Cord Blood Transplant, Cyclophosphamide, Fludarabine, and Total-Body Irradiation in Treating Patients With High-Risk Hematologic Diseases

Registration Number
NCT06013423
Lead Sponsor
Fred Hutchinson Cancer Center
Brief Summary

This phase II trial studies how well giving an umbilical cord blood transplant together with cyclophosphamide, fludarabine, and total-body irradiation (TBI) works in treating patients with hematologic diseases. Giving chemotherapy, such as cyclophosphamide, fludarabine and thiotepa, and TBI before a donor cord blood transplant (CBT) helps stop the growth of ...

Detailed Description

OUTLINE: Patients are assigned to 1 of 2 arms.
...

Recruitment & Eligibility

Status
RECRUITING
Sex
All
Target Recruitment
54
Inclusion Criteria
  • Patients aged 6 months to =< 65 years at time of consent.

  • Acute myelogenous leukemia (AML):

    • Complete first remission (CR1), complete second remission (CR2) or greater (CR2+), must have < 5% marrow blasts at the time of transplant.
    • Patients in morphologic remission with persistent cytogenetic, flow cytometric, or molecular aberrations are eligible.
  • Acute lymphoblastic leukemia (ALL):

    • Complete first remission (CR1) at high risk for relapse such as any of the following:

      • Presence of any high-risk cytogenetic abnormalities such as t(9;22), t(1;19), t(4;11) or other MLL rearrangements (11q23) or other high-risk molecular abnormality.
      • Failure to achieve MRD- complete remission after induction therapy.
      • Persistence or recurrence of minimal residual disease on therapy.
      • Any patient unable to tolerate consolidation and/or maintenance chemotherapy as would have been deemed appropriate by the treating physician.
      • Other high-risk features not defined above.
    • Complete second remission (CR2) or greater (CR2+).

      • Note: ALL with less than 5% blasts at time of transplant but persistent cytogenetic, flow cytometric or molecular aberrations are eligible.
  • Other acute leukemias: Acute leukemias of ambiguous lineage or mixed phenotype with less than 5% blasts. Leukemias in morphologic remission with persistent cytogenetic, flow cytometric or molecular aberrations are eligible.

  • Chronic Myeloid Leukemia (CML): Excluding refractory blast crisis. To be eligible in first chronic phase (CP1) patient must have failed or be intolerant to tyrosine kinase inhibitor therapy.

  • Myelodysplastic syndromes (MDS) and myeloproliferative disorders (MPD) other than myelofibrosis:

    • MDS/MPD overlap syndromes without myelofibrosis.
    • MDS/ MPD patients must have less than 10% bone marrow myeloblasts and absolute neutrophil count (ANC) > 0.2 (growth factor supported if necessary) at transplant work-up.
  • Non-Hodgkin lymphoma (NHL) at high-risk of relapse or progression if not in remission:

    • Eligible patients with aggressive histology (such as, but not limited to, diffuse large B-cell NHL, mantle cell NHL, and T-cell histology) in CR by PET/CT imaging.
    • Eligible patients with indolent B-cell NHL (such as, but not limited to, follicular, small cell or marginal zone NHL) will have 2nd or subsequent progression with PR or CR by PET/CT imaging.
  • Blastic plasmacytoid dendritic cell neoplasm (BPDCN) in morphologic remission.

  • Only for adult patients, to prevent graft rejection, patients who received only non-lymphodepleting agents for their malignancy (hypomethylating agents, venetoclax, hydroxyurea, TKIs etc.), or patients who received lymphodepleting chemotherapy > 3 months prior to scheduled admission, may receive fludarabine 25 mg/m^2 daily x 3 days for lymphodepletion 14-42 days (aiming for 2-4 weeks) at the discretion of the principal investigator (PI).

  • For patients > 18 years old, Karnofsky score ≥ 70%. For patients =< 18 years old, Lansky score ≥ 50%.

  • Calculated creatinine clearance > 70 ml/min.

  • Bilirubin < 1.5 mg/dL (unless benign congenital hyperbilirubinemia or hemolysis).

  • Alanine transaminase (ALT) < 3 x upper limit of normal (ULN).

  • For patients > 18 years old, pulmonary function (spirometry and corrected diffusing capacity for carbon monoxide [DLCO]) > 60% predicted. For patients =< 18 years old, or any patient unable to perform pulmonary function tests, O2 saturation > 92% on room air.

  • Left ventricular ejection fraction > 50%.

  • Albumin > 3.0 g/dL.

  • For patients > 18 years old, Hematopoietic Cell Transplantation Comorbidity index (HCT-CI) =< 5.

  • UCB units will be selected according to current umbilical cord blood graft selection algorithm. One or two UCB units may be used to achieve the required cell dose.

  • The UCB graft is matched at 4-6 HLA-A, B, DRB1 antigens with the recipient. This may include 0-2 antigen mismatches at the A or B or DRB1 loci. Unit selection based on cryopreserved nucleated cell dose and HLA-A, B, DRB1 using intermediate resolution A, B antigen and DRB1 allele typing.

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Exclusion Criteria
  • Diagnosis of myelofibrosis or other malignancy with moderate-severe bone marrow fibrosis.
  • Patients persistent with central nervous system (CNS) involvement in cerebrospinal fluid (CSF) or CNS imaging at time of screening0
  • Prior checkpoint inhibitors/ blockade in the last 12 months.
  • Two prior stem cell transplants of any kind.
  • One prior autologous stem cell transplant within the preceding 12 months.
  • Prior allogeneic transplantation.
  • Prior involved field radiation therapy that would preclude safe delivery of 400cGy total body irradiation (TBI) in the opinion of radiation oncology.
  • Active and uncontrolled infection at time of transplantation.
  • HIV infection.
  • Inadequate performance status/ organ function.
  • Pregnancy or breast feeding.
  • Patient or guardian unable to give informed consent or unable to comply with the treatment protocol including appropriate supportive care, long-term follow-up, and research tests.
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Study & Design

Study Type
INTERVENTIONAL
Study Design
SINGLE_GROUP
Arm && Interventions
GroupInterventionDescription
Arm I (myeloablative UCBT)Diagnostic ImagingSee detailed description.
Arm II (myeloablative UCBT)ThiotepaSee detailed description.
Arm I (myeloablative UCBT)Total-Body IrradiationSee detailed description.
Arm II (myeloablative UCBT)Bone Marrow AspirateSee detailed description.
Arm I (myeloablative UCBT)EchocardiographySee detailed description.
Arm II (myeloablative UCBT)Survey AdministrationSee detailed description.
Arm I (myeloablative UCBT)Bone Marrow AspirateSee detailed description.
Arm II (myeloablative UCBT)Umbilical Cord Blood TransplantationSee detailed description.
Arm I (myeloablative UCBT)Umbilical Cord Blood TransplantationSee detailed description.
Arm II (myeloablative UCBT)Biospecimen CollectionSee detailed description.
Arm II (myeloablative UCBT)EchocardiographySee detailed description.
Arm II (myeloablative UCBT)Multigated Acquisition ScanSee detailed description.
Arm II (myeloablative UCBT)Total-Body IrradiationSee detailed description.
Arm I (myeloablative UCBT)Biospecimen CollectionSee detailed description.
Arm I (myeloablative UCBT)Multigated Acquisition ScanSee detailed description.
Arm I (myeloablative UCBT)Survey AdministrationSee detailed description.
Arm II (myeloablative UCBT)Diagnostic ImagingSee detailed description.
Arm I (myeloablative UCBT)CyclophosphamideSee detailed description.
Arm I (myeloablative UCBT)CyclosporineSee detailed description.
Arm I (myeloablative UCBT)Fludarabine PhosphateSee detailed description.
Arm I (myeloablative UCBT)Mycophenolate MofetilSee detailed description.
Arm II (myeloablative UCBT)CyclophosphamideSee detailed description.
Arm II (myeloablative UCBT)CyclosporineSee detailed description.
Arm II (myeloablative UCBT)Fludarabine PhosphateSee detailed description.
Arm II (myeloablative UCBT)Mycophenolate MofetilSee detailed description.
Primary Outcome Measures
NameTimeMethod
Overall survivalAt 1 year

Will be assessed after optimized cord blood transplant (CBT) in adults and children with hematologic malignancies. Will be calculated using the Kaplan-Meier method.

Secondary Outcome Measures
NameTimeMethod
Incidence of grade II-IV and III-IV aGVHDAt day 180

Will be calculated within the competing risks framework considering relapse/ death without developing GVHD, death in the absence of relapse, and relapse as competing events, respectively.

Incidence of chronic graft-versus-host disease (cGVHD)At 1, 2 and 3 years

Will be calculated within the competing risks framework considering relapse/ death without developing GVHD, death in the absence of relapse, and relapse as competing events, respectively.

Incidence of grade II-IV and III-IV acute graft-versus-host disease (aGVHD)At day 100

Will be calculated within the competing risks framework considering relapse/ death without developing GVHD, death in the absence of relapse, and relapse as competing events, respectively.

Time to immunosuppression cessationUp to 1 year

Will be assessed using CTCAE v 5.0.

Cumulative incidence of neutrophil and platelet engraftmentUp to 1 year

Will be calculated within the competing risks framework considering death without neutrophil or platelet recovery, respectively, as completing events

Incidences of graft failureUp to 1 year

Will be calculated within the competing risks framework considering death without engraftment before day 21 as a competing event.

Pattern of donor chimerismUp to 1 year

Will be assessed using CTCAE v 5.0.

Incidence of pre-engraftment syndrome (PES)Up to 1 year

Will be assessed using CTCAE v 5.0.

Incidence of relapseAt 1, and 2 years after CBT
Organ distribution of GVHDUp to 1 year

Will be calculated within the competing risks framework considering death without neutrophil or platelet recovery, respectively, as completing events

Incidence of adverse eventsUp to 1 year

Will be assessed using Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v 5.0).

Incidence of transplant related mortality (TRM)At 100 days, 6 months, 1 and 2 years

Trial Locations

Locations (1)

Fred Hutch/University of Washington Cancer Consortium

🇺🇸

Seattle, Washington, United States

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