Combining Romidepsin and Pralatrexate in Relapsed/Refractory T-Cell Lymphoma: Are Two Drugs Better Than One?

In a phase I trial of patients with relapsed/refractory peripheral T-cell lymphoma (PTCL), combining romidepsin and pralatrexate – two agents approved by the U.S. Food and Drug Administration for this indication – led to an overall response rate (ORR) of 71 percent, doubling the ORR that had previously been seen with either agent alone.

“PTCL is a group of rare, heterogeneous malignancies with an aggressive course, characterized by relative insensitivity to conventional chemotherapy and an inferior prognosis, compared [with] their B-cell counterparts,” Jennifer E. Amengual, MD, from the Center for Lymphoid Malignancies and Hebert Irving Comprehensive Cancer Center at Columbia University Medical Center in New York, and colleagues explained in the report published in Blood. Adding agents or transplantation to CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) has led to “modest and marginal” improvements in survival, but by combining two new agents, the authors hoped to exploit the synergy observed in preclinical models of PTCL, without increasing toxicity.

This single-center, dose-escalation trial included 29 patients (median age = 54 years; range = 23-73 years) with previously treated PTCL. Patients were required to have an Eastern Cooperative Oncology Group performance status score of ≤2 and adequate organ and marrow function. People were ineligible for inclusion if they had central nervous system disease or lymphomatous meningitis or took concomitant CYP3A4 inhibitors.

Seven patients (24%) had B-cell lymphomas and 18 (62%) had T-cell lymphomas, while four (14%) had blastic plasmacytoid dendritic neoplasm or Hodgkin lymphoma.

The median number of prior systemic therapies was three (range = 1-16 therapies), including two patients (7%) who previously received pralatrexate.

Patients received pralatrexate (10-25 mg/m2) and romidepsin (12-14 mg/m2) on one of three dosing schedules:

  • days 1, 8, and 15 of a 28-day cycle (schedule A; n=11)
  • days 1 and 8 of a 21-day cycle (schedule B; n=15)
  • days 1 and 15 of a 28-day cycle (schedule C; n=3)

All 29 patients were evaluable for toxicity. Most adverse events (AEs) were grade 1 or 2, and included nausea (n=19; 66%), fatigue (n=15; 52%), anorexia (n=7; 24%), diarrhea (n=7; 24%), and fever (n=7; 24%). Grade 3 toxicities included anemia (n=7; 29%), oral mucositis (n=4; 14%), thrombocytopenia (n=4; 14%), and neutropenia (n=3; 10%).

Five grade 4 toxicities were observed: thrombocytopenia (n=4; 14%), neutropenia (n=3; 10%), sepsis (n=2; 7%), fever (n=1; 3%), and pneumonia (n=1; 3%).

“All patients recovered from AEs within one to two weeks of study drug administration,” according to the authors.

Across the different dosing levels and schedules, dose reductions were most commonly required to manage neutropenia, thrombocytopenia, and mucositis. “Both pralatrexate and romidepsin produce thrombocytopenia, which creates pause in thinking about how these drugs should be combined,” the researchers wrote. “Fortunately, the thrombocytopenia seen with these agents is short-lived and reversible.”

There were three dose-limiting toxicities (2 cases of grade 3 oral mucositis and 1 case of grade 4 sepsis), leading the authors to recommend pralatrexate 25 mg/m2 and romidepsin 12 mg/m2 on days one and 15 of a 21-day treatment cycle as the appropriate phase II dosing schedule.

Twenty-three patients were evaluable for response; six patients were excluded from the efficacy analysis because they experienced progressive disease during cycle one (n=5) or switched therapy in cycle one because of toxicity (n=1).

Thirteen patients responded to treatment (assessed using Lugano classification), for an ORR of 57 percent. Among the 14 patients with PTCL, ORR was 71 percent (n=10/14), including four complete responses and six partial responses.

Pharmacokinetic analyses (available in 27 patients) confirmed the synergistic activity observed in preclinical trials, with no difference in the effects of romidepsin against pralatrexate. However, patients receiving the higher doses of pralatrexate had a slightly higher concentration of romidepsin, suggesting that “the co-administration leads to an increase in the relative exposure of each drug compared to what has been seen by the single agents,” they wrote.

“The strategy of defining unique doublets active in PTCL, and leveraging the recent promising advances in experimental drug development, offers an opportunity to reconfigure the paradigm of care for patients in both the upfront and relapsed or refractory setting,” the researchers concluded.

This early-phase study is limited by its small patient population, single-center design, and lack of a comparator arm.

Celgene and Spectrum Pharmaceuticals provided funding for the study.

The authors report no financial conflicts.


Amengual JE, Lichtenstein R, Lue J, et al. A phase I study of romidepsin and pralatrexate reveals marked activity in relapsed and refractory T-cell lymphoma. Blood. 2017 November 15. [Epub ahead of print]