Autoimmune Complications after

Cord Blood Transplantation

Annalisa Ruggeri, MD Eurocord, Hôpital Saint Louis, Paris

Background

Autoimmunity after HSCT is reported in several conditions:

• Transfer of donor autoimmunity • Altered immunity associated with chronic GVHD • Appearance or new development of residual host

autoimmunity

Daikeler, Best Pract, 2007

Onset of secondary AD after allo/auto HSCT: BM, PBSC

Adoptive transfer of autoimmune disease from donor to recipients

Autoimmune diseases Graft sources Reference

Psoriasis Syngeneic BM BJD, 1997

Psoriatic arthritis Sibling BM Rheumatology, 1999

Celiac disease Sibling BM BMT, 1997

Vitiligo Sibling BM JAAD, 2002

Type I diabetis mellitus Sibling BM Lancet, 1993

Autoimmune thyroiditis Sibling PBSC BMT, 1997 and 1999

Crohn’s disease PBSC Gut, 2003

Myasthenia gravis Unknown NEJM, 1983

Daikeler, Best Pract, 2007

Few case reports / small series autoimmune disease Most of the AD reported are autoantibodies mediated and organ

specific, more rarely multisistemic

Autoimmune Cytopenias

Rheumatic Diseases : Barnabe Semin Arthritis Rheum 2008 * After autologous HSCT Athritis SPA, RA, Infectious Polyarthritis CMV Koch 2000, Burns 1993 SLE Nephritis, Autoantibodies, APS Imamura 2002, Boghati 2007 Vasculitis Pulmonary Renal Syndrome Kingdon1994, Mc Cloy 1996, Seiden

1990 * After allogeneic HSCT Arthritis Oligoarthrtitis, Psoriasic Arthritis Daikeler 1999, Snowden 1998 Vasculitis ANCA, microPAN, Jejunal vasculitis Shetti, 2002, Almoallim 2005,

Other AD reported after allo / auto HSCT (BM or PBSC) for malignant and non malignant diseases

• No larger studies reporting the incidence of autoimmune disease after HSCT

• Daikeler etal. recently showed 7% of incidence of new AD in a cohort of patients with AD transplanted with autologous HSC

* Increase in the use of cord blood as an alternative source of adults HSC for allotransplant * CB lymphocytes are immature * Most of the CBT are HLA mismatched = > High incidence of secondary AD after CBT? Daikeler, Blood 2013

Aims and Methods

To identify the incidence and risk factors of secondary autoimmune disease (AD) after CBT

Questionnaire to all EBMT centers

Status at last follow-up Sec AD: Yes /No; Yes Cases No Control group = No sec AD Specific questionnaire for sec AD

Analysis of 778 patients, 52 developed AD (n=52) and the remaining who did not developed AD (n=726)

Diagnosis of AD after CBT :

n = 52 (41 AIC + 11 others)

Median time of onset : 191 days (27-4267)

Median time of onset : 377 days (70-1116)

• Type Autoimmune Disease after CBT: AIHA 20 ITP 11 Evans Syndrome 9 Immune neutropenia 1 Thyroiditis 3 Glomerulonephritis 2 Graves disease 1 Psoriasis 1 , Psoriasis arthritis 1 2 Crohn‘s 1 Rheumatoid arthritis 1 Lupus 1

• Post transplant events at time of onset of AD: aGvHD (n=3), c GvHD (n=6) Preceding infections (n=10)

Patients characteristics, n=778

Pts characteristics

AD pts (n=52) Non AD pts (n=726)

P

Female sex 37% 44%

Age at HSCT 5 (0.2-45.3) yrs 16 (0.1-66.5) yrs <0.0001 Year of HSCT 2006 (1995-2008) 2006 (1992-2008) 0.05

Type of Donor Unrelated 96% 92% 0.25 Indication for CBT

ALL 21% 31%

AML 10% 26%

MDS 8% 11%

AA 12% 8%

Severe Combined Immune Deficiency

12% 7% Malignant vs non malignant, <0.0001

CML 10% 5%

NHL 0 4%

Hemoglobinopathy 0 2%

Histiocytosis 4% 2%

Metabolic diseases 23% 2%

Others 2% 0%

Graft characteristics, n= 778

Pts characteristics AD pts (N=52)

Non AD pts (N=726)

P

Graft Single cord 85% 81% 0.48

Double cord 15% 19%

HLA compatibility

5/6+6/6 66% 48% 0.02

Conditioning

RIC 82% 76% 0.32

TBI 18% 35% 0.013

Serotherapy 76% 78% 0.73

Recipient CMV status

Positive 46% 60% 0.05

Cumulative incidence of AD after CBT, n= 778

Overall incidence Incidence by type of diagnosis

0 12 24 36 48 60

0.0

0.2

0.4

0.6

0.8

1.0

6(±1)% at 3 years

0 12 24 36 48 60

0.0

0.2

0.4

0.6

0.8

1.

14% non malignant disorders

5% malignant disorders

HR 1.85, p = 0.0001

Risks Factors for AD after CBT Mutivariate Analysis

p HR 95%CI Interval from diagnosis to transplant > median 0.034 0.30 0.51 0.17 Malignant disease versus others 0.0001 1.85 1.05 3.27

Overall Survival at 5 years

Secondary AD after CBT (as time dependent variable) was not associated with overall survival (p=0.43)

OS: 50 ± 2%, n=778

Outcome of pts with new onset of AD (n=52): 40 Alive, 12 Dead>>> 6 patients died from AD (3 AIHA,

2 Evans syndrome, and 1 ITP); 4 patients died of TRM and 2 of relapse

Treatment of patients having developed an AD Hematologic AD: From the 40 patients with AIHA, ITP, or Evans syndrome, 7 received steroids only and

33 additional IST, mainly rituximab (RTX) and cyclosporine A (CSA). Nineteen patients needed 2nd line treatment (mainly RTX) and 13 achieved CR or PR 5-year OS was 91% for patients who developed ITP, 59% for those with AIHA, and

67% for those with Evans syndrome

Non Hematologic AD: • Two of the 3 patients with autoimmune thyroiditis (hypothyroidism) received

replacement therapy with thyroxin • Psoriasis was treated with CSA and prednisone or topical tacrolimus • Membranous glomerulonephritis with prednisone or CSA • The patient with SLE responded to steroid and CSA treatment (CR) • Ulcerative colitis was successfully treated with steroids and tacrolimus and RA

with prednisone and methotrexate

Occurence of autoimmune disease after CBT does not seem different from other stem cell sources

In hematological malignancies the CI of developing AD was 4% In non malignant diseases, 14%

The difference could be related to: • Different diagnosis (autoimmune disease background of non

malignant disorders) • Difference of pretransplant treatment • Difference in type of conditioning regimen (non malignant disease

mainly non myeloablative)

Autoimmune Diseases: is it more frequent after CB vs PBSC or BM transplantation??

Conclusion

• In our study the CI of development of AD after CBT was 6%

• AIHA and ITP were observed most commonly and earlier and therefore have to be considered as a possible reason for unexplained cytopenia post UCBT

• Comparative studies analyzing CBT versus BM and PBSC are necessary to determine whether AD disease is more frequent in CBT or in other types of graft

Acknowledgments

Autoimmune disease WP of EBMT

Dominique Farge, MD, Chair Thomas Daikeler, MD Myriam Labopin, MD

Manuela Badoglio

Eliane Gluckman, MD FRCP Project Leader

Vanderson Rocha, MD PhD

Scientific Director Annalisa Ruggeri, MD

Agnès Devergie, MD

Federica Giannotti , MD

Myriam Pruvost, PA

Fernanda Volt, MT Chantal Kenzey Data Manager

EUROCORD TEAM 2012-2013

Erick Xavier, MD