Immune Reconstitution and Infection Patterns after Early Alemtuzumab and Reduced Intensity Transplantation for Nonmalignant Disorders in Pediatric Patients

Sima T. Bhatt, Jeffrey J. Bednarski, Julia Berg, Kathryn Trinkaus, Lisa Murray, Robert Hayashi, Ginny Schulz, Monica Hente, Michael Grimley, Ka Wah Chan, Naynesh Kamani, David Jacobsohn, Michael Nieder, Gregory Hale, Lolie Yu, Roberta Adams, Jignesh Dalal, Michael A. Pulsipher, Paul Haut, Sonali ChaudhuryJeffrey Davis, Jennifer Jaroscak, Martin Andreansky, Jennifer Willert, Shalini Shenoy

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Hematopoietic stem cell transplantation (HSCT) is a therapeutic option for many nonmalignant disorders (NMD) and is curative or prevents disease progression. Reduced-intensity conditioning (RIC) in HSCT for NMD may reduce regimen-related acute toxicities and late complications. Myeloablation is often replaced by immune suppression in RIC regimens to support donor engraftment. The pace of immune reconstitution after immune suppression by RIC regimens is influenced by agents used, donor source, and graft-versus-host disease prophylaxis/treatment. In a multicenter trial (NCT 00920972) of HSCT for NMD, a RIC regimen consisting of alemtuzumab, fludarabine, and melphalan was substituted for myeloablation. Alemtuzumab was administered early (days −21 to −19) to mitigate major lymphodepletion of the incoming graft and the risk of graft rejection. Immune reconstitution and infectious complications were prospectively monitored for 1-year post-HSCT. Seventy-one patients met inclusion criteria for this report and received marrow or peripheral blood stem cell transplants. Immune reconstitution and infections are reported for related donor (RD) and unrelated donor (URD) transplants at 3 time-points (100 days, 6 months, and 1 year post-HSCT). Natural killer cell recovery was rapid, and numbers normalized in both cohorts by day +100. Mean CD3, CD4, and CD8 T-lymphocyte numbers normalized by 6 months after RD HSCT and by 1 year in the URD group. CD4 and CD8 T-lymphocyte counts were significantly higher in patients who received RD HSCT at 6 months and at 1 year, respectively, post-HSCT compared with patients who received URD HSCT. The pace of CD19 B-cell recovery was markedly different between RD and URD cohorts. Mean B-cell numbers were normal by day 100 after RD HSCT but took 1 year post-HSCT to normalize in the URD cohort. Despite these differences in immune reconstitution, the timing and nature of infections did not differ between the groups, presumably because of comparable T-lymphocyte recovery. Immune reconstitution occurred at a faster pace than in prior reports using RIC with T-cell depletion. The incidence of infections was similar for both cohorts and occurred most frequently in the first 100 days post-HSCT. Viral and fungal infections occurred at a lower incidence in this cohort, with “early” alemtuzumab compared with regimens administering serotherapy in the peritransplantation period. Patients were susceptible to bacterial infections primarily in the first 100 days irrespective of donor source and had no increase in mortality from the same. The overall mortality rate from infections was 1.4% at 1 year. Close monitoring and prophylaxis against bacterial infections in the first 100 days post-HSCT is necessary but is followed by robust immune reconstitution, especially in the T-cell compartment.

Original languageEnglish (US)
JournalBiology of Blood and Marrow Transplantation
DOIs
StateAccepted/In press - Jan 1 2018
Externally publishedYes

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Hematopoietic Stem Cell Transplantation
Transplantation
Pediatrics
Infection
Unrelated Donors
Tissue Donors
T-Lymphocytes
Lymphocyte Count
Transplants
Bacterial Infections
alemtuzumab
B-Lymphocytes
Melphalan
Passive Immunization
Mortality
Mycoses
Incidence
Graft Rejection
Graft vs Host Disease
Virus Diseases

Keywords

  • Immune reconstitution
  • Nonmalignant disorders
  • Reduced-intensity conditioning
  • Stem cell transplant

ASJC Scopus subject areas

  • Hematology
  • Transplantation

Cite this

Immune Reconstitution and Infection Patterns after Early Alemtuzumab and Reduced Intensity Transplantation for Nonmalignant Disorders in Pediatric Patients. / Bhatt, Sima T.; Bednarski, Jeffrey J.; Berg, Julia; Trinkaus, Kathryn; Murray, Lisa; Hayashi, Robert; Schulz, Ginny; Hente, Monica; Grimley, Michael; Chan, Ka Wah; Kamani, Naynesh; Jacobsohn, David; Nieder, Michael; Hale, Gregory; Yu, Lolie; Adams, Roberta; Dalal, Jignesh; Pulsipher, Michael A.; Haut, Paul; Chaudhury, Sonali; Davis, Jeffrey; Jaroscak, Jennifer; Andreansky, Martin; Willert, Jennifer; Shenoy, Shalini.

In: Biology of Blood and Marrow Transplantation, 01.01.2018.

Research output: Contribution to journalArticle

Bhatt, ST, Bednarski, JJ, Berg, J, Trinkaus, K, Murray, L, Hayashi, R, Schulz, G, Hente, M, Grimley, M, Chan, KW, Kamani, N, Jacobsohn, D, Nieder, M, Hale, G, Yu, L, Adams, R, Dalal, J, Pulsipher, MA, Haut, P, Chaudhury, S, Davis, J, Jaroscak, J, Andreansky, M, Willert, J & Shenoy, S 2018, 'Immune Reconstitution and Infection Patterns after Early Alemtuzumab and Reduced Intensity Transplantation for Nonmalignant Disorders in Pediatric Patients', Biology of Blood and Marrow Transplantation. https://doi.org/10.1016/j.bbmt.2018.10.008
Bhatt, Sima T. ; Bednarski, Jeffrey J. ; Berg, Julia ; Trinkaus, Kathryn ; Murray, Lisa ; Hayashi, Robert ; Schulz, Ginny ; Hente, Monica ; Grimley, Michael ; Chan, Ka Wah ; Kamani, Naynesh ; Jacobsohn, David ; Nieder, Michael ; Hale, Gregory ; Yu, Lolie ; Adams, Roberta ; Dalal, Jignesh ; Pulsipher, Michael A. ; Haut, Paul ; Chaudhury, Sonali ; Davis, Jeffrey ; Jaroscak, Jennifer ; Andreansky, Martin ; Willert, Jennifer ; Shenoy, Shalini. / Immune Reconstitution and Infection Patterns after Early Alemtuzumab and Reduced Intensity Transplantation for Nonmalignant Disorders in Pediatric Patients. In: Biology of Blood and Marrow Transplantation. 2018.
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AU - Berg, Julia

AU - Trinkaus, Kathryn

AU - Murray, Lisa

AU - Hayashi, Robert

AU - Schulz, Ginny

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N2 - Hematopoietic stem cell transplantation (HSCT) is a therapeutic option for many nonmalignant disorders (NMD) and is curative or prevents disease progression. Reduced-intensity conditioning (RIC) in HSCT for NMD may reduce regimen-related acute toxicities and late complications. Myeloablation is often replaced by immune suppression in RIC regimens to support donor engraftment. The pace of immune reconstitution after immune suppression by RIC regimens is influenced by agents used, donor source, and graft-versus-host disease prophylaxis/treatment. In a multicenter trial (NCT 00920972) of HSCT for NMD, a RIC regimen consisting of alemtuzumab, fludarabine, and melphalan was substituted for myeloablation. Alemtuzumab was administered early (days −21 to −19) to mitigate major lymphodepletion of the incoming graft and the risk of graft rejection. Immune reconstitution and infectious complications were prospectively monitored for 1-year post-HSCT. Seventy-one patients met inclusion criteria for this report and received marrow or peripheral blood stem cell transplants. Immune reconstitution and infections are reported for related donor (RD) and unrelated donor (URD) transplants at 3 time-points (100 days, 6 months, and 1 year post-HSCT). Natural killer cell recovery was rapid, and numbers normalized in both cohorts by day +100. Mean CD3, CD4, and CD8 T-lymphocyte numbers normalized by 6 months after RD HSCT and by 1 year in the URD group. CD4 and CD8 T-lymphocyte counts were significantly higher in patients who received RD HSCT at 6 months and at 1 year, respectively, post-HSCT compared with patients who received URD HSCT. The pace of CD19 B-cell recovery was markedly different between RD and URD cohorts. Mean B-cell numbers were normal by day 100 after RD HSCT but took 1 year post-HSCT to normalize in the URD cohort. Despite these differences in immune reconstitution, the timing and nature of infections did not differ between the groups, presumably because of comparable T-lymphocyte recovery. Immune reconstitution occurred at a faster pace than in prior reports using RIC with T-cell depletion. The incidence of infections was similar for both cohorts and occurred most frequently in the first 100 days post-HSCT. Viral and fungal infections occurred at a lower incidence in this cohort, with “early” alemtuzumab compared with regimens administering serotherapy in the peritransplantation period. Patients were susceptible to bacterial infections primarily in the first 100 days irrespective of donor source and had no increase in mortality from the same. The overall mortality rate from infections was 1.4% at 1 year. Close monitoring and prophylaxis against bacterial infections in the first 100 days post-HSCT is necessary but is followed by robust immune reconstitution, especially in the T-cell compartment.

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