Pembrolizumab for the treatment of progressive multifocal leukoencephalopathy following anti‐CD19 CAR‐T therapy: a case report

Abstract Progressive multifocal leukoencephalopathy (PML) is an opportunistic brain infection with few treatment options and poor survival when reversal of the underlying immune dysfunction is not achievable. JC polyomavirus reactivation resulting in PML can rarely complicate chimeric antigen receptor T‐cell (CAR‐T) therapy. We describe successful treatment of PML with Programmed death‐1 (PD‐1) blockade using pembrolizumab, 4 months following axicabtagene ciloleucel. Radiological features of immune reconstitution inflammatory syndrome without clinical deterioration were seen. Evidence of anti‐viral immune reconstitution by in vitro detection of JC‐specific T‐cells and sustained neurological recovery in this patient suggest PD‐1 blockade may be an effective treatment approach for PML post‐CAR‐T.


CD19-targeted chimeric antigen receptor T-cell (CAR-T) therapy has
revolutionised the treatment of aggressive B-cell malignancies but is associated with unique toxicities including cytokine release syndrome and immune effector cell-mediated neurological syndrome (ICANS). Bcell aplasia and resultant hypogammaglobulinaemia are also common and confer an increased risk of viral infection [1].
Progressive multifocal leukoencephalopathy (PML) is a severe, demyelinating infection of the central nervous system caused by the reactivation of latent JC polyomavirus (JCV). Profound immunosuppression allows replication-driven neurotropic JCV variants to cause lytic infection of oligodendrocytes/glial cells, leading to progressive neurological decline and short survival unless immune reconstitution occurs [2]. Of the anti-viral pharmacotherapies that have been prospectively trialled (cytarabine, cidofovir, mefloquine), none have shown clinical benefit [2]. Mirtazapine, a 5-HT2A receptor antagonist, can block JCV entry into glial cells and although no survival benefit has been demonstrated, it has been recommended at diagnosis [3]. Adoptive BK virus-specific cytotoxic T-lymphocytes (CTL) have been used successfully in three cases [4]. Expression of the inhibitory Programmed death-1 (PD-1) co-receptor is high on T-cells isolated from patients with PML [5], and the use of PD-1 checkpoint inhibitors to reinvigorate JCV-specific T-cell responses has shown promise [6][7][8][9].
Here we describe the first reported case of PML post-CAR-T therapy treated successfully with PD-1 blockade.

CASE DESCRIPTION
A 41-year-old man with bulky mediastinal large B-cell lymphoma (LBCL), refractory to R-CHOP, ICE, and R-DHAP chemotherapy was referred for CD19-CAR-T therapy. Bridging comprised gemcitabine/cisplatin and axicabtagene ciloleucel (axi-cel) was infused following lymphodepletion with fludarabine and cyclophosphamide.
Excellent CAR-T expansion was observed ( Figure S3). Complications  Figure 2G), which has been associated with response to PD-1 blockade in PML [8]. Eighteen months post PML diagnosis, the patient remains neurologically stable, has returned to normal activity, and remains in CMR.

DISCUSSION
To date, two other published cases also report PML following CAR-T for LBCL, but we report the first successful use of pembrolizumab.
The first case describes a 68-year-old woman, diagnosed with PML 7 months post-axi-cel, in whom clinical and radiological stabilization of PML (but not clearance of blood/CSF viremia) was achieved with mirtazapine, mefloquine, IVIG, and ultimately CTL immunotherapy [11]. The second case describes a 61-year-old woman diagnosed with PML 14 months post-axi-cel, but who died from sepsis prior to initiation of therapy [12]. PML arising post-CAR-T is likely to be a cumulative effect of multiple immunosuppressive insults, including lymphodepletion with fludarabine [13], corticosteroids for CAR-T immunotoxicity [14], post-CAR CD4+ lymphopenia [2], and B-cell aplasia/hypogammaglobulinaemia.
Further, patients with LBCL are at higher risk of PML due to their underlying lymphoproliferative disease, prior SCT, and rituximab exposure [2]. PML arising post-CAR-T is therefore likely Our case highlighted several learning points. First, negative JCV PCR in CSF should not preclude further investigation of PML using brain biopsy if there is clinical suspicion. Second, the unilateral lesion on MRI at day 13, in retrospect, was potentially a PML 'herald' lesion rather than an ICANS-associated WM lesion. Two-thirds of MRI manifestations in asymptomatic PML are unilateral [15] and ICANSassociated WM abnormalities are typically bilateral [16]. Our view is that unilateral MRI lesions in the setting of ICANS should be followed up with interval imaging to exclude other emerging pathologies.
PML-IRIS is the paradoxical clinical deterioration observed in PML following immune reconstitution and is associated with specific neuroradiological features, particularly contrast enhancement on MRI PD-1 blockade is a promising novel therapeutic approach for PML [6][7][8][9], but there is not yet consensus on its role [6,[18][19][20]. Our patient did not develop any clinical complications of pembrolizumab or recrudescence of CAR-T toxicity and achieved a remarkable neurological recovery following 3 doses.
Whilst further studies are required, our case suggests that PD-1 blockade may be a well-tolerated and efficacious treatment for PML in the post-CAR-T setting.

ACKNOWLEDGMENTS
We thank the patient and his wife for written permission to submit the report. We also thank the UCLH Use of Medicines Committee for granting access to the pembrolizumab, and in particular to pharmacists Fiona Clark and Simon O'Callaghan.