Download Emerging Role of CD20 Blockade in Allogeneic Hematopoietic Cell

REVIEW
Emerging Role of CD20 Blockade in Allogeneic
Hematopoietic Cell Transplantation
Mohamed A. Kharfan-Dabaja,1,2 Ali Bazarbachi3
There is growing evidence incriminating B lymphocytes in the pathogenesis of graft-versus-host disease
(GVHD). Better understanding of the role of B lymphocytes has uncovered new therapeutic approaches,
such as CD20 blockade, which appear to be improving outcomes in allogeneic hematopoietic cell transplant
recipients. Administration of the chimeric murine/human anti-CD20 monoclonal antibody, rituximab, prior
to hematopoietic cell allografting or as part of preparative regimens appears to reduce treatment-related
mortality and to improve posttransplant outcomes mainly by decreasing the incidence and severity of acute
GVHD. This beneficial effect of rituximab has not had an impact, to the same extent on the incidence of
chronic GVHD, which remains a significant cause of morbidity and mortality following hematopoietic cell
allografting. Alternatively, rituximab has been shown to be effective for treatment of cGVHD, but data is
limited because of the lack of randomized controlled clinical trials and the small sample size in most of
the published series. Incorporation of rituximab into the therapeutic armamentarium of Epstein-Barr
virus-associated posttransplant lymphoproliferative disorder has clearly improved the overall prognosis of
this dreadful disease. This review highlights the evolving role of CD20 blockade in allogeneic hematopoietic
cell transplantation and the need to continue to refine B cell depletion strategies in this setting.
Biol Blood Marrow Transplant 16: 1347-1354 (2010) Ó 2010 American Society for Blood and Marrow Transplantation
KEY WORDS: Allogeneic hematopoietic cell transplantation, CD20 blockade, Rituximab
INTRODUCTION
B lymphocytes play a vital role in humoral immunity mainly by producing antibodies (Abs) responsible
for neutralizing antigens such as microbes or toxins
[1]. There is growing data suggesting that B cells also
contribute to immune response by production of
pro-inflammatory cytokines, antigen presentation,
and other immunoregulatory functions [2-7]. Chronic
graft-versus-host disease (cGVHD) shares clinical and
laboratory manifestations analogous to autoimmune
diseases known to produce Abs against host tissues
[8-10]. There is growing evidence incriminating B
lymphocytes in the pathogenesis of GVHD. Miklos
et al. [11] showed that minor histocompatibility
From the 1Department of Blood and Marrow Transplantation, H.
Lee Moffitt Cancer Center, Tampa, Florida; 2Department of
Oncologic Sciences, H. Lee Moffitt Cancer Center/University
of South Florida, Tampa, Florida; and 3Department of Internal
Medicine, American University of Beirut, Beirut, Lebanon.
Financial disclosure: See Acknowledgments on page 1352.
Correspondence and reprint requests: Mohamed A. KharfanDabaja, M.D., FACP, Department of Blood and Marrow Transplantation, H. Lee Moffitt Cancer Center 12902 Magnolia
Drive, FOB-3, Tampa, FL, 33612 (e-mail: Mohamed.
[email protected]).
Received October 30, 2009; accepted January 7, 2010
Ó 2010 American Society for Blood and Marrow Transplantation
1083-8791/$36.00
doi:10.1016/j.bbmt.2010.01.005
antigens (mHAs) are capable of eliciting B-cell responses in vivo. Development of Abs to several mHAs
encoded on the Y chromosome mostly in male recipients of female hematopoietic cell grafts were strongly
associated with a higher incidence of cGVHD and
maintenance of disease remission [12].
Rituximab, a genetically engineered chimeric murine/human IgG1 k anti-CD20 monoclonal Ab (mAb),
is currently approved by the United States Food and
Drug Administration for the treatment of various
subtypes of B cell non-Hodgkin lymphomas (NHL).
Clinical studies have demonstrated the efficacy of
rituximab for the treatment of autoimmune diseases
such as rheumatoid arthritis [13,14] and immune
thrombocytopenia purpura (ITP) [15], among others.
Rituximab has been shown to be feasible to combine
with allogeneic hematopoietic cell transplantation (alloHCT) preparative regimens, showing an encouraging
lower incidence and severity of acute GVHD (aGVHD)
[16,17]. Rituximab is also effective for treatment of
corticosteroid-refractory cGVHD [18-26]. We hereby
provide a comprehensive review of the growing role of
CD20 blockade in the setting of allo-HCT.
Rituximab as Part of Preparative Regimens for
Hematopoietic Cell Allografting
Developing novel strategies aimed at decreasing
the incidence and severity of GVHD is a definite
1347
1348
M. A. Kharfan-Dabaja and A. Bazarbachi
priority, particularly as the number of allo-HCT using
alternative donors, especially HLA-mismatched, in
recipients of more advanced age continues to grow
worldwide. In 2001, Khouri et al. [16] reported outcomes using a conditioning regimen of intravenous
fludarabine (Flu) and cyclophosphamide (Cy) in 20
patients, at a median age of 51 years (31-68) years,
with follicular NHL (N 5 18) or small lymphocytic
leukemia (N 5 2) who received granulocyte-colony
stimulating factor (G-CSF) mobilized peripheral
blood stem cells (PBSC) from matched-related donors
(MRD) [16]. Nine (45%) of 20 patients received
rituximab at a dose of 375 mg/m2 on day 26 and
1000 mg/m2 on days 11, 18, and 115 postallografting. GVHD prophylaxis consisted of tacrolimus plus
methotrexate (5 mg/m2 on days 11, 13, and 16). In
this study, G-CSF 5 mg/kg was administered daily, via
a subcutaneous route, from day 0 until granulocyte
counts reached above 1 103/mL. All patients achieved
hematopoietic recovery with a median time to neutrophil engraftment of 11 (10-16) days for the 20 patients
who didn’t receive rituximab and 10 days for the 9 patients who did receive rituximab. Interestingly, the
cumulative incidence of grade II-IV aGVHD was
only 20% (95% confidence interval [CI]: 8%-45%).
These results are encouraging especially when considering that rates of aGVHD are generally over 40% [27].
It is unclear whether the beneficial effect of anti-CD20
therapy on aGVHD is the result of B cell depletion per
se or other mechanisms that affect antigen presentation. However, addition of rituximab did not show
a similar benefit on cGVHD where the cumulative
incidence was reported at 64% (95% CI: 38%-88%).
Recently, a follow-up by Khouri et al. [17] reported
encouraging outcomes in 47 consecutive patients,
at a median age of 53 years (33-68 years), with relapsed
follicular NHL who underwent allo-HCT from MRD
(N 5 45) or matched-unrelated donors (N 5 2) using
the same regimen of intravenous Flu, Cy, and rituximab. In this study, rituximab was administered at
a dose of 375 mg/m2 (day 213) and 1000 mg/m2
(days 26, 11, and 18). GVHD prophylaxis consisted
of tacrolimus plus methotrexate (MTX; 5 mg/m2 on
days 11, 13, and 16); an additional MTX dose at
day 111, and 3 doses of intravenous equine antithymocyte globulin (ATG; days 25, 24, and 23) were administered to allograft recipients of unrelated-donor
grafts. Median donor T cells chimerisms on day 130
and day 190 were 89% and 99%, respectively. Graft
failure was reported in 3 cases (1 primary, 2 secondary).
Estimated progression-free survival (PFS) and overall
survival (OS) at a median of 60 (19-94) months
were 83% (95% CI: 69%-91%) and 85% (95% CI:
85%-95%), respectively. The authors report an
impressive incidence of grade II-IV aGVHD of only
11%. Once again, adding rituximab did not show a similar decrease on the overall incidence of cGVHD,
Biol Blood Marrow Transplant 16:1347-1354, 2010
which was reported at 60%. However, the incidence
of extensive cGVHD was 36% (95% CI: 25%-53%).
Interestingly, the fact that only 5 patients were still
undergoing immunosuppressive therapy at the last
follow-up would suggest that the addition of rituximab
might have contributed to reducing the overall burden
of cGVHD.
The relative lack of reduction in the overall incidence of cGVHD is particularly puzzling especially
as peripheral blood CD191 cells remained undetectable up to 9 months following administration of rituximab [17]. This observation suggests that the role of B
lymphocytes in the pathogenesis of cGVHD is only
a small part of the story. The BMT Clinical Trials
Network (BMT CTN) is currently evaluating a multicenter phase II clinical trial (BMT CTN protocol
0701) using intravenous Flu, Cy, and rituximab combination, as previously described [17], in patients with
follicular NHL beyond first complete response to
confirm earlier findings.
Glass et al. [28] reported outcomes of 59 evaluable
(out of 65 enrolled) patients with high-risk aggressive
lymphoma who received a preparative regimen of
Flu, busulfan, and Cy. GVHD prophylaxis consisted
of mycophenolate mofetil plus tacrolimus. Patients
were randomized to receive 4 doses of rituximab starting at days 121 and 1175 postallografting or none.
The 1-year estimated incidence of aGVHD (.grade
I), relapse rate, PFS, and OS in surviving patients
were 73%, 28%, 39%, and 49%, respectively. The
authors report that addition of rituximab did not result
in significant differences in regards to these aforementioned outcomes.
Furthermore, Kharfan-Dabaja et al. [29] has shown
that adding rituximab, to various Flu-based preparative
regimens, at a dose of 375 mg/m2 on days 11 and 18
postallografting, is feasible and does not affect timely
hematopoietic engraftment in a series of 12 patients
with various CD201 hematologic malignancies [29].
In this series, GVHD prophylaxis consisted of tacrolimus plus mycophenolate mofetil (N 5 8) or MTX
(N 5 4). The median donor chimerism at day 190
for unsorted bone marrow (BM), CD3, and CD33 by
polymerase chain reaction/short tandum repeats
(PCR/STR) were 95% (70%-100%), 87.5% (59%100%), and 100% (100%), respectively. The incidence
of grade II-IV aGVHD was 74.6%.
The difference in rates of aGVHD among
these studies could be explained by many factors
including the difference in the proportion of patients
receiving alternative donors [28,29] or mismatched
donors [29], the time and dose of rituximab administration [16,17,28,29], and the cumulative dose of
rituximab administered to the patient, among others.
Unfortunately, most of the data on the use of
rituximab in preparative regimens is from small data
series. These studies are summarized in Table 1.
10%‡
Various FLU-based
regimens
PBSC 5 12
Case series
Kharfan-Dabaja et al. [29], 2008
12
Randomized
Glass et al. [28], 2008
65†
MRD 5 7
MUD 5 3
MMD 5 2
Flu-Bu-Cy±ATG
Flu-Cy
PBSC 5 45
BM 5 2
PBSC 5 59
MRD 5 45
MUD 5 2
MRD 5 17
MUD 5 32
47
Single arm, prospective
Khouri et al. [17], 2008
N indicates number of patients evaluated; MRD, matched-related donor; Flu, fludarabine; Bu, busulfan; Cy, cyclophosphamide; ATG, antithymocyte globulin; MUD, matched-unrelated donor; MMD, mismatched donor;
PBSC, G-CSF mobilized peripheral blood stem cells; BM, bone marrow cells; NRM, nonrelapse mortality; GVHD, graft-versus-host disease.
*Rituximab administered to 9 of 20 patients only.
†Only 59 evaluable for analysis.
‡Represents 100-day mortality.
§Flu-Cy: fludarabine 25 mg/m2 i.v. (days 26 to 22) and cyclophosphamide 1000 mg/m2 i.v. (days 23 and 22) in 11 patients; fludarabine 30 mg/m2 i.v. and cyclophosphamide 750 mg/m2 (days 26 to 24) in 9 patients. FluCy: fludarabine 30 mg/m2 i.v. and cyclophosphamide 750 mg/m2 (days 25 to 23). Flu-Bu-Cy 6 ATG: fludarabine total dose of 125 mg/m2, busulfan total dose of 12 mg/kg, cyclophosphamide total dose of 120 mg/kg;
ATG at discretion of treating physician.
Acute II-IV 5 74.6%
32%
15%
Acute II-IV 5 20%
Chronic 5 64%
Acute II-IV 5 11%
Chronic 5 60%
Acute >I 5 73%
10%
375 mg/m (on day 26) and 1000 mg/m
(on days +1, +8, +15)*
375 mg/m2 (on day 213) and 1000 mg/m2
(on days 26, +1, +8)
375 mg/m2 4 doses each time
starting on days +21 and +175
versus.
None
375 mg/m2 on days +1 and +8
PBSC5 20
Consecutive patients
Khouri et al. [16 ], 2001
20
MRD 5 20
Flu-Cy§
2
Cell Source
Donor Source
N
Study Design
Author [Ref], Year
Table 1. Studies Evaluating Administration of Rituximab in the Peritransplant Setting
Preparative
Regimen
Rituximab Dose and Schedule
2
NRM
Incidence of GVHD
Biol Blood Marrow Transplant 16:1347-1354, 2010
Anti-CD20 Therapy in Allogeneic HCT
1349
An ongoing phase II clinical trial, at the Moffitt
Cancer Center, is currently evaluating a novel preparative regimen for hematopoietic cell allografting
that combines pentostatin, pharmacokinetic-targeted
doses of intravenous busulfan, and rituximab 375
mg/m2 (on days 221, 214, and 27 prior to stem cell
infusion, and on days 11 and 18 postcell infusion).
Of note, in this study rituximab is being administered
only to patients with CD201 expressing malignancies.
Preliminary results of this study will be presented at
the annual meting of the American Society for Blood
and Marrow Transplantation in Orlando, FL in 2010.
Prior Administration of Rituximab Results in
Lower Incidence and Severity of aGVHD
The precise mechanisms by which B cell blockade
reduces the incidence and severity of aGVHD remain
in large part is undefined. Ho et al. [30] evaluated an in
vivo purging approach using standard doses of rituximab administered prior to a conditioning regimen of
BEAM (carmustine, etoposide, cytarabine, and melphalan) plus alemtuzumab. Five patients with follicular
NHL, at a median age of 50.9 years (42.6-55.8 years),
received rituximab 375 mg/m2 4 doses within 12
weeks preceding conditioning therapy. Alemtuzumab
was administered at a dose of 20 mg intravenously on
days 25 to 21. GVHD prophylaxis consisted of cyclosporine. Patients received G-CSF starting on day 17
posttransplantation until neutrophil engraftment. At
a median of 524 (371-719) days, 4 of the 5 patients
were alive and 3 were in complete remission [30].
The authors report cGVHD in 2 patients (1 limited,
1 extensive). The relative small size of this series and
administration of alemtuzumab during the preparative
phase limit the ability to draw objective conclusions
about the potential benefit of administering rituximab
prior to allograft conditioning.
Ratanatharathorn et al. [31] compared outcomes of
allo-HCT recipients with B cell NHL, registered in
the Center for International Blood and Marrow
Transplant (CIBMTR) database between 1999 and
2004, who received (R[1], N 5 179) or did not receive
(R[2], N 5 256) prior rituximab. Median age for R(1)
and R(2) groups were similar (P 5 .42) at 50 years (2267 years) and 50 years (22-70 years), respectively.
Donor recipient sex-matching status was comparable
among the groups (P 5 .76) but the group of patients
who received prior rituximab R(1) had a higher incidence of unrelated donors (32% versus 19%, P 5
.002). Primary endpoint was incidence of grade II-IV
and grade III-IV aGVHD. Prior administration of
rituximab resulted in significant decrease in the cumulative incidence of grade II-IV and grade III-IV
aGVHD (grade II-IV aGVHD in R[1] 5 36% (95%
CI: 29%-43%) and R[2] 5 48% (95% CI: 41%-54%),
P 5 0.01; grade III-IV aGVHD in R[1] 5 12%
1350
M. A. Kharfan-Dabaja and A. Bazarbachi
(95% CI: 8%-18%) and R[2] 5 23% (95% CI: 18%29%), P 5 .002). Prior rituximab did not influence the
cumulative incidence of cGVHD at 3 years (R[1] 5
56% (95% CI: 48%-64%) versus R[2] 5 53% (95%
CI: 47%-60%), P 5 .58). Interestingly, prior treatment with rituximab was associated with lower
treatment-related mortality in multivariable analysis
(relative risk [RR] 5 0.68, 95% CI: 0.47-1.00, P 5
.05) [31]. These findings suggest a beneficial role of
rituximab, preceding allografting, which results in a
lower incidence and severity of aGVHD and relatively
lower treatment-related mortality. However, this
retrospective analysis is limited by the several shortcomings of large registry studies, particularly a nonhomogeneous patient population and donor source,
a variety of conditioning and GVHD prophylaxis
regimens, and observer- and center-dependent differences in assigning GVHD scores, among others.
Prospective randomized trials are certainly needed to
confirm these findings.
Rituximab for Treatment of CorticosteroidRefractory cGVHD
cGVHD remains a significant source of morbidity
and impaired quality of life in patients undergoing
allo-HCT. Limited therapies are available to offer patients with corticosteroid-refractory cGVHD. Additionally, there is no consensus regarding the best
therapy for patients with cGVHD who fail to respond
or progress on systemic corticosteroids treatment.
Ratanatharathorn et al. [32] described the first case using rituximab for treatment of cGVHD manifesting as
refractory ITP, resulting in successful normalization
of platelet counts and remission of cGVHD symptoms. Subsequently, Ratanatharathorn et al. [18]
reported an overall response rate (ORR) of 50% in 8
patients treated for refractory cGVHD with rituximab
375 mg/m2 once a week for 4 doses. Other groups
have shown ORR ranging from 43% to 83% using
similar doses and schedule of rituximab [19-23,25].
Interestingly, Von Bonin et al. [24] reported an ORR
of 69% using a lower dose of rituximab at 50 mg/m2
weekly in a series of 13 patients treated for corticosteroid-refractory cGVHD.
A systematic review and meta-analysis by KharfanDabaja et al. [26] reported a pooled proportion of ORR
and mortality of 66% (95% CI: 57%-74%) and 15.8%
(95% CI: 8.3%-25.3%), respectively. The pooled
proportions of ORR according to organ-specific
responses were as follows: skin, 60% (95% CI: 41%78%), oral mucosa, 36% (95% CI: 12%-65%), hepatic,
29% (95% CI: 12%-51%), gastrointestinal, 31%
(95% CI: 7%- 62%), and pulmonary, 30% (95% CI:
11%-53%) [26]. Responses to ocular and musculoskeletal cGVHD were also observed, ranging from 13%38% and 75%-100%, respectively [18,22,24,26]. The
Biol Blood Marrow Transplant 16:1347-1354, 2010
totality of evidence demonstrates that the skin is
the most responsive organ, particularly in cases of
lichenoid or sclerodermatous cGVHD [26]. These
results are summarized in Table 2.
Interestingly, administration of rituximab was also
shown to facilitate dose reduction of corticosteroids.
For instance, Mohty et al. [23] reported 86% median
dose reduction of glucocorticoids in 11 (73%) of 15
cases treated with rituximab. Similarly, Cutler et al.
[20] reported a 75% median dose reduction of systemic
corticosteroids more than two-thirds of patients
treated with rituximab. Larger multicenter prospective
trials using a uniform response criterion are needed to
better establish the efficacy of rituximab for the treatment of cGVHD.
Rituximab for Treatment of Posttransplant
Lymphoproliferative Disorder (PTLD)
PTLD is a relatively rare but serious complication
of immunosuppression in recipients of solid organ
or HCT [33]. The majority of cases are of B-cell origin
with expression of CD20 [34-36]. PTLD is commonly
associated with active Epstein-Barr virus (EBV)
infection and are invariably found in the setting of
T cell dysfunction [34,37].
The incidence of PTLD in the setting of allo-HCT
has been reported to range between 0.2% to 1.2%, and
the majority of cases occur within the first year of transplantation [38-40]. Patients with acquired aplastic
anemia who received prior ATG were reported to
have an incidence of PTLD as high as 13% [40]. Risk
factors associated with development of PTLD in the
post-allo-HCT setting include T cell depletion, older
age at transplantation, immune deficiency, and ATG
use [38-41]. Use of an anti-CD3 mAb has also been
reported to be associated with PTLD [40].
Early recognition, withdrawal of immunosuppression, and prompt administration of rituximab have
been shown to improve outcomes in patients with
PTLD in the setting of allogeneic HCT as well as solid
organ transplantation [42-45]. The first successful use
of rituximab for treatment of PTLD in the setting of
allo-HCT was reported by Faye et al. [46] in 1998.
Subsequently, small series have shown that rituximab
administered at a dose of 375 mg/m2 once a week for
4 doses induces ORRs ranging from 66% to 83% in
patients with PTLD [44,47]. Monitoring for EBV
using quantitative PCR and preemptive treatment
with rituximab is a reasonable strategy in recipients
of T cell-depleted allografts or when using ATG
[48,49].
Addition of rituximab to the therapeutic armamentarium for PTLD has clearly improved prognosis of
this previously dreadful disease, which used to be
associated with a mortality of over 90% in the prerituximab era [39]. Additional strategies involving cellular
Biol Blood Marrow Transplant 16:1347-1354, 2010
Anti-CD20 Therapy in Allogeneic HCT
1351
Table 2. Studies Evaluating the Efficacy of Rituximab in Patients with Corticosteroid-Refractory cGVHD
Author [Ref], Year
N
Median (Range)
Age
Rituximab Dose No. of Doses
ORR %
Organ-Specific Response
Ratanatharathorn
et al. [18 ], 2003
Retrospective
case series
8
46 (28-58)
375 mg/m2 weekly 4
50%
Canninga-Van Dijk,
et al. [19], 2004
Prospective
(not controlled)
6
37 (17-50)
375 mg/m2 weekly 4
83%
Cutler et al. [20], 2006
Prospective
(not controlled)
Prospective
(not controlled)
30*
42 (21-62)
375 mg/m2 weekly 4
68%
3
35 (33-42)
375 mg/m2 weekly 4
Dermatologic (1/8, 13%)
Ophthalmic (1/8, 13%)
Hepatic (0/8, 0%)
Pulmonary (1/3, 33%)
Dermatologic (5/6, 83%)
Hepatic (2/5, 40%)
Oral mucosa (5/6, 83%)
Dermatologic (52% decrease
in BSA by 1 year)
Dermatologic (3/3, 100%)
Ophthalmic (0/3, 0%)
Hepatic (0/2, 0%)
Pulmonary (0/1, 0%)
Dermatologic (63%)
Ophthalmic (43%)
Hepatic (25%)
Gastrointestinal (75%)
Pulmonary (38%)
Oral mucosa (30%)
Musculoskeletal (80%)
Dermatologic (69%)
Hepatic (66%)
Gastrointestinal (20%)
Pulmonary (0%)
Dermatologic (5/9, 56%)
Ophthalmic (0/4, 0%)
Hepatic (0/3, 0%)
Gastrointestinal (0/2, 0%)
Pulmonary (0/2, 0%)
Oral mucosa (4/8, 50%)
NE
Okamoto et al. [21], 2006
Study Design
NE
Zaja et al. [22], 2007
Retrospective
38
48 (22-61)
375 mg/m2 weekly 4
65%
Mohty et al [23], 2008
Retrospective
15
50 (20-67)
375 mg/m2 weekly 4
66%
Von Bonin et al. [24], 2008
Retrospective
13
60 (40-67)
50 mg/m2 weekly 3
69%
Teshima et al. [25], 2009
Prospective
case series
7
48 (24-55)
375 mg/m2 weekly 4
Kharfan-Dabaja
et al. [26], 2009
Systematic
review/meta-analysis†
43%
CR 5 0%
PR 5 43%
SD 5 43%
66%‡
111
—
50 mg/m2 and 375 mg/m2
Dermatologic (60%)‡
Hepatic (29%)‡
Gastrointestinal (31%)‡
Pulmonary (30%)‡
Oral mucosa (36%)‡
N indicates number of patients evaluated; ORR, overall response rate; CR, complete response; PR, partial response; SD, stable disease; NE, not extractable; BSA, body surface area; cGVHD, chronic graft-versus-host disease.
*Only 28 patients were evaluable.
†Did not include Teshima et al. [25], which was not published at time meta-analysis was performed.
‡Represents pooled proportion.
immunotherapy such as EBV-specific cytotoxic T
lymphocytes have proven to be effective but remain experimental at this time [50].
DISCUSSION
Antigen presentation necessary for optimal T cell
proliferation and response is mediated by a number
of cell types including B lymphocytes [51,52]. B cells
may have both pathogenic and protective roles in
alloreactivity. Crawford et al. [53] has shown that B
cells provide additional and essential antigen presentation capabilities above that provided by dendritic cells,
promoting expansion and permitting the generation of
memory and effector T cells. Using a B cell-deficient
mouse model where mice received rabbit anti-m IgM
for B cell depletion or rabbit immunoglobulin as
control, Schultz et al. [54] demonstrated that B cells
are necessary for T cell priming to minor histocompatibility antigens and development of GVHD. In addition, clinical studies evaluating adult haploidentical
hematopoietic cell transplantation have shown that
profound T cell and B cell depletion is a promising
strategy that results in fast engraftment kinetics and
relatively reduced rates of GVHD in this setting
[55]. Apart from CD34 cells, CD3/CD19-depleted
allografts also contain CD342 progenitors, graftfacilitating cells, and natural killer (NK) cells [55].
NK cells have been shown to play a significant role
in modulating and enhancing the ability of B lymphocytes to process and present antigens to T cells [56].
Correlative studies have also shown that elevated
levels of B cell activating factor (BAFF), a key regulator
of normal B lymphocyte homeostasis, is associated
with increased disease activity in patients with
1352
M. A. Kharfan-Dabaja and A. Bazarbachi
cGVHD [57]. Commercial availability of diagnostic
tests to measure BAFF could provide the basis for
preemptive strategies that may allow for earlier
therapeutic intervention in patients with cGVHD
[57]. This could potentially reduce morbidity from
cGVHD, especially if treatment is initiated before
severe clinical symptomatology and irreversible organ
damage ensues. Moreover, direct inhibition of BAFF
represents an attractive B cell depleting strategy for
treatment of GVHD. A recombinant fully humanized
IgG1 l mAb, namely belimumab, capable of binding
BAFF/BlyS with high affinity and preventing its binding to BAFF receptors, was found to be well tolerated
and to reduce peripheral B cell levels in patients with
systemic lupus erythematosus [58].
Better understanding of the role of B lymphocytes
in the pathogenesis of GVHD has uncovered new
therapeutic approaches, such as CD20 blockade, that
are improving outcomes in allogeneic HCT recipients.
As detailed above, administration of rituximab prior to
allogeneic HCT or as part of preparative regimens
appears to improve clinical outcomes, mostly by
decreasing the incidence and severity of aGVHD
[16,17,31]. This beneficial effect of rituximab has not
had an impact on the incidence of cGVHD to the
same extent. Interestingly, cGVHD occurs despite
undetectable levels of B lymphocytes, for up to
9 months, following administration of rituximab [17].
This clearly highlights our limited understanding of
the role(s), direct or indirect, of B lymphocytes in the
pathogenesis of cGVHD. The heterogeneity of rituximab dosing regimens used in clinical studies (or small
series) reported herein in regard to dose administered,
frequency of administration, and cumulative rituximab
exposure is noteworthy. Studies reported by Khouri
et al. [16,17] suggest that using higher doses of
rituximab (1000 mg/m2) results in lower incidence of
aGVHD [16,17]. However, prospective randomized
studies comparing high-dose (1000 mg/m2) versus
standard dose (375 mg/m2) rituximab using similar
schedule of administration are necessary to address
this issue.
Rituximab has also been shown to be effective for
treatment of cGVHD involving various organs [1826]. Responses to rituximab were observed even at
a weekly low dose of 50 mg/m2 [24]. The ability of
rituximab to facilitate tapering down the dose of
corticosteroids is particularly remarkable because
chronic exposure to increased cumulative doses of
corticosteroids results in detrimental outcomes in
patients with corticosteroid-refractory cGVHD. Conceptually, earlier intervention with CD20 blockade in
combination with corticosteroids, represents a logical
approach that could potentially facilitate a faster
taper of corticosteroids. An ongoing phase II clinical
trial led by Stanford University (ClinicalTrials.gov
Identifier: NCT00350545) is evaluating whether
Biol Blood Marrow Transplant 16:1347-1354, 2010
administration of 4 weekly doses of rituximab as
first-line treatment for cGVHD will allow tapering
prednisone to a dose of 0.25 mg/kg/day by 6 months
without clinical flare-up.
As the use of rituximab continues to expand, it is
important to balance the benefits of rituximab therapy
against the potential risks of developing serious infections [59]. A theoretical concern with CD20 blockade
in the setting of hematopoietic cell allografting is the
potential to blunt the adoptive graft-versus-tumor response by interfering with B cell antigen presentation
and consequently tumor-directed alloreactivity.
Finally, incorporation of rituximab into the therapeutic armamentarium of PTLD has clearly improved
the overall prognosis of patients who develop PTLD
following allo-HCT or solid organ transplantation.
Early recognition of PTLD, especially in high-risk
cases, discontinuation of immune suppression whenever possible, and prompt initiation of rituximab,
before rapid progression, are strategies that result in
improved responses when treating PTLD.
ACKNOWLEDGMENTS
Financial disclosure: The authors have nothing to
disclose.
REFERENCES
1. Abbas AK, Lichtman AH, Pober JS. B cell activation and antibody production. In: Cellular and Molecular Immunology,
3rd ed. Philadelphia, PA: W.B. Saunders Company; 1997
p. 195-212.
2. Schultze JL, Michalak S, Seamon MJ, et al. CD40-activated
human B cells: an alternative source of highly efficient antigen presenting cells to generate autologous antigen-specific
T cells for adoptive immunotherapy. J Clin Invest. 1997;100:
2757-2765.
3. von Bergwelt-Baildon MS, Vonderheide RH, Maecker B, et al.
Human primary and memory cytotoxic T lymphocyte responses
are efficiently induced by means of CD40-activated B cells as antigen-presenting cells: potential for clinical application. Blood.
2002;99:3319-3325.
4. Schaerli P, Willimann K, Lang AB, Lipp M, Loetscher P,
Moser B. CXC chemokine receptor 5 expression defines follicular homing T cells with B cell helper function. J Exp Med. 2000;
192:1553-1562.
5. Harris DP, Haynes L, Sayles PC, et al. Reciprocal regulation of
polarized cytokine production by effector B and T cells. Nat
Immunol. 2000;1:475-482.
6. Do RK, Chen-Kiang S. Mechanism of BLyS action in B cell
immunity. Cytokine Growth Factor Rev. 2002;13:19-25.
7. Kayagaki N, Yan M, Seshasayee D, et al. BAFF/BLyS receptor 3
binds the B cell survival factor BAFF ligand through a discrete
surface loop and promotes processing of NF-kappaB2. Immunity. 2002;17:515-524.
8. Patriarca F, Skert C, Sperotto A, et al. The development of autoantibodies after allogeneic stem cell transplantation is related
with chronic graft-vs-host disease and immune recovery. Exp
Hematol. 2006;34:389-396.
9. Svegliati S, Olivieri A, Campelli N, et al. Stimulatory autoantibodies to PDGF receptor in patients with extensive chronic
graft-versus-host disease. Blood. 2007;110:237-241.
Anti-CD20 Therapy in Allogeneic HCT
Biol Blood Marrow Transplant 16:1347-1354, 2010
10. Ratanatharathorn V, Ayash L, Lazarus HM, Fu J, Uberti JP.
Chronic graft-versus-host disease: clinical manifestation and
therapy. Bone Marrow Transplant. 2001;28:121-129.
11. Miklos DB, Kim HT, Zorn E, et al. Antibody response to DBY
minor histocompatibility antigen is induced after allogeneic
stem cell transplantation and in healthy female donors. Blood.
2004;103:353-359.
12. Miklos DB, Kim HT, Miller KH, et al. Antibody responses to
H-Y minor histocompatibility antigens correlate with chronic
graft-versus-host disease and disease remission. Blood. 2005;
105:2973-2978.
13. Cohen SB, Emery P, Greenwald MW, et al. Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy:
results of a multicenter, randomized, double-blind, placebocontrolled, phase III trial evaluating primary efficacy and safety
at twenty-four weeks. Arthritis Rheum. 2006;54:2793-2806.
14. Jois RN, Masding A, Somerville M, Gaffney K, Scott DG. Rituximab therapy in patients with resistant rheumatoid arthritis:
real-life experience. Rheumatology (Oxford). 2007;46:980-982.
15. Saleh MN, Gutheil J, Moore M, et al. A pilot study of the antiCD20 monoclonal antibody rituximab in patients with refractory immune thrombocytopenia. Semin Oncol. 2000;27(Suppl
12):99-103.
16. Khouri IF, Saliba RM, Giralt SA, et al. Nonablative allogeneic
hematopoietic transplantation as adoptive immunotherapy for
indolent lymphoma: low incidence of toxicity, acute
graft-versus-host disease, and treatment-related mortality. Blood.
2001;98:3595-3599.
17. Khouri IF, McLaughlin P, Saliba RM, et al. Eight-year experience with allogeneic stem cell transplantation for relapsed follicular lymphoma after nonmyeloablative conditioning with
fludarabine, cyclophosphamide, and rituximab. Blood. 2008;
111:5530-5536.
18. Ratanatharathorn V, Ayash L, Reynolds C, et al. Treatment of
chronic graft-versus-host disease with anti-CD20 chimeric
monoclonal antibody. Biol Blood Marrow Transplant. 2003;9:
505-511.
19. Canninga-van Dijk MR, van der Straaten HM, Fijnheer R,
Sanders CJ, van den Tweel JG, Verdonck LF. Anti-CD20
monoclonal antibody treatment in 6 patients with therapyrefractory chronic graft-versus-host disease. Blood. 2004;104:
2603-2606.
20. Cutler C, Miklos D, Kim HT, et al. Rituximab for steroidrefractory chronic graft-versus-host disease. Blood. 2006;108:
756-762.
21. Okamoto M, Okano A, Akamatsu S, et al. Rituximab is effective
for steroid-refractory sclerodermatous chronic graft-versus-host
disease. Leukemia. 2006;20:172-173.
22. Zaja F, Bacigalupo A, Patriarca F, et al. Treatment of refractory
chronic GVHD with rituximab: a GITMO study. Bone Marrow
Transplant. 2007;40:273-277.
23. Mohty M, Marchetti N, El-Cheikh J, Faucher C, Furst S,
Blaise D. Rituximab as salvage therapy for refractory chronic
GVHD. Bone Marrow Transplant. 2008;41:909-911.
24. von Bonin M, Oelschlagel U, Radke J, et al. Treatment of
chronic steroid-refractory graft-versus-host disease with lowdose rituximab. Transplantation. 2008;86:875-879.
25. Teshima T, Nagafuji K, Henzan H, et al. Rituximab for the
treatment of corticosteroid-refractory chronic graft-versushost disease. Int J Hematol. 2009;90:253-260.
26. Kharfan-Dabaja MA, Mhaskar AR, Djulbegovic B, Cutler C,
Mohty M, Kumar A. Efficacy of rituximab in the setting of steroid-refractory chronic graft-versus-host disease: a systematic
review and meta-analysis. Biol Blood Marrow Transplant. 2009;
15:1005-1013.
27. Hari P, Carreras J, Zhang MJ, et al. Allogeneic transplants in follicular lymphoma: higher risk of disease progression after reduced-intensity compared to myeloablative conditioning. Biol
Blood Marrow Transplant. 2008;14:236-245.
28. Glass B, Hasenkamp J, Gorlitz A, et al. Rituximab for graftversus-host disease-prophylaxis after allogeneic stem cell
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
1353
transplantation given as treatment of high risk relapse of aggressive lymphoma: results of a randomized phase II study. Blood.
2008;112:689-690 (abs# 1974).
Kharfan-Dabaja MA, Tate C, Perkins J, et al. Rituximab is feasible to administer to allograft recipients with advanced CD201
malignancies and does not affect timely hematopoietic engraftment. Biol Blood Marrow Transplant. 2008;14(Suppl 2):121-122
(abs# 330).
Ho AY, Devereux S, Mufti GJ, Pagliuca A. Reduced-intensity
rituximab-BEAM-CAMPATH allogeneic haematopoietic stem
cell transplantation for follicular lymphoma is feasible and induces durable molecular remissions. Bone Marrow Transplant.
2003;31:551-557.
Ratanatharathorn V, Logan B, Wang D, et al. Prior rituximab
correlates with less acute graft-versus-host disease and better
survival in B-cell lymphoma patients who received allogeneic peripheral blood stem cell transplantation. Br J Haematol. 2009;
145:816-824.
Ratanatharathorn V, Carson E, Reynolds C, et al. Anti-CD20
chimeric monoclonal antibody treatment of refractory immune-mediated thrombocytopenia in a patient with chronic
graft-versus-host disease. Ann Intern Med. 2000;133:275-279.
Svoboda J, Kotloff R, Tsai DE. Management of patients with
post-transplant lymphoproliferative disorder: the role of rituximab. Transpl Int. 2006;19:259-269.
Hanto DW, Frizzera G, Gajl-Peczalska KJ, Simmons RL.
Transplantation. 1985;39:461-472.
Hanto DW, Birkenbach M, Frizzera G, et al. Confirmation of
the heterogeneity of posttransplant Epstein-Barr virus-associated B cell proliferations by immunoglobulin gene rearrangement analyses. Transplantation. 1989;47:458-464.
Gottschalk S, Rooney CM, Heslop HE. Post-transplant lymphoproliferative disorders. Annu Rev Med. 2005;56:29-44.
Cohen JI. Epstein-Barr virus lymphoproliferative disease associated with acquired immunodeficiency. Medicine (Baltimore).
1991;70:137-160.
Landgren O, Gilbert ES, Rizzo JD, et al. Risk factors for lymphoproliferative disorders after allogeneic hematopoietic cell
transplantation. Blood. 2009;113:4992-5001.
Gross TG, Steinbuch M, DeFor T, et al. B cell lymphoproliferative disorders following hematopoietic stem cell transplantation: risk factors, treatment and outcome. Bone Marrow
Transplant. 1999;23:251-258.
Curtis RE, Travis LB, Rowlings PA, et al. Risk of lymphoproliferative disorders after bone marrow transplantation: a multiinstitutional study. Blood. 1999;94:2208-2216.
Buyck HC, Ball S, Junagade P, Marsh J, Chakrabarti S. Prior immunosuppressive therapy with antithymocyte globulin increases
the risk of EBV-related lymphoproliferative disorder following
allo-SCT for acquired aplastic anaemia. Bone Marrow Transplant. 2009;43:813-816.
Tsai DE, Hardy CL, Tomaszewski JE, et al. Reduction in immunosuppression as initial therapy for posttransplant lymphoproliferative disorder: analysis of prognostic variables and
long-term follow-up of 42 adult patients. Transplantation.
2001;71:1076-1088.
Oertel SH, Verschuuren E, Reinke P, et al. Effect of anti-CD
20 antibody rituximab in patients with post-transplant lymphoproliferative disorder (PTLD). Am J Transplant. 2005;5:
2901-2906.
Milpied N, Vasseur B, Parquet N, et al. Humanized anti-CD20
monoclonal antibody (Rituximab) in post transplant B-lymphoproliferative disorder: a retrospective analysis on 32 patients.
Ann Oncol. 2000;11(Suppl 1):113-116.
Choquet S, Leblond V, Herbrecht R, et al. Efficacy and safety of
rituximab in B-cell post-transplantation lymphoproliferative
disorders: results of a prospective multicenter phase 2 study.
Blood. 2006;107:3053-3057.
Faye A, Van Den Abeele T, Peuchmaur M, et al. Anti-CD20
monoclonal antibody for post-transplant lymphoproliferative
disorders. Lancet. 1998;352:1285.
1354
M. A. Kharfan-Dabaja and A. Bazarbachi
47. Faye A, Quartier P, Reguerre Y, et al. Chimaeric anti-CD20
monoclonal antibody (rituximab) in post-transplant B-lymphoproliferative disorder following stem cell transplantation in children. Br J Haematol. 2001;115:112-118.
48. Weinstock DM, Ambrossi GG, Brennan C, Kiehn TE,
Jakubowski A. Preemptive diagnosis and treatment of
Epstein-Barr virus-associated post transplant lymphoproliferative disorder after hematopoietic stem cell transplant: an
approach in development. Bone Marrow Transplant. 2006;37:
539-546.
49. Lowe T, Bhatia S, Somlo G. Second malignancies after allogeneic hematopoietic cell transplantation. Biol Blood Marrow
Transplant. 2007;13:1121-1134.
50. Heslop HE, Perez M, Benaim E, Rochester R,
Brenner MK. Transfer of EBV-specific CTL to prevent
EBV lymphoma post bone marrow transplant. J Clin Apher.
1999;14:154-156.
51. Constant S, Schweitzer N, West J, Ranney P, Bottomly K. B
lymphocytes can be competent antigen-presenting cells for
priming CD41 T cells to protein antigens in vivo. J Immunol.
1995;155:3734-3741.
52. Liu Y, Wu Y, Ramarathinam L, et al. Gene-targeted B-deficient
mice reveal a critical role for B cells in CD4 T cell response. Int
Immunol. 1995;7:1353-1362.
Biol Blood Marrow Transplant 16:1347-1354, 2010
53. Crawford A, MacLeod M, Schumacher T, Corlett L, Gray D.
Primary T cell expansion and differentiation in vivo requires antigen presentation by B cells. J Immunol. 2006;176:3498-3506.
54. Schultz KR, Paquet J, Bader S, HayGlass KT. Requirement for
B cells in T cell priming to minor histocompatibility antigens
and development of graft-versus-host disease. Bone Marrow
Transplant. 1995;16:289-295.
55. Bethge WA, Haegele M, Faul C, et al. Haploidentical allogeneic
hematopoietic cell transplantation in adults with reducedintensity conditioning and CD3/CD19 depletion: fast engraftment and low toxicity. Exp Hematol. 2006;34:1746-1752.
56. Jennings P, Yuan D. NK cell enhancement of antigen presentation by B lymphocytes. J Immunol. 2009;182:2879-2887.
57. Sarantopoulos S, Stevenson KE, Kim HT, et al. High levels of
B-cell activating factor in patients with active chronic graftversus-host disease. Clin Cancer Res. 2007;13:6107-6114.
58. Furie R, Stohl W, Ginzler E, et al. Biologic activity and safety of
belimumab, a neutralizing anti-B-lymphocyte stimulator (BlyS)
monoclonal antibody: a phase I trial in patients with systemic
lupus erythematosus. Arthritis Res Ther. 2008;10. R109.
59. Carson KR, Evens AM, Richey EA, et al. Progressive multifocal
leukoencephalopathy after rituximab therapy in HIV-negative
patients: a report of 57 cases from the research on adverse
drug events and reports project. Blood. 2009;113:4834-4840.