The prognosis for Peripheral T cell lymphomas (PTCL) remains poor in comparison to B cell
NHL. This is largely due to lower response rates and less durable responses to standard
combination chemotherapy regimens such as CHOP. Whether CDOP plus Chidamide can improve the
prognosis for PTCL.
Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of lymphoproliferative disorder
arising from mature T-cells of post-thymic origin. PTCL represent a relatively uncommon group
of hematologic malignancies within non-Hodgkin lymphomas (NHL), accounting for about 10% of
NHL cases. The prognosis for PTCL remains poor in comparison to B-cell NHL. This is largely
due to lower response rates and less durable responses to standard combination chemotherapy
regimens such as CHOP. Progress has been further hampered by the relative rarity and the
biological heterogeneity of the diseases. Among PTCL cases worldwide, the most common
subtypes include PTCL-not otherwise specified (PTCL-NOS; 26%), angioimmunoblastic T-cell
lymphoma (AITL; 18.5%), NK/T-cell lymphoma (10%), adult T-cell leukemia/lymphoma (ATLL; 10%),
ALK-positive anaplastic large cell lymphoma (ALCL; 7%) and ALK-negative ALCL (6%); subtypes
such as enteropathy-associated T-cell lymphoma (EATL; <5%) and primary cutaneous ALCL are
relatively rare (<2%) with ALCL more common than NK/T or ATLL in the United States.
PTCLs are less responsive to and have less frequent durable remissions with standard
chemotherapy regimens such as CHOP and thus carry a poorer prognosis compared to diffuse
large B-cell lymphomas. In prospective randomized studies, PTCLs have been included with
aggressive B-cell lymphomas. However, it has not been possible to assess the impact of
chemotherapy in this subgroup of patients with PTCLs due to small sample size. Only limited
data exist from randomized trials comparing the efficacy of chemotherapy regimens exclusively
in patients with PTCL.
CHOP chemotherapy is the most commonly used first-line regimen for patients with PTCL.
However, with the exception of ALK+ ALCL, outcomes are disappointing compared to the
favorable results achieved with DLBCL. Chemotherapy regimens that are more intensive than
CHOP have not shown any significant improvement in OS in patients with PTCL, with the
exception of ALCL.
CHOP chemotherapy is frequently curative in only the small number of patients with favorable
prognostic features. As previously discussed, retrospective analysis from the International
T-cell Lymphoma Project showed that anthracycline-based chemotherapy did not favorably impact
survival in patients with the most common forms of PTCLs, namely PTCL-NOS and AITL. In a
retrospective study conducted by the British Columbia cancer agency, the 5-year OS rate for
patients with PTCL-NOS primarily treated with CHOP or CHOP-like regimens was only 35%; among
these patients, the 5-year OS rates were higher in patients with low-risk IPI scores compared
with those with high-risk IPI scores (64% vs. 22%, respectively). In addition, patients with
ALK-positive ALCL had superior clinical outcome compared to those with ALK-negative ALCL
(5-year OS 58% vs. 34%, respectively). The addition of etoposide to CHOP (CHOEP regimen)
compared with CHOP alone was evaluated in a randomized study by the German High-grade NHL
Study Group (DSHNHL). In relatively young patients with favorable prognosis aggressive NHL
(age ≤60 years; normal LDH levels), the CHOEP regimen resulted in significantly higher CR
rate (88% vs. 79%; P=0.003) and 5-year EFS rate (69% vs. 58%; P=0.004). No difference was
observed in OS outcomes between the regimens. It should also be noted that in this study, the
majority of patients had B-cell histology, with only 14% diagnosed with T-cell NHL (with 12%
of patients having ALCL, PTCL-NOS, or AITL histology).36 In an analysis of a large cohort of
patients with PTCL treated within the DSHNHL trials, patients with ALK- positive ALCL had
favorable outcomes with CHOP or CHOP with etoposide (CHOEP). Three-year EFS and OS rates were
76% and 90%, respectively, for patients with ALK-positive ALCL. The corresponding outcomes
were 50% and 67.5%, respectively, for AITL, 46% and 62%, respectively, for ALK-negative ALCL
and 41% and 54%, respectively, for PTCL-NOS. Among those with T-cell lymphoma, CHOEP was
associated with a trend for improved EFS among relatively young patients (age <60 years) and
is an option for these patients. CHOP-21 appeared to be the standard regimen for patients age
>60 years, given that the addition of etoposide did not provide an advantage in these older
patients due to increased toxicity. Among patients with ALK-negative ALCL, AITL and PTCL-NOS,
those with low-risk IPI scores (IPI <1) had a relatively favorable prognosis; contrastingly,
patients with higher risk IPI scores derived minimal benefit from CHOP or CHOEP.
Histone deacetylases (HDACs) are involved in the remodeling of chromatin and play a key role
in the epigenetic regulation of gene expression. HDACs act as transcription repressors by
removing acetyl groups from the e-amino- terminus of lysine residues within histones to
promote tighter winding of DNA around histone proteins. Elevated expression or activity of
HDACs is implicated in the development and progression of cancer. Inhibition of HDAC enzymes
results in increased histone acetylation, thereby inducing an open chromatin conformation and
transcription of previously dormant genes. At least 18 human HDACs have been identified and
are grouped into four classes. HDAC enzymes class I (HDAC1, 2, 3, and 8), class II (HDAC4, 5,
7, and 9 as IIa, and HDAC6 and 10 as IIb), and class IV (HDAC11) utilize a zinc-catalyzed
mechanism for deacetylation of histones and non-histone proteins, whereas class III (SIRT
1-7) HDACs are NAD+ dependent deacetylase enzymes. Although the precise biological functions
of individual HDACs are still largely unknown, the importance of HDAC enzymes in the
malignant phenotype has been most closely associated with Class I HDACs 1-3. In addition,
Class IIb HDACs 6 and 10 have been found to play a role in the expression and stability of
tumor angiogenesis gene products.
The synthesis of small-molecule HDAC inhibitors (HDACi) has been an active focus in the field
of anticancer drug discovery in recent years. Several different chemical classes of HDACi
have been described, including hydroxamic acids, carboxylic or short-chain fatty acids,
cyclic peptides, and benzamides. Examples of each of these classes have entered clinical
development as antitumor agents. Among them, the hydroxamic acid vorinostat (SAHA) and cyclic
peptide romidepsin (FK-228) were approved in the United States for the treatment of cutaneous
T-cell lymphoma, and very recently, romidepsin for peripheral T-cell lymphoma.
chidamide (CS055/HBI-8000), a new member of the benzamide class of HDACi. Chidamide inhibits
HDAC1, 2, 3, and 10 in the low nanomolar concentration range with broad spectrum antitumor
activity in vitro and in vivo. Mechanism studies have demonstrated that chidamide stimulates
human immune cell-mediated tumor cell killing activity with increased expression of genes and
proteins involved in natural killer (NK) cell functions.
Chidamide was found to be a low nanomolar inhibitor of HDAC1, 2, 3, and 10, the HDAC isotypes
well documented to be associated with the malignant phenotype. Significant and broad spectrum
in vitro and in vivo anti- tumor activity, including a wide therapeutic index, was observed.
Chidamide was also shown to enhance the cytotoxic effect of human peripheral mononuclear
cells ex vivo on K562 target cells, accompanied by the upregulation of proteins involved in
NK cell functions. Furthermore, the expression of a number of genes involved in immune cell-
mediated antitumor activity was observed to be upregulated in peripheral white blood cells
from two T-cell lymphoma patients who responded to chidamide administration.
- Patients aged over 18 years are eligible.
- Patients must be diagnosed of de love peripheral T cell lymphoma (include PTCL not
otherwise specified, angioimmunoblastic T cell lymphoma, ALK negative anapestic large
cell lymphoma and enteropathy-associated T cell lymphoma). Patients must be
- ECOG PS of 0, 1, 2 at screening.
- Serum biochemical values with the following limit: - creatine </= 2.0 mg/dl, - total
bilirubin </= 2.0mg/dl, - transaminases (SG PT) </= 3X ULN
- Ability to understand an provide signed informed consent.
- Presence of active systemic infection.
- Any coexisting medical condition that in the judgment of the treating physician is
likely to interfere with study procedures or results.
- Nursing women, women of childbearing potential with positive urine pregnancy test, or
women of childbearing potential who are not willing to maintain adequate contraception
(such as birth control pills, IUD, diaphragm, abstinence, or condoms by their partner)
over the entire course of the study.
- Patients whom the investigators considered were not applicable.