Report Details Rare Case of Acquired Hemophilia A Secondary to Immune Checkpoint Inhibition

A case report published in JTO Clinical and Research Reports chronicles a patient who acquired hemophilia A during treatment with an immune checkpoint inhibitor (ICI). This rare immune-related adverse event (irAE) has only been previously reported 4 times in the context of ICI treatment.

Acquired hemophilia A (AHA) occurs when a patient develops clotting factor VIII (FVIII) autoantibodies but has no history of bleeding disorders. Hemophilia is characterized by spontaneous bleeding events that may be life threatening, and up to half of AHA cases may have unknown origins. While it is rare, AHA has been associated with autoimmune or inflammatory diseases and other conditions.

The case report marks the fifth time AHA in the context of ICI use has been documented. A 56-year-old man diagnosed with extensive-stage SCLC (ES-SCLC) was given 4 cycles of palliative therapy including carboplatin, etoposide, and atezolizumab. Subsequent CT scans showed a significant partial response to the regimen. After 16 months of disease control on atezolizumab, the patient developed asymptomatic normocytic anemia. An outpatient hematologic investigation and blood transfusion were done.

The hematologic investigation showed recurrent anemia and potential FVIII inhibitor acquisition, although there was no clinical evidence of bleeds, bruising, SCLC progression, or decompensated liver disease. AHA was diagnosed based on reduced FVIII activity and further signs of acquired FVIII inhibitors. In this case, AHA was considered most likely to be an irAE based on the use of atezolizumab and the absence of signs that the condition may have arisen from other known causes.

Blood transfusion was the first management strategy, then clotting factor correction and suppression of factor inhibition were implemented. Atezolizumab was also discontinued. A week later, the patient returned to the hospital presenting with a hematoma in the left upper limb and chest wall. He initially responded to prednisone, then continued on prednisone while receiving transfusion support.

Despite responding to treatment initially, the hematoma progressed, and the left shoulder showed new hemarthrosis in imaging studies. The patient received 3 doses of activated recombinant factor VII over 6 hours, then was started on 100g of rituximab weekly before discharge.

Prednisone was reduced to 15mg and over the following 4 weeks, and a total of 4 doses of rituximab were administered. Three months after initial presentation, a positron emission tomography with CT showed a complete metabolic response and there were no further bleeding events.

This case, taken with the previous 4 reported cases of ICI-induced AHA, show that while rare, this severe irAE can occur and has been successfully treated with hemostatic factor support as well as immunosuppression. The escalation of immunosuppression—in this case with rituximab—was also effective and within published guidelines. In this case and others, elevated activated partial thromboplastin time was persistent and FVIII inhibitors remained for months, even after clinical improvements.

AHA has also been associated with ES-SCLC itself, and the authors highlighted another case of AHA secondary to ES-SCLC but prior to treatment. AHA was successfully treated with corticosteroids to eradicate FVIII inhibitors ahead of chemotherapy, and the disease was under control for more than a year without FVIII inhibitor recurrence. Considering a paraneoplastic cause is important when diagnosing AHA after ICI use, but it can be difficult to differentiate.

Overall, the case highlights the possibility of severe irAEs with ICI use and the importance of clinician awareness.

“Clinicians should be alert to the possibility of severe immune-related hematologic toxicity secondary to ICIs,” the authors concluded. “The management of immune-mediated AHA was in keeping with published guidelines, and to date, all reported cases have revealed improvement with factor support and immunosuppression.” Further research is still needed to determine the longer-term outcomes of AHA secondary to ICIs.

Reference

Fletcher J, Bird R, McLean A, O’Byrne K, Xu W. Acquired hemophilia A secondary to an immune checkpoint inhibitor: a case report. JTO Clin Res Rep. Published online September 19, 2022. doi:10.1016/j.jtocrr.2022.100409