Durable Remissions in Acquired Hemophilia Patients with Inhibitor-Titer-Based Tailoring of Treatment Strategy Optimizing Rituximab Usuage – a Case Series from Single Institution in Saudi Arabia
Authors: Zaidi Syed Ziauddin A. , Iqbal Shahid , Tailor Imran Khan , Motabi Ibraheem H , Al-Shehry Nawal F , Elghazaly Assem Abdelkhalik , Al-Mudaibigh Samer , Zaidi AbdulRehman Z , Al-Humaidi Abdulaziz 
Published: October 2019

Abstract
Acquired Hemophilia (AH) may lead to fatal bleeds. Relapse remains a major challenge as 1/3 of patients with AH do not achieve durable CR with immunosuppressive therapies (IST). Patients’ acceptance for cyclophosphamide (being a chemotherapeutic agent) for treating AH remains poor as compared to biological agent rituximab (R) and steroids (St). However, when fixed number of doses of R are utilized along with prolonged courses of St, considerable morbidity is seen.
In quest of durable remission and prevention of relapse, we hypothesized that a strategy of targeting antibody producing B cells along with inhibitor (Inh) monitoring and titrated number of R doses earlier in the course of therapy with one additional dose beyond complete disappearance of Inh may result in better chances of prolonged remission and even cure.
Here we report excellent outcome with our strategy used for three consecutive patients including a patient with multiple relapses and high titer Inh (819 BU) in whom all other therapies had failed to produce durable remission. Median time to CR from addition of R was 6 weeks (range 3-6). With a median follow up of 16-72 months none has relapsed yet.
CASE #1
A student was diagnosed to have bleeding diathesis in November 2007 in Kuwait at the age of 13 years and was treated with FFP, FVIII, rFVIIa and St. He presented in December 2007 to pediatric hematology complaining of swellings in the muscles, hematuria, hematemesis, severe abdominal pain and bruising for the last 2 weeks. He had tenderness in hypogastrium and right iliac fossa, multiple skin bruises with multiple swellings over extremities. Eventually he was diagnosed to have AH with FVIII Inh of > 850 BU. He had intra-abdominal and multiple joint bleeds on imaging. He was managed with rFVIIa, IVIG, St and cyclophosphamide. Because of persistent low FVIII level (0.17%) he was given 4 doses of R along with prolonged steroid course. This resulted in normalization of FVIII level and Inh disappearance. However, soon he suffered 3 quick relapses with bleeding treated with 2 doses of R, St and IVIG. He returned in relapse with right thigh swelling, hematuria, and epistaxis in February 2013 (FVIII < 1 % and Inh 57.6 BU). He was treated again with rFVIIa and a dose of R. He was then referred to our team with Inh 115.2 BU. After giving him rFVIIa and starting St we added R on a weekly basis and prednisolone 1mg/kg daily. Inh disappeared after the 6th dose. He received the additional R dose (#7) on April 14, 2013. At this point, we could start immediate tapering of his 40 mg prednisolone dose and discontinued by July 2013. His FVIII level later rose to 200 % with undetectable Inh. He is off St since September 2013. He remains in CR after more than 16 months of his last dose of R.
CASE #2
This 20-year-old lady presented to ER in March, 2013 with sudden onset swelling of the right hand, bluish discoloration and moderate wrist pain for 3 days. She gave past history of migratory joints swelling. Her mother had thrombocytopenia for the last 7 years. She had a tender warm swelling of right hand with bluish discoloartion, remarkably decreased ROM of the right wrist. She was admitted under internal medicine with possible diagnosis of CTD. Investigations revealed an ANC of 1.16x10^9/L; and an isolated prolonged PTT of 102.9 seconds that after mixing with pooled normal plasma (1:1) was 91.9 seconds. FVIII level was 0.20% and FVIII Inh was 22.4 BU. Based on further investigations a diagnosis of SLE with APLA and AH was made. rFVIIa was given, and by rheumatology team prednisolone 40 mg daily along with HCQ 400mg started on 17 March 2013 (prednisolone was tapered to discontinuation by October 2013). As bleeding manifestations continued, R 500mg weekly doses were started on 27th March 2013. After a few days of the 3rd dose, her Inh had disappeared and FVIII level had normalized. We gave her 4th dose after it according to our strategy and then started quick prednisone tapering. Patient remains in CR under follow up.
CASE #3
A 28-year-old female was diagnosed to have acquired hemophilia after severe postpartum bleeding in February 2008 with FVIII Inh titer of 49.92 BU. After rFVIIa, with ongoing prednisolone her Inh level rose to 230 BU and she refused to consent for cyclophosphamide. She required 7 weekly doses of R after which Inh disappeared. Then one additional (8th) dose of R was given. Later she had an early abortion and then twin pregnancy in August 2012 without relapse. She remains in CR 6 years after her last treatment.

Disclosures
Off Label Use: Rituximab is a genetically engineered monoclonal antibody that targets a specific protein, known as CD20 found on the surface of normal and malignant B-lymphocytes. Use of Rituximab treatment for other than FDA approved indications include a rare condition of acquired factor VIII inhibitors in individuals without inherited hemophilia as an autoimmune phenomenon that may lead to life-threatening bleeding. Due to the low incidence rate of acquired inhibitors, published data consists of only case reports, and reviews.