ii. EBV infections/Post-transplant lymphoproliferative disorder (PTLD)
1. Marked increased risk of Epstein-Barr virus-related complications with the addition of anti-thymocyte globulin to a non-myeloablative conditioning prior to unrelated umbilical cord blood transplantation. Claudio G Brunstein, Daniel J Weisdorf, Todd DeFor, Juliet N Barker, Jakub Tolar, Jo-Anne H van Burik, and John E Wagner. Blood. 2006;108:2874-2880. 
Epstein Barr Virus (EBV)-viremia and post-transplant lymphoproliferative disorder (PTLD) are well recognized complications of allogeneic HSCT. These complications have been associated with unrelated donor transplants, HLA mismatch, anti-thymocyte globulin (ATG) administration, and ex-vivo or in vivo T-cell depletion. A retrospective analysis at two institutions found the incidence of EBV PTLD after a myeloablative (MA) preparative therapy and umbilical cord blood (UCB) transplant to be low. A recent analysis found no significant difference in the risk of serious viral infections, including PTLD, in recipients of unrelated donor UCB or unmanipulated marrow. However, an increased number of cases of EBV PTLD has been observed by the authors of this study leading to a new analysis of EBV-related complications in patients transplanted with UCB with the aim of assessing the incidence and identifying potential risk factors.
The authors evaluated the incidence of EBV-related complications in 335 patients undergoing UCB transplant with a MA or non-myeloablative (NMA) preparative regimen. The incidence of EBV-related complications was a 4.5% overall, 3.3% for MA, and 7% for NMA transplants. However, the incidence of EBV-related complications was significantly higher in a subset of patients treated with a NMA preparative regimen that included anti-thymocyte globulin (ATG) versus those that did not (21% vs. 2%, p<0.01). Nine of 11 patients who developed EBV PTLD received rituximab (anti-CD20 antibody), with the five responders alive and disease free at a median of 26 months. Use of ATG in recipients of a NMA preparative regimen warrants close monitoring for evidence of EBV reactivation and potentially preemptive therapy with rituximab.
As an increasing number of transplant centers use a NMA preparative regimen in the context of UCB transplantation, there needs to be an awareness of this new risk. The magnitude of the risk caused the authors of this report to alter their consent for those receiving ATG, and to notify patients previously treated. Further, these observations demand closer monitoring in recipients of UCB and ATG for evidence of EBV reactivation after transplant and the consideration of pre-emptive anti-CD20 therapy.
In recipients of UCB, early diagnosis, reduction of immune suppression when possible and the use of rituximab are the principal options in those with EBV-related complications. Alternatively, monitoring for EBV with therapeutic intervention only in those with increasing viral load may be a safer approach. Recent data suggest that EBV viral load monitoring with preemptive rituximab therapy is highly effective in controlling viral proliferation and avoiding progression into EBV PTLD.
2. Post-transplant lymphoproliferative disease: association with induction therapy? Dharnidharka VR. Drugs. 2006;66:429-38.
This is a review of the relationship between antibody induction therapy and the development of post-transplant lymphoproliferative disease (PTLD). Although the article concerns solid organ transplants, it contains much useful information.
PTLD has emerged over the last two decades as a major complication of solid-organ transplantation. It is characterized by B-cell proliferation and lymph node masses in a transplant recipient who is receiving immunosuppressive therapy to prevent organ rejection. Although the cellular proliferation is uncontrolled, PTLD differs somewhat from true malignancies in that the immune system may still regain control of B-cell proliferation if the amount of external immunosuppression is decreased. The most severe cases of PTLD, in which the ability to regain control of proliferation is lost, are classified as frank lymphomas. Many cases of PTLD are causally related to infections with the Epstein-Barr virus (EBV).
Much of the article consists of a review of the literature regarding the relative risk (RR) for PTLD with the use of different commercially available induction antibody agents. All of the agents block T-cell activation and proliferation, one of the central processes in the immune response to an allograft. These anti-T-cell agents either competitively occupy an activating receptor or initiate a lytic/inactivating signal to the T cell. The Table lists the different agents available, their targeted antigens and the adjusted RR for PTLD as reported in various studies (references available in the original article).
| Induction antibody Agent |
Ligand |
RR for PTLD |
| Muromonab CD3 |
CD3 |
9.5 |
|
|
6.0 |
|
|
1.71 |
|
|
1.72 |
|
|
1.16 |
|
|
|
| Equine-derived antithymocyte globulin |
Multiple |
1.50 |
|
|
1.61 |
|
|
|
| Antilymphocyte globulin |
Multiple |
1.35 |
|
|
|
| Rabbit-derived antithymocyte globuin |
Multiple |
3.00 |
|
|
1.17 |
|
|
|
| Basiliximab |
Interleukin-2 |
1.83 |
|
receptor |
1.14 |
|
|
|
| Daclizumab |
Interleukin-2 |
1.92 |
|
receptor |
1.14 |
|
|
|
| Alemtuzumab |
CD52 |
Not known |
The authors point out that most of the studies cited are retrospective studies of large databases that can evaluate long-term follow-up and represent a "real world" situation but cannot evaluate the totality of immunosuppression or eliminate confounders. All prospective induction antibody drug trials, which are typically sponsored by drug companies, have not shown an elevated PTLD risk with any of the commercially available induction antibody agents to date (which would preclude further development of that drug). A prospective trial of antibody induction that uses PTLD as a primary endpoint and has a long-term follow-up would be desirable. A more realistic and achievable goal would be to incorporate viral serological testing pre-transplant and serial viral polymerase chain reaction monitoring post-transplant in future prospective transplant trials.
3. Efficacy and safety of rituximab in B-cell post-transplantation lymphoproliferative disorders: results of a prospective multicenter phase 2 study. Choquet S, Leblond V, Herbrecht R, Socie G, Stoppa AM, Vandenberghe P, Fischer A, Morschhauser F, Salles G, Feremans W, Vilmer E, Peraldi MN, Lang P, Lebranchu Y, Oksenhendler E, Garnier JL, Lamy T, Jaccard A, Ferrant A, Offner F, Hermine O, Moreau A, Fafi-Kremer S, Morand P, Chatenoud L, Berriot-Varoqueaux N, Bergougnoux L, Milpied N. Blood. 2006;107:3053-7.
The authors point out that there is no consensus on the optimal treatment for posttransplantation lymphoproliferative disorder (PTLD), and no previous reports of prospective trials. A dose reduction or termination of immunosuppressive therapy is the first step in management and can lead to partial or complete regression in some cases. Other options include radiotherapy, pharmacotherapy (with interferon-α or antiviral drugs), and chemotherapy. Antibodies directed against B-cell CD21 and CD24 surface antigens yielded complete remission in 60% of patients with B-cell PTLD, with long-term survival rates of 35% in hematopoietic stem cell transplantation (HSCT) patients. However, these antibodies are no longer produced. Recently, rituximab, a mouse/human chimeric anti-CD20 monoclonal antibody has been used. The results of retrospective studies are encouraging but inconsistent, with response rates ranging from 20% to 100%, and the small number of patients enrolled in these studies and their heterogeneity make the results difficult to assess.
This prospective trial, the first to test a treatment for PTLD, was designed to evaluate the efficacy and safety of rituximab in patients with B-PTLD after solid organ transplantation (SOT). Forty-six patients were included and 43 patients were analyzed. Patients were eligible if they had untreated B-PTLD that was not responding to tapering of immunosuppression. Treatment consisted of 4 weekly injections of rituximab at 375 mg/m2. At day (d) 80, 37 (86%) patients were alive, and the response rate was 44.2%, including 12 complete response/unconfirmed complete response (CR/CRu). The only factor predictive of a response at d 80 was a normal lactate dehydrogenase level (P = .007, odds ratio [OR] = 6.9). At d 360, responses were maintained in 68% of patients, and 56% of patients were alive. The overall survival rate at 1 year was 67%.
The authors concluded that rituximab is effective and safe in PTLD, with stable responses at 1 year. The response rate and overall survival might be improved by combining rituximab with other treatments.
4. Posttransplant lymphoproliferative disorder after umbilical cord blood transplantation in children. Gong JZ, Bayerl MG, Sandhaus LM, Sebastian S, Rehder CW, Routbort M, Lagoo AS, Szabolcs P, Chiu J, Comito M, Buckley PJ. Am J Surg Pathol. 2006;30:328-36.
Posttransplant lymphoproliferative disorder (PTLD) represents a group of heterogeneous lesions ranging from a reactive process to true malignant lyumphoma. B-cell clonality is frequently present, but clonality itself may not predict malignant potential. PTLD may arise after solid organ or hematopietic cell transplantation, the latter developing earlier and being more likely to present with disseminated disease with early and rapid organ dysfunction. EBV is found in nearly 100% of PTLD after BMT whereas up to 15% of PTLD after solid organ transplantation is EBV negative. The majority of PTLD arising in patients with solid organ transplantation are of recipient origin, whereas those after BMT are usually from donor.
Factors that can become contributing factors for PTLD in umbilical cord blood transplantation (UCBT) are the relatively limited numbers of T cells infused, HLA donor-recipient mismatches, and the use of antithymocyte globulin (ATG). Previous data has suggested a 2% incidence of PTLD after UCBT, equivalent to the incidence after BMT.
This is a report of 7 cases of PTLD arising in children who received UCBT. There were 4 females and 3 males with a median age of 3 years (range, 1-16 years). All 7 patients received UCBT, including 1 patient who received multiple units and 1 transplanted under nonmyeloablative condition. The time interval from UCBT to PTLD averaged 4 months (range, 2 weeks to 9 months). Patients typically presented with high-stage disease with visceral organ involvement, especially lung and gastrointestinal tract. Histology of the PTLDs showed monomorphic morphology in 5 cases and polymorphic morphology in the remaining 2 cases. Bone marrow biopsies were performed in 3 cases and were negative for PTLD. Epstein-Barr virus (EBV) was detected in the PTLD in all 7 patients by in situ hybridization. Evidence of past EBV infection was found in the recipients, but the EBV genome was not detected in the donor cord blood samples, suggesting that donor cord blood was not the source of EBV infection. The origin of the PTLD was investigated in 5 cases. PTLD was of host origin in 2 patients who failed engraftment and of donor origin in the remaining 3 patients who had complete engraftment. Similar results have been reported by others and some investigators have suggested that EBV was passed to donor cells by residual infected host cells. Nevertheless testing for EBV in larger numbers of cord blood samples is necessary for a better understanding of the EBV status in cord blood.
Four of 5 patients with monomorphic PTLD failed to demonstrate significant responses to rituximab and/or reduction of immunosuppression and died within 1 month after diagnosis. The remaining 2 patients with polymorphic PTLD showed complete response to therapy. One patient was alive 35 months after transplant, and the other patient died of infection 6 months after transplant.
The authors concluded that PTLD arising after UCBT in children occurs early after transplant and represents a serious EBV-related complication. PTLD may be of donor or recipient origin depending on engraftment status. Both monomorphic and polymorphic histology may be seen, and monomorphic histology appears to predict an unfavorable prognosis. From the current series and the limited published cases, the value of rituximab in the management of these patients is uncertain. In general, a combination of monomorphic morphology and high-stage disease predicts a poor outcome, regardless of treatment.
5. Fatal early-onset epstein-barr virus-associated posttransplantation lymphoproliferative disease after successful adult dual-unit umbilical cord blood transplantation. Poh SB, Hsiao LT, Yang CF, Chiou TJ, Chen PM. Biol Blood Marrow Transplant. 2005;11:732-3.
The authors report a 28-year-old woman with severe aplastic anemia for 5 years who developed posttransplantation lymphoproliferative disease (PTLD). Her transplant was from 2 unrelated umbilical cord blood donors with 1 mismatched HLA locus. She was conditioned with cyclophosphamide, TBI, ATG, and methylprednisolone without antiviral prophylaxis. Some engraftment of both units was documented on days 21 and 28. By day 42 cells from only one unit could be detected, and on day 77 engraftment of neutrophils (ANC >500/µL) and platelets (>20,000/µL) with 100% of cells from a single unit, was documented.
The patient complained of nasal obstruction beginning on day 115, and a 4 cm mass was found on nasopharyngeal computed tomography. Biopsy on day 126 showed a diffuse large B-cell lymphoma and EBV-associated PTLD. She died of neutropenia with sepsis on day 146, 20 days after the diagnosis of PTLD.
6. Low incidence of Epstein-Barr virus-associated posttransplantation lymphoproliferative disorders in 272 unrelated-donor umbilical cord blood transplant recipients. Barker JN, Martin PL, Coad JE, DeFor T, Trigg ME, Kurtzberg J, Weisdorf DJ, Wagner J. Biol Blood Marrow Transplant. 2001;7:395-9.
Umbilical cord blood (UCB) is being increasingly used for transplantation, but the ability of neonatal T cells to regulate Epstein-Barr virus (EBV)-associated lymphoproliferation is unknown. Because UCB transplantation (UCBT) is associated with a relatively low infused dose of donor T cells, frequent donor-recipient HLA disparity, and use of antithymocyte globulin during conditioning, they hypothesized that the risk of EBV-associated posttransplantation lymphoproliferative disorders (EVB-PTLD) after UCBT may be increased. To investigate the incidence of EBV-PTLD after UCBT, they analyzed 272 unrelated-donor UCBTs performed from August 1993 to December 1999 at Duke University Medical Center and the University of Minnesota.
Five cases of EBV-PTLD were identified, with a cumulative incidence of 2% (95% confidence interval, 0.3%-3.7%) at 2 years. EBV-PTLD affected UCB recipients aged 1 to 49 years (median, 8 years), with 4 patients undergoing transplantation for leukemia and 1 for immunodeficiency. Patients received UCB grafts that were HLA matched (n = 1) or mismatched at 1 (n = 1) or 2 (n = 3) HLA loci. Diagnoses occurred at 4 to 14 months (median, 6 months) after UCBT, with 4 of 5 patients having preceding grade II to IV acute graft-versus-host disease and 1 being diagnosed at autopsy. Treatment of 4 patients consisted of withdrawal of immunosuppressive treatment and administration of rituximab, with 2 of 4 patients responding.
Thus, the incidence of EBV-PTLD after unrelated-donor UCBT appears similar to that observed after transplantation using unrelated bone marrow (BM) and compares favorably with unrelated-donor T-cell-depleted BM transplantation. Because adoptive immunotherapy with donor lymphocytes is not an available option for recipients of unrelated-donor UCBT, new therapeutic strategies are needed, and rituximab appears promising.
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