Low-Dose Chemotherapy Appears Promising in Pediatric PTLD

NEW YORK—A low-dose cyclophosphamide/prednisone regimen is effective for treating children with refractory lymphoproliferative disease after a solid organ transplant, according to results of a prospective study including 36 children. The total response rate was 86% for this group, which is the largest series of post-transplant lymphoproliferative disorder (PTLD) patients treated uniformly with chemotherapy. Two-year overall survival was 73%.

While the results are "encouraging," more work needs to be done, said Thomas G. Gross, MD, PhD, director, Division of Pediatric Hematology/Oncology, Ohio State University School of Medicine, Columbus. "We need to make some improvements in decreasing the relapse rate, in treating relapsed disease, and in treating patients with fulminant PTLD, which continues to be a difficult group," Dr. Gross said at the First International Symposium on Childhood and Adolescent Non-Hodgkin’s Lymphoma.

The next logical step, Dr. Gross said, is to add an antibody therapy to this "backbone" of chemotherapy. Notably, researchers from Columbia University are piloting a "more aggressive" therapy of cyclophosphamide, prednisone, and rituximab (Rituxan) (CPR) in patients with refractory PTLD (Orjuela M et al: Clin Cancer Res, in press).

In addition, a currently pending Children’s Oncology Group (COG) trial will evaluate the CPR regimen in children, adolescents, and young adults with CD20-positive PTLD. Dr. Gross, the principal investigator in that trial, said he hopes this could be a way to achieve tumor control without adding toxicity.

According to preliminary results from the Columbia group’s pilot study, including data on seven treated patients, "response rates have been excellent, and toxicity has been low," Dr. Gross said. "Interestingly, two patients presented with fulminant disease, and one is now greater than 1 year out in continuous complete remission."

The Gold Standard

The gold standard for the treatment of PTLD in the solid organ transplant population is withdrawal or reduction of immunosuppression plus or minus antiviral therapy, Dr. Gross said. With this approach, remission rates of from 40% to 60% have been reported. For patients with refractory PTLD, or those who do not respond or have a complication upon withdrawal or reduction of immunosuppression, outcomes are historically poor due to risk of rejection, infection, and increased susceptibility to treatment-related toxicity.

Chemotherapy in the refractory PTLD population not only is cytotoxic to the lymphoproliferative process but also can provide enough immunosuppression to prevent or treat allograft rejection, Dr. Gross said. Unfortunately, the literature on chemotherapy in refractory PTLD is small and inconsistent. He noted that the Israel Penn International Transplant Tumor Registry includes 37 cases of children who received different chemotherapy regimens for PTLD after a solid organ transplant. In this population, the 1- and 2-year overall survival rates were 61% and 54%, respectively.

Dr. Gross and his colleagues sought to clarify the role of chemotherapy in pediatric patients by undertaking a study of low-dose chemotherapy with cyclophosphamide (600 mg/m²) and prednisone (2 mg/kg/d for 5 days) every 3 weeks for six cycles. Patients with evidence of central nervous system (CNS) disease were treated with intrathecal methotrexate. Reduction of immunosuppression and use of antiviral therapy were at the discretion of each transplant team.

Although it was not initially designed to be a pediatric study, the oldest patient enrolled was 17 years of age, Dr. Gross said, with a median age of 4.9 years. Median time from transplant to PTLD was 5.3 months. Most patients (83%) had extranodal disease, and 25% had evidence of the disease in the CNS. Previous PTLD therapy included reduction or withdrawal of immunosuppression in every patient, and almost all also received antiviral therapy. About one quarter had partial surgical resection, and a few received rituximab (5%) and interferon alfa (3%)

Complete response to cyclophosphamide/prednisone was achieved in 27 patients (77%), and 3 (9%) had a partial response, for a total response rate of 86%. The four patients with fulminant PTLD did "poorly" as a group, Dr. Gross said, with three nonresponders and one partial response. Excluding fulminant PTLD, the overall response rate was 100%.

The relapse rate was 18% (five patients), which was "higher than we wanted, and certainly higher than what is seen with more standard dose regimens," Dr. Gross said. Of the five relapsers, only one is alive; three have died of progressive disease and one of infection.

There were two treatment-related deaths (5%), including one due to pulmonary hemorrhage and one from sepsis with neutropenia on therapy.

Median follow-up is now 3 years. Overall survival at 2 years was 73%, and remains stable at that level past 72 months. Two-year relapse-free survival is 69%, also remaining stable for the duration of the follow-up.

For now, the low-dose cyclophosphamide/prednisone combination looks at least promising in children, even if results are preliminary. "I think we still need studies to see if it would be effective in adults, since that may be a different disease," Dr. Gross added.