Case Report Received: March 20, 2014 Accepted after revision: September 3, 2014 Published online: November 6, 2014
Chemotherapy 2014;60:47–53 DOI: 10.1159/000368072
Progressive Multifocal Leukoencephalopathy in Patients with a Hematological Malignancy: Review of Therapeutic Options Alexander Kalisch a Martin Wilhelm a Frank Erbguth b Josef Birkmann a
Departments/Institutes of a Oncology and b Neurology, Paracelsus Medical University, Nuremberg, Germany
Key Words Progressive multifocal leukoencephalopathy · JC virus · Serotonin receptor antagonists
Abstract In the context of 2 patients with hematological malignancy who developed progressive multifocal leukoencephalopathy (PML), we review the current therapeutic options for this serious complication. Both patients had lymphoma and had been pretreated with the antibody rituximab. Diagnosis of PML was obtained upon the detection of the JC virus. The outcome was fatal in both cases. So far, no standard therapeutic approach for JC virus infection has been established in HIV-negative patients with hematological malignancies and the outcome is usually fatal. Serotonin receptor antagonists might have a beneficial effect by blocking the virus from entering the cells. Although hopes for the efficacy of mefloquine were disappointed by the results of 1 study, several case reports describe improvements in neurological impairment when this drug is administered. Taking the desperate situation of this patient group into consideration, the combination of mirtazapine and mefloquine might be worthy of an attempt. © 2014 S. Karger AG, Basel
© 2014 S. Karger AG, Basel 0009–3157/14/0601–0047$39.50/0 E-Mail [email protected] www.karger.com/che
Case Report 1
We describe a 61-year-old female patient admitted to our hospital in November 2009; she was experiencing a tendency to fall towards the right side and difficulty with writing (right-hander). These symptoms had worsened continually over 5 weeks. Upon admission, the patient presented with orientation of all her faculties and in good general health. The neurological examination showed no impairment in the cranial nerves or of the sensormotor functions. No signs of headache or meningism were apparent. Upon examination of her coordination, a positive Romberg’s sign with a tendency to fall towards the right side was noticed. The finger-nose-test of the right side was uncertain and slowed. All other physical examinations showed no distinct abnormalities. Laboratory findings upon admission were normal, except for a slight monocytosis of 17% (1–9%) and hypogammaglobulinemia, i.e. IgA 22 mg/dl (70–400 mg/dl), IgG 474 mg/dl (700–1,600 mg/dl) and IgM 52 mg/dl (40–230 mg/dl). In immunofixation tests, polyclonal precipitation lines with a condensation line of IgM and lambda were visible. The CD4 cell count in the blood was markedly reduced to 150 cells/μl; this was confirmed several times on flow-cytometry. The CD8 cell count was 490 cells/μl with Alexander Kalisch, MD Department/Institute of Oncology Paracelsus Medical University, Prof. Ernst Nathan Strasse 1 DE–90419 Nuremberg (Germany) E-Mail alexander.kalisch @ klinikum-nuernberg.de
Downloaded by: St. Andrews University 138.251.14.35 - 11/26/2014 8:57:11 AM
a
b
c
Fig. 1. a Coronal T2-FLAIR shows high parietal subcortical signal intensity only in the white matter, omitting the gyri. b Coronal T1 with gadolinium shows no enhancement. c Axial T2 shows subcortical intensity without mass effect.
Medical History In 1985, this patient had been diagnosed with breast cancer followed by breast-conserving surgery, and had been in complete remission since. In 2001, an initial diagnosis of follicular lymphoma grade II, stage I was established. Up till 2003, a watch-and-wait strategy was conducted. In 2003, progressive disease was evident. Five courses of R-CHOP induced a complete remission. A weekly maintenance therapy with α-interferon was given thereafter. In 2005, after 2 years in remission, a relapse was recorded. After 6 courses of rituximab, fludarabine, mitoxantrone and cyclophosphamide, a complete remission was again achieved. This was followed by rituximab maintenance therapy. Antibody therapy was stopped due to suspicion of allergic alveolitis. In 2009, a relapse was again evident. After 6 courses of monotherapy with bendamustine, a complete remission was once more achieved. Neither a transformation to highgrade malignant lymphoma nor a relapse of the breast cancer was observed during the whole period. Twenty-nine months after the last administration of rituximab, the first neurological symptoms were noted. In total, 15 standard doses of rituximab (375 mg/m2) had been administered. Cranial MRI at admission to the hospital showed a lefthemispheric, leukoencephalopathic alteration of the brain, with hyperintense signal changes on diffusionweighted imaging but no uptake of contrast material or edema and no characteristic mass. The cerebrospinal fluid (CSF) showed no abnormalities (fig. 1) that would sug48
Chemotherapy 2014;60:47–53 DOI: 10.1159/000368072
gest lymphoma or infection; only an oligoclonal IgMband was detected that corresponded to the finding in the blood serum, but no onconeural antibodies were found. The CSF was analyzed for JC virus, cytomegalovirus, herpes simplex virus 1/2 and human herpes virus-6 on PCR with none of the suspected pathogens being detected. Due to clinical and radiological signs of PML, we started therapy with the serotonin receptor antagonist mirtazapine, even though PCR tests for the JC virus were still negative. Starting at 15 mg/day, we were able to slowly increase the dose up to 45 mg/day without any problems. In the meantime, neurological symptoms were progressive with increasing pareses of the entire right half of the body and loss of truncal control. Leukoecephalitic changes of the left hemisphere and new lesions within the right hemisphere were seen on MRI. We decided to perform a cerebral biopsy, and were able to amplify the JC virus on PCR. After the definite establishment of the diagnosis, we started additional therapy with the orally administered antimalarial agent mefloquine, beginning with a loading dose of 250 mg for the first 3 days. We planned to administer a weekly dose of 250 mg. Due to the rapid progression of the neurological symptoms, only 1 further dose of mefloquine after the initial loading dose could be given. The patient died from central regulatory failure only 2 months after the onset of symptoms.
Case Report 2
We describe a 75-year-old female patient, who was admitted to the neurological unit of our hospital in May 2011 due to the sudden onset of severe occipital headache. Kalisch/Wilhelm/Erbguth/Birkmann
Downloaded by: St. Andrews University 138.251.14.35 - 11/26/2014 8:57:11 AM
a CD4/CD8 ratio of 0.31. The B lymphocyte count in the peripheral blood was 15% (i.e. in the normal range). The patient was tested and found to be HIV-negative.
Medical History In this patient, chronic lymphocytic leukemia (CLL) had been diagnosed in 2003. Since she was asymptomatic, a watch-and-wait strategy was decided upon. In 2006, as progress of the lymphoma was apparent, a monotherapy with chlorambucil was started. In 2009, a diffuse large B cell lymphoma was detected, which was regarded as a transformation of the CLL (i.e. Richter’s syndrome). She received 6 courses of R-CHOP. From that point in time until the admission due to the neurological impairment, the patient needed no chemotherapy or immunmodulatory substances. Twenty-one months after the last administration of rituximab, the first neurological symptoms were noted. In total, this patient had been administered only 6 standard doses of rituximab (375 mg/m2). After admission to our oncological ward, in order to exclude a diagnosis of cerebral lymphoma, a spinal fluid puncture and a new MRI of the brain were performed. The second MRI showed no new features, apart from an absence of uptake of radiopaque material in the lesions. Cytological and laboratory tests of the CSF were without abnormalities. The CSF was tested for cytomegalovirus, herpes simplex virus 1/2 and JC virus on PCR. The JC viReview of Therapeutic Options for PML
rus was detected, with an exorbitantly high virus load of 56,000,000 copies/ml. In the meantime, the patient showed rapid neurological impairment with grave dementia. About 1 month after the onset of symptoms and only 1 day after the definite establishment of the diagnosis of PML, our patient died from central regulatory failure.
Discussion
The JC virus is a DNA-virus and belongs to the group of polyomaviruses. It was first detected in 1971 in a patient with CLL, John Cunningham, and was named after him by using his initials [1]. The primary infection usually occurs during childhood, so that antibodies against the virus can be detected in about 90% of the adult population. Primary infection is usually clinically asymptomatic. There is a lifelong persistence of the virus in various cell types like lymphocytic tissue, kidney and lung. Furthermore, an asymptomatic renal excretion of the virus is detectable in 20–40% of the population. In the case of severe cellular immunodeficiency, the virus may be reactivated [2]. Probably via infected circulating B cells, which are able to penetrate the blood-brain barrier, glial cells can be infected via the 5HT2A serotonin receptor [2]. As a result of the lytic destruction of myelin-producing glial cells and depending on the main damage area, progressive neurological symptoms are observed, e.g. personality changes, ataxia and pareses. This variety is typical for progressive multifocal leukoencephalopathy. Diagnosis is confirmed by MRI and viral detection in the CSF or brain tissue. Reactivation of the JC virus with the clinical manifestation of progressive multifocal leukoencephalopathy only occurs in the case of severe cellular immunodeficiency. In 80% of the cases, reactivation is associated with an HIV infection. One major risk factor is a CD4 cell count of
Chemotherapy 2014;60:47–53 DOI: 10.1159/000368072
Progressive Multifocal Leukoencephalopathy in Patients with a Hematological Malignancy: Review of Therapeutic Options Alexander Kalisch a Martin Wilhelm a Frank Erbguth b Josef Birkmann a
Departments/Institutes of a Oncology and b Neurology, Paracelsus Medical University, Nuremberg, Germany
Key Words Progressive multifocal leukoencephalopathy · JC virus · Serotonin receptor antagonists
Abstract In the context of 2 patients with hematological malignancy who developed progressive multifocal leukoencephalopathy (PML), we review the current therapeutic options for this serious complication. Both patients had lymphoma and had been pretreated with the antibody rituximab. Diagnosis of PML was obtained upon the detection of the JC virus. The outcome was fatal in both cases. So far, no standard therapeutic approach for JC virus infection has been established in HIV-negative patients with hematological malignancies and the outcome is usually fatal. Serotonin receptor antagonists might have a beneficial effect by blocking the virus from entering the cells. Although hopes for the efficacy of mefloquine were disappointed by the results of 1 study, several case reports describe improvements in neurological impairment when this drug is administered. Taking the desperate situation of this patient group into consideration, the combination of mirtazapine and mefloquine might be worthy of an attempt. © 2014 S. Karger AG, Basel
© 2014 S. Karger AG, Basel 0009–3157/14/0601–0047$39.50/0 E-Mail [email protected] www.karger.com/che
Case Report 1
We describe a 61-year-old female patient admitted to our hospital in November 2009; she was experiencing a tendency to fall towards the right side and difficulty with writing (right-hander). These symptoms had worsened continually over 5 weeks. Upon admission, the patient presented with orientation of all her faculties and in good general health. The neurological examination showed no impairment in the cranial nerves or of the sensormotor functions. No signs of headache or meningism were apparent. Upon examination of her coordination, a positive Romberg’s sign with a tendency to fall towards the right side was noticed. The finger-nose-test of the right side was uncertain and slowed. All other physical examinations showed no distinct abnormalities. Laboratory findings upon admission were normal, except for a slight monocytosis of 17% (1–9%) and hypogammaglobulinemia, i.e. IgA 22 mg/dl (70–400 mg/dl), IgG 474 mg/dl (700–1,600 mg/dl) and IgM 52 mg/dl (40–230 mg/dl). In immunofixation tests, polyclonal precipitation lines with a condensation line of IgM and lambda were visible. The CD4 cell count in the blood was markedly reduced to 150 cells/μl; this was confirmed several times on flow-cytometry. The CD8 cell count was 490 cells/μl with Alexander Kalisch, MD Department/Institute of Oncology Paracelsus Medical University, Prof. Ernst Nathan Strasse 1 DE–90419 Nuremberg (Germany) E-Mail alexander.kalisch @ klinikum-nuernberg.de
Downloaded by: St. Andrews University 138.251.14.35 - 11/26/2014 8:57:11 AM
a
b
c
Fig. 1. a Coronal T2-FLAIR shows high parietal subcortical signal intensity only in the white matter, omitting the gyri. b Coronal T1 with gadolinium shows no enhancement. c Axial T2 shows subcortical intensity without mass effect.
Medical History In 1985, this patient had been diagnosed with breast cancer followed by breast-conserving surgery, and had been in complete remission since. In 2001, an initial diagnosis of follicular lymphoma grade II, stage I was established. Up till 2003, a watch-and-wait strategy was conducted. In 2003, progressive disease was evident. Five courses of R-CHOP induced a complete remission. A weekly maintenance therapy with α-interferon was given thereafter. In 2005, after 2 years in remission, a relapse was recorded. After 6 courses of rituximab, fludarabine, mitoxantrone and cyclophosphamide, a complete remission was again achieved. This was followed by rituximab maintenance therapy. Antibody therapy was stopped due to suspicion of allergic alveolitis. In 2009, a relapse was again evident. After 6 courses of monotherapy with bendamustine, a complete remission was once more achieved. Neither a transformation to highgrade malignant lymphoma nor a relapse of the breast cancer was observed during the whole period. Twenty-nine months after the last administration of rituximab, the first neurological symptoms were noted. In total, 15 standard doses of rituximab (375 mg/m2) had been administered. Cranial MRI at admission to the hospital showed a lefthemispheric, leukoencephalopathic alteration of the brain, with hyperintense signal changes on diffusionweighted imaging but no uptake of contrast material or edema and no characteristic mass. The cerebrospinal fluid (CSF) showed no abnormalities (fig. 1) that would sug48
Chemotherapy 2014;60:47–53 DOI: 10.1159/000368072
gest lymphoma or infection; only an oligoclonal IgMband was detected that corresponded to the finding in the blood serum, but no onconeural antibodies were found. The CSF was analyzed for JC virus, cytomegalovirus, herpes simplex virus 1/2 and human herpes virus-6 on PCR with none of the suspected pathogens being detected. Due to clinical and radiological signs of PML, we started therapy with the serotonin receptor antagonist mirtazapine, even though PCR tests for the JC virus were still negative. Starting at 15 mg/day, we were able to slowly increase the dose up to 45 mg/day without any problems. In the meantime, neurological symptoms were progressive with increasing pareses of the entire right half of the body and loss of truncal control. Leukoecephalitic changes of the left hemisphere and new lesions within the right hemisphere were seen on MRI. We decided to perform a cerebral biopsy, and were able to amplify the JC virus on PCR. After the definite establishment of the diagnosis, we started additional therapy with the orally administered antimalarial agent mefloquine, beginning with a loading dose of 250 mg for the first 3 days. We planned to administer a weekly dose of 250 mg. Due to the rapid progression of the neurological symptoms, only 1 further dose of mefloquine after the initial loading dose could be given. The patient died from central regulatory failure only 2 months after the onset of symptoms.
Case Report 2
We describe a 75-year-old female patient, who was admitted to the neurological unit of our hospital in May 2011 due to the sudden onset of severe occipital headache. Kalisch/Wilhelm/Erbguth/Birkmann
Downloaded by: St. Andrews University 138.251.14.35 - 11/26/2014 8:57:11 AM
a CD4/CD8 ratio of 0.31. The B lymphocyte count in the peripheral blood was 15% (i.e. in the normal range). The patient was tested and found to be HIV-negative.
Medical History In this patient, chronic lymphocytic leukemia (CLL) had been diagnosed in 2003. Since she was asymptomatic, a watch-and-wait strategy was decided upon. In 2006, as progress of the lymphoma was apparent, a monotherapy with chlorambucil was started. In 2009, a diffuse large B cell lymphoma was detected, which was regarded as a transformation of the CLL (i.e. Richter’s syndrome). She received 6 courses of R-CHOP. From that point in time until the admission due to the neurological impairment, the patient needed no chemotherapy or immunmodulatory substances. Twenty-one months after the last administration of rituximab, the first neurological symptoms were noted. In total, this patient had been administered only 6 standard doses of rituximab (375 mg/m2). After admission to our oncological ward, in order to exclude a diagnosis of cerebral lymphoma, a spinal fluid puncture and a new MRI of the brain were performed. The second MRI showed no new features, apart from an absence of uptake of radiopaque material in the lesions. Cytological and laboratory tests of the CSF were without abnormalities. The CSF was tested for cytomegalovirus, herpes simplex virus 1/2 and JC virus on PCR. The JC viReview of Therapeutic Options for PML
rus was detected, with an exorbitantly high virus load of 56,000,000 copies/ml. In the meantime, the patient showed rapid neurological impairment with grave dementia. About 1 month after the onset of symptoms and only 1 day after the definite establishment of the diagnosis of PML, our patient died from central regulatory failure.
Discussion
The JC virus is a DNA-virus and belongs to the group of polyomaviruses. It was first detected in 1971 in a patient with CLL, John Cunningham, and was named after him by using his initials [1]. The primary infection usually occurs during childhood, so that antibodies against the virus can be detected in about 90% of the adult population. Primary infection is usually clinically asymptomatic. There is a lifelong persistence of the virus in various cell types like lymphocytic tissue, kidney and lung. Furthermore, an asymptomatic renal excretion of the virus is detectable in 20–40% of the population. In the case of severe cellular immunodeficiency, the virus may be reactivated [2]. Probably via infected circulating B cells, which are able to penetrate the blood-brain barrier, glial cells can be infected via the 5HT2A serotonin receptor [2]. As a result of the lytic destruction of myelin-producing glial cells and depending on the main damage area, progressive neurological symptoms are observed, e.g. personality changes, ataxia and pareses. This variety is typical for progressive multifocal leukoencephalopathy. Diagnosis is confirmed by MRI and viral detection in the CSF or brain tissue. Reactivation of the JC virus with the clinical manifestation of progressive multifocal leukoencephalopathy only occurs in the case of severe cellular immunodeficiency. In 80% of the cases, reactivation is associated with an HIV infection. One major risk factor is a CD4 cell count of
