Myeloablative Umbilical Cord Blood Transplantation in Hematological Diseases

NCT ID: NCT00309842

Last Updated: 2020-09-10

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 213 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2005-07-28
• Study Completion Date: 2019-11-22

Brief Summary

RATIONALE: Giving chemotherapy drugs, such as fludarabine and cyclophosphamide, and total-body irradiation before a donor umbilical cord blood stem cell transplant helps stop the growth of cancer cells and prepares the patient's bone marrow for the stem cells. When the healthy stem cells from a donor 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 make an immune response against the body's normal cells. Giving cyclosporine and mycophenolate mofetil may stop this from happening.

PURPOSE: This phase II trial is studying how well giving fludarabine and cyclophosphamide together with total-body irradiation works in treating patients who are undergoing an umbilical cord blood transplant for hematologic cancer.

Detailed Description

OBJECTIVES:

Primary

• Determine the 1-year survival of patients undergoing unrelated umbilical cord blood transplantation (UCBT) for hematologic malignancies treated with myeloablative preparative regimen comprising fludarabine, cyclophosphamide, and fractionated total-body irradiation.

Secondary

• Determine the incidence of transplant-related mortality at 6 months after UCBT.
• Evaluate the pattern of chimerism after double UCBT.
• Determine the incidence of neutrophil engraftment at day 42 after UCBT.
• Determine the incidence of platelet engraftment at 6 months after UCBT.
• Determine the incidence of grade II-IV and grade III-IV acute graft-versus-host disease (GVHD) at day 100 after UCBT.
• Determine the incidence of chronic GVHD at 1 year after UCBT.
• Determine the disease-free survival at 1 and 2 years after UCBT.
• Determine the incidence of relapse at 1 year after UCBT.

OUTLINE: This is a nonrandomized, open-label, multicenter study.

• Preparative Regimen: Patients receive fludarabine IV over 1 hour on days -8 to -6 and cyclophosphamide IV on days -7 and -6. Patients also undergo total-body irradiation twice daily on days -4 to -1.
• Umbilical Cord Blood Transplantation (UCBT): Patients undergo 1 or 2 units of UCBT on day 0. Patients receive filgrastim (G-CSF) IV once daily beginning on day 1 and continuing until blood counts recover.
• Graft-versus-host disease (GVHD) prophylaxis: Patients receive cyclosporine IV over 2 hours 2 or 3 times daily beginning on day -3 and continuing until day 100 followed by a taper until day 180. Patients also receive mycophenolate mofetil IV or orally 2 or 3 times a day beginning on day -3 and continuing until day 30 or 7 days after engraftment in the absence of acute GVHD.

After completion of study treatment, patients are followed periodically for at least 5 years.

PROJECTED ACCRUAL: A total of 150 patients will be accrued for this study.

Conditions

Acute Myeloid Leukemia; Acute Lymphocytic Leukemia; Chronic Myelogenous Leukemia; Myelofibrosis; MDS; Refractory Anemia; Chronic Lymphocytic Leukemia; Prolymphocytic Leukemia; Non-Hodgkin's Lymphoma; Leukemia; Lymphoma; Multiple Myeloma; Myelodysplastic Syndromes

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Unrelated UCBT for Blood Cancers

Patients undergoing unrelated umbilical cord blood transplantation (UCBT) for hematologic malignancies treated with myeloablative preparative regimen comprising fludarabine phosphate, mycophenolate mofetil, filgrastim, cyclophosphamide, cyclosporine and fractionated total-body irradiation.

Group Type: EXPERIMENTAL

filgrastim

Intervention Type: BIOLOGICAL

All patients will receive G-CSF 5 mcg/kg/day intravenously(IV) (dose rounded to vial size) based on the actual body weight IV beginning on day +1 after umbilical cord blood (UCB) infusion. G-CSF will be administered daily until the absolute neutrophil count (ANC) exceeds 2.5 x 10\^9/L for three consecutive days.

cyclophosphamide

Intervention Type: DRUG

Cyclophosphamide to be administered with high volume fluid flush and mesna (MT(S) 9006) at 10:00am, or per institutional routine, on days-7 and -6 after fludarabine. Cyclophosphamide 60mg/kg/day intravenous (IV) x 2 days, total dose 120 mg/kg (days -7 and -6) Dosing is calculated based on Actual BodyWeight (ABW) unless ABW \> 30 kg above Ideal BodyWeight (IBW), in which case the dose should be computed using adjusted body weight.

cyclosporine

Intervention Type: DRUG

Patients will receive cyclosporine (CSA) therapy beginning on day -3 maintaining a level of \> 200 ng/mL. For adults the initial dose will be 2.5 mg/kg intravenously (IV) over 2 hours every 12 hours. For children \< 40 kg the initial dose will be 2.5 mg/kg IV over 2 hours every 8 hours.

fludarabine phosphate

Intervention Type: DRUG

Fludarabine 25 mg/m2/day intravenously (IV) x 3 days, total dose 75 mg/m2 (days -8 to -6);

mycophenolate mofetil

Intervention Type: DRUG

All patients will begin mycophenolate mofetil (MMF) on day -3. Patients ≥ 40 kilograms will receive MMF at the dose of 3 grams/day divided into 2 or 3 doses (every 12 or 8 hours).

Pediatric patient (<40 kilograms) will receive MMF at the dose of 15 mg/kg three times a day.

umbilical cord blood transplantation

Intervention Type: PROCEDURE

The product is infused via intravenous (IV) drip directly into the central line without a needle, pump or filter.

total-body irradiation

Intervention Type: RADIATION

The recommended TBI is 165 cGy given twice daily for a total dose of 1320 cGy (days -4 to -1).

Interventions

filgrastim

All patients will receive G-CSF 5 mcg/kg/day intravenously(IV) (dose rounded to vial size) based on the actual body weight IV beginning on day +1 after umbilical cord blood (UCB) infusion. G-CSF will be administered daily until the absolute neutrophil count (ANC) exceeds 2.5 x 10\^9/L for three consecutive days.

Intervention Type: BIOLOGICAL

cyclophosphamide

Cyclophosphamide to be administered with high volume fluid flush and mesna (MT(S) 9006) at 10:00am, or per institutional routine, on days-7 and -6 after fludarabine. Cyclophosphamide 60mg/kg/day intravenous (IV) x 2 days, total dose 120 mg/kg (days -7 and -6) Dosing is calculated based on Actual BodyWeight (ABW) unless ABW \> 30 kg above Ideal BodyWeight (IBW), in which case the dose should be computed using adjusted body weight.

Intervention Type: DRUG

cyclosporine

Patients will receive cyclosporine (CSA) therapy beginning on day -3 maintaining a level of \> 200 ng/mL. For adults the initial dose will be 2.5 mg/kg intravenously (IV) over 2 hours every 12 hours. For children \< 40 kg the initial dose will be 2.5 mg/kg IV over 2 hours every 8 hours.

Intervention Type: DRUG

fludarabine phosphate

Fludarabine 25 mg/m2/day intravenously (IV) x 3 days, total dose 75 mg/m2 (days -8 to -6);

Intervention Type: DRUG

mycophenolate mofetil

All patients will begin mycophenolate mofetil (MMF) on day -3. Patients ≥ 40 kilograms will receive MMF at the dose of 3 grams/day divided into 2 or 3 doses (every 12 or 8 hours).

Pediatric patient (<40 kilograms) will receive MMF at the dose of 15 mg/kg three times a day.

Intervention Type: DRUG

umbilical cord blood transplantation

The product is infused via intravenous (IV) drip directly into the central line without a needle, pump or filter.

Intervention Type: PROCEDURE

total-body irradiation

The recommended TBI is 165 cGy given twice daily for a total dose of 1320 cGy (days -4 to -1).

Intervention Type: RADIATION

Other Intervention Names

G-CSF; Cytoxan; CSA; Fludara; MMF; UCBT; TBI

Eligibility Criteria

Inclusion Criteria

• Acute myeloid leukemia (AML): high risk CR1 (as evidenced by preceding myelodysplastic syndrome [MDS], high risk cytogenetics, ≥ 2 cycles to obtain complete remission [CR], erythroblastic or megakaryocytic leukemia; CR2+. All patients must be in CR as defined by hematological recovery, AND <5% blasts by light microscopy within the bone marrow with a cellularity of ≥15%.
• Very high risk pediatric patients with AML. Patients <21 years, however, are eligible with (M2 marrow) with < or = 25% blasts in marrow after having failed one or more cycles of chemotherapy. This group of patients will be analyzed separately.
• Acute lymphocytic leukemia (ALL): high risk CR1 [t(9;22), t (1:19), t(4;11) or other MLL rearrangements] hypodiploidy, or IKZF1 abnormalities), DNA index < 0.81, > 1 cycle to obtain CR or presence minimal residual disease (MRD). Patients in CR2+ are eligible. All patients must be in CR as defined by hematological recovery, AND <5% blasts by light microscopy within the bone marrow with a cellularity of ≥15%.
• Very high risk pediatric patients with ALL. patients <21 years are also considered high risk CR1 if they had M2 or M3 marrow at day 42 from the initiation of induction or M3 marrow at the end of induction. They are eligible once they achieved a complete remission
• Chronic myelogenous leukemia (CML) excluding refractory blast crisis. To be eligible in first chronic phase (CP1) patient must have failed or be intolerant to imatinib mesylate.
• Plasma Cell leukemia after initial therapy, who achieved at least a partial remission
• Advanced myelofibrosis
• Myelodysplasia (MDS) IPSS Int-2 or High risk (i.e. RAEB, RAEBt) or refractory anemia with severe pancytopenia or high risk cytogenetics. Blasts must be < 10% by a representative bone marrow aspirate morphology.
• Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), marginal zone B-cell lymphoma or follicular lymphoma are eligible if there was disease progression/relapse within 12 of achieving a partial or complete remission. Patients who had remissions lasting > 12 months, are eligible after at least two prior therapies. Patients with bulky disease (nodal mass greater than 5 cm) should be considered for debulking chemotherapy before transplant.
• Lymphoplasmacytic lymphoma, mantle-cell lymphoma, prolymphocytic leukemia are eligible after initial therapy in CR1+ or PR1+.
• Large cell NHL > CR2/> PR2. Patients in CR2/PR2 with initial short remission (<6 months) are eligible.
• Lymphoblastic lymphoma, Burkitt's lymphoma, and other high-grade NHL after initial therapy if stage III/IV in CR1/PR1 or after progression if stage I/II < 1 year.
• Multiple myeloma beyond PR2. Patients with chromosome 13 abnormalities, first response lasting less than 6 months, or β-2 microglobulin > 3 mg/L, may be considered for this protocol after initial therapy.
• Recipients must have a Karnofsky score (adults) ≥ 80 % or Lansky score ≥ 50% (pediatrics), and proper organ function.

Exclusion Criteria

• Active infection at time of transplantation
• History of human immunodeficiency virus (HIV) infection
• Pregnant or breast feeding.
• Chemotherapy refractory large cell and high grade NHL
• If < or = 18 years old, prior myeloablative transplant within the last 6 months. If >18 years old prior myeloablative allotransplant or autologous transplant
• Extensive prior therapy including > 12 months alkylator therapy or > 6 months alkylator therapy with extensive radiation.
• Patients who have received Y-90 ibritumomab (Zevalin) or I-131 tostumomab (Bexxar), as part of their salvage therapy.

• Maximum Eligible Age: 55 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Masonic Cancer Center, University of Minnesota

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Claudio G. Brunstein, MD, PhD

Role: STUDY_CHAIR

Masonic Cancer Center, University of Minnesota

Locations

Masonic Cancer Center at University of Minnesota

Minneapolis, Minnesota, United States

Fred Hutchinson Cancer Research Center

Seattle, Washington, United States

Countries

United States

References

Verneris MR, Brunstein CG, Barker J, MacMillan ML, DeFor T, McKenna DH, Burke MJ, Blazar BR, Miller JS, McGlave PB, Weisdorf DJ, Wagner JE. Relapse risk after umbilical cord blood transplantation: enhanced graft-versus-leukemia effect in recipients of 2 units. Blood. 2009 Nov 5;114(19):4293-9. doi: 10.1182/blood-2009-05-220525. Epub 2009 Aug 25.

Reference Type: RESULT

PMID: 19706886 (View on PubMed)

MacMillan ML, Weisdorf DJ, Brunstein CG, Cao Q, DeFor TE, Verneris MR, Blazar BR, Wagner JE. Acute graft-versus-host disease after unrelated donor umbilical cord blood transplantation: analysis of risk factors. Blood. 2009 Mar 12;113(11):2410-5. doi: 10.1182/blood-2008-07-163238. Epub 2008 Nov 7.

Reference Type: DERIVED

PMID: 18997171 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

UMN-MT2005-10

Identifier Type: OTHER

Identifier Source: secondary_id

UMN-0507M71475

Identifier Type: OTHER

Identifier Source: secondary_id

2005LS043

Identifier Type: -

Identifier Source: org_study_id