By Craig Sauter, MD
How does Pembrolizumab (MK-3475), also known as Pembro, after Autologous Stem Cell Transplantation in Patients with T-Cell Non-Hodgkin Lymphoma help? So this was a multi-side phase 2 single armed study. Originally designed with multiple cohorts looking at the role of Pembrolizumab (Pembro) maintenance, following high dose chemotherapy and autologous stem cell transplant in consolidation for various lymphomas.
The abstract presented at ASH was cohort C, which is looking specifically at the patient's proceeding to consolidative autonomous transplant for peripheral T-cell lymphomas. So this was a 21 subject cohort with various peripheral T-cell lymphoma, histologies. What was deemed to be promising would be 60% progression-free survival interval at 18 months.
As of reporting at the study, 13 of the 17 subjects were progression free, thus meeting promising end point at least within this specific cohort on the phase 2. While on autonomous transplant and first remission for peripheral T-cell lymphoma has remained a standard of care. The outcomes have been somewhat modest with anywhere from 30 to 50% of patients progressing within the first 18 to 36 months following high dose therapy in first remission.
So the intention of the study was to pro prolong progression-free survival. The data analysis was somewhat encouraging in a limited subject study of only 21 subjects.
Pembrolizumab (MK-3475), often known as Pembro, is a humanized monoclonal anti-PD-1 antibody in the experimental stage of development. Its goal is to reactivate antitumor immunity by interfering with the interaction of PD-1 on T cells and its ligands, PD-L1 and PD-L2. Pembrolizumab (Pembro) suppresses the PD-1 pathway via a process known as dual-ligand inhibition.
Pembrolizumab (Pembro) is now being studied as a potential treatment for over 30 distinct forms of cancer, both as a monotherapy and in combination with other medications. By the end of 2014, it is expected that the pembrolizumab (Pembro) development program will have expanded to include more than 24 clinical trials spanning 30 different types of tumors, recruiting over 6,000 patients at approximately 300 clinical trial sites around the world, including additional Phase 3 studies.
I think the biggest question is if we really believe that this is a promising approach we would, as investigators like to highlight that there's many different histologies with potentially different natural histories even within peripheral T-cell or T-cell, non-Hodgkin's lymphomas.
And those histologies were represented within the study, but it be, can be difficult to really discern the sub histologies that may benefit from this approach, especially in a relatively small cohort of 21 subjects. So the largest question is if we really believe that this is moving the needle. I would say potentially, but it would need to be confirmed at a larger later phase level, optimally within a random assignment study compared against placebo or other maintenance strategies.
But given the relative rarity of peripheral T-cell lymphomas, this would be difficult to conduct. Another major question was also safety of checkpoint inhibitors following autologous transplant. As reported on the study it was not without consequence, 17 of the 21 subjects experienced at least a grade 2 treatment related adverse event.
And there were 3 subjects with grade 3 events. There were no grade 4 or grade 5 events on the study. Most of these adverse events were as expected with checkpoint inhibition, particularly around gastrointestinal complications with the checkpoint inhibitor Pembrolizumab (Pembro).
I would not label these data as practice changing. I think it's hypothesis generating whether or not sub histologies that may have more preferred up regulation of PD-1 or more susceptibility to checkpoint inhibition. Whether or not that this can motivate or catalyze later phase studies in the sub histologies.
Again, highlighting the potential difficulty of enrolling in a study with such rare disease histologies as peripheral T-cell lymphoma.
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Except for ALK+ anaplastic large cell lymphoma, peripheral T cell lymphomas (PTCL) are a diverse group of cancers with a poor prognosis (ALCL). To enhance progression-free survival, most institutions consider autologous stem cell transplantation (ASCT) in first remission to be standard of therapy (PFS). Despite this, more than half of patients who receive ASCT will relapse.
A multicenter phase II study of the anti-PD-1 monoclonal antibody pembrolizumab (Pembro) given after ASCT for different subtypes of lymphoma, after getting their informed consent. The arm C enrolled PTCL patients who were in their first remission. The 18-month PFS rate with ASCT in chemosensitive T-NHL is expected to be between 40 and 50%. We anticipated that pembrolizumab (Pembro) consolidation therapy would raise PFS at 18 months to 70%. With a sample size of 21, the treatment would be considered promising if at least 13 patients remained alive and disease-free 18 months following ASCT.
Twenty-one people signed up from January 2017 to July 2020. The median age was 58. The most prevalent histology was PTCL NOS (52%). Extranodal NK/T-cell lymphoma, nasal type (14%), ALK- ALCL (10%), and monomorphic epitheliotropic intestinal T-cell lymphoma (5%). The average number of prior treatments was one. Prior to ASCT, 90% of patients had a complete metabolic response (CMR).
All patients who received at least one dosage of the study's medication were included in the toxicity evaluation (n = 21). At least 17 individuals had toxicity during the trial, including grade 1 (n = 5/21; 24), grade 2 (n = 8/21; 38), and grade 3 (n = 3/21; 14). Nausea (n = 5/21; 24%), alkaline phosphatase increase (n = 4/21; 19%), diarrhea (n = 4/21; 19%), abdominal discomfort (n = 3/21; 14%), hypothyroidism (n = 3/21; 14%), alanine aminotransferase (ALT) elevation (n = 2/21; 10%), anemia (n = 2/21; 10%), arthralgia (n = Abdominal discomfort (n = 1/21), colitis (n = 1/21), diarrhea (n = 1/21), ALT elevation (n = 2/21), AST elevation (n = 1/21), and headache (n = 1/21) were the most common grade 3 adverse events.
Consolidation therapy with pembrolizumab (Pembro) following ASCT is feasible and positive results and an excellent PFS, thereby meeting the primary goal of the study. This is the first trial to demonstrate that PD-1 inhibition could help with PTCL consolidation therapy. Because sensitivity to this therapy may differ amongst PTCL histologic or molecular subgroups, subsequent research may identify a subpopulation most likely to benefit from this technique, necessitating a wider confirmatory evaluation.
I'm uncertain of that. We participated in this study at my previous institution. Many of us believe that maintenance therapy following autologous transplant for lymphomas should be investigated. They should be conducted rationally. There have been some failures in investigation, including Rituximab maintenance for relapse refractory large cell lymphoma following autologous transplant.
But there have also been successful successes such as Brentuximab Vedotin maintenance in higher risk relapse or refractory hodgkin's lymphoma, patients that are proceeding to autologous transplant. There was previously another multi-center phase 2, looking at Romidepsin, which reported out eventually as being positive towards the primary end point, specifically again within T-cell lymphomas, so I think that this warrant's investigation as we would consider this a standard of care, this treatment approach being a standard of care and the use of maintenance can prolong progression-free intervals so that needs to be rigorously investigated.
I would say that the key takeaway is that this will not change practice. We do not have random assignment data suggesting that autologous transplant in the majority of peripheral T-cell lymphoma patients has a demonstrable benefit, at least within a prospective later phase study. Many of us, including larger academic centers, do approach these patients with first remission, consolidated autologous transplant. But again those outcomes are relatively sobering. So interventions with maintenance therapy, at least with conducted within rigorous clinical studies continue to be warranted.
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Craig S. Sauter, MD - About The Author, Credentials, and Affiliations
Craig Sauter, MD practices medical oncology, is the Director of Cleveland Clinic's Blood & Marrow Transplant (BMT) Program. Dr. Sauter is a native Clevelandite who completed medical school at Case Western Reserve University. He did his residency in internal medicine at the University of Michigan Hospitals and his fellowship in hematology/medical oncology at Memorial Sloan Kettering Cancer Center in New York City, where he served as Chief Fellow. Prior to joining Cleveland Clinic, he oversaw the Adult BMT program at Memorial Sloan Kettering.
Dr. Sauter has served as Co-Chair of the Lymphoma Working Committee of the Center for International Blood and Marrow Transplant Research and as Chairperson of the Tri-State Transplant Consortium. His study focuses on using BMT and cellular therapy to improve the prognosis of patients with relapsed and treatment-resistant non-Hodgkin's lymphoma. He received a house staff teaching award during his fellowship and has worked on the education committee of the American Society of Gene and Cell Therapy due to his commitment for medical education.
Merck - Merck Announces Generic Name for MK-3475, Merck’s Investigational anti-PD-1 Antibody: Pembrolizumab. Merck, May 30, 2014
ASH Publications - A Phase 2 Study of Pembrolizumab (MK-3475) after Autologous Stem Cell Transplantation in Patients with T-Cell Non-Hodgkin Lymphoma. ASH Publications, NOVEMBER 15, 2022