Inhibitor Eradication In Acquired Haemophilia A: Final Results of European Acquired Haemophilia Registry (EACH2)
Authors: Collins Peter W , Baudo Francesco , Knoebl Paul , Levesque Herve , Nemes Laszlo , Pellegrini Fabio , Tengborn Lilian , Huth-Kuehne Angela 
Published: October 2019

Abstract 715

The optimal first line immunosuppression (IS) for eradicating factor (F)VIII inhibitors in acquired haemophilia A (AHA) is controversial. Steroids and cyclophosphamide are commonly used and there has been recent interest in the role of rituximab. Prospective randomised controlled trials (RCTs) would be challenging and in their absence registries may provide useful data to guide clinical practice. EACH2 collected data on 281 analysable patients who received first line IS. Complete remission (CR) was defined as inhibitor undetectable, FVIII>70IU/dL and IS stopped. Stable CR was defined as CR without relapse. A higher proportion of patients achieved CR with steroids and a cytotoxic (predominantly cyclophosphamide) (77%) than those treated with steroids alone (58%) (P<0.005) or a rituximab based regimen (61%) (P<0.02). The 12 patients treated with rituximab alone had the lowest proportion achieving CR (42%). Median time to normal FVIII and undetectable inhibitor was similar in the steroid alone and steroid and cytotoxic groups (about 5 weeks) but slower in those treated with a rituximab based regimens (about 9 weeks), although this was in part due to the slow response of patients treated with rituximab alone. Relapse was most common after initial treatment with steroids alone (19%). In this group relapse was diagnosed a median (range) 134 (13-695) days after stopping IS. In contrast, only 1 patient (4%) who achieved a CR with a rituximab based regimen relapsed. Stable CR after first line treatment was highest after steroids plus a cytotoxic (67%) and rituximab plus another IS (64%). Stable CR was lower in the steroids alone (48%) and rituximab alone groups (42%). Patients who achieved CR after first line IS had higher FVIII and lower inhibitor titres compared with those who did not, median (IQR) for FVIII 2 (1-7) compared to 1 (1-4)IU/dL (P<0.005) and inhibitor titre 13 (4-45) compared to 31 (7-75)BU/mL P<0.03. To minimise bias, propensity score matched analysis based on age, weight, gender, FVIII level, inhibitor titre and underlying aetiology was performed to compare oral prednisone plus oral cyclophosphamide with oral prednisone alone (n=70 in each arm). This showed an odds ratio (95% CI) of achieving a stable CR of 3.25 (1.51-6.99) (P<0.003) in favour of combined treatment despite the prednisone alone group being treated with a higher mean dose of prednisone/kg (P<0.005). There were insufficient patients to perform a propensity score matched analysis with the rituximab group. There was no statistically significant difference in survival between the groups and similarly a proportion of patients were alive and in CR at final follow up (FU), median (IQR) FU was 246 (66-665) days. In conclusion, stable CR after first line IS was more likely following combination therapy with oral prednisone and cyclophosphamide than oral prednisone alone. Although a lower proportion of patients achieved CR with rituximab based regimens than steroids plus cytotoxics the lower relapse rate resulted in a comparable proportion achieving stable CR. Stable CR after rituximab alone was low, although there were only 12 patients. These are the best data available to date relating to the response to first line IS in AHA and will be useful for informing treatment guidelines and designing future RCTs.

Table. Outcome of first line immunosuppression (IS) for AHA. Regimen Age Years FVIII at diagnosis (IU/dL) Inhibitor titre at diagnosis (BU/mL) CR after 1st line IS N (%) Days from start of IS Relapse (%) Stable CR after 1st line IS % Alive and in CR at final FU % Inhibitor -ve FVIII >70 IU/dL IS stopped Steroids alone n=142 75 (63–81) 3 (1–6) 13 (5–43) 83 (58) 34 (17–76) 32 (15–51) 108 (55–208) 19 48 60 13–104 0–28 0.1–1020 5–321 3–551 11–1169 Steroids and cytotoxics n=88 76 (63–80) 1 (1–4) 22 (8–67) 68 (77) 32 (12–77) 40 (18–81) 74 (52–151) 14 67 60 16–101 0–34 0.4–2800 0–386 2–386 1–386 All rituximab regimen n=51 74 (5–78) 2 (0–7) 16 (6–62) 31 (61) 65 (29–144) 64 (28–206) 43 (22–96) 4 59 67 14–104 0–20 0.1–2176 10–436 10–569 17–257 Rituximab plus another IS n=39 75 (57–78) 2 (0–7) 16 (9–62) 26 (67) 47 (28–96) 38 (28–141) 55 (26–96) 4 64 61 14–104 0–20 0.1–2176 10–436 10–569 17–257 Rituximab alone n=12 69 (65–77) 1 (0–8) 16 (3–71) 5 (42) 53, 145, 209, 334* 145, 209, 252, 334* 21, 21, 21, 21, 22* 0 42 70 50–85 0–15 1–460 Data are median, interquartile range (IQR) and range, * actual days due to low number of patients.

Disclosures:

Collins: NovoNordisk: Consultancy, Honoraria, The EACH2 registry was funded by Novonordisk; Baxter Healthcare: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Off Label Use: The use of Rituximab for the treatment of acquired haemophilia. Baudo:NovoNordisk: Consultancy, Honoraria, NovoNordisk fund the EACH2 registry, Speakers Bureau; Bayer Healthcare: Honoraria, Speakers Bureau. Knoebl:NovoNordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees, NovoNordisk fund the EACH2 registry, Research Funding; Baxter Healthcare: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Levesque:NovoNordisk: NovoNordisk fund the EACH2 registry. Nemes: NovoNordisk: Novonordisk fund the EACH2 registry. Pellegrini:Novonordisk: Consultancy, Honoraria, Speakers Bureau, The EACH2 registry is funded by Novonordisk. Tengborn:NovoNordisk: NovoNordisk fund the EACH2 registry. Huth-Kuehne:NovoNordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees, NovoNordisk fund the EACH2 registry; Baxter Healthcare: Consultancy, Membership on an entity's Board of Directors or advisory committees.