WAS (2)

imunologie.lf2.cuni.cz

WAS (2)

Emerging indications for HSCT

ESID - Prague May 2007

in primary immunodeficiency

Dr. Andy Gennery,

Newcastle upon Tyne, UK


ESID - Prague May 2007

What Are You Waiting For?

Dr. Andy Gennery,

Newcastle upon Tyne, UK


Overview

• Current Results (SCETIDE)

• Improving parameters

• A new way to think about immunodeficiency

• New indications for HSCT


SCETIDE REGISTRY

STEM CELL TRANSPLANTATION FOR

IMMUNODEFICIENCIES IN EUROPE

Marina Cavazzana-Calvo – Andrew

Cant

Andy Gennery – Mary Slatter

and

the members of the SCETIDE working group

Prepared by Pierre TAUPIN and Paul LANDAIS

Laboratoire de Biostatistique et d’Informatique

Médicale Hôpital Necker. Paris. France.


Primary disease in SCID patients (n=744)

28%

3%

10%

11%

48%

ADA def

B+

B-

Ret. Dysg.

Other SCID


Probability of survival in SCID patients after HSCT

according to period (« before 1995 » versus « after 1995 »)

After 1995 (n=315)

Before 1995 (n=360)

10 years

Survival rate

After 1995 : 70%

Before 1995 : 55%

P=0.0002


SCID and HLA-matching, 1990-2006

Geno (n=73)

MUD (n=78)

Pheno (n=41)

Mismatch (n=262)

10 years

Survival rate

Geno : 86%

Pheno : 79%

MUD : 72%

Mismatch : 59%

P=0.0002


Primary disease in non SCID

19%

12%

patients (n = 828)

6%

21%

42%

WAS

T Cell Def

Phagocytic cell di

Hemophagocytic

other inborn


Probability of survival in NON-SCID patients after HSCT

according to period (« before 1995 » versus « after 1995 »)

After 1995 (n=457)

Before 1995 (n=287)

10 years

Survival rate

After 1995 : 61%

Before 1995 : 54%

P=0.007


Probability of survival in NON-SCID patients after HSCT

according to donor-recipient compatibility

Geno n=250

Pheno n=58

MUD n=213

mmRel n=223

10 years

Survival rate

Geno : 72%

MUD : 64%

Pheno : 57%

mmRel : 40%

P


CD40 Ligand deficiency


CD40 Ligand deficiency


(%)

Observed : expected cases (%)

100%

90%

80%

70%

60%

50%

40%

30%

20%

10%

0%

by age at registration

0 5 10 15 20 25 30 35

Age (years)


0.00 0.25 0.50 0.75 1.00

0.00 0.25 0.50 0.75 1.00

Kaplan-Meier survival estimate

Kaplan-Meier survival estimates, by sex

0 10 20 30 40 50

analysis time

0 10 20 30 40 50

analysis time

F M


HSCT for CGD 1985 - 2000

Well 11 / 11

Inflamed 7 / 7

Active fungus 5 / 9

Seger RA, Gungor T, Belohradsky BH, et al. Treatment of chronic granulomatous disease with

myeloablative conditioning and an unmodified hemopoietic allograft: a survey of the European

experience, 1985-2000. Blood 2002;100:4344-50


HSCT for CGD 1985 - 2000

Resolution of inflammatory lung disease


HSCT for CGD 1985 - 2000


HSCT - what’s new?

• Better HLA typing

• New stem cell sources

• New conditioning regimens

• New viral detection and treatment

• Better supportive care

• New approaches to GvHD


HSCT : which donor?

♦ HLA identical sibling

♦ Other family member - match/1Ag

mismatch

♦ Matched unrelated donor

♦ Cord blood

♦ Mismatched - haploidentical parent

Routine:

HLA Class I - low resolution molecular typing

HLA Class II - high resolution molecular typing


Outcome

Survival post 2000

Overall Cord Haplo

79% 72% 82%

B cell function

Overall Cord Haplo

88% 92% 71%


Reduced Intensity HSCT - GOS

Rao et al, Blood 2004


Reduced Intensity HSCT

• Prolonged risk of viral re-activation

CMV, EBV, adenovirus

• Changing chimerism

• Late aGvHD > 100 days

Rao et al, Blood 2004


Graft versus Host disease

• Ciclosporine A

• Tacrolimus

• Steroids

• MMF

• Infliximab

• Basiliximab/Dacluzimab

• MSC


Viral infection

• CMV EBV HHV6 Adeno

• PCR early detection

• Ganciclovir Cidofovir

• Rituximab

• Specific cytotoxic T cells

• IVIG

• ⇓ Immunosuppression


Infection

Immune system “failure”

Autoimmunity

Immunodeficiency

Inflammation

Malignancy


New Indications

• 6th child consanguineous Pakistani parents

• RSV +ve bronchiolitis aged 2 weeks

• Delayed clearance of RSV from respiratory tract (5+ weeks)

• Subsequently no significant infection


• Lymphopenia

CD3 194

CD19 307

CD56/CD16 480

CD8 30

CD4 149

• impaired PHA

• TCR VB distribution

normal

IMMUNOLOGY

• Immunoglobulins

IgG 8.41 (on IVIG)

IgA 0.25

IgM 0.35

absence of antibody

response to Tet and

HiB despite 4

vaccinations


• Karyotype normal 46XX

but

5/163 Inv (7) (p13q35)

2/163 t(7:14) (p13:q11)

2/163 t(7:22) (p13:q11)

2/163 break point in chromosome 7

11/163 chromosome 7/14 rearrangements (7%)

• MMC sensitive ( ∆ FA)

• radiosensitive

• NBS - homozygous mutation nbs1 1089C ⇒ A resulting in

prematurely truncated protein (nibrin ( nibrin)


NBS REGISTRY

Hiel JA et al, Nijmegen Breakage Syndrome;

Arch.dis.child 2000

• 55 patients none with 1089C to A

• 19/55 (35%) died at age 0.5-24 years of infection

(5), malignancy (5) and lymphoma (9).

• Life expectancy reduced because of

malignancy/fatal infection.


ICF Syndrome

• Fragility of paracentromeric heterochromatin of Ch 1, 9, 16

• Multibranched chromosomes, triradials

• Facial anomolies

• Hypertelorism, flat nasal bridge, epicanthic folds

• Immunodeficiency

• Agammaglobulinaemia, variable T cell defect


• Variable outcome

ICF Syndrome

• Brown et al 1995 Hum Genet 1995;96:411-6

– 13 patients

– 1 died post BMT

– 4 others died infection (median 10/12)

– 1 A&W, now dead (infection, age 12 yrs)


Clinical Presentation

• First child, no parental consanguinity

• Recurrent chest infection (?PCP) -

agammaglobulinaemia

• Slightly low set ears – cytogenetics


• Commenced scIg – Co-trimoxazole,

Itraconazole

• Developed persistent diarrhoea (SRSV and

polio 2)

• Failure to thrive (25th


Table 1. Pre- and Post-HSCT immunological parameters in 3 patients with ICF

syndrome

Pre HSCT

CD3 (cells/µL) 3031

(1400-8000 )

Patient 1 Patient 2 Patient 3

3802

(1400-8000 )

2480

(900-4500)

CD19 (cells/µL) 795

725

950

(600-3100) (100-1400) (200-2100)

CSM B cell (%) N/A 0% N/A

IgM (g/L) 0.1 (0.43-1.9) 0.08 (0.43-1.9) < 0.04

IgA (g/L)


IPEX syndrome (OMIM 304930)

Immune dysregulation,

polyendocrinopathy,

enteropathy, X-L

• Mutations in FOXP3

• FOXP3 - critical regulator of CD4+CD25+

• Genetic heterogeneity

• cases of late onset with mild clinical features

• male patients w/o FOXP3 mutations

• female patients w. similar features

• “IPEX-like” syndrome? (H. Ochs)


IPEX syndrome - features

• Diarrhoea

• Failure to thrive

• IDDM/1

• Hypothyroidism

• Eczema

• Haemolytic anaemia

• Thrombocytopenia

• Recurrent infections

• Lymphadenopathy

• Hepatosplenomegaly

• Polyarticular arthritis

• Asthma

• Ulcerative colitis

• Glomerulonephropathy

• Interstitial nephritis

• Metabolic acidosis

• Hypotonia / muscle atrophy

Wildin, et al. J Med Genet 2002

Gambineri, et al. Curr Opin Rheumatol 2003


• From birth - severe eczema

• 2 / 52 - pneumonia / respiratory distress

-S aureus/ sputum

- Pseudomonas, Enterobacter / BAL

• 5 / 52 - episodic secretory diarrhoea

• Failure to thrive [


Patient 1

• Anti-islet cell Ab’s

• Anti-enterocyte Ab’s

• Anti-smooth muscle Ab’s

• Direct Coombs test

• Eosinophilia (2x10 9 /l)

• Raised IgE (31720 kU/l)

Laboratory results

• Persistent diarrhoea +

• DM type 1 -

• Hypothyroidism -

• Eczema +

• Failure to thrive +

• anaemia/DCT +

• Thrombocytopenia -

• Lymphadenopathy -

• Hepatosplenomegaly +

• Recurrent infections +

• Eosinophilia +

• Raised IgE +

• Typical small bowel b X +

Genetic analysis of FOXP3

did not reveal any mutation(s) so far

(H Ochs; T Torgerson)


Conditioning

• Campath 1H 0.2 mg/kg x5

3/52 pre BMT

• Bu 4mg/kg d-10 to d-7

• Cy 50 mg/kg d-5 to d-2

• CsA and steroids

• HLA id sister: bone marrow

6.8x10 8 /kg nucl. cells

6x10 6 /kg CD34+ cells

Patient 1 - BMT

Post-BMT

• Ne engraftment d+15

• Plt engraftment d+34

• normal stools

d+10

• off TPN +3/52

• started solids, milk

• normal gut histology

• negative autoab’s / DCT

• Wt 25 th / Ht 2 nd percentile

• swallowing incoordination

• “slipping” chimerism


Treg Plots Pt 2

R3 R3

Pre BMT Post BMT


Newcastle HSCT

April 2005-March 2006 April 2006-March 2007

• HIgE

• CHARGE

• CHH

• ICF

• CGD (2)

• Familial HLH

• CD4 lymphopenia

• CID

• IPEX

• CVID

• Partial TAP deficiency

• ZAP 70 K-like

• CD40L deficiency

• Griscelli

• SLE

• Autoimmune enteropathy +

• HyperIgD

• ALPS

• T-B- SCID

• RD

• RD

• CGD (3)

• ALPS

• JAK3 SCID

• Zeta chain deficient SCID

• IL7Ra SCID (2)

• Osteopetrosis (3, 2 TCIRG1)

• CgC SCID

• ADA SCID

• Undefined SCID with histiocytoma

WAS (2)

• Autoimmune enteropathy

• JIA (Auto)


Case 1 - Male 14 years

• ‘poor wound healing’, from age 5

• Warts, from age 7

• Repeated styes, from age 7

• Abscess drained in 2002, following insect bite, age 10

• Discharging ear infections, last few years

Imm Hx

• Age 12, all up to date

• Heaf test was unreactive

• BCG given in school: Nov 2004

• Immediately after vaccine, local swelling, red, painful

and febrile and heaf site was visible

• Subsequent skin rash


Ix for Lymphoma

• Abscess noted in axillary LN - drained and BCG biopsied -

BCG seen

• Treatment began with Isoniziad / Rifampicin

• Skin rash reappeared after 10/7 treatment

• Complications of treatment

• Relapse off treatment

• Clinically stable on maintenance therapy, growing and healthy

• On Moxifloxacin, Ethambutol, Clarythromycin, IFNg


Candidate diseases

• IFNg / IL12 deficiency

• CID (T cell deficiency)

• CD4 lymphopenia

• Myelodysplasia

Blood immunology

Present Absent

• Lymphocytes

• T cells B cells

• NK cells

• Phagocytes

• Monocytes


Blood counts

Date 7/02 4/05 6/05 10/05 3/06 10/06 3/07

Event Abscess BCG NGH

Hb 13.3 7.8 9.4 12.4 13.3 15.9 14.0

WBC 4.8 1.7 4.7 2.2 1.6 1.6 3.3

Neut 2.4 0.9 4.11 1.52 0.92 0.69 2.1

Lymph 2.1 0.4 0.37 0.35 0.44 0.73 0.93

Mono 0.00 0.00 0.03 0.02 0.01 0.01 0.00

Platelet 439 274 371 319 233 239 297


Subsets

2005 06 07 08 09 2006

CD3+ 257 216 89 269

524

CD19+ 4 0 0 0

0

CD3+CD4+ 147 115 43 155

277

CD3+CD8+ 108 95 44 110

235

CD4+25+ % 35 35 33

37

CD3+DR+ % 17 19 9

14

NK 0 0 0 0

0

11


Proliferations

Mitogen Patient Normal

Control 43 170

PHA/2 22816 124730

ConA 15945 193118

PMA 1774 132289

PMA/I 32326 169110

Anti-CD3 685 173691

Anti-CD3 + IL2 27029 232798

IL2 1314 90582

PPD 375 80452


Other immunology

• IgG initially very high, now normal

•IgM low

•IgA low

• IgE 29

• Neutrophil function burst OK

phagocytosis OK

• Autoantibodies SM 1:160 only


Other T cell immunology

• Normal TCR VB families

• Normal ADA/PNP,

• CD4+/45RA+/27+ (naïve) 9%

• CD4-/45RA+/27+ (naïve) 16%

• CD4-/45RA+/27- (effector) 2%

• CD40L expression appears normal


Histopathology

April 05 skin

No well-formed granulomata, necrosis +, MΦs + (CD68R+),

neutrophils +, sparse lymphocytes, AFB +, few B cells, more

plasma cells, plenty of DCs

axillary node

Definite granulomata, epithelioid cells +, no giant cells

August 05 skin

Neutrophilic adenitis (drug reaction or immunodeficiency)

September 05 LN

Abscess, neutrophils, MΦs seen, no granulomata

July 06 skin

Fibrosis, small granulomata seen and many eosinophils. Few T

cells, many plasma cells


Bone Marrows

July 05

Hypocellular, reduced but normal

erythropoiesis and myelopoiesis, no

granulomata

Oct 06

Hypoplastic, reduced granulopoeisis.

Plasma cells and tissue macrophages +

Fanconi, PNH, karyotypic abn: excluded


Imaging

• Leeds

• CT chest & abdo May 05

– Axillary lymphangitis, HSM, hypodense lesions in spleen, no

mesenteric adenitis

• NGH

• CT Oct 06

– Lymphadenopathy in chest, with consolidations

• US

– Calcifications in spleen


Imaging


Patel et al.

• 11 patients with late onset, disseminated mycobacterial infection.

• Profound monocytopenia, B cell penia, normal Ig production, variable

T cell penia

• Also severe HPV, EBV, Histoplasma, Cryptococcus

• PAP – independent of marrow failure. Macrophage / Monocytes

found in lung fluid.

• Initially normal marrow became dysplastic in a number, and

transformed to CMMol in one.

• Trisomy 8 found in half.

• Melanoma and squamous carcinomas

• Defects explored:

• Normal GM-CSF production, and no antibodies to GM-CSF.

• No response to G- or GM-CSF

• Recurrence to be expected.

• 1 BMT, died of lung complications 30 days later


From now…

• Do we put him back on IFNγ?

• Do we transplant him?

• Do we transplant him now or leave him?

• Any other ideas to explore the diagnosis


History - 14 year old Male

• May 2003 ∆ ITP

– Poor response to Ig and prednisolone

• March 2004 splenectomy

• Repeated adenopathy

– Biopsies and BMA/Ts have all been ‘reactive’

• January 2006 proptosis

– Spontaneous partial resolution


Lymphadenopathy

• November 2004 received BCG

• March 2005 presented with painless axillary lymphadenopathy

• Also reported mouth ulcers and earache some cervical LNS

– Mantoux, sputa negative

– CXR non specific

• April 2005 returned with ulcers, glands and cough

• Neutropenia (0.49)

• Raised platelets (964)

• ESR 8

• BMA - ‘reactive’ with a germinal centre

• L axillary LN - ‘reactive’ only


Proptosis

• Jan 2006 admitted with fever, lymphadenopathy, sore

throat, chest pain, proptosis of right eye

• Eczema over head and neck

• MRI identified a 2-3mm rim of abnormal tissue within the

globe, above the superior rectus muscle. ‘Inflammatory’

debris was seen in other sinuses.

•Resolution reported.

•Nov 2006, seen by Mr Neoh (RVI):

only 1mm of proptosis


• November 2006

Recent history / referral trigger

• Bruising and petechiae

• Platelets 5

Investigations

• Platelets 3 - 964 - 3 (large volume)

• LDH 482 - 791

• WBC 2.48 - 14.7

• Neutrophils 0.49 - 10.68 (steroid response)

• ESR 8 - 11

• CRP 20


Summary

• Destructive thrombocytopenia, initially responsive to

splenectomy

• Proptosis (resolving, 1 year duration) seems most likely a

result of inflammatory sinusitis, but ?infective, ?neoplastic,

?vasculitis, ?sarcoidosis

Working differential diagnosis

• Autoimmune disease with additional evidence of immune

dysregulation

–ALPS

WAS

–XLP

– Lymphoma


• Anterior Uveitis

Developments since Feb

• Recovered on steroid +/- antimicrobials

• Chesty cough

• Otherwise he had been well

Action

• To come in for antibiotics for chest

• Serious concern re possibility of fungus

• Needs scan of eyes as definitely more proptosis


Imaging


Immunology

Test 01/05/07 26/02/07 Units Range

Lymphocytes 3787 3802 cells/ul

T cells (CD3+) 819 934 cells/ul (800 to 3500)

NK cells (CD16+/CD56+) 86 140 cells/ul (70 to 1200)

B cells (CD19+) 2831 2719 cells/ul (200 to 600)

CD8+ T cells 268 371 cells/ul (200 to 1200)

CD4+ T cells 473 463 cells/ul (400 to 2100)

Activated T cells - % 46 38 %

CD4 / CD25 T cells - % 9 11 %

T Cell Receptor Alpha / Beta 94 91 %

T Cell Receptor Gamma / Delta 6 9 %

CD27-IgM+IgD+ (naive) 91 81 %

CD27+IgM+IgD+ (memory) 2

More magazines by this user
Similar magazines