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Page 10 of 20 Ma et al. J Cancer Metastasis Treat 2022;8:25 https://dx.doi.org/10.20517/2394-4722.2022.17

Forodesine
Purine nucleoside phosphorylase (PNP) seems important in T-cell biology, and forodesine is a novel oral
[80]
PNP inhibitor that has been approved in Japan for the treatment of R/R PTCL . Of 41 evaluable patients,
the ORR was 25% (CR 10%). Given the mechanism of action, the AEs were expected with grade 3/4
lymphopenia (96%), leukopenia (42%), neutropenia (35%), and thrombocytopenia (25%). Five patients (3
with AITL, 2 with PTCL NOS) developed secondary B-cell lymphomas. The drug has not been approved
elsewhere.

Mogamulizumab
Mogamulizumab is an antibody that targets C-C chemokine receptor 4 (CCR4) and was approved in Japan
for R/R PTCL with CCR4 expression (mostly ATLL) almost a decade ago. In order to study other ATLL
patient populations, a phase II international study was conducted in 22 centers to compare mogamulizumab
and investigator’s choice (IC): pralatrexate, gemcitabine plus oxaliplatin (GemOx), or dexamethasone,
cisplatin, and cytarabine (DHAP) . The ORR was 11% (CR 2%) in the mogamulizumab arm compared to
[81]
0% in the IC arm. Though treatment was well tolerated, mogamulizumab did not improve outcomes for this
difficult-to-treat group of patients. In addition, caution must be taken if mogamulizumab is given to
patients prior to allogeneic stem cell transplant because there is an increased risk of graft-versus-host-
disease (GVHD)-related mortality, which is normally tempered by CCR4-expressing Tregs that would be
inhibited by the drug .
[82]
Chidamide
In China, chidamide, another HDAC inhibitor, was approved for the treatment of R/R PTCL patients in
[71]
2014 based on the trial that produced an ORR of 29% with a median DOR of 10 months . There are many
clinical trials studying chidamide-based combinations in the treatment of Chinese patients with PTCL.

Investigational novel agents
Given the need for more efficacious treatments in this difficult group of diseases, there are many new
targeted agents being studied as single agents. Below we discuss data from investigational novel agents as
single agents and summarize ongoing studies in Table 2.

Azacytidine
The serendipitous discovery of the effectiveness of azacytidine in the treatment of AITL began with the
treatment of 2 patients with both AITL and chronic myelomonocytic leukemia who achieved CR [83,84] . Due
to recurrent mutations in the epigenetic machinery in AITL and PTCL TFH, azacytidine is a logical choice
[85]
of therapy and is associated with an ORR of 9/12 (75%) with 6/12 achieving CR . All patients had a TET2
mutation, and some had additional mutations in DNMT3A, IDH2, and RHOA. The median PFS and OS
were 15 months and 21 months, respectively. Since then, there have been many clinical studies testing
azacytidine in combinations to treat patients with untreated and R/R PTCL.

Phosphatidylinositol 3-kinase (PI3K) inhibitors
Duvelisib, a dual PI3K-δ,γ inhibitor, has been studied in patients with R/R PTCL (NCT03372057) with
treatment limited by low CD4 counts . Various doses were studied, but the patients enrolled in the
[86]
expansion phase received oral duvelisib 75 mg twice daily for 2 cycles, followed by 25 mg twice daily until
disease progression or toxicity . The ORR in 78 evaluable patients in the expansion phase was 50%
[87]
(CR 32%) with a median DOR of 233 days. The most common grade 3 or 4 adverse events included
neutropenia (38.5%), ALT and AST elevation (24.4%, 21.8%, respectively) . Of note, 3 deaths from
[87]
pneumonitis, Epstein-Barr associated lymphoproliferative disorder, and sepsis occurred on trial, possibly
due to treatment. Due to the risk of infections, trial investigators recommend antiviral prophylaxis to be