Stefanie von Matt1, Ulrike Bacher2, Yara Banz3, Behrouz Mansouri Taleghani2, Urban Novak1 and Thomas Pabst1
Department of Medical Oncology; Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
Department of Hematology and Central Hematology Laboratory;
Inselspital, Bern University Hospital, University of Bern, Bern,
3 Institute of Pathology, University of Bern, Bern, Switzerland.
Prof. Thomas Pabst, MD; Department of Medical Oncology; University
Hospital; 3010 Bern; Switzerland. Tel.: +41 31 632 8430; Fax: +41 31
632 3410; E-mail: email@example.com
Published: May 1, 2023
Received: December 30, 2022
Accepted: April 16, 2023
Mediterr J Hematol Infect Dis 2023, 15(1): e2023025 DOI 10.4084/MJHID.2023.025
| This is an Open Access article distributed
under the terms of the Creative Commons Attribution License
which permits unrestricted use, distribution, and reproduction in any
medium, provided the original work is properly cited.
Autologous stem cell transplantation (ASCT) following high-dose
chemotherapy is applied as salvage therapy in patients with relapsed
disease or as first-line consolidation in high-risk DLBCL with
chemo-sensitive disease. However, the prognosis of relapsing DLBCL
post-ASCT remained poor until the availability of CAR-T cell treatment.
To appreciate this development, understanding the outcome of these
patients in the pre-CAR-T era is essential.
Methods: We retrospectively analyzed 125 consecutive DLBCL patients who underwent HDCT/ASCT.
After a median follow-up of 26 months, OS and PFS were 65% and 55%.
Fifty-three patients (42%) had a relapse (32 patients, 60%) or
refractory disease (21 patients, 40%) after a median of 3 months
post-ASCT. 81% of relapses occurred within the first year post-ASCT
with an OS of 19% versus 40% at the last follow-up in patients with
later relapses (p=0.0022). Patients with r/r disease after ASCT had
inferior OS compared to patients in ongoing remission (23% versus 96%;
p<0.0001). Patients relapsing post-ASCT without salvage therapy
(n=22) had worse OS than patients with 1-4 subsequent treatment lines
(n=31) (OS 0% versus 39%; median OS 3 versus 25 months; p<0.0001).
Forty-one (77%) of patients relapsing after ASCT died, 35 of which due
Additional therapies can extend OS but mostly cannot prevent death in
DLBCL relapsing/refractory post-ASCT. This study may serve as a
reference to emerging results after CAR-T treatment in this population.
large B-cell lymphoma, not otherwise specified (DLBCL, NOS) responds
effectively to immunochemotherapy, with R-CHOP (rituximab,
cyclophosphamide, doxorubicin, vincristine, prednisone) being the
first-line standard.[1-6] In up to 60% of patients, this treatment provides definite complete remission.[7,8]
Nevertheless, 30-50% of patients will suffer from relapsed or
progressive disease, mostly within the first two years. The current
treatment of choice for this patient population is salvage chemotherapy
followed by high-dose chemotherapy (HDCT) with peripheral autologous
hematopoietic stem cell transplantation (ASCT).[9-12] The most widely used HDCT regimens are BEAM (carmustine, etoposide, cytarabine, melphalan),[11,13] or BeEAM with bendamustine replacing BCNU.[14,15]
HDCT followed by ASCT is a successful treatment option for many
patients with relapsed DLBCL or high-risk presentation, this treatment
is associated with relevant toxicity; importantly, up to 50% of these
patients will still relapse or are refractory to this treatment.[16-19]
Prognosis of these patients is dismal, and treatment options have been
limited so far. Some r/r patients may not receive further interventions
after HDCT/ASCT due to lack of response to salvage chemotherapy, poor
general condition, or the patient’s request, and they undergo
palliative treatment. For patients eligible for further therapies,
options comprise chemotherapy, immunotherapy, radiotherapy, or
combinations of these, in selected cases, allogeneic hematopoietic stem
cell transplantation, a second ASCT, or, more recently, CAR (chimeric
antigen receptor) T-cell therapy.[11,20]
CAR T-cell therapy is a promising new option for patients with DLBCL
after two or more therapy lines fail. Recent studies have shown
remarkable CR rates of between 40% to 58%.[21-26] On
the other hand, CAR T-cell therapy can be associated with relevant
specific complications, including cytokine release syndrome (CRS) or
CAR T-cell-related encephalopathy syndrome (CRES/ICANS).[21-25,27-29]
We performed a retrospective study to describe the outcome of patients
with DLBCL after HDCT/ASCT and to determine how high-risk or relapsed
DLBCL was managed in clinical practice before the availability of CAR-T
Patients and Methods
single-center, non-interventional, retrospective study analyzed the
outcome of all consecutive patients with relapsed DLBCL or patients
with high-risk presentation who underwent HDCT/ASCT between May 2005
and February 2019 at the University Hospital of Bern, Switzerland.
Treatment for DLBCL prior to HDCT/ASCT was applied in various referring
centers in Switzerland. Inclusion criteria were the diagnosis of either
high-risk DLBCL or relapsed DLBCL (with the subtypes shown in Table 1),
age of at least 18 years at first diagnosis, and sufficient information
on remission status after HDCT with ASCT. Patients with high-risk
presentation who were consolidated with ACST after first-line therapy
had to have a chemo-sensitive disease and had to achieve partial or
complete remission before consolidation.
1. Patient characteristics, lymphoma subtypes, stage and international
prognostic index, B-symptoms, CNS infiltration and infiltration of bone
marrow at first diagnosis in patients with or without relapsed or
refractory disease after ASCT.
were divided into two groups depending on their response to HDCT/ASCT.
The first group included patients with r/r disease after ASCT. The
second group comprised patients in ongoing remission without relapse of
DLBCL. All patients gave written informed consent, and this analysis
was approved by the local ethics committee of Bern, Switzerland.
Clinical data for this study were collected from the local electronic
patient information system at the University Hospital Bern.
Furthermore, information was obtained from the local Management and
Resource System for Stem Cell Transplantation (MARCELL), providing
specific information on the stem cell transplantation procedures at the
University Hospital Bern.
Methods and Definitions. At first diagnosis, patients were staged according to the Ann Arbor classification, and the international prognostic index (IPI) was used for risk stratification.
Remission status was determined according to the revised response
criteria of the international working group for malignant lymphoma
before ASCT, 100 days after ASCT, and at annual follow-up.
Response was classified as complete remission (CR), partial remission
(PR), stable disease (SD), and progressive disease (PD). CR was defined
as complete disappearance of clinical lymphoma evidence and
disease-related symptoms. PR was defined as a measurable disease
reduction of at least 50% and no occurrence of new lesions. Patients
with SD did not fulfill CR/PR or PD criteria. The occurrence of new
lesions or the increase of previously reported tumor masses by more
than 50% were defined as PD.[32,33]
endpoints were overall survival and progression-free survival. PFS was
defined as the time from ASCT until the first evidence of
relapse/progression or death from any cause. OS was defined as the time
from ASCT until death from any cause.
and OS were calculated using the Kaplan-Meier method. Survival
differences between subgroups were identified by the log-rank test.
Univariate analysis was calculated for the factors: age at first
diagnosis, transformed lymphoma vs. de novo origin, presence of
B-symptoms at first diagnosis, bone marrow infiltration at first
diagnosis, radiotherapy administered during first or second-line
therapy, the interval between first-line therapy until
relapse/progression, the performance of CD34+ cell positive selection,
remission status at ASCT, the interval from ASCT to
relapse/progression, number of therapies prior to HDCT/ASCT, and number
of further therapies after post-ASCT relapse. P values of <0.05 were
assumed to be statistically significant. All data were conducted with
GraphPad Prism, and calculations were done by Excel.
This study included 125 consecutive patients with DLBCL who received
HDCT/ASCT either as first-line consolidation due to high-risk
presentation or as salvage therapy for relapsed DLBCL. Clinical
characteristics at first diagnosis are summarized in Table 1.
63% of the patients were male. The median age at first diagnosis was 58
years (range, 23-76 years). DLBCL NOS (not otherwise specified) was the
most common lymphoma subtype (48%). B-symptoms at first diagnosis were
present in 44 patients (35%), bone marrow infiltration and central
nervous system infiltration were observed in 27 (22%) and 13 patients
Transformed lymphoma was present in 23
patients, with 16 (70%) being initially diagnosed with follicular
lymphoma, five (22%) with CLL, and one patient (4%) each with marginal
zone lymphoma or nodular lymphocyte-predominant Hodgkin lymphoma. 73%
of the patients had advanced-stage disease with Ann Arbor stages III
(29 pts; 24%) or IV (59 pts; 49%). IPI for risk stratification at first
diagnosis was a high-intermediate risk in 35 patients (38%) and high
risk in 27 patients (29%).
As described above, patients were
distributed into two groups depending on the disease control (relapse
or progression) after HDCT/ASCT. Both cohorts were comparable regarding
age, gender, lymphoma subtypes, stages, and IPI at first diagnosis (Table 1).
Previous therapies before ASCT. Details on the treatment given before HDCT/ASCT are presented in Table 2.
Patients had a median of two treatment lines before ASCT (range 1-3).
Fifty-one patients (41%) received HDCT/ASCT after only one line of
therapy due to high-risk presentation, 68 patients (55%) after two, and
6 patients (5%) after three lines of treatment. For first-line
treatment, 93% of patients received the CHOP regimen, and 94% of CHOP
chemotherapies were combined with rituximab.
- Table 2. Overview on therapies used in one to three previous lines before ASCT.
High-dose chemotherapy and autologous stem cell transplantation.
HDCT/ASCT was performed after a median interval of 8 months from the
initial diagnosis. Conditioning regimens in 93% were either the BeEAM
(59%) or BEAM (34%). 7% of patients received either melphalan alone or
the combination of carmustine and thiotepa as conditioning treatment.
Detailed information on HDCT and ASCT is presented in Table 3.
- Table 3. Characteristics
of autologous stem cell transplantation (ASCT) in patients with or
without relapsed/ refractory disease after ASCT.
Salvage therapy at relapse/progression after HDCT/ASCT.
Fifty-three patients (42%) developed relapse or progression after a
median interval of 3 months from ASCT (range 1 to 145 months).
Thirty-one patients - 58% of all patients with relapse/progression,
respectively - received further therapies. Twenty-one patients were
treated with one therapy line, and ten patients had two to four
treatment lines for relapsing disease after ASCT, with a median of one
therapy line (range 0 to 4 lines). 22 patients had no further therapy
due to poor general condition or by the patient’s wish.
following further therapies were administered: cytotoxic chemotherapy
(25 patients), radiotherapy (five patients), second HDCT/ASCT (three
patients), and allogeneic hematopoietic stem cell transplantation
(three patients). Three patients received immunotherapy targeting PD-1
(nivolumab: two patients; pidilizumab: one patient), one patient had
blinatumomab, five patients were given ibrutinib, and one patient
received the antibody-drug conjugate brentuximab vedotin, as listed in Table 4.
- Table 4. Therapies patients with relapsed or refractory disease received after ASCT.
Outcome. Details on the outcome of the patients after HDCT/ASCT are depicted in Table 5.
The median follow-up of the entire patient cohort was 26 months.
Forty-four patients (35%) died after a median of six months (range
1-64), 35 (80% of the patients) due to disease progression, six due to
therapy-related reasons (in five cases due to HDCT associated
toxicities, and in one case related to subsequent allogeneic
transplantation) and six from other causes.
- Table 5. Outcome of
patients with or without relapsed or refractory disease after ASCT.
Median follow up, overall survival, progression-free survival, state of
remission, relapse and death.
The median OS of the entire population was 26 months, and the OS rate at the last follow-up was 65% (Figure 1C).
As expected, patients with r/r disease after ASCT had worse overall
survival compared to patients in ongoing remission (OS at last
follow-up: 23% vs. 96%; median OS: 9 vs. 38 months; p <0.0001; Figure 1D).
Progression-free survival (PFS) of the entire cohort at the last
follow-up was 55%, with a median duration of response of 19 months (Figure 1A). Relapsed or refractory disease occurred in 42% of patients after a median interval of 3 months.
factors were identified to be associated with survival rates: interval
of relapse from first-line therapy and interval from HDCT/ASCT, number
of therapies prior to HDCT/ASCT, and the number of treatment lines
after post-ASCT relapse. 38% of patients showed an early relapse after
first-line therapy, defined as relapsed disease or progression within
the first year. These patients had inferior OS and PFS compared to
patients who relapsed after 12 months or later (OS rate at 26 months:
48% vs. 75%, p = 0.0008; PFS rate: 33% vs. 69%, p < 0.0001; Figure 3A/B).
only patients with r/r disease (n=53) following HDCT/ASCT were
considered, early relapse or progression within the first 12 months
after ASCT occurred in 81% of these patients. 19% of the patients had a
late-onset relapse (an occurrence of relapse ≥ 12 months after ASCT).
Patients with early relapse or progression had lower OS than patients
with late onset of relapse post-ASCT (OS rate at 26 months: 19% vs.
40%, p= 0.0009, Figure 3D).
the patients’ outcome regarding the number of therapies prior to HDCT/
ASCT, a significant benefit was observed in those patients who received
HDCT/ASCT after the first-line therapy because of high-risk
presentation (n= 51), compared to those patients who had two to three
lines of treatment prior to HDCT/ASCT (OS rate at 26 months: 78% vs.
55%, p= 0.0161; PFS rate: 75% vs. 42%, p= 0.0054; Figure 4 A/B).
all patients with r/r disease following HDCT/ASCT, the OS rate was only
23% after a median follow-up of 26 months after ASCT. Patients who
received no other therapy despite relapse/progression after ASCT due to
poor general condition or according to the patient’s wish had an even
worse outcome compared to patients with additional treatment line(s) in
this situation (OS rate at 26 months 0% vs. 39%, p >0.0001, Figure 2A).
42% of patients received no further therapy, 40% were treated with one,
and 19% with two or more therapy lines, corresponding to OS rates of 0%
vs. 24% vs. 70% (p> 0.0001; Figure 2B). Thus, in relapsed patients, the OS was longer with an increasing number of therapy lines.
||Figure 1. Progression-free survival (PFS) and overall survival (OS) from ACST represented as the whole cohort of patients (A and B) and compared according to their response to ASCT (C and D).
2. Progression-free survival (PFS) and overall survival (OS) from ASCT
in patients with relapsed or refractory disease after ASCT depending on
receiving further therapies or not (A and B) and on number on subsequent therapy lines (C and D).
||Figure 3. PFS and OS from ASCT depending on the time of relapse after first-line therapy (A and B) or after ASCT (C and D).
||Figure 4. PFS and OS from ASCT depending on number of therapy lines prior to HDCT/ACST (A and B).
No differences were
detected in OS and PFS rates of specific subsets when data were
adjusted for the following variables: de novo versus transformed
lymphoma (OS p=0.7369; PFS p=0.7909), age higher/lower than 60 years
(OS p= 0.3617; PFS p= 0.2655), B-symptoms present at first diagnosis
yes/no (OS p=0.9446; PFS p=0.7619), bone marrow infiltration present at
first diagnosis yes/no (OS p=0.6139; PFS p=0.3870), radiotherapy
administered before ASCT yes/no (OS p=0.4674; PFS p=0.8150), and CR at
ASCT yes/no (OS p=0.4271; PFS p=0.1398) (Supplementary material, Figure S1).
Considering the introduction of CAR-T cell therapies for aggressive lymphatic malignancies in Europe and elsewhere,[24,25]
we aimed to further characterize the outcomes of patients with DLBCL
with a specific focus on those with failure after HDCT/ASCT. We
retrospectively investigated a cohort of 125 patients with DLBCL
treated with HDCT/ASCT in a single academic/ tertiary center and
studied, in particular, the subset of patients who relapsed or
developed progression following HDCT/ASCT and who could have benefited
from CAR-T therapy, had it then been available.
by others, the present study demonstrates that HDCT, followed by ASCT,
provides excellent long-term outcomes in patients with relapsed or
refractory DLBCL, achieving stable remission after this salvage therapy
option.[9,34,35] In our analysis
comprising 125 recipients of HDCT/ASCT due to relapsed DLBCL or
high-risk presentation, the ORR was 61% for the total cohort. That 55%
of patients in ongoing remission following HDCT/ASCT showed encouraging
OS and PFS of 96% with a median duration of 38 months.
contrast, the prognosis for patients with r/r disease after HDCT/ASCT
is poor, especially in those with characteristics such as high IPI or
early relapse within 12 months following ASCT.[11,34]
In our study, 42% of patients developed relapses or showed progression
after HDCT/ASCT. Although 58% of these patients with failure of
HDCT/ASCT received other therapeutic approaches, 77% rapidly died after
a median interval of 6 months, mostly due to lymphoma progression.
Likewise, in the CORAL study, 29% of patients with r/r DLBCL after ASCT
had poor survival, with a median OS of 10 months and a 1-year OS of
We evaluated the impact of various
parameters on the outcomes of our HDCT/ASCT cohort. Significant impact
on survival could only be verified for the duration of the response to
first-line therapy, the duration of response after HDCT/ASCT, the
number of therapies prior to HDCT/ASCT, and the number of subsequent
therapies after post-ASCT relapse. We documented a median interval to
progression following ASCT of only 3 months, and 81% of relapses
occurred within 12 months after ASCT, demonstrating that DLBCL relapses
are associated with rapid kinetics, early manifesting after HDCT/ASCT.
Furthermore, the OS rate was only 19% in patients with early relapses
(<12 months) post-ASCT, as compared to late relapses (≥12 months
after ASCT) with an OS rate of 40%. These results correspond with
previous studies demonstrating early relapses following ASCT in 65-80%
of patients, associated with a significantly worse OS compared to later
time points of relapse.[12,36] Other parameters such as the histopathological origin (transformed vs. de novo DLBCL) [37-41] and CD34+ selection[42-45] had no significant impact on the prognosis of the recipients of HDCT/ASCT in our cohort.
options for patients with r/r DLBCL following ASCT were so far limited.
Allogeneic stem cell transplantation may provide a certain graft versus
lymphoma effect.[46-48] However, only a few DLBCL
patients are, in fact, candidates for this approach due to its high
transplant-related mortality and high relapse rates. Only three
patients in our cohort received an allogeneic SCT, which is
representative of the limited use of this option for r/r DLBCL patients.
CAR-T cell therapies, recently introduced, offer patients with r/r DLBCL a promising new option with CR rates of up to 58%.[24,49,50] In several studies, ORR of 52-85% with 40-58% CR rates were achieved by CAR-T cell therapy in patients with r/r DLBCL.[21,24-26,51,52] However, long-term outcomes will still be awaited in the next decades.
In addition, novel immunotherapies such as polatuzumab vedotin, tafasitamab,
glofitamab, or mosunetuzumab are additional promising new options for
DLBCL patients ineligible for HDCT/ASCT or for those whom CAR-T therapy
is no option due to its toxicity, or due to its logistic or financial
An obvious limitation of our study is its
retrospective single-center design covering a large timespan, including
various DLBCL subtypes, heterogeneity in conditioning regimen, and
inevitable lack of some data in a few patients. Nevertheless, our study
demonstrates the adverse prognosis of DLBCL patients after HDCT/ASCT
failure and the limited efficacy of subsequent therapeutic approaches,
including a second HDCT/ASCT, allogeneic SCT, radiation, cytotoxic
treatment, and traditional monoclonal antibody therapies. Our study
emphasizes the urgent need to make CAR-T cell therapies available to
all patients with r/r DLBCL following HDCT/ASCT failure.
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S1. PFS and OS analyzed according to various parameters like presence
or absence of CD34+ stem cell selection (Figure A and B), transformed
versus de novo lymphoma (Figure C and D), age at first diagnosis <
versus ≥ 60 years (Figure E and F), presence or absence of b symptoms
(Figure G and H) and bone marrow infiltration (Figure I and J) at first
diagnosis, radiotherapy given during first- or second line therapy
(Figure K and L) and remission state at ASCT (Figure M and N).