TY - JOUR
T1 - SCID patients with ARTEMIS vs RAG deficiencies following HCT
T2 - increased risk of late toxicity in ARTEMIS-deficient SCID
AU - Schuetz, Catharina
AU - Neven, Benedicte
AU - Dvorak, Christopher C
AU - Leroy, Sandrine
AU - Ege, Markus J
AU - Pannicke, Ulrich
AU - Schwarz, Klaus
AU - Schulz, Ansgar S
AU - Hoenig, Manfred
AU - Sparber-Sauer, Monika
AU - Gatz, Susanne A
AU - Denzer, Christian
AU - Blanche, Stephane
AU - Moshous, Despina
AU - Picard, Capucine
AU - Horn, Biljana N
AU - de Villartay, Jean-Pierre
AU - Cavazzana, Marina
AU - Debatin, Klaus-Michael
AU - Friedrich, Wilhelm
AU - Fischer, Alain
AU - Cowan, Morton J
PY - 2014/1/9
Y1 - 2014/1/9
N2 - A subgroup of severe combined immunodeficiencies (SCID) is characterized by lack of T and B cells and is caused by defects in genes required for T- and B-cell receptor gene rearrangement. Several of these genes are also involved in nonhomologous end joining of DNA double-strand break repair, the largest subgroup consisting of patients with T(-)B(-)NK(+)SCID due to DCLRE1C/ARTEMIS defects. We postulated that in patients with ARTEMIS deficiency, early and late complications following hematopoietic cell transplantation might be more prominent compared with patients with T(-)B(-)NK(+)SCID caused by recombination activating gene 1/2 (RAG1/2) deficiencies. We analyzed 69 patients with ARTEMIS and 76 patients with RAG1/2 deficiencies who received transplants from either HLA-identical donors without conditioning or from HLA-nonidentical donors without or with conditioning. There was no difference in survival or in the incidence or severity of acute graft-versus-host disease regardless of exposure to alkylating agents. Secondary malignancies were not observed. Immune reconstitution was comparable in both groups, however, ARTEMIS-deficient patients had a significantly higher occurrence of infections in long-term follow-up. There is a highly significant association between poor growth in ARTEMIS deficiency and use of alkylating agents. Furthermore, abnormalities in dental development and endocrine late effects were associated with alkylation therapy in ARTEMIS deficiency.
AB - A subgroup of severe combined immunodeficiencies (SCID) is characterized by lack of T and B cells and is caused by defects in genes required for T- and B-cell receptor gene rearrangement. Several of these genes are also involved in nonhomologous end joining of DNA double-strand break repair, the largest subgroup consisting of patients with T(-)B(-)NK(+)SCID due to DCLRE1C/ARTEMIS defects. We postulated that in patients with ARTEMIS deficiency, early and late complications following hematopoietic cell transplantation might be more prominent compared with patients with T(-)B(-)NK(+)SCID caused by recombination activating gene 1/2 (RAG1/2) deficiencies. We analyzed 69 patients with ARTEMIS and 76 patients with RAG1/2 deficiencies who received transplants from either HLA-identical donors without conditioning or from HLA-nonidentical donors without or with conditioning. There was no difference in survival or in the incidence or severity of acute graft-versus-host disease regardless of exposure to alkylating agents. Secondary malignancies were not observed. Immune reconstitution was comparable in both groups, however, ARTEMIS-deficient patients had a significantly higher occurrence of infections in long-term follow-up. There is a highly significant association between poor growth in ARTEMIS deficiency and use of alkylating agents. Furthermore, abnormalities in dental development and endocrine late effects were associated with alkylation therapy in ARTEMIS deficiency.
KW - B-Lymphocytes/immunology
KW - DNA-Binding Proteins/deficiency
KW - Endonucleases
KW - Female
KW - Follow-Up Studies
KW - Graft vs Host Disease/etiology
KW - HLA Antigens/immunology
KW - Hematopoietic Stem Cell Transplantation
KW - Homeodomain Proteins/genetics
KW - Humans
KW - Lymphocyte Depletion
KW - Male
KW - Mutation
KW - Nuclear Proteins/deficiency
KW - Risk Factors
KW - Severe Combined Immunodeficiency/complications
KW - T-Lymphocytes/immunology
KW - Transplantation Conditioning
KW - Treatment Outcome
U2 - 10.1182/blood-2013-01-476432
DO - 10.1182/blood-2013-01-476432
M3 - Article
C2 - 24144642
SN - 0006-4971
VL - 123
SP - 281
EP - 289
JO - Blood
JF - Blood
IS - 2
ER -