Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. Guidelines differ from study to study, and identify who can or cannot participate. There is no guarantee that every individual who qualifies and wants to participate in a trial will be enrolled. Contact the study team to discuss study eligibility and potential participation.
Inclusion Criteria - Patient Enrollment:
- 6 months to < 22 years at enrollment.
- Diagnosed with ALL, AML, or MDS for which an allogeneic hematopoietic stem cell
transplant is indicated. Complete Remission (CR) status will not be confirmed at the
time of enrollment. CR as defined in these sections is required to proceed with the
actual HCT treatment plan.
- Has not received a prior allogeneic hematopoietic stem cell transplant.
- Does not have a suitable human leukocyte antigen (HLA)-matched sibling donor available
for stem cell donation.
- Has an eligible haploidentical related family donor based on at least intermediate
resolution HLA typing.
- Patients who also have an eligible 8/8 MUD adult donor based on confirmatory high
resolution HLA typing are eligible for randomization to Arm A or Arm B.
- Patients who do not have an eligible MUD donor are eligible for enrollment to Arm
C.
- All patients and/or their parents or legal guardians must sign a written informed
consent.
- All institutional, Food and Drug Administration (FDA), and National Cancer Institute
(NCI) requirements for human studies must be met.
- Co-Enrollment on other trials.
- Patients will not be excluded from enrollment on this study if already enrolled
on other protocols for treatment of high risk and/or relapsed ALL, AML and MDS.
This is including, but not limited to, COG AAML1831, COG AALL1821, the EndRAD
Trial, as well as local institutional trials. We will collect information on all
co-enrollments.
- Patients will not be excluded from enrollment on this study if receiving
immunotherapy prior to transplant as a way to achieve remission and bridge to
transplant. This includes chimeric antigen receptor (CAR) T cell therapy and
other immunotherapies.
Inclusion Criteria - Patient to Proceed to HCT:
- Karnofsky Index or Lansky Play-Performance Scale ≥60 on pre-transplant evaluation.
Karnofsky scores must be used for patients ≥ 16 years of age and Lansky scores for
patients =< 16 years of age (within 4 weeks of starting therapy).
- A serum creatinine based on age/gender as follows:
6 months to < 1 year: 0.5 mg/dL (Male); 0.5 mg/dL (Female);
1. to < 2 years 0.6 mg/dL (Male); 0.6 mg/dL (Female);
2. to < 6 years 0.8 mg/dL (Male); 0.8 mg/dL (Female);
6 to < 10 years: 1 mg/dL (Male); 1 mg/dL (Female) 10 to < 13 years: 1.2 mg/dL (Male);
1.2 mg/dL (Female) 13 to < 16 years: 1.5 mg/dL (Male); 1.4 mg/dL (Female) >= 16 years:
1.7 mg/dL (Male); 1.4 mg/dL (Female); OR
- A 24 hour urine Creatinine clearance ≥ 60 mL/min/1.73 m^2; OR
- A glomerular filtration rate (GFR) ≥ 60 mL/min/1.73 m^2. GFR must be performed using
direct measurement with a nuclear blood sampling method OR direct small molecule
clearance method (iothalamate or other molecule per institutional standard).
- Note: Estimated GFR (eGFR) from serum creatinine, cystatin C or other estimates
are not acceptable for determining eligibility.
- Serum glutamic-oxaloacetic transaminase (SGOT) aspartate aminotransferase [AST] or
serum glutamate pyruvate transaminase (SGPT) aminotransferase [ALT] < 5 x upper limit
of normal (ULN) for age.
- Total bilirubin < 2.5 mg/dL, unless attributable to Gilbert's Syndrome.
- Shortening fraction of ≥ 27% by echocardiogram or radionuclide scan (MUGA); OR
- Ejection fraction of ≥ 50% by echocardiogram or radionuclide scan (MUGA), choice of
test according to local standard of care.
- Forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and
corrected carbon monoxide diffusing capability (DLCO) must all be ≥ 50% of predicted
by pulmonary function tests (PFTs).
- For children who are unable to perform for PFTs (e.g., due to age or
developmental delay), the criteria are: no evidence of dyspnea at rest, oxygen
(O2) saturation (Sat) > 92% on room air by pulse oximetry, not on supplemental O2
at rest, and not on supplemental O2 at rest.
- ALL high-risk in first complete remission (CR1) for whom transplant is indicated.
Examples include: induction failure, treatment failure as per minimal residual disease
by flow cytometry > 0.01% after consolidation and not eligible for AALL1721 or
AALL1721 not available/unwilling to enroll, hypodiploidy (< 44 chromosomes) with MRD+
> 0.01% after induction, persistent or recurrent cytogenetic or molecular evidence of
disease during therapy requiring additional therapy after induction to achieve
remission (e.g. persistent molecular BCR-ABL positivity), T cell ALL with persistent
MRD > 0.01% after consolidation.
- ALL in second complete remission (CR2) for whom transplant is indicated. Examples
include: B-cell: early (≥ 36 months from initiation of therapy) bone marrow (BM)
relapse, late BM relapse (≥ 36 months) with MRD ≥ 0.1% by flow cytometry after first re-induction therapy; T or B-cell: early (< 18 months) isolated extramedullary (IEM),
late (≥ 18 months) IEM, end-Block 1 MRD ≥ 0.1%; T-cell or Philadelphia chromosome positive (Ph+): BM relapse at any time.
- ALL in ≥ third complete remission (CR3).
- Patients treated with chimeric antigen receptor T-cells (CART) cells for whom
transplant is indicated. Examples include: transplant for consolidation of CART, loss
of CART persistence and/or B cell aplasia < 6 months from infusion or have other
evidence (e.g., MRD+) that transplant is indicated to prevent relapse.
- AML in CR1 for whom transplant is indicated. Examples include those deemed high risk
for relapse as described in AAML1831:
- FLT3/ITD+ with allelic ratio > 0.1 without bZIP CEBPA, NPM1;
- FLT3/ITD+ with allelic ratio > 0.1 with concurrent bZIP CEBPA or NPM1 and with
evidence of residual AML (MRD >= 0.05%) at end of Induction;
- Presence of RAM phenotype or unfavorable prognostic markers (other than FLT3/ITD)
per cytogenetics, fluorescence in situ hybridization (FISH), next generation
sequencing (NGS) results, regardless of favorable genetic markers, MRD status or
FLT3/ITD mutation status;
- AML without favorable or unfavorable cytogenetic or molecular features but with
evidence of residual AML (MRD ≥ 0.05%) at end of Induction;
- Presence of a non-ITD FLT3 activating mutation and positive MRD (≥ 0.05%) at end
of Induction 1 regardless of presence of favorable genetic markers;
- AML in ≥ CR2;
- MDS with < 5% blasts by morphology and flow cytometry (if available) on the
pre-transplant bone marrow evaluation;
- Complete remission (CR) is defined as < 5% blasts by morphology and flow cytometry (if
available) on the pre-transplant bone marrow evaluation with minimum sustained
absolute neutrophil count (ANC) of 300 cells/microliter for 1 week or ANC > 500
cells/microliter. We will be collecting data from all approaches to MRD evaluation
performed including NGS and polymerase chain reaction (PCR).
Donor Eligibility Criteria:
- Matched Unrelated Donors:
Unrelated donor candidates must be matched at high resolution at a minimum of 8/8 alleles
(HLA-A, -B, -C, -DRB1). One-antigen HLA mismatches are not permitted. HLA matching of
additional alleles is recommended according to National Marrow Donor Program (NMDP)
guidelines,110 but will be at the discretion of local centers.
- Haploidentical Matched Family Members:
- Minimum match level full haploidentical (at least 5/10; HLA-A, -B, -C, -DRB1,
-DQB1 alleles). The following issues (in no particular order) should be
considered in choosing a haploidentical donor:
- Absent or low patient donor-specific antibodies (DSA);
- Mean fluorescence intensity (MFI) of any anti-donor HLA antibody by
solid phase immunoassay should be < 2000. Donors with higher levels are
not eligible;
- If a screening assay against pooled HLA antigens is used, positive
results must be followed with specificity testing using a single
antigen assay. The MFI must be < 2000 unless the laboratory has
validated higher threshold values for reactivity for HLA antigens
(such as HLA-C, -DQ, and -DP), that may be enhanced in
concentration on the single antigen assays. Donor anti- recipient
antibodies are of unknown clinical significance and do not need to
be sent or reported.
- Consult with Study Chair for the clinical significance of any
recipient anti-donor HLA antibody.
- If centers are unable to perform this type of testing, please
contact the Study Chair to make arrangements for testing.
- If killer immunoglobulin testing (KIR) is performed: KIR status by mismatch,
KIR-B, or KIR content criteria can be used according to institutional
guidelines.
- ABO compatibility (in order of priority):
- Compatible or minor ABO incompatibility
- Major ABO incompatibility
- CMV serostatus:
- For a CMV seronegative recipient: the priority is to use a CMV
seronegative donor when feasible.
- For a CMV seropositive recipient: the priority is to use a CMV
seropositive donor when feasible.
- Age: younger donors including siblings/half-siblings, and second degree
relatives (aunts, uncles, cousins) are recommended, even if < 18 years.
- Size and vascular access appropriate by center standard for peripheral blood stem cell
(PBSC) collection if needed.
- Haploidentical matched family members: screened by center health screens and found to
be eligible.
- Unrelated donors: meet eligibility criteria as defined by the NMDP or other unrelated
donor registries. If the donor does not meet the registry eligibility criteria but an
acceptable eligibility waiver is completed and signed per registry guidelines, the
donor will be considered eligible for this study.
- Human immunodeficiency virus (HIV) negative.
- MUD donors and post-transplant cyclophosphamide haplo donors should be asked to
provide BM. If donors refuse and other donors are not available, PBSC is allowed.
TCR-alpha beta/CD19 depleted haplo donors must agree to donate PBSC.
- Must give informed consent.
- Haploidentical matched family members: Institution standard of care donor consent
and Protocol-specific Donor Consent for Optional Studies.
- Unrelated donors: standard NMDP Unrelated Donor Consent.
- Not pregnant.
Exclusion Criteriam - Patient Enrollment:
- Patients with genetic disorders (generally marrow failure syndromes) prone to
secondary AML/ALL with known poor outcomes because of sensitivity to alkylator therapy
and/or TBI are not eligible (Fanconi Anemia, Kostmann Syndrome, Dyskeratosis
Congenita, etc). Patients with Downs syndrome because of increased toxicity with
intensive conditioning regimens.
- Patients with any obvious contraindication to myeloablative HCT at the time of
enrollment.
- Female patients who are pregnant are ineligible as many of the medications used in
this protocol could be harmful to unborn children and infants.
- Sexually active patients of reproductive potential who have not agreed to use an
effective contraceptive method for the duration of their study participation.
Exclusion Criteria - Patient to Proceed to HCT:
- Patients with uncontrolled fungal, bacterial, viral, or parasitic infections are
excluded. Patients with history of fungal disease during chemotherapy may proceed if
they have a significant response to antifungal therapy with no or minimal evidence of
disease remaining by computed tomography (CT) evaluation.
- Patients with active central nervous system (CNS) leukemia or any other active site of
extramedullary disease at the time of initiation of the conditioning regimen are not
permitted.
- Note: Those with prior history of CNS or extramedullary disease, but with no
active disease at the time of pre-transplant workup, are eligible.
- Pregnant or breastfeeding females are ineligible as many of the medications used in
this protocol could be harmful to unborn children and infants.
Note: Other protocol defined Inclusion/Exclusion Criteria may apply.
Eligibility last updated 12/22/22. Questions regarding updates should be directed to the study team contact.