Leukoencephalopathy and papovavirus infection after treatment with chemotherapy and anti-CD20 monoclonal antibody

Paola Matteucci, Michele Magni, Massimo Di Nicola, Carmelo Carlo-Stella, Caterina Uberti and Alessandro M. Gianni

Goldberg et al1 recently reported a few unusual viral infections after high-dose chemotherapy with autologous blood stem cell rescue associated to peritransplantation rituximab. In their paper, the authors describe 4 cases of either JC papovavirus or cytomegaloviral (CMV) infections after chemotherapy and rituximab administration. Although a direct correlation with anti-CD20 therapy remains to be demonstrated, concerns were expressed about the clustering of these rituximab-treated cases in view of the broad and increasing use of the anti-CD20 monoclonal antibody in non-Hodgkin lymphoma (NHL) treatment. We report here one additional case of progressive multifocal leukoencephalopathy associated with peritransplantation rituximab in a heavily pretreated lymphoma patient.

A 56-year-old man had a clinical history of Hodgkin disease, nodular sclerosis, diagnosed in 1974. He had stage II E A disease and was treated with a mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) regimen for 6 cycles, subtotal-nodal irradiation, and splenectomy, achieving a complete clinical remission. In October 1998 he was diagnosed as having diffuse large cell NHL, stage IV A. At that time, slides of both diagnoses were evaluated, confirming the 2 different diseases. Between November 1998 and July 1999 he received cyclophosphamide, hydroxydaunomycin, vincristine, and prednisone (CHO[P]) for 6 cycles, and then mesna, ifosfamide, mitoxantrone, and etoposide (MINE) for 6 cycles, achieving a complete remission. He was admitted in our department 1 year later with progressive disease, presenting with enlarged cervical nodes and pulmonary, bone, and bone marrow disease localizations. Serological tests for hepatitis B virus (HBV), hepatitis C virus (HCV), HIV 1/2, CMV, Epstein-Barr virus (EBV), herpes zoster virus (HZV), herpes simplex virus (HSV) 1 and 2, and Toxotest were positive, except for HIV 1/2, indicating past exposure to the corresponding pathogen. Active infection by HCV-RNA genotype 2a/2c was also demonstrated (Table 1). The patient underwent salvage high-dose sequential chemotherapy, including 6 overall doses of rituximab at 375 mg/m2 (R-HDS).2The treatment lasted from July 2000 to January 2001 and comprised dexamethasone, cytarabine, and cisplatin ([D]HAP) for 3 cycles → cyclophosphamide 5.6 g/m2 plus 2 rituximab 375 mg/m2 infusions before stem cell harvest → cytosine arabinoside 1.5 g/m2 every 12 hours for 6 days → stem cell rescue and subsequent stem cell harvest, both preceded by rituximab 375 mg/m2 infusion → etoposide 2.4 g/m2 plus cisplatin 100 mg/m2 plus stem cell rescue → high-dose BCNU, etoposide, cytosine arabinoside, and melphalan (HD-BEAM) plus stem cell rescue. Two additional weekly doses of rituximab, 375 mg/m2, ended the treatment. Stem cells harvested after chemotherapy with cytosine arabinoside plus rituximab were negative for lymphoma cell contamination (as assessed by polymerase chain reaction [PCR] using a patient's specific primer) and were used to support the final myeloablative BEAM regimen. The patient achieved a complete clinical and molecular remission. The treatment was well tolerated, and the patient was discharged in good clinical conditions. Consolidation radiotherapy (30 Gy) on sacral region was given on an outpatient setting. On day +20 from the end of treatment, the patient developed an asymptomatic CMV infection, documented by a positive pp65 assay (3 and 4 positive nuclei/200 000 cells), and was treated with gancyclovir in our outpatient department until negativization of the assay in 2 consecutive controls. Seven months later, the patient presented with progressive pulmonary and bone disease, confirmed by computed tomography (CT)–scan as well as by histological and immunophenotypic analysis of the pulmonary localizations. At that time, complete serological tests were repeated, confirming the presence of HCV-RNA. The patient was treated with vinorelbine (25 mg/m2) in association with rituximab, 375 mg/m2, for 7 overall courses, achieving a partial response. In February 2002, soon after the end of the last dose of rituximab, the patient experienced mental status changes and ataxia. A brain CT scan revealed multiple hypodense lesions, while magnetic resonance imaging (MRI) showed areas of white matter disease consistent with a demyelinating process. A cerebrospinal fluid examination was positive for BK papovavirus DNA. Despite treatment with cidofovir, the patient died in April 2002.

Table 1.

Main laboratory and serological tests

The present report adds to the list of unusual viral infections in patients treated with high-dose chemotherapy and rituximab. Of note, the BK papovavirus isolated here causes leukoencephalopathy with 10-fold less frequency3 compared with the JC papovavirus responsible for the 2 cases of progressive multifocal leukoencephalopathy reported by Goldberg et al.1 The contributory role of rituximab, if any, is only tentative and far from being proved.4,5 However, this additional case further strengthens the need for an accurate surveillance and reporting of rare viral infections that might occur in heavily pretreated lymphoma patients receiving peritransplantation rituximab.