Stem Cell Transplant for Immunologic or Histiocytic Disorders

Phase 2

Completed

• Conditions: Hemophagocytic Lymphohistiocytosis; X-Linked Lymphoproliferative Disorders; Immunologic Deficiency Syndromes; Chediak-Higashi Syndrome; Griscelli Syndrome; Langerhans-Cell Histiocytosis
• Interventions: Procedure: Stem Cell Transplant; Drug: Fludarabine; Drug: Melphalan; Drug: Anti-thymocyte globulin (ATG); Drug: Campath 1H; Drug: Cyclosporin A; Drug: Mycophenolate mofetil; Drug: Intravenous immunoglobulin (IVIG)

• Registration Number: NCT00176865
• Lead Sponsor: Masonic Cancer Center, University of Minnesota

Brief Summary

This study tests the clinical outcomes of a preparative regimen of fludarabine (FLU), anti-thymocyte globulin (ATG)/or Campath, and melphalan; followed by hematopoietic stem cell transplant, and a post transplant regimen of Cyclosporin A (CsA) in patients with immunologic or histiocytic disorders. The researchers hypothesize that this regimen will have a positive effect on post transplant engraftment and the incidence of graft-versus-host-disease (GVHD).

Patients will be randomized biologically into one of 3 arms based upon donor availability: (a) human leukocyte antigen (HLA) genotypic matched sibling donor, (b) HLA phenotypic matched unrelated peripheral blood stem cell (PBSC) donor, (c) two HLA 0-2 antigen mismatched unrelated cord blood donors (double cord).

Detailed Description

Prior to transplantation, subjects will receive Melphalan, Fludarabine and Anti-Thymocyte Globulin (ATG) or Campath. These three drugs are being given to subjects to help the new stem cells take and grow. On the day of transplantation, subjects will receive stem cells transfused via intravenous (IV) catheter.

After stem cell transplantation, subjects will be given Cyclosporin A (CsA) and mycophenolate mofetil (MMF) to reduce the risk of graft-versus-host disease, the complication that occurs when the donor's stem cells react against the patient.

Study Timeline

• Study Start: 2002-08
• Study First Submitted: 2005-09-12
• Study First Submitted QC: 2005-09-12
• Study First Posted: 2005-09-15
• Primary Completion: 2012-08
• Study Completion: 2014-08
• Results First Submitted: 2015-05-06
• Results First Submitted QC: 2017-03-03
• Results First Posted: 2017-04-14
• Status Verified: 2017-12
• Last Update Submitted: 2017-12-03
• Last Update Posted: 2017-12-28

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 19

Inclusion Criteria

Patients with immunodeficiencies or histiocytic disorders 0-35 years of age with an acceptable stem cell donor and disease characteristic defined by the following:

• Patients with histocytic disorders (hemophagocytic lymphohistiocytosis of any etiology and refractory Langerhans cell histiocytosis) who do not meet eligibility criteria for a myeloablative transplant procedure
• Patients with immunodeficiency disorders in whom residual immune function may not require a fully myeloablative preparative regimen or patient is ineligible for standard myeloablative preparative regimen (any form of severe combined immunodeficiency [SCID], or other immunodeficiency with T cell defect)
• Patients with immunodeficiency disorders that have had poor outcome with myeloablative stem cell transplants (including, but not limited to, common variable immunodeficiency [CVID], Wiskott Aldrich Syndrome [WAS] if > 5 years of age, ataxia telangiectasia)
• Patients with immunodeficiencies or histocytic disorders that require a second stem cell transplant (SCT) for any reason

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Exclusion Criteria

• Karnofsky or Lansky performance score <70
• Glomerular filtration rate (GFR)<30% predicted
• Cardiac function <50% normal by echocardiogram
• Serum creatinine > 2x normal for age/weight
• Pregnant or lactating females
• Active serious infection that has not had an adequate course of therapy pre-SCT. Any patient with acquired immune deficiency syndrome (AIDS) or AIDS-related complex (ARC) or human immunodeficiency virus (HIV) seropositivity

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm 1 - Matched sibling donor	Fludarabine	Stem Cell Transplant: human leukocyte antigen (HLA) genotypic matched sibling donor and pre-treatment with fludarabine, melphalan, anti-thymocyte globulin or Campath 1H and post-treatment with Cyclosporin A, mycophenolate mofetil and Intravenous immunoglobulin (IVIG)
Arm 1 - Matched sibling donor	Melphalan	Stem Cell Transplant: human leukocyte antigen (HLA) genotypic matched sibling donor and pre-treatment with fludarabine, melphalan, anti-thymocyte globulin or Campath 1H and post-treatment with Cyclosporin A, mycophenolate mofetil and Intravenous immunoglobulin (IVIG)
Arm 1 - Matched sibling donor	Anti-thymocyte globulin (ATG)	Stem Cell Transplant: human leukocyte antigen (HLA) genotypic matched sibling donor and pre-treatment with fludarabine, melphalan, anti-thymocyte globulin or Campath 1H and post-treatment with Cyclosporin A, mycophenolate mofetil and Intravenous immunoglobulin (IVIG)
Arm 1 - Matched sibling donor	Stem Cell Transplant	Stem Cell Transplant: human leukocyte antigen (HLA) genotypic matched sibling donor and pre-treatment with fludarabine, melphalan, anti-thymocyte globulin or Campath 1H and post-treatment with Cyclosporin A, mycophenolate mofetil and Intravenous immunoglobulin (IVIG)
Arm 1 - Matched sibling donor	Mycophenolate mofetil	Stem Cell Transplant: human leukocyte antigen (HLA) genotypic matched sibling donor and pre-treatment with fludarabine, melphalan, anti-thymocyte globulin or Campath 1H and post-treatment with Cyclosporin A, mycophenolate mofetil and Intravenous immunoglobulin (IVIG)
Arm 1 - Matched sibling donor	Intravenous immunoglobulin (IVIG)	Stem Cell Transplant: human leukocyte antigen (HLA) genotypic matched sibling donor and pre-treatment with fludarabine, melphalan, anti-thymocyte globulin or Campath 1H and post-treatment with Cyclosporin A, mycophenolate mofetil and Intravenous immunoglobulin (IVIG)
Arm 2 - Matched unrelated donor	Stem Cell Transplant	Stem Cell Transplant: HLA phenotypic matched unrelated peripheral blood stem cell (PBSC) donor and pre-treatment with fludarabine, melphalan, anti-thymocyte globulin or Campath 1H and post-treatment with Cyclosporin A, mycophenolate mofetil and Intravenous immunoglobulin (IVIG)
Arm 2 - Matched unrelated donor	Anti-thymocyte globulin (ATG)	Stem Cell Transplant: HLA phenotypic matched unrelated peripheral blood stem cell (PBSC) donor and pre-treatment with fludarabine, melphalan, anti-thymocyte globulin or Campath 1H and post-treatment with Cyclosporin A, mycophenolate mofetil and Intravenous immunoglobulin (IVIG)
Arm 2 - Matched unrelated donor	Cyclosporin A	Stem Cell Transplant: HLA phenotypic matched unrelated peripheral blood stem cell (PBSC) donor and pre-treatment with fludarabine, melphalan, anti-thymocyte globulin or Campath 1H and post-treatment with Cyclosporin A, mycophenolate mofetil and Intravenous immunoglobulin (IVIG)
Arm 3 - Mismatched double cord donors	Stem Cell Transplant	Stem Cell Transplant: two HLA 0-2 antigen mismatched unrelated cord blood donors (double cord) and pre-treatment with fludarabine, melphalan, anti-thymocyte globulin or Campath 1H and post-treatment with Cyclosporin A, mycophenolate mofetil and Intravenous immunoglobulin (IVIG)
Arm 3 - Mismatched double cord donors	Fludarabine	Stem Cell Transplant: two HLA 0-2 antigen mismatched unrelated cord blood donors (double cord) and pre-treatment with fludarabine, melphalan, anti-thymocyte globulin or Campath 1H and post-treatment with Cyclosporin A, mycophenolate mofetil and Intravenous immunoglobulin (IVIG)
Arm 3 - Mismatched double cord donors	Melphalan	Stem Cell Transplant: two HLA 0-2 antigen mismatched unrelated cord blood donors (double cord) and pre-treatment with fludarabine, melphalan, anti-thymocyte globulin or Campath 1H and post-treatment with Cyclosporin A, mycophenolate mofetil and Intravenous immunoglobulin (IVIG)
Arm 3 - Mismatched double cord donors	Anti-thymocyte globulin (ATG)	Stem Cell Transplant: two HLA 0-2 antigen mismatched unrelated cord blood donors (double cord) and pre-treatment with fludarabine, melphalan, anti-thymocyte globulin or Campath 1H and post-treatment with Cyclosporin A, mycophenolate mofetil and Intravenous immunoglobulin (IVIG)
Arm 3 - Mismatched double cord donors	Campath 1H	Stem Cell Transplant: two HLA 0-2 antigen mismatched unrelated cord blood donors (double cord) and pre-treatment with fludarabine, melphalan, anti-thymocyte globulin or Campath 1H and post-treatment with Cyclosporin A, mycophenolate mofetil and Intravenous immunoglobulin (IVIG)
Arm 3 - Mismatched double cord donors	Cyclosporin A	Stem Cell Transplant: two HLA 0-2 antigen mismatched unrelated cord blood donors (double cord) and pre-treatment with fludarabine, melphalan, anti-thymocyte globulin or Campath 1H and post-treatment with Cyclosporin A, mycophenolate mofetil and Intravenous immunoglobulin (IVIG)
Arm 1 - Matched sibling donor	Campath 1H	Stem Cell Transplant: human leukocyte antigen (HLA) genotypic matched sibling donor and pre-treatment with fludarabine, melphalan, anti-thymocyte globulin or Campath 1H and post-treatment with Cyclosporin A, mycophenolate mofetil and Intravenous immunoglobulin (IVIG)
Arm 2 - Matched unrelated donor	Campath 1H	Stem Cell Transplant: HLA phenotypic matched unrelated peripheral blood stem cell (PBSC) donor and pre-treatment with fludarabine, melphalan, anti-thymocyte globulin or Campath 1H and post-treatment with Cyclosporin A, mycophenolate mofetil and Intravenous immunoglobulin (IVIG)
Arm 2 - Matched unrelated donor	Melphalan	Stem Cell Transplant: HLA phenotypic matched unrelated peripheral blood stem cell (PBSC) donor and pre-treatment with fludarabine, melphalan, anti-thymocyte globulin or Campath 1H and post-treatment with Cyclosporin A, mycophenolate mofetil and Intravenous immunoglobulin (IVIG)
Arm 1 - Matched sibling donor	Cyclosporin A	Stem Cell Transplant: human leukocyte antigen (HLA) genotypic matched sibling donor and pre-treatment with fludarabine, melphalan, anti-thymocyte globulin or Campath 1H and post-treatment with Cyclosporin A, mycophenolate mofetil and Intravenous immunoglobulin (IVIG)
Arm 2 - Matched unrelated donor	Fludarabine	Stem Cell Transplant: HLA phenotypic matched unrelated peripheral blood stem cell (PBSC) donor and pre-treatment with fludarabine, melphalan, anti-thymocyte globulin or Campath 1H and post-treatment with Cyclosporin A, mycophenolate mofetil and Intravenous immunoglobulin (IVIG)
Arm 2 - Matched unrelated donor	Mycophenolate mofetil	Stem Cell Transplant: HLA phenotypic matched unrelated peripheral blood stem cell (PBSC) donor and pre-treatment with fludarabine, melphalan, anti-thymocyte globulin or Campath 1H and post-treatment with Cyclosporin A, mycophenolate mofetil and Intravenous immunoglobulin (IVIG)
Arm 2 - Matched unrelated donor	Intravenous immunoglobulin (IVIG)	Stem Cell Transplant: HLA phenotypic matched unrelated peripheral blood stem cell (PBSC) donor and pre-treatment with fludarabine, melphalan, anti-thymocyte globulin or Campath 1H and post-treatment with Cyclosporin A, mycophenolate mofetil and Intravenous immunoglobulin (IVIG)
Arm 3 - Mismatched double cord donors	Intravenous immunoglobulin (IVIG)	Stem Cell Transplant: two HLA 0-2 antigen mismatched unrelated cord blood donors (double cord) and pre-treatment with fludarabine, melphalan, anti-thymocyte globulin or Campath 1H and post-treatment with Cyclosporin A, mycophenolate mofetil and Intravenous immunoglobulin (IVIG)
Arm 3 - Mismatched double cord donors	Mycophenolate mofetil	Stem Cell Transplant: two HLA 0-2 antigen mismatched unrelated cord blood donors (double cord) and pre-treatment with fludarabine, melphalan, anti-thymocyte globulin or Campath 1H and post-treatment with Cyclosporin A, mycophenolate mofetil and Intravenous immunoglobulin (IVIG)

Primary Outcome Measures

Name	Time	Method
Number of Subjects With Mixed Chimerism	Day 100	\>10% Donor Cells at Day 100

Secondary Outcome Measures

Name	Time	Method
Percentage of Donor Chimerism at 100 Days	Day 100	The percent of recipient bone marrow and blood cells that are of donor origin.
Percentage of Donor Chimerism at 180 Days	Day 180	The percent of recipient bone marrow and blood cells that are of donor origin.
Incidence of Grade 2-4 Acute Graft Versus Host Disease (aGVHD)	Day 100	Acute graft versus host disease (aGVHD) is a reaction occurring within the first 100 days after transplant where the T- cells of the donor graft attacks the recipient's (host's) skin, GI tract, liver and other organs. The severity of aGVHD is graded on a scale of 1 - 4 with the highest number representing the most severe disease.
Incidence of Grade 3-4 Acute Graft Versus Host Disease (aGVHD)	Day 100	Acute graft versus host disease (aGVHD) is a reaction occurring within the first 100 days after transplant where the T- cells of the donor graft attacks the recipient's (host's) skin, GI tract, liver and other organs. The severity of aGVHD is graded on a scale of 1 - 4 with the highest number representing the most severe disease.
Incidence of Chronic Graft Versus Host Disease (cGVHD)	6 months and 1 year	Chronic graft versus host disease (cGVHD) is a reaction which typically develops 3 to 6 months after transplant where the T- cells of the donor graft attacks the recipient's (host's) skin, GI tract, liver and other organs.
Number of Subjects Alive at 100 Days	Day 100
Number of Subjects Alive at One Year	Day 365
Compare Quality of Life (QOL)	Pretransplant, 1 year, 2 years and 5 years
Percentage of Donor Chimerism at 365 Days	Day 365	The percent of recipient bone marrow and blood cells that are of donor origin.

Trial Locations

Locations (1)

Masonic Cancer Center University of Minnesota; 🇺🇸 Minneapolis, Minnesota, United States