Abstract 1423

Acquired factor VIII (FVIII) inhibitor is an uncommon condition, with an incidence of ≂f1.5 cases/million/year, as reported by Collins et al. (Blood 2007. 109: p. 1870–1877) in a two year observational study in the UK. However, this is a serious condition, characterized by auto-antibodies against circulating factor VIII and has high mortality from bleeding. Controlling the acute bleeding event with FVIII inhibitor bypassing agents like recombinant activated factor VII or activated prothrombin complex concentrates is of utmost importance. Equally important is the eradication of inhibitor, in order to restore normal hemostasis. There are several approaches for inhibitor eradication, including, but not limited to, the use of Corticosteroids, Cyclophosphamide, Azathioprine, Vincristine, IVIG, Cyclosporine, Mycophenolate and, recently, Rituximab, either singly, or, in different combinations. However, there is no single standard approach. We report 4 cases of acquired FVIII inhibitor from our center that were initially treated with factor VIII bypassing agents. Inhibitor eradication was achieved by using a combination of Rituximab, Prednisone and Cyclophosphamide.

Table 1:

Patient Demographics and Co-morbid conditions

PatientAge (in years)Sex/RaceCo-morbid conditions
1 44 F/White Multiple Sclerosis 
2 67 M/White Rheumatoid arthritis 
3 83 F/White Hypertension 
4 66 M/Middle Eastern Diabetes Mellitus, Obstructive uropathy 
PatientAge (in years)Sex/RaceCo-morbid conditions
1 44 F/White Multiple Sclerosis 
2 67 M/White Rheumatoid arthritis 
3 83 F/White Hypertension 
4 66 M/Middle Eastern Diabetes Mellitus, Obstructive uropathy 
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Table 2:

Treatment Details

PatientHemoglobin(g/dl) Range:12.0-16.0WBC(x109/l)PT(in seconds) Range:11.5-15.5PTT(in seconds) Range:23.2-36
1 12.6 9.8 347 12.3 83 
2 9.6 9.4 299 11.9 79 
3 7.9 10.5 555 13.4 97.5 
4 9.5 18.7 275 14.3 95.2 
PatientHemoglobin(g/dl) Range:12.0-16.0WBC(x109/l)PT(in seconds) Range:11.5-15.5PTT(in seconds) Range:23.2-36
1 12.6 9.8 347 12.3 83 
2 9.6 9.4 299 11.9 79 
3 7.9 10.5 555 13.4 97.5 
4 9.5 18.7 275 14.3 95.2 
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Table 3:

Treatment Details

PatientTreatment DurationCyclophosphamidePrednisoneRituximab
1 3 cycles of 28 days each 500mg iv day 1 200mg PO days 2-5,q4weeks x 3 cycles 100mg PO days 1-5,q 4 weeks x 3 cycles 375mg/m2 day 1, then q 4 weeks x 3 doses 
2 6 cycles of 21 days each 500mg iv day 1 200mg PO days 2-5,q 3 weeks x 6 cycles 100mg PO days 1-5,q 3 weeks x6 cycles 375mg/m2 day 1, then q 4 weeks x 3 doses 
3 4 cycles of 28 days each 500mg iv day 1 200mg PO days 2-5,q 4 weeks x 4 cycles 100mg PO days 1-5,q 4 weeks x 4 cycles 375mg/m2 day 1, then q weekly x 3 doses; then q 4 week x 3 doses 
4 3 cycles of 28 days each 500mg day 1 200mg PO days 2-5,q 4 weeks x 3 cycles 100mg PO days 1-5,q 4 weeks x 4 cycles 375mg/m2 day 1, then q weekly x 3 doses; then q 4 week x 3 doses 
PatientTreatment DurationCyclophosphamidePrednisoneRituximab
1 3 cycles of 28 days each 500mg iv day 1 200mg PO days 2-5,q4weeks x 3 cycles 100mg PO days 1-5,q 4 weeks x 3 cycles 375mg/m2 day 1, then q 4 weeks x 3 doses 
2 6 cycles of 21 days each 500mg iv day 1 200mg PO days 2-5,q 3 weeks x 6 cycles 100mg PO days 1-5,q 3 weeks x6 cycles 375mg/m2 day 1, then q 4 weeks x 3 doses 
3 4 cycles of 28 days each 500mg iv day 1 200mg PO days 2-5,q 4 weeks x 4 cycles 100mg PO days 1-5,q 4 weeks x 4 cycles 375mg/m2 day 1, then q weekly x 3 doses; then q 4 week x 3 doses 
4 3 cycles of 28 days each 500mg day 1 200mg PO days 2-5,q 4 weeks x 3 cycles 100mg PO days 1-5,q 4 weeks x 4 cycles 375mg/m2 day 1, then q weekly x 3 doses; then q 4 week x 3 doses 
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Table 4:

Factor VIII Activity (in%): Baseline and Post-Treatment (Range: 50-180%)

PatientBaselinePostcycle1Postcycle2Postcycle3Postcycle4Postcycle5Postcycle6
1 1 6 13 95    
2 1 NA NA 14 12 28 123 
3 15 1 2 36 124   
4 6 2 21 137    
PatientBaselinePostcycle1Postcycle2Postcycle3Postcycle4Postcycle5Postcycle6
1 1 6 13 95    
2 1 NA NA 14 12 28 123 
3 15 1 2 36 124   
4 6 2 21 137    

NA: not available

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Fig. 1
Fig. 1. Factor VIII activity trend with treatment
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Factor VIII activity trend with treatment

Fig. 1
Fig. 1. Factor VIII activity trend with treatment
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Factor VIII activity trend with treatment

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Table 5:

Factor VIII inhibitor titer (in Bethesda Units): Baseline and Post-Treatment (Normal: Undetectable)

PatientBaselinePostcycle1Postcycle2Postcycle3Postcycle4Postcycle5Postcycle6
#1 17.2 1.7 1.2 Undetectable    
#2 117 NA NA NA NA NA NA 
#3 416 307 177 Undetectable    
#4 20.9 10.8 Undetectable     
PatientBaselinePostcycle1Postcycle2Postcycle3Postcycle4Postcycle5Postcycle6
#1 17.2 1.7 1.2 Undetectable    
#2 117 NA NA NA NA NA NA 
#3 416 307 177 Undetectable    
#4 20.9 10.8 Undetectable     

NA: not available

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Fig. 2
Fig. 2. Factor VIII inhibitor trend with treatment
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Factor VIII inhibitor trend with treatment

Fig. 2
Fig. 2. Factor VIII inhibitor trend with treatment
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Factor VIII inhibitor trend with treatment

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Table 6: Follow up

PatientTime from last treatment (in months)Most recent factor VIII activity (Range: 50-180%)Inhibitor titer
#1 9 100% NA 
#2 6 126% NA 
#3 16 105% Undetectable 
#4 3 55% Undetectable 
PatientTime from last treatment (in months)Most recent factor VIII activity (Range: 50-180%)Inhibitor titer
#1 9 100% NA 
#2 6 126% NA 
#3 16 105% Undetectable 
#4 3 55% Undetectable 

NA: not available

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Complete and sustained remission was achieved in all 4 patients (100%).All 4 patients tolerated the therapy well. None of the patients had significant adverse effects like neutropenia, hemorrhagic cystitis or other complications, either immediately or during follow up. Thus, the combined use of Cyclophosphamide, Rituximab and Prednisone seems to be an effective and safe regimen for inhibitor eradication in patients with acquired FVIII inhibitor.

Disclosures:

Off Label Use: Rituximab.For th purpose of auto-antibody supression.

Topics:
factor viii antibody, factor viii, rituximab, cyclophosphamide, prednisone, autoantibodies, follow-up, acute hemorrhage, adrenal corticosteroids, adverse effects

Author notes

*

Asterisk with author names denotes non-ASH members.

© 2010 by The American Society of Hematology
2010
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