Post transplant lymphoproliferative disease


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Post transplant lymphoproliferative disease

  1. 1. P s t n p n l h po frted e s o tr s l ty o rl ai i a e -a a mp ie v s
  2. 2. a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 5 7 e6 3 Available online at journal homepage: ArticlePost-transplant lymphoproliferative diseaseS. RajagopalanConsultant, Department of Nephrology, Apollo Hospital, Chennai, Indiaarticle info abstractArticle history: Post-transplant lymphoproliferative disorder/disease (PTLD) is a B-cell proliferation dis-Received 16 January 2013 order following infection with EpsteineBarr virus due to therapeutic immunosuppressionAccepted 18 January 2013 after organ transplantation. The more intense the immunosuppression, the higher theAvailable online 30 January 2013 incidence of PTLD and the earlier it occurs. The cornerstone of successful treatment of PTLD is reduction or withdrawal of immunosuppression.Keywords: Copyright ª 2013, Indraprastha Medical Corporation Ltd. All rights reserved.TransplantImmunosuppressionEBVB cellsPTLDTransplant patients may develop infectious mononucleosis- immunosuppression in these patients. In terms of lympho-like lesions or polyclonal polymorphic B-cell hyperplasia due proliferative disease occurring in the allograft itself, it de-to EpsteineBarr virus (EBV) infection. Some of these B cells pends on the graft in question. The lungs very frequently aremay undergo mutations which will render them malignant, a site of involvement in patients undergoing heart-lung, orgiving rise to a lymphoma. Most cases of PTLD are observed in heart alone, transplant. In cardiac transplant, the heart itselfthe first post-transplant year. Reduction of immunosup- seldom is involved. In renal allografts, the graft kidney ispression inherently carries the risk of allograft dysfunction or affected approximately one third of the time, which is similarloss. The reversibility, partial or complete, with reduction of to graft involvement rates in liver and bone marrow trans-immunosuppression, differentiates PTLD from the lympho- plant cases.proliferative disorders observed in patients who are immu- The incidence in renal transplant recipients is around 1 pernocompetent. Studies have documented the adverse impact cent, a risk of lymphoma about 20 times greater than in theof subclinical CMV (cytomegalovirus) and EBV viremia on graft general population. The two main aetiological mechanismsfunction.1 are EBV infection and immunosuppression. EBV infection can be detected in about 90 per cent of patients and is almost al- ways a primary infection. Thus, seronegative recipients are1. Epidemiology, morbidity and mortality those predominantly at risk and this explains why children are commonly affected in contrast to lymphoma in the gen-The incidence of PTLD varies with the type of transplanted eral population.allograft. It is much higher in heart or heart-lung transplants, Swinnen et al examined the incidence of PTLD in patientspresumably reflecting the need for more intense undergoing cardiac transplant and using OKT3 (murine E-mail address:$ e see front matter Copyright ª 2013, Indraprastha Medical Corporation Ltd. All rights reserved.
  3. 3. 58 a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 5 7 e6 3monoclonal anti-CD3 antibody) as immunosuppression and retrospective review of 32 patients, the 5-year survival ratefound an incidence of 6.2% in patients who had received a dose was 59%, with 45% of patients diagnosed within the first yearof 75 mg or less. The mean time to development of PTLD was 11 following transplantation. Six out of 8 patients surgicallymonths, compared with an incidence of 35.25% and a mean treated remain alive and disease free. Characteristics asso-interval of 1.5 months in patients who received doses of ciated with poorer survival were diagnosis within the first yeargreater than 75 mg. With prednisolone and azathioprine alone, post-transplant, monoclonal tumors, and presentation withthe mean time to developing PTLD is 50 months. Cyclosporin an infectious mononucleosis-like syndrome.6therapy reduced this to 5 months. Use of tacrolimus and use of LeBlond et al, in a series of 61 patients who had undergoneantilymphocyte globulins have been associated with much kidney, lung, liver, or heart transplantation, found that factorsearlier and more frequent presentation of PTLD.2 predictive for shorter survival (univariate analysis) in PTLD Majority of PTLDs are of non-Hodgkin’s lymphoma subtype included a performance status (PS) greater than or equal to 2,and makeup about 93% of lymphoma encountered in this increased number of sites involved (i.e., >1 versus 1), primarysetting. Out of those 86% of post-transplant lymphomas are of central nervous system (CNS) involvement, T-cell origin,B-cell origin and about 14% of lymphomas are of T-cell origin, monoclonality, nondetection of EBV in the tumor, and treat-whereas less than 1% are of null cell origin.3 ment based on chemotherapy (in addition to reduction in Cohen (1991) reviewed cases of PTLD in the literature immunosuppression).7involving renal, cardiac, heart-lung, liver, and bone marrowtransplantation. In the case of renal allografts, 60% of patientsdeveloped PTLD within 6 months of transplantation, but the 2. Pathophysiologymean time was 32 months. He noted that patients treatedwith cyclosporin had a mean time to development of PTLD of 5 The disease is an uncontrolled proliferation of B lymphocytesmonths. Survivors were more likely to have a shorter time following infection with EpsteineBarr virus. EBV is a herpesinterval to development of PTLD than those who died, they virus that is thought to infect as much as 95% of the adultwere more likely to have polyclonal lesions and B-cell hyper- population. Primary infection with EBV usually results in mild,plasia, and they were more likely to have involvement of graft self-limiting illness in childhood and the clinical syndrome ofor lymph nodes.4 infectious mononucleosis in adults. It was found over 3 de- Shapiro et al found an overall incidence of PTLD of 1.9% in cades ago by electron microscopy of cells cultured froma population of 1316 patients undergoing kidney transplants a Burkitt lymphoma. Since 1968, it has been known to causeat the University of Pittsburgh from 1989 to 1997. The inci- infectious mononucleosis and has been associated with non-dence in adults was 1.2%, with a much higher incidence in Hodgkin lymphoma and oral hairy leukoplakia in patientspediatric patients (i.e., 10.1%). The time interval to diagnosis of with HIV infection and with nasopharyngeal carcinoma, par-PTLD ranged from less than 1 month to 49 months in adults. ticularly in Southeast Asia.The 1- and 5-year patient and graft survival rates in adults Once a person is infected with EBV, the virus persists forwere 93% and 86% and 80% and 60%, respectively. The authors life as a result of latency in B-cell lymphocytes and chronicconcluded that although PTLD is more common in renal replication in the cells of the oropharynx. The EBV genome istransplant pediatric recipients receiving tacrolimus, they have a linear DNA molecule that encodes for approximately 100a more favorable prognosis.5 viral proteins that are expressed during replication. The CD21 PTLD forms a heterogenous group of tumors, ranging from molecule on the surface of the B-cell is the target receptor ofB-cell hyperplasia to immunoblastic lymphoma, the latter the EBV glycoprotein envelope. Infection of B-cell lympho-portending a more grim prognosis. All PTLD, however, irre- cytes with EBV results in either viral replication and B-cellspective of histology, is potentially, and frequently, fatal. lysis (i.e., lytic replication) or a transformation of the cell withMortality rates could be as high as 60e100%. The presentation only partial EBV genome expression (i.e., latency). Cell trans-and clinical course are variable. At one end of the spectrum is formation is associated with B-cell activation and continuousaggressive disease with diffuse involvement, resulting in proliferation. In patients who are immunocompetent, prolif-rapid demise of the patient; at the other end of the spectrum eration of these transformed B cells usually is controlled byare localized lesions that are indolent and slow growing over cytotoxic T cells. This is not the case, however, with patientsmonths, as opposed to days or weeks. The former occur early who are the post-transplantation period and are more often poly- The viral genome expresses only 9 proteins during latency,clonal lesions. Late-onset PTLD tends to be monoclonal and when it adopts an episomal configuration. This createsheralds a worse prognosis. Polyclonal lesions, however, have increased difficulty for T-cell recognition, facilitating persis-a more favorable prognosis. They, unlike monoclonal lesions, tent EBV infection, which is thought to occur in restingtend to occur early and are responsive to reduction of memory B cells. The 9 proteins expressed are EBV latentimmunosuppression. Primary CNS involvement is associated membrane proteins ([LMP], i.e., LMP-1, LMP-2A, LMP-2B) andwith significantly higher mortality rates, 88% at 6 months in EBV nuclear antigens ([NA], i.e., EBNA-1, EBNA-2, EBNA-3A,one study. CNS disease requires intrathecal therapy or local- EBNA-3B, EBNA-3C, EBNA-LP). LMP-1 is considered to be anized radiation therapy because intravenous chemotherapy oncogene. Its expression results in increased levels of CD23,and monoclonal antibodies do not cross the blood-brain bar- which is a B-cell activation antigen. LMP-1 also is known torier adequately. induce expression of bcl-2, which inhibits apoptosis of an Hauke et al reported their experience with PTLD occurring infected cell. LMP-2 prevents reactivation of EBV in latentlyin patients after solid organ transplantation. In this infected cells. EBNA-1 is responsible for maintaining the
  4. 4. a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 5 7 e6 3 59episomal configuration of the latent virus. EBNA-2 up-regu- may be seen with isolated or multiple tumors often involvinglates the expression of LMP-1 and LMP-2, which are necessary the gastrointestinal tract, the lungs, or the allograft. Finally,for transformation of the B-cell. one may see an EBV-negative type of PTLD which is of late EBV infection results in both a humoral and cellular im- onset and clinically resembles non-Hodgkin’s lymphoma. Inmune response by the host. Cellular immunity is thought to be those patients with localized organ involvement, the brain isthe more important of the two in terms of regulation and frequently involved, much more often than in lymphoma incontrol of proliferation of the infected B lymphocytes by the general population.means of CD4 and CD8 cytotoxic T cells and natural killer Whether PTLD presents as localized or disseminated dis-cells. Antibodies to viral capsid and nuclear proteins are pro- ease, the tumors are aggressive and rapidly progressive andduced, the presence of which facilitates the diagnosis of EBV often are fatal. Clinical presentation is very variable and in-infection. In individuals who are immunocompetent, these cludes fever (57%), lymphadenopathy (38%), gastrointestinalmechanisms work well to prevent outgrowth of EBV-infected symptoms (27%), infectious mononucleosis-like syndromelymphocytes. In patients who are immunodeficient, a number that can be fulminant (19%), pulmonary symptoms (15%), CNSof factors compromise these mechanisms. Production of an symptoms (13%), and weight loss (9%). Patients may reportinterleukin-10, an endogenous anti-T cell cytokine, has also fever, weight loss, anorexia, lethargy, sore throat, swollenbeen implicated. glands, diarrhea, abdominal pain, shortness of breath, neu- The immunosuppression required to preserve graft function rological symptoms, or symptoms that initially would notpost-transplantation results in impairment of T-cell immunity suggest a diagnosis of PTLD. The most common sites forand allows for uncontrolled proliferation of EBV-infected involvement are lymph nodes (59%), liver (31%), lung (29%),B cells, resulting in monoclonal or polyclonal plasmacytic kidney (25%), bone marrow (25%), small intestine (22%), spleenhyperplasia, B-cell hyperplasia, B-cell lymphoma, or immuno- (21%), CNS (19%), large bowel (14%), tonsils (10%), and salivaryblastic lymphoma. Immune surveillance is impaired. As dis- glands (4%).cussed above, this outgrowth usually is regulated by cytotoxic Tcells and natural killer cells. In the initial stages, the proliferation is polyclonal. With 4. Evaluationmutation and selective growth, the lesion becomes oligoclonaland, later, monoclonal. Cyclosporin was demonstrated many A diagnosis of PTLD is made by having a high index of suspi-years ago to actually promote the proliferation of B lympho- cion in the appropriate clinical setting; histopathological evi-cytes in vitro. Additionally, lymphocytes from patients treated dence of lymphoproliferation on tissue biopsy; and thewith cyclosporin following transplantation do not exhibit an presence of EBV DNA, RNA, or protein in tissue.appropriate T-cell response to EBV-infected B cells in vitro. The EBV status of the recipient usually is established pre-The activity of natural killer cells is reduced for several transplantation. Donor EBV status is not always sought rou-months post-transplantation, impairing cellular immune tinely because the incidence of infection with EBV in theresponsedthe most important regulator of proliferation. general population is so high. In primary EBV infection, EBVDepletion of T cells by use of anti-T-cell antibodies (ATG, ALG viral capsid antigen (VCA) immunoglobulin M (IgM) titers areand OKT3) in the prevention or treatment of transplant elevated.rejection further increases the risk of developing post- Reactivation of EBV infection is characterized by more thantransplant lymphoproliferative disorder. a 4-fold rise in EBV VCA immunoglobulin G (IgG) titers, com- Other risk factors that have been identified as predictive for pared with previously recorded EBV VCA IgG titers. No changethe development of PTLD include use of OKT3, anti- in titer suggests past infection.lymphocyte globulin, recipient pretransplant EBV seronega- These tests can be performed as part of a PTLD workup.tivity and donor EBV seropositivity. The incidence of PTLD has Elevated titers of antibodies to VCA have been identified inbeen found to be significantly higher in patients who are EBV recipients of solid organ grafts who developed PTLD. Theseronegative pretransplant, compared with those who are absence of change in EBV antibody titers does not excludeseropositive (23.1% versus 0.7%) in Cockfield’s 1993 analysis.8 a diagnosis of PTLD. However, increases in EBV viral load inHowever, experience at the University of Pittsburgh, in the the peripheral blood have been detected in patients prior tocase of intestinal transplantation, the incidence of PTLD is as the onset of lymphoproliferative disease, and a decrease inhigh in patients who are EBV seropositive pretransplantation these levels has occurred following effective treatment ofas in patients who are seronegative. PTLD. EBV viral load can be monitored by means of polymer- ase chain reaction (PCR). High viral loads have been found in a high proportion of patients with PTLD, but a high EBV viral3. Presentation and clinical features titer is not diagnostic. This test is not standardized, and not all patients with PTLD have a high viral load.9PTLD usually presents as one of four clinical syndromes. An In addition to a high degree of vigilance in the appropriateonset similar to acute infectious mononucleosis with con- clinical setting, histological confirmation of lymphoprolifera-stitutional upset and tonsilar and cervical lymph node tion is mandatory. Histopathologically, the lesion may dem-enlargement is the most common mode of presentation dur- onstrate plasmacytic hyperplasia, B-cell hyperplasia, B-celling the first year. Second a fulminating picture with wide- lymphoma, or immunoblastic lymphoma. The pathologicalspread infiltration and ominous prognosis can present within diagnosis of PTLD is based on the WHO classification and in-weeks of the transplant. Later, a more indolent presentation cludes 4 main categories: (1) early lesions, (2) polymorphic
  5. 5. 60 a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 5 7 e6 3 Nondetection of EBV is associated with tumors that present late, usually are monoclonal, and are more resistant to treat- ment. They are more likely to be disseminated and are less likely to achieve complete remission (Fig. 2). Establishing the clonality of the lesion is important. Tu- mors can be monoclonal, oligoclonal, polyclonal, or mixed. Some lymphomas may appear polyclonal by surface immu- noglobulin staining but are monoclonal by immunoglobulin rearrangement. Reports of patients with multiple disease sites, one lesion of which was monoclonal while a distant lesion was polyclonal, have occurred. Monoclonal PTLD has a worse prognosis, so multiple biopsy sites may be useful in defining prognosis in an individual with more than one lesion. Do not assume that if one site is polyclonal, all disease sites are polyclonal. PTLD does not demonstrate the 8:14 or 8:22 translocations associated with Burkitt lymphoma. PTLD can- not be differentiated into benign or malignant tumors. TheFig. 1 e Biopsy of gingival tissue, with haematoxylin and mortality rate is high, independent of histology.eosin stain demonstrates polymorphous infiltrate of With regard to T-cell lymphoproliferative disorders, theseatypical lymphoid cells, which is consistent with post- lesions predominantly are monoclonal.transplant lymphoproliferative disease (PTLD). T-cell PTLD usually is not associated with EBV infection and does not respond to immunosuppression dose reduction. It carries an unfavorable prognosis.PTLD, (3) monomorphic PTLD, and (4) classic Hodgkin lym- Radiological evaluation includes computerized tomogra-phoma (Fig. 1).10 phy scan of chest, abdomen, pelvis, and head, looking for In practice, a clear separation between the different sub- evidence of hepatosplenomegaly, lymphadenopathy, ortypes is not always possible; early lesions, polymorphic PTLD, abnormal mass.and monomorphic PTLD probably represent a spectrum of T-cell lymphoproliferative disorders not associated withdiseases.11 EBV infection tend to occur at extranodal sites. Reports exist of Immunohistologic staining can be used to confirm the PTLD presenting in the oral cavity.presence of EBV. In situ hybridization with the EBV-encoded Gastrointestinal PTLD usually involves the small and largeRNA (EpsteineBarr early region [EBER]-1) probe (labels EBV- intestine and most common presentation is fever, abdominalencoded RNA in infected cells) is a reliable means of detect- pain or perforation.12ing EBV in tissue. It also requires demonstration of the pres- It has been observed that gastric PTLD is more common inence of EBV DNA or protein in the biopsied tissue. renal allograft recipients compared to other solid organ Fig. 2 e EBV early RNA (EBER) in PTLD tissue.
  6. 6. a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 5 7 e6 3 61transplantation but the exact cause of this difference is not dose of OKT3 used and time interval between transplantationwell understood.13 and the onset of PTLD. Six of the patients had polyclonal dis- ease, and 13 had monoclonal. A large proportion of these pa- tients presented early post-transplantation with diffuse and5. Treatment aggressive disease. Those who survived and did not respond to initial management were treated with the combination che-Starzl et al were the first to suggest reduction, or withdrawal, motherapeutic regimen ProMACE-CytaBOM (prednisone,of immunosuppression as a treatment option for PTLD.14 This Adriamycin, Cytoxan, etoposide, arabinoside cytosine, bleo-serves to allow the patient’s natural immunity to recover and mycin, Oncovin, and methotrexate). Of the 8 patients whogain control over proliferating EBV-infected cells. Most pa- received chemotherapy, all had monoclonal disease. Thistients with benign PTLD respond well to this management regimen was felt to be adequately immunosuppressive toapproach. People with malignant disease often respond obviate the need to continue with other immunosuppressiveinadequately to these measures, and more aggressive treat- agents during chemotherapy, and no episodes of graft rejectionment is necessary. A reduction in immunosuppressive ther- occurred. Seventy five per cent of patients achieved a completeapy is not effective for CNS PTLD. remission, and no cases of relapse occurred at 38 months.2 T-cell PTLD usually is not associated with EBV infection The CHOP combination (cyclophosphamide, Adriamycin,and does not respond to immunosuppression dose reduction. Oncovin, and prednisone) has been used with high remission Additional measures that have been used include surgical rates in cardiac transplant patients. However, the dose ofexcision of the lesion (which can be curative in cases of doxorubicin in ProMACE-CytaBOM is half that used in CHOP,localized disease), antiviral therapy, localized radiation ther- making ProMACE-CytaBOM less cardiotoxic and a moreapy and chemotherapy, alfa interferon, intravenous gamma attractive therapeutic regimen.globulin, cytotoxic T lymphocytes, and monoclonal anti- Benkerrou et al reported the long-term outcome of severe,bodies, each with varying degrees of success. aggressive PTLD following bone marrow and solid organ trans- Acyclovir and ganciclovir both inhibit lytic EBV DNA rep- plantation treated with B-cell antibodies, anti-CD21, anti-CD24.lication in vitro. Ganciclovir is more potent than acyclovir. Eligibility criteria included lymphoproliferations not responsiveHowever, the majority of EBV-infected cells in lymphoproli- to reduction in immunosuppression or rapidly progressive dis-ferative lesions are transformed B cells. Acyclovir inhibits only ease. Complete remission was achieved in 61% of patients, withthe replication of linear EBV DNA and is ineffective against a relapse rate of 8%. The overall long-term survival rate was ofepisomal EBV DNA, which is the conformation of the EBV the order of 46% at 61 months, although survival rates weregenome in latent B lymphocytes. lower among bone marrow transplant recipients (35%) com- Interferon alfa has been found effective in the treatment of pared with solid organ transplant patients (55%). They alsoB-cell PTLD in some patients. It functions as both a proin- identified as poor prognostic markers multivisceral disease,flammatory and antiviral agent. Interferon alfa inhibits the CNS involvement, and late-onset PTLD, which are findings thatoutgrowth of EBV-transformed B cells, and decreases the are consistent with results published by other authors.18oropharyngeal shedding of EBV. It inhibits T helper cells, Rituximab, an anti-CD20 monoclonal antibody, has beenwhich release cytokines (i.e., interleukin IL-4, IL-6, IL-10) that used to treat non-Hodgkin lymphoma. Milpied et al in Francepromote B-cell proliferation.15 reported promising results, with response rates of 65%, in Intravenous immunoglobulin has been used as adjunctive patients with PTLD treated with rituximab following solidtherapy in the management of PTLD. Deficiency or absence of organ transplantation.19 According to Gross et al, rituximabantibody against one of the EBNAs in patients post-trans- can be combined with low-dose chemotherapy to createplantation has been associated with the subsequent devel- a safe and effective treatment for pediatric patients whoopment of PTLD. Decreasing EBV viral load has been reported have EpsteineBarr virus and PTLD following solid-organto be associated with increased levels of antibody against transplantation.20EBNAs. These 2 factors provide the rationale for the use of Papadopoulous et al postulated that the use of donor leu-intravenous immunoglobulin in the management of PTLD. It kocyte infusions might treat PTLD effectively in the allografthas been used mainly in combination with interferon alfa.16,17 recipient. They based this hypothesis on the premise that the A high mortality rate has been associated with the use of donor has cytotoxic T lymphocytes, which are presensitizedchemotherapy in the management of transplant-associated to the EBV responsible for the lymphoproliferation in thelymphoproliferative disease. In Cohen’s (1991) review of the recipientdthe EBV being donor in origin. They studied 5 pa-value of chemotherapy and radiotherapy for the treatment of tients who developed malignant B-cell lymphoma afterPTLD in transplant recipients, neither chemotherapy nor receiving T-cell depleted allogeneic bone marrow trans-radiotherapy demonstrated any survival advantage compared plantation. EBV DNA was detected in each tissue sample. Allwith overall survival rates of 31%. In fact, survival rates were patients achieved complete clinical and pathological remis-worse, at 23% and 20%, respectively. sion in response to unirradiated infusions of donor leuko- Swinnen et al, however, report a retrospective study of 19 cytes.21 The EBV-specific cytotoxic T lymphocytes from thecardiac transplant recipients with PTLD who initially were donor, in the case of bone marrow transplantation, have thetreated with reduced immunosuppression and acyclovir. The capability of recognizing and destroying EBV-infected B cellspatients had all received OKT3 (i.e., monoclonal anti-T-cell in the recipient. Solid organ transplant patients, however,antibody) as part of their immunosuppressive regimen. A sta- develop PTLD that can be recipient or donor in origin, which intistically significant reciprocal relationship exists between the each case would have to be determined before initiation of
  7. 7. 62 a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 5 7 e6 3treatment. In the case of PTLD that is recipient in origin, to referencesobtain cytotoxic T lymphocytes the recipient’s T cells wouldneed to be stimulated against EBV ex vivodtechnology that isnot yet available. 1. Li L, Chaudhuri A, Weintraub LA, et al. Subclinical cytomegalovirus and EpsteineBarr virus viremia are associated with adverse outcomes in pediatric renal6. Prevention transplantation. Pediatr Transplant. 2007;11:187e195 [PubMed]. 2. Swinnen LJ, Costanzo-Nordin MR, Fisher SG, et al. IncreasedProphylactic measures may include screening of donors and incidence of lymphoproliferative disorder afterrecipients for baseline EBV data, risk stratification, and using immunosuppression with the monoclonal antibody OKT3 ingrafts from donors who are EBV seronegative where possible cardiac-transplant recipients. N Engl J Med. Dec 20for seronegative recipients. 1990;323(25):1723e1728 [Medline]. 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Post-that the incidence of PTLD was lower with prophylactic anti- transplant lymphoproliferative disorder in renal allograftviral treatment.24 recipients. Clinical experience and risk factor analysis in Birkeland et al reported that primary or reactivated EBV a single center. Transplantation. Jul 1993;56(1):88e96infection correlated with acute graft rejection and the inci- [Medline].dence of PTLD. They additionally found that the use of acy- 9. Rooney CM, Loftin SK, Holladay MS. Early identification ofclovir (3200 mg/d for 3 months post-transplantation) was EpsteineBarr virus-associated posttransplantation lymphoproliferative disease. Br J Haematol. Janprotective against primary or reactivated EBV infection and 1995;89(1):98e103 [Medline].that the addition of mycophenolate mofetil resulted in further 10. Swerdlow SH, Webber SA, Chadburn A, Ferry JA.reduction of infection or reactivation. These patients also had Posttransplant lymphoproliferative disorders. 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  9. 9. A oo op a ht:w wa oo op a . m/ p l h si l t / w . lh si lc l t: p / pl t soT ie:t s/ iecm/op a A oowt r t :t t ro H si l p l t h p /w t . ts lYuu eht:w wyuu e o a oo op a i io tb :t / w . tb . m/p lh si ln a p/ o c l ts dFcb o :t :w wf e o k o T e p lH si lae o kht / w .cb o . m/h A oo op a p/ a c l tsSd sa :t :w wsd sa . t p l_ op a l eh r ht / w .i h rn / oo H si l i e p/ le e e A l tsL kd :t :w wlkd . m/ mp n/p l -op ai e i ht / w . e ic c n n p/ in n o o ay ooh si l a l tsB ght:w wl s l el ./ l :t / w .t a h a hn o p/ e tk t i