Unrelated Donor Transplant Versus Immune Therapy in Pediatric Severe Aplastic Anemia

Michael Pulsipher

Status: Completed

Conditions: Severe Aplastic Anemia

Treatments: Radiation: low-dose total body irradiation (TBI); Drug: rabbit anti-thymocyte globulin (ATG); Drug: cyclophosphamide; Procedure: Matched Unrelated Donor Hematopoietic Stem Cell Transplant; Drug: cyclosporine; Procedure: Immunosuppressive Therapy (IST); Drug: methotrexate; Drug: fludarabine; Drug: horse anti-thymocyte globulin (ATG)

Study type: Interventional

Funder types: Other

Identifiers

NCT02845596

TransIT NMD 1601

Details and patient eligibility

About

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.

Full 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.

Enrollment: 40 estimated patients

Sex: All

Ages: Under 25 years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Other

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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40 participants in 2 patient groups

Immunosuppressive Therapy

Active Comparator group

Description:

Patient will receive standard immunosuppressive therapy combination of drugs: horse anti-thymocyte globulin (ATG) and cyclosporine.

Treatment:

Drug: horse anti-thymocyte globulin (ATG)

Procedure: Immunosuppressive Therapy (IST)

Drug: cyclosporine

Matched Unrelated Stem Cell Transplant

Active Comparator group

Description:

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.

Treatment:

Drug: fludarabine

Drug: methotrexate

Drug: cyclophosphamide

Procedure: Matched Unrelated Donor Hematopoietic Stem Cell Transplant

Drug: cyclosporine

Drug: rabbit anti-thymocyte globulin (ATG)

Radiation: low-dose total body irradiation (TBI)