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170
RESEARCH ARTICLE
©Copyright 2022 by Turkish Society of Hematology
Turkish Journal of Hematology, Published by Galenos Publishing House
Turk J Hematol 2022;39:170-177
Received/Geliş tarihi: February 8, 2022
Accepted/Kabul tarihi: June 6, 2022
Address for Correspondence/Yazışma Adresi: Ömür Kayıkçı, M.D., Memorial Bahçelievler Hospital, Clinic of
Hematology, İstanbul, Turkey
E-mail : omursunuz@yahoo.com ORCID: orcid.org/0000-0002-9216-2802
Non-kutanöz Periferik T-hücreli Lenfomalarda Klinik Özellikler ve Tedavi Sonuçlarına ilişkin
Gerçek Yaşam Deneyimi:Türk Hematoloji Araştırma ve Eğitim Grubunun Çok Merkezli
Çalışması
Ömür Kayıkçı1, Özgür Mehtap2, İsmail Sarı3, Fatih Demirkan4, Cengiz Beyan5, Güven Çetin6, Filiz Vural7,
Mehmet Yılmaz8, Erman Öztürk9, Seval Akpınar10, Bülent Eser11, Mehmet Gündüz12, Yahya Büyükaşık13,
Bahriye Payzın14, Rahşan Yıldırım15, Mehmet Hilmi Doğu16, Atilla Özkan17, Engin Kelkitli18, Emre Tekgündüz1
1Memorial Bahçelievler Hospital, Clinic of Hematology, İstanbul, Turkey
2Kocaeli University Faculty of Medicine, Department of Hematology, Kocaeli, Turkey
3Memorial Ataşehir Hospital, Clinic of Hematology, İstanbul, Turkey
4Dokuz Eylül University Faculty of Medicine, Division of Hematology, İzmir, Turkey
5Ufuk University Faculty of Medicine, Division of Hematology, Ankara, Turkey
6Bezmialem Vakıf University Faculty of Medicine, Department of Hematology, İstanbul, Turkey
7Ege University Faculty of Medicine, Department of Hematology, İzmir, Turkey
8Sanko University Faculty of Medicine, Department of Hematology, Gaziantep, Turkey
9Medeniyet University Training and Research Hospital, Clinic of Hematology, İstanbul, Turkey
10Namık Kemal University Faculty of Medicine, Department of Hematology, Tekirdağ, Turkey
11Medical Park Hospital, Clinic of Hematology, İstanbul, Turkey
12Biruni University Hospital, Clinic of Hematology, İstanbul, Turkey
13Hacettepe University Faculty of Medicine, Department of Hematology, Ankara, Turkey
14İzmir Katip Çelebi University Atatürk Training and Research Hospital, Clinic of Hematology, İzmir, Turkey
15İstinye University Faculty of Medicine, Department of Hematology, İstanbul, Turkey
16Liv Hospital, Clinic of Hematology, İstanbul, Turkey
17Yeditepe University Hospital, Clinic of Hematology, İstanbul, Turkey
18Ondokuz Mayıs University Faculty of Medicine, Department of Hematology, Samsun, Turkey
Real-Life Experience Regarding Clinical Characteristics and
Treatment Outcome in Non-Cutaneous Peripheral T-Cell
Lymphomas: A Multicenter Study of the Turkish Hematology
Research and Education Group (ThREG)
DOI: 10.4274/tjh.galenos.2022.2022.0052
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Turk J Hematol 2022;39:170-177 Kayıkçı Ö. et al: PTCL Experience in Turkey
Introduction
Peripheral T-cell lymphomas (PTCLs) are an uncommon and quite
heterogeneous group of disorders, representing only 10%-15%
of all non-Hodgkin lymphomas (NHLs). The relatively common
subtypes are peripheral T-cell lymphoma not otherwise specified
(PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITCL),
anaplastic large cell lymphoma (ALCL) either with or without
the expression of the anaplastic lymphoma kinase (ALK), and
enteropathy-associated T-cell lymphoma (EATL) [1].
Although anthracycline-containing CHOP/CHOP-like chemotherapy
regimens have been regarded as standard first-line therapies,
the prognosis of patients with PTCLs is generally poor compared
with that of patients with B-cell NHLs. In a previous registration
study from British Columbia, the 5-year overall survival
(OS) rate for patients with PTCL-NOS treated primarily with
CHOP/CHOP-like regimens was only 35% [2]. In addition, the
median OS and progression-free survival (PFS) rates of patients
who did not undergo autologous hematopoietic cell
transplantation (auto-HCT) after relapse were 5.5 and 3.1,
months, respectively [3].
Apart from some subtypes, PTCLs are aggressive in nature with
rapid disease progression and poor response to treatment.
Molecular studies over the last few years have greatly contributed
to our understanding of the pathogenesis of PTCLs. Some of
these new molecular findings have been added to the revised
edition of the World Health Organization (WHO) classification
of 2016 as they refine both classification and diagnostic criteria
[4].
Although both molecular and clinical studies have been
increasing in recent years, we still have little knowledge
concerning real-life practice with PTCLs. In this study, we
aimed to investigate the clinical characteristics and treatment
outcomes of a large population-based cohort of systemic non-
cutaneous PTCL patients.
Materials and Methods
We conducted a multicenter retrospective analysis of
190 patients consecutively diagnosed and treated with
non-cutaneous PTCLs between 2008 and 2016, who had at
least the minimal required essential data in their medical
records. A tissue biopsy was performed for all patients for
diagnostic purposes; all cases were pathologically confirmed
by pathologists and classified in accordance with the 2008
WHO classification of hematological malignancies. At the
time of diagnosis, the staging workup included medical/
Objective: Peripheral T-cell lymphomas (PTCLs) are an uncommon and
quite heterogeneous group of disorders, representing only 10%-15%
of all non-Hodgkin lymphomas. Although both molecular and clinical
studies have increased in recent years, we still have little knowledge
regarding real-life practice with PTCLs. In this study, we aimed to
investigate the clinical characteristics and treatment outcomes of a
large population-based cohort of patients presenting with systemic
non-cutaneous PTCL.
Materials and Methods: We conducted a multicenter retrospective
analysis of 190 patients consecutively diagnosed and treated with
non-cutaneous PTCLs between 2008 and 2016.
Results: Considering all first-line treatment combinations, the overall
response rate was 65.9% with 49.4% complete remission (n=81) and
16.5% partial response (n=27). The 5-year overall survival and event-
free survival rates were significantly different between the transplant
and non-transplant groups (p<0.01, and p=0.033, respectively).
Conclusion: The retrospective analysis of a large volume of real-life
data on the Turkish experience regarding non-cutaneous PTCL patients
showed consistent results compared to other unselected PTCL cohorts
with some minor differences in terms of survival and transplantation
outcomes. The long-term outcome of patients who receive autologous
hematopoietic cell transplantation as part of upfront consolidation or
salvage therapy is favorable compared to patients who are unable to
receive high-dose therapy.
Keywords: Lymphomas, Autologous stem cell transplantation, T-cell
lymphomas, Non-Hodgkin lymphoma
Amaç: Periferik T-hücreli lenfomalar (PTHL) nadir görülen, oldukça
heterojen bir grup hastalıktır ve tüm non-Hodgkin lenfomaların
sadece %10-15’ini oluşturur. Son yıllarda hem moleküler hem de
klinik çalışmalar artmış olsa da PTHL’ler üzerindeki gerçek yaşam
verileri hakkında hala çok az bilgiye sahibiz. Bu çalışmada, sistemik,
kutanöz olmayan PTHL hastaları içeren geniş popülasyon tabanlı hasta
grubunun klinik özellikleri ve tedavi sonuçlarını araştırmayı amaçladık.
Gereç ve Yöntemler: 2008 ve 2016 yılları arasında kutanöz olmayan
PTHL tanısı ile tedavi edilen 190 ardışık hastanın geriye dönük analizini
gerçekleştirdik.
Bulgular: Tüm birinci basamak tedavi kombinasyonları dikkate
alındığında, genel yanıt oranı; tam remisyon (n=81) %49,4 ve kısmi
yanıt (n=27) %16,5 olmak üzere %65,9 saptandı. Beş yıllık genel ve
olaysız sağkalım oranları, transplant ve transplant olmayan gruplar
arasında önemli ölçüde farklıydı (sırasıyla, p<0,01 ve p=0,033).
Sonuç: Kutanöz olmayan PTHL hastalarıyla ilgili geniş geriye dönük
gerçek yaşam veri analizini kapsayan Türkiye deneyimi, sağkalım
ve transplantasyon sonuçları açısından bazı küçük farklar içerse de
seçilmemiş diğer PTHL serileriyle benzer sonuçlar göstermiştir. Planlı
veya kurtarma tedavisinin bir parçası olarak otolog hematopoietik
hücre transplantasyonu olan hastaların uzun dönem sonuçları, yüksek
doz tedavi almayan hastalara kıyasla daha iyiydi.
Anahtar Sözcükler: Lenfomalar, Otolog kök hücre nakli, T-hücreli
Lenfomalar, Non-Hodgkin lenfoma
Öz
Abstract
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Turk J Hematol 2022;39:170-177
Kayıkçı Ö. et al: PTCL Experience in Turkey
family history, physical examination, complete blood count,
liver function tests, renal profile, and computed tomography
(CT) or fluorodeoxyglucose-positron emission tomography/CT
(FDG-PET/CT) scans of the neck, chest, abdomen, and pelvis.
Bone marrow biopsy was performed for all patients. The Ann
Arbor Staging System was used for staging. Bulky disease was
considered when lymph nodes were 10 cm or more in size, or
when the mediastinal mass occupied more than one-third of
the chest diameter on imaging studies. Results were analyzed in
terms of the clinical characteristics and laboratory parameters
at diagnosis and response to different treatment regimens. All
patients started on treatment were evaluated for response and
outcome.
The study was conducted according to 1964 Declaration of
Helsinki. All patients gave written informed consent at the time
of hospital admission and before any diagnostic evaluation,
invasive procedures, or chemotherapy in line with the standard
policies of the participating centers.
Statistical Analysis
Data were collected regarding patients’ age at diagnosis, date
of diagnosis, histopathology findings, stage, International
Prognostic Index (IPI) score, details regarding response to
first-line therapy, duration of response, last follow-up, and
date of death. Due to the retrospective design of the study,
we were unable to acquire all relevant information regarding
the management of patients throughout the course of the
disease. Data regarding response to second and further lines
of chemotherapy and indications for auto-HCT were not
available for analysis. Responses were evaluated and reported
by the treating physician. Complete response was defined as
the resolution of clinically apparent lymphadenopathy and
radiographic complete response was established using CT
and/or FDG-PET/CT. PFS was defined as the time from initiation
of therapy to the time of documented progression, death, or
last follow-up. Descriptive statistics were used for baseline
patient characteristics. OS was calculated from the date of the
start of treatment to the date of death or loss to follow-up.
Kaplan-Meier analysis was performed using SPSS 19 (IBM Corp.,
Armonk, NY, USA) and statistical significance was verified using
the log-rank test. Values of p<0.05 were accepted as statistically
significant.
Results
Patients and Disease Characteristics
The patient characteristics of our cohort are detailed in Table
1. A total of 190 patients were enrolled and analyzed within
the study period. The group of patients included 63 women
and 127 men whose median age at the initiation of therapy
was 54.0 (19-79) years. According to the WHO classification,
PTCL-NOS was the most common histological subtype (43.2%),
followed by ALCL (32.1%). According to Ann Arbor staging,
most of the patients (69.8%) had advanced-stage disease (III-
IV). On the other hand, most patients had good performance
status with 83.4% having Eastern Cooperative Oncology Group
performance status of ≤2, but half of the patients had high-
intermediate/high-risk disease according to IPI scores.
Treatment Regimens, Responses, and Outcomes
Treatment regimens and patient responses are summarized in
Table 2. The majority of patients (n: 168; 92.3%) were treated
Table 1. Patient characteristics.
Characteristics Number (%)
Age, years (n: 190)
Median (range) 54.0 (19-79)
Sex (n: 190)
Female 63 (33.2)
Male 127 (66.8)
Diagnosis (n: 190)
PTCL-NOS 82 (43.2)
ALK+ ALCL 19 (10.0)
ALK- ALCL 42 (22.1)
AITCL 24 (12.6)
Extranodal NK/T-cell lymphoma, nasal type 15 (7.9)
Enteropathy-associated T-cell lymphoma 5 (2.6)
Others 3 (1.6)
Ann Arbor staging (n: 182)
119 (10.4)
236 (19.8)
351 (28.0)
4 76 (41.8)
ECOG performance status (n: 163)
037 (22.7)
160 (36.8)
239 (23.9)
320 (12.3)
4 7 (4.3)
IPI (n: 151)
Low 40 (26.5)
Low-intermediate 38 (25.2)
High-intermediate 36 (23.8)
High 37 (24.5)
Bulky disease (n: 180)
Absent 163 (90.6)
Present 17 (9.4)
PTCL-NOS: Peripheral T-cell lymphoma not otherwise specified; ALK: anaplastic
lymphoma kinase; ALCL: anaplastic large cell lymphoma; ECOG: Eastern Cooperative
Oncology Group; IPI: International Prognostic Index.
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with CHOP or CHOP-like regimens as initial therapy. Fifty-five
patients underwent consolidation with upfront auto-HCT after
the first achievement of CR. Fourteen patients (7.7%) were
treated with other types of chemotherapy regimens. Of these
patients, 9, 3, 1, and 1 received hyper-CVAD, SMILE, DEVIC, and
DHAP regimens, respectively. Data regarding treatment lines
of the study cohort were available for 182 patients. At the
time of study entry, 98 (53.9%), 48 (26.4%), 17 (9.3%), and 19
(10.4%) patients had received first-line, second-line, third-line,
and fourth-line therapy or beyond, respectively. The median
follow-up of the surviving patients was 13.3 (1-91) months.
Considering all first-line treatment combinations, the overall
response rate (ORR) was 65.9% with 49.4% complete remission
(CR) (n=81) and 16.5% partial response (PR) (n=27). Median PFS
and median OS were 6.7 and 28.8 months, respectively (Figure
1). The type of first-line chemotherapy did not have any impact
on OS (p=0.207). We also analyzed the effect of induction
regimens in terms of intensity. The OS of patients who received
CHOP, intensive therapies (EPOCH, DHAP, SMILE, hyper-CVAD),
or others (patients who received neither CHOP nor any other
type of intensive regimen) were similar (p=0.35).
Median PFS and OS data for each histological subtype are
detailed in Table 3. There was no statistically significant
difference among histological subtypes of PTCLs regarding PFS
(p=0.551) and OS (p=0.241) regardless of whether we treated
ALK+ and ALK- ALCL as one entity (ALCL) or evaluated them
separately (data not shown) (Figure 2).
Fifty-seven (30%) patients proceeded to transplantation either
as upfront consolidation (n=51) or after the first CR (n=6). Due
to the limited number of patients who received auto-HCT as
salvage therapy, we treated all patients who underwent auto-
HCT as a uniform group. The median PFS (8.9 vs. 5.8 months;
p=0.033) and OS (48.6 vs. 18.1 months; p<0.01) rates were
Table 2. Treatment regimens and response to treatment.
First-line treatment regimens (n: 182) Number (%)
CHOP-like regimens 168 (92.3)
CHOP 127 (69.8)
CHOEP 23 (12.6)
CVP 7 (3.8)
COEP 7 (3.8)
EPOCH 4 (2.2)
Others 14 (7.7)
Hyper-CVAD 9 (5.0)
SMILE 3 (1.7)
DEVIC 1 (0.5)
DHAP 1 (0.5)
Response to treatment (n: 164)
CR 81 (49.4)
PR 27 (14.8)
SD 16 (9.8)
PD 40 (24.4)
Auto-HCT (n: 190)
Yes 57 (30.0)
PTCL-NOS 29
ALK+ ALCL 1
ALK- ALCL 10
AITCL 9
Extranodal NK/T-cell lymphoma 6
Enteropathy-associated T-cell lymphoma 1
Other 1
No 133 (70.0)
CR: Complete remission; PR: partial remission; SD: stable disease; PD: progressive
disease; Auto-HCT: autologous hematopoietic cell transplantation; PTCL-NOS:
peripheral T-cell lymphoma not otherwise specified; ALK: anaplastic lymphoma kinase;
ALCL: anaplastic large cell lymphoma; AITCL: angioimmunoblastic T-cell lymphoma.
Figure 1. Five-year progression-free survival (PFS) and overall survival (OS) rates for all patients.
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Kayıkçı Ö. et al: PTCL Experience in Turkey
significantly superior in patients who underwent auto-HCT
compared to patients who did not (Figure 3). The favorable
impact of auto-HCT on survival outcomes was independent of
risk factors at the time of diagnosis such as Ann Arbor stage,
performance status, or extranodal disease (data not shown).
Bulky disease (p<0.001) and high IPI score (p<0.001) were
significantly associated with poor OS, but the presence of B
symptoms at the time of diagnosis did not have any impact on
OS (p=0.614).
Figure 2. Five-year progression-free survival (PFS) and overall survival (OS) rates according to histological subtypes.
ALCL: Anaplastic large cell lymphoma; PTCL-NOS: peripheral T-cell lymphoma not otherwise specified.
Table 3. Median overall survival and progression-free survival according to histological subtypes.
Histologic subtype Median OS (95% CI)
(months) Log-rank test p Median PFS (95% CI)
(months) Log-rank test p
ALCL Not reached
0.241
6.9 (3.9-9.9)
0.551
PTCL-NOS 32.6 (22.0-43.3) 6.6 (5.2-8.0)
Other 22 (14.3-29.7) 5.9 (3.7-8.1)
OS: Overall survival; CI: confidence interval; PFS: progression-free survival; ALCL: anaplastic large cell lymphoma; PTCL-NOS: peripheral T-cell lymphoma not otherwise specified.
Figure 3. Five-year progression-free survival (PFS) and overall survival (OS) in the transplant and non-transplant groups.
Auto-HCT: Autologous hematopoietic cell transplantation.
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Discussion
PTCLs constitute an uncommon group of all lymphomas that
show distinct racial and epidemiological variations and are
generally associated with poor prognosis compared to their
B-cell counterparts. Molecular and clinical studies have
increased in recent years, leading to the development of new
targeted therapies. However, standard conventional therapies
such as CHOP and CHOP-like regimens are still used in first-
line protocols, and we have little knowledge about the clinical
characteristics and treatment results of PTCL patients who are
treated off-study [5]. Therefore, our report reflects the Turkish
experience regarding data about PTCLs in a homogeneous
population of Caucasian individuals in routine practice.
In our results concerning the particular PTCL histological
subtypes, the proportions of PTCL-NOS (43.2%) and ALCL
(32.1%) were much higher compared to the results of datasets
from the United States and Europe (Swedish, Danish, and Czech
data), possibly due to epidemiological diversity [6,7,8,9,10].
Although all samples were directly reviewed by experienced
hematopathologists in the centers participating in the present
study, the lack of central pathology review may have had an
impact on the diagnostic classification of the study cohort. There
is also the considerable limitation of immunohistochemical and
morphological T-lymphoproliferation diagnostics, and we should
bear in mind that the classification of PTCLs is an evolving field.
Recent studies have highlighted the importance of molecular
genetics and gene-expression profiling in the classification
and prognosis of PTCLs [11,12,13]. Two studies clearly showed
that the OS of ALK- ALCL patients with DUSP22 rearrangement
demonstrated by fluorescence in situ hybridization was similar
to that of ALK+ cases with 5-year OS being 85%-90% [12,13].
Therefore, it is quite possible that at least some of our patients
diagnosed with PTCL-NOS would be reclassified into other
subtypes by molecular signatures [10,11]. New insights into
the pathology of PTCLs will help improve the differentiation of
lymphoma subtypes [14].
According to published data, the present ORR (65.9%) and CR
(49.4%) rates and median OS (28.8 months) are similar for all
PTCL patients, while the median PFS (6.7 months) obtained
here is lower compared to the rates in other published series
[7,10,15,16]. This may be due to the high percentage of patients
with advanced stages and high-risk features, or it may be due
to the inability to clearly determine the molecular properties
that can influence the prognosis. The addition of etoposide to
CHOP (CHOEP) as first-line treatment is beneficial in younger
(<60 years) ALK+ ALCL patients, but the outcomes of patients
with ALK- ALCL, AITCL, and PTCL-NOS and higher IPI scores are
disappointing [17]. The poor PFS of the present study cohort
seems to be associated with the relatively limited number
(26.5%) of patients in the low-risk IPI group.
In our cohort, we also confirmed a higher proportion of
long-term survivors with ALCL compared to other PTCL subtypes.
Data from the Swedish Lymphoma Registry concerning 219
cases of ALCL revealed 5-year OS rates of 79% and 38% and
5-year PFS rates of 63% and 31% for ALK+ and ALK- cases,
respectively [8,18]. On the other hand, we could not clearly
determine the survival of ALCL+ and ALCL- patients due to the
small number of ALCL cases, which is a limitation of our study.
The benefits of auto-HCT as upfront consolidation in the
treatment of PTCLs are still being debated due to the relatively
limited number of randomized trials and the heterogeneity of
the disease. Prospective data indicate that long-term outcomes
of ALK+ ALCL patients who receive upfront auto-HCT are
encouraging, with 63% OS at 10 years compared to patients
with other PTCL subtypes (21%) [19]. Long-term results of the
NORDIC prospective study of previously untreated patients with
PTCLs who received CHOEP induction and upfront auto-HCT
as consolidation showed 41% OS at 10 years in the intent-to-
treat population [20,21]. Recent recommendations based on the
published results of non-randomized studies support the use of
first-line auto-HCT in patients with PTCLs, with the exception
of ALK+ ALCL [22,23]. Due to the retrospective design of this
study, we were unable to get information regarding indications
for auto-HCT and factors affecting post-transplant outcomes.
Therefore, we do not know why most of the patients did not
receive auto-HCT as upfront consolidation. Auto-HCT is also
an effective treatment modality as second-line consolidation,
especially for patients who achieve CR/PR with salvage
chemotherapy. The 5-year OS of PTCL patients who underwent
auto-HCT in the second-line setting was reported to be
40%-45% [24,25]. The incorporation of novel drugs including
but not limited to brentuximab vedotin, belinostat, and
romidepsin in the treatment armamentarium of PTCLs may
change the impact of auto-HCT on the long-term outcomes of
patients.
An international cohort study including 775 newly diagnosed
PTCL patients showed poor outcomes of patients with primary
refractory disease or short PFS (<24 months) after first-line
treatment. The prognosis of these patients was very poor with
only 5 months of median OS [25]. Although our study cohort
included PTCL patients at different stages of disease, 80.2% of
patients had received first- or second-line therapy at the time
of inclusion. A median PFS of 6.7 months and 48.3% of the
patients having high-risk IPI scores indicate that we included
relatively high-risk PTCL patients in our study cohort. Therefore,
we speculate that auto-HCT may overcome the poor prognosis
of high-risk PTCL patients.
Lack of central pathology review and a retrospective design are
the important limitations of this study. Another shortcoming
of the study is that our database did not capture relevant data
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Kayıkçı Ö. et al: PTCL Experience in Turkey
regarding salvage treatment regimens in cases of relapsed/
refractory disease and the impact of radiotherapy or novel agents
like brentuximab on outcome parameters. Although we included
190 patients, cases of the specific WHO-defined PTCL subtypes
were relatively limited. We were unaware of the motivations for
proceeding to auto-HCT on a case-by-case basis. The decision to
perform auto-HCT may be related to the treatment policy of the
center, patient preferences, contraindications to transplant, or
combinations thereof. On the other hand, we are aware that the
pathological subclassification of patients may change based on
the 2016 WHO classification instead of the older 2008 version.
Conclusion
Our retrospective real-life data analysis showed consistent
results compared to other unselected PTCL cohorts, with some
minor differences in terms of survival (PFS with first-line
treatment) and transplantation outcomes. A substantial problem
remains with the low efficacy of induction (CHOP or CHOP-
like) regimens for high-risk and advanced-stage PTCL patients.
Auto-HCT may overcome some poor prognostic markers of PTCL
like high-intermediate/high-risk IPI and short PFS. Prospective,
multinational, randomized trials are still warranted to improve
the treatment results of PTCL patients presenting with advanced
stages and high-risk features.
Ethics
Ethics Committee Approval: Memorial Hospital Ethics
Committee (date: 09.12.2021/decision no: 27).
Informed Consent:All patients gave written informed consent
at the time of hospital admission and before any diagnostic
evaluation, invasive procedures, or chemotherapy in line with
the standard policies of the participating centers.
Authorship Contributions
Concept: E.T., Ö.K., İ.S.; Design: E.T., Ö.K., İ.S.; Data Collection or
Processing: E.T., Ö.K., İ.S.; Analysis or Interpretation: E.T., Ö.K.,
İ.S.; Writing: E.T., Ö.K., İ.S.; Final Approval: Ö.K., Ö.M., İ.S., F.D.,
C.B., G.Ç., F.V., M.Y., E.Ö., S.A., B.E., M.G., Y.B., B.P., R.Y., M.H.D.,
A.Ö., E.K., E.T.
Conflict of Interest:No conflict of interest was declared by the
authors.
Financial Disclosure: The authors declared that this study
received no financial support.
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