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

NCT02646839 | Enrolling By Invitation Phase 2 DMC

• 1 other identifier: PBMTC ONC1401
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 11

Brief Summary

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.

Conditions

Acute Lymphoblastic Leukemia; Acute Myeloid Leukemia; Myelodysplastic Syndromes

Keywords

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

Outcome Measures

Primary Outcomes (2)

• Disease free survival at 1 year post HCT

  1 year

• 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

  1 year

Secondary Outcomes (10)

• 1- and 2-year overall survival (OS) for children undergoing TCR αβ+CD3+/CD19+ cell depleted favorably KIR-mismatched haplo-HCT

  2 years

• Cumulative incidence of neutrophil and platelet engraftment, primary and secondary rejection, NTM, and relapse in KIR favorable haplo-HCT recipients

  1 year

• Cumulative incidence of overall grades II-IV and III-IV acute GVHD in KIR favorable haplo-HCT recipients

  5 years

• 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.

  1 year

• 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

  1 year

Study Arms (1)

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) αβ+CD3+/CD19+ cells from CliniMacs TCR alpha-beta-Biotin system

Device: CliniMacs TCR alpha-beta-Biotin system

Interventions

CliniMacs TCR alpha-beta-Biotin system DEVICE

Graft ex vivo depleted of T cell receptor (TCR) αβ+CD3+/CD19+ cells

KIR Favorable Transplant

Eligibility Criteria

• Age: Up to 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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.
• Any ALL patient undergoing allogeneic HCT at participating centers is eligible for the ALL deep sequence MRD portion of the trial.
• 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.
• Age \< 22 years
• 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.
• Has not received a prior allogeneic hematopoietic stem cell transplant.
• Does not have a suitable HLA-matched sibling donor available for stem cell donation.
• 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).
• Has a suitable HLA KIR favorable haploidentical matched family member available for stem cell donation.
• 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.

You may not qualify if:

• Pregnant or lactating females are ineligible as many of the medications used in this protocol could be harmful to unborn children and infants.
• 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.
• 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.
• 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).

Sponsors & Collaborators

• Michael Pulsipher: lead
• University of California, San Francisco: collaborator
• Children's Hospital of Philadelphia: collaborator
• Medical College of Wisconsin: collaborator
• Ann & Robert H Lurie Children's Hospital of Chicago: collaborator
• New York Medical College: collaborator
• UCSF Benioff Children's Hospital Oakland: collaborator
• Vanderbilt University: collaborator
• Rady Children's Hospital, San Diego: collaborator

Study Sites (11)

Children's Hospital Los Angeles

Los Angeles, California, 90027, United States

Location

Children's Hospital Oakland

Oakland, California, 94609, United States

Location

Stanford University Medical Center

Palo Alto, California, 94305, United States

Location

Rady Children's Hospital

San Diego, California, 92123, United States

Location

University of California, San Francisco

San Francisco, California, 94143, United States

Location

Lurie Children's Hospital

Chicago, Illinois, 60611, United States

Location

New York Medical Center

Valhalla, New York, 10595, United States

Location

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

Vanderbilt University - Monroe Carell Jr. Children's Hospital

Nashville, Tennessee, 37232, United States

Location

University of Utah, Primary Children's Hospital

Salt Lake City, Utah, 84112, United States

Location

Medical College of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

Related Publications (2)

• Dvorak CC, Long-Boyle JR, Holbrook-Brown L, Abdel-Azim H, Bertaina A, Vatsayan A, Talano JA, Bunin N, Anderson E, Flower A, Lalefar N, Higham CS, Kapoor N, Klein O, Odinakachukwu MC, Cho S, Jacobsohn DA, Collier W, Pulsipher MA. Effect of rabbit ATG PK on outcomes after TCR-alphabeta/CD19-depleted pediatric haploidentical HCT for hematologic malignancy. Blood Adv. 2024 Dec 10;8(23):6003-6014. doi: 10.1182/bloodadvances.2024012670.

  PMID: 39042892 DERIVED

• Pulsipher MA, Ahn KW, Bunin NJ, Lalefar N, Anderson E, Flower A, Cairo MS, Talano JA, Chaudhury S, Kitko CL, Duke JL, Monos D, Leung W, Dvorak CC, Abdel-Azim H. KIR-favorable TCR-alphabeta/CD19-depleted haploidentical HCT in children with ALL/AML/MDS: primary analysis of the PTCTC ONC1401 trial. Blood. 2022 Dec 15;140(24):2556-2572. doi: 10.1182/blood.2022015959.

  PMID: 35776909 DERIVED

MeSH Terms

Conditions

Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Leukemia, Myeloid; Bone Marrow Diseases

Study Officials

• Michael Pulsipher, MD

  Children's Hospital Los Angeles

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Head of Section of Blood and Marrow Transplantation

Study Record Dates

• First Submitted: December 21, 2015
• First Posted: January 6, 2016
• Study Start: October 1, 2015
• Primary Completion: November 1, 2025
• Study Completion: December 1, 2025
• Last Updated: May 4, 2025

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (11)