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Ibrutinib plus R-CHOP improves survival among younger patients with aggressive lymphoma subtype
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The addition of ibrutinib to standard R-CHOP chemotherapy improved EFS, PFS and OS among patients aged younger than 60 years with untreated nongerminal center B-cell diffuse large B-cell lymphoma, according to results of a randomized, phase 3 study published Journal of Clinical Oncology.
The combination, however, appeared associated with increased toxicity and resulted in worse outcomes among patients aged older than 60 years.
“The interaction between age and toxicity was surprising [because] it was not observed within the context of the phase 1 trial that we have published,” Anas Younes, MD, chief of the lymphoma service and Steven Greenberg chair at Memorial Sloan Kettering Cancer Center, told HemOnc Today. “At the present time, there is no obvious biological explanation, but this will be addressed through planned extensive correlative studies. R-CHOP plus ibrutinib is not commonly given to patients with other types of lymphoma.”
DLBCL accounts for as many as 40% of all lymphoma cases, making it the most common form of lymphoma in the world. A previous phase 1 study appeared to demonstrate the safety of ibrutinib (Imbruvica; Pharmacyclics, Janssen) in combination with R-CHOP chemotherapy — which consists of rituximab (Rituxan; Genentech, Biogen) plus cyclophosphamide, doxorubicin, vincristine and prednisone — among patients with untreated B-cell lymphoma, including DLBCL.
Younes and colleagues specifically investigated whether ibrutinib improves the efficacy of R-CHOP in patients with untreated nongerminal center B-cell or activated B-cell diffuse large B-cell lymphoma.
Researchers randomly assigned 838 patients (median age, 62 years; range, 19-88; 53.3% men) to R-CHOP with ibrutinib at 560 mg daily (n = 419) or with placebo (n = 419) in a 21-day cycle for six or eight cycles, depending upon institutional guidelines.
Three-quarters of the patients (75.9%) had the activated B-cell DLBCL subtype.
EFS among the intent-to-treat population and patients with the activated B-cell subtype served as the study’s primary endpoint. Secondary endpoints included PFS, OS and safety.
Median follow-up was 34.8 months.
Results showed that the addition of ibrutinib to R-CHOP did not improve EFS compared with placebo and R-CHOP in the intent-to-treat population (HR = 0.93; 95% CI, 0.72-1.2) or the activated B-cell population (HR = 0.94; 95% CI, 0.7-1.27).
Ibrutinib also did not increase PFS (HR = 0.91; 95% CI, 0.71-1.18), OS (HR = 0.99; 95% CI, 0.71-1.38) or rates of overall response (89.3% vs. 93.1%) and complete response (67.3% vs. 68%) among the intent-to-treat population.
However, results of a preplanned subgroup analysis showed that among patients aged younger than 60 years, the ibrutinib regimen improved EFS (HR = 0.57; 95% CI, 0.38-0.88), PFS (HR = 0.55; 95% CI, 0.35-0.86) and OS (HR = 0.33; 95% CI, 0.16-0.67) compared with the placebo regimen, with a slight increase in serious adverse events (35.7% vs. 28.6%).
In patients aged older than 60 years, the ibrutinib regimen yielded worse EFS (HR = 1.228; 95% CI, 0.887-1.669), PFS (HR = 1.2; 95% CI, 0.866-1.664), and OS (HR = 1.44; 95% CI, 0.963-2.152) than the placebo regimen, with a larger percentage of serious adverse events (63.4% vs. 38.2%).
Researchers wrote that older patients had worse outcomes with ibrutinib because of higher toxicity, which led to a premature discontinuation of R-CHOP. Whereas a similar proportion of younger patients in the ibrutinib and placebo groups received at least six cycles of R-CHOP (92.9% vs. 93%), the proportion among older patients was lower in the ibrutinib group (73.3% vs. 88.8%).
The most common serious adverse events among patients in the ibrutinib vs. placebo groups included febrile neutropenia (18.8% vs. 10.5%), pneumonia (6.7% vs. 3.3%), neutropenia (4.1% vs. 3.1%), diarrhea (3.6% vs. 1%) and anemia (3.6% vs. 1.2%). Ibrutinib-treated patients aged older than 60 years experienced substantially higher rates of nearly all serious adverse events than their younger counterparts, including febrile neutropenia (21.4% vs. 14.3%), lung infection (5% vs. 0.6%) and atrial fibrillation (4.2% vs. 1.3%).
“Unfortunately, older patients could not tolerate ibrutinib plus R-CHOP,” Younes said. “The obvious next step is to try a combination with more selective Bruton tyrosine kinase inhibitors, or to implement strict monitoring and prophylaxis strategies.”
An unintended selection bias for more favorable patients as part of the screening for this trial could explain the surprising results, John P. Leonard, MD, medical director of the lymphoma program at Weill Cornell Medicine, wrote in an accompanying editorial.
“This explanation is supported by the relatively long time from diagnosis to treatment in this study of 27 days, which is greater than that observed in [previous studies],” Leonard wrote. “Longer time to treatment in DLBCL has been associated with a more favorable outcome with R-CHOP, which suggests that patients with more aggressive/unfavorable disease require treatment sooner, whereas those with less aggressive/more favorable lymphoma may tend to be able to delay therapy to allow clinical trial screening and enrollment, particularly when a biomarker assessment is mandatory for study entry.” – by John DeRosier
Disclosures: Younes reports honoraria from AbbVie, Janssen, Merck, Roche and Takeda, and research funding from AstraZeneca, Curis, Genentech, Janssen, Pharmacyclics and Roche. Please see the study for all other authors’ relevant financial disclosures. Leonard reports consultant/advisory roles with ADC Therapeutics, AstraZeneca, Bayer AG, BeiGene, Biotest, Bristol-Myers Squibb, Celgene, Epizyme, Genentech, Gilead Sciences, Karyopharm Therapeutics, MEI Pharma, Merck, MorphoSys, Novartis, Nordic Nanovector, Pfizer, Roche, Sandoz, Sutter Medical Group, Sunesis Pharmaceuticals and United Therapeutics.
Perspective
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Stephen M. Ansell, MD, PhD
It’s been really challenging to show that adding an additional agent to R-CHOP benefits all patients in clinical trials. This is the fourth or fifth randomized trial in newly diagnosed DLBCL evaluating the addition of an agent to R-CHOP that has not met its primary endpoint.
What often happens in these studies is that the treatment in the control arm, in this case R-CHOP, performs better than expected, so any difference in outcome is difficult to identify. A second issue is that a new side effect, which makes it difficult for patients to stay on treatment, may develop with the novel combination and so the experimental arm of the study performs less well. For example, other studies analyzed lenalidomide (Revlimid, Celgene) in combination with R-CHOP chemotherapy, and found that it appeared to improve outcomes but increased the frequency of neutropenia. Similarly, ibrutinib also affects blood counts and increases neutropenia, which leads to increased adverse events, and the adverse events are more evident in older patients than younger patients.
In this phase 3 trial of ibrutinib plus R-CHOP compared to R-CHOP, elderly patients were adversely affected when ibrutinib was added and an overall benefit for ibrutinib plus R-CHOP was not seen when all patients were analyzed. However, when only younger patients were considered, they tolerated the treatment well and appeared to benefit from the addition of ibrutinib to R-CHOP.
However, because the main endpoints of this trial were not met, the FDA is likely to be critical of the results and will probably not approve the combination for frontline use. To get the combination of ibrutinib plus R-CHOP approved, there will need to be a repeat of the study that focuses only on younger patients to show that this is a superior combination compared with placebo plus R-CHOP.
A second strategy could be to decrease the dose of ibrutinib and test the lower dose in a follow-up trial focusing on older patients. However, when a lower dose of ibrutinib is chosen, additional research may be needed to confirm that the lower dose adequately inhibits Bruton tyrosine kinase and that the desired immune-associated effects are still seen at lower doses. One will then need to go back and test whether the new lower dose is tolerable in older patients before you move ahead with a specific study.
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