A Diagnostic of Acquired Hemophilia Following PD1/PDL1 Inhibitors in Advanced Melanoma: The Experience of Two Patients and a Literature Review

Abstract

Acquired hemophilia A (AHA) is a rare bleeding disorder caused by the development of specific autoantibodies against factor VIII (FVIII). Immunotherapy is a recent therapeutic option that targets the patient’s self-tolerance against tumor cells. Because therapeutic effects of the immune checkpoint inhibitors (ICIs) are mediated by enhancing the immune response to restore antitumor immunity, autoimmune-related adverse effects can be seen in up to 80% of patients during treatment and after treatment. A rare hematologic ICIs-related adverse event is AHA. Hereafter we report two cases of AHA developed during anti-PD-1 immunotherapy for advanced melanoma: one secondary to treatment with nivolumab and one secondary to pembrolizumab. Both patients were treated with activated FVII (Novoseven®, Novo Nordisk, Bagsværd, Denmark) as hemostatic treatment combined with the eradication of antibodies anti-FVIII obtained with rituximab. In the last few years these drugs have significantly improved the therapeutic armamentarium for the management of AHA. Indeed, while FVIIa has proven to be an effective and safe tool for the treatment of acute bleeding related to FVIII autoantibodies, rituximab is a promising alternative for the autoantibodies’ elimination and the restoration of normal hemostasis. Our finding supports the use of this combination even in AHA secondary to ICIs treatment.

Acquired bleeding disorders secondary to immune checkpoint inhibitors: a case report and systematic literature review

“…Refer to Table 1 for a description of reported cases of acquired factor inhibitors and aVWD by systematic review of the literature. Six cases of AHA were identified, one case of aVWD, and one case of factor V inhibitor were identified in the literature [3][4][5][6][7][8]. The median time to onset was 6.5 weeks (range: 2-68 weeks).…”

Rare Immune-Related Adverse Events (irAEs): Approach to Diagnosis and Management

“…This is a rare bleeding disorder associated with auto-antibodies to factor VIII. Onset tends to be early and has been reported between 8 to 14 weeks after commencing ICIs [ 68 , 69 ]. Patients generally present with bleeding, which can be severe and life-threatening.…”

“…Bleeding manifestations tend to be into skin, muscle, mucous membranes, gastrointestinal and urinary tract. Laboratory analyses demonstrate prolonged APTT, not correcting with mixing of normal plasma and evidence of an acquired factor VIII inhibitor [ 49 , 68 ]. Patients have been successfully treated with corticosteroids, recombinant factor VII, rituximab and cyclophosphamide [ 69 – 71 ].…”

Durable remission of thrombotic thrombocytopenic purpura in the setting of pembrolizumab therapy

“…Due to the immune upregulating effects of Pembrolizumab and other immune checkpoint inhibitors, various immune mediated side effects have been reported with these medications including colitis, dermatitis, hepatitis, pneumonitis, and immune mediated thrombocytopenia, among others (incidence rate of ~27%) 3,4 . Pembrolizumab itself has been reported to be associated with type 1 diabetes, acquired hemophilia, neuromyelitis optica spectrum disorder, myasthenia gravis, and giant cell arteritis 5–9 . This report details a case of thrombotic thrombocytopenic purpura in a patient treated with pembrolizumab.…”

“…3,4 Pembrolizumab itself has been reported to be associated with type 1 diabetes, acquired hemophilia, neuromyelitis optica spectrum disorder, myasthenia gravis, and giant cell arteritis. [5][6][7][8][9] This report details a case of thrombotic thrombocytopenic purpura in a patient treated with pembrolizumab.…”