Bone Marrow Transplantation (2002) 30, 963–966  2002 Nature Publishing Group All rights reserved 0268–3369/02 $25.00 www.nature.com/bmt Case report Progressive multifocal leukoencephalopathy after stem cell transplantation, unsuccessfully treated with cidofovir

S Osorio1, R de la Ca´mara1, N Golbano1, E Marti1, CG Fedele4, S Nieto2, R Manzanares3 and JM Ferna´ndez-Ran˜ada1

1Department of Hematology, Hospital de la Princesa, Madrid, Spain; 2Department of Pathology, Hospital de la Princesa, Madrid Spain; 3Department of Radiology, Hospital de la Princesa, Madrid, Spain; and 4Centro Nacional de Microbiologı´a, Instituto Carlos III, Madrid, Spain

Summary: the first case of PML after SCT treated with this antiviral agent. Cidofovir, with activity in vitro against Papoviridae, We report a patient with progressive multifocal leuko- has been given to patients with HIV infection with contro- encephalopathy (PML) after autologous stem cell trans- versial results. The experience in HIV-negative patients is plantation (SCT) for non-Hodgkin’s lymphoma (NHL). limited to four cases,10–13 all of whom had a poor outcome. This is an unusual association, and to date only seven cases have been reported. This is the first case of PML after SCT treated with cidofovir, and the fifth case Case report treated with this drug in a patient without human immunodeficiency virus (HIV) infection. In the previous A 60-year-old man diagnosed with mantle cell lymphoma four patients treated with cidofovir the outcome was received an autologous SCT in first complete remission discouraging, as was the case in this patient. (CR) after three different regimens of chemotherapy. The Bone Marrow Transplantation (2002) 30, 963–966. conditioning regimen consisted of cyclophosphamide (4800 doi:10.1038/sj.bmt.1703704 mg/24 h ϫ 2 days) and fractionated total body irradiation Keywords: progressive multifocal leukoencephalopathy; (total dose 12 Gy), followed by infusion of CD34-selected stem cell transplantation; cidofovir peripheral blood stem cells (5 ϫ 106 CD34 cells/kg). Five months after SCT he developed a clinical and radiological picture that was diagnosed as bronchiolitis obliterans. Due to this complication the patient began treatment with Progressive multifocal leukoencephalopathy is a neurologi- prednisone (1 mg/kg/day) with a good response, although cal demyelinating disorder caused by JC polyomavirus, first long-term oxygen therapy was needed. The prednisone dose reported in 1958 in a patient with chronic lymphocytic leu- was progressively decreased, but 5 months later (in the 10th 1 kemia. JC virus is ubiquitous, and the seroprevalence is month after SCT) he again needed high doses due to up to 60% in young adults and up to 80% in elderly bronchiolitis reactivation. 2 people. Primary infection usually occurs during childhood Eleven months after SCT the patient developed a pro- 2 and is often asymptomatic. During primary infection the gressive weakness in his right arm and leg, dysphasia and virus is transported to the kidney where it persists indefi- apraxia. A cerebral MRI scan showed a focal area of white nitely. Disorders associated with severe cellular immuno- matter abnormality involving the left precentral area, with- deficiency such as hematological malignancies, solid out enhancement on post-gadolinium T1 weighted images, tumors, connective tissue diseases, transplant patients, suggestive of PML (Figure 1). Cerebrospinal fluid (CSF) treatment with immunosuppressive agents, and especially examination disclosed normal values for glucose, protein HIV infection, can cause reactivation of the virus and PML. and white cells, without evidence of malignancy. Microbio- In immunocompromised patients the differential diagnoses logical analysis for bacteria, mycobacterium, fungi, entero- of PML should be made with other central nervous system virus, herpes virus, and JC virus (by PCR) were all nega- infections (as for example tuberculosis, fungi, nocardia, tive. Histological examination of sterotactic biopsies from CMV) and noninfectious diseases such as lymphoma. So the white matter lesion showed multiple foci of demyelin- 3–9 far, PML has been reported in seven cases after SCT. ation (Figure 2) with large hyperchromatic oligodendro- Here, we report a case after autologous transplant for non- cytes, some with ground glass nuclei and a central zone, Hodgkin’s lymphoma treated with cidofovir. This case is corresponding to viral inclusions (Figure 3). This histology is typical of PML. The JC virus genome was demonstrated 14 Correspondence: Dr R de la Ca´mara, Servicio de Hematologı´a, Hospital by PCR in the brain tissue. At the time of PML diagnosis, de la Princesa, C/Diego de Leo´n No. 62, Madrid 28006, Spain the lymphoma remained in complete remission, and the + Received 18 February 2002; accepted 26 June 2002 CD4 lymphocyte count was 535/mm3. As there were pre- Progressive multifocal leukoencephalopathy after STC S Osorio et al 964

Figure 3 HE: Intranuclear inclusion in an oligodendrocyte correspond- ing to viral elements (arrow) (ϫ40).

Figure 1 Axial proton density images show a focal high intensity signal in the subcortical white matter of the left frontal region, which spreads towards the semiovale centrum.

Figure 4 MRI performed 2 months after initiation of cidofovir treatment. Axial T2-weighted images disclose progression of the left frontal lesion Figure 2 HE: Foci of demyelination can be seen (arrow). Oligodendro- and new lesions in the right frontal lobe and in the corpus callosum body. cyte nuclei surrounding the demyelination foci are hyperchromatic (ϫ2). Discussion

liminary data showing that cidofovir could improve the Progressive multifocal leukoencephalopathy after SCT is course in some patients affected with PML, the patient an unusual complication, with only seven cases reported to received a total of six doses of cidofovir (each of 5 mg/kg; date.3–9 The main characteristics of these cases are summar- two initial doses with a 1-week interval between doses and ized in Table 1. Five patients received autologous trans- four subsequent doses at 2 weekly intervals, each preceded plants, and two allogeneic SCTs from matched unrelated by probenecid and i.v. saline). Therapy was tolerated with- donors. The underlying diseases were three chronic out complications, but in spite of the treatment the patient myeloid leukemias, three NHL, and one acute myeloid leu- experienced rapid and progressive neurologic deterioration, kemia. As with our case, the majority of these patients (all with complete aphasia, right hemiplegia and dysphagia. An except one) were conditioned with cyclophosphamide and MRI performed after five doses of cidofovir showed clear total body irradiation. The bone marrow was only manipu- progression of the lesions (Figure 4). The patient died 5 lated in one case (purged by mafosfamide). The median months after the start of the neurological symptoms. time of commencing the neurological symptoms after the

Bone Marrow Transplantation Progressive multifocal leukoencephalopathy after STC S Osorio et al 965 Table 1 Reported cases of PML after SCT

Author Underlying Transplant Time from CD4 count Treatment Response to Evolution disease conditioning transplant treatment cell source to PML

Mesquita 19923 NHL Autologous 1 month Not available None Death before CY-TBI diagnosis Bone marrow Owen 19944 CML Allogeneic matched 17 months 300–400/mm3 Ara-C No Death 2 months unrelated donor (i.v. and i.t) after diagnosis CY-TBI Bone marrow O’Shaughnessy CML Allogeneic matched 5 months Not available Ara-C No Death a few 19945 unrelated donor (i.v. and i.t.) months after CY-TBI diagnosis Bone marrow Seong 19966 CML Autologous 17 months Not available Ara-C (i.v.) Not available No information CY-TBI IFN-alpha available Bone marrow and PBSC Przepiorka 19977 NHL Autologous 8 months 149/mm3 Interleukin-II Yes Alive 1 year after CY-TBI diagnosis without Bone marrow and neurological PBSC impairment Re 19988 NHL Autologous 13 months 340/mm3 Interleukin II Yes Alive 2 years after BEAM Ara-C (i.t.) diagnosis with Bone marrow neurological impairment Coppo 19989 AML Autologous 13 months 163/mm3 Interleukin-II No Death 4 months CY-TBI IFN-alpha after diagnosis Bone marrow AS101 purged by Ara-C (i.t.) mafosfamide

NHL = non-Hodgkin’s lymphoma; AML = acute myeloid leukemia; CML = chronic myeloid leukemia; CY-TBI = cyclophosphamide and total body irradiation; i.v. = intravenous; i.t. = intrathecal; IFN = interferon; PBSC = peripheral blood stem cells. transplant was 10.5 months (1–17 months), similar to our Four HIV-negative patients with PML treated with cido- patient (9 months). The CD4 count was only available in fovir have been reported.10–13 The underlying diagnoses four patients and ranged from 149 to 348/mm3, figures were: idiopathic CD4 lymphocytopenia, chronic lympho- lower than the CD4 count in our case (535/mm3). These cytic leukemia, dermatomyositis and systemic lupus ery- data suggest that although the CD4 count is an important thematosus. The outcome was fatal in all of these patients, predisposing factor, as in HIV patients, other factors may a few months after the diagnosis has been made. Although, be implicated in PML after BMT. This is also supported in one of the patients, disappearance of the JC virus genome by the fact that even in the transplant patients with the low- from the cerebrospinal fluid and stabilization of the MRI est CD4 counts, these were not as low as in HIV patients picture were noted initially, the patient finally died.10 Ours with PML.15–17 Most patients with HIV infection and PML is the first transplant patient treated with this drug and the have CD4 counts less than 100/mm3. evolution was no better than in previously reported cases. Another interesting aspect of our case is the treatment This short experience with cidofovir in HIV-negative with cidofovir. This antiviral agent, with in vitro activity patients is thus discouraging. against Papovaviridae, has been used in patients with HIV Of the seven patients with PML after BMT only two and PML with some favorable outcomes.15,17–19 However, had prolonged survival times (more than 1 year, and one the improvement observed in HIV patients may be due to is probably cured). Both of them received treatment with the effect of concomitant highly active antiretroviral ther- interleukin-2.7,8 It is also interesting that both showed an apy (HAART). To assess this possibility some studies have increase in CD4 counts from 149/mm3 to 364/mm3, and compared the treatment of PML patients with HAART from 340/mm3 to 540/mm3. It is difficult to determine if alone and HAART plus cidofovir. A higher rate of JC virus this positive outcome was related to the treatment or to the DNA neutralization in the CSF, and a better outcome has partial reconstitution of the immune system which could been found in some,15,17 but not all cidofovir studies.16 have been spontaneous or due to the treatment itself. Cidofovir is generally well tolerated, and the most common In summary, cidofovir was of no clinical value in our reported adverse effects are nephrotoxicity (manifested case of PML after SCT, as in other HIV-negative cases usually as proteinuria), vomiting, neutropenia and ocular reported in the literature. Other therapies should be investi- hypotony.20 gated in this unusual clinical context.

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