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Low-Dose Chemotherapy for Epstein-Barr Virus–Positive Post-Transplantation Lymphoproliferative Disease in Children After Solid Organ Transplantation

From the Departments of Pediatrics, Pathology and Microbiology, Surgery, and Preventive and Societal Medicine, University of Nebraska Medical Center, Omaha, NE; Departments of Pediatrics and Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; and Department of Pediatrics, Children's Hospital Research Medical Center, Seattle, WA

Address reprint requests to Thomas G. Gross, MD, PhD, Children's Hospital, 700 Children's Dr, Columbus, OH 43205-2696; e-mail: tgross{at}chi.osu.edu

	ABSTRACT

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PURPOSE: To evaluate the efficacy of a low-dose chemotherapy regimen in children with Epstein-Barr virus (EBV) –positive, post-transplantation lymphoproliferative disease (PTLD) after organ transplantation who have experienced failure with front-line therapy for PTLD.

PATIENTS AND METHODS: Eligible patients received cyclophosphamide (600 mg/m² intravenous for 1 day) and prednisone (2 mg/kg orally for 5 days) every 3 weeks for six cycles.

RESULTS: Thirty-six patients treated on study were assessable for analyses. Front-line therapies for PTLD before study entry included immune suppression reduction or withdrawal (n = 36), antiviral therapy (n = 33), surgical resection (n = 8), rituximab (n = 2), and interferon alfa (n = 1). Reasons for failure of front-line therapy included progressive disease (PD; n = 33) and persistent disease with concurrent allograft rejection (n = 3). Thirty patients (83%) had stage III to IV disease, 92% had extranodal disease, and 75% had three sites of disease. The overall response rate was 83% (75% complete response + 8% partial response). The relapse rate was 19%, with only one of five relapsed patients alive and disease-free. Four patients presented with fulminant, disseminated PTLD; only one of these four patients achieved a response, and all four died of PD. Two patients died of treatment-related toxicity. Three patients (8%) experienced allograft loss, but two of the three patients are alive and disease-free after a second transplantation. The 2-year overall, relapse-free, and failure-free (without PTLD and with functioning original allograft) survival rates were 73%, 69%, and 67%, respectively.

CONCLUSION: This low-dose chemotherapy regimen is effective for children with EBV-positive, nonfulminant PTLD who have experienced treatment failure with front-line therapy, and this study represents the largest series of PTLD patients treated prospectively with a uniform chemotherapy regimen.

	INTRODUCTION

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Epstein-Barr virus (EBV) –associated post-transplantation lymphoproliferative disease (PTLD) is a heterogeneous spectrum of disease. After solid organ transplantation (SOT), PTLD occurs more frequently in children than adults.^1-3 PTLD remains a major cause of morbidity and mortality in recipients of SOT, with survival unchanged for the past several decades.⁴ Reduction of immune suppression remains the standard front-line therapy for PTLD. The success of reduction/withdrawal of immunosuppression varies greatly, with response rates ranging from 20% to 86%. The variability in success rates may be explained in part by the spectrum of PTLD, with localized or polymorphic disease more likely to respond.^1,5,6 Additionally, it is difficult to standardize reduction of immunosuppression because of variable risk of rejection between patients and types of transplanted organs and the difficulty in comparing levels of immunosuppression between patients and different immunosuppressive agents or combination of agents.

The treatment of patients with PTLD who experience treatment failure with reduction/withdrawal of immunosuppression is particularly challenging because of increased toxicity from cytotoxic therapies, increased susceptibility to life-threatening infections, and the necessity to maintain the allograft. The outcome for patients with PTLD who experience failure with reduction/withdrawal of immunosuppression is also quite variable, with disease-free survival rates reported to be between 0% and 70%.^5-25 In this study, children who had progressive PTLD despite reduction/withdrawal of immunosuppression with or without other therapies for PTLD and/or who developed rejection necessitating change of therapy to salvage the allograft were eligible to receive a chemotherapy regimen consisting of low-dose cyclophosphamide and prednisone. It was hypothesized that this regimen would be effective by simultaneously controlling the lymphoproliferative process, preventing or treating allograft rejection, and minimizing treatment-related mortality (TRM) in children with EBV-positive PTLD who had experienced failure with front-line therapy.

	PATIENTS AND METHODS

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All patients were treated in compliance with regulations and guidelines of the institutional review boards of participating centers. Preliminary results have been published on some of the patients.^26,27 Forty-one patients at 14 centers from August 1995 to April 2001 were treated on this study. Five patients achieved a complete response (CR), but no further data was obtained. Assessable patients must have completed chemotherapy and had data submitted for the following: previous therapies before study entry, disease extent and clinical presentation at time of study entry, response to therapy, allograft status, and vital status. Follow-up data for disease status, allograft status, and vital status were requested yearly. Thirty-six patients (88%) were assessable for analyses.

Study Eligibility
Study eligibility required a tissue biopsy with histology consistent with PTLD using WHO criteria,²⁸ with evidence of EBV (either by EBV early RNA in situ hybridization or latent membrane protein immunohistochemistry), and failure of front-line therapy, which must have been, at minimum, a reduction of immunosuppressive therapy for 1 week. Patients who received additional therapies for PTLD were also eligible. Front-line therapy failure was defined as progressive disease (PD) and/or development of allograft rejection necessitating change of therapy to salvage the allograft. All patients underwent evaluation for disease extent before study entry. Evaluation included clinical symptoms and computed tomography scans of head, chest, abdomen, and pelvis. Lumbar puncture and bone marrow analysis were recommended but not performed on all patients before study entry. Although some patients had polymerase chain reaction (PCR) for EBV DNA performed on blood, marrow, or CSF, the detection of EBV DNA by PCR was not used for staging. CNS and/or marrow disease was defined as cytologic evidence of PTLD. Patients with radiographic evidence of PTLD in the CNS were not eligible. Patients were restaged after the second or third cycle of chemotherapy, at the end of therapy, and at times when PD or relapse was suspected.

Treatment
Treatment consisted of cyclophosphamide (600 mg/m² intravenous for 1 day) and prednisone (1 mg/kg orally twice a day for 5 days) repeated every 3 weeks for six cycles. If there was evidence of tumor cells or EBV DNA by PCR in the CSF but no radiographic evidence of PTLD in the CNS, patients received intrathecal methotrexate at standard doses (ie, less than 1 year old, 6 mg; 1 to 2 years old, 8 mg; 2 to 3 years old, 10 mg; and more than 3 years old, 12 mg) with each cycle of chemotherapy until the CSF became negative for tumor cells and/or EBV DNA. Patients received intravenous hydration of 200 mL/m² of normal saline over 2 hours before and 1 hour after cyclophosphamide infusion. Neither tumor lysis prophylaxis nor a uroprotectant for hemorrhagic cystitis prophylaxis were used. Prophylactic antiemetics and hematopoietic growth factors were used per institutional guidelines. Supportive care recommendations included the use of irradiated blood products and Pneumocystis carinii prophylaxis with trimethoprim-sulfamethoxazole at 5 mg/kg orally twice a day 2 to 3 times a week. The use of antiviral therapy and immune suppression management was left to the discretion of the treating physician. It was recommended to minimize the use of ganciclovir because of additive myelosuppression. Reduction or discontinuation of calcineurin inhibitors was encouraged during chemotherapy. Treatment of rejection episodes occurring during chemotherapy was left to the discretion of the transplantation physician, although steroid boluses were recommended. It was recommended that the maintenance immune suppression be restarted 3 weeks after the last chemotherapy cycle and at doses less than those used before development of PTLD (eg, 50% to 75%), if clinically feasible.

Definitions
There exists a cohort of PTLD patients with rapidly progressive, disseminated disease and a dismal outcome.^29,30 Clinical criteria were developed prospectively in an attempt to better define this group of patients. The clinical criteria for fulminant PTLD (F-PTLD) were PTLD presenting with disseminated disease (ie, Ann Arbor stage IV disease), with tissue biopsy of at least one site of involvement; fever (> 38°C); and evidence of multiple organ compromise as defined by two or more of the following: requirement of vasopressor medications, mechanical ventilation, renal failure, coagulopathy, and/or severe cytopenias (defined as total WBC < 1,500/µL, hemoglobin < 8.0 gm/dL, and/or platelets < 100,000/µL).

Staging was assessed by both the Murphy³¹ and Ann Arbor³² classifications. Also, sites of disease were assessed as noncontiguous sites of lymph node involvement and/or number of extranodal organs involved.

CR was defined as complete resolution of all clinical symptoms and all known sites of disease for at least 4 weeks. CR was dated from the time all lesions and symptoms disappeared. Partial response (PR) was defined as complete resolution of all clinical symptoms and a reduction by at least 50% in the size of all measurable tumors for at least 4 weeks and absence of new lesions. Stable disease was defined as a decrease of less than 50% or increase of no more than 25% of any tumor and no evidence of new lesions. PD was defined as a 25% or greater increase in any tumor, appearance of new lesions, or worsening of clinical symptoms.

TRM was defined as death from any cause other than PTLD while receiving chemotherapy. Failure-free survival (FFS) was determined by defining a failure as inability to achieve CR, relapse of PTLD after achieving CR, or loss of the original allograft.

Statistical Analysis
The Kaplan-Meier method was used to estimate the overall survival, relapse-free survival, and FFS distributions. Crude rates are reported for TRM and response. Ninety-five percent CIs are provided for each outcome measure.

	RESULTS

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Patient Characteristics
Patient demographic data are listed in Table 1. The majority of patients received liver and/or small bowel transplantations, reflecting the transplantation populations of the two centers with the largest enrollment. All patients were less than 18 years of age, with a median age of 4.9 years. The median time from transplantation to diagnosis of PTLD was 5.4 months; however, the range was 2 months to 8 years.

Outcome
Specific organ toxicities associated with this chemotherapy regimen were not collected. Cause of death and loss of allograft function were assessed. Causes of death included PD (n = 4, all patients with F-PTLD), relapsed disease (n = 4), and TRM (n = 2). One patient died of pulmonary hemorrhage within 7 days of starting chemotherapy. The autopsy revealed extensive PTLD throughout the lungs, with one lesion that was necrotic and hemorrhagic and eroding through the pulmonary pleura. It was felt that the chemotherapy had caused the tumor to necrose, leading to the fatal hemorrhage. One patient died of sepsis with Candida fungemia and Gram-negative sepsis during a period of therapy-induced neutropenia after chemotherapy. Loss of graft function occurred in three patients (8%) after discontinuation of chemotherapy. All three patients underwent retransplantation; two of the three patients remain alive and disease free, and the other patient died of relapsed PTLD. Five patients (19%) developed recurrent PTLD. Of note, none of the five patients with marrow and/or CNS disease relapsed. Four of the five patients who experienced relapse subsequently received salvage therapy consisting of standard-dose chemotherapy and/or irradiation. Only one of the five patients with recurrent PTLD remains alive and disease free.

Table 4 lists the responses to chemotherapy for the 36 patients. The overall response rate was 83% (95% CI, 80% to 100%). CR was achieved in 75% of patients (95% CI, 61% to 89%). The outcome of patients with F-PTLD was dismal, with only one patient achieving a PR and all patients dying of PD. With F-PTLD patients excluded, the CR rate was 90% (95% CI, 80% to 97%). The median follow-up time at analysis was 32 months, with a range of 12 to 80 months. The 2-year overall survival rate of all patients was 73% (95% CI, 58% to 88%; Fig 1). No deaths have been observed more than 18 months from initiation of chemotherapy. The 2-year relapse free survival rate was 69% (95% CI, 53% to 85%; Fig 2). No relapses have been observed more than 18 months after chemotherapy. The 2-year FFS rate was 67% (95% CI, 52% to 82%), with failure defined as inability to achieve CR, relapse of PTLD after achieving CR, or loss of the original allograft.

View larger version (12K): [in this window] [in a new window]   Fig 1. Overall survival for patients with post-transplantation lymphoproliferative disease after treatment with low-dose chemotherapy.

View larger version (12K): [in this window] [in a new window]   Fig 2. Relapse-free survival for patients with post-transplantation lymphoproliferative disease after treatment with low-dose chemotherapy.

	DISCUSSION

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Various treatment approaches have been used. Interferon alfa has been reported to be efficacious in treating PTLD in some instances.^20-22 Responses were reported to be observed in approximately 80% of patients. However, the overall survival suffered because of infection, rejection, and recurrent disease.²¹ Early studies using anti–B-cell monoclonal antibodies (anti-CD21 and anti-CD24) for the treatment of PTLD in SOT recipients suggested a high response rate, but long-term follow-up demonstrated only a 50% disease-free survival rate.²³ More recently, anti-CD20 antibody (rituximab) has been used in patients with PTLD. There are numerous anecdotal reports that claim rituximab is effective in the treatment of PTLD. A study of 25 patients receiving rituximab therapy for PTLD after SOT demonstrated a 65% response rate but a 26% relapse rate.²⁴ One treatment strategy that is used by many transplantation centers is to use rituximab in patients who have experienced failure with reduction of immunosuppression. Using this strategy, one study showed that two of four patients achieved CR, but one of these patients relapsed.³⁵ A larger study of 46 patients with PTLD after SOT who experienced failure with reduction of immunosuppression and subsequently received rituximab resulted in a 46% response rate (32% CR + 14% PR), but more than 50% of patients progressed or died by 3 months.²⁷ It is clear that rituximab is effective in certain patients with PTLD. However, patient and disease characteristics predicting which patients will benefit from rituximab are presently undetermined. Of note, the two patients in this study who had experienced treatment failure with reduction of immunosuppression and rituximab remain disease free more than 2 years after chemotherapy.

The attractiveness of chemotherapy in treating patients with PTLD who experienced failure with reduction of immunosuppression is the potent cytotoxicity against aberrant lymphoproliferation and the concurrent immunosuppressive effect, which is usually sufficient to prevent or treat allograft rejection. However, treatment-related morbidity and TRM as a result of end organ toxicity and infections can be problematic. Results from published studies demonstrate that standard chemotherapy regimens for non-Hodgkin's lymphoma (NHL; eg, cyclophosphamide, doxorubicin, vincristine, and prednisone; prednisone, methotrexate, doxorubicin, cyclophosphamide, and etoposide–cytarabine, bleomycin, vincristine, and methotrexate; etoposide, methylprednisolone, cytarabine, and cisplatin; and so on) are effective in inducing a CR, with relapse and allograft loss being relatively rare events (ie, < 5%). However, TRM remains problematic, ranging from 25% to 70%.^5-20 The largest experience of chemotherapy in PTLD patients comes from the Israel Penn International Transplant Tumor Registry, with 193 patients with PTLD who received chemotherapy. A third of the patients were reported to be alive at 3 years after developing PTLD, but only 37% died of PTLD; thus, approximately one third of the patients died because of TRM.³⁴ In general, children with PTLD seem to tolerate standard NHL chemotherapy regimens better than adults. In the largest pediatric series using chemotherapy to treat PTLD, nine of 10 patients achieved CR, and seven of 10 patients were disease free and alive at a median follow-up time of 19 months.⁵

The strengths of this study are that it is a prospective trial with multicenter participation and has relative uniformity of patients. Although only 36 patients were assessable for analyses, this study represents the largest series of PTLD patients treated with a uniform chemotherapy regimen. These results demonstrate that this regimen is effective in treating the majority of children with PTLD who have experienced treatment failure with front-line therapy. Using this regimen, the 2-year overall survival, relapse-free survival, and FFS rates (without PTLD and with functioning original allograft) are 73%, 69%, and 67%, respectively.

The relapse rate observed (19%) was higher than observed with standard NHL chemotherapy regimens, suggesting that a subset of patients require more intensive therapy. Because of small sample size, no factor could be identified that predicted patients at risk for relapse in this cohort. Additionally, the outcome after relapse was poor, with only one of five patients successfully treated with salvage chemotherapy and irradiation. The four patients who presented with disseminated, rapidly progressing disease and multiorgan failure or F-PTLD did poorly, with only one of four patients achieving any response (PR) and all patients dying of PD. These results suggest that this regimen is insufficient to control the disease in patients with F-PTLD. Intensification of chemotherapy has been shown to result in better control of F-PTLD, but patients died of organ toxicity or infection.⁹

One of the weaknesses of this study is the limitation to children. PTLD observed in children may be different than that observed in adult patients. In general, pediatric patients with PTLD have had superior outcomes compared with adults.³³ PTLD in children tends to occur earlier after transplantation and is typically EBV-positive and associated with primary EBV infection.² In adults, PTLD tends to occur later after transplantation, is more often EBV negative, and has a poorer prognosis. Therefore, PTLD observed in adults may represent a more malignant disease. Although one might expect less TRM using this low-dose chemotherapy regimen in adult patients with PTLD, it remains to be determined whether this regimen would be as effective in controlling the PTLD in adult patients.

Another weakness of this study, as in most studies evaluating treatment of PTLD, is the heterogeneity of the disease. Although conflicting results exist in the literature, factors that have been reported to predict an unfavorable outcome for PTLD include histology (monomorphic v polymorphic),^5,10 clonality (monoclonal v polyclonal),^10,14,18 extent of disease (> one site of disease),^10,23,33 presence of CNS disease,^10,36 EBV negativity of tumor cells,^17,18 and late presentation after transplantation (> 1 year).^10,19,33 Central pathology review was requested, but it was not required for study entry and was not obtained in more than half of the patients. Therefore, analysis of histology and clonality could not be performed. Attempts to achieve some degree of disease uniformity included the requirement of EBV positivity of tumor cells and the clinical requirement of disease that had failed front-line therapy. This cohort was characterized by the following factors that have been associated with favorable outcome: young age, EBV-positive disease, and short time from transplantation to PTLD, with two thirds of patients presenting before 1 year from time of transplantation (data not shown). However, most patients had extensive disease; 83% of patients had stage III to IV disease, 92% had extranodal disease, and 75% had three sites of disease. Additionally, 91% of patients had PD at time of study entry, despite other therapies.

In summary, this report represents the largest cohort of PTLD patients to date treated in a prospective fashion with a uniform chemotherapy regimen. Weaknesses of the study include lack of central pathology review and heterogeneity of patients, disease, and therapies before study entry. However, the results of this study demonstrate that this low-dose chemotherapy regimen is relatively safe and effective in treating children with EBV-positive, nonfulminant PTLD who had experienced treatment failure with front-line therapy after SOT. It remains to be determined whether these regimens would be effective in a similar cohort of adult patients with PTLD. Additionally, it seems that intensifying therapy is necessary to lower the relapse rate and improve the outcome of F-PTLD. The addition of anti–B-cell antibody is an attractive strategy because it potentially increases disease control without cumulative toxicity.^37,38 Finally, to truly impact the survival of patients with PTLD, large, prospective, multicenter studies are needed to better define prognostic factors and determine the most effective therapies.

	Authors' Disclosures of Potential Conflicts of Interest

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Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other Steven H. Hinrich NIH (A) Alan N. Langnas Fujisan (A) Ruth A. McDonald Genentech (A)

Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) $100,000 (N/R) Not Required

	Acknowledgment

 
We thank the research coordinators at each institution for providing data and, specifically, Jene Pierson, Ann Steffey, Alison Seidl, and Mary Morris for providing centralized data collection and coordination. The following investigators are acknowledged for their participation in this study: M.L. Schmidt (University of Illinois, Chicago, IL), M. Wollman (Children's Hospital of Pittsburgh, Pittsburgh, PA), and the following members of the Pediatric Blood and Marrow Consortium: F. Goldman (University of Iowa Hospitals and Clinics, Iowa City, IA), M. Joyce (Nemour Children's Clinic, Jacksonville, FL) M. Neider (Rainbow-Babies and Children's Hospital, Cleveland, OH), and A. Bendel (Children's Health Care, Minneapolis, MN).

	NOTES

 
Supported by Grant No. R03 CA 78204-01 (T.G.G.) from the National Cancer Institute and Grant No. 6605-01 from the Leukemia and Lymphoma Society (T.C.G., J.C.L., and T.G.G.).

Presented in part at the 3rd Symposium on Immunodeficiencies and Malignancies, Berlin, Germany, February 7-9, 2001; the 44th Annual Meeting of the Society of Hematology, Philadelphia, PA, December 6-10, 2002; and the 1st International Conference on Childhood Non-Hodgkin's Lymphoma, New York, NY, April 10-12, 2003.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
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Submitted July 27, 2004; accepted May 8, 2005.

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