| Eligibility |
Inclusion Criteria:
- Acquired and Inherited Bone Marrow Failure Conditions Associated with Trilinear Bone
Marrow Failure
- Acquired Aplastic Anemia
1. Must meet criteria for severe or very severe aplastic anemia (AA), defined
by:
i. Bone marrow biopsy demonstrating cellularity of <25% overall or bone
marrow biopsy that is overall hypocellular for age by pathology report with
reductions in any two hematopoietic lineages (myeloid, erythroid, or
megakaryocyte)
ii. In addition, 2 of the following must be met:
1. absolute neutrophil count (ANC) < 500/µL (severe) or < 200/µL (very
severe). Current ANC or last ANC prior to start of Granulocyte-colony
stimulating factor (G-CSF) may be used.
2. platelets < 30,000/µL or transfusion dependence
3. absolute reticulocyte count < 40,000/µL
iii. Negative evaluation for inherited bone marrow failure conditions (see
below)
iv. Must not have accompanying diagnosis of myelodysplastic syndrome
2. Patients meeting other eligibility criteria may receive study therapy as the
initial treatment approach provided an eligible unrelated or mismatched
related ("haplo") donor is available
3. Patients who have received prior immune suppression therapy will be eligible
if they have refractory or relapsed disease defined as per treating
clinician's judgement, at least 12 weeks after initiation of immune
suppression therapy. Relapsed patients who previously met hematologic
criteria for severe aplastic anemia do not have to meet these hematologic
criteria for severe aplastic anemia at time of relapse to be eligible for
transplant.
- Paroxysmal Nocturnal Hemoglobinuria
1. Patients must have testing (eg. Flow Cytometry demonstrating cells with
absent cluster of differentiation 55 (CD55) or cluster of differentiation 59
(CD59) expression demonstrating a PNH clone in greater than 10% of
peripheral blood red blood cells and/or granulocytes, along with clinical or
laboratory evidence of intravascular hemolysis, such as:
i. Elevated Lactate dehydrogenase (LDH)
ii. Low to absent serum haptoglobin
iii. Hemoglobinuria
iv. Reticulocytosis
v. Studies demonstrating aberrant complement activation
2. Patients who have small paroxysmal nocturnal hemoglobinuria (PNH) clones, no
evidence of hemolysis, and meet criteria for severe or very severe AA as
defined above, will be classified as acquired AA for treatment
stratification.
- Fanconi Anemia
1. To be eligible, patients must meet the following criteria:
i. Must have evidence of BM failure, defined as a bone marrow biopsy
demonstrating cellularity of <25% in addition to peripheral blood cytopenias
ii. Must have chromosomal breakage (stress) testing performed demonstrating
increased sensitivity to DNA damage caused by mitomycin C (MMC) or
diepoxybutane (DEB)
iii. Specific testing to define the subtype of Fanconi Anemia through
genetic sequencing for causative mutations or complementation group studies
is strongly recommended, though not required.
- Dyskeratosis Congenita and related telomere disorders
1. To be eligible, patients must meet the following criteria:
i. Must have evidence of BM failure, defined as a bone marrow biopsy
demonstrating cellularity of <25% in addition to peripheral blood cytopenias
ii. Must have lymphocyte telomere length analysis performed at a Clinical
Laboratory Improvement Amendments (CLIA)-certified facility, demonstrating
telomeres <1%ile for age
iii. Specific gene sequencing testing to define the causative genetic
mutation is strongly recommended, though not required.
- Shwachman-Diamond Syndrome
1. To be eligible, patients must meet the following criteria:
i. Must have genetic testing confirming a mutation in the
Shwachman-Bodian-Diamond syndrome (SBDS) gene, and/or classic clinical
features of Shwachman-Diamond Syndrome, including pancreatic insufficiency,
musculoskeletal anomalies, and endocrinopathies
ii. Must have developed trilineage BM failure, including BM cellularity <
25%.
2. Patients meeting the above criteria for Shwachman-Diamond syndrome will be
eligible for conditioning regimen #1 with dosing of Total Body Irradiation
(TBI) and cyclophosphamide according to the dyskeratosis congenita regimen
- Inherited Bone Marrow Failure Conditions Associated with Predominant Single Lineage
Failure
- Severe Congenital Neutropenia
1. To be eligible, patients must meet the following criteria:
i. Have a baseline ANC < 500/µL prior to G-CSF therapy
ii. Require chronic G-CSF therapy greater than 3 doses per week in order to maintain an ANC
> 1000/µL
iii. Have genetic testing demonstrating mutation(s) in a gene known to cause severe
congenital neutropenia and/or have negative testing for autoimmune causes of neutropenia or
BM biopsy demonstrating myeloid lineage arrest at neutrophil precursor stage.
iv. History of severe bacterial or fungal infection associated with neutropenia, including,
but not limited to, pneumonia, osteomyelitis, mastoiditis, or bacteremia. If no infection
history, must otherwise have evidence of toxicity due to chronic G-CSF therapy, including
osteopenia, splenomegaly or isolated cytogenetic abnormalities.
- Isolated disorders of erythropoiesis:
1. Includes, but not limited to: i. Diamond-Blackfan Anemia (DBA) ii. Congenital
Dyserythropoietic Anemia (CDA) iii. Congenital Sideroblastic Anemia (CSA) 2.
Eligibility criteria include: i. Chronic red blood cell (RBC) Transfusion Dependence,
with minimum frequency of every 8 weeks ii. BM aspirate and biopsy demonstrating
selective erythroid hypoplasia or dyserythropoiesis iii. For patients with DBA, must
have failed at least one therapeutic trial with corticosteroids iv. Acquired viral and
autoimmune causes of hypo-productive anemia have been excluded v. Specific genetic
testing attempting to define the causative mutation is recommended but not required
o Congenital Thrombocytopenia Syndromes
1. Includes, but is not limited to, patients with Congenital Amegakaryocytic
Thrombocytopenia caused by mutations in the MPL gene 2. Eligibility criteria include:
i. Platelet transfusion dependence with a minimum transfusion frequency of every 8
weeks ii. Infectious, autoimmune, and other causes of secondary thrombocytopenia have
been excluded iii. Genetic sequencing of the MPL gene is required iv. Additional
genetic testing for causes of familial thrombocytopenia is recommended but not
required
- Organ function status
- Renal: Serum creatinine <1.5x upper limit of normal for age
- Hepatic: Transaminases <500 upper limit of normal. Bilirubin <2.5 mg/dL, (unless
elevation due to Gilberts disease or known hemolytic anemia).
- Cardiac: shortening fraction >= 27%
- Pulmonary: Diffusing Capacity (DLCO) >= 50% predicted in patients old enough to
comply with pulmonary function testing (PFTs) or no baseline oxygen requirement
for younger patients.
- Lansky or Karnofsky performance >= 60
- Infectious disease criteria
- No active, untreated infections
- Patients with likely bacterial infections must be receiving appropriate
antibacterial therapy and demonstrating therapy response
- Patients with likely fungal infections must have had at least 2 weeks of
appropriate anti-fungal antibiotics and be asymptomatic.
- Patients with symptoms consistent with active viral infection will be deferred
until viral symptoms resolve. Patients with evidence of cytomegalovirus (CMV),
Epstein-Barr virus (EBV) or other known viremia must receive appropriate therapy
to clear viremia prior to initiating study therapy.
- Signed consent by parent/guardian or able to give consent if >= 18 years
Exclusion Criteria:
- Patients who do not meet disease, organ or infectious criteria.
- Patients with a clinical diagnosis of myelodysplastic syndrome (MDS) defined by
combination of bone marrow dysplasia and classic cytogenetic lesion (Monosomy 7,
Trisomy 8 eg.), with or without excess blasts.
- Patients with no suitable closely Human leukocyte antigen (HLA)-matched unrelated or
related haploidentical matched donor available. Patients with suitable fully matched
related donor are also not eligible.
- Pregnant females. All females of childbearing potential must have negative pregnancy
test.
Donor selection and eligibility:
• Donor selection will comply with 21 Code of Federal Regulations (CFR 1271) of the U.S.
Food and Drug Administration's Code of Federal Regulations
Donor testing:
- Unrelated donor meets National Marrow Donor Program criteria for donation
- For partially matched related donors, Children's Hospital of Philadelphia (CHOP) bone
marrow transplant (BMT) standard procedures apply for determining donor eligibility,
including donor screening and testing for relevant communicable disease agents and
diseases. The donor collection program is FACT accredited.
- For partially matched related donors, if subject has genetically confirmed iBMF
syndrome, related donor must be evaluated for this disorder and testing must be
negative
- Infectious disease testing of donor will be per current Blood and Marrow Transplant
Program Standards of Practice as per 21 CFR Part 1271. Donor medical records and
history are reviewed to confirm that the donor is free of infectious risk factors and
meets donor eligibility criteria as defined by 21 CFR 127.
Donor matching
- High resolution HLA typing at HLA-A, -B, -C, DRB1, and DQB1 loci
- Unrelated donor
- Donor must be an antigen and allele match at = 8/10 HLA Loci
- In donor with 2 mismatches, only one mismatch involving HLA-A, -B, or -DRB1 will be
allowed
- Donor and collection center willing to undergo mobilization and apheresis
- Partially matched related donor
- Related donor must be = 5/10 but < 10/10 HLA match
- Donor must be willing to undergo G-CSF mobilization and stem cell apheresis.
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