Combined immunosuppression for acquired hemophilia A: CyDRi is a highly effective low-toxicity regimen

Abstract

Acquired hemophilia A (AHA) is a rare severe autoimmune bleeding disorder with significant morbidity and mortality. Although critical for disease control, there is no consensus for the best immunosuppressive regimen. Most authors use steroids first line, followed by other agents for steroid failures. Upfront combined regimens offer the advantage of reduced steroid exposure and toxicity as well as increased efficacy. We retrospectively analyzed data from 32 patients with AHA treated on an identical such institutional protocol: cyclophosphamide 1000 mg on days 1 and 22, dexamethasone 40 mg on days 1, 8, 15, and 22, and rituximab 100 mg on days 1, 8, 15, and 22 (the regimen was termed CyDRi). All patients received at least 1 cycle of CyDRi. If necessary, CyDRi was repeated until remission, no sooner than day 43 of the previous cycle. Bleeding control was rapidly achieved. The median time for bleeding control was 15.5 days (range, 0-429 days; interquartile range, 2.5-29.5 days). Thirty-one (96.8%) of 32 patients achieved durable complete remission (CR); 29 (90.6%) of 32 patients were alive at last follow-up, all of them in CR. The median time to reach first CR was 77 days (range, 19-939 days; interquartile range, 31-115 days). Toxicity and side effects were acceptable and milder than those of commonly used, prolonged steroid therapies. In conclusion, the CyDRi regimen produced markedly higher CR rates and overall survival than currently used sequential regimens. Taken together, CyDRi proved to be an attractive option for the immunosuppression of elderly patients with AHA.

Graphical abstract

Figure 1.

Overall survival of the cohort treated with CyDRi. Kaplan-Meier curve was plotted for the entire cohort (N = 32). Median follow-up was 779.5 (range, 27-3319; IQR, 455.5-1868.2) days. For each patient, day 1 was the day of first admission, which was typically also day 1 of the first cycle of CyDRi.

Figure 2.

Bleeding control in the cohort treated with CyDRi. Kaplan-Meier curve was plotted for the entire cohort (N = 32). Median time to bleeding control was 15.5 (range, 0-429; IQR, 2.5-29.5) days. Median follow-up for the cohort was 779.5 (range, 27-3319; IQR, 455.5-1868.2) days.

Figure 3.

First CR. (A) Kaplan-Meier curves were plotted for the entire cohort (N = 32). TTCR was median 77 (range, 19-939; IQR, 31-115) days. There were 31 remission events in the cohort (96.9%). (B) Kaplan-Meier curves for CR were plotted for 2 subgroups: patients with high titer (>20 BU, 14 patients) and low titer (≤20 BU, 18 patients) anti-FVIII antibodies (P = .009). Median follow-up for the cohort was 779.5 (range, 27-3319; IQR, 455.5-1868.2) days.

Figure 4.

First CR duration. For this analysis, Kaplan-Meier curves were plotted from time 0, the time when patients achieved a first CR. Relapses were not considered as separate events in this analysis (n = 31 CR events). (A) CR duration of the entire cohort (n = 31). (B) In the comparison of 2 subgroups (patients with high [>2] and low [≤2] comorbidity index), there were 8 and 23 remission events, respectively (P = .002). Median observation time after first CR was a median of 630 (range, 17-3178; IQR, 280.5-1577.0) days. For the 3 relapses, subsequent CR durations ranged from 161 to 1385 days (median, 1372 days).