Ibrutinib Add-on 'Almost Certainly' Saves
Lives in DLBCL

M. Alexander Otto, MMS, PA

November 09, 2021

The 3-year event-free survival was 100% when ibrutinib (Imbruvica) was added to standard treatment for two genetic subtypes of diffuse large B-cell lymphoma (DLBCL) among patients age 60 years or younger, according to National Cancer Institute investigators.

These patients had either MCD or N1 subtypes of activated B-cell-like (ABC) DLBCL. Both subtypes depend heavily on chronic active B-cell receptor signaling, which can be blocked by Bruton tyrosine kinase (BTK) inhibitors such as ibrutinib.

Without the addition of ibrutinib, the 3-year event-free survival was only  42.9% in MCD and 50% in N1 disease.

All patients also received standard R-CHOP therapy, which includes rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone.

The findings were reported November 4 in the journal Cancer Cell.

Given the "exceptional response," with all MCD and N1 patients alive without disease 3 years after diagnosis, lead investigator Wyndham Wilson, MD, PhD, of the Lymphoid Malignancies Branch at the National Cancer Institute, Bethesda, Maryland, said that there is now "a compelling rationale for doctors to consider adding ibrutinib to standard chemotherapy for the initial treatment of younger patients with non-GCB [germinal center B cell-like] DLBCL."

For the MCD and N1 subtypes in particular, "the use of ibrutinib with R-CHOP would almost certainly save lives," the authors write.

Approached for comment, medical oncologist and blood cancer specialist Ajay Gopal, MD, a professor of medicine at the University of Washington, Seattle, was more cautious.

"While these data are provocative and should be followed up, in the absence of prospective phase 3 data in this prespecified population showing the same results, ibrutinib plus R-CHOP would in no way be considered standard for any subset of untreated DLBCL," he said.

PHOENIX Arises From the Flames

Gopal was an investigator on the phase 3 PHOENIX trial, which failed on its primary survival endpoint for ibrutinib plus R-CHOP in treatment naive, non-GCB patients. Because of that failure, ibrutinib is not currently used in the front-line with standard treatment, he said.

The new findings come from a new analysis of data from this trial.  

Although older patients in the trial had no benefit, probably because they stopped treatment early because of tolerance issues, a secondary analysis did reveal benefit for patients 60 years or younger.

The NCI team wanted to find out who in the younger group benefited most, so they correlated genetic subtypes with trial outcomes. The final analysis included 38 patients with MCD disease and 11 N1 patients 60 years or younger.

The team found no benefit with ibrutinib add-on with a third genetic subtype, BN2 disease. Benefit in the fourth subtype, A53, couldn't be determined for lack of data.

Building a Case for Molecular Profiling

The subtypes are based on characteristic mutations and were classified in the study using the LymphGen algorithm, which was invented by several of the authors and submitted for a patent by NCI. The investigators said their findings demonstrate its clinical utility.

Donald Moore, PharmD, a hematology/oncology pharmacist and researcher at the Levine Cancer Institute in Charlotte, North Carolina, agreed.

The findings "highlight the importance of molecular profiling in DLBCL due to the heterogeneity of this disease and really showcases how therapy could be tailored to improve outcomes for patients," he said.

Moore was also more bullish than Gopal on the study results. "It is really exciting to see such robust outcomes for a couple different specific ABC subtypes" amid the considerable and ongoing efforts to improve upon the long-time standard, R-CHOP, he said.

Although identification of non-GCB DLBCL is routine in clinical practice, there are no commercially available tests to identify ABC subtypes. The authors noted, however, that it requires sequencing about 20 genes in biopsy samples, a relatively small number.

This study was funded by the National Institutes of Health. The original PHOENIX trial was funded by Janssen, marketer of ibrutinib. Wilson and several of his co-authors are inventors on an NIH patent application covering the use of BTK inhibitors in genetic subtypes of DLBCL. Several authors are employees of Johnson & Johnson (Janssen). Gopal has disclosed no relevant financial relationships. Moore is an advisor for Oncopeptides and AstraZeneca.

Cancer Cell. Published online November 4, 2021. Abstract

M. Alexander Otto is a physician assistant with a master's degree in medical science, and an award-winning medical journalist who has worked for several major news outlets before joining Medscape. He is an MIT Knight Science Journalism fellow. Email: aotto@mdedge.com

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