|
|||||||||
|
|
|
|
|
|
|
|
|
|
|
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Unité d'Immunologie et
d'Hématologie Pédiatriques, Service de
Réanimation Pédiatrique and INSERM U429,
Hôpital Necker Enfants-Malades; Service
d'Hématologie Clinique, Groupe hospitalier
Pitié-Salpétrière; Service de Pneumologie,
Hôtel-Dieu, Paris; Laboratoire de Virologie Medicale
Moléculaire, Faculté de Medecine de Grenoble, Domaine de la
Merci, La Tronche; Service de Pneumologie, Hôpital Foch, Suresnes
Cedex; Service de Néphrologie, Service d'Hématologie, CHU
de Poitiers, Poitiers; Service d'Hépatologie Pédiatrique,
Hôpital Bicêtre, Le Kremlin Bicêtre Cedex; Service
d'Hépatologie, Hôpital Henri Mondor, Créteil;
Service de Nephrologie et de transplantation rénale, CHU de Caen,
Besançon Cedex.
Severe T-cell immunodeficiency after solid organ or bone marrow
transplantation may result in the uncontrolled outgrowth of latently
Epstein-Barr virus-infected B cells, leading to B-lymphoproliferative disorder (BLPD). Given the potentially important pathogenic role of
IL-6 in BLPD, it was tested whether the in vivo neutralization of IL-6
by a monoclonal anti-IL-6 antibody could contribute to the control of
BLPD. Safety and efficacy were assessed in 12 recipients of
transplanted organs who had BLPD refractory to the reduction of
immunosuppression over 8 days. Five patients received 0.4 mg/kg per
day. The next 7 patients received 0.8 mg/kg per day. Treatment was
scheduled to last 15 days. It was completed in 10 patients, and in the
other 2 patients was discontinued early (days 10 and 13, respectively)
because of disease progression. Treatment tolerance was good, and no
major side effects were observed. High C-reactive protein levels were
found in 9 patients before treatment but were normalized under
treatment in all patients, demonstrating efficient IL-6 neutralization.
Complete remission (CR) was observed in 5 patients and partial
remission (PR) in 3 patients. Relapse was observed in 1 of these 8 patients in whom remission was observed. This relapse was unresponsive
to treatment. Disease was stable in 1 patient, but it progressed in 3 patients. Seven patients are alive and well. Two patients died because
of disease progression, and 3 patients died while in CR (chronic
rejection in 2 patients and BLPD sequelae in 1 patient). These data
suggest that the anti-IL-6 antibody is safe and should be further
explored in the treatment of BLPD.
(Blood. 2001;97:1590-1597) B-lymphoproliferative disorder (BLPD) is a severe
complication of organ and bone marrow transplantation (BMT) caused by
the Epstein-Barr virus (EBV).1-7 EBV latently infects B
cells, which become immortalized by expressing part of the viral genome
that persists in an episomal form.8 The growth of
EBV-infected B cells is controlled by cytotoxic T cells.9
In vivo severe T-cell immunodeficiency, such as occurs in patients with
inherited cellular immunodeficiency10 or acquired
immunodeficiency syndrome11 and in recipients of solid
organ or bone marrow transplants,12-14 may result in the
uncontrolled outgrowth of EBV-infected B cells, leading to BLPD. BLPD
occurs in 1% to 15% of organ recipients and in 0.5% to 24% of bone
marrow recipients, depending on the type of transplantation, the ages
of donor and recipient, the intensity of immunosuppression, and the
method of T-cell depletion.15-18 The overall prognosis of
BLPD is poor, and the disease is fatal in 40% to 60% of affected
recipients of transplanted organs15,19-22 and in 90% of
affected BMT recipients.15,23-25 Treatment strategy is
still controversial. Antiviral therapy (acyclovir, ganciclovir) is
ineffective at preventing the persistence of episomal EBV associated with the latent phase. Although such treatment has not been
definitively shown to be effective against BLPD, remission has
occasionally been reported.15,26 Chemotherapy and
radiotherapy are of limited value, at least in early-onset
EBV-associated BLPD.15,27 Surgery may save the patient's
life in cases of localized BLPD.15 Preliminary data have
suggested improved survival with the use of interferon- We investigated the effect of a monoclonal anti-interleukin-6 (IL-6)
antibody on B-cell growth in patients with BLPD. IL-6 is a
multifunctional cytokine produced by monocytes, fibroblasts, endothelial cells, and other cell types. It plays an important role in
the proliferation and maturation of B cells.36-39
Overproduction of this cytokine is thought to be involved in the
pathogenesis of lymphoid malignancies, high-grade B-cell
lymphomas,40,41 and myelomas42-44 in
particular. It has also been shown that IL-6 promotes the growth of
EBV-infected B cells,45,46 that patients with BLPD produce
abnormally high levels of IL-6,45,47 and that B-cell lines
derived from BLPD express the p80 chain of the IL-6
receptor.48 In addition, the transfection of
EBV-transformed B cells with human IL-6 cDNA greatly increases
the proliferation of these cells both in vivo and in
vitro.49,50 Durandy et al48 showed that
anti-IL-6 mAb could inhibit the growth of several BLPD-derived B-cell
lines in severe combined immunodeficiency disease (SCID) mice in vivo.
This treatment led to complete remission in most mice and to
tumor-free, long-term survival in 40% of mice.
Given the probable importance of IL-6 in BLPD pathogenesis, we tested,
in a phase 1-2 clinical trial, the toxicity and efficacy of anti-IL-6
mAb treatment against BLPD occurring after organ transplantation. We
report here the results of a trial in 12 patients.
Monoclonal anti-IL-6 antibody
Protocol design
Patient enrollment BLPD was diagnosed based on the presence of a lymphoproliferative syndrome with detectable tumors consisting of EBV-positive B lymphocytes. EBV was detected immunohistologically, with anti-LMP antibodies, by polymerase chain reaction (PCR) detection of the EBV genome, or by Southern blot analysis or by in situ hybridization (see below).For inclusion in the study, patients could be of any age but had to have acquired BLPD after organ transplantation and to have satisfied at least one of the following criteria: (1) be unresponsive to the tapering of immunosuppression for a minimum of 8 days; (2) have histologically invasive disease with nodal capsule disruption; (3) have rapidly progressive multiple lymphoproliferative lesions, excluding those from surgery. BLPD unresponsive to the tapering of immunosuppression treatment for a minimum of 8 days was defined as no change in C-reactive protein (CRP) level, fever, or other general manifestations, and no decrease in tumor size detected by clinical assessment and appropriate imaging tests. No other BLPD treatments were given in association with the anti-IL-6 antibody. If disease progression was observed during the administration of anti-IL-6 antibody, treatment could be stopped and another treatment could be proposed. Twelve patients were included in the study between September 1995 and August 1998. The final data were collected on June 30, 1999. Anti-IL-6 antibody dose and administration The monoclonal anti-IL-6 antibody BE-8 was diluted in 2 mL/kg 5% glucose serum and administered as a 30-minute intravenous infusion once a day for 15 days. To evaluate toxicity and the dose dependency of the effects of the anti-IL-6 antibody, a dose escalation trial was performed. Patients 1 to 3 received a dose of 0.4 mg/kg per day. Patients 4 and 5 received a 1 mg/kg bolus on day 1, which was followed by injections of 0.4 mg/kg per day. These doses were well tolerated (see "Results"); hence, the remaining 7 patients received a third regimen consisting of a 1 mg/kg bolus followed by injections of 0.8 mg/kg per day. CRP was determined on day 3. In all patients, if CRP levels did not normalize by day 3, the dose given was doubled for the remaining 12 days of treatment, whatever the initial dose.Study criteria The end point of this dose escalation study was the determination of the toxicity of anti-IL-6 antibody administration and its efficacy against BLPD, as assessed 4 months after treatment. We evaluated the toxicity of BE-8 in patients using the World Heath Organization Toxicity Criteria. Blood pressure, temperature, and heart rate were monitored every 10 minutes during BE-8 infusion, then every hour for 3 hours and every 3 hours until the next injection. Hematologic, renal, and liver function tests were conducted every day during treatment and on days 22, 30, 60, and 120.Clinical symptoms of BLPD were monitored (examination of all affected sites, fever) every day during treatment, then once per week for 2 weeks, and then once per month for 6 months. Tumor size was determined by radiologic imaging (computed tomography and/or magnetic resonance imaging and/or ultrasound imaging) on days 15, 30, and 120. Biologic variables were also studied. CRP was determined every 3 days during treatment, then once per week for 2 weeks, and then on days 60 and 120. PCR tests for the detection of EBV-DNA in blood and determinations of serum immunoglobulin levels, monoclonal immunoglobulin components, and specific antibodies against EBV were carried out every 2 weeks for 1 month and then on days 60 and 120. Complete remission (CR) was defined as the complete clinical and radiologic disappearance of tumors at all sites, the disappearance of associated biologic signs (high levels of CRP, detection of circulating B cells expressing the EBV genome), and the absence of newly involved sites. Partial remission (PR) was defined as at least a 50% decrease in measurable tumor localization, with the disappearance of fever and no newly involved sites. Stable disease (SD) was defined as no significant change in tumor measurements and no newly involved sites. Progressive disease (PD) was defined as an increase in the size of tumor lesions or the appearance of new lesions. Immunologic investigations The following B- and T-cell-specific mAbs were used, as previously described,31 to characterize T and B lymphocytes in blood and in organ tissue samples when available: anti-immunoglobulin heavy-chain and light-chain isotypes30; anti-CD19, CD20, CD24, CD21, and CD23 antibodies (Immunotech, Marseilles, France); and anti-CD3, CD4, and CD8 antibodies (BD, San Diego, CA). Analyses were performed by indirect immunofluorescence cytofluorometry. Fresh cells were used for membrane immunofluorescence analysis and fixed cells for intracytoplasmic staining. Immunoperoxidase staining of biopsy sections was performed as previously described.52 Serum immunoglobulin levels were determined by nephelometry, and monoclonal immunoglobulin components were determined by immunofixation.53 Serum IL-6 levels were determined using a specific anti-IL-6 enzyme-linked immunosorbent assay (ELISA) assay (CLB, Amsterdam, The Netherlands), as previously described.48Virologic investigations EBV-DNA was detected in frozen material by Southern blot analysis using a randomly primed 32P-labeled probe specific for the BamHI W internal repeats of the virus, in situ hybridization with EBV-specific probes,54 PCR analysis,55 or any combination thereof. Specific antibodies (IgG and IgM isotypes) against EBV (viral capsid antigen, early antigen, EBV nuclear antigen) in organ transplant recipients were detected by an ELISA assay. Immunoperoxidase staining of biopsy sections was also performed for LMP1.52Clonality studies Immunoglobulin gene rearrangement studies of proliferative B cells were performed by Southern blotting, using a probe for the sequence encoding the heavy-chain joining region (JH). BLPD was considered to be monoclonal if a single immunoglobulin rearrangement was obtained for the abnormal specimen analyzed, regardless of whether a single monoclonal serum component had been detected by immunofixation. BLPD was considered to be oligoclonal if no unique immunoglobulin heavy-chain rearrangement was observed, several serum monoclonal immunoglobulin components were detected through immunofixation, or both.
Patients and BLPD characteristics Median age at the onset of BLPD was 35 years (range, 1 year to 62 years). Organs transplanted were lung (n = 5), kidney (n = 3), liver (n = 3), and heart (n = 1). The characteristics of the BLPD are shown in Table 1. In all patients, biopsy of BLPD lesions was performed to confirm the B-lymphocyte phenotype of infiltrating cells and the presence of EBV (Table 1).
All patients were on immunosuppressive treatment at the time of BLPD
onset (Table 2). Eight patients had
received highly aggressive immunosuppressive therapy because of graft
rejection; in 4 patients, this occurred less than 3 months before the
onset of BLPD. In all patients, immunosuppression was reduced when BLPD was diagnosed. In none of these patients did immunosuppression tapering
for at least 8 days affect the BLPD lesions (ie, tumors were not
reduced, as shown by appropriate imaging and clinical examination).
Tapering of immunosuppression also had no effect on fever or serum CRP
levels. All patients were, therefore, considered unresponsive to the
tapering of immunosuppression over an 8-day period.
One patient (patient 12) had been injected with an anti-CD20 antibody that had no effect on BLPD, 2 months before anti-IL-6 antibody treatment. In all other patients, no other treatment was performed before the initiation of anti-IL-6 mAb antibody therapy. Treatment characteristics and tolerance Treatment was scheduled to last 15 days. It was completed in 10 patients, and in the other 2 patients it was stopped early (on day 10 for patient 4 and on day 13 for patient 7) because of disease progression. One patient (patient 2) received a second course of anti-IL-6 antibody treatment after a relapse of BLPD. No major side effect was observed during any of the 13 courses of anti-IL-6 antibody treatment. One patient (patient 4) had moderate allergic manifestations erythema on both hands after each anti-IL-6 antibody
injectionthat responded to antihistamine treatment. One patient
(patient 3) had paresthesia on day 2, which then disappeared spontaneously. Two patients (patients 2, 9) had moderately high levels
of arterial blood pressure, which resolved after sublingual nifedipine
treatment. On day 2, patient 3 was examined for hyperkalemia associated
with hyperphosphoremia and hypocalcemia, all of which resolved within 1 day. These biochemical manifestations were interpreted as a
lytic syndrome.
Pharmacologic data As high CRP concentration is known to be an in vivo hallmark of high levels of IL-6 synthesis.56-58 We assessed the effects of the treatment on CRP and IL-6 levels to determine the pharmacologic effects of the anti-IL-6 antibody. High serum CRP concentrations were found in 9 of 12 patients, and 5 of 9 patients had fever (Table 1). In all patients, CRP concentration decreased and fever disappeared after treatment, suggesting that systemic IL-6 was neutralized (Figure 1). CRP normalized within 3 days of the initiation of treatment in 7 of these 9 patients, whereas it was necessary to double the anti-IL-6 antibody dose on day 3 for 2 patients (patients 6, 11) even though the initial dose given to these patients was 0.8 mg/kg.
As shown in Table 3, serum IL-6
concentration was evaluated in 8 patients before treatment (after
tapering immunosuppression) and was found to be elevated in 5 patients.
In the 4 patients who survived for more than 2 months, IL-6 normalized
or decreased significantly. Serum IL-6 concentration could not be
analyzed during or immediately after treatment because of the formation of immune complexes between IL-6 and anti-IL-6 antibody that were also
detected in the ELISA assay.
Evaluation of anti-IL-6 antibody treatment on disease outcome Twelve patients were treated with 13 courses of anti-IL-6 antibody injection. Median follow-up time after treatment was 20 months (range, 9-33 months). CR was achieved in 5 patients (patients 1, 3, 5, 6, 8), 4 months after the initiation of treatment (Table 3). In patient 1, tumor size had decreased by 50% on day 12 of treatment, and CR was achieved on day 21. Examination of an endobronchial lesion on day 21 showed that no infiltrating tumor cells were present. Neither necrosis nor T-cell infiltration was detected. Patient 3 presented on day 2 with hyperkalemia associated with hyperphosphoremia and hypocalcemia, suggestive of a lytic syndrome. By day 3, the tumor size had decreased, and CR was achieved 5 weeks after the initiation of treatment. It was not possible to perform an examination of the lesion after CR was achieved. In patient 5, tumor size began to decrease 30 days after treatment, and CR was achieved 4 months after treatment. Examination of the lungs confirmed that infiltrating tumor cells were no longer present and that there was no necrosis, nor were there infiltrating T cells. In patient 6, tumor reduction was observed 30 days after treatment, and CR was achieved 2 months after treatment. Analysis showed that the infiltrating cells had been replaced by severe necrosis. In patient 8, pleuritis had disappeared by day 3, and CR was achieved on day 15. No pathologic examination was performed.None of these patients had a relapse of BLPD. All can be considered cured of BLPD. However, 3 of these 5 patients died 10, 13, and 36 months after treatment because of chronic rejection in 2 patients and severe liver hilum necrosis in the other, which may be considered a sequela of BLPD. Two patients are alive and well 21 and 33 months, respectively, after anti-IL-6 antibody treatment. Partial remission was observed in 3 patients (patients 2, 9, 12). In patient 2, pleurisy decreased by the third day after treatment, mediastinal nodes were half their size 1 month after treatment, and BLPD decreased by approximately 90% only 2 months after treatment. However, BLPD relapsed 5 months after treatment. This patient received a second course of anti-IL-6 antibody treatment, which was ineffective. This patient eventually died of progressive disease. In patient 9, a decrease in tumor size became detectable 15 days after the initiation of treatment. This PR made it possible to perform surgery and retransplantation that had not previously been feasible. Pathologic examination of the liver showed necrosis of 80% of the tumor that was infiltrated by T cells and histiocytic cells. This patient was alive and well, in complete remission, at the 21-month follow-up. In patient 12, a slight decrease in tumor size was observed by day 30. Three months later, the tumor decreased by 90%. Nine months after treatment, this patient was still in PR and had a small persistent lesion in the lung but no associated manifestations. Before the anti-IL-6 antibody treatment, this patient received a course of anti-CD20 antibody that had no effect on BLPD. Anti-IL-6 antibody treatment was effective in 8 patients (5 in CR, 3 in PR). The reintroduction of highly aggressive immunosuppression in 3 of these patients because of episodes of rejection did not lead to BLPD relapse. Stable disease was observed in one patient (patient 11), who was then treated with anti-CD20 antibody, which also failed to control BLPD. This patient was then treated by surgery and retransplantation and is alive and well, in complete remission, 19 months after treatment. In 3 patients, treatment did not prevent disease progression (patients 4, 7, 10). Patient 10 died within 1 month because of disease progression, despite the use of chemotherapy. In patients 7 and 10, anti-IL-6 antibody treatment was stopped on days 10 and day 13, respectively, because of disease progression, but chemotherapy led to complete remission. These 2 patients are still alive and well and in CR 22 and 26 months, respectively, after treatment. Anti-IL-6 antibody treatment was effective at controlling associated signs of BLPD such as high CRP concentration and fever. This treatment was also shown to be effective by PCR detection of the EBV genome in the blood and the determination of serum immunoglobulin concentration by immunofixation. For 7 patients, the EBV genome was detected in the blood before treatment. We were able to evaluate 6 of these patients after treatment. The EBV genome was no longer detectable in the blood 2 to 4 months after treatment in 5 of these 6 patients. Six of 10 patients with detectable serum monoclonal immunoglobulin components on immunofixation were evaluated after treatment. In 5 of them, the monoclonal immunoglobulin components had disappeared. Most of the survivors developed full antibody responses to EBV, including anti-EBNA antibodies (Table 2). Analysis of factors that might have influenced disease outcome BLPD characteristics such as clonality, EBV genome detection in blood, monoclonal immunoglobulin component, number or localization of affected sites, and time to BLPD onset and patient characteristics such as age, type of transplantation, and type of initial disease were tested as possible factors influencing outcome after anti-IL-6 antibody treatment.The dose of anti-IL-6 antibody given (0.4 vs 0.8 mg/kg) did not affect
its efficacy (Table 3). Although no firm conclusions can be drawn
because of the small number of patients, time to BLPD onset seemed to
be the only factor affecting treatment efficacy. Indeed, for the 7 patients in whom BLPD occurred within 6 months of transplantation, CR
was achieved in 4 patients and PR was achieved in 2 patients (Table
4). Conversely, for the 5 patients in
whom BLPD occurred more than 5 years after BLPD, CR was achieved in only one patient and PR in another, who eventually had a relapse, whereas the disease progressed in 3.
In this phase 1-2 clinical trial, 12 patients with BLPD after organ transplantation were treated intravenously by daily injections of 0.4 to 0.8 mg/kg per day of a mouse monoclonal anti-IL-6 antibody (B-E8)51 for 15 days in 10 patients and for 10 and 13 days, respectively, in 2 other patients. This antibody has previously been used to treat patients with myeloma,56 B lymphoma related to EBV infection in the patients with HIV,59 Castleman disease,60 and severe rheumatoid arthritis.61 In all these studies, treatment was well tolerated. The treatment was also well tolerated in this study, and no major side effects were reported for any of the doses of anti-IL-6 mAb used. These data suggest that this mAb is safe for use in therapeutic trials at doses up to 0.8 mg/kg per day for 15 days. To determine the pharmacologic kinetics of anti-IL-6 mAb antibody, we analyzed CRP and IL-6 levels. CRP is produced by human hepatocytes in response to IL-6 stimulation58 and is known to be indicative of the presence of high levels of IL-6.56-58 Nine patients had high CRP levels. The normalization of serum CRP concentration by treatment in all 9 patients suggests that IL-6 was systematically neutralized. Two of these 9 patients, both of whom received an initial anti-IL-6 antibody dose of 0.8 mg/kg, had persistently high CRP levels after 3 days of treatment. The dose of anti-IL-6 mAb was therefore increased, resulting in the normalization of CRP concentration. This suggests that CRP determination during treatment may be useful for assessing whether a pharmacologic effect has been achieved. However, CRP concentration was not predictive of treatment efficacy. Treatment was clinically effective in 8 patients (5 in CR, 3 in PR). BLPD relapsed in only one of these 8 patients and then became insensitive to treatment. These data indicate that the anti-IL-6 mAb may be useful in the treatment of severe BLPD. In all cases, prior immunosuppression tapering for an 8-day period had no effect on BLPD. However, one could argue that this delay is too short and that the observed remissions could be related to a delayed effect of immunosuppression reduction. This is unlikely because the observed remission rate under immunosuppression tapering is generally lower than the one observed in our series (8 of 12 patients). Moreover, this 8-day period of immunosuppression reduction has been previously proposed as an appropriate delay to allow treatment by anti-B-cell monoclonal antibodies.32 The efficacy of anti-IL-6 antibody may be similar to that of anti-B-cell mAb, as complete remission was achieved in 61% of the 58 patients with BLPD treated with anti-B mAbs.32 Anti-IL-6 mAb treatment was not effective in 4 patients (1 in SD, 3 in PD). However, for 3 of these 4 patients, improvements were achieved with another treatment (surgery in 1 patient and chemotherapy in 2 patients). Thus, the lack of efficacy of the anti-IL-6 mAb did not preclude the use of alternative therapies such as surgery and chemotherapy. These encouraging data require confirmation in a larger group of patients, allowing statistical analysis and including patients with post-BMT BLPD, which is known to induce a poorer outcome.32 It may also be of value to perform a phase 3 clinical trial in which anti-IL-6 antibody treatment could be compared to or associated with other forms of treatment (eg, anti-CD20 [anti-B cell]) mAbs or cytotoxic T lymphocytes in patients who have undergone BMT12,29). Clonality, type of transplantation, and sites affected did not seem to influence treatment efficacy. The only factor that seemed to have a strong effect on efficacy was time to BLPD onset. These findings require confirmation in a larger series of patients. However, similar results were reported by Benkerrou et al,32 who showed in a multivariate analysis that the late onset of BLPD was a major risk factor for the failure of anti-B-cell mAb treatment. Late-onset BLPD may be caused by a different physiopathogenic mechanism, with secondary oncogenic events (such as bcl-2 rearrangements, c-myc, n-ras, and p53 mutations) and LMP1 deletions62-65 responsible for the formation of true lymphomas. In such cases, B-cell proliferation could be insensitive to anti-B-cell or anti-IL-6 antibody treatment but responsive to chemotherapy. Our data, which are consistent with those obtained for SCID mice
injected with B-cell lines derived from patients with
BLPD,48 suggest that IL-6 may, in some cases, have a major
role in BLPD growth. Pathologic examination after treatment was
possible in 4 patients in whom treatment was effective. In 2 patients,
extensive tumor necrosis was observed. In one, infiltrating T cells and histiocytic cells replaced infiltrating B cells. In 2 other cases, complete resolution of BLPD was observed. No firm conclusions can be drawn from these data concerning the mechanism of BLPD resolution after anti-IL-6 antibody treatment. There are several possibilities. First, IL-6 may act as an autocrine-paracrine growth factor and may promote the growth of EBV-infected B cells. Indeed, IL-6
has been shown to promote the growth of EBV-infected B
cells45,46 and patients with BLPD produce abnormally high
levels of IL-6.45,47 A tumorigenic role for IL-6 in BLPD
was also suggested by the results of experiments in which
EBV-transformed B cells were transfected with human IL-6 cDNA:
transfection significantly increased the proliferation of these cells
in vivo and in vitro.49,50 These observations suggest that
original tumor cells (EBV-infected B cells), stromal cells, or both
Submitted February 10, 2000; accepted November 8, 2000.
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.
Reprints: Elie Haddad, Service de Nephrologie Pediatrique, 48 Blvd Serrurier, 75019 Paris, France; e-mail: elie.haddad{at}rdb.ap-hop-paris.fr.
1.
Frizzera G, Hanto D, Gajl-Peczalska K, et al.
Polymorphic diffuse B-cell hyperplasias and lymphomas in renal transplant recipients.
Cancer Res.
1981;41:4262-4279
2.
Schubach W, Hackman R, Neiman P, Miller G, Thomas E.
A monoclonal immunoblastic sarcoma in donor cells bearing Epstein-Barr virus genomes following allogeneic marrow grafting for acute lymphoblastic leukemia.
Blood.
1982;60:180-187 3. Hanto D, Najarian J. Advances in the diagnosis and treatment of EBV-associated lymphoproliferative diseases in immunocompromised hosts. J Surg Oncol. 1985;30:215-220[Medline] [Order article via Infotrieve]. 4. Nalesnik M, Jaffe R, Starzl T, et al. The pathology of posttransplant lymphoproliferative disorders occurring in the setting of cyclosporine A-prednisone immunosuppression. Am J Pathol. 1988;133:173-192[Abstract].
5.
Cleary M, Nalesnik M, Shearer W, Sklar J.
Clonal analysis of transplant-associated lymphoproliferations based on the structure of the genomic termini of the Epstein-Barr virus.
Blood.
1988;72:349-352 6. Katz B, Raab-Traub N, Miller G. Latent and replicating forms of Epstein-Barr virus DNA in lymphomas and lymphoproliferative diseases. J Infect Dis. 1989;160:589-598[Medline] [Order article via Infotrieve]. 7. d'Amore E, Manivel J, Gajl-Peczalska K, et al. B-cell lymphoproliferative disorders after bone marrow transplant: an analysis of ten cases with emphasis on Epstein-Barr virus detection by in situ hybridization. Cancer. 1991;68:1285-1295[CrossRef][Medline] [Order article via Infotrieve]. 8. Kieff E. Epstein-Barr virus and its replication. In: Fields BN KD,Howley PM,Chanock RM,et al., eds. Fields Virology. Philadelphia: Lippincott-Raven; 1996:2343. 9. Rickinson A, Kieff E. Epstein-Barr virus: In: Fields BN KD, Howley PM, Chanock RM, et al, eds. Fields Virology. Philadelphia: Lippincott-Raven; 1996:2397. 10. Shearer W, Ritz J, Finegold M, et al. Epstein-Barr virus-associated B-cell proliferations of diverse clonal origins after bone marrow transplantation in a 12-year-old patient with severe combined immunodeficiency. N Engl J Med. 1985;312:1151-1159[Abstract]. 11. Birx D, Redfield R, Tosato G. Defective regulation of Epstein-Barr virus infection in patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related disorders. N Engl J Med. 1986;314:874-879[Abstract].
12.
Papadopoulos EB, Ladanyi M, Emanuel D, et al.
Infusions of donor leukocytes to treat Epstein-Barr virus-associated lymphoproliferative disorders after allogeneic bone marrow transplantation.
N Engl J Med.
1994;330:1185-1191
13.
Lucas KG, Small TN, Heller G, Dupont B, O'Reilly RJ.
The development of cellular immunity to Epstein-Barr virus after allogeneic bone marrow transplantation.
Blood.
1996;87:2594-2603
14.
Cen H, Williams P, McWilliams H, Breinig M, Ho M, McKnight J.
Evidence for restricted Epstein-Barr virus latent gene expression and anti-EBNA antibody response in solid organ transplant recipients with posttransplant lymphoproliferative disorders.
Blood.
1993;81:1393-1403 15. Cohen J. Epstein-Barr virus lymphoproliferative disease associated with acquired immunodeficiency. Medicine. 1991;70:137-160[CrossRef][Medline] [Order article via Infotrieve]. 16. Thomas J, Allday M, Crawford D. Epstein-Barr virus-associated lymphoproliferative disorders in immunocompromised individuals. Adv Cancer Res. 1991;57:329-380[Medline] [Order article via Infotrieve].
17.
Curtis RE, Travis LB, Rowlings PA, et al.
Risk of lymphoproliferative disorders after bone marrow transplantation: a multi-institutional study.
Blood.
1999;94:2208-2216
18.
Hale G, Waldmann H.
Risks of developing Epstein-Barr virus-related lymphoproliferative disorders after T-cell-depleted marrow transplants: CAMPATH Users.
Blood.
1998;91:3079-3083 19. Starzl T, Nalesnik M, Porter K, et al. Reversibility of lymphomas and lymphoproliferative lesions developing under cyclosporin-steroid therapy. Lancet. 1984;1:583-587[Medline] [Order article via Infotrieve]. 20. Swinnen L, Costanzo-Nordin M, Fisher S, et al. Increased incidence of lymphoproliferative disorders after immunosuppression with the monoclonal antibody OKT3 in cardiac-transplant recipients. N Engl J Med. 1990;323:1723-1728[Abstract].
21.
Langnas A, Shaw BJ, Antonson D, et al.
Preliminary experience with intestinal transplantation in infants and children.
Pediatrics.
1996;97:443-448 22. Ho M, Jaffe R, Miller G, et al. The frequency of Epstein-Barr virus infection and associated lymphoproliferative syndrome after transplantation and its manifestations in children. Transplantation. 1988;45:719-727[Medline] [Order article via Infotrieve].
23.
Fischer A, Landais P, Friedrich W, et al.
Bone marrow transplantation (BMT) in Europe for primary immunodeficiencies other than severe combined immunodeficiency: a report from the European Group for BMT and the European Group for Immunodeficiency.
Blood.
1994;83:1149-1154
24.
Shapiro R, McClain K, Frizzera G, et al.
Epstein-Barr virus associated B cell lymphoproliferative disorders following bone marrow transplantation.
Blood.
1988;71:1234-1243 25. Ash R, Casper J, Chitambar C, et al. Successful allogeneic transplantation of T-cell-depleted bone marrow from closely HLA-matched unrelated donors. N Engl J Med. 1990;322:485-494[Abstract]. 26. Pirsch J, Stratta R, Sollinger H, et al. Treatment of severe Epstein-Barr virus-induced lymphoproliferative syndrome with ganciclovir: two cases after solid organ transplantation. Am J Med. 1989;86:241-244[CrossRef][Medline] [Order article via Infotrieve]. 27. Garrett T, Chadburn A, Barr M, et al. Posttransplantation lymphoproliferative disorders treated with cyclophosphamide-doxorubicin-vincristine-prednisone chemotherapy. Cancer. 1993;72:2782-2785[CrossRef][Medline] [Order article via Infotrieve]. 28. Shapiro R, Chauvenet A, McGuire W, et al. Treatment of B-cell lymphoproliferative disorders with interferon alfa and intravenous gamma globulin. N Engl J Med. 1988;318:1334[Medline] [Order article via Infotrieve]. 29. Rooney C, Smith C, Ng C, et al. Use of gene-modified virus-specific T lymphocytes to control Epstein-Barr-virus-related lymphoproliferation. Lancet. 1995;345:9-13[CrossRef][Medline] [Order article via Infotrieve]. 30. Blanche S, Le Deist F, Veber F, et al. Treatment of severe Epstein-Barr virus-induced polyclonal B-lymphocyte proliferation by anti-B-cell monoclonal antibodies: two cases after HLA-mismatched bone marrow transplantation. Ann Intern Med. 1988;108:199-203. 31. Fischer A, Blanche S, Le Bidois J, et al. Anti-B-cell monoclonal antibodies in the treatment of severe B-cell lymphoproliferative syndrome following bone marrow and organ transplantation. N Engl J Med. 1991;324:1451-1456[Abstract].
32.
Benkerrou M, Jais J, Leblond V, et al.
Anti-B-cell monoclonal antibody treatment of severe posttransplant B-lymphoproliferative disorder: prognostic factors and long-term outcome.
Blood.
1998;92:3137-3147
33.
Kuehnle I, Huls MH, Liu Z, et al.
CD20 monoclonal antibody (rituximab) for therapy of Epstein-Barr virus lymphoma after hemopoietic stem-cell transplantation.
Blood.
2000;95:1502-1505 34. Faye A, Van Den Abeele T, Peuchmaur M, Mathieu-Boue A, Vilmer E. Anti-CD20 monoclonal antibody for post-transplant lymphoproliferative disorders [letter]. Lancet. 1998;352:1285[Medline] [Order article via Infotrieve].
35.
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 36. Van Snick J. Interleukin-6: an overview. Annu Rev Immunol. 1990;8:253-278[Medline] [Order article via Infotrieve]. 37. Hirano T, Akira S, Taga T, Kishimoto T. Biological and clinical aspects of interleukin 6. Immunol Today. 1990;11:443-449[CrossRef][Medline] [Order article via Infotrieve].
38.
Kishimoto T.
The biology of interleukin-6.
Blood.
1989;74:1-10
39.
Kishimoto T, Akira S, Narazaki M, Taga T.
Interleukin-6 family of cytokines and gp130.
Blood.
1995;86:1243-1254
40.
Emilie D, Coumbaras J, Raphael M, et al.
Interleukin-6 production in high-grade B lymphomas: correlation with the presence of malignant immunoblasts in acquired immunodeficiency syndrome and in human immunodeficiency virus-seronegative patients.
Blood.
1992;80:498-504 41. Akira S, Taga T, Kishimoto T. Interleukin-6 in biology and medicine. Adv Immunol. 1993;54:1-78[Medline] [Order article via Infotrieve]. 42. Kawano M, Hirano T, Matsuda T, et al. Autocrine generation and requirement of BSF-2/IL-6 for human multiple myelomas. Nature. 1988;332:83-85[CrossRef][Medline] [Order article via Infotrieve].
43.
Shimizu S, Yoshioka R, Hirose Y, Sugai S, Tachibana J, Konda S.
Establishment of two interleukin 6 (B cell stimulatory factor 2/interferon beta 2)-dependent human bone marrow-derived myeloma cell lines.
J Exp Med.
1989;169:339-344
44.
Klein B, Zhang X, Lu Z, Bataille R.
Interleukin-6 in human multiple myeloma.
Blood.
1995;85:863-872
45.
Tosato G, Tanner J, Jones K, Revel M, Pike S.
Identification of interleukin-6 as an autocrine growth factor for Epstein-Barr virus-immortalized B cells.
J Virol.
1990;64:3033-3041
46.
Tosato G, Seamon K, Goldman N, et al.
Monocyte-derived human B-cell growth factor identified as interferon-beta 2 (BSF-2, IL-6).
Science.
1988;239:502-504 47. Tosato G, Jones K, Breinig M, McWilliams H, McKnight J. Interleukin-6 production in posttransplant lymphoproliferative disease. J Clin Invest. 1993;91:2806-2814. 48. Durandy A, Emilie D, Peuchmaur M, et al. Role of IL-6 in promoting growth of human EBV-induced B-cell tumors in severe combined immunodeficient mice. J Immunol. 1994;152:5361-5367[Abstract].
49.
Tohyama N, Karasuyama H, Tada T.
Growth autonomy and tumorigenicity of interleukin 6-dependent B cells transfected with interleukin 6 cDNA.
J Exp Med.
1990;171:389-400
50.
Scala G, Quinto I, Ruocco M, et al.
Expression of an exogenous interleukin 6 gene in human Epstein Barr virus B cells confers growth advantage and in vivo tumorigenicity.
J Exp Med.
1990;172:61-68 51. Wijdenes J, Clement C, Klein B, et al. Human recombinant dimeric IL-6 binds to its receptor as detected by anti-IL-6 monoclonal antibodies. Mol Immunol. 1991;28:1183-1192[CrossRef][Medline] [Order article via Infotrieve].
52.
Jarry A, Cerf-Bensussan N, Brousse N, Guy-Grand D, Muzeau F, Potet F.
Same peculiar subset of HML1+ lymphocytes present within normal intestinal epithelium is associated with tumoral epithelium of gastrointestinal carcinomas.
Gut.
1988;29:1632-1638 53. Fischer A, Simon F, Le Deist F, Blanche S, Griscelli C, Fischer A. Prospective study of the occurrence of monoclonal gammopathies following bone marrow transplantation in young children. Transplantation. 1990;49:731-735[Medline] [Order article via Infotrieve]. 54. Fermand J, Gozlan J, Bendelac A, Delauche-Cavallier M, Brouet J, Morinet F. Detection of Epstein-Barr virus in epidermal skin lesions of an immunocompromised patient. Ann Intern Med. 1990;112:511-515.
55.
Rozenberg F, Lebon P.
Amplification and characterization of herpesvirus DNA in cerebrospinal fluid from patients with acute encephalitis.
J Clin Microbiol.
1991;29:2412-2417
56.
Klein B, Wijdenes J, Zhang X, et al.
Murine anti-interleukin-6 monoclonal antibody therapy for a patient with plasma cell leukemia.
Blood.
1991;78:1198-1204 57. Brandt S, Bodine D, Dunbar C, Nienhuis A. Dysregulated interleukin-6 expression produces a syndrome resembling Castleman's disease in mice. J Clin Invest. 1990;86:592-599. 58. Heinrich P, Castell J, Andus T. Interleukin-6 and the acute phase response. Biochem J. 1990;265:621-636[Medline] [Order article via Infotrieve].
59.
Emilie D, Wijdenes J, Gisselbrecht C, et al.
Administration of an anti-interleukin-6 monoclonal antibody to patients with acquired immunodeficiency syndrome and lymphoma: effect on lymphoma growth and on B clinical symptoms.
Blood.
1994;84:2472-2479
60.
Beck J, Hsu S, Wijdenes J, et al.
Brief report: alleviation of systemic manifestations of Castleman's disease by monoclonal anti-interleukin-6 antibody.
N Engl J Med.
1994;330:602-605 61. Wendling D, Racadot E, Wijdenes J. Treatment of severe rheumatoid arthritis by anti-interleukin 6 monoclonal antibody. J Rheumatol. 1993;20:259-262[Medline] [Order article via Infotrieve].
62.
Knowles D, Cesarman E, Chadburn A, et al.
Correlative morphologic and molecular genetic analysis demonstrates three distinct categories of posttransplantation lymphoproliferative disorders.
Blood.
1995;85:552-565
63.
Kingma D, Weiss W, Jaffe E, Kumar S, Frekko K, Raffeld M.
Epstein-Barr virus latent membrane protein-1 oncogene deletions: correlations with malignancy in Epstein-Barr virus-associated lymphoproliferative disorders and malignant lymphomas.
Blood.
1996;88:242-251 64. Smir B, Hauke R, Bierman P, et al. Molecular epidemiology of deletions and mutations of the latent membrane protein 1 oncogene of the Epstein-Barr virus in posttransplant lymphoproliferative disorders. Lab Invest. 1996;75:575-588[Medline] [Order article via Infotrieve].
65.
Murray P, Swinnen L, Constandinou C, et al.
BCL-2 but not its Epstein-Barr virus-encoded homologue, BHRF1, is commonly expressed in posttransplantation lymphoproliferative disorders.
Blood.
1996;87:706-711
66.
Taga T, Kawanishi Y, Hardy R, Hirano T, Kishimoto T.
Receptors for B cell stimulatory factor 2: quantitation, specificity, distribution, and regulation of their expression.
J Exp Med.
1987;166:967-981 67. Tanner J, Tosato G. Impairment of natural killer functions by interleukin-6 increases lymphoblastoid cell tumorigenicity in athymic mice. J Clin Invest. 1991;88:239-247.
© 2001 by The American Society of Hematology.
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
|
 |
|
  A. E. Hoffman, T. Zheng, R. G. Stevens, Y. Ba, Y. Zhang, D. Leaderer, C. Yi, T. R. Holford, and Y. Zhu Clock-Cancer Connection in Non-Hodgkin's Lymphoma: A Genetic Association Study and Pathway Analysis of the Circadian Gene Cryptochrome 2 Cancer Res., April 15, 2009; 69(8): 3605 - 3613. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Y. Zafar, D. N. Howell, and J. P. Gockerman Malignancy After Solid Organ Transplantation: An Overview Oncologist, July 1, 2008; 13(7): 769 - 778. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. K. Hong, M. L. Gulley, W.-H. Feng, H.-J. Delecluse, E. Holley-Guthrie, and S. C. Kenney Epstein-Barr Virus Lytic Infection Contributes to Lymphoproliferative Disease in a SCID Mouse Model J. Virol., November 15, 2005; 79(22): 13993 - 14003. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Islas-Ohlmayer, A. Padgett-Thomas, R. Domiati-Saad, M. W. Melkus, P. D. Cravens, M. d. P. Martin, G. Netto, and J. V. Garcia Experimental Infection of NOD/SCID Mice Reconstituted with Human CD34+ Cells with Epstein-Barr Virus J. Virol., December 15, 2004; 78(24): 13891 - 13900. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Bachetti, L. Comini, E. Pasini, and R. Ferrari Anti-cytokine therapy in chronic heart failure: new approaches and unmet promises Eur. Heart J. Suppl., November 1, 2004; 6(suppl_F): F16 - F21. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. P. Thompson and R. Kurzrock Epstein-Barr Virus and Cancer Clin. Cancer Res., February 1, 2004; 10(3): 803 - 821. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Trikha, R. Corringham, B. Klein, and J.-F. Rossi Targeted Anti-Interleukin-6 Monoclonal Antibody Therapy for Cancer: A Review of the Rationale and Clinical Evidence Clin. Cancer Res., October 15, 2003; 9(13): 4653 - 4665. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. C.M. Straathof, C. M. Bollard, C. M. Rooney, and H. E. Heslop Immunotherapy for Epstein-Barr Virus-Associated Cancers in Children Oncologist, February 1, 2003; 8(1): 83 - 98. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X.-y. R. Song, T. J. Torphy, D. E. Griswold, and D. Shealy Coming of Age:Anti-Cytokine Therapies Mol. Interv., February 1, 2002; 2(1): 36 - 46. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Corbellino, G. Bestetti, C. Scalamogna, S. Calattini, M. Galazzi, L. Meroni, D. Manganaro, M. Fasan, M. Moroni, M. Galli, et al. Long-term remission of Kaposi sarcoma-associated herpesvirus-related multicentric Castleman disease with anti-CD20 monoclonal antibody therapy Blood, December 1, 2001; 98(12): 3473 - 3475. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
 |
 |
|||||||
 |
 |
 |
 |
 |
 |
 |
 |
||
| Copyright © 2001 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
Top
Abstract
Introduction
and the
intravenous infusion of high-dose immunoglobulins.