Nivolumab-Induced Hemophilia A Presenting as Gastric Ulcer Bleeding in a Patient With NSCLC

Abstract

A 68-year-old man was diagnosed with metastatic lung squamous cell carcinoma. He had a tumor proportion score for programmed cell death–1 (PD-1) ligand of 80% (clone 22C3), manifested disease progression after carboplatin–S-1 therapy, and was then treated with nivolumab at 3 mg/kg every 2 weeks. He achieved a near complete response and continued treatment. After 17 months, he was admitted to our department with melena and anemia, and upper gastrointestinal endoscopy revealed gastric ulcer bleeding (Fig. 1A). He was diagnosed with nonsteroidal anti-inflammatory drug–related ulcer because he took diclofenac sodium without a proton-pump inhibitor. Repeated therapeutic endoscopic procedures failed to stop the bleeding. Coagulation tests revealed a prolonged activated partial thromboplastin time (APTT) of 71 s, although his APTT was normal (28 s) before carboplatin–S-1 therapy. His factor VIII (FVIII) level was 3% (normal reference, 60% to 150%) and his FVIII inhibitor level was 15 Bethesda units (normal reference, undetectable). The patient reported no personal or family history of hemophilia A or bleeding, giving rise to a diagnosis of acquired hemophilia A (AHA). The patient was given oral prednisone at 1 mg/kg daily, but the gross bleeding persisted, leading to hemorrhagic shock and acute prerenal failure. Intravenous cyclophosphamide (15 mg/kg) and recombinant activated factor VII (rFVIIa) were then administered. The bleeding stopped within 1 week. A follow-up endoscopy performed 3 weeks after initiation of cyclophosphamide and rFVIIa revealed amelioration of gastric ulcer (Fig. 1B). AHA is a rare hemorrhagic disorder caused by autoantibodies to FVIII. Mucocutaneous, soft tissue, or gastrointestinal bleeding is common in AHA, but the rarity of the disorder tends to result in delayed diagnosis and treatment.1Kruse-Jarres R. Kempton C.L. Baudo F. et al.Acquired hemophilia A: updated review of evidence and treatment guidance.Am J Hematol. 2017; 92: 695-705Crossref PubMed Scopus (182) Google Scholar AHA has been associated with autoimmune diseases, childbirth, hematologic or solid cancers, or certain medications.1Kruse-Jarres R. Kempton C.L. Baudo F. et al.Acquired hemophilia A: updated review of evidence and treatment guidance.Am J Hematol. 2017; 92: 695-705Crossref PubMed Scopus (182) Google Scholar Approximately 10% of AHA patients were found to have a malignancy, and several cases of NSCLC associated with the presence of FVIII inhibitors have been described.1Kruse-Jarres R. Kempton C.L. Baudo F. et al.Acquired hemophilia A: updated review of evidence and treatment guidance.Am J Hematol. 2017; 92: 695-705Crossref PubMed Scopus (182) Google Scholar, 2Kondo H. Shigekiyo T. Kojima A. et al.Acquired factor VIII inhibitor in a patient with adenocarcinoma of the lung.Jpn J Clin Oncol. 1992; 22: 49-53PubMed Google Scholar, 3Aggelopoulou E. Evangelatos G. Tzavida K. et al.Acquired hemophilia and anti-Hu paraneoplastic neurologic syndrome in small cell lung cancer.Am J Med Sci. 2017; 354: 438-439Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar The pathogenesis of FVIII inhibitor production in cancer patients is not known, but it might be the result of a B cell–mediated autoimmune response directed against an antigen shared by the tumor and FVIII. In the present case, however, the patient achieved a long-lasting response to nivolumab, with seriate radiologic evaluation showing sustained disease regression. Lung cancer was therefore not likely the cause of AHA in this patient. The generation of autoantibodies to FVIII has been attributed to drugs such as interferon.1Kruse-Jarres R. Kempton C.L. Baudo F. et al.Acquired hemophilia A: updated review of evidence and treatment guidance.Am J Hematol. 2017; 92: 695-705Crossref PubMed Scopus (182) Google Scholar Ipilimumab-induced hemophilia A in a melanoma patient was also recently described.4Delyon J. Mateus C. Lambert T. Hemophilia A induced by ipilimumab.N Engl J Med. 2011; 365: 1747-1748Crossref PubMed Scopus (71) Google Scholar Although the mechanisms of how anti–PD-1 therapy modulates autoimmunity to such hematologic disorders remain unclear, widespread activation of T cells induced by anti–PD-1 therapy might lead to autoantibody production.5Postow M.A. Sidlow R. Hellmann M.D. Immune-related adverse events associated with immune checkpoint blockade.N Engl J Med. 2018; 378: 158-168Crossref PubMed Scopus (2135) Google Scholar The present case of AHA was therefore likely related to nivolumab therapy. In addition to elimination of the underlying condition responsible for triggering the FVIII autoantibodies, the therapeutic strategy for patients with AHA includes treatment of the acute bleeding episodes and eradication of the autoantibodies.1Kruse-Jarres R. Kempton C.L. Baudo F. et al.Acquired hemophilia A: updated review of evidence and treatment guidance.Am J Hematol. 2017; 92: 695-705Crossref PubMed Scopus (182) Google Scholar For a life-threatening hemorrhage, bypass agents (rFVIIa and activated prothrombin complex concentrate) are considered as the preferred first-line treatment option.1Kruse-Jarres R. Kempton C.L. Baudo F. et al.Acquired hemophilia A: updated review of evidence and treatment guidance.Am J Hematol. 2017; 92: 695-705Crossref PubMed Scopus (182) Google Scholar Actually, gastric ulcer bleeding of the current case was successfully controlled by administration of rFVIIa. On the other hand, the two most common immunosuppressive therapies for eradication of inhibitory autoantibodies are administration of corticosteroids either alone or in combination with cyclophosphamide.1Kruse-Jarres R. Kempton C.L. Baudo F. et al.Acquired hemophilia A: updated review of evidence and treatment guidance.Am J Hematol. 2017; 92: 695-705Crossref PubMed Scopus (182) Google Scholar In our case, prednisone was discontinued to avoid exacerbation of gastric ulcer bleeding and cyclophosphamide was administered. It is recommended to monitor with FVIII levels and inhibitor titers regularly until the inhibitor becomes undetectable and FVIII activity levels normalize.1Kruse-Jarres R. Kempton C.L. Baudo F. et al.Acquired hemophilia A: updated review of evidence and treatment guidance.Am J Hematol. 2017; 92: 695-705Crossref PubMed Scopus (182) Google Scholar Immunosuppressive therapy including cyclophosphamide achieved remission of anti-FVIII autoantibodies in approximately 60% to 80% of patients after a median of 5 to 6 weeks.1Kruse-Jarres R. Kempton C.L. Baudo F. et al.Acquired hemophilia A: updated review of evidence and treatment guidance.Am J Hematol. 2017; 92: 695-705Crossref PubMed Scopus (182) Google Scholar As far as we are aware, this is the first detailed description of the development of AHA presenting as gastric ulcer bleeding in a patient with NSCLC treated with nivolumab. Hematologic adverse events are rare but have been documented with immune checkpoint inhibitors (Table 1).6Nair R. Gheith S. Nair S.G. Immunotherapy-associated hemolytic anemia with pure red-cell aplasia.N Engl J Med. 2016; 374: 1096-1097Crossref PubMed Scopus (59) Google Scholar, 7Gordon I.O. Wade T. Chin K. et al.Immune-mediated red cell aplasia after anti-CTLA-4 immunotherapy for metastatic melanoma.Cancer Immunol Immunother. 2009; 58: 1351-1353Crossref PubMed Scopus (62) Google Scholar, 8Shiuan E. Beckermann K.E. Ozgun A. et al.Thrombocytopenia in patients with melanoma receiving immune checkpoint inhibitor therapy.J Immunother Cancer. 2017; 5: 8Crossref PubMed Scopus (87) Google Scholar, 9Brahmer J.R. Lacchetti C. Schneider B.J. et al.Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline.J Clin Oncol. 2018; 36: 1714-1768Crossref PubMed Scopus (1961) Google Scholar With the increasing use of nivolumab, physicians should be aware of this serious side effect.Table 1Rare Hematologic Adverse Events Associated With Immune Checkpoint InhibitorsHematologic Adverse EventGeneral Treatment StrategiesReferenceHemolytic anemiaPrednisoneIf no improvement, consider additional immunosuppression such as rituximab, IVIG, cyclosporine, and mycophenolate mofetil6Nair R. Gheith S. Nair S.G. Immunotherapy-associated hemolytic anemia with pure red-cell aplasia.N Engl J Med. 2016; 374: 1096-1097Crossref PubMed Scopus (59) Google ScholarPure red blood cell aplasiaPrednisoneIf no improvement, consider additional immunosuppression such as cyclosporine, cyclophosphamide, and IVIG6Nair R. Gheith S. Nair S.G. Immunotherapy-associated hemolytic anemia with pure red-cell aplasia.N Engl J Med. 2016; 374: 1096-1097Crossref PubMed Scopus (59) Google Scholar, 7Gordon I.O. Wade T. Chin K. et al.Immune-mediated red cell aplasia after anti-CTLA-4 immunotherapy for metastatic melanoma.Cancer Immunol Immunother. 2009; 58: 1351-1353Crossref PubMed Scopus (62) Google ScholarThrombocytopeniaPrednisoneIVIG may be used with prednisone when a more-rapid increase in platelet count is required8Shiuan E. Beckermann K.E. Ozgun A. et al.Thrombocytopenia in patients with melanoma receiving immune checkpoint inhibitor therapy.J Immunother Cancer. 2017; 5: 8Crossref PubMed Scopus (87) Google ScholarAcquired hemophiliaAcute bleeding episodes: bypass agents (rFVIIa, activated prothrombin complex concentrate)Inhibitor eradication: prednisone alone or with cyclophosphamide4Delyon J. Mateus C. Lambert T. Hemophilia A induced by ipilimumab.N Engl J Med. 2011; 365: 1747-1748Crossref PubMed Scopus (71) Google ScholarIVIG, intravenous immunoglobulin; rFVIIa, recombinant activated factor VII. Open table in a new tab IVIG, intravenous immunoglobulin; rFVIIa, recombinant activated factor VII.