This phase II trial studies how well giving treosulfan together with fludarabine phosphate and total-body irradiation (TBI) works in treating patients with hematological cancer who are undergoing umbilical cord blood transplant (UCBT). Giving chemotherapy, such as treosulfan and fludarabine phosphate, and TBI before a donor UCBT helps stop the growth of cancer cells and helps stop the patient's immune system from rejecting the donor's stem cells. When the stem cells from a related or unrelated donor, that do not exactly match the patient's blood, are infused into the patient, they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving cyclosporine (CsA) and mycophenolate mofetil (MMF) after the transplant may stop this from happening.
PRIMARY OBJECTIVES: I. Graft failure/rejection and secondary graft failure. II. Day -200 non-relapse mortality. SECONDARY OBJECTIVES: I. Platelet engraftment by six months. II. Grade II-IV and III-IV acute graft-versus-host disease (GVHD) at day 100 and one year. III. Chronic GVHD. IV. Clinically significant infections. V. Overall survival. VI. Relapse or disease progression. VII. Immune reconstitution (Fred Hutchinson Cancer Research Center \[FHCRC\] only). VIII. Emergence of a dominant unit (FHCRC only). OUTLINE: Patients are assigned to 1 of 2 arms. ARM I (low risk for graft failure): Patients receive a conditioning regimen comprising fludarabine phosphate intravenously (IV) over 1 hour once daily (QD) on days -6 to -2 and treosulfan IV over 120 minutes on days - 6 to -4. Patients undergo TBI on day -1. Patients then undergo donor UCBT on day 0. Patients receive GVHD prophylaxis comprising cyclosporine IV over 1 hour or orally (PO) 2-3 times daily on days -3 to 100, followed by a taper in the absence of GVHD. Patients also receive mycophenolate mofetil IV 3 times daily on days 0 to 40, followed by a taper in the absence of GVHD. ARM II (high risk for graft failure): Patients receive a conditioning regimen, TBI, donor UCBT, GVHD prophylaxis, and mycophenolate mofetil as in Arm I. After completion of the study treatment, patients are followed up at 6 months and 1 and 2 years.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
130
Given IV or PO
Given IV
Correlative studies
Given IV
TBI administered day -1: 200 cGy (or escalated to 300 cGy, 400 cGy, or 450 cGy per protocol statistical section)
Given IV
Undergo single or double unit UCBT
University of Colorado Hospital
Aurora, Colorado, United States
Oregon Health and Science University
Portland, Oregon, United States
Fred Hutch/University of Washington Cancer Consortium
Seattle, Washington, United States
Number of Participants With Graft Failure/Rejection
Patients will be considered primary graft failure provided they meet any criteria listed below, in the absence of documented disease persistence/recurrence or active bone marrow infection (ex. Cytomegalovirus (CMV)): i. Absence of 3 consecutive days with neutrophils \>500/u1 combined with host CD3+ peripheral blood chimerism ≥50% at day 42 ii. Absence of 3 consecutive days with neutrophils \>500/u1 under any circumstances at day 55 iii. Death after day 28 with neutrophil count \<100/u1 without any evidence of engraftment (\< 5% donor CD3+) iv. Primary autologous count recovery with \< 5% donor CD3+ peripheral blood chimerism at count recovery and without relapse
Time frame: Up to 100 days
Number of Participants With Secondary Graft Failure
Secondary graft failure is defined as decline of neutrophil count to \<500/ul with loss of donor chimerism after day 55
Time frame: Up to 2 years
Number of Patients With Non-relapse Mortality (NRM)
Defined as death from any cause without sign of disease progression or relapse. Loss to follow up are censored, whereas disease relapse or progression are considered competing risks.
Time frame: At day -200
Number of Participants Surviving by 1 Year
Overall survival was measured from the first day of CBT infusion until death from any cause.
Time frame: At 1 year
The Number of Participants Alive at Two-years Follow up.
Overall survival of participants after two-years of follow up.
Time frame: Up to 2 years
Non-relapse Mortality
Death of any cause other than relapse or disease progression was considered.
Time frame: Up to 2 years
Duration (Days) Until Participants Obtained Platelet Engraftment
Summarized using a range and median of measure in days until participants reached platelet engraftment. Platelet engraftment was defined as the first of 7 consecutive days when the platelet count exceeded 20 x 109/L (untransfused).
Time frame: At 6 months
Number of Participants With Acute Graft-versus-host Disease (GVHD) Grade II-IV by Day 100
Grade I GVHD is characterized as mild disease, grade II GVHD as moderate, grade III as severe, and grade IV life-threatening. Diagnosing and grading acute GVHD is based on clinical findings (the organ stage, response to treatment and whether GVHD was a major cause of death) and frequently varies between transplant centers and independent reviewers.
Time frame: Day 100
Incidence of Acute or Chronic Graft-versus-host Disease (GVHD)
Overall GVHD is determined based on the organ stage, response to treatment and whether GVHD was a major cause of death. Chronic GVHD will be defined according to the National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease. Described as mild, moderate, or severe as graded according to the attached Organ Scoring Sheet. Symptoms consistent with both chronic and acute GVHD occurring after day 100 will be considered overlap chronic GVHD syndrome.
Time frame: At 1 year
Incidence of Relapse or Disease Progression
Cumulative incidence estimates using non-relapse mortality as competitive event.
Time frame: Up to 2 years
Number of Participants Surviving up to 2 Years Without Disease Progression
Progression-free survival is the time interval from start of treatment to documented evidence of disease progression. Disease progression was defined by European LeukemiaNet 2017 criteria and International Working Group (IWG) within 3 years of transplant.
Time frame: Up to 2 years
Incidence of Clinically Significant Infections
Collected and graded according to the modified National Cancer Institute Common Toxicity Criteria.
Time frame: At 6 months
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