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

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

slide2

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)
slide3

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
slide4

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
slide5

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

slide6

Complete DiGeorge Syndrome

  • (diagnosis at 2 months)
  • microdeletion 22q11 not found
  • prophylaxis started :
  • cotrimoxazole + itraconazole + IVIG
slide8

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)

slide9

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

slide11

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
slide12

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+

slide13

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

slide14

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

slide15

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
slide16

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
slide17

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
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