First-Line Ibrutinib/Rituximab Combination Shows Benefit for Younger Patients With CLL

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First-line therapy with the combination of ibrutinib (Imbruvica) and rituximab (Rituxan) reduced disease progression by two-thirds compared with standard chemotherapy using fludarabine, cyclophosphamide, and rituximab (FCR) in younger patients with chronic lymphocytic leukemia (CLL), according to the late-breaking results of the ECOG-ACRIN E1912 trial presented at the 2018 American Society of Hematology (ASH) Annual Meeting & Exposition.1 This is the first phase III trial to compare the newer chemotherapy-free regimen with standard-of-care FCR in younger patients with CLL.

We found ibrutinib-based therapy is both more effective and less toxic than our previous best therapy for patients with CLL aged 70 and younger.
— Tait D. Shanafelt, MD

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“We found ibrutinib-based therapy is both more effective and less toxic than our previous best therapy for patients with CLL aged 70 and younger,” said lead author Tait D. Shanafelt, MD, of Stanford University School of Medicine, Stanford, California. “These findings have immediate practice-changing implications. They establish the combination of ibrutinib plus rituximab as the most effective first-line treatment to date for these patients.”

“The most important take-home message from this late-breaking study is that it demonstrates a shift away from chemotherapy to targeted therapy to improve outcomes for our patients,” said Aaron T. Gerds, MD, MS, of Cleveland Clinic Taussig Cancer Center. “This study should change practice.” Dr. Gerds moderated a press conference where these results were presented.

CLL is a common lymphoid malignancy, accounting for 11% of all lymphoid neoplasms. Over the past decade, several new targeted therapies for CLL have been approved by the U.S. Food and Drug Administration. FCR is the most active chemoimmunotherapy regimen to date, and it is mainly used as first-line therapy in younger patients with CLL, although half of all people who develop CLL are aged 70 or older.

“Half of our patients with CLL cannot tolerate FCR,” Dr. Shanafelt told listeners. “Ibrutinib/rituximab is a pill-based therapy that is effective as initial treatment for older patients with CLL. It is the only pill-based therapy for the front-line treatment of CLL. Prior to this study, ibrutinib-based therapy had not been compared with FCR for younger patients with CLL.”

Study Details

Between January 31, 2014, and June 9, 2016, E1912 randomly assigned 529 patients with CLL in a 2:1 ratio to first-line therapy with ibrutinib/rituximab vs FCR. In the experimental arm, ibrutinib was given alone for the first month, and rituximab was added for a total of 7 cycles, followed by ibrutinib alone until disease progression. FCR was given for 6 cycles.

Patients enrolled in the trial were aged 70 years or younger (range = 28–70 years; median = 57 years), were symptomatic and required treatment for CLL, had no deletion of 17p, and were able to tolerate FCR. The median age was 58 years, and 40% were aged 60 or older. About half had Rai stage I to II disease, and 43% had Rai stage III to IV. About 71% had IgVH-unmutated CLL.

The new therapy [with ibrutinib and rituximab] is less toxic than historical chemotherapy.
— Tait D. Shanafelt, MD

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“In this group of patients, CLL has a greater impact on life expectancy because it has developed at a younger age than is typical. Patients enrolled in the trial were a higher-risk group than in historical studies,” he noted.

At a median follow-up of 33.4 months, the median progression-free survival and overall survival had not yet been reached at the time of the ASH meeting. The combination of ibrutinib and rituximab reduced the likelihood of disease progression by 65% compared with FCR. In the ibrutinib/rituximab arm, 37 disease progression events occurred in 354 patients vs 40 events in 175 patients on the FCR arm—a statistically significant difference favoring the experimental arm (P < .00001). In a subgroup analysis of progression-free survival, ibrutinib-based therapy was superior to FCR regardless of age, sex, performance status, and disease stage.

“There was a markedly lower risk of death in the ibrutinib arm,” Dr. Shanafelt said. Overall survival was also improved by 83% in the ibrutinib/rituximab arm. There were 4 deaths out of 354 patients vs 10 deaths out of 175 patients in the FCR arm (P = .0003).

“The new therapy is less toxic than historical chemotherapy,” he added. Ibrutinib plus rituximab was associated with a much lower burden of adverse events than FCR. Overall, grade 3 to 5 treatment-related adverse events were reported in 58.5% of the experimental arm vs 72% of the FCR arm (P = .004). The rate of grade 3 to 5 adverse events was significantly lower in the ibrutinib-containing arm as follows: neutropenia, 22.7% vs 43.7%, respectively; anemia, 2.6% vs 12%; thrombocytopenia, 2.9% vs 13.9%; any infection, 7.1% vs 19%; and neutropenic fever, 2.3% vs 15.8% (P < .001 for all). However, ibrutinib-treated patients had significantly more grade 3 to 5 hypertension compared with FCR: 7.4% vs 1.9% (P = .01).

Unanswered Questions

These results represent a paradigm shift from 6 months of treatment with intravenous chemotherapy to unlimited treatment with oral agents. The next question is whether chronic therapy can be eliminated. Two National Cancer Institute (NCI)-sponsored trials are planned to explore that issue.

The NCI trials will treat patients with CLL aged 70 years and older using the backbone of ibrutinib plus obinutuzumab (Gazyva) and compare that to a regimen of ibrutinib, obinutuzumab, and venetoclax (Venclexta).

“The question is whether giving patients more aggressive therapy upfront will allow them to stop therapy after 12 months of venetoclax and not require chronic ibrutinib. If that is the case, side effects and expense would be reduced,” Dr. Shanafelt commented.


  • The combination of ibrutinib and rituximab improved progression-free survival and overall survival compared with standard-of-care FCR as first-line therapy in symptomatic younger patients with CLL.
  • Severe side effects were significantly less frequent with ibrutinib-based therapy.

Another question is whether rituximab is necessary in these younger patients. “The short answer is that we don’t know. Our study did not answer that question. Two studies in elderly patients suggest that rituximab provides no clear improvement in progression-free survival, but we can’t extrapolate that to younger patients. Without direct evidence, given a survival advantage for ibrutinib/rituximab in E1912, we have to proceed with caution,” Dr. Shanafelt continued.

He said that the phase III FLAIR trial in the United Kingdom is comparing both arms used in E1912 but adding an additional arm of ibrutinib alone. Results should provide the answer to whether rituximab can be eliminated.

“Cross-trial comparisons are dangerous,” Dr. Gerds commented. “We need the FLAIR data before we can eliminate rituximab. This is important because it has economic implications as well as clinical implications for patients.” 

DISCLOSURE: Dr. Shanafelt has patents and royalties with the Mayo Clinic and has received research funding from Celgene, GlaxoSmithKline, Genentech, AbbVie, Pharmacyclics, and Janssen. Dr. Gerds has received research funding from Samus Therapeutics, Imago BioSciences, Genentech, Roche, Celgene, Apexx Oncology, CTI BioPharma, and Incyte and is a consultant for Celgene, Apexx Oncology, CTI BioPharma, and Incyte.


1. Shanafelt T, Wang XV, Kay NE, et al: A randomized phase III study of ibrutinib-based therapy vs standard fludarabine, cyclophosphamide, and rituximab chemoimmunotherapy in untreated younger patients with chronic lymphocytic leukemia (CLL): A trial of the ECOG-ACRIN Cancer Research Group (E1912). 2018 ASH Annual Meeting & Exposition. Abstract LBA4. Presented December 3, 2018.

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