Clinical trial NCT02845596: Unrelated Donor Transplant Versus Immune Therapy in Pediatric Severe Aplastic Anemia
Official title: Unrelated Donor Transplant Versus Immune Therapy in Pediatric Severe Aplastic Anemia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Severe Aplastic Anemia
Lead sponsor: Pediatric Transplantation & Cellular Therapy Consortium
Sponsor class: OTHER
First posted: 2016-07-27
Enrollment: 40
Sex: ALL
Maximum age (years): 25
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

Brief 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Percentage of patients randomized to HSCT that actually complete HSCT
timeFrame: 4 years
Secondary outcomes:
measure: Time from screening consent to randomization
timeFrame: 4 years
measure: Number of patients that fail to receive their primary assigned therapy (HSCT or IST).
timeFrame: 4 years
measure: Reasons why patients fail to receive their primary assigned therapy (HSCT or IST).
timeFrame: 4 years
measure: Treatment-related mortality at one year from randomization in both arms
timeFrame: 1 Year
measure: Overall Survival at one year from randomization in both arms
timeFrame: 1 Year
measure: Time from randomization to neutrophil recovery in both arms
timeFrame: 4 years
measure: Time from randomization to platelet recovery in both arms
timeFrame: 4 years
measure: Time from randomization to red blood cell recovery in both arms
timeFrame: 4 years
measure: Time from randomization to cessation of immune suppression recovery in both arms
timeFrame: 4 years
measure: Rates of primary and secondary graft rejection in the MUD HSCT arm
timeFrame: 4 years
measure: Rates of grade II-IV and III-IV acute GVHD, and extensive chronic GVHD in the MUD HSCT arm
timeFrame: 4 years
measure: Rates of IST response
timeFrame: 4 years
measure: Rates of IST relapse
timeFrame: 4 years
measure: Rates of secondary MDS or AML in both treatment arms.
timeFrame: 4 years
measure: Rates of other secondary malignancies in both treatment arms.
timeFrame: 4 years
measure: Development of symptomatic PNH in both treatment arms.
timeFrame: 4 years
measure: Incidence of significant infection in both treatment arms
timeFrame: 4 years
measure: Time to immune reconstitution in the HSCT arm
timeFrame: 4 years
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: Palo Alto
country: United States
facility: Stanford Lucile Packard Children's Hospital
state: California
city: San Francisco
country: United States
facility: UCSF
state: California
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: Queens
country: United States
facility: Cohen Children's Medical Center
state: New York
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Dallas
country: United States
facility: UT Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: Texas Children's Hospital
state: Texas
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center
state: Washington
city: Madison
country: United States
facility: University of Wisconsin
state: Wisconsin
Study officials:
affiliation: Children's Hospital Los Angeles
name: Michael Pulsipher, MD
role: STUDY_CHAIR
affiliation: Boston's Childrens Hospital
name: David A Williams, MD
role: STUDY_CHAIR
References: