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1Department of Haematology, Princess Alexandra Hospital, Brisbane,
2University of Queensland, Brisbane, Queensland, Australia
3Department of Haematology, Gold Coast University Hospital, Gold Coast,
4Institute of Haematology, Royal Prince Alfred Hospital, Sydney, New South
5Department of Haematology, St Vincent’s Hospital, Sydney, New South Wales,
6Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia
7Department of Haematology and Olivia Newton John Cancer Research Institute,
The Austin Hospital, Melbourne, Victoria, Australia
8Royal Adelaide Hospital, Adelaide, South Australia, Australia
9Department of Haematology, Sir Charles Gairdner Hospital, Nedlands, Western
10Department of Haematology, Westmead Hospital, Sydney, New South Wales,
11University of Sydney, Sydney, New South Wales, Australia
12Royal Hobart Hospital, Hobart, Tasmania, Australia
13University of Tasmania, Hobart, Tasmania, Australia
14Department of Haematology, Canberra Hospital, Canberra, Australian Capital
15Australian National University, Canberra, Australian Capital Territory, Australia
Management and Outcomes of Diffuse Large B-cell
Lymphoma Post-transplant Lymphoproliferative
Disorder in the Era of PET and Rituximab:
A Multicenter Study From the Australasian
StephenBoyle1,2, Joshua W. D.Tobin2,3, JacintaPerram4, NadaHamad5,6, VeenaGullapalli5, AllisonBarraclough7,
LydiaSingaraveloo8, Min-HiHan9, RichardBlennerhassett10,11, NilesNelson12, Anna M.Johnston12,13, DiptiTalaulikar14,15,
KrishnaKarpe16, AbirBhattacharyya10, Chan YoonCheah9,17, ElangoSubramoniapillai18, WaqasBokhari18,
CindyLee8, Eliza A.Hawkes7,19,20, AndrewJabbour21, Simone I.Strasser11,22, Steven J.Chadban11,23,24,
ChristinaBrown4,11, PeterMollee1,2, GregHapgood1,2
Correspondence: Greg Hapgood (firstname.lastname@example.org).
There are limited data on post-transplant lymphoproliferative disorder (PTLD) in the era of positron emission tomography (PET)
and rituximab (R). Furthermore, there is limited data on the risk of graft rejection with modern practices in reduction in immu-
nosuppression (RIS). We studied 91 patients with monomorphic diffuse large B-cell lymphoma PTLD at 11 Australian centers:
median age 52 years, diagnosed between 2004 and 2017, median follow-up 4.7 years (range, 0.5–14.5 y). RIS occurred in 88%
of patients. For patients initially treated with R-monotherapy, 45% achieved complete remission, rising to 71% with the addition of
rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone (R-CHOP) for those not in complete remission. For patients
initially treated with R-CHOP, the complete remission rate was 76%. There was no difference in overall survival (OS) between
R-monotherapy and R-chemotherapy patients. There was no difference in OS for patients with systemic lymphoma (n = 68) versus
central nervous system (CNS) involvement (n = 23) (3-y OS 72% versus 73%; P = 0.78). Treatment-related mortality was 7%. End
of treatment PET was prognostic for patients with systemic lymphoma with longer OS in the PET negative group (3-y OS 91%
versus 57%; P = 0.01). Graft rejection occurred in 9% (n = 4 biopsy-proven; n = 4 suspected) during the entire follow-up period
with no cases of graft loss. RIS and R-based treatments are safe and effective with a low likelihood of graft rejection and high cure
rate for patients achieving complete remission with CNS or systemic PTLD.
Post-transplant lymphoproliferative disorders (PTLDs) rep-
resent a heterogeneous group of lymphoid proliferations due to immunosuppression in solid organ transplant recipients.1 The
incidence depends on the type of transplant ranging from 0.5%
16Department of Renal Medicine, Canberra Hospital, Canberra, Australian Capital
17University of Western Australia, Crawley, Western Australia, Australia
18Royal Brisbane Hospital, Brisbane, Queensland, Australia
19Eastern Health, Box Hill, Victoria, Australia
20University of Melbourne, Melbourne, Victoria, Australia
21Department of Cardiology, St Vincent’s Hospital, Sydney, New South Wales, Australia
22AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital,
Sydney, New South Wales, Australia
23Department of Renal Medicine, Royal Prince Alfred Hospital, Sydney, New South
24Kidney Node, Charles Perkins Centre, University of Sydney, Sydney, New South
Supplemental digital content is available for this article.
Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.
on behalf of the European Hematology Association. This is an open-access
article distributed under the terms of the Creative Commons Attribution-Non
Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible
to download and share the work provided it is properly cited. The work cannot be
changed in any way or used commercially without permission from the journal.
HemaSphere (2021) 5:11(e648).
Received: 5 May 2021 / Accepted: 8 September 2021
Boyle et al DLBCL PTLD in the PET/CT Era
to 10% and is rising due to a greater number of transplants and
increasing age of the recipient.2,3
PTLDs represent a spectrum from polyclonal proliferations
(polymorphic PTLD) that are usually Epstein-Barr virus (EBV)
positive to lymphoid cancers indistinguishable to those seen in
nonimmunosuppressed populations (monomorphic PTLD).4
The majority of monomorphic PTLDs are histologically dif-
fuse large B-cell lymphoma (DLBCL).4–7 Iatrogenic immuno-
suppression results in a reduction in T-cell immune surveillance
enabling an EBV-driven B-cell proliferation to occur that may
result in malignant transformation. The pathogenesis of EBV-
negative PTLD is less clear.1
Rituximab is a monoclonal antibody directed against CD20
and is effective in CD20+ B-cell PTLD.8–11 The international
PTLD-1 trials have shaped current treatment approaches. In the
rst, a sequential treatment approach was used with 4 cycles of
weekly rituximab followed by cyclophosphamide, doxorubicin,
vincristine, prednisolone (CHOP) chemotherapy.5 In the exten-
sion of this trial, risk-stratied sequential treatment was used
where complete remission to rituximab induction identied a
group with favorable progression-free survival (PFS) who only
required additional rituximab monotherapy, while R-CHOP
consolidation for those who did not achieve complete remission
with rituximab alone appeared safe and effective.6 Consequently,
guidelines recommend initial RIS, followed by rituximab and
then either R-CHOP chemotherapy for persistent or progressive
disease or rituximab monotherapy for those in complete remis-
sion.12 Patients with central nervous system (CNS) involvement
were excluded from the PTLD-1 trials, and there remains lim-
ited data regarding their outcomes in the era of rituximab.
The management of PTLD requires a balance between pre-
serving the graft and delivering effective lymphoma therapy to
achieve cure. A reduction in immunosuppression (RIS) restores
EBV-specic and anti-tumor immunity, yet this may increase the
risk of graft rejection. The incidence of graft rejection with RIS
is difcult to dene. Current recommendations for RIS are based
on guidelines developed in the early 2000s for renal transplant
recipients and recommend: stop antimetabolites (mycopheno-
late and azathioprine), reduce calcineurin inhibitors (tacrolimus
and cyclosporine) by 25%–50% and maintain or reduce cor-
ticosteroids.13 Although these represent common clinical prac-
tice, there is limited evidence to guide this practice and variation
exists based on type of organ transplant.
There are limited data describing outcomes in PTLD in the
era of rituximab and 18F-uorodeoxyglucose (FDG) positron
emission tomography-computed tomography (PET). The pur-
pose of this study was to assess the management practices and
outcomes in a population-based cohort in the era of PET and
rituximab. We focused on monomorphic DLBCL PTLD as this
is the most common histological subtype for which treatment is
likely to be most standardized.
We conducted a multicenter, retrospective study involving
11 Australian tertiary referral centers. The study protocol was
reviewed and approved by each institutional regulatory commit-
tee. Inclusion criteria were1: aged ≥ 18 years with a known solid
organ transplant2; diagnosis of monomorphic DLBCL PTLD
between January 2004 and December 20173; and staged by PET.
Patients with PTLD post allogeneic stem cell transplantation
were excluded. We collected data on1: baseline demographics
including transplant type and immunosuppression at the time of
diagnosis2; patterns of RIS with PTLD treatment3; the incidence
of graft rejection during and after lymphoma treatment (dened
as early <1 year; late ≥1 year from diagnosis) based on clini-
cal suspicion or biopsy4; treatment delivered; and5 lymphoma
response and survival outcomes. Central pathology review was
We examined responses according to treatment. Rituximab
primary (R-primary) was dened as patients managed with ini-
tial rituximab monotherapy followed by response assessment.
Patients in remission would undergo observation or receive
further rituximab monotherapy versus patients with persistent
or progressive disease receiving rituximab, cyclophosphamide,
doxorubicin, vincristine, prednisolone (R-CHOP). Rituximab-
chemotherapy (R-chemotherapy) was dened as patients receiving
rituximab-based chemotherapy at diagnosis. The chemotherapy
regimens were grouped into R-CHOP, reduced-intensity regi-
mens, intensive treatment (non-CNS-directed), and CNS-directed
treatment. Imaging modality selected for restaging was per physi-
cian discretion. Staging and response assessment was dened by
sites according to international lymphoma criteria (negative—
complete remission—Deauville score 1–3, where available).14
PFS was dened as the time from diagnosis until progressive
disease, relapse, or death from any cause. Overall survival (OS)
was dened as the time from diagnosis until death from any cause.
Disease-specic survival (DSS) was dened as the time from diag-
nosis until death from lymphoma or treatment-related toxicity.
Treatment-related mortality (TRM) was dened as death due to
toxicity from lymphoma treatment during or within 3 months
from the completion of treatment. Comparisons between groups
were performed using chi-square test for categorical variables.
The Kaplan-Meier method was used to estimate OS, PFS, and
DSS and survival curves were compared using the log-rank test.
Hazard ratios (HRs) and associated 95% condence intervals
(CIs) were estimated using Cox proportional hazards regres-
sion analysis. Variables that showed different distribution across
groups (P < 0.1) were included in the Cox regression models that
used OS as the dependent variable to identify potential indepen-
dent prognostic factors. A landmark analysis at 6 months post-
diagnosis was performed to assess the prognostic value of end of
treatment PET in systemic PTLD cases.
A total of 91 patients fullled the inclusion criteria (Figure1).
The baseline characteristics for all patients are shown in Table1.
Figure 1. Overview of all study patients. R-primary is deﬁned as patients
initially managed with rituximab monotherapy. R-chemotherapy is deﬁned as
patients initially managed with rituximab-based chemotherapy. *Includes 2
patients with systemic and CNS involvement. CNS = central nervous system; DLBCL
= diffuse large B-cell lymphoma; PTLD = post-transplant lymphoproliferative disorder.
(2021) 5:11 www.hemaspherejournal.com
The median follow-up was 4.7 years (range, 0.5–14.5 y). The
median age at PTLD diagnosis was 52 years (range, 18–81 y).
The median time from transplantation to PTLD diagnosis was
7.1 years (range, 0.16–36 y).
Treatment and outcomes
Immunosuppression at time of PTLD diagnosis was known
for 86 (95%) patients (See Supplementary Table 1, http://
links.lww.com/HS/A202). This included a calcineurin inhib-
itor for 74 patients [86%] plus a second agent in 58 [67%]
of these patients). The commonest regimens were tacrolimus/
mycophenolate (n = 30, 35%), tacrolimus/azathioprine (n = 13,
15%), and tacrolimus monotherapy (n = 13, 15%). Almost all
patients were also taking maintenance prednisolone.
No patients had RIS as the sole strategy. Seventy-two (79%)
patients had data available to evaluate degree of RIS. RIS
occurred in 63 of 72 patients. Given the heterogeneity in patterns
of RIS and types of transplant, we elected to dene 3 groups of
RIS1: Cessation of immunosuppression: calcineurin inhibitor
and second agent ceased entirely (n = 20; 28%)2; Moderate RIS:
50% or more reduction of the calcineurin inhibitor (n = 22;
31%)3; and Minimal RIS: documented RIS but either to a level
of <50% reduction in calcineurin inhibitor dose or reduction
of the second agent only (n = 21; 29%). Nine patients (12%)
did not have any RIS. All patients received rituximab or ritux-
imab-based chemotherapy concurrently with, or shortly after
RIS, rather than being restaged after RIS alone. There was a
higher incidence of moderate RIS or cessation of immunosup-
pression in patients receiving R-chemotherapy compared to
R-monotherapy (See Supplementary Table 4, http://links.lww.
Patients with systemic PTLD—rituximab primary strategy
For patients with systemic lymphoma (ie, no CNS involvement)
(n = 68), rituximab monotherapy was administered rst-line in 24
patients (35%), including those with stage IV disease (n = 14; 58%)
and high international prognostic index (IPI ≥ 3 n = 10; 48%)
(Figures1 and 2). For the 20 patients with PET assessments,
9 (45%) achieved complete remission and did not receive sub-
sequent chemotherapy, of which, 8 remained in remission.
Other responses were: partial remission n = 7, stable disease
n = 2, progressive disease n = 2; 8 of these patients subse-
quently received R-CHOP chemotherapy. For all 24 patients,
11 subsequently received R-chemotherapy (10 R-CHOP, 1
rituximab, cyclophosphamide, prednisolone) and responses
were: complete remission n = 6, stable disease n = 2,
progressive disease n = 1, TRM n = 2. The complete remission
rate increased to 71% after the addition of R-CHOP for patients
not in complete remission after rituximab monotherapy.
Patients with systemic PTLD—initial R-chemotherapy
Of the 44 systemic PTLD patients treated with initial
R-chemotherapy, 37 received R-CHOP. Responses were: com-
plete remission n = 28 (76%), partial remission n = 3, progres-
sive disease n = 2 (TRM n = 2, not performed n = 1, missing
n = 1). The median number of cycles was 6. For the remain-
ing 7 patients, there was heterogeneity in regimens (dose-ad-
justed etoposide, prednisolone, vincristine, cyclophosphamide,
doxorubicin, rituximab, cyclophosphamide, vincristine, pred-
nisolone, rituximab, cyclophosphamide, etoposide, vincristine,
prednisolone, cyclophosphamide, vincristine, doxorubicin,
dexamethasone/methotrexate, cytarabine (Hyper-CVAD), and
rituximab, dexamethasone, cytarabine, carboplatin), and we
categorized these as reduced-intensity regimens intensive treat-
ment (non-CNS directed or CNS directed) (See Supplementary
Table 2, http://links.lww.com/HS/A202).
Patients with CNS involvement
There were 23 patients with CNS involvement: primary CNS
lymphoma (n = 21) and systemic plus CNS involvement (n = 2)
(Table2 and Figure3). The median age at PTLD diagnosis was
55 years (range, 22–80 y). The median time from transplantation
to PTLD diagnosis was 8.5 years (range, 0.5–36 y). Nineteen of
the cases occurred in renal transplant recipients. The proportion
of cases with CNS involvement was higher in renal transplant
recipients compared to other transplant recipients (41% versus
9%; P < 0.001). Tumor EBV in situ hybridization was positive
Baseline Characteristics for 91 Patients With Monomorphic
Characteristic N (%)
Median age at PTLD diagnosis (range) 52 y (18–81 y)
Median time from organ transplantation to PTLD (range) 7.1 y (0.16–36 y)
Age ≥60 at PTLD diagnosis 29/91 (32)
Less than 12 mo from transplantation to PTLD 18/91 (20)
Male gender 57/91 (63)
Heart 6/91 (7)
Lung 13/91 (14)
Liver 23/91 (25)
Kidney only 41/91 (45)
ECOG performance status
0–1 60/81 (74)
≥2 21/81 (26)
1 3/91 (3)
1E 28/91 (31)
2 6/91 (7)
3 3/91 (3)
4 51/91 (56)
0–1 30/76 (40)
2–3 33/76 (43)
4–5 13/76 (17)
Tumor EBV status (EBER ISH pos) 52/87 (60)
B symptoms present 29/82 (35)
Nodal involvement 49/91 (54)
Gastrointestinal 33/91 (36)
Central nervous system 23/91 (25)
Bone 20/91 (22)
Liver 12/91 (13)
Bone marrow 9/91 (10)
Nodal involvement only 9/91 (10)
Graft 7/91 (8)
≥1 extranodal site 32/91 (35)
Bulky disease (>10 cm) 4/87 (5)
Raised LDH 47/84 (56)
Hypoalbuminemia (<35 g/L) 47/89 (53)
Raised beta 2 microglobulin 19/28 (68)
aPatients with more than 1 solid organ transplantation: 4 kidney/pancreas, 1 kidney/liver, 1 heart/
lung, 1 heart/kidney, and 1 heart/lung/liver transplant recipients.
bOther extranodal involvement: mesentery (n = 6), pharynx (n = 5), thyroid (n = 3), spleen (n =
2), pleura (n = 2), and 1 case each of skin, muscle, kidney, adrenal, pancreas, pericardium, vulva,
parotid gland, base of tongue, and orbit involvement.
DLBCL = diffuse large B-cell lymphoma; EBER ISH = Epstein-Barr encoding region in situ hybrid-
ization; EBV = Epstein-Barr virus; ECOG = Eastern Cooperative Oncology Group; IPI = International
Prognostic Index; LDH = lactate dehydrogenase; PTLD = post-transplant lymphoproliferative disorder.
Boyle et al DLBCL PTLD in the PET/CT Era
As rst-line therapy, RIS occurred in 13 of 14 patients for
whom data was available. Five patients had minimal RIS, 6
patients had moderate RIS and 2 patients had complete cessa-
tion of immunosuppression. No patient had RIS as a sole treat-
ment modality. Rituximab was used in 21 of 23 patients. For the
2 patients who did not receive rituximab, one died of progres-
sive disease and the other had resection and radiotherapy alone
and achieved complete remission. Rituximab monotherapy was
initiated in 5 patients. Four of these patients also received radio-
therapy with the following responses: complete remission n = 1,
stable disease n = 1, progressive disease n = 2. The patient who
did not receive radiotherapy achieved a partial remission with
rituximab monotherapy and then received CNS-directed che-
motherapy and achieved a partial remission and remained alive
at last follow-up.
A total of 18 patients received rituximab-based chemother-
apy: 2 initially received rituximab monotherapy (as above) and
15 received CNS-directed therapy up front. CNS-directed reg-
imens incorporated high-dose methotrexate with or without
cytarabine: rituximab, methotrexate, procarbazine, vincristine
n = 3, rituximab, carmustine, teniposide, prednisolone n = 4, ritux-
imab, methotrexate, procarbazine, vincristine, cytarabine n = 3,
R-Hyper-CVAD n = 2, Rituximab plus high-dose methotrex-
ate n = 6 (See Supplementary Table 2, http://links.lww.com/
HS/A202). The average number of cycles received was 5.0. For
these patients, outcomes were complete remission n = 14 (82%),
partial remission n = 3. The remaining patient initially received
R-CHOP for systemic plus CNS PTLD and was analyzed as
such. This patient died from a complication of treatment after
the rst cycle of CNS-directed chemotherapy and was the only
TRM event (4%) in the CNS PTLD cohort. Ten patients received
radiotherapy in total (consolidative n = 6).
End of treatment PET in systemic PTLD
Of the 68 patients with systemic PTLD, 53 had end of treat-
ment PET imaging. Reasons for not performing imaging were
(n = 15): TRM n = 5, lymphoma deaths n = 2, or missing data
n = 8. In a 6-month landmark analysis, achieving complete
remission at end of treatment PET was predictive of OS (3-y
OS PET negative 91% versus PET positive 57%; P = 0.01)
(Figure 4). For patients achieving complete remission, only 3
(7%) patients subsequently relapsed.
Figure 2. Outcomes for patients with systemic lymphoma receiving rituximab-primary treatment. *Pt did not undergo imaging after R-monotherapy
but achieved CR after R-CP. Three pts restaged with CT or MRI only: One pt had PD on CT with rituximab monotherapy and died of TRM with R-CHOP. One
pt had SD on CT with rituximab monotherapy and died of TRM with R-CHOP. One pt achieved CR with rituximab monotherapy only and was restaged with
MRI only (stage IE—orbital disease). Ca = cancer; CMR = complete metabolic remission; CR = complete remission; CT = computed tomography; ESRF = end-stage renal failure; FU =
follow-up; PD = progressive disease; PET = positron emission tomography; PR = partial remission; PTLD = post-transplant lymphoproliferative disorder; R-CP = rituximab, cyclophosphamide,
prednisolone; R-CHOP = rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone; SD = stable disease; TRM = treatment-related mortality; Tx = transplantation.
Baseline Characteristics for 23 Patients With Central Nervous
System Involvement With Monomorphic DLBCL PTLD.
Characteristic N (%) (n = 23)
Median age at PTLD diagnosis (range) 55 y (22–80 y)
Median time from organ transplantation to PTLD (range) 8.54 y (0.53–36.1 y)
Heart 2/23 (9)
Lung 1/23 (4)
Liver 1/23 (4)
Kidney 19/23 (83)
0–1 17/22 (77)
≥2 5/22 (23)
EBV positive 19/22 (86)
Deep region of the braina9/22 (41)
CSF flow cytometry positive 1/14 (7)
CSF cytology positive 2/16 (12)
CSF protein raised 10/17 (59)
Elevated LDH 9/20 (45)
aDeep region defined as any involvement of basal ganglia, corpus callosum, brain stem, or
CSF = cerebrospinal fluid; DLBCL = diffuse large B-cell lymphoma; EBV = Epstein-Barr virus;
ECOG PS = Eastern Cooperative Oncology Group performance status; LDH = lactate dehydroge-
nase; LDH = lactate dehydrogenase; PTLD = post-transplant lymphoproliferative disorder.
(2021) 5:11 www.hemaspherejournal.com
A total of 30 patients (33%) died. TRM was 7%. All treat-
ment-related deaths were due to sepsis with 3 occurring in
the rst cycle of R-CHOP, 1 occurring in the second cycle of
R-CHOP and the remaining 2 occurring later in treatment reg-
imens involving R-Hyper-CVAD. There were 10 deaths due to
lymphoma: 8 patients died with refractory lymphoma (median
OS 7.4 mo), while only 2 patients relapsed beyond 1 year and
died (relapse at 4.2 and 8.4 y postdiagnosis, respectively). Eleven
deaths were unrelated to PTLD and due to infection (n = 7),
renal failure (n = 2), lung cancer (n = 1), or graft failure (liver)
(n = 1). The cause of death was unknown in 3 cases.
For patients with systemic lymphoma, we examined outcomes
in patients receiving rituximab monotherapy (n = 24) compared
with rituximab-chemotherapy (n = 44) as initial treatment.
There were no signicant differences in baseline characteristics
between groups (Table 3). There was no signicant difference
in OS (P = 0.13), PFS (P = 0.49), or DSS (P = 0.69) between
the 2 groups (Figure5A–C). For the entire cohort, 3-year and
5-year OS rates were 72.7% and 66.4%, respectively; 3-year
and 5-year PFS rates were 69.2% and 60.9%, respectively. EBV
tumor status was available in 65 of 68 (n = 33 positive; n = 32
negative) patients with systemic PTLD. There was no signi-
cant difference in OS (3 y OS EBV pos 75% versus EBV neg
64%; P = 0.42) or PFS (3 y EBV pos 75% versus EBV neg 67%;
P = 0.33) based on EBV status.
For patients with CNS involvement, 3-year PFS and OS rates
were 73.1% and 73.1%, respectively. There was no signicant
difference in OS or PFS comparing patients with CNS involve-
ment to patients with systemic lymphoma (OS 73.1% versus
72.5%; P = 0.78 and PFS 73.1% versus 70.3%; P = 0.85)
(Figure6A and B).
In a univariate analysis for all patients, the following base-
line characteristics were signicant predictors of worse OS and
were included in the multivariate analysis: age ≥ 60 (P = 0.001),
serum albumin <35 g/L (P = 0.044), bone marrow involvement
(P = 0.001), Eastern Cooperative Oncology Group (ECOG)
score ≥2 (P = 0.006), elevated lactate dehydrogenase (LDH)
(P = 0.004), stage III/IV disease (P = 0.017), presence of B
Figure 3. Treatment received and outcomes for 23 patients with CNS PTLD. *Also received EBV cytotoxic T lymphocytes + ibrutinib. ^Two patients
with systemic and CNS involvement. CNS = central nervous system; CR = complete remission; EBV = Epstein-Barr virus; PD = progressive disease; PR = partial remission; PTLD =
post-transplant lymphoproliferative disorder; RT = radiotherapy; SD = stable disease; TRM = treatment-related mortality.
Figure 4. Six-month landmark analysis of OS for systemic lymphoma
patients based on EOT PET. CMR = complete metabolic remission; EOT = end of
treatment; OS = overall survival; PET = positron emission tomography.
Baseline Characteristics for Patients With Systemic Lymphoma
Treated With Rituximab Monotherapy Versus Rituximab-chemo-
therapy As Initial Treatment.
(n = 24) (%)
(n = 44) (%) P
Median age (y) 50.8 50.6 0.82
Age >60 9/24 (38) 11/44 (25) 0.28
ECOG ≥2 7/21 (33) 9/38 (24) 0.43
Stage III/IV 17/24 (70) 33/44 (75) 0.71
IPI 3–5 10/21 (48) 23/36 (64) 0.23
EBV positive 12/24 (50) 21/41 (51) 0.92
B symptoms 7/21 (33) 20/39 (51) 0.18
Raised LDH 13/23 (57) 25/41 (61) 0.73
Bulky disease (≥10 cm) 0/24 (0) 4/41 (10) 0.29
EBV = Epstein-Barr virus; ECOG = Eastern Cooperative Oncology Group performance status; IPI =
International Prognostic Index; LDH = lactate dehydrogenase.
Boyle et al DLBCL PTLD in the PET/CT Era
symptoms (P = 0.073), and thoracic organ transplant (heart or
lung) (P = 0.074) (See Supplementary Table 3, http://links.lww.
com/HS/A202). Multivariate analysis demonstrated only elevated
LDH (HR, 3.58; P = 0.025; 95% CI, 1.17-10.8) and ECOG ≥2
(HR, 3.46; P = 0.006; 95% CI, 1.43-8.33) remained signicant
predictors of worse OS. In a univariate analysis for patients
receiving rituximab monotherapy, IPI (HR, 5.44; P = 0.045; 95%
CI, 1.03-28.55) and response to rituximab induction (HR, 10.75;
P = 0.027; 95% CI, 1.31-90.9) were prognostic for OS.
Incidence of graft rejection
Graft rejection was uncommon with suspected rejection
occurring in 8 patients (9%), which was conrmed by biopsy in
4 patients (4%) during follow-up (See Supplementary Table 4,
http://links.lww.com/HS/A202). Only 1 patient had biop-
sy-proven rejection during treatment (R-CHOP). Another
patient had biopsy-proven rejection in complete remission 9
months from PTLD diagnosis. A third patient was clinically
suspected of having rejection during treatment but not biop-
sied. The remaining 2 biopsy-proven graft rejections occurred
more than 2 years from PTLD diagnosis (both kidney trans-
plant recipients with histological evidence of chronic graft
rejection). Four patients had clinically suspected graft rejec-
tion. RIS (no reduction versus any reduction) was not a risk
factor for development of suspected graft rejection (P = 0.26)
or biopsy-proven graft rejection (P = 0.44). There were no
cases of transplant loss due to rejection. There were no differ-
ences in the incidence of graft rejection between patients man-
aged with a rituximab primary versus initial R-chemotherapy
strategy (See Supplementary Table 4, http://links.lww.com/
This is the largest assessment of patients with DLBCL PTLD
staged with PET and managed in the rituximab era. Our data
demonstrate similar response rates, OS and TRM to the PTLD-1
risk-stratied sequential treatment trial. The rituximab-primary
approach appeared safe and effective compared to an initial
rituximab-chemotherapy approach. The OS of patients with
CNS involvement appeared similar to patients with systemic
lymphoma. The incidence of graft rejection was lower than pre-
viously reported. End of treatment PET was prognostic for OS.
Taken together, these data support that current practices with
RIS and rituximab-based treatments are safe and effective with
a low likelihood of graft rejection and high cure rate for patients
achieving complete remission with CNS or systemic PTLD.
The PTLD-1 trial dened current practices with RIS and
risk-stratied sequential treatment beginning with rituximab
monotherapy.6 Our results are broadly comparable to the
PTLD-1 trial (complete remission rate to rituximab 25%, over-
all response rate to chemotherapy 88%, 3-y estimated response
duration and OS 82% and 70%, respectively) and other stud-
ies.7,15 For our patients initially treated with rituximab mono-
therapy (rituximab-primary), 45% achieved complete remission
with no TRM, rising to 71% after the addition of R-CHOP
for those not in complete remission. For patients treated with
initial R-CHOP, the rate of complete remission was 76%. Our
3-year PFS and OS rates were 69.2% and 72.7%, respectively.
Outcomes for patients requiring chemotherapy in routine prac-
tice were comparable to the trial setting.
Figure 5. Survival for patients with systemic lymphoma treated with
rituximab monotherapy vs rituximab-chemotherapy as initial treat-
ment: OS (A); PFS (B); DSS (C). DSS = disease-speciﬁc survival; OS = overall
survival; PFS = progression-free survival.
Figure 6. OS (A) and PFS (B) based on the presence or absence of
CNS involvement at diagnosis. CNS = central nervous system; OS = overall sur-
vival; PFS = progression-free survival.
(2021) 5:11 www.hemaspherejournal.com
Consistent with recent reports,15,16 our outcomes for patients
treated with a rituximab-primary approach were similar to
rituximab-chemotherapy as an initial approach. These data
demonstrate that a minority of patients can be cured with RIS
and rituximab monotherapy without exposing them to che-
motherapy and supports the current practice of risk-stratied
sequential treatment. This avoids the high TRM rate (~30%)
previously seen with initial CHOP chemotherapy after failure
to respond to RIS.17 The PTLD-1 trials reported a TRM rate
of 11% with rituximab induction followed by CHOP,5 and the
risk-stratied sequential therapy trial reported a rate of 8%
where granulocyte colony stimulating factor and antibiotic pro-
phylaxis were mandated.6 Our data demonstrated a TRM rate
of 7%, which is higher than ~2% in immunocompetent DLBCL
patients receiving combination rituximab-chemotherapy.18
The limited data available suggest that DLBCL PTLD with
CNS involvement has been associated with a poor prognosis, the
frequency is higher (~15%) than the immunocompetent popula-
tion and the disease is almost always EBV positive.19–22 A large
assessment of CNS PTLD reported 3-year PFS and OS rates of
32% and 43%, respectively; however, this study included other
PTLD subtypes and not all patients received rituximab.20 Our
data demonstrated 25% of patients had CNS involvement with
a high proportion in renal transplant patients and 86% of cases
were EBV positive. Most patients (16/23) did not receive RIS and
rituximab monotherapy but rather RIS with initial CNS-directed
rituximab-based chemotherapy with only 1 treatment-related
death. In the univariate analysis, the presence of CNS involve-
ment was not prognostic. While numbers are small, surpris-
ingly, the 3-year OS was comparable to patients with systemic
lymphoma (73.1% versus 72.5%). These results are consider-
ably better than historical series, although favorable outcomes
for patients treated with rituximab have been reported.22 These
ndings may be due to RIS protocols, the almost universal use
of rituximab, the use of CNS-directed chemotherapy regimens,
radiotherapy, or improved supportive care.
CNS DLBCL PTLD is almost universally EBV positive and
patients receive immunosuppression to prevent graft rejection
that impairs EBV-specic T-cell immunity. In this setting, rit-
uximab may exert a direct and indirect anti-lymphoma effect.
Rituximab depletes circulating B-cells, the principle reservoir of
EBV, regardless of whether they are EBV-infected or not. RIS
enables restoration of EBV-specic T-cell immunity that is a crit-
ical step that occurs in conjunction with rituximab.
RIS has been the cornerstone of PTLD management for
decades, yet concerns remain regarding graft rejection. RIS has
had variable responses (40%–70%) and rejection rates (5%–
30%).23–25 The only prospective study of RIS was conducted
prior to rituximab and reported responses in only 12% and rejec-
tion in 37%.26 We assessed the incidence of graft rejection, both
clinical and biopsy-proven, with current practices of RIS and
the availability of rituximab. Almost all (88%) patients under-
went RIS (29% minimal, 31% moderate, and 28% cessation)
and 80% of all patients received chemotherapy. Graft rejection
occurred in 8 patients (9%), which was conrmed by biopsy in
only 4 patients (4%) during follow-up. Only 1 patient had biop-
sy-proven rejection during treatment. Importantly, there were
no cases of transplant loss due to rejection. Increased awareness
and monitoring for early signs of rejection would have led to
alterations in immunosuppression to avoid overt rejection. We
and others have previously demonstrated that RIS during and
after rituximab ± chemotherapy does not lead to a deterioration
in renal graft function.27,28 Our data suggest that graft rejection
may be lower in the modern era with RIS when used with ritux-
imab ± concurrent or sequential chemotherapy, which provides
signicant immunosuppression by itself. Prospective trials are
needed to determine the optimal approach to RIS in PTLDs.
Although PTLDs are FDG-avid lymphomas,29 there is limited
data regarding the prognostic value of end of treatment PET in
PTLD.30 The PTLD-1 trials were conducted with CT imaging. We
performed a 6-month landmark analysis to explore the value of
end of treatment PET in systemic PTLD. End of treatment PET
was prognostic with OS signicantly longer for patients achiev-
ing complete remission. Only 3 (7%) patients achieving com-
plete remission subsequently relapsed. This demonstrates that
most PTLD patients achieving complete remission will be cured.
Our data conrm the ndings of a previous report regarding the
prognostic value of end of treatment PET.31
The typical limitations of retrospective nonrandomized design
apply to this study. Treatment was based on physician preference
and there may have been reasons why a rituximab-primary or
rituximab-chemotherapy approach was chosen (ie, patient-re-
lated or lymphoma-related variables). We analyzed monomor-
phic DLBCL and compared outcomes with the PTLD-1 trial.
Monomorphic DLBCL comprised ~75%–80% of patients in the
PTLD-1 trials, yet other histologies, with variable management
practices and prognoses, were included. This limits the applica-
tion of our data to non-DLBCL PTLD histologies. Furthermore,
during this study period (2004–2017), management practices
evolved, largely driven by data from the PTLD-1 trials. As this
is a retrospective study, imaging modality selected for restaging
was per physician discretion.
In the largest assessment of PET staged patients managed in
the era of rituximab, this real-world data demonstrate signi-
cant improvements in survival in recent decades and provides
valuable insights in management. Future clinical trials are nec-
essary to determine the optimal patterns of RIS and to improve
survival with the addition of effective novel agents that can be
safely delivered to immunocompromised transplant recipients.
The rarity and complexity of PTLD are barriers to conduct-
ing prospective trials and future international collaboration to
address these issues will be essential.
AB received conference sponsorship from Roche. DT received
honoraria from Roche, Janssen, Takeda, Amgen; she received
research funding from Roche, Janssen; and she received advi-
sory boards from Amgen, Janssen and Roche. NH received
Honoraria/Speaker’s fees from Abbvie and Novartis. EAH
received Honoraria/Speaker’s fees from Roche, Janssen, Takeda,
Bristol-Myers Squibb; she received advisory boards from
Janssen, Celgene, Merck Sharp Dohme, Roche; she received
research funding from Bristol-Myers Squibb, Celgene, Merck
Sharp Dohme, Astra Zeneca; and she received travel expenses
from Takeda, Roche, Janssen. AJ received honoraria from
Janssen; he received advisory boards from Roche, Janssen,
Merck Sharp Dohme; and he received travel support from Roche.
CYC received Honoraria/Consulting/Advisory board from
Roche, Janssen, MSD, Gilead, Ascentage Pharma, Acerta, Loxo
Oncology, TG therapeutics; he research funding from Celgene,
Roche, Abbvie; and he received travel expenses from Roche. SIS
received honoraria or advisory board participation from Gilead
Sciences, Bayer Healthcare, Ipsen, Eisai, MSD, Bristol-Myers
Squibb, Roche, AbbVie, CSL Behring, Astra Zeneca, Novartis,
Astellas. PM received Janssen Membership on an entity’s Board
of Directors or advisory committees and Research Funding;
he received membership on an entity’s Board of Directors or
advisory committees from BMS/Celgene, Amgen, Takeda, Pzer,
Caelum Membership. GH received advisory board from Roche.
All the other authors have no conicts of interest to disclose.
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