piperidines and Leukoencephalopathy--Progressive-Multifocal

Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease associated with immunocompromised states. We describe a case of PML, which developed after prolonged ibrutinib use and a low burden of chronic lymphocytic leukemia disease. The delay in diagnosis of the patient despite multiple presentations to medical providers across different facilities suggests that there is a lack of awareness of PML as a potential complication of ibrutinib. Treatments with postulated anti-John Cunningham polyomavirus agents and IL-2 were ineffective, likely due to the advanced state of the patient's disease. Although recent evidence indicates that ibrutinib may enhance cell-mediated immunity, consistent with elevated CD4+ and CD8+ T cells and appropriate T-cell response to mitogens in the patient, ibrutinib-mediated inhibition of the humoral function may contribute to PML pathogenesis. As the duration of ibrutinib use is often indefinite, and the number of indications for ibrutinib continues to grow, recognition and further evaluation of the link between PML and ibrutinib is warranted.

Topics: Adenine; Aged; Antineoplastic Agents; Disease Progression; Fatal Outcome; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Leukoencephalopathy, Progressive Multifocal; Magnetic Resonance Imaging; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines

Topics: Humans; Immune Reconstitution Inflammatory Syndrome; Leukoencephalopathy, Progressive Multifocal; Piperidines; Pyrimidines

Progressive multifocal leukoencephalopathy (PML) is a generally fatal infection of the cerebrum by the JC virus. It occurs in a range of primary and secondary immunosuppressed states and has become more common with AIDS and increasing the use of immunosuppressive therapies. Recently, Ibrutinib, a Bruton's Tyrosine Kinase Inhibitor (BTKi), has also been associated with PML. Here, we describe the case of a 77-year-old man treated for relapsed Chronic Lymphocytic Leukemia (CLL) with Ibrutinib, who eventually developed a fatal cerebellar granule cell variant of PML confirmed on autopsy. The case adds to the growing body of literature finding such an association with BTKis and highlights the importance of clinical vigilance in patients receiving such therapy.

Topics: Adenine; Aged; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Leukoencephalopathy, Progressive Multifocal; Lymphoma, B-Cell; Male; Piperidines

Progressive multifocal leukoencephalopathy (PML) with subsequent immune reconstitution inflammatory syndrome (IRIS) is a rare disease associated with compromised immune systems. It has never been described in a patient taking tofacitinib.. A 49-year-old woman with history of systemic lupus erythematous treated with tofacitinib presented with several weeks of intermittent fevers and altered mental status. MRI revealed multifocal T2-weighted FLAIR hyperintensities in the subcortical white matter, including the subcortical U-fibers, without mass effect or contrast enhancement, compatible with PML. Tofacitinib was stopped and the patient's symptoms initially improved. However, the patient presented again less than a week after discharge with three days of left arm weakness, left facial droop, dysarthria, and one day of confusion. Repeat MRI demonstrated interval progression in T2/FLAIR hyperintensities with development of patchy gadolinium enhancement on T1-post contrasted sequences, consistent with development of IRIS in the setting of tofacitinib cessation.. This is the first case describing PML-IRIS in the setting of administration and subsequent cessation of tofacitinib.

Topics: Contrast Media; Female; Gadolinium; Humans; Immune Reconstitution Inflammatory Syndrome; JC Virus; Leukoencephalopathy, Progressive Multifocal; Middle Aged; Piperidines; Pyrimidines

Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease of the central nervous system, caused by reactivation of John Cunningham polyomavirus, affecting mainly patients in an immunocompromised state. Recently, drug-associated PML is gaining attention as more cases of PML in connection with the use of various immunomodulatory drugs emerge. Over the last couple of years, sporadic reports have occurred about a possible association between PML and the use of a new immunomodulatory drug, ibrutinib (Imbruvica), primarily indicated for the treatment of various B-cell malignancies.. Herein, we report a case of a 62-year-old female patient with bilateral mantle cell lymphoma of conjunctiva diagnosed at IVA clinical stage (according to the Ann Arbor staging of lymphomas) of the disease. As a first line of treatment, the patient was given 6 cycles of rituximab-based chemotherapy followed by a complete remission. Seven years later, the patient relapsed, at which point the treatment with ibrutinib was initiated. Three weeks after the initial dosage, the patient started to show signs of progressive neurological symptomatology and died 4 months thereafter due to bilateral bronchopneumonia. Due to unspecific MRI signs and negative PCR results, the diagnosis of PML was confirmed only postmortem.. This case report demonstrates a possible severe adverse effect of the immunomodulatory drug ibrutinib and the importance of a multidisciplinary approach in its diagnosis. Since PML is a rare but highly fatal disease, it is of utmost importance to be aware of the possible connection with the use of this drug to prevent missed or delayed diagnosis, considering that timely therapeutic intervention is crucial for improved prognosis.

Topics: Adenine; Fatal Outcome; Female; Humans; Leukoencephalopathy, Progressive Multifocal; Lymphoma, Mantle-Cell; Middle Aged; Piperidines; Pyrazoles; Pyrimidines

Topics: Adenine; Aged; Antineoplastic Agents; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Leukoencephalopathy, Progressive Multifocal; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines

Progressive multifocal leukoencephalopathy (PML) is a devastating neurological disease observed nearly exclusively in immunocompromised patients. Recently, the introduction of monoclonal antibodies significantly inhibiting the immune system such as rituximab has led to an increase in PML cases. Although rituximab-based immunochemotherapy remains the standard of treatment for chronic lymphocytic leukemia (CLL), the importance of Bruton's tyrosine kinase inhibitors such as ibrutinib is steadily increasing. However, long-term experiences regarding possible side effects of these new substances are rare. Here, we report the development of eventually fatal PML possibly associated with ibrutinib therapy for CLL after multiple prior treatment lines, including rituximab. To the best of our knowledge, this is the first study to report such findings. Since the last course of rituximab was applied over 3 years ago, it is conceivable that the strong B cell inhibition by ibrutinib led to PML. With increased awareness of this potential side effect, further clinical studies are certainly warranted to evaluate this possible association.

Topics: Adenine; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Brain; Disease Progression; Fatal Outcome; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Leukoencephalopathy, Progressive Multifocal; Male; Mefloquine; Mianserin; Mirtazapine; Multimodal Imaging; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines