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Study Demonstrates Subtype-Specific Benefit for Ibrutinib in Diffuse Large B-cell Lymphoma


NEW YORK (GenomeWeb) – Results of a trial of the drug ibrutinib in patients with diffuse large B-cell cell lymphoma have demonstrated that those with one molecular subtype of the disease have a significantly higher response rate to the drug than those with the other subtype.

Published yesterday in Nature Medicine, the study — led by researchers from the National Cancer Institute — supports further efforts now underway to develop the drug as a treatment specifically for patients with the activated B-cell-like (ABC) subtype and not the germinal center B-cell-like (GCB) subtype of DLBCL.

Overall, the findings represent an important first step toward a future in which molecular diagnostic methods to distinguish these two subtypes will inform a more personalized or precision approach to treatment.

More than a decade after the first studies demonstrating that diffuse large B-cell lymphomas are actually made up of two molecularly and clinically distinct subtypes, the incorporation of molecular subtyping into the treatment of DLBCL has remained largely theoretical and experimental.

Louis Staudt, the lead author of the new ibrutinib study and director of the National Cancer Institute's Center for Cancer Genomics, told GenomeWeb this week that based on the results, researchers are already moving forward with a follow-up Phase III trial in which patients with non-GCB DLBCL are being randomized to treatment with ibrutinib plus chemotherapy versus chemotherapy alone.

In their Phase II study, Staudt and his colleagues enrolled 80 DLBCL patients that had relapsed or had not responded to prior treatment. All patients received ibrutinib, and responses were seen in 25 percent of patients overall, including eight patients with complete responses.

Using a profiling method that relied on Affymetrix arrays, the researchers found that 38 patients in the trial had gene expression indicating they were in the ABC subtype. Twenty others tested into the GCB subtype, and another 17 were deemed unclassified.

When the team analyzed the results based on patients' ABC or GCB subtype, they found that ibrutinib produced complete or partial responses in 37 percent of patients with ABC DLBCL but only a single patient with GCB DLBCL.

Another five of the unclassified patients also responded to the drug.

Based on these results, the investigators concluded that gene expression testing to distinguish ABC or GCB status could be an important tool for future clinical trials involving ibrutinib to identify patients who may be more likely to respond to the drug.

Fittingly, Janssen Pharmaceuticals is now collaborating with Staudt and his co-investigator Wyndham Wilson on an international Phase III trial of standard DLBCL chemotherapy (called R-CHOP) with or without ibrutinib, excluding patients with the GCB subtype.

At the annual meeting of the American Society of Clinical Oncology earlier this year, clinicians highlighted two other Phase III trials of R-CHOP combined with novel targeted drugs.

In one, called REMoDL-B, researchers are using Illumina's DASL platform and a method using 20 genes to distinguish the cell-of-origin subtypes to provide equal proportions of ABC and GCB patients for randomization with either R-CHOP alone, or R-CHOP plus Takeda's bortezomib (Velcade).

A second Phase III trial is using a different test, initially developed by the Leukemia Lymphoma Molecular Profiling Project, which relies on NanoString's nCounter platform. This trial, ROBUST, is assessing the efficacy of adding the Celgene drug lenalidomide (Revlimid) to R-CHOP in only patients with ABC DLBCL.

According to speakers at ASCO, the advancement of these and other ABC subtype-specific drugs has in turn been the major spur for the development of more accurate and reproducible molecular diagnostics, such as NanoString's test, to distinguish ABC from GCB lymphomas.

Initially, the ABC and GCB cell-of-origin subtypes were defined using voluminous gene-expression data. Further experiments have since refined the genes required into smaller but still accurate signatures that can potentially support commercial clinical tests.

NanoString has said it is planning to seek regulatory approval for the test it is developing as a companion diagnostic for Revlimid.

A number of other technologies have also been harnessed for DLBCL cell-of-origin subtyping. Recently, a team of French researchers published an alternative method, which relies on reverse transcriptase multiplex ligation-dependent probe amplification (RT-MLPA), capillary electrophoresis, and freely available software.

Cleveland Clinic researchers have also developed an RT-PCR method using Primera Dx's ICEPlex system, now Qiagen's Modaplex, which is currently available through the clinic's reference lab as a clinical test.

However, ABC or GCB status may not paint the full picture in terms of response to targeted drugs like ibrutinib and others, and more accurate prediction of response may require the incorporation of other molecular diagnostic strategies as well.

For example, in the NIH-group's study, not all ABC patients who responded to ibrutinib carried the same mutations in the B-cell receptor that might be expected to confer sensitivity to the drug.

"That was probably the most interesting scientific finding, that you didn't need to have a mutation in the B-cell receptor signaling components to be strongly addicted to B-cell receptor signaling and respond to ibrutinib," Staudt said.

"The reasons are not completely worked out but we are currently studying this more in the lab, and we have been able to show that the B-cell receptor is being stimulated by self-antigens in its own microenvironment, which may be a non-genetic way to stimulate signaling," he explained.

This data suggests that future DLBCL trials involving ibrutinib should not restrict enrollment to subjects with CD79A- or CD79B-mutated tumors, an approach suggested by some earlier data, as this would overlook ibrutinib-responsive tumors among the larger ABC-subtype group.

Meanwhile, it was also clear from the data that not all ABC patients responded to the drug, Staudt explained.

"Clearly, there may be a subtype of a subtype that is B-cell receptor addicted, and perhaps another that is not," he said. This is also a subject of ongoing research for the group.