Hui-Qiang Huang MD, Zheng
Yan MD
Sun Yat-Sen University Cancer Center, SYSUCC
Guangzhou, China
 |
| Hui-Qiang Huang, MD PhD Professor |
Peripheral T-cell lymphoma (PTCL)
incidence in Asia is significantly higher than that in European and American continents.
Due to the large population, the
number of patients in China is enormous, so the progress
of T-cell lymphoma treatment always draws the attentions of Chinese
Hematologist/Oncologists.
Compared with B cell lymphoma, overall, the progress of T-cell lymphoma treatment is relatively slower,
but with a
number of novel
drugs are under investigation, and breakthrough progresses have been made on
individual subtypes.
Chemotherapy
Status quo, Stagnant
Currently the first-line chemotherapy regimens recommended by the National Comprehensive Cancer Network (NCCN) guidelines for PTCL came from
the treatment experience of B-cell lymphoma,
including
cyclophosphamide + doxorubicin + vincristine +
prednisone (CHOP); CHOP + etoposide (CHOEP); adjusted cyclophosphamide + vincristine + doxorubicin + dexamethasone, alternating with methotrexate plus cytarabine (HyperCVAD/MA); dose adjusted etoposide + prednisone +
vincristine + cyclophosphamide + doxorubicin
(EPOCH) etc., but no evidence shows which regimen is superior to the others.
There is research suggested that CHOP + etoposide can benefit young patient with ALK (+) anaplastic
large cell lymphoma (ALCL) [1],
but no consensus has reached yet.
Bendamustine
and gemcitabine showed some, but yet unsatisfactory activity, in the treatment of relapsed/refractory (R/R) PTCL[2].
CHOP or CHOP-like regimen is still the most commonly used regimen in practice.
According to the perspective study of International T-cell Lymphoma Project in 1000 patients with PTCL,
the 5-year overall survival (OS) rate was 44% (presented by Massimo
Federico on the 2015 T-cell Lymphoma Forum).
According to various reports, ALK (+)ALCL has the best prognosis, with 5-year OS rates ranging from 60%
to 80%; the prognosis of ALK (-) ALCL is slightly inferior, with 5-year OS rates of 35% ~ 50%; the 5-year OS rates
of PTCL - NOS) and Angioimmunoblastic
T-cell lymphoma (AITL) are 20% ~ 40%; Gastrointestinal and hepatosplenic T-cell lymphoma have the
worst prognosis, with median OSs of a few months[2-16]
.
Small sample size, nonrandomized studies showed that hematopoietic
stem cell transplant (HSCT) can benefit patients with PTCL, especially as first-line
treatment in fit young patients, with 5-years OS rates of 45% ~ 80% in selective patients[17-19, 16, 15].
Autologous
HSCT could be considered as first-line consolidation treatment for fit young
patients, and allogeneic or autologous HSCT is a choice for patients with relapsed
disease.
Asparaginase, a game changer
The treatment outcomes
of NK/T-cell lymphoma (NKTCL) were very poor in the past. However, due to the
introduction of asparaginase-containing chemotherapy and the optimization
of radiotherapy, the situation has
been significantly changed in recent years.
Methotrexate + ifosfamide
+ L-asparaginase + etoposide (SMILE) and
L-asparaginase + methotrexate + dexamethasone (AspaMetDex) are the current
guidelines recommended regimens[20], both of which have strong toxicity
and inconvenience for administration. Therefore, various other asparaginase-containing
regimens are used in practice, all of which demonstrated favorable efficacy.
P-Gemox Promising
P-Gemox regimen (pegaspargase + gemcitabine + oxaliplatin
) introduced by Sun Yat-Sen University Cancer Center (Guangzhou, China) showed
very impressive activity in the treatment of NKTCL. When it is combined with
radiotherapy, the 4-year OS rate of early stage patients is up to 90%; when
combined with autologous HSCT, the survival rate of patients with advanced or R/R
disease can reach 60% (unpublished data).
All in all, asparaginase-based
chemotherapies have significantly improved the outcomes of patients with NKTCL.
Currently, a phase III clinical trial of P-Gemox on NKTCL is under way(NCT02085655).
New chemotherapy agent
Pralatrexate
Pralatrexate, a novel folic acid antagonist, can selectively accumulate in tumor
cells to block the synthesis of purines and pyrimidines.
In the pivotal PROPEL study in R/R PTCL patients, the complete remission (CR) rate and
objective response rate (ORR) were 11% and 29%, respectively; the median progression-free survival (PFS) and OS were 3.5 and
14.5 months, respectively[21]. Also see below:
Table 1. Pralatrexate clinical trial data
CR
|
ORR
|
mPFS
(m)
|
mOS
(m)
|
|
Pralatrexate
|
11%
|
29%
|
3.5
|
14.5
|
The U.S. food and drug administration (FDA) has approved
pralatrexate. Pralatrexate + romidepsin in preclinical studies and animal
models have shown strong synergy, and this combination is currently in a phase I study [22].
In another trial, pralatrexate + low-dose bexarotene were used in
the treatment of 14 cases of R/R mycosis fungoides. The combination was well tolerated and 7 cases responded. It seems that pralatrexate in combination was better
than monotherapy[23].
Histone Deacetylase Inhibitors (HDACi)
Romidepsin and belinostat
HDACi for PTCL has
been the "hot spot" in recent years.
Romidepsin and belinostat have been approved for R/R PTCL in the US.
In three romidepsin
monotherapy for R/R PTCL trials, the CR rates were 15% -22%, ORRs were 22%
-38%, median OS in one of the trials was 11.3 months[24].
In a recent phase Ib/II trial, romidepsin was combined with CHOP
for 37 patients with newly diagnosed PTCL. The median PFS was 21.3 months and 3-year
OS rate was 70.7% (presented by Bertrand Coiffier on the 2015 T-cell Lymphoma Forum).
In a phase Ⅱ trial, belinostat was
used to treat 129 patients with R/R PTCL, the CR rate and ORR were 10% and 26%,
respectively, and the median response duration was 8.3 months[2]. Also see below in table.
Table 2. HDACi clinical trials data in US
CR
|
ORR
|
mOS
(m)
|
mPFS
(m)
|
3-year
OS
|
|
Romidepsin
|
15-22%
|
22-38%
|
11.3 (1
trial)
|
||
Romidepsin+CHOP
|
21.3
|
70.7%
|
|||
Belinostat
|
10%
|
26%
|
8.3
|
As HDACi,
belinostat and romidepsin can enhance tumor-suppressor gene transcription, but
their mechanism of action may not limit to this.
HDACi made in China
Chidamide is a
novel HDACi made in China. In the pivotal phase IIb trial, 83 patients
with R/R PTCL were enrolled, in which 79 cases were eligible for evaluation. The CR
rate and ORR were 14% and 28%, respectively. The median OS was 43 months (presented
by Shi Yuankai on the 2015 T-cell Lymphoma Forum). Also see blow in table 3.
It's main end point
ORR is comparable to pralatrexate and romidepsin, yet its safety and tolerability
seem better than those of the two drugs. The main side effect is manageable hematologic
toxicity.
Chidamide is
already available in China at present, and finished phase I trial in the US. Trials
in Japan and Taiwan are also ongoing.
Table 3. Chidamide clinical trial data
Patients
No.
|
CR
|
ORR
|
mOS
(m)
|
|
Chidamide
|
83 (79
eligible for evaluation)
|
14%
|
28%
|
21.4
|
Immunotherapy
Monoclonal antibodies(MoAbs) Mogamulizumab CCR4 MoAbs
Mogamulizumab is chemokine receptor 4 (CCR4) monoclonal antibody, which exerts
anticancer effect through antibody dependent cellular toxicity (ADCC).
The results of two
studies with mogamulizumab in patients with relapsed CCR4 positive PTCL are
showed in the table below.
Table 4. Mogamulizumab
monotherapy clinical trial data
Trial
|
CR
|
ORR
|
mOS
(m)
|
mPFS (m)
|
8/26
|
50%
|
13.7
|
5.2
|
|
14%
|
35%
|
3
|
In a randomized
phase II study of mogamulizumab in combination
with (group A) or without (group B) VCAP-AMP-VEC
for
newly diagnosed CCR4 positive adult T-cell leukemia/lymphoma (ATLL) patients, 29
and 24 patients were randomized into the group A and B,
respectively. Both the CR rate and ORR were better in the mogamulizumab group
(Table 5), suggesting that mogamulizumab may be used in combination with
cytotoxic drug as first-line treatment for patients with ATLL[27].
Table 5. Mogamulizumab
combination therapy clinical trial data
Group
|
Patients
No.
|
CR
|
ORR
|
Mogamulizumab + VCAP-AMP-VECP (A)
|
29
|
52%
|
86%
|
VCAP-AMP-VECP (B)
|
24
|
33%
|
75%
|
VCAP: vincristine +
cyclophosphamide + Doxorubicin + prednisone;
AMP: Doxorubicin + Ranimustine + prednisone; VECP: vincristine + etoposide + prednisone + cyclophosphamide
In Europe, mogamulizumab was used to treat 38 patients with R/R PTCL
in a randomized phase I/II trial, the ORR and stable disease (SD) were 11% and
34%, respectively[28].
Antibody drug conjugate
Brentuximab vedotin
consists of the chimeric monoclonal antibody brentuximab (which targets the
cell-membrane protein CD30) linked to the antimitotic agent monomethyl
auristatin E (MMAE). CD30 is a cell surface marker of HL and systemic anaplastic
large cell lymphoma (sALCL).
Previous studies
confirmed the significant activity of brentuximab vedotin in R/R HL. According to
a 2013 ASH report, the CR rate was as high as 75%. The drug has been approved in
the US, European Union and Canada.
Brentuximab vedotin in sALCL
At ASH 2014, the results
of pivotal phase II clinical trial with brentuximab vedotin were presented. Fifty-eight
patients with R/R sALCL were enrolled, with
86% patients responded to treatment, and the CR rate was 59%. Data shown in
table below (presented by Barbara on the 2014 ASH).
Table 6. Brentuximab vedotin in sALCL clinical trial data
CR
|
ORR
|
mPFS
(m)
|
mOS
(m)
|
4-y
OS
|
|
Brentuximab
vedotin newly treated
|
59%
|
86%
|
20
|
55.1
|
64%
|
In this trial, 19 (50%)
of the 38 CR cases remained complete
remission, and the median PFS and OS were not reached, at the last time
follow-up. The median OS and PFS were not reached either in the 16 CR cases who
underwent HSCT. In the 22 CR cases who did not undergo HSCT, the median PFS was
39.4 months and median OS was not reached.
Based on the prominent
outcomes, the US FDA and European drug
administration (EMA) have approved brentuximab vedotin for the treatment of
R/R sALCL.
Most impressively, the
4-years OS rate in this study was as high as 64%, suggesting that brentuximab
vedotin can result in long-term remission in sALCL, so the value of brentuximab
vedotin in front-line treatment warrants investigation.
Brentuximab vedotin in PTCL, Impressive
In a phase II
trial, 34 cases of PTCL was treated with brentuximab vedotin, with a ORR of
41%, median PFS of 2.6 months[29].
In a recent phase II
trial in 32 cases with mycosis fungoides /Sézary syndrome (MF/SS), the ORR
and 1-year PFS rates were 70% and 54% respectively, indicating that brentuximab
vedotin possibly act on tumor microenvironment (presented by Kim Y. on the 2015
T-cell Lymphoma Forum).
In another phase I trial,
brentuximab vedotin was combined with cyclophosphamide + doxorubicin +
prednisone (CHP) as first-line treatment in 26 patients with PTCL. The CR rate and ORR were 88% and 100%
respectively; the 2-years OS and PFS rates were 80% and 54%, respectively[30].
Table 7. Brentuximab vedotin combination regimen in PTCL clinical trial data
CR
|
ORR
|
2-year PFS
|
2-year OS
|
|
Brentuximab vedotin + CHP
|
88%
|
100%
|
54%
|
80%
|
Other Immunotherapy on the horizon
Alemtuzumab is anti-CD52 monoclonal antibody. In two small
sample size phase II trials with alemtuzumab treatment in PTCL, the ORR were
36% and 60%, respectively[31, 32]. Alemtuzumab in
combination with DHAP regimen (dexamethasone + cytarabine + cisplatin) in 24
patients with R/R PTCL. Half of the patients responded, including 5 CRs. However,
79% of the patients experienced grade III/IV leukopenia[33].
Anti-PD-1/PD-L1 antibodies
showed remarkable efficacy in a variety of tumors, and currently a trial with anti-PD-L1
antibody in the treatment of MF/SS is underway (presented by Holbrook Kohrt on
the 2015 T-cell Lymphoma Forum).
CD4 is a cell membrane
protein of T lymphocyte. However, the activity of anti-CD4 antibody in the
treatment of PTCL is somewhat disappointing. In a phase II trial, 21 R/R PTCL
patients were treated with zanolimumab (a CD4 monoclonal antibody). The ORR and
CR rate were 10% and 24% respectively[34].
Small molecule kinase inhibitor
ALK fusion gene blocker
Crizotinib is a small
molecule kinase inhibitors targeting ALK fusion gene. Italian researchers studied
crizotinib in the treatment of 11 cases with R/R ALK (+) non-hodgkin’s lymphoma
(NHL). As a result, 10 patients (90.9%) achieved ORR, in which 9 cases (100%) with
ALCL achieved CR and one case (50%) with DLBCL achieved partial response (PR). The
ALK fusion genes became negative in the CR patients, indicating that molecular
remissions were achieved. The 2-year PFS and OS rates were 63.7% and 72.7%
respectively[35].
Table 8. Crizotinib clincal trial data in ALK(+) NHL
ORR (NHL)
|
CR (ALCL)
|
PR (DLBCL)
|
2-year
PFS (NHL)
|
2-year
OS(NHL)
|
|
Crizotinib
|
10/11
|
9/9
|
1/2
|
63.7%
|
72.7%
|
Aurora A Kinase inhibitor
Alisertib is a aurora A kinase inhibitor. In a phase Ⅱ trial in the
treatment of 48 patients with R/R NHL (including 8
cases of PTCL), the overall ORR was 27%,
and the
ORR in PTCL patients was 50%[36].
A phase III clinical trial of alisertib vs. investigator’s
choice in the treatment of R/R PTCL is currently ongoing[37]. Preclinical study also showed that
alisertib and romidepsin has synergistic effect against
PTCL (presented
by Michelle A. Fanale on the 2015 T-cell Lymphoma Forum).
Farnesyltransferase inhibitor
Tipifarnib is a farnesyltransferase inhibitor. In a phase
II study treating 8 patients with R/R PTCL, 3 patients achieved CR and one
achieved PR[38].
Other drugs on the Horizon
Table 9. Other drugs on the horizon for PCTL
Drug
|
Target
|
Patient
|
ORR
|
mPFS
(m)
|
Immunity
and tumor microenvironment
|
R/R
PTCL, 3 phase II trials
|
22-30%
|
||
CD25
(IL-2 receptor)
|
R/R
PTCL, 27 cases
|
47%
(overall);
62%
(CD25 +);
46%
(CD25 -)
|
6
|
|
Newly diagnosed PTCL, 49 cases
|
63%
|
12
|
||
NF-κB
|
R/R
PTCL/CTCL, 15 cases, 12 cases assessable
|
67%
|
-
|
|
Selinexor (presented by Sharon
Shacham on the 2015 T-cell Lymphoma Forum)
|
XPO1 (a
nuclear output
protein)
|
R/R PTCL, 7 cases
|
2/7
|
-
|
In addition, PI3K inhibitors, anti-KIR3DL2
antibody, and organic arsenic agent darinaparsin are under investigation.
Summary
In newly diagnosed
PTCL, except ALK (+) ALCL and early stage NKTCL, the prognosis is
unsatisfactory; in R/R PTCL, except CD30 (+) or ALK (+) ALCL, the prognosis is very
poor.
Therefore, clinical
trials are strongly recommended for patients with poor prognosis subtypes and
relapse/refractory disease.
Similar with solid tumors, the efficacy of
cytotoxic drugs have limited room for improvement.
The future is more likely rely on targeted drugs.
In the targeted drugs available, except brentuximab
vedotin which specifically targets CD30, and crizotinib which targets
ALK fusion
gene have prominent antitumor activity, other targeted drugs are barely satisfactory.
In the near future,
we need to discover more targets and develop more targeted drugs for the
treatment of PTCL. On the other side, the combination of more than one targeted
drugs or targeted drugs in combination with cytotoxic drugs also warrant
investigation.
References:
20 National
Comprehensive Cancer Network (NCCN). The NCCN Clinical Practice Guidelines in
Oncology (NCCN Guidelines®): Non-Hodgkin's Lymphomas (version 1.2015).
Available at: http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed
January 11, 2015.
27 Ishida
T, Jo T, Takemoto S et al. Dose-intensified chemotherapy alone
or in combination with mogamulizumab in newly diagnosed aggressive adult T-cell
leukaemia-lymphoma: a randomized phase II study. British journal
of haematology. 2015.
