Study of Ibrutinib in CLL Shows a Benefit, but Raises Crucial Questions

Efforts to target key mechanisms in the development of chronic lymphocytic leukemia (CLL), one of the most common lymphoid cancers, have led to several new treatments. Among these, ibrutinib emerged as a strong approach for patients who were too frail for aggressive treatment.1 But for healthier patients with CLL, the benefit of this drug remained unknown for a time.

A phase 3 study published in the New England Journal of Medicine showed a benefit for ibrutinib plus rituximab for these more fit patients.2 Although the data help clarify the potential role of ibrutinib in CLL, they also raise difficult questions about the future of this treatment approach.

The standard first-line treatment for otherwise healthy CLL patients 70 years or younger has been a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab (FCR). Patients with immunoglobulin heavy-chain variable region (IGHV)-mutated disease had particularly good results with this treatment: roughly half remained progression-free for up to 8 years after initial treatment. However, substantial toxic effects in the aftermath of treatment, including myelosuppression, risk of myelodysplasia, and infectious complications, have led researchers to explore other avenues of therapy — in particular, ibrutinib.

Ibrutinib inhibits Bruton tyrosine kinase (BTK), a B-cell signaling protein involved in B-cell development, differentiation, proliferation, and survival. After studies showed the drug to be effective for patients with relapsed CLL and then frail patients with untreated CLL, researchers have been eager to investigate its role in first-line therapy for younger patients.

Most studies so far have explored the use of ibrutinib as a monotherapy. This trial, however, led by Tait Shanafelt, MD, of Stanford University School of Medicine, California, combined ibrutinib with rituximab, and compared the regimen with the standard treatment of FCR.

The study began with 529 patients, all with previously untreated CLL. A total of 354 patients, all 70 years or younger, were randomly assigned to receive ibrutinib-rituximab treatment, consisting of 1 cycle of ibrutinib, followed by 6 cycles of ibrutinib-rituximab combined, and then ibrutinib alone, taken indefinitely until disease progression. The 175 patients in the control group received 6 cycles of FCR chemoimmunotherapy. The primary end point was progression-free survival (PFS), with overall survival (OS) as the secondary end point.

Patients in the ibrutinib-rituximab group received 1 dose of 420 mg per day of ibrutinib during day 1 to day 28 of each of the 6 cycles, until either their disease progressed or the side effects became intolerable. Alongside this dosage, they also received rituximab, during cycles 2 through 7. The FCR group received 6 cycles of FCR.

At a median follow-up of 33.6 months, Dr Shanafelt and the team found a benefit for the experimental treatment. At that point, 89.4% of patients in the experimental group had experienced no disease progression, compared with 72.9% in the control group. OS rates echoed the benefit: 98.8% of patients in the experimental group were still alive, compared with 91.5% of patients in the control group.

The researchers wondered if treatment efficacy would be different for patients with the IGHV-mutated CLL. Dividing the existing patients into 2 subgroups, they found that for patients carrying the mutation, the 2 protocols were nearly identical — and in fact, FCR proved 0.3% more effective. For those without the mutation, however, the ibrutinib-rituximab combination was superior to FCR: with 90.7% PFS at 3 years, compared with 62.5%, respectively. Patients in the experimental group without IGHV-mutated disease also experienced fewer serious infections.

Researchers concluded that treatment with ibrutinib-rituximab was superior to FCR with regard to both PFS and OS. They reported a 65% lower risk of progression and an 83% lower risk of death. This superior PFS was also present in high-risk subgroups, including patients with Rai stage III or stage IV disease, chromosome 11q22.3 deletion, and unmutated IGHV.

Study coauthor Jacqueline Claudia Barrientos, MD, associate professor at the Feinstein Institutes for Medical Research in New York, emphasized that the study does not provide any evidence that the addition of rituximab improved outcomes or remission duration beyond what is achieved by ibrutinib alone. Because the study didn’t include an ibrutinib-monotherapy arm, there’s no way to know. “I don’t believe that we should move to using combination ibrutinib plus rituximab for frontline except in specific cases, such as uncontrolled autoimmune complications or in a patient with a very aggressive disease that requires combined therapy because monotherapy is taking too long to work,” Dr Barrientos said.

She also pointed out that widespread use of ibrutinib as a frontline treatment would raise several issues. Although ibrutinib appears to cause less myelosuppression than FCR, she said, “there are still other issues that can affect quality of life.” These include bleeding, joint pain, diarrhea, cardiac arrhythmias, and other side effects. Dr Barrientos noted that because ibrutinib needs to be taken indefinitely, sorting out these complications is vital.

Cost is another concern. Again, the long-term nature of ibrutinib therapy is the issue: the drug may be too expensive to sustain treatment. In a 2015 paper in the Journal of Oncology Practice, Dr Shanafelt discussed the potential financial burden that would confront the movement toward novel targeted agents, such as ibrutinib, for frontline treatment of CLL.3 This shift, Dr Shanafelt wrote, “will dramatically increase individual out-of-pocket and societal costs of caring for patients with CLL. These cost considerations may undermine the potential promise of these agents by limiting access and reducing adherence.”

Nitin Jain, MD, associate professor of medicine at MD Anderson Cancer Center, Houston, Texas, who was not involved with the study, was optimistic about the findings. The results, he said, were not just statistically significant but also clinically significant.  “This study establishes a new treatment paradigm for younger patients with CLL,” he says. However, he emphasized that this benefit is restricted to patients with IGVH-unmutated disease, per the study findings.

As Dr Jain sees it, the study is just one more piece of the puzzle showing how ibrutinib and new drugs may best benefit patients with CLL. “Several ongoing randomized studies are evaluating combinations of targeted therapies with chemoimmunotherapy,” Dr Jain noted. “The results of these studies will further help define the optimal frontline approach for patients with CLL.”

Disclosure: The study was supported by the National Cancer Institute and Pharmacyclics. Some of the authors of the study reported receiving payments from the pharmaceutical industry. For a full list of disclosures, please refer to the original study.

References

  1. Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373(25):2425-2437.
  2. Shanafelt TD, Wang XV, Kay NE, et al. Ibrutinib–Rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med. 2019;381(5):432-443.
  3. Shanafelt TD, Borah BJ, Finnes HD, et al. Impact of ibrutinib and idelalisib on the pharmaceutical cost of treating chronic lymphocytic leukemia at the individual and societal levels. J Oncol Pract. 2015;11(3):252-258.