Ibrutinib Alone for Older Patients With Untreated CLL

Alexander M. Castellino, PhD

December 03, 2018

SAN DIEGO — In older patients >65 years with untreated chronic lymphocytic leukemia (CLL), a new study has shown that that ibrutinib (Imbruvica, Pharmacyclics/Janssen) alone or in combination with rituximab (Rituxan, Roche/Genentech) provides superior progression-free survival (PFS) compared with the standard of care combination of bendamustine (Bendeka, Teva) and rituximab. There was no significant difference in PFS between the two ibrutinib groups, suggesting that the addition of rituximab was unnecessary.

Jennifer Woyach, MD

"Our results establish that ibrutinib should be a standard of care for older patients with CLL — it is more effective than the best available chemoimmunotherapy regimen," said lead study author Jennifer A. Woyach, MD, of The Ohio State University Comprehensive Cancer Center in Columbus, Ohio.

These results come from the Alliance A041202, a multicenter study from the National Cancer Institute's National Clinical Trials Network study. They were presented here at the American Society of Hematology (ASH) 2018 Annual Meeting, and simultaneously published December 1 in the New England Journal of Medicine.

Kanti R. Rai, MD, from the Feinstein Institute for Medical Research in Manhasset, New York. He was not involved in the study and was approached for comment.

Rai told Medscape Medical News that this was a large, multicenter, well-conducted study, with extensive oversight for safety and efficacy.

PFS was superior in the ibrutinib-containing arms; there was also a hint of an overall survival (OS) advantage in favor of ibrutinib, Rai suggested. "Ibrutinib emerges superior to the combination of bendamustine and rituximab," Rai said.


Elderly Patients Are Representative in CLL

He also pointed out that elderly patients are representative of the CLL population, but have been systematically excluded from clinical trials. Being elderly, they typically have comorbidities with compromised organ functions, which usually excludes them from participating in trials.

"This study was conducted in the typical CLL patient," Rai noted. In addition, the control treatment of bendamustine and rituximab is currently the standard used in the clinical management of these patients, he added.

Lead author Woyach couldn't agree more. CLL is most common in older people, but most clinical trials for CLL have been conducted in younger adults, she pointed out.  This trial is one of just a few that have included only patients older than 65 years, Woyach explained. "The findings also suggest that when designing trials for CLL in older patients, ibrutinib is the efficacy standard by which other drugs should be measured," she added.

Woyach noted that the approval of ibrutinib was based on its comparison with chlorambucil (Leukeran, GlaxoSmithKline), which is not very effective and is considered obsolete. "This is the first prospective, randomized Phase 3 study, which compared ibrutinib regimens with the more commonly used regimen of bendamustine and rituximab," she noted.

Nadia Khan, MD, from the department of hematology/oncology at Fox Chase Cancer Center in Philadelphia, echoed similar sentiments, but went further to make the case for the combination of bendamustine and rituximab.

"The results from the ALLIANCE study continue to support the preferential use of ibrutinib in older patients in the up-front setting," she said. 

Response rates with single-agent ibrutinib outperformed bendamustine–rituximab and the addition of rituximab to ibrutinib did not appear to make a meaningful impact on response, she noted.

"However, despite these results, the use of chemoimmunotherapy and bendamustine–rituximab, in particular, may be a consideration for some older patients due to preference for a 6-month treatment plan over indefinite therapy with ibrutinib," she told Medscape Medical News

In light of the adverse-effect profile of ibrutinib, medical comorbidities such as a history of uncontrolled atrial fibrillation or refractory hypertension, for example, may sway treatment preference toward bendamustine–rituximab over ibrutinib in an older patient, she explained.  

Study Details

The phase 3 study randomly assigned patients with treatment-naïve symptomatic CLL to receive ibrutinib alone (n = 182), ibrutinib + rituximab (n = 182), or bendamustine + rituximab (n = 183). At the time of progression, patients receiving the combination of bendamustine and rituximab were allowed to cross over and receive ibrutinib.  

Patients had a median age of 71 years, and two thirds were men. Slightly more than half (54%) had high-risk disease, according to modified Rai staging, and 46% had intermediate-risk disease; 53% had ZAP70-unmethylated disease [surrogate for IgVH-unmutated status]; 27% had del(17p13.1) or del(11q22.3) disease.

Patients were followed for a median of 38 months. Median PFS was not reached for patients in either ibrutinib group and was 43 months for patients in the bendamustine + rituximab group. The 2-year PFS was 87% with ibrutinib, 88% with the ibrutinib–rituximab combination, and 74% for the bendamustine–rituximab combination (P < .001).

With hazard ratios of 0.39 for ibrutinib and 0.38 for ibrutinib–rituximab combination compared with bendamustine–rituximab, patients in either ibrutinib group were at a greater than 60% reduced risk for progression or death.

For all patients except those in the ZAP70-methylated disease group, PFS was longer with the ibrutinib regimens compared with the bendamustine–rituximab combination. "In the low-risk subgroup of patients who are IgVH mutated, there does not appear to be a difference in PFS at this time between the three regimens; however, it will take longer follow-up to really be able to answer this question [whether PFS will be longer with the ibrutinib groups compared with bendamustine–rituximab], Woyach told Medscape Medical News.

Overall survival rates at 2 years were similar across the groups: 90% with ibrutinib, 94% with ibrutinib–rituximab, and 95% with bendamustine–rituximab.

When asked why the PFS benefits did not translate into survival benefits, Woyach told Medscape Medical News: "The follow-up is probably not long enough to show a survival advantage in this older patient population where there are other causes of death besides CLL."

She pointed out that survival may also have been impacted by the cross-over study design. "Patients enrolled on bendamustine–rituximab who progressed could cross over to ibrutinib, which makes it much more difficult to ever see an advantage in survival," she said.

The response rate was lower with the bendamustine–rituximab combination (81%) vs ibrutinib alone (93%) and ibrutinib–rituximab (94%). Although complete response rates were higher in the bendamustine–rituximab group (26%) vs ibrutinib monotherapy (7%) and ibrutinib–rituximab (12%), more patients in the control group showed minimal residual disease (8% for bendamustine–rituximab, 1% for ibrutinib monotherapy, and 4% for ibrutinib–rituximab combination).

Grade 3/4 hematologic malignancies were lower with ibrutinib-based therapy and nonhematologic malignancies were higher with ibrutinib-based therapy. "Most adverse events with ibrutinib decrease in frequency with time, with the exception of hypertension," Woyach told Medscape Medical News.  "Many of the side effects occur early, although some persist throughout treatment and 14% of patients on each ibrutinib arm discontinued therapy due to toxicity," she added.

Should Ibrutinib Be Continued Indefinitely?

In this trial, ibrutinib was administered until disease progression or unacceptable toxicity. However, in clinical practice, can ibrutinib treatment be continued until disease progression? 

Woyach responded that at a median follow-up of 38 months, more than 60% of patients in each ibrutinib group were still receiving therapy.  "In the relapsed/refractory patient population where studies have gone on longer, there are patients who are still receiving ibrutinib for more than 8 years.  We do not know the maximum time that someone can take ibrutinib, but it is possible to continue therapy for many years," she said.

"The results of this analysis also raise the issue of whether indefinite therapy with a BTK [Bruton's tyrosine kinase] inhibitor such as ibrutinib is needed," Woyach and colleagues write in the NEJM study. "The significantly lower rates of undetectable minimal residual disease with the ibrutinib-containing regimens compared with the bendamustine plus rituximab suggest that treatment with ibrutinib must be continued indefinitely," they added. Woyach noted that future trials are designed to evaluate this question.

ASH 2018 Annual Meeting:  Abstract 6.
Presented December 2, 2018. 

N Engl J Med. Published online December 1. Full text


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