Haematologica 2002; 87:(07)ECR26
[Medline] [prev] [index] [next]Progressive multifocal leukoencephalopathy shortly after the diagnosis of follicular lymphoma in a patient treated with fludarabine
Lluís Rodríguez, Josep-Maria Ribera, Montserrat Batlle, Blanca Xicoy, José-Luis Mate*, Fuensanta Millá, Evarist Feliu
Hematology and Pathology* Departments. Hospital Universitari Germans Trias i Pujol, Badalona. Universitat Autònoma de Barcelona, Spain
Correspondence: Josep-Maria Ribera, Hematology Department. Hospital Universitari Germans Trias i Pujol, C/Canyet s/n, 08916, Badalona. Telephone: +34934978987. Fax: +34934978995. E-mail: jmribera@ns.hugtip.scs.es
Progressive multifocal leukoencephalopathy (PML) is an opportunistic infection caused by human polyomavirus JC that usually affects patients with lymphoproliferative disorders in advanced stages. We report the case of a 58-year-old patient with follicular lymphoma (FL) treated with fludarabine who developed a PML two months after the diagnosis. A low CD4 lymphocyte count was present at FL diagnosis. This feature, together with immunosuppresion caused by fludarabine could explain the early onset of PML in this patient.
The use of the purine analogs such as fludarabine in the treatment of low grade non-Hodgkin's lymphomas (NHL) and chronic lymphocytic leukemia (CLL) is associated with infectious complications different from those seen in patients treated with schedules including alkylating agents and anthracyclines. In addition to infections by Gram-positive and Gram-negative bacterias, patients may develop opportunistic infections, mainly caused by atypical mycobacteria, fungi, viruses, Listeria monocytogenes, and Pneumocystis carinii.1 The sustained reduction in T-cell lymphocyte count, particularly CD4+ cells, is the main contributing factor to the increased incidence of infectious episodes associated with fludarabine therapy.
Progressive multifocal leukoencephalopathy (PML) is an opportunistic infectious disease of the central nervous system caused by human polyomavirus JC (JCV) that almost exclusively affects immunocompromised patients.2 It was originally described in patients with chronic lymphocytic leukemia (CLL) and Hodgkin's disease, usually in advanced stages. PML arising in early phases of NHL is an infrequent event. We describe a patient with follicular lymphoma treated with fludarabine who developed PML shortly after diagnosis.
A 58-year-old man was admitted to our hospital because of lymphadenopathy in the cervical, supraclavicular, and axillary regions, and hepatosplenomegaly 3 cm below the costal margins. A diagnosis of grade II follicular lymphoma was made by biopsy of a left axillary lymph node. The immunophenotypic analysis showed positivity for CD20, CD10, CD79a and kappa chains. Bcl-2 was positive by immunoperoxidase staining of the lymph node biopsy. At diagnosis the white cell count was 3.1x109/L, with 65% neutrophils, 17% lymphocytes, 16% monocytes and 3% eosinophils. The CD4+ lymphocyte count was 0.2x109/L. Serological tests for HIV by ELISA were negative. The bone marrow biopsy study was normal. The patient began a monthly FCM schedule (fludarabine, 25 mg/m2 IV, days 1-3; cyclophosphamide, 200 mg/m2 IV, days 1-3 and mitoxantrone, 6 mg/m2 IV, day 1). Two weeks after the second FCM cycle, the patient developed behavioral changes, left central facial paralysis and left hemiparesis. A cranial computed tomography (CT) scan revealed a subcortical right frontal lesion, with white matter involvement, with no mass effect or contrast enhancement. Cranial magnetic resonance (MR) imaging showed a confluent infiltrative lesion within the right frontal lobe. The lesion showed hyperintensity in T2-weighted images (Figure 1), whereas on T1-weighted imaging, it appeared as an area of decreased signal intensity, with neither gadolinium enhancement nor mass effect. Two lesions with the same characteristics were identified in the right parietal lobe. The cerebrospinal fluid (CSF) study showed a glucose level of 65 mg/dL and a protein content of 0.36 g/L without cells. Polymerase chain reaction (PCR) in CSF was positive for JCV. A stereotactic biopsy of the right frontal lobe lesion showed focal demyelination in association with reactive astrocytosis displaying atypical nuclei. Some oligodendrocyte nuclei were enlarged, and several contained nuclear inclusions. No evidence of lymphoma was present in the biopsy. Cidofovir (350 mg every week) was administrated intravenously.3 However, no response was obtained and the patient died two months after the onset of neurological symptoms.
PML is caused by cytolytic destruction of oligodendrocytes by JCV, resulting in lesions that appear initially in a sparse, asymmetric distribution. With disease progression, the foci of demyelination or plaques can enlarge and coalesce . This opportunistic infection affects immunosuppressed patients and has been reported in association with hematologic malignancies, cancer chemotherapy, immunosuppression for rheumatic diseases or after organ transplantation, chronic inflammatory diseases such as sarcoidosis, tuberculosis and non-tropical sprue, and AIDS. The incidence of PML in hematologic malignancies is 0.07%.4 Brain biopsy shows white matter demyelination, oligodendrocytes showing nuclei with viral inclusions and reactive astrocytosis.
The appearance of opportunistic infections after fludarabine treatment is related to the cellular immunosuppression caused by this drug. Among malignant hematologic diseases, PML has been specially reported in CLL. Although lymphocyte CD4 levels are usually low in CLL patients, it has been suggested that immunosuppression induced by fludarabine is the main factor for the development of PML.5-7 However, in these patients, PML occurs in advanced phases, in which fludarabine has been given as rescue therapy. The neurological symptoms usually occur between 5 and 18 months after fludarabine. Anaisse et al.1 performed a logistic regression analysis of the factors associated with the development of major infections in fludarabine-treated CLL patients, showing advanced Rai stage (III-IV), previous cytolytic treatment, granulocyte counts lower than 1x109/L, high serum creatinine levels, CD4 counts lower than 50x106/L, previous or concomitant corticosteroid therapy, age higher than 65 years and IgG levels lower than 400 mg/dL to be relevant. The patient herein reported was treated with cidofovir without response and had rapid progression to death. This did not allow us to use cytosine arabinoside, a drug that has shown activity against PML (II).
There are some unusual features in our case. First, the diagnosis of PML in a patient with follicular NHL, second, the development of PML shortly after the onset of therapy, and third, the short period between the last dose of fludarabine and the diagnosis PML. However, PML has been described in patients with follicular lymphoma without fludarabine treatment,9 as well as in patients with idiopathic CD4+ lymphocytopenia.10 Our patient had a low CD4 count at diagnosis, probably associated with the follicular lymphoma. It is possible that this state of immunosuppression could have been enhanced by fludarabine treatment, leading to the early development of PML.Funding
Supported in part by grant P-EF-01 from Fundación Internacional José Carreras para la Lucha contra la Leucemia.
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