Combined Treatment With Pembrolizumab and Allogenic BK Virus-Specific T Cells in Progressive Multifocal Leukoencephalopathy

Results

The 57-year-old male patient was in complete remission of stage IV nodal marginal zone lymphoma (nMZL; R-CHOP-21 treatment) diagnosed 4 years before PML onset. He presented with a mild right hemiparesis lasting 1 week. A brain MRI revealed multiple, diffusion impaired, hyperintense T2-weighted fluid-attenuated inversion-recovery (FLAIR) lesions, mainly in the left hemisphere. There was no gadolinium enhancement arguing against a cerebral manifestation of the original lymphoma occurring rarely in patients with nMZL. After rapid clinical progression reflected by an increase of leukoencephalopathy in the subsequent brain MRI 4 days later, the diagnosis of PML was confirmed by the detection of JC virus DNA in the CSF (40 copies/mL, high sensitivity PCR; Unilabs A/S, Copenhagen, Denmark). Apart from signs of increased blood-brain barrier permeability, CSF analysis remained normal. CT scans and a bone marrow biopsy showed no signs of recurrent or novel B cell lymphoma.

Four weeks after onset, we initiated treatment with pembrolizumab (2 mg/kg body weight) with a dosage interval of 4 to 6 weeks.¹ Three weeks after the initial dose (week 7), the patient was readmitted to hospital because of progressive hemiparalysis with a plegic right arm, cognitive deficits, and nonfluent aphasia. We intensified treatment with pembrolizumab by reducing the interval to 2 weeks, in accordance with another pembrolizumab protocol of a PML case.⁶ After 5 treatment courses (week 14), the patient achieved a stable clinical condition, but JC viral load in CSF increased to 10,000 copies/mL and further progression of leukoencephalopathy was evident by MRI. At week 23, cranial MRI showed no further progression, but brain atrophy was observed in affected areas. Viral load in CSF was still high (2,262 copies/mL). To enhance virus elimination, we initiated a 5/10 partially human leukocyte antigen (HLA)-matched allogenic BK virus-specific T cell transfusion.⁴ T cells from a HLA-matched healthy donor from alloCELL registry (20,000 CD3⁺ cells/kg bodyweight) were administered twice 7 weeks apart (week 24, 31), followed by 5 infusions of pembrolizumab (Figure). Both treatments were tolerated very well. In particular, we did not observe any signs of graft vs host disease. Viral load in CSF dropped to 495 copies/mL (week 46). Brain MRI revealed a slight reduction of FLAIR lesions with a progressive atrophy of affected regions in the left hemisphere and no more diffusion restriction. The patient's clinical condition, particularly aphasia and cognitive deficits, further improved after administration of the virus-specific T cells. However, the right arm remained plegic.

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Figure Treatment (Pembrolizumab, BK Virus-Specific T Cells), MRI Monitoring, JC Viral Load, and Clinical Course (NIHSS)

Clinical and MRI stability in particular concerning FLAIR lesions were achieved after the fourth and fifth infusion of pembrolizumab, respectively (11 and 14 weeks after onset). The initial prominent marginal diffusion impairment as a sign of viral activity was no longer detectable 32 weeks after onset. The peak of JC virus load in the cerebral fluid was 10,000 copies/mL 15 weeks after onset. FLAIR = T2-weighted fluid-attenuated inversion-recovery (scoring: hyperintensity); Gd+ = gadolinium enhancement; DWI = diffusion-weighted imaging (scoring: hyperintensity); MRI scoring = - nonexistent, + mild, ++ moderate, +++ profound, and ++++ severe; NIHSS = NIH Stroke Scale.