Dr. Birgit Marchand Paediatric Allergy/ Immunology Registrar Women’s & Children’s Hospital, Adelaide

Initial presentation:

5 month old male infant

Bronchiolitis

Mild eczema

Thrombocytopenia ?ITP

▪ Persistent platelets 20-50sWCH haematology

Bone marrow biopsy megakaryocytes present

100

75

50

37

25

Size

(kD)

WASP

S 1 2

S = Precision Plus Protein Standards

1 = 7859 Lab Control – PBMCs

2 = 7861 Lab Control – PBMCs

3 = 7864 Lab Control – PBMCs

4 = 7901 Lab Control – PBMCs

5 = Patient TE – PBMCs

6 = Mother of Patient TE – PBMCs

7 = Sister of Patient TE – PBMCs

< ~66 kD

WASP

3 4 5 6 7Mutational analysis

• X linked thrombocytopenia phenotype

• Mutation is c559+GG>A in intron 6• 5.6% WASP expression • Was Ochs Score = 2

Immune function• Normal IgG, M with slightly raised

IgA• Normal lymphocyte subsets and

proliferation• Not neutropenic• Protective vaccine responses to

diphtheria, tetanus and pneumococcus

Immediate risks: Severe bleeding brain, bowel, lung

Long-term risks: Autoimmune disease, infection, lymphatic

malignancy

TAPID discussion: Is bone marrow transplantation justifiable?

HLA matched sibling suitable bone marrow donor

1) Is his c559+5G>A Intron 6 splice site mutation predictive?

- Mutation is not predictive of overall survival or onset of events (Albert et al. 2010)

- Strong genotype-phenotype correlation in 50 Japanese patients (Imai et al. 2004)

2) Significance of his 5% WASP expression - WASP expression had no influence on overall survival

or event free survival (Albert et al. 2010)- Strong protein expression/ phenotype correlation

(Imai et al. 2004)

3) a) Long-term complications – Overall Survival

XLT Overall Survival:• 96% at 30 years • 81% at 60 years

3) b) Long-term complications – Event Free Survival

Event free survival: • 56% by age 30

Adverse effect:• 14% severe bleeding• 10% life threatening

infection• 5% malignancy• 15% autoimmunity

Author Total # Patients

# BMT Event Free Survival

Overall Survival

Overall Engraftment Rate

Comment

Ozsahinet al (2008)

96 WAS 45 MSD 88% at 7 years

Morattoet al (2011)

66 WAS 39 MSD 95%

Oshimaet al (2015)

24 XLT 7 MSD17 non-MSD

83% 100% HSCT following myeloablativetransplant is curative

Splenectomy:

Increases platelet count, but risk of infection

Favoured in XLT Treatment Algorithm (Worth et al, 2015)

Gene therapy:

Experimental option for WAS patients without suitable donor (Pecci, 2016)

Thrombopoietin receptor agonist:

Eltrombopag increased platelet counts but did not improve platelet activation in WAS/XLT patients (Gerritset al, 2015)

Restoration of normal platelet count Peace of mind Reduce risk of onset of infection, autoimmune

disease and malignancy 0/ low WASP expression poor outcome WAS Ochs score may be unreliable and change Best performed at young age and with Matched

Sibling Donor BMT recommended by eminent immunologists

In favour of BMT for XLT:

Overall survival for XLT same as general population Controversial significance of WASP expression and

relevance to XLT Hard to predict future on what is known re mutation Transplant related mortality 5% in MSD Risk of rejection Risk of delayed mixed donor chimerism Infertility GVHD Secondary cancer Donor welfare

Against BMT for XLT:

Albert et al. Blood 2010; 115:3231-3238 Gerrits et al.Blood 2015; 126(11):1367-1378 Imai et al. Blood 2004; 103: 456-464 Moratto et al. Blood 2011; 118: 1675-1684 Oshima et al. J Clin Immunology 2015; 35:15-21 Ozsahin et al. Blood 2008; 111:434-445 Pecci, A. Clin Genet 2016: 89: 141-153 Worth & Thrasher. Expert Review of Clin

Immunology 2015; 11:9, 1015-1032