Unrelated Donor Transplant Versus Immune Therapy in Pediatric Severe Aplastic Anemia

The purpose of this study is to determine the feasibility of comparing outcomes of patients treated de novo with immunosuppressive therapy (IST) versus matched unrelated donor (MUD) hematopoietic stem cell transplant (HSCT) for pediatric acquired severe aplastic anemia.

Study Overview

• Status: Completed
• Conditions: Severe Aplastic Anemia
• Intervention / Treatment: Drug: cyclophosphamide; Drug: cyclosporine; Drug: horse anti-thymocyte globulin (ATG); Procedure: Immunosuppressive Therapy (IST); Drug: rabbit anti-thymocyte globulin (ATG); Radiation: low-dose total body irradiation (TBI); Drug: methotrexate; Procedure: Matched Unrelated Donor Hematopoietic Stem Cell Transplant; Drug: fludarabine

Detailed Description

A major challenge in treating pediatric Severe Aplastic Anemia (SAA) is the determination of best primary therapy for patients who lack a fully matched related donor for HSCT. Good survival outcomes have been seen with IST, but initial and late failures, CSA dependence, persistent cytopenias and secondary Myelodysplastic Syndrome (MDS) / Acute Myeloid Leukemia (AML) in a portion of patients leave considerable room for improvement. MUD HSCT survival in SAA has markedly improved, but a direct comparison of this approach with IST is necessary to determine whether this approach is feasible and will lead to better Event Free Survival. This trial will address the feasibility of randomization, test whether patients can be evaluated in a timely fashion and safely begin therapy with MUD HSCT or IST, and give a preliminary assessment of the safety of up-front MUD HSCT. If successful, this trial will lead to a future prospective trial comparing directly IST to MUD HSCT in this disease.

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90027
      • Children's Hospital Los Angeles
    • Palo Alto, California, United States, 94304
      • Stanford Lucile Packard Children's Hospital
    • San Francisco, California, United States, 94123
      • UCSF
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Boston Children's Hospital
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center
  • New York
    • Queens, New York, United States, 11040
      • Cohen Children's Medical Center
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
  • Texas
    • Dallas, Texas, United States, 75390
      • UT Southwestern Medical Center
    • Houston, Texas, United States, 77030
      • Texas Children's Hospital
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutchinson Cancer Research Center
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 25 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Confirmed diagnosis of idiopathic SAA, defined as:

   • Bone marrow cellularity <25%, or <30% hematopoietic cells.
   • Two out of three of the following (in peripheral blood): neutrophils <0.5 x109/L, platelets <20 x109/L, reticulocyte count <60 x109/L with hemoglobin <8g/dL.
2. Age ≤25 years old.
3. No suitable fully matched related donor available (minimum 6/6 match for Human Leukocyte antigen (HLA) -A and B at intermediate or high resolution and DRB1 at high resolution using DNA based typing).
4. At least two unrelated donors noted on National Marrow Donor Program (NMDP) search who are well matched (9/10 or 10/10 for HLA-A, B, C, DRB1, and DQB1 using high resolution).
5. Signed informed consent for the randomized trial by patient and/or legal guardian.
6. Adequate organ function defined as in the judgment of the investigator, there is not irreversible organ damage that would preclude the patient from meeting the organ function inclusion criteria for HSCT listed in section 2.3.4 by the intended time of HSCT (6-8 weeks after randomization) or preclude patients from receiving horse ATG.

Exclusion Criteria:

1. Inherited bone marrow failure syndromes (IBMFS). The diagnosis of Fanconi anemia must be excluded by diepoxybutane (DEB) or equivalent testing on peripheral blood or marrow. Telomere length testing should be sent on all patients to exclude Dyskeratosis congenita, but if results are delayed or unavailable and there are no clinical manifestations of DC, patients may enroll. If patients have clinical characteristics suspicious for Shwachman Diamond syndrome, this syndrome must be excluded by pancreatic isoamylase testing or gene mutation analysis. Note: pancreatic isoamylase testing is not accurate in children less than 3 years.
2. Clonal cytogenetic abnormalities or fluorescence In Situ Hybridization (FISH) pattern consistent with pre-myelodysplastic syndrome (pre-MDS) or MDS on marrow examination (see section 4.2.3.1 for details of the required MDS FISH panel).
3. Known severe allergy to horse ATG.
4. Prior allogeneic stem cell transplant.
5. Prior solid organ transplant.
6. Infection with human immunodeficiency virus (HIV).
7. Active Hepatitis B or C. This should be excluded in patients where there is clinical suspicion of hepatitis (e.g. elevated LFTs).
8. Female patients who are pregnant or breast-feeding.
9. Prior malignancies except resected basal cell carcinoma or treated cervical carcinoma in situ.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Immunosuppressive Therapy; Patient will receive standard immunosuppressive therapy combination of drugs: horse anti-thymocyte globulin (ATG) and cyclosporine.	Drug: cyclosporine; cyclosporine; Drug: horse anti-thymocyte globulin (ATG); horse anti-thymocyte globulin (ATG); Other Names: ATGAM; Procedure: Immunosuppressive Therapy (IST); Immunosuppressive Therapy (IST)
Active Comparator: Matched Unrelated Stem Cell Transplant; Patient will under go matched unrelated donor transplant of hematopoietic stem cells as their therapy using fludarabine, cyclophosphamide, rabbit anti-thymocyte globulin (ATG), and low-dose total body irradiation (TBI) as preparative regimen and cyclosporine and methotrexate for graft versus host disease (GVHD) prevention.	Drug: cyclophosphamide; cyclophosphamide; Drug: cyclosporine; cyclosporine; Drug: rabbit anti-thymocyte globulin (ATG); rabbit anti-thymocyte globulin (ATG); Other Names: Thymoglobulin; Radiation: low-dose total body irradiation (TBI); low-dose total body irradiation (TBI); Drug: methotrexate; methotrexate; Procedure: Matched Unrelated Donor Hematopoietic Stem Cell Transplant; Matched Unrelated Donor (MUD) Hematopoietic Stem Cell Transplantation (HSCT); Drug: fludarabine; fludarabine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of patients randomized to HSCT that actually complete HSCT	Feasibility of comparing outcomes of patients treated de novo with IST versus matched unrelated donor HSCT for pediatric acquired severe aplastic anemia as defined by percentage of patients randomized to HSCT that actually complete HSCT.	4 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time from screening consent to randomization	To measure the time from screening consent and randomization of patients to initiation of the preparative regimen of those randomized to HSCT.	4 years
Number of patients that fail to receive their primary assigned therapy (HSCT or IST).	Number of patients fail to receive their primary assigned therapy (HSCT or IST).	4 years
Reasons why patients fail to receive their primary assigned therapy (HSCT or IST).	Reasons why patients fail to receive their primary assigned therapy (HSCT or IST).	4 years
Treatment-related mortality at one year from randomization in both arms	Number of deaths that are treatment related	1 Year
Overall Survival at one year from randomization in both arms	percentage of enrolled patients living at 1 year post randomization	1 Year
Time from randomization to neutrophil recovery in both arms	Time from randomization to neutrophil recovery in both arms	4 years
Time from randomization to platelet recovery in both arms	Time from randomization to platelet recovery in both arms	4 years
Time from randomization to red blood cell recovery in both arms	Time from randomization to red blood cell recovery in both arms	4 years
Time from randomization to cessation of immune suppression recovery in both arms	Time from randomization to cessation of immune suppression recovery in both arms	4 years
Rates of primary and secondary graft rejection in the MUD HSCT arm	Rates of primary and secondary graft rejection in the MUD HSCT arm	4 years
Rates of grade II-IV and III-IV acute GVHD, and extensive chronic GVHD in the MUD HSCT arm	Rates of grade II-IV and III-IV acute GVHD, and extensive chronic GVHD in the MUD HSCT arm	4 years
Rates of IST response	Rates of IST response	4 years
Rates of IST relapse	Rates of IST relapse	4 years
Rates of secondary MDS or AML in both treatment arms.	Rates of secondary MDS or AML in both treatment arms.	4 years
Rates of other secondary malignancies in both treatment arms.	Rates of other secondary malignancies in both treatment arms.	4 years
Development of symptomatic PNH in both treatment arms.	Development of symptomatic PNH in both treatment arms.	4 years
Incidence of significant infection in both treatment arms	Incidence of significant infection in both treatment arms	4 years
Time to immune reconstitution in the HSCT arm	Time to immune reconstitution in the HSCT arm	4 years

Collaborators and Investigators

• Sponsor: Michael Pulsipher
• Investigators: Study Chair: David A Williams, MD, Boston's Childrens Hospital; Study Chair: Michael Pulsipher, MD, Children's Hospital Los Angeles

Study record dates

Study Major Dates

• Study Start: August 1, 2016
• Primary Completion (Actual): November 3, 2020
• Study Completion (Actual): July 19, 2023

Study Registration Dates

• First Submitted: May 9, 2016
• First Submitted That Met QC Criteria: July 22, 2016
• First Posted (Estimated): July 27, 2016

Study Record Updates

• Last Update Posted (Actual): May 11, 2025
• Last Update Submitted That Met QC Criteria: May 6, 2025
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Bone Marrow Failure Disorders; Hematologic Diseases; Bone Marrow Diseases; Anemia; Anemia, Aplastic; Anti-Infective Agents; Antineoplastic Agents; Antifungal Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Reproductive Control Agents; Antimetabolites, Antineoplastic; Antimetabolites; Dermatologic Agents; Folic Acid Antagonists; Nucleic Acid Synthesis Inhibitors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Calcineurin Inhibitors; Methotrexate; Cyclophosphamide; Fludarabine; Cyclosporine; Cyclosporins; Antilymphocyte Serum; Thymoglobulin; Immunosuppressive Agents
• Other Study ID Numbers: TransIT NMD 1601

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED