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The addition of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib (Imbruvica) to R-CHOP chemotherapy improved survival in patients ages 60 and younger with the MCD and N1 subtypes of non-germinal center B-cell (GCB) diffuse large B-cell lymphoma (DLBCL), according to an analysis of the .

In patients with the MCD subtype, 3-year event-free survival (EFS) and overall survival (OS) rates were both 100% with added ibrutinib and 48% and 69.6%, respectively, with R-CHOP alone, reported Louis Staudt, MD, PhD, of the National Cancer Institute in Bethesda, Maryland, and colleagues.

For patients with the N1 subtype, the 3-year EFS and OS were again 100% with the ibrutinib addition versus 50% with R-CHOP alone, they noted in .

"People thought the [PHOENIX] trial didn't work," said Staudt in a statement. "But there was something interesting going on -- if you just considered younger patients under the age of 60, they had a real benefit from ibrutinib, and we now understand why."

failed to show a survival benefit with the addition of ibrutinib to R-CHOP in patients with newly diagnosed non-GCB DLBCL. However, a subset analysis among younger patients showed that added ibrutinib resulted in EFS and OS rates that were 10.8% and 12.3% higher compared with chemotherapy alone, while there was no benefit in older patients.

"The effect of patient age on response to ibrutinib was a secondary, not primary, endpoint of the PHOENIX trial," explained Staudt and colleagues. Thus, "this highly significant association was considered a subset analysis, implying that the benefit of ibrutinib for younger patients might represent a fortuitous association."

However, they also noted that the failure of ibrutinib to improve survival in older patients could be due to its added toxicity, which resulted in reduced administration of chemotherapy.

In this analysis, the researchers wanted to test whether classifying DLBCL into genetic subtypes (MCD, N1, BN2, and A53) would allow for the identification of patients who benefited from ibrutinib. They performed DNA and RNA sequencing on tumor biopsies from 773 of 838 patients in the PHOENIX trial, with patients 60 and younger making up 44% of the cohort. Subtypes were determined through the use of an algorithm call LymphGen.

While Staudt and team found survival improvements in younger patients with the MCD and N1 subtypes, they noted no survival benefit in patients with the BN2 subtype. As for those with the A53 subtype, they could not identify those cases with the data available.

They also found that there was a benefit with added ibrutinib in younger patients without MCD or N1 subtypes, but that the effect was smaller.

The new analysis "casts the PHOENIX trial in a new light by providing a mechanistic basis for the survival benefit of adding ibrutinib to R-CHOP in younger DLBCL patients," the authors wrote.

"Our observation that the ibrutinib benefit was most pronounced in specific molecular subsets of younger patients is inconsistent with this being a chance finding, but rather indicates that there is a biological basis for the observed survival benefit," they added. "The survival benefit in the ibrutinib arm was especially pronounced for the MCD and N1 subtypes, suggesting that the use of ibrutinib with R-CHOP would almost certainly save lives among such patients."

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