DR FLOWERS: So at the ASH meeting in 2012, the group from the Mayo Clinic presented their data on the R-squared/CHOP regimen combining lenalidomide with the R-CHOP regimen. And the combinations that have occurred in the 2 trials that I’ll talk about are slightly different in terms of the dosing of lenalidomide, slightly different in terms of the duration, number of days of lenalidomide that were given. But I would say across the 2 trials, the similarities between the ways that it’s given are probably greater than the differences.
And the keys to this approach have really been based on the belief that even with the standard R-CHOP therapy, that there still is a proportion of diffuse large B-cell lymphoma patients who are relapsing early and have poor outcomes even with standard R-CHOP.
There are data in the relapsed setting for evidence of lenalidomide being particularly active in the non-GCB or ABC subtype of diffuse large B-cell lymphoma. And so that’s probably the proportion of patients where this might be expected to be most active. In this particular trial, they allowed all patients with diffuse large B-cell lymphoma to go on the trial and looked at combining lenalidomide with R-CHOP in this regimen.
In the Phase I portion of the trial, they started with a dose of lenalidomide at 15 mg, where it was given from days 1 through 10 and then dose escalated up to 25 mg, where it was, a little bit to my surprise, well tolerated in combination with R-CHOP. And then it extended this into the Phase II, where they enrolled 45 patients at a dose of lenalidomide of 25 mg with the R-CHOP regimen. So again, lenalidomide given on days 1 through 10 of the cycle.
This was a regimen that produced a relatively high response rate in these patients with relatively similar toxicity to what was seen in R-CHOP in other trials. There was a fair amount of neutropenia, so about 80-plus percent of patients had Grade 3 or 4 neutropenia and a fair amount of anemia and thrombocytopenia. Relatively limited neutropenic fever, infections, though, on that trial were seen there and in the other trial that I will discuss.
What the Mayo Clinic did in their trial that was a little bit controversial and at least a little bit interesting was they compared their R-squared/CHOP regimen to an older group of patients that were treated at their institution who had R-CHOP. They were matched based on clinical characteristics that you might expect to be predictive of survival in diffuse large B-cell lymphoma and suggest that this R-squared/CHOP had benefits in progression-free survival compared to that matched group.
Now, that’s not exactly a fair comparison, and that’s why we do randomized controlled trials to determine what the benefits are of these novel regimens. But this is at least promising data to suggest that this is something that should move forward into the Phase III setting.
The other trial that addressed this same issue was also presented at the ASH meeting by the Italian group, where they looked at R-CHOP given on an every 21-day basis with lenalidomide. Here, they gave it for days 1 through 14 of the trial. Again, this was given for 6 total cycles of therapy with the standard kinds of dosing of R-CHOP that are given in Italy.
The characteristics of the patient population were fairly similar to what we would see out in community practice, and so I think this is fairly representative. In both of those trials, they allowed small numbers of patients with follicular lymphoma, Grade IIIB. So I think it’s hard to interpret the results with respect to that population. And really, the majority of the findings should be limited to the diffuse large B-cell setting. But their outcomes were fairly similar to what I just described for the Mayo group.
And so this is now moving into the Phase III setting in a randomized controlled trial in the United States.
DR LOVE: And any comments in terms of the effect of adding in the lenalidomide based on subtypes, specifically the ABC subtype?
DR FLOWERS: I think it’s a little bit premature to interpret that in both of these trials. We need a little bit more follow-up, and then we need more data on the subtype-specific results from these 2 studies. And it may even require a combination of the data from these 2 trials in the subtype to know exactly what the benefits are there.
There are suggestions from the relapsed setting, and particularly data from Myron Czuczman’s group, that suggests that in the non-GCB subtype, that single-agent lenalidomide is quite active in that population of diffuse large B-cell patients.
DR LOVE: Jon, any comments about this? And any way you explain to your fellows, et cetera, in terms of the difference of the subtypes and biologically why you might see response to lenalidomide or ibrutinib in one versus the other?
DR FRIEDBERG: Right. So I think these results are intriguing. And one of the challenges now in development of new regimens in large cell lymphoma is that we do well enough that it can be hard in a Phase II study to really know what the signal should be to go on to the next level. And I would agree that the data from the Mayo Clinic looks appealing enough and this is safe enough and easy enough, that this is a very rational combination to take forward.
Where I do find it somewhat disappointing is I’m a little further along than Chris in the concept of the subtype. And basically, I thought that the Mayo Clinic data did really support the previous observation that the real effect of lenalidomide seemed to be on the — we’ll say non-GCB subtype, because it’s by immunohistochemistry.
Now, the criticism of using this in practice has been, at least up until very recently, you’re using an immunohistochemistry correlate to try to define subtype. And it’s probably only about 80% accurate. I think it’s probably the case, though, in my mind, that that’s still not so bad and that to do studies today using these types of agents in all comers of large cell lymphoma is really probably a mistake. When we know that the differences between GCB and ABC by gene expression profiling are potentially as profound as the differences between marginal-zone lymphoma and follicular lymphoma, it’s just that they tend to look the same under the microscope.
So I would have been more pleased if the ECOG plan had been to try to do this in a subset of the patients, likely an ABC subset.
There are other gene expression profiling ways to categorize large-cell lymphoma, looking at the stroma, for example. And in the higher-risk, stromal-2 type of gene expression profiling. One could envision that lenalidomide has an anti-angiogenic component. Similarly with B-cell receptor active agents, there is an observation that the B-cell receptor pathway seems to be enhanced in the ABC subtype. And there are other gene expression profiles that are looking at BCR or B-cell receptor subtype of large cell lymphoma.
So it’s certainly my hope and I’ve been trying to push this concept for a couple of years, that very quickly our approach to diffuse large B-cell lymphoma in the de novo setting, at least experimentally, will be based on these rational subsets rather than taking everybody with large cell lymphoma, treating them the same way and then looking back at what the outcomes are.