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KIR Favorable Mismatched Haplo Transplant and KIR Polymorphism in ALL/AML/MDS Allo-HCT Children
Trial ID: NCT02646839
This is a phase II, open-label, non-randomized, prospective study of haploidentical transplantation using KIR-favorable donors for children with acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) undergoing allogeneic hematopoietic cell transplantation (HCT). The relationship of KIR2DL1 polymorphisms to survival in children with these diseases undergoing any approach to allogeneic HCT during the study time frame will also be determined.
The Role of KIR-favorably Mismatched Haploidentical Transplantation and KIR-polymorphisms in Determining Outcomes of Children With ALL/AML/MDS Undergoing Allogeneic Hematopoietic Cell Transplantation
2.3.1 Inclusion Criteria for the Biology (KIR2DL1 Polymorphisms/ALL MRD), Comparative
Outcomes, and Cost Effectiveness Trial
1. Any patient with ALL, AML, or MDS who is deemed eligible for and undergoes HCT at
participating centers who provides consent for the KIR2DL1 polymorphisms, comparative
outcomes and cost-effectiveness portion of the trial.
2. Any ALL patient undergoing allogeneic HCT at participating centers is eligible for the
ALL deep sequence MRD portion of the trial.
3. Patients ineligible for the KIR-favorable haploidentical phase II trial who require
T-cell depletion may be treated using TCR αβ+CD3+/CD19+ cell depletion. These patients
will be followed descriptively on this portion of the trial. Preparative regimen will
be at the discretion of the transplant center, but the options associated with this
protocol are recommended.
2.3.2 Inclusion Criteria for the KIR-favorable Haploidentical Phase II trial:
1. Age < 22 years
2. Disease and disease status:
- ALL high-risk in first remission (<5% blasts by morphology pre-transplant)
meeting criteria for transplant. Example CR1 indications: induction failure (>5%
blasts by morphology on post-induction BM), minimal residual disease greater than
or equal to 1% marrow blasts by morphology after induction, minimal residual
disease by flow cytometry >0.01% after consolidation, hypodiploidy (<44
chromosomes), 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).
- ALL in second remission: B-cell; early (less than or equal to 36 months from
initiation of therapy) BM relapse, late BM relapse with MRD >0.1% by flow
cytometry after first induction therapy; T-cell or Ph+ with BM relapse at any
time; very early (less than 18 months from initiation of therapy) isolated
extramedullary relapse (T or B-cell)
- Myelodysplastic syndrome (MDS): Any 2001 WHO classification subtype (Appendix I).
RAEB-2 patients may proceed directly to transplant, but may also receive
induction chemotherapy before transplant. Patients with ≥20% morphologic marrow
blasts will require induction therapy to reduce morphologic marrow blasts below
5% before transplant.
- High-risk AML defined as monosomy 5, del 5q, monosomy 7, M6, M7, t(6;9),
FLT3-ITD, or patients who have greater than or equal to 25% blasts by morphology
after induction, or who do not achieve CR after 2 courses of therapy. Also,
patients with ≥ 0.1% MRD or evidence of progressive extramedullary disease after
- AML in second or subsequent morphologic remission.
3. Has not received a prior allogeneic hematopoietic stem cell transplant.
4. Does not have a suitable HLA-matched sibling donor available for stem cell donation.
5. Does not have a suitable matched or single antigen mismatched related or unrelated
donor available at any time (noted by search), or it is in the patient's best interest
as judged by the attending to move forward with stem cell transplantation rather than
wait for an unrelated donor to become available (refer to subsection 2.5.1 for further
6. Has a suitable HLA KIR favorable haploidentical matched family member available for
stem cell donation.
7. 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.
8. Able to give informed consent if > 18 years, or with a legal guardian capable of
giving informed consent if < 18 years.
9. Adequate organ function (within 4 weeks of initiation of preparative regimen), defined
- Pulmonary: FEV1, FVC, and corrected DLCO must all be ≥ 50% of predicted by
pulmonary function tests (PFTs). For children who are unable to perform for PFTs
due to age, the criteria are: no evidence of dyspnea at rest and no need for
- Renal: Creatinine clearance or radioisotope GFR ³ 70 mL/min/1.73 m2 or a serum
creatinine based on age/gender as follows:
Age Maximum Serum Creatinine (mg/dL) Male Female 1 to < 2 years 0.6 0.6 2 to < 6 years 0.8
0.8 6 to < 10 years 1 1 10 to < 13 years 1.2 1.2 13 to < 16 years 1.5 1.4
≥ 16 years 1.7 1.4 The threshold creatinine values in this Table were derived from the
Schwartz formula for estimating GFR utilizing child length and stature data published by
- Cardiac: 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.
- Hepatic: \SGOT (AST) or SGPT (ALT) < 5 x upper limit of normal (ULN) for age.
Conjugated bilirubin < 2.5 mg/dL, unless attributable to Gilbert's Syndrome.
1. Pregnant or lactating females are ineligible as many of the medications used in this
protocol could be harmful to unborn children and infants.
2. Patients with HIV or uncontrolled fungal, bacterial or viral infections are excluded.
Patients with history of fungal disease during induction therapy may proceed if they
have a significant response to antifungal therapy with no or minimal evidence of
disease remaining by CT evaluation.
3. Patients with active CNS leukemia or any other active site of extramedullary disease
at the time of enrollment 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.
4. Patients with genetic disorders (generally marrow failure syndromes) prone to
secondary AML/ALL with known poor outcome are not eligible (Fanconi Anemia, Kostmann
Syndrome, Dyskeratosis Congenita, etc).
device: CliniMacs TCR alpha-beta-Biotin system