Treatment with Yttrium-90 (90Y)-Ibritumomab
Tiuxetan (Zevalin®) in Diffuse Large B-Cell Llymphoma: A
Meta-Analysis
Sophie
Auger-Quittet, Yohan Duny, Jean-Pierre Daures, Philipe Quittet
Sophie
Auger-Quittet, Internal Medicine, Clinic Beausoleil, Montpellier, France
Yohan
Duny, Jean-Pierre Daures, Biostatistical and Epidemiology, INSERM Unit EA 2415,
Montpellier, France
Philipe
Quittet, Hematology, University Hospital
Saint-Eloi, Montpellier, France
Correspondence to: Sophie AUGER, MD, Internal medicine
department, Clinic Beausoleil, 119 avenue, Lod¨¨ve,
34000 Montpellier, France
Email: Sophie-auger@numericable.fr
Telephone: + 33467759758
Fax: +334679907
Received: February 28,
2015 Revised: April 26, 2015
Accepted: May 1, 2015
Published online: July 6, 2015
ABSTRACT
Background: Diffuse large
B-cell lymphoma (DLBCL) is the most frequently diagnosed non-Hodgkin's lymphoma
(NHL). Current treatment paradigm in first line, is based on immunochemotherapy
and, in case of relapse or refractory, on a salvage therapy with high-dose
chemotherapy followed by autologous stem cell transplantation (ASCT).
Yttrium-90 (90Y)-ibritumomab tiuxetan (Zevalin®), off label, offers a new
therapeutic approach for DLBCL, both as first-line induction or consolidation
and in relapsed or refractory disease. Data on this subject is increasingly
being reported as well in consolidation as alone, in first line or after. To
assess efficacy and find the best place of Zevalin in DLBCL, we conducted a
literature review and meta-analysis of randomized clinical trials and
observational studies on the effect of Zevalin treatment in this setting,
except in ASCT.
Materials and Methods: The primary goal was to assess the effect of Zevalin on overall
response rate (ORR) and complete response rate (CRR) then assess the 2-year
overall survival (OS2y) and 2-year progression-free survival rates (PFS2y).
Results: Sixteen studies
were identified (399 patients) with DLBCL receiving Zevalin as consolidation or
as treatment alone. The ORR and CRR were 74.8% (n=374) and 67.4% (n=365),
respectively. Outcomes were superior when Zevalin is used in consolidation
after immunochemotherapy induction at first line of treatment. OS2y and PFS2y
were 87.5% and 82.8%, respectively. The primary toxicity was neutropenia
(49.9%).
Conclusion: The use of
Zevalin in patients with DLBCL is safe and effective.
© 2015 ACT. All
rights reserved.
Key words: Diffuse Large B cell lymphoma; 90Y-ibritumomab tiuxetan;
Zevalin®; Radioimmunotherapy
Auger-Quittet S,
Duny Y, Daures JP, Quittet P. Treatment with Yttrium-90 (90Y)-Ibritumomab
Tiuxetan (Zevalin®) in Diffuse Large B-Cell Llymphoma: A
Meta-Analysis. International Journal of Hematology Research 2015; 1(2): 61-69
Available from: URL: http://www.ghrnet.org/index.php/ijhr/article/view/1093
IMPLICATIONS FOR PRACTICE
Diffuse large B
cell lymphoma (DLBCL) is currently treated by 8 cycles of immune-chemotherapy
in first line and in case of relapse followed by autologous bone marrow
transplantation. These treatments give often toxicity and are not feasible in
elderly or frail patients. In order to reduce toxicity, we can reduce
chemotherapy. Zevalin® is a radio-immunotherapy, offering a new
therapeutic approach for DLBCL, both as first-line (induction or as
consolidation) or in relapsed or refractory disease.
Zevalin is commonly used in
follicular lymphoma and, several studies have evaluated the use of Zevalin in
DCLBL, but it is not yet uniformly accepted as a treatment in this setting. A
trial is ongoing in elderly patients.
This meta-analysis aims to
give a first assessment of efficacy and safety of use Zevalin® in
DCLBL treatment, and could allow change the actual practice in reducing cycles
of chemotherapy.
INTRODUCTION
The current treatment paradigm for Diffuse large B-cell lymphoma
(DLBCL) in first line is based on immunochemotherapy and, in case of relapse or
refractory, on a salvage therapy with high-dose chemotherapy followed by
autologous stem cell transplantation (ASCT). Use of involved field radiation is
common in case of advanced systemic disease or bulky disease. However, many
patients, particularly the elderly, are not suitable candidates for these
treatments. The principle of radio-immunotherapy offers a new therapeutic
approach for DLBCL, both as first-line (induction or as consolidation) and also
in relapsed or refractory disease.
The use of 90Y-ibritumomab
tiuxetan (Zevalin) in indolent lymphomas has been established as an effective
treatment option[1]. In DLBCL, several studies have evaluated the
use of Zevalin, but it is not yet uniformly accepted as a treatment in this
setting. To date, only one study with a randomized patient population has been
reported[2] and the majority of studies have enrolled patients with
a mix of lymphoma subtypes. One phase 2 study of note was designed to assess
efficacy and safety of Zevalin in consolidation in patients with DCLBL after
chemotherapy induction[3]. In the initial phase 1/2 study in
relapsed or refractory patients with intermediate grade disease[4],
objective response rates were 43% with 29% of patients achieving complete
response (CR). In a multicenter phase 2 trial in relapsed/refractory DLBCL, the
overall response rate (ORR) was 53% in patients pretreated with chemotherapy
while ORR was 19% in patients pretreated with chemotherapy + Rituximab[5].
It remains
important to determine whether Zevalin is an effective treatment option for
DLBCL patients. To provide further evidence, we performed the first non-comparative
meta-analysis of randomized trials, prospective and observational studies on
the effect of Zevalin in patients with DLBCL.
MATERIALS
AND METHODS
Data Sources
and Searches
Overall methods were adapted from MOOS and PRISMA guidelines for
meta-analyses[6,7]. A literature search was conducted to identify
randomized controlled trials and observational studies of Zevalin in adult
patients with DLBCL. On June 30, 2013, a systematic literature search was
performed on the following databases: the National Library of Medicine PubMed
(http://www.ncbi.nlm.nih.gov/pubmed/), the American Society of Hematology
(http://www.hematologylibrary.org/), the European Haematology Association
(http://www.haematologica.org/), and the American Society of Clinical Oncology (http://meetinglibrary.asco.org/abstracts).
The search terms were B cell lymphoma [MeSh] and ZEVALIN® or
yttrium-90 (90Y)-ibritumomab tiuxetan. The results were limited to
studies in adult humans that were reported in the English or French language.
Study Selection
The publication searches, study selection, and data extraction were
carried out independently by two investigators (SA, PQ); discrepancies were
solved by discussion between authors until consensus. Studies were included in
the meta-analysis if they matched all pre-specified eligibility criteria.
Studies were excluded for the following reasons: (1) patients had mantle cell
lymphoma, Richter lymphoma, or indolent lymphoma (except for transformed
follicular lymphoma); (2) patients were <18 years of age; (3) patients had
consolidation with Z-BEAM regimen; and (4) patients had allogeneic stem cell
transplantation. Studies with patient populations of mixed lymphomas were
included if the required data for patients with DLBCL were extractable from the
reports. Studies enrolling fewer than 5 patients were not included due to risk
of extreme bias. Review articles and registers were not included. There was no
restriction in study design and reports in abstract form were allowed. When
duplicate publications were found, only the most complete or most recent
version was retained. For the first screening, titles and abstracts were
reviewed for relevancy. Then, the full-text of each retained article was
scrutinized for whether it met the pre-specified inclusion and exclusion
criteria.
Data Extraction
and Quality Assessment
From eligible studies, two investigators independently extracted data
using selected forms. Between-study variables included information on study
characteristics [author(s), publication year, journal, study design, follow-up
duration], sample characteristics [Ann Arbor stage, International Prognostic
Index (IPI), first-line status, number of prior treatments, use of rituximab in
prior therapy, sample size], type of treatment before Zevalin (drug and
administration route) and outcome definition. For each study, baseline
demographics (mean age, gender), response data [ORR, CR, overall survival (OS),
and progression-free survival (PFS)], and toxicity data (incidence of grade 3/4
hematological and non-hematological adverse events after 90Y-ibritumomab
tiuxetan) were extracted if available. Individual data were used where
possible. Classical tools [ie, Newcastle-Ottawa Scale (NOS) or Jadad scale] to
assess study quality were not utilized in all included studies; therefore, the
investigators chose a quality assessment score on compounded items extracted
from classical quality assessment scales (study design, randomization, and
individual data). This quality assessment is detailed in appendix table I (available
online as a supplementary file). Both reviewers independently assessed study
quality in a blinded manner.
Data Synthesis
and Analysis
The primary assessment for this study was ORR and complete response
rate (CRR). The definition of ORR was based on international criteria.
Secondary assessments included OS, PFS, and grade 3/4 toxicities. For PFS and
OS, the mean values were estimated by including censored data. The mean
duration of platelets <50¡Á109 per liter was also
assessed.
We defined the
effect of Zevalin treatment as a weighted median proportion (event rate). To
account for expected heterogeneity, a mixed effects analysis (random effects
model) is used to combine studies within each subgroup. The study-to-study
variance (tau-squared) is assumed to be the same for all subgroups - this value
is computed within subgroups and then pooled across subgroups. Summary
estimates of event rates were obtained using the fixed effects model method
when heterogeneity was not significant. The percentage of variability beyond
chance was estimated using the I² statistic[8,9]. An I² statistic
for which values are over 50% (p-value<0.1) may indicate substantial
heterogeneity. To explain heterogeneity, the effects of quantitative covariates
on study event rates were investigated using mixed-effects meta-regression
(Method of Moments). Qualitative covariates were investigated using mixed
effects analysis. Results of fixed effects analysis (pwithin) is given as an
indication.
The risk of
publication bias was assessed using the one-tailed Egger¡¯s test[10]
and graphically by the funnel plot, which plots the natural logit of even rate
versus their standard error. Additionally, Duval and Tweedie's trim-and-fill
method was used[11]. A p-value < 0.05 was considered statistically
significant in all analyses. In sensitivity analyses, the impact of study
selection was addressed by a ¡°one-study removed¡± meta-analysis approach.
Secondary
analyses included estimation of ORR and CRR in treatment-naive patients (at
first line), in rituximab-naïve patients, according to use of chemotherapy
associated to Zevalin, according to number of cycle of chemotherapy induction
if it¡¯s used (performed for PFS and OS too), and according to the design of
study.
All analyses
were performed using Comprehensive Meta-analysis [Comprehensive Meta-analysis
Version 2.2.048 November 7, 2008. Biostat, 14 North Dean Street, Englewood, NJ
07631, USA] and STATA (Stata/SE 12.1 for Windows Revision 09 Jul 2013 Copyright
1985-2011 StataCorp LP 4905 Lakeway Drive College Station, TX 77845 USA).
RESULTS
Study Selection
and Description
A flow diagram of the search results is presented in Figure 1.
A total of 221
records were identified through electronic databases. Removing search overlap
and irrelevant studies based on title and abstract review reduced the results
to 36 records. After full-text analysis, 16 studies were selected for inclusion
in the meta-analysis (10 Abstracts, 6 Articles). Study types included 1
randomized trial[2] 1 prospective phase I/II trial[4], 10
phase II trials[3,5,12-20], 1 observational study[21],
and 2 prospective studies[22,23].
Study
characteristics, including design, populations, and outcome are provided in
Table 1.
Across the 16 studies, 399 patients with DLBCL received Zevalin alone or associated with chemotherapy. The dose was administered by intravenous injection at 0.3 or 0.4 mCi/Kg according to platelet count. In 10 studies, patients were treatment-naïve. In 5 studies, patients received only Zevalin in the actual line of treatment without induction therapy. In 8 studies, patients received prior rituximab. The median follow-up was 31.1 months (range, 13.9-51.6). Two publications represented the same study but provided complementary data[13,14] and were thus included together. Strategies were used to check for possible confounding bias (appendix Table I). The studies were classified according to their design.
Overall
Response Rate
The ORR was 74.8% (95% CI, 59.7-85.5) for 374 DCLBL patients after
Zevalin (Figure 2). Heterogeneity was high (I²>50%, p<0.001).
In patients
receiving chemotherapy and Zevalin (n=209), ORR was 90.7% (95% CI,
85.2-94.4). In patients receiving Zevalin alone (n=147), ORR was 49.7%
(95% CI, 41.7-57.8) (Appendix Figure 1A). There was high heterogeneity between
the 2 groups (pbetween<0.001, pwithin=0.64). ORRs were superior in patients
receiving <6 cycles of chemotherapy [90.8% (95% CI, 64.4-98.2) vs¡Ý6 cycles 83.5% (95% CI, 63.6-93.7)] without heterogeneity between
groups (pbetween=0.51, pwithin=0.64).
In patients
receiving Zevalin (alone or with chemotherapy) at first line (n=322),
ORR was 85.9% (95% CI, 71.4-93.7) vs 49.2% (95% CI, 24.1-74.8) in 52 at
second line and plus treated patients (Appendix Figure 1B). Heterogeneity
between the 2 groups was high (pbetween =0.012, pwithin<0.001).
The ORR was
higher for 213 patients having previously received rituximab [80.7% (95% CI,
57.4-92.9)] than for the 143 rituximab-naïve patients [65.2% (95% CI,
35.7-86.4)], without significant heterogeneity between the groups
(pbetween=0.34, pwithin<0.001) (Appendix Figure 1C).
In the
sub-analysis by study design, ORR was higher at 80.7% (95% CI, 65.1-90.3) in
phase II and phase III trials (n=345 patients) than in retrospective
studies [n=29 patients; ORR=49.3% (95% CI, 18.2-80.9)] with
heterogeneity between the 2 groups (pbetween=0.09, pwithin<0.001).
Complete
Response Rate
The CRR was 67.4% (95% CI, 47-82.8) for 365 patients with DLBCL (Figure
3), with high heterogeneity (I² >50%, p<0.001).
For 138
patients receiving Zevalin alone, CRR was 29.1% (95% CI, 22.1-37.3) vs
85.9% (95% CI, 80.3-90.1) for 209 patients receiving associated chemotherapy
(Appendix Figure 2A). Heterogeneity between both groups was high (pbetween<0.001,
pwithin=0.78). CR rates were better in patients receiving <6
cycles of chemotherapy [86.4% (95% CI, 44.6-98)] compared to those receiving ¡Ý 6 cycles [76.8% (95% CI, 50.5-91.4)], without significant
heterogeneity between groups (pbetween=0.59, pwithin<0.001).
In patients
receiving Zevalin (alone or with chemotherapy) at first line (n=322),
the CRR was 79.4% (95% CI, 58.6-91.3) while in patients who were at second line
and plus treated (n=43), the CRR was lower at 32.6% (95% CI, 9.5-69)
(Appendix Figure 2B). Heterogeneity between both groups was high (pbetween=0.03,
pwithin<0.001).
The CRR was
higher for 213 patients having previously received rituximab [72.4% (95% CI,
48.9-87.9)] than for the 134 rituximab-naïve patients [56.9% (95% CI,
27.5-82.4)], without significant heterogeneity between the groups (pbetween=0.40,
pwithin<0.001) (Appendix Figure 2C).
In the
sub-analysis according to study design, the CRR was higher at 75.5% (95% CI,
53.9-89) in phase II and phase III trials (n=336) compared with other studies (n=29;
34% (95% CI, 8-75.8) with heterogeneity between groups (pbetween=0.09,
pwithin<0.001).
2-Year Overall
Survival and 2-Year Progression-Free Survival
For 218 assessable patients, 2-year OS after Zevalin was 87.5% (95% CI,
81.6-91.7) with moderate heterogeneity (I2<50%, p=0.22) (Figure 4).
Two-year PFS
was 82.8% (95% CI, 77-87.3) with nonsignificant heterogeneity (I2=0%,
p=0.57) (Figure 5).
For patients
receiving <6 cycles vs. ¡Ý6 cycles of chemotherapy, 2-year OS and 2-year PFS
were 92.36% (95% CI, 81.5-97.3) and 87.8% (95% CI, 80.6-92.6) vs. 86.5% (95%
CI, 73.7-93.6) and 77.9% (95% CI, 68.5-85.1), respectively. Heterogeneity
between the 2 groups was moderate for OS (pbetween=0.32, pwithin=0.20)
and high for PFS (pbetween=0.05, pwithin=0.95).
The percentage
of relapse for 356 assessable patients was 24.3% (95% CI, 12-43.1) with high
heterogeneity (I2>50%, p<0.001).
Toxicity
Grade 3/4 non-hematologic toxicities were estimated at 11.3% (95% CI,
6.4-19.2): thrombocytopenia at 27.1% (95% CI, 16.5-41.3), and neutropenia at
50.8% (95% CI, 41.5-58.2). A total of 12.3% (95% CI, 5.8-24.1) of 224 patients
received a transfusion. In patients receiving <6 cycles of chemotherapy, 1% (95%
CI, 1-14.3) experienced grade 3/4 non-hematologic toxicity, 21.3% (95% CI,
5.8-54.5) had grade 3/4 thrombocytopenia, 47% (95% CI, 35.9-58.4) had grade 3/4
neutropenia, and 6.9% (95% CI, 2.1-20.7) received a transfusion.
Investigating
heterogeneity
In a univariate mixed-effects meta-regression analysis [evaluating age,
sex, proportion of Ann Arbor stage III/IV, proportion of IPI >2, publication
year, and sample size (Table 2A and B)], ORR and CRR were both significantly
correlated with publication year with superior responses observed in more
recent publications (p=0.01 for both, tau squared=0.74 for ORR and 1.09
for CRR). There was a trend for correlation between ORR and proportion of
patients with Ann Arbor stage III/IV (p=0.12) but the slope was very low
(0.01).
There were no
significant correlation between trial quality (prospective, retrospective,
reported as an abstract or an article, etc.) and ORR or CRR using univariate
mixed effects meta-regression analysis. A ¡°one study removed¡± approach did not
substantially modify results for these parameters (Figure 6).
Publication
bias
Results of an Egger¡¯s test showed significant evidence of publication
bias on ORR (p=0.02). This is consistent with an asymmetrical shape of
the funnel plot shown in Figure 7A. There were three missing studies for ORR.
Adding three studies using a trim-and-fill method reduced ORR (67.2%; 95% CI,
50.7-80.3) (Figures 7A and 7B).
DISCUSSION
The goal of our meta-analysis was to evaluate the role of Zevalin,
associated or not with chemotherapy, in DLBCL patients. This report is unique
in that it is the first, to our knowledge, to show in a large sample of
patients, the clinical outcomes of Zevalin in this setting.
Use of 90Y- ibritumomab tiuxetan in DLBCL resulted in an ORR of 74.8%
and a CRR of 67.4%. In all sub-analyses, the ORR and CRR varied according to
treatment status and chemotherapy induction. Use of Zevalin alone provided poor
outcomes. As expected, response was higher when patients received first-line
Zevalin after chemotherapy induction. Surprisingly, patients who received fewer
than 6 cycles of chemotherapy had superior outcomes compared to those who
received 6 or more cycles. This could be due to less toxicity or an expected
better prognosis in these patients. At 2 years, OS and PFS were 87.5% and
82.8%, respectively.
Current
first-line treatment for DLBCL consists of immunochemotherapy with
cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab (R-CHOP)
or R-CHOP-like therapy for 6 to 8 cycles every 14 days or 21 days. Coiffier et
al report that 6 cycles regimen has resulted in 2- and 5-year PFS and OS rates
of 57% and 54% and 70% and 58%, respectively, but was associated with
significant toxicities, particularly in frail patients (24,25). More recently,
an attenuated dose of R-CHOP was proposed in an attempt to maintain efficacy
and improve safety in elderly patients. Use of R-miniCHOP resulted in 2-year
PFS and OS rates of 47% and 59%, respectively (26). In this study(26), the
three last cycles of R-CHOP were primarily responsible for improved CRR. As
shown in our sub-analysis, <6 cycles of chemotherapy followed by Zevalin
resulted in a CRR equal to or better than 6 cycles with superior 2-year PFS and
OS. In comparison, maintenance therapy with 4 cycles of weekly rituximab, every
6 months during a 2-year span leads to 2-year OS and 2-year PFS of 72% and 71%,
respectively; this was lower than results observed in our study (27).
Relapsed or
refractory patients with DLBCL may benefit from high-dose therapy followed by
ASCT if they are still responding to salvage therapy (28). However, some
patients are not candidates for ASCT due to age and comorbidity and a regimen
that is easily tolerated yet provides a reasonable response rate may be an
attractive alternative to more toxic regimens. Even if treatment with Zevalin
alone showed inferior results, it could be a good option for very frail
patients, in whom an anthracycline-based chemotherapy regimen is not feasible.
Primary
toxicities were neutropenia (49.9%) and thrombocytopenia (31.6%) which were
higher than what was observed with attenuated R-CHOP (26). However, toxicities
decreased when patients received <4 cycles of chemotherapy induction.
We caution
that the results of our analysis are to be interpreted as descriptive and not
comparative. Use of abstracts and no available of individual data were some
limits of this work. Moreover, ideally, formal meta-analyses should solely
include RCTs. While there is a lack of RCTs on the use of Zevalin in the DLBCL
setting, 14 of the 16 included studies were prospective in nature, including 10
phase II trial, which we believe strengthens our findings. No study had a particular
impact, as shown by the ¡®one study removed¡¯ approach. Analysis of publication
bias revealed no evidence of bias for CRR but indicated a lack of 3 studies for
ORR. Therefore, ORR was corrected by adding 3 studies via the trim-and-fill
method giving a corrected ORR of approximately 67%. In comparison, in one study
that utilized attenuated R-CHOP (26), the ORR was 87.5% with 62% achieving CR
and 2-year OS at 59%. Our results showed a lower ORR but better CRR and
patients had an improved 2-year OS.
Despite the use of a random model, the heterogeneity in the design of
the studies may be a limitation to this analysis. The ORR and CRR were found to
be higher in the RCT and prospective studies. The heterogeneity of the studies
was principally related to the type of patients and induction chemotherapy. The
best results for ORR and CRR were obtained in patients at first line when
Zevalin is associated to induction chemotherapy. Use of Rituximab in induction
improved ORR and CRR but did not adequately explain heterogeneity. Patients
were also heterogeneous in terms of age, sex, previous treatment, and year of
publication. We could not explore the previous treatment effect because data
were not always reported. Using univariate meta-regression analysis for year of
publication, ORR and CRR were better in recent publications. One study gives
leverage for ORR and CRR (4). This could be explained by improving
effectiveness of induction chemotherapy but more likely because in recent
studies patients were in first line. Surprisingly, there was no effect on stage
or IPI.
Conlusions
Until the ongoing RCTs that compare Zevalin to other consolidation or
nothing are published, this meta-analysis provides valuable information due to
a large sampling of patients and may provide support for the modification of
current management practices in DCLBL. Place of Zevalin could be at first-line
treatment after induction immunochemotherapy. In frail patients, it could allow
decrease or replace chemotherapy to decrease toxicities and spare the quality
of life.
Acknowledgment
We thank Jean Francois ROSSI, MD, PhD.
Authorship: {S.AUGER;
P.QUITTET}collected data. {S.AUGER; Y.DUNY; JP.DAURES} analyzed the data.
{S.AUGER; P.QUITTET}wrote the paper. All authors reviewed the manuscript.
CONFLICT OF INTERESTS
The authors have no conflicts of interest to declare.
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Peer reviewer: Mingqiang
Ren, Cancer Center of Georgia Regents University, CN-2125C, 1120 15th Street,
Augusta, GA 30912, USA.
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