Disclosures:

1
Disclosures
Immunoglobulin Therapy for PIDD
Melvin Berger, M.D., Ph.D., Rainbow, Babies
Childrens Hospital Case Western Reserve
University, Cleveland, OH

• Consulting AHIP (CDC), CSL-Behring, FFF,
  Grifols, Pfizer, Talecris
• Speakers bureaus CSL-Behring, Talecris,
• Research support Talecris, NIH
• Advisory Committees/Councils IDF, CIS
• Off label Dosages, Use of IGIV by sub-cu route

2
Major Antibody Deficiency Syndromes

• Brutons (X-linked) Agammaglobulinemia
• Transient Hypogam. of Infancy
• (Delayed Maturation of Humoral Immunity)
• Common Variable Immune Deficiency
• Hyper IgM Syndromes (X-linked and others)
• SCID s/p HSCT
• IgA Deficiency
• Specific Antibody Deficiency

3
Criteria for Determining the Need for
Immunoglobulin Replacement Therapy

• It must be demonstrated that
• The patient has significant and clearly
  documented infectious morbidity
• Other disorders (allergy, anatomic defects) have
  been sought and treated aggressively.
• Other modes of therapy (antimicrobial,
  anti-inflammatory) inadequate or poorly tolerated
• There is a laboratory abnormality confirming
  immunodeficiency

Practice Parameters of Joint Council of Allergy,
Asthma and Immunology Bonilla FA, et al. Ann
Allergy, Asthma, and Immunology. 200594S1-S63.
4
What is Immune Globulin (Human) ?

• Made from Pooled Plasma From 10,000 Donors
• All use cold ethanol fractionation (Cohn)
• Content 95 IgG IgA and other constituents
  vary in different products
• Stabilizers, chemical treatments and forms vary
• All products use multiple safety steps beginning
  with donor selection, screening, specific viral
  inactivation/removal steps in manufacture
• Usual regimen 300-800 mg/kg Q 21-28 days IV or
  50-200 mg/kg/wk sub-cutaneously (SC)
• Higher doses in pts with sinus, lung disease
• True anaphylaxis rare, even with IgA def.
  patients

5
Landmarks in the History of Immunoglobulin
Replacement Therapy
Renewed interest in SCIG as alternative to IV
therapy, especially for home use5
IVIG introduced and becomes standard therapy due
to reduction of bacterial and non-bacterial
infections4
Janeway and Gitlin prefer IM injections, and
this becomes standard of care in US2
1952
1953
1980
1955
1990s
2006
Bruton treats first patient diagnosed with
agammaglobulinemia with SC injections of immune
serum globulin (ISG)1
Berger introduces battery-powered pumps to slowly
administer IM ISG by SC route3
First Sub-cu IgG Licensed in US

• Bruton OC. Pediatrics. 19529722-728.
• Berger M. Clin Immunol. 20041121-7.
• Berger M. et al. Ann Intern Med. 19809855-56.
• Quartier P. et al. Jour Pediatrics.
  19991345589-596.
• Abrahamsen TG. Et al. Pediatrics.
  1996981127-1131.

6
Infection Frequency Is Reduced by Immunoglobulin
Replacement
Patients () with at least one infection1
Busse PJ, et al. J Allergy Clin Immunol.
20021091001-1004. Skull S, Kemp A. Arch Dis
Child. 199674527-530.
7

Increased Efficacy of 0.05 gr/kg/wk vs 0.025
gr/kg/wk ISG (im) UK MRC Working Party on
Hypogammaglobulinemia Study
c. 1957, published by HMSO 1970
____________________________________

• Condition p
• Febrile Episodes
• Otitis Media
• Pneumonia
• Death (51/176 overall) NS
• Diarrhea NS
• Skin eye conditions NS
• Weight gain NS

8
Efficacy of High vs. Standard Doses of IGIV in
PIDD Patients

• standard
  high p
• (adults 300 mg/kg/mo)
  (600 mg/kg/mo)
• (kids 400 mg/kg/mo)
  (800 mg/kg/mo)
  
  
• Infections 3.52.6
  2.52.4 0.004
• Days Infected 33
  21 0.015

n41 2/3 adults Eijkhout et al Ann Int Med
135 165-174, 2002.
9
Adverse Effects of IVIG

• Related to Underlying Infection
• Rate Related
• Non-Rate Related
• Related to High Dose Rx

10
Adverse Effects of IgG

• True Anaphylaxis-very rare
• Anaphylactoid (Rate related)
• Febrile
• Excess Fluid Volume and/or Salt Load
• Headache-Migraine- Aseptic Meningitis
• Renal Complications
• Thrombotic Complications
• Local Site Reactions from SCIG
• Viral Transmission (potential)

11
Renal and Thrombotic Complications

• Renal failure most often related to sucrose in
  certain products, usually transient
• Hyperviscosity may occur in patients with
  pre-disposing factors receiving high doses of
  IVIG
• Activation of leukocytes and/or platelets may
  occur, resulting in clots or transfusion-related
  acute lung injury (TRALI)

Headache, Migraine, Aseptic Menningitis

• ? Different reactions or a spectrum- mild
  headaches common,
  usually
  rate-related
• Onset of severe migraine or meningitis symptoms
  may be delayed. More common in patients with
  prior history of migraine.
• Severe headaches and/or aseptic meningitis more
  frequent with high dose Rx and in neurologic
  diseases

Pierce and Jain Transfusion Med Rev 17 241
(2003)
12
Pharmacokinetics of IgG after IV Infusion
13
Fractionating Total Dose into More Frequent Small
Infusions Evens Out IgG Level Over Time
14
(No Transcript)
15
Systemic Adverse Events During IM, IV, and SC
Immunoglobulin Infusions
Based on separate studies, not a head-to-head
evaluation
Pal. Lancet. 1991 338162.
16
Comparison of IV and SQ Dosing

• 70 kg patient receiving 500 mg/kg q 4 wks
• 35 grams 700 ml of 5 IV solution or
• 350 ml of 10 IV
  solution
• 220 ml of 16 sub-cu
  solution 20 ml every 3rd
  day (11/mo)
• 55 ml/wk (2-3 sites- 2.5
  hrs, 1 site-6-8 hrs)

17
SCIG Doses and Infections in North American and
(EuropeBrazil) Clinical Trials
Annual rate of
Annualized rate of other infections
other infections
4.4
4.3
CSL Behring, Data on File, Ochs et al, J Clin
Immunol 26 265 (2006) .
18
SCIG Reactions in CE1200 Study
___________________________________________

• Local reactions occurred in most patients
  initially.
• Reactions clearly decreased with continued
  therapy
• Multiple studies report systemic reactions
• patients on sub-cu. Severe rxns extremely
  rare.
• Local reactions mostly mild or moderate
• Only 3 subjects withdrew because of
  injection-site
• AEs

Ochs et al
19
North America QoL Study
Nicolay U et al. J Clin Immunol 2006 26 6572.
20
Promoting Patient Autonomy

• Home/Partner/Parent Administration of IVIG
• Subcutaneous IgG
• self infusion possible
• usually smaller doses given more
  frequently
• may decrease adverse events by
  dampening variations in serum IgG level
• Careful selection of patients and appropriate
  follow-up essential

21
Who Patients in whom sub-cu might be preferred

• Poor venous access
• Adverse effects anaphylactoid reactions,
  post-infusion migraines, risk of renal failure or
  hyperviscosity, thromboses
• Patients who run out of gas at end of IV dosing
  interval
• Patients who are remote from infusion facility
  (college students)
• Patients who work, go to school, or have busy
  schedule- convenience
• Patients who want to feel independent

22
Guidelines for IgG Therapy(Regardless of Route)

• Dose and Interval- Individualize
• Route- Location, Logistics, cost
• Treat the patient, not the numbers
• monitor and document outcome. Follow-up
• determined by clinical status of pt.
• Use of IgG levels
• Adverse Effects Rate related (IV), Non-rate
• related. Replacement different than high
  dose
• Safety Monitoring Liver Renal Function,
• CBC, tests for blood borne infections

23
Important Issues for the Doctor-Patient Discussion
24
Which Route to Use? Advantages of SC and IV
Administration
Berger M. Clin Immunol. 20041121-7.
25
Which Route to Use?Disadvantages of SC and IV
Administration
Berger M. Clin Immunol. 20041121-7.
26
Conclusions

• Antibody Replacement is a mainstay of
• treatment for PID
• IgG mainly is replaced
• IgG replacement should be individualized
• both IV and Sub-cu preparations available
  in
• the US. Dose Requirements may vary
• Current Ig preparations are believed safe, but
• we must always be cautious and monitor pts.