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Bone Marrow Transplantation for
Severe Combined Immune Deficiency
Eyal Grunebaum, MD
Context Bone marrow transplantation (BMT) using stem cells obtained from a family-
related, HLA-identical donor (RID) is the optimal treatment for patients with severe combined immune deficiency (SCID). In the absence of an RID, HLA-mismatched re-lated donors (MMRDs) are often used. However, compared with RIDs, use of MMRDs for BMT is associated with reduced survival and inferior long-term immune reconsti- tution. Use of HLA-matched unrelated donors (MUDs) represents another potentialalternative for BMT.
Objective To compare outcomes and immune reconstitution in a large cohort of pa-
tients with SCID who received RID, MUD, or MMRD BMT.
Design, Setting, and Patients Retrospective study of medical records from 94 in-
fants diagnosed as having SCID who received BMT between 1990 and 2004 at 1 Ca-
SEVERECOMBINEDIMMUNEDEFI- nadianand1Italianpediatricreferralcenter.Thirteen,41,and40patientsreceived RID, MUD, and MMRD BMT, respectively.
Main Outcome Measures Survival and graft failure, along with incidence of graft-
vs-host disease, infections, and other complications; immune reconstitution was as- sessed in children who survived for more than 2 years after BMT.
Results Survival after RID BMT was highest. Twelve (92.3%) of 13 patients who
received RID BMT, 33 (80.5%) of 41 who received MUD BMT, and 21 (52.5%) of 40 patients who received MMRD BMT survived. Compared with MMRD BMT, survival matopoietic stem cell transplantation.
was significantly higher with RID (P = .008) or with MUD (P = .03). Graft failures and need for repeat BMT were more common in patients receiving MMRD BMT than inthose who underwent MUD BMT. Long-term reconstitution of a full T-cell repertoire was achieved more frequently following MUD BMT (94.7%) than after MMRD BMT (61.1%) (P=.02). Acute graft-vs-host disease was documented in 73.1% of patients following MUD BMT but in only 45% after MMRD BMT (P=.009). Conversely, inter- stitial pneumonitis was observed more frequently after MMRD BMT (14 [35.0%] of 40) than after MUD BMT (3 [7.3%] of 41; P=.002).
Conclusion Our study suggests that in the absence of a relative with identical HLA,
MUD BMT may provide better engraftment, immune reconstitution, and survival for experience of BMT for SCID from Eu-rope revealed that in 294 recipients of Author Affiliations: Division of Immunology/
Allergy, Department of Paediatrics (Drs Grunebaum,
Atkinson, and Roifman and Ms Reid), and Infection, Immunity, Injury and Repair Program, Research In- careful analysis of survival according to stitute (Drs Grunebaum and Roifman), Hospital for Sick Children and University of Toronto, Toronto, On- tario; and Department of Pediatrics and Angelo No- civelli Institute for Molecular Medicine (Drs Maz-zolari, Porta, and Notarangelo), and Pediatric Bone Marrow Transplantation Unit, Department of Pedi- atrics (Ms Dallera), University of Brescia Spedali Civili,Brescia, Italy.
Corresponding Author: Chaim M. Roifman, MD,
FRCPC, Division of Immunology/Allergy, Depart-ment of Paediatrics, Infection, Immunity, Injury and cell depletion required to prevent graft- ence.5,6,10-14 However, the literature has Repair Program, Research Institute, Hospital for Sick Children and University of Toronto, 555 University Ave,Toronto, Ontario, Canada M5G 1X8 (chaim.roifman 508 JAMA, February 1, 2006—Vol 295, No. 5 (Reprinted)
2006 American Medical Association. All rights reserved.
BONE MARROW TRANSPLANTATION FOR IMMUNE DEFICIENCY vival separately during the first and sec- scribed.11 Serum levels of IgG, IgM, IgA, gens of tetanus, polio, or hepatitis B were tals’ ethics boards. Written consent for stricted T-cell repertoire, decreased thy- Bone Marrow Transplantation
than 50/µL, and natural killer cell counts tion index was calculated as the ratio be- Patients
frequency of different T-cell receptor V␤ scribed.19,21 Skewed T-cell repertoire (oli- phalan, fludarabine, or methotrexate.
B) and class II (DR) using serology.
selection (24 patients) as previously de- specific oligonucleotide probes.11 To de- tions, the selective and inconsistent na- cord blood). To assess the effect of vari- Follow-up and Complications
Laboratory Evaluations
the introduction of new antiviral agents, 2006 American Medical Association. All rights reserved.
(Reprinted) JAMA, February 1, 2006—Vol 295, No. 5 509
BONE MARROW TRANSPLANTATION FOR IMMUNE DEFICIENCY BMT (TABLE 1), MUD BMT (TABLE 2),
or MMRD BMT (TABLE 3), respec-
tively, were included in this study.
Statistical Analysis
statistically significant at PϽ.05.
Patient Groups
software, version 9.1 (SAS Institute Inc, pected results were 5 or fewer in cells.
For comparison of continuous data, t Table 1. Diagnosis, Complications, and Outcomes of Patients With SCID Undergoing RID BMT
Phenotype/
Complications and Infections
Posttransplantation
Complications
Molecular Defect
After BMT
Contact, mo
Cause of Death
at Last Contact
Abbreviations: AC, autoimmune cytopenia; ADA, significantly reduced adenosine deaminase activity; AGvHD, acute graft-vs-host disease; BMT, bone marrow transplantation; FOXP3, mutation in the FOXP3 gene; IL-7R␣, mutation in the gene for ␣ chain of the interleukin 7 receptor; Omenn, Omenn syndrome; RAG, mutation in the recombination-activating gene; RID, family-related, HLA-identical donor; SCID, severe combined immune deficiency; T− BϩNKϩ, T-cell count and function reduced, B-cell count normal orincreased, and natural killer cell count normal; ␥c, mutation in the gene for common ␥ chain of the interleukin 2 receptor; ZAP70, mutation in the ZAP70 gene.
510 JAMA, February 1, 2006—Vol 295, No. 5 (Reprinted)
2006 American Medical Association. All rights reserved.
BONE MARROW TRANSPLANTATION FOR IMMUNE DEFICIENCY Table 2. Diagnosis, Complications, and Outcomes of Patients With SCID Undergoing MUD BMT
Phenotype/
Molecular
Complications and Infections
Posttransplantation
Complications
After BMT
Contact, mo
Cause of Death
at Last Contact
Abbreviations: AC, autoimmune cytopenia; ADA, significantly reduced adenosine deaminase activity; AGvHD, acute graft-vs-host disease; ARTEMIS, mutation in the ARTEMIS gene; BMT, bone marrow transplantation; CD3␦, mutation in the CD3␦ gene; CGvHD, chronic graft-vs-host disease; IL-7R␣, mutation in the gene for ␣ chain of the interleukin 7 receptor;JAK3, mutation in the Jak-3 gene; MUD, HLA-matched unrelated donor; Omenn, Omenn syndrome; RAG, mutation in the recombination-activating gene; RMRP, mutation RNA com-ponent of the mitochondrial RNA-processing endoribonuclease gene; SCID, severe combined immune deficiency; T−BϩNK−, T-cell count and function reduced, B-cell count normalor increased, NK cells absent; T−B−NKϩ, T-cell count and function reduced, B-cell count reduced, natural killer cell count normal; T−BϩNKϩ, T-cell count and function reduced,B-cell count normal or increased, natural killer cell count normal; ␥c: mutation in the gene for common ␥ chain of the interleukin 2 receptor; ZAP70, mutation in the ZAP70 gene.
2006 American Medical Association. All rights reserved.
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BONE MARROW TRANSPLANTATION FOR IMMUNE DEFICIENCY Table 3. Diagnosis, Complications, and Outcomes of Patients With SCID Undergoing MMRD BMT
Phenotype/
Molecular
Complications and Infections
Posttransplantation
Complications
After BMT
Contact, mo
Cause of Death
at Last Contact
Pneumocystis jiroveci interstitial P jiroveci interstitial pneumonitis Abbreviations: AC, autoimmune cytopenia; AGvHD, acute graft-vs-host disease; ARTEMIS, mutation in the ARTEMIS gene; BMT, bone marrow transplantation; CGvHD, chronic graft- vs-host disease; IL-7R␣, mutation in the gene for ␣ chain of the interleukin 7 receptor; JAK3, mutation in the Jak-3 gene; MMRD, HLA-mismatched related donor; Omenn, Omennsyndrome; RAG, mutation in the recombination-activating gene; SCID, severe combined immune deficiency; T−B−NKϩ, T-cell count and function reduced, B-cell count reduced,natural killer cell count normal; T−BϩNKϩ, T-cell count and function reduced, B-cell count normal or increased, natural killer cell count normal; ␥c, mutation in the gene for common ␥ chain of the interleukin 2 receptor.
512 JAMA, February 1, 2006—Vol 295, No. 5 (Reprinted)
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BONE MARROW TRANSPLANTATION FOR IMMUNE DEFICIENCY RID BMT (P=.62), 12 (92.3%) of 13 fe- males receiving MUD BMT (P = .19), versity of Brescia (P = .26). Only 2 MMRD BMT (P = .11). Two-factor Cox Survival After BMT
(80.9%) (P=.62), and 12 of 20 (60%) vived (FIGURE). Survival following
(P=.26) patients surviving in the later (P = .03) than with MMRD BMT
(TABLE 4). While survival of RID BMT
Figure. Survival of Patients With SCID Who Received a Bone Marrow Transplant From a RID,
than that of MMRD BMT recipients(P = .008), survival after RID BMT was 84.6% (11/13), not significantly dif- vival for patients with Bϩ SCID. Simi-larly, the survival of patients with B− BMT was 52.9% (9/17), practically iden-tical to the 52.1% survival for patients were males. Seven (87.5%), 21 (75.0%),and 13 (44.8%) survived, compared For patients who received multiple transplants, survival was calculated from the date of the last transplanta-tion. RID indicates family-related, HLA-identical donor; MUD, HLA-matched unrelated donors; and MMRD, Table 4. Outcomes Following BMT for Severe Combined Immune Deficiency
No. of Patients/Total (%)
P Value
Abbreviations: BMT, bone marrow transplantation; MMRD, HLA-mismatched related donor; MUD, HLA-matched unrelated donor; RID, family-related, HLA-identical donor.
2006 American Medical Association. All rights reserved.
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BONE MARROW TRANSPLANTATION FOR IMMUNE DEFICIENCY tory tract infections after MMRD BMT.
Engraftment and Long-term
Immune Reconstitution
BMT (P = .06). After MUD BMT, 1 pa- ease of the liver, while another had bone Complications Following BMT
rized in Table 4. Lower respiratory tract tients and 14 (35.0%) of 40 patients fol- respectively (P=.002). Importantly, in- MUD BMT included fatal Streptococ- RID BMT (TABLE 5), 26 MUD BMT
cus viridans sepsis in 1 patient and (TABLE 6), and 18 MMRD BMT pa-
tients (TABLE 7) who had survived for
tation, particularly after MMRD BMT.
2 years or more after transplantation.
developed Pneumocystis jiroveci pneu- received MUD BMT (P = .001). Respi- monia after treatment with rituximab.
and 2 died of P jiroveci–associated pneu- MMRD BMT (P=.009). Acute graft-vs- after MUD BMT (P = .008) but not sig- ference (P=.08) that did not achieve sta- However, grade III or higher acute graft- plantation, late complications were rare.
cant. Acute graft-vs-host disease was the 514 JAMA, February 1, 2006—Vol 295, No. 5 (Reprinted)
2006 American Medical Association. All rights reserved.
BONE MARROW TRANSPLANTATION FOR IMMUNE DEFICIENCY tients, with no significant statistical dif- Table 5. Immune Reconstitution After RID BMT for Severe Combined Immune Deficiency
Lymphocytes, ϫ 106/µL
T-Cell Receptor
Time Since
CD3ϩCD4ϩ
CD3ϩCD8ϩ
Stimulation
T-Cell Receptor
Excision Cycles/106
Diversity
Lymphocytes
Abbreviations: BMT, bone marrow transplantation; ND, not determined; RID, family-related, HLA-identical donor.
*Abnormality.
Table 6. Immune Reconstitution After MUD BMT for Severe Combined Immune Deficiency
Lymphocytes, ϫ 106/µL
T-Cell Receptor
Time Since
CD3ϩCD4ϩ
CD3ϩCD8ϩ
Stimulation
T-Cell Receptor
Excision Cycles/106
Diversity
Lymphocytes
Abbreviations: BMT, bone marrow transplantation; MUD, HLA-matched unrelated donor; ND, not determined.
*Abnormality.
†Following treatment with anti-CD20 monoclonal antibody.
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BONE MARROW TRANSPLANTATION FOR IMMUNE DEFICIENCY these reports may reflect variability in pa- tient selection, techniques of T-cell deple- tion, or, alternatively, inconsistent defi- nition of criteria for HLA matching.6 Our study, which details large groups of SCID T-cell receptor variable ␤ chain expres- rate for patients who received RID BMT.
vided a unique opportunity for direct and host disease, a rigorous depletion of do- patients with SCID is to fully restore im- normal unrestricted lives indefinitely.
Table 7. Immune Reconstitution After MMRD BMT for Severe Combined Immune Deficiency
Lymphocytes, ϫ 106/µL
T-Cell Receptor
Time Since
CD3ϩCD4ϩ
CD3ϩCD8ϩ
Stimulation
T-Cell Receptor
Excision Cycles/106
Diversity
Lymphocytes
Abbreviations: BMT, bone marrow transplantation; MMRD, HLA-mismatched related donor; ND, not determined.
*Abnormality.
516 JAMA, February 1, 2006—Vol 295, No. 5 (Reprinted)
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BONE MARROW TRANSPLANTATION FOR IMMUNE DEFICIENCY BMT (P = .002). Indeed, interstitial or genetic defect. We found that the sur- vival of patients with B− SCID, such as tions in the RAG-1, RAG-2, and ARTE- MIS genes, was not different from the transient and limited to the skin in most tions. It was conducted at only 2 centers tablish strict guidelines to assist in the iting subgroup analyses. Patients were not ence has been strikingly different. We did contrary, in many cases we used this time graft-vs-host disease, significantly lower tients’ nutritional status, factors well tion, suggesting that this mode of treat- mortality rates were not different for pa- grade acute graft-vs-host disease will be required to reveal whether there is a sig- gether these results may challenge the in- Author Contributions: The first 2 authors, Dr Grune-
baum and Dr Mazzolari, contributed equally. Dr Roif-man had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Grunebaum, Porta, Acquisition of data: Grunebaum, Mazzolari, Porta, Dallera, Atkinson, Reid, Notarangelo, Roifman.
Analysis and interpretation of data: Grunebaum, lower respiratory tract.6,25 We show here Mazzolari, Porta, Reid, Notarangelo, Roifman.
2006 American Medical Association. All rights reserved.
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BONE MARROW TRANSPLANTATION FOR IMMUNE DEFICIENCY Drafting of the manuscript: Grunebaum, Mazzolari, Financial Disclosures: None reported.
Audrey and Donald Campbell Chair of Immunology, Dallera, Reid, Notarangelo, Roifman.
Funding/Support: Mutation analysis performed by Dr
University of Toronto, provided partial salary support Critical revision of the manuscript for important in- Notarangelo was partially supported by the Nocivelli for Dr Roifman. The Canadian Immunodeficiency So- tellectual content: Grunebaum, Mazzolari, Porta, Foundation. The MIUR-FIRB (grant RBNE01899JJ- ciety partially supported data collection at the Hospi- Atkinson, Reid, Notarangelo, Roifman.
003 to Dr Notarangelo) partially supported mutation tal for Sick Children and the Jeffrey Modell Founda- Statistical analysis: Grunebaum, Notarangelo.
analysis in infants with T− Bϩ SCID and the AFM- tion partially supported the molecular analysis.
Obtained funding: Notarangelo, Roifman.
Telethon (grant GATA0203 to Dr Notarangelo) par- Role of the Sponsors: The sources of support for this
Administrative, technical, or material support: tially supported mutation analysis in infants with T− B− study had no role in the design and conduct of the SCID. The European Union (EURO-POLICY-PID grant study, collection, management, analysis, and inter- Study supervision: Grunebaum, Mazzolari, Porta, 006411) and the MIUR-COFIN 2004 to Dr Notaran- pretation of the data, or preparation, review, or ap- gelo partially supported data collection. In addition, the REFERENCES
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