Medical Roundtable: Peripheral T-Cell Lymphomas: A Practical Approach to Newly Diagnosed and Relapsed Patients

Moderator: Steven M. Horwitz, MD¹

Discussants: Alison Moskowitz, MD¹; Michelle Fanale, MD²; Andrei Shustov, MD³

From Memorial Sloan Kettering Cancer Center, New York, NY¹; MD Anderson Cancer Center, Houston, TX²; University of Washington Medical Center, Seattle, WA³

Address for correspondence: Steven M. Horwitz, MD, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065

E-mail: [email protected]

DR. HORWITZ: My name is Dr. Steven Horwitz from Memorial Sloan-Kettering Cancer Center. I’m joined today by Drs. Alison Moskowitz, Memorial Sloan-Kettering, Michelle Fanale of MD Anderson, and Andrei Shustov, University of Washington in Seattle. Thank you all for joining us for this conversation on T-cell lymphoma. My colleagues are all well known as experts in T-cell lymphomas. Those of you who treat these diseases recognize the systemic T-cell lymphomas as one of our greater challenges in hematologic malignancies in terms of the treatment options for patients and the frequent lack of definitive data to guide our decisions.

I thought what we would do today is have a very practical discussion about the way we think about these diseases, the decisions we make, and the way we make those decisions. I'll start off by asking when you get a referral of a patient with a new diagnosis of peripheral T-cell lymphoma (PTCL), what are some of the basic things that you first think about in terms of approaching a new patient?

DR. SHUSTOV: I think one of the biggest challenges in T-cell lymphomas still remains making the proper diagnosis. In general, pathologists in the United States have a pretty good idea when they see T-cell lymphomas, however, subclassification remains a challenge even for expert hematopathologists due to frequent histologic overlap between the subtypes of PTCL, and even with non-malignant autoimmune disorders. I frequently see patients who are diagnosed with or misdiagnosed with a different subtype of T-cell lymphoma. The most challenging is differentiation between angioimmunoblastic T-cell lymphoma (AITL), anaplastic large cell T-cell lymphoma (ALCL), and PTCL not otherwise specified (PTCL-NOS), especially when the latter patients have high expression of CD30 and/or bear features resembling AITL.

Sometimes they are a slam-dunk diagnosis, but frequently our hematopathologists reverse the diagnosis after doing additional studies on the biopsy material. The most recent case I've seen in my clinic for consultation was a patient with a diagnosis of extranodal NK-cell lymphoma that was reclassified as a gamma-delta T-cell lymphoma after additional work-up. I truly believe that it is advisable that majority, if not all PTCL cases are reviewed by expert hematopathology teams at academic centers that see large volumes of these cases.

I think it's very important to educate community physicians and patients about a proper PTCL diagnosis, especially now that more targeted therapies are being developed and the gene expression profiling techniques will probably lead to identification of specific pathways that are amenable to therapy with specific biologic agents.

DR. FANALE: I'd like to expand upon what Andrei just said. For me the next step after confirming the pathology diagnosis is to think about two things. To think about whether or not this patient is a patient who might be eligible for an ongoing front-line trial, typically if the patient meets eligibility criteria for one of our ongoing front-line trials I would really recommend to the patient to consider being enrolled in that trial, and I also think about whether the patient, if he or she enters into remission with front-line therapy, can be considered for a consolidative autologous stem cell transplant.

I think it's very important to educate community physicians and patients about a proper PTCL diagnosis. Right now, our ongoing front-line trial is the ECHELON-2 trial which is evaluating brentuximab vedotin (BV) plus cyclophosphamide, doxorubicin, prednisone (CHP [BV-CHP]) chemotherapy compared to standard of care cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) chemotherapy, and that trial is based on the promising data that we've seen in the initial phase I trial that combined BV plus CHP chemotherapy followed by maintenance BV which demonstrated both high and durable complete remission (CR) rates.1 BV is an antibody drug conjugate that's targeted at CD30 and carries initial US Food and Drug Administration approval for patients who have relapsed or refractory ALCL which has a 100% level of CD30 positivity and then also has a National Comprehensive Cancer Network listing for treating other types of relapsed or refractory CD30 positive PTCL as well.

Also there is another upcoming front-line trial, which is to combine pralatrexate plus CHOP. If a patient isn't eligible for a clinical trial or it's just not feasible for that patient to enroll in a clinical trial, I will then look further at what would be potentially the best standard of care option for that patient.

I'll look at the patient's age and performance status and if they are generally less than age 65 or so and if otherwise well, I'll preferentially treat that patient with CHOEP which is CHOP plus etoposide. And then, for a patient who's either older than this or has multiple other comorbidities, I would treat that patient typically with CHOP alone.

DR. HORWITZ: Thank you, we'll go further into the selection of initial therapies but first circle back, I was curious as to how often your center comes to a different diagnosis than the referring center, and are there pitfalls you see that alert you to be suspicious of diagnosis.

DR. SHUSTOV: I'd say probably 10% of cases that we see at our center will be reclassified by our hematopathologists. In most cases, they do not necessarily reverse the diagnosis, but provide further clarification. It is occurring to me that in the community, pathologists are less likely to call the subtype of T-cell lymphoma and limit the report to the general description of T-cell lymphoprolipherative disorder, or state something like “consistent with T-cell lymphoma with features of AITL, or with features of anaplastic lymphoma.” I would admit though, that sometimes it's very difficult to identify the specific subtype of PTCL even in the expert hands; but I'd say these cases would constitute no more than 5% of PTCL patients.

DR. HORWITZ: And in your experience is it mostly fine tuning a T-cell lymphoma diagnosis, or do you see totally different diagnoses?

DR. MOSKOWITZ: Usually review by expert hematopathologists simply leads to fine-tuning the T-cell lymphoma diagnosis, however, I occasionally see significant changes in diagnosis. Often, alterations or clarification of a diagnosis are made possible only after we provide the pathologist with clinical history. For example, a lymph node biopsy may be interpreted as ALCL, however the knowledge that the particular patient has a history of mycosis fungoides would lead the pathologist to consider the diagnosis of large cell transformation of mycosis fungoides rather than ALCL. In such a case, molecular studies are helpful in confirming that the lymph node findings originate from the same clone as that in the original mycosis fungoides lesions, rather than representing a second primary.

DR. FANALE: Very occasionally, I've seen patients truly “with a misdiagnosis and a complete revision of diagnosis” and, usually, those pitfalls that I've seen them occasionally have been the young patients—the young patients who generally have disease in the thorax and neck, who are treated as though they have classical Hodgkin lymphoma, who have very significant progression of disease on standard of care treatment. So it's important that not all cases that have CD30 positivity are classical Hodgkin lymphoma even if the patient is young.

DR. HORWITZ: I often think the systemic T-cell lymphomas usually behave in an aggressive fashion so when the clinical picture and the diagnosis don't really fit, I think about getting a second biopsy before we finalize the diagnosis. Of course, when people are ill with obviously progressing disease, you may need to move more quickly.

I often think the systemic T-cell lymphomas usually behave in an aggressive fashion so when the clinical picture and the diagnosis don't really fit, I think about getting a second biopsy before we finalize the diagnosis. To move on, when you first see a patient, what is the decision tree in your mind in terms of picking therapy or planning therapy, or what kind of things do you consider?

DR. MOSKOWITZ: The first thing I think about when deciding upon treatment for a patient with T-cell lymphoma is whether or not I plan to use a curative approach to therapy. As was mentioned by Michelle, this decision is partly based upon the patients’ comorbidities and age. For patients who are eligible for curative therapy, our frontline approach for the most common types of T-cell lymphoma is to use CHOP with or without etoposide followed by consideration for autologous stem cell transplant in first remission. There are certainly individuals for whom such an aggressive strategy would not be appropriate due to age or co-morbidities. In these individuals, we may consider CHOP-based therapy alone or sometimes even milder approaches aimed at disease control.

DR. HORWITZ: Andrei, are you similar in the CHOP/CHOEP paradigm? And if so, what do you think of those data? How do you decide between the two and when do you do that regimen versus something different?

DR. SHUSTOV: I think I will double or triple what Michelle and Alison just said; for me, the two most important decisions that I have to make in the first encounter with patients with newly diagnosed PTCL are: 1) whether we're going to pursue curative approach strategy; and 2) whether the patient can tolerate the intensity of treatments that would provide him/her with the best chance of cure or long term remission. Patients who are elderly and have high risk disease would be very hard to cure, especially considering that the consolidative transplant might carry high rates of morbidity or mortality; more conservative strategies might be appropriate in these cases. On the other hand, younger and more fit patients might benefit more from intensified initial regimens—ie, CHOEP—followed by high-dose therapy and either autologous or allogeneic stem cell transplant (ALLO).

I usually have a long initial discussion with patients and families during which we decide on the intent of treatment and what to expect from certain regimens in terms of toxicities. I typically choose CHOEP regimen (or infusional version, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin [EPOCH]) for younger patients based on recent German data, even though this was a retrospective study and benefit of adding etoposide only approached statistical significance for the majority of PTCL subtypes.2 In older patients, I try to avoid anthracyclines, especially in the palliative intent setting, based on the retrospective analysis by the International T-Cell Lymphoma Project, and frequently use CEOP regimen (CHOEP minus anthracycline).3 I find that the majority of older patients tolerate this treatment somewhat better than anthracycline-containing combinations like CHOP.

In the very elderly and frail patients, I try to avoid combination chemotherapy all together. It is a somewhat easier decision for patients with AITL. Some of them are more indolent than other sub-types, and I would treat such patients with immunomodulatory approach, ie with a combination of prednisone and cyclosporine; then, I would consider single agent therapy with one of the recently approved agents for relapsed and refractory PTCL. I would also double what Michelle said in regard to making the best attempt to enroll patients into open clinical trials, because the current standards are not really satisfactory for many T-cell lymphoma patients.

DR. HORWITZ: It sounds like we all approach a new patient similarly. However, several of our up front trials are randomized against CHOP as opposed to CHOEP. When you're consenting a patient to those trials, how do you explain it to a patient or how important do you think the etoposide is?

DR. SHUSTOV: I share your frustration with quite a few of the current study designs for that exact reason. Some of these are confirmatory trials after conditional approvals of the new agents and are important. However, as often happens, in the confirmatory trials, we use controls that are a default from a lot of historical data, or the “common” way that the majority of patients are being treated. It is really a challenge when you consent patients to studies where a control arm is something that you think might not be quite adequate.

Having said that, the CHOEP study that was mentioned several times is a retrospective subgroup analysis and the addition of etoposide had marginal benefit that approached significance, but certainly was not a home run. I don't think we are ready to say that etoposide provides survival advantage in T-cell lymphoma patients and dismiss clinical trials in favor of just giving a patient the CHOEP, even though CHOP is admittedly not the best comparator. I discuss this controversy with patients and tell them frankly that the data that we base addition of etoposide on are not the best evidence one may have. Then, I ask patients to decide which approach sounds more reasonable to them and they make their choice.

DR. FANALE: To expand just slightly upon what Andrei said, I do emphasize to the patient and to the referring doctors that if you look at National Comprehensive Cancer Network guidelines, CHOP, CHOEP, EPOCH, all of these are potential options. So there's really not yet one trial that would say that one is clearly superior to the other at this time. I also emphasize to the patient and to the referring clinician that the only way, let's say, the patient could get the targeted agent plus the chemotherapy and have that 50% chance of, potentially, receiving that combination is really through the randomized clinical trial.

DR. HORWITZ: That was excellent, thank you. So you have alluded to this a bit. How much does subtype specific treatment come into play?

DR. MOSKOWITZ: At this point in time, outside of a clinical trial, for PTCL-NOS, AITL, and ALCL, the front-line approach would typically be CHOEP followed by autologous stem cell transplant. As Michelle mentioned, for a patient with ALCL, I would offer enrollment on the ECHELON-2 study in which patients are randomized to CHOP or BV-CHP, in order to give patients the option of potentially receiving BV.

For AITL, we are now obtaining molecular testing for certain mutations, particularly IDH2, because we currently have a study open with an IDH2 inhibitor that specifically enrolls patients with IDH2-mutant AITL. Because the testing takes some time to get back, we typically test patients’ biopsies at the time of diagnosis, so that we know if they're eligible for future clinical trials in case their disease does not respond to upfront therapy.

There are T-cell lymphoma subtypes that we treat quite differently from the entities discussed so far. For human T-lymphotropic virus-1 associated adult T-cell lymphoma, for example, the data with CHOP are really not good and we typically used EPOCH with the aim to consolidate with an allogeneic stem cell transplant.

Likewise, for hepatosplenic T-cell lymphoma, we have not observed good responses with the CHOP-based therapy and therefore we typically use platinum-based or ifosfamide-based therapy upfront with the aim to consolidate with allogeneic stem cell transplant. Extranodal NK/T-cell lymphoma is another entity for which CHOP is typically not effective and we have adopted asparaginase-based regimens, such as dexamethasone, methotrexate, ifosfamide, L-asparaginase, etoposide (SMILE) for this disease.

DR. SHUSTOV: I completely agree with Alison; for more common nodal lymphomas it is really hard at this point to base a treatment decision on histology, at least, in the front-line setting. However, some of the rare and unique subtypes, we generally treat with a completely different approach (ie, extranodal NK-cell lymphomas, enteropathy-associated T-cell lymphomas, adult T-cell leukemia/lymphomas).

DR. HORWITZ: Excellent. I’m curious, in a patient with ALCL who refused randomization of the ECHELON-2 trial, would you give them BV-CHP off study or would you discuss that as an alternative were they not to participate in the trial?

DR. FANALE: No. I don't urge treatment that's not approved for a particular line of therapy off clinical protocol with the exception that, let's say, if a patient is not a candidate for chemotherapy in second line setting for a particular lymphoma such as Hodgkin lymphoma—then, I would reference published data like Alison's data for a second line use of BV say for classical Hodgkin lymphoma and work with the insurance company to get the drug approved for that patient population, but if a patient just doesn't want to go on trial because they don't like the 50/50 chance of receiving BV-CHP compared to CHOP and they say, “I really want the 100% chance. Why don't you just contact my insurance?” I will explain to them the rationale of why the trial is being conducted including the hope that if the endpoints are met and the regimen is approved for front-line therapy then patients in the future can get BV-CHP at any oncology clinic, but I tell them for now it is a protocol based treatment option.

DR. HORWITZ: That's a very good answer. Can we now touch on the idea of transplant vs no transplant in first remission. Always, sometimes, never; how do you all think about that?

DR. SHUSTOV: I think that the idea of consolidative transplant is very heavily debated and discussed at the majority of specialized PTCL meetings. The reason for that is controversial nature of current clinical evidence. In the absence of randomized trials it is very hard to compare prospective phase II trial data to historical controls. You can interpret this in two ways; you might say, well, these are good data, outcome numbers look better than historical controls, and all patients with PTCL should have a consolidative transplant; or you can say, well, I don't have randomized data, and only a randomized study would really tell us whether post-induction consolidative transplant improves survival.

That is why it is such a controversial subject, and we agree that the phase II perspective studies of transplantation are hampered by significant bias; patients who are able and willing to travel to academic centers, were more robust and able to tolerate high dose therapy. They also have chemosensitive disease and that puts them in a completely different category than those you see in populational or retrospective studies, or other historical control trials.

Having said that, when I talk to patients, and I think that this is where I involve patients into treatment decision very heavily, I present them with the data and say that it is not wrong to do or not do the transplant in first CR. I make patients and family a big part of the decision. When they ask me what would give the patient the best chance being in remission five years from today, my answer is transplant, however, the data are not perfect, and the curative potential of autologous transplant in PTCL is not known.

DR. FANALE: So typically here, we would refer most patients on for front-line consolidative autologous stem cell transplant, I think, some exceptions are the ones that Andrei already touched on. If we're seeing a patient who has PTCL-NOS and this patient is the very rare patient who has early stage disease, with really no significant risk factors, that patient, unless there were pathologic features that showed a higher level of aggressiveness as Alison commented on, this patient might be one where we might defer doing the consolidative stem cell transplant for particularly if the patient’s disease entered into remission very quickly, but this still is controversial.

I'm not sure how you practice within each of your centers, but another patient, or where we would potentially defer, is a patient with fairly limited nasal NK/T-cell lymphoma, a patient that we’ve treated, let's say, with the dexamethasone, etoposide, ifosfamide, carboplatin (DeVIC) chemotherapy regimen plus a concomitant high-dose radiation, we typically historically here have deferred doing consolidative stem cell transplant for that patient population.

In terms of what Andrei commented on for when we might consider an ALLO and for a frontline consolidation, here we typically would not. The exception to that rule is that I've had a couple of patients here who have PTCL with a secondary hemophagocytic lymphohistiocytosis syndrome and then, for those patients because the concern is that the autologous stem cell transplant probably wouldn't be enough and for those patients given that they have such a dismal prognosis from the secondary hemophagocytic lymphohistiocytosis, we send those patients on for an ALLO.

DR. MOSKOWITZ: To expand upon early stage extranodal NK/T-cell lymphoma, I agree with Michelle that we wouldn't use an autologous stem cell transplant in first remission. Typically, for patients with localized disease, we recommend 2 cycles of SMILE followed by involved field radiation. Our patients treated with this approach have typically done quite well without needing a transplant.

DR. HORWITZ: That was great. If there are no further comments on upfront therapy, we can move over to relapse setting. When you see a patient at relapse, what are your strategies and how do you approach that patient?

DR. MOSKOWITZ: The first question in my mind when a patient is either not responding to or relapsing following front-line therapy is: what is my ultimate goal? For a patient who is fit and refractory to CHOP or has relapsed after CHOP or autologous stem cell transplant, my ultimate goal would be to try to get them to an ALLO. My choice of treatment following front-line therapy depends upon whether or not we are aiming for an ALLO as well as whether a donor has been identified for the patient.

Usually, if a patient just relapsed following front-line therapy, we are not necessarily ready to proceed quickly to ALLO. This may be because a donor has not yet been identified or because the patients’ eligibility for an ALLO is not clear. In this situation, my choice of treatment would be something that can be continued, potentially for several months, while we get things in place for the transplant. Treatment options in this situation would include the approved single agents for T-cell lymphoma, such as romidepsin, belinostat, pralatrexate, as well as BV (which would be specific for ALCL). In addition, I would consider enrollment on a promising clinical trial. Among these options, my choice of treatment typically depends upon the side effect profile and/or schedule, which is individualized for the patient. The one caveat would be that I typically will aim to use a histone deacetylase inhibitor (HDAC) inhibitor as my first choice for a patient with AITL.

Usually, if a patient just relapsed following front-line therapy, we are not necessarily ready to proceed quickly to ALLO. This may be because a donor has not yet been identified or because the patients’ eligibility for an ALLO is not clear. If my patient has a donor available and we are ready to move quickly to transplant, I would use one of the multi-agent regimens, such as ifosfamide, carboplatin, etoposide (ICE) or cisplatin, cytosine arabinoside, dexamethasone (DHAP), with the aim to try to get them into remission and relatively quickly proceed to transplant. The problem with using one of these types of regimens for everyone in the second-line setting is that the treatment cannot be continued indefinitely due to cumulative toxicity; therefore we need to know that we are ready to proceed to transplant if we are going to use one of the more intense regimens.

DR. HORWITZ: How do the others approach relapse?

DR. FANALE: Generally, a lot of similarities with what Alison discussed. Typically, it's if we're going to be sending the patient on for consideration for ALLO, I think the favor would be to try to use a regimen that has a high CR rate knowing that there is a trend toward improved progression free survival for the patient who enters into CR when compared to those who did not. I think the only slight difference might be just the timing and the selection, so, typically, here, even if the patient doesn't actually have a definite established donor quite yet we'll typically favor a combination type of a treatment approach, so whether or not that would be a platinum-based regimen such as ICE, as Alison mentioned, or gemcitabine-based chemotherapy regimen or similar.

I would generally favor one of those options, usually, over a single-agent therapeutic approach just knowing that the CR rates, generally, with exception of BV for ALCL are, generally, ranging about the 10%–15% range. And then, of course, first priority would be if there is a clinical trial available whether that's with a doublet of targeted agents or with the targeted agent plus chemotherapy in the relapse setting, we would typically favor that approach for a patient being considered for a stem cell transplant, ALLO approach.

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.

It's kind of a coin toss decision outside clinical trials. Certainly, participation in studies in relapse setting is the high priority. We are all really looking forward to developing doublet combinations of novel agents, ie studies like the one Michelle is running at MD Anderson with a combination of alisertib and romidepsin.

DR. MOSKOWITZ: I'll echo what both Andrei and Michelle said that our choice of treatment is individualized and depends upon side-effect profile and the schedule. With regard to novel agents, I am also very excited about the studies that will be opening with the PI-3 kinase inhibitor, IPI-145. There have been promising results seen with single-agent IPI-1455 and we will be opening a study evaluating it in combination with bortezomib or romidepsin.

In addition, I mentioned earlier the IDH2 inhibitor, which we're studying right now in patients with AITL that is characterized by the presence of the IDH2 mutation. It would be exciting to see if targeting a specific mutation in this disease translates into responses.

DR. HORWITZ: Great, I think that was fantastic. I would like to thank Drs. Moskowitz, Shustov, and Fanale for a very thorough impractical discussion on how they approach and manage patients with T-cell lymphoma. I’m impressed that there is significant consistency among these experts in terms of how they manage these uncommon and often challenging lymphomas in terms of upfront combination chemotherapy approaches, combination considerations for the use of transplantation, as well as their enthusiasm for and dedication to incorporating clinical trials as part of everyday management.

References

1. Fanale MA, Horwitz SM, Forero-Torres A, et al. Brentuximab vedotin in the front-line treatment of patients with CD30+ peripheral T-cell lymphomas: results of a phase I study. J Clin Oncol. 2014;32(28):3137–3143.

2. Schmitz N, Trümper L, Ziepert M, et al. Treatment and prognosis of mature T-cell and NK-cell lymphoma: an analysis of patients with T-cell lymphoma treated in studies of the German High-Grade Non-Hodgkin Lymphoma Study Group. Blood. 2010;116(18):3418–3425. doi: 10.1182/blood-2010-02-270785. Epub 2010 Jul 21.

3. Vose J, Armitage J, Weisenburger D, for the International T-Cell Lymphoma Project. J Clin Oncol. 2008;26(25):4124–4130. doi: 10.1200/JCO.2008.16.4558. Epub 2008 Jul 14.

4. O’Connor OA, Ozcan M, Jacobsen ED, et al. First multicenter, randomized phase 3 study in patients with relapsed/refractory peripheral T-cell lymphoma: alisertib versus investigator’s choice. Paper to be presented at: American Society of Hematology 57th Annual Meeting & Exposition; December 5–8, 2015; Orlando, FL.

5. Horwitz SM, Porcu P, Flinn I, et al. Duvelisib (IPI-145), a phosphoinositide-3-kinsae-γδ inhibitor, shows activity in patients with relapsed/refractory T-cell lymphoma. Paper presented at: American Society of Hematology 56th Annual Meeting & Exposition; December 6–9, 2014; San Francisco, CA.

Moderator: Steven M. Horwitz, MD¹

Discussants: Alison Moskowitz, MD¹; Michelle Fanale, MD²; Andrei Shustov, MD³

From Memorial Sloan Kettering Cancer Center, New York, NY¹; MD Anderson Cancer Center, Houston, TX²; University of Washington Medical Center, Seattle, WA³

Address for correspondence: Steven M. Horwitz, MD, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065

E-mail: [email protected]

DR. HORWITZ: My name is Dr. Steven Horwitz from Memorial Sloan-Kettering Cancer Center. I’m joined today by Drs. Alison Moskowitz, Memorial Sloan-Kettering, Michelle Fanale of MD Anderson, and Andrei Shustov, University of Washington in Seattle. Thank you all for joining us for this conversation on T-cell lymphoma. My colleagues are all well known as experts in T-cell lymphomas. Those of you who treat these diseases recognize the systemic T-cell lymphomas as one of our greater challenges in hematologic malignancies in terms of the treatment options for patients and the frequent lack of definitive data to guide our decisions.

I thought what we would do today is have a very practical discussion about the way we think about these diseases, the decisions we make, and the way we make those decisions. I'll start off by asking when you get a referral of a patient with a new diagnosis of peripheral T-cell lymphoma (PTCL), what are some of the basic things that you first think about in terms of approaching a new patient?

DR. SHUSTOV: I think one of the biggest challenges in T-cell lymphomas still remains making the proper diagnosis. In general, pathologists in the United States have a pretty good idea when they see T-cell lymphomas, however, subclassification remains a challenge even for expert hematopathologists due to frequent histologic overlap between the subtypes of PTCL, and even with non-malignant autoimmune disorders. I frequently see patients who are diagnosed with or misdiagnosed with a different subtype of T-cell lymphoma. The most challenging is differentiation between angioimmunoblastic T-cell lymphoma (AITL), anaplastic large cell T-cell lymphoma (ALCL), and PTCL not otherwise specified (PTCL-NOS), especially when the latter patients have high expression of CD30 and/or bear features resembling AITL.

Sometimes they are a slam-dunk diagnosis, but frequently our hematopathologists reverse the diagnosis after doing additional studies on the biopsy material. The most recent case I've seen in my clinic for consultation was a patient with a diagnosis of extranodal NK-cell lymphoma that was reclassified as a gamma-delta T-cell lymphoma after additional work-up. I truly believe that it is advisable that majority, if not all PTCL cases are reviewed by expert hematopathology teams at academic centers that see large volumes of these cases.

I think it's very important to educate community physicians and patients about a proper PTCL diagnosis, especially now that more targeted therapies are being developed and the gene expression profiling techniques will probably lead to identification of specific pathways that are amenable to therapy with specific biologic agents.

DR. FANALE: I'd like to expand upon what Andrei just said. For me the next step after confirming the pathology diagnosis is to think about two things. To think about whether or not this patient is a patient who might be eligible for an ongoing front-line trial, typically if the patient meets eligibility criteria for one of our ongoing front-line trials I would really recommend to the patient to consider being enrolled in that trial, and I also think about whether the patient, if he or she enters into remission with front-line therapy, can be considered for a consolidative autologous stem cell transplant.

I think it's very important to educate community physicians and patients about a proper PTCL diagnosis. Right now, our ongoing front-line trial is the ECHELON-2 trial which is evaluating brentuximab vedotin (BV) plus cyclophosphamide, doxorubicin, prednisone (CHP [BV-CHP]) chemotherapy compared to standard of care cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) chemotherapy, and that trial is based on the promising data that we've seen in the initial phase I trial that combined BV plus CHP chemotherapy followed by maintenance BV which demonstrated both high and durable complete remission (CR) rates.1 BV is an antibody drug conjugate that's targeted at CD30 and carries initial US Food and Drug Administration approval for patients who have relapsed or refractory ALCL which has a 100% level of CD30 positivity and then also has a National Comprehensive Cancer Network listing for treating other types of relapsed or refractory CD30 positive PTCL as well.

Also there is another upcoming front-line trial, which is to combine pralatrexate plus CHOP. If a patient isn't eligible for a clinical trial or it's just not feasible for that patient to enroll in a clinical trial, I will then look further at what would be potentially the best standard of care option for that patient.

I'll look at the patient's age and performance status and if they are generally less than age 65 or so and if otherwise well, I'll preferentially treat that patient with CHOEP which is CHOP plus etoposide. And then, for a patient who's either older than this or has multiple other comorbidities, I would treat that patient typically with CHOP alone.

DR. HORWITZ: Thank you, we'll go further into the selection of initial therapies but first circle back, I was curious as to how often your center comes to a different diagnosis than the referring center, and are there pitfalls you see that alert you to be suspicious of diagnosis.

DR. SHUSTOV: I'd say probably 10% of cases that we see at our center will be reclassified by our hematopathologists. In most cases, they do not necessarily reverse the diagnosis, but provide further clarification. It is occurring to me that in the community, pathologists are less likely to call the subtype of T-cell lymphoma and limit the report to the general description of T-cell lymphoprolipherative disorder, or state something like “consistent with T-cell lymphoma with features of AITL, or with features of anaplastic lymphoma.” I would admit though, that sometimes it's very difficult to identify the specific subtype of PTCL even in the expert hands; but I'd say these cases would constitute no more than 5% of PTCL patients.

DR. HORWITZ: And in your experience is it mostly fine tuning a T-cell lymphoma diagnosis, or do you see totally different diagnoses?

DR. MOSKOWITZ: Usually review by expert hematopathologists simply leads to fine-tuning the T-cell lymphoma diagnosis, however, I occasionally see significant changes in diagnosis. Often, alterations or clarification of a diagnosis are made possible only after we provide the pathologist with clinical history. For example, a lymph node biopsy may be interpreted as ALCL, however the knowledge that the particular patient has a history of mycosis fungoides would lead the pathologist to consider the diagnosis of large cell transformation of mycosis fungoides rather than ALCL. In such a case, molecular studies are helpful in confirming that the lymph node findings originate from the same clone as that in the original mycosis fungoides lesions, rather than representing a second primary.

DR. FANALE: Very occasionally, I've seen patients truly “with a misdiagnosis and a complete revision of diagnosis” and, usually, those pitfalls that I've seen them occasionally have been the young patients—the young patients who generally have disease in the thorax and neck, who are treated as though they have classical Hodgkin lymphoma, who have very significant progression of disease on standard of care treatment. So it's important that not all cases that have CD30 positivity are classical Hodgkin lymphoma even if the patient is young.

DR. HORWITZ: I often think the systemic T-cell lymphomas usually behave in an aggressive fashion so when the clinical picture and the diagnosis don't really fit, I think about getting a second biopsy before we finalize the diagnosis. Of course, when people are ill with obviously progressing disease, you may need to move more quickly.

I often think the systemic T-cell lymphomas usually behave in an aggressive fashion so when the clinical picture and the diagnosis don't really fit, I think about getting a second biopsy before we finalize the diagnosis. To move on, when you first see a patient, what is the decision tree in your mind in terms of picking therapy or planning therapy, or what kind of things do you consider?

DR. MOSKOWITZ: The first thing I think about when deciding upon treatment for a patient with T-cell lymphoma is whether or not I plan to use a curative approach to therapy. As was mentioned by Michelle, this decision is partly based upon the patients’ comorbidities and age. For patients who are eligible for curative therapy, our frontline approach for the most common types of T-cell lymphoma is to use CHOP with or without etoposide followed by consideration for autologous stem cell transplant in first remission. There are certainly individuals for whom such an aggressive strategy would not be appropriate due to age or co-morbidities. In these individuals, we may consider CHOP-based therapy alone or sometimes even milder approaches aimed at disease control.

DR. HORWITZ: Andrei, are you similar in the CHOP/CHOEP paradigm? And if so, what do you think of those data? How do you decide between the two and when do you do that regimen versus something different?

DR. SHUSTOV: I think I will double or triple what Michelle and Alison just said; for me, the two most important decisions that I have to make in the first encounter with patients with newly diagnosed PTCL are: 1) whether we're going to pursue curative approach strategy; and 2) whether the patient can tolerate the intensity of treatments that would provide him/her with the best chance of cure or long term remission. Patients who are elderly and have high risk disease would be very hard to cure, especially considering that the consolidative transplant might carry high rates of morbidity or mortality; more conservative strategies might be appropriate in these cases. On the other hand, younger and more fit patients might benefit more from intensified initial regimens—ie, CHOEP—followed by high-dose therapy and either autologous or allogeneic stem cell transplant (ALLO).

I usually have a long initial discussion with patients and families during which we decide on the intent of treatment and what to expect from certain regimens in terms of toxicities. I typically choose CHOEP regimen (or infusional version, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin [EPOCH]) for younger patients based on recent German data, even though this was a retrospective study and benefit of adding etoposide only approached statistical significance for the majority of PTCL subtypes.2 In older patients, I try to avoid anthracyclines, especially in the palliative intent setting, based on the retrospective analysis by the International T-Cell Lymphoma Project, and frequently use CEOP regimen (CHOEP minus anthracycline).3 I find that the majority of older patients tolerate this treatment somewhat better than anthracycline-containing combinations like CHOP.

In the very elderly and frail patients, I try to avoid combination chemotherapy all together. It is a somewhat easier decision for patients with AITL. Some of them are more indolent than other sub-types, and I would treat such patients with immunomodulatory approach, ie with a combination of prednisone and cyclosporine; then, I would consider single agent therapy with one of the recently approved agents for relapsed and refractory PTCL. I would also double what Michelle said in regard to making the best attempt to enroll patients into open clinical trials, because the current standards are not really satisfactory for many T-cell lymphoma patients.

DR. HORWITZ: It sounds like we all approach a new patient similarly. However, several of our up front trials are randomized against CHOP as opposed to CHOEP. When you're consenting a patient to those trials, how do you explain it to a patient or how important do you think the etoposide is?

DR. SHUSTOV: I share your frustration with quite a few of the current study designs for that exact reason. Some of these are confirmatory trials after conditional approvals of the new agents and are important. However, as often happens, in the confirmatory trials, we use controls that are a default from a lot of historical data, or the “common” way that the majority of patients are being treated. It is really a challenge when you consent patients to studies where a control arm is something that you think might not be quite adequate.

Having said that, the CHOEP study that was mentioned several times is a retrospective subgroup analysis and the addition of etoposide had marginal benefit that approached significance, but certainly was not a home run. I don't think we are ready to say that etoposide provides survival advantage in T-cell lymphoma patients and dismiss clinical trials in favor of just giving a patient the CHOEP, even though CHOP is admittedly not the best comparator. I discuss this controversy with patients and tell them frankly that the data that we base addition of etoposide on are not the best evidence one may have. Then, I ask patients to decide which approach sounds more reasonable to them and they make their choice.

DR. FANALE: To expand just slightly upon what Andrei said, I do emphasize to the patient and to the referring doctors that if you look at National Comprehensive Cancer Network guidelines, CHOP, CHOEP, EPOCH, all of these are potential options. So there's really not yet one trial that would say that one is clearly superior to the other at this time. I also emphasize to the patient and to the referring clinician that the only way, let's say, the patient could get the targeted agent plus the chemotherapy and have that 50% chance of, potentially, receiving that combination is really through the randomized clinical trial.

DR. HORWITZ: That was excellent, thank you. So you have alluded to this a bit. How much does subtype specific treatment come into play?

DR. MOSKOWITZ: At this point in time, outside of a clinical trial, for PTCL-NOS, AITL, and ALCL, the front-line approach would typically be CHOEP followed by autologous stem cell transplant. As Michelle mentioned, for a patient with ALCL, I would offer enrollment on the ECHELON-2 study in which patients are randomized to CHOP or BV-CHP, in order to give patients the option of potentially receiving BV.

For AITL, we are now obtaining molecular testing for certain mutations, particularly IDH2, because we currently have a study open with an IDH2 inhibitor that specifically enrolls patients with IDH2-mutant AITL. Because the testing takes some time to get back, we typically test patients’ biopsies at the time of diagnosis, so that we know if they're eligible for future clinical trials in case their disease does not respond to upfront therapy.

There are T-cell lymphoma subtypes that we treat quite differently from the entities discussed so far. For human T-lymphotropic virus-1 associated adult T-cell lymphoma, for example, the data with CHOP are really not good and we typically used EPOCH with the aim to consolidate with an allogeneic stem cell transplant.

Likewise, for hepatosplenic T-cell lymphoma, we have not observed good responses with the CHOP-based therapy and therefore we typically use platinum-based or ifosfamide-based therapy upfront with the aim to consolidate with allogeneic stem cell transplant. Extranodal NK/T-cell lymphoma is another entity for which CHOP is typically not effective and we have adopted asparaginase-based regimens, such as dexamethasone, methotrexate, ifosfamide, L-asparaginase, etoposide (SMILE) for this disease.

DR. SHUSTOV: I completely agree with Alison; for more common nodal lymphomas it is really hard at this point to base a treatment decision on histology, at least, in the front-line setting. However, some of the rare and unique subtypes, we generally treat with a completely different approach (ie, extranodal NK-cell lymphomas, enteropathy-associated T-cell lymphomas, adult T-cell leukemia/lymphomas).

DR. HORWITZ: Excellent. I’m curious, in a patient with ALCL who refused randomization of the ECHELON-2 trial, would you give them BV-CHP off study or would you discuss that as an alternative were they not to participate in the trial?

DR. FANALE: No. I don't urge treatment that's not approved for a particular line of therapy off clinical protocol with the exception that, let's say, if a patient is not a candidate for chemotherapy in second line setting for a particular lymphoma such as Hodgkin lymphoma—then, I would reference published data like Alison's data for a second line use of BV say for classical Hodgkin lymphoma and work with the insurance company to get the drug approved for that patient population, but if a patient just doesn't want to go on trial because they don't like the 50/50 chance of receiving BV-CHP compared to CHOP and they say, “I really want the 100% chance. Why don't you just contact my insurance?” I will explain to them the rationale of why the trial is being conducted including the hope that if the endpoints are met and the regimen is approved for front-line therapy then patients in the future can get BV-CHP at any oncology clinic, but I tell them for now it is a protocol based treatment option.

DR. HORWITZ: That's a very good answer. Can we now touch on the idea of transplant vs no transplant in first remission. Always, sometimes, never; how do you all think about that?

DR. SHUSTOV: I think that the idea of consolidative transplant is very heavily debated and discussed at the majority of specialized PTCL meetings. The reason for that is controversial nature of current clinical evidence. In the absence of randomized trials it is very hard to compare prospective phase II trial data to historical controls. You can interpret this in two ways; you might say, well, these are good data, outcome numbers look better than historical controls, and all patients with PTCL should have a consolidative transplant; or you can say, well, I don't have randomized data, and only a randomized study would really tell us whether post-induction consolidative transplant improves survival.

That is why it is such a controversial subject, and we agree that the phase II perspective studies of transplantation are hampered by significant bias; patients who are able and willing to travel to academic centers, were more robust and able to tolerate high dose therapy. They also have chemosensitive disease and that puts them in a completely different category than those you see in populational or retrospective studies, or other historical control trials.

Having said that, when I talk to patients, and I think that this is where I involve patients into treatment decision very heavily, I present them with the data and say that it is not wrong to do or not do the transplant in first CR. I make patients and family a big part of the decision. When they ask me what would give the patient the best chance being in remission five years from today, my answer is transplant, however, the data are not perfect, and the curative potential of autologous transplant in PTCL is not known.

DR. FANALE: So typically here, we would refer most patients on for front-line consolidative autologous stem cell transplant, I think, some exceptions are the ones that Andrei already touched on. If we're seeing a patient who has PTCL-NOS and this patient is the very rare patient who has early stage disease, with really no significant risk factors, that patient, unless there were pathologic features that showed a higher level of aggressiveness as Alison commented on, this patient might be one where we might defer doing the consolidative stem cell transplant for particularly if the patient’s disease entered into remission very quickly, but this still is controversial.

I'm not sure how you practice within each of your centers, but another patient, or where we would potentially defer, is a patient with fairly limited nasal NK/T-cell lymphoma, a patient that we’ve treated, let's say, with the dexamethasone, etoposide, ifosfamide, carboplatin (DeVIC) chemotherapy regimen plus a concomitant high-dose radiation, we typically historically here have deferred doing consolidative stem cell transplant for that patient population.

In terms of what Andrei commented on for when we might consider an ALLO and for a frontline consolidation, here we typically would not. The exception to that rule is that I've had a couple of patients here who have PTCL with a secondary hemophagocytic lymphohistiocytosis syndrome and then, for those patients because the concern is that the autologous stem cell transplant probably wouldn't be enough and for those patients given that they have such a dismal prognosis from the secondary hemophagocytic lymphohistiocytosis, we send those patients on for an ALLO.

DR. MOSKOWITZ: To expand upon early stage extranodal NK/T-cell lymphoma, I agree with Michelle that we wouldn't use an autologous stem cell transplant in first remission. Typically, for patients with localized disease, we recommend 2 cycles of SMILE followed by involved field radiation. Our patients treated with this approach have typically done quite well without needing a transplant.

DR. HORWITZ: That was great. If there are no further comments on upfront therapy, we can move over to relapse setting. When you see a patient at relapse, what are your strategies and how do you approach that patient?

DR. MOSKOWITZ: The first question in my mind when a patient is either not responding to or relapsing following front-line therapy is: what is my ultimate goal? For a patient who is fit and refractory to CHOP or has relapsed after CHOP or autologous stem cell transplant, my ultimate goal would be to try to get them to an ALLO. My choice of treatment following front-line therapy depends upon whether or not we are aiming for an ALLO as well as whether a donor has been identified for the patient.

Usually, if a patient just relapsed following front-line therapy, we are not necessarily ready to proceed quickly to ALLO. This may be because a donor has not yet been identified or because the patients’ eligibility for an ALLO is not clear. In this situation, my choice of treatment would be something that can be continued, potentially for several months, while we get things in place for the transplant. Treatment options in this situation would include the approved single agents for T-cell lymphoma, such as romidepsin, belinostat, pralatrexate, as well as BV (which would be specific for ALCL). In addition, I would consider enrollment on a promising clinical trial. Among these options, my choice of treatment typically depends upon the side effect profile and/or schedule, which is individualized for the patient. The one caveat would be that I typically will aim to use a histone deacetylase inhibitor (HDAC) inhibitor as my first choice for a patient with AITL.

Usually, if a patient just relapsed following front-line therapy, we are not necessarily ready to proceed quickly to ALLO. This may be because a donor has not yet been identified or because the patients’ eligibility for an ALLO is not clear. If my patient has a donor available and we are ready to move quickly to transplant, I would use one of the multi-agent regimens, such as ifosfamide, carboplatin, etoposide (ICE) or cisplatin, cytosine arabinoside, dexamethasone (DHAP), with the aim to try to get them into remission and relatively quickly proceed to transplant. The problem with using one of these types of regimens for everyone in the second-line setting is that the treatment cannot be continued indefinitely due to cumulative toxicity; therefore we need to know that we are ready to proceed to transplant if we are going to use one of the more intense regimens.

DR. HORWITZ: How do the others approach relapse?

DR. FANALE: Generally, a lot of similarities with what Alison discussed. Typically, it's if we're going to be sending the patient on for consideration for ALLO, I think the favor would be to try to use a regimen that has a high CR rate knowing that there is a trend toward improved progression free survival for the patient who enters into CR when compared to those who did not. I think the only slight difference might be just the timing and the selection, so, typically, here, even if the patient doesn't actually have a definite established donor quite yet we'll typically favor a combination type of a treatment approach, so whether or not that would be a platinum-based regimen such as ICE, as Alison mentioned, or gemcitabine-based chemotherapy regimen or similar.

I would generally favor one of those options, usually, over a single-agent therapeutic approach just knowing that the CR rates, generally, with exception of BV for ALCL are, generally, ranging about the 10%–15% range. And then, of course, first priority would be if there is a clinical trial available whether that's with a doublet of targeted agents or with the targeted agent plus chemotherapy in the relapse setting, we would typically favor that approach for a patient being considered for a stem cell transplant, ALLO approach.

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.

It's kind of a coin toss decision outside clinical trials. Certainly, participation in studies in relapse setting is the high priority. We are all really looking forward to developing doublet combinations of novel agents, ie studies like the one Michelle is running at MD Anderson with a combination of alisertib and romidepsin.

DR. MOSKOWITZ: I'll echo what both Andrei and Michelle said that our choice of treatment is individualized and depends upon side-effect profile and the schedule. With regard to novel agents, I am also very excited about the studies that will be opening with the PI-3 kinase inhibitor, IPI-145. There have been promising results seen with single-agent IPI-1455 and we will be opening a study evaluating it in combination with bortezomib or romidepsin.

In addition, I mentioned earlier the IDH2 inhibitor, which we're studying right now in patients with AITL that is characterized by the presence of the IDH2 mutation. It would be exciting to see if targeting a specific mutation in this disease translates into responses.

DR. HORWITZ: Great, I think that was fantastic. I would like to thank Drs. Moskowitz, Shustov, and Fanale for a very thorough impractical discussion on how they approach and manage patients with T-cell lymphoma. I’m impressed that there is significant consistency among these experts in terms of how they manage these uncommon and often challenging lymphomas in terms of upfront combination chemotherapy approaches, combination considerations for the use of transplantation, as well as their enthusiasm for and dedication to incorporating clinical trials as part of everyday management.

References

1. Fanale MA, Horwitz SM, Forero-Torres A, et al. Brentuximab vedotin in the front-line treatment of patients with CD30+ peripheral T-cell lymphomas: results of a phase I study. J Clin Oncol. 2014;32(28):3137–3143.

2. Schmitz N, Trümper L, Ziepert M, et al. Treatment and prognosis of mature T-cell and NK-cell lymphoma: an analysis of patients with T-cell lymphoma treated in studies of the German High-Grade Non-Hodgkin Lymphoma Study Group. Blood. 2010;116(18):3418–3425. doi: 10.1182/blood-2010-02-270785. Epub 2010 Jul 21.

3. Vose J, Armitage J, Weisenburger D, for the International T-Cell Lymphoma Project. J Clin Oncol. 2008;26(25):4124–4130. doi: 10.1200/JCO.2008.16.4558. Epub 2008 Jul 14.

4. O’Connor OA, Ozcan M, Jacobsen ED, et al. First multicenter, randomized phase 3 study in patients with relapsed/refractory peripheral T-cell lymphoma: alisertib versus investigator’s choice. Paper to be presented at: American Society of Hematology 57th Annual Meeting & Exposition; December 5–8, 2015; Orlando, FL.

5. Horwitz SM, Porcu P, Flinn I, et al. Duvelisib (IPI-145), a phosphoinositide-3-kinsae-γδ inhibitor, shows activity in patients with relapsed/refractory T-cell lymphoma. Paper presented at: American Society of Hematology 56th Annual Meeting & Exposition; December 6–9, 2014; San Francisco, CA.

Moderator: Steven M. Horwitz, MD¹

Discussants: Alison Moskowitz, MD¹; Michelle Fanale, MD²; Andrei Shustov, MD³

From Memorial Sloan Kettering Cancer Center, New York, NY¹; MD Anderson Cancer Center, Houston, TX²; University of Washington Medical Center, Seattle, WA³

Address for correspondence: Steven M. Horwitz, MD, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065

E-mail: [email protected]

DR. HORWITZ: My name is Dr. Steven Horwitz from Memorial Sloan-Kettering Cancer Center. I’m joined today by Drs. Alison Moskowitz, Memorial Sloan-Kettering, Michelle Fanale of MD Anderson, and Andrei Shustov, University of Washington in Seattle. Thank you all for joining us for this conversation on T-cell lymphoma. My colleagues are all well known as experts in T-cell lymphomas. Those of you who treat these diseases recognize the systemic T-cell lymphomas as one of our greater challenges in hematologic malignancies in terms of the treatment options for patients and the frequent lack of definitive data to guide our decisions.

I thought what we would do today is have a very practical discussion about the way we think about these diseases, the decisions we make, and the way we make those decisions. I'll start off by asking when you get a referral of a patient with a new diagnosis of peripheral T-cell lymphoma (PTCL), what are some of the basic things that you first think about in terms of approaching a new patient?

DR. SHUSTOV: I think one of the biggest challenges in T-cell lymphomas still remains making the proper diagnosis. In general, pathologists in the United States have a pretty good idea when they see T-cell lymphomas, however, subclassification remains a challenge even for expert hematopathologists due to frequent histologic overlap between the subtypes of PTCL, and even with non-malignant autoimmune disorders. I frequently see patients who are diagnosed with or misdiagnosed with a different subtype of T-cell lymphoma. The most challenging is differentiation between angioimmunoblastic T-cell lymphoma (AITL), anaplastic large cell T-cell lymphoma (ALCL), and PTCL not otherwise specified (PTCL-NOS), especially when the latter patients have high expression of CD30 and/or bear features resembling AITL.

Sometimes they are a slam-dunk diagnosis, but frequently our hematopathologists reverse the diagnosis after doing additional studies on the biopsy material. The most recent case I've seen in my clinic for consultation was a patient with a diagnosis of extranodal NK-cell lymphoma that was reclassified as a gamma-delta T-cell lymphoma after additional work-up. I truly believe that it is advisable that majority, if not all PTCL cases are reviewed by expert hematopathology teams at academic centers that see large volumes of these cases.

I think it's very important to educate community physicians and patients about a proper PTCL diagnosis, especially now that more targeted therapies are being developed and the gene expression profiling techniques will probably lead to identification of specific pathways that are amenable to therapy with specific biologic agents.

DR. FANALE: I'd like to expand upon what Andrei just said. For me the next step after confirming the pathology diagnosis is to think about two things. To think about whether or not this patient is a patient who might be eligible for an ongoing front-line trial, typically if the patient meets eligibility criteria for one of our ongoing front-line trials I would really recommend to the patient to consider being enrolled in that trial, and I also think about whether the patient, if he or she enters into remission with front-line therapy, can be considered for a consolidative autologous stem cell transplant.

I think it's very important to educate community physicians and patients about a proper PTCL diagnosis. Right now, our ongoing front-line trial is the ECHELON-2 trial which is evaluating brentuximab vedotin (BV) plus cyclophosphamide, doxorubicin, prednisone (CHP [BV-CHP]) chemotherapy compared to standard of care cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) chemotherapy, and that trial is based on the promising data that we've seen in the initial phase I trial that combined BV plus CHP chemotherapy followed by maintenance BV which demonstrated both high and durable complete remission (CR) rates.1 BV is an antibody drug conjugate that's targeted at CD30 and carries initial US Food and Drug Administration approval for patients who have relapsed or refractory ALCL which has a 100% level of CD30 positivity and then also has a National Comprehensive Cancer Network listing for treating other types of relapsed or refractory CD30 positive PTCL as well.

Also there is another upcoming front-line trial, which is to combine pralatrexate plus CHOP. If a patient isn't eligible for a clinical trial or it's just not feasible for that patient to enroll in a clinical trial, I will then look further at what would be potentially the best standard of care option for that patient.

I'll look at the patient's age and performance status and if they are generally less than age 65 or so and if otherwise well, I'll preferentially treat that patient with CHOEP which is CHOP plus etoposide. And then, for a patient who's either older than this or has multiple other comorbidities, I would treat that patient typically with CHOP alone.

DR. HORWITZ: Thank you, we'll go further into the selection of initial therapies but first circle back, I was curious as to how often your center comes to a different diagnosis than the referring center, and are there pitfalls you see that alert you to be suspicious of diagnosis.

DR. SHUSTOV: I'd say probably 10% of cases that we see at our center will be reclassified by our hematopathologists. In most cases, they do not necessarily reverse the diagnosis, but provide further clarification. It is occurring to me that in the community, pathologists are less likely to call the subtype of T-cell lymphoma and limit the report to the general description of T-cell lymphoprolipherative disorder, or state something like “consistent with T-cell lymphoma with features of AITL, or with features of anaplastic lymphoma.” I would admit though, that sometimes it's very difficult to identify the specific subtype of PTCL even in the expert hands; but I'd say these cases would constitute no more than 5% of PTCL patients.

DR. HORWITZ: And in your experience is it mostly fine tuning a T-cell lymphoma diagnosis, or do you see totally different diagnoses?

DR. MOSKOWITZ: Usually review by expert hematopathologists simply leads to fine-tuning the T-cell lymphoma diagnosis, however, I occasionally see significant changes in diagnosis. Often, alterations or clarification of a diagnosis are made possible only after we provide the pathologist with clinical history. For example, a lymph node biopsy may be interpreted as ALCL, however the knowledge that the particular patient has a history of mycosis fungoides would lead the pathologist to consider the diagnosis of large cell transformation of mycosis fungoides rather than ALCL. In such a case, molecular studies are helpful in confirming that the lymph node findings originate from the same clone as that in the original mycosis fungoides lesions, rather than representing a second primary.

DR. FANALE: Very occasionally, I've seen patients truly “with a misdiagnosis and a complete revision of diagnosis” and, usually, those pitfalls that I've seen them occasionally have been the young patients—the young patients who generally have disease in the thorax and neck, who are treated as though they have classical Hodgkin lymphoma, who have very significant progression of disease on standard of care treatment. So it's important that not all cases that have CD30 positivity are classical Hodgkin lymphoma even if the patient is young.

DR. HORWITZ: I often think the systemic T-cell lymphomas usually behave in an aggressive fashion so when the clinical picture and the diagnosis don't really fit, I think about getting a second biopsy before we finalize the diagnosis. Of course, when people are ill with obviously progressing disease, you may need to move more quickly.

I often think the systemic T-cell lymphomas usually behave in an aggressive fashion so when the clinical picture and the diagnosis don't really fit, I think about getting a second biopsy before we finalize the diagnosis. To move on, when you first see a patient, what is the decision tree in your mind in terms of picking therapy or planning therapy, or what kind of things do you consider?

DR. MOSKOWITZ: The first thing I think about when deciding upon treatment for a patient with T-cell lymphoma is whether or not I plan to use a curative approach to therapy. As was mentioned by Michelle, this decision is partly based upon the patients’ comorbidities and age. For patients who are eligible for curative therapy, our frontline approach for the most common types of T-cell lymphoma is to use CHOP with or without etoposide followed by consideration for autologous stem cell transplant in first remission. There are certainly individuals for whom such an aggressive strategy would not be appropriate due to age or co-morbidities. In these individuals, we may consider CHOP-based therapy alone or sometimes even milder approaches aimed at disease control.

DR. HORWITZ: Andrei, are you similar in the CHOP/CHOEP paradigm? And if so, what do you think of those data? How do you decide between the two and when do you do that regimen versus something different?

DR. SHUSTOV: I think I will double or triple what Michelle and Alison just said; for me, the two most important decisions that I have to make in the first encounter with patients with newly diagnosed PTCL are: 1) whether we're going to pursue curative approach strategy; and 2) whether the patient can tolerate the intensity of treatments that would provide him/her with the best chance of cure or long term remission. Patients who are elderly and have high risk disease would be very hard to cure, especially considering that the consolidative transplant might carry high rates of morbidity or mortality; more conservative strategies might be appropriate in these cases. On the other hand, younger and more fit patients might benefit more from intensified initial regimens—ie, CHOEP—followed by high-dose therapy and either autologous or allogeneic stem cell transplant (ALLO).

I usually have a long initial discussion with patients and families during which we decide on the intent of treatment and what to expect from certain regimens in terms of toxicities. I typically choose CHOEP regimen (or infusional version, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin [EPOCH]) for younger patients based on recent German data, even though this was a retrospective study and benefit of adding etoposide only approached statistical significance for the majority of PTCL subtypes.2 In older patients, I try to avoid anthracyclines, especially in the palliative intent setting, based on the retrospective analysis by the International T-Cell Lymphoma Project, and frequently use CEOP regimen (CHOEP minus anthracycline).3 I find that the majority of older patients tolerate this treatment somewhat better than anthracycline-containing combinations like CHOP.

In the very elderly and frail patients, I try to avoid combination chemotherapy all together. It is a somewhat easier decision for patients with AITL. Some of them are more indolent than other sub-types, and I would treat such patients with immunomodulatory approach, ie with a combination of prednisone and cyclosporine; then, I would consider single agent therapy with one of the recently approved agents for relapsed and refractory PTCL. I would also double what Michelle said in regard to making the best attempt to enroll patients into open clinical trials, because the current standards are not really satisfactory for many T-cell lymphoma patients.

DR. HORWITZ: It sounds like we all approach a new patient similarly. However, several of our up front trials are randomized against CHOP as opposed to CHOEP. When you're consenting a patient to those trials, how do you explain it to a patient or how important do you think the etoposide is?

DR. SHUSTOV: I share your frustration with quite a few of the current study designs for that exact reason. Some of these are confirmatory trials after conditional approvals of the new agents and are important. However, as often happens, in the confirmatory trials, we use controls that are a default from a lot of historical data, or the “common” way that the majority of patients are being treated. It is really a challenge when you consent patients to studies where a control arm is something that you think might not be quite adequate.

Having said that, the CHOEP study that was mentioned several times is a retrospective subgroup analysis and the addition of etoposide had marginal benefit that approached significance, but certainly was not a home run. I don't think we are ready to say that etoposide provides survival advantage in T-cell lymphoma patients and dismiss clinical trials in favor of just giving a patient the CHOEP, even though CHOP is admittedly not the best comparator. I discuss this controversy with patients and tell them frankly that the data that we base addition of etoposide on are not the best evidence one may have. Then, I ask patients to decide which approach sounds more reasonable to them and they make their choice.

DR. FANALE: To expand just slightly upon what Andrei said, I do emphasize to the patient and to the referring doctors that if you look at National Comprehensive Cancer Network guidelines, CHOP, CHOEP, EPOCH, all of these are potential options. So there's really not yet one trial that would say that one is clearly superior to the other at this time. I also emphasize to the patient and to the referring clinician that the only way, let's say, the patient could get the targeted agent plus the chemotherapy and have that 50% chance of, potentially, receiving that combination is really through the randomized clinical trial.

DR. HORWITZ: That was excellent, thank you. So you have alluded to this a bit. How much does subtype specific treatment come into play?

DR. MOSKOWITZ: At this point in time, outside of a clinical trial, for PTCL-NOS, AITL, and ALCL, the front-line approach would typically be CHOEP followed by autologous stem cell transplant. As Michelle mentioned, for a patient with ALCL, I would offer enrollment on the ECHELON-2 study in which patients are randomized to CHOP or BV-CHP, in order to give patients the option of potentially receiving BV.

For AITL, we are now obtaining molecular testing for certain mutations, particularly IDH2, because we currently have a study open with an IDH2 inhibitor that specifically enrolls patients with IDH2-mutant AITL. Because the testing takes some time to get back, we typically test patients’ biopsies at the time of diagnosis, so that we know if they're eligible for future clinical trials in case their disease does not respond to upfront therapy.

There are T-cell lymphoma subtypes that we treat quite differently from the entities discussed so far. For human T-lymphotropic virus-1 associated adult T-cell lymphoma, for example, the data with CHOP are really not good and we typically used EPOCH with the aim to consolidate with an allogeneic stem cell transplant.

Likewise, for hepatosplenic T-cell lymphoma, we have not observed good responses with the CHOP-based therapy and therefore we typically use platinum-based or ifosfamide-based therapy upfront with the aim to consolidate with allogeneic stem cell transplant. Extranodal NK/T-cell lymphoma is another entity for which CHOP is typically not effective and we have adopted asparaginase-based regimens, such as dexamethasone, methotrexate, ifosfamide, L-asparaginase, etoposide (SMILE) for this disease.

DR. SHUSTOV: I completely agree with Alison; for more common nodal lymphomas it is really hard at this point to base a treatment decision on histology, at least, in the front-line setting. However, some of the rare and unique subtypes, we generally treat with a completely different approach (ie, extranodal NK-cell lymphomas, enteropathy-associated T-cell lymphomas, adult T-cell leukemia/lymphomas).

DR. HORWITZ: Excellent. I’m curious, in a patient with ALCL who refused randomization of the ECHELON-2 trial, would you give them BV-CHP off study or would you discuss that as an alternative were they not to participate in the trial?

DR. FANALE: No. I don't urge treatment that's not approved for a particular line of therapy off clinical protocol with the exception that, let's say, if a patient is not a candidate for chemotherapy in second line setting for a particular lymphoma such as Hodgkin lymphoma—then, I would reference published data like Alison's data for a second line use of BV say for classical Hodgkin lymphoma and work with the insurance company to get the drug approved for that patient population, but if a patient just doesn't want to go on trial because they don't like the 50/50 chance of receiving BV-CHP compared to CHOP and they say, “I really want the 100% chance. Why don't you just contact my insurance?” I will explain to them the rationale of why the trial is being conducted including the hope that if the endpoints are met and the regimen is approved for front-line therapy then patients in the future can get BV-CHP at any oncology clinic, but I tell them for now it is a protocol based treatment option.

DR. HORWITZ: That's a very good answer. Can we now touch on the idea of transplant vs no transplant in first remission. Always, sometimes, never; how do you all think about that?

DR. SHUSTOV: I think that the idea of consolidative transplant is very heavily debated and discussed at the majority of specialized PTCL meetings. The reason for that is controversial nature of current clinical evidence. In the absence of randomized trials it is very hard to compare prospective phase II trial data to historical controls. You can interpret this in two ways; you might say, well, these are good data, outcome numbers look better than historical controls, and all patients with PTCL should have a consolidative transplant; or you can say, well, I don't have randomized data, and only a randomized study would really tell us whether post-induction consolidative transplant improves survival.

That is why it is such a controversial subject, and we agree that the phase II perspective studies of transplantation are hampered by significant bias; patients who are able and willing to travel to academic centers, were more robust and able to tolerate high dose therapy. They also have chemosensitive disease and that puts them in a completely different category than those you see in populational or retrospective studies, or other historical control trials.

Having said that, when I talk to patients, and I think that this is where I involve patients into treatment decision very heavily, I present them with the data and say that it is not wrong to do or not do the transplant in first CR. I make patients and family a big part of the decision. When they ask me what would give the patient the best chance being in remission five years from today, my answer is transplant, however, the data are not perfect, and the curative potential of autologous transplant in PTCL is not known.

DR. FANALE: So typically here, we would refer most patients on for front-line consolidative autologous stem cell transplant, I think, some exceptions are the ones that Andrei already touched on. If we're seeing a patient who has PTCL-NOS and this patient is the very rare patient who has early stage disease, with really no significant risk factors, that patient, unless there were pathologic features that showed a higher level of aggressiveness as Alison commented on, this patient might be one where we might defer doing the consolidative stem cell transplant for particularly if the patient’s disease entered into remission very quickly, but this still is controversial.

I'm not sure how you practice within each of your centers, but another patient, or where we would potentially defer, is a patient with fairly limited nasal NK/T-cell lymphoma, a patient that we’ve treated, let's say, with the dexamethasone, etoposide, ifosfamide, carboplatin (DeVIC) chemotherapy regimen plus a concomitant high-dose radiation, we typically historically here have deferred doing consolidative stem cell transplant for that patient population.

In terms of what Andrei commented on for when we might consider an ALLO and for a frontline consolidation, here we typically would not. The exception to that rule is that I've had a couple of patients here who have PTCL with a secondary hemophagocytic lymphohistiocytosis syndrome and then, for those patients because the concern is that the autologous stem cell transplant probably wouldn't be enough and for those patients given that they have such a dismal prognosis from the secondary hemophagocytic lymphohistiocytosis, we send those patients on for an ALLO.

DR. MOSKOWITZ: To expand upon early stage extranodal NK/T-cell lymphoma, I agree with Michelle that we wouldn't use an autologous stem cell transplant in first remission. Typically, for patients with localized disease, we recommend 2 cycles of SMILE followed by involved field radiation. Our patients treated with this approach have typically done quite well without needing a transplant.

DR. HORWITZ: That was great. If there are no further comments on upfront therapy, we can move over to relapse setting. When you see a patient at relapse, what are your strategies and how do you approach that patient?

DR. MOSKOWITZ: The first question in my mind when a patient is either not responding to or relapsing following front-line therapy is: what is my ultimate goal? For a patient who is fit and refractory to CHOP or has relapsed after CHOP or autologous stem cell transplant, my ultimate goal would be to try to get them to an ALLO. My choice of treatment following front-line therapy depends upon whether or not we are aiming for an ALLO as well as whether a donor has been identified for the patient.

Usually, if a patient just relapsed following front-line therapy, we are not necessarily ready to proceed quickly to ALLO. This may be because a donor has not yet been identified or because the patients’ eligibility for an ALLO is not clear. In this situation, my choice of treatment would be something that can be continued, potentially for several months, while we get things in place for the transplant. Treatment options in this situation would include the approved single agents for T-cell lymphoma, such as romidepsin, belinostat, pralatrexate, as well as BV (which would be specific for ALCL). In addition, I would consider enrollment on a promising clinical trial. Among these options, my choice of treatment typically depends upon the side effect profile and/or schedule, which is individualized for the patient. The one caveat would be that I typically will aim to use a histone deacetylase inhibitor (HDAC) inhibitor as my first choice for a patient with AITL.

Usually, if a patient just relapsed following front-line therapy, we are not necessarily ready to proceed quickly to ALLO. This may be because a donor has not yet been identified or because the patients’ eligibility for an ALLO is not clear. If my patient has a donor available and we are ready to move quickly to transplant, I would use one of the multi-agent regimens, such as ifosfamide, carboplatin, etoposide (ICE) or cisplatin, cytosine arabinoside, dexamethasone (DHAP), with the aim to try to get them into remission and relatively quickly proceed to transplant. The problem with using one of these types of regimens for everyone in the second-line setting is that the treatment cannot be continued indefinitely due to cumulative toxicity; therefore we need to know that we are ready to proceed to transplant if we are going to use one of the more intense regimens.

DR. HORWITZ: How do the others approach relapse?

DR. FANALE: Generally, a lot of similarities with what Alison discussed. Typically, it's if we're going to be sending the patient on for consideration for ALLO, I think the favor would be to try to use a regimen that has a high CR rate knowing that there is a trend toward improved progression free survival for the patient who enters into CR when compared to those who did not. I think the only slight difference might be just the timing and the selection, so, typically, here, even if the patient doesn't actually have a definite established donor quite yet we'll typically favor a combination type of a treatment approach, so whether or not that would be a platinum-based regimen such as ICE, as Alison mentioned, or gemcitabine-based chemotherapy regimen or similar.

I would generally favor one of those options, usually, over a single-agent therapeutic approach just knowing that the CR rates, generally, with exception of BV for ALCL are, generally, ranging about the 10%–15% range. And then, of course, first priority would be if there is a clinical trial available whether that's with a doublet of targeted agents or with the targeted agent plus chemotherapy in the relapse setting, we would typically favor that approach for a patient being considered for a stem cell transplant, ALLO approach.

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.

It's kind of a coin toss decision outside clinical trials. Certainly, participation in studies in relapse setting is the high priority. We are all really looking forward to developing doublet combinations of novel agents, ie studies like the one Michelle is running at MD Anderson with a combination of alisertib and romidepsin.

DR. MOSKOWITZ: I'll echo what both Andrei and Michelle said that our choice of treatment is individualized and depends upon side-effect profile and the schedule. With regard to novel agents, I am also very excited about the studies that will be opening with the PI-3 kinase inhibitor, IPI-145. There have been promising results seen with single-agent IPI-1455 and we will be opening a study evaluating it in combination with bortezomib or romidepsin.

In addition, I mentioned earlier the IDH2 inhibitor, which we're studying right now in patients with AITL that is characterized by the presence of the IDH2 mutation. It would be exciting to see if targeting a specific mutation in this disease translates into responses.

DR. HORWITZ: Great, I think that was fantastic. I would like to thank Drs. Moskowitz, Shustov, and Fanale for a very thorough impractical discussion on how they approach and manage patients with T-cell lymphoma. I’m impressed that there is significant consistency among these experts in terms of how they manage these uncommon and often challenging lymphomas in terms of upfront combination chemotherapy approaches, combination considerations for the use of transplantation, as well as their enthusiasm for and dedication to incorporating clinical trials as part of everyday management.

References

1. Fanale MA, Horwitz SM, Forero-Torres A, et al. Brentuximab vedotin in the front-line treatment of patients with CD30+ peripheral T-cell lymphomas: results of a phase I study. J Clin Oncol. 2014;32(28):3137–3143.

2. Schmitz N, Trümper L, Ziepert M, et al. Treatment and prognosis of mature T-cell and NK-cell lymphoma: an analysis of patients with T-cell lymphoma treated in studies of the German High-Grade Non-Hodgkin Lymphoma Study Group. Blood. 2010;116(18):3418–3425. doi: 10.1182/blood-2010-02-270785. Epub 2010 Jul 21.

3. Vose J, Armitage J, Weisenburger D, for the International T-Cell Lymphoma Project. J Clin Oncol. 2008;26(25):4124–4130. doi: 10.1200/JCO.2008.16.4558. Epub 2008 Jul 14.

4. O’Connor OA, Ozcan M, Jacobsen ED, et al. First multicenter, randomized phase 3 study in patients with relapsed/refractory peripheral T-cell lymphoma: alisertib versus investigator’s choice. Paper to be presented at: American Society of Hematology 57th Annual Meeting & Exposition; December 5–8, 2015; Orlando, FL.

5. Horwitz SM, Porcu P, Flinn I, et al. Duvelisib (IPI-145), a phosphoinositide-3-kinsae-γδ inhibitor, shows activity in patients with relapsed/refractory T-cell lymphoma. Paper presented at: American Society of Hematology 56th Annual Meeting & Exposition; December 6–9, 2014; San Francisco, CA.