Progressive multifocal leukoencephalopathy in a patient with B-cell lymphoma during rituximab-containing chemotherapy: case report and review of the literature
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- Yokoyama, H., Watanabe, T., Maruyama, D. et al. Int J Hematol (2008) 88: 443. doi:10.1007/s12185-008-0168-2
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Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by the JC polyomavirus. We describe a rare case of PML in a 48-year-old female patient with diffuse large B-cell lymphoma who received rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) therapy. While she was undergoing five cycles of R-CHOP, she noticed gradually progressive neurological symptoms, such as slurred speech and gait disturbance, and she eventually developed high-grade fever. She also developed Pneumocystis jiroveci pneumonia. The neurological symptoms deteriorated thereafter, and she developed spastic quadriparesis and bulbar palsy. Magnetic resonance imaging showed hyperintensity within the right cerebellar hemisphere on T2-weighted images. Polymerase chain reaction-based tests of the cerebrospinal fluid revealed the presence of the JC virus. Despite intravenous and intrathecal cytarabine treatment, the patient died of PML 5 months after it was diagnosed. Retrospective analysis of her laboratory data showed that her CD4+ T-cell count before R-CHOP therapy had decreased to 68 μL−1. Thus, when administering rituximab-containing chemotherapy, even to patients with no prior history of opportunistic infections, attention should be paid to the potential occurrence of PML, particularly in patients with low CD4+ T-cell counts.
KeywordsProgressive multifocal leukoencephalopathyLymphomaRituximabCD4+ T-cell countsJC virus
Progressive multifocal leukoencephalopathy (PML), a demyelinating disease of the central nervous system (CNS), is associated with high rates of morbidity and mortality, and occurs almost exclusively in immunocompromised patients . The JC virus (JCV), a human polyomavirus, is the etiologic agent of PML . It accumulates to high concentrations in oligodendrocytes, causing their destruction by cytolysis , and accumulates in astrocytes as well. PML was previously considered a very rare disease; however, its prevalence in association with acquired immunodeficiency syndrome (AIDS) has increased steadily in recent years. However, there have been several cases of PML reported in patients with hematological malignancies not associated with AIDS but related to fludarabine therapy, mainly those diagnosed with chronic lymphocytic leukemia [4, 5]. The newer forms of treatment, such as purine analogs for hematological malignancies, have augmented the incidence of PML. We herein describe an extremely rare case of PML that developed in a patient with diffuse large B-cell lymphoma (DLBCL) during cyclophosphamide (CPA), doxorubicin (DXR), vincristine (VCR), and prednisolone combined with rituximab (R-CHOP) therapy, and review the relevant literature.
2 Case report
In June 2006, a previously healthy 48-year-old Japanese female complained of severe pain in her buttocks and was referred to our hospital. A computerized tomography (CT) scan revealed an extensive osteolytic mass in her right iliac region and para-aortic lymphadenopathy. An open biopsy and subsequent histological examination of the right iliac mass revealed it to be DLBCL. The patient was diagnosed with stage II disease, and classified as being in a low-risk group by the International Prognostic Index criteria. She was treated with the CHOP regimen (day 1, intravenous: CPA 750 mg m−2, DXR 50 mg m−2, and VCR 1.4 mg m−2; days 1−5, oral: prednisolone 100 mg) and concurrent rituximab at a dose of 375 mg m−2; she tolerated the treatment well.
In October 2006, while she was undergoing five cycles of chemotherapy and achieved a complete response (CR), she noticed gradually progressive neurological symptoms, such as double vision, slurred speech, clumsiness of the right hand, and gait disturbance. Her neurological symptoms continued to worsen, and she eventually developed high-grade fever and was admitted to our hospital. On physical examination, all vital signs except the body temperature were normal. Breath sounds were clear and oxygen saturation was normal. She appeared fully alert and oriented, although neurological examination revealed cerebellar dysmetria by finger-to-nose and heel-to-knee tests, which was worse on the right side. The patient was fully ambulatory, although her gait appeared relatively wide-stanced. There were no signs of sensory disturbance or unilateral pyramidal tract lesions.
Laboratory studies revealed a leukocyte count of 9,200 μL−1 (neutrophils, 8,400 μL−1; lymphocytes, 460 μL−1), hemoglobin of 10.6 g μL−1, platelet count of 37.5 × 104 μL−1, LDH of 281 IU L−1 [normal range (NR), <229 IU L−1], and C-reactive protein of 12.5 mg dL−1 (NR <0.1 mg L−1). Lymphocyte subset analysis revealed an absolute CD4+ T-cell count of 68 cells μL−1. Serum immunoglobulin (Ig) concentrations were 720 mg dL−1 IgG (after that, the level of IgG was reduced to 391 mg dL−1), 256 mg dL−1 IgA, and 74 mg dL−1 IgM. Her serum level of soluble interleukin-2 receptor was elevated to 1,490 U mL−1(NR <531 U mL−1). Her serology was negative for hepatitis B, hepatitis C, syphilis, human immunodeficiency virus (HIV), and human T-cell leukemia virus type I. Routine cultures for bacteria and fungi were negative. The total cell count in the cerebrospinal fluid (CSF) was 1 cell μL−1, with normal levels of glucose and protein, and a negative Gram’s stain. Herpes simplex virus DNA was not detected in the patient’s CSF by the polymerase chain reaction (PCR).
After 7 days the patient’s respiratory status suddenly deteriorated. A chest X-ray and CT scan showed bilateral infiltrates expanding diffusely. The DNA sequence specific to Pneumocystis jiroveci was detected in the specimen obtained from the bronchoalveolar lavage fluid by PCR. Bacterial culture was negative and microscopic examination did not show any lymphoma cells. Antigens of cytomegalovirus, Candida, Aspergillus, and Cryptococcus were not detected. She was started on sulfamethoxazole and trimethoprim. Prednisolone at a dosage of 40 mg, twice daily, was also prescribed. Her respiratory symptoms improved with the treatment of Pneumocystis jiroveci pneumonia (PCP), and the abnormal findings on the chest X-ray and CT scan were normalized. Moreover, she developed adenovirus-, JC virus-, and BK virus-related hemorrhagic cystitis.
PML was diagnosed, and intravenous injections of cytarabine were given accordingly at a dosage of 2 mg kg−1 for five consecutive days. Despite the treatment, the patient’s neurological condition continued to worsen. A repeat MRI showed progressive worsening of the radiological findings. The patient subsequently received an intrathecal injection of cytarabine at a dose of 20 mg per day. However, the therapy was unsuccessful, and she died 8 months after the diagnosis of DLBCL, i.e., 5 months after the onset of PML.
Progressive multifocal leukoencephalopathy is an uncommon demyelinating disease of the CNS caused by lytic infection of oligodendrocytes with JCV . Up to 64% of healthy adults shed JCV in the urine in the absence of any clinical symptoms, which suggests that asymptomatic, active JCV infection is common in immunocompromised persons . The clinical manifestations of PML are hypothesized to occur when B cells infected with JCV are activated under an immunosuppressed condition; subsequently, JCV enters the brain, where astrocytes and oligodendrocytes support JCV replication, resulting in neurological damage . The disease is characterized by the development of disseminated demyelinating plaques in the cerebral white matter and adjacent areas . Death within 6 months is common.
JCV reactivation is typically observed among patients with severe immunodeficiency. The cause of the immunologic deficit is mostly a long-standing hematological disorder, HIV infection, hematological malignancies, immunosuppressive medications, or immunosuppressive treatment after organ transplantation . In the HIV-infected population, PML is strongly correlated with depressed CD4+ T-cell counts . Rare cases of PML have been reported among patients with lymphoma . Our report details the clinical features of a patient with DLBCL who developed both PML and PCP. Because both PML and PCP are opportunistic infections, we suspected a preceding immunosuppressed state, and identified a decrease in absolute CD4+ T-cell counts at the initial presentation of DLBCL. The patient had no underlying diseases that might cause immunodeficiency, such as additional malignancies or AIDS. The definition of idiopathic CD4+ T-lymphocytopenia is consistent with this condition , but it is not certain if this is an abnormality directly related to malignant lymphoma. On the other hand, a reduction in the CD4+ T-cell count is noted at the initial examination in some patients with malignant lymphoma, suggesting a possibility for the development of an opportunistic infection. The present patient developed PCP and viral hemorrhagic cystitis in addition to PML. We believe that we should be cautious regarding the development of an opportunistic infection in patients with a low CD4+ T-cell count at the initial examination, and the R-CHOP regimen should be accompanied by supportive care such as trimethoprim–sulfamethoxazole to prevent PCP under close observation. For patients with a low CD4+ T-cell count before the initiation of treatment, both the risk of developing an opportunistic infection following the R-CHOP regimen and the prognosis of malignant lymphoma should be assessed: if the latter is relatively favorable, one should consider the possiblity of omitting either rituximab or glucocorticoids in the drug combination treatment of the R-CHOP regimen. In recipients of bone marrow transplants, PML has also been associated with rituximab treatment [5, 10]. To our knowledge, however, initial R-CHOP immunochemotherapy for B-cell lymphoma has not previously been identified as a treatment with an increased risk of PML.
A definitive diagnosis of PML can be based on the concomitant presence of a compatible clinical and neuroimaging picture and characteristic histopathologic features with JCV detection in the brain tissue . However, brain biopsy is an invasive method with considerable risks. In addition, the severity and extent of this disease are so marked that patients with PML are often in a poor clinical condition with an impaired hemostatic system, making noninvasive diagnostic methods highly desirable. Therefore, some studies have developed and validated less-invasive diagnostic methods based on the amplification of the JCV-target DNA from CSF by PCR. Fong et al.  showed that the sensitivity and specificity of JCV DNA by PCR were 74 and 96%, respectively, and the positive and negative predictive values were 89.5 and 88.5%, respectively, before the highly active antiretroviral therapy (HAART) era.
The MRI findings in patients with PML present characteristic images. There should be areas of decreased signal intensity on T1-weighted images and increased signal intensity on T2-weighted images . The images are dominated by T2-signal abnormalities of the white matter [3, 14]. This is reflected by a slight tissue swelling in acute lesions and atrophy in end-stage areas during the demyelination process. Most lesions remain hyperintense on T2-weighted images because the tissue water content increases after the replacement of oligodendrocytes by astrocytes. Tissue destruction continues in clinically progressive patients. Generally, the lesions in PML are not contrast-enhanced by gadolinium and do not show a substantial mass effect. DWI reliably distinguishes intracellular edema from interstitial water accumulation. Intracellular edema is seen in acute cell damage, which is usually followed by cell death. Cell death as observed in the periphery of the cerebral lesions is explained as oligodendrocyte necrosis in the areas of demyelination .
In a randomized controlled trial involving 57 patients with HIV infection and biopsy-confirmed PML, cytarabine administered either intravenously or intrathecally did not improve the prognosis compared with antiretroviral therapy alone . For PML associated with AIDS, HAART is relatively effective . Although there have been no large-scale clinical trials on treatment for PML in the absence of AIDS, there is evidence that cytarabine decreases JCV replication and multiplication in vitro . There have also been studies on improvement in non-HIV-related PML when cytarabine is given intravenously, intrathecally, or both [18–20]. The most successful of them, an open-label study involving 19 patients who had PML without HIV infection, showed that intravenous cytarabine at a dosage of 2 mg kg−1 daily for five consecutive days appeared to stabilize the neurological and functional status in seven patients (36%) at 2–4.5 years of follow-up, despite significant bone marrow toxicity complications . Based on these studies, we chose cytarabine for the treatment of PML in the present case.
A recent study reported that approximately 80% of PML patients have AIDS, 13% have hematological malignancies, 5% are transplant recipients, and 2% have chronic inflammatory diseases . Since 1990, when purine analogs first became available, the incidence of PML has increased . The Food and Drug Administration alert in December 2006 reported that two patients with systemic lupus erythematosus died after treatment with rituximab. Thus, this new class of medication, such as purine analogs and rituximab used in treating hematological malignancies, may increase the number of patients at risk of developing PML [5, 12]. CD4+ T-cell counts of less than 200 μL−1 are known to be a risk factor for the development of PML . For those patients with reduced CD4 T-cell counts and T-cell deviations (compromised cellular immunity), the administration of rituximab or the application of the CHOP regimen may impair humoral immunity, which in turn may lead to the onset of PML. For the present patient, the CHOP regimen that preceded rituximab caused a decrease in the IgG level, and the subsequent rituximab administration resulted in a further reduction in IgG (the level ultimately reaching 391 mg/dL). It was suggested that the R-CHOP regimen may compromise humoral immunity in patients with a reduced CD4+ T-cell count and expose them to a risk of developing PML or other opportunistic infections. This was true in our case: our patient’s CD4+ T-cell count before R-CHOP therapy was 68 μL−1. Thus, when a variegated neurological symptom is noted during rituximab-containing chemotherapy, one must consider the possibility of PML while making a differential diagnosis.
This study was supported in part by grants from the Ministry of Health, Labor, and Welfare, Japan.