Introduction
Progressive multifocal leukoencephalopathy (PML) is a viral infection caused by the human polyomavirus 2, more commonly known as the John Cunningham virus (JCV). JCV can cross the blood-brain barrier into the central nervous system (CNS) and infect oligodendrocytes and astrocytes, possibly through the 5-HT2A serotonin receptor [ 1 ]. JCV is ubiquitous and remains dormant in the CNS; JCV DNA can be detected in both non-PML-affected and PML-affected (see below) brain tissue [ 2 ]. Immunodeficiency and immunosuppression increase the risk of reactivation of JCV. In the brain, it causes subcortical white lesions by destroying oligodendrocytes, the myelin-producing cells of the CNS. Whether this represents the direct reactivation of JCV within the CNS or seeding of newly reactivated JCV via blood or lymphatic system is not yet well determined, however, it is believed that usually PML is triggered by the reactivation of the endemic JCV. Although up to 90% of healthy individuals have serum antibodies to this virus, less than 10% show evidence of ongoing viral replication [ 3 ]. Confusion and cognitive impairment are the most common clinical symptoms (54%), followed by mono-/hemiparesis (33%), weakened coordination (25%), and speech disorders (21%) [ 4 ]. Currently, the diagnosis is based mainly on cerebrospinal fluid (CSF) PCR for JCV and characteristic imaging, with brain biopsy required in only 25% of cases. JCV predominantly causes leukoencephalopathy in immunocompromised patients, including acquired immunodeficiency syndrome and post-organ transplantation. However, with the increased use of monoclonal antibodies for various lymphoproliferative disorders, more cases have been reported in non-human-immunodeficiency virus (HIV) patients on drugs such as natalizumab, and in particular rituximab. In 1 study of patients with a hematological malignancy treated with rituximab, PML was found to occur in 8 of 10,000 clinically suspected and 0.8 of 10,000 confirmed cases [ 5 ]. Obinutuzumab is a humanized type II anti-CD 20 antibody, widely used in combination with chemotherapy as the therapeutic backbone for a variety of lymphoproliferative disorders, including chronic lymphocytic leukemia (CLL). It induces antibody-depended cytotoxicity, phagocytosis, and cell death. There are very rare reported cases of PML after long-term exposure to obinutuzumab [ 6 ].
Case Report
Our case is a 75-year-old female patient who presented with anemia (hemoglobin 99 g/L), thrombocytopenia (platelet count 78,000 × 10 9 /L), and chronic lymphocytosis (absolute lymphocyte count 152,000 × 10 9 /L). Past medical history was significant for diverticulosis with recurrent diverticulitis, migraines, and localized skin psoriasis not on systemic therapy. Physical examination showed lymphadenopathy and mild splenomegaly. Flow cytometry from peripheral blood showed presence of monoclonal B-cell population, expressing CD 19, 20, 5, dim 23, 200 and kappa light chain restricted. Bone marrow revealed extensive (>90%) lymphocytic infiltrate with minimal hematopoiesis. Fluorescence in situ hybridization was negative for the following: 13q-, trisomy 12, and 17p-. Immunoglobulin heavy chain variable genes were mutated. She was diagnosed with Rai stage IV CLL, low risk. Due to significant disease burden she required debulking with prednisone, 100 mg PO (approximately 1.5 mg/kg) daily × 5 days ( Fig. 1 ). After a short course of prednisone for disease debulking, she was started on front-line therapy of obinutuzumab and venetoclax. Following the first obinutuzumab infusion, the patient reached complete resolution of lymphocytosis (ALC 0.23 × 10 9 /L); however, she developed febrile neutropenia and was treated with broad-spectrum antibiotics and granulocyte colony stimulating factor. After the second dose of obinutuzumab, she developed community-acquired pneumonia, which resolved after a course of amoxiclav and azithromycin. She developed a concurrent profound change in her mentation, becoming increasingly disoriented and slow to answer questions. Blood chemistry revealed hypercalcemia (corrected calcium level 3.12 mmol/L). Work-up for hypercalcemia did not yield any obvious causes. After IV pamidronate, calcium levels normalized, and she improved clinically. Unfortunately, she developed concomitant perforated diverticulitis, which was treated with antibiotics and a Hartmann’s procedure. She recovered and decided to continue therapy after discussions regarding goals of care. After completing the loading dose of obinutuzumab, she was started on venetoclax on a ramping up dose. Four days after this loading dose of obinutuzumab, she presented to the emergency department with forgetfulness and irrational behavior. Collateral history obtained from her family revealed symptoms slowly progressing over a month. She had no acute confusion or hallucinations. Physical examination was unremarkable. Family members suspected PML, so further obinutuzumab infusions were discontinued, and venetoclax was put on hold. Due to concomitant dyspnea and cough, the patient was tested and diagnosed with a COVID infection. Magnetic resonance imaging (MRI) T2-weighted imaging of the head showed asymmetrical signal changes extensively involved the gray matter in the left frontal lobe, extending inferiorly into the deep white matter, reaching the midbrain ( Fig. 2 ). They were consistent with PML. Subsequently, the patient developed delirium and was admitted for expedited work-up and supportive care. She started IV acyclovir for a presumed viral infection with no improvement. CSF analysis showed a small CD5 positive small mature kappa light chain restricted monotypic B-cell lymphocyte population, positive for CD19, CD5, and negative for CD20, CD23, CD34, and CD10 expression. Sample was tested negatively for paraneoplastic disease profile (IgG and IgM); it was borderline positive for neurological disease profile (IgG and IgM). Qualitative polymerase chain reaction for JCV was positive confirming a PML diagnosis. As discussed with the patient’s family, we decided to pursue a trial of intravenous immunoglobulin (IVIG), dosed at 0.4 g/kg. Initially, there was a transient improvement in clinical symptoms following the first day of IVIG infusion. However, over the following week delirium was noted, and the patient began to clinically deteriorate again. Therapy was switched to palliative, focusing on symptoms control. The patient died 1 month after the initial IVIG dose described above.
Discussion
PML is a rare but serious brain disorder that can occur due to reactivation of the JCV secondary to obinutuzumab treatment. Primary risk factors for PML include HIV infection, chemotherapy, or immunosuppressive therapy resulting in CD4+ and CD8+ T-cell lymphopenia. Based on laboratory testing (normal immunoglobulin level, absolute neutrophil count (ANC), and CBC), our patient was not severely immunocompromised; however, their clinical course was complicated by febrile neutropenia, GI, and respiratory infections. Prior to the obinutuzumab and venetoclax therapy initiation, she tested negatively for HIV, hepatitis B and C. Quantitative IgG level was normal (8.74 g/L). Prior to obinutuzumab start, ANC was 3.11 × 10 9 /L. Shortly after the first dose of obinutuzumab, ANC decreased to 0.91 × 10 9 /L but neutropenia resolved in 2 days after granulocyte colony stimulating factor injections. Three days after the first obinutuzumab infusion, the patient’s ALC decreased (nadir 0.23 × 10 9 /L) but resolved to 1.22 × 10 9 /L after 1 month. Repeated IgG level was normal (6.65 g/L). The CD4/CD8 ratio was 3.38:1 with no definitively aberrant immunophenotype.
PML after rituximab administration is rare but uncommon. A 20-year review from the Southern network on adverse reactions presented 52 cases of rituximab-associated PML among patients with non-Hodgkin lymphoma or CLL [ 5 ]. PML secondary to obinutuzumab is even less frequent. There are 4 cases described in the literature ( Table 1 ). Yokota et al. [ 7 ] reported PML in a patient with follicular lymphoma treated with obinutuzumab and bendamustine after an ineffective course of rituximab. The patient developed visual field defects and cognitive decline, with imaging revealing parieto-occipital white matter lesions. JCV DNA was confirmed in brain tissue. Despite treatment with mefloquine and mirtazapine, the patient died 6 months after symptom onset [ 7 ]. The second case is of a patient receiving obinutuzumab maintenance therapy who developed PML symptoms just before the third cycle, including left-sided motor and sensory deficits with upper motor neuron signs [ 8 ]. Laboratory results showed mild hypogammaglobulinemia, and imaging revealed a right parietal lesion consistent with PML; however, no treatments were discussed [ 8 ]. Our patient had an atypical course with very short exposure to obinutuzumab, and no evidence of compromised immune system.
Table 1.
Summary of case findings from the literature on PML development following obinutuzumab administration
PCR, polymerase chain reaction; JCV, John Cunningham virus; DNA, deoxyribonucleic Acid; FLAIR, fluid-attenuated inversion recovery; DWI, diffusion-weighted imaging; T2, relaxation time or spin-spin relaxation; Ig, immunoglobulin; CLL, chronic lymphocytic leukemia; CSF, cerebrospinal fluid; IVIG, intravenous immunoglobulin; R-CHOP, Rituximab, Cyclophosphamide, Hydroxydaunorubicin, Oncovin and Prednisone; PR, partial response.
| Paper (year) | Regimen | Symptoms | Laboratory findings | Neuroimaging | Treatment | Outcome |
| Pejsa et al. [ 6 ] (2019) | Obinutuzumab + chlorambucil for CLL; 6 cycles completed | Blurred vision; later cognitive and neurological decline | CSF JC virus PCR positive | T2 hyperintense subcortical lesions (initially mimicked PRES) | IVIG (no benefit) | Alive but severely disabled after 6 months |
| Yokota et al. [ 7 ] (2018) | Obinutuzumab + bendamustine (G-B); prior rituximab (12 cycles, ineffective); 3-year G-B maintenance | Visual field defect, cognitive decline, left homonymous hemianopsia | Brain biopsy PCR: JCV DNA 5 × 10 8 copies/μg | T2/FLAIR/DWI hyperintensity in left parieto-occipital white matter; multifocal lesions | Mefloquine + mirtazapine | Died 6 months after symptom onset |
| Diiavati et al. [ 8 ] (2016) | Obinutuzumab monotherapy; symptoms started before 3rd maintenance dose | Difficulty walking, left hemiparesis, sensory loss, hyperreflexia, Babinski sign | Mild hypogammaglobulinemia (IgG 510, IgM <18, IgA <26 mg/dL) | Right parietal lesion; T1 hypointense, T2-FLAIR hyperintense with peripheral diffusion restriction and edema | Not reported | Not reported |
| Diamantopoulos et al. [ 9 ] (2022) | R-CHOP ×8 → PR; rituximab ×2 years → PR; relapse treated with obinutuzumab + bendamustine ×6 → PR | Gait imbalance, memory issues → hemianopsia, hemiparesis, expressive dysphasia, dysgraphia, ataxia | CSF PCR: JCV 1.3 × 10 7 copies/mL; normal lymphocytes, no B cells | Extensive bilateral leukopathy (parietal, temporal, occipital, cerebellum) | Not reported | Not reported |
The next case was reported by Pejsa et al. [ 6 ] of a patient with CLL who developed PML after 6 cycles of obinutuzumab and chlorambucil. Initial symptoms were limited to blurred vision, but progressed to significant neurological decline. JCV was detected in the CSF, and MRI showed T2 hyperintense lesions. Despite IVIG therapy, the patient remained severely disabled 6 months after onset [ 6 ]. Finally, the last case was of a 54-year-old man who developed PML following multiple lines of therapy including obinutuzumab for relapsed follicular lymphoma [ 9 ]. Neurological symptoms progressed rapidly from gait imbalance to severe visual, motor, and language deficits. JCV was confirmed in the CSF, and MRI showed widespread bilateral white matter involvement. No treatment or outcome was reported in this case [ 9 ].
PML has been increasingly reported in association with SARS-CoV-2 infection. Recent case reports suggest that COVID-19 may contribute to PML development through multiple mechanisms, including virus-induced immune dysregulation, lymphopenia, and reactivation of latent infections. In a patient with B-cell CLL, PML occurred following COVID-19 vaccination and subsequent SARS-CoV-2 infection, highlighting the complex interplay between immune suppression, infection, and vaccine-related immune modulation [ 10 ]. Similarly, a case of PML in multiple myeloma following SARS-CoV-2 infection emphasized that COVID-19-related immune dysfunction and B-cell depletion from therapies may predispose patients to JC virus reactivation [ 11 ]. Furthermore, another report described PML triggered by COVID-19 in an individual with previously undiagnosed HIV, suggesting that SARS-CoV-2 can unmask latent immunodeficiency and precipitate JC virus reactivation even in undiagnosed cases [ 12 ]. Collectively, these findings suggest that SARS-CoV-2 infection and its immunological consequences may act as a precipitating factor for PML in susceptible individuals.
Symptoms of PML are very nonspecific; however, healthcare providers should have a high degree of suspicion in recognizing the symptoms promptly. Patients receiving mAbs, including obinutuzumab, should be monitored for signs and symptoms of PML as prompt intervention is crucial in reducing mortality. In our case, the patient’s proper diagnosis was delayed because symptoms were not monitored under a “high alert zone” and the patient was exposed to a short course of obinutuzumab. JCV reactivation occurs usually after long-term use of immunosuppressive medications, in particular after solid organ or bone marrow transplantation, as well as in patients who developed acquired immunodeficiency syndrome complex. Family members of affected patients are more familiar with a patient’s cognition status and thus emphasize the importance of collateral history.
There is no standardized treatment for PML. In addition to supportive care, treatment focuses on restoring the immune system to fight off the reactivated JCV. The first step is discontinuation of any immunosuppressive therapy. Plasma exchange is another option; however, there is little evidence of its efficacy in treating PML. IVIG infusions are rarely used; however, they have the potential to improve symptoms based on the anti-inflammatory mechanism of action. Although in our case IVIG infusions did not induce PML remission, it still resulted in a transient improvement in cognition. A recent case report showed clinical and radiological improvement monthly IVIG in a 52-year-old patient with PML. Further studies should explore the impact of greater IVIG doses and repeated administration as potential therapies for PML [ 13 ].
Newer therapies with directly isolated allogeneic virus-specific (DIAVIS) T cells are a promising treatment option for PML [ 14 ]. In this recent study, patients treated with DIAVIS T cells had a higher 12-month survival rate compared to patients receiving best supportive treatment (69% vs. 45%, p = 0.02) [ 14 ]. These results highlight DIAVIS T cells as a potential therapy to reduce mortality and improve functional outcome in PML patients; however, more studies are required to understand its mechanism of action.
Another promising treatment is combination therapy of antiviral, mirtazapine, and IVIG. A recent study showed the efficacy of long-term IVIG and mirtazapine use in PML patients [ 15 ]. This was a similar result observed in another case report of HIV-associated PML treated with a combination therapy of mirtazapine, mefloquine, and IVIG [ 16 ]. Additionally, a 2019 case report demonstrated a favorable response of gray-matter JCV lesions in an HIV patient to mirtazapine [ 17 ]. More studies are needed to understand the mechanism of action of these therapies in targeting JCV lesions and assess potential long-term side effects. Overall, PML prognosis remains poor with high mortality and morbidity including irreversible neurological consequences.
Conclusion
PML is a rare but fatal complication of obinutuzumab. Prescribers should be aware of early clinical signs such as changes in cognitive status. History obtained from family members is important to recognize early changes in cognition. Therapies such as IVIG that are directed toward immune system restoration may be beneficial; however, there remains a critical unmet need for more effective treatments for PML.
Statement of Ethics
Research Ethics Board (REB) approval is not required for this study in accordance with our local guidelines. The research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki. Written informed consent for publication was obtained from the patient’s family for publication of the details of their medical case and any accompanying images. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000549388 ).
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
This study was not supported by any sponsor or funder.
Author Contributions
A.R.M. and R.K. wrote and reviewed the manuscript. All authors approved the final version to be published and agreed to act as guarantors of the work.
Data Availability Statement
All data that support the findings of this study are included in this article. Further inquiries can be directed to the corresponding author.
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