Long-term impact of prior rituximab therapy and early lymphocyte recovery on auto-SCT outcome for diffuse large B-cell lymphoma

Article (PDF Available)inBone marrow transplantation 47(1):82-7 · February 2011with20 Reads
DOI: 10.1038/bmt.2011.29 · Source: PubMed
Abstract
Early lymphocyte recovery following auto-SCT for non-Hodgkin's lymphoma (NHL) has been reported to be associated with improved outcome. The significance of early lymphocyte recovery following a stem cell transplant in NHL subtype diffuse large B-cell lymphoma (DLBCL) in the rituximab era remains unclear. Patients who underwent an auto-SCT at our institution for DLBCL during the time period 1998-2008 (n=115) were included in the study. Patient characteristics were well-balanced in both rituximab naïve and rituximab-exposed groups. Prior rituximab therapy did not affect lymphocyte recovery on day 14 or day 28. Lymphocyte recovery on day 14 and day 28 and prior rituximab had no impact on survival after auto-SCT for DLBCL, despite early benefit. Other factors such as age, stage at presentation, number of salvage regimens, mobilization procedure, conditioning regimen, pre-transplant radiation therapy and pre-transplant disease status had no impact on survival. Our data showed that the survival benefit with early lymphocyte recovery and prior rituximab seen in previous reports may be lost with longer follow-up. Prior rituximab therapy does not appear to influence the lymphocyte count at days 14 and 28 following auto-SCT. Our findings suggest that future trials should consider manipulating the immune system as a post transplant intervention to improve long-term outcome.
ORIGINAL ARTICLE
Long-term impact of prior rituximab therapy and early lymphocyte
recovery on auto-SCT outcome for diffuse large B-cell lymphoma
DG Stover
1
, VK Reddy
1
, Y Shyr
2
, BN Savani
1,3
and N Reddy
1,3
1
Division of Hematology/Oncology, Vanderbilt University Medical Center, Nashville, TN, USA;
2
Department of Biostatistics,
Vanderbilt University Medical Center, Nashville, TN, USA and
3
Department of Medicine, Vanderbilt University Medical Center,
Nashville, TN, USA
Early lymphocyte recovery following auto-SCT for non-
Hodgkin’s lymphoma (NHL) has been reported to be
associated with improved outcome. The significance of
earlylymphocyterecoveryfollowingastemcelltransplant
in NHL subtype diffuse large B-cell lymphoma (DLBCL)
in the rituximab era remains unclear. Patients who
underwent an auto-SCT at our institution for DLBCL
during the time period 1998–2008 (n ¼ 115) were included
in the study. Patient characteristics were well-balanced in
both rituximab naı
¨
ve and rituximab-exposed groups. Prior
rituximab therapy did not affect lymphocyte recovery on
day 14 or day 28. Lymphocyte recovery on day 14 and day
28 and prior rituximab had no impact on survival after
auto-SCT for DLBCL, despite early benefit. Other factors
such as age, stage at presentation, number of salvage
regimens, mobilization procedure, conditioning regimen,
pre-transplant radiation therapy and pre-transplant disease
status had no impact on survival. Our data showed that the
survival benefit with early lymphocyte recovery and prior
rituximab seen in previous reports may be lost with longer
follow-up. Prior rituximab therapy does not appear to
influence the lymphocyte count at days 14 and 28 following
auto-SCT. Our findings suggest that future trials should
consider manipulating the immune system as a post
transplant intervention to improve long-term outcome.
Bone Marrow Transplantation (2012) 47, 8287;
doi:10.1038/bmt.2011.29; published online 28 February 2011
Keywords:
diffuse large B-cell lymphoma; rituximab; auto-
SCT; early lymphocyte recovery; absolute lymphocyte count
Introduction
Relapsed diffuse large B-cell lymphoma (DLBCL) is often
curable with high-dose therapy followed by auto-SCT. The
Parma trial published in the pre-rituximab era is the only
prospective randomized trial that established auto-SCT as
the standard of care for eligible patients with relapsed
refractory large B-cell lymphoma.
1
Several factors have
been recognized as potential prognostic factors on trans-
plant outcome. In non-Hodgkin’s lymphoma (NHL),
chemotherapy-sensitive disease, rituximab use either at
initial diagnosis or at disease relapse, higher stem cell dose
infusion and relapse greater than 12 months from the time
of initial diagnosis have all been associated with improved
outcome in patients undergoing auto-SCT.
2,3
Rituximab
appears to improve the clinical outcome among patients
undergoing high-dose therapy.
4
Recently it has been
suggested that in patients who received auto-SCT for
NHL, early recovery of the lymphocyte count, defined
typically as an absolute lymphocyte count (ALC), at
approximately 2–4 weeks following therapy has been
associated with superior progression-free and OS in
patients with NHL.
5,6
Recovery of certain lymphocyte subsets suggests anti-
tumor effects of self immune system. Specifically, early
recovery of the natural killer cell subtype is of clinical
significance and may be of prognostic value.
7
Previous studies that have identified early recovery of the
lymphocyte count as an independent prognostic factor in
predicting outcome, grouped several NHL histologies and
did not specifically look at DLBCL. Long-term impact of
rituximab, which is known to deplete B lymphocytes by
binding to the CD20 domain, on early lymphocyte recovery
and transplant outcome is lacking.
To address these major shortcomings, we evaluated
patients with only diffuse large B-cell histology who were
either rituximab naı
¨
ve or exposed to rituximab during their
course of treatment followed by auto-SCT. In this study,
we study the effects of early recovery of the lymphocyte
count on patient outcome.
Patients and methods
Sample size and data collection
One hundred and fifteen consecutive patients who under-
went auto-SCT for relapsed DLBCL at a single institution
between January 1998 and December 2008 were included
in our systematic analysis. In order to perform clinically
meaningful analysis of eight different variables on outcome,
Received 2 August 2010; revised 24 November 2010; accepted 23
December 2010; published online 28 February 2011
Correspondence: Dr N Reddy, Division of Hematology/Oncology,
Department of Medicine, Vanderbilt University Medical Center, 2655
The Vanderbilt Clinic, Nashville, TN 37232-5505, USA.
E-mail: Nishitha.reddy@vanderbilt.edu
Bone Marrow Transplantation (2012) 47, 82–87
& 2012 Macmillan Publishers Limited All rights reserved 0268-3369/12
www.nature.com/bmt
we determined that a sample size of at least 80 patients with
complete data set was required for this study. This study
was approved by the Vanderbilt University Institutional
Review Board, and was in accordance with the United
States Federal Regulations and Declaration of Helsinki.
Patient’s basic demographic data (age, gender), disease-
related information (stage, grade, histology, age at diag-
nosis, stage at diagnosis, and pre-transplant therapy
including presence or absence of rituximab), stem cell
mobilization, conditioning regimens, engraftment, relapse
and survival information were collected from the institu-
tion’s electronic medical record and the social security
death index. OS was defined as the percentage of patients
alive at the completion of the study from diagnosis; death
from any cause defined an event. The primary outcome
analysis of this study was to determine if ALC at day 14
following an auto-SCT in patients with DLBCL can predict
survival in the rituximab era.
DLBCL and histologies
Pathology that was reviewed and confirmed by hemato-
pathologists at Vanderbilt University as DLBCL was
included in the study. Patients with a diagnosis of T-cell-
rich large B cell, histiocytic-rich large B cell and follicular
grade 3 with diffuse B cell-like features were also included.
ALC
ALC (10
9
/L) at 14
±
1 day and 28
±
1 day following auto-
logous stem cell infusion were reported. Based on previous
reports, it was determined that ALCs of 500 cells/mL at day 14
or 1000 cells/mL at day 28 were accepted cutoff values and
could be dichotomized at this level of significance.
First line, salvage, and rituximab exposure
Patients underwent initial treatment with CHOP (CY 750 mg/
m
2
day 1; doxorubicin 50 mg/m
2
day 1; VCR 1.4 mg/m
2
day 1
and prednisone 100 mg/day days 1–5) or R-CHOP. Salvage
therapy consisted of etoposide 40 mg/m
2
on days 1–4;
methylprednisolone 500 mg/m
2
on days 1–5; cytarabine
200 mg/m
2
on day 5 and cisplatin 25 mg/m
2
on days 1–4,
DHAP (dexamethasone 40 mg/day days 1–4, cytarabine 4 g/m
2
day 2 and cisplatin 100 mg/m
2
day 1) or Ifosfamide 5000 mg/
m
2
day 1, etoposide 75 mg/m
2
days 2, 3 and 4, Carboplatin
area under curve (AUC) ¼ 5onday2.Patientswhohadno
exposure to rituximab either at the time of diagnosis or at
relapse were termed rituximab naı
¨
ve, and patients who have
had any exposure during the course of therapy and have
received at least two doses of 375 mg/mt
2
of rituximab before
auto-SCT were defined as being exposed to rituximab.
Stem cell mobilization and conditioning regimens
Stem cells were collected either via peripheral blood or BM
harvest. Patients who were inadequately mobilized from
peripheral blood underwent BM harvest. Stem cells were
mobilized with CY alone, G-CSF alone or with CY and
G-CSF in combination. Conditioning regimens included
the following: 96 patients, CY 7200 mg/m
2
, etoposide
2000 mg/m
2
and BCNU 400 mg/ m
2
, 4 patients received
CY 60 mg/m
2
and TBI 12 Gy, 10 patients received BCNU
300 mg/m
2
, etoposide 100 mg/m
2
, ARA-C 100 mg/m
2
and
melphalan 140 mg/m
2
or BCNU 300 mg/m
2
, etoposide
100 mg/m
2
, ARA-C 100 mg/m
2
and CY 35 mg/kg.
Response criteria
Response criteria were based on guidelines from the
International workshop on NHL.
8
CR was defined as
complete radiological regression of all previous measurable
disease or BM involvement. Partial response was defined
as a reduction of 75% or greater reduction in the sum of
the products of the longest and perpendicular diameter of
measurable lesions. Based on these criteria, all data were
individually verified regarding the best response status just
before auto-SCT after administration of at least 2–4 cycles
of chemotherapy.
Statistical analysis
Data was analyzed using SPSS software (v.17) (SPSS,
Chicago, IL, USA). OS was reported by using Kaplan–Meier
analysis. The difference between survival curves was tested for
statistical significance using log-rank test. ALC at two time
intervals (day 14 and day 28) were assessed as a continuous
variable and dichotomized as either 500 cells/mL at day 14 or
X1000 cells/mL at day 28, as previously described, or as X
median lymphocyte count at day 14 (660 cells/mL) or day 28
(1020 cells/mL). Univariate analysis was performed on several
other disease-related factors that were determined apriori.
The factors analyzed include, remission status at the time of
transplant, stem cell dose, number of chemotherapy regimens
and prior rituximab exposure. w
2
-tests were used to determine
the relationship between all categorical variables. Cox-
proportional hazard model was used for multivariable
analysis. For association between continuous variables and
categories Mann–Whitney U rank sum tests were used. All
P-values reported were two-sided and statistical significance
was declared at Po0.05. Cases with missing values were
deleted from the final analysis.
Results
Patient characteristics
Baseline characteristics are reported in Table 1. A total of one
hundred and ten patients were included in the final analysis.
Five patients were excluded because of lack of complete data
sets. There were no significant differences among patients who
were exposed to rituximab or those who were rituximab naı
¨
ve
regarding age, sex, stage, pre-transplant remission status,
number of pre-transplant regimens or conditioning regimens.
Patients in the rituximab-exposed group did have a statistically
significant number of patients with a diagnosis of DLBCL—
with follicular grade 3 type. Sixty nine (78.4%) patients
continued to be in CR at day 100 post-auto-SCT evaluation.
Nineteen (21.6%) patients had persistent diseases requiring
further therapy. Five patients (5.6%) died before day 100.
OS of patients following auto-SCT
The median survival of patients following auto-SCT for
DLBCL was 78 months (range 3–186 months) (Figure 1a).
Among patients who were rituximab naı
¨
ve, the median
Lymphocyte recovery and auto-SCT outcome in diffuse large B-cell lymphoma
DG Stover et al
83
Bone Marrow Transplantation
survival was 50 months. In patients who had received
rituximab therapy, the median survival was 98 months.
At the time analysis, 69 (60.5%) patients were alive
after median follow-up of 22.3 months (range 3.2–184.3
months). 18 (15.6%) patients were alive beyond 5 years
post-auto-SCT. Prior rituximab showed a initial survival
advantage, however on long-term follow-up, benefit was
lost owing to late relapses (P ¼ 0.12) (Figure 1b).
Univariate and multivariate analysis
In a univariate analysis from the time of auto-SCT, it
appears that prior rituximab therapy significantly improved
the overall outcome of patients with a hazard ratio of 0.5
(95% CI: 0.27–0.95) and P ¼ 0.03. In the multivariate
analysis considering factors such as age, stage and ALC-14,
prior rituximab therapy has no impact on patient outcome
hazard ratio ¼ 0.71 (95% CI: 0.33–1.47) Tables 2 and 3.
The number of salvage regimens required before the
transplant did not appear to have an impact on the overall
outcome of patients in either group.
Pre-transplant disease status and outcome
Forty (56%) patients were in CR and 25 (35%) in PR in the
prior rituximab group compared with 13 (32%) and 17
(41%) in CR and PR, respectively, in the rituximab naı
¨
ve
cohort. The difference in rates of CR did not reach
statistical significance (P ¼ 0.07). Patients with complete
response before the transplant appeared to have a trend
towards improved survival (P ¼ 0.06) (Figure 2a). The
number of salvage regimens before auto-SCT also did not
significantly impact the ALC or survival (Figure 2b).
Lymphocyte recovery and outcome
ALC at day þ 14 (ALC-14) and at day þ 28 (ALC-28)
after auto-SCT were available on 90/110 patients and
85/110 patients, respectively. There was no significant
difference in either ALC-14 or ALC-28 in patients who were
rituximab exposed or naı
¨
ve (Figures 3a and b). Neither
ALC-14 nor ALC-28 was associated with a significant
difference in transplant outcome, irrespective of rituximab
status (Figure 4). Both ALC-14 and ALC-28 were analyzed as
continuous and categorical variables without any significant
difference in outcome. Analyzing ALC neither above or
below 500 cells/mL nor above or below the median ALC
resulted in any significant difference in outcome (data not
shown). Patients with an ALC of 1000 cells/mL at day 28 had
an initial improved survival compared with patients with less
than 1000 cells/mL at day 28 (P ¼ 0.03). This survival benefit
was however lost with long-term follow-up.
Discussion
Our results demonstrate that the early survival advantage
seen post- auto-SCT in patients with an early lymphocyte
recovery is lost with long-term follow-up. The advantages
of prior rituximab exposure were also lost in the long term.
0 50 100 150 200
0
20
40
60
80
100
22±8%
Months
Percent survival
0 50 100 150 200
0
20
40
60
80
100
R-No
R-Yes
P =0.12
26±10.3%
20±9%
Months
Percent survival
Figure 1 (a) OS of 110 patients with DLBCL after auto-SCT. (b) Survival
of all patients who were rituximab naı
¨
ve and rituximab exposed.
Table 1 Baseline characteristics of patients who were exposed to
rituximab and those who were rituximab naı
¨
ve
Patient characteristics Rituximab
(n ¼ 69)
Rituximab naı
¨
ve
(n ¼ 41)
Sex
Male 43 27
Female 26 14
Age at diagnosis
Median 52 years 46 years
Range 24–69 24–64
Stage at diagnosis (%)
(I, II) 36% 29%
(III/IV) 64% 71%
Histology (%)
DLBCL 81% 98%
DLBCL-T-cell-rich B cell 9% 2%
DLBCL-follicular grade 3 10% 0% (P ¼ 0.01)
#Pre-transplant salvage regimens
Mean 1.4 1.3
Range 1–5 1–4
Pre-transplant disease status (%)
CR 56% 32% (P ¼ 0.07)
Partial response 35% 41%
Conditioning regimen (%)
CBV 95% 76%
Cy/TBI 1% 18%
BEAC or BEAM 4% 6%
Abbreviations: BEAC ¼ BCNU, etoposide, ARA-C and CY; CBV ¼ CY,
BCNU and etoposide; DLBCL ¼ diffuse large B-cell lymphoma.
Lymphocyte recovery and auto-SCT outcome in diffuse large B-cell lymphoma
DG Stover et al
84
Bone Marrow Transplantation
Our data also showed prior rituximab had no impact on
early lymphocyte recovery.
The current standard of care for eligible patients with
relapsed DLBCL is high-dose therapy followed by an
auto-SCT. Previous data suggest that lymphocyte recovery
greater than or equal to 500 cells/mL at day þ 14 after auto-
SCT is an independent prognostic factor, and is associated
with improved disease-free and OS in NHL as well as other
hematological malignancies.
7,9,10
These studies however
grouped patients with several histologies. The number of
peripheral blood autograft absolute lymphocytes infused
appear to correlate with day 15 ALC.
11
The role of rituximab on lymphocyte recovery and its
effects on other lymphocyte subsets such as T cells and NK
cells are largely unknown. Rituximab is known to cause
lymphopenia by depleting the B cells. Rituximab does not
appear to impact the T cells or NK cells. These effects may
last for as long as 6 months for full recovery of
lymphocytes.
12
In mantle cell lymphoma, the ALC at day 15 (ALC-15)
following an auto-SCT was associated with a significant
improvement in clinical outcome. ALC-15 X 500 cell/mL
had an improved PFS and OS.
13
The exact mechanism as to
why early lymphocyte recovery would lead to improved
survival in patients following auto-SCT is unclear. It has
been hypothesized that early effective immune recovery
may contribute to the graft vs tumor effect. Our results
however do not draw similar conclusions in DLBCL. The
quantitative early recovery of lymphocytes is effective in
eradicating residual disease as demonstrated by the early
survival advantage. This does not, however, translate to
prolonged disease-free interval suggesting the loss of the
ability of immune reconstituting cells to maintain the graft
vs tumor effect. A recently published study by Porrata
et al.
7
included lymphocyte subset analysis in patients who
were all treated with prior rituximab therapy, reported the
NK cell subset was associated with superior PFS and OS
among a heterogeneous group of NHL patients.
Our study lacks data on lymphocyte subsets. We,
however, report our analysis in a large homogenous
population with the longest follow up of patients. Our
results are in agreement with the published results by
Tiwari et al.,
14
who demonstrated that the routine use of
GM-CSF post transplant alters the prognostic significance
of early lymphocyte recovery.
14
In DLBCL, lymphopenia at the time of diagnosis or
relapse defined as an ALC of o1.0 10
9
/L was an
independent prognostic marker for OS. This was an
independent prognostic factor irrespective of the inter-
national prognostic index.
15,16
Furthermore, the use
of rituximab improves OS in patients with a low ALC.
17
In the future; it would be interesting to see if specific
lymphocyte subsets at the time of relapse can predict
response to chemotherapy, as immune reconstitution
involves several components of the immune response
including reconstitution of functional B cells and effective
APCs, reappearance of CTLs and NK cells that aid in
eradication of minimal residual disease.
18
As rituximab becomes increasingly prominent in the
treatment of DLBCL, understanding its impact on both
long-term disease control as well as host immunity is
critical. Recent studies have suggested that incorporation of
rituximab into not only first-line therapy, but also salvage
Table 2 Univariate analysis of survival
Factor HR 95% CI P-value
Stage I vs II, III and IV
II 2.92 0.38–22.67 0.58
III 3.32 0.44–25.27
IV 2.94 0.38–22.52
Pre-SCT radiation 0.53 0.23–1.21 0.11
Pre-SCT rituximab 0.6 0.32–1.13 0.11
Pre-SCT disease status (CR vs PR) 0.95 0.47–1.9 0.06
Pre-SCT number of chemotherapy
regimens to obtain response
(two or more vs one)
1.53 0.21–11.19 0.19
ALC.14 (4median 660 10
9
/L) 0.93 0.32–2.68 0.89
ALC.14 (4500 10
9
/L) 1.29 0.53–3.18 0.31
ALC.28 (4median 660 10
9
/L) 0.92 0.43–1.94 0.18
Abbreviations: ALC ¼ absolute lymphocyte count; CI ¼ confidence inter-
val; HR ¼ hazard ratio.
Table 3 Multivariate analysis of survival
Factor HR 95% CI P-value
Age 1.01 0.977–1.044 0.56
Stage (I vs others) 1.49 0.700–3.186 0.30
Pre-SCT rituximab 0.70 0.331–1.470 0.34
ALC 14 (4median 660 10
9
/L) 1.00 0.999–1.001 0.73
Abbreviations: ALC ¼ absolute lymphocyte count; CI ¼ confidence inter-
val; HR ¼ hazard ratio.
0
50 100 150 200
0
20
40
60
80
100
CR=yes
CR=No
P =0.06
30.4±10.3%
18.7±8.7%
Months
Percent survival
0 50 100 150 200
0
20
40
60
80
100
S=1 regimen (18±8%)
S 2 regimens (39±20%)
P =0.19
months
Percent survival
Figure 2 (a, b) Survival of patients as a function of pre-transplant disease
status or number of pre-transplant salvage regimens.
Lymphocyte recovery and auto-SCT outcome in diffuse large B-cell lymphoma
DG Stover et al
85
Bone Marrow Transplantation
and even auto-SCT may result in improved outcomes.
4,19
In conjunction with other chemotherapeutic regimens
or auto-SCT, rituximab use has been associated with
prolonged hypogammaglobulinemia and idiopathic neu-
tropenia; however neither of these sequelae has been
definitively associated with increased rate of infection.
20
Less clear, however, is the impact of rituximab on
host immunity and subsequent risk of relapse. Specifically
in DLBCL, loss of major histocompatibility class II
expression was shown to correlate with worse outcome,
theorized to be secondary to impaired host immunosur-
veillance. Infiltration of DLBCL by FOXP3 þ (T-regula-
tory) cells at the time of diagnosis was demonstrated to
correlate with poor outcome.
21,22
Though intriguing, both
of these studies utilized primarily samples from the pre-
rituximab era. As described above, the impact of rituximab
on lymphocyte recovery and subsequent outcomes remains
controversial; two prospective studies of rituximab suggest
significantly different results. As rituximab becomes utilized
in more patients and in multiple stages of treatment, it will
be important to continue to evaluate the short- and long-
term impact of rituximab treatment on host immune
composition and capacity, particularly given the growing
body of evidence supporting a critical host-lymphoma
interaction. Future studies should evaluate the role of
immunomodulatory drugs in an attempt to sustain the
immunosurveillance effects among patients with large
B-cell lymphoma.
In conclusion, this study demonstrates that rituximab
does not have an impact on ALC at day 14 or 28 after auto-
SCT for DLBCL. Rituximab may not hinder lymphocyte
recovery and negatively affect immune reconstitution. The
survival benefit with early lymphocyte recovery and prior
rituximab exposure may be lost with longer follow up.
Future studies should focus on lymphocyte subsets in
the rituximab era. Our study is limited by the inherent
weakness related to its retrospective nature. There is a need
for prospective studies with posttransplant treatment
interventions to prevent late relapses even in patients in
the favorable group with prior rituximab exposure, and
rapid early lymphocyte recovery after auto-SCT.
No rituximab
Rituximab
No rituximab
Rituximab
0
500
1000
1500
ALC14 (k/
μ
l)
0
1000
2000
3000
4000
ALC28 (k/
μ
l)
Figure 3 Effect of rituximab on ALC after auto-SCT on day þ 14
(a, no rituximab n ¼ 22; rituximab n ¼ 65) and day þ 28 (b, no rituximab
n ¼ 19; rituximab n ¼ 65).
0 50 100 150
200
0
20
40
60
80
100
P =0.08
ALC<500 (18.4±9%)
ALC 500 (25.0±21.6%)
Months
Percent survival
0 50 100 150 200
0
20
40
60
80
100
ALC14< 500 (17.5±8.8%)
ALC14>500 (20.7±17.8%)
P =0.31
Months
Percent survival
0 40 80 120 160 200
0
20
40
60
80
100
P=0.09
ALC1000 (25.1±11.7%)
ALC<1000 (20±9.1%)
*46.2±8.6%
*78.7±7.3%
* 5-yr survival (P = 0.03)
Months
Percent survival
0 50 100 150 200
0
20
40
60
80
100
ALC28<median (15.7±8%)
ALC28>median (30.4±11.6%)
P =0.1
Months
Percent survival
Figure 4 OS with DLBCL after auto-SCT as a function of ALC of less than 500 cells/mL vs greater than or equal to 500 cells/mL. (a)Day þ 14 entire
cohort. (b)Day þ 14 only patients who received rituximab. (c)Day þ 28 entire cohort. (d)Day þ 28 only patients who received rituximab.
Lymphocyte recovery and auto-SCT outcome in diffuse large B-cell lymphoma
DG Stover et al
86
Bone Marrow Transplantation
Conflict of interest
The authors declare no conflict of interest.
Acknowledgements
We would like to acknowledge Carole Hunt for her contri-
bution toward this manuscript. Vanderbilt CTSA Grant 1 UL1
RR024975 from NCRR/NIH, and 5K-12 CA090625-09.
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Lymphocyte recovery and auto-SCT outcome in diffuse large B-cell lymphoma
DG Stover et al
87
Bone Marrow Transplantation
    • "In addition to the evaluation of predictive value of different clinical features, we investigated also the impact of early lymphocyte recovery after autoHCT on the outcomes of transplant. Early lymphocyte recovery after autoHCT has been shown to be associated with positive clinical outcome in non-Hodgkin lymphoma [26]. However, there are limited and conflicting data on whether it affects posttransplantation outcome in HL272829. "
    [Show abstract] [Hide abstract] ABSTRACT: Despite the well-defined role of autologous haematopoietic stem cell transplantation (autoHCT) in the treatment of patients with relapsed or refractory Hodgkin lymphoma (HL), relapse remains the main cause of transplant failure. We retrospectively evaluated long-term outcome and prognostic factors affecting survival of 132 patients with refractory (n = 89) or relapsed HL (n = 43) treated with autoHCT following modified BEAM. With a median follow-up of 68 months, the 10-year overall survival (OS) and progression-free survival (PFS) were 76 and 66 %, respectively. The 10-year cumulative incidence of second malignancies was 7 %. In multivariate analysis, age ≥45 years, more than one salvage regimens and disease status at transplant worse than CR were factors predictive for poor OS. In relapsed HL, age at transplant, response duration (<12 vs. ≥12 months) and the number of salvage regimens were independent predictors for PFS. In the refractory setting, disease status at autoHCT and the number of salvage regimens impacted PFS. The number of risk factors was inversely correlated with PFS in both relapsed and refractory HL (p = 0.003 and <0.001, respectively). The median PFS for patients with >1 risk factor in the relapsed and refractory setting was 5 and 11 months, respectively, in comparison with the median PFS not reached for patients with 0-1 risk factor in both settings. We conclude that high proportion of patients with relapsed/refractory HL can be cured with autoHCT. However, the presence of two or more risk factors helps to identify poor prognosis patients who may benefit from novel treatment strategies.
    Full-text · Article · Sep 2013
    • "Therefore, killing by CD20-redirected ATC may further reduce the tumor burden and induce endogenous CD20- specific antilymphoma responses. The use of rituximab has been encouraging but controversial in terms of overall survival benefit when it has been used in preparative regimens or as consolidation after HDC and SCT to reduce the incidence of relapse [2,2425262728293031. Rituximab consolidation after SCT may have improved outcomes for patients with aggressive B cell NHL [25,26,28,31]. "
    [Show abstract] [Hide abstract] ABSTRACT: PURPOSE: A phase I trial of infusing anti-CD3 x anti-CD20 bispecific antibody (CD20Bi) armed activated T cells (aATC) was conducted in high-risk/refractory non-Hodgkins Lymphoma (NHL) patients to determine whether aATC infusions are safe, affect immune recovery, and induce an anti-lymphoma effect. METHOD: Ex vivo expanded ATC from 12 patients were armed with CD20Bi, cryopreserved, and infused after autologous stem cell transplant (SCT). Patients underwent SCT after high dose chemotherapy and aATC infusions were started on day +4. The patients received 1 infusion of aATC/week for 4 weeks after SCT with doses of 5, 10, 15, and 20 x 10(9). RESULTS: aATC infusions were safe and did not impair engraftment. The major side effects were chills, fever, hypotension and fatigue. The mean number of IFN-γ EliSpots directed at lymphoma (DAUDI, p = 0.0098) and NK targets (K562, p < 0.0051) and the mean specific cytotoxicity directed at DAUDI (p=0.037) and K562 (p =0.002) from Pre SCT to post SCT were significantly higher. The increase in IFN-γ EliSpots from pre SCT to post SCT in patients who received armed ATC after SCT were significantly higher than those in patients who received SCT alone (p=0.02). Serum IL-7, IL-15, MIP-1β, IP-10, MIP-1α, and MIG increased within hours after infusion. Polyclonal and specific antibodies were near normal 3 months after SCT. CONCLUSIONS: aATC infusions were safe, increased innate and specific anti-lymphoma cell immunity without impairing antibody recovery after SCT.
    Full-text · Article · Mar 2013
  • Article · Sep 2011