Peripheral T-cell lymphoma: novel backbone

In this issue of Blood, Amengual et al report the results of a single-institution dose-escalation phase 1 study of pralatrexate plus romidepsin for patients with relapsed/refractory non-Hodgkin lymphoma. This combination resulted in a very high response rate in patients with previously treated peripheral T-cell lymphoma (PTCL).¹ 

PTCL represents only 10% to 15% of the non-Hodgkin lymphomas in Western developed countries, but up to 35% or more in some Asian countries.²  Traditionally, standard therapies used for B-cell lymphomas such as cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP-based therapies) were used for first-line therapies for PTCL; second-line therapies included standard salvage therapies such as ifosfamide, carboplatin, and etoposide. However, the results using these types of standard therapies have resulted in few patients with PTCL having long-term disease-free survival.³  Recently, several new single agents have been approved for relapsed PTCL including pralatrexate (an antifolate agent), romidepsin and belinostat (histone deacetylase inhibitors), and brentuximab vedotin (antitubulin agent conjugated to an anti-CD30 antibody). However, with the exception of brentuximab vedotin, the single-agent response rates in relapsed PTCL is ∼25% to 30%.^4-7 

The authors wanted to create a novel platform for the therapy of PTCL, rather than just adding another agent to the standard CHOP backbone. Based on a preclinical model of PTCL, the combination of pralatrexate and romidepsin was found to be synergistic. This resulted in the described trial of a standard 3 + 3 dose escalation phase 1 study of the 2 agents evaluating the best schedule and pharmacokinetic profile with acceptable toxicity. Although the majority of patients did have relapsed PTCL (n = 18), other subtypes of non-Hodgkin lymphomas were eligible for the study (29 total patients enrolled). The recommended phase 2 dose was determined to be pralatrexate 25 mg/m² and romidepsin 12 mg/m² every 14 days on a 28-day cycle. Among the evaluable patients, 10/14 (71%) of PTCL patients achieved a response and 4/14 (29%) had a complete response. However, the median duration of response was only 4.3 months.¹ 

What are the lessons learned from this study? Because the 2 agents in this study have demonstrated almost exclusively activity in PTCL and not B-cell lymphomas, limiting the trial to relapsed/refractory PTCL patient may have enhanced the ability to evaluate a larger number of PTCL patients with this novel combination. The second lesson is that well-designed studies based on animal model systems and synergy are beneficial when setting up a prospective clinical trial. The 2 agents in this trial, pralatrexate and romidepsin, were predicted to have a high response rate in PTCL and, indeed, they demonstrated this in the trial. However, animal model information should not be used in isolation because the models do not always accurately predict clinical responses or toxicity issues in patients. We must also incorporate tumor genomic profiling information to subset the broad categories of PTCL. This will assist physicians who treat lymphoma patients to formulate a hypothesis for agents used in clinical trials with specific subtypes of PTCL. For example, through profiling, at least 2 subtypes of PTCL-not otherwise specified have been identified: the GATA 3 and TBX21 subtypes.⁸  Possible targeting of the phosphatidylinositol 3-kinase and mTOR pathways in the GATA3 subtype vs targeting of the NF-κB and STAT pathways in the TBX21 subtypes needs to be tested in clinical trials. Finally, if rationally designed novel doublet or triplet combinations are found to be successful for relapsed PTCL, should we consider them as a new backbone for front-line treatment of high-risk PTCL patients instead of the standard CHOP backbone therapies? With such poor outcomes for standard therapy in high-risk PTCL patients, clinical trials of a novel combination with a new backbone should be offered on clinical trials with correlative studies to learn from every patient. Because PTCL is a rare lymphoma, we should encourage enrollment of as many patients as possible with PTCL on clinical trials to improve our knowledge base for all future PTCL patients.