Version May 2024
INTRODUCTION — Post-transplant lymphoproliferative disorders (PTLD) are lymphoid and/or plasmacytic proliferations that occur in the setting of solid organ or allogeneic hematopoietic cell transplantation as a result of immunosuppression. They are among the most serious and potentially fatal complications of transplantation. While the majority appears to be related to the presence of Epstein-Barr virus (EBV), EBV-negative disease does occur. Three general types of PTLD have been described in transplant recipients:
●Early lesion (ie, plasmacytic hyperplasia and infectious mononucleosis-like PTLD) – This presents as an infectious mononucleosis-type acute illness characterized by polyclonal B cell proliferation with no evidence to suggest malignant transformation.
●Polymorphic PTLD – Polymorphic PTLD are polyclonal or monoclonal lymphoid infiltrates that demonstrate evidence of malignant transformation but do not meet all of the criteria for one of the B cell or T/NK cell lymphomas recognized in immunocompetent patients.
●Monomorphic PTLD – Monomorphic PTLD are monoclonal lymphoid proliferations that meet the criteria for one of the B cell or T/NK cell lymphomas recognized in immunocompetent patients.
These conditions lie along a continuum of disease and are categorized by the 2008 World Health Organization classification system as PTLD [1]. Of importance, small B cell lymphoid neoplasms (eg, follicular lymphomas, small lymphocytic lymphoma) and marginal zone (MALT) lymphomas arising in the post-transplant setting are not considered PTLD.
The treatment and prevention of PTLD following solid organ and allogeneic hematopoietic cell transplant will be reviewed here. The diagnosis of PTLD and the development of other secondary malignancies following transplant are discussed separately. (See "Epidemiology, clinical manifestations, and diagnosis of post-transplant lymphoproliferative disorders" and "Secondary cancers after hematopoietic cell transplantation" and "Malignancy after solid organ transplantation".)
PREVENTION — Since the development of PTLD is related to the degree of immunosuppression and infection with Epstein-Barr virus (EBV) and cytomegalovirus (CMV), prevention largely relies upon limiting patient exposure to aggressive immunosuppressive regimens, rapid withdrawal and/or tapering of agents required for graft acceptance, and anti-viral prophylaxis. Attention to such measures may lessen the incidence of PTLD. In addition, many transplant centers have incorporated EBV monitoring into the routine evaluation of patients at high risk for PTLD, and preemptively treat PTLD at the time of viral reactivation with anti-B cell monoclonal antibody treatment. For seronegative hematopoietic cell transplant recipients, avoiding seropositive donors when there are multiple donor options available can also reduce the risk of PTLD. (See "Epidemiology, clinical manifestations, and diagnosis of post-transplant lymphoproliferative disorders", section on 'Measurement of EBV viral load'.)
Tapering immunosuppressive therapy — Maintenance immunosuppressive therapy is used in the transplant setting to help prevent acute rejection, loss of the allograft, and graft-versus-host disease. While the degree of immunosuppression required and the timing of immunosuppression withdrawal differs with the clinical setting, there is general agreement that more aggressive withdrawal of immunosuppression to maintenance target concentrations is associated with lower incidence of PTLD. At times this approach is not practical, however, and alternatives are needed.
As an example, a relatively high incidence of PTLD was found with the introduction of tacrolimus (FK506) for renal allograft recipients. Therefore, the aggressive tapering of this agent may limit the development of this disorder. In one review of 82 children who received renal allografts with tacrolimus-based regimens, the incidence of PTLD was 17 percent (5 of 29 patients) among patients transplanted between 1989 and 1992 [2]. The prevalence fell to 4 percent (2 of 53 cases) for those transplanted from early 1993 to 1996, a finding attributed in part to a policy of aggressive tapering of tacrolimus (and corticosteroids) to a lower maintenance target trough concentration of 5 to 9 ng/mL [3].
Details regarding the use of immunosuppressive therapy post-transplant are presented separately. (See "Kidney transplantation in adults: Maintenance immunosuppressive therapy" and "Heart transplantation in adults: Induction and maintenance of immunosuppressive therapy" and "Maintenance immunosuppression following lung transplantation" and "Prevention of graft-versus-host disease" and "Treatment of chronic graft-versus-host disease".)
Antiviral prophylaxis — Although ganciclovir inhibits EBV replication in vitro, it is not routinely given as prophylaxis in hematopoietic cell transplant recipients due to the limited data regarding its efficacy in preventing PTLD and concerns regarding bone marrow suppression in this population. Data regarding the efficacy of antiviral prophylaxis in the prevention of PTLD in solid organ recipients is also limited. Many solid organ recipients receive acyclovir for herpes simplex virus (HSV) prophylaxis and valganciclovir or ganciclovir for cytomegalovirus (CMV) prophylaxis in the post-transplant setting. A matched case controlled study showed that for every 30 days of acyclovir use the odds ratio for developing PTLD was 0.83, and for every 30 days of ganciclovir use, the odds ratio for developing PTLD was 0.62 [4]. (See "Prevention of viral infections in hematopoietic cell transplant recipients" and "Prevention of cytomegalovirus infection in lung transplant recipients", section on 'Universal prophylaxis' and "Prophylaxis of infections in solid organ transplantation", section on 'Cytomegalovirus'.)
The high incidence of PTLD among EBV-seronegative recipients of EBV-seropositive donor organs suggests that the ability to suppress primary EBV infection and/or detect and subsequently treat early infection may minimize the subsequent development of PTLD [4-7]. Support for the use of antiviral prophylaxis in the prevention of PTLD comes from retrospective studies and single-arm prospective studies described below.
●The effectiveness of both the prophylactic use of antiviral agents and the early detection of primary EBV infection with polymerase chain reaction (PCR) followed by antiviral therapy and lowering of the immunosuppressive regimen was evaluated in 40 children receiving a liver allograft [5]. The schedule of antiviral prophylaxis was determined by risk to develop PTLD as follows:
•High-risk patients (eg, donor EBV-positive, recipient EBV-negative) were administered a minimum of 100 days of intravenous ganciclovir (6 to 10 mg/kg per day).
•Low-risk patients (eg, donor EBV-negative, recipient EBV-positive or -negative; donor and recipient EBV-positive) received intravenous ganciclovir only during the period of hospitalization followed by oral acyclovir (40 mg/kg per day).
Target tacrolimus levels were lowered to 2 to 5 ng/mL in patients in whom a rising viral copy number was detected by PCR performed once per month. PTLD, which was defined as histologic evidence of B cell proliferation, was treated with the reinstitution of intravenous ganciclovir and the withdrawal of tacrolimus. At a mean follow-up of approximately 260 days, the following results were reported:
•Among 18 high-risk children, there were no cases of PTLD and one case of EBV infection (which resolved).
•Among 22 low-risk patients, two cases of PTLD occurred, both of which resolved after tacrolimus was stopped; there was one case of EBV increase, which also resolved.
The 5 percent incidence of PTLD with this regimen compares favorably to the incidence of 10 percent previously reported from this same center. This lower incidence combined with the finding that no high-risk patient developed PTLD suggests that aggressive preemptive therapy and frequent monitoring for early EBV infection, which (when detected) is managed by intravenous ganciclovir and reductions in immunosuppression, may lower the incidence of PTLD. (See 'Preemptive treatment of viral reactivation' below.)
●A retrospective multicenter case-control study of renal transplant recipients also found that prophylactic antiviral therapy reduced the risk of PTLD [4]. In this report of 100 biopsy-confirmed cases and 375 matched controls, the risk of PTLD during the first year post-transplant decreased by 38 percent for every 30 days of treatment with ganciclovir (OR of 0.62, 95% CI 0.38-1.0). The addition of immune globulin to ganciclovir does not appear to provide added benefit to ganciclovir alone among patients at increased risk for PTLD [8].
●In one large retrospective database study, use of prophylaxis with anti-CMV immunoglobulin during the first four months after kidney transplantation significantly reduced the incidence of PTLD during the first year post-transplant, but not in the subsequent five years [9]. This may have been due to temporary anti-EBV protection from the substantial anti-EBV reactivity present in the immunoglobulin preparations employed.
Preemptive treatment of viral reactivation — Many transplant centers incorporate EBV monitoring into the routine evaluation of patients at high risk for PTLD and preemptively treat at the time of viral reactivation.
Transplant centers and society guidelines differ with regard to EBV surveillance, and there is no consensus regarding the optimal approach. Surveillance for viral reactivation is discussed separately. (See "Epidemiology, clinical manifestations, and diagnosis of post-transplant lymphoproliferative disorders", section on 'Measurement of EBV viral load'.)
We treat preemptively when EBV monitoring demonstrates >1000 EBV genome equivalents/mL, but we first confirm the value before initiating prophylactic treatment. We and most centers administer preemptive rituximab therapy for patients at high risk of EBV-associated PTLD. Some centers favor reducing immunosuppression as prophylaxis.
Examples of studies that have examined prophylaxis include:
●In one prospective study of high-risk patients undergoing partially T cell depleted allogeneic hematopoietic cell transplantation (HCT), a single infusion of rituximab given to 15 patients with EBV reactivation (ie, ≥1000 EBV genome equivalents/mL) resulted in complete response in 14, as evidenced by prevention of PTLD and complete clearance of EBV-DNA from the peripheral blood [10].
●Another study of 70 children undergoing reduced intensity conditioning with alemtuzumab T cell depletion followed by allogeneic HCT prospectively monitored EBV viral load [11]. Patients who developed a viral load >40,000 copies/mL within three months of transplant or with a low CD3 count were treated preemptively with rituximab. When compared with historical controls, this approach was associated with a lower incidence of PTLD (1.4 versus 21.7 percent), especially among viremic patients (3 versus 63 percent). Although patients who received rituximab had significantly delayed B cell reconstitution, this was not associated with an increase in infectious mortality.
●In another study, reduction or suspension of immunosuppression was employed when EBV reactivation was detected (ie, ≥300 genomic copies per 105 peripheral blood mononuclear cells) [12]. This preemptive modulation of immunosuppression was accomplished in 28 patients without negatively influencing transplant-related mortality, overall, or event-free survival.
PRETREATMENT ASSESSMENT — The pretreatment evaluation of patients with PTLD both determines the extent of the disease and provides information about the individual's comorbidities that are likely to have an impact on treatment options.
While most elements of the patient’s history are pertinent to the problem at hand, some are particularly relevant to treatment selection. These include the patient’s performance status (table 1) and comorbidities, the type of transplant, the immunosuppressive regimen used, the status of the graft, the potential impact of graft failure, and the presence of graft-versus-host disease (in hematopoietic cell transplant recipients).
In addition to a history and physical examination, it is our practice to perform the following pretreatment studies in patients with PTLD:
●Laboratory studies include a complete blood count with differential, chemistries with liver and renal function and electrolytes, lactate dehydrogenase (LDH), albumin, HIV, hepatitis B, Epstein-Barr virus (EBV) serology with quantitative polymerase chain reaction (PCR), and cytomegalovirus (CMV) PCR. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy".)
●Contrast-enhanced computed tomography (CT) of the chest, abdomen, and pelvis should be performed in patients suspected of having PTLD. This study provides critical information on the measurement of disease prior to treatment, and aids in staging [13]. When available, we suggest obtaining a combined positron emission tomography (PET)/CT scan as a measure of disease activity [14]. (See "Pretreatment evaluation and staging of non-Hodgkin lymphomas", section on 'Imaging'.)
●Assessment of the function of the transplanted organ.
●Unilateral bone marrow aspiration and biopsy is suggested for patients with cytopenias.
●If involvement of the central nervous system is suspected, further evaluation should include gadolinium-enhanced magnetic resonance imaging (MRI) of the head and cerebral spinal fluid (CSF) analysis. (See "Epidemiology, clinical manifestations, and diagnosis of post-transplant lymphoproliferative disorders", section on 'Central nervous system lymphoma'.)
●A study of cardiac function (eg, echocardiogram or MUGA) should be performed for patients with a history of cardiac disease (and no heart transplant) and for those who plan to undergo anthracycline-based chemotherapy (eg, R-CHOP).
●Patients with childbearing potential should receive counseling about the potential effect of treatment on their fertility and options for fertility-preserving measures. (See "Fertility and reproductive hormone preservation: Overview of care prior to gonadotoxic therapy or surgery".)
TREATMENT
Choice of treatment — Management of PTLD has varied significantly according to the PTLD subtype and the type of transplant, as well as from institution to institution [15-17]. The main options for initial treatment are reduction of immunosuppression, immunotherapy with the CD20 monoclonal antibody rituximab, chemotherapy, radiation therapy, or a combination of these. Other treatments, such as adoptive immunotherapy with EBV-specific cytotoxic T cells, are generally reserved for persistent disease despite initial therapy, or for those patients treated at selective sites capable of performing these types of treatments, or for patients willing and able to travel to such sites. This approach could be used more widely with greater availability of EBV-specific cytotoxic T cells. A choice among therapies must take into consideration the aggressiveness of the PTLD, the expected time to response of individual therapies, and associated toxicities. Of importance, rituximab is only effective in CD20-positive PTLD.
The two main goals of therapy are eradication of the PTLD and preservation of graft function. Not uncommonly, these goals conflict and one must take precedence. As an example, reduction of immunosuppression is commonly employed for PTLD eradication, but increases the risk of graft rejection and/or graft-versus-host disease. Reduction of immunosuppression may be preferred when alternative organ support is available (eg, renal or renal/pancreas transplant). In contrast, there will be cases in which worsening graft function in vital organs (eg, heart transplant) necessitates continued immunosuppression and dictates the need for alternative therapies.
The World Health Organization classification of tumors of the hematopoietic and lymphoid tissues uses morphologic, immunophenotypic, genetic, and clinical features to define four main categories of PTLD [1]. Our initial management is largely dependent upon the type of PTLD:
●Early lesions – For most patients with early lesions, we suggest reduction of immunosuppression alone rather than in combination with other therapies. Other agents are generally reserved for those patients with residual disease despite reduced immunosuppression or for those who cannot tolerate reduction of immunosuppression. (See 'Early lesions' below.)
●Polymorphic PTLD – For most patients with polymorphic PTLD that expresses CD20 (CD20+ PTLD), we suggest the use of rituximab in addition to reduction of immunosuppression, as tolerated, rather than reduction of immunosuppression alone. Chemotherapy and surgery may be considered in addition for a subset of patients with systemic or localized disease, respectively. (See 'Polymorphic PTLD' below.)
●Monomorphic PTLD – For patients with monomorphic CD20+ PTLD, we suggest the use of rituximab, either alone or in combination with chemotherapy in addition to reduction of immunosuppression, if possible. Single agent rituximab may be considered for patients who have minimal symptoms and for those who are not candidates for initial chemotherapy (eg, poor performance status). All other patients with CD20+ PTLD are offered rituximab plus combination chemotherapy (eg, CHOP), administered concurrently or sequentially. Patients whose tumors do not express CD20 are not candidates for rituximab therapy and are treated with combination chemotherapy plus reduction of immunosuppression, if possible. Surgery is reserved for patients with complications such as perforation or obstruction. Where available, cytotoxic EBV-specific T cells may be preferred over chemotherapy, due to less blood count suppression and other toxicities. (See 'Monomorphic PTLD' below.)
●Classic Hodgkin lymphoma-like PTLD – Classic Hodgkin lymphoma-like PTLD is the least common form of PTLD, and there is a paucity of data regarding management. For most patients with classic Hodgkin lymphoma-like PTLD we suggest management with chemotherapy with or without radiation therapy according to protocols used for classic Hodgkin lymphoma.
Our approach is generally consistent with practice guidelines proposed by the National Comprehensive Cancer Network (NCCN), the British Committee for Standards in Haematology, the British Transplantation Society, and the European best practice guidelines for renal transplantation [18-20]. While these guidelines differ in detail, they all recognize a benefit from reduction of immunosuppression and the need to balance this with the risk of graft rejection.
Early lesions — Early lesions are characterized by polyclonal B cell proliferation with no evidence to suggest malignant transformation [1]. For most patients with early lesions, we suggest reduction of immunosuppression alone rather in combination with immunotherapy (eg, rituximab), chemotherapy, or antivirals. This preference is largely based upon uncontrolled trials that have suggested the efficacy of reduction of immunosuppression and the desire to avoid potential harms associated with more intensive therapy. Rituximab may be considered for those patients with CD20 positive PTLD with residual disease despite reduction of immunosuppression or for those who cannot tolerate reduction of immunosuppression. While antiviral prophylaxis may decrease the incidence of PTLD, antiviral therapy has yet to demonstrate convincing efficacy in the treatment of PTLD [21]. (See 'Antiviral prophylaxis' above.)
Reduction in immunosuppression — Reduction of immunosuppression should be incorporated into the initial management of all patients with PTLD unless concerns regarding graft rejection or graft-versus-host disease make this approach unfeasible. Data regarding the efficacy of reduction of immunosuppression come largely from uncontrolled observational studies in which patients also received other treatment strategies. The majority of early lesions either resolve completely or improve significantly within three to five weeks [22-24]. Responses are seen less commonly in other types of PTLD. Reduction of immunosuppression increases the risk of allograft rejection, which may result in death among those with heart, lung, and liver allografts. However, a careful decrease in immunosuppressive therapy based upon the individual's clinical features and type of allograft can result in both a high response rate and a low rate of rejection and allograft loss.
●In one study, 42 solid organ transplant recipients with PTLD were treated with reduction of immunosuppression, and 12 also underwent surgical removal of all apparent disease [23]. Overall, 31 (74 percent) achieved complete remission (CR). Among those treated with reduction of immunosuppression alone, 63 percent had a complete or partial response with a median time to documentation of response of 3.6 weeks. The response was best among patients with early onset disease; in comparison, patients with late onset or extensive disease (as manifested by elevated serum lactate dehydrogenase [LDH], organ dysfunction, and multiorgan involvement) were much less likely to benefit. The response rate was 89 percent in patients with none of these risk factors, compared with none of seven patients with two or three risk factors. Twelve patients developed acute rejection, but only one lost the graft because of rejection. At a median follow-up of almost three years, 55 percent of patients were alive and 50 percent were in CR.
●In another study, 148 solid organ transplant recipients with PTLD treated with reduction of immunosuppression had an overall response rate to reduction of immunosuppression of 45 percent (37 percent complete) [25]. Approximately 40 percent developed acute rejection and 60 percent required subsequent chemotherapy. Acute rejection did not appear to correlate with the degree of reduction of immunosuppression. Three-year overall survival (OS) was 55 percent. Predictors of worse outcomes included older age (>50 years), B symptoms, bone marrow or liver involvement, weight loss, hepatitis C virus infection, elevated LDH, and dyspnea. Three-year OS was 100 percent in those with no risk factors and 8 percent in patients with two or more risk factors.
●In a French, multicenter, retrospective study of 104 adults who developed PTLD after renal or simultaneous renal/pancreatic transplantation between 1990 and 2007, estimated rates of graft loss or the combined endpoint of graft loss or death with a functioning graft at 10 years post onset of PTLD were 44 percent and 64 percent, respectively [26]. On multivariate analysis, risk factors of graft loss were PTLD stage greater than I to II and calcineurin inhibitor (CNI) withdrawal. Risk factors for graft loss and mortality were PTLD stage greater than I to II, CNI withdrawal, and age over 60 years. Type and location of PTLD, year of diagnosis, and chemotherapy regimen were not independent risk factors. Multivariate analysis determined CNI withdrawal as the most important risk factor for graft loss (HR = 3.07, CI 95% 1.04-9.09) and death (HR: 4.00, CI 95% 1.77-9.04). While long-term stable renal function after definitive CNI withdrawal for PTLD has been reported, this study suggests that withdrawal is associated with reduced graft and patient survival.
The optimal reduction of immunosuppression regimen to ensure regression of disease is unknown. Different regimens have been tried based upon the severity of PTLD [18,27]. The regimen adopted is based upon the severity of the disease in combination with the health risk associated with the possible loss of the allograft. Immunosuppression should be reduced to the lowest tolerated level. Often a reduction to 25 to 50 percent of baseline is used if alternative organ support is available (eg, renal or renal/pancreas transplant). For heart and lung transplants, immunosuppression is generally reduced to 50 percent of baseline.
Polymorphic PTLD — Polymorphic PTLD are polyclonal or monoclonal lymphoid infiltrates that demonstrate evidence of malignant transformation but do not meet all of the criteria for one of the B cell or T/NK cell lymphomas recognized in immunocompetent patients [1]. For most patients with polymorphic PTLD that expresses CD20, we suggest the use of rituximab in addition to reduction of immunosuppression, as tolerated, rather than reduction of immunosuppression alone or this combination with chemotherapy. Patients whose tumors do not express CD20 are not candidates for rituximab therapy and are treated with combination chemotherapy plus reduction of immunosuppression, as tolerated. Surgery may be considered, in addition, for a subset of patients with localized disease.
There is a paucity of data regarding the efficacy of different treatment options in this patient population. Most information comes from retrospective or prospective observational studies that combined polymorphic and monomorphic PTLD cases. These are described in the subsequent sections. The preference for rituximab therapy rather than combined rituximab plus chemotherapy in this patient population places a high value on avoiding toxicities associated with chemotherapy with the understanding that polymorphic PTLD is expected to be less clinically aggressive than monomorphic PTLD. However, the combination of chemotherapy plus rituximab may be occasionally preferred for the treatment of young patients with a good performance status with large volume disease.
Monomorphic PTLD — Monomorphic PTLD are monoclonal lymphoid proliferations that meet the criteria for one of the B cell or T/NK cell lymphomas recognized in immunocompetent patients [1]. The first step in the management of patients with monomorphic PTLD is reduced immunosuppression as described above. However, only a small minority of cases will respond to reduction of immunosuppression alone [28]. Patients who are not candidates for reduction of immunosuppression and those who do not have a complete response to this intervention have been treated with chemotherapy, immunotherapy, and occasionally surgical resection [18,23,24,29,30]. There are no randomized trials comparing these treatment options. Instead, data largely come from expert opinion, retrospective analyses and uncontrolled prospective trials. Our approach is similar to that proposed by various consensus guidelines [18,31,32]. (See 'Reduction in immunosuppression' above.)
For patients with monomorphic PTLD that expresses CD20 (CD20+ PTLD), we suggest the use of reduction of immunosuppression plus the anti-CD20 monoclonal antibody rituximab, either alone or in combination with chemotherapy. Single agent rituximab may be considered for patients who have minimal symptoms and for those who are not candidates for initial chemotherapy (eg, poor performance status). All other patients with CD20+ PTLD are offered rituximab plus combination chemotherapy (eg, CHOP), administered concurrently or sequentially. Patients whose tumors do not express CD20 are not candidates for rituximab therapy and are treated with combination chemotherapy plus reduction of immunosuppression alone.
The optimal method for withdrawal of immunosuppression in this setting is unknown and different regimens have been tried. As described above, the choice for a particular patient must take into account the severity of disease in combination with the health risk associated with allograft loss. Except in the setting of follicular lymphoma, our practice is to discontinue the calcineurin inhibitor and the anti-metabolite, continue low-dose prednisone at 5 mg/d and initiate chemotherapy. After completion of chemotherapy, we usually restart an mTOR inhibitor. If the mTOR is not tolerated, we begin azathioprine or mycophenolate. We have had excellent results with this approach. In our experience, the early aggressive near complete discontinuation of immunosuppression seems to allow for full dose chemotherapy, which is tolerated better.
Studies that have evaluated these approaches are described in the following sections.
Rituximab — While the ideal treatment of CD20+ PTLD is not known, most clinicians incorporate immunotherapy directed against the CD20 antigen. Support for this approach comes from nonrandomized studies of immunotherapy in PTLD and extrapolation of data from randomized studies and meta-analyses regarding the use of these agents in other conditions. Anti-CD20 monoclonal antibodies (eg, rituximab) have become a key component to the treatment of other CD20 positive non-Hodgkin lymphomas, such as diffuse large B cell lymphoma and follicular lymphoma, based upon a demonstrated survival benefit. (See "Initial treatment of stage II to IV follicular lymphoma", section on 'Immunotherapy-based treatment' and "Initial treatment of advanced stage diffuse large B cell lymphoma", section on 'Incorporation of rituximab'.)
Rituximab plus combination chemotherapy has been shown to reduce the risk of renal graft impairment [33]. Some experts favor use of rituximab as a single agent [34] with plans to proceed to alternative therapies if there is an inadequate response [33-35]. It is uncertain if continuing rituximab after completion of chemotherapy is beneficial. The major toxicities of rituximab include infusion reactions (ie, fevers, rigors, and hypotension) and infections related to immunosuppression. Rituximab also imposes a risk of hepatitis B reactivation among patients positive for hepatitis B surface antigen (HBsAg) or antibodies against hepatitis B core antigen (anti-HBc). Isolated neutropenia can also occur in some rare instances. Typically, the neutropenia is responsive to growth factor support with G-CSF. (See "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy", section on 'Rituximab' and "Secondary immunodeficiency induced by biologic therapies", section on 'Rituximab' and "Hepatitis B virus reactivation associated with immunosuppressive therapy".)
Single agent rituximab achieves CR in approximately 20 percent of patients with PTLD following either solid organ or hematopoietic cell transplantation [19,30,36-51]. Achieving CR after rituximab induction therapy identifies a group of patients with CD20+ PTLD who do not require chemotherapy.
Examples of studies that evaluated rituximab therapy in patients with CD20+ PTLD include:
●Single agent rituximab (375 mg/m2 per week for four weeks) was employed in a prospective trial involving 43 evaluable patients with previously untreated B cell PTLD that did not respond to tapering of immunosuppression [42]. The overall response rate was 44 percent, while overall survival was 86 and 67 percent at 80 days and one year, respectively. The only baseline factor predicting response at day 80 was a normal level of serum lactate dehydrogenase (odds ratio 6.9; 95% CI 1.7-28).
●In another study, 60 solid organ transplant recipients with PTLD treated with single agent rituximab had an overall response rate of 59 percent (42 percent CR) [52]. Half experienced disease progression within six months of completion of rituximab therapy. Median overall survival was 35 months with one and two-year overall survival rates of 73 and 52 percent, respectively.
●In an international phase II trial, four additional courses of rituximab (every 21 days) were administered to the 37 of 148 patients (25 percent) who achieved CR after four weekly doses of rituximab induction therapy for CD20+ PTLD [53]. At three years, the estimated progression-free survival and overall survival were 89 and 91 percent, respectively, among those who achieved CR after rituximab induction therapy.
Monitoring of the EBV viral load may predict clinical response of the tumor to rituximab. (See "Epidemiology, clinical manifestations, and diagnosis of post-transplant lymphoproliferative disorders", section on 'Measurement of EBV viral load'.)
Chemoimmunotherapy — Chemotherapy is usually administered in conjunction with rituximab for patients with CD20+ PTLD. Patients whose tumors do not express CD20 are not candidates for rituximab therapy and are treated with chemotherapy alone.
We suggest R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) for most patients with PTLD; we offer CHOP (without rituximab) to those patients whose PTLD does not express CD20. Other chemotherapy regimens used for non-Hodgkin lymphoma may be appropriate in select cases [24,54-61]. There have been no randomized trials comparing different chemotherapy regimens in PTLD, and a choice is generally made based upon physician experience and side effect profile. Similarly, the ideal timing of chemotherapy with respect to rituximab therapy (ie, concurrent versus sequential) is not known.
When rituximab is used in combination with chemotherapy, CR rates increase to approximately 65 percent [50]. There are no trials that directly compare chemoimmunotherapy to rituximab alone in CD20+ PTLD. Examples of trials of R-CHOP or CHOP in PTLD include:
●In an international phase II trial, 70 patients with CD20+ PTLD that had not responded to reduction of immunosuppression were treated with single agent rituximab (375 mg/m2 per week for four weeks) followed by a four-week rest and then four cycles of chemotherapy with CHOP administered every 21 days with growth factor support [50]. Patients with progression during rituximab therapy were treated with CHOP (without rituximab). The overall response rate was 90 percent (68 percent complete), with the majority of complete responses occurring after CHOP. Median progression-free and overall survival were 4.0 and 6.6 years, respectively. The main severe toxicities were leucopenia and infection. Treatment-related mortality (TRM) was 11 percent.
●In another international phase II trial, the 111 of 126 (88 percent) patients with CD20+ PTLD who failed to achieve CR after rituximab induction therapy were treated with four cycles of R-CHOP [53]. Median survival was 6.6 years and three-year estimated survival was 70 percent. Rates of severe (grade 3/4) infections and TRM were 34 and 8 percent, respectively.
●CHOP achieved a 50 percent CR and 20 percent partial response rate among 10 patients with refractory or relapsed PTLD after treatment with rituximab [62].
Data regarding the use of other regimens is mainly limited to small case series. Older adults (ie, over age 60 years) or those with cardiac disease may be considered for non-anthracycline containing regimens used to treated diffuse large B cell lymphoma in these populations. Of importance, given the lack of activity of many of these chemotherapy regimens in the central nervous system (CNS), patients with PTLD involving the CNS should be considered for treatment with protocols used for central nervous system lymphoma [63-69]. (See "Initial treatment of advanced stage diffuse large B cell lymphoma", section on 'Older adults' and "Initial treatment of advanced stage diffuse large B cell lymphoma" and "Secondary central nervous system lymphoma: Treatment and prognosis".)
Radiation therapy — For patients with localized disease and those with central nervous system involvement, involved-field radiation therapy, alone or in combination, may be beneficial [18,70-72]. Data regarding efficacy is largely extrapolated from studies of radiation therapy in localized diffuse large B cell lymphoma and in primary CNS lymphoma. This is discussed in more detail separately. (See "Initial treatment of limited stage diffuse large B cell lymphoma", section on 'Radiation alone is not acceptable' and "Secondary central nervous system lymphoma: Treatment and prognosis".)
Adoptive immunotherapy — Adoptive immunotherapy uses EBV-specific cytotoxic T lymphocytes (EBV-CTLs) or donor lymphocyte infusion (DLI) in an attempt to kill dividing B cells in EBV-associated PTLD [73-84]. Most data using this approach come from retrospective series and small observational studies in hematopoietic cell transplantation (HCT) recipients. In this population, prevention of and remission of EBV-induced PTLD have been achieved in this manner in as many as 90 percent of patients [73,77-80,85-88]. The major complication of adoptive immunotherapy is acute and chronic graft-versus-host disease (GVHD) [73]. DLI may produce GVHD, which does not appear to be a problem with EBV-CTLs [89,90].
●In a single center retrospective analysis, 49 HCT recipients with biopsy-proven EBV-positive PTLD were treated with unselected DLI (30 patients) or EBV-specific cytotoxic T cell lines (19 patients) [87]. The overall response rate was 84 percent, did not differ by treatment modality, and included patients with central nervous system involvement. A clinical response was usually seen within 15 days of infusion, and complete radiologic resolution occurred by six months. At a median follow-up of 80 months, all deaths attributable to PTLD occurred within 4.3 months; the cumulative incidence of EBV-specific mortality at 12 months was 21 to 24 percent for both groups. The cumulative incidences of acute or chronic GVHD attributed to DLI at one year were 14 percent and 14 percent, respectively. No recipient of EBV-specific cytotoxic T cells developed de novo acute or chronic GVHD or a flare of preexisting GVHD.
●A phase II multicenter clinical trial of adoptive immunotherapy in 33 patients with PTLD who had failed to respond to conventional treatment the overall response rate to partly HLA-matched T cells was 64 and 52 percent at five weeks and six months, respectively [91].
Given the risk of GVHD and the availability of other treatment modalities, we reserve the use of adoptive immunotherapy for patients with EBV-associated PTLD that persists following initial therapy. EBV-specific CTLs are an attractive therapeutic option, but they are not available at many centers.
PROGNOSIS — Information concerning mortality of patients with PTLD is largely based on case reports and retrospective studies. Although the prognosis varies with clonality and extent of disease, published series suggest overall survival rates ranging between 25 to 35 percent [92]. Mortality with monomorphic PTLD has been reported to be as high as 80 percent [93]. T cell lymphomas have an extremely poor prognosis [8,9,94].
While prognostic factors have been identified in patients with PTLD, none has been validated in a prospective fashion [95-98].
●The largest experience relating to prognostic factors with PTLD in renal transplant recipients comes from a French registry of adult renal transplant recipients [99]. Among the 500 patients diagnosed with PTLD between 1998 and 2007, the estimated rates of five- and 10-year survival were 53 and 45 percent, respectively. Multivariable analysis identified five variables at the time of diagnosis that were independently associated with inferior survival: older age (>55 years), serum creatinine >1.5 mg/dL (133 microM/L), elevated LDH, location of disease (central nervous system or serous membrane invasion), and monomorphic or T cell histology.
●In a study from the Israel Penn International Transplant Tumor Registry, the clinical features associated with survival were analyzed among 402 patients with PTLD enrolled in this database from the years 1968 to 2000 [96]. Increased mortality rates were associated with a diagnosis within six months versus after six months from transplant surgery (64 versus 54 percent), increasing age, multiple versus single sites (73 versus 53 percent), absence of surgery (100 versus 55 percent), and allograft plus other organ involvement versus allograft involvement alone (64 versus 31 percent).
●In a multivariate analysis of 61 patients, an Eastern Cooperative Oncology Group (ECOG) performance status ≥2 (table 1) and more than one site of involvement were associated with significantly worse outcomes [95]. At a median follow-up of 22 months, median survival for patients with one or two of these factors was 34 months and one month, respectively. The International Prognostic Index, which is useful for determining prognosis in B cell non-Hodgkin lymphoma in immunocompetent patients, was less useful in this setting (table 2). (See "Pretreatment evaluation and staging of non-Hodgkin lymphomas", section on 'Prognosis'.)
●In a multicenter study of 80 solid organ transplant recipients with PTLD, who were diagnosed between 1998 and 2008, three-year progression-free and overall survival rates were 57 and 62 percent, respectively [100]. Adverse prognostic factors at the time of PTLD diagnosis included CNS involvement, bone marrow involvement, and hypoalbuminemia. Subjects with zero, one, or ≥2 of these risk factors had three-year overall survival rates of 93, 68, and 11 percent, respectively.
Of importance, many of these studies included patients diagnosed with PTLD prior to the availability of rituximab (anti-CD20 antibody), which appears to have improved outcomes in CD20+ PTLD [100,101]. The use of cytotoxic EBV-specific T cells may improve survival further. (See 'Rituximab' above.)
RETRANSPLANTATION — A paucity of data exists concerning solid organ retransplantation in patients with a history of PTLD [102,103]:
●In the largest cohort study based upon the OPTN/UNOS database, outcomes were reported among 69 transplant recipients who survived PTLD and underwent retransplantation [103]. The retransplant surgeries included 27 kidney, 22 liver, nine lung, six heart, four intestine, and one pancreas. Average time for the period from PTLD to retransplant, time from transplant to retransplant, and time for patient survival after retransplant were approximately 2.6, 5.7, and 2.1 years, respectively. At follow-up, overall patient and allograft survival was 86 and 74 percent, respectively.
●One retrospective study reported the outcomes of six patients with kidney retransplantation after cure of EBV-related monoclonal B cell lymphoma [102]. Five of six patients had the PTLD confined to the graft, with all six undergoing allograft nephrectomy in addition to their other treatment. The subsequent time interval from PTLD to retransplant was longer, ranging from 4.1 to 10.6 years. At 24 to 47 months, all patients had functioning grafts without recurrent PTLD.
SUMMARY AND RECOMMENDATIONS
●Post-transplant lymphoproliferative disorders (PTLD) are serious and potentially fatal complications of chronic immunosuppression in solid organ and hematopoietic cell transplant (HCT) recipients. The pathogenesis of PTLD in most patients relates to the outgrowth of Epstein-Barr virus (EBV)-positive B cell proliferations in the setting of chronic T cell immunosuppression. However, EBV-negative tumors and T cell tumors can also occur. (See "Epidemiology, clinical manifestations, and diagnosis of post-transplant lymphoproliferative disorders".)
●The prevention of PTLD largely relies upon limiting patient exposure to aggressive immunosuppressive regimens, aggressive withdrawal and tapering of agents required for graft acceptance, and anti-viral prophylaxis. Many transplant centers have incorporated EBV monitoring into the routine evaluation of patients at high risk for PTLD and preemptive treatment of PTLD at the time of viral reactivation with rituximab or reduced immunosuppression. (See 'Prevention' above.)
●Management of PTLD has varied significantly according to the type of lymphoproliferative disease present, as well as from institution to institution. Immunosuppression reduction is the cornerstone of therapy. Additional therapies include immunotherapy with the CD20 monoclonal antibody rituximab, chemotherapy, radiation therapy, or a combination of these. Other treatments, such as adoptive immunotherapy with EBV specific cytotoxic T cells, are generally reserved for persistent disease despite initial therapy. (See 'Treatment' above.)
●Our initial management is largely dependent upon the type of PTLD:
•Early lesions – For most patients with early lesions, we suggest reduction of immunosuppression alone rather than in combination with other therapies (Grade 2B). Other agents are generally reserved for those patients with residual disease despite reduced immunosuppression or for those who cannot tolerate reduction of immunosuppression. (See 'Early lesions' above.)
•Polymorphic PTLD – For most patients with polymorphic PTLD that expresses CD20 (CD20+ PTLD), we suggest the use of rituximab in addition to reduction of immunosuppression, as tolerated, rather than reduction of immunosuppression alone or this combination with chemotherapy (Grade 2C). (See 'Polymorphic PTLD' above.)
•Monomorphic PTLD – For patients with monomorphic CD20+ PTLD, we suggest the use of rituximab, either alone or in combination with chemotherapy in addition to reduction of immunosuppression (Grade 2B). Single agent rituximab may be considered for patients who have minimal symptoms and for those who are not candidates for initial chemotherapy. All other patients with CD20+ PTLD are offered rituximab plus combination chemotherapy, administered concurrently or sequentially. Patients whose tumors do not express CD20 are not candidates for rituximab therapy and are treated with combination chemotherapy plus reduction of immunosuppression. Surgery is reserved for patients with complications such as perforation or obstruction. (See 'Monomorphic PTLD' above.)
•Classic Hodgkin lymphoma-like PTLD – Classic Hodgkin lymphoma-like PTLD is the least common form of PTLD and there is a paucity of data regarding management. For most patients with classic Hodgkin lymphoma-like PTLD we suggest management with chemotherapy with or without radiation therapy according to protocols used for classic Hodgkin lymphoma (Grade 2C). (See "Treatment of favorable prognosis early (stage I-II) classic Hodgkin lymphoma" and "Initial treatment of advanced (stage III-IV) classic Hodgkin lymphoma".)
●There is a paucity of information concerning mortality of patients with PTLD. Although the prognosis varies with clonality and extent of disease, published series suggest overall survival rates ranging between 25 to 35 percent. Mortality with monomorphic PTLD and T cell PTLD are higher. (See 'Prognosis' above.)
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