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Page 6 of 20 Ma et al. J Cancer Metastasis Treat 2022;8:25 https://dx.doi.org/10.20517/2394-4722.2022.17

progression-free survival (PFS) was 48.2 months and 20.8 months after a median follow-up of 36.2 months
in the Bv-CHP and CHOP arms, respectively. The median OS was not reached for either group, but the
hazard ratio was 0.66 (95%CI: 0.46-0.95), P = 0.0244. The ORR and CR rate for the Bv-CHOP and CHOP
arms were 83% and 68% vs. 72% and 56%, respectively. Both groups had similar rates of adverse events (AE),
grade 3 or higher AE, and serious AE. This is now the standard of care in patients with CD30-positive
PTCL, though the trial was enriched for ALCL and not sufficiently powered for other subtypes. The 5-year
update demonstrated that after a median follow-up of 47.6 months, the median PFS was 62.3 months vs.
22.8 months and median OS was not reached vs. 54 months in the Bv-CHP and CHOP arms,
respectively . A multicenter study is now recruiting to study Bv-CHP in patients with untreated PTCL
[54]
with less than 10% CD30 expression (NCT04569032).

Does adding a novel agent to CHOP-like regimens improve outcomes?
Save the addition of brentuximab vedotin in CD30-positive PTCL, the treatment for PTCL has not shared
the same advancement of B-cell lymphomas with the addition of the CD20 monoclonal antibody rituximab
despite many recent attempts to add additional targeted agents FDA-approved in the relapsed or refractory
[55]
(R/R) setting to the CHOP-backbone in the past 5 years .

Pralatrexate plus CHOP-like Combinations
Pralatrexate was the first drug approved for patients with relapsed or refractory PTCL. It is a folate analog
that binds the reduced folate carrier (RFC), leading to the inhibition of dihydrofolate reductase (DHFR)
[56]
intracellularly . PROPEL was an international single-arm Phase 2 study conducted in patients with R/R
PTCL that led to the US FDA approval in 2009 . Following cyclophosphamide, etoposide, vincristine, and
[57]
prednisone (COEP) on day 1 of each cycle, pralatrexate was added on days 15, 22, and 29 in a phase 2 study
to treat 33 patients with untreated PTCL . The ORR was 70% (CR 50%). After a median follow-up of 21.5
[58]
months, the estimated 2-year PFS and OS were 64% and 80%, respectively. Common grade 3 or 4 AE
included anemia (27%), febrile neutropenia (18%), and mucositis (18%). This combination did not
demonstrate improvement in outcomes seen with CHOP and was not deemed a regimen that warranted
additional exploration by the authors.

The sequential addition of pralatrexate followed by COEP did not improve outcomes compared to CHOP,
so the folate analog metabolic inhibitor was added to CHOP (Fol-CHOP) in a phase I study
(NCT02594267) . The study was completed in October 2020, but the results are not readily available at the
[5]
time of writing this manuscript.

Romidepsin plus CHOP (Ro-CHOP)
It has been a decade since romidepsin, a histone deacetylase (HDAC) inhibitor, was approved in some
countries based on the phase II study in patients with R/R PTCL by Coiffier et al. [59-61] . The phase III Ro-
CHOP study (NCT01796002) comparing CHOP with CHOP plus romidepsin in patients with untreated
PTCL, excluding ALK-positive ALCL, was a highly anticipated trial. Unfortunately, the clinical trial revealed
that the addition of romidepsin did not improve ORR, PFS, or OS compared to CHOP alone . After a
[4]
median follow up of almost 28 months, the study failed to meet its primary endpoint with a median PFS of
12.0 months compared to 10.2 months in the Ro-CHOP and CHOP groups, respectively. The hazard ratio
[4]
of 0.81 was not significant (P = 0.096) . The secondary endpoints of overall response rate (ORR) and OS
were also not statistically different, but the addition of HDAC inhibitor, however, was associated with more
treatment-emergent adverse events related to cytopenias and gastrointestinal side effects. This led to the
withdrawal of romidepsin’s PTCL indication in August 2021, though appeals are pending.