Histologic Distinctions and Optimized Imaging Carve New Paths for Individualized PTCL Management

The diverse histologies that comprise peripheral T-cell lymphoma (PTCL) promote a range of treatment challenges exacerbated by an armamentarium derived from therapies developed in patients with aggressive B-cell lymphomas, according to Neha Mehta-Shah, MD, MSCI. In a presentation at the 2024 SOHO Annual Meeting, Mehta-Shah discussed treatment strategies to augment survival outcomes in the relapsed setting, ways that improved risk-stratification tools can benefit patients in the frontline setting, and developments on the horizon in the realm of histology-specific treatments.¹

“The reality for most of us who practice in clinic is that most of our patients with [PTCL] have a 5-year survival of 25% to 35%,” Mehta-Shah, assistant professor, Washington University in St. Louis, Missouri, said during her presentation. Multiple attempts to augment outcomes in PTCL have included the use of autologous stem cell transplantation (ASCT) for patients who are chemotherapy sensitive, the addition of etoposide to cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone (CHOP), and adding novel agents to standard therapy, which has often resulted in more toxicity without improving efficacy, Mehta-Shah said.

Expanding on her experience with CHOP, Mehta-Shah said she orders a PET scan after 4 cycles of therapy and if the patient demonstrates some degree of chemotherapy sensitivity, it’s followed by 2 more cycles and then possibly an ASCT. “Although that is not everyone’s practice, I do this because of what has been shown in the registry studies. In patients who are not treated with intent-to-transplant, the 5-year overall survival [OS] and progression-free survival is about 20% less than those who were treated with the intent-to-transplant,” Mehta-Shah said.^2,3

Adding an agent such as etoposide to the CHOP backbone resulted in an objective response rate (ORR) of 82% and a complete response (CR) rate of 51%, as shown from a pooled analysis from the German National Lymphoma Study Group.⁴

Novel Therapies

A number of novel therapies have been evaluated in PTCL and have gained FDA approval. For example, histone deacetylase inhibitors, such as romidepsin (Istodax) and belinostat (Beleodaq) have led to ORRs of 25% and 26%, respectively, as well as the CD30 targeted approach, brentuximab vedotin (Adcetris), which has demonstrated an ORR of 69%.⁵

“The other group of therapies that we’re excited about are the PI3K inhibitors. These agents have response rates in the 50% range and CRs in the 33% range,” Mehta-Shah said. She emphasized that greater activity was observed in patients with the T follicular helper (TFH) phenotype, which are specialized providers of T cell help to B cells and are essential for germinal center formation.⁶

A US intergroup study (NCT0483201) is evaluating optimizing therapy for patients with PTCL, according to Mehta-Shah. This phase 2 study is currently enrolling patients who have CD30-less expressing PTCLs. Patients will be randomly assigned to receive either CHOP or CHOP plus azacitidine or CHOP plus duvelisib (Copiktra). “Patients are stratified for the TFH phenotype, as well as by age, to try to maximize the chance that we see a signal,” Mehta-Shah said.

Identifying Optimal Therapy

Although having a number of therapies to choose from is promising, efforts remain to determine which patients are best suited to receive or not receive these treatments, Mehta-Shah emphasized. “The question is how do we determine who needs all this therapy and who needs less therapy,” she said.

A comprehensive picture might be determined by examining a number of criteria: interim imaging, minimal residual disease (MRD) evaluation, or other predictive biomarkers.

Using interim PET scans based on the Lugano criteria can help determine if risk is predictive of OS and event-free survival (EFS), which improves on the predictive value of baseline clinical characteristics. In addition, baseline total metabolic tumor volume is another PET characteristic that is predictive of OS and EFS, Mehta-Shah noted.

Investigators then took lessons from those involved in treating B-cell lymphoma to determine if measuring the amount of tumor DNA in the blood can predict response or early progression.

In a prospective study (NCT03297697), Foley et al,7 evaluated the utility of MRD testing via T-cell receptor (TCR) next-generation sequencing in PTCL. Investigators reported that patients with negative TCR MRD post-ASCT remain in remission at median follow-up of 32.5 months. They recommended that the negative predictive value of TCR NGS MRD post-ASCT should be further evaluated.

As she closed her presentation, Mehta-Shah said, “I think there are lots of ways to do better than what we're doing right now, and I'm very hopeful that the work in the relapsed/refractory setting will lead to improved treatment for patients with PTCL. Through personalized therapy, through the use of histologic-based therapy, imaging, and MRD testing, we'll be able to translate that to the community.”

References

1. Mehta-Shah N. Optimizing Frontline Treatment for PTCL. Presented at: 12th Annual Meeting of the Society of Hematologic Oncology (SOHO 2024). September 4-7, 2024. Houston, TX.
2. Mehta-Shah N, Ito K, Bantilan K, et al. Baseline and interim functional imaging with PET effectively risk stratifies patients with peripheral T-cell lymphoma. Blood Adv. 2019;3(2):187-197. doi:10.1182/bloodadvances.2018024075
3. Ellin F, Landström J, Jerkeman M, Relander T. Real-world data on prognostic factors and treatment in peripheral T-cell lymphomas: a study from the Swedish Lymphoma Registry. Blood. 2014;124(10):1570–1577. doi:10.1182/blood-2014-04-573089
4. Schmitz N, Trümper L, Ziepert M, et al. Treatment and prognosis of mature T-cell and NK-cell lymphoma: an analysis of patients with T-cell lymphoma treated in studies of the German High-Grade Non-Hodgkin Lymphoma Study Group. Blood. 2010;116(18):3418-3425. doi:10.1182/blood-2010-02-270785
5. Mehta-Shah N. Emerging strategies in peripheral T-cell lymphoma. Hematology Am Soc Hematol Educ Program. 2019;2019(1):41–46. doi:10.1182/hematology.2019000012
6. Mehta-Shah N, Jacobsen E, Zinzani P, et al. Duvelisib in patients with relapsed/refractory peripheral t-cell lymphoma from the phase 2 PRIMO trial expansion phase: outcomes by baseline histology. HemaSphere. 2021.7:e3891642. doi:10.1097/01.HS9.0000971392.38916.42
7. Foley NC, Russler-Germain D, Watckins M, et al. A multi-institutional prospective cohort study of minimal residual disease in peripheral T-cell lymphoma: Impact of autologous stem cell transplant. J Clin Oncol. 2023;41(suppl 16):7563. doi:10.1200/JCO.2023.41.16_suppl.7563