The following article features coverage from the American Society of Hematology (ASH) 2018 meeting. Click here to read more of Cancer Therapy Advisor‘s conference coverage.

The combination of ibrutinib and rituximab provided superior progression-free survival and, after follow-up, superior overall survival, compared with the current standard of care, chemoimmunotherapy (CIT) fludarabine, cyclophosphamide, and rituximab (FCR), in treatment-naive patients younger than 70 years with chronic lymphocytic leukemia (CLL), according to research presented at a late-breaking abstract session at the 2018 American Society of Hematology (ASH) Annual Meeting in San Diego, California ( Identifer: NCT02048813).1

“The need for indefinite therapy should be evaluated in future clinical trials testing novel-agent combination therapy,” stated Tait Shanafelt, MD, of Stanford University in California.

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Citing a 2016 study from The Lancet Oncology, Dr Shanafelt said that although CIT is the most active regimen in fit patients with CLL to date,2 the findings that he presented on behalf of the North American Intergroup “have immediate practice-changing implications and establish ibrutinib-based therapy as the most efficacious first-line therapy for patients with CLL.”

The efficacy and durability of ibrutinib in CLL have previously been demonstrated across key studies: one that showed its activity in relapsed/refractory disease and others demonstrating its efficacy compared with chlorambucil. The efficacy of CIT compared with FCR has not been examined previously.

In the phase 3 study, patient characteristics were well balanced across treatment cohorts, explained Dr Shanafelt. Patients with CLL were enrolled if they were treatment-naive, required treatment according to iwCLL 2008 standards, were younger than 70 years (overall median age was 58 years), had an Eastern Cooperative Oncology Group score of 0 to 2, creatinine clearance above 40, could tolerate FCR, and had no deletion 17p when evaluated with FISH.

Participants were randomly assigned in a 2:1 ratio to receive ibrutinib (420 mg/day until disease progression) and rituximab (50 mg/m2 on day 1 of cycle 2; 325 mg/m2 on day 2 of cycle 2; 500 mg/m2 on day 1 of cycles 3-7) or 6 courses of intravenous fludarabine (25 mg/m2) and cyclophosphamide (250 mg/m2) days 1 to 3 with rituximab (50 mg/m2 on day 1 of cycle 1; 325 mg/m2 on day 2 of cycle 1; 500 mg/m2 on day 1 of cycles 2-6) every 28 days. 

Although 529 patients underwent randomization (intent-to-treat population), some patients were determined to be ineligible, resulting in 498 evaluable patients.

The researchers found that at 36 months following treatment, overall survival in patients treated with the ibrutinib/rituximab (IR) combination was 92%, which was better than in trials GCLLSG CLL8 and GCLLSG CLL10, where it was approximately 86% and 90%, respectively. Progression-free survival (PFS) was also superior at 73% compared with approximately 65% and 70%, respectively.

For PFS, the hazard ratio favored the IR regimen across all CLL subgroups. “The most important question among the CLL community is the performance in the subgroups of IGVH mutation status,” remarked Dr Shanafelt. “You will note there is a precipitous dip in advantage for ibrutinib in the IGVH unmutated patients; there also does appear to be an advantage in mutated patients, but it is a small subgroup [and] a wide confidence interval, and the confidence interval does include 1.”

There were 14 total patient deaths across the study: 10 in the FCR arm and 4 in the IR arm. Six of the deaths in the FCR arm were attributed to CLL, whereas only 1 of the deaths in the IR arm were due to CLL. The FCR arm had half as many patients, but it still had a higher rate of events or deaths compared to the IR cohort. “This difference also reached statistical significance, and crossed the protocol-specified boundary for superiority, which led the data safety monitoring committee to recommend the release of the data,” Dr Shanafelt said.

The occurrence of adverse events of grade 3 or higher was significantly lower in the IR arm compared with the FCR cohort (58.5% vs 72.1%, P = .004). And, according to Dr Shanafelt, the IR combination was well tolerated in patients younger than 70 years with CLL.

Disclosure: The study was funded by the National Cancer Institute (NCI). For a complete list of author disclosures, please refer to the original abstract.

Read more of Cancer Therapy Advisor‘s coverage of the ASH 2018 meeting by visiting the conference page.


  1. Shanafelt TD, Wang V, Kay NE, et al. A randomized phase 3 study of ibrutinib (PCI-32765)-based therapy vs. standard fludarabine, cyclophosphamide, and rituximab (FCR) chemoimmunotherapy in untreated younger patients with chronic lymphocytic leukemia (CLL): a trial of the ECOG-ACRIN cancer research group (E1912). Oral presentation at: 2018 American Society of Hematology 60th Annual Meeting & Exposition; December 1-4, 2018; San Diego, California. Abstract LBA-4.
  2. Eichhorst B, Fink A-M, Bahlo J, et al. First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2016. 17(7):928-942.