DR YOUNES: So the ABC/GCB, which is based on gene expression profiling — and now there’s a platform that can be used, will be used in the future to, again, classify patients into ABC versus GCB, and then there will be about 20% of the patients will be called “unclassified.” That’s the standard approach for cell-of-origin classification. And, if you do that, at least in retrospective studies that have been published, if you have an ABC subtype, the outcome with standard R-CHOP chemotherapy is worse than the GCB subtype.

And this has been evolved to apply the same cell-of-origin classification but using immunohistochemistry, and there are different algorithms to classify the patients with large cell lymphoma based on immunohistochemistry. And the most widely used one is called the Hans algorithm. That gives you 2 classifications, GCB and non-GCB. So we don’t call it ABC. And there are no “unclassified” patients.

So this is now mainly used to stratify patients for clinical trials. In clinical practice, we really rarely make decisions based on the cell of origin. ABC or GCB, you can treat with R-CHOP as good as anything else. If you want to use R-EPOCH, it wouldn’t be wrong. We’re still waiting for the randomized trial comparing R-CHOP versus R-EPOCH. We hope the results will come out sometime next year. But outside clinical trials, R-CHOP remains the standard of care for ABC or GCB, regardless of age.

DR LOVE: Can you talk a little bit about some of the specific pathways that have been targeted and, particularly, some of the novel agents that are being looked at?

DR YOUNES: So for large-cell lymphoma, again, for clinical trial stratification, you can stratify for ABC/GCB. And the biggest example here, the ibrutinib, where if you treat patients with relapsed large cell lymphoma with the BTK inhibitor ibrutinib, the response rate is low, relatively low, 23% response rate in all comers. But if you stratify by cell of origin for the ABC or non-GCB, the response rate goes up to 43%, whereas for the GCB it’s only about 5%.

So that helps in, again, selecting patients, but the whole idea here is that the ABC subtype have more of an activated B-cell receptor signaling pathway and NF-kappaB pathway. So, therefore, they should respond to BTK-targeted therapy, which shoots for both B-cell receptor activation and NF-kappaB. But there’s a lot of other pathways that are activated in diffuse large B-cell lymphoma that can be seen in both the ABC and GCB subtype, PI3 kinase pathway, JAK-STAT pathway and then in MYC/BCL-2, of course, pathway.

And there are drugs that target these pathways, all undergoing testing in the clinical trials. Unfortunately, as of today there’s not a single drug approved for the relapsed large cell lymphoma in more than 3 decades, with the exception of pixantrone that’s approved in Europe but not approved in the United States. So it’s an unmet medical need in a wide-open space, everyone trying to get their drug approved in that space, which will be great progress if we can find a drug that works for this patient population.

Hodgkin Lymphoma

Diffuse Large B-Cell Lymphoma and T-Cell Lymphoma

Myelodysplastic Syndromes and Myeloproliferative Disorders

Multiple Myeloma

Chronic Lymphocytic Leukemia

Mantle-Cell Lymphoma