Progressive multifocal leucoencephalopathy with peripheral ...

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acute myeloblastic leukemia, and who subsequently developed progressive multifocal leucoencephalopathy, an unusual pathology in this context. Progressive ...

Bone Marrow Transplantation, (1999) 23, 401–403  1999 Stockton Press All rights reserved 0268–3369/99 $12.00

Case report Progressive multifocal leucoencephalopathy with peripheral demyelinating neuropathy after autologous bone marrow transplantation for acute myeloblastic leukemia (FAB5) P Coppo1, JPh Laporte1, M Aoudjhane1, P Lebon2, F Isnard1, S Lesage1, NC Gorin1 and A Najman1 1

Service des Maladies du Sang, Centre Hospitalier et Universitaire Saint-Antoine, Paris; and 2Service de Bacte´riologie-Virologie, Hoˆpital Saint Vincent de Paul, Paris, France

Summary: Progressive multifocal leucoencephalopathy is an opportunistic JC virus-related pathology occurring in immunocompromised patients. We report a case of severe cellular immunodeficiency in a patient who underwent autologous bone marrow transplantation for acute myeloblastic leukemia, and who subsequently developed progressive multifocal leucoencephalopathy, an unusual pathology in this context. Progressive multifocal leucoencephalopathy was preceded by a peripheral demyelinating neuropathy. We discuss the possible link between these two neuropathies, the possible aggravation or activation from CMV infection, as well as the possible contribution of bone marrow purging in the resultant cellular immunodeficiency. Keywords: progressive multifocal leucoencephalopathy; acute leukaemia; peripheral neuropathy; autoBMT; immunodeficiency; immunotherapy

Progressive multifocal leucoencephalopathy (PML) is a JC papovavirus opportunist infection, which occurs in immunocompromised patients, and leads to oligodendrocyte demyelinization. PML incidence has increased sharply over the past decade in the same way as AIDS. In AIDS patients, evolution is generally fatal within a period of 4 months1,2 and is strongly related to the CD4⫹ lymphocyte count.3 It also occurs in patients treated with immunosuppressive agents such as cyclosporin, methotrexate or cyclophosphamide for systemic diseases, in chronic lymphocytic leukemia or in patients with Hodgkin’s disease.4–6 To date, a few cases have been reported in patients who have undergone bone marrow transplantation7,8 but only one case has been reported after autologous bone marrow transplantation.9 This rare occurrence in the setting of either allogenic or autologous bone marrow transplantation leads us to report a further case which is the first that we have Correspondence: Dr P Coppo, Service des Maladies du Sang, Centre Hospitalier et Universitaire Saint-Antoine, 75012 Paris, France Received 20 April 1998; accepted 10 August 1998

observed among more than 150 ABMT performed for AML in our institution. Case report A 38-year-old woman presented with PML after autologous bone marrow transplant (ABMT). In March 1994, she was referred to Saint-Antoine Hospital for acute leukemia. Her past medical history included chronic hepatitis C (blood transfusion-related), cone biopsy for in situ cervical cancer and two pregnancies by caesarean section. Bone marrow aspirate revealed 100% blasts classified as M5 in the FAB classification. The first course of induction chemotherapy in March 1994 comprised daunorubicin (45 mg/m2, day 2 to day 4), vincristine (2 mg, day 1), and mitoxantrone (12 mg/m2 days 2 to 6). She did not achieve complete remission (CR): 7% of suspect monocytoid cells were still present in the bone marrow aspirate. Subsequent therapy included: aracytine (1000 mg/m2/12 h days 1 to 4), amsacrine (120 mg/m2 days 1 to 3), and a consolidation course: aracytine (1000 mg/m2/12 h, days 1 to 4), idarubicin (10 mg/m2/12 h, days 1 to 3) and aracytine (100 mg/m2/ 12 h, days 1 to 7), VP16 (150 mg/m2/12 h, days 1 to 3). CR was finally reached in July 1994. The main complication was a CMV infection which occurred during the second induction course. CMV IgM serology and CMV viremia were positive. She was treated with DHPG and intravenous immunoglobulins and did well. Central nervous system (CNS) prophylaxis consisted of six weekly intrathecal injections of methotrexate (15 mg) and methylprednisolone (20 mg). She did not have an HLA-identical sibling donor and therefore underwent ABMT in October with bone marrow purged by mafosfamide8 (MNC = 0.5 ⫻ 108/kg). Conditioning was with cyclophosphamide (60 mg/kg days 1 to 2) plus total body irradiation (10 Gy). During the aplastic period, CMV infection recurred with CMV RNA and CMV DNA detected in blood by polymerase chain reaction (PCR) assay. CMV was also present in urine samples. Further DHPG was given. After ABMT she remained cytopenic, with a white blood cell count below 2.8 ⫻ 109/l, platelets of less than 10 ⫻ 109/l and a hemoglobin level below 9 g/dl. Seven months post-ABMT,

PML after ABMT for AML FAB5 P Coppo et al



bone marrow infusion start of IL-2 and interferon therapy start of AS101




CD4+ CD8+ NK



0 Dec 12 ⫹

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Figure 1 Evolution of CD4 , CD8 and NK cells after reinfusion of the CD34 negative fraction of the autologous bone marrow harvest and during immunomodulatory treatment.

she developed progressive bilateral symmetric parasthesia from toes to thighs and then in the extremities of the fingers. Diminished pinprick sensation in these regions also occurred. An electromyogram revealed diminished nerve conduction and neuromuscular biopsy revealed an evolving axonal demyelining neuropathy. Thirteen months postABMT, in December 1995, she developed CNS problems with normal oral comprehension but difficulties finding words, acalculia, right homonymous hemianopia and disorientation in time. There was no headache or fever. Right pyramidal track signs developed subsequently. Cerebral MRI showed low signal intensity in sequence T1 and high signal intensity T2 in the left occipital and temporal subcortical white matter with no mass effect or mass enhancing. Cerebrospinal fluid (CSF) cytology, sugar and protein were normal, as were alpha-interferon levels and CSF protein electrophoresis. The diagnosis of PML was confirmed by DNA JC virus detection in the CSF by PCR. Herpessimplex virus and varicella zoster virus infection by PCR were negative. HIV 1-2 and HTLV 1-2 serologies were negative; Epstein–Barr virus serology was positive for IgG. CMV serology was positive for IgM. Lymphocyte subpopulation counts revealed profound cellular immunodeficiency: CD4⫹, CD8⫹ and CD3⫹ lymphocyte counts were respectively 163/mm3, 433/m m3 (relative increase) and 949/mm3. The natural killer (NK) count was 183/mm3. The patient remained in CR. In order to enhance cellular immunity, she was treated for 4 weeks with interleukin210,11 (8 ␮g per dose three times weekly subcutaneously). She also received alpha-interferon12–15 (3 ␮g three times weekly) subcutaneously, AS10116 (4.5 mg three times weekly) subcutaneously and intrathecal injections of aracytine17,18 plus alpha-interferon (30 mg and 1 ␮g, respectively, four times weekly alternately for a total of 20 doses of each agent), and G-CSF. The CD34 negative fraction19 of the bone marrow back-up stored without manipulation after CR, comprising 0.2 ⫻ 108 cells/kg was reinfused in December 1995 in an attempt to increase the lymphocyte population. As shown in Figure 1, a slight increase in CD4 cells was observed just after the

bone marrow infusion and the beginning of immunostimulatory therapy with IL-2 and AS101. Likewise, the level of CD8 cells and NK cells measured by flow cytometry increased but results were not sustained, and declined during the last month in spite of continued treatment. Neurologic deterioration was continuous. In January 1996, the patient had almost complete aphasia, cortical blindness and could not respond to simple orders. MRI showed spread of lesions toward the corpus callosum and thalamus. In February 1996 her last MRI showed spread of lesions towards the cortex, thalamus and brainstem. She died in CR, 4 months following the diagnosis of PML, with profound neurological dysfunction. Discussion This case highlights the risks associated with acquired cellular immunodepression following intensive chemotherapy; PML is usually only observed in patients with profound immunodepression. We found no obvious reason for this profound immunocellular depression which led to development of viral infections including JC virus, CMV virus and hepatitis C reactivation. Chemotherapy was given at standard doses, as was conditioning for ABMT. There was no serological evidence for HIV infection and HIV serology was negative before chemotherapy, before ABMT and when PML was diagnosed. The impact of bone marrow purging by mafosfamide on hematologic recovery, and particularly on the occurrence of a cellular immunodepression,20 may be most relevant. Indeed, the long-term consequences of bone marrow purging are still uncertain. Nevertheless, in our experience21 and in the light of existing literature, PML remains exceptional in this context, and is probably linked to an individual susceptibility and/or to facilitating factors, such as CMV infection. CMV infection, which was detectable during the whole disease course from the time of induction therapy, may have

PML after ABMT for AML FAB5 P Coppo et al

had an enhancing effect on the appearance of PML and on the associated peripheral demyelinating neuropathy. Indeed, CMV infection preceding PML has been reported after allogenic bone marrow transplantation.8 Likewise, CMV enhances JC virus DNA replication in human fibroblast cultures although these cells are not conducive for JC virus.22 To our knowledge, no cases of PML with peripheral neuropathy have been reported. An attempt to detect JC virus on neuromuscular biopsy was negative (C Lacroix, Hoˆpital de Biceˆtre, Le Kremlin-Biceˆtre, France). The ability of JC virus to proliferate in nonsusceptible cells after CMV infection may explain the unusual sites of involvement by the former such as the peripheral nervous system.22 In our patient, JC virus was detected in the bone marrow aspirate. Other authors have reported the presence of JC virus in urine samples.23 These findings are still unusual and difficult to interpret but they could mean that JC virus can spread through many tissues in immunocompromised patients. None of the treatments we used attenuated PML evolution and the patient survived for 4 months following diagnosis, with a CD4⫹ lymphocyte level between 34 and 100/mm3 which agrees with the study of Fong et al.3 Interleukin-2 is widely known to be valuable in treating acquired immunodeficiency syndroms,10,11 and alpha-interferon is efficacious in treating PML, significantly increasing survival rates in many studies.12–15 The role of aracytine is more controversial.12,17,18 AS101 is a synthetic derivative of tellurium which has a marked stimulatory effect on several cytokines involved in immune responses.16 However, in spite of using all these agents and a transitory increase in CD4–CD8 and NK cells, evolution of the disease was not modified. Acknowledgements We thank Pr B Sredni and Pr M Albeck (Cair Institute, Bar-Ilan University, Israel) for providing AS101.

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6 Morgenstem LB, Pardo CA. Progressive multifocal leucoencephalopathy complicating treatment for Wegener’s granulotomasis. J Rheumatol 1995; 22: 1593–1595. 7 O’Shaughnessy D, Goldman JM, Roddie M et al. Dizziness and confusion after bone marrow transplantation. Br Med J 1994; 309: 262–265. 8 Owen RG, Pathmore RD, Smith GM et al. Cytomegalovirusinduced T-cell proliferation and the development of progressive multifocal leucoencephalopathy following bone marrow transplantation. Br J Haematol 1995; 89: 196–198. 9 Mesquita R, Parravicini C, Bjorkholm M et al. Macrophage association of polymavirus in progressive multifocal leukoencephalopathy: an immunohistochemical and ultrastructural study. Case report. APMIS 1992; 100: 993–1000. 10 Martin A, Giedlin MA, Zimmerman RJ. The use of recombinant human interleukin-2 in treating infectious diseases. Curr Opin Biotechnol 1993; 4: 722–726. 11 Janice P, Dutcher MD. Therapeutic strategies for cytokines. Curr Opin Oncol 1995; 7: 566–571. 12 Heide W, Kompf D, Reusche E et al. Failure of cytarabine/interferon therapy in progressive multifocal leucoencephalopathy. Ann Neurol 1995; 37: 412–413. 13 Berger JR, Pall L, Arthur J et al. A pilot study of recombinant alpha 2A interferon in the treatment of AIDS related progressive multifocal leucoencephalopathy. Neurology 1992; 42 (Suppl. 3): 257. 14 Brigden D, Freestone DS. Interferon in acute leukemia and chronic viral infections. In: Behan P (ed). Immunology of Nervous Infections. Progress in Brain Research. Elsevier: 1983, pp 97–103. 15 Colosimo C, Lebon P, Martelli M et al. Alpha-interferon therapy in a case of probable progressive multifocal leucoencephalopathy. Acta Neurol Belg 1992; 92: 24–29. 16 Sredni B, Tichler T, Shani A et al. Predominance of TH1 response in tumor-bearing mice and cancer patients treated with AS101. J Natl Cancer Inst 1996; 88: 1276–1284. 17 Guarino M, D’Alessandro R, Rinaldi R et al. Progressive multifocal leucoencephalopathy in AIDS: treatment with cytosine-arabinoside. AIDS 1995; 9: 819–820. 18 Nicoli F, Chave B, Peragut JC, Gastaut JL. Efficacity of cytarabine in progressive multifocal leucoencephalopathy in AIDS. Lancet 1992; 339: 306. 19 Bensiger WI, Buckner CD, Shannon-Dorcy K et al. Transplantation of allogeneic CD34⫹ peripheral blood stem cells in patients with advanced hematologic malignancy. Blood 1996; 88: 4132–4138. 20 Skorski T, Kawalec M, Hoser G et al. The kinetics of immunologic and hematologic recovery in mice after lethal total body irradiation and reconstitution with syngenic bone marrow cells treated or untreated with mafosfamide (ASTAZ). Bone Marrow Transplant 1988; 3: 543–551. 21 Laporte JP, Douay L, Lopez M et al. 125 adult patients with primary acute leukemia autografted with marrow purged by mafosfamide: a 10 year single institution experience. Blood 1994; 84: 3810–3818. 22 Heilbronn R, Albrecht R, Stephan I et al. Human cytomegalovirus induces JC virus DNA replication in human fibroblasts. Proc Natl Acad Sci USA 1993; 90: 11406–11410. 23 Myers C, Frisque RJ, Arthur RR. Direct isolation and characterisation of JC virus from urine samples of renal and bone marrow transplant patients. J Virol 1989; 63: 4445–4449.


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