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Gleeson, M, Peckitt, C, To, YM et al. (25 more authors) (2018) CHOP versus GEM-P in
previously untreated patients with peripheral T-cell lymphoma (CHEMO-T): a phase 2,
multicentre, randomised, open-label trial. Lancet Haematol, 5 (5). e190-e200.
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www.thelancet.com/haematology Vol 5 May 2018
e190
Articles
CHOP versus GEM-P in previously untreated patients with
peripheral T-cell lymphoma (CHEMO-T): a phase 2,
multicentre, randomised, open-label trial
Mary Gleeson, Clare Peckitt, Ye Mong To, Laurice Edwards, Jacqueline Oates, Andrew Wotherspoon, Ayoma D Attygalle, Imene Zerizer,
Bhupinder Sharma, Sue Chua, Ruwaida Begum, Ian Chau, Peter Johnson, Kirit M Ardeshna, Eliza A Hawkes, Marian P Macheta, Graham P Collins,
John Radford, Adam Forbes, Alistair Hart, Silvia Montoto, Pamela McKay, Kim Benstead, Nicholas Morley, Nagesh Kalakonda, Yasmin Hasan,
Deborah Turner, David Cunningham
Summary
Background Outcomes with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) or CHOP-like
chemotherapy in peripheral T-cell lymphoma are poor. We investigated whether the regimen of gemcitabine, cisplatin,
and methylprednisolone (GEM-P) was superior to CHOP as front-line therapy in previously untreated patients.
Methods We did a phase 2, parallel-group, multicentre, open-label randomised trial in 47 hospitals: 46 in the UK and
one in Australia. Participants were patients aged 18 years and older with bulky (tumour mass diameter >10 cm) stage I
to stage IV disease (WHO performance status 0–3), previously untreated peripheral T-cell lymphoma not otherwise
specified, angioimmunoblastic T-cell lymphoma, anaplastic lymphoma kinase-negative anaplastic large cell
lymphoma, enteropathy-associated T-cell lymphoma, or hepatosplenic γδ T-cell lymphoma. We randomly assigned
patients (1:1) stratified by subtype of peripheral T-cell lymphoma and international prognostic index to either CHOP
(intravenous cyclophosphamide 750 mg/m², doxorubicin 50 mg/m², and vincristine 1·4 mg/m² [maximum 2 mg] on
day 1, and oral prednisolone 100 mg on days 1–5) every 21 days for six cycles; or GEM-P (intravenous gemcitabine
1000 mg/m² on days 1, 8, and 15, cisplatin 100 mg/m² on day 15, and oral or intravenous methylprednisolone 1000 mg
on days 1–5) every 28 days for four cycles. The primary endpoint was the proportion of patients with a CT-based
complete response or unconfirmed complete response on completion of study chemotherapy, to detect a 20%
superiority of GEM-P compared with CHOP, assessed in all patients who received at least one cycle of treatment and
had an end-of-treatment CT scan or reported clinical progression as the reason for stopping trial treatment. Safety
was assessed in all patients who received at least one dose of study medication. This trial is registered with
ClinicalTrials.gov (NCT01719835) and the European Clinical Trials Database (EudraCT 2011-004146-18).
Findings Between June 18, 2012, and Nov 16, 2016, we randomly assigned 87 patients to treatment, 43 to CHOP and
44 to GEM-P. A planned unmasked review of ecacy data by the independent data monitoring committee in
November, 2016, showed that the number of patients with a confirmed or unconfirmed complete response with
GEM-P was non-significantly inferior compared with CHOP and the trial was closed early. At a median follow-up of
27·4 months (IQR 16·6–38·4), 23 patients (62%) of 37 assessable patients assigned to CHOP had achieved a complete
response or unconfirmed complete response compared with 17 (46%) of 37 assigned to GEM-P (odds ratio 0·52, 95%
CI 0·21–1·31; p=0·164). The most common adverse events of grade 3 or worse in both groups were neutropenia
(17 [40%] with CHOP and nine [20%] with GEM-P), thrombocytopenia (4 [10%] with CHOP and 13 [30%] with GEM-P,
and febrile neutropenia (12 [29%] with CHOP and 3 [7%] with GEM-P). Two patients (5%) died during the study, both
in the GEM-P group, from lung infections.
Interpretation The number of patients with a complete response or unconfirmed complete response did not dier
between the groups, indicating that GEM-P was not superior for this outcome. CHOP should therefore remain the
reference regimen for previously untreated peripheral T-cell lymphoma.
Funding Bloodwise and the UK National Institute of Health Research.
Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.
Introduction
Peripheral T-cell lymphoma is a rare and heterogeneous
subgroup of non-Hodgkin lymphomas, and comprises
approximately 10% of all non-Hodgkin lymphomas in
Europe and America.1 Randomised prospective trials in
patients with peripheral T-cell lymphoma are scarce and
hence there is no consensus on the optimal chemotherapy
for previously untreated patients, although combination
chemotherapy with cyclo- phosphamide, doxorubicin,
vincristine, and prednisolone (CHOP) is widely used, with
consolidative autologous stem-cell transplantation
considered in eligible patients. However, for most patients,
Lancet Haematol 2018;
5: e190–200
See Comment page e182
The Royal Marsden NHS
Foundation Trust, London and
Surrey, UK (M Gleeson FRCPath,
C Peckitt MSc, Y M To BSc,
L Edwards BSc, J Oates,
A Wotherspoon FRCPath,
A D Attygalle FRCPath,
I Zerizer MSc, B Sharma FRCR,
S Chua FRCR, R Begum BSc,
I Chau MD,
D Cunningham FMedSci); Cancer
Research UK Centre, University
of Southampton,
Southampton, UK
(Prof P Johnson FRCP);
University College Hospital
London, London, UK
(K M Ardeshna FRCPath); Olivia
Newton John Cancer Research
Institute, Austin Health,
Melbourne, VA, Australia
(E A Hawkes FRACP); Eastern
Health, Melbourne, VA,
Australia (E A Hawkes);
Blackpool Teaching Hospitals,
Blackpool, UK
(M P Macheta FRCPath); Oxford
Cancer and Haematology
Centre, Churchill Hospital,
Oxford, UK (G P Collins DPhil);
University of Manchester and
the Christie NHS Foundation
Trust, Manchester Academic
Health Science Centre,
Manchester, UK
(Prof J Radford MD); Royal
Cornwall Hospital, Truro, UK
(A Forbes FRCPath);
New Victoria Hospital,
Glasgow, UK (A Hart FRCPath);
St Bartholomew’s Hospital,
London, UK (S Montoto PhD);
Beatson West of Scotland
Cancer Centre, Glasgow, UK
(P McKay FRCPath);
Gloucestershire Hospitals NHS
Foundation Trust,
Gloucestershire, UK
(K Benstead FRCR); Sheffield
Teaching Hospitals NHS
Foundation Trust, Sheffield, UK
(N Morley FRCPath); University
Articles
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of Liverpool, Liverpool, UK
(N Kalakonda PhD); Sandwell
and West Birmingham
Hospitals NHS Trust,
Birmingham, UK
(Y Hasan FRCPath); and Torbay
and South Devon NHS Trust,
Torquay, UK (D Turner FRCPath)
Correspondence to:
Prof David Cunningham,
Department of Medicine, Royal
Marsden Hospital, Downs Road,
Sutton, Surrey SM2 5PT, UK
david.cunningham@rmh.nhs.
uk
outcomes with CHOP are poor, with only 33% to 43%
achieving a complete response2–4 and 38·5% achieving
5-year overall survival;5 therefore, a superior upfront
regimen for peripheral T-cell lymphoma is urgently
required. Previous evidence suggested that the addition of
etoposide to CHOP (CHOEP) might improve event-free
survival for younger patients (aged ≤60 years) without
increased lactate dehydrogenase,6 but no benefit for
overall survival was apparent and this approach is not
widely applicable.
The nucleoside analogue gemcitabine is not euxed by
the multidrug resistance gene-1–P glycoprotein (MDR-1–
Pgp), which is overexpressed in some peripheral T-cell
lymphomas7,8 on the tumour cells, residual lympho cytes,
or in the endothelium8 and has shown activity both as
monotherapy9–11 and in combination with platinum and
steroids12–20 in patients with relapsed or refractory
peripheral T-cell lymphoma. The regimen of intravenous
gemcitabine 1000 mg/m² on days 1, 8, and 15 of a cycle,
intravenous cisplatin 100 mg/m² on day 15, and oral or
intravenous methylprednisolone 1000 mg on days 1–5
(GEM-P) administered every 28 days is associated with
69% to 100% of pretreated patients with peripheral T-cell
lymphoma achieving an objective response, and 19% to
50% achieving a complete response;14–16 a median
progression-free survival of 12 months has been reported
in the largest retrospective series.16
Given the poor outcomes associated with CHOP as
front-line therapy in peripheral T-cell lymphoma and the
promising data in relapsing and refractory peripheral
Research in context
Evidence before this study
CHOP combination chemotherapy (cyclophosphamide,
doxorubicin, vincristine, and prednisolone) is widely used for
treatment of peripheral T-cell lymphoma; however, outcomes
with CHOP are poor for most patients. We investigated GEM-P
chemotherapy (gemcitabine, methylprednisolone, and
cisplatin) compared with CHOP in previously untreated patients
with peripheral T-cell lymphoma. We searched PubMed on
Dec 4, 2017, for English-language articles published from
January, 1998, to October, 2017, and searched abstracts from
the American Society of Hematology and American Society of
Clinical Oncology published between 2015–17 with the search
terms “T-cell lymphoma”, “chemotherapy”, and “gemcitabine”,
excluding studies in which patients with non-nodal peripheral
T-cell lymphoma forms were assessed exclusively. We identified
30 reports showing activity of gemcitabine in peripheral T-cell
lymphoma; three with gemcitabine as monotherapy and nine
with a combination of gemcitabine with platinum and steroids
predominantly in pretreated populations, including three
retrospective reports on GEM-P specifically in peripheral T-cell
lymphoma. Different combinations of gemcitabine with other
novel drugs, with or without the addition of platinum, in the
treatment of peripheral T-cell lymphoma were also reported in
the scientific literature, including one randomised trial that
assessed the combination of gemcitabine, cisplatin,
prednisolone and thalidomide versus CHOP in treatment-naive
patients. However, there were no reported randomised studies
on the combination of gemcitabine, platinum, and steroids
alone versus CHOP in the front-line setting.
Added value of this study
Our phase 2 trial is one of the few randomised studies in
previously untreated patients with peripheral T-cell lymphoma
and is an important addition to the evidence-base. The findings
confirm the poor outcomes for peripheral T-cell lymphoma
within a prospective trial cohort and indicate that CHOP should
remain the reference regimen at present. Our trial was the first
prospective study to assess an ¹⁸F-FDG-PET-CT response in
patients with peripheral T-cell lymphoma as part of a
pre-planned substudy, and the data suggest that
¹⁸F-FDG-PET-CT might be a more sensitive tool than contrast-
enhanced CT for determining response in peripheral T-cell
lymphoma, as it might better distinguish between a residual
fibrotic mass present after chemotherapy versus viable tumour.
Furthermore, obtaining a complete response by ¹⁸F-FDG-PET-CT
was independently prognostic for superior progression-free
survival in multivariable analysis, whereas complete response by
CT was not. Additionally, we reported the incidence and pattern
of CNS relapse in peripheral T-cell lymphoma from a prospective
trial. Determination of the subtype of peripheral T-cell
lymphoma in our study was revised for around a fifth of the
patients, highlighting the diagnostic challenges in peripheral
T-cell lymphoma. Despite GEM-P showing non-significant
inferiority for the endpoint of CT-based confirmed and
unconfirmed complete response compared with CHOP, there
were no differences in either progression-free survival or overall
survival between the groups; future study design in this
indication should be powered for primary endpoints of survival
rather than complete response, which might not be an accurate
surrogate endpoint (particularly when assessed by contrast-
enhanced CT) in peripheral T-cell lymphoma.
Implications of all the available evidence
Taken together, current evidence supports the use of
gemcitabine as an effective therapy in the management of
peripheral T-cell lymphoma. However, our randomised phase 2
study did not suggest superiority of GEM-P over CHOP in the
front-line setting for previously untreated patients and
therefore, CHOP should remain the reference regimen in this
indication for previously untreated patients. Although GEM-P
has shown efficacy in patients with peripheral T-cell lymphoma,
at present it should be reserved for patients with relapsed or
refractory disease. A superior upfront induction regimen is
urgently required for patients with treatment-naive peripheral
T-cell lymphoma, and future incorporation of novel drugs could
enhance the efficacy of front-line therapy in this indication. Trials
are ongoing (ClinicalTrials.gov NCT01777152, NCT01796002,
and NCT02561273) to address this research question.
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T-cell lymphoma with GEM-P, the UK National Cancer
Research Institute (NCRI) Lymphoma Clinical Study
Group started the CHEMO-T trial in 2012 to investigate
the potential superiority of GEM-P compared with CHOP
in previously untreated patients with peripheral T-cell
lymphoma.
Methods
Study design and participants
We did a phase 2, parallel-group, multicentre, open-
label randomised trial at 47 hospitals: 46 in the UK and
one in Australia (appendix pp 1–2).
Eligible participants were patients aged 18 years and
older with previously untreated histologically confirmed
peripheral T-cell lymphoma of the WHO 2008 subtypes:21
peripheral T-cell lymphoma not otherwise specified,
angioimmunoblastic T-cell lymphoma, anaplastic lymph-
oma kinase (ALK) negative anaplastic large cell T-cell
lymphoma, enteropathy-associated T-cell lymphoma, and
hepatosplenic γδ T-cell lymphoma.
For participation in the study, patients were required
to have bulky stage I (tumour mass diameter >10 cm) to
stage IV disease; a WHO performance status of 0–3
(patients with a performance status of 3 were only
eligible if this was deemed to be related to a lymphoma);
adequate cardiac, renal, hepatic, and bone marrow
function (absolute neutrophil count ≥1·0 × 10/L,
white blood cell count ≥3·0 × 10/L, platelet count
≥100·0 × 10/L, and haemoglobin concentration
≥9·0 g/dL unless related to disease). Patients with CNS
or leptomeningeal involvement, positive serology for
HIV-1, active hepatitis B or C, or a history of malignancy
within the preceding 5 years (with the exception of
curatively treated skin cancers or carcinoma in situ of
the cervix) and poorly controlled diabetes or other
comorbidities which would preclude the safe delivery of
treatment within the trial, were ineligible, as were
patients without at least one site of measurable disease
at baseline (measurable in two perpendicular dimensions
and ≥1 cm on the longest diameter on contrast-enhanced
CT scan, except for patients with enteropathy-associated
T-cell lymphoma following complete surgical resection).
Corticosteroids, not exceeding a maximum of
prednisolone 100 mg/day (or equivalent corticosteroid
dose) for 7 days, for symptoms related to lymphoma
before starting study treatment were permitted, but
preferably not instituted before an ¹F-fluoro-
deoxyglucose (FDG) PET-CT scan at baseline. If cortico-
steroids were instituted before the baseline scan, they
were required to be discontinued 24 h beforehand and
patients were required to have a serum glucose
concentration of 8·0 mmol/L or lower immediately
before the scan.
The protocol was approved by the UK Medicines and
Healthcare products Regulatory Agency and London
Riverside South West Research Ethics Committee.
Ethics approval in Australia was from The Eastern
Health Human Research Ethics Committee. Patients
provided written informed consent.
Randomisation
We assigned patients (1:1) to either CHOP or GEM-P.
Randomisation was done centrally by the clinical trials
unit at the Institute for Cancer Research (ICR)
independently of the trial team and investigators using a
minimisation procedure from the beginning of the
trial and first patient, without a burn-in period. The
stratification variables of locally-determined histological
subtype and International Prognostic Index risk group
(low 0–1 vs intermediate 2–3 vs high 4–5) were used for
computer-based minimisation. We factored in a proba-
bility component (ie, 80% chance of an incoming patient
being allocated to an unbalanced group). Given the
dierences in the administration schedules between the
chemotherapy regimens under assessment, it was not
possible to mask patients to the treatment they were
receiving.
Procedures
Patients in the CHOP group received cyclophosphamide
750 mg/m², doxorubicin 50 mg/m², and vincristine
1·4 mg/m² (up to a maximum of 2 mg) intravenously on
day 1, and oral prednisolone 100 mg on days 1–5 every
21 days, for six cycles. Patients in the GEM-P group
received intravenous gemcitabine 1000 mg/m² on days 1,
8, and 15, intravenous cisplatin 100 mg/m² on day 15,
and oral or intravenous methylprednisolone 1000 mg on
days 1–5 every 28 days, for four cycles. The rationale for
administering four cycles of GEM-P (rather than
six cycles) was that because GEM-P is a platinum-based
regimen used mainly for patients with relapsed or
refractory disease, we anticipated that most patients
would have achieved a maximum response with this type
of regimen by the fourth cycle.
For both treatment groups, dose modifications were
required for treatment-related toxicities in accordance
with the study protocol. Dose banding as per local
guidelines was permitted. Administration of supportive
medication, including antiemetic therapy, prophylaxis
for tumour lysis, granulocyte-colony stimulating factor
(G-CSF), prophylaxis for Pneumocystis jirovecii
pneumonia, fluid and electrolyte administration relating
to cisplatin, and administration of prophylaxis for CNS
relapse, was given in accordance with local practice.
Criteria for withdrawing a patient from study treatment
were interruption of study treatment for more than
3 weeks for reasons of toxicity (or for >4 weeks for
reasons other than toxicity), disease progression,
withdrawal of consent, unacceptable treatment-related
toxicity, pregnancy, patient non-compliance, or other
events precluding further administration of study drugs
as judged by the study chief investigator (DC).
On completion of study treatment, patients with a
complete response or unconfirmed complete response
See Online for appendix
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could proceed to high-dose chemotherapy and autologous
stem-cell transplantation at the local investigator’s
discretion. Consolidation radiotherapy to sites of initial
bulk or residual disease was also permitted at the end of
treatment at the investigator’s discretion.
Patients were assessed at baseline, at each attendance
for treatment, 30 days after completion of treatment,
and subsequently every 3 months for 1 year, then every
6 months until year 2, and every year thereafter for a
maximum follow-up of 5 years. Laboratory monitoring
with a full blood-cell count (haemoglobin, white cells,
neutrophils, and platelets) and biochemistry (sodium,
potassium, urea, creatinine, calcium, magnesium,
phosphate, lactate dehydrogenase, total bilirubin, liver
transaminases, alkaline phosphatase, serum albumin,
and blood glucose concentrations) were done at
baseline, on each day of treatment, and at 30 days after
completion of study treatment. At baseline all patients
had a contrast enhanced CT scan of the neck, thorax,
abdomen and pelvis and an ¹F-FDG-PET-CT scan done
within 28 days of randomisation, and a bone marrow
biopsy was required within 6 weeks of randomisation.
CT scans were also required during treatment (after
cycles 2 and 4 for patients on CHOP and after cycles 1
and 3 for patients on GEM-P). Both a contrast enhanced
CT scan and an ¹F-FDG-PET-CT scan were done at the
end of treatment. Any clinical suspicion of relapse or
progression was confirmed radiologically or on bone
marrow aspirate or trephine if disease was marrow-
based only.
All patients enrolled were required to submit their
diagnostic tissue for central histopathology review
within 28 days of randomisation; CT and
¹F-FDG-PET-CT responses were also centrally assessed.
Site accreditation, data collation, and quality control for
¹F-FDG-PET-CT imaging was done by the UK PET
Core Lab (London, UK).
Outcomes
The primary endpoint of the trial was the proportion of
patients who achieved an investigator-assessed, CT-based
complete response or unconfirmed complete response on
completion of study chemotherapy, according to the
International Workshop Standardized Response Criteria
for non-Hodgkin lymphoma.22
The primary endpoint was locally assessed and analysed
as randomised in the assessable population, defined as all
eligible patients who received at least one cycle of treatment
and had an end of treatment scan or reported clinical
progression as a reason for stopping trial treatment. A
patient with no CT imaging but a report of clinical
progression as reason for stopping trial treatment was
categorised as having progressed.
A preplanned primary endpoint sensitivity analysis
was done in the intention-to-treat (ITT) population
including all eligible patients who received at least one
cycle of treatment; patients with no end-of-treatment-CT
assessment were counted as non-responders. A second
preplanned primary endpoint sensitivity analysis was
done as treated in the per-protocol population defined as
all patients who received the planned number of cycles
and were either assessable by CT or had reported clinical
progression at the end of treatment.
The secondary endpoints of the trial were overall
survival, progression-free survival, partial response, stable
disease, progressive disease, and toxicity, and the propor-
tion of patients with metabolic complete response
determined by ¹F-FDG-PET-CT, according to the Revised
Response Criteria for Malignant Lymphoma.23 A secondary
endpoint assessing ¹F-FDG-PET-CT response specifically
was deemed to be of particular importance at the time of
study design, as the role of this outcome in peripheral
T-cell lymphoma had not previously been assessed in a
dedicated, prospective cohort of patients with peripheral
37 assessed for end-of-treatment
response*
37 assessed for end-of-treatment
response*
43 assigned to CHOP
42 started treatment
33 completed full treatment
(1 not assessable for end-of-
treatment assessment)
87 enrolled and randomly assigned
1 excluded from the ITT
population because of
change of diagnosis
9 withdrawn
5 progression (included for
end-of-treatment
response assessment)
1 toxicity
1 protocol non-compliance
(excluded from the ITT
analysis)
2 physician’s choice
44 assigned to GEM-P
44 started treatment
26 completed full treatment
18 withdrawn
5 progression (included
for end-of-treatment
response assessment)
5 toxicity (3 included
for end-of-treatment
response assessment)
1 change in diagnosis or
ineligible (excluded
from the ITT analysis)
2 death
3 physician’s choice
(included for end-of-
treatment response
assessment)
2 patient’s choice
Figure 1: Trial profile
Toxicity reasons for early study withdrawal were neutropenic sepsis (n=1) in CHOP; and tinnitus (n=2), hearing loss
(n=1), peripheral neuropathy (n=1), and thrombocytopenia and anaemia (n=1) in GEM-P. Two deaths occurred in the
GEM-P group, both due to lung infections. One patient chose to discontinue GEM-P and commence CHOP off-study
at the time of study closure. GEM-P=gemcitabine, cisplatin, and methylprednisolone. CHOP=cyclophosphamide,
doxorubicin, vincristine, and prednisolone. ITT=intention-to-treat. *Includes three patients with clinical progression.
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T-cell lymphoma. All patients receiving at least one dose
of study medication were included in the safety analysis
and analysed as treated. The severity of adverse events was
defined according to the National Cancer Institute
Common Terminology Criteria for Adverse Events
version 4.0. The worst toxicity per organ per patient was
considered.
A planned subgroup analysis was done to determine the
factors associated with complete response or unconfirmed
complete response by treatment arm in the assessable
population with the following factors: peripheral T-cell
lymphoma subtype, International Prognostic Index, sex,
B symptoms, age, disease stage, WHO performance
status, presence of extranodal disease, and raised lactate
dehydrogenase concentration.
Statistical analysis
We calculated the patient sample size for this trial
estimating that 50% of patients in the CHOP group and
70% of patients in the GEM-P group would achieve a
complete response or unconfirmed complete response
by CT, with an odds ratio of 2·33. We calculated that
93 patients per group were required to detect this
dierence with 5% significance (two-sided) and
80% power. Continuity correction was not used.
A planned formal interim analysis with 90% power to
show non-inferiority for review by an independent data
monitoring committee was due after the first 51 patients
in each group had been assessed for end-of-treatment
response; however, this milestone was not reached as
the trial closed before accruing 51 patients per group.
A lower 90% one-sided CI of dierence in the number
of patients achieving a confirmed or unconfirmed
complete response between treatments was expected
to be greater than 25% (ie, a non-inferiority margin
of 25%).
The number of patients achieving a complete response
or unconfirmed complete response at the end of study
chemotherapy was reported by treatment group with
95% CI using normal approximation and compared
between groups using logistic regression, with odds ratio
(OR [95% CI]) for CHOP versus GEM-P. Additionally,
a logistic regression model was fitted to adjust for the
stratification variables, with OR (95% CI) for CHOP
versus GEM-P.
In the planned subgroup analysis, we used logistic
regression to assess treatment dierences in responses
within the predefined subgroups, with results displayed
as ORs in a Forest plot. Progression events were defined
as clinical or radiological documented disease pro-
gression or death from any cause. Patients recording
no event were censored at the last follow-up date.
Progression-free survival and overall survival were
calculated from the date of randomisation until a
progression or death event occurred, respectively, using
Kaplan-Meier methods and compared between groups
using a log-rank test. Additionally, a Cox proportional
hazards model was fitted to adjust for the stratification
variables and to calculate a hazard ratio (HR [95% CI]) for
CHOP versus GEM-P. The ITT population was used for
survival analyses.
We assessed the following factors aecting overall sur-
vival and progression-free survival using Cox regression
CHOP (six
cycles; n=43)
GEM-P (four
cycles; n=44)
Sex
Men 30 (70%) 32 (73%)
Women 13 (30%) 12 (27%)
Age (years; median IQR) 64 (54–69) 61 (50–70)
Aged >60 years 27 (63%) 24 (55%)
IPI score
0–1 9 (21%) 8 (18%)
2–3 26 (60%) 25 (57%)
4–5 8 (19%) 11 (25%)
Local histology
PTCL not otherwise specified 19 (44%) 18 (41%)
ALK-negative ALCL 6 (14%) 8 (18%)
AITL 17 (40%) 17 (39%)
EATL 1 (2%) 1 (2%)
Hepatosplenic γδ T-cell lymphoma 0 0
Central histology
PTCL not otherwise specified 11 (26%) 10 (23%)
ALK-negative ALCL 4 (9%) 4 (9%)
AITL 22 (51%) 17 (39%)
EATL 1 (2%) 0
Panniculitis-like T-cell lymphoma 0 1 (2%)
PTCL not otherwise specified or
panniculitis-like T-cell lymphoma
0 1 (2%)
Not assessable 5 11 (25%)
Stage
I 1 (2%) 0
II 8 (19%) 3 (7%)
III 16 (37%) 16 (36%)
IV 18 (42%) 25 (57%)
B symptoms present 26 (60%) 27 (61%)
Increased lactate dehydrogenase 27 (63%) 27 (61%)
Extranodal sites present 25 (58%) 30 (68%)
WHO performance status
0 17 (40%) 21 (48%)
1 19 (44%) 18 (41%)
2 7 (16%) 5 (11%)
Data are n (%) except where indicated otherwise. CHOP=cyclophosphamide,
doxorubicin, vincristine, and prednisolone. GEM-P=gemcitabine, cisplatin, and
methylprednisolone. IPI=International Prognostic Index. PTCL=peripheral T-cell
lymphoma. ALK-negative ALCL=anaplastic lymphoma kinase-negative anaplastic
large cell lymphoma. AITL=angioimmunoblastic T-cell lymphoma.
EATL=enteropathy-associated T-cell lymphoma.
Table 1: Baseline characteristics of all randomly assigned patients
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analysis in the ITT population combining both treatment
groups: age, sex, disease stage, WHO performance
status, B symptoms, presence of raised lactate dehydro-
genase, International Prognostic Index risk group,
subtype of peripheral T-cell lymphoma, number of
extranodal sites, treatment arm, local CT response after
study chemotherapy, central ¹F-FDG-PET-CT response
after study chemo therapy, and autologous stem-cell
transplantation following first-line treatment. For safety
analyses, the proportion of patients reporting toxicities of
grade 3 or worse was compared between groups using a
χ² test.
The data analysis was generated using Stata version 14.
The trial was overseen by trial management and trial
steering committees and an independent data monitoring
committee. This trial is registered with ClinicalTrials.gov
(NCT01719835) and the European Clinical Trials Database
(EudraCT 2011-004146-18).
Role of the funding source
The trial sponsor (The Royal Marsden Hospital, London,
UK) was responsible for randomisation, data gathering,
entry, and validation, reports of serious adverse events,
organisation of the central histopathology review and
central response assessment, statistical analysis, and
production of the report. The funder of the study had no
role in study design, data collection, data analysis,
data interpretation, or writing of the report. The
corresponding author had full access to all the data in the
study and had final responsibility for the decision to
submit for publication.
Results
Between June 18, 2012, and Nov 16, 2016, we randomly
assigned 87 patients to study treatment, 43 to CHOP and
44 to GEM-P (figure 1). Before the formal interim
analysis, interim results from a planned unmasked
independent review of ecacy data by the independent
data monitoring committee in November, 2016, showed
that fewer patients had achieved a complete response or
unconfirmed complete response with GEM-P than with
CHOP. The committee concluded there was a high
likelihood that GEM-P would be inferior to CHOP at the
end of the trial, as indicated by the one-sided 80% CI for
dierence. The trial was subsequently closed to
recruitment and all patients treated in the GEM-P group
were oered the option to change to CHOP o-study at
the time of study closure as per the recommendations of
the data monitoring committee and trial management
group. The last dose of study treatment on trial was
administered on Feb 23, 2017.
Patient baseline and disease characteristics were well
balanced between groups (table 1). All 71 patients with
sucient tissue for central histopathology review had
the diagnosis of peripheral T-cell lymphoma confirmed
centrally, although the subtype of peripheral T-cell
lymphoma was revised for 16 patients (23%).
After receiving four cycles of GEM-P, one patient in the
GEM-P group received an additional two cycles for
persistent bone marrow infiltration before autologous
stem cell transplantation. 16 patients (38%) of 42 treated
with CHOP and 23 (52%) of 44 treated with GEM-P had
at least one treatment delay, and 18 patients (43%) of
42 treated with CHOP and 21 (48%) of 44 treated with
GEM-P had at least one dose reduction on study. Median
total dose received and dose intensities for each drug by
treatment group are in table 2.
The proportions of CHOP and GEM-P treatments
requiring G-CSF support were 135 (62%) of 219 and
70 (54%) of 130, respectively. Two patients (5%) of 43 in
the CHOP group and four (9%) of 44 in the GEM-P group
received prophylaxis for CNS relapse during the study:
four (9%) received intrathecal methotrexate, one (2%)
received intrathecal methotrexate plus methotrexate,
cytarabine, and hydrocortisone, and one (2%) received
unspecified therapy.
Investigator-assessed end of treatment response by
contrast-enhanced CT was available for 74 patients
(37 in each group; table 3). At a median follow-up of
CHOP GEM-P
Cyclophosphamide Doxorubicin Vincristine Prednisolone Gemcitabine Cisplatin Methylprednisolone
Total dose received (mg) 7960 (5080–8760) 540 (342–588) 12 (7–12) 2400 (1500–3000) 18262·5 (7060–21900) 361·5 (201·5–707·5) 20 000 (7500–20 000)
Relative dose intensity 98·1 (90·5–100) 97·9 (91·9–100·0) 99·2 (85·7–100·0) 97·0 (89·7–100·0) 86·5 (69·2–95·9) 82·2 (41·6–97·4) 98·1 (83·3–100·0)
Data are median (IQR).
Table 2: Total chemotherapy dose received by patients and dose intensity achieved
CHOP (six cycles;
n=43)
GEM-P (four cycles;
n=44)
Overall response 28 (75·7) 25 (67·6)
Complete response or unconfirmed complete response* 23 (62·2) 17 (45·9)
Partial response 5 (13·5) 8 (21·6)
Stable disease 2 (5·4) 3 (8·1)
Progressive disease 4 (10·8) 6 (16·2)
Progressive disease assessed clinically 3 (8·1) 3 (8·1)
Not done or not assessable 6 7
Data are n (%) of those who had an assessment. CHOP=cyclophosphamide, doxorubicin, vincristine, and prednisolone.
GEM-P=gemcitabine, cisplatin, and methylprednisolone. *p=0·164.
Table 3: End of treatment response by CT
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27·4 months (IQR 16·6–38·4), 23 patients (62%) of
37 assigned to CHOP had achieved a complete response
or unconfirmed complete response compared with
17 (46%) of 37 assigned to GEM-P (OR 0·52, 95% CI
0·21–1·31; p=0·164; adjusted OR for stratification factors
0·53 (0·19–1·46, p=0·22). Given the higher proportion of
patients with stage IV disease in the GEM-P group versus
CHOP, the logistic regression was adjusted for stage as
well as for stratification variables, but this did not make
any dierence to the complete response outcome by
randomisation result (OR 0·50, 95% CI 0·18–1·40;
p=0·19). Sensitivity analyses of the primary endpoint in
both the ITT and per-protocol populations showed no
dierences between the treatment groups (appendix p 3).
The inferiority of complete response outcomes with
GEM-P was consistent across subgroups (figure 2).
After chemotherapy, four (9%) of 43 patients in the
CHOP group underwent radiotherapy; no patients
in the GEM-P arm received radiotherapy. Stem cells
were collected for 16 patients (37%) of 43 in the CHOP
group and 15 (34%) of 44 in the GEM-P group, with
11 (26%) in CHOP and 13 (30%) in GEM-P proceeding
to autologous stem-cell transplantation in first remis-
sion. Second-line chemotherapy was administered to
15 patients (35%) of 43 in the CHOP group and 20
(45%) of 44 in the GEM-P group.
Survival was assessed in the ITT population (84 patients
[97%] of 87). Three patients (two in the CHOP group, one
in the GEM-P group) were excluded from the ITT
population following treatment assign ment, two because
of a change in diagnosis from peripheral T-cell lymphoma
not otherwise specified to Hodgkin’s lymphoma after
randomisation and a third patient was deemed to be
ineligible following treatment assignment because of
cardiac impairment. 2-year progression-free survival was
38·0% (95% CI 22·9–52·9) in the GEM-P group and
36·6% (21·4–52·0) in the CHOP group (HR 1·07, 95% CI
0·61–1·85, p=0·82; appendix p 4). Two patients (2%) of
84 had CNS relapses (both isolated CNS recurrences);
both patients had peripheral T-cell lymphoma not
otherwise specified, were treated with CHOP, and
developed progression in the CNS after cycle 1 and
cycle 5, respectively. 2-year overall survival was 63·9%
(95% CI 45·7–77·4) in the GEM-P group and 51·0%
(32·8–67·4) in the CHOP group (HR 0·69, 95% CI
0·35–1·38, p=0·30; appendix p 5).
ALK negative ALCL (central)
AITL (central)
PTCL NOS or EATL (central)
IPI risk group
0–1
2
3
4–5
Sex
Male
Female
B symptoms absent
B symptoms present
Age
≤60 years
>60 years
Stage I/II
Stage III
Stage IV
WHO performance status 0
WHO performance status 1
Extranodal sites absent
Extranodal sites present
Lactate dehydrogenase not elevated
Lactate dehydrogenase elevated
All
4/4 (100%)
21/38 (55%)
8/18 (44%)
10/12 (83%)
15/26 (58%)
10/20 (50%)
5/16 (31%)
30/52 (58%)
10/22 (45%)
19/29 (66%)
21/45 (47%)
15/31 (48%)
25/43 (58%)
5/7 (71%)
16/27 (59%)
19/40 (48%)
23/33 (70%)
13/32 (41%)
17/27 (63%)
23/47 (49%)
21/28 (75%)
19/66 (41%)
40/84 (48%)
GEM-P betterCHOP better
Odds ratio (95% Cl)
1·0 1·6 3·2 6·40·01 0·05 0·2 0·4 0·8
Events/patients (%) Odds ratio (95% CL)
p value
..
0·692 (0·189–2·553)
0·036 (0·003–0·484)
1·00 (0·048–20·83)
1·050 (0·220–5·003)
0·667 (0·113–3·919)
0·055 (0·004–0·805)
0·529 (0·174–1·615)
0·476 (0·086–0·395)
2·063 (0·434–9·804)
0·200 (0·056–0·713)
0·889 (0·216–3·662)
0·358 (0·102–1·251)
0·250 (0·007–8·560)
1·200 (0·257–5·593)
0·363 (0·101–1·316)
0·727 (0·161–3·281)
0·563 (0·134–2·362)
1·687 (0·346–8·222)
0·267 (0·080–0·891)
1·212 (0·216–6·800)
0·343 (0·102–1·158)
0·52 (0·21–1·31)
..
0·578
0·012
1·00
0·951
0·654
0·034
0·264
0·395
0·363
0·013
0·870
0·107
0·442
0·816
0·123
0·679
0·432
0·517
0·032
0·827
0·085
0·164
Figure 2: Factors potentially predictive of a complete response or unconfirmed complete response
Data are from an analysis of outcomes at end of treatment. CHOP=cyclophosphamide, doxorubicin, vincristine, and prednisolone. GEM-P=gemcitabine, cisplatin, and
methylprednisolone. ALK-negative ALCL= anaplastic lymphoma kinase-negative anaplastic large cell T-cell lymphoma. AITL=angioimmunoblastic T-cell lymphoma. PTCL
NOS=peripheral T-cell lymphoma not otherwise specified. EATL=enteropathy-associated T-cell lymphoma. IPI=International Prognostic Index. ··=data not obtainable.
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Significant risk factors associated with superior overall
survival in univariable analysis (appendix p 6) were a
complete response or unconfirmed complete response
on completion of treatment determined by CT, a
complete response on completion of treatment
determined by ¹F-FDG-PET-CT, and autologous stem-
cell trans plantation consolidation in first remission.
No factor remained independently prognostic for over-
all survival in multivariable analysis (appendix p7).
Presence of raised lactate dehydrogenase, an
International Prognostic Index score of more than 1,
and presence of more than one extranodal site
was associated with inferior progression-free survival
in univariable analysis (appendix p 8), while patients
with a complete response or unconfirmed complete
response to induction determined by CT or a complete
response to induction determined by ¹F-FDG-PET-CT
or undergoing auto logous stem-cell transplantation
consolidation in first remission had superior
progression-free survival. In multivariable analysis
presence of raised lactate dehydro genase concentrations
at diagnosis was independently associated with inferior
progression-free survival; by contrast, attainment of a
complete response by ¹F-FDG-PET-CT to study treat-
ment or presence of a low or low-intermediate risk
international prognostic index score was independently
associated with superior progression-free survival
(appendix p9)
Two patients (5%) died during the study, both in the
GEM-P group, from lung infections. Up to Nov 7, 2017,
33 patients (39%) of 84 had died in the ITT population,
18 (44%) of 41 in the CHOP group (13 from disease
progression and five from sepsis) and 15 (35%) of 43 in
the GEM-P group (nine from disease progression, three
from sepsis, one cardiac event, one from ischaemic colitis
and disease progression, and one from metastatic cancer).
Safety was assessed for 86 patients (99%) who received
a dose of study treatment. CHOP was associated with
more febrile neutropenia of all grades (table 4). GEM-P
was associated with more thrombocytopenia of all
grades and grade 3 or worse; however, thrombocytopenia
was not associated with increased bleeding. GEM-P was
also associated with more tinnitus. There were
38 serious adverse events in the CHOP group and
43 in the GEM-P group.
In the ¹F-FDG-PET-CT substudy, 79 (91%) of 87 patients
assessed had FDG-avid disease at baseline on central
review of imaging. End-of-treatment response by
¹F-FDG-PET-CT or CT was assessable in 70 patients
(89%) of 79 (appendix p 10); although the incidence of
complete response as determined by ¹F-FDG-PET-CT
was lower in the GEM-P group than in the CHOP group,
the dierence between groups was less marked than
between-group dierences for complete response
assessment by contrast-enhanced CT. The proportion of
agreement between ¹F-FDG-PET-CT and contrast-
enhanced CT for deter mining a complete response was
77·3%. For 40 patients with a complete response by
¹F-FDG-PET-CT on com pletion of study treatment, the
corresponding contrast-enhanced CT data were: 24 (60%)
with a complete response, seven (18%) with an uncon-
firmed complete response, five (13%) with a partial
response, two (5%) with stable disease, and two (5%) with
progressive disease.
CHOP (n=42) GEM-P (n=44)
Grade 1–2 Grade 3 Grade 4 Grade 1–2 Grade 3 Grade 4
Acute renal toxicity 0 0 0 1 (2%) 1 (2%) 0
Alopecia* 27 (64%) 0 0 12 (27%) 0 0
Anaemia 23 (55%) 4 (10%) 0 22 (50%) 5 (11%) 1 (2%)
Constipation 18 (43%) 0 0 20 (45%) 1 (2%) 0
Cerebrovascular accident 0 0 0 0 0 1 (2%)
Diarrhoea 15 (36%) 0 0 13 (30%) 2 (5%) 0
Dyspnoea 4 (10%) 0 0 6 (14%) 0 0
Fatigue 29 (69%) 2 (5%) 0 35 (80%) 0 0
Febrile neutropenia† 0 10 (24%) 2 (5%) 1 (2%) 3 (7%) 0
Fever 11 (26%) 3 (7%) 0 11 (25%) 2 (5%) 1 (2%)
Haemorrhage 4 (10%) 0 0 7 (16%) 0 1 (2%)
Headache* 4 (10%) 0 0 13 (30%) 0 0
Hyperglycaemia 1 (2%) 1 (2%) 0 3 (7%) 1 (2%) 0
Hypertension 1 (2%) 1 (2%) 0 3 (7%) 1 (2%) 0
Hypotension 3 (7%) 1 (2%) 0 5 (11%) 1 (2%) 0
Indigestion 14 (33%) 0 0 8 (18%) 0 0
Infection 8 (19%) 7 (17%) 0 14 (32%) 4 (9%) 2 (5%)
Infusion reaction 1 (2%) 0 0 1 (2%) 1 (2%) 0
Mood disturbance 6 (14%) 0 0 7 (16%) 1 (2%) 0
Mucositis* 20 (48%) 1 (2%) 0 11 (25%) 0 0
Nausea 17 (40%) 0 0 22 (50%) 1 (2%) 0
Neuropathy 11 (26%) 1 (2%) 0 7 (16%) 0 0
Neutropenia 5 (12%) 2 (5%) 15 (36%) 7 (16%) 5 (11%) 4 (9%)
Pulmonary embolus 0 2 (5%) 1 (2%) 0 1 (2%) 0
Pruritus 7 (17%) 0 0 9 (20%) 0 0
Skin rash 7 (17%) 0 0 12 (27%) 0 0
Thrombocytopenia† 8 (19%) 1 (2%) 3 (7%) 16 (36%) 8 (18%) 5 (11%)
Tinnitus* 1 (2%) 0 0 12 (27%) 0 0
Vomiting 12 (29%) 1 (2%) 0 13 (30%) 2 (5%) 0
Weight loss 10 (24%) 1 (2%) 0 9 (20%) 1 (2%) 0
Other toxicity 23 (55%) 5 (12%) 1 (2%) 27 (61%) 9 (20%) 2 (5%)
Data are n (%) for adverse events of grade 1–2 occurring in at least 10% of patients and all grade 3–5 events.
Two patients (5%) died during the study, both in the GEM-P group, from lung infections. Other adverse events with
CHOP of grade 3 or worse were superior mesenteric artery thrombosis (grade 3), muscle weakness (grade 3), insomnia
(grade 3), hyponatraemia (grade 4), tumour lysis (grade 3), pain left hip and legs (grade 3), swelling in left knee
(grade 3), and squamous cell carcinoma cheek (grade 3). Other adverse events with GEM-P of grade 3 or worse were
right flank pain (grade 3), abdominal pain (grade 3), colonic perforation (grade 4), hip pain (grade 3), chest pain (grade
3), chest/abdominal pain (grade 3), paraneoplastic occurrence (grade 4), raised alanine transaminase (grade 3), bone
pain (grade 3), dehydration (grade 3), hypokalaemia (grade 3), raised alanine transaminase (grade 3), and cellulitis
(grade 3). CHOP=cyclophosphamide, doxorubicin, vincristine, and prednisolone. GEM-P=gemcitabine, cisplatin, and
methylprednisolone. *p<0.05 for all grades. †p<0.05 for all grades and grade 3 or worse.
Table 4: Adverse events by treatment
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Discussion
The number of complete responses or unconfirmed
complete responses in the GEM-P group was non-
significantly inferior to the CHOP group, indicating that
the primary endpoint of the trial would not be met. A
planned subgroup analysis showed that the eect was
consistent across subgroups.
As part of a preplanned analysis, we also assessed the
proportion of agreement between contrast-enhanced CT
and ¹F-FDG-PET-CT for determining a complete
response, and found it to be around 77%. This discrepancy
was probably mainly due to the presence of persistent
non-FDG-avid nodes discernible on contrast-enhanced
CT after chemotherapy and ¹F-FDG-PET-CT might be
better able to distinguish between a residual fibrotic
mass following chemotherapy versus viable tumour in
peripheral T-cell lymphoma. The rate of early withdrawal
before completing study treatment for reasons other
than disease progression was higher in the GEM-P group
with more participants withdrawing for toxicity and by
choice; there were also two deaths on treatment with
GEM-P, both due to lung infections. Patients treated in
the CHOP group had more febrile neutropenia than
those in the GEM-P group; by contrast, patients treated
with GEM-P had more thrombocytopenia of all grades
and grade 3 or worse than those treated with CHOP,
although this did not lead to a substantial increase in
bleeding events. GEM-P was also associated with a
significant increased risk of grade 1-2 tinnitus, which led
two patients to withdraw early from the study.
Relative dose intensity was lower in the GEM-P group
than in the CHOP group, although this might mainly
reflect the dose modifications that were required with the
GEM-P regimen according to blood results on the day of
treatment. However, there were two separate instances
where a day of GEM-P treatment was incorrectly omitted
rather than delayed, resulting in two protocol violations,
although it seems unlikely that this modification would
have significantly negatively aected the primary
endpoint assessment in the GEM-P arm. At the median
follow-up of 27·4 months there was no dierence in
either 2-year progression-free survival or overall survival
between the treatment groups. In a Cox regression
analysis of the ITT population, significant risk factors
associated with superior overall survival included a
complete response at end of treatment determined either
by CT or by ¹F-FDG-PET-CT, and autologous stem-cell
transplantation consolidation in first remission in
univariable analysis. However, no factors remained
independently significant for overall survival in multi-
variable analysis. In multivariable analysis of the factors
associated with progression-free survival, presence of
a raised lactate dehydrogenase concentration at pre-
sentation was prog nostic of inferior progression-free
survival, whereas a low or low-intermediate risk
international prognostic index score or a complete res-
ponse to study treatment determined by ¹F-FDG-PET-CT
was independently associated with superior progression-
free survival.
The number of patients who withdrew from the study
for reasons other than disease progression was higher in
the GEM-P group than in the CHOP group, and
consequently more patients receiving GEM-P proceeded to
second-line chemotherapy. This might explain the absence
of a survival dierence between arms at this time, as the
numbers undergoing autologous stem-cell transplantation
in first remission were similar between groups, although
this remains to be further investigated. However, given
that the inferior incidence of complete responses and
unconfirmed complete responses in the GEM-P group
was not associated with inferior progression-free survival
or overall survival for these patients, complete response
(particularly when assessed by contrast-enhanced CT)
might not be an accurate surrogate endpoint in peripheral
T-cell lymphoma. Future studies in this area should
therefore better investigate this point, and perhaps should
be designed with primary endpoints that incorporate
survival. Indeed, measuring endpoints such as 24-month
event-free survival in peripheral T-cell lymphoma might be
an important predictor of overall survival; one study
showed that patients achieving 24-month event-free
survival had superior overall survival compared with those
who did not reach this milestone.24
Although our study closed early to recruitment, this
phase 2 trial is an important addition to the prospective
evidence-base for this rare subtype of non-Hodgkin
lymphoma and is, to our knowledge, the third ran domised
trial reported with treatment-naive patients with
peripheral T-cell lymphoma. All participants had the
diagnosis and subtype of peripheral T-cell lymphoma
confirmed centrally by two expert lymphoma pathologists;
for around 23% of patients with peripheral T-cell
lymphoma the subtype was revised, highlighting that
there are challenges to accurately diagnosing peripheral
T-cell lymphoma. Additionally, although extensive future
work is necessary, our study reports, to our knowledge, the
first dedicated prospective trial to assess ¹F-FDG-PET-CT
responses in patients with peripheral T-cell lymphoma, all
of which were done at accredited sites, underwent central
quality control, and were centrally assessed by an expert
¹F FDG PET-CT physician. Our study also adds important
data from a prospective trial cohort on the incidence of
CNS relapse in peripheral T-cell lymphoma, which at the
time of writing has been reported in two patients with
peripheral T-cell lymphoma not otherwise specified and
occurred during study treatment.
However, the limitations of our study also need to be
acknowledged. Firstly, and most importantly, as the trial
closed early to recruitment it was not adequately powered
to assess the primary study endpoint. Another potential
limitation of the study is in the interpretation of dose
intensity for GEM-P; this regimen was administered
weekly for 3 weeks out of 4, with the dose adjusted on
each day of treatment in accordance with the blood
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counts on the day of treatment, which is in contrast to
CHOP where treatment is administered once every
3 weeks allowing more time for count recovery.
Despite the absence of international consensus on the
gold-standard therapy for previously untreated patients
with peripheral T-cell lymphoma, CHOP has been
adopted by many countries as the reference regimen.25
With the exception of ALK-positive anaplastic large cell
T-cell lymphoma26 the outcomes with CHOP or CHOP-
like therapy appear to be suboptimum, with a 5-year
overall survival of only 38·5%, as reported in a meta-
analysis.5 Attempts to surpass outcomes with CHOP
have proven largely unsuccessful, except a subgroup
analysis by the German High-Grade NHL Study Group
that showed improved event-free survival but no overall
survival benefit with CHOEP for younger patients
(≤60 years) with peripheral T-cell lymphoma with
normal lactate dehydrogenase concentrations treated
within aggressive non-Hodgkin lymphoma clinical
trials.6 Therefore, optimising therapy for newly
diagnosed patients remains an important unmet
medical need.
MDR-1/Pgp is known to be overexpressed in peripheral
T-cell lymphoma7,8 in the lymphoma cells, residual
lymphocytes, and endothelium,8 and this might account
for the reported ecacy of the nucleoside analogue
gemcitabine in peripheral T-cell lymphoma, which is not
a substrate of the eux pump.27 The activity of intravenous
gemcitabine monotherapy (1200 mg/m² on days 1, 8, and
15 of a 28-day cycle) was first reported in 1998 in a phase 2
study9 of 13 patients with relapsed or refractory peripheral
T-cell lymphoma unspecified or patients with mycosis
fungoides with an objective response of 69% and
complete response of 8%. Similar ecacy was shown in
another study10 (objective response 60% and complete
response 20%) in a cohort of ten patients with relapsed or
refractory T-cell lymphoma using the same dosing
schedule. A subsequent study in 2010 confirmed this
ecacy (objective response 51%, complete response 23%)
in a larger number of relapsed or refractory patients (n=39)
with some durable remissions.11
Various combinations of gemcitabine with platinum
and steroid in relapsed or refractory peripheral T-cell
lymphoma have also been reported in the scientific
literature with encouraging results (objective response
36%–100%) and acceptable toxicity.12–20,28 Specifically, the
GEM-P regimen has been assessed in three retrospective
studies including patients with peripheral T-cell
lymphoma, predominantly with relapsed or refractory
disease, with reported objective responses of 69%–100%
(complete response 19%–50%) and some durable
remisisons.14–16 Furthermore, some novel regimens incor-
porating gemcitabine have been assessed in treatment-
naive patients in the peripheral T-cell lymphoma
setting,4,8,29,30 including one randomised trial,4 and all have
shown encouraging results for gemcitabine in this
indication excepting one.8 In one trial, patients were
assigned either to CHOP (n=51) or a combination of
gemcitabine 800 mg/m² on days 1 and 8, cisplatin
25 mg/m² intra venously on days 1–3, prednisolone
60 mg/m² orally on days 1–5, and thalidomide 200 mg
orally once per day continuously (n=52); this regimen was
associated with a significant improvement in the
proportion of patients achieving a response, 2-year
progression-free survival, and 2-year overall survival.4
Our study confirms the poor outcomes for patients
with peripheral T-cell lymphoma in the setting of a
prospective randomised trial.5,25 Recruitment to the trial
was closed early as there was strong evidence that the
primary endpoint—to detect superiority of GEM-P over
CHOP by a comparison of the CT-based complete
responses and unconfirmed complete responses at end
of treatment—would not be met, although this was not
reflected in inferior progression-free survival or overall
survival at 2 years in the GEM-P group. More patients
also withdrew from the GEM-P group than from the
CHOP group for reasons other than disease progression.
The dose of cisplatin 100 mg/m² administered in GEM-P
was associated with more grade 1–2 tinnitus (compared
with CHOP), which led three patients to withdraw early
before completing study treatment; this dose therefore
appears to be at the upper limit of what is tolerable in
terms of ototoxicity, but further assessment of the dosing
limit would be necessary to establish tolerability.
Nevertheless, we have revised the dose of cisplatin
administered with GEM-P at The Royal Marsden
Hospital (London, UK) to a total dose of 75 mg/m², in
line with the dose used in other regimens containing
gemcitabine and platinum,4,31 with the expectation that
this might reduce the incidence of ototoxicity.
Although our data show that GEM-P has ecacy in
terms of response and survival in peripheral T-cell
lymphoma, in our randomised study it was inferior to
CHOP for treatment-naive patients with this disease.
One possible exception for the use of this type of regimen
upfront might be when front-line anthracycline-based
chemotherapy is contraindicated to avoid cardiotoxicity.
In conclusion, although further studies are warranted,
our phase 2 randomised trial suggests that CHOP
should, for the time being, remain the reference regimen
for previously untreated patients with peripheral T-cell
lymphoma and that GEM-P is best reserved for the
relapsed and refractory setting at present.
Contributors
DC designed the study, had study oversight, and contributed to data
interpretation, and writing and approval of the report. MG gathered,
analysed, and interpreted the data, did the literature searches, and wrote
the report. CP designed the study, analysed and interpreted the data,
produced figures, and wrote the report. AW and ADA did the central
histopathological review. IZ and BS did the central CT response
assessment and SC did the central ¹F-FDG-PET-CT response
assessments. YMT, LE, and JO gathered, interpreted, and analysed the
data. RB coordinated the collection of biological specimens. IC, PJ,
KMA, EAH, MPM, GPC, JR, AF, AH, SM, PM, KB, NM, NK, YH,
and DT gathered and interpreted data. All authors reviewed and
approved the final version of the report.
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Declaration of interests
IC has received research funding from Eli-Lilly, Janssen-Cilag,
Sanofi Oncology, Merck Serono, and Novartis; participated on advisory
boards for Sanofi Oncology, Eli-Lilly, Bristol-Myers Squibb,
Merck Sharpe Dohme (MSD), Bayer, Roche, and Five Prime Therapeutics;
and received honoraria from Taiho, Pfizer, Amgen, and Eli-Lill y.
EAH has received research funding from Bristol-Myers Squibb, Celgene,
Merck-Serono, and MSD; participated on advisory boards for Celgene and
Janssen; and received speaker fees and travel expenses from Bristol-Myers
Squibb, Roche, and Janssen and travel expenses from Takeda. SM has
received honoraria from Roche and travel support from Gilead. NM has
received conference support and participated on advisory boards for
Roche. DC has received research funding from Amgen, AstraZeneca,
Bayer, Celgene, Medimmune, Merck Serono, Merrimack, and Sanofi.
All other authors declare no competing interests.
Acknowledgments
Bloodwise provided funding (grant reference number 12070) and Cancer
Research UK provided endorsement for this trial. Site accreditation, data
collation, and quality control for ¹F-FDG-PET-CT imaging was done by
Lucy Pike on behalf of the UK PET Core lab (London, UK). The UK
National Health Service provided funding to the UK National Institute
for Health Research (NIHR) Biomedical Research Centres at The Royal
Marsden Hospital/Institute of Cancer Research (London, UK). GPC
acknowledges support from the Blood Theme of the Oxford National
Institute for Health Research Biomedical Research Centre (Oxford, UK).
References
1 Vose JM, Armitage J, Weisenburger D, et al. International peripheral
T-cell and natural killer/T-cell lymphoma study: pathology findings
and clinical outcomes international T-cell lymphoma project.
J Clin Oncol 2008; 26: 4124–30.
2 Pautier P, Devidas A, Delmer A, et al. Angioimmunoblastic-like
T-cell non Hodgkin’s lymphoma: outcome after chemotherapy in
33 patients and review of the literature. Leuk Lymphoma 1999;
32: 545–52.
3 Simon A, Peoch M, Casassus P, et al. Upfront VIP-reinforced-ABVD
(VIP-rABVD) is not superior to CHOP/21 in newly diagnosed
peripheral T cell lymphoma. Results of the randomized phase III
trial GOELAMS-LTP95. Br J Haematol 2010; 151: 159–66.
4 Li L, Duan W, Zhang L, et al. The ecacy and safety of gemcitabine,
cisplatin, prednisone, thalidomide versus CHOP in patients with
newly diagnosed peripheral T-cell lymphoma with analysis of
biomarkers. Br J Haematol 2017; 178: 772–80.
5 Abouyabis AN, Shenoy PJ, Sinha R, Flowers CR, Lechowicz MJ.
A systematic review and meta-analysis of regimens for peripheral
T-cell lymphoma. ISRN Hematol 2011; 2011: 623924.
6 Schmitz N, Trümper L, Ziepert M, et al. Treatment and prognosis of
mature T-cell and NK-cell lymphoma: an analysis of patients with
T-cell lymphoma treated in studies of the German High-Grade
Non-Hodgkin Lymphoma Study Group. Blood 2010; 116: 3418–25.
7 Pescarmona E, Pignoloni P, Puopolo M, et al. p53 over-expression
identifies a subset of nodal peripheral T-cell lymphomas with a
distinctive biological profile and poor clinical outcome.
J Pathol 2001; 195: 361–66.
8 Mahadevan D, Unger JM, Spier CM, et al. Phase 2 trial of combined
cisplatin, etoposide, gemcitabine, and methylprednisolone (PEGS)
in peripheral T-cell non-Hodgkin lymphoma: Southwest Oncology
Group Study S0350. Cancer 2013; 119: 371–79.
9 Zinzani PL, Magagnoli M, Bendandi M, et al. Therapy with
gemcitabine in pretreated peripheral T-cell lymphoma patients.
Ann Oncol 1998; 9: 1351–53.
10 Sallah S, Wan JY, Nguyen NP. Treatment of refractory T-cell
malignancies using gemcitabine. Br J Haematol 2001; 113: 185–87.
11 Zinzani PL, Venturini F, Stefoni V, et al. Gemcitabine as single
agent in pretreated T-cell lymphoma patients: evaluation of the
long-term outcome. Ann Oncol 2010; 21: 860–63.
12 Chau I, Harries M, Cunningham D, et al. Gemcitabine, cisplatin
and methylprednisolone chemotherapy (GEM-P) is an eective
regimen in patients with poor prognostic primary progressive or
multiply relapsed Hodgkin’s and non-Hodgkin’s lymphoma.
Br J Haematol 2003; 120: 970–77.
13 Emmanouilides C, Colovos C, Pinter-Brown L, et al. Pilot study of
fixed-infusion rate gemcitabine with cisplatin and dexamethasone
in patients with relapsed or refractory lymphoma.
Clin Lymphoma 2004; 5: 45–49.
14 Ng M, Waters J, Cunningham D, et al. Gemcitabine, cisplatin and
methylprednisolone (GEM-P) is an eective salvage regimen in
patients with relapsed and refractory lymphoma. Br J Cancer 2005;
92: 1352–57.
15 Arkenau H-T, Chong G, Cunningham D, et al. Gemcitabine,
cisplatin and methylprednisolone for the treatment of patients with
peripheral T-cell lymphoma: the Royal Marsden Hospital
experience. Haematologica 2007; 92: 271–72.
16 Yim KL, Ashley S. Assessment of gemcitabine, cisplatin and
methylprednisolone (GEM-P) combination treatment for
non-Hodgkin T cell lymphoma. Med Oncol 2012; 29: 3535–39.
17 Dong M, He X, Liu P, et al. Gemcitabine-based combination
regimen in patients with peripheral T-cell lymphoma.
Med Oncol 2013; 30: 351.
18 Park BB, Kim WS, Suh C, et al. Salvage chemotherapy of
gemcitabine, dexamethasone, and cisplatin (GDP) for patients with
relapsed or refractory peripheral T-cell lymphomas: a consortium
for improving survival of lymphoma (CISL) trial. Ann Hematol 2015;
94: 1845–51.
19 Qi F, Dong M, He X, et al. Gemcitabine, dexamethasone, and
cisplatin (GDP) as salvage chemotherapy for patients with relapsed
or refractory peripheral T cell lymphoma-not otherwise specified.
Ann Hematol 2017; 96: 245–51.
20 Skamene T, Crump M, Savage KJ, et al. Salvage chemotherapy and
autologous stem cell transplantation for peripheral T-cell
lymphoma: a subset analysis of the Canadian Cancer Trials Group
LY.12 randomized phase 3 study. Leuk Lymphoma 2017; 58: 2319–27.
21 Swerdlow SH, Campo E, Harris NL, Jae ES, Pileri SA, Stein H.
WHO classification of tumours of haematopoistic and lymhphoid
tissues, fourth edtion. Lyon: IARC Press; 2008.
22 Cheson BD, Horning SJ, Coier B, et al. Report of an international
workshop to standardize response criteria for non-Hodgkin’s
lymphomas. J Clin Oncol 1999; 17: 1244–53.
23 Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria
for malignant lymphoma. J Clin Oncol 2007; 25: 579–86.
24 Maurer MJ, Ellin F, Srour L, et al. International assessment of
event-free survival at 24 months and subsequent survival in
peripheral T-cell lymphoma. J Clin Oncol 2017; 35: 4019–26.
25 Ellin F, Landstr J, Jerkeman M, Relander T. Real-world data on
prognostic factors and treatment in peripheral T-cell lymphomas:
a study from the Swedish Lymphoma Registry. Blood 2015;
124: 1570–78.
26 Savage KJ, Harris NL, Vose JM, et al. ALK- anaplastic large-cell
lymphoma is clinically and immunophenotypically dierent from both
ALK + ALCL and peripheral T-cell lymphoma, not otherwise specified:
report from the international peripheral T-cell lymphoma project.
Blood J 2008; 111: 5496–505.
27 Bergman AM, Pinedo HM, Talianidis I, et al. Increased
sensitivity to gemcitabine of P-glycoprotein and multidrug
resistance-associated protein-overexpressing human cancer cell
lines. Br J Cancer 2003; 88: 1963–70.
28 Yao Y, Tang Y, Zhu Q, et al. Gemcitabine, oxaliplatin and
dexamethasone as salvage treatment for elderly patients with
refractory and relapsed peripheral T-cell lymphoma.
Leuk Lymphoma 2013; 54: 1194–200.
29 Kim JG, Sohn SK, Chae YS, et al. CHOP plus etoposide and
gemcitabine (CHOP-EG) as front-line chemotherapy for patients
with peripheral T cell lymphomas. Cancer Chemother Pharmacol
2006; 58: 35–39.
30 Jia B, Hu S, Yang J, et al. Comparison of gemcitabin, cisplatin, and
dexamethasone (GDP), CHOP, and CHOPE in the first-line
treatment of peripheral T-cell lymphomas. Hematology 2016;
21: 536–41.
31 Crump M, Kuruvilla J, Couban S, et al. Randomized comparison of
gemcitabine, dexamethasone, and cisplatin versus dexamethasone,
cytarabine, and cisplatin chemotherapy before autologous stem-cell
transplantation for relapsed and refractory aggressive lymphomas:
NCIC-CTG LY.12. J Clin Oncol 2014; 32: 3490–96.
