DR. SHUSTOV: I'll consolidate what Michelle and Alison just said. I think we're on the same page. To me, the most important decision (even more important in the relapse setting) is to figure out whether we are still going to try to cure the lymphoma or we will pursue a palliative approach for which now we have several treatment options. So again, I’d have a long discussion with the patient, whether we're going to try and cure the disease, or we will pursue a palliative approach.
If this is a curative approach strategy and we're heading toward ALLO, we would start searching for the donor immediately. The choice of salvage therapy depends on duration of first remission. Primary refractory disease patients who failed CHOP, CHOEP, or EPOCH outright or within 3 months, I typically consider using the single agent approach, because even ICE and DHAP type regimens don’t work well for these patients. I put my “money” into HDAC inhibitors or antifolates, or other targeted therapy, if this is anaplastic lymphoma.
For patients who had at least 6 months remission from the initial therapy, younger patients who are still fit, I agree, I would consider standard salvage regimens like DHAP, etoposide, methylprednisolone, high-dosecytarabine, cisplatin (ESHAP) and ICE, and then, follow this with allograft.
DR. HORWITZ: You have all talked about allografting, I have two questions. What is your best guess in terms of percentage of patients you see with relapsed T-cell lymphoma who actually undergo ALLO at some point and do you ever consider autologous transplantation in those who didn't have it as part of their initial therapy?
DR. SHUSTOV: It certainly depends on the type of the academic center that patients are referred to, and we all practice at academic institutions with very strong ALLO programs. In patients who we select for a curative approach (one half to two thirds) we will at least make the best effort to take them to allogeneic grafting. Patients might fall off this track if they don't respond to salvage therapies or develop significant treatment/disease-related complications, ie fungal infections, organ toxicities, poor performance status, etc. Overall, I'd say that we successfully take about half of the patients with relapsed PTCL that are willing to pursue curative approach to allograft.
In addition, I consider autologous stem cell transplant in relapse setting for three situations. One is relapsed ALK-positive ALCL, some patients with ALK-negative ALCL who have had long initial remission and after relapse, and achieved second remission with BV or other salvage therapy. Finally, I’d consider auto-transplant in patients with AITL who achieved second CR with salvage therapy.
DR. HORWITZ: In terms of the relapse setting—some of you talked about angioimmunoblastic and HDAC inhibitors or BV for ALCL—when you have a relapse patient with PTCL-NOS, how do you pick a second line agent if you're not going directly to transplant, and are there new drugs that you're particularly excited about?
DR. FANALE: To answer your questions in terms of how I might choose a targeted agent for a patient who has PTCL-NOS and doesn't have AITL or ALCL, if the patient isn't eligible for trial or trial isn't feasible for that patient, I'll typically look at schedule, and then I'll look at side effect profile. For instance, for comparison, there are two HDAC inhibitor drugs right now approved, romidepsin and belinostat, so I think that potentially in a private practice setting, belinostat might be one when you look at the efficacy, being generally, around equivalent on where a patient might prefer that regimen because of the fact that they come in for five days in a row and then, their treatment is done for that cycle.
At a larger referral center to which patients are often traveling back and forth, it can be quite difficult for a patient to stay in town to do five days of treatment in a row. Often, these patients will prefer the romidepsin schedule because of the fact that they're coming back in once per week for three weeks in a row per cycle. The other way that I'll look at it is side effect profile, so, let's say, pralatrexate compared to the HDAC inhibitors, I will usually favor the HDAC inhibitors because of the potential side effect of mucositis with pralatrexate, although I have been able to manage through the mucositis by giving the patients more of a cutaneous T-cell lymphoma dosing format.
There had been a high level of interest in new emerging agents such as the aurora A-kinase inhibitors, alisertib, and that trial is now complete and the data are to be presented at The American Society of Hematology’s Annual Meeting this year.4 Other new therapies that are emerging are the PI3K inhibitors such as duvelisib and others. One advantage for many of the drugs in current trials is that they are oral agents.
My interest also lies in the combination approach, such as two or three targeted agent combinations, with the goal that if you see favorable CR rates and progression-free survival rates in the relapsed setting that you can then potentially move these treatments to the front-line setting to potentially move beyond the CHOP-based platform of therapies.
DR. SHUSTOV: For patients outside anaplastic lymphoma where, obviously, most of us would likely use BV, given the response rate to this agent, the decision is really based on convenience of the schedule, toxicity profile, and—sometimes—patient’s preference. So, toxicity and quality of life become kind of more decision-driving factors than disease biology. I’d have a discussion with patients about all three drugs, how they are administered, and what toxicities can be expected. Four-hour infusion of romidepsin might not be acceptable for some patients who have to travel long distances to treatment centers. They may prefer more rapid infusion (they would favor a trial of pralatrexate; or, as Alison mentioned, patient prefers a five-day/daily versus weekly administration.