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The study began in 2015, was completed in 2020, and is pending analysis and publication of the results. Two
phase II frontline studies investigate the safety and efficacy of adding chidamide, an HDAC inhibitor, or
apatinib, a multitargeted kinase inhibitor, to CHOP in China (NCT03268889 and NCT03631862,
respectively). Table 1 summarizes completed and ongoing trials studying CHOP-like regimens with and
without targeted therapies.

THE MANY NEW DRUGS COMING ALONG IN PTCL
Approved agents
About 70% of patients with PTCL treated with chemotherapy eventually will relapse or have refractory
disease, and these patients have particularly poor outcomes. The British Columbia Cancer Agency
Lymphoid Cancer found that patients with PTCL who relapse or are refractory to first-line therapy had a
short median PFS of 3.1 months and median OS of 5.5 months . Over the past decade, the FDA approved
[67]
pralatrexate in the United States in 2009, romidepsin for PTCL in the United States in 2011,
mogamulizumab for ATLL in Japan in 2012, belinostat in the United States in 2014, brentuximab vedotin in
CD30-positive ALCL and mycosis fungoides in the United States in 2014, chidamide in China in 2014 based
on registration trials [57,59,68-71] . Treatment with novel agents in the relapsed and refractory setting is associated
[7,8]
with improved survival compared to additional, less efficacious chemotherapy . In August 2021,
romidepsin was withdrawn from the indication, despite the efficacy of novel combinations. Over the past 5
years, pralatrexate has been approved in Japan and China, romidepsin, forodesine, and mogamulizumab
were approved for the treatment of R/R PTCL in Japan, and numerous other targeted agents have been
studied worldwide.

Pralatrexate
As previously mentioned, pralatrexate was the first novel agent approved in the treatment of R/R PTCL in
[57]
2009 based on the results from the phase 2 registration PROPEL study . The ORR in these patients was
29%, and treatment was associated with a median duration of response (DOR) of 12.4 months . In the past
[57]
5 years, pralatrexate has been studied around the world and has obtained additional FDA approvals in Asia.
In two phase II registration studies in Japan and China, pralatrexate was studied in R/R PTCL, resulting in
ORRs of 45%-52% (CR 9%-10%) in patients from both cohorts [72,73] . The most common AEs included
mucositis (68%-88%), thrombocytopenia (37%-68%), and liver function test abnormalities (41%-64%).
Almost half of the patients (48%-49%) developed serious AEs, including febrile neutropenia and
pneumonia. A study in Taiwan using pralatrexate in R/R PTCL is also ongoing (NCT03150602).
Pralatrexate remains an important option in the treatment of these patients with R/R PTCL.

Romidepsin
Romidepsin was studied in patients with R/R T-cell lymphomas with ORR ranging from 25% to 34%,
leading to its approval in R/R CTCL in 2009 and R/R PTCL in 2011 [59,74,75] . More recently, the HDAC
inhibitor has been studied in 40 Japanese patients with R/R PTCL, leading to FDA approval in Japan .
[76]
There were no unexpected AEs, and the most common grade 3 or higher AEs included lymphopenia (74%),
neutropenia (54%), leukopenia (46%), and thrombocytopenia (38%). The ORR was 43% with 23% of patients
achieving a CR, which is better than previous cohorts. In patients with the rarer subtype, extranodal
NK/T-cell lymphoma (ENKTCL), however, treatment with romidepsin is associated with reactivation of
EBV infection, likely due to changes in histone acetylation of genes that normally play a role in viral
repression . Phosphodiesterase inhibitors have been shown to prevent romidepsin-induced EBV
[77]
reactivation in preclinical studies that may lead to future studies . As mentioned above, however,
[78]
romidepsin was unexpectedly withdrawn from the PTCL indication after the highly anticipated phase 3 Ro-
CHOP trial failed to meet its primary endpoint, though combination studies are ongoing.