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Ibrutinib plus rituximab 'more effective and less toxic' than chemoimmunotherapy for chronic lymphocytic leukemia
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A combination of ibrutinib and rituximab improved PFS and OS compared with standard chemoimmunotherapy among patients with previously untreated chronic lymphocytic leukemia, according to results of a randomized, phase 3 trial published in The New England Journal of Medicine.
“These results will fully usher the treatment of chronic lymphocytic leukemia into a new era,” Tait D. Shanafelt, MD, Jeanie and Stew Ritchie professor of medicine in the hematology division of the department of medicine at Stanford University, said in a press release. “We’ve found that this combination of targeted treatments is both more effective and less toxic than the previous standard of care for these patients. It seems likely that, in the future, most patients will be able to forego chemotherapy altogether.”
In the phase 3 trial, Shanafelt and colleagues randomly assigned 529 patients aged 70 years or younger (mean age, 56.7 years; 67.3% men) with previously untreated CLL in a 2:1 ratio to one of the following regimens:
- ibrutinib (Imbruvica; Pharmacyclics, Janssen) and rituximab (Rituxan; Genentech, Biogen) for six cycles after one ibrutinib cycle, followed by ibrutinib until disease progression (n = 354); or
- six cycles of chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab (n = 175).
PFS served as the study’s primary endpoint, with OS as a secondary endpoint.
Median follow-up was 33.6 months, at which time 279 patients in the ibrutinib-rituximab group (78.8%) continued on ibrutinib and 132 patients in the chemoimmunotherapy group (75.4%) continued to be monitored.
Results showed that at 3 years, ibrutinib plus rituximab conferred significantly better PFS than the chemoimmunotherapy regimen (89.4% vs. 72.9%; HR for progression or death = 0.35; 95% CI, 0.22-0.56) as well as significantly better OS (98.8% vs. 91.5%; HR = 0.17; 95% CI, 0.05-0.54). A subgroup analysis of 281 patients without an immunoglobulin heavy-chain variable region (IGHV) mutation showed better PFS at 3 years with ibrutinib and rituximab vs. chemoimmunotherapy (90.7% vs. 62.5%; HR for progression or death = 0.26; 95% CI, 0.14-0.5). Researchers observed no significant difference in PFS among 114 patients with IGHV-mutated CLL (87.7% with ibrutinib and rituximab vs. 88% with chemoimmunotherapy; HR for progression or death = 0.44; 95% CI, 0.14-1.36).
The two groups demonstrated comparable incidence of grade 3 or higher adverse events, which occurred among 80.1% (n = 282) of patients in the ibrutinib-rituximab group and 79.7% (n = 126) of patients in the chemoimmunotherapy group.
Grade 3 or higher cardiac toxic effects occurred among 23 patients who received ibrutinib and rituximab, including 13 cases of atrial fibrillation or atrial flutter, compared with three patients who received chemoimmunotherapy, including two cases of atrial fibrillation. However, the ibrutinib-rituximab group had a lower prevalence of grade 3 or higher infectious complications (10.5% vs. 20.3%; P <.001).
“This is one of those situations we don’t often have in oncology,” Shanafelt said in the press release. “The new treatment is both more effective and better tolerated. This represents a paradigm shift in how these patients should be treated. We can now relegate chemotherapy to a fallback plan rather than a first-line course of action.”
Disclosures: Shanafelt reports grant support from AbbVie, Celgene, Cephalon, GlaxoSmithKline, Hospira, Merck, Pharmacyclics and Polyphenon E International, as well as a patent on green tea extract epigallocatechin gallate in combination with chemotherapy for CLL. Please see the study for all other authors’ relevant financial disclosures.
Perspective
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Nicole Lamanna, MD
This study supports the continued trend away from chemoimmunotherapy for patients with CLL, given the plethora of novel agents that have been approved in the past few years. However, there are still select patients for whom chemoimmunotherapy might be beneficial.
The discussion of whether to use fludarabine, cyclophosphamide and rituximab or chemoimmunotherapy still comes up for patients with IGHV-mutated CLL. In this study, PFS was no different among patients with IGHV-mutated CLL treated with fludarabine, cyclophosphamide and rituximab vs. ibrutinib and rituximab. This is the one subgroup of patients for whom this discussion is still relevant.
Unfortunately, the study does not address whether combining rituximab with ibrutinib is necessary, as there was no ibrutinib monotherapy arm. We don’t know whether rituximab added anything because patients continued ibrutinib indefinitely anyway. We’re not sure that patients need antibody therapy with ibrutinib; this has been a topic of debate in several studies. For example, the ALLIANCE 041202 trial did not show any PFS or OS advantage with the ibrutinib-rituximab combination vs. ibrutinib monotherapy.
Continued follow-up of this study will be needed to evaluate potential long-term toxic effects and/or changes to disease biology with indefinite use of ibrutinib.
NewYork-Presbyterian/Columbia University Medical Center
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