Rituximab for Treatment of Resistant Inhibitors in Severe Haemophilia a: A Consecutive National Cohort.
Authors: Liesner Raina , Mathias Mary , Hanley John , Keenan Russell , Keeling David M. , Laffan Michael , Chalmers Elizabeth , Hay Charles R.M. , Maclean Rhona , Rangarajan Savita , Williams Mike , Perry David J. , Collins Peter 
Published: April 2020

Patients with severe haemophilia A (SHA, FVIII &lt;1 IU/dL) and inhibitors to factor VIII, who are resistant to standard immune tolerance (ITI), often have significant morbidity and progressive arthropathy and may be extremely challenging and expensive to manage. Recently, the use of rituximab to treat resistant inhibitors has attracted much interest. Our review of the world literature (July 2008) identified 28 case reports of patients with SHA and inhibitors treated with rituximab. 16 of 28 (57%) achieved an undetectable Bethesda titre. Of the patients who received concomitant FVIII, 15 of 20 (75%) achieved a negative Bethesda titre compared with 1 of 7 (14%) of those treated without FVIII. These data, however, are potentially unreliable because positive outcomes are more likely to be reported and follow up is often short, with relapses unlikely to be reported. We, therefore, collected information on all patients in the UK with SHA treated with rituximab for resistant inhibitors until May 2008. There were 15 patients from 7 centres (9 included in world literature) with a median age of 6 (range 2–37) yrs. There was a disproportionate number of Africans in the cohort compared to the UK population. All had failed at least one previous ITI. Patients were initially treated with 4 weekly doses of rituximab at 375mg/m2, 12 received concomitant FVIII and 4 received additional immunosuppression. One patient had headaches and nausea at the time of the rituximab. Median follow up was 104 (range 30–256) weeks. CR was defined as a negative Bethesda titre, PR as an inhibitor titre &lt;5BU with measurable FVIII recovery or clinical improvement.

Age Yrs Ethnicity Mutation Historic peak titre BU/ml No. failed ITI No. Ritux doses FVIII regimen Immuno suppress Time to negative Bethesda Weeks or lowest titre ( ) Relapse Time to relapseWeeks 2nd CR WeeksFollow up Negative Bethesda 3 Cauc C6124T 162 2 4 100/kg/d No 4 Yes 43 No 58 12 Cauc C6496T 125 4 4 To keep FVIII &gt;5IU/dL Vincrist Steroid 4 Yes 156 Yes 204 11 Cauc C1336T 59 1 4 200/kg/d No 44 Yes x2 56 Yes 256 4 Cauc Inv 22 900 1 4 100/kg x3/week Steroid azathio 24 No NA NA 182 10 African Del exon 14 292 2 4 200/kg/d No 84 No NA NA 104 Partial response 3 African Del C5620 369 1 4 200/kg/d No (0.7) No NA NA 84 2 African Inv 22 39 1 4 200/kg/d No (0.5) No NA NA 56 7 African Inv 22 222 1 4 200/kg/d No (1.8) No NA NA 30 4 African G1595A 700 1 4+4 200/kg/d No (1) No NA NA 108 6 Cauc Inv 22 510 2 4+2 200/kg/d Vincrist steroid (1) Yes 2 NA 46 No response 13 African No data 28 1 4 None No NA NA NA NA 104 16 Asian Del intron 18–21 &gt;4000 2 4 None No NA NA NA NA 156 6 Cauc Frame shift C1876 780 1 4 200/kg/d Steroid NA NA NA NA 156 2 African Inv 22 6300 1 4 200/kg/d No NA NA NA NA 56 37 Cauc No data 780 1 4 None No NA NA NA NA 104

A negative Bethesda titre was achieved in 5 patients (33%) and was sustained in 2 (13%). Of the 3 who relapsed, 2 achieved a second negative Bethesda after further treatment (one with FVIII and one with FVIII + rituximab). The other did not respond to further rituximab without FVIII. Of the 5 patients with a PR one relapsed but 4 continue to be managed on FVIII with prolonged follow up and without significant bleeding. They appear to have been converted from high to low responders. Therefore, 8 of 15 (53%) of patients have had a prolonged benefit from rituximab treatment. There were 5 non responders, including all 3 who did not receive concomitant FVIII. Therefore, 8 of 12 (67%) patients who received FVIII had a clinical benefit. These data are a consecutive national cohort with prolonged follow up and are therefore less likely to be affected by reporting bias. The results are inferior to the published literature but demonstrate that, in patients with SHA and inhibitors resistant to standard ITI, rituximab in association with FVIII leads to sustained clinical improvement in a significant proportion of patients, although complete eradication of the inhibitor is uncommon.