Mismatched Related Donor Versus Matched Unrelated Donor Stem Cell Transplantation for Children, Adolescents, and Young Adults With Acute Leukemia or Myelodysplastic Syndrome

Recruiting

Trial ID: NCT05457556

Purpose

This phase III trial compares hematopoietic (stem) cell transplantation (HCT) using mismatched related donors (haploidentical [haplo]) versus matched unrelated donors (MUD) in treating children, adolescents, and young adults with acute leukemia or myelodysplastic syndrome (MDS). HCT is considered standard of care treatment for patients with high-risk acute leukemia and MDS. In HCT, patients are given very high doses of chemotherapy or radiation therapy, which is intended to kill cancer cells that may be resistant to more standard doses of chemotherapy; unfortunately, this also destroys the normal cells in the bone marrow, including stem cells. After the treatment, patients must have a healthy supply of stem cells reintroduced or transplanted. The transplanted cells then reestablish the blood cell production process in the bone marrow. The healthy stem cells may come from the blood or bone marrow of a related or unrelated donor. If patients do not have a matched related donor, doctors do not know what the next best donor choice is or if a haplo related donor or MUD is better. This trial may help researchers understand whether a haplo related donor or a MUD HCT for children with acute leukemia or MDS is better or if there is no difference at all.

Official Title

A Multi-Center, Phase 3, Randomized Trial of Matched Unrelated Donor (MUD) Versus HLA-Haploidentical Related (Haplo) Myeloablative Hematopoietic Cell Transplantation for Children, Adolescents, and Young Adults (AYA) With Acute Leukemia or Myelodysplastic Syndrome (MDS)

Stanford Investigator(s)

Eligibility


Inclusion Criteria:

   - PATIENT INCLUSION CRITERIA FOR ENROLLMENT:

   - 6 months to < 22 years at enrollment

   - Diagnosed with ALL, AML, or MDS for which an allogeneic hematopoietic stem cell
   transplant is indicated. Complete Remission (CR) status will not be confirmed at the
   time of enrollment. CR as defined in these sections is required to proceed with the
   actual HCT treatment plan

   - Has not received a prior allogeneic hematopoietic stem cell transplant

   - Does not have a suitable human leukocyte antigen (HLA)-matched sibling donor available
   for stem cell donation

   - Has an eligible haploidentical related family donor based on at least intermediate
   resolution HLA typing

      - Patients who also have an eligible 8/8 MUD adult donor based on confirmatory high
      resolution HLA typing are eligible for randomization to Arm A or Arm B.

      - Patients who do not have an eligible MUD donor are eligible for enrollment to Arm
      C

   - All patients and/or their parents or legal guardians must sign a written informed
   consent

   - All institutional, Food and Drug Administration (FDA), and National Cancer Institute
   (NCI) requirements for human studies must be met

   - Co-Enrollment on other trials

      - Patients will not be excluded from enrollment on this study if already enrolled
      on other protocols for treatment of high risk and/or relapsed ALL, AML and MDS.
      This is including, but not limited to, COG AAML1831, COG AALL1821, the EndRAD
      Trial, as well as local institutional trials. We will collect information on all
      co-enrollments

      - Patients will not be excluded from enrollment on this study if receiving
      immunotherapy prior to transplant as a way to achieve remission and bridge to
      transplant. This includes chimeric antigen receptor (CAR) T cell therapy and
      other immunotherapies

   - PATIENT INCLUSION CRITERIA TO PROCEED TO HCT:

   - 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 (within 4 weeks of starting therapy)

   - A serum creatinine based on age/gender as follows:

   6 months to < 1 year: 0.5 mg/dL (Male); 0.5 mg/dL (Female)

      1. to < 2 years: 0.6 mg/dL (Male); 0.6 mg/dL (Female)

      2. to < 6 years: 0.8 mg/dL (Male); 0.8 mg/dL (Female)

   6 to < 10 years: 1 mg/dL (Male); 1 mg/dL (Female) 10 to < 13 years: 1.2 mg/dL (Male);
   1.2 mg/dL (Female) 13 to < 16 years: 1.5 mg/dL (Male); 1.4 mg/dL (Female) >= 16 years:
   1.7 mg/dL (Male); 1.4 mg/dL (Female)

      - OR

   - A 24 hour urine Creatinine clearance >= 60 mL/min/1.73 m^2

      - OR

   - A glomerular filtration rate (GFR) >= 60 mL/min/1.73 m^2. GFR must be performed using
   direct measurement with a nuclear blood sampling method OR direct small molecule
   clearance method (iothalamate or other molecule per institutional standard)

      - Note: Estimated GFR (eGFR) from serum creatinine, cystatin C or other estimates
      are not acceptable for determining eligibility

   - Serum glutamic-oxaloacetic transaminase (SGOT) aspartate aminotransferase [AST] or
   serum glutamate pyruvate transaminase (SGPT) aminotransferase [ALT] < 5 x upper limit
   of normal (ULN) for age

   - Total bilirubin < 2.5 mg/dL, unless attributable to Gilbert's Syndrome

   - 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

   - Forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and
   corrected carbon monoxide diffusing capability (DLCO) must all be >= 50% of predicted
   by pulmonary function tests (PFTs).

      - For children who are unable to perform for PFTs (e.g., due to age or
      developmental delay), the criteria are: no evidence of dyspnea at rest, oxygen
      (O2) saturation (Sat) > 92% on room air by pulse oximetry, not on supplemental O2
      at rest, and not on supplemental O2 at rest

   - ALL high-risk in first complete remission (CR1) for whom transplant is indicated.
   Examples include: induction failure, treatment failure as per minimal residual disease
   by flow cytometry > 0.01% after consolidation and not eligible for AALL1721 or
   AALL1721 not available/unwilling to enroll, hypodiploidy (< 44 chromosomes) with MRD+
   > 0.01% after induction, 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), T cell ALL with persistent
   MRD > 0.01% after consolidation.

   - ALL in second complete remission (CR2) for whom transplant is indicated. Examples
   include: B-cell: early (=< 36 months from initiation of therapy) bone marrow (BM)
   relapse, late BM relapse (>= 36 months) with MRD >= 0.1% by flow cytometry after first
   re-induction therapy; T or B-cell: early (< 18 months) isolated extramedullary (IEM),
   late (>= 18 months) IEM, end-Block 1 MRD >= 0.1%; T-cell or Philadelphia chromosome
   positive (Ph+): BM relapse at any time

   - ALL in >= third complete remission (CR3)

   - Patients treated with chimeric antigen receptor T-cells (CART) cells for whom
   transplant is indicated. Examples include: transplant for consolidation of CART, loss
   of CART persistence and/or B cell aplasia < 6 months from infusion or have other
   evidence (e.g., MRD+) that transplant is indicated to prevent relapse

   - AML in CR1 for whom transplant is indicated. Examples include those deemed high risk
   for relapse as described in AAML1831:

      - FLT3/ITD+ with allelic ratio > 0.1 without bZIP CEBPA, NPM1

      - FLT3/ITD+ with allelic ratio > 0.1 with concurrent bZIP CEBPA or NPM1 and with
      evidence of residual AML (MRD >= 0.05%) at end of Induction

      - Presence of RAM phenotype or unfavorable prognostic markers (other than FLT3/ITD)
      per cytogenetics, fluorescence in situ hybridization (FISH), next generation
      sequencing (NGS) results, regardless of favorable genetic markers, MRD status or
      FLT3/ITD mutation status

      - AML without favorable or unfavorable cytogenetic or molecular features but with
      evidence of residual AML (MRD >= 0.05%) at end of Induction

      - Presence of a non-ITD FLT3 activating mutation and positive MRD (>= 0.05%) at end
      of Induction 1 regardless of presence of favorable genetic markers.

   - AML in >= CR2

   - MDS with < 5% blasts by morphology and flow cytometry (if available) on the
   pre-transplant bone marrow evaluation

   - Complete remission (CR) is defined as < 5% blasts by morphology and flow cytometry (if
   available) on the pre-transplant bone marrow evaluation with minimum sustained
   absolute neutrophil count (ANC) of 300 cells/microliter for 1 week or ANC > 500
   cells/microliter. We will be collecting data from all approaches to MRD evaluation
   performed including NGS and polymerase chain reaction (PCR)

   - DONOR ELIGIBILITY CRITERIA:

   - Matched Unrelated Donors:

Unrelated donor candidates must be matched at high resolution at a minimum of 8/8 alleles
(HLA-A, -B, -C, -DRB1). One-antigen HLA mismatches are not permitted. HLA matching of
additional alleles is recommended according to National Marrow Donor Program (NMDP)
guidelines, but will be at the discretion of local centers

   - Haploidentical Matched Family Members:

      - Minimum match level full haploidentical (at least 5/10; HLA-A, -B, -C, -DRB1,
      -DQB1 alleles). The following issues (in no particular order) should be
      considered in choosing a haploidentical donor:

         - Absent or low patient donor-specific antibodies (DSA)

            - Mean fluorescence intensity (MFI) of any anti-donor HLA antibody by
            solid phase immunoassay should be < 2000. Donors with higher levels are
            not eligible.

               - If a screening assay against pooled HLA antigens is used, positive
               results must be followed with specificity testing using a single
               antigen assay. The MFI must be < 2000 unless the laboratory has
               validated higher threshold values for reactivity for HLA antigens
               (such as HLA-C, -DQ, and -DP), that may be enhanced in
               concentration on the single antigen assays. Donor anti- recipient
               antibodies are of unknown clinical significance and do not need to
               be sent or reported.

               - Consult with Study Chair for the clinical significance of any
               recipient anti-donor HLA antibody.

               - If centers are unable to perform this type of testing, please
               contact the Study Chair to make arrangements for testing.

         - If killer immunoglobulin testing (KIR) is performed: KIR status by mismatch,
         KIR-B, or KIR content criteria can be used according to institutional
         guidelines.

         - ABO compatibility (in order of priority):

            - Compatible or minor ABO incompatibility

            - Major ABO incompatibility

         - CMV serostatus:

            - For a CMV seronegative recipient: the priority is to use a CMV
            seronegative donor when feasible

            - For a CMV seropositive recipient: the priority is to use a CMV
            seropositive donor when feasible

         - Age: younger donors including siblings/half-siblings, and second degree
         relatives (aunts, uncles, cousins) are recommended, even if < 18 years

   - Size and vascular access appropriate by center standard for peripheral blood stem cell
   (PBSC) collection if needed

   - Haploidentical matched family members: screened by center health screens and found to
   be eligible

   - Unrelated donors: meet eligibility criteria as defined by the NMDP or other unrelated
   donor registries. If the donor does not meet the registry eligibility criteria but an
   acceptable eligibility waiver is completed and signed per registry guidelines, the
   donor will be considered eligible for this study

   - Human immunodeficiency virus (HIV) negative

   - Not pregnant

   - MUD donors and post-transplant cyclophosphamide haplo donors should be asked to
   provide BM. If donors refuse and other donors are not available, PBSC is allowed.
   TCR-alpha beta/CD19 depleted haplo donors must agree to donate PBSC

   - Must give informed consent:

      - Haploidentical matched family members: Institution standard of care donor consent
      and Protocol-specific Donor Consent for Optional Studies

      - Unrelated donors: standard NMDP Unrelated Donor Consent

Exclusion Criteria:

   - PATIENT EXCLUSION CRITERIA FOR ENROLLMENT:

   - Patients with genetic disorders (generally marrow failure syndromes) prone to
   secondary AML/ALL with known poor outcomes because of sensitivity to alkylator therapy
   and/or TBI are not eligible (Fanconi Anemia, Kostmann Syndrome, Dyskeratosis
   Congenita, etc). Patients with Downs syndrome because of increased toxicity with
   intensive conditioning regimens.

   - Patients with any obvious contraindication to myeloablative HCT at the time of
   enrollment

   - Female patients who are pregnant are ineligible as many of the medications used in
   this protocol could be harmful to unborn children and infants

   - Sexually active patients of reproductive potential who have not agreed to use an
   effective contraceptive method for the duration of their study participation

   - PATIENT EXCLUSION CRITERIA TO PROCEED TO HCT:

   - Patients with uncontrolled fungal, bacterial, viral, or parasitic infections are
   excluded. Patients with history of fungal disease during chemotherapy may proceed if
   they have a significant response to antifungal therapy with no or minimal evidence of
   disease remaining by computed tomography (CT) evaluation

   - Patients with active central nervous system (CNS) leukemia or any other active site of
   extramedullary disease at the time of initiation of the conditioning regimen 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

   - Pregnant or breastfeeding females are ineligible as many of the medications used in
   this protocol could be harmful to unborn children and infants

Intervention(s):

procedure: Biospecimen Collection

procedure: Bone Marrow Aspiration

drug: Busulfan

drug: Cyclophosphamide

procedure: Echocardiography

drug: Fludarabine

procedure: Haploidentical Hematopoietic Cell Transplantation

biological: Lapine T-Lymphocyte Immune Globulin

procedure: Lumbar Puncture

procedure: Matched Unrelated Donor Hematopoietic Cell Transplantation

drug: Melphalan

drug: Methotrexate

procedure: Multigated Acquisition Scan

drug: Mycophenolate Mofetil

procedure: Myeloablative Conditioning

other: Quality-of-Life Assessment

other: Questionnaire Administration

biological: Rituximab

procedure: T-Cell Depletion Therapy

drug: Tacrolimus

drug: Thiotepa

radiation: Total-Body Irradiation

Recruiting

Contact Information

Stanford University
School of Medicine
300 Pasteur Drive
Stanford, CA 94305