Use of Transplant Persists as Appropriate Option in PTCLs

Backed by experience, but not randomized data, most institutions have established practices for transplant in patients with peripheral T-cell lymphomas.

No consensus exists on the optimal management of peripheral T-cell lymphomas (PTCLs). Treatment is largely based on regimens developed for more common B-cell lymphomas, leaving much to be desired in terms of treatment outcomes.

Hematopoietic stem cell transplantation (HCT) offers a greater chance of long-term remission, but not all patients are eligible for this aggressive procedure. “PTCL is unique in the sense that there are very few randomized trials upon which to base our practice,” said Steven I. Park, MD, from the Levine Cancer Institute and the University of North Carolina at Chapel Hill. “The disease is relatively uncommon, highly heterogenous, and has many subtypes with different underlying disease biology.”

In the absence of randomized, controlled data, the role of HCT in PTCLs remains controversial. ASH Clinical News spoke with Dr. Park and other lymphoma experts about this difficult clinical question.

Many Diseases, Few Answers

PTCLs are estimated to account for between 10% and 15% of all non-Hodgkin lymphomas.1

The most commonly occurring subtype of PTCL is PTCL-NOS (not otherwise specified), which includes all T-cell lymphomas that do not fit into any other categories. Other subtypes include:

  • anaplastic large cell lymphoma (ALCL), which is more common in North America and Europe
  • angioimmunoblastic T-cell lymphoma (AITL), which is more common in Europe
    natural killer/T-cell lymphoma (NKTCL) and adult T-cell leukemia/lymphoma (ATLL), which are more common in Asia2

There is no identified unique marker that is common to all PTCL subtypes, and thus, no treatment regimen works in all patients, according to Deepa Jagadeesh, MD, from Cleveland Clinic and Case Western Reserve University in Ohio. Given the limited treatment options, the five-year overall survival (OS) rate for most subtypes of the disease is about 30% to 35%, she said.

Historically, the most commonly used treatment regimen was cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), with etoposide sometimes added (CHEOP) for patients younger than 60 years old. More recently, data from the phase III ECHELON-2 trial showed that patients with previously untreated CD30-positive PTCLs derived benefit from treatment with a regimen that included brentuximab vedotin.3

The ECHELON-2 trial compared the safety and efficacy of brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone (BV-CHP) with CHOP in 452 patients with PTCLs. The addition of brentuximab vedotin more than doubled median progression-free survival (PFS): 48.2 months in the BV-CHP group versus 20.8 months in the CHOP group.

“One thing to keep in mind though is this study was heavily weighted for ALCL,” Dr. Jagadeesh noted. “The challenge that people who treat PTCL face is whether these data apply to other subtypes because the numbers were small compared with ALCL.”

Who Benefits From Transplant – and When?

More new approaches are needed for patients with PTCLs, as many who receive conventional combination chemotherapy will not experience durable disease remissions, according to Ranjana Advani, MD, from Stanford Cancer Institute in Palo Alto, California.

Transplant may fill that need. There are certain nuances by subtypes, of course, but retrospective data have suggested a benefit with consolidation with autologous HCT (AHCT) in patients who have achieved a complete remission after first-line therapy, she noted.

Steven M. Horwitz, MD, an investigator on ECHELON-2 from Memorial Sloan Kettering Cancer Center in New York, agreed. “The best data that we have that transplant benefits patients are in those with chemotherapy-sensitive disease who achieve complete remission in the frontline setting,” he said. “Whereas, if you look at data that includes all-comers or patients who only achieve stable disease or partial remission, it is much less clear that there is any benefit.”

Dr. Park’s practice also uses ASHCT for patients with PTCLs in first remission who are considered fit enough for the transplant and conditioning, with a notable exception of ALK-positive ALCL, in which upfront AHCT is not indicated.

“Age is a factor, but we focus more on the patient’s performance status to determine their transplant eligibility,” Dr. Park said.

However, Dr. Advani noted that there are no large, randomized trials comparing transplant outcomes with observation. Instead, most data are from phase II trials or retrospective analyses.

For example, a retrospective study from Korea looked at outcomes among 31 patients with PTCL who achieved complete (n=23) or partial (n=8) remission prior to AHCT with high-dose chemotherapy with busulfan, cyclophosphamide, and etoposide. Their three-year PFS rate was 64.5%.4

A 2012 Danish prospective trial evaluated outcomes in 115 patients with treatment-naïve PTCLs who received induction with either CHOEP or CHOP then proceeded to consolidation with high-dose chemotherapy/ASHCT. Rates of five-year OS and PFS were 51% and 44%, respectively.5

Dr. Park was an investigator on the COMPLETE trial, one of the largest prospective registration studies in PTCLs.6 Patients who achieved complete remission proceeded to either ASHCT (n=36) or observation (n=83). With a median follow-up of 2.8 years, median OS was not reached in the transplant group, compared with 57.6 months in the observation group (p=0.06).

If the study had been adjusted for the baseline patient characteristics, the difference in survival outcomes might have been even more significant, Dr. Park added. Participants in the observation group had more favorable characteristics, he explained, and “in multivariable analysis, AHCT was associated with significantly better survival, especially in subsets of patients with advanced-stage disease or high International Prognostic Index scores.” Dr. Park said. Patients with AITL also appeared to derive more benefit from AHCT in first remission compared with other PTCL subtypes.

However, Dr. Advani noted that it is hard to rule out selection bias in these trials. “We don’t know if the good outcomes post-transplant are due to the transplant or due to a highly selected patient population who might have done well anyways,” she said.

Often though, she said, if the patient has primary refractory disease or has only achieved a partial response, AHCT does not work. In these cases, allogeneic HCT (alloHCT) may be considered.

Autologous or Allogeneic?

Until recently, data on the role of alloHCT were limited.

“Compared with AHCT, alloHCT is probably more effective in disease control, but it is more toxic and has higher treatment-related mortality and morbidity,” Dr. Park said.

Although AHCT in first remission is often preferred, certain PTCL subtypes carry a worse prognosis, such as hepatosplenic T-cell lymphoma, and upfront alloHCT may be an alternative.

At the 2019 American Society of Clinical Oncology Annual Meeting, Norbert Schmitz, PhD, from University Hospital Münster in Germany, presented results from the randomized Autologous or Allogeneic Transplantation in T-cell lymphoma (AATT) trial, which compared survival outcomes after consolidation with AHCT or alloHCT in patients with newly diagnosed PTCLs.7 After induction, participants were randomly assigned to AHCT with BEAM chemotherapy (carmustine, etoposide, cytarabine, and melphalan) or alloHCT with fludarabine, busulfan, and cyclophosphamide conditioning.

There were no significant differences in three-year event-free survival or OS between the two transplant types; however, about one-third of patients assigned to alloHCT died from treatment-related mortality, compared with no patients assigned to AHCT.

Still, Dr. Horwitz said that these findings do not answer the question of the optimal transplant approach, because more than one-third of patients could not proceed to transplant as intended due to progression, and almost one-third of patients assigned to alloHCT died from toxicity.

“The question for us is rarely ‘allogeneic versus autologous’,” he said. “Our strategy is response-based. If our patients are chemotherapy-sensitive and achieve a complete response, we consider AHCT as consolidation of first remission. If they only achieve a partial response or stable disease, we think they are unlikely to benefit from high-dose therapy and AHCT, so we consider other strategies, which can include alloHCT.”

Transplant in Relapse

AlloHCT also can be considered in the relapsed setting, Dr. Park said, as data suggest little benefit for AHCT after disease relapse.

In a 2019 study, Italian researchers reported that, at a median follow-up of 40 months, the four-year OS rate was 34% in patients with relapsed/refractory T-cell lymphomas who underwent alloHCT.8 The four-year second-line failure-free survival rate was 14%.

At the 2020 American Society of Hematology Annual Meeting, Neha Mehta-Shah, MD, of Washington University School of Medicine in St. Louis, and colleagues presented data from a retrospective study of more than 500 patients with relapsed or refractory mature T-cell lymphoma who underwent alloHCT.9 After alloHCT, the two-year PFS rate was 45.8%, and the five-year PFS was 39.4%. Median OS rates at two and five years were 59.1% and 50.8%, respectively.

More than half of patients were in complete remission at time of transplant, which the researchers noted was associated with longer survival.

These data demonstrate that alloHCT in the relapsed setting is potentially curative, Dr. Horwitz said, but, he added, “alloHCT is one of the most medically aggressive treatments we offer so it is important that we do it under optimal circumstances. If we cannot do it under optimal disease control, we have to think seriously about not doing it at all.”

Remaining Challenges

The gold standard for progress in treatment of PTCLs would be a randomized clinical trial, according to Dr. Advani, but this would be difficult to do given the rarity of the disease, its heterogeneity, and the difficulty of randomizing patients to either aggressive treatment or no treatment.

“We have to study if consolidation with AHCT for patients in complete remission is meaningful or not,” Dr. Advani said. “This is an important question. Right now, we are just doing things more as a knee-jerk reaction.”

Researchers also continue to try to improve upon the efficacy and safety of induction chemotherapy regimens, Dr. Park said.

“The current treatment is mostly based on CHOP or CHOEP, but we have learned that, in certain subtypes, like CD30-positive PTCLs, especially ALCL, that BV-CHP is more effective,” Dr. Park said. “The question is, as we hope to have more effective first-line chemotherapy regimens, what will be the role of AHCT?”

In the future, hopefully more effective treatment options in the frontline setting will make the use of transplant even less compelling, he said.

“Until survival outcomes reach the levels seen with other lymphomas types – perhaps in the 80% or greater range – transplant will likely maintain a role in PTCLs,” Dr. Horwitz said. “Once we have developed better and more effective upfront regimens, the use of transplant will likely be phased out naturally.”

In the meantime, better treatment options are needed to get more patients to complete remission prior to transplant, Dr. Jagadeesh added. More options for relapsed disease also are badly needed.

“Most of the agents we have for relapsed disease have an overall response rate of about 30% to 35%,” she said. “When treated with these drugs, patients are not going into remission and their disease will progress.”

According to Dr. Park, progress in PTCLs will rely on researchers gaining a better understanding of the diseases’ biology, “such as identifying biologic markers to predict response to various treatments, including HCT.” For example, one recent analysis looking at these markers showed that patients with ALK-negative ALCL and PTCL-NOS who did not have gene rearrangements in DUSP22 had superior survival outcomes after upfront high-dose therapy followed by AHCT, while those who had gene rearrangements in DUSP22 did not seem to benefit from upfront AHCT.10

Finally, although it is not ready for primetime, much work is being done in PTCLs to adapt cellular immunotherapy, including chimeric antigen receptor T-cell therapy.

“Targeting T-cell antigens in T-cell lymphoma has been challenging. Ongoing efforts are evaluating other potential markers, such as CD30,” Dr. Jagadeesh said. “Hopefully we will see exciting progress in the next few years.” —By Leah Lawrence

References

  1. Leukemia & Lymphoma Society. Peripheral T-Cell Lymphoma Facts. Accessed February 4, 2021, from https://www.lls.org/sites/default/files/file_assets/peripheraltcelllymphomafacts.pdf.
  2. Lymphoma Research Foundation. Peripheral T-Cell Lymphoma. Accessed February 4, 2021, from https://lymphoma.org/aboutlymphoma/nhl/ptcl/.
  3. 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.
  4. Ahn J-S, Yang D-H, Jung S-H, et al. Autologous stem cell transplantation with busulfan, cyclophosphamide, and etoposide as an intensifying frontline treatment in patients with peripheral T cell lymphomas: a multicenter retrospective trial. Ann Hematol. 2013;92:789-797.
  5. d’Amore F, Relander T, Lauritzsen GF, et al. Up-front autologous stem-cell transplantation in peripheral T-cell lymphoma: NLG-T-01. J Clin Oncol. 2012;30:3093-3099.
  6. Park SI, Horwitz SM, Foss FM, et al. The role of autologous stem cell transplantation in patients with nodal peripheral T-cell lymphomas in first complete remission: report from COMPLETE, a prospective, multicenter cohort study. Cancer. 2019;125:1507-1517.
  7. Shmitz N, Truemper L, Ziepert M, et al. First-line therapy of T-cell lymphoma: allogeneic or autologous transplantation for consolidation—final results of the AATT study. J Clin Oncol. 2019; DOI: 10.1200/JCO.2019.37.15_suppl.7503.
  8. Mussetti A, Martinetti N, Cieri N, et al. Real-life feasibility of salvage allogeneic transplantation in peripheral T-cell lymphomas. Bone Marrow Transplantation.2019;54:1237-1244.
  9. Mehta-Shah N, Kommalapati A, Teja S, et al. Successful treatment of mature T-cell lymphoma with allogeneic stem cell transplantation: the largest multicenter retrospective analysis. Abstract 41. Presented at the 62nd ASH Annual Meeting and Exposition; December 5-8, 2020.
  10. Pederson MB, Relander T, Lauritzsen GF, et al. The impact of upfront autologous transplant on the survival of adult patients with ALCL and PTCL-NOS according to their ALK, DUSP22 and TP63 gene rearrangement status – a joined Nordic Lymphoma Group and Mayo Clinic Analysis. Abstract 624. Blood.2017;130 (supplement 1):822.