[CIS-PAGID] Factor 8 deficiency with inhibitors and infusion reactions

[Lengkeek, Marguerite S. LCDR]

Dear Colleagues,
	I would appreciate your assistance with a 7 yr old male with severe
hemophilia A (factor 8 less than 1%) with factor 8 inhibitors that were
first detected at age 15 month old.  He was started on immune tolerance
therapy at that time with recombinant factor 8 at 150 U/kg/day and 1 month
course of Rituximab.  The Rituximab caused the inhibitor to disappear
temporarily, but led to multiple line infections and a severe mycobacterial
skin infection around his port.  He required 3 months of IV and then PO
antibiotics and 6 months of IVIG replacement.  He has had no further
problems with infections in the past 5 years.  
	
	Around 1-2 years old, he was treated with recombinant factor 7a
(older formulation) due to the inhibitors to factor 8.  He had hives and
itching with those infusions and required pre-treatment with Benadryl. In
April 2010, he was again found to have factor 8 inhibitors, so was started
on Humate P (human factor 8 von willebrand factor concentrate) at high doses
for immune tolerance, but he developed hand itching and throat irritation
and discomfort during the infusions.  He was switched to Alphanate (another
brand of factor 8 von willebrand concentrate) at 200 u/kg and is doing well
on this daily treatment.  He also requires frequent infusions of Novo 7 (new
formulation of recombinant factor 7a) for active bleeding every 2-12 hours.
He is now having similar reactions with hand itching, mild hand swelling and
redness and sore, itchy throat.  No hives currently and no difficulty
breathing or swallowing. He is currently on Benadryl Q6 hours, Zantac BID
and recently started on Prednisolone 10 mg BID, but still has the itching
sensation.  They tried to slow the infusions from IV push to over 3-5
minutes without change.

	In the package insert for Novo 7 (recombinant) it lists allergic
reactions, pruritus and rash in 1% of the patients.   It cautions patients
with history of hypersensitivity to factor 7a, mouse, hamster or bovine
proteins.  In the package insert for Humate P (human), it lists
allergic/anaphylactic reactions with hives, chest tightness, rash, edema and
pruritus in 5% of patients.  The patient has no h/o allergic rhinitis or
food allergies and had negative limited RAST to foods and aeroallergens and
total IgE of only 2.5.  RAST for mouse, hamster and beef was not ordered.
He has no h/o asthma or other drug allergies.

My questions are:
Does he have an underlying immune dysregulation problem?

Would immunosuppressants help his factor 8 inhibitor problem?   If yes, any
suggestions other than steroids?  Cellcept?

Rituximab is apparently not successful for factor 8 inhibitors.  Any
thoughts on Belimumab /Benlysta or other treatments for
autoantibodies/pathologic antibodies? 

What other labs should be ordered?   He hasn’t had flow cytometry or
quantitative immunoglobulins recently, but hasn’t had infections since the
Rituximab many years ago.  Any concern for cross reacting antibodies to
beef, mouse and hamster if no food allergy or allergic rhinitis symptoms?  

Would a desensitization protocol work for Novo 7 (recombinant factor 7a)?
He continues on this med every 2-12 hours despite the reactions depending on
his bleeding.   Is the mechanism non specific mast cell degranulation?  Any
suggestions for a similar drug desensitization protocol that I could use as
a reference? 

Has anyone had experience with reactions to these infusions?   

This treatment is extremely expensive and the inhibitors can cause him
severe morbidity if he has a major bleed.  I would appreciate any assistance
with this complicated case.

Sincerely,

Marguerite S. Lengkeek, MD
LCDR, MC, USN
Division Head, Allergy and Immunology
Naval Medical Center San Diego
Naval Training Center
2051 Cushing Rd.
San Diego, CA  92106
(619) 524-1519 


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