Associate Attending Physician
Department of Medicine
Memorial Sloan Kettering Cancer Center
Associate Professor of Medicine
Weill-Cornell Medical Center
New York, New York
Steven M. Horwitz, MD, has disclosed that he has received funds for research support from ADC Therapeutics, Aileron, Celgene, Forty Seven, Infinity/Verastem, Kyowa-Hakko-Kirin, Millennium/Takeda, Seattle Genetics, and Trillium and consulting fees from ADC Therapeutics, Affimed, Aileron, Angimmune, BeiGene, Corvus, Forty Seven, Infinity/Verastem, Innate Pharma, Kura, Kyowa-Hakko-Kirin, Merck, Millennium/Takeda, miRagen, Mundipharma, Portola, Seattle Genetics, and Syros.
The results of 2 interesting clinical trials in peripheral T-cell lymphoma (PTCL) were presented in June at the 2019 ASCO annual meeting. In this commentary, I highlight learnings from both studies—one on a transplant comparison and the other on a PD-1–targeted immunotherapy.
Transplant in Newly Diagnosed PTCL: Autologous vs Allogeneic
Schmitz and colleagues presented final results from the Lymphoma Study Association’s Autologous or Allogeneic Transplantation in T-Cell Lymphoma (AATT) randomized clinical trial. This study enrolled 103 eligible patients younger than 60 years of age with newly diagnosed PTCL, including PTCL not otherwise specified, angioimmunoblastic T-cell lymphoma, and anaplastic large-cell lymphoma (ALK negative), among other subtypes. The patients were treated with 4 courses of CHOEP-14, and then those with a response or without progression were treated with DHAP and randomized to either allogeneic stem cell transplant (if donor available; preceded by fludarabine, busulfan, and cyclophosphamide) or autologous transplant (preceded by BEAM).
The results suggest that 3-year event-free survival (EFS) was similar in the intention-to-treat population at approximately 40% in each arm (P = .58). In patients who received transplants, the 3-year EFS rate was higher (~ 63%) but again failed to reach statistical significance between arms (P = .430). The OS rate at 3 years for patients who received transplants was 70% with autologous transplant vs 57% with allogeneic transplant (P = .408). A total of 46 patients (45%) achieved a CR or unconfirmed CR and an additional 17 patients had lesser responses or stable disease. Eight subjects in the allogeneic transplant arm died of transplant-related mortality whereas 7 patients in the autologous arm died of lymphoma. Ultimately, these results do not broadly support allogeneic transplant in PTCL in first remission.
The study was hoped to show a significant EFS improvement at 3 years in patients who received allogeneic stem cell transplant (primary endpoint), but ultimately, it was halted due to futility, as 28% of subjects had disease progression prior to transplant, 37% stopped participation before transplant, and 14% of patients in the allogeneic arm (7/49) were without a suitable donor and received autologous transplant instead.
Allogeneic stem cell transplant has never been widely endorsed or practiced as a strategy for PTCL in first remission. The benefits of dose intensity with autologous transplant in first remission are supported to date by phase II studies only; no randomized studies have been performed and the likelihood of benefit in retrospective analyses has been mixed. Allogeneic transplant, due to the significant risk of transplant-related mortality, is generally relegated to the relapsed setting or used only in those histologies where chemotherapy alone or autologous transplant appear unlikely to provide durable benefit, such as adult T-cell leukemia/lymphoma, hepatosplenic T-cell lymphoma, or other aggressive gamma/delta lymphomas. What this study does highlight is the pressing problem in T-cell lymphoma of optimizing frontline therapy to improve remissions.
PD-1 Inhibition in PTCL: Sintilimab
Natural killer (NK)/T-cell lymphoma cells can have high expression of PD-L1 due to upregulation from Epstein-Barr virus infection. Patients with relapsed extranodal NK/T-cell lymphoma have a poor prognosis with a median OS of only approximately 6 months. Results from an earlier study of the immune checkpoint inhibitor pembrolizumab in 7 patients with NK/T-cell lymphoma who had failed multiple regimens showed 5 of 7 patients achieved durable CRs with PD-1 inhibition.
At ASCO 2019, Tao and colleagues presented results from the ORIENT-4, a single-arm phase II study of the PD-1 inhibitor sintilimab (IBI308) in patients with relapsed/refractory extranodal NK/T-cell lymphoma (nasal). In the study, 28 heavily pretreated patients with NK/T-cell lymphoma who had failed asparaginase-based regimens (median: 3 previous lines) and had at least 1 measurable or FDG-avid lesion were treated with single-agent sintilimab 200 mg every 3 weeks. A total of 19 patients responded (68%; 2 CRs and 17 PRs), with the majority having ongoing responses at the time of the report (median follow-up: 15 months). Of note, 5 patients who initially experienced pseudoprogression subsequently went on to respond or achieved stable disease. In a subgroup analysis, Epstein-Barr virus negativity, lack of B symptoms, normal lactate dehydrogenase, and no bone marrow involvement were associated with better ORRs. Median OS was not reached, with a 1-year OS rate of 82.1%. The most common adverse events were decreased lymphocytes, fever, leukocytopenia, hypothyroidism, pseudoprogression, increased thyroid-stimulating hormone, and hyperglycemia, but these were all grade 1/2 with the exception of 2 patients with grade 3 decreased lymphocyte count.
This prospective study offers an important confirmation of the initial very small study reporting on the utility of PD-1 checkpoint inhibition in patients with NK/T-cell lymphoma. Sintilimab appears active and well tolerated in this challenging setting and invites further study regarding its potential as a treatment option for these patients.
For a discussion of the latest data from the ECHELON-2 trial of brentuximab vedotin in frontline PTCL, click here. What are your most pressing questions about PTCL therapy today? Join the conversation by leaving a question or comment below.
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