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Page 2 of 20 Ma et al. J Cancer Metastasis Treat 2022;8:25 https://dx.doi.org/10.20517/2394-4722.2022.17

such a wide range in subtypes, clinical manifestations, and response to therapies, clinical trials are often
limited by small numbers and lack of representation for the whole spectrum of disease. Adding to the
complexity, prevalence also varies geographically, suggesting both genetic and environmental factors. In
North America, the most frequent subtypes are PTCL not otherwise specified (NOS), angioimmunoblastic
T-cell lymphoma (AITL), and ALK-positive anaplastic large cell lymphoma (ALCL), at 34%, 16%, and 16%,
[2]
respectively . In Europe, the most diagnosed subtypes are PTCL NOS, AITL, and ALK-negative ALCL,
making up 34%, 29%, and 9% of the cases, respectively . In Asia, however, the most common subtypes are
[3]
adult T-cell leukemia/lymphoma (ATLL), PTCL NOS, and NK/T-cell lymphoma (NKTCL) at 25%, 22%,
and 22% of PTCL cases, respectively . With the exception of ALK-positive ALCL, the PTCL carry a poor
[3]
prognosis with the 5-year overall survival (OS) ranging from 14% in ATLL, 20% for enteropathy-type, 32%
for AITL and PTCL NOS, to 59% in ALK-negative ALCL and 70% in ALK-positive ALCL .
[3]
The poor outcomes are broadly related to intrinsic chemo-resistance, with at least 15%-20% of cases that are
primary refractory to frontline treatment and short progression-free survival (PFS) in patients who do
initially respond. Based on the very disappointing results of standard chemotherapy in the majority of PTCL
subtypes, excluding ALK-positive ALCL, it should not come as a surprise that one additional novel agent
combined with the chemotherapy backbone has often yielded disappointing results . In addition,
[4-6]
retrospective data have demonstrated that patients who received novel drugs had improved outcomes when
[7,8]
compared to those who were never treated with targeted agents , further suggesting that combinations of
novel agents could yield the future treatment for patients with PTCL. In this review, based on the intrinsic
characteristics of these diseases, we present the merits of shifting to a chemotherapy-free paradigm.

THE MOLECULAR DRIVERS OF PTCL
In T-cell lymphomagenesis, the molecular pathways are poorly understood given the wide array of clinical
and biologic presentations associated with so many subtypes, but despite these challenges, it has been
possible to identify some recurring themes. We describe below the more prominent genetic and epigenetic
aberrations described in PTCL NOS and AITL.

Mutation in epigenetic factors
Epigenetics refer to clonal changes in the pattern of gene expression without alterations in the primary
genetic sequence. Over the last 10 years, it has become evident that PTCL are characterized by gross
epigenetic dysregulation. The first suggestion that epigenetic pathways were relevant in the pathogenesis of
PTCL comes from the clinic, where PTCL exhibit a consistent sensitivity to the histone deacetylase
inhibitors (HDAC). PTCL are in fact the only malignant disease for which we have 4 HDAC inhibitors
approved as monotherapy around the world. Only about thirty percent of patients can expect a response to
HDAC inhibitors, but the duration of response that patients may experience is indeed remarkable. For
example, cutaneous T-cell lymphomas (CTCL), for which HDAC inhibitors were first approved, are
diseases currently being redefined and reclassified based on their genetic, epigenetic, and transcriptional
changes landscape [9,10] .

The epigenetic machinery is responsible for maintaining the adaptative transcriptional memory of normal
T-cells, and this improves the efficiency of T-helper subsets to transcribe inducible genes when needed [11,12] .
Dysregulation of epigenetic modulation likely contributes to the progression of normal T-cells in the
development of PTCL, especially with recurrent reports of mutations in genes involved in methylation,
acetylation, and other epigenetic functions [13-16] . These mutations may lead to hypomethylation across the
genome to silence tumor suppressor genes, especially in specific subtypes including AITL and PTCL with
T-follicular helper (TFH) phenotype, which may be targeted with novel treatment paradigms.