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In R/R ENKTCL where there is high Programmed death ligand 1 (PDL1) expression (54% of cases),
however, pembrolizumab is associated with an ORR of 6/14 (43%) to 7/7 (100%) with 2/7 (29%) to 5/7 (71%)
achieving a CR [94-96] . Given the expression of PDL1 in ENKTCL, avelumab, an anti-PDL1 monoclonal
[97]
antibody, has been used in a phase 2 trial with R/R ENKTCL . Out of 21 patients, the ORR was 38% (CR
24%) with a median PFS of 2.7 months after a median follow-up of 15.7 months. In this patient population,
the trial was terminated because of lower response rate than expected. Avelumab is also being studied alone
in a phase 2 trial in R/R PTCL (NCT03046953) as well as in a phase 1 trial in combination with interleukin-
15 (NCT03905135).

Immunotherapy agents have been studied in combination to treat PTCL without cases of hyperprogression,
warranting further study as later discussed below.

Cerdulatinib
Spleen tyrosine kinase (SYK) and Janus kinase (JAK) are enzymes important in cellular processes and have
[98]
been found to be important in T-cell lymphomagenesis . Cerdulatinib is a SYK, JAK1, and JAK3 inhibitor
that is being studied in R/R lymphomas, including PTCL (NCT01994382). 65 patients with R/R PTCL were
treated with cerdulatinib in a phase 2 study, resulting in an ORR of 36.2% in 58 evaluable patients . Of
[98]
note, the AITL/TFH subtype had a higher ORR of 51.9% (CR 37%) with a median DOR of 12.9 months after
a median follow-up of 16.4 months. The most common treatment-emergent grade 3 or higher adverse
events were elevation in amylase (23%), anemia (20%), elevation in lipase (18.5%) as well as neutropenia
[58]
(12%) and sepsis (9.2%) . As we understand disease biology, we can better tailor treatments to optimize
efficacy while limiting side effects.

Alisertib
Alisertib is an aurora kinase inhibitor that was randomized against investigator’s choice of pralatrexate,
romidepsin, and gemcitabine in the phase III LUMIERE trial in patients with R/R PTCL . Surprisingly, the
[99]
ORR and CR rates achieved with alisertib compared to comparators were 33% and 18% vs. 45% and 27%,
respectively. The median PFS and OS did not differ significantly between the two groups.

Valemetostat
Given known epigenetic dysfunction found in PTCL, valemetostat, a selective inhibitor of enhancer of zeste
homolog 1 and 2 (EZH1/EZH2), has been studied in R/R PTCL patients [100,101] . EZH1 and EZH2 catalyze
methylation of histone 3 to downregulate gene expression, and dysregulation of the delicate balance of
[101]
tumor suppression and cell processes may lead to lymphomagenesis . Valemetostat is given orally once a
day until disease progression or toxicity, leading to an ORR of 48% . Longer follow-up is needed for these
[101]
ongoing studies.

NOVEL DRUG COMBINATIONS: COULD THEY FORM THE BASIS OF NEW TREATMENT
PLATFORMS?
The track record of adding targeted therapies to CHOP-based chemotherapy has so far mostly been
disappointing, and the field is looking to study novel combinations in the treatment of both untreated and
R/R PTCL. We discuss the combinations where data are available and list other ongoing trials with novel
combination in Table 3.

Azacytidine and Romidepsin
Preclinical data by Marchi et al. show that the combination of HDAC inhibitors and HMAs are synergistic
in modulating gene expression leading to the rationale development of this regimen in patients with
PTCL [102,103] . Twenty-three patients (10 untreated, 13 R/R) were evaluable in the phase 2 trial with oral