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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 95 No. 4 (February 15), 2000:
pp. 1502-1505
BRIEF REPORT
CD20 monoclonal antibody (rituximab) for therapy of Epstein-Barr
virus lymphoma after hemopoietic stem-cell transplantation
Ingrid Kuehnle,
M. Helen Huls,
Zhensheng Liu,
Micah Semmelmann,
Robert A. Krance,
Malcolm K. Brenner,
Cliona M. Rooney, and
Helen E. Heslop
From the Center for Cell and Gene Therapy and Texas Children's
Cancer Center, Baylor College of Medicine, Houston, Texas.
 |
Abstract |
After bone marrow transplantation (BMT) using T-cell-depleted
marrow from an unrelated donor or HLA-mismatched related donor, the
risk of developing lymphoproliferative disease associated with the
Epstein-Barr virus (EBV) ranges from 1% to 25%. We have shown that
administration of donor-derived EBV-specific cytotoxic T lymphocytes
(CTL) is effective prophylaxis and treatment for this complication, and
we routinely generate CTL for high-risk patients. However, EBV lymphoma
can occur in recipients of matched-sibling transplants for whom CTL are
unavailable or in patients for whom CTL administration is
contraindicated. We report on 3 such patients, who were successfully
and safely treated with rituximab, a CD20 monoclonal antibody. The
patients remain disease free 7, 8, and 9 months, respectively, after
therapy. We conclude that CD20 antibody may be a useful alternative
treatment strategy in patients with EBV lymphoma after BMT.
(Blood. 2000;95:1502-1505)
© 2000 by The American Society of Hematology.
| |
Introduction |
The risk of B-cell lymphoproliferative disease (LPD)
after bone marrow transplantation (BMT) has been associated with the receipt of bone marrow from HLA-mismatched family members or unrelated donors. If the infused donor marrow is treated with antibodies that
selectively deplete T cells to decrease the risk of graft-versus-host disease (GVHD), Epstein-Barr virus (EBV) LPD occurs in 12% to 25% of
patients.1-4 Treatment of LPD has focused largely on
enhancing the immune response to EBV. Adoptive immunotherapy with
unselected donor leukocytes, which contain high precursor frequencies
of cytotoxic T lymphocytes (CTL) reactive with EBV in most seropositive individuals, has proved to be effective.5 However, such
unmanipulated products may also contain a high frequency of
alloreactive T lymphocytes and induce GVHD.3-6 To avoid the
problem of alloreactivity, we routinely generate donor-derived
EBV-specific CTL for patients at high risk of EBV LPD.7-9
This strategy has reconstituted immunity to EBV and reduced the rate of
EBV lymphoma in recipients of marrow from unrelated or mismatched
donors from 11.5% to 0% when used prophylactically.8,9
EBV-specific CTL have also been efficacious as therapy.9
However, there are some limitations to using CTL. Occasionally,
EBV-associated LPD develops in low-risk patients after matched-sibling
BMT when prophylactic CTL are not available. Furthermore, in patients
in whom EBV LPD develops after autologous BMT or intensive
chemotherapy, use of donor-derived T cells is not a therapeutic option.
There are also certain clinical situations in which CTL therapy may
produce morbidity or be ineffective. For example, adoptively
transferred CTL may not persist in patients receiving steroids at the
time of treatment or may cause inflammation in patients with bulky or
infiltrative disease in which morbidity from CTL-induced inflammatory
responses occur.9,10 Finally, resistance to the infused CTL
can develop through mutations of EBV epitopes recognized by the
CTL.11
Other immunologic treatments for EBV-associated LPD include
anti-B-cell antibodies, such as anti-CD21 and anti-CD24.12
However, the antibodies used in studies of these agents are not
currently available for routine clinical applications and did not have
consistent activity against EBV lymphomas arising after
BMT.13 Recently, a chimeric human-mouse antibody against
the B-cell antigen CD20 (rituximab) was approved by the US Food and
Drug Administration (FDA) for the treatment of relapsed
CD20-positive low-grade or follicular lymphoma.14,15 Its
potential efficacy in the treatment of other B-cell malignant diseases
is currently being investigated. We here demonstrate in 3 patients with
posttransplantation lymphoma that anti-CD20 is well tolerated and can
be used successfully.
| |
Study design |
Transplantation procedure
BMT was performed according to institutional review board
(IRB)-approved protocols. One patient received marrow from a matched sibling and 2 received marrow from matched unrelated donors. All patients received cytarabine (3 g/m2 of body surface area
[BSA]; 6 doses) and cyclophosphamide (45 mg/kg of body
weight; 2 doses), with mesna (45 mg/kg of body weight, divided into 5 doses) administered before and 3, 6, 9, and 12 hours after each dose of
cyclophosphamide.16 Antithymocyte globulin was administered
to recipients of unrelated-donor marrow as part of the conditioning
regimen to enhance immunosuppression. The patients also received
total-body irradiation in 8 fractions, for a total of 12 Gy
(matched-sibling marrow recipient) or 14 Gy (unrelated-donor marrow
recipients). Marrow from the unrelated donors was depleted of T
lymphocytes with use of the anti-T-cell antibodies CD6 and CD8 and
rabbit complement.16 Beginning 2 days before BMT, both the
recipient of the matched-sibling marrow and the recipients of the
matched-unrelated-donor marrow received cyclosporine in a dosage that
was adjusted to attain plasma levels of 200 to 350 ng/mL. The recipient
of the T-cell-replete matched-sibling marrow received additional
prophylaxis with a short course of methotrexate.
Detection of EBV DNA and meaning of levels
Peripheral blood mononuclear cells (PBMC) were isolated from blood
samples on lymphopreparation gradients (10-40 mL each). Genomic DNA was
then isolated on an anion exchange column (Qiagen, Valencia,
CA) from 1 × 106 to
1 × 107 mononuclear cells, and samples of 0.01 to
103 ng were amplified with primer sequences that detect a
single copy of an EBV-DNA BamHI-C segment, as previously
described.17 Positivity was defined as a detectable
EBV-specific signal on Southern blotting with 0.01 ng of DNA from
BL2/B95-8 or IB4 cells (which both contain 2 integrated EBV genomes per
cell) diluted in 1 mg of DNA from an EBV genome-negative cell line,
BL41. We previously demonstrated that the EBV load in peripheral blood
can be used as a direct measure of the onset of posttransplantation
LPD.17 Measurement of EBV DNA in healthy donors
showed the median EBV genome copy number per microgram of peripheral
blood DNA was 20 (range, 0-400). The onset of posttransplantation LPD
is usually preceded by an increase in EBV load, and a 1 to 3 log
increase in EBV DNA has been found to be highly predictive of
subsequent development of EBV lymphoma.
Immunophenotyping
For cell-surface phenotyping, PBMC were incubated with combinations
of fluorescein isothiocyanate-conjugated or phycoerythrin-conjugated monoclonal antibodies to CD3, CD4, CD8, CD16, CD56, CD19, and CD20
(Becton Dickinson, San Jose, CA). Cells were analyzed on a MoFlo flow
cytometer (Cytomation, Fort Collins, CO).
| |
Results and discussion |
Patients
Case 1: High-risk patient with no available CTL.
UTN2110, a 2-year-old boy with acute myelogenous leukemia
(ALL) in second clinical remission, received an
HLA-identical, T-cell-depleted marrow transplant from an unrelated
donor. His posttransplantation course was complicated by GVHD of the
liver and skin. On day 228 after BMT, fever, hepatomegaly, diffuse
cervical and inguinal adenopathy, and elevated levels of transaminases
developed. The patient was found to have extremely high EBV DNA levels
(20 000 genomes/µg) in the peripheral blood, which we previously
showed correlate strongly with the development of EBV
lymphoma.17 Donor-derived EBV-specific CTL were not
available, and the preexisting GVHD precluded use of donor lymphocytes.
On day 237 after BMT, the patient received a single dose of rituximab
(375 mg/m2 of BSA). As shown in Figure
1, DNA copy numbers decreased within 7 days after the treatment, accompanied by normalization of levels of transaminases and resolution of clinical findings and symptoms. The
patient remains disease free 9 months after treatment with rituximab.
Case 2: High-risk patient with pulmonary infiltrates receiving
steroid therapy.
UTNJ23, a 4-year-old boy with relapsed ALL, was
given a T-cell-depleted graft from a matched unrelated donor. The
patient's EBV DNA levels increased from 40 to 4000 genomes per µg
over 3 weeks. On day 90 after BMT, he received 1 dose of
2 × 107 donor-derived EBV-specific CTL in an
IRB-approved protocol.18 The following week, an
intercurrent upper respiratory tract infection with fever and a left
lower lobe pulmonary infiltrate developed. The pulmonary infiltrate was
thought to be likely due to the respiratory tract infection, although
the possibility that it was caused by an inflammatory response mediated
by the infused CTL could not be excluded.
After initiation of steroid therapy, the patient improved clinically,
but the pulmonary infiltrates recurred when the steroids were
discontinued. EBV DNA concentrations decreased initially in response to
the CTL but, as shown in Figure 1, increased again when the
corticosteroid dosage was increased. Additional CTL were not administered because of concern that this might exacerbate the
patient's respiratory condition, so the patient received 1 dose of
rituximab (375 mg/m2 of BSA). EBV DNA decreased
rapidly to undetectable levels, the pulmonary infiltrates resolved, and the patient remains clinically well 8 months after therapy. Although it
is impossible to distinguish the relative contributions of the
EBV-specific CTL and the CD20 antibody to the therapeutic response,
CD20 antibody was a useful alternative to an additional dose of CTL in
this clinical situation, where there was concern that the CTL might
exacerbate the patient's respiratory insufficiency.
Case 3: EBV LPD in a low-risk BMT recipient with no CTL available.
UTNJ34, a 13-year-old boy with chronic myelogenous
leukemia, received an unmanipulated bone marrow transplant
from a matched sibling. After BMT, he received a short course of
steroid therapy for grade I GVHD. Thirty-three days after BMT, the
patient presented with persistent fever; an extensive infection workup
yielded negative results. On day 60 after BMT, bilateral cervical and
inguinal tenderness and adenopathy and splenomegaly developed. EBV DNA levels became markedly elevated at the time the adenopathy appeared. A
lymph node biopsy showed histologic characteristics of large-cell lymphoma, and in situ hybridization was positive for EBV DNA. Because
the patient was at low risk for posttransplantation EBV lymphoma,
donor-derived EBV-specific CTL were not available for him. Therefore,
he received 1 dose of rituximab (375 mg/m2 of BSA), which
resulted in clinical improvement in adenopathy, resolution of fever,
and a decrease in EBV DNA to normal levels. Seven months after
treatment, the patient remains well and EBV DNA continues to be undetectable.
Rituximab is a CD20 antibody recently approved by the FDA for therapy
of relapsed CD20-positive follicular lymphoma.14,15 Because
this antibody has a human component, its half life is longer than that of murine antibodies: rituximab has induced profound B-cell depletion for 6 months. We phenotyped peripheral blood from the
3 BMT patients in this study, starting 5 months after the
administration of rituximab therapy to the time of the
most recent follow-up (Table 1). The 2 patients given rituximab 9 months ago and 7 months ago, respectively,
have normal B-cell numbers and levels of immunoglobulins. The third
patient, who was given the CD20 infusion 8 months ago,
continues to have profound B-cell deficiency and hypogammaglobulinemia.
None of our patients had an increase in opportunistic infections. There
is one other report of CD20 administration after BMT.19 The
patient also responded rapidly to the first dose of this therapy, which
led us to choose a single dose with subsequent close monitoring of EBV
DNA levels. Although these results need to be confirmed in larger
series, they do illustrate a potential role for therapy with CD20 as an
adjuvant to approaches using T-cell immunotherapy to treat EBV
lymphoma.
View this table:
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Table 1.
Phenotyping results and levels of immunoglobulins in 3 patients before and after administration of rituximab
|
|
Might CD20 therapy eventually replace adoptive immunotherapy with
donor-derived T cells or CTL? There are potential detrimental effects
of CD20 therapy. The profound B-cell depletion may further exacerbate
immunodeficiency in transplant recipients, although eventual recovery
should occur because CD20 is not expressed on B-cell precursors. It is
also unclear whether a lack of EBV-infected B cells will retard
recovery of EBV-specific immunity and thereby allow the development of
lymphomas later in the posttransplantation course. Moreover, it is
unclear whether depletion of the B-cell reservoir of EBV will result in
development of a primary infection in the future. Finally, CD20
therapy may cause selection of a CD20-negative population of
proliferating B cells, as has been reported in a few patients with
lymphoma.20 Ultimately, both CD20 and EBV-specific CTL may
be needed to achieve optimal results.
Mortality from EBV lymphoma may be reduced in other ways. Studies have
shown that the risk is lowered if methods that deplete donor B cells as
well as donor T cells are used. In a large review of patients whose
marrow transplants were treated with the CAMPATH series of
antibodies, the EBV-LPD rate was < 2%.21 A low rate also
occurred after elutriation, which removes > 90% of B cells from the
donor graft.22 In another study, addition of a monoclonal antibody that depleted B cells to the T-cell-depletion regimen reduced
the occurrence of EBV-LPD from 7 of 19 historical controls to none of
the next 19 patients.23 Hence, it seems
likely that the introduction of modified methods of graft manipulation,
coupled with the availability of antibody and cellular-based therapies, should substantially reduce future mortality from EBV lymphoma in BMT recipients.
| |
Footnotes |
Submitted June 28, 1999; accepted October 11, 1999.
Supported by grant CA 61384 from the National Cancer Institute.
Reprints: Helen Heslop, Center for Cell and Gene
Therapy, Baylor College of Medicine, 1102 Bates Street, Suite 1140, Houston, TX 77030; e-mail: hheslop{at}bcm.tmc.edu.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
| |
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Top
Abstract
Introduction