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Postallogeneic transplantation progressive multifocal leukoencephalopathy successfully treated by nivolumab

Successful treatment of progressive multifocal leukoencephalopathy (PML) has recently been reported with immune checkpoint inhibitors in patients with lymphoproliferative diseases, HIV infection or idiopathic lymphopenia (Rauer et al, 2019; Walter et al, 2019; Cortese et al, 2019). PML, caused by reactivation of the John Cunningham virus (JCV), is also a rare complication of immunosuppression due to allogeneic stem cell transplantation (allo-SCT) (Yuan et al, 2018). PML has a dismal prognosis, and treating or withdrawing the underlying cause of immunosuppression is part of the therapeutic strategy. Immunomodulation in the specific context of allo-SCT is particularly challenging as it can lead to severe complications, notably graft versus host disease (GvHD) (Singh et al, 2016; Haverkos et al, 2017). We describe here a 47-year-old female patient who developed PML after allo-SCT, which was successfully and safely treated by the immune checkpoint inhibitor nivolumab. This patient was diagnosed in our institution with a normal karyotype, NPM1-mutated, FLT3-negative acute myeloid leukaemia (AML). She achieved complete cytological remission after induction therapy, with a 4 log reduction in NPM1 minimal residual disease (MRD). She then received three courses of high-dose cytarabine as consolidation treatment. Relapse unfortunately occurred 14 months after the initial diagnosis and a second cytological and molecular complete remission was obtained after salvage therapy by gemtuzumab ozogamycine and cytarabine. She then proceeded to allo-SCT with an 8/10 mismatched unrelated donor. Because of the risk of graft rejection and GvHD, the allo-SCT conditioning regimen was highly immunosuppressive, comprising thiotepa, busulfan, fludarabine, antithymocyte globulin and high-dose post-transplant cyclophosphamide. As no GvHD occurred, prophylaxis with mycophenolate mofetil and cyclosporine was definitively stopped six months after allo-SCT. Seven months post-allo-SCT, the patient presented with left homolateral hemianopsia. Magnetic resonance imaging (MRI) of the brain showed right occipital white-matter lesions that were hyperintense on fluid-attenuated inversion recovery (FLAIR) and hypointense on T1-weighted sequencing, and not enhanced with gadolinium (Fig 1A). Cerebrospinal fluid (CSF) analysis showed normal glucose and protein concentration as well as normal cell count and cytology. Routine cultures and PCRs for bacteria, fungi and viruses were negative. However, CSF analysis remarkably contained 154 DNA copies of JCV per milliliter. At this time, the CD4 T cell level was inferior to 100/mm and NPM1 MRD evaluation was still negative in the blood. Over the next few weeks, the patient’s neurological symptoms worsened with frank left hand motor deficit and distal myoclonus. Repeated CSF analyses showed a dramatic increase of JC viral load (Fig 1C) to 180 and 47 377 copies per milliliter respectively two and four weeks after the first CSF analysis, and an MRI confirmed the progression of PML with the extension of occipital lesions and the appearance of lesions in the corpus callosum. The typical MRI images of the brain, the positivity of a CSF JC viral load with an increase parallel to the worsening of neurological symptoms, and the absence of an alternative cause made the diagnosis of PML highly probable. Risk factors for developing PML are not clearly defined in the setting of allo-SCT. Several studies have indicated a significant correlation between profound and prolonged immunodeficiency, JCV reactivation and PML. It is likely that in our patient the highly immunosuppressive conditioning regimen, including post-transplant high-dose cyclophosphamide, antithymocyte globulin and fludarabine, was an important risk factor for developing PML. Therapeutic options for post-allo-SCT PML are limited and so far largely ineffective. Withdrawing immunosuppressive therapies is an option but was not possible in this case as they were all stopped one month before the onset of neurological symptoms. In order to overcome the immune exhaustion and eventually restore JCV-specific cellular immune response (Barber et al, 2006), the patient received the immune checkpoint inhibitor nivolumab on a compassionate use basis. She provided written informed consent to receive off-label treatment. We initially used twicemonthly low-doses (1 mg/kg) of nivolumab for the two first infusions, as severe GvHD had been reported in patients receiving immune checkpoint inhibitors after allo-SCT (Singh et al, 2016). The third dose was administrated at 3 mg/kg as no GvHD occurred. Two weeks after nivolumab initiation, the JC viral load significantly decreased in the CSF and was undetectable after four weeks. An MRI twelve weeks after nivolumab initiation showed that this also led to a decrease of hyperintense FLAIR lesions and right occipital parenchymental atrophy (Fig 1B). Interferon-gamma Elispot for JCV was negative at PML diagnosis and two weeks after nivolumab initiation, but became positive four weeks later, suggesting restoration of JCV-specific CD8 T cells. The patient completely recovered from any motor deficit and remained stable regarding ophthalmological symptoms. Correspondence