SCID genotype and 6-month posttransplant CD4 count predict survival and immune recovery

Elie Haddad; Brent R. Logan; Linda M. Griffith; Rebecca H. Buckley; Roberta E. Parrott; Susan E. Prockop; Trudy N. Small; Jessica Chaisson; Christopher C. Dvorak; Megan Murnane; Neena Kapoor; Hisham Abdel-Azim; Imelda C. Hanson; Caridad Martinez; Jack J.H. Bleesing; Sharat Chandra; Angela R. Smith; Matthew E. Cavanaugh; Soma Jyonouchi; Kathleen E. Sullivan; Lauri Burroughs; Suzanne Skoda-Smith; Ann E. Haight; Audrey G. Tumlin; Troy C. Quigg; Candace Taylor; Blachy J. Dávila Saldaña; Michael D. Keller; Christine M. Seroogy; Kenneth B. Desantes; Aleksandra Petrovic; Jennifer W. Leiding; David C. Shyr; Hélène Decaluwe; Pierre Teira; Alfred P. Gillio; Alan P. Knutsen; Theodore B. Moore; Morris Kletzel; John A. Craddock; Victor Aquino; Jeffrey H. Davis; Lolie C. Yu; Geoffrey D.E. Cuvelier; Jeffrey J. Bednarski; Frederick D. Goldman; Elizabeth M. Kang; Evan Shereck; Matthew H. Porteus; James A. Connelly; Thomas A. Fleisher; Harry L. Malech; William T. Shearer; Paul Szabolcs; Monica S. Thakar; Mark T. Vander Lugt; Jennifer Heimall; Ziyan Yin; Michael A. Pulsipher; Sung Yun Pai; Donald B. Kohn; Jennifer M. Puck; Morton J. Cowan; Richard J. O’Reilly; Luigi D. Notarangelo

doi:10.1182/blood-2018-03-840702

SCID genotype and 6-month posttransplant CD4 count predict survival and immune recovery

Elie Haddad^*, Brent R. Logan, Linda M. Griffith, Rebecca H. Buckley, Roberta E. Parrott, Susan E. Prockop, Trudy N. Small, Jessica Chaisson, Christopher C. Dvorak, Megan Murnane, Neena Kapoor, Hisham Abdel-Azim, Imelda C. Hanson, Caridad Martinez, Jack J.H. Bleesing, Sharat Chandra, Angela R. Smith, Matthew E. Cavanaugh, Soma Jyonouchi, Kathleen E. SullivanLauri Burroughs, Suzanne Skoda-Smith, Ann E. Haight, Audrey G. Tumlin, Troy C. Quigg, Candace Taylor, Blachy J. Dávila Saldaña, Michael D. Keller, Christine M. Seroogy, Kenneth B. Desantes, Aleksandra Petrovic, Jennifer W. Leiding, David C. Shyr, Hélène Decaluwe, Pierre Teira, Alfred P. Gillio, Alan P. Knutsen, Theodore B. Moore, Morris Kletzel, John A. Craddock, Victor Aquino, Jeffrey H. Davis, Lolie C. Yu, Geoffrey D.E. Cuvelier, Jeffrey J. Bednarski, Frederick D. Goldman, Elizabeth M. Kang, Evan Shereck, Matthew H. Porteus, James A. Connelly, Thomas A. Fleisher, Harry L. Malech, William T. Shearer, Paul Szabolcs, Monica S. Thakar, Mark T. Vander Lugt, Jennifer Heimall, Ziyan Yin, Michael A. Pulsipher, Sung Yun Pai, Donald B. Kohn, Jennifer M. Puck, Morton J. Cowan, Richard J. O’Reilly, Luigi D. Notarangelo

^*Corresponding author for this work

Pediatrics

Research output: Contribution to journal › Article › peer-review

144 Scopus citations

Abstract

The Primary Immune Deficiency Treatment Consortium (PIDTC) performed a retrospective analysis of 662 patients with severe combined immunodeficiency (SCID) who received a hematopoietic cell transplantation (HCT) as first-line treatment between 1982 and 2012 in 33 North American institutions. Overall survival was higher after HCT from matched-sibling donors (MSDs). Among recipients of non-MSD HCT, multivariate analysis showed that the SCID genotype strongly influenced survival and immune reconstitution. Overall survival was similar for patients with RAG, IL2RG, or JAK3 defects and was significantly better compared with patients with ADA or DCLRE1C mutations. Patients with RAG or DCLRE1C mutations had poorer immune reconstitution than other genotypes. Although survival did not correlate with the type of conditioning regimen, recipients of reduced-intensity or myeloablative conditioning had a lower incidence of treatment failure and better T- and B-cell reconstitution, but a higher risk for graft-versus-host disease, compared with those receiving no conditioning or immunosuppression only. Infection-free status and younger age at HCT were associated with improved survival. Typical SCID, leaky SCID, and Omenn syndrome had similar outcomes. Landmark analysis identified CD4¹ and CD4¹CD45RA¹ cell counts at 6 and 12 months post-HCT as biomarkers predictive of overall survival and long-term T-cell reconstitution. Our data emphasize the need for patient-tailored treatment strategies depending upon the underlying SCID genotype. The prognostic significance of CD4¹ cell counts as early as 6 months after HCT emphasizes the importance of close follow-up of immune reconstitution to identify patients who may need additional intervention to prevent poor long-term outcome.

Original language	English (US)
Pages (from-to)	1737-1749
Number of pages	13
Journal	Blood
Volume	132
Issue number	17
DOIs	https://doi.org/10.1182/blood-2018-03-840702
State	Published - Oct 25 2018

Funding

This work was supported by the Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases (NIAID) and the Office of Rare Diseases Research (ORDR), National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH); Public Health Service grant/cooperative agreements U54-AI082973 (Principal Investigator [PI]: M.J.C.), U54-NS064808 and U01-TR001263 (PI: J. P. Krischer), and R13-AI094943 (M.J.C.); and the Division of Intramural Research, NIAID, NIH. The PIDTC is a part of the Rare Diseases Clinical Research Network of ORDR, NCATS. Collaborative work of the PIDTC with the Pediatric Blood and Marrow Transplant Consortium is supported by the U54 grants above, along with support from the Pediatric Blood and Marrow Transplant Consortium Operations Center by the St. Baldrick’s Foundation and grant/cooperative agreement U10HL069254 (PI: M.A.P.) from the National Heart, Lung and Blood Institute (NHLBI) and the National Cancer Institute (NCI), NIH. Collaborative work of the PIDTC with the Center for International Blood and Marrow Transplant Research is supported by grant/cooperative agreement U24-CA76518 (PI: M.M. Horowitz) from the NCI, NHLBI, and NIAID, NIH and grant/cooperative agreement U01HL069294 from the NHLBI and NCI, NIH; contracts HHSH250201200016C and HHSH234200637015C with the Health Resources and Services Administration/Department of Health and Human Services; and grants N00014-13-1-0039 and N00014-14-1-0028 from the Office of Naval Research.

ASJC Scopus subject areas

Biochemistry
Immunology
Hematology
Cell Biology

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10.1182/blood-2018-03-840702

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Haddad, E., Logan, B. R., Griffith, L. M., Buckley, R. H., Parrott, R. E., Prockop, S. E., Small, T. N., Chaisson, J., Dvorak, C. C., Murnane, M., Kapoor, N., Abdel-Azim, H., Hanson, I. C., Martinez, C., Bleesing, J. J. H., Chandra, S., Smith, A. R., Cavanaugh, M. E., Jyonouchi, S., ... Notarangelo, L. D. (2018). SCID genotype and 6-month posttransplant CD4 count predict survival and immune recovery. Blood, 132(17), 1737-1749. https://doi.org/10.1182/blood-2018-03-840702

@article{48998ac19aa2442ea4807130590be53b,

title = "SCID genotype and 6-month posttransplant CD4 count predict survival and immune recovery",

abstract = "The Primary Immune Deficiency Treatment Consortium (PIDTC) performed a retrospective analysis of 662 patients with severe combined immunodeficiency (SCID) who received a hematopoietic cell transplantation (HCT) as first-line treatment between 1982 and 2012 in 33 North American institutions. Overall survival was higher after HCT from matched-sibling donors (MSDs). Among recipients of non-MSD HCT, multivariate analysis showed that the SCID genotype strongly influenced survival and immune reconstitution. Overall survival was similar for patients with RAG, IL2RG, or JAK3 defects and was significantly better compared with patients with ADA or DCLRE1C mutations. Patients with RAG or DCLRE1C mutations had poorer immune reconstitution than other genotypes. Although survival did not correlate with the type of conditioning regimen, recipients of reduced-intensity or myeloablative conditioning had a lower incidence of treatment failure and better T- and B-cell reconstitution, but a higher risk for graft-versus-host disease, compared with those receiving no conditioning or immunosuppression only. Infection-free status and younger age at HCT were associated with improved survival. Typical SCID, leaky SCID, and Omenn syndrome had similar outcomes. Landmark analysis identified CD41 and CD41CD45RA1 cell counts at 6 and 12 months post-HCT as biomarkers predictive of overall survival and long-term T-cell reconstitution. Our data emphasize the need for patient-tailored treatment strategies depending upon the underlying SCID genotype. The prognostic significance of CD41 cell counts as early as 6 months after HCT emphasizes the importance of close follow-up of immune reconstitution to identify patients who may need additional intervention to prevent poor long-term outcome.",

author = "Elie Haddad and Logan, {Brent R.} and Griffith, {Linda M.} and Buckley, {Rebecca H.} and Parrott, {Roberta E.} and Prockop, {Susan E.} and Small, {Trudy N.} and Jessica Chaisson and Dvorak, {Christopher C.} and Megan Murnane and Neena Kapoor and Hisham Abdel-Azim and Hanson, {Imelda C.} and Caridad Martinez and Bleesing, {Jack J.H.} and Sharat Chandra and Smith, {Angela R.} and Cavanaugh, {Matthew E.} and Soma Jyonouchi and Sullivan, {Kathleen E.} and Lauri Burroughs and Suzanne Skoda-Smith and Haight, {Ann E.} and Tumlin, {Audrey G.} and Quigg, {Troy C.} and Candace Taylor and {D{\'a}vila Salda{\~n}a}, {Blachy J.} and Keller, {Michael D.} and Seroogy, {Christine M.} and Desantes, {Kenneth B.} and Aleksandra Petrovic and Leiding, {Jennifer W.} and Shyr, {David C.} and H{\'e}l{\`e}ne Decaluwe and Pierre Teira and Gillio, {Alfred P.} and Knutsen, {Alan P.} and Moore, {Theodore B.} and Morris Kletzel and Craddock, {John A.} and Victor Aquino and Davis, {Jeffrey H.} and Yu, {Lolie C.} and Cuvelier, {Geoffrey D.E.} and Bednarski, {Jeffrey J.} and Goldman, {Frederick D.} and Kang, {Elizabeth M.} and Evan Shereck and Porteus, {Matthew H.} and Connelly, {James A.} and Fleisher, {Thomas A.} and Malech, {Harry L.} and Shearer, {William T.} and Paul Szabolcs and Thakar, {Monica S.} and {Vander Lugt}, {Mark T.} and Jennifer Heimall and Ziyan Yin and Pulsipher, {Michael A.} and Pai, {Sung Yun} and Kohn, {Donald B.} and Puck, {Jennifer M.} and Cowan, {Morton J.} and O{\textquoteright}Reilly, {Richard J.} and Notarangelo, {Luigi D.}",

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month = oct,

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doi = "10.1182/blood-2018-03-840702",

language = "English (US)",

volume = "132",

pages = "1737--1749",

journal = "Blood",

issn = "0006-4971",

publisher = "Elsevier B.V.",

number = "17",

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Haddad, E, Logan, BR, Griffith, LM, Buckley, RH, Parrott, RE, Prockop, SE, Small, TN, Chaisson, J, Dvorak, CC, Murnane, M, Kapoor, N, Abdel-Azim, H, Hanson, IC, Martinez, C, Bleesing, JJH, Chandra, S, Smith, AR, Cavanaugh, ME, Jyonouchi, S, Sullivan, KE, Burroughs, L, Skoda-Smith, S, Haight, AE, Tumlin, AG, Quigg, TC, Taylor, C, Dávila Saldaña, BJ, Keller, MD, Seroogy, CM, Desantes, KB, Petrovic, A, Leiding, JW, Shyr, DC, Decaluwe, H, Teira, P, Gillio, AP, Knutsen, AP, Moore, TB, Kletzel, M, Craddock, JA, Aquino, V, Davis, JH, Yu, LC, Cuvelier, GDE, Bednarski, JJ, Goldman, FD, Kang, EM, Shereck, E, Porteus, MH, Connelly, JA, Fleisher, TA, Malech, HL, Shearer, WT, Szabolcs, P, Thakar, MS, Vander Lugt, MT, Heimall, J, Yin, Z, Pulsipher, MA, Pai, SY, Kohn, DB, Puck, JM, Cowan, MJ, O’Reilly, RJ & Notarangelo, LD 2018, 'SCID genotype and 6-month posttransplant CD4 count predict survival and immune recovery', Blood, vol. 132, no. 17, pp. 1737-1749. https://doi.org/10.1182/blood-2018-03-840702

TY - JOUR

T1 - SCID genotype and 6-month posttransplant CD4 count predict survival and immune recovery

AU - Haddad, Elie

AU - Logan, Brent R.

AU - Griffith, Linda M.

AU - Buckley, Rebecca H.

AU - Parrott, Roberta E.

AU - Prockop, Susan E.

AU - Small, Trudy N.

AU - Chaisson, Jessica

AU - Dvorak, Christopher C.

AU - Murnane, Megan

AU - Kapoor, Neena

AU - Abdel-Azim, Hisham

AU - Hanson, Imelda C.

AU - Martinez, Caridad

AU - Bleesing, Jack J.H.

AU - Chandra, Sharat

AU - Smith, Angela R.

AU - Cavanaugh, Matthew E.

AU - Jyonouchi, Soma

AU - Sullivan, Kathleen E.

AU - Burroughs, Lauri

AU - Skoda-Smith, Suzanne

AU - Haight, Ann E.

AU - Tumlin, Audrey G.

AU - Quigg, Troy C.

AU - Taylor, Candace

AU - Dávila Saldaña, Blachy J.

AU - Keller, Michael D.

AU - Seroogy, Christine M.

AU - Desantes, Kenneth B.

AU - Petrovic, Aleksandra

AU - Leiding, Jennifer W.

AU - Shyr, David C.

AU - Decaluwe, Hélène

AU - Teira, Pierre

AU - Gillio, Alfred P.

AU - Knutsen, Alan P.

AU - Moore, Theodore B.

AU - Kletzel, Morris

AU - Craddock, John A.

AU - Aquino, Victor

AU - Davis, Jeffrey H.

AU - Yu, Lolie C.

AU - Cuvelier, Geoffrey D.E.

AU - Bednarski, Jeffrey J.

AU - Goldman, Frederick D.

AU - Kang, Elizabeth M.

AU - Shereck, Evan

AU - Porteus, Matthew H.

AU - Connelly, James A.

AU - Fleisher, Thomas A.

AU - Malech, Harry L.

AU - Shearer, William T.

AU - Szabolcs, Paul

AU - Thakar, Monica S.

AU - Vander Lugt, Mark T.

AU - Heimall, Jennifer

AU - Yin, Ziyan

AU - Pulsipher, Michael A.

AU - Pai, Sung Yun

AU - Kohn, Donald B.

AU - Puck, Jennifer M.

AU - Cowan, Morton J.

AU - O’Reilly, Richard J.

AU - Notarangelo, Luigi D.

PY - 2018/10/25

Y1 - 2018/10/25

N2 - The Primary Immune Deficiency Treatment Consortium (PIDTC) performed a retrospective analysis of 662 patients with severe combined immunodeficiency (SCID) who received a hematopoietic cell transplantation (HCT) as first-line treatment between 1982 and 2012 in 33 North American institutions. Overall survival was higher after HCT from matched-sibling donors (MSDs). Among recipients of non-MSD HCT, multivariate analysis showed that the SCID genotype strongly influenced survival and immune reconstitution. Overall survival was similar for patients with RAG, IL2RG, or JAK3 defects and was significantly better compared with patients with ADA or DCLRE1C mutations. Patients with RAG or DCLRE1C mutations had poorer immune reconstitution than other genotypes. Although survival did not correlate with the type of conditioning regimen, recipients of reduced-intensity or myeloablative conditioning had a lower incidence of treatment failure and better T- and B-cell reconstitution, but a higher risk for graft-versus-host disease, compared with those receiving no conditioning or immunosuppression only. Infection-free status and younger age at HCT were associated with improved survival. Typical SCID, leaky SCID, and Omenn syndrome had similar outcomes. Landmark analysis identified CD41 and CD41CD45RA1 cell counts at 6 and 12 months post-HCT as biomarkers predictive of overall survival and long-term T-cell reconstitution. Our data emphasize the need for patient-tailored treatment strategies depending upon the underlying SCID genotype. The prognostic significance of CD41 cell counts as early as 6 months after HCT emphasizes the importance of close follow-up of immune reconstitution to identify patients who may need additional intervention to prevent poor long-term outcome.

AB - The Primary Immune Deficiency Treatment Consortium (PIDTC) performed a retrospective analysis of 662 patients with severe combined immunodeficiency (SCID) who received a hematopoietic cell transplantation (HCT) as first-line treatment between 1982 and 2012 in 33 North American institutions. Overall survival was higher after HCT from matched-sibling donors (MSDs). Among recipients of non-MSD HCT, multivariate analysis showed that the SCID genotype strongly influenced survival and immune reconstitution. Overall survival was similar for patients with RAG, IL2RG, or JAK3 defects and was significantly better compared with patients with ADA or DCLRE1C mutations. Patients with RAG or DCLRE1C mutations had poorer immune reconstitution than other genotypes. Although survival did not correlate with the type of conditioning regimen, recipients of reduced-intensity or myeloablative conditioning had a lower incidence of treatment failure and better T- and B-cell reconstitution, but a higher risk for graft-versus-host disease, compared with those receiving no conditioning or immunosuppression only. Infection-free status and younger age at HCT were associated with improved survival. Typical SCID, leaky SCID, and Omenn syndrome had similar outcomes. Landmark analysis identified CD41 and CD41CD45RA1 cell counts at 6 and 12 months post-HCT as biomarkers predictive of overall survival and long-term T-cell reconstitution. Our data emphasize the need for patient-tailored treatment strategies depending upon the underlying SCID genotype. The prognostic significance of CD41 cell counts as early as 6 months after HCT emphasizes the importance of close follow-up of immune reconstitution to identify patients who may need additional intervention to prevent poor long-term outcome.

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U2 - 10.1182/blood-2018-03-840702

DO - 10.1182/blood-2018-03-840702

M3 - Article

C2 - 30154114

AN - SCOPUS:85055612463

SN - 0006-4971

VL - 132

SP - 1737

EP - 1749

JO - Blood

JF - Blood

IS - 17

ER -

SCID genotype and 6-month posttransplant CD4 count predict survival and immune recovery

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