Clinical Trials /

KIR Favorable Mismatched Haplo Transplant and KIR Polymorphism in ALL/AML/MDS Allo-HCT Children

NCT02646839

Description:

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.

Related Conditions:
  • Acute Lymphoblastic Leukemia
  • Myelodysplastic Syndromes
Recruiting Status:

Enrolling by invitation

Phase:

Phase 2

Trial Eligibility

Document

KIR Favorable Mismatched Haplo Transplant and KIR Polymorphism in <span class="go-doc-concept go-doc-disease">ALL</span>/AML/<span class="go-doc-concept go-doc-disease">MDS</span> Allo-HCT Children

Title

  • Brief Title: KIR Favorable Mismatched Haplo Transplant and KIR Polymorphism in ALL/AML/MDS Allo-HCT Children
  • Official Title: 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
  • Clinical Trial IDs

    NCT ID: NCT02646839

    ORG ID: PBMTC ONC1401

    Trial Conditions

    Acute Lymphoblastic Leukemia

    Acute Myeloid Leukemia

    Myelodysplastic Syndromes

    Trial Interventions

    Drug Synonyms Arms

    Trial Purpose

    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.

    Detailed Description

    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
    immunosuppressive regimens.

    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
    patients.

    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.

    Trial Arms

    Name Type Description Interventions
    KIR Favorable Transplant Experimental To assess in a multi-center setting whether the disease-free survival (DFS) at one-year post-HCT for children with high-risk ALL, AML and MDS can be improved following favorably KIR-mismatched haplo-HCT using a graft ex vivo depleted of T cell receptor (TCR) +CD3+/CD19+ cells from CliniMacs TCR alpha-beta-Biotin system

    Eligibility Criteria

    Inclusion Criteria:

    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
    induction chemotherapy.

    - 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),
    defined as:

    - 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
    supplemental oxygen.

    - 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
    the CDC.45

    - 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.

    Exclusion Criteria:

    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

    Primary Outcome Measures

    Disease free survival at 1 year post HCT

    1 yr disease free survival of patients transplanted with donors homozygous for KIR2DL1-C245 will be compared to patients with donors hetero- or homozygous for KIRD2DL1-R245 polymorphisms

    Secondary Outcome Measures

    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

    Trial Keywords

    Acute Lymphoblastic Leukemia (ALL)

    Acute Myeloid Leukemia (AML)

    Myelodysplastic Syndrome (MDS)

    KIR-Favorable

    Haploidentical Transplantation

    Allogeneic Hematopoietic Cell Transplantation