ITP at the NIH: Focus on Immune Dysregulation and Modulation

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ITP at the NIH Focus on Immune Dysregulation and
Modulation

• Patrick F. Fogarty, M.D.

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The NIH Mission

• Uncover new knowledge that will advance the
  Nation's capacity to protect and improve health
• conducting research in its own laboratories
• supporting the research of non-Federal scientists
  in universities, medical schools, hospitals, and
  research institutions
• helping in the training of research investigators
• fostering communication of medical information
• Funding 300 in 1887? 23.4 billion in 2002

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Presidents FY 2003 Budget 608.6 M for research
on autoimmunity
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NIH Initiative on Autoimmune Diseases (Title XIX)
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ITP A model of autoimmunity

• Frequency
• approximately 1/10,000 adults
• 0.2 of hospital admissions
• Well-defined target tissue
• autoantibodies against platelet antigens ?
  thrombocytopenia
• measure of response to treatment
• Model for other autoimmune disorders

Berchtold, MacMillan 1989
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from Cines NEJM 2002346995
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T Cell Profiles Splenectomy
12 ITP patients following splenectomy
6 responders
6 non-responders
8 Healthy controls
T cell profiles?
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T cell Receptor

• Molecular technique (DNA)
• Assess the spectrum of T cells in individuals
  patients

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Discussion

• Different baseline, versus splenectomy effect?
• assessment of T cell profiles before and after
  splenectomy (2 patients)
• T cell repertoire characteristics remarkably
  normal in samples drawn at all timepoints
• both patients responders
• Potentially useful in predicting response to
  splenectomy?

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High-Dose Cyclophosphamide and Autologous CD34
Selected Hematopoietic Cell Support for Chronic
Refractory ITP

• Age 18-65
• Autoimmune thrombocytopenia
• - platelets lt 20,000/?l
• - episodic bleeding requiring transfusions
  
• or causing major lifestyle impairment
• Refractory to
• - steroids x gt 3 months
• - splenectomy
• - IVIg and WinRho

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Patient CharacteristicsAccrual through 6/2003
Characteristics
n20
Median age (range)
42.0 (17-56) Sex (MF)
812 Median duration of
dz (range) 9 y (7
mo-40y) Coombs-positive (Evans Syndrome)
10 (6) Prior treatments - Steroids/Splenectomy/I
VIg 20 - anti-d
(WinRho) 15
- ChemoRx (VCR or oral cytoxan)
18 - rituximab 3 -
H. pylori treatment 1
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Autologous Transplantation for ITP Treatment
Schema
IVIg 1gm/kg
IVIg 1gm/kg
Apheresis goal gt 2x106 CD34/kg
G-CSF 5 µg/kg/day
G-CSF 10 µg/kg/day
Cytoxan 50 mg/kg/day
CD34 reinfusion
0
2
4
-12
-10
-8
-6
-4
-2
Study Day
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Clinical Course Patient 002Complete Response
prednisone
platelets x k/ul
IVIg
plt transfusion
PBSC
Days
Time Post-Transplantation ?
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Response16 patients evaluable, median f/u 28 mo
(9-54 mo)

• Complete Response 6/20 patients (30)
• ? self-sustained platelet count of 100,000/?l
• ? five patients ? 18 mo f/u (54, 39, 24, 21, 21
  mo)
• Partial Response 3/20 patients (15)
• ? self-sustained platelet count of gt50,000/?l for
  gt6 weeks
• ? reduction of bleeding episode frequency and
  transfusion requirements (platelets lt 50,000µl)
• No relapses to date
• Inevaluable 4/20 patients

No correlation with degree of T cell depletion
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Daclizumab in ITP

• IL-2 receptor
• activated T cells
• binding causes proliferation
• IL-2 secretion by ITP T cells
• chronic ITP ? serum IL-2
• ITP ? sIL-2R

?
Erduran et al., 1998 Semple et al., 1996
from Immunology, IIIrd ed. Roit et al. 1993
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Daclizumab
anti-IL-2 receptor antibody

• Binds to IL-2 receptor
• Blocks IL-2 driven T cell responses
• Clinical uses
• Kidney transplant (? rejection, immunomodulator
  use)
• autoimmune uveitis, epidermolysis bullosa,
  psoriasis (responses)
• Low toxicity
• cyclosporine, mycophenolate

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NIH Study 03-CC-0046 Daclizumab in ITP

• Eligibility
• age over 18 years
• platelets lt 30K/uL
• failed adequate course of prednisone
• stable immunomodulator regimen ? 2 months

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NIH Study 03-CC-0046 Daclizumab in ITP

• Study period Two phases
• Weeks 0-8 Daclizumab administration
• Five infusions every 2 weeks (NIH/home)
• Monitor platelet count, bleeding symptoms
• Weeks 8-20
• Observation
• Follow-up visits
• Immunomodulator dose reduction (week 12)

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Daclizumab Endpoints

• Number of responses at week 12
• complete (gt100,000/uL), partial (gt 30,000/uL)
• number of continued responses at weeks 20, 32
• Immunomodulator Dose Reduction
• Biologic Endpoints
• cd25 expression
• sIL-2R
• platelet glycocalicin index

and increment of at least 50 of baseline
platelet count
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Acknowledgments
Hematology Branch Dept. of Transfusion
Richard Huhn, MD Medicine
Ryotaro Nakamura, MD Elizabeth J.
Read, MD Adeira Greene, RN
Susan F. Leitman, MD Alois Gratwohl, MD Neal
S.Young, MD Dept. of Laboratory
Medicine A. John Barrett, MD
Margaret Rick, MD Cynthia E. Dunbar, MD
Donna Jo McCloskey, RN Vaccine
Research Center Daniel Douek, MD, PhD
Brenna Hill, PhD Javier Guenaga
New York Presbyterian James B. Bussel, MD
NIH Clinical Center patient care staff