Donor lymphocyte infusion as a treatment of a complete digeorge syndrome
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Donor lymphocyte infusion as a treatment of a complete DiGeorge syndrome. K.Zdráhalová 2 , E.Mejstříková 1,2 ,T.Kalina 1,2 ,P.Sedláček 2 , A. Janda 1 , H.Žižková 3 , Z.Sieglová 3 ,A.Šedivá 1 , J.Bartůňková 1 , J.Starý 2 , P.Kobylka 3 , P.Hubáček 2,4 , O.Hrušák 1,2

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Donor lymphocyte infusion as a treatment of a complete DiGeorge syndrome

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Donor lymphocyte infusion as a treatment of a complete digeorge syndrome

Donor lymphocyte infusion as a treatment of a complete DiGeorge syndrome

K.Zdráhalová2, E.Mejstříková1,2,T.Kalina1,2,P.Sedláček2, A. Janda1, H.Žižková3, Z.Sieglová3,A.Šedivá1, J.Bartůňková1, J.Starý2, P.Kobylka3 , P.Hubáček 2,4, O.Hrušák1,2

2Department of Pediatric Hematology and Oncology,

1Department of Immunology,

3Institute of Hematology and Blood Transfusion,

4Department of Pediatrics,

Prague, Czech Republic


Donor lymphocyte infusion as a treatment of a complete digeorge syndrome

Introduction - DiGeorge syndrome

  • the most common deletion syndrome in humans –

  • monoallelic microdeletion of 22q11.2 (DiGeorge

  • and velo-cardio-facial sy, conotruncal anomaly)

  • variable phenotype even in pts with the same deletion

  • manifestation:("CATCH22")

  • mainly heart defects; hypoparathyroidism

  • thymic hypoplasia  immunodeficiency, facialdysmorphism, developmental and behavioral problems

  • Deletion or interstitial deletion of 10p13 - other rare cause of DiGeorge sy (type II)


Donor lymphocyte infusion as a treatment of a complete digeorge syndrome

  • Patient: male, born June 18th 2004, now 10 months

  • Family history: healthy parents, 0 siblings

  • Personal history: 1st pregnancy, polyhydramnios  amniocentesis  normal karyotype 46, XY

  • term delivery, fetal hypoxia  Cesarian section,

  • resuscitation, intubation, artificial ventilation

  • esophageal atresia + tracheoesophageal fistula:

  • D+2 operation

  • bilateral choanal atresia: D+5 operation

  • congenital heart defects: D+13 operation


Donor lymphocyte infusion as a treatment of a complete digeorge syndrome

  • Stigmatisation:

  • face

  • genitals

  • eyes

  • CNS

  • CHARGE association

  • (Coloboma, Heart disease, Atresia choanae, Retarded growth +

  • development and/or CNS anomalies, Genital anomalies and/or

  • hypogonadism, Ear anomalies and/or deafness)

  • Problems:

  • recurrent infections, septicemias

  • recurrent respiratory distress  ventilation

  • apneas, irritability, states of altered consciousness


Donor lymphocyte infusion as a treatment of a complete digeorge syndrome

  • Immunology:

  • lymphocyte subsets in 2 months of age:

  • CD3+ 0%

  • NK 40%

  • CD4+ 0%

  • CD8+ 0%

  • CD19+ 58%

    • absent T cells

  • response to mitogens: absent

  • MRI -absent thymus

at 12.8.04

prior DLI 16.12.05

10

CD4 (10^9/L)

1

CD8 (10^9/L)

CD3 (10^9/L)

CD19 (10^9/L)

0,1

NK (10^9/L)

0,01

0,001

0,0001


Donor lymphocyte infusion as a treatment of a complete digeorge syndrome

  • Complete DiGeorge Syndrome

  • (diagnosis at 2 months)

  • microdeletion 22q11 not found

  • prophylaxis started :

  • cotrimoxazole + itraconazole + IVIG


Donor lymphocyte infusion as a treatment of a complete digeorge syndrome

2 months of age


Donor lymphocyte infusion as a treatment of a complete digeorge syndrome

1st donor lymphocyte infusion

age 6 months

unrelated donor from register, 8/10 (B, Cw)

no conditioning

no GVHD prevention

1x 106/kg CD3+; 0.2x 106/kg CD34+

due to mistake non irradiated blood products administered (7 times prior 1st DLI, 1 time after 1st DLI)


Donor lymphocyte infusion as a treatment of a complete digeorge syndrome

1st donorlymphocyteinfusion(cont.)

Between 1st and 2nd DLI

  • Complications:D+10:

  • isolated skin

  • aGVHD

  • (stage 3, grade II)

  • sepsis

  • cardiopulmonary

  • instability

  • capillary leak sy

10

after ATG

8

10

days post 1st DLI

0

1

CD3 (10^9/L)

CD4 (10^9/L)

0,1

CD8 (10^9/L)

0,01

0,001

Chimerism:

D+10 donordetected

0,0001

after ATG


Donor lymphocyte infusion as a treatment of a complete digeorge syndrome

aGVHD, Capillary leak sy


Donor lymphocyte infusion as a treatment of a complete digeorge syndrome

  • Immunosupressive therapy:

  • rATG Fresenius(25mg/kg 3x D+10, D+12, D+14)

  • CsA

  • corticosteroids- MP (2mg/kg)

  • GVHD resolved

  • corticosteroids - 2 weeks 2 mg/kg, 1 week 1 mg/kg,

  • 1 week 0.5 mg/kg, then tapered (D+35)

  • CsA continued

  • *****

  • D+33 last extubation!- aged 7 months


Donor lymphocyte infusion as a treatment of a complete digeorge syndrome

2nd donor lymphocyte infusion

age 7 months, D+36 after 1st DLI

the same donor

no conditioning

prevention of GVHD: CsA (continued)

0.89x 106/kg CD3+


Donor lymphocyte infusion as a treatment of a complete digeorge syndrome

2nd donor lymphocyte infusion (cont.)

EBV

  • Complications:

  • D+27EBV infection:

  • (B cell proliferation,

  • oligoclonality, IgM;

  • no clinical

  • manifestation)

  • withdrawal of CsA

  • Rituximab(375 mg/m2)

  • proliferation of

  • CD8+ activated T

  • cells started

10

rituximab

CD3

CD8

10^9/L

CD4

1

0

27

days post 2nd DLI

0,1

0,01

0,001

0

CD19


Donor lymphocyte infusion as a treatment of a complete digeorge syndrome

Chimerism after 1st and 2nd DLI

chimerism in FACSorted T lymphocytes CD3+ (D+41 and D+55 CD4+ and CD8+): mainly donor

chimerism in non separated blood: recipient mainly, donor detected

proliferation of activated T cells, severe liver GVHD

acute GVHD

1st DLI

2nd DLI

d 0

d 8

d 19

d 10

d 25

d 10

d 34

d 41

d 55

last non irradiated trf

EBV infection and prior rituximab

No proof of engraftment of non irradiated blood transfusions


Donor lymphocyte infusion as a treatment of a complete digeorge syndrome

  • D+34:jaundice - bilirubin 4 mg/dL

  • dif.dg.:

  • hepatic GVHD

  • EBV lymphoproliferation(EBV in blood 0; in organs?)

  • hepatic infection- not found

  • *********

  • D+352nd Rituximab(375 mg/m2)

  • D+41 corticosteroids(MP 1 mg/kg) hepatic aGVHD

  • neutropenia - granulo 215!

  • D+55 preventive ATB, antimycotics


Donor lymphocyte infusion as a treatment of a complete digeorge syndrome

  • D+45 - D+49: agranulocytosis (0 granulo)

  •  corticosteroids(MP 2 mg/kg)

  • CsA

  • G-CSF5x

  • D+52: granulo 3000

  • bilirubin 13.7 mg/dL

  •  isolated liver GVHD stage 3, grade III


Donor lymphocyte infusion as a treatment of a complete digeorge syndrome

  • D+56: rATG Fresenius 1 dose, 25mg/kg

  • D+57:  bilirubin 23.8 mg/dL

  •  isolated liver GVHD stage 4, grade IV

  • *********

  •  corticosteroids (D+63 1.5 mg/kg, D+83 1 mg/kg)

  • CsA continues

  • Current status:

  • D+108 after 2nd DLI, age 10 months

  •  bilirubin 7.6 mg/dL

  • CD8 activated T cells absolutely decreased

  • slight gradual psychomotor development


Donor lymphocyte infusion as a treatment of a complete digeorge syndrome

Patient aged 10 months

Thank you.


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