What Is the Optimal Frontline Treatment for PTCL?

Neha Mehta-Shah, MD
Assistant Professor of Medicine, Division of Oncology, Washington University Medical School, St. Louis, MO
Steven M. Horwitz, MD
Medical oncologist, Memorial Sloan Kettering Cancer Center

At the 2020 American Society of Hematology (ASH) Annual Meeting, researchers presented five-year results from the phase III ECHELON-2 trial, showing that patients with previously untreated CD30-positive peripheral T-cell lymphoma (PTCL) derived benefit from a frontline regimen of brentuximab vedotin (BV) – an antibody-drug conjugate directed to CD30 – plus cyclophosphamide, doxorubicin, and prednisone (CHP). The combination provided a meaningful improvement in progression-free survival (PFS) and overall survival (OS) compared with standard-of-care cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP).

When the three-year results were originally presented in 2018, they were considered practice-changing, particularly for patients with anaplastic large cell lymphoma (ALCL). This was the first prospective trial in PTCL to show an OS benefit. However, it was – and remains – less clear how to interpret the results for patients with other subtypes of PTCL, which can include PTCL-NOS (not otherwise specified), angioimmunoblastic T-cell lymphoma (AITL), natural killer (NK)-/T-cell lymphoma, and adult T-cell leukemia/lymphoma.

In this edition of Drawing First Blood, ASH Clinical News invited Neha Mehta-Shah, MD, of Washington University School of Medicine in St. Louis, and Steven M. Horwitz, MD, of Memorial Sloan Kettering Cancer Center, to debate the appropriate frontline treatment for T-cell lymphoma: CHOP or BV-CHP. Dr. Mehta-Shah was asked to argue in favor of CHOP and Dr. Horwitz was asked to argue in favor of BV-CHP.


Neha Mehta-Shah, MD: In patients with PTCL, the goal of frontline therapy is cure. We usually pick anthracycline-based therapies such as CHOP or CHOP with etoposide (CHOEP). The overall response to CHOP and CHOEP seen in multiple studies is approximately 80%. When etoposide is added to CHOP, the complete remission rate increases from about 40% to 50%. The goal of therapy for these patients is to achieve complete remission with the hope that it is durable. CHOP and CHOEP are effective therapies in T-cell lymphoma and do cure a subset of patients. These rates can be augmented further when autologous hematopoietic cell transplantation is performed in first remission.

Steven M. Horwitz, MD: One simple reason to recommend BV-CHP over the established standards of care is that all of our data with CHOP and CHOEP are either retrospective or prospective phase II data. None the less, these data have shown that those regimens can be effective at achieving remission, long-term remission, or cure.

In the randomized, double-blind, phase III ECHELON-2 trial, BV-CHP was studied against CHOP in patients where at least 10% of the lymphoma cells expressed CD30.1,2 The use of BV more than doubled PFS, from 20.8 months to 48.2 months, along with a significant increase in OS, without increased toxicity. We do not have any other comparable data that shows an OS benefit in upfront treatment of T-cell lymphoma.

Now, we certainly think of CHOP as a standard of care in PTCL, but clinicians who treat patients with T-cell lymphoma are unsatisfied, as it too often provides inadequate disease control. Many providers add etoposide because, for some patients, it is a more potent regimen.

Single-agent BV had a very high response rate, 86%, in patients with relapsed ALCL, and individuals with ALCL comprised most of the ECHELON-2 study population.3 Based on that level of efficacy, it was rational to drop the vincristine and explore BV in upfront therapy.

“The goal of therapy for patients [with peripheral T-cell lymphoma] is to achieve complete remission with the hope that it is durable.”

–Neha Mehta-Shah, MD

Outside of ALCL, trial data are helpful, but less compelling or unequivocal. Looking at the population of patients with relapsed AITL and PTCL-NOS, the overall response rate with BV was approximately 40%, but there were fewer complete responses and with less durable remissions than seen in ALCL. In this setting, BV appears to be an active agent, likely more active than vincristine, without significantly more toxicity. In ECHELON-2, patients with AITL and PTCL-NOS were part of the intent-to-treat population, but unlike the group with ALCL, these subsets were not powered to allow for an independent assessment.

Dr. Mehta-Shah: Right, the ECHELON-2 study, which led to the approval of BV-CHP, enrolled predominantly patients with ALCL. BV targets the protein CD30, which is universally expressed on ALCL. We know that, in the relapsed/refractory setting, this agent is more active in that histology than others.

Thinking about participants with other PTCL subtypes, the differences in outcomes become less pronounced. It is not clear if BV-CHP is superior to CHOP or roughly equivalent. Based on the activity of BV in the relapsed/refractory setting, that is expected. In young fit patients with AITL and PTCL-NOS, where we believe etoposide can increase the complete remission rate over CHOP, there may be an advantage with CHOEP over BV-CHP. Similarly, BV-CHP is probably equivalent to CHOP in that population.

The other important thing to consider is that ECHELON-2 included only patients with 10% or higher CD30 expression and, in the real-world population, many patients have less than 10% expression. It is not as clear that giving CHOP or CHOEP results in different outcomes compared with BV-CHP in that population.

Dr. Horwitz: That is an important distinction to make: ECHELON-2 compared BV-CHP with CHOP only. There was no direct comparison to CHOEP. There are people for whom we think etoposide is important; for example, some patients with T-cell lymphoma have underlying hemophagocytic lymphohistiocytosis, for which etoposide appears to be an important therapy. There also are individuals for whom we may prefer to give a more dose-intense therapy every two weeks, rather than CHOP or BV-CHP in three-week cycles, and the ECHELON-2 trial does not address whether we can do that with BV-CHP.

“My long-term hope is that the upfront therapies will become so effective that transplant becomes unnecessary.”

–Steven M. Horwitz, MD

Dr. Mehta-Shah: Also, the ECHELON-2 study was designed to enroll at least 70% patients with ALCL, which was predicted (and proven) to be the histology for which BV-CHP would be most helpful. The rest of the diseases in PTCL were underrepresented. BV-CHP extended OS and PFS above CHOP in patients with ALCL, so BV-CHP could be the standard of care for this population.

However, patients with ALCL, both expressing ALK and not expressing ALK, make up about 30% of all PTCL, so they are still the minority. The most common subtypes of PTCL are PTCL-NOS and AITL. ECHELON-2 was not designed or powered to make conclusions based on efficacy of BV-CHP over CHOP in those histologic subtypes.

Even in the last five to 10 years, we have learned so much more about the biologies of the different subtypes of T-cell lymphoma. In the past, all these diseases were lumped together and studied, whether prospectively or retrospectively. We are starting to understand that the genetics of all these diseases – their driving transcriptional pathways, how they respond to therapy, and their complications – are different. Hopefully, this will lead to histology-specific treatment for patients with PTCL in the future.

Some of those efforts are already underway, specifically to look at patients who have a T-follicular helper (TFH) phenotype PTCL, which encompasses AITL and PTCL-NOS with TFH phenotype. This subtype seems to have a specific genetic landscape and there are likely certain therapies that are more active in this phenotype. Those are being studied in the frontline setting. For example, a study looking at azacitidine plus CHOP presented at the 2020 ASH Annual Meeting demonstrated an overall response rate after three cycles of 85%, including a complete response rate of 87% for patients with TFH PTCL by the end of treatment.4 These observations are going to lead to a randomized phase II U.S. Intergroup study of azacitidine plus CHOP or CHOEP compared with duvelisib plus CHOP or CHOEP versus CHOP or CHOEP. I am hoping that studies like these are going to shed light on how to personalize therapy for PTCL in the upfront setting.

Dr. Horwitz: I agree, the data for ECHELON-2 is strongest for patients with ALCL. Other datasets are beset with similar issues. For example, the main CHOEP data in PTCL included mostly patients with ALCL.5 It is fair to ask whether the ECHELON-2 data can be applied to more underrepresented subtypes. However, no other study in PTCL has allowed us to statistically analyze subtypes independently and make any kind of definitive conclusion. That is, so far, the nature of almost all the data we have in the field.

Dr. Mehta-Shah: Also, because T-cell lymphoma is a rare disease, most of the data exist from registry studies and phase II trials. There are very few landmark phase III studies in this patient population.

Several attempts have been made to add to CHOP-based therapy, so some of the evidence base supporting CHOP includes data from the control arms for those studies, as well as data from phase II studies evaluating the efficacy of CHOP- or CHOEP-based therapy. Often, adding agents to the CHOP backbone does not significantly improve outcomes.
For example, a smaller single-institution series that I worked on with Dr. Horwitz and others showed that, when patients were treated with CHOP with or without etoposide and the intention to transplant in first remission, the five-year PFS is about 45%.6 Large registry studies from the International Peripheral T-Cell Lymphoma Project, the Swedish Lymphoma Registry, and others have articulated similar survival outcomes with CHOP and CHOEP.7

Dr. Horwitz: Many of the prior attempts to add treatment to a CHOP backbone in PTCL increased toxicity. We saw that with alemtuzumab, where increased toxicity overrode any potential benefit.8 Etoposide also adds some hematologic toxicity. However, with BV-CHP, the additional efficacy does not come with any significant difference in toxicity.

Dr. Mehta-Shah: Also, as Dr. Horwitz alluded to, in PTCL, dose intensity probably matters. According to a randomized phase III study presented at the 2020 ASH Annual Meeting evaluating CHOP with or without romidepsin, the regimens led to similar outcomes, but it was difficult to maintain the dose intensity of CHOP when romidepsin was added.9 The similarities in outcomes were thought to be related to dose interruptions or discontinuations in the romidepsin arm relative to the CHOP arm.

Another important question to answer is who is most likely to benefit from transplant, and if we can identify those patients using imaging or molecular phenotyping like cell-free DNA. Dr. Horwitz and I are fortunate to work in a community where people are committed to working together to answer all these questions.

Dr. Horwitz: ECHELON-2 was a huge step forward. It was the first time we have shown an OS benefit for a group of patients with PTCL in treating with anything other than CHOP. There are certainly patients whose disease is not cured and will still relapse, even with BV-CHP, but it is a more effective platform on which to build.

As Dr. Mehta-Shah said, efforts are underway to identify more effective therapies for certain populations of patients, as well as to identify techniques – like measurable residual disease monitoring – to predict who is on the way to being cured and who needs a change in treatment strategy.

Transplant is still a big part of the discussion. My long-term hope is that the upfront therapies will become so effective that transplant becomes unnecessary. Realistically though, despite all the progress, it will be a while until we get there.

References

  1. Horwitz SM, O’Connor OA, Pro B, et al. The ECHELON-2 Trial: 5-year results of a randomized, double-blind, phase 3 study of brentuximab vedotin and CHP (A+CHP) versus CHOP in frontline treatment of patients with CD30-positive peripheral T-cell lymphoma. Blood. 2020;136(Suppl 1):3-5.
  2. Horwitz S, O’Connor OA, Pro B, et al. Brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma (ECHELON-2): a global, double-blind, randomized, phase 3 trial. Lancet. 2019;393:229-240.
  3. Pro B, Advani R, Brice P, et al. Five-year results of brentuximab vedotin in patients with relapsed or refractory systemic anaplastic large cell lymphoma. Blood. 2017;130(25):2709-2717.
  4. Ruan J, Moskowitz AJ, Mehta-Shah N, et al. Multi-center phase II study of oral azacitidine (CC-486) plus CHOP as initial treatment for peripheral T-cell lymphoma (PTCL). Blood. 2020;136(Supplement 1):33-34.
  5. 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.
  6. Mehta N, Maragulia JC, Moskowitz A, et al. A retrospective analysis of peripheral T-cell lymphoma treated with the intention to transplant in the first remission. Clin. Lymphoma Myeloma Leuk. 2013;13(6):664-670.
  7. Ellin F, Landström J, Jerkeman M, Relander T. Real-world data on prognostic factors and treatment in peripheral T-cell lymphomas: a study from the Swedish Lymphoma Registry. Blood. 2014;124(10):1570-1577.
  8. Wulf GG, Altmann B, Ziepert M, et al. Alemtuzumab plus CHOP versus CHOP in elderly patients with peripheral T-cell lymphoma: the DSHNHL2006-1B/ACT-2 trial. Leukemia. 2021;35:143-155.
  9. Bachy E. Camus V, Thieblemont C, et al. Final analysis of the Ro-CHOP phase III (conducted by LYSA): romidepsin plus CHOP in patients with peripheral T-cell lymphoma. Blood. 2020;136(Supplement 1):32-33.