Detection of cases of progressive multifocal leukoencephalopathy associated with new biologicals and targeted cancer therapies from the FDA’s adverse event reporting system

Raisch, Dennis W.; Rafi, John; Chen, Cheng; Bennett, Charles L.

doi:10.1080/14740338.2016.1198775

Cited by 82 publications

(59 citation statements)

References 50 publications

(64 reference statements)

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“…In interpreting our findings, several factors, particularly epidemiology of melanoma, natalizumab‐associated progressive multifocal leukoencephalopathy (PML), various aspects of the TOUCH Risk Management (RiskMAP) Action Plan, and the Safety Surveillance Program in this RiskMAP (Table 3), potential pathophysiology, and an overview of pharmacovigilance efforts for opportunistic complications of medications, should be considered 6, 7, 8, 9, 10, 11, 13, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47.…”

Section: Discussionmentioning

confidence: 99%

“…A longer therapy duration would be expected if natalizumab caused melanoma via an immunologic pathway, unless existing nevi were already premalignant lesions. PML occurs after a long duration of rituximab and a short duration of brentuximab vedotin and ibrutinib (drugs used for hematologic malignancies), and after a variable time period following natalizumab 7, 8, 10, 13, 40, 41, 42, 43, 44, 46.…”

Section: Discussionmentioning

confidence: 99%

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Melanoma complicating treatment with natalizumab for multiple sclerosis: A report from the Southern Network on Adverse Reactions (SONAR)

et al. 2017

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A 43‐year‐old female with multiple sclerosis developed urethral melanoma. The only potential risk factor was treatment with natalizumab, a humanized monoclonal antibody against α4 integrins. To investigate the risk‐exposure relationship, we reviewed this case, all other published cases, and cases of natalizumab‐associated melanoma reported to regulatory agencies. Data sources included the Food and Drug Administration's (FDA) Adverse Event Reporting System (FAERS) (2004–2014), a FDA Advisory Committee Meeting Report, and peer‐reviewed publications. In the United States, the manufacturer maintains an FDA‐mandated Tysabri Safety Surveillance Program (part of the Tysabri Outcomes Unified Commitment to Health (TOUCH)) of natalizumab‐treated patients. We statistically compared reporting completeness for natalizumab‐associated melanoma cases in FAERs for which information was obtained entirely from the TOUCH program versus cases where FAERS information was supplemented by TOUCH program information. FAERS included 137 natalizumab‐associated melanoma reports in patients with multiple sclerosis. Median age at melanoma diagnosis was 45 years (range: 21–74 years). Changes in preexisting nevi occurred in 16%, history of cutaneous nevi occurred in 22%, diagnosis within 2 years of beginning natalizumab occurred in 34%, and 74% had primary surgical treatment. Among seven natalizumab‐treated MS patients who developed biopsy‐confirmed melanoma on treatment and reported in the literature, median age at diagnosis was 41 years (range: 38–48 years); and the melanoma diagnosis occurred following a median of 12 natalizumab doses (range: 1–77 doses). A history of mole or nevi was noted in four patients and a history of prior melanoma was noted in one patient. Completeness scores for reports were significantly lower for FAERS cases reported from the TOUCH program versus FAERS cases supplemented by TOUCH information (median score of 2 vs. 4 items out of 8‐possible items, P < 0.0007). Clinicians should monitor existing nevi and maintain suspicion for melanoma developing in natalizumab‐treated patients. The TOUCH Safety Surveillance Program, currently focused on progressive multifocal leukoencephalopathy, should be expanded to include information on other serious complications including malignancies, particularly if they are immunologic in nature.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Melanoma complicating treatment with natalizumab for multiple sclerosis: A report from the Southern Network on Adverse Reactions (SONAR)

et al. 2017

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“…PML was not reported in ibrutinib-treated patients until recently [15]. A recent review of the FDA's adverse event reporting system detected ten cases of PML in patients treated with ibrutinib, five of them in combination with rituximab [16]. CD8+ T cells are the predominant immune cells found in proximity to PML lesions and are thought to be the primary suppressors of viral resurgence.…”

Section: Discussionmentioning

confidence: 99%

“…Monoclonal antibodies targeting both T and B cells have also been linked to development of PML [17]. With the introduction of targeted cancer therapies such as ibrutinib and idelalisib, their role in the development of PML is starting to evolve [16]. Ibrutinib is the first approved drug that targets the B cell receptor pathway.…”

Section: Discussionmentioning

confidence: 99%

Atypical Infections in Chronic Lymphocytic Leukemia and Mantle Cell Lymphoma Patients Treated with Ibrutinib

Rimon¹,

Wienberger²,

Herzog-Tzarfati³

et al. 2017

J Blood Lymph

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Ibrutinib is an oral Bruton's tyrosine kinase inhibitor with clinical efficacy in several B cell malignancies. In a pooled analysis of clinical trials evaluating ibrutinib, grade 3-4 infections were reported in 14% of patients. We screened consecutive patients on ibrutinib therapy for chronic lymphocytic leukemia (CLL) or mantle cell lymphoma (MCL) for infectious complications. Patients were hospitalized with documented infections uncommon to this patient population including Legionella pneumonia, Campylobacter bacteremia and fatal progressive multifocal leukoencephalopathy (PML). All patients received prior therapies for CLL/MCL. Immunological evaluation of these patients demonstrated immunoglobulin depression and profound lymphopenia with severe depletion in both B and CD4 T cell counts, suggesting defects in both humoral and T cell mediated immunity. This data support a broader immunosuppressive effect for ibrutinib than initially anticipated. While responding patients may show later recovery of B cell function, profound immunosuppression may occur at earlier treatment time points, particularly in previously treated patients. Closer patient monitoring during the first months of ibrutinib therapy may be desirable.

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“…More than 90% of all adults are seropositive for JCV, but symptomatic infection is limited to immunocompromised individuals. Iat-DOI: 10.1159/000490617 rogenic causes of PML have been associated with immunosuppressive antibodies and agents [5]. Here, we report a case of PML associated with ibrutinib use in a patient with chronic lymphocytic leukemia (CLL) and review the impact of ibrutinib on host immunity.…”

Section: Introductionmentioning

confidence: 99%

Ibrutinib Use Complicated by Progressive Multifocal Leukoencephalopathy

et al. 2018

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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.

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Detection of cases of progressive multifocal leukoencephalopathy associated with new biologicals and targeted cancer therapies from the FDA’s adverse event reporting system

Cited by 82 publications

References 50 publications

Melanoma complicating treatment with natalizumab for multiple sclerosis: A report from the Southern Network on Adverse Reactions (SONAR)

Melanoma complicating treatment with natalizumab for multiple sclerosis: A report from the Southern Network on Adverse Reactions (SONAR)

Atypical Infections in Chronic Lymphocytic Leukemia and Mantle Cell Lymphoma Patients Treated with Ibrutinib

Ibrutinib Use Complicated by Progressive Multifocal Leukoencephalopathy

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