Letter to the Editor
Progressive multifocal leukoencephalopathy in the course of combined therapy with bendamustine and rituximab
Leucoencefalopatía multifocal progresiva en el curso de terapia combinada con bendamustina y rituximab
Marta Rosas Cancio-Suárez
, Ignacio Barbolla Díaz, Andrés González-García
Corresponding author
Servicio de Medicina Interna, Hospital Universitario Ramón y Cajal, Madrid. Spain
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] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Servicio de Medicina Interna, Hospital Universitario Ramón y Cajal, Madrid. Spain" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Leucoencefalopatía multifocal progresiva en el curso de terapia combinada con bendamustina y rituximab" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Progressive multifocal leukoencephalopathy (PML) is caused by the reactivation of a polyomavirus commonly referred to as the JC virus (JCV). In most cases, the infection by this virus is indolent, but its reactivation in circumstances of immunosuppression can affect the central nervous system causing a loss of white matter, with diverse and progressive symptoms depending on the location and the extent: ranging from motor disorders and behavioral disturbances to death.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">We present the case of a 71-year-old man with a history of B-cell chronic lymphocytic leukemia (B-CLL) who began with symptoms of progressive gait instability and self-limiting episodes of diplopia. The patient received 4 cycles of fludarabine and cyclophosphamide at diagnosis with a good response. Subsequently, several cycles of <span class="elsevierStyleItalic">bendamustine</span> and rituximab were given due to persistent anemia and thrombocytopenia, with a steady return to normal figures. After a year in active treatment with an absence of the clinical condition, he came to the consultancy presenting the aforementioned symptoms.</p><p id="par0015" class="elsevierStylePara elsevierViewall">The examination revealed dysmetria in the finger-to-nose test, a predominantly right tremor at rest, and walking with a narrow base of support and trouble turning. The rest of the physical examination did not present remarkable findings.</p><p id="par0020" class="elsevierStylePara elsevierViewall">The lab results revealed pancytopenia, 467 lactate dehydrogenase, and 13.5 C-reactive protein, with the rest of the parameters within normality. The serologic tests for human immunodeficiency virus (HIV), hepatitis B, C, and syphilis were negative. The total CD4 count was 77.8 U. The cranial magnetic resonance imaging (MRI) revealed acute lesions in the left parietal temporal juxtacortical white matter and in the cerebellar peduncle without enhancement. The appearance of the cerebrospinal fluid (CSF) was normal, with no detection of spinal fluid protein concentration, WBC concentration, or B-CLL cells. The microbiological study of the CSF demonstrated the presence of JCV by polymerase chain reaction. The patient's neurological symptoms progressed with mixed aphasia, left eye closure paresis, horizontal nystagmus in all directions, facial hypoesthesia, and severe trunk ataxia, unable to maintain a sitting position. A new cranial MRI showed progression of the PML lesions. As the last dose of rituximab had been received 50 days ago, it was decided to perform plasmapheresis for drug removal. Intravenous cidofovir treatment was given due to neurological and functional deterioration, with poor evolution and gradual clinical progression. Finally, the patient died 3 months after the diagnosis of PML.</p><p id="par0025" class="elsevierStylePara elsevierViewall">PML is the product of lytic infection of the glial cells by the JC virus, which triggers a leukoencephalopathy predominantly in the posterior supratentorial white matter. The majority of the non-HIV-related cases have underlying lymphoproliferative disorders, generally associated with B-cell proliferation.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Many of them had received treatment with rituximab, a drug associated with the development of PML, both in patients with lymphoproliferative disorders and in those with underlying autoimmune disease. According to the review by Berger et al.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> 11 confirmed cases of PML in autoimmune disorders approved for treatment with rituximab have been described. The mean latency time from the first dose of rituximab to the onset of PML was 16 months, both in patients with established autoimmune and lymphoproliferative disease. The prognosis of these patients is poor, with a mortality of up to 90% of the cases.</p><p id="par0030" class="elsevierStylePara elsevierViewall">Although PML is associated with rituximab therapy, our patient's clinical course was atypical, increasing the possibility of an association with bendamustine therapy. In our bibliographic search we found this to be the third case of PML described in relation to bendamustine.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> Our patient developed PML after having been on rituximab treatment for 6 years without neurological symptoms. In the case we describe, PML manifested 9 months after the start of treatment with rituximab and bendamustine, which corresponds to the data described about the natural cycle of the disease.</p><p id="par0035" class="elsevierStylePara elsevierViewall">Although bendamustine has been associated with a lower subsequent development of infectious disease, we must be aware of its possible association with PML. The limited bibliography in relation to this disease does not allow us to make a direct association between bendamustine and the development of PML, but it does allow us to remain alert to the possibility of its appearance, and especially in those patients receiving combined treatment with rituximab.</p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Rosas Cancio-Suárez M, Barbolla Díaz I, González-García A. Leucoencefalopatía multifocal progresiva en el curso de terapia combinada con bendamustina y rituximab. Med Clin (Barc). 2020;155:513–514.</p>" ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:5 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "John E. Greenlee. Leucoencefalopatía multifocal progresiva (LMP) - Trastornos neurológicos - Manual MSD versión para profesionales. 2019. [accessed 23 Mar 2019]. Available from: <a target="_blank" href="https://www.msdmanuals.com/es-es/professional/trastornos-neurol%C3%B3gicos/infecciones-cerebrales/leucoencefalopat%C3%ADa-multifocal-progresiva-lmp">https://www.msdmanuals.com/es-es/professional/trastornos-neurol%C3%B3gicos/infecciones-cerebrales/leucoencefalopat%C3%ADa-multifocal-progresiva-lmp</a>." ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "National Organization for Rare Disorders (NORD). Leucoencefalopatía multifocal progresiva. 2016. [accessed 3 Apr 2019]. 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Lossos" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s12185-012-1118-6" "Revista" => array:6 [ "tituloSerie" => "The Japanese Society of Hematology" "fecha" => "2012" "volumen" => "96" "numero" => "2" "paginaInicial" => "274" "paginaFinal" => "278" ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/23870206/0000015500000011/v1_202012152105/S2387020620305180/v1_202012152105/en/main.assets" "Apartado" => array:4 [ "identificador" => "43309" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Letters to the Editor" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/23870206/0000015500000011/v1_202012152105/S2387020620305180/v1_202012152105/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020620305180?idApp=UINPBA00004N" ]
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