

“Chemotherapy is genotoxic and carries the risk for long-term complications,” Dr. Wierda added. “Patients treated with the FCR regimen, for example, have a 3% to 5% incidence of myelodysplastic syndromes.”

CLL14, a trial conducted by the German CLL study group, also found positive outcomes in progression-free survival for patients randomly assigned to venetoclax/obinutuzumab vs chlorambucil/obinutuzumab.6 For patients receiving venetoclax/obinutuzumab, progression-free survival at 2 years was comparable to that achieved with ibrutinib (80%–90%), with the added advantage of fixed-duration treatment.

“Despite the improvements in progression-free survival, the challenge with ibrutinib-based therapy is that it requires patients to remain on treatment,” Dr. Wierda explained. “With the CLL14 trial, it was important to show that we could still achieve improvements in progression-free survival with small-molecule–based therapy with fixed-duration treatment.”

That said, for a subset of patients with IgHV mutation, Dr. -Wierda acknowledged that chemoimmunotherapy may still be the best option. As evidenced by the CLL8 trial, he noted, more than half of patients with IgHV-mutated CLL experienced long-term progression-free survival, and 60% tested negative for minimal residual disease. Moreover, this plateau was not achieved in patients randomly assigned to bendamustine-based treatment.

“If you’re thinking about chemoimmunotherapy, FCR is the best treatment to give patients because of this plateau,” he concluded. “It’s potentially curative in half of patients with IgHV mutation.”

Dr. Brown: Chemoimmunotherapy to Remain in CLL Treatment Repertoire

According to Dr. Brown, Director of the CLL Center at Dana-Farber Cancer Institute and Professor of Medicine at Harvard Medical School, there remains an important role for chemoimmunotherapy in CLL, despite the positive outcomes achieved with targeted agents. “With or without obinutuzumab, ibrutinib substantially improves progression-free survival compared with chlorambucil and compared with chemoimmunotherapy as well, in the overall enrolled patient population,” said Dr. Brown. “Venetoclax/obinutuzumab also improved progression-free survival compared with chlorambucil/obinutuzumab on the CLL14 trial.”

"I content that ibrutinib did not improve overall survival compared with chemoimmunotherapy."
— Jennifer R. Brown, MD, PhD

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Nevertheless, Dr. Brown noted that improvements in progression-free survival have yet to translate to an overall survival benefit that is clear in these trials. “If patients were actually living longer, progression-free survival would matter, but they’re not, likely because rapid use of a targeted agent in the second-line setting for those who need it results in comparable benefits,” she observed. “I contend that front-line ibrutinib did not improve overall survival compared with chemoimmunotherapy in the majority of patients.”

According to Dr. Brown, the overall survival benefit reported in the RESONATE-2 trial was due to a poor comparator of chlorambucil monotherapy and limited crossover to the ibrutinib arm at the time of disease progression. When obinutuzumab was added to ibrutinib and compared with obinutuzumab/chlorambucil in the iLLUMINATE study, the overall survival curves were identical, as they also were in the Alliance trial. Moreover, said Dr. Brown, although ECOG E1912 reported an overall survival benefit based on extremely few events, many of the deaths were not clearly related to the disease or its treatment.

Furthermore, not all patients are achieving improved progression-free survival with small-molecule inhibitors compared with chemoimmunotherapy. Data from the ECOG and Alliance trials showed that low-risk IgHV-mutated patients did equally well with chemoimmunotherapy vs targeted agents. And in the CLL14 study, patients with low-risk IgHV mutation randomly assigned to chlorambucil/obinutuzumab performed identically to those on the venetoclax/obinutuzumab arm.

What’s more, shared Dr. Brown, this mutated subgroup has the potential for prolonged treatment-free remission—or even cure—with chemoimmunotherapy. Results from the long-term MD Anderson phase II study showed that 55% of patients with IgHV-mutated disease treated with the FCR regimen remained in remission with more than 12-year follow-up; hence, they may be cured.

“In what disease do we give up potentially curative therapy for the requirement of continuous therapy with ongoing residual disease, cumulative side effects, and clearly no cure, which is what we’re talking about with ibrutinib?” said Dr. Brown. “Even if ibrutinib did eventually yield similar 12-year progression-free survival, it would still have the requirement of continuous therapy, toxicity, and cost.”

Nonhematologic and Financial Toxicities

As Dr. Brown discussed, hematologic toxicity is clearly worse with chemoimmunotherapy than targeted agents. However, as evidenced by data from the ECOG E1912 trial, nonhematologic toxicity with ibrutinib and rituximab is “quite significant.” Grade 3 or higher treatment-related adverse events throughout observation included hypertension (18.8%), cardiac toxicity (6.5%), diarrhea (4.3%), atrial fibrillation (3.2%), hemorrhage (1.1%), and ventricular arrhythmia or cardiac arrest (0.9%). On the Alliance trial, which had an older patient population, nonhematologic toxicity was even worse; the chance of dying of an adverse event on either of the ibrutinib arms was 7%, with the median follow-up of 2.5 years.

Financial toxicity is another concern. One analysis of the impact of oral targeted therapy moving from the relapsed setting to the front-line setting showed a six-fold increase in cost.7 “Clearly, novel agents are not saving money,” said Dr. Brown, who emphasized that the financial impact extends beyond the health-care system. “Out-of-pocket costs for Medicare patients receiving ibrutinib in the front-line setting have been estimated at $60,000. The majority of patients cannot afford this.”

Finally, Dr. Brown stated, given the proven success of small-molecule inhibitors in the second-line setting, using novel agents too early could cost patients a line of therapy down the line. “We don’t know that chemoimmunotherapy will work after ibrutinib, but we do know that ibrutinib works well in the second-line setting,” she concluded. “That’s something to consider as we manage this chronic disease over a patient’s lifetime.” 

DISCLOSURE: Dr. Wierda reported no conflicts of interest. Dr. Brown has served as a consultant for AbbVie, Acerta, AstraZeneca, Beigene, Catapult, Dynamo Therapeutics, Juno/Celgene, Kite, Novartis, Octapharma, Pfizer, Pharmacyclics, Sunesis, TG Therapeutics, and Verastem; has received honoraria from Janssen; has received research funding from Gilead, Loxo, Sun, and Verastem; and has served on data safety monitoring boards for Morphosys and Invectys.


1. Wierda WG, Brown JR: Evolving strategies in first-line chronic lymphocytic leukemia: Is there a role for chemoimmunotherapy? NCCN 2019 Annual Congress: Hematologic Malignancies. Debate. Presented September 27, 2019.

2. Barr PM, Robak T, Owen C, et al: Sustained efficacy and detailed clinical follow-up of first-line ibrutinib treatment in older patients with chronic lymphocytic leukemia: Extended phase 3 results from RESONATE-2. Haematologica 103:1502-1510, 2018.

3. Moreno C, Greil R, Demirkan F, et al: Ibrutinib + obinutuzumab versus chlorambucil + obinutuzumab as first-line treatment in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma: Results from phase 3 iLLUMINATE. 2018 ASH Annual Meeting & Exposition. Abstract 691.

4. Woyach JA, Ruppert AS, Heerema NA, et al: Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med 379:2517-2528, 2018.

5. Shanafelt TD, Wang V, Kay NE, et al: A randomized phase III study of ibrutinib (PCI-32765)-based therapy vs. standard fludarabine, cyclophosphamide, and rituximab (FCR) chemoimmunotherapy in untreated younger patients with chronic lymphocytic leukemia: A trial of the ECOG-ACRIN Cancer Research Group (E1912). 2018 ASH Annual Meeting & Exposition. Abstract LBA-4.

6. Fischer K, Al-Sawaf O, Bahlo J, et al: Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med 380:2225-2236, 2019.

7. Barnes JI, Divi V, Begaye A, et al: Cost-effectiveness of ibrutinib as first-line therapy for chronic lymphocytic leukemia in older adults without deletion 17p. Blood Adv 2:1946-1956, 2018.