Donor Umbilical Cord Blood Transplant in Treating Patients With Hematologic Cancer

Transplantation of Umbilical Cord Blood in Patients With Hematological Malignancies Using a Reduced-Intensity Preparative Regimen (A Multi-Center Trial Coordinated by the FHCRC)

This phase II trial is studying how well umbilical cord blood transplant from a donor works in treating patients with hematological cancer. Giving chemotherapy and total-body irradiation (TBI) before a donor umbilical cord blood transplant helps stop the growth of cancer and abnormal cells and helps stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from an 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 make an immune response against the body's normal cells (called graft-versus-host disease). Giving cyclosporine and mycophenolate mofetil before and after transplant may stop this from happening.

Study Overview

• Status: Completed
• Conditions: Lymphoma; Acute Myeloid Leukemia; Refractory Hodgkin Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Acute Lymphoblastic Leukemia; Myelodysplastic Syndrome; Chronic Phase Chronic Myelogenous Leukemia; Recurrent Small Lymphocytic Lymphoma; Chronic Myelogenous Leukemia; Refractory Chronic Lymphocytic Leukemia; Recurrent Plasma Cell Myeloma; Myeloproliferative Neoplasm; Recurrent T-Cell Non-Hodgkin Lymphoma; Refractory Mantle Cell Lymphoma; Recurrent Chronic Lymphocytic Leukemia; Refractory Small Lymphocytic Lymphoma; Aggressive Non-Hodgkin Lymphoma; Indolent Non-Hodgkin Lymphoma; Recurrent Follicular Lymphoma; Refractory Follicular Lymphoma; T-Cell Non-Hodgkin Lymphoma; Mixed Phenotype Acute Leukemia; Recurrent Lymphoplasmacytic Lymphoma; Refractory Lymphoplasmacytic Lymphoma; Refractory Chronic Myelogenous Leukemia
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Drug: Cyclophosphamide; Radiation: Total-Body Irradiation; Drug: Fludarabine Phosphate; Drug: Mycophenolate Mofetil; Drug: Cyclosporine; Procedure: Umbilical Cord Blood Transplantation; Procedure: Allogeneic Hematopoietic Stem Cell Transplantation

Detailed Description

PRIMARY OBJECTIVES:

I. Estimate probability of one year survival.

II. Demonstrate equivalent or improved engraftment rates with a non-anti-thymocyte globulin (ATG) based conditioning regimen. Patients will be considered graft failure/rejections provided they meet any of the criteria listed below:

• Absence of 3 consecutive days with neutrophils >= 500/ul combined with host cluster of differentiation (CD)3 peripheral blood chimerism >= 50% at day 42
• Absence of 3 consecutive days with neutrophils >= 500/ul under any circumstances at day 55
• Death after day 28 with neutrophil count < 100/ul without any evidence of engraftment (< 5% donor CD3)
• Primary autologous count recovery with < 5% donor CD3 peripheral blood chimerism at count recovery and without relapse

SECONDARY OBJECTIVES:

I. Six month non-relapse mortality.

II. Overall incidence of graft failure/rejection. Patients will be considered graft failure/rejections provided they meet any of the criteria listed below:

• Absence of 3 consecutive days with neutrophils >= 500/ul combined with host CD3 peripheral blood chimerism >= 50% at day 42
• Absence of 3 consecutive days with neutrophils >= 500/ul under any circumstances at day 55
• Death after day 28 with neutrophil count < 100/ul without any evidence of engraftment (< 5% donor CD3)
• Primary autologous count recovery with < 5% donor CD3 peripheral blood chimerism at count recovery and without relapse

III. Kinetics of chimeric reconstitution.

IV. Incidence of neutrophil engraftment by day 42.

V. Incidence of platelet engraftment by six months.

VI. Incidence of grade II-IV and III-IV acute graft-versus-host disease (GvHD) at day 100.

VII. Incidence of one year chronic GvHD.

VIII. Incidence of clinically significant infections at 6 months, 1 year, 2 years.

IX. Probability of one and two year survival.

X. Incidence of one and two year relapse or disease progression.

XI. Fred Hutchinson Cancer Research Center (FHCRC) patients: Kinetics of immune reconstitution, with both functional and quantitative assays.

XII. FHCRC patients: Examination of possible immunologic factors leading to emergence of a dominant unit.

OUTLINE:

CONDITIONING REGIMEN: Patients receive fludarabine phosphate intravenously (IV) over 1 hour on days -6 to -2 and cyclophosphamide IV over 1-2 hours on day -6. Patients undergo a lower dose of total-body irradiation (TBI) on day -1.

UMBILICAL CORD BLOOD TRANSPLANT: Patients undergo donor umbilical cord blood infusion on day 0.

IMMUNOSUPRESSIVE THERAPIES: Patients receive cyclosporine IV over 1 hour every 8-12 hours on days -3 to +180 and mycophenolate mofetil IV or orally (PO) every 8 hours on days 0 to +96.

After completion of study treatment, patients are followed periodically for up to 2 years.

• Study Type: Interventional
• Enrollment (Actual): 73
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University Of Colorado Hospital
    • Denver, Colorado, United States, 80218
      • Colorado Blood Cancer Institute
  • Utah
    • Salt Lake City, Utah, United States, 84143
      • LDS Hospital
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutch/University of Washington Cancer Consortium
    • Seattle, Washington, United States, 98101
      • VA Puget Sound Health Care System
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Froedtert and The Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 69 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients > 70 may be considered if performance status > 80% or Eastern Cooperative Oncology Group (ECOG) =< 1 and comorbidity score < 3; these patients must be discussed with the principal investigator (PI), Rachel Salit prior to enrollment

• Adequate cardiac function defined as absence of decompensated congestive heart failure, or uncontrolled arrhythmia and:

  • Left ventricular ejection fraction >= 35% or
  • Fractional shortening > 22%
• Adequate pulmonary function defined as diffusion capacity of carbon monoxide (DLCO) > 30% predicted, and absence of oxygen (O2) requirements
• Adequate hepatic function; patients with clinical or laboratory evidence of liver disease will be evaluated for the cause of liver disease, its clinical severity in terms of liver function, histology, and the degree of portal hypertension; patients with fulminant liver failure, cirrhosis with evidence of portal hypertension or bridging fibrosis, alcoholic hepatitis, esophageal varices, a history of bleeding esophageal varices, hepatic encephalopathy, or correctable hepatic synthetic dysfunction evidenced by prolongation of the prothrombin time, ascites related to portal hypertension, bacterial or fungal abscess, biliary obstruction, chronic viral hepatitis with total serum bilirubin > 3 mg/dL, and symptomatic biliary disease will be excluded
• Adequate renal function defined as creatinine =< 2.0 mg/dl (adults) or creatinine clearance > 40 ml/min (pediatrics)
• All adults with a creatinine > 1.2 or a history of renal dysfunction must have estimated creatinine clearance > 40 ml/min
• Performance status score: Karnofsky (for adults) >= 60 or ECOG 0-2; Lansky (for children) score >= 50
• If recent mold infection, e.g., Aspergillus, must be cleared by infectious disease
• Second hematopoietic cell transplant: Must be >= 3 months after prior myeloablative transplant
• Patients who have received < 2 cycles of multiagent chemotherapy and patients who have received no multiagent chemotherapy within the 3 months previous to umbilical cord blood transplant (UCBT) as well as patients experiencing graft failure following previous allogeneic transplant
• Acute myeloid leukemia/acute lymphoblastic leukemia, including biphenotypic acute leukemia or mixed-lineage leukemia: Must have < 5% morphologic marrow blasts in an evaluable marrow (> 25% of normal cellularity for age) collected less than one month prior to start of conditioning; patients persistently aplastic for greater than one month since completing last chemotherapy are also eligible with the approval of the PI or designee
• Chronic myelogenous leukemia: All types, except refractory blast crisis; chronic phase patients must have failed or been intolerant to Gleevec or other tyrosine kinase inhibitors; at time of transplant, patients must have < 5% blasts in an evaluable marrow (> 25% of normal cellularity for age) by morphology within the bone marrow
• Myelodysplastic syndrome (MDS): Any subtype; morphologic blasts must be less than 5% in an evaluable marrow (> 25% of normal cellularity for age); if blasts are 5% or more, patient requires induction chemotherapy pre-transplant to reduce blast count to less than 5%; patients who have a hypocellular marrow in the absence of excess blasts that is related to the underlying disease or as a result of treatment for MDS may also be eligible with the approval of the PI or designee
• Large-cell lymphoma and aggressive T-cell lymphoma: With chemotherapy sensitive disease that has failed autologous transplant or patients who are ineligible for an autologous transplant; chemotherapy sensitive disease is defined as >= 50% reduction in the size of the tumor with the chemotherapy regimen immediately preceding transplant
• Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): Must be refractory to fludarabine (fludarabine phosphate) or fail to have a complete or partial response after therapy with a regimen containing fludarabine (or another nucleoside analog, e.g. cladribine [2-CDA], pentostatin) or experience disease relapse within 12 months after completing therapy with a regimen containing fludarabine (or another nucleoside analog)
• Hodgkin disease: Must have received and failed frontline therapy
• Follicular lymphoma, marginal zone B-cell lymphoma, lymphoplasmacytic lymphoma, mantle-cell lymphoma, and indolent T-cell lymphomas: Must have progressed with the most recent remission duration being < 6 months; patients with bulky disease should be considered for debulking chemotherapy before transplant; patients with refractory disease are eligible, unless they have bulky disease and an estimated tumor doubling time of less than one month
• Multiple myeloma: Must have received prior chemotherapy; consolidation of chemotherapy by autografting prior to nonmyeloablative hematopoietic cell transplant (HCT) is permitted
• Myeloproliferative syndromes

• DONOR: Cord blood (CB) donor selection will be based on institutional guidelines and in general should be selected to optimize both human leukocyte antigen (HLA) match and cell dose; additionally, CB grafts shall consist of one or two CB donors based on, but not exclusively determined by, cell dose (total nucleated cell [TNC]/kg and CD34/kg), HLA matching and disease status and indication for transplant; attending preference will be allowed for single versus double unit as well as the degree of mismatching based on patient specific factors, as long as the following minimum criteria are met:

  • HLA matching

    • Minimum requirement: The CB graft(s) must be matched at a minimum at 4/6 HLA-A, B, DRB1 loci with the recipient. Therefore 0-2 mismatches at the A or B or DRB1 loci based on intermediate resolution A, B antigen and DRB1 allele typing for determination of HLA-match is allowed
    • HLA-matching determined by high-resolution typing is allowed per institutional guidelines as long as the minimum criteria are met

  • Selection of two CB units is mandatory when a single cord blood unit does not meet the following criteria:

    • Match grade 6/6; TNC Dose >= 2.5 x 10^7/kg
    • Match grade 5/6 or 4/6; TNC dose >= 4.0 (+/- 0.5) x 10^7/kg
  • If two CB units are used, the total cell dose of the combined units must be at least 3.0 x 10^7 TNC per kilogram recipient weight based on pre-cryopreservation numbers, with each CB unit containing a MINIMUM of 1.5 x 10^7 TNC/kg
  • The minimum recommended CD34/kg cell dose should be 2 x 10^5 CD34/kg, total dose from a single or combined double
  • The unmanipulated CB unit(s) will be Food and Drug Administration (FDA) licensed or will be obtained under a separate investigational new drug (IND), such as the National Marrow Donor Program (NMDP) Protocol 10-CBA conducted under BB IND-7555 or another IND sponsored by (1) a participating institution or (2) an investigator at FHCRC or one of the participating institutions
  • FHCRC only: Up to 5% of cord blood product, when ready for infusion, may be withheld for research purposes as long as thresholds for infused TNC dose are met; threshold for double unit transplantation is >= 3.0 x 10^7/kg; these products will be used to conduct studies involving the immunobiology of double cord transplantation and kinetics of engraftment

Exclusion Criteria:

• Patients with an available 5-6/6 HLA-A, B, DRB1 matched sibling donor
• Pregnancy or breastfeeding
• Evidence of human immunodeficiency virus (HIV) infection or known HIV positive serology
• Uncontrolled viral or bacterial infection at the time of study enrollment
• Active or recent (prior 6 month) invasive fungal infection without infectious disease (ID) consult and approval
• Active central nervous system malignancy
• Patients who have received >= 2 cycles of multiagent chemotherapy within the 3 months previous to UCBT; patients who have had previous autologous transplant within 12 months of UCBT are excluded regardless of history of recent treatment
• DONOR: Any cord blood units with < 1.5 x 10^7 total nucleated cells per kilogram recipient weight
• DONOR: Any cord blood units without the full maternal testing and negative results for hepatitis A, B, C, HIV, and human T-lymphotropic virus (HTLV-1) viruses; any additional available virology results on the unit itself will be reviewed but are not mandated, complete or always available; cord blood units are presumed to be cytomegalovirus (CMV) negative regardless of serologic testing due to passive transmission of maternal CMV antibodies

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (chemotherapy, transplant); CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV over 1 hour on days -6 to -2 and cyclophosphamide IV over 1-2 hours on day -6. Patients undergo a lower dose of TBI on day -1. UMBILICAL CORD BLOOD TRANSPLANT: Patients undergo donor umbilical cord blood infusion on day 0. IMMUNOSUPRESSIVE THERAPIES: Patients receive cyclosporine IV over 1 hour every 8-12 hours on days 0 to +180 and mycophenolate mofetil IV or PO every 8 hours on days -3 to +96.

Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Cyclophosphamide; Given IV; Other Names: Cytoxan; CTX; (-)-Cyclophosphamide; 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate; Carloxan; Ciclofosfamida; Ciclofosfamide; Cicloxal; Clafen; Claphene; CP monohydrate; CYCLO-cell; Cycloblastin; Cycloblastine; Cyclophospham; Cyclophosphamid monohydrate; Cyclophosphamidum; Cyclophosphan; Cyclophosphane; Cyclophosphanum; Cyclostin; Cyclostine; Cytophosphan; Cytophosphane; Fosfaseron; Genoxal; Genuxal; Ledoxina; Mitoxan; Neosar; Revimmune; Syklofosfamid; WR- 138719; Radiation: Total-Body Irradiation; Undergo TBI; Other Names: Total Body Irradiation; Whole-Body Irradiation; Drug: Fludarabine Phosphate; Given IV; Other Names: 2-F-ara-AMP; Beneflur; Fludara; 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-; SH T 586; Drug: Mycophenolate Mofetil; Given IV or PO; Other Names: Cellcept; MMF; Drug: Cyclosporine; Given IV; Other Names: 27-400; Sandimmune; Ciclosporin; CsA; Neoral; Gengraf; Sandimmun; Cyclosporin; Cyclosporin A; OL 27-400; SangCya; Procedure: Umbilical Cord Blood Transplantation; Undergo umbilical cord blood transplant; Other Names: Cord Blood Transplantation; UCB transplantation; Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Undergo umbilical cord blood transplant; Other Names: Allogeneic Hematopoietic Cell Transplantation; Allogeneic Stem Cell Transplantation; HSC; HSCT

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	Kaplan-Meier and cumulative incidence estimates will be used.	At 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Median Time to ANC > 500		By day 55
Number of Participants With Graft Failure/Rejection	descriptive	By day 55
Time to Platelet Engraftment of > 20,000 Cells Per mm3	median and range	By 6 months
Percent of Patients With Grade II-IV Acute Graft Versus Host Disease	Chi-square test was used to determine percent of grade II-IV GVHD using Glucksberg criteria	By day 100
Percent of Patients With Acute GVHD Grades III-IV	Fischer's exact test was used to determined percent of patients with acute grade III-IV GVHD by Glucksberg criteria	100 days
Percent of Patients With Chronic GVHD	Kaplan-Meier and cumulative incidence estimates will be used to measure percent of patients with chronic GVHD by NIH consensus criteria.	At 2 years
Percent of Patients With Non-relapse Mortality	Kaplan-Meier and cumulative incidence estimates	6 months
Percent of Patients With Non-relapse Mortality	Kaplan-Meier and cumulative incidence estimates	1 year

Collaborators and Investigators

• Sponsor: Fred Hutchinson Cancer Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Rachel Salit, Fred Hutch/University of Washington Cancer Consortium

Study record dates

Study Major Dates

• Study Start (Actual): June 25, 2008
• Primary Completion (Actual): July 31, 2018
• Study Completion (Actual): July 31, 2018

Study Registration Dates

• First Submitted: July 25, 2008
• First Submitted That Met QC Criteria: July 25, 2008
• First Posted (Estimate): July 28, 2008

Study Record Updates

• Last Update Posted (Actual): December 27, 2019
• Last Update Submitted That Met QC Criteria: December 17, 2019
• Last Verified: December 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Disease Attributes; Bone Marrow Diseases; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Neoplasms, Plasma Cell; Leukemia, B-Cell; Lymphoma; Lymphoma, Follicular; Myelodysplastic Syndromes; Multiple Myeloma; Leukemia; Leukemia, Myeloid; Recurrence; Lymphoma, Non-Hodgkin; Lymphoma, Mantle-Cell; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Waldenstrom Macroglobulinemia; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Lymphoid; Lymphoma, T-Cell; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Chronic-Phase; Myeloproliferative Disorders; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Dermatologic Agents; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Cyclophosphamide; Fludarabine; Fludarabine phosphate; Mycophenolic Acid; Cyclosporine; Cyclosporins
• Other Study ID Numbers: 2239.00 (Other Identifier: Fred Hutch/University of Washington Cancer Consortium); P30CA015704 (U.S. NIH Grant/Contract); NCI-2009-01551 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); 2239 (Fred Hutch/University of Washington Cancer Consortium)