Ineffective treatment of PML with pembrolizumab

Case report

A 38-year-old Caucasian man was diagnosed with combined immunoglobulin (Ig) G and IgA deficiency and subsequently treated with IV immunoglobulins at regular intervals. In addition, he developed recurrent severe immune thrombocytopenia, responsive to high dose of methylprednisolone, azathioprine, and at last rituximab.

As Behçet disease had additionally been diagnosed, continued immunotherapy consisted of oral prednisolone 10 mg/d and recurrent application of IV or subcutaneous immunoglobulins at a 14- or 21-day interval.

In 2018, the patient developed progressive hemianopsia and left-sided hemiparesis. Multiple fluid-attenuated inversion recovery hyperintense lesions in cerebral white matter could be detected on MRI (figure e-1A, links.lww.com/NXI/A153). PCR amplification of JCPyV DNA revealed a very high copy number (2,561,955 copies/mL) in the CSF. Cellular immune status showed complete B-cell depletion (0 cell/µL) and low T-cell counts, especially in CD4⁺ lymphocytes (CD3⁺698 cells/µL, CD4⁺ 181/µL, CD8⁺ 511/µL, CD4/CD8 ratio 0.35). The patient was treated with 2 courses of pembrolizumab (2 mg/kg of body weight, 3-week interval) in addition to continued recurrent administration of IV immunoglobulins (20 g every second weeks). One week after the last administration of pembrolizumab, the patient developed a status epilepticus and required temporary intensive care unit treatment. MRI showed progression of PML (figure e-1B and C, links.lww.com/NXI/A153), without evidence of gadolinium-enhancing lesions as a possible indicator of immune reconstitution inflammatory syndrome. JCPyV DNA viral load in CSF increased to 7,685,000 copies/mL. Pembrolizumab treatment was not continued because of the poor general condition of the patient, who died 4 weeks later.

To get further insights into the pathophysiology, we retrospectively performed a detailed immunologic assessment for evaluation of potential treatment effects of pembrolizumab in our and a previously published case (reference case), who was diagnosed for PML and initially evaluated for anti-PD-1 treatment at our clinic.²

Polyclonal immune response (figure, A) and PD-1 expression of CD4⁺ and CD8⁺ memory T cells of both patients were average before pembrolizumab administration (figure, B; T1). After 2 courses of pembrolizumab (T2), PD-1 was downregulated in the presented case (figure B; T2 was not available for the reference case).¹ JCPyV VP1-specific T cells at baseline were present among CD8⁺, but very low among CD4⁺ T cells in the presented case (figure, C). Further analysis showed higher amounts of progenitor-exhausted memory T cells (% T-cell factor-1⁺ of PD-1⁺CD45RA⁻) in the reference case² at baseline (figure, D; T1), as well as healthy controls, and a notable increase in terminally exhausted memory T cells (% Ki-67⁺ of PD-1⁺ CD45RA⁻) in the fatal case after pembrolizumab administration (figure, E).³

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Figure Immunologic assessment of pembrolizumab treatment in the presented and reference case

CD4⁺ and CD8⁺ T cells were analyzed by flow cytometry after isolation of peripheral blood mononuclear cells (healthy controls (○), n = 9, the presented patient (◆), and the reference case (▲)). Cytokine production was analyzed after 6 hours of stimulation from PBMC isolated before (T1) and after (T2) pembrolizumab administration. CD4 (A–E) and CD8 (F–J) T-cell IFN-γ expression after phorbol-12-myristate 13-acetate/ionomycin/brefeldin A (PMA, A) or JCVyV-VP1 peptide (VP1, C) stimulation is indicated. PD-1 expression of CD45RA⁻ memory T cells (B). T-cell factor-1 expression of PD-1⁺ CD45RA⁻ memory T cells (progenitor-exhausted memory T cells, D) and Ki-67 expression of PD-1⁺ CD45RA⁻ memory T cells (terminally exhausted memory T cells, E) are outlined.