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Romidepsin was also added to CHOEP but the trial was stopped because there was no improvement in the
[62]
primary endpoint of PFS .
Azacytidine and CHOP
Given the enrichment of mutations related to the epigenetic machinery in AITL and PTCL NOS TFH, an
oral hypomethylating agent (HMA), azacytidine was added to the CHOP backbone in a phase II study that
prioritized PTCL TFH subtypes (NCT03542266). At a median follow up of 21 months, the CR was 75%
overall (n = 20) and 88% in patients with TFH subtypes (n = 17) . The 2-year OS was 68% for the entire
[63]
cohort and 76% for TFH subtypes, with an estimated median PFS of 36 months . In addition, the TET2
[64]
mutations were associated with CR (P = 0.007), favorable PFS (P = 0.004), and OS (P = 0.015) in contrast to
DNMT3A mutations, which were associated with a worse PFS (P = 0.016) . The biomarker approach may
[63]
be a promising way to decide which patient gets the right treatment. Longer follow-up is needed to
determine the impact on survival.

A phase II cooperative group study is testing the addition of duvelisib or azacytidine to CHOP with or
without etoposide in patients with CD30-negative PTCL (NCT04803201).

Alemtuzumab plus CHOP
The phase 3 Act-2 trial added alemtuzumab (a monoclonal antibody targeting CD52) to CHOP in older
[64]
patients with untreated PTCL and also failed to demonstrate improvement compared to CHOP alone .
There was no statistically significant benefit in ORR, EFS, PFS, or OS, but there were higher rates of toxicity,
[64]
including grade 3 or higher infections (40% vs. 21%) . The planned sample sizes for elderly and younger
cohorts were not reached due to poor accrual.

Lenalidomide plus CHOP
Lenalidomide, an oral immune modulator that acts by inhibiting cereblon, was added to 8 cycles of CHOP
[65]
chemotherapy as frontline therapy to treat older patients with AITL in a phase 2 trial . Patients also
received 4 injections of intrathecal methotrexate during the study. The ORR was 56% (CR 41%), which was
not better than CHOP alone in historic controls (e.g., ECHELON-2 study) [6,65] . After a median follow-up of
45 months, the 2-year PFS and OS were 42% and 59%, respectively. The most common AE was neutropenia,
with 71% of patients developing grade 4 neutropenia. In addition, 23% developed grade 3 or 4 infections and
5% succumbed to grade 5 sepsis. The authors did not believe the results warranted the addition of
lenalidomide to CHOP in this subset of patients. Lenalidomide is being studied with CHOP-like therapies
in different populations, both with CHOP (NCT04922567) and CHOEP in the frontline setting
(NCT02561273) with results pending.

Nivolumab and EPOCH
A multicenter pilot study investigating nivolumab with EPOCH showed that 78% of 18 patients enrolled
developed immune related adverse events (irAEs), and 44% required discontinuation of nivolumab due to
irAEs . The trial protocol permitted patients to receive one cycle of chemotherapy prior to enrollment, and
[66]
interestingly, patients who received one cycle of EPOCH prior to the addition of nivolumab to subsequent
cycles did not experience dose-limiting irAEs. These data suggest pre-treatment with chemotherapy may
result in less toxicity. Of note, the ORR was 83% at the end of induction and 2 patients proceeded with a
consolidative autologous stem cell transplant .
[66]
Ongoing “CHOP-like plus” Trials
There are still many studies looking to add targeted agents to combination chemotherapy and results are
pending. In China, a phase 3 study comparing decitabine plus CHOP vs. CHOP is ongoing (NCT03553537).