Prolonged survival in HIV-associated Progressive Multifocal Leukoencephalopathy treated with Pembrolizumab: a case series on treatment and long-term follow-up

Patient 1, a 71-year-old HIV-positive male with a baseline CD4 count of 372/mmc and undetectable plasma HIV-RNA under successful cART with tenofovir alafenamide/emtricitabine/darunavir/cobicistat + dolutegravir (TAF/FTC/DRV/c + DTG) due to a previous virological rebound without resistance on TAF/FTC + D. He was recovering from non-Hodgkin B-cell lymphoma when the diagnosis of PML was formulated. The MRI showed a T2 and FLAIR hyperintensity in the white matter of the left frontal lobe (superior and middle frontal gyri, and precentral gyrus), predominantly involving the arcuate fibers and extending to the centrum semiovale and corona radiata, along with a linear, gyriform hypointense rim on Susceptibility Weighted Imaging (SWI), involving the subcortical frontal region. There was no mass effect, and only a faint peripheral patchy contrast enhancement. These MRI findings were typical of PML. The LP was not examined for PD-1 expression in T cells at baseline. PD-1 expression in the CSF and whole blood (WB) remained undetectable throughout the study period when examined. The patient showed no cells expressing PD-1 in CSF at 4–8 months from baseline interval, while in WB, there was an increase from CD8 + 0.1%, CD4 + 0.5% at baseline to CD8 + 1.6%, CD4 + 2.3% at 4–8 months. This patient received eight administrations of Pembrolizumab on a monthly basis, with a scheme partially different from the other PLWH in the case series, due to the lack of evidence of a precise length of the experimented regimen at the time, the absence of toxicities and the good clinical response. Along with the pembrolizumab injection, he also underwent intensive speech therapy and neuropsychological evaluations several times during the follow-up period. A two-year follow-up assessment by neuropsychologists showed improvement in complex mnesic mechanisms and speech production evaluation. Notably, the patient was alive at 3.5 years with clinical and MRI three years from baseline showed stability of all brain lesions, lack of contrast enhancement, and in the absence of signs of disease reactivation, fully autonomous in activities of daily living.

Patient 2, a 41-year-old female, was diagnosed with HIV infection at the same time of the PML presentation. She had a baseline CD4 count of 8/mmc and baseline serum HIV-RNA of 8279 copies/ml, along with HCV co-infection. At baseline, she presented with progressive speech impairment, balance deficits and ataxia. Baseline MRI showed the presence of bilateral and symmetrical hyperintensities on FLAIR and T2 with corresponding hypointensities on T1, involving the bilateral cerebellar hemispheres, vermis, and bilateral middle cerebellar peduncles, without contrast enhancement and mass effect. Also, JCV-DNA was detected at CSF examination. Taken into account the history, imaging findings could be compatible with JCV granule cell neuronopathy (JCVGCN). Also, JCV-DNA was detected at CSF examination. She was promptly started on cART and pembrolizumab. During treatment period, there were significant changes in JCV-specific PD-1 expression, with decreased activity in CSF and WB from baseline to 4–8 months: despite initial high expression levels, CD8 + and CD4 + PD-1 expression decreased from 85.5% and 86.7–72.3% and 43.9% in WB at 4–8 months, respectively. Regarding JCV specific T cells response, we observed a non-detectable response at baseline, while an improvement was observed after the first dose of pembrolizumab administration (127 IFNg SFC/106 PBMC) until 4–8 months (100 IFNg SFC/106 PBMC). The patient was alive at 19 months with clinical improvement, recovering partially from production aphasia and reacquiring partial motor abilities.

Patient 3, a 43-year-old male diagnosed with HIV infection in 2022, with a baseline CD4 count of 91/mmc and undetectable plasma HIV-RNA under 4 months cART with BIC/TAF/FTC, was recovering from a recent episode of neurotoxoplasmosis, for which he underwent effective treatment with sulfadiazine and pyrimethamine. After recovering from the disease, he experienced an episode of neurological worsening, with the new onset of tremors, confusion, and production aphasia so he was transferred in our facility and an MRI was performed, showing bilateral, patchy cortical and subcortical hyperintense lesions. There was no mass effect. T1 images after contrast administration showed marginal enhancement of some lesions. These MR imaging findings were not typical for PML. At baseline, CD4 + and CD8 + PD-1 expression in CSF and WB were very high (86% and 87% in CSF and 55.5% and 77.7% in WB, respectively) showing variations during the study period, with an initial high expression followed by a decrease at 1–4 months in circulating CD4 and CD8 T cells (50.2% and 36.8%, respectively). Unfortunately, this decrease did not correspond to an improvement of T cells specific response. Notably, lumbar puncture was not performed for 4–8 months. The patient was alive at 12 months follow-up. Final MRI showed reduction in lesion size, persistent FLAIR hyperintensities, and evidence of ventricular and sulcal expansion as for a mild cerebral atrophy. He also experienced a clear clinical improvement, reacquiring independence in activities of daily living. Patient 4, a 51-year-old male, was diagnosed with PML at the same time as HIV diagnosis, with a baseline CD4 count of 103/mmc and a plasma HIV-RNA of 327,208 copies/mL; also JCV virus in blood was of 1169000 cp/ml. During hospitalization, he also presented with systemic CMV infection, with a CMV-DNA PCR of 332556 cp/ml, fever, treated with intravenous ganciclovir, cART and pembrolizumab. PD-1 high expression in circulating and in CSF CD4 + and CD8 + T cells was showed at 1–4 months. After 1 dose of pembrolizumab, the patient died 60 days after PML diagnosis, due to worsening neurological status and respiratory complications. An MRI performed ten days before death showed increase -compared to the previous MRI- extension of the multifocal hyperintensity in T2 and FLAIR images involving the subcortical and deep white matter of the frontal and temporal lobes bilaterally, the left insular cortex, the cingulate gyrus on both sides, the left nucleus-capsular region, the corpus callosum, both cerebral peduncles, the pons, and the left middle cerebellar peduncle. On DWI larger lesions showed slightly restricted diffusion along its margins, and some little lesions showed high restriction, the appearance on DWI probable varied with lesions stage. No contrast enhancement was observed. Of interest, some lesions had a slight mass effect. Table 2 summarizes immunological values on circulating and in CSF CD4 and CD8 T cells of enrolled PLWH. Meanwhile, Fig. 1 reports PLWH’ MRI pattern throughout the study.

Table 2 Immunological parameters Fig. 1figure 1

MRI imaging. Patient 1 (first Row, a-d): FLAIR (a) and T1-weighted post-contrast images (b) from the first MRI exam, and the corresponding FLAIR (c) and T1-weighted post-contrast images (d) after three years. The initial exam shows a FLAIR hyperintensity in the white matter of the left frontal lobe, involving the subcortical U fibers, with no mass effect and faint marginal enhancement (arrow in b), consistent with typical PML findings. Over time, the FLAIR lesion remains stable, while contrast enhancement resolves (arrow in d). Patient 3 (second Row, e-h): FLAIR (e) and T1-weighted post-contrast images from the first MRI exam, and the corresponding FLAIR (g) and T1-weighted post-contrast images (h) after 12 months. The initial FLAIR images reveal bilateral, patchy, ill-defined cortical and subcortical hyperintense lesions without mass effect; some lesions exhibit faint marginal enhancement. These imaging findings are atypical for PML. The follow-up MRI shows a reduction in lesion size, persistent FLAIR hyperintensities, and evidence of ventricular and sulcal expansion. Patient 4 (third row, i-n): Single MRI exam with FLAIR (i), DWI (l), coronal T2 (m), and T1-weighted post-contrast (n) images. The MRI demonstrates multiple FLAIR hyperintense lesions involving the white matter of multiple bilateral lobes, the splenium, left internal capsule, and nucleus pallidus. DWI reveals variable signal intensities: lesions in the left frontal and right periventricular regions show a low-signal core surrounded by a high-signal rim, with a punctate high signal in the globus pallidus and intermediate-to-low signal in the corpus callosum. Coronal T2 imaging shows a slight mass effect on the left ventricle, which appears reduced in size compared to the contralateral side. No contrast enhancement is observed

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