Allogeneic hematopoietic stem cell transplantation (HCT) using matched related and unrelated
donors is well-accepted therapy for children with subtypes of high-risk acute lymphoblastic
leukemia (ALL) and acute myeloid leukemia (AML). For the 40-50% of children who do not have
matched donors available, HCT approaches have varied by center and regional preferences. HCT
physicians in France and North America tend to use human leukocyte antigen (HLA)-mismatched
umbilical cord blood (UCB), while those in many large centers in Germany, parts of Asia, and
selected US centers favor HLA-haploidentical donors. Both approaches have improved
significantly through the years for a variety of reasons, including better supportive care,
cell processing techniques that now deliver more consistently high-quality products,
understanding of the importance of cell dose, and key modifications of preparative and
Both stem cell sources offer distinct advantages and disadvantages. T-cell-depleted
haploidentical approaches with killer-cell immunoglobulin-like receptor (KIR) mismatches
have been shown to lead to less relapse in patients with AML13 and, in some studies,
children with ALL as well. Disadvantages to this approach have been vulnerability to viral
infection and the requirement for an ex vivo T-cell depletion procedure that is currently
under IND. Cord blood is readily available and is permissive of some degree of HLA mismatch,
but current studies show no advantage in survival compared with matched unrelated donors.
Recently, a randomized study of one vs. two UCB units based on a hypothesis of decreased
relapse incidence with two units resulted in equivalent outcomes in both arms. Neutrophil
engraftment and immune recovery after UCB transplantation is relatively slow, leading to a
higher risk of transplant-related mortality; in addition, larger patients require two cord
units, dramatically increasing the cost of stem cell procurement. No direct comparisons of
these two stem cell sources (haploidentical vs. UCB) have been performed in pediatric
Recently, investigators at St. Jude Children's Research Hospital published excellent
outcomes using haploidentical donors with grafts depleted for CD3+ cells by an ex vivo
Miltenyi CliniMACS system. Their recent cohort of AML and ALL patients treated without total
body irradiation (TBI) had a 5-year survival of 8815% in 19 consecutive patients, with 17
surviving long-term and disease-free and only 2 patients died of progressive leukemia. These
results compared favorably with the 5-year survival of 7038% for transplantations using
matched siblings and 6117% for matched unrelated donors treated with identical leukemia
protocols with indications for transplantation defined a priori. These preliminary results
suggest that a strategy of using favorable KIR-mismatched haploidentical transplantation may
lead to a better outcome than other alternative donor approaches without the side effects of
TBI. This protocol is a phase II trial seeking to establish the feasibility and preliminary
outcomes with this approach in a multi-institutional setting.
In addition to KIR-HLA matching, KIR allele polymorphism may also affect transplant
outcomes.Recent data from St. Jude showed that in 312 pediatric HCTs, the patients who
received a donor graft containing the functionally stronger KIR2DL1 allele with arginine at
amino acid position 245 (KIR2DL1-R245) had better survival (p=0.0028) and a lower relapse
rate (p=0.022) than those who received a donor graft that contained only the functionally
weaker KIR2DL1 allele with cysteine at the same position (KIR2DL1-C245). Patients who
received a KIR2DL1-R245-positive graft with an HLA-C receptor-ligand mismatch had the best
survival (p=0.00004) and lowest risk of leukemia relapse (p=0.005). Thus, both KIR-HLA
matching and KIR allele polymorphism have prognostic value. We will attempt to prospectively
confirm these results in this multicenter trial.
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.
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 details).
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),
- 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 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).
Minimum Eligible Age: N/A
Maximum Eligible Age: 21 Years
Eligible Gender: Both
1- and 2-year overall survival (OS) for children undergoing TCR +CD3+/CD19+ cell depleted favorably KIR-mismatched haplo-HCT
Cumulative incidence of neutrophil and platelet engraftment, primary and secondary rejection, NTM, and relapse in KIR favorable haplo-HCT recipients
Cumulative incidence of overall grades II-IV and III-IV acute GVHD in KIR favorable haplo-HCT recipients
Compare the 2-year DFS and OS of patients transplanted using favorably KIR-mismatched haplo-HCT with other ALL, AML, and MDS patients concurrently transplanted using other approaches at the participating centers.
Compare the 2-year DFS and OS of patients transplanted using favorably KIR-mismatched haplo-HCT with other ALL, AML, and MDS patients concurrently transplanted using 4/6 and 5/6 HLA-matched cord blood reported to the CIBMTR
Test sensitivity of flow cytometry MRD for all patients; in ALL patients, compare flow cytometry MRD with IgH and TCR next-generation-sequencing (NGS) MRD pre- and post-HCT for predicting relapse, DFS, and OS in children undergoing allog-HCT.
To compare costs of transplantation using favorably KIR-mismatched haplo-HCT with patients receiving alternative donor transplantation at centers participating in the trial
1- and 2-year event free survival (DFS) for children undergoing TCR +CD3+/CD19+ cell depleted favorably KIR-mismatched haplo-HCT
Cumulative incidence of chronic GVHD in KIR favorable haplo-HCT recipients.
Cumulative incidence of mild, moderate, and severe cGVHD