Outcome of Progressive Multifocal Leukoencephalopathy Treated by Interleukin‐7

Abstract

Restoring anti-JC virus (JCV) immunity is the only treatment of progressive multifocal leukoencephalopathy (PML). Interleukin-7 is a cytokine that increases number and function of T cells. We analyzed a population of PML patients who received recombinant human IL-7 (rhIL-7) to estimate survival and its determinants. Methods: After exclusion of patients with missing data or receiving other immunotherapies, findings from 64 patients with proven PML who received rhIL-7 between 2007 and 2020 were retrospectively analyzed. Logistic regression was used to analyze variables associated with one-year survival. Results: Underlying conditions were HIV/AIDS (n = 27, 42%), hematological malignancies (n = 16, 25%), primary immunodeficiencies (n = 13, 20%), solid organ transplantation (n = 4, 6%) and chronic inflammatory diseases (n = 4, 6%). One-year survival was 54.7% and did not differ by underlying condition. Survival was not associated with baseline characteristics, but with a >50% increase in blood lymphocytes (OR 4.1, 95%CI 1.2-14.9) and CD4 + T cells (OR 5.9, 95%CI 1.7-23.3), and a > 1 log copies/mL decrease in cerebrospinal fluid JCV DNA (OR 7.6, 95%CI 1.6-56.1) during the first month after rhIL-7 initiation. Side effects were mainly local and flu-like symptoms (n = 8, 12.5%) and PML-immune reconstitution inflammatory syndrome (IRIS) (n = 5, 8%). Interpretation: In this non-controlled retrospective study, survival did not differ from that expected in HIV/AIDS patients, but might have been improved in those with hematological malignancies, primary immunodeficiencies and transplant recipients. RhIL-7 might have contributed to the increase in blood lymphocytes and decrease in CSF JCV replication that were associated with better survival.

Progressive Multifocal Leukoencephalopathy Treated by Immune Checkpoint Inhibitors

“…18 The raw effect of ICI add-on to standard of care on survival is difficult to ascertain in a noncontrolled study. Similarly to what we observed in a recently published survey of patients with PML treated with recombinant human IL-7, 2 1-year survival in HIV/AIDS patients (50%) did not differ from that reported for standard of care, although, as for the other patients in this study, a selection bias accounting for the decision to pursue ICIs as add-on to ART cannot be excluded. In this study, survival of patients with hematological malignancy (50%) and primary immunodeficiency (57.1%) was greater than historically reported, suggesting a potential benefit of ICI add-on to standard of care.…”

“…1 Because there is no effective antiviral treatment against JCV, recovery of antiviral immune responses remains the only available treatment of PML. Emerging therapeutic strategies aimed at promoting this recovery have received increasing attention, including the use of cytokines such as interleukin-7 (IL-7), 2 adoptive transfer of anti-polyomavirus specific T cells, 3 and immune checkpoint inhibitors (ICIs). 4,5 Inhibitory immune checkpoint molecules such as programmed cell death-1 (PD-1) are receptors expressed by activated T cells that play a vital role in the maintenance of peripheral tolerance.…”

“… 1 Because there is no effective antiviral treatment against JCV, recovery of antiviral immune responses remains the only available treatment of PML. Emerging therapeutic strategies aimed at promoting this recovery have received increasing attention, including the use of cytokines such as interleukin‐7 (IL‐7), 2 adoptive transfer of anti‐polyomavirus specific T cells , 3 and immune checkpoint inhibitors (ICIs). 4 , 5 …”

Bridging the Gap: Immunotherapy in Progressive Multifocal Leukoencephalopathy

“…We favored IL-7 based on its safety, the main adverse effect being injection site reactions and transient flu-like symptoms, and a lower rate of IRIS (5.8%). 13 Given the immune reconstitution observed in this case (both in the periphery and on CNS pathology), we could suggest that rh-IL-7 was sufficient to reinvigorate anti-JCV responses. However, our patient's poor outcome illustrates that time to introduce treatment is likely key to prevent severe neurologic damage.…”

“…Large case series tend to suggest it might be beneficial, especially in patients with a grim prognosis. [13][14][15] Unfortunately, the availability of these treatments is still limited to expert centers. Finally, international controlled clinical trials are needed to ascertain efficacy and safety.…”