Double Cord Versus Haploidentical (BMT CTN 1101)
Sponsor
Medical College of Wisconsin (Other)
Overall Status
Completed
CT.gov ID
NCT01597778
Collaborator
National Heart, Lung, and Blood Institute (NHLBI) (NIH), National Cancer Institute (NCI) (NIH), Blood and Marrow Transplant Clinical Trials Network (Other), National Marrow Donor Program (Other)
368
39
2
99.4
9.4
0.1
Study Details
Study Description
Brief Summary
Hematopoietic cell transplants (HCT)are one treatment option for people with leukemia or lymphoma. Family members,unrelated donors or banked umbilical cordblood units with similar tissue type can be used for HCT. This study will compare the effectiveness of two new types of bone marrow transplants in people with leukemia or lymphoma: one that uses bone marrow donated from family members with only partially matched bone marrow; and, one that uses two partially matched cord blood units.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Detailed Description
Reduced intensity conditioning (RIC) blood or marrow transplantation (BMT) has allowed older and less clinically fit patients to receive potentially curative treatment with allogeneic HCT for high risk or advanced hematological malignancies. Patients lacking an HLA-matched sibling may receive a graft from a suitably HLA-matched unrelated donor. However, up to a third of patients will not have an HLA-matched sibling or a suitably matched adult unrelated donor (i.e., no more than a mismatch at a single locus). Even when a suitably matched unrelated donor is identified, data from the National Marrow Donor Program (NMDP) indicate that a median of four months is required to complete searches that result in transplantation; thus, some number of patients succumb to their disease while awaiting identification and evaluation of a suitably matched adult unrelated donor.
Single or dual center studies have shown that partially HLA-mismatched related bone marrow (haplo-BM) and unrelated double umbilical cord blood (dUCB) are valuable sources of donor cells for RIC HCT, thus extending this treatment modality to patients who lack other donors. In order to study the reproducibility, and thus, the wider applicability of these two alternative donor strategies, The Blood and Marrow Transplantation Clinical Trials Network (BMT CTN) conducted two parallel multicenter prospective Phase II clinical trials. These two studies evaluated the safety and efficacy of related haplo-BM (BMT CTN 0603) and dUCB (BMT CTN 0604) transplantation after RIC. Both of these alternative donor approaches produced early results similar to that reported with unrelated donor, and even HLA-matched sibling, HCT. These data demonstrate not only the efficacy of both of these approaches, but also that both can be safely exported from the single center setting. Both haplo-BM and dUCB grafts can be obtained rapidly for greater than 90% of patients lacking an HLA-matched donor. This study will test the hypothesis that progression free survival at two years after RIC haplo-BM transplantation is similar to the progression free survival after RIC dUCB transplantation.
Study Design
Study Type:
Interventional
Actual Enrollment
:
368 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Multi-Center, Phase III, Randomized Trial of RIC and Transplantation of (dUCB) Versus HLA-Haplo Related Bone Marrow for Patients With Hematologic Malignancies.(BMT CTN #1101)
Actual Study Start Date
:
Jun 1, 2012
Actual Primary Completion Date
:
Sep 11, 2020
Actual Study Completion Date
:
Sep 11, 2020
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Haploidentical Bone Marrow Transplant Participants will receive haploidentical bone marrow transplant using a reduced intensity conditioning regimen. |
Biological: Haploidentical Bone Marrow Transplant
The conditioning regimen consists of:
Fludarabine (Flu)30 mg/m2 IV Days -6, -5, -4, -3, -2 Cyclophosphamide (Cy) 14.5 mg/kg IV Days -6, -5 Total body irradiation (TBI) 200cGy Day -1
The GVHD prophylaxis regimen consists of:
Cy 50 mg/kg IV Days 3, 4 Tacrolimus (IV or PO) beginning Day 5 Mycophenolate mofetil (MMF) 15 mg/kg po three times a day, maximum dose 1 g po TID beginning Day 5 until Day 35
|
| Experimental: Double Umbilical Cord Blood Transplant Participants will receive a double umbilical cord blood transplant using a reduced intensity conditioning regimen. |
Biological: Double Umbilical Cord Blood Transplant
The preparative regimen consists of:
Fludarabine 40 mg/m2 IV Days -6, -5, -4,-3, -2 Cyclophosphamide 50 mg/kg IV Day -6 Total Body Irradiation (TBI) 200 cGy Day -1 for patients who have received cytotoxic chemotherapy within the 3 months of enrollment or an autologous transplant within 24 months of enrollment or 300 cGy Day -1 for patients who have not received cytotoxic chemotherapy within the 3 months of enrollment and who have not received an autologous transplant within 24 months of enrollment.
The GVHD prophylaxis regimen consists of:
Cyclosporine beginning Day -3 with dose adjusted to maintain a trough level of 200-400 ng/mL.
Mycophenolate mofetil (MMF) 15 mg/kg po three times a day, maximum dose 1 g po TID beginning Day -3 until Day 35
|
Outcome Measures
Primary Outcome Measures
- Percentage of Participants With Progression Free Survival (PFS) [Year 2]
The primary endpoint is PFS at 2 years post-randomization. Death or disease relapse/progression will be considered as events. The time to event is defined as the time interval from randomization to relapse/progression, to death or to last follow-up, whichever comes first. Relapse is defined by either morphological or cytogenetic evidence of acute leukemia consistent with pre-transplant features, or radiologic evidence of progressive lymphoma. Minimal residual disease will not be considered evidence of relapse, however, minimal residual disease that progresses will be considered as relapse and the date of relapse will be the date of detection of minimal residual disease that prompted an intervention by the treating physician. Finally, institution of any therapy to treat persistent, progressive or relapsed disease, including withdrawal of immunosuppressive therapy or DLI, will be considered evidence of relapse/progression regardless of whether the criteria described above are met.
Secondary Outcome Measures
- Percentage of Participants With PFS by Treatment Arms in Subgroups [Year 2]
Participants' primary diagnosis was categorized into two large groups: leukemia versus lymphoma. Age was dichotomized into two large groups: age <= 59 versus age > 59. The Kaplan-Meier estimate for PFS at 2 years post-randomization are provided for each subgroup.
- Percentage of Participants With Neutrophil Recovery [Day 56]
Neutrophil recovery is defined as achieving an absolute neutrophil count greater than or equal to 500/mm^3 for three consecutive measurements on three different days. The first of the three days will be designated the day of neutrophil recovery.
- Percentage of Participants With Platelet Recovery [Day 100]
Platelet recovery is defined by two different metrics as the first day of a sustained platelet count greater than 20,000/mm^3 or greater than 50,000/mm^3 with no platelet transfusions in the preceding seven days. The first day of the sustained platelet count will be designated the day of platelet engraftment.
- Participants With Primary Graft Failure [Day 56]
Primary graft failure is defined as less than 5% donor chimerism on all measurements up to and including Day 56.
- Percentage of Participants With Secondary Graft Failure [Year 2]
Secondary graft failure is defined as initial donor chimerism ≥ 5% declining to < 5% on subsequent measurements with time to secondary graft failure beginning at the first day of primary engraftment.
- Percentage of Participants With Acute Graft-versus-Host Disease (aGVHD) [Day 180]
The cumulative incidences of grade II - IV and III - IV acute aGVHD will be determined.
- Percentage of Participants With Chronic Graft-versus-Host Disease (cGHVD) [Year 2]
The cumulative incidence of cGVHD from the time of transplant will be determined. Data were collected directly from providers and chart review according to the recommendations of the NIH Consensus Conference.
- Percentage of Participants With Overall Survival [Year 2]
Overall survival is defined as the time interval between date of randomization and death from any cause or for surviving patients, to last follow-up. The time interval between date of transplant and death from any cause or for surviving patients, to last follow-up are also analyzed.
- Percentage of Participants With Treatment-related Mortality (TRM) [Day 100, Day 180, Year 1, and Year 2]
The cumulative incidence of TRM will be estimated, event for this endpoint is death without evidence of disease progression or recurrence.
- Percentage of Participants With Relapse/Progression [Year 1, year 2]
Incidence of relapse/progression will be estimated using cumulative incidence function, treating death in remission as a competing risk. Relapse is defined by either morphological or cytogenetic evidence of acute leukemia consistent with pre-transplant features, or radiologic evidence of progressive lymphoma. When in doubt, the diagnosis of recurrent or progressive lymphoma should be documented by tissue biopsy. Minimal residual disease will not be considered evidence of relapse, however, minimal residual disease that progresses will be considered as relapse and the date of relapse will be the date of detection of minimal residual disease that prompted an intervention by the treating physician. Finally, institution of any therapy to treat persistent, progressive or relapsed disease, including withdrawal of immunosuppressive therapy or DLI, will be considered evidence of relapse/progression regardless of whether the criteria described above are met.
- Toxicities [Day 28, Day 56, Day 180, 1 year, and 2 years]
They are all Grade ≥ 3 toxicities based on NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4.
- Participants With Infections [Up to 2 years]
All Grade 2 and 3 infections will be reported. Grade 1 CMV infections through Day 56 will also be reported.
- Hospital Admission and Length of Stay [Month 6]
Total Time Alive and Not Hospitalized within 6 Months Post Randomization
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
to 70 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
-
Patients 18 to 70 years old
-
Patients must have available both: a)One or more potential related mismatched donors (biologic parent(s) or siblings (full or half) or children). At least low resolution DNA based human leukocyte antigen (HLA) typing at HLA-A, -B, and -DRB1 for potential haploidentical sibling donors is required. b)At least two potential umbilical cord blood units identified. Each unit must have a minimum of 1.5 x 107/kg pre-cryopreserved total nucleated cell dose. For non-red blood cell depleted units, the minimum pre-cryopreserved total nucleated cell dose of each unit must be at least 2.0 x 107/kg. Units must be HLA matched at a minimum of 4/6 to the recipient at HLA-A, HLA-B (at low resolution using DNA based typing) and HLA-DRB1 (at high resolution using DNA based typing). Confirmatory typing is not required for randomization.
-
Acute Lymphoblastic Leukemia (ALL) in first complete remission (CR1) that is NOT considered favorable-risk as defined by the presence of at least one of the following: Adverse cytogenetics such as t(9;22), t(1;19), t(4;11), other Mixed Lineage Leukemia (MLL) rearrangements; White blood cell counts of greater than 30,000/mcL (B-ALL) or greater than 100,000/mcL (T-ALL)at diagnosis; Recipient age older than 30 years at diagnosis; Time to CR greater than 4 weeks
-
Acute Myelogeneous Leukemia (AML) in CR1 that is NOT considered as favorable-risk. Favorable risk is defined as having one of the following: t(8.21) without CKIT mutation, inv(16) without CKIT mutation or t(16;16), normal karyotype with mutated NPM1 and not FLT-ITD, normal karyotype with double mutated CEBPA, Acute promyelocytic leukemia (APL) in first molecular remission at end of consolidation
-
Acute Leukemias in 2nd or subsequent CR
-
Biphenotypic/Undifferentiated/Prolymphocytic Leukemias in first or subsequent CR, adult T-cell leukemia/lymphoma in first or subsequent CR
-
Burkitt's lymphoma: second or subsequent CR
-
Lymphoma fulfilling the following criteria: Chemotherapy-sensitive (at least stable disease lymphomas that have failed at least 1 prior regimen of multi-agent chemotherapy and are INELIGIBLE for an autologous transplant. Patients with chronic lymphocytic leukemia (CLL) are not eligible regardless of disease status.
-
Performance status: Karnofsky score greater than or equal to 70%.
Additional Patient Inclusion Criteria for Conditioning:
-
Patients with Adequate Physical Function as Measured by: a. Cardiac: Left ventricular ejection fraction at rest must be greater than or equal to 40%, or shortening fraction less than 25%; b. Hepatic: Bilirubin less than or equal to 2.5 mg/dL, except for patients with Gilbert's syndrome or hemolysis. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and Alkaline Phosphatase less than 5 x upper limit of normal; c. Renal: Serum creatinine within normal range, or if serum creatinine outside normal range, then renal function (measured or estimated creatinine clearance or GFR)greater than 40 mL/min/1.73m^; d. Pulmonary: Diffusing capacity of the lung for carbon monoxide (DLCO) (corrected for hemoglobin), forced expiratory volume in one second (FEV1), and forced vital capacity (FVC) greater than 50% predicted;
-
Additional Patient Inclusion Criteria for Patients Assigned to Haploidentical BM Arm: Patients must be HLA typed at high resolution using DNA based typing at the following HLA-loci: HLA-A, -B, -C and DRB1 and have available a related haploidentical BM donor with 2, 3, or 4 HLA-mismatches. A unidirectional mismatch in either the graft versus host or host versus graft direction is considered a mismatch. The donor and recipient must be HLA identical for at least one antigen (using high resolution DNA based typing) at the following genetic loci: HLA-A, HLA-B, HLA-C, and HLA-DRB1. Fulfillment of this criterion shall be considered sufficient evidence that the donor and recipient share one HLA haplotype, and typing of additional family members is not required.
-
Additional Patient Inclusion Criteria for Patients Assigned to Double Umbilical Cord
Blood Arm:
-
Patients must have available two UCB units fulfilling the following criteria:
-
Each unit must have a minimum of 1.5 x 107/kg pre-cryopreserved total nucleated cell dose. For non-red blood cell depleted units, the minimum pre-cryopreserved total nucleated cell dose of each unit must be at least 2.0 x107/kg.
-
Units must be HLA matched at a minimum of 4/6 to the recipient at HLA -A, HLA-B (at low resolution using DNA based typing), and HLA -DRB1 (at high resolution using DNA based typing).
-
Additional graft selection criteria specified in section 2.5
-
Patients must have received at least one cycle of the cytotoxic chemotherapy regimens (or regimen of similar intensity) listed in Appendix D within 3 months of enrollment (measured from the start date of chemotherapy) OR have had an autologous transplant within 24 months of enrollment OR receive 300 cGy as part of the preparative regimen
Exclusion Criteria:
-
Patients with suitably matched related or unrelated donor, as defined per institutional practice.
-
Recipients of prior autologous hematopoietic stem cell transplantation are ineligible if disease recurrence occurred less than 6 months from their autologous stem cell transplant.
-
Current uncontrolled bacterial, viral or fungal infection (currently taking medication with evidence of progression of clinical symptoms or radiologic findings).
-
Prior allogeneic HCT.
-
Patients with history of primary idiopathic myelofibrosis or any severe marrow fibrosis.
-
Planned use of prophylactic donor lymphocyte infusion (DLI) therapy.
-
Anti-donor HLA antibodies.
Additional exclusion criteria:
-
Pregnancy or breast-feeding.
-
Evidence of HIV infection or known HIV positive serology.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of Alabama at Birmingham | Birmingham | Alabama | United States | 35233 |
| 2 | Arizona Cancer Center | Phoenix | Arizona | United States | 85013 |
| 3 | City of Hope National Medical Center | Duarte | California | United States | 91010-3000 |
| 4 | University of California at Los Angeles | Los Angeles | California | United States | 90095 |
| 5 | Stanford Hospital and Clinics | Stanford | California | United States | 94305 |
| 6 | University of Florida College of Medicine (Shands) | Gainesville | Florida | United States | 32610-0277 |
| 7 | Florida Hospital Cancer Institute | Orlando | Florida | United States | 32804 |
| 8 | Emory University | Atlanta | Georgia | United States | 30322 |
| 9 | BMT Program at Northside Hospital | Atlanta | Georgia | United States | 30342 |
| 10 | University of Kansas Hospital | Kansas City | Kansas | United States | 66160 |
| 11 | Johns Hopkins University | Baltimore | Maryland | United States | 21231 |
| 12 | DFCI Massachustts General Hospital | Boston | Massachusetts | United States | 02114 |
| 13 | DFCI Brigham & Women's Hospital | Boston | Massachusetts | United States | 02115 |
| 14 | University of Michigan Medical Center | Ann Arbor | Michigan | United States | 48109 |
| 15 | Karmanos Cancer Institute/BMT | Detroit | Michigan | United States | 48201 |
| 16 | Univeristy of Minnesota | Minneapolis | Minnesota | United States | 55455 |
| 17 | Mayo Clinic Rochester | Rochester | Minnesota | United States | 55905 |
| 18 | Roswell Park Cancer Center | Buffalo | New York | United States | 14203 |
| 19 | Mt. Sinai Medical Center | New York | New York | United States | 10029 |
| 20 | Memorial Sloan Kettering Cancer Center | New York | New York | United States | 10065 |
| 21 | University of Rochester Medical Center | Rochester | New York | United States | 14642 |
| 22 | Stony Brook University Medical Center | Stony Brook | New York | United States | 11794-7122 |
| 23 | University of North Carolina Hospital at Chapel Hill | Chapel Hill | North Carolina | United States | 27599-7305 |
| 24 | Duke University Medical Center | Durham | North Carolina | United States | 27705 |
| 25 | Jewish Hospital BMT Program | Cincinnati | Ohio | United States | 45236 |
| 26 | University Hospitals of Cleveland, Case Western | Cleveland | Ohio | United States | 44106-5061 |
| 27 | Cleveland Clinic Foundation | Cleveland | Ohio | United States | 44195 |
| 28 | Ohio State / Arthur G. James Cancer Hospital | Columbus | Ohio | United States | 43210 |
| 29 | University of Oklahoma Medical Center | Oklahoma City | Oklahoma | United States | 73104 |
| 30 | Penn State College of Medicine - The Milton S. Hershey Medical Center | Hershey | Pennsylvania | United States | 17033 |
| 31 | University of Pennsylvania Cancer Center | Philadelphia | Pennsylvania | United States | 19104 |
| 32 | Medical University of South Carolina | Charleston | South Carolina | United States | 29425 |
| 33 | Vanderbilt University Medical Center | Nashville | Tennessee | United States | 37232 |
| 34 | Univesity of Texas, MD Anderson CRC | Houston | Texas | United States | 77030 |
| 35 | Texas Transplant Institute | San Antonio | Texas | United States | 78229 |
| 36 | Virginia Commonwealth University | Richmond | Virginia | United States | 23298 |
| 37 | Fred Hutchinson Cancer Research Center | Seattle | Washington | United States | 98109-1024 |
| 38 | West Virginia University | Morgantown | West Virginia | United States | 26506-9162 |
| 39 | Medical College of Wisconsin | Milwaukee | Wisconsin | United States | 53211 |
Sponsors and Collaborators
- Medical College of Wisconsin
- National Heart, Lung, and Blood Institute (NHLBI)
- National Cancer Institute (NCI)
- Blood and Marrow Transplant Clinical Trials Network
- National Marrow Donor Program
Investigators
- Study Director: Mary Horowitz, MD, MS, Center for International Blood and Marrow Transplant Research (CIBMTR), Medical College of Wisconsin
Study Documents (Full-Text)
More Information
Additional Information:
Publications
- Eapen M, O'Donnell P, Brunstein CG, Wu J, Barowski K, Mendizabal A, Fuchs EJ. Mismatched related and unrelated donors for allogeneic hematopoietic cell transplantation for adults with hematologic malignancies. Biol Blood Marrow Transplant. 2014 Oct;20(10):1485-92. doi: 10.1016/j.bbmt.2014.05.015. Epub 2014 May 23. Review.
- Roth JA, Bensink ME, O'Donnell PV, Fuchs EJ, Eapen M, Ramsey SD. Design of a cost-effectiveness analysis alongside a randomized trial of transplantation using umbilical cord blood versus HLA-haploidentical related bone marrow in advanced hematologic cancer. J Comp Eff Res. 2014 Mar;3(2):135-44. doi: 10.2217/cer.13.95.
Responsible Party:
Medical College of Wisconsin
ClinicalTrials.gov Identifier:
NCT01597778
Other Study ID Numbers:
- BMTCTN1101
- 2U10HL069294-11
- 5U24CA076518
First Posted:
May 14, 2012
Last Update Posted:
Dec 1, 2021
Last Verified:
Nov 1, 2021
Individual Participant Data (IPD) Sharing Statement:
Yes
Plan to Share IPD:
Yes
Studies a U.S. FDA-regulated Drug Product:
No
Studies a U.S. FDA-regulated Device Product:
No
Product Manufactured in and Exported from the U.S.:
No
Keywords provided by Medical College of Wisconsin
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | dUCB | Haplo-BM |
|---|---|---|
| Arm/Group Description | Participants will receive double unrelated cord blood transplant using a reduced intensity conditioning regimen. Double unrelated cord blood Transplant: The conditioning regimen consists of: Fludarabine 40 mg/m2 IV Days -6, -5, -4, -3, -2 Cyclophosphamide 50 mg/kg IV Day -6 Total Body Irradiation (TBI): - 200 cGy Day -1 for patients who have received cytotoxic chemotherapy within the last 3 months or an autologous transplant within 24 months of enrollment; - 300 cGY Day -1 for patients who have not received cytotoxic chemotherapy within 3 months of enrollment or an autologous transplant within 24 months of enrollment Day 0 will be the day of the double UCB transplant The GVHD prophylaxis regimen consists of: Cyclosporine beginning Day -3 with dose adjusted to maintain a trough level of 200-400 ng/mL. Tacrolimus (trough level of 5-15 ng/mL) may be substituted for cyclosporine if the patient is intolerant of cyclosporine or per institutional practice. Mycophenolate mofetil (MMF) 15 mg/kg po TID, maximum dose 1 g po TID beginning Day-3 until Day 35 Supportive care includes: - Filgrastim (G-CSF) 5 mcg/kg/day beginning Day 1 until ANC >1500/mm3 for 3 consecutive measurements on at least two different days | Participants will receive haploidentical bone marrow transplant using a reduced intensity conditioning regimen. Haploidentical Bone Marrow Transplant: The conditioning regimen consists of: Fludarabine (Flu)30 mg/m2 IV Days -6, -5, -4, -3, -2 Cyclophosphamide (Cy) 14.5 mg/kg IV Days -6, -5 Total body irradiation (TBI) 200cGy Day -1 Day 0 will be the day of infusion of non-T-cell depleted bone marrow The GVHD prophylaxis regimen consists of: Cy 50 mg/kg IV Days 3, 4 Tacrolimus (IV or PO) beginning Day 5 with dose adjusted to maintain a trough level of 5-15 ng/mL. Cyclosporine (trough level of 200-400 ng/mL) may be substituted for tacrolimus if the patient is intolerant of tacrolimus or per institutional practice. Mycophenolate mofetil (MMF) 15 mg/kg po three times a day, maximum dose 1 g po TID beginning Day 5 until Day 35 Supportive care includes: - Filgrastim (G-CSF) 5 mcg/kg/day beginning Day 5 until ANC >1500/mm3 for 3 consecutive measurements on at least two different days |
| Period Title: Overall Study | ||
| STARTED | 186 | 182 |
| COMPLETED | 172 | 153 |
| NOT COMPLETED | 14 | 29 |
Baseline Characteristics
| Arm/Group Title | dUCB | Haplo-BM | Total |
|---|---|---|---|
| Arm/Group Description | Participants will receive double unrelated cord blood transplant using a reduced intensity conditioning regimen. Double unrelated cord blood Transplant: The conditioning regimen consists of: Fludarabine 40 mg/m2 IV Days -6, -5, -4, -3, -2 Cyclophosphamide 50 mg/kg IV Day -6 Total Body Irradiation (TBI): - 200 cGy Day -1 for patients who have received cytotoxic chemotherapy within the last 3 months or an autologous transplant within 24 months of enrollment; - 300 cGY Day -1 for patients who have not received cytotoxic chemotherapy within 3 months of enrollment or an autologous transplant within 24 months of enrollment Day 0 will be the day of the double UCB transplant The GVHD prophylaxis regimen consists of: Cyclosporine beginning Day -3 with dose adjusted to maintain a trough level of 200-400 ng/mL. Tacrolimus (trough level of 5-15 ng/mL) may be substituted for cyclosporine if the patient is intolerant of cyclosporine or per institutional practice. Mycophenolate mofetil (MMF) 15 mg/kg po TID, maximum dose 1 g po TID beginning Day-3 until Day 35 Supportive care includes: - Filgrastim (G-CSF) 5 mcg/kg/day beginning Day 1 until ANC >1500/mm3 for 3 consecutive measurements on at least two different days | Participants will receive haploidentical bone marrow transplant using a reduced intensity conditioning regimen. Haploidentical Bone Marrow Transplant: The conditioning regimen consists of: Fludarabine (Flu)30 mg/m2 IV Days -6, -5, -4, -3, -2 Cyclophosphamide (Cy) 14.5 mg/kg IV Days -6, -5 Total body irradiation (TBI) 200cGy Day -1 Day 0 will be the day of infusion of non-T-cell depleted bone marrow The GVHD prophylaxis regimen consists of: Cy 50 mg/kg IV Days 3, 4 Tacrolimus (IV or PO) beginning Day 5 with dose adjusted to maintain a trough level of 5-15 ng/mL. Cyclosporine (trough level of 200-400 ng/mL) may be substituted for tacrolimus if the patient is intolerant of tacrolimus or per institutional practice. Mycophenolate mofetil (MMF) 15 mg/kg po three times a day, maximum dose 1 g po TID beginning Day 5 until Day 35 Supportive care includes: - Filgrastim (G-CSF) 5 mcg/kg/day beginning Day 5 until ANC >1500/mm3 for 3 consecutive measurements on at least two different days | Total of all reporting groups |
| Overall Participants | 186 | 182 | 368 |
| Age (years) [Median (Full Range) ] | |||
| Median (Range) |
58.2
|
59.9
|
58.8
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
89
47.8%
|
76
41.8%
|
165
44.8%
|
| Male |
97
52.2%
|
106
58.2%
|
203
55.2%
|
| Ethnicity (NIH/OMB) (Count of Participants) | |||
| Hispanic or Latino |
22
11.8%
|
21
11.5%
|
43
11.7%
|
| Not Hispanic or Latino |
164
88.2%
|
159
87.4%
|
323
87.8%
|
| Unknown or Not Reported |
0
0%
|
2
1.1%
|
2
0.5%
|
| Race (NIH/OMB) (Count of Participants) | |||
| American Indian or Alaska Native |
3
1.6%
|
1
0.5%
|
4
1.1%
|
| Asian |
9
4.8%
|
15
8.2%
|
24
6.5%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
1
0.5%
|
1
0.3%
|
| Black or African American |
27
14.5%
|
34
18.7%
|
61
16.6%
|
| White |
145
78%
|
126
69.2%
|
271
73.6%
|
| More than one race |
0
0%
|
0
0%
|
0
0%
|
| Unknown or Not Reported |
2
1.1%
|
5
2.7%
|
7
1.9%
|
| Karnofsky Performance Score (Count of Participants) | |||
| >=90 |
126
67.7%
|
111
61%
|
237
64.4%
|
| <90 |
59
31.7%
|
71
39%
|
130
35.3%
|
| Missing |
1
0.5%
|
0
0%
|
1
0.3%
|
| Primary Diagnosis (Count of Participants) | |||
| Acute Lymphoblastic Leukemia |
31
16.7%
|
32
17.6%
|
63
17.1%
|
| Acute Myelogeneous Leukemia |
98
52.7%
|
98
53.8%
|
196
53.3%
|
| Biphenotypic/Undifferentiated/Prolymphocytic Leukemia |
1
0.5%
|
5
2.7%
|
6
1.6%
|
| Hodgkin's Lymphoma |
10
5.4%
|
8
4.4%
|
18
4.9%
|
| Large Cell Lymphoma |
21
11.3%
|
19
10.4%
|
40
10.9%
|
| Follicular Non-Hodgkin's Lymphoma |
7
3.8%
|
5
2.7%
|
12
3.3%
|
| T-cell Leukemia/Lymphoma |
4
2.2%
|
3
1.6%
|
7
1.9%
|
| Mantle Cell Lymphoma |
6
3.2%
|
5
2.7%
|
11
3%
|
| Other Lymphoma |
8
4.3%
|
7
3.8%
|
15
4.1%
|
| Disease Risk for Leukemia Patients (N=272) (Count of Participants) | |||
| First Complete Remission |
99
53.2%
|
117
64.3%
|
216
58.7%
|
| Second Complete Remission |
35
18.8%
|
20
11%
|
55
14.9%
|
| Third or More |
0
0%
|
1
0.5%
|
1
0.3%
|
| Disease Risk for Lymphoma Patients (N=96) (Count of Participants) | |||
| Complete Response |
20
10.8%
|
14
7.7%
|
34
9.2%
|
| Partial Response |
25
13.4%
|
25
13.7%
|
50
13.6%
|
| Follicular or Non-Hodgkin's |
7
3.8%
|
5
2.7%
|
12
3.3%
|
| Cytogenetics for Leukemia (Count of Participants) | |||
| Favorable |
17
9.1%
|
20
11%
|
37
10.1%
|
| Intermediate |
61
32.8%
|
56
30.8%
|
117
31.8%
|
| Poor |
43
23.1%
|
45
24.7%
|
88
23.9%
|
| Not Available |
13
7%
|
17
9.3%
|
30
8.2%
|
| HLA Matching Score for Haploidentical Donor at Randomization (Count of Participants) | |||
| 3/6 |
46
24.7%
|
39
21.4%
|
85
23.1%
|
| 4/6 |
22
11.8%
|
16
8.8%
|
38
10.3%
|
| 4/8 |
0
0%
|
1
0.5%
|
1
0.3%
|
| 5/8 |
1
0.5%
|
0
0%
|
1
0.3%
|
| 6/8 |
1
0.5%
|
1
0.5%
|
2
0.5%
|
| Not Required* |
116
62.4%
|
125
68.7%
|
241
65.5%
|
| HLA Matching Score for Cord Blood Unit 1 at Enrollment (Count of Participants) | |||
| 4/6 |
83
44.6%
|
82
45.1%
|
165
44.8%
|
| 5/6 |
73
39.2%
|
75
41.2%
|
148
40.2%
|
| 6/6 |
30
16.1%
|
25
13.7%
|
55
14.9%
|
| HLA Matching Score for Cord Blood Unit 2 at Enrollment (Count of Participants) | |||
| 4/6 |
99
53.2%
|
99
54.4%
|
198
53.8%
|
| 5/6 |
66
35.5%
|
64
35.2%
|
130
35.3%
|
| 6/6 |
21
11.3%
|
19
10.4%
|
40
10.9%
|
| Pre-cryopreservation total nucleated cell count (cells x 10^7/kg) [Median (Full Range) ] | |||
| Median (Full Range) [cells x 10^7/kg] |
5.13
|
5.59
|
5.15
|
| Post-thaw total nucleated cell count (cells x 10^7/kg) [Median (Full Range) ] | |||
| Median (Full Range) [cells x 10^7/kg] |
4.32
|
3.12
|
4.32
|
| Total nucleated cell count at infusion (cells x 10^7/kg) [Median (Full Range) ] | |||
| Median (Full Range) [cells x 10^7/kg] |
2.95
|
26.82
|
4.46
|
| Pre-cryopreservation CD34+ cell count (cells x 10^6/kg) [Median (Full Range) ] | |||
| Median (Full Range) [cells x 10^6/kg] |
0.23
|
0.21
|
0.22
|
| Post-thaw CD34+ cell count (cells x 10^6/kg) [Median (Full Range) ] | |||
| Median (Full Range) [cells x 10^6/kg] |
0.20
|
0.17
|
0.20
|
| CD34+ cell count at infusion (cells x 10^6/kg) [Median (Full Range) ] | |||
| Median (Full Range) [cells x 10^6/kg] |
0.13
|
2.87
|
0.20
|
| Pre-cryopreservation CD3+ cell count (cells x 10^6/kg) [Median (Full Range) ] | |||
| Median (Full Range) [cells x 10^6/kg] |
7.79
|
0.00
|
7.38
|
| Post-thaw CD3+ cell count (cells x 10^6/kg) [Median (Full Range) ] | |||
| Median (Full Range) [cells x 10^6/kg] |
6.97
|
7.47
|
6.97
|
| CD3+ cell count at infusion (cells x 10^6/kg) [Median (Full Range) ] | |||
| Median (Full Range) [cells x 10^6/kg] |
5.50
|
29.66
|
8.05
|
| HCT-comorbidity index (CI) (Count of Participants) | |||
| >=3 |
71
38.2%
|
68
37.4%
|
139
37.8%
|
| 2 |
26
14%
|
23
12.6%
|
49
13.3%
|
| 1 |
26
14%
|
23
12.6%
|
49
13.3%
|
| 0 |
52
28%
|
53
29.1%
|
105
28.5%
|
| CMV Status at Transplant (Count of Participants) | |||
| Positive |
98
52.7%
|
99
54.4%
|
197
53.5%
|
| Negative |
76
40.9%
|
68
37.4%
|
144
39.1%
|
| Missing |
1
0.5%
|
0
0%
|
1
0.3%
|
| Time from Diagnosis to Transplant (day) [Median (Full Range) ] | |||
| Median (Full Range) [day] |
283
|
219
|
233
|
| Prior Autologous Transplant (Count of Participants) | |||
| Prior Autologous Transplant |
16
8.6%
|
16
8.8%
|
32
8.7%
|
| No Prior Autologous Transplant |
170
91.4%
|
166
91.2%
|
336
91.3%
|
| Number of Regimens Prior to Transplant (Count of Participants) | |||
| 5 |
4
2.2%
|
7
3.8%
|
11
3%
|
| 4 |
6
3.2%
|
6
3.3%
|
12
3.3%
|
| 3 |
14
7.5%
|
8
4.4%
|
22
6%
|
| 2 |
8
4.3%
|
10
5.5%
|
18
4.9%
|
| 1 |
17
9.1%
|
10
5.5%
|
27
7.3%
|
| 0 |
2
1.1%
|
0
0%
|
2
0.5%
|
| Unknown |
124
66.7%
|
126
69.2%
|
250
67.9%
|
| Disease Risk Index (Count of Participants) | |||
| Low |
23
12.4%
|
14
7.7%
|
37
10.1%
|
| Intermediate |
119
64%
|
120
65.9%
|
239
64.9%
|
| High |
35
18.8%
|
37
20.3%
|
72
19.6%
|
| Not Available |
9
4.8%
|
11
6%
|
20
5.4%
|
Outcome Measures
| Title | Percentage of Participants With Progression Free Survival (PFS) |
|---|---|
| Description | The primary endpoint is PFS at 2 years post-randomization. Death or disease relapse/progression will be considered as events. The time to event is defined as the time interval from randomization to relapse/progression, to death or to last follow-up, whichever comes first. Relapse is defined by either morphological or cytogenetic evidence of acute leukemia consistent with pre-transplant features, or radiologic evidence of progressive lymphoma. Minimal residual disease will not be considered evidence of relapse, however, minimal residual disease that progresses will be considered as relapse and the date of relapse will be the date of detection of minimal residual disease that prompted an intervention by the treating physician. Finally, institution of any therapy to treat persistent, progressive or relapsed disease, including withdrawal of immunosuppressive therapy or DLI, will be considered evidence of relapse/progression regardless of whether the criteria described above are met. |
| Time Frame | Year 2 |
Outcome Measure Data
| Analysis Population Description |
|---|
| The primary endpoint analysis is performed using the intent-to-treat principle so that all randomized patients are included in the analysis. |
| Arm/Group Title | dUCB | Haplo-BM |
|---|---|---|
| Arm/Group Description | Participants will receive double unrelated cord blood transplant using a reduced intensity conditioning regimen. Double unrelated cord blood Transplant: The conditioning regimen consists of: Fludarabine 40 mg/m2 IV Days -6, -5, -4, -3, -2 Cyclophosphamide 50 mg/kg IV Day -6 Total Body Irradiation (TBI): - 200 cGy Day -1 for patients who have received cytotoxic chemotherapy within the last 3 months or an autologous transplant within 24 months of enrollment; - 300 cGY Day -1 for patients who have not received cytotoxic chemotherapy within 3 months of enrollment or an autologous transplant within 24 months of enrollment Day 0 will be the day of the double UCB transplant The GVHD prophylaxis regimen consists of: Cyclosporine beginning Day -3 with dose adjusted to maintain a trough level of 200-400 ng/mL. Tacrolimus (trough level of 5-15 ng/mL) may be substituted for cyclosporine if the patient is intolerant of cyclosporine or per institutional practice. Mycophenolate mofetil (MMF) 15 mg/kg po TID, maximum dose 1 g po TID beginning Day-3 until Day 35 Supportive care includes: - Filgrastim (G-CSF) 5 mcg/kg/day beginning Day 1 until ANC >1500/mm3 for 3 consecutive measurements on at least two different days | Participants will receive haploidentical bone marrow transplant using a reduced intensity conditioning regimen. Haploidentical Bone Marrow Transplant: The conditioning regimen consists of: Fludarabine (Flu)30 mg/m2 IV Days -6, -5, -4, -3, -2 Cyclophosphamide (Cy) 14.5 mg/kg IV Days -6, -5 Total body irradiation (TBI) 200cGy Day -1 Day 0 will be the day of infusion of non-T-cell depleted bone marrow The GVHD prophylaxis regimen consists of: Cy 50 mg/kg IV Days 3, 4 Tacrolimus (IV or PO) beginning Day 5 with dose adjusted to maintain a trough level of 5-15 ng/mL. Cyclosporine (trough level of 200-400 ng/mL) may be substituted for tacrolimus if the patient is intolerant of tacrolimus or per institutional practice. Mycophenolate mofetil (MMF) 15 mg/kg po three times a day, maximum dose 1 g po TID beginning Day 5 until Day 35 Supportive care includes: - Filgrastim (G-CSF) 5 mcg/kg/day beginning Day 5 until ANC >1500/mm3 for 3 consecutive measurements on at least two different days |
| Measure Participants | 186 | 182 |
| Number (95% Confidence Interval) [percentage of participants] |
35.0
18.8%
|
41.1
22.6%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | dUCB, Haplo-BM |
|---|---|---|
| Comments | The primary null hypothesis of the study is that there is no difference between the 2 year PFS probabilities for dUCB vs. haplo-BM. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.4092 |
| Comments | Statistical significance was determined using a pre-specified threshold of 0.05. Final p-value is adjusted for the interim looks per study design. | |
| Method | Z-test to compare the Kaplan-Meier Est. | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Difference in Kaplan-Meier estimates |
| Estimated Value | 6.1 | |
| Confidence Interval |
(2-Sided) 95% -5.2 to 17.4 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | dUCB, Haplo-BM |
|---|---|---|
| Comments | The null hypothesis of the study is that there is no difference between the 2 year PFS probabilities for dUCB vs. haplo-BM after adjustment for age, performance score, and disease type. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.060 |
| Comments | Statistical significance was determined using a pre-specified threshold of 0.05 | |
| Method | Regression, Cox | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 1.30 | |
| Confidence Interval |
(2-Sided) 95% 0.99 to 1.70 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Percentage of Participants With PFS by Treatment Arms in Subgroups |
|---|---|
| Description | Participants' primary diagnosis was categorized into two large groups: leukemia versus lymphoma. Age was dichotomized into two large groups: age <= 59 versus age > 59. The Kaplan-Meier estimate for PFS at 2 years post-randomization are provided for each subgroup. |
| Time Frame | Year 2 |
Outcome Measure Data
| Analysis Population Description |
|---|
| The randomized participants are included in the analysis. |
| Arm/Group Title | dUCB | Haplo-BM |
|---|---|---|
| Arm/Group Description | Participants will receive double unrelated cord blood transplant using a reduced intensity conditioning regimen. Double unrelated cord blood Transplant: The conditioning regimen consists of: Fludarabine 40 mg/m2 IV Days -6, -5, -4, -3, -2 Cyclophosphamide 50 mg/kg IV Day -6 Total Body Irradiation (TBI): - 200 cGy Day -1 for patients who have received cytotoxic chemotherapy within the last 3 months or an autologous transplant within 24 months of enrollment; - 300 cGY Day -1 for patients who have not received cytotoxic chemotherapy within 3 months of enrollment or an autologous transplant within 24 months of enrollment Day 0 will be the day of the double UCB transplant The GVHD prophylaxis regimen consists of: Cyclosporine beginning Day -3 with dose adjusted to maintain a trough level of 200-400 ng/mL. Tacrolimus (trough level of 5-15 ng/mL) may be substituted for cyclosporine if the patient is intolerant of cyclosporine or per institutional practice. Mycophenolate mofetil (MMF) 15 mg/kg po TID, maximum dose 1 g po TID beginning Day-3 until Day 35 Supportive care includes: - Filgrastim (G-CSF) 5 mcg/kg/day beginning Day 1 until ANC >1500/mm3 for 3 consecutive measurements on at least two different days | Participants will receive haploidentical bone marrow transplant using a reduced intensity conditioning regimen. Haploidentical Bone Marrow Transplant: The conditioning regimen consists of: Fludarabine (Flu)30 mg/m2 IV Days -6, -5, -4, -3, -2 Cyclophosphamide (Cy) 14.5 mg/kg IV Days -6, -5 Total body irradiation (TBI) 200cGy Day -1 Day 0 will be the day of infusion of non-T-cell depleted bone marrow The GVHD prophylaxis regimen consists of: Cy 50 mg/kg IV Days 3, 4 Tacrolimus (IV or PO) beginning Day 5 with dose adjusted to maintain a trough level of 5-15 ng/mL. Cyclosporine (trough level of 200-400 ng/mL) may be substituted for tacrolimus if the patient is intolerant of tacrolimus or per institutional practice. Mycophenolate mofetil (MMF) 15 mg/kg po three times a day, maximum dose 1 g po TID beginning Day 5 until Day 35 Supportive care includes: - Filgrastim (G-CSF) 5 mcg/kg/day beginning Day 5 until ANC >1500/mm3 for 3 consecutive measurements on at least two different days |
| Measure Participants | 186 | 182 |
| By Primary Disease of Leukemia |
34.8
18.7%
|
41.7
22.9%
|
| By Primary Disease of Lymphoma |
35.6
19.1%
|
39.3
21.6%
|
| By Age Group <= 59 years |
37.9
20.4%
|
39.6
21.8%
|
| By Age Group > 59 years |
31.6
17%
|
42.4
23.3%
|
| Title | Percentage of Participants With Neutrophil Recovery |
|---|---|
| Description | Neutrophil recovery is defined as achieving an absolute neutrophil count greater than or equal to 500/mm^3 for three consecutive measurements on three different days. The first of the three days will be designated the day of neutrophil recovery. |
| Time Frame | Day 56 |
Outcome Measure Data
| Analysis Population Description |
|---|
| The transplanted participants are included in the analysis. A total of 26 patients (11 on the dUCB arm and 15 on the Haplo-BM arm) who did not proceed to the study transplant are excluded. |
| Arm/Group Title | dUCB | Haplo-BM |
|---|---|---|
| Arm/Group Description | Participants will receive double unrelated cord blood transplant using a reduced intensity conditioning regimen. Double unrelated cord blood Transplant: The conditioning regimen consists of: Fludarabine 40 mg/m2 IV Days -6, -5, -4, -3, -2 Cyclophosphamide 50 mg/kg IV Day -6 Total Body Irradiation (TBI): - 200 cGy Day -1 for patients who have received cytotoxic chemotherapy within the last 3 months or an autologous transplant within 24 months of enrollment; - 300 cGY Day -1 for patients who have not received cytotoxic chemotherapy within 3 months of enrollment or an autologous transplant within 24 months of enrollment Day 0 will be the day of the double UCB transplant The GVHD prophylaxis regimen consists of: Cyclosporine beginning Day -3 with dose adjusted to maintain a trough level of 200-400 ng/mL. Tacrolimus (trough level of 5-15 ng/mL) may be substituted for cyclosporine if the patient is intolerant of cyclosporine or per institutional practice. Mycophenolate mofetil (MMF) 15 mg/kg po TID, maximum dose 1 g po TID beginning Day-3 until Day 35 Supportive care includes: - Filgrastim (G-CSF) 5 mcg/kg/day beginning Day 1 until ANC >1500/mm3 for 3 consecutive measurements on at least two different days | Participants will receive haploidentical bone marrow transplant using a reduced intensity conditioning regimen. Haploidentical Bone Marrow Transplant: The conditioning regimen consists of: Fludarabine (Flu)30 mg/m2 IV Days -6, -5, -4, -3, -2 Cyclophosphamide (Cy) 14.5 mg/kg IV Days -6, -5 Total body irradiation (TBI) 200cGy Day -1 Day 0 will be the day of infusion of non-T-cell depleted bone marrow The GVHD prophylaxis regimen consists of: Cy 50 mg/kg IV Days 3, 4 Tacrolimus (IV or PO) beginning Day 5 with dose adjusted to maintain a trough level of 5-15 ng/mL. Cyclosporine (trough level of 200-400 ng/mL) may be substituted for tacrolimus if the patient is intolerant of tacrolimus or per institutional practice. Mycophenolate mofetil (MMF) 15 mg/kg po three times a day, maximum dose 1 g po TID beginning Day 5 until Day 35 Supportive care includes: - Filgrastim (G-CSF) 5 mcg/kg/day beginning Day 5 until ANC >1500/mm3 for 3 consecutive measurements on at least two different days |
| Measure Participants | 175 | 167 |
| Number (95% Confidence Interval) [percentage of participants] |
94.9
51%
|
98.8
54.3%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | dUCB, Haplo-BM |
|---|---|---|
| Comments | The null hypothesis is that there is no difference between the neutrophil engraftment post-transplantation for dUCB vs. haplo-BM. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.046 |
| Comments | Statistical significance was determined using a pre-specified threshold of 0.05 | |
| Method | Gray's test for cumulative Incidence | |
| Comments | Estimate cumulative incidence functions from competing risks data and test equality of 2 trt grps. Death before neutrophil recovery is competing risk. | |
| Title | Percentage of Participants With Platelet Recovery |
|---|---|
| Description | Platelet recovery is defined by two different metrics as the first day of a sustained platelet count greater than 20,000/mm^3 or greater than 50,000/mm^3 with no platelet transfusions in the preceding seven days. The first day of the sustained platelet count will be designated the day of platelet engraftment. |
| Time Frame | Day 100 |
Outcome Measure Data
| Analysis Population Description |
|---|
| The transplanted participants are included in the analysis. A total of 26 patients (11 on the dUCB arm and 15 on the Haplo-BM arm) who did not proceed to the study transplant are excluded. |
| Arm/Group Title | dUCB | Haplo-BM |
|---|---|---|
| Arm/Group Description | Participants will receive double unrelated cord blood transplant using a reduced intensity conditioning regimen. Double unrelated cord blood Transplant: The conditioning regimen consists of: Fludarabine 40 mg/m2 IV Days -6, -5, -4, -3, -2 Cyclophosphamide 50 mg/kg IV Day -6 Total Body Irradiation (TBI): - 200 cGy Day -1 for patients who have received cytotoxic chemotherapy within the last 3 months or an autologous transplant within 24 months of enrollment; - 300 cGY Day -1 for patients who have not received cytotoxic chemotherapy within 3 months of enrollment or an autologous transplant within 24 months of enrollment Day 0 will be the day of the double UCB transplant The GVHD prophylaxis regimen consists of: Cyclosporine beginning Day -3 with dose adjusted to maintain a trough level of 200-400 ng/mL. Tacrolimus (trough level of 5-15 ng/mL) may be substituted for cyclosporine if the patient is intolerant of cyclosporine or per institutional practice. Mycophenolate mofetil (MMF) 15 mg/kg po TID, maximum dose 1 g po TID beginning Day-3 until Day 35 Supportive care includes: - Filgrastim (G-CSF) 5 mcg/kg/day beginning Day 1 until ANC >1500/mm3 for 3 consecutive measurements on at least two different days | Participants will receive haploidentical bone marrow transplant using a reduced intensity conditioning regimen. Haploidentical Bone Marrow Transplant: The conditioning regimen consists of: Fludarabine (Flu)30 mg/m2 IV Days -6, -5, -4, -3, -2 Cyclophosphamide (Cy) 14.5 mg/kg IV Days -6, -5 Total body irradiation (TBI) 200cGy Day -1 Day 0 will be the day of infusion of non-T-cell depleted bone marrow The GVHD prophylaxis regimen consists of: Cy 50 mg/kg IV Days 3, 4 Tacrolimus (IV or PO) beginning Day 5 with dose adjusted to maintain a trough level of 5-15 ng/mL. Cyclosporine (trough level of 200-400 ng/mL) may be substituted for tacrolimus if the patient is intolerant of tacrolimus or per institutional practice. Mycophenolate mofetil (MMF) 15 mg/kg po three times a day, maximum dose 1 g po TID beginning Day 5 until Day 35 Supportive care includes: - Filgrastim (G-CSF) 5 mcg/kg/day beginning Day 5 until ANC >1500/mm3 for 3 consecutive measurements on at least two different days |
| Measure Participants | 175 | 167 |
| Platelet recovery to 20K |
86.9
46.7%
|
91.6
50.3%
|
| Platelet recovery to 50K |
78.3
42.1%
|
84.4
46.4%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | dUCB, Haplo-BM |
|---|---|---|
| Comments | The null hypothesis is that there is no difference between the platelet engraftment to 20k post-transplantation for dUCB vs. haplo-BM. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.160 |
| Comments | Statistical significance was determined using a pre-specified threshold of 0.05 | |
| Method | Gray's test for cumulative Incidence | |
| Comments | Estimate cumulative incidence functions from competing risks data and test equality of 2 trt grps. Death before Platelet recovery is competing risk. | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | dUCB, Haplo-BM |
|---|---|---|
| Comments | The null hypothesis is that there is no difference between the platelet engraftment to 50k post-transplantation for dUCB vs. haplo-BM. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.146 |
| Comments | Statistical significance was determined using a pre-specified threshold of 0.05. | |
| Method | Gray's test for cumulative Incidence | |
| Comments | Estimate cumulative incidence functions from competing risks data and test equality of 2 trt grps. Death before Platelet recovery is competing risk. | |
| Title | Participants With Primary Graft Failure |
|---|---|
| Description | Primary graft failure is defined as less than 5% donor chimerism on all measurements up to and including Day 56. |
| Time Frame | Day 56 |
Outcome Measure Data
| Analysis Population Description |
|---|
| The transplanted participants are included in the analysis. A total of 26 patients (11 on the dUCB arm and 15 on the Haplo-BM arm) who did not proceed to the study transplant are excluded. |
| Arm/Group Title | dUCB | Haplo-BM |
|---|---|---|
| Arm/Group Description | Participants will receive double unrelated cord blood transplant using a reduced intensity conditioning regimen. Double unrelated cord blood Transplant: The conditioning regimen consists of: Fludarabine 40 mg/m2 IV Days -6, -5, -4, -3, -2 Cyclophosphamide 50 mg/kg IV Day -6 Total Body Irradiation (TBI): - 200 cGy Day -1 for patients who have received cytotoxic chemotherapy within the last 3 months or an autologous transplant within 24 months of enrollment; - 300 cGY Day -1 for patients who have not received cytotoxic chemotherapy within 3 months of enrollment or an autologous transplant within 24 months of enrollment Day 0 will be the day of the double UCB transplant The GVHD prophylaxis regimen consists of: Cyclosporine beginning Day -3 with dose adjusted to maintain a trough level of 200-400 ng/mL. Tacrolimus (trough level of 5-15 ng/mL) may be substituted for cyclosporine if the patient is intolerant of cyclosporine or per institutional practice. Mycophenolate mofetil (MMF) 15 mg/kg po TID, maximum dose 1 g po TID beginning Day-3 until Day 35 Supportive care includes: - Filgrastim (G-CSF) 5 mcg/kg/day beginning Day 1 until ANC >1500/mm3 for 3 consecutive measurements on at least two different days | Participants will receive haploidentical bone marrow transplant using a reduced intensity conditioning regimen. Haploidentical Bone Marrow Transplant: The conditioning regimen consists of: Fludarabine (Flu)30 mg/m2 IV Days -6, -5, -4, -3, -2 Cyclophosphamide (Cy) 14.5 mg/kg IV Days -6, -5 Total body irradiation (TBI) 200cGy Day -1 Day 0 will be the day of infusion of non-T-cell depleted bone marrow The GVHD prophylaxis regimen consists of: Cy 50 mg/kg IV Days 3, 4 Tacrolimus (IV or PO) beginning Day 5 with dose adjusted to maintain a trough level of 5-15 ng/mL. Cyclosporine (trough level of 200-400 ng/mL) may be substituted for tacrolimus if the patient is intolerant of tacrolimus or per institutional practice. Mycophenolate mofetil (MMF) 15 mg/kg po three times a day, maximum dose 1 g po TID beginning Day 5 until Day 35 Supportive care includes: - Filgrastim (G-CSF) 5 mcg/kg/day beginning Day 5 until ANC >1500/mm3 for 3 consecutive measurements on at least two different days |
| Measure Participants | 175 | 167 |
| Count of Participants [Participants] |
13
7%
|
10
5.5%
|
| Title | Percentage of Participants With Secondary Graft Failure |
|---|---|
| Description | Secondary graft failure is defined as initial donor chimerism ≥ 5% declining to < 5% on subsequent measurements with time to secondary graft failure beginning at the first day of primary engraftment. |
| Time Frame | Year 2 |
Outcome Measure Data
| Analysis Population Description |
|---|
| The transplanted participants are included in the analysis. A total of 26 patients (11 on the dUCB arm and 15 on the Haplo-BM arm) who did not proceed to the study transplant are excluded. |
| Arm/Group Title | dUCB | Haplo-BM |
|---|---|---|
| Arm/Group Description | Participants will receive double unrelated cord blood transplant using a reduced intensity conditioning regimen. Double unrelated cord blood Transplant: The conditioning regimen consists of: Fludarabine 40 mg/m2 IV Days -6, -5, -4, -3, -2 Cyclophosphamide 50 mg/kg IV Day -6 Total Body Irradiation (TBI): - 200 cGy Day -1 for patients who have received cytotoxic chemotherapy within the last 3 months or an autologous transplant within 24 months of enrollment; - 300 cGY Day -1 for patients who have not received cytotoxic chemotherapy within 3 months of enrollment or an autologous transplant within 24 months of enrollment Day 0 will be the day of the double UCB transplant The GVHD prophylaxis regimen consists of: Cyclosporine beginning Day -3 with dose adjusted to maintain a trough level of 200-400 ng/mL. Tacrolimus (trough level of 5-15 ng/mL) may be substituted for cyclosporine if the patient is intolerant of cyclosporine or per institutional practice. Mycophenolate mofetil (MMF) 15 mg/kg po TID, maximum dose 1 g po TID beginning Day-3 until Day 35 Supportive care includes: - Filgrastim (G-CSF) 5 mcg/kg/day beginning Day 1 until ANC >1500/mm3 for 3 consecutive measurements on at least two different days | Participants will receive haploidentical bone marrow transplant using a reduced intensity conditioning regimen. Haploidentical Bone Marrow Transplant: The conditioning regimen consists of: Fludarabine (Flu)30 mg/m2 IV Days -6, -5, -4, -3, -2 Cyclophosphamide (Cy) 14.5 mg/kg IV Days -6, -5 Total body irradiation (TBI) 200cGy Day -1 Day 0 will be the day of infusion of non-T-cell depleted bone marrow The GVHD prophylaxis regimen consists of: Cy 50 mg/kg IV Days 3, 4 Tacrolimus (IV or PO) beginning Day 5 with dose adjusted to maintain a trough level of 5-15 ng/mL. Cyclosporine (trough level of 200-400 ng/mL) may be substituted for tacrolimus if the patient is intolerant of tacrolimus or per institutional practice. Mycophenolate mofetil (MMF) 15 mg/kg po three times a day, maximum dose 1 g po TID beginning Day 5 until Day 35 Supportive care includes: - Filgrastim (G-CSF) 5 mcg/kg/day beginning Day 5 until ANC >1500/mm3 for 3 consecutive measurements on at least two different days |
| Measure Participants | 175 | 167 |
| Number (95% Confidence Interval) [percentage of participants] |
2.6
1.4%
|
3.4
1.9%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | dUCB, Haplo-BM |
|---|---|---|
| Comments | The null hypothesis is that there is no difference between the secondary graft failure probabilities post-transplantation for dUCB vs. haplo-BM. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.693 |
| Comments | Statistical significance was determined using a pre-specified threshold of 0.05. | |
| Method | Gray's test for cumulative Incidence | |
| Comments | Estimate cumulative incidence functions from competing risks data and test equality of 2 trt grps. Death before 2nd graft failure is competing risk. | |
| Title | Percentage of Participants With Acute Graft-versus-Host Disease (aGVHD) |
|---|---|
| Description | The cumulative incidences of grade II - IV and III - IV acute aGVHD will be determined. |
| Time Frame | Day 180 |
Outcome Measure Data
| Analysis Population Description |
|---|
| The transplanted participants are included in the analysis. A total of 26 patients (11 on the dUCB arm and 15 on the Haplo-BM arm) who did not proceed to the study transplant are excluded. |
| Arm/Group Title | dUCB | Haplo-BM |
|---|---|---|
| Arm/Group Description | Participants will receive double unrelated cord blood transplant using a reduced intensity conditioning regimen. Double unrelated cord blood Transplant: The conditioning regimen consists of: Fludarabine 40 mg/m2 IV Days -6, -5, -4, -3, -2 Cyclophosphamide 50 mg/kg IV Day -6 Total Body Irradiation (TBI): - 200 cGy Day -1 for patients who have received cytotoxic chemotherapy within the last 3 months or an autologous transplant within 24 months of enrollment; - 300 cGY Day -1 for patients who have not received cytotoxic chemotherapy within 3 months of enrollment or an autologous transplant within 24 months of enrollment Day 0 will be the day of the double UCB transplant The GVHD prophylaxis regimen consists of: Cyclosporine beginning Day -3 with dose adjusted to maintain a trough level of 200-400 ng/mL. Tacrolimus (trough level of 5-15 ng/mL) may be substituted for cyclosporine if the patient is intolerant of cyclosporine or per institutional practice. Mycophenolate mofetil (MMF) 15 mg/kg po TID, maximum dose 1 g po TID beginning Day-3 until Day 35 Supportive care includes: - Filgrastim (G-CSF) 5 mcg/kg/day beginning Day 1 until ANC >1500/mm3 for 3 consecutive measurements on at least two different days | Participants will receive haploidentical bone marrow transplant using a reduced intensity conditioning regimen. Haploidentical Bone Marrow Transplant: The conditioning regimen consists of: Fludarabine (Flu)30 mg/m2 IV Days -6, -5, -4, -3, -2 Cyclophosphamide (Cy) 14.5 mg/kg IV Days -6, -5 Total body irradiation (TBI) 200cGy Day -1 Day 0 will be the day of infusion of non-T-cell depleted bone marrow The GVHD prophylaxis regimen consists of: Cy 50 mg/kg IV Days 3, 4 Tacrolimus (IV or PO) beginning Day 5 with dose adjusted to maintain a trough level of 5-15 ng/mL. Cyclosporine (trough level of 200-400 ng/mL) may be substituted for tacrolimus if the patient is intolerant of tacrolimus or per institutional practice. Mycophenolate mofetil (MMF) 15 mg/kg po three times a day, maximum dose 1 g po TID beginning Day 5 until Day 35 Supportive care includes: - Filgrastim (G-CSF) 5 mcg/kg/day beginning Day 5 until ANC >1500/mm3 for 3 consecutive measurements on at least two different days |
| Measure Participants | 175 | 167 |
| grade II - IV |
34.9
18.8%
|
28.1
15.4%
|
| grade III - IV |
8.6
4.6%
|
7.2
4%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | dUCB, Haplo-BM |
|---|---|---|
| Comments | The null hypothesis is that there is no difference between the aGVHD grade II - IV probabilities post-transplantation for dUCB vs. haplo-BM. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.142 |
| Comments | Statistical significance was determined using a pre-specified threshold of 0.05. | |
| Method | Gray's test for cumulative Incidence | |
| Comments | Estimate cumulative incidence functions from competing risks data and test equality of 2 trt grps. Death prior to aGVHD is competing risk. | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | dUCB, Haplo-BM |
|---|---|---|
| Comments | The null hypothesis is that there is no difference between the aGVHD grade III - IV probabilities post-transplantation for dUCB vs. haplo-BM. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.604 |
| Comments | Statistical significance was determined using a pre-specified threshold of 0.05. | |
| Method | Gray's test for cumulative Incidence | |
| Comments | Estimate cumulative incidence functions from competing risks data and test equality of 2 trt grps. Death prior to aGVHD is competing risk. | |
| Title | Percentage of Participants With Chronic Graft-versus-Host Disease (cGHVD) |
|---|---|
| Description | The cumulative incidence of cGVHD from the time of transplant will be determined. Data were collected directly from providers and chart review according to the recommendations of the NIH Consensus Conference. |
| Time Frame | Year 2 |
Outcome Measure Data
| Analysis Population Description |
|---|
| The transplanted participants are included in the analysis. A total of 26 patients (11 on the dUCB arm and 15 on the Haplo-BM arm) who did not proceed to the study transplant are excluded. |
| Arm/Group Title | dUCB | Haplo-BM |
|---|---|---|
| Arm/Group Description | Participants will receive double unrelated cord blood transplant using a reduced intensity conditioning regimen. Double unrelated cord blood Transplant: The conditioning regimen consists of: Fludarabine 40 mg/m2 IV Days -6, -5, -4, -3, -2 Cyclophosphamide 50 mg/kg IV Day -6 Total Body Irradiation (TBI): - 200 cGy Day -1 for patients who have received cytotoxic chemotherapy within the last 3 months or an autologous transplant within 24 months of enrollment; - 300 cGY Day -1 for patients who have not received cytotoxic chemotherapy within 3 months of enrollment or an autologous transplant within 24 months of enrollment Day 0 will be the day of the double UCB transplant The GVHD prophylaxis regimen consists of: Cyclosporine beginning Day -3 with dose adjusted to maintain a trough level of 200-400 ng/mL. Tacrolimus (trough level of 5-15 ng/mL) may be substituted for cyclosporine if the patient is intolerant of cyclosporine or per institutional practice. Mycophenolate mofetil (MMF) 15 mg/kg po TID, maximum dose 1 g po TID beginning Day-3 until Day 35 Supportive care includes: - Filgrastim (G-CSF) 5 mcg/kg/day beginning Day 1 until ANC >1500/mm3 for 3 consecutive measurements on at least two different days | Participants will receive haploidentical bone marrow transplant using a reduced intensity conditioning regimen. Haploidentical Bone Marrow Transplant: The conditioning regimen consists of: Fludarabine (Flu)30 mg/m2 IV Days -6, -5, -4, -3, -2 Cyclophosphamide (Cy) 14.5 mg/kg IV Days -6, -5 Total body irradiation (TBI) 200cGy Day -1 Day 0 will be the day of infusion of non-T-cell depleted bone marrow The GVHD prophylaxis regimen consists of: Cy 50 mg/kg IV Days 3, 4 Tacrolimus (IV or PO) beginning Day 5 with dose adjusted to maintain a trough level of 5-15 ng/mL. Cyclosporine (trough level of 200-400 ng/mL) may be substituted for tacrolimus if the patient is intolerant of tacrolimus or per institutional practice. Mycophenolate mofetil (MMF) 15 mg/kg po three times a day, maximum dose 1 g po TID beginning Day 5 until Day 35 Supportive care includes: - Filgrastim (G-CSF) 5 mcg/kg/day beginning Day 5 until ANC >1500/mm3 for 3 consecutive measurements on at least two different days |
| Measure Participants | 175 | 167 |
| Number (95% Confidence Interval) [percentage of participants] |
22.0
11.8%
|
26.2
14.4%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | dUCB, Haplo-BM |
|---|---|---|
| Comments | The null hypothesis is that there is no difference between the cGVHD probabilities post-transplantation for dUCB vs. haplo-BM. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.361 |
| Comments | Statistical significance was determined using a pre-specified threshold of 0.05. | |
| Method | Gray's test for cumulative Incidence | |
| Comments | Estimate cumulative incidence functions from competing risks data and test equality of 2 trt grps. Death before cGVHD is competing risk. | |
| Title | Percentage of Participants With Overall Survival |
|---|---|
| Description | Overall survival is defined as the time interval between date of randomization and death from any cause or for surviving patients, to last follow-up. The time interval between date of transplant and death from any cause or for surviving patients, to last follow-up are also analyzed. |
| Time Frame | Year 2 |
Outcome Measure Data
| Analysis Population Description |
|---|
| The randomized or transplanted participants are included in the analyses. |
| Arm/Group Title | dUCB | Haplo-BM |
|---|---|---|
| Arm/Group Description | Participants will receive double unrelated cord blood transplant using a reduced intensity conditioning regimen. Double unrelated cord blood Transplant: The conditioning regimen consists of: Fludarabine 40 mg/m2 IV Days -6, -5, -4, -3, -2 Cyclophosphamide 50 mg/kg IV Day -6 Total Body Irradiation (TBI): - 200 cGy Day -1 for patients who have received cytotoxic chemotherapy within the last 3 months or an autologous transplant within 24 months of enrollment; - 300 cGY Day -1 for patients who have not received cytotoxic chemotherapy within 3 months of enrollment or an autologous transplant within 24 months of enrollment Day 0 will be the day of the double UCB transplant The GVHD prophylaxis regimen consists of: Cyclosporine beginning Day -3 with dose adjusted to maintain a trough level of 200-400 ng/mL. Tacrolimus (trough level of 5-15 ng/mL) may be substituted for cyclosporine if the patient is intolerant of cyclosporine or per institutional practice. Mycophenolate mofetil (MMF) 15 mg/kg po TID, maximum dose 1 g po TID beginning Day-3 until Day 35 Supportive care includes: - Filgrastim (G-CSF) 5 mcg/kg/day beginning Day 1 until ANC >1500/mm3 for 3 consecutive measurements on at least two different days | Participants will receive haploidentical bone marrow transplant using a reduced intensity conditioning regimen. Haploidentical Bone Marrow Transplant: The conditioning regimen consists of: Fludarabine (Flu)30 mg/m2 IV Days -6, -5, -4, -3, -2 Cyclophosphamide (Cy) 14.5 mg/kg IV Days -6, -5 Total body irradiation (TBI) 200cGy Day -1 Day 0 will be the day of infusion of non-T-cell depleted bone marrow The GVHD prophylaxis regimen consists of: Cy 50 mg/kg IV Days 3, 4 Tacrolimus (IV or PO) beginning Day 5 with dose adjusted to maintain a trough level of 5-15 ng/mL. Cyclosporine (trough level of 200-400 ng/mL) may be substituted for tacrolimus if the patient is intolerant of tacrolimus or per institutional practice. Mycophenolate mofetil (MMF) 15 mg/kg po three times a day, maximum dose 1 g po TID beginning Day 5 until Day 35 Supportive care includes: - Filgrastim (G-CSF) 5 mcg/kg/day beginning Day 5 until ANC >1500/mm3 for 3 consecutive measurements on at least two different days |
| Measure Participants | 186 | 182 |
| OS post-randomization |
45.7
24.6%
|
57.0
31.3%
|
| OS post-transplant |
46.8
25.2%
|
59.4
32.6%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | dUCB, Haplo-BM |
|---|---|---|
| Comments | The null hypothesis is that there is no difference between the OS probabilities at year 2 post-randomization for dUCB vs. haplo-BM. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0373 |
| Comments | Statistical significance was determined using a pre-specified threshold of 0.05. | |
| Method | Log Rank | |
| Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | dUCB, Haplo-BM |
|---|---|---|
| Comments | The null hypothesis is that there is no difference between the OS probabilities at year 2 post-transplant for dUCB vs. haplo-BM. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0235 |
| Comments | Statistical significance was determined using a pre-specified threshold of 0.05. | |
| Method | Log Rank | |
| Comments | ||
| Title | Percentage of Participants With Treatment-related Mortality (TRM) |
|---|---|
| Description | The cumulative incidence of TRM will be estimated, event for this endpoint is death without evidence of disease progression or recurrence. |
| Time Frame | Day 100, Day 180, Year 1, and Year 2 |
Outcome Measure Data
| Analysis Population Description |
|---|
| The randomized or transplanted participants are included in the analyses. |
| Arm/Group Title | dUCB | Haplo-BM |
|---|---|---|
| Arm/Group Description | Participants will receive double unrelated cord blood transplant using a reduced intensity conditioning regimen. Double unrelated cord blood Transplant: The conditioning regimen consists of: Fludarabine 40 mg/m2 IV Days -6, -5, -4, -3, -2 Cyclophosphamide 50 mg/kg IV Day -6 Total Body Irradiation (TBI): - 200 cGy Day -1 for patients who have received cytotoxic chemotherapy within the last 3 months or an autologous transplant within 24 months of enrollment; - 300 cGY Day -1 for patients who have not received cytotoxic chemotherapy within 3 months of enrollment or an autologous transplant within 24 months of enrollment Day 0 will be the day of the double UCB transplant The GVHD prophylaxis regimen consists of: Cyclosporine beginning Day -3 with dose adjusted to maintain a trough level of 200-400 ng/mL. Tacrolimus (trough level of 5-15 ng/mL) may be substituted for cyclosporine if the patient is intolerant of cyclosporine or per institutional practice. Mycophenolate mofetil (MMF) 15 mg/kg po TID, maximum dose 1 g po TID beginning Day-3 until Day 35 Supportive care includes: - Filgrastim (G-CSF) 5 mcg/kg/day beginning Day 1 until ANC >1500/mm3 for 3 consecutive measurements on at least two different days | Participants will receive haploidentical bone marrow transplant using a reduced intensity conditioning regimen. Haploidentical Bone Marrow Transplant: The conditioning regimen consists of: Fludarabine (Flu)30 mg/m2 IV Days -6, -5, -4, -3, -2 Cyclophosphamide (Cy) 14.5 mg/kg IV Days -6, -5 Total body irradiation (TBI) 200cGy Day -1 Day 0 will be the day of infusion of non-T-cell depleted bone marrow The GVHD prophylaxis regimen consists of: Cy 50 mg/kg IV Days 3, 4 Tacrolimus (IV or PO) beginning Day 5 with dose adjusted to maintain a trough level of 5-15 ng/mL. Cyclosporine (trough level of 200-400 ng/mL) may be substituted for tacrolimus if the patient is intolerant of tacrolimus or per institutional practice. Mycophenolate mofetil (MMF) 15 mg/kg po three times a day, maximum dose 1 g po TID beginning Day 5 until Day 35 Supportive care includes: - Filgrastim (G-CSF) 5 mcg/kg/day beginning Day 5 until ANC >1500/mm3 for 3 consecutive measurements on at least two different days |
| Measure Participants | 186 | 182 |
| Day 100 Post Randomization |
5.5
3%
|
3.4
1.9%
|
| Day 100 Post Transplant |
6.9
3.7%
|
3.6
2%
|
| Day 180 Post Randomization |
10.4
5.6%
|
4.5
2.5%
|
| Day 180 Post Transplant |
13.1
7%
|
4.8
2.6%
|
| 1 Year Post Randomization |
14.8
8%
|
6.7
3.7%
|
| 1 Year Post Transplant |
16.0
8.6%
|
7.9
4.3%
|
| 2 Year Post Randomization |
17.9
9.6%
|
10.5
5.8%
|
| 2 Year Post Transplant |
18.6
10%
|
10.7
5.9%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | dUCB, Haplo-BM |
|---|---|---|
| Comments | The null hypothesis is that there is no difference between the TRM probabilities post-randomization for dUCB vs. haplo-BM. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.039 |
| Comments | Statistical significance was determined using a pre-specified threshold of 0.05. | |
| Method | Gray's test for cumulative Incidence | |
| Comments | Estimate cumulative incidence functions from competing risks data and test equality across the two treatment groups. | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | dUCB, Haplo-BM |
|---|---|---|
| Comments | The null hypothesis is that there is no difference between the TRM probabilities post-transplantation for dUCB vs. haplo-BM | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.030 |
| Comments | Statistical significance was determined using a pre-specified threshold of 0.05. | |
| Method | Gray's test for cumulative Incidence | |
| Comments | Estimate cumulative incidence functions from competing risks data and test equality across the two treatment groups. | |
| Title | Percentage of Participants With Relapse/Progression |
|---|---|
| Description | Incidence of relapse/progression will be estimated using cumulative incidence function, treating death in remission as a competing risk. Relapse is defined by either morphological or cytogenetic evidence of acute leukemia consistent with pre-transplant features, or radiologic evidence of progressive lymphoma. When in doubt, the diagnosis of recurrent or progressive lymphoma should be documented by tissue biopsy. Minimal residual disease will not be considered evidence of relapse, however, minimal residual disease that progresses will be considered as relapse and the date of relapse will be the date of detection of minimal residual disease that prompted an intervention by the treating physician. Finally, institution of any therapy to treat persistent, progressive or relapsed disease, including withdrawal of immunosuppressive therapy or DLI, will be considered evidence of relapse/progression regardless of whether the criteria described above are met. |
| Time Frame | Year 1, year 2 |
Outcome Measure Data
| Analysis Population Description |
|---|
| The randomized or transplanted participants are included in the analyses. |
| Arm/Group Title | dUCB | Haplo-BM |
|---|---|---|
| Arm/Group Description | Participants will receive double unrelated cord blood transplant using a reduced intensity conditioning regimen. Double unrelated cord blood Transplant: The conditioning regimen consists of: Fludarabine 40 mg/m2 IV Days -6, -5, -4, -3, -2 Cyclophosphamide 50 mg/kg IV Day -6 Total Body Irradiation (TBI): - 200 cGy Day -1 for patients who have received cytotoxic chemotherapy within the last 3 months or an autologous transplant within 24 months of enrollment; - 300 cGY Day -1 for patients who have not received cytotoxic chemotherapy within 3 months of enrollment or an autologous transplant within 24 months of enrollment Day 0 will be the day of the double UCB transplant The GVHD prophylaxis regimen consists of: Cyclosporine beginning Day -3 with dose adjusted to maintain a trough level of 200-400 ng/mL. Tacrolimus (trough level of 5-15 ng/mL) may be substituted for cyclosporine if the patient is intolerant of cyclosporine or per institutional practice. Mycophenolate mofetil (MMF) 15 mg/kg po TID, maximum dose 1 g po TID beginning Day-3 until Day 35 Supportive care includes: - Filgrastim (G-CSF) 5 mcg/kg/day beginning Day 1 until ANC >1500/mm3 for 3 consecutive measurements on at least two different days | Participants will receive haploidentical bone marrow transplant using a reduced intensity conditioning regimen. Haploidentical Bone Marrow Transplant: The conditioning regimen consists of: Fludarabine (Flu)30 mg/m2 IV Days -6, -5, -4, -3, -2 Cyclophosphamide (Cy) 14.5 mg/kg IV Days -6, -5 Total body irradiation (TBI) 200cGy Day -1 Day 0 will be the day of infusion of non-T-cell depleted bone marrow The GVHD prophylaxis regimen consists of: Cy 50 mg/kg IV Days 3, 4 Tacrolimus (IV or PO) beginning Day 5 with dose adjusted to maintain a trough level of 5-15 ng/mL. Cyclosporine (trough level of 200-400 ng/mL) may be substituted for tacrolimus if the patient is intolerant of tacrolimus or per institutional practice. Mycophenolate mofetil (MMF) 15 mg/kg po three times a day, maximum dose 1 g po TID beginning Day 5 until Day 35 Supportive care includes: - Filgrastim (G-CSF) 5 mcg/kg/day beginning Day 5 until ANC >1500/mm3 for 3 consecutive measurements on at least two different days |
| Measure Participants | 186 | 182 |
| 1 Year Post Randomization |
41.1
22.1%
|
37.6
20.7%
|
| 1 Year Post Transplant |
38.7
20.8%
|
35.1
19.3%
|
| 2 Year Post Randomization |
47.1
25.3%
|
48.4
26.6%
|
| 2 Year Post Transplant |
43.5
23.4%
|
45.8
25.2%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | dUCB, Haplo-BM |
|---|---|---|
| Comments | The null hypothesis is that there is no difference between the relapse/progression probabilities post-randomization for dUCB vs. haplo-BM. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.968 |
| Comments | Statistical significance was determined using a pre-specified threshold of 0.05. | |
| Method | Gray's test for cumulative Incidence | |
| Comments | Estimate cumulative incidence functions from competing risks data and test equality of 2 trt grps. Death prior to relapse is competing risk. | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | dUCB, Haplo-BM |
|---|---|---|
| Comments | The null hypothesis is that there is no difference between the relapse/progression probabilities post- transplantation for dUCB vs. haplo-BM. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.907 |
| Comments | Statistical significance was determined using a pre-specified threshold of 0.05. | |
| Method | Gray's test for cumulative Incidence | |
| Comments | Estimate cumulative incidence functions from competing risks data and test equality of 2 trt grps. Death prior to relapse is competing risk. | |
| Title | Toxicities |
|---|---|
| Description | They are all Grade ≥ 3 toxicities based on NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4. |
| Time Frame | Day 28, Day 56, Day 180, 1 year, and 2 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| The transplanted participants are included in the analysis. A total of 26 patients (11 on the dUCB arm and 15 on the Haplo-BM arm) who did not proceed to the study transplant are excluded. |
| Arm/Group Title | dUCB | Haplo-BM |
|---|---|---|
| Arm/Group Description | Participants will receive double unrelated cord blood transplant using a reduced intensity conditioning regimen. Double unrelated cord blood Transplant: The conditioning regimen consists of: Fludarabine 40 mg/m2 IV Days -6, -5, -4, -3, -2 Cyclophosphamide 50 mg/kg IV Day -6 Total Body Irradiation (TBI): - 200 cGy Day -1 for patients who have received cytotoxic chemotherapy within the last 3 months or an autologous transplant within 24 months of enrollment; - 300 cGY Day -1 for patients who have not received cytotoxic chemotherapy within 3 months of enrollment or an autologous transplant within 24 months of enrollment Day 0 will be the day of the double UCB transplant The GVHD prophylaxis regimen consists of: Cyclosporine beginning Day -3 with dose adjusted to maintain a trough level of 200-400 ng/mL. Tacrolimus (trough level of 5-15 ng/mL) may be substituted for cyclosporine if the patient is intolerant of cyclosporine or per institutional practice. Mycophenolate mofetil (MMF) 15 mg/kg po TID, maximum dose 1 g po TID beginning Day-3 until Day 35 Supportive care includes: - Filgrastim (G-CSF) 5 mcg/kg/day beginning Day 1 until ANC >1500/mm3 for 3 consecutive measurements on at least two different days | Participants will receive haploidentical bone marrow transplant using a reduced intensity conditioning regimen. Haploidentical Bone Marrow Transplant: The conditioning regimen consists of: Fludarabine (Flu)30 mg/m2 IV Days -6, -5, -4, -3, -2 Cyclophosphamide (Cy) 14.5 mg/kg IV Days -6, -5 Total body irradiation (TBI) 200cGy Day -1 Day 0 will be the day of infusion of non-T-cell depleted bone marrow The GVHD prophylaxis regimen consists of: Cy 50 mg/kg IV Days 3, 4 Tacrolimus (IV or PO) beginning Day 5 with dose adjusted to maintain a trough level of 5-15 ng/mL. Cyclosporine (trough level of 200-400 ng/mL) may be substituted for tacrolimus if the patient is intolerant of tacrolimus or per institutional practice. Mycophenolate mofetil (MMF) 15 mg/kg po three times a day, maximum dose 1 g po TID beginning Day 5 until Day 35 Supportive care includes: - Filgrastim (G-CSF) 5 mcg/kg/day beginning Day 5 until ANC >1500/mm3 for 3 consecutive measurements on at least two different days |
| Measure Participants | 175 | 167 |
| Toxicities Reported at Day 0-28 : Infusion Toxicities |
19
|
7
|
| Toxicities Reported at Day 0-28 : Oral Mucositis |
2
|
2
|
| Toxicities Reported at Day 0-28 : Cystitis Noninfective |
1
|
1
|
| Toxicities Reported at Day 0-28 : Acute Kidney Injury |
4
|
4
|
| Toxicities Reported at Day 0-28 : Chronic Kidney Disease |
0
|
2
|
| Toxicities Reported at Day 0-28 : Hemorrhage |
2
|
6
|
| Toxicities Reported at Day 0-28 : Hypotension |
12
|
10
|
| Toxicities Reported at Day 0-28 : Cardiac Arrhythmia |
6
|
6
|
| Toxicities Reported at Day 0-28 : Left Ventricular Systolic Dysfunction |
2
|
0
|
| Toxicities Reported at Day 0-28 : Somnolence |
2
|
1
|
| Toxicities Reported at Day 0-28 : Thrombotic Thrombocytopenic Purpura |
3
|
1
|
| Toxicities Reported at Day 0-28 : Capillary Leak Syndrome |
1
|
0
|
| Toxicities Reported at Day 0-28 : Hypoxia |
9
|
9
|
| Toxicities Reported at Day 0-28 : Dyspnea |
7
|
0
|
| Toxicities Reported at Day 0-28 : ALT |
3
|
6
|
| Toxicities Reported at Day 0-28 : AST |
2
|
4
|
| Toxicities Reported at Day 0-28 : Bilirubin |
3
|
1
|
| Toxicities Reported at Day 0-28 : Alkaline Phosphatase |
4
|
1
|
| Toxicities Reported at Day 0-28 : Abnormal Liver Symptoms |
2
|
4
|
| Toxicities Reported at Day 0-28 : Received Dialysis |
2
|
1
|
| Toxicities Reported at Day 0-28 : Seizure |
0
|
0
|
| Toxicities Reported at Day 29-56 : Infusion Toxicities |
0
|
0
|
| Toxicities Reported at Day 29-56 : Oral Mucositis |
3
|
2
|
| Toxicities Reported at Day 29-56 : Cystitis Noninfective |
2
|
1
|
| Toxicities Reported at Day 29-56 : Acute Kidney Injury |
3
|
3
|
| Toxicities Reported at Day 29-56 : Chronic Kidney Disease |
2
|
3
|
| Toxicities Reported at Day 29-56 : Hemorrhage |
2
|
4
|
| Toxicities Reported at Day 29-56 : Hypotension |
5
|
5
|
| Toxicities Reported at Day 29-56 : Cardiac Arrhythmia |
3
|
2
|
| Toxicities Reported at Day 29-56 : Left Ventricular Systolic Dysfunction |
2
|
1
|
| Toxicities Reported at Day 29-56 : Somnolence |
4
|
1
|
| Toxicities Reported at Day 29-56 : Thrombotic Thrombocytopenic Purpura |
6
|
1
|
| Toxicities Reported at Day 29-56 : Capillary Leak Syndrome |
0
|
1
|
| Toxicities Reported at Day 29-56 : Hypoxia |
6
|
5
|
| Toxicities Reported at Day 29-56 : Dyspnea |
9
|
6
|
| Toxicities Reported at Day 29-56 : ALT |
7
|
1
|
| Toxicities Reported at Day 29-56 : AST |
5
|
1
|
| Toxicities Reported at Day 29-56 : Bilirubin |
3
|
1
|
| Toxicities Reported at Day 29-56 : Alkaline Phosphatase |
2
|
0
|
| Toxicities Reported at Day 29-56 : Abnormal Liver Symptoms |
4
|
4
|
| Toxicities Reported at Day 29-56 : Received Dialysis |
3
|
2
|
| Toxicities Reported at Day 29-56 : Seizure |
0
|
0
|
| Toxicities Reported at Day 57-180 : Infusion Toxicities |
0
|
0
|
| Toxicities Reported at Day 57-180 : Oral Mucositis |
1
|
1
|
| Toxicities Reported at Day 57-180 : Cystitis Noninfective |
1
|
2
|
| Toxicities Reported at Day 57-180 : Acute Kidney Injury |
9
|
7
|
| Toxicities Reported at Day 57-180 : Chronic Kidney Disease |
1
|
4
|
| Toxicities Reported at Day 57-180 : Hemorrhage |
3
|
6
|
| Toxicities Reported at Day 57-180 : Hypotension |
12
|
10
|
| Toxicities Reported at Day 57-180 : Cardiac Arrhythmia |
4
|
3
|
| Toxicities Reported at Day 57-180 : Left Ventricular Systolic Dysfunction |
2
|
1
|
| Toxicities Reported at Day 57-180 : Somnolence |
5
|
2
|
| Toxicities Reported at Day 57-180 : Thrombotic Thrombocytopenic Purpura |
3
|
1
|
| Toxicities Reported at Day 57-180 : Capillary Leak Syndrome |
1
|
0
|
| Toxicities Reported at Day 57-180 : Hypoxia |
22
|
7
|
| Toxicities Reported at Day 57-180 : Dyspnea |
21
|
8
|
| Toxicities Reported at Day 57-180 : ALT |
6
|
4
|
| Toxicities Reported at Day 57-180 : AST |
8
|
5
|
| Toxicities Reported at Day 57-180 : Bilirubin |
8
|
3
|
| Toxicities Reported at Day 57-180 : Alkaline Phosphatase |
4
|
4
|
| Toxicities Reported at Day 57-180 : Abnormal Liver Symptoms |
6
|
5
|
| Toxicities Reported at Day 57-180 : Received Dialysis |
2
|
2
|
| Toxicities Reported at Day 57-180 : Seizure |
0
|
0
|
| Toxicities Reported at Day 181-365 : Infusion Toxicities |
0
|
0
|
| Toxicities Reported at Day 181-365 : Oral Mucositis |
2
|
0
|
| Toxicities Reported at Day 181-365 : Cystitis Noninfective |
2
|
1
|
| Toxicities Reported at Day 181-365 : Acute Kidney Injury |
4
|
6
|
| Toxicities Reported at Day 181-365 : Chronic Kidney Disease |
2
|
2
|
| Toxicities Reported at Day 181-365 : Hemorrhage |
3
|
5
|
| Toxicities Reported at Day 181-365 : Hypotension |
3
|
9
|
| Toxicities Reported at Day 181-365 : Cardiac Arrhythmia |
4
|
5
|
| Toxicities Reported at Day 181-365 : Left Ventricular Systolic Dysfunction |
2
|
0
|
| Toxicities Reported at Day 181-365 : Somnolence |
3
|
5
|
| Toxicities Reported at Day 181-365 : Thrombotic Thrombocytopenic Purpura |
4
|
1
|
| Toxicities Reported at Day 181-365 : Capillary Leak Syndrome |
0
|
1
|
| Toxicities Reported at Day 181-365 : Hypoxia |
8
|
10
|
| Toxicities Reported at Day 181-365 : Dyspnea |
10
|
11
|
| Toxicities Reported at Day 181-365 : ALT |
4
|
4
|
| Toxicities Reported at Day 181-365 : AST |
5
|
4
|
| Toxicities Reported at Day 181-365 : Bilirubin |
5
|
5
|
| Toxicities Reported at Day 181-365 : Alkaline Phosphatase |
6
|
4
|
| Toxicities Reported at Day 181-365 : Abnormal Liver Symptoms |
3
|
3
|
| Toxicities Reported at Day 181-365 : Received Dialysis |
1
|
4
|
| Toxicities Reported at Day 181-365 : Seizure |
0
|
2
|
| Toxicities Reported at Day 363-730 : Infusion Toxicities |
0
|
0
|
| Toxicities Reported at Day 363-730 : Oral Mucositis |
3
|
1
|
| Toxicities Reported at Day 363-730 : Cystitis Noninfective |
1
|
2
|
| Toxicities Reported at Day 363-730 : Acute Kidney Injury |
3
|
3
|
| Toxicities Reported at Day 363-730 : Chronic Kidney Disease |
1
|
0
|
| Toxicities Reported at Day 363-730 : Hemorrhage |
2
|
0
|
| Toxicities Reported at Day 363-730 : Hypotension |
6
|
5
|
| Toxicities Reported at Day 363-730 : Cardiac Arrhythmia |
0
|
2
|
| Toxicities Reported at Day 363-730 : Left Ventricular Systolic Dysfunction |
0
|
1
|
| Toxicities Reported at Day 363-730 : Somnolence |
0
|
4
|
| Toxicities Reported at Day 363-730 : Thrombotic Thrombocytopenic Purpura |
1
|
0
|
| Toxicities Reported at Day 363-730 : Capillary Leak Syndrome |
0
|
0
|
| Toxicities Reported at Day 363-730 : Hypoxia |
6
|
7
|
| Toxicities Reported at Day 363-730 : Dyspnea |
4
|
8
|
| Toxicities Reported at Day 363-730 : ALT |
1
|
4
|
| Toxicities Reported at Day 363-730 : AST |
0
|
4
|
| Toxicities Reported at Day 363-730 : Bilirubin |
1
|
3
|
| Toxicities Reported at Day 363-730 : Alkaline Phosphatase |
1
|
3
|
| Toxicities Reported at Day 363-730 : Abnormal Liver Symptoms |
2
|
5
|
| Toxicities Reported at Day 363-730 : Received Dialysis |
1
|
2
|
| Toxicities Reported at Day 363-730 : Seizure |
0
|
1
|
| Overall Toxicities Reported Day 0-730: Infusion Toxicities |
19
|
7
|
| Overall Toxicities Reported Day 0-730: Oral Mucositis |
9
|
6
|
| Overall Toxicities Reported Day 0-730: Cystitis Noninfective |
6
|
6
|
| Overall Toxicities Reported Day 0-730: Acute Kidney Injury |
22
|
19
|
| Overall Toxicities Reported Day 0-730: Chronic Kidney Disease |
5
|
9
|
| Overall Toxicities Reported Day 0-730: Hemorrhage |
12
|
12
|
| Overall Toxicities Reported Day 0-730: Hypotension |
31
|
32
|
| Overall Toxicities Reported Day 0-730: Cardiac Arrhythmia |
14
|
14
|
| Overall Toxicities Reported Day 0-730: Left Ventricular Systolic Dysfunction |
8
|
3
|
| Overall Toxicities Reported Day 0-730: Somnolence |
13
|
13
|
| Overall Toxicities Reported Day 0-730: Thrombotic Thrombocytopenic Purpura |
14
|
4
|
| Overall Toxicities Reported Day 0-730: Capillary Leak Syndrome |
2
|
2
|
| Overall Toxicities Reported Day 0-730: Hypoxia |
41
|
34
|
| Overall Toxicities Reported Day 0-730: Dyspnea |
38
|
35
|
| Overall Toxicities Reported Day 0-730: ALT |
18
|
19
|
| Overall Toxicities Reported Day 0-730: AST |
19
|
18
|
| Overall Toxicities Reported Day 0-730: Bilirubin |
18
|
13
|
| Overall Toxicities Reported Day 0-730: Alkaline Phosphatase |
14
|
12
|
| Overall Toxicities Reported Day 0-730: Abnormal Liver Symptoms |
15
|
18
|
| Overall Toxicities Reported Day 0-730: Received Dialysis |
8
|
9
|
| Overall Toxicities Reported Day 0-730: Seizure |
0
|
3
|
| Title | Participants With Infections |
|---|---|
| Description | All Grade 2 and 3 infections will be reported. Grade 1 CMV infections through Day 56 will also be reported. |
| Time Frame | Up to 2 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| The transplanted participants are included in the analysis. |
| Arm/Group Title | dUCB | Haplo-BM |
|---|---|---|
| Arm/Group Description | Participants will receive double unrelated cord blood transplant using a reduced intensity conditioning regimen. Double unrelated cord blood Transplant: The conditioning regimen consists of: Fludarabine 40 mg/m2 IV Days -6, -5, -4, -3, -2 Cyclophosphamide 50 mg/kg IV Day -6 Total Body Irradiation (TBI): - 200 cGy Day -1 for patients who have received cytotoxic chemotherapy within the last 3 months or an autologous transplant within 24 months of enrollment; - 300 cGY Day -1 for patients who have not received cytotoxic chemotherapy within 3 months of enrollment or an autologous transplant within 24 months of enrollment Day 0 will be the day of the double UCB transplant The GVHD prophylaxis regimen consists of: Cyclosporine beginning Day -3 with dose adjusted to maintain a trough level of 200-400 ng/mL. Tacrolimus (trough level of 5-15 ng/mL) may be substituted for cyclosporine if the patient is intolerant of cyclosporine or per institutional practice. Mycophenolate mofetil (MMF) 15 mg/kg po TID, maximum dose 1 g po TID beginning Day-3 until Day 35 Supportive care includes: - Filgrastim (G-CSF) 5 mcg/kg/day beginning Day 1 until ANC >1500/mm3 for 3 consecutive measurements on at least two different days | Participants will receive haploidentical bone marrow transplant using a reduced intensity conditioning regimen. Haploidentical Bone Marrow Transplant: The conditioning regimen consists of: Fludarabine (Flu)30 mg/m2 IV Days -6, -5, -4, -3, -2 Cyclophosphamide (Cy) 14.5 mg/kg IV Days -6, -5 Total body irradiation (TBI) 200cGy Day -1 Day 0 will be the day of infusion of non-T-cell depleted bone marrow The GVHD prophylaxis regimen consists of: Cy 50 mg/kg IV Days 3, 4 Tacrolimus (IV or PO) beginning Day 5 with dose adjusted to maintain a trough level of 5-15 ng/mL. Cyclosporine (trough level of 200-400 ng/mL) may be substituted for tacrolimus if the patient is intolerant of tacrolimus or per institutional practice. Mycophenolate mofetil (MMF) 15 mg/kg po three times a day, maximum dose 1 g po TID beginning Day 5 until Day 35 Supportive care includes: - Filgrastim (G-CSF) 5 mcg/kg/day beginning Day 5 until ANC >1500/mm3 for 3 consecutive measurements on at least two different days |
| Measure Participants | 175 | 167 |
| # Patients with Infections |
102
54.8%
|
102
56%
|
| Grade 1 CMV through Day 56 |
94
50.5%
|
84
46.2%
|
| Title | Hospital Admission and Length of Stay |
|---|---|
| Description | Total Time Alive and Not Hospitalized within 6 Months Post Randomization |
| Time Frame | Month 6 |
Outcome Measure Data
| Analysis Population Description |
|---|
| The randomized participants are included in the analysis. |
| Arm/Group Title | dUCB | Haplo-BM |
|---|---|---|
| Arm/Group Description | Participants will receive double unrelated cord blood transplant using a reduced intensity conditioning regimen. Double unrelated cord blood Transplant: The conditioning regimen consists of: Fludarabine 40 mg/m2 IV Days -6, -5, -4, -3, -2 Cyclophosphamide 50 mg/kg IV Day -6 Total Body Irradiation (TBI): - 200 cGy Day -1 for patients who have received cytotoxic chemotherapy within the last 3 months or an autologous transplant within 24 months of enrollment; - 300 cGY Day -1 for patients who have not received cytotoxic chemotherapy within 3 months of enrollment or an autologous transplant within 24 months of enrollment Day 0 will be the day of the double UCB transplant The GVHD prophylaxis regimen consists of: Cyclosporine beginning Day -3 with dose adjusted to maintain a trough level of 200-400 ng/mL. Tacrolimus (trough level of 5-15 ng/mL) may be substituted for cyclosporine if the patient is intolerant of cyclosporine or per institutional practice. Mycophenolate mofetil (MMF) 15 mg/kg po TID, maximum dose 1 g po TID beginning Day-3 until Day 35 Supportive care includes: - Filgrastim (G-CSF) 5 mcg/kg/day beginning Day 1 until ANC >1500/mm3 for 3 consecutive measurements on at least two different days | Participants will receive haploidentical bone marrow transplant using a reduced intensity conditioning regimen. Haploidentical Bone Marrow Transplant: The conditioning regimen consists of: Fludarabine (Flu)30 mg/m2 IV Days -6, -5, -4, -3, -2 Cyclophosphamide (Cy) 14.5 mg/kg IV Days -6, -5 Total body irradiation (TBI) 200cGy Day -1 Day 0 will be the day of infusion of non-T-cell depleted bone marrow The GVHD prophylaxis regimen consists of: Cy 50 mg/kg IV Days 3, 4 Tacrolimus (IV or PO) beginning Day 5 with dose adjusted to maintain a trough level of 5-15 ng/mL. Cyclosporine (trough level of 200-400 ng/mL) may be substituted for tacrolimus if the patient is intolerant of tacrolimus or per institutional practice. Mycophenolate mofetil (MMF) 15 mg/kg po three times a day, maximum dose 1 g po TID beginning Day 5 until Day 35 Supportive care includes: - Filgrastim (G-CSF) 5 mcg/kg/day beginning Day 5 until ANC >1500/mm3 for 3 consecutive measurements on at least two different days |
| Measure Participants | 186 | 182 |
| Mean (Standard Deviation) [Days] |
127.1
(48.3)
|
141.2
(42.5)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | dUCB, Haplo-BM |
|---|---|---|
| Comments | The null hypothesis is that there is no difference between the total duration of hospitalization within 6 months post-randomization for dUCB vs. haplo-BM. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0003 |
| Comments | Statistical significance was determined using a pre-specified threshold of 0.05. | |
| Method | Wilcoxon (Mann-Whitney) | |
| Comments | ||
Adverse Events
| Time Frame | Adverse event reporting and monitoring were conducted throughout the study, up to 2 years. | |||
|---|---|---|---|---|
| Adverse Event Reporting Description | Adverse event (AE) reporting was conducted according to the BMT CTN's manual of operating procedures (MOP). Unexpected, grade 3-5 AE were reported through an expedited AE reporting system. Expected AEs were reported using National Cancer Institute (NCI)'s Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 at regular intervals and reported in the secondary outcome "Toxicities". All fatal (Grade 5) expected adverse events were reported in an expedited manner. | |||
| Arm/Group Title | dUCB | Haplo-BM | ||
| Arm/Group Description | Participants will receive double unrelated cord blood transplant using a reduced intensity conditioning regimen. Double unrelated cord blood Transplant: The conditioning regimen consists of: Fludarabine 40 mg/m2 IV Days -6, -5, -4, -3, -2 Cyclophosphamide 50 mg/kg IV Day -6 Total Body Irradiation (TBI): - 200 cGy Day -1 for patients who have received cytotoxic chemotherapy within the last 3 months or an autologous transplant within 24 months of enrollment; - 300 cGY Day -1 for patients who have not received cytotoxic chemotherapy within 3 months of enrollment or an autologous transplant within 24 months of enrollment Day 0 will be the day of the double UCB transplant The GVHD prophylaxis regimen consists of: Cyclosporine beginning Day -3 with dose adjusted to maintain a trough level of 200-400 ng/mL. Tacrolimus (trough level of 5-15 ng/mL) may be substituted for cyclosporine if the patient is intolerant of cyclosporine or per institutional practice. Mycophenolate mofetil (MMF) 15 mg/kg po TID, maximum dose 1 g po TID beginning Day-3 until Day 35 Supportive care includes: - Filgrastim (G-CSF) 5 mcg/kg/day beginning Day 1 until ANC >1500/mm3 for 3 consecutive measurements on at least two different days | Participants will receive haploidentical bone marrow transplant using a reduced intensity conditioning regimen. Haploidentical Bone Marrow Transplant: The conditioning regimen consists of: Fludarabine (Flu)30 mg/m2 IV Days -6, -5, -4, -3, -2 Cyclophosphamide (Cy) 14.5 mg/kg IV Days -6, -5 Total body irradiation (TBI) 200cGy Day -1 Day 0 will be the day of infusion of non-T-cell depleted bone marrow The GVHD prophylaxis regimen consists of: Cy 50 mg/kg IV Days 3, 4 Tacrolimus (IV or PO) beginning Day 5 with dose adjusted to maintain a trough level of 5-15 ng/mL. Cyclosporine (trough level of 200-400 ng/mL) may be substituted for tacrolimus if the patient is intolerant of tacrolimus or per institutional practice. Mycophenolate mofetil (MMF) 15 mg/kg po three times a day, maximum dose 1 g po TID beginning Day 5 until Day 35 Supportive care includes: - Filgrastim (G-CSF) 5 mcg/kg/day beginning Day 5 until ANC >1500/mm3 for 3 consecutive measurements on at least two different days | ||
All Cause Mortality |
||||
| dUCB | Haplo-BM | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 97/186 (52.2%) | 74/182 (40.7%) | ||
Serious Adverse Events |
||||
| dUCB | Haplo-BM | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 4/186 (2.2%) | 9/182 (4.9%) | ||
| Cardiac disorders | ||||
| Cardio-respiratory arrest | 1/186 (0.5%) | 1 | 0/182 (0%) | 0 |
| Injury, poisoning and procedural complications | ||||
| Arterial injury | 1/186 (0.5%) | 1 | 0/182 (0%) | 0 |
| Infusion related reaction | 1/186 (0.5%) | 1 | 0/182 (0%) | 0 |
| Vascular access complication | 0/186 (0%) | 0 | 1/182 (0.5%) | 1 |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||
| Acute myeloid leukemia | 0/186 (0%) | 0 | 1/182 (0.5%) | 1 |
| Nervous system disorders | ||||
| Central nervous system lesion | 0/186 (0%) | 0 | 1/182 (0.5%) | 1 |
| Syncope | 0/186 (0%) | 0 | 1/182 (0.5%) | 1 |
| Psychiatric disorders | ||||
| Psychiatric disorders Delirium | 1/186 (0.5%) | 1 | 0/182 (0%) | 0 |
| Respiratory, thoracic and mediastinal disorders | ||||
| Supraventricular tachycardia | 0/186 (0%) | 0 | 1/182 (0.5%) | 1 |
| Respiratory failure | 0/186 (0%) | 0 | 2/182 (1.1%) | 2 |
| Vascular disorders | ||||
| Embolism | 0/186 (0%) | 0 | 1/182 (0.5%) | 1 |
| Hypotension | 0/186 (0%) | 0 | 1/182 (0.5%) | 1 |
Other (Not Including Serious) Adverse Events |
||||
| dUCB | Haplo-BM | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 1/186 (0.5%) | 0/182 (0%) | ||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||
| Myelodysplastic syndrome | 1/186 (0.5%) | 1 | 0/182 (0%) | 0 |
Limitations/Caveats
[Not Specified]
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Adam Mendizabal, PhD |
|---|---|
| Organization | The Emmes Company |
| Phone | (301) 251-1161 ext 10221 |
| amendizabal@emmes.com |
Responsible Party:
Medical College of Wisconsin
ClinicalTrials.gov Identifier:
NCT01597778
Other Study ID Numbers:
- BMTCTN1101
- 2U10HL069294-11
- 5U24CA076518
First Posted:
May 14, 2012
Last Update Posted:
Dec 1, 2021
Last Verified:
Nov 1, 2021