- Email: [email protected]
Progressive Multifocal Leukoencephalopathy After Therapy for Chronic Lymphocytic Leukemia
Case Report Progressive Multifocal Leukoencephalopathy After Therapy for Chronic Lymphocytic Leukemia Jacob Laubach Abstract Progressive multifocal leukoencephalopathy (PML) is a lethal degenerative disorder of the central nervous system caused by reactivation of latent polyomavirus JC in the immunosuppressed host. Although the condition is most prevalent among individuals with HIV, it also occurs in association with other diseases and therapies that compromise immune function, including lymphoproliferative disorders (LPDs) treated with chemotherapy. Herein, the clinical course of an individual with chronic lymphocytic leukemia who developed PML after treatment with fludarabine, cyclophosphamide, and rituximab is described. The report highlights diagnostic challenges posed by nonspecific neurologic symptoms and radiographic findings that can be associated with PML. The ensuing discussion describes important discoveries that have contributed to the understanding of PML, clinical and diagnostic characteristics of the disease, specific features of LPD-associated PML, and treatment strategies for this condition. Clinical Leukemia, Vol. 3, No. 2, E24-E26, 2009; DOI: 10.3816/CLK.2009.n.011 Keywords: Cyclophosphamide, Cytarabine, Fludarabine, JC virus, Rituximab
Case Report A 77-year-old man with a history of hypertension, atrial fibrillation, and chronic lymphocytic leukemia (CLL) presented with left-sided facial droop, left upper extremity weakness, and gait disturbance. After the diagnosis of CLL over 10 years earlier, the patient experienced no symptoms attributable to CLL until 2006, when he developed fatigue associated with progressive leukocytosis (white blood cell [WBC] count, approximately 40,000/μL), anemia (hemoglobin, 10 g/dL), and thrombocytopenia (platelet count, approximately 50,000/μL). He was treated by his primary oncologist at that time with 1 cycle of fludarabine, cyclophosphamide, and rituximab. He received 3 additional doses of rituximab monotherapy at 3-week intervals. The patient’s hemoglobin and WBC count normalized after therapy, and his platelet count doubled. Six months after receiving therapy, the patient developed a left-sided facial droop. Weakness of the left upper extremity and gait disturbance developed over the ensuing weeks. An electromyogram was suggestive of ulnar entrapment, and an initial magnetic resonance imaging (MRI) scan of the brain revealed apparent chronic infarct involving the posterior right middle cerebral artery territory and deep white matter tracts of the right cerebral peduncle. The patient subsequently became dysarthric, with a left homonymous hemianopsia and left-sided facial droop in a lower motor neuron pattern. Arm flexion, shoulder shrug, and hand-grip strength were diminished on the left. The patient was unable to extend his left wrist and fingers. A bilateral lower extremity sensory deficit was present in a stocking-glove distribution. The left patellar deep tendon reflex was hyperreflexic. A nerve conduction study demonstrated widespread moderate length-dependent sensorimotor neuropathy with superimposed left axonal neuropathy involving the median nerve. MRA of the brain and neck revealed no vascular abnormalities. Repeat MRI of the brain demonstrated extensive, confluent T2 signal abnormality in the posterior right frontal lobe and right parietal lobe (Figure 1). The patient’s hemoglobin was 14 g/dL, the platelet count was 80,000/μL, and the WBC count was 10,000/μL, with a Medical Oncology, Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, MA Submitted: Jul 16, 2008; Revised: Oct 13, 2008; Accepted: Dec 11, 2008 Address for correspondence: Jacob Laubach, MD, Medical Oncology, Hematologic Malignancies, Dana-Farber Cancer Institute, 44 Binney St, Suite D1B30, Boston, MA 02115 Fax: 617-632-6624; e-mail: [email protected] This article might include the discussion of investigational and/or unlabeled uses of drugs and/or devices that might not be approved by the FDA. Electronic forwarding or copying is a violation of US and international copyright laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1931-6925, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA. www.copyright.com 978-750-8400.
E24
Clinical Leukemia • August 2009
Figure 1 A
Brain MRI With Horizontal and Coronal Images B
C
D
Horizontal (A, B) and coronal (C, D) MRI scans of the brain demonstrating confluent T2 signal abnormality in posterior right frontal and right parietal lobes. Abbreviation: MRI = magnetic resonance imaging
differential of 44% segmented neutrophils, 10% bands, 16% lymphocytes, and 17% variable lymphocytes. His electrolytes and renal function were normal. Vitamin B12 was 495 pg/mL (normall), folate was 10.5 ng/mL (normal), and thyroid-stimulating hormone was 1.75 mIU/mL (normal). A serum protein electrophoresis showed decreased B globulins with no paraprotein. The sedimentation rate was 12 mm/h. HIV antibody was negative. Cerebrospinal fluid (CSF) findings included protein, 67 mg/dL (elevated); glucose, 55 mg/dL (normall); and 3 nucleated cells/mL. No monoclonal B-cell population was present in the CSF. Cerebrospinal fluid cytomegalovirus and Epstein-Barr virus (EBV) by polymerase chain reaction (PCR) were negative. Polymerase chain reaction JC virus DNA was detected in the CSF. These findings support a diagnosis of progressive multifocal leukoencephalopathy (PML) in an individual treated for a lymphoproliferative disorder. The patient was treated with intravenous cytarabine 2 mg/kg for 5 days. Progressive neurologic decline continued despite this therapeutic intervention, and the patient died from the disease approximately 1 year after initially receiving treatment for CLL.
Discussion The association between JC virus infection and PML was first established in 1971 by Padgett and colleagues, who cultured the virus from postmortem brain tissue of an individual with PML.1 Epidemiologic analysis subsequently demonstrated that exposure to JC virus and seroconversion are widespread, as 65% of adolescents and up to 80% of adults have antibodies against the virus.2 Although early studies suggested that persistent infection occurs primarily in the immunocompromised host,3 subsequent investigation demonstrated that JC virus DNA can be found in both the kidney4 and B-lymphocytes5 of immunocompetent individuals. That PML occurs as a result of JC virus reactivation rather than primary infection was suggested by the work of Arthur and colleagues, who observed JC viruria only in bone marrow transplant recipients who were seropositive before transplantation.6 Based on these findings, it is currently held that immune deficiency related to HIV
infection, immunosuppressive therapies, autoimmune disorders, or other conditions that compromise immune function can lead to JC virus reactivation, systemic infection, and the clinical findings observed in patients with PML. Although reactivated JC virus can infect multiple organs,7 the clinical hallmarks of PML are neurologic symptoms such as visual deficits, dysarthria, loss of motor and sensory function, ataxia, and altered mental status.8 These manifestations of the disease highlight the neurotropic nature of the JC virus, which infects and destroys myelinproducing oligodendrocytes. As illustrated by this case, brain lesions in PML typically appear on MRI as areas of increased T2 signal that may be patchy or confluent.9 As such, they are difficult to distinguish from other causes of central nervous system damage, such as ischemic injury, that produce similar radiographic findings. Cerebrospinal fluid PCR for JC viral DNA is sensitive (72%-92%) and specific (92%-100%) for the diagnosis of PML and, when positive, obviates the need for brain biopsy.10 However, results of CSF PCR for the JC virus must be interpreted with caution in HIV-positive individuals, who could harbor subclinical JC virus within the CSF.11 Although PML most often occurs in the setting of HIV infection, approximately 15% of cases occur in individuals with lymphoproliferative disorders (LPDs) such as CLL, chronic myelogenous leukemia, and Hodgkin disease.8 Interestingly, the incidence rate of LPD-associated PML appears to have increased substantially over the past decade.12 Moreover, the distribution of LPD-associated PML has also changed. Prior to 1989, most reports of LPD-associated PML occurred in patients with Hodgkin disease (63%) treated with alkylating agents and/or radiation therapy.12 Since 1989, however, the condition has occurred in association with CLL (46%) more than with Hodgkin disease (25%). These trends in both the incidence and distribution of the disease have been attributed to use in the current era of purine analogues and rituximab for the treatment of CLL and other LPDs. The immunosuppressive effects of fludarabine are well-characterized; the drug causes T-lymphocyte suppression that persists for up to 13 months and thus predisposes individuals treated with fludarabine-based regimens to various opportunistic infections such as Listeria, Pneumocystis carinii, and
Clinical Leukemia • August 2009
E25
PML After Therapy for CLL mycobacteria.13 Rituximab, meanwhile, is a chimeric monoclonal antibody with specificity for the CD20 antigen found on the surface of B-lymphocytes. Because of its effect on B-lymphocytes, rituximab is also immunosuppressive, and its use has been associated with reactivation of hepatitis B, hepatitis C, parvovirus B19, and EBV.14-17 Case reports of PML in patients treated with rituximab-containing regimens first emerged in 2002.18,19 Progressive multifocal leukoencephalopathy generally responds poorly to therapy. The individual with HIV-associated PML should be initiated on highly active antiretroviral therapy (HAART) if naive to antiretroviral therapy and continued on HAART if already receiving it, as this intervention has resulted in significant improvement in 1-year survival.20 The antiviral agent cidofovir has also been used in the treatment of patients with HIV-associated PML, though the results have been largely disappointing and do not support use of the agent in this setting.21 In addition to antiviral therapy, other approaches have been attempted in the management of HIV-associated PML. A clinical response was observed in 3 of 11 patients with HIV-associated PML who received topotecan, for example, though significant bone marrow suppression occurred as a result of therapy.22 Among individuals with LPD-associated PML, the mortality rate exceeds 90%.12 In this patient population, intravenous cytarabine might be of benefit. In an open-label trial involving 19 patients with non–HIV-associated PML, intravenous cytarabine administered at 2 mg/kg daily for 5 days led to a neurologic response in 7 patients.23 Myelosuppression was the primary toxicity associated with this therapy.
2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14.
15. 16.
Conclusion The widespread use of both purine analogues and rituximab in the treatment of patients with non-Hodgkin lymphoma necessitates vigilant monitoring for PML and other opportunistic infections that can occur in this setting. In particular, neurologic symptoms in a patient so treated should prompt appropriate diagnostic testing, including CSF analysis and even brain biopsy if necessary, as radiographic findings are nonspecific and can be misleading.
Disclosures
18. 19.
20.
21.
The author reports no relevant financial conflicts of interest.
References
22. 23.
1. Padgett BL, Walker DL, ZuRhein GM, et al. Cultivation of papova-like virus from
E26
17.
human brain with progressive multifocal leucoencephalopathy. Lancet 1971; 1:125760. Padgett BL, Walker DL. Prevalence of antibodies in human sera against JC virus, an isolate from a case of progressive multifocal leukoencephalopathy. J Infect Dis 1973; 127:467-70. Coleman DV, Wolfendale MR, Daniel RA, et al. A prospective study of human polyomavirus infection in pregnancy. J Infect Dis 1980; 142:1-8. Tominaga T, Yogo Y, Kitamura T, et al. Persistence of archetypal JC virus DNA in normal renal tissue derived from tumor-bearing patients. Virology 1992; 186:73641. Dorries K, Vogel E, Gunther S, et al. Infection of human polyomaviruses JC and BK in peripheral blood leukocytes from immunocompetent individuals. Virology 1994; 198:59-70. Arthur RR, Shah KV, Charache P, et al. BK and JC virus infections in recipients of bone marrow transplants. J Infect Dis 1988; 158:563-9. Grinnell BW, Padgett BL, Walker DL. Distribution of nonintegrated DNA from JC papovavirus in organs of patients with progressive multifocal leukoencephalopathy. J Infect Dis 1983; 147:669-75. Gallia GL, Houff SA, Major EO, et al. Review: JC virus infection of lymphocytes– revisited. J Infect Dis 1997; 176:1603-9. Whiteman ML, Post MJ, Berger JR, et al. Progressive multifocal leukoencephalopathy in 47 HIV-seropositive patients: neuroimaging with clinical and pathologic correlation. Radiology 1993; 187:233-40. Cinque P, Scarpellini P, Vago L, et al. Diagnosis of central nervous system complications in HIV-infected patients: cerebrospinal fluid analysis by the polymerase chain reaction. AIDS 1997; 11:1-17. Dorries K, Arendt G, Eggers C, et al. Nucleic acid detection as a diagnostic tool in polyomavirus JC induced progressive multifocal leukoencephalopathy. J Med Virol 1998; 54:196-203. Garcia-Suarez J, de Miguel D, Krsnik I, et al. Changes in the natural history of progressive multifocal leukoencephalopathy in HIV-negative lymphoproliferative disorders: impact of novel therapies. Am J Hematol 2005; 80:271-81. Saumoy M, Castells G, Escoda L, et al. Progressive multifocal leukoencephalopathy in chronic lymphocytic leukemia after treatment with fludarabine. Leuk Lymphoma 2002; 43:433-6. Law JK, Ho JK, Hoskins PJ, et al. Fatal reactivation of hepatitis B post-chemotherapy for lymphoma in a hepatitis B surface antigen-negative, hepatitis B core antibodypositive patient: potential implications for future prophylaxis recommendations. Leuk Lymphoma 2005; 46:1085-9. Hsieh CY, Huang HH, Lin CY, et al. Rituximab-induced hepatitis C virus reactivation after spontaneous remission in diffuse large B-cell lymphoma. J Clin Oncol 2008; 26:2584-6. Tinchon C, Auner HW, Beham-Schmid C, et al. Symptomatic Epstein-Barr virus reactivation in a patient with acute myeloid leukaemia and treatment with the monoclonal anti-CD20 antibody rituximab. Eur J Haematol 2002; 69:50-3. Klepfish A, Rachmilevitch E, Schattner A. Parvovirus B19 reactivation presenting as neutropenia after rituximab treatment. Eur J Intern Med 2006; 17:505-7. Matteucci P, Magni M, Di Nicola M, et al. Leukoencephalopathy and papovavirus infection after treatment with chemotherapy and anti-CD20 monoclonal antibody. Blood 2002; 100:1104-5. Goldberg SL, Pecora AL, Alter RS, et al. Unusual viral infections (progressive multifocal leukoencephalopathy and cytomegalovirus disease) after high-dose chemotherapy with autologous blood stem cell rescue and peritransplantation rituximab. Blood 2002; 99:1486-8. Antinori A, Cingolani A, Lorenzini P, et al. Clinical epidemiology and survival of progressive multifocal leukoencephalopathy in the era of highly active antiretroviral therapy: data from the Italian Registry Investigative Neuro AIDS (IRINA). J Neurovirol 2003; 9(suppl 1):47-53. Marra CM, Rajicic N, Barker DE, et al. A pilot study of cidofovir for progressive multifocal leukoencephalopathy in AIDS. AIDS 2002; 16:1791-7. Royal W III, Dupont B, McGuire D, et al. Topotecan in the treatment of acquired immunodeficiency syndrome-related progressive multifocal leukoencephalopathy. J Neurovirol 2003; 9:411-9. Aksamit AJ. Treatment of non-AIDS progressive multifocal leukoencephalopathy with cytosine arabinoside. J Neurovirol 2001; 7:386-90.
Clinical Leukemia • August 2009
Case Report A 77-year-old man with a history of hypertension, atrial fibrillation, and chronic lymphocytic leukemia (CLL) presented with left-sided facial droop, left upper extremity weakness, and gait disturbance. After the diagnosis of CLL over 10 years earlier, the patient experienced no symptoms attributable to CLL until 2006, when he developed fatigue associated with progressive leukocytosis (white blood cell [WBC] count, approximately 40,000/μL), anemia (hemoglobin, 10 g/dL), and thrombocytopenia (platelet count, approximately 50,000/μL). He was treated by his primary oncologist at that time with 1 cycle of fludarabine, cyclophosphamide, and rituximab. He received 3 additional doses of rituximab monotherapy at 3-week intervals. The patient’s hemoglobin and WBC count normalized after therapy, and his platelet count doubled. Six months after receiving therapy, the patient developed a left-sided facial droop. Weakness of the left upper extremity and gait disturbance developed over the ensuing weeks. An electromyogram was suggestive of ulnar entrapment, and an initial magnetic resonance imaging (MRI) scan of the brain revealed apparent chronic infarct involving the posterior right middle cerebral artery territory and deep white matter tracts of the right cerebral peduncle. The patient subsequently became dysarthric, with a left homonymous hemianopsia and left-sided facial droop in a lower motor neuron pattern. Arm flexion, shoulder shrug, and hand-grip strength were diminished on the left. The patient was unable to extend his left wrist and fingers. A bilateral lower extremity sensory deficit was present in a stocking-glove distribution. The left patellar deep tendon reflex was hyperreflexic. A nerve conduction study demonstrated widespread moderate length-dependent sensorimotor neuropathy with superimposed left axonal neuropathy involving the median nerve. MRA of the brain and neck revealed no vascular abnormalities. Repeat MRI of the brain demonstrated extensive, confluent T2 signal abnormality in the posterior right frontal lobe and right parietal lobe (Figure 1). The patient’s hemoglobin was 14 g/dL, the platelet count was 80,000/μL, and the WBC count was 10,000/μL, with a Medical Oncology, Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, MA Submitted: Jul 16, 2008; Revised: Oct 13, 2008; Accepted: Dec 11, 2008 Address for correspondence: Jacob Laubach, MD, Medical Oncology, Hematologic Malignancies, Dana-Farber Cancer Institute, 44 Binney St, Suite D1B30, Boston, MA 02115 Fax: 617-632-6624; e-mail: [email protected] This article might include the discussion of investigational and/or unlabeled uses of drugs and/or devices that might not be approved by the FDA. Electronic forwarding or copying is a violation of US and international copyright laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1931-6925, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA. www.copyright.com 978-750-8400.
E24
Clinical Leukemia • August 2009
Figure 1 A
Brain MRI With Horizontal and Coronal Images B
C
D
Horizontal (A, B) and coronal (C, D) MRI scans of the brain demonstrating confluent T2 signal abnormality in posterior right frontal and right parietal lobes. Abbreviation: MRI = magnetic resonance imaging
differential of 44% segmented neutrophils, 10% bands, 16% lymphocytes, and 17% variable lymphocytes. His electrolytes and renal function were normal. Vitamin B12 was 495 pg/mL (normall), folate was 10.5 ng/mL (normal), and thyroid-stimulating hormone was 1.75 mIU/mL (normal). A serum protein electrophoresis showed decreased B globulins with no paraprotein. The sedimentation rate was 12 mm/h. HIV antibody was negative. Cerebrospinal fluid (CSF) findings included protein, 67 mg/dL (elevated); glucose, 55 mg/dL (normall); and 3 nucleated cells/mL. No monoclonal B-cell population was present in the CSF. Cerebrospinal fluid cytomegalovirus and Epstein-Barr virus (EBV) by polymerase chain reaction (PCR) were negative. Polymerase chain reaction JC virus DNA was detected in the CSF. These findings support a diagnosis of progressive multifocal leukoencephalopathy (PML) in an individual treated for a lymphoproliferative disorder. The patient was treated with intravenous cytarabine 2 mg/kg for 5 days. Progressive neurologic decline continued despite this therapeutic intervention, and the patient died from the disease approximately 1 year after initially receiving treatment for CLL.
Discussion The association between JC virus infection and PML was first established in 1971 by Padgett and colleagues, who cultured the virus from postmortem brain tissue of an individual with PML.1 Epidemiologic analysis subsequently demonstrated that exposure to JC virus and seroconversion are widespread, as 65% of adolescents and up to 80% of adults have antibodies against the virus.2 Although early studies suggested that persistent infection occurs primarily in the immunocompromised host,3 subsequent investigation demonstrated that JC virus DNA can be found in both the kidney4 and B-lymphocytes5 of immunocompetent individuals. That PML occurs as a result of JC virus reactivation rather than primary infection was suggested by the work of Arthur and colleagues, who observed JC viruria only in bone marrow transplant recipients who were seropositive before transplantation.6 Based on these findings, it is currently held that immune deficiency related to HIV
infection, immunosuppressive therapies, autoimmune disorders, or other conditions that compromise immune function can lead to JC virus reactivation, systemic infection, and the clinical findings observed in patients with PML. Although reactivated JC virus can infect multiple organs,7 the clinical hallmarks of PML are neurologic symptoms such as visual deficits, dysarthria, loss of motor and sensory function, ataxia, and altered mental status.8 These manifestations of the disease highlight the neurotropic nature of the JC virus, which infects and destroys myelinproducing oligodendrocytes. As illustrated by this case, brain lesions in PML typically appear on MRI as areas of increased T2 signal that may be patchy or confluent.9 As such, they are difficult to distinguish from other causes of central nervous system damage, such as ischemic injury, that produce similar radiographic findings. Cerebrospinal fluid PCR for JC viral DNA is sensitive (72%-92%) and specific (92%-100%) for the diagnosis of PML and, when positive, obviates the need for brain biopsy.10 However, results of CSF PCR for the JC virus must be interpreted with caution in HIV-positive individuals, who could harbor subclinical JC virus within the CSF.11 Although PML most often occurs in the setting of HIV infection, approximately 15% of cases occur in individuals with lymphoproliferative disorders (LPDs) such as CLL, chronic myelogenous leukemia, and Hodgkin disease.8 Interestingly, the incidence rate of LPD-associated PML appears to have increased substantially over the past decade.12 Moreover, the distribution of LPD-associated PML has also changed. Prior to 1989, most reports of LPD-associated PML occurred in patients with Hodgkin disease (63%) treated with alkylating agents and/or radiation therapy.12 Since 1989, however, the condition has occurred in association with CLL (46%) more than with Hodgkin disease (25%). These trends in both the incidence and distribution of the disease have been attributed to use in the current era of purine analogues and rituximab for the treatment of CLL and other LPDs. The immunosuppressive effects of fludarabine are well-characterized; the drug causes T-lymphocyte suppression that persists for up to 13 months and thus predisposes individuals treated with fludarabine-based regimens to various opportunistic infections such as Listeria, Pneumocystis carinii, and
Clinical Leukemia • August 2009
E25
PML After Therapy for CLL mycobacteria.13 Rituximab, meanwhile, is a chimeric monoclonal antibody with specificity for the CD20 antigen found on the surface of B-lymphocytes. Because of its effect on B-lymphocytes, rituximab is also immunosuppressive, and its use has been associated with reactivation of hepatitis B, hepatitis C, parvovirus B19, and EBV.14-17 Case reports of PML in patients treated with rituximab-containing regimens first emerged in 2002.18,19 Progressive multifocal leukoencephalopathy generally responds poorly to therapy. The individual with HIV-associated PML should be initiated on highly active antiretroviral therapy (HAART) if naive to antiretroviral therapy and continued on HAART if already receiving it, as this intervention has resulted in significant improvement in 1-year survival.20 The antiviral agent cidofovir has also been used in the treatment of patients with HIV-associated PML, though the results have been largely disappointing and do not support use of the agent in this setting.21 In addition to antiviral therapy, other approaches have been attempted in the management of HIV-associated PML. A clinical response was observed in 3 of 11 patients with HIV-associated PML who received topotecan, for example, though significant bone marrow suppression occurred as a result of therapy.22 Among individuals with LPD-associated PML, the mortality rate exceeds 90%.12 In this patient population, intravenous cytarabine might be of benefit. In an open-label trial involving 19 patients with non–HIV-associated PML, intravenous cytarabine administered at 2 mg/kg daily for 5 days led to a neurologic response in 7 patients.23 Myelosuppression was the primary toxicity associated with this therapy.
2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14.
15. 16.
Conclusion The widespread use of both purine analogues and rituximab in the treatment of patients with non-Hodgkin lymphoma necessitates vigilant monitoring for PML and other opportunistic infections that can occur in this setting. In particular, neurologic symptoms in a patient so treated should prompt appropriate diagnostic testing, including CSF analysis and even brain biopsy if necessary, as radiographic findings are nonspecific and can be misleading.
Disclosures
18. 19.
20.
21.
The author reports no relevant financial conflicts of interest.
References
22. 23.
1. Padgett BL, Walker DL, ZuRhein GM, et al. Cultivation of papova-like virus from
E26
17.
human brain with progressive multifocal leucoencephalopathy. Lancet 1971; 1:125760. Padgett BL, Walker DL. Prevalence of antibodies in human sera against JC virus, an isolate from a case of progressive multifocal leukoencephalopathy. J Infect Dis 1973; 127:467-70. Coleman DV, Wolfendale MR, Daniel RA, et al. A prospective study of human polyomavirus infection in pregnancy. J Infect Dis 1980; 142:1-8. Tominaga T, Yogo Y, Kitamura T, et al. Persistence of archetypal JC virus DNA in normal renal tissue derived from tumor-bearing patients. Virology 1992; 186:73641. Dorries K, Vogel E, Gunther S, et al. Infection of human polyomaviruses JC and BK in peripheral blood leukocytes from immunocompetent individuals. Virology 1994; 198:59-70. Arthur RR, Shah KV, Charache P, et al. BK and JC virus infections in recipients of bone marrow transplants. J Infect Dis 1988; 158:563-9. Grinnell BW, Padgett BL, Walker DL. Distribution of nonintegrated DNA from JC papovavirus in organs of patients with progressive multifocal leukoencephalopathy. J Infect Dis 1983; 147:669-75. Gallia GL, Houff SA, Major EO, et al. Review: JC virus infection of lymphocytes– revisited. J Infect Dis 1997; 176:1603-9. Whiteman ML, Post MJ, Berger JR, et al. Progressive multifocal leukoencephalopathy in 47 HIV-seropositive patients: neuroimaging with clinical and pathologic correlation. Radiology 1993; 187:233-40. Cinque P, Scarpellini P, Vago L, et al. Diagnosis of central nervous system complications in HIV-infected patients: cerebrospinal fluid analysis by the polymerase chain reaction. AIDS 1997; 11:1-17. Dorries K, Arendt G, Eggers C, et al. Nucleic acid detection as a diagnostic tool in polyomavirus JC induced progressive multifocal leukoencephalopathy. J Med Virol 1998; 54:196-203. Garcia-Suarez J, de Miguel D, Krsnik I, et al. Changes in the natural history of progressive multifocal leukoencephalopathy in HIV-negative lymphoproliferative disorders: impact of novel therapies. Am J Hematol 2005; 80:271-81. Saumoy M, Castells G, Escoda L, et al. Progressive multifocal leukoencephalopathy in chronic lymphocytic leukemia after treatment with fludarabine. Leuk Lymphoma 2002; 43:433-6. Law JK, Ho JK, Hoskins PJ, et al. Fatal reactivation of hepatitis B post-chemotherapy for lymphoma in a hepatitis B surface antigen-negative, hepatitis B core antibodypositive patient: potential implications for future prophylaxis recommendations. Leuk Lymphoma 2005; 46:1085-9. Hsieh CY, Huang HH, Lin CY, et al. Rituximab-induced hepatitis C virus reactivation after spontaneous remission in diffuse large B-cell lymphoma. J Clin Oncol 2008; 26:2584-6. Tinchon C, Auner HW, Beham-Schmid C, et al. Symptomatic Epstein-Barr virus reactivation in a patient with acute myeloid leukaemia and treatment with the monoclonal anti-CD20 antibody rituximab. Eur J Haematol 2002; 69:50-3. Klepfish A, Rachmilevitch E, Schattner A. Parvovirus B19 reactivation presenting as neutropenia after rituximab treatment. Eur J Intern Med 2006; 17:505-7. Matteucci P, Magni M, Di Nicola M, et al. Leukoencephalopathy and papovavirus infection after treatment with chemotherapy and anti-CD20 monoclonal antibody. Blood 2002; 100:1104-5. Goldberg SL, Pecora AL, Alter RS, et al. Unusual viral infections (progressive multifocal leukoencephalopathy and cytomegalovirus disease) after high-dose chemotherapy with autologous blood stem cell rescue and peritransplantation rituximab. Blood 2002; 99:1486-8. Antinori A, Cingolani A, Lorenzini P, et al. Clinical epidemiology and survival of progressive multifocal leukoencephalopathy in the era of highly active antiretroviral therapy: data from the Italian Registry Investigative Neuro AIDS (IRINA). J Neurovirol 2003; 9(suppl 1):47-53. Marra CM, Rajicic N, Barker DE, et al. A pilot study of cidofovir for progressive multifocal leukoencephalopathy in AIDS. AIDS 2002; 16:1791-7. Royal W III, Dupont B, McGuire D, et al. Topotecan in the treatment of acquired immunodeficiency syndrome-related progressive multifocal leukoencephalopathy. J Neurovirol 2003; 9:411-9. Aksamit AJ. Treatment of non-AIDS progressive multifocal leukoencephalopathy with cytosine arabinoside. J Neurovirol 2001; 7:386-90.
Clinical Leukemia • August 2009