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Tenalisib and Romidepsin
Tenalisib, a selective PI3K and SIK3 inhibitor, was studied in combination with romidepsin in 33 patients
[106]
with R/R T-cell lymphomas . In the phase 1/2 trial, there were no dose-limiting toxicities, but the most
frequent grade 3 or 4 treatment-emergent adverse events included thrombocytopenia (21%), ALT elevation
(18%), and neutropenia (15%). The ORR was 63% in 27 evaluable patients (CR 26%), and 3 out of 6 PTCL
[106]
patients who achieved a CR were bridged to transplant .

Immune Checkpoint Inhibitors Combined with Epigenetic Modifiers
To improve on the results of the doublets: romidepsin plus azacytidine and romidepsin plus pralatrexate,
[107]
two innovative trials are combining immune checkpoint inhibitors with epigenetic modifiers . In the
phase 1 EMBOLDEN trial, pembrolizumab, an anti-PD1 monoclonal antibody, is combined with decitabine
and/or pralatrexate and has resulted in an ORR of 2/13 (CR 1/13). Durvalumab in different combinations
with pralatrexate, azacytidine, and romidepsin in the phase I/IIa DURABILITY trial has promising results
with an ORR of 3/5 (CR 3/5). These trials are ongoing and actively enrolling patients (NCT03240211,
NCT03161223).

CHIMERIC ANTIGEN RECEPTOR (CAR) T CELL THERAPY
CAR T cell therapy has been approved for B-cell malignancies and is currently in development for T-cell
malignancies. Due to the genetic engineering of T-cells to target neoplastic T-cells, several considerations
have arisen, such as T-cell aplasia, fratricide, and the contamination of modified T-cells with neoplastic T-
[108]
cells that can lead to resistance . Targets have included CD4, CD5, CD7, CD30, and TCR beta chain-1
(TRBC1) have progressed to clinical trials as summarized in Table 4. Results in patients are limited. LB1901
is a CAR T cell therapy targeting CD4, for example, has resulted in low CD4 T-cell counts, leading to a
clinical hold . A phase I trial using autologous CD5 CAR T-cells to bridge 9 patients with R/R T-cell
[109]
malignancies to allogeneic transplant resulted in ORR of 44% without T-cell aplasia . CD30-targeted CAR
[110]
T cell therapies have been studied in ALCL where of 2 patients treated, 1 had a CR and 1 died of
[111]
progression . This is a promising modality for treating patients with R/R disease.
CONCLUSION
The future of PTCL care could look like a precision oncology-based approach where the biology of the
disease is targeted for optimal efficacy and limited side effects. Combination chemotherapy has been the
default standard of care, but the minority of patients are cured and there are lasting side effects that may
impact quality of life. Rather than categorizing patients with PTCL, the future may focus on subtypes to
make more appropriate application of clinical trials rather than extrapolating to all patients, even when rarer
subtypes are not represented. Patients with ATLL have a range of outcomes based on the subtype of disease,
but more treatments need to be developed for the aggressive acute and lymphomatous types. HDAC
inhibitors are approved for R/R PTCL but can be associated with hyperprogression in ATLL, highlighting
that caution is needed when generalizing clinical trials. Historically, patients with ALCL are associated with
better outcomes and CD30-targeted therapy have improved outcome, but more options are needed in those
who relapse. Given the enrichment of epigenetic dysregulation as pathogenesis, AITL and TFH are
associated with better outcomes when treated with hypomethylating agents and HDAC inhibitors, and there
are ongoing trials around the world that are building on the success of these doublets. Patients with
ENKTCL have aggressive disease that have found success with immunotherapy in the R/R setting, which
can be a different story for patients with nodal PTCL. Nivolumab may be associated with hyperprogression
as a single agent, and yet, it has also been found to be efficacious when combined with other drugs, both
chemotherapy and targeted agents. CAR T cell therapy offers another modality of treating patients with R/R
disease but is still early in development.