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.

SAN DIEGO — Progression-free survival was higher with ibrutinib compared with bendamustine plus rituximab (BR, or chemoimmunotherapy [CIT]) in untreated, older patients with chronic lymphocytic leukemia (CLL), according to new data concurrently presented at the 2018 American Society for Hematology (ASH) Annual Meeting and Exposition, 1 in San Diego, California, and published in the New England Journal of Medicine.2

The rationale for the trial was based on the fact that the current strength of evidence for ibrutinib as a frontline treatment for CLL may be a bit weak: “While ibrutinib has been FDA-approved for untreated CLL since 2016, it has only been compared to chlorambucil, which is relatively ineffective, and never before to aggressive CIT,” the presenters of a plenary session at the ASH meeting noted in an abstract released before their talk.1

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Of the 4 chemoimmunotherapy options for CLL, fludarabine/cyclophosphamide/rituximab (FCR) appears to be the best in terms of contributing to the longest progression-free survival, conferring a survival advantage of a median of 5 to 6 years. Although this is durable, the regimen is also the likeliest to produce adverse events, so it is generally not considered standard treatment for older individuals.

In the phase 3 Alliance A041202 trial, backed by the National Cancer Institute’s National Clinical Trials Network, ibrutinib-containing regimens (ibrutinib alone, ibrutinib plus rituximab) led to superior PFS compared with standard CIT in older individuals with CLL. The investigators suggested it should now be the standard-of-care treatment for patients aged 65 and older.

The study’s lead investigator, Jennifer Woyach, MD, the Ohio State University Comprehensive Cancer Center, Columbus, said in a press briefing that ibrutinib was “more effective than the best available chemoimmunotherapy regimen.” The addition of rituximab did not improve outcomes or prolong PFS compared with ibrutinib alone.3

For the trial, 547 patients were analyzed from December 9, 2013 to May 16, 2016. The cohorts were distributed as follows: 183 patients (176 evaluable for primary end point) were assigned to receive bendamustine plus rituximab, 182 patients (178 evaluable for primary end point) to receive ibrutinib alone, and 182 (170 evaluable for primary end point) were slated to receive ibrutinib plus rituximab.3

Thirty patients crossed over from chemoimmunotherapy to ibrutinib.

Median PFS was 43 months with BR, and has not yet been reached for either ibrutinib arm. The estimated progression-free survival at 2 years is near 75% with bendamustine plus rituximab, compared with 87% with ibrutinib and 88% with ibrutinib plus rituximab.

Median OS has not been reached for any arm, although 2-year OS estimates for BR, ibrutinib, and ibrutinib plus rituximab were 95%, 90%, and 94%, respectively, the study abstract authors noted.

Death occurred during treatment or within 30 days after treatment discontinuation in 2 patients (1%) in the bendamustine-plus-rituximab group, 13 (7%) people in the ibrutinib group, and 13 (7%) individuals in the ibrutinib-plus-rituximab group. Death occurred within the first 6 cycles of treatment, ie, within 30 days after the sixth cycle.

Overall response rate is lower with BR compared with ibrutinib alone or ibrutinib/rituximab (81% v 93% v 94%, respectively). Complete response rates and rates of minimal residual disease negativity at 9 months, however, are higher with BR.

“Responses with ibrutinib do tend to deepen over time, so this early time point may not be reflective of the overall MRD-negative responses in these patients,” Dr Woyach remarked. “As well, we do not yet have data showing that deeper responses lead to longer remissions with ibrutinib, so the prevalence of partial responses in this group is expected and not of concern.”

Despite some new promising data, there were some serious adverse events (AEs) reported by the researchers, which they described in the New England Journal of Medicine article on December 1, 2018.2 Grade 5 AEs were seen in 5 (2.8%), 14 (7.8%), and 14 (7.7%) patients (P = .07), which the authors wrote in the journal was much higher than they expected. They attributed the higher-than-usual proportion of adverse effects to the crossover design of the trial and the fact that the patient sample was so small.

In addition, the rate of secondary cancers was 13% for patients in the bendamustine-plus-rituximab group (excluding events that occurred after crossover), 13% in the ibrutinib group, and 16% in the ibrutinib-plus-rituximab group.

By a median follow-up of 38 months, there had been 66 deaths, and overall survival at this time is not different among the arms.

“At the time of this analysis, the most common causes of death associated with the ibrutinib-containing regimens, aside from CLL, included unexplained or unwitnessed death, infection, and secondary cancers,” the investigators wrote. “It is not clear that these events occur more frequently with ibrutinib than with bendamustine plus rituximab, but they will be monitored closely in long-term follow-up.”

“BTK inhibition with ibrutinib is not without significant toxicity in old patients, so close monitoring is still warranted,” Dr Woyach wrote on her final slide.

Disclosures: Multiple authors declare affiliations with the pharmaceutical industry. For a complete list of 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. Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib alone or in combination with Rituximab produces superior progression free survival (PFS) compared with bendamustine plus Rituximab in untreated older patients with chronic lymphocytic leukemia (CLL): results of Alliance North American Intergroup Study A041202. Oral presentation at: American Society of Hematology 60th Annual Meeting &Exposition; December 1-4, 2018; San Diego, CA. Abstract 6.
  2. American Society of Hematology. Major trials show benefits of new therapy regimens for cancer and blood disorders. Published December 1, 2018. Accessed December 2, 2018.
  3. Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL [published online December 1, 2018]. N Engl J Med. doi: 10.1056/NEJMoa1812836