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

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

  • ORG STUDY ID: PBMTC ONC1401
  • NCT ID: NCT02646839

Conditions

  • Acute Lymphoblastic Leukemia
  • Acute Myeloid Leukemia
  • Myelodysplastic Syndromes

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 88±15% 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 70±38% for transplantations using
      matched siblings and 61±17% 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

NameTypeDescriptionInterventions
KIR Favorable TransplantExperimentalTo 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) αβ+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.
    
              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
                      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 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
            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).
          
    Maximum Eligible Age:21 Years
    Minimum Eligible Age:N/A
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Disease free survival at 1 year post HCT
    Time Frame:1 year
    Safety Issue:
    Description:

    Secondary Outcome Measures

    Measure:1- and 2-year overall survival (OS) for children undergoing TCR αβ+CD3+/CD19+ cell depleted favorably KIR-mismatched haplo-HCT
    Time Frame:2 years
    Safety Issue:
    Description:
    Measure:Cumulative incidence of neutrophil and platelet engraftment, primary and secondary rejection, NTM, and relapse in KIR favorable haplo-HCT recipients
    Time Frame:1 year
    Safety Issue:
    Description:
    Measure:Cumulative incidence of overall grades II-IV and III-IV acute GVHD in KIR favorable haplo-HCT recipients
    Time Frame:5 years
    Safety Issue:
    Description:
    Measure: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.
    Time Frame:1 year
    Safety Issue:
    Description:
    Measure: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
    Time Frame:1 year
    Safety Issue:
    Description:
    Measure: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.
    Time Frame:1 year
    Safety Issue:
    Description:
    Measure:To compare costs of transplantation using favorably KIR-mismatched haplo-HCT with patients receiving alternative donor transplantation at centers participating in the trial
    Time Frame:1 year
    Safety Issue:
    Description:
    Measure:1- and 2-year event free survival (DFS) for children undergoing TCR αβ+CD3+/CD19+ cell depleted favorably KIR-mismatched haplo-HCT
    Time Frame:2 years
    Safety Issue:
    Description:
    Measure:Cumulative incidence of chronic GVHD in KIR favorable haplo-HCT recipients.
    Time Frame:1 year
    Safety Issue:
    Description:
    Measure:Cumulative incidence of mild, moderate, and severe cGVHD
    Time Frame:1 year
    Safety Issue:
    Description:

    Details

    Phase:Phase 2
    Primary Purpose:Interventional
    Overall Status:Enrolling by invitation
    Lead Sponsor:Michael Pulsipher, MD

    Trial Keywords

    • Acute Lymphoblastic Leukemia (ALL)
    • Acute Myeloid Leukemia (AML)
    • Myelodysplastic Syndrome (MDS)
    • KIR-Favorable
    • Haploidentical Transplantation
    • Allogeneic Hematopoietic Cell Transplantation

    Last Updated

    July 28, 2021