Unrelated Donor Transplant Versus Immune Therapy in Pediatric Severe Aplastic Anemia

Severe Aplastic Anemia Clinical Trial

Official title:

Unrelated Donor Transplant Versus Immune Therapy in Pediatric Severe Aplastic Anemia

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02845596
• Other study ID #: TransIT NMD 1601
• Status: Active, not recruiting
• Phase: N/A
• Start date: August 2016
• Est. completion date: April 2024

Study information

• Verified date: October 2023
• Source: Children's Hospital Los Angeles
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 40
• Est. completion date: April 2024
• Est. primary completion date: April 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 25 Years

Eligibility

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.

Related Conditions & MeSH terms

• Anemia
• Anemia, Aplastic
• Severe Aplastic Anemia

Intervention

Drug:
• cyclosporine
cyclosporine

Procedure:
• Matched Unrelated Donor Hematopoietic Stem Cell Transplant
Matched Unrelated Donor (MUD) Hematopoietic Stem Cell Transplantation (HSCT)

Drug:
• horse anti-thymocyte globulin (ATG)
horse anti-thymocyte globulin (ATG)
• rabbit anti-thymocyte globulin (ATG)
rabbit anti-thymocyte globulin (ATG)
• methotrexate
methotrexate
• fludarabine
fludarabine
• cyclophosphamide
cyclophosphamide

Radiation:
• low-dose total body irradiation (TBI)
low-dose total body irradiation (TBI)

Procedure:
• Immunosuppressive Therapy (IST)
Immunosuppressive Therapy (IST)

Locations

Country	Name	City	State
United States	Children's Hospital Colorado	Aurora	Colorado
United States	Boston Children's Hospital	Boston	Massachusetts
United States	Cleveland Clinic	Cleveland	Ohio
United States	UT Southwestern Medical Center	Dallas	Texas
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	Texas Children's Hospital	Houston	Texas
United States	Children's Hospital Los Angeles	Los Angeles	California
United States	University of Wisconsin	Madison	Wisconsin
United States	Stanford Lucile Packard Children's Hospital	Palo Alto	California
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Cohen Children's Medical Center	Queens	New York
United States	UCSF	San Francisco	California
United States	Fred Hutchinson Cancer Research Center	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Michael Pulsipher, MD

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	Treatment-related mortality at one year from randomization in both arms	Number of deaths that are treatment related	1 Year
Secondary	Overall Survival at one year from randomization in both arms	percentage of enrolled patients living at 1 year post randomization	1 Year
Secondary	Time from randomization to neutrophil recovery in both arms	Time from randomization to neutrophil recovery in both arms	4 years
Secondary	Time from randomization to platelet recovery in both arms	Time from randomization to platelet recovery in both arms	4 years
Secondary	Time from randomization to red blood cell recovery in both arms	Time from randomization to red blood cell recovery in both arms	4 years
Secondary	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
Secondary	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
Secondary	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
Secondary	Rates of IST response	Rates of IST response	4 years
Secondary	Rates of IST relapse	Rates of IST relapse	4 years
Secondary	Rates of secondary MDS or AML in both treatment arms.	Rates of secondary MDS or AML in both treatment arms.	4 years
Secondary	Rates of other secondary malignancies in both treatment arms.	Rates of other secondary malignancies in both treatment arms.	4 years
Secondary	Development of symptomatic PNH in both treatment arms.	Development of symptomatic PNH in both treatment arms.	4 years
Secondary	Incidence of significant infection in both treatment arms	Incidence of significant infection in both treatment arms	4 years
Secondary	Time to immune reconstitution in the HSCT arm	Time to immune reconstitution in the HSCT arm	4 years