DR EVENS: Sixty-seven-year-old Hispanic man presents with left-sided shoulder and anterior chest wall pain. He had a 10- x 7- x 7-cm enhancing mass that infiltrated his pec minor and major and encased the left brachial plexus and axillary vessels. Biopsy showed a CD5-positive diffuse large B-cell lymphoma with a Ki-67 over 80% that was MYC-positive, molecular study by FISH, and had a double hit by immunohistochemistry. The MYC and the BCL2 immunostains were both over 80%.
He had a performance status of 1 at presentation. His LDH was over 600. He has a history of BPH, hypertension. His final stage was IIIBE with infiltration — or I should say external extension into the vessels, nerves and to his muscles.
And so I think the initial question would be, in someone, how do we incorporate some of these newer — and there’s been a multitude of papers over the last several months and last 1 year, looking not just at MYC by molecular studies but by immunohistochemistry with BCL2.
DR LOVE: Julie?
DR EVENS: And would you approach him any different in terms of R-CHOP or other therapy?
DR VOSE: Mm-hmm. So true double hit is defined as the molecular FISH.
DR EVENS: He was not that.
DR VOSE: He definitely doesn’t meet the true definition. However, there are some newer studies looking at immunohistochemistry, which showed that patients that are above a certain threshold on the C-MYC and BCL2 by immunohistochemistry also have a worse prognosis, although not quite as bad as the double hit. And it’s not necessarily the same population 100%, not 100% overlap.
So still, on this patient, he has enough of the high-risk characteristics, IPI, advanced-stage, and the C-MYC positivity, I probably would choose to treat him with R-EPOCH or —
DR EVENS: Dose-adjusted R-EPOCH.
DR VOSE: Dose-adjusted R-EPOCH. He would probably fit on the Intergroup study, actually, that’s open right now for that patient population.
DR EVENS: He also had the CD5 positivity, which is an adverse risk factor.
DR VOSE: Right.
DR EVENS: I should have mentioned, his IPI was 4.
DR VOSE: Well, that one’s pretty controversial, too. CD5.
DR EVENS: Yes.
DR LOVE: So Jon, agree, disagree?
DR FRIEDBERG: So I agree. We are participating in this study of EPOCH-R for MYC-positive patients. I’d just make a couple of comments on these recent studies.
So probably about 10% of diffuse large B-cell lymphoma is double hit by FISH, meaning that you can actually find a break-apart of MYC as well as a 14;18 translocation. But up to 25 to 30% of diffuse large B-cell lymphoma have double-hit features by immunohistochemistry. And two papers in the JCO last fall really showed that that group who had double-hit features by immunohistochemistry really had a poor outcome. Both of those studies, I thought, were very well-done studies, because each of them had a test group and then a validation set. So essentially in that issue of JCO, there were 4 independent sets of diffuse large B-cell lymphoma that demonstrated this really inferior outcome.
So the question is — and the inferior outcome is profound. In fact, I’ve tried to do this on the back of an envelope. Probably the vast majority of the people who are progressing through R-CHOP fall into this group. And in fact, if we could fix this problem, we might fix diffuse large B-cell lymphoma.
So I agree that R-CHOP is inadequate for this group of patients. The question is, do we know that anything is better? So 1 knee-jerk response is, if it’s MYC-positive, let’s treat this like we would treat Burkitt’s lymphoma. And the problem there is that the median age of this group of patients in those 2 studies in the JCO was 69 years. So this tends to be a disease of older patients like this patient. And their ability to even tolerate a CODOX-M/IVAC regimen or other Burkitt’s type of regimen is quite limited.
When it was attempted, there was this paper published by Mead of CODOX-M/IVAC included aggressive-histology large cell. They went back and looked at the double-hit cases. Those patients did terribly. So it’s not even clear that Burkitt’s-like therapy makes a difference.
So the question is, why are we excited about EPOCH-R? It’s because there is data in Burkitt’s lymphoma from the NCI, a pretty select group of Burkitt’s lymphoma, that EPOCH-R has a very favorable outcome. And some of those cases might have had diffuse large B-cell lymphoma that was MYC-positive. The issue is that in really pushing the investigators at the NCI, the number of true double-hit cases that they’ve treated with EPOCH-R is extremely limited. So I think it’s a very good clinical trial question.
And outside of a clinical trial, I think it’s something you could use and defend yourself, because it’s an active regimen for diffuse large B-cell lymphoma and Burkitt’s lymphoma. But I’m not so optimistic it’s really going to change the natural history of this disease. And this is an area where we really need new agents. And honestly, if you had a new agent that you thought worked, you’d only need to treat 25 or 30 patients to really show a positive outcome, because these outcomes are dismal. Median progression-free survivals of 6 to 8 months, and primary refractory disease is really the big problem.
DR LOVE: So Andy, what happened?
DR EVENS: Initially he did well. So we did choose dose-adjusted R-EPOCH. He had some trouble with it but I can tell you, after the first cycle, his LDH completely normalized. The mass shrunk by 80%. We were able to get him through 6 cycles. We weren’t able to dose-adjust up too much. And he went into a PET CR. We consolidated with radiation to the initial bulk in his left upper chest. That was the good news.
The bad news, I can tell you, about 2 months ago — so this was about 8 weeks after treatment — he had a severe relapse. And on biopsy he now had a double hit. And I think in retrospect I didn’t mention there’s a lot of necrosis on the initial specimen, which is obviously going to affect your sensitivity of picking up gene rearrangements. This was probably a real double hit from the very beginning. And maybe you kind of wrestle with yourself. And maybe we should have consolidated with a transplant. But we had a clinical trial of a new MYC inhibitor. He went on that, but he just blew through that and died about 3 weeks after the initial progression.