PTCL and ICIs: a matter of time and subtype

In this issue of Blood, Merrill et al¹ report the result of a phase 2, nonrandomized, multicenter, single-arm study of pembrolizumab, used as consolidation therapy in patients with peripheral T-cell lymphoma (PTCL) after autologous stem cell transplant (ASCT) in first complete remission (CR1) and demonstrated 18-month progression-free survival (PFS) and overall survival (OS) of 83.6% and 94.4%, respectively.

Over the past few years, immunotherapeutic approaches including immune-checkpoint inhibitors (ICIs) and chimeric antigen receptor T cell (CAR-T) therapy have fundamentally revolutionized the paradigm of cancer treatment, enabling the possibility of long-term survival in patients with very advanced and refractory disease. As of December 2021, there are 8 Food and Drug Administration–approved ICIs available for 17 different malignancies. There has been increasing successful use of these agents in multiple settings including in earlier-stage disease and maintenance therapy, as single agents and in combination with other classes of ICI, with cytotoxic chemotherapy, and with biological and/or targeted therapies. Unfortunately, despite the development of such promising immune therapeutic strategies, PTCLs continue to represent a true unmet need as the initial immunotherapy trials were disappointing.

Merrill et al in this well-written study report the result of a phase 2, nonrandomized, multicenter, single-arm study of the anti-PD-1 monoclonal antibody pembrolizumab used as consolidation therapy in patients with PTCL after ASCT in CR1. Only 21 patients were treated on study with 14 (67%) completing 8 cycles of treatment. Among all evaluable patients, 13 of 21 were alive and progression free at 18 months. The estimated 18-month PFS and OS were 83.6% and 94.4%, respectively. This is a small but positive study that (just) achieved the primary end point of 18-month PFS post-ASCT with improvement from 40% to 50% based on historical data to 83.6% in this study. Toxicity in the study was in line with the described toxicity of pembrolizumab.² Unfortunately, follow-up on the study is not available after the 18-month point, but this strategy appears promising. This interesting study highlights several important and recurrent issues that once again exemplify the complexity of the field. It also raises the need to answer some fundamental key questions to be able to move forward and truly advance treatment for patients with PTCL.

PTCLs are a group of rare, biologically heterogeneous and generally aggressive T-cell mature lymphoid malignancies with an unfavorable natural history as demonstrated by the 5-year OS of about 25% with standard chemotherapy and median PFS and OS in the relapsed/refractory (R/R) setting of less than 6 months.³ The role of ASCT in CR1 is still a topic of debate due to the lack of prospective, randomized trials and conflicting results from retrospective analysis, despite being suggested by most of the guidelines for fit patients. In a recent randomized trial comparing the role of stem cell transplant (allogeneic vs autologous) in CR1, only 65% of the patients enrolled could go on to receive the assigned transplant consolidation mostly because of early disease progression.⁴ This is a key factor that underscores that the best chance to get patients with PTCL into a good remission is to improve first-line treatment with the introduction or addition of novel T-cell-specific agents. Even the patients who made it to autologous transplant had a substantial relapse rate of 36% at a median follow-up of 42 months. The study published by Merrill and coauthors incorporated ASCT in CR1. However, the study raises the question whether the ICIs could provide benefit and less toxicity in CR1 in specific subtypes of disease (eg, extranodal natural killer [NK]/T-cell lymphoma [ENKTL]) that appear to be very sensitive to this class of drugs. Ultimately, it will be interesting to see whether ICIs and novel agents could be added just to consolidation or could obviate the need for standard chemotherapy in the frontline setting.

The history of ICIs in PTCL is checkered due to very heterogeneous responses to treatment and early reports of hyperprogression, possibly related to the tumor suppression function of PD-1 in specific subtypes such as adult T-cell leukemia and lymphoma⁵ and other nodal PTCLs.⁶ There have been significant successes. For example, Kwong et al⁷ first reported that PD-1 blockade was highly active in R/R ENKTL in a series of 7 cases. Its outstanding activity was subsequently confirmed in a phase 2 study of 28 patients with Asp-resistant ENKTL that were treated with the PD-1 inhibitor sintilimab. Due to its promising activity, immunotherapy has recently been used in frontline treatment in advanced-stage disease in patients with newly diagnosed stage III/IV ENKTL in combination with P-GEMOX with CR rate, 1-year PFS, and 1-year OS of 77.8%, 66.7%, and 100%, respectively.⁸ A very small series of patients with treatment-naive nodal PTCL treated with a combination of azacitidine, romidepsin, and durvalumab exhibited very high CR rate (3 out of 5 patients treated). Lastly, multiple trials exploring the role of different ICIs used alone and in combination with epigenetic agents in the relapsed, refractory setting are showing encouraging results with no evidence of hyperprogression, suggesting that these agents could be incorporated into earlier lines of treatment.^9,10 

In summary, the scientific community dedicated to advancing the care of rare diseases such PTCL should collaborate to answer fundamental questions that as of today remain open. For example, what is the role of ASCT in CR1? Are there different consolidation approaches with less toxicity profiles that can be tailored to disease subtype-specific sensitivity?

Conflict-of-interest disclosure: E.M. reports research funding from Merck, Celgene/BMS, Astex Pharmaceuticals, Myeloid Therapeutics, and Dren Bio. Data Safety Monitoring Committee: Everest Clinical Research.