Yuhan Fu,Shu Chen,Anzi Wang,Jingyuan Luo,Qing Li
Combining Low-Dose Rituximab and Bortezomib as Immunosuppressive Therapy for Acquired Hemophilia A: 6 Case Series
Acquired hemophilia A,Immunosuppression treatment,Bortezomib,Rituximab
Acquired hemophilia A (AHA) is a rare bleeding disorder caused by autoantibodies against factor VIII. Persistently positive inhibitor titers increase the risk of bleeding. Upfront combined regimen with multiple mechanisms has the potential to shorten remission time to lower bleeding risk and reduce immunosuppressor exposure time. We administered lowered dose of rituximab and bortezomib in combination with corticosteroids and cyclophosphamide (rituximab: 100 mg weekly × 4 or 500 mg once in week 1, bortezomib: 0.65 mg/m2 once in week 1, prednisone: 1 mg/kg daily, cyclophosphamide: 11.5–2 mg/kg daily). We retrospectively analyzed 6 cases (male = 3, female = 3, median age = 51 years) treated on this therapeutic regimen. All patients achieved complete remission (range from19 to 66 days); adverse event: infection (1/6). This is the first time that this regimen has been reported for treating AHA. It has shown good therapeutic efficacy and the potential to shorten the time to CR. The incidence of adverse events is within a reasonable range. This regimen is feasible and offers a new alternative treatment for AHA.
Combining Low-Dose Rituximab and Bortezomib as Immunosuppressive Therapy for Acquired Hemophilia A: 6 Case Series

Acquired hemophilia A (AHA) is a rare bleeding disorder caused by autoantibodies against factor VIII. Persistently positive inhibitor titers increase the risk of bleeding. Upfront combined regimen with multiple mechanisms has the potential to shorten remission time to lower bleeding risk and reduce immunosuppressor exposure time. We administered lowered dose of rituximab and bortezomib in combination with corticosteroids and cyclophosphamide (rituximab: 100 mg weekly × 4 or 500 mg once in week 1, bortezomib: 0.65 mg/m2 once in week 1, prednisone: 1 mg/kg daily, cyclophosphamide: 11.5–2 mg/kg daily). We retrospectively analyzed 6 cases (male = 3, female = 3, median age = 51 years) treated on this therapeutic regimen. All patients achieved complete remission (range from19 to 66 days); adverse event: infection (1/6). This is the first time that this regimen has been reported for treating AHA. It has shown good therapeutic efficacy and the potential to shorten the time to CR. The incidence of adverse events is within a reasonable range. This regimen is feasible and offers a new alternative treatment for AHA.

Acquired hemophilia A (AHA) is a rare, life-threatening bleeding disorder caused by autoantibodies against coagulation factor VIII (FVIII). Its incidence is approximately 1 to 1.5 per million population per year [1, 2], which occurs mainly in the elderly. About half cases are idiopathic. Common causes include malignancy, autoimmune disorders, infections, postpartum state, dermatologic conditions and certain medications [2–4]. Recently, acquired hemophilia post-COVID-19 vaccination has also been reported [5]. Eradicating inhibitors is the fundamental treatment for curing AHA. All adults should accept immunosuppressive treatment (IST) as soon as they are diagnosed [6, 7]. In general, IST response rates are high, but the time to CR can be very long, increasing the risk of bleeding and the time of steroids exposure. Therefore, we tried a upfront multidrug combination regimen aimed at shortening response times as well as achieving higher response rates. Steroids, cyclophosphamide and rituximab are commonly used medication to treat AHA, but bortezomib is rarely used. McFadyen et al. [8] and Zhou et al. [9] respectively reported bortezomib monotherapy in successfully eradicating inhibitors in an AHA patient as second-line after rituximab and cyclophosphamide and as directly first-line therapy. These provide clinical evidence to manage AHA with bortezomib. Bortezomib could help to clear inhibitors by effectively depleting plasma cells. The combination of these four drugs is able to remove inhibitors from a broader range of immunosuppressive mechanisms. Considering the potential for increased IST-related toxicity with multidrug combination, we used low doses of rituximab and bortezomib. We report 6 cases of acquired hemophilia patients treated with this therapeutic regimen from 2021 in our center. It showed good curative effect and potency in shortening time to CR.

In this retrospective case series, 6 patients with a confirmed diagnosis of AHA admitted to the Second Affiliated Hospital of Chongqing Medical University from 2021.9 to 2022.9 were included in this case series. All patients manifested with unknown etiology of bleeding accompanied by isolated prolonged aPTT. All patients were diagnosed using aPTT mixed study, coagulation factor measurement, FVIII autoantibody detection(Bethesda assay), and autoimmune disease screening. The four-drug combination regimen consists of: low-dose rituximab (100 mg IV weekly × 4 or 500 mg once in week 1), low-dose bortezomib (0.65 mg/m2 IV once in week 1), prednisone (1 mg/kg PO daily for maximum of 6 weeks), cyclophosphamide (1.5–2 mg/kg PO daily for maximum of 6 weeks). Usually, the dose of prednisone was gradually reduced after two consecutive decreasing of inhibitor titer which was examined weekly. Five patients were managed with this regimen as first-line treatment. One patient received this regimen as second-line therapy after initial treatment of prednisone and cyclophosphamide. Complete response (CR) is defined as Inhibitor titer < 0.6 BU/ml, FVIII activity (FVIII:C) ≥ 50%, immunosuppressants are discontinued or restored to premorbid doses. Partial response (PR) is defined as FVIII: C ≥ 50%, inhibitor titer ≥ 0.6 BU/ml, no new bleeding occurred within 24 h after the end of hemostasis. Relapse is defined as FVIII:C < 50% and inhibitor titer ≥ 0.6 BU/ml after complete or partial remission [10, 11].

Data was represented as the median with interquartile range.

Table 1 presents the clinical characteristics of 6 AHA patients managed with our regimen.

Table 2 presents the hemostatic therapy conditions. All patients achieved successful hemostasis. Hemostatic agents included prothrombin complex concentrate (PCC:25–40 iu/kg), rFVIIa (90 µg/kg), fresh frozen plasma (FFP), and cryoprecipitate. Because of financial burden, part patients didn’t accept bypassing agents. Three patients used rFVIIa because of severe or continued bleeding. In particular, rFVIIa presented a better hemostatic effect. Cases 3 and 4 were initially given PCC or FFP, respectively. However, bleeding could not be stopped until we changed to rFVIIa. Case 1 had severe bleeding in the left forearm, which was complicated by development of compartment syndrome, and retroperitoneal hematoma. Patient was treated with rFVIIa 90 µg/kg q3h initially, followed by alternating rFVIIa (90 µg/kg q6 h) and PCC (40iu/kg q6 h) for financial reasons, and the limb was saved. There were no thrombotic events in these patients. Two patients developed long-term complications associated with bleeding: left hand mobility dysfunction from compartment syndrome in case 1 and left femoral nerve injury from iliopsoas hematoma in case 5.

Five patients received this regimen as first-line therapy and all of them achieved CR (19–66 days, median: 49 days). Case 2 received this strategy as second-line treatment (after initiation of prednisone and cyclophosphamide), and the CR time was on day 41 after sequential therapy. One patient with COPD developed fungal pneumonia during the treatment period (28 days after IST). Steroid treatment was discontinued, antifungal therapy was initiated, and cyclophosphamide therapy was continued. It took another 20 days to achieve CR. Two patients experienced relapse after CR (case 1: 97 days, case 4: 46 days). Case 1 relapsed because of a new mild pulmonary infection. The inhibitor titers increased to 1.8 BU/ml accompanied by decreased FVIII:C (36%), prolonged aPTT (65.9 s) and slight ecchymosis. Considering the low inhibitor titer and minimal bleeding on presentation, only anti-infective therapy was initiated, and negative inhibitor was achieved within 2 weeks. Case 4 relapsed without obvious precipitating factors. Patient presented with only slight gingival bleeding, FVIII activity of 21%, and elevated inhibitor titer of 4.8 BU/mL, and was treated with prednisone and cyclophosphamide. Two weeks later, the inhibitor titer turned negative.

In this case series, the CR is 100% (6/6). In patients who received this regimen as first-line therapy, the time to CR is 19 to 66 days(median:49 days). As second-line therapy in a patient, the time to CR is 41 days after sequential therapy, and the total time to CR is 70 days. Infection occurred in a patient(16.7%) and relapse happened in 2 cases(33.3%). Review of findings involving treatment with steroid and cyclophosphamide in large cohorts [11–13], the CR is similar(80–88.5%), relapse is from 5.4 to 12% and infection is from 9.4% to 27%. Time to CR ranged from 14 to135 days(median: 39–139 days). The CR in our series shows a good result. Although there may be occasionality because of small sample, it should be non-inferior even superior compared with steroid combined cyclophosphamide regimen. This is because it is an intensive IST based on corticosteroid combined with cyclophosphamide therapy, and the result is reasonable. The infection (16.7%) and relapse (33.3%) seem relatively high. However, infection and relapse both occurred in one patient with COPD. We consider that it is more related to the underlying disease, COPD, which has high risk of infection, and relapse may be attributed to new pulmonary infection associated with COPD. AHA associated with COPD is infrequent and the relapse and infection may be overestimated. In summary, the relapse and infection rates are in a reasonable range. In particular, the maximum time to CR is relatively short and the time to CR doesn’t vary significantly. Our regimen shows good potential in shortening the time to CR. There are several limitations in our series. Sample size is limited, and all cases were retrospective and there was no control, which may raise potential for selection bias and confounding concerns. It’s necessary to design a prospective cohort study to enrich clinical evidence in the future. Finally, low dose rituximab and bortezomib in addition to steroids and cyclophosphamide is feasible as first- or second-line therapy for AHA and may shorten the time to CR. We did not observe an apparently higher infection risk associated with IST. The age of our case series was relatively young, and whether this regimen increases infection risk in the more elderly is unknown. This regimen may increase infection events in patients who have comorbid conditions with high infection risk like COPD, individual therapy is necessary in such patients. In summary, our treatment strategy offers a new alternative treatment for AHA.