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Clinical Cancer Research Vol. 9, 3945S-3952S, September 1, 2003
© 2003 American Association for Cancer Research

Session IV: CLINICAL STUDIES: SOLID TUMORS

A Pilot Study of Chemoimmunotherapy (Cyclophosphamide, Prednisone, and Rituximab) in Patients with Post-Transplant Lymphoproliferative Disorder following Solid Organ Transplantation1

Manuela Orjuela, Thomas G. Gross, Ying-Kuen Cheung, Bachir Alobeid, Erin Morris and Mitchell S. Cairo2

Departments of Pediatrics [M. O., E. M., M. S. C.], Biostatistics [Y-K. C.], and Pathology [B. A.], Columbia University, New York, New York 10032, and Department of Pediatrics, Ohio State University, Columbus, Ohio 43205 [T. G. G.]


   ABSTRACT
Top
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 
Purpose: We have previously demonstrated a >80% complete response (CR) rate with cyclophosphamide/prednisone (Cy/Pred) chemotherapy alone in patients with post-transplant lymphoproliferative disease (PTLD) after solid organ transplantation (SOT), but only a 58% 2-year event-free survival. The response rate to immunotherapy (rituximab) is only about 46% with a 54% relapse/progression rate. In this study, we investigated the use of a combination of Cy/Pred with rituximab as treatment for this disease.

Experimental Design: Patients received two to six courses of cyclophosphamide (600 mg/m2, on day 1 of each course) and prednisone (1 mg/kg, every 12 h x 10 doses), given every 3 weeks. The first two courses were given in combination with 4–6 weekly doses of rituximab (375 mg/m2, i.v.). Imaging studies were done every 2 months to document response.

Results: There were six PTLD patients (two fulminant); age, 4–23 year; sex, male:female (3:3); status post SOT (two cardiac, two liver, two renal); median onset, 39 months (10–144 months). Fifty percent were polyclonal, 100% were CD20+, and 83% were EBV+. The overall response rate was 100% (five CRs and one PR). All five CRs showed no evidence of disease, and one PR eventually progressed and died of fulminant disease. All allografts in surviving patients were functional. There was no grade III/IV toxicity and/or no infectious complications related to the combination of Cy/Pred with rituximab. Median follow-up was 12.5 months (range, 4–29 months).

Conclusions: These preliminary results suggest that the combination of Cy/Pred and targeted immunotherapy (rituximab) is well tolerated and may be more efficacious in patients with PTLD after SOT. Future prospective larger trials with longer follow-up investigating this combination will be required to confirm these preliminary results.


   Introduction
Top
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 REFERENCES
 
EBV-associated PTLD3 is a major cause of morbidity and mortality in children after SOT. Many studies have shown that children are at higher risk for developing PTLD, probably because of a higher rate of primary infection with EBV after transplant (1, 2, 3) . It is estimated that ~500 cases of PTLD occur in the United States each year. Of these, there are estimated to be between 100 and 125 cases of PTLD in children.

The outcome of PTLD has been limited by a lack of uniformity in diagnostic criteria and uniform treatment strategies. There are numerous studies looking at histology, clonality, and molecular aberrations in cellular and viral genes as prognostic factors, and the results are not conclusive (4, 5, 6, 7, 8, 9, 10, 11) . Outcome has also been correlated to clinical presentation (2 , 12) . Patients with an infectious mononucleosis-like illness do well with reduction of immune suppression with or without other therapies. Patients with fulminant, disseminated, systemic disease that clinically resembles septic shock do poorly despite therapy. The majority of PTLD patients present with lymphomatous lesions (localized or disseminated) that are often extranodal. Successful treatment of these patients is a therapeutic challenge, in part because of increased susceptibility to toxicity and life-threatening infections and the necessity to maintain the allograft. Although reduction of immune suppression may be sufficient in controlling the disease, patients who do not tolerate reduction of immune suppression (i.e., graft rejection), or do not respond to immune suppression reduction, require more aggressive therapy and have a much poorer prognosis, with a mortality reported to be as high as 50–90%.

Antiviral agents (acyclovir or ganciclovir) and/or i.v. immunoglobulin have been used extensively for prophylaxis and treatment of PTLD, but the efficacy of antivirals in treating PTLD is uncertain because antivirals are seldom used without other interventions (e.g., reduction of immunosuppression; Ref. 13 ). Other treatment approaches include local control with surgery and/or radiotherapy, which are very effective in curing localized disease, but this represents only a small percentage of patients. IFN-{alpha} has been used to treat PTLD that was refractory to immune suppression reduction with a complete remission rate of about 70%, but death caused by relapse, allograft rejection, and infection have been problematic, resulting in disease-free survival of less than 50% (14 , 15) .

Successful treatment of PTLD necessitates controlling the inherent B-cell proliferation and facilitating the development of an appropriate EBV-CTL response. The use of anti-B-cell antibodies to treat PTLD decreases B-cell proliferation and does not inhibit EBV-CTL development. Immunotherapy for PTLD using anti-B-cell antibodies was first attempted using anti-CD21 and anti-CD24 with a 55% long-term disease-free survival (16) . More recently, when anti-CD20 antibodies have been used, the response rate has been reported to be 65%, with an 18% relapse rate; 4% died of rejection, and 12% died of infection (17) . In a much larger cohort and with longer follow-up, the overall response rate was only 46%, with an additional 56% of patients either progressing or dying on study (18) .

For patients who fail reduction of immune suppression by not resolving the PTLD and/or developing rejection, cytotoxic chemotherapy is attractive because it will treat both processes. Previous results demonstrated high response rates, but also high rates of death because of treatment-related toxicity and disease-free survival <50% (19 , 20) . Therefore, a trial using a low-dose chemotherapy regimen of Cy/Pred was conducted (21) . Remission rates and allograft survival were high (>80% and >90% if fulminant PTLD cases were excluded), and treatment-related toxicity was low (5%). The 2-year survival was 73%, but disease-free survival was only 58% (12) .

A recent study has demonstrated improved disease-free survival of nontransplant patients with B-cell NHL by the addition of rituximab to standard chemotherapy (22) , whereas other studies have shown good response rates to rituximab alone (17 , 18 , 23) . Therefore, rituximab was added to the low-dose chemotherapy regimen for PTLD that is refractory to reduction of immune suppression to try to improve disease control without adding toxicity.


   Materials and Methods
Top
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 REFERENCES
 
Patients.
Eligibility for treatment on this pilot regimen was restricted to patients followed at CHNYP who developed biopsy-proven, CD20-positive PTLD after SOT, and who had disease progression despite decreased immunosuppression. At the time of initial diagnosis, eligible patients were treated with decreased immunosuppression by their primary transplant physicians. Patients were referred for evaluation and treatment by the Pediatric Oncology Service of CHNYP after 1.5–6 weeks of decreased immunosuppression (median duration of decreased immunosuppression before CPR, 5 weeks; mean, 4.25 weeks), when they were deemed by the solid organ transplant services to have failed to respond to reduced immunosuppression. Patients had not previously received chemotherapy or immunotherapy (including rituximab) before treatment on this regimen. All patients had radiologically measurable disease (Table 1)Citation .


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  		Table 1 Patient demographics

 
Treatment.
Patients received two to six courses of cyclophosphamide (600 mg/m2, on day 1 of each course) and 2 mg/kg/day prednisone (every 12 h) for 5 days (or the equivalent dose of methylprednisolone over 5 days), repeated every 21 days. For the first 6 weeks, patients received weekly doses of rituximab (375 mg/m2) beginning with the first day of cyclophosphamide administration. All patients received their chemotherapy through central venous access catheters. All treatment was administered in the outpatient clinic, except the initial treatment given to those patients with fulminant PTLD who were hospitalized when treatment was begun.

Response Evaluation.
Patients were evaluated at presentation to the Pediatric Oncology Service with CT scans and PET, when available. Once therapy with CPR began, patients were evaluated after two, four, and six cycles of therapy, or at the completion of therapy and then every 3 months thereafter. Radiographic response was assessed using current Working Group Criteria (24) . Complete blood counts and renal and hepatic profiles were followed weekly while patients were receiving cyclophosphamide and then monthly once off therapy. Quantitative immunoglobulin levels (IgG, IgM, and IgA) were followed at baseline and then every 2 months or at the time a patient presented with fever.

Hematopathology.
Biopsy specimens for all patients were examined independently by two hematopathologists at CHNYP and were confirmed to have PTLD. Diagnostic tissues included: three lymph node biopsies, a tonsillectomy specimen and a duodenal biopsy (case 2), a biopsy of terminal ileum-cecum (case 1), and a biopsy of abdominal wall mass (case 4). Sections of formalin-fixed, paraffin-embedded tissues were stained with H&E for routine microscopic examination. Lesions were classified according to the recently proposed WHO classification system (25) . Extra sections were cut for IHC, ISH, and for DNA extraction and molecular analysis by PCR. An immunostain for CD20 (L26; DAKO Corp., Carpenteria, CA) was performed after antigen retrieval in citrate buffer (pH 6.0), and a LMP-1 immunostain (DAKO Corp.) was performed after microwave antigen retrieval. Antibody binding was detected using the Envision Plus kit (DAKO Corp.) using 3,3'-diaminobenzidine as a chromogen on a DAKO autostainer. EBER was detected by ISH using anti-EBV probe (NCL-EBV; Novocastra Laboratories Ltd., Newcastle-upon-Tyne, United Kingdom).

When possible, fresh tumor samples were also examined by flow cytometry to expedite documentation of presence of CD20-positive cells in the tumor tissue. PCR molecular analysis was used to determine presence of JH rearrangement as a marker for B-cell clonal proliferation. JH rearrangement was determined with oligonucleotide primers that amplify rearrangements between the immunoglobulin heavy chain variable genes (FRIII) and the joining region, followed by heteroduplex analysis and PAGE.

Statistical Analysis.
The overall survival of patients in this study was summarized using Kaplan-Meier estimates (Fig. 1)Citation . A patient’s survival time was calculated as the time from start of therapy to April 1, 2003, or until death (n = 6; Ref. 26 ). The response rate of the patients was summarized with an exact 95% confidence interval.



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  		Fig. 1. Kaplan-Meier survival curve. Probability to overall patient survival by Kaplan-Meier method.

 

   Results
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 REFERENCES
 
Patient Characteristics.
Between May 2000 and August 2002, we treated six patients on our CPR pilot protocol. The six patients (age, 4–23 years; three males and three female) developed PTLD after cardiac, liver, and renal transplants. The six patients developed PTLD between 10 and 144 months after undergoing SOT and progressed after initial therapy with reduced immunosuppression. Clinical and pathological presentation of these patients is described in Table 1Citation . Patients had undergone heart (patients 1 and 5), liver (patients 3 and 4), or kidney (patients 2 and 6) transplants and were followed by the Pediatric Cardiology Transplant, Pediatric Nephrology, and Pediatric Gastroenterology services at CHNYP. Two patients (patients 1 and 6 in Table 1Citation ) had fulminant PTLD, requiring initial hospitalization in the intensive care unit. Patients had received immunosuppression for a median of 39 months (range, 10–144 months). Immunosuppression before the development of PTLD included the use of cyclosporin A, tacrolimus, mycophenolate mofetil, azathioprine, and prednisone. All patients presented with adenopathy in the area of Waldeyer’s ring, as well as in other areas including abdominal (patients 1 and 3) and retroperitoneal (patient 3). Two patients (patients 2 and 3) also had lung nodules.

Hematopathology.
Pathological characterization of tumor cells demonstrated that three tumors were monoclonal (either by PCR and/or by flow cytometry), whereas two had polyclonal cell populations (clonality could not be assessed in tumor tissue from patient 4). All were CD20+, and five of six tumors were EBV+ by either EBER (four cases) or LMP (one case; Table 1Citation ). Morphologically, four patients had tumors that were polymorphic, whereas two had monomorphic histology (Fig. 2, A and B)Citation . Patient 6 is represented in Fig. 2, B–DCitation , demonstrating H&E, CD20 expression, and EBER positivity. All pathology findings are summarized in Table 1Citation . Two of the cases (the tonsil from patient 2 and the biopsy of the abdominal wall mass from patient 4) showed diffuse proliferation of large atypical lymphoid cells with brisk mitotic activity and variable necrosis (Fig. 2A)Citation , changes consistent with monomorphic PTLD/diffuse large cell lymphoma. The large cells were positive for the CD20 antigen (by IHC) and for EBER (by ISH). The lymph node biopsies from patients 3, 5, and 6 showed effacement of normal architecture by a rather diffuse proliferation of atypical and polymorphic lymphoid cells, including medium-sized lymphoid cells, variable numbers of plasma cells, and large transformed lymphoid cells, consistent with polymorphic PTLD (Fig. 2B)Citation . The colon biopsy showed polymorphic infiltrate in the lamina propria with large atypical cells. The majority of lymphoid cells in these infiltrates (especially the large cells) were positive for the CD20 antigen (by IHC; Fig. 2CCitation ) in all cases and for EBER (by ISH; Fig. 2DCitation ) and/or LMP-1 (by IHC) in three of the cases. Molecular analysis by PCR method was performed in four cases, and clonal rearrangements of the JH gene were detected in two cases, whereas one additional case in which PCR was not performed was found to be monoclonal by flow cytometry (Table 1)Citation . One case (patient 2) was found to have a clonal rearrangement of the JH gene detectable in peripheral blood lymphocytes.



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  		Fig. 2. Pathology. A, PTLD, monomorphic (diffuse large B-cell lymphoma; patient 2). There is a monotonous proliferation of large transformed lymphoid cells with necrosis (H&E, x20). B, PTLD, polymorphic (patient 6). There is diffuse effacement of the nodal architecture by a mixed proliferation of large transformed cells, plasma cells, and medium-sized lymphoid cells (H&E, x20). C, the vast majority of cells in this polymorphic PTLD (patient 6) are CD20 positive [CD20 immunoperoxidase stain (L26; Dako), x40]. D, ISH for EBER shows staining (patient 6) in frequent lymphoid cells of variable sizes (EBER; Novacastra, x40).

 
Response.
The overall response rate was 100% (95% confidence interval, 54–100%). Five patients achieved CR, and one achieved a PR (24) . All five patients who achieved CR are currently without evidence of disease (Table 2)Citation . As an example, Fig. 3ACitation shows CT images of pulmonary nodules in patient 2. These disappeared completely after two courses of CPR (Fig. 3B)Citation . Fig. 4, A and BCitation , show PET scan images of PTLD (patient 5) that cleared with one cycle of CPR (Fig. 4, C and D)Citation . The patient (patient 2) who had a clonal population of cells detectable in peripheral blood achieved clinical and radiological remission by 4 weeks, however, she achieved molecular remission only 12 months later. The patient (patient 6) who achieved only PR had fulminant PTLD. Initially, he had an excellent response to the first two cycles of CPR. His clinically palpable extensive adenopathy disappeared, and he was able to have an excellent quality of life. However, 2.5 months after beginning therapy, his disease began to progress and did not respond to additional therapy. He died of disseminated disease 16 weeks after beginning therapy (Table 2)Citation . The median duration of response was 12.5 months (mean duration of response, 15 months).


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  		Table 2 Patient response after two to six courses of Cy/Pred and six weekly doses of rituximab (24)

 


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  		Fig. 3. Chest CT at diagnosis (A) and after treatment (B; patient 2). A, pulmonary nodules at diagnosis. B, disappearance of pulmonary nodules evident in A (CR after two cycles of CPR).

 


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  		Fig. 4. PET scan at diagnosis (A and B) and after treatment (C and D; patient 5). A and B, cervical, hilar, axillary, and periaortic adenopathy at diagnosis. C and D, disappearance of cervical, hilar, axillary, and periaortic adenopathy evident in A and B (CR after one cycle of CPR).

 
Toxicity to CPR.
All patients tolerated therapy well. None required RBC or platelet transfusions or granulocyte colony-stimulating factor. Patients did not exceed National Cancer Institute Common Toxicity Criteria (version 2.0) grade 2 for hemoglobin, grade 2 for platelet counts, or grade 3 for absolute neutrophil count. Infectious toxicities were limited to grade 1 or 2. No patients were hospitalized for febrile neutropenia or developed infectious complications. Three patients had decreased immunoglobulin levels after administration of rituximab. All three had decreased IgM levels, whereas two had decreased IgG levels. One patient had profoundly decreased IgG (121 mg/dl) and received two infusions of i.v. {gamma}-globulin.

Allograft Function.
All patients’ allografts tolerated the CPR treatment well, and none developed rejection while on therapy. One patient developed mild and transient organ rejection 2 months after coming off therapy (Table 2)Citation . All patients remained on decreased immunosuppression throughout treatment with CPR. With the exception of the patient who developed mild rejection and the patient who died, all patients have continued on pretreatment levels of lowered immunosuppression.


   Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
REFERENCES
 
The incidence of PTLD in children after SOT is approximately 4% (1 , 2) . The risk factors associated with developing PTLD in SOT recipients include type of organ transplanted (highest in lung, bowel, and combined), age of recipient (especially less than 5 years of age), the use of T-cell antibody therapy (OKT3), frequency of rejection episodes requiring intensified immunosuppression, EBV seropositivity at the time of organ transplantation, and the recent use of tacrolimus (FK506; Refs. 1 and 27, 28, 29 ). In contrast, the risk of PTLD among recipients after allogeneic stem cell transplantation may range as high as 20–25% and includes additional risk factors such as use of unrelated donors, mismatched donors, T-cell depletion, and the development of grade II–IV acute graft versus host disease (30) . PTLD is a heterogeneous disease that includes a spectrum from lymphoid hyperplasia with polymorphic cell populations to lesions with monomorphic blastic cell populations. Knowles et al. (4) recently classified the histological pattern of PTLD into three distinct categories: (a) plasmacytic hyperplasia; (b) polymorphic B-cell hyperplasia and polymorphic B-cell lymphoma; and (c) immunoblastic lymphoma or multiple myeloma. The majority of cases of PTLD in children after SOT occur within the first year after organ transplanation (early) versus after the first year (late), and over 90% of PTLD occurring within 6 months after transplantation are serologically EBV positive when host EBV cytotoxic lymphocyte immunity is usually at a very low level (5 , 29) .

The mainstay of treatment of PTLD after SOT has been a reduction in the intensity of immunosuppressive medications (6 , 7) . Although this approach has a reasonable success rate in patients with polymorphic histology, less than one-third of children with monomorphic histology respond to simple reduction of immunosuppressive medications (7) . Furthermore, reducing immunosuppressive medications after SOT for the treatment of PTLD significantly increases the risk of organ allograft rejection and failure. Successful treatment of PTLD requires controlling EBV-induced B-cell proliferation and transformation and enhancing the development of specific EBV CTLs (31) .

Antiviral therapy including acyclovir and, recently, ganciclovir has been suggested as a potential therapeutic approach for EBV-associated PTLD (13) . However, in a large review, the survival rate for transplant recipients treated with acyclovir was similar to the overall survival rate in similar patients not treated with acyclovir (13) . A large study of patients with EBV PTLD indicated that a few pathological lesions contained replicating EBV DNA, but the vast majority contained latent EBV DNA (32) . Acyclovir only inhibits viral replication but does not prevent EBV-induced B-cell transformation. Therefore, this and other similar antiviral drugs would not be expected to be effective in EBV PTLD, because the majority of cells have become latently infected with EBV (33) .

Immunomodulation with IFN and/or i.v. {gamma}-globulin has additionally been attempted in patients with PTLD after SOT but, unfortunately, has been associated with mixed results (14 , 34) . The most successful therapy for EBV-associated PTLD after allogeneic stem cell transplantation has been the infusion of donor leukocytes from the original family or unrelated donor (35) . Recently, a small number of patients with PTLD after SOT have also received partially HLA-matched allogeneic EBV-specific CTLs from a frozen bank of CTLs derived from healthy blood donors (36) . Unfortunately, most patients with PTLD after SOT do not have the availability of HLA-matched infusion of donor leukocytes from the original donor, and the risk of serious acute graft versus host disease is still considerably high.

The use of aggressive combinations of chemotherapy has additionally been investigated in patients with PTLD after SOT. Initial results indicated a high mortality rate and a high failure rate after combination aggressive cytotoxic chemotherapy (19) . Recent investigations in both children and adults with PTLD after SOT have indicated a high response rate with less toxicity and mortality with low-dose combination chemotherapy (7 , 20) . We recently demonstrated that very low-dose chemotherapy (Cy/Pred) induces a significantly high CR rate with minimum morbidity and mortality in children with PTLD after SOT (21) . However, despite a very high (>90%) response rate with Cy/Pred, the 2-year event-free survival is only approximately 58% in children with PTLD after SOT (12) . Therefore, whereas low-dose chemotherapy reduces the morbidity and mortality in patients with PTLD after SOT, it does not result in a high percentage of long-term event-free survival.

Previous studies with anti-B-cell monoclonal antibodies (anti-CD21 and anti-CD24) suggested a high response rate but only a 50% long-term disease-free survival in a small number of solid organ transplant recipients who developed PTLD (37) . In additional studies with monoclonal anti-B-cell antibodies in patients with PTLD after SOT, the long-term disease-free survival is still only around 50–55% (16) . A recently developed chimeric antibody that consists of variable regions from the heavy and light chains of the murine anti-CD20 antibody and human IgG1 and {kappa} constant regions was demonstrated to induce significant responses in adults with low and intermediate non-PTLD-associated B-NHL (38) . Subsequently, Czuczman et al. (23) demonstrated a 100% response rate in untreated adult patients with indolent non-PTLD B-NHL with combination rituximab and CHOP chemotherapy (chemoimmunotherapy). Most recently, Coiffier et al. (22) demonstrated that chemoimmunotherapy (using rituximab and CHOP chemotherapy) compared with chemotherapy alone with CHOP in elderly patients with diffuse large B-cell lymphomas resulted in a significant improvement in disease-free survival and overall survival.

Initial studies using monoimmunotherapy (rituximab) in patients with PTLD reported a 65% response rate with an 18% relapse rate and a 16% mortality rate after rituximab alone (17) . However, in a much larger cohort and with longer follow-up in a multicenter open-label Phase II trial of rituximab therapy in patients with PTLD, the overall response rate was only 46% with an additional 56% of patients either progressing or dying on study (18) . These results suggest that although single-agent rituximab therapy may be of some benefit in controlling EBV-transformed B-cell proliferation, single-agent immunotherapy is not likely to result in a high percentage of long-term sustained remissions and enhanced event-free survival.

On the basis of single-agent data of rituximab and our recent data of Cy/Pred low-dose chemotherapy, we began to pilot the combination of CPR in patients with PTLD after SOT who either had fulminant PTLD or those with nonfulminant PTLD who failed previous medical therapy with reduced immunosuppression. In small numbers of patients, we have demonstrated that CPR is a well-tolerated regimen in patients with PTLD after SOT and is associated with minimal toxicity (no patients developing grade III or IV toxicity). Furthermore, we have demonstrated a 100% overall response rate (85% CR and 15% PR) to CPR in this small number of patients with PTLD after SOT. Additionally, despite one patient with fulminant PTLD that ultimately progressed after a PR and who died of progressive PTLD, this chemoimmunotherapy regimen (CPR) has resulted in patients with PTLD after SOT having sustained disease-free survival and event-free survival ranging between 8 and 29 months after CPR.

In summary, PTLD after SOT is a heterogeneous disease that is secondary to EBV-induced B-cell transformation and decreased host-specific EBV CTL cellular immunity. Approaches that inhibit B-cell proliferation and transformation and/or enhance the induction of EBV CTL activity will likely result in a significant improvement in the outcome of patients with PTLD after SOT. The use of combined chemotherapy and immunotherapy (chemoimmunotherapy) with CPR seems to be a promising new approach to patients with PTLD after SOT. A much larger cohort of patients with larger follow-up is required to determine whether this regimen will result in an improvement in long-term event-free survival and decrease the PTLD relapse rate and allograft rejection rate in patients with PTLD after SOT. Additionally, biological studies investigating changes in circulating EBV DNA, the induction of EBV-specific CTLs, and the molecular genetic features of PTLD will lead to a more rational approach to future therapeutic investigations in this disease.


   ACKNOWLEDGMENTS
 
We acknowledge the Renal, Cardiac, and Liver Solid Organ Transplant Teams at Columbia Presbyterian Medical Center at Columbia University for referral of patients and collaboration on this study, and we acknowledge Linda Rahl for expert editorial assistance in the development of this manuscript.


   FOOTNOTES
 
1 Presented at the "Ninth Conference on Cancer Therapy with Antibodies and Immunoconjugates," October 24–26, 2002, Princeton, NJ. This study was supported in part by a grant from the Pediatric Cancer Research Foundation. Back

2 To whom requests for reprints should be addressed, at Herbert Irving Comprehensive Cancer Center, Columbia University, 161 Fort Washington, Irving 7, New York, NY 10032. Phone: (212) 305-8316; Fax: (212) 305-8428; E-mail: mc1310{at}columbia.edu Back

3 The abbreviations used are: PTLD, post-transplant lymphoproliferative disease; SOT, solid organ transplantation; NHL, non-Hodgkin’s lymphoma; CHNYP, The Children’s Hospital of the New York Presbyterian Medical Center; CPR, cyclophosphamide/prednisone/rituximab; CT, computerized tomography; PET, positron emission tomography; IHC, immunohistochemical analysis; ISH, in situ hybridization; LMP, latent membrane protein; EBER, EBV-encoded RNA; CHOP, cyclophosphamide-Adriamycin-vincristine-prednisone; Cy/Pred, cyclophosphamide/prednisone; CR, complete response; PR, partial response. Back


   REFERENCES
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 

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