JCO Article Insights: Final Analysis of ...

In this JCO Article Insights episode, Alexandra Rojek provides a summary on "Romidepsin Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone Versus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Patients With Previously Untreated Peripheral T-Cell Lymphoma: Final Analysis of the Ro-CHOP Trial" by Camus et al published February 16th, 2024 and the associated editorial written by Dr. Mehta-Shah and Dr. Horwitz.

TRANSCRIPT

The guest on this podcast episode has no disclosures to declare.

Alexandra Rojek: Hello and welcome to JCO Article Insights. I'm your host, Alexandra Rojek, and today we will be discussing a clinical trial update published in the May 10th issue of JCO addressing the long term follow up of the addition of romidepsin to CHOP chemotherapy for previously untreated peripheral T-cell lymphoma, or PTCL. This report by Camus et al discusses a five-year follow up of the original Ro-CHOP trial, which did not meet its primary endpoint of progression free survival. The original Ro-CHOP study, conducted by the LYSA group, was published in 2021 in JCO and was conducted as a one-to-one randomized phase III study of Ro-CHOP versus CHOP for patients aged 18 to 80 years with PTCL. 98 international centers were included, and the study enrolled patients between 2013 and ‘17. Nodal follicular helper T-cell, or TFH lymphoma was defined in this study follow-up as a PTCL expressing at least two of five TFH markers according to the latest classifications. The study's primary endpoint was PFS with secondary endpoints of OS and duration of response, or DOR. Five year follow up was reached in December 2022.

In the original study report, the addition of romidepsin to CHOP did result in a reduction of dose intensity of chemotherapy. However, in this updated follow up, there were no new safety signals reported. A total of 421 patients were enrolled in the trial with a median age of 65 years. Notably, those who were randomized to the Ro-CHOP arm had a higher proportion of IPI 4-5 scores at 33%, versus 24% of those who were assigned to CHOP alone despite randomization. Nearly half of patients carried a histologic diagnosis of angioimmunoblastic T-cell lymphoma. 30% were characterized as PTCL NOS, not otherwise specified, 10% ALK negative anaplastic large cell lymphoma, leaving 13% reported as other. Over 60% of patients had stage four disease at enrollment, with nearly half having more than two sites of extranodal involvement. Median follow up was six years with a median PFS of 12 months for Ro-CHOP and 10.2 months for CHOP, which did not reach statistical significance as reported in the original study publication. Estimated five year OS available as a part of this clinical trial update was 50% for Ro-CHOP and 43% for CHOP alone, and also did not reach significance. There was, however, a longer duration of response observed in the Ro-CHOP arm at 52 months versus 24 months for CHOP, which is a new finding in this extended follow up of the study.

In an effort to better understand whether there are subgroups which may benefit from romidepsin despite the overall negative outcome of this study, the authors are able to provide new insights from this Ro-CHOP study in line with our current and updated understanding of PTCL. When the authors evaluated the study population for subgroups which may benefit from addition of romidepsin, TFH lymphomas, which included angioimmunoblastic, follicular, and NOS subtypes, were noted to have an improved response to the addition of this HDAC inhibitor. This subgroup, numbering 201 patients, experienced a mean PFS of over 19 months with Ro-CHOP versus over 10 months for those who received CHOP, and this difference achieved statistical significance. Similarly, there was a higher complete response rate and longer duration of response for those in the TFH subgroup who received romidepsin.

The authors also make note that those patients in this subgroup with high IPI appeared to particularly benefit. However, those in the PTCL NOS group who did not fit the TFH subtype experienced poor outcomes with shorter PFS and OS as compared to other histologic subtypes, which is in line with other reported data in the field. The authors in this update also report on treatments and outcomes after first progression or relapse of disease, which includes a total of 274 patients, of whom 251 received second line therapy. The median PFS in OS after progression or relapse was only 3.3 months and 11.5 months, respectively, and again, patients with the TFH subtype experienced a longer median OS than other included histologies. Only 8% of patients proceeded to undergo autologous stem cell transplantation overall, and 5% underwent allogeneic stem cell transplantation.

While the authors note that they did not observe any notable outcome differences between various included second line therapies, they do note of a possible benefit of the antibody drug conjugate brentuximab vedotin or BV in combination with chemotherapy backbones. Those who received a BV containing regimen in the second line experienced a better CR rate and a longer PFS, too. However, the OS too was not significantly different. Again, the authors note that most of the benefit of the addition of BV to chemotherapy in the second line appeared focused on this TFH lymphoma subgroup. Of note, CD30 status was not recorded as a part of the study for included patients and could not be further reported on.

The findings of the authors present in this subgroup analysis of the negative Ro-CHOP study seek to find benefit in future lessons for patients with these rare lymphomas who do not have a multitude of effective treatments available to them. The subgroup benefit in this clinical trial update based on the TFH phenotype fits our evolving understanding of PTCL in the modern era. Mutations characteristic of the TFH subgroup, in this case often involved in chromatin modification and the tumor microenvironment, have been linked to improved responses when treating with epigenetic targeting drugs such as romidepsin, thus making the findings of TFH lymphoma in the Ro-CHOP trial confirmatory of what we would expect from correlative studies. Despite the benefit of Ro-CHOP for those with TFH lymphoma, this updated analysis of a major frontline study of PTCL highlights the critical need in the T-cell lymphoma field to, first of all, better understand and separate what we have come to recognize as the heterogeneous diseases historically lumped together as PTCL. This historic classification, based on a lack of deeper molecular understanding of disease biology is unlikely to represent the true biologic diversity of its component subtypes, including the focus on TFH lymphoma presented here. The second critical unmet need, which this subgroup analysis highlights, is the need to investigate the benefit of new therapeutic agents in these distinct subgroups of PTCL, where the need for improved survival outcomes is sorely needed when examining historical outcomes with currently available therapies, both in the frontline setting as well as those in the relapsed refractory group.

The associated editorial, written by Dr. Mehta-Shah and Dr. Horwitz, elegantly discusses the challenges of designing studies in rare diseases such as PTCL, which are both biologically informed as well as appropriately powered. As the authors discuss, it is rare to get a second chance for a drug, as is the case for romidepsin, where these negative results led to its voluntary withdrawal in PTCL, affecting availability of the drug for patients in the relapsed setting, as well as future clinical trials, which could have had potential for success. Additionally, better understanding of the biological underpinnings of PTCL needs to lead to better designed and appropriately powered clinical trials, as these subsets of patients are in great need of therapeutic advances. While none of these tasks is easy nor straightforward, this clinical trial update of the RoCHOP study suggests a path forward from learning from prior, promising yet failed attempts at moving the standard of care for frontline therapy of T-cell lymphoma forward.

This is Alexandra Rojek thank you for listening to JCO Article Insights. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at ascp.org/podcasts.

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