Acute Biphenotypic Leukemia, Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Burkitt Lymphoma, Chronic Lymphocytic Leukemia, Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Follicular Lymphoma, Lymphoblastic Lymphoma, Lymphoplasmacytic Lymphoma, Mantle Cell Lymphoma, Marginal Zone Lymphoma, Myelodysplastic Syndrome, Myelofibrosis, Non-Hodgkin Lymphoma, Plasma Cell Myeloma, Prolymphocytic Leukemia, Refractory Anemia, Small Lymphocytic Lymphoma
Conditions
Brief summary
This phase II trial studies how well giving an umbilical cord blood transplant together with cyclophosphamide, fludarabine, and total-body irradiation (TBI) works in treating patients with hematologic disease. Giving chemotherapy, such as cyclophosphamide and fludarabine, and TBI before a donor umbilical cord blood transplant helps stop the growth of cancer and abnormal cells and helps stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving cyclosporine and mycophenolate mofetil after transplant may stop this from happening.
Detailed description
OUTLINE: Patients are assigned to 1 of 2 arms. ARM I: Patients receive myeloablative conditioning comprising fludarabine intravenously (IV) over 30 minutes on days -8 to -6, cyclophosphamide IV on days -7 and -6, and undergo high-dose TBI twice daily (BID) on days -4 to -1. Patients then undergo single- or double-unit UCBT on day 0. ARM II: Patients receive myeloablative conditioning comprising fludarabine IV over 30-60 minutes on days -6 to -2, cyclophosphamide IV on day -6, thiotepa IV over 2-4 hours on days -5 and -4, and middle-intensity TBI once daily (QD) on days -2 and -1. Patients then undergo single- or double-unit UCBT on day 0. Patients receive GVHD prophylaxis comprising cyclosporine IV over 1 hour every 8 or 12 hours, then cyclosporine orally (PO) (if tolerated), on days -3 to 100 with taper on day 101. Patients also receive mycophenolate mofetil IV every 8 hours on days 0 to 7 and then PO (if tolerated) three times daily (TID) on days 8-30. Mycophenolate mofetil is tapered to BID on day 30 or 7 days after engraftment if there is no acute GVHD, and then tapered over 2-3 weeks beginning on day 45 (or 15 days after engraftment if engraftment occurred \> day 30) after engraftment if there continues to be no evidence of acute GVHD. After completion of study treatment, patients are followed up at 6 months, 1 year, and 2 years.
Interventions
DRUGCyclophosphamide
Given IV
DRUGCyclosporine
Given IV and PO
Undergo double-unit UCBT
DRUGFludarabine
Given IV
OTHERLaboratory Biomarker Analysis
Correlative studies
DRUGMycophenolate Mofetil
Given IV and PO
RADIATIONTotal-Body Irradiation
Undergo high-dose or moderate-intensity TBI
PROCEDUREUmbilical Cord Blood Transplantation
Undergo UCBT
DRUGThiotepa
Given IV
Sponsors
Fred Hutchinson Cancer Center
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Months to 65 Years
Healthy volunteers
No
Inclusion criteria
* GRAFT CRITERIA: * UCB units will be selected according to current umbilical cord blood graft selection algorithm; one or 2 UCB units may be used to achieve the required cell dose * The UCB graft is matched at 4-6 human leukocyte antigen (HLA)-A, B, DRB1 antigens with the recipient; this may include 0-2 antigen mismatches at the A or B or DRB1 loci; unit selection based on cryopreserved nucleated cell dose and HLA-A,B, DRB1 using intermediate resolution A, B antigen and DRB1 allele typing * If 2 UCB units are required to reach the target cell dose, each unit must be a 4-6 antigen match to the recipient * Age and Disease Criteria: * High-dose TBI regimen: 6 months to =\< 45 years * Middle-intensity TBI regimen: 6 months to =\< 65 years * Conditioning regimen selection should be based on the underlying disease, presence of minimum residual disease (MRD), age, co-morbidities, and attending physician * Acute myeloid leukemia, including biphenotypic acute leukemia or mixed-lineage leukemia: * All patients must be in complete remission (CR) as defined by hematologic recovery and \< 5% blasts by morphology/flow cytometry in a representative bone marrow sample with cellularity \>= 15% for age; patients who do not have high-risk features (for example preceding myelodysplastic syndrome \[MDS\], high-risk cytogenetics, \>= 2 cycles to obtain CR, erythroblastic or megakaryocytic leukemia or \>= CR2) must be discussed with the principal investigator (PI) prior to enrollment and at the Patient Care Conference or equivalent group such as the pediatric leukemia board as an alternative * Patients in whom adequate marrow/biopsy specimens cannot be obtained to determine remission status by morphologic assessment, but have fulfilled criteria of remission by flow cytometry, recovery of peripheral blood counts with no circulating blasts, and/or normal cytogenetics (if applicable) may still be eligible; reasonable attempts must be made to obtain an adequate specimen for morphologic assessment, including possible repeat procedures; these patients must be discussed with the PI prior to enrollment; patients persistently aplastic for greater than one month since completing last chemotherapy are also eligible with PI approval * Very high risk pediatric/young adult patients with acute myeloid leukemia (AML): Patients =\< 25 years, however, are eligible with (M2 marrow) with =\< 25% blasts in marrow after having failed one or more cycles of chemotherapy; this group of patients will be analyzed separately * Acute lymphoblastic leukemia, including biphenotypic acute leukemia or mixed-lineage leukemia: * All patients must be in CR as defined by \< 5% blasts by morphology; flow cytometry in a representative bone marrow sample with cellularity \>= 15% for age; patients who do not have high-risk disease (high risk CR1, greater than one cycle to obtain CR or \>= CR2) must be discussed with the PI prior to enrollment and at the Patient Care Conference or equivalent group such as the pediatric leukemia board as an alternative * Patients in whom adequate marrow/biopsy specimens cannot be obtained to determine remission status by morphologic assessment, but have fulfilled criteria of remission by flow cytometry, recovery of peripheral blood counts with no circulating blasts, and/or normal cytogenetics (if applicable) may still be eligible; reasonable attempts must be made to obtain an adequate specimen for morphologic assessment, including possible repeat procedures; these patients must be discussed with the principal investigator Ann Dahlberg prior to enrollment; patients persistently aplastic for greater than one month since completing last chemotherapy are also eligible with PI approval * Chronic myelogenous leukemia excluding refractory blast crisis; to be eligible in first chronic phase (CP1) patient must have failed or be intolerant to imatinib mesylate * Advanced myelofibrosis * Myelodysplasia (MDS) International Prognostic Scoring System (IPSS) intermediate (Int)-2 or high risk (i.e., refractory anemia with excess blasts \[RAEB\], RAEB in transformation \[RAEBt\]) or refractory anemia with severe pancytopenia or high risk cytogenetics; blasts must be \< 10% by a representative bone marrow aspirate morphology * Lymphoblastic lymphoma, Burkitt's lymphoma, and other high-grade non-Hodgkin lymphoma (NHL) after initial therapy if stage III/IV in first partial response (PR1) or after progression if stage I/II \< 1 year; stage III/IV patients are eligible after progression in CR/PR * Chronic lymphocytic leukemia /small lymphocytic lymphoma (CLL/SLL), marginal zone B-cell lymphoma, lymphoplasmacytic lymphoma or follicular lymphoma that have progressed after at least two different prior therapies; patients with bulky disease (nodal mass greater than 5 cm) should be considered for debulking chemotherapy before transplant; these patients must be presented at primary care center (PCC) prior to enrollment, given potential competing eligibility on autotransplant protocols * Mantle-cell lymphoma, prolymphocytic leukemia: Eligible after initial therapy in \>= CR1 or \>= PR1 * Large cell NHL \> CR2/\> second partial response (PR2): * Patients in CR2/PR2 with initial short remission (\< 6 months) are eligible * These patients must be presented at PCC prior to enrollment, given potential competing eligibility on autotransplant protocols * Multiple myeloma beyond PR2: Patients with chromosome 13 abnormalities, first response lasting less than 6 months, or beta-2 microglobulin \> 3 mg/L, may be considered for this protocol after initial therapy * Performance status score: Karnofsky (for adults) \>= 70% or Eastern Cooperative Oncology Group (ECOG) 0-1 or Lansky (for children) \>= 50% * Creatinine \< 2.0 mg/dL (for adults) or creatinine clearance \> 60 ml/min (for children) * Patients with clinical or laboratory evidence of liver disease will be evaluated for the cause of liver disease, its clinical severity in terms of liver function, histology, and the degree of portal hypertension; patients with fulminant liver failure, cirrhosis with evidence of portal hypertension or bridging fibrosis, alcoholic hepatitis, esophageal varices, a history of bleeding esophageal varices, hepatic encephalopathy, or correctable hepatic synthetic dysfunction evidenced by prolongation of the prothrombin time, ascites related to portal hypertension, bacterial or fungal abscess, biliary obstruction, chronic viral hepatitis with total serum bilirubin \> 3 mg/dL, and symptomatic biliary disease will be excluded * Diffusion capacity for carbon monoxide corrected (DLCOcorr) \> 50% normal or a pediatric patient who is unable to perform pulmonary function tests (PFTs) but has adequate pulmonary function * Left ventricular ejection fraction \> 45% or shortening fraction \> 26%
Exclusion criteria
* Uncontrolled viral or bacterial infection at the time of study enrollment * Active or recent (prior 6 month) invasive fungal infection without interdisciplinary (ID) consult and approval * History of human immunodeficiency virus (HIV) infection * Pregnant or breastfeeding * Chemotherapy refractory large cell and high grade NHL (i.e., progressive disease after \> 2 salvage regimens) * Patients with history of prior myeloablative transplant containing full dose TBI (greater than 8 gray \[Gy\]) will not be eligible for Regimen A; however, they may still enroll on Regimen B if they otherwise meet inclusion and
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | 1 year post-transplant | Overall survival defined as patient being alive at 1 year post-transplant. Monitoring will take place separately for the single and double UCBT cohorts. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Level of Chimerism at Multiple Time Points | Baseline up to 2 years post-transplant | Peripheral blood chimerism studies (sorted for CD3, CD14, CD33, CD56 cells) were collected for all UCBT recipients for days 28, 56, 80, 365, and 730 post-transplant. The combined median of the percent donor, along with full range, is captured to show change in level of chimerism at multiple time points up to 2 years post-transplant. Monitoring will take place separately for the single and double UCBT cohorts. |
| Incidence of Transplant-related Mortality (TRM) | At 6 months post-transplant | Defined as death due to complication (other than relapse) within 6 months following UCBT. Monitoring will take place separately for the single and double UCBT cohorts. |
| Neutrophil Engraftment | Up to day 42 post-transplant | Neutrophil engraftment after UCBT is defined as the first day of absolute neutrophil count (ANC) ≥ 5 x 10⁸/L for 3 consecutive measures. Monitoring will take place separately for the single and double UCBT cohorts. |
| Platelet Engraftment | Up to 6 months post-transplant | Platelet (PLT) engraftment after UCBT is defined as the first day of platelet count \> 20,000/μl without subsequent transfusions for 7 days. Monitoring will take place separately for the single and double UCBT cohorts. |
| Progression-free Survival (PFS) | Up to 2 years post-transplant | PFS is defined as the time (in days) from UCBT until the disease progresses or the patient dies from any cause, with incidence measured up to 2 years post-transplant. Monitoring will take place separately for the single and double UCBT cohorts. Measure will be reported as the median amount of days from full minimum and maximum range. |
| Event of Chronic Graft-verses-host-disease (cGVHD) | Up to 2 years post-transplant | Each event of cGVHD level will be assessed overall as either 'Limited' (mild and with single organ involvement) or 'Extensive' (involvement of two or more organs with symptoms) based on extent of skin rash, volume of diarrhea, and maximum bilirubin level, per protocol Appendix I, GVHD Staging and Grading. Monitoring will take place separately for the single and double UCBT cohorts. |
| Event of Clinically Significant Infections | Up to 2 years post-transplant | Each event of infection will be assessed to determine whether or not it is clinically significant. An infection is defined as clinically significant when it is scored as ≥ grade 3 (where worse outcomes are associated with higher grading) in accordance with the CTCAE version 3.0/protocol Appendix VI, and constitutes a Serious Adverse Event (SAE). Monitoring will take place separately for the single and double UCBT cohorts. |
| Incidence of Relapse | At 1 and 2 years post-transplant | Relapse is defined as post-transplant disease recurrence in participants who had initially recovered or improved, with incidence measured from Day 0 to 1 year post-transplant, and from 1 year post-transplant to 2 years post-transplant. Monitoring will take place separately for the single and double UCBT cohorts. |
| Event of Grade II-IV and III-IV Acute Graft-versus-host Disease (aGVHD) | Up to day 100 post-transplant | Each event of aGVHD will be assigned an overall aGVHD score based on extent of skin rash, volume of diarrhea, and maximum bilirubin level, per protocol Appendix I, GVHD Staging and Grading. Scores reported range from most mild at 2, to worse at 4. Monitoring will take place separately for the single and double UCBT cohorts. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Regimen A: High-dose TBI + Fludarabine + Cyclophosphamide Patients enrolled to receive myeloablative conditioning comprising fludarabine IV over 30 minutes on days -8 to -6, cyclophosphamide IV on days -7 and -6, and undergo high-dose TBI BID on days -4 to -1. Patients then undergo single- or double-unit UCBT on day 0.
Patients to receive GVHD prophylaxis comprising cyclosporine IV over 1 hour every 8 or 12 hours, then cyclosporine PO (if tolerated), on days -3 to 100 with taper on day 101. Patients also receive mycophenolate mofetil IV every 8 hours on days 0 to 7 and then PO (if tolerated) TID on days 8-30. Mycophenolate mofetil is tapered to BID on day 30 or 7 days after engraftment if there is no acute GVHD, and then tapered over 2-3 weeks beginning on day 45 (or 15 days after engraftment if engraftment occurred \> day 30) after engraftment if there continues to be no evidence of acute GVHD.
Cyclophosphamide: Given IV
Cyclosporine: Given IV and PO
Fludarabine: Given IV
Laboratory Biomarker Analysis: Correlative studies
Mycophenolate Mofetil: Given IV and PO
Total-Body Irradiation: Undergo high-dose TBI
Umbilical Cord Blood Transplantation: Undergo UCBT (either single- or double-cord) | 108 |
| Regimen B: Middle-intensity TBI + Fludarabine + Cyclophosphamide + Thiotepa Patients enrolled to receive myeloablative conditioning comprising fludarabine IV over 30-60 minutes on days -6 to -2, cyclophosphamide IV on day -6, thiotepa IV over 2-4 hours on days -5 and -4, and middle-intensity TBI QD on days -2 and -1. Patients then undergo single- or double-unit UCBT on day 0.
Patients to receive GVHD prophylaxis comprising cyclosporine IV over 1 hour every 8 or 12 hours, then cyclosporine PO (if tolerated), on days -3 to 100 with taper on day 101. Patients also receive mycophenolate mofetil IV every 8 hours on days 0 to 7 and then PO (if tolerated) TID on days 8-30. Mycophenolate mofetil is tapered to BID on day 30 or 7 days after engraftment if there is no acute GVHD, and then tapered over 2-3 weeks beginning on day 45 (or 15 days after engraftment if engraftment occurred \> day 30) after engraftment if there continues to be no evidence of acute GVHD.
Cyclophosphamide: Given IV
Cyclosporine: Given IV and PO
Fludarabine: Given IV
Laboratory Biomarker Analysis: Correlative studies
Mycophenolate Mofetil: Given IV and PO
Total-Body Irradiation: Undergo moderate-intensity TBI
Umbilical Cord Blood Transplantation: Undergo UCBT (either single- or double-cord)
Thiotepa: Given IV | 27 |
| Total | 135 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 24 | 9 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Relapse | 8 | 3 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Regimen A: High-dose TBI + Fludarabine + Cyclophosphamide | Regimen B: Middle-intensity TBI + Fludarabine + Cyclophosphamide + Thiotepa | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 52 Participants | 14 Participants | 66 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 56 Participants | 13 Participants | 69 Participants |
| Age, Continuous | 22 years | 24.5 years | 22.5 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 33 Participants | 4 Participants | 37 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 73 Participants | 23 Participants | 96 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 3 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) Asian | 9 Participants | 5 Participants | 14 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 1 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 6 Participants | 1 Participants | 7 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 16 Participants | 1 Participants | 17 Participants |
| Race (NIH/OMB) White | 68 Participants | 17 Participants | 85 Participants |
| Sex: Female, Male Female | 45 Participants | 14 Participants | 59 Participants |
| Sex: Female, Male Male | 63 Participants | 13 Participants | 76 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 24 / 108 | 9 / 27 |
| other Total, other adverse events | 73 / 108 | 25 / 27 |
| serious Total, serious adverse events | 47 / 108 | 7 / 27 |
Outcome results
Primary
Overall Survival
Overall survival defined as patient being alive at 1 year post-transplant. Monitoring will take place separately for the single and double UCBT cohorts.
Time frame: 1 year post-transplant
Population: Analysis population is all patients who underwent UCB transplant on study, whether completed treatment on study or relapsed at later timepoint.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Regimen A: High-dose TBI + Fludarabine + Cyclophosphamide; Single-cord Transplant | Overall Survival | 28 Participants |
| Regimen B: Middle-intensity TBI + Fludarabine + Cyclophosphamide + Thiotepa; Single-cord Transplant | Overall Survival | 15 Participants |
| Regimen A: High-dose TBI + Fludarabine + Cyclophosphamide; Double-cord Transplant | Overall Survival | 53 Participants |
| Regimen B: Middle-intensity TBI + Fludarabine + Cyclophosphamide + Thiotepa; Double-cord Transplant | Overall Survival | 7 Participants |
Secondary
Change in Level of Chimerism at Multiple Time Points
Peripheral blood chimerism studies (sorted for CD3, CD14, CD33, CD56 cells) were collected for all UCBT recipients for days 28, 56, 80, 365, and 730 post-transplant. The combined median of the percent donor, along with full range, is captured to show change in level of chimerism at multiple time points up to 2 years post-transplant. Monitoring will take place separately for the single and double UCBT cohorts.
Time frame: Baseline up to 2 years post-transplant
Population: Participants who received UCBT on study with chimerism data available within window as specified in protocol.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Regimen A: High-dose TBI + Fludarabine + Cyclophosphamide; Single-cord Transplant | Change in Level of Chimerism at Multiple Time Points | Combined median of CD14 at days (24, 56, 80, 180, 365, 730) | 100 percentage chimerism (%) |
| Regimen A: High-dose TBI + Fludarabine + Cyclophosphamide; Single-cord Transplant | Change in Level of Chimerism at Multiple Time Points | Combined median of CD33 at days (24, 56, 80, 180, 365, 730) | 100 percentage chimerism (%) |
| Regimen A: High-dose TBI + Fludarabine + Cyclophosphamide; Single-cord Transplant | Change in Level of Chimerism at Multiple Time Points | Combined median of CD3 at days (24, 56, 80, 180, 365, 730) | 100 percentage chimerism (%) |
| Regimen A: High-dose TBI + Fludarabine + Cyclophosphamide; Single-cord Transplant | Change in Level of Chimerism at Multiple Time Points | Combined median of CD56 at days (24, 56, 80, 180, 365, 730) | 100 percentage chimerism (%) |
| Regimen B: Middle-intensity TBI + Fludarabine + Cyclophosphamide + Thiotepa; Single-cord Transplant | Change in Level of Chimerism at Multiple Time Points | Combined median of CD33 at days (24, 56, 80, 180, 365, 730) | 100 percentage chimerism (%) |
| Regimen B: Middle-intensity TBI + Fludarabine + Cyclophosphamide + Thiotepa; Single-cord Transplant | Change in Level of Chimerism at Multiple Time Points | Combined median of CD3 at days (24, 56, 80, 180, 365, 730) | 100 percentage chimerism (%) |
| Regimen B: Middle-intensity TBI + Fludarabine + Cyclophosphamide + Thiotepa; Single-cord Transplant | Change in Level of Chimerism at Multiple Time Points | Combined median of CD14 at days (24, 56, 80, 180, 365, 730) | 100 percentage chimerism (%) |
| Regimen B: Middle-intensity TBI + Fludarabine + Cyclophosphamide + Thiotepa; Single-cord Transplant | Change in Level of Chimerism at Multiple Time Points | Combined median of CD56 at days (24, 56, 80, 180, 365, 730) | 100 percentage chimerism (%) |
| Regimen A: High-dose TBI + Fludarabine + Cyclophosphamide; Double-cord Transplant | Change in Level of Chimerism at Multiple Time Points | Combined median of CD14 at days (24, 56, 80, 180, 365, 730) | 100 percentage chimerism (%) |
| Regimen A: High-dose TBI + Fludarabine + Cyclophosphamide; Double-cord Transplant | Change in Level of Chimerism at Multiple Time Points | Combined median of CD33 at days (24, 56, 80, 180, 365, 730) | 100 percentage chimerism (%) |
| Regimen A: High-dose TBI + Fludarabine + Cyclophosphamide; Double-cord Transplant | Change in Level of Chimerism at Multiple Time Points | Combined median of CD56 at days (24, 56, 80, 180, 365, 730) | 100 percentage chimerism (%) |
| Regimen A: High-dose TBI + Fludarabine + Cyclophosphamide; Double-cord Transplant | Change in Level of Chimerism at Multiple Time Points | Combined median of CD3 at days (24, 56, 80, 180, 365, 730) | 100 percentage chimerism (%) |
| Regimen B: Middle-intensity TBI + Fludarabine + Cyclophosphamide + Thiotepa; Double-cord Transplant | Change in Level of Chimerism at Multiple Time Points | Combined median of CD14 at days (24, 56, 80, 180, 365, 730) | 100 percentage chimerism (%) |
| Regimen B: Middle-intensity TBI + Fludarabine + Cyclophosphamide + Thiotepa; Double-cord Transplant | Change in Level of Chimerism at Multiple Time Points | Combined median of CD56 at days (24, 56, 80, 180, 365, 730) | 100 percentage chimerism (%) |
| Regimen B: Middle-intensity TBI + Fludarabine + Cyclophosphamide + Thiotepa; Double-cord Transplant | Change in Level of Chimerism at Multiple Time Points | Combined median of CD3 at days (24, 56, 80, 180, 365, 730) | 100 percentage chimerism (%) |
| Regimen B: Middle-intensity TBI + Fludarabine + Cyclophosphamide + Thiotepa; Double-cord Transplant | Change in Level of Chimerism at Multiple Time Points | Combined median of CD33 at days (24, 56, 80, 180, 365, 730) | 100 percentage chimerism (%) |
Secondary
Event of Chronic Graft-verses-host-disease (cGVHD)
Each event of cGVHD level will be assessed overall as either 'Limited' (mild and with single organ involvement) or 'Extensive' (involvement of two or more organs with symptoms) based on extent of skin rash, volume of diarrhea, and maximum bilirubin level, per protocol Appendix I, GVHD Staging and Grading. Monitoring will take place separately for the single and double UCBT cohorts.
Time frame: Up to 2 years post-transplant
Population: Participants who received UCBT on study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Regimen A: High-dose TBI + Fludarabine + Cyclophosphamide; Single-cord Transplant | Event of Chronic Graft-verses-host-disease (cGVHD) | Extensive cGVHD | 14 events |
| Regimen A: High-dose TBI + Fludarabine + Cyclophosphamide; Single-cord Transplant | Event of Chronic Graft-verses-host-disease (cGVHD) | Limited cGVHD | 12 events |
| Regimen B: Middle-intensity TBI + Fludarabine + Cyclophosphamide + Thiotepa; Single-cord Transplant | Event of Chronic Graft-verses-host-disease (cGVHD) | Limited cGVHD | 6 events |
| Regimen B: Middle-intensity TBI + Fludarabine + Cyclophosphamide + Thiotepa; Single-cord Transplant | Event of Chronic Graft-verses-host-disease (cGVHD) | Extensive cGVHD | 5 events |
| Regimen A: High-dose TBI + Fludarabine + Cyclophosphamide; Double-cord Transplant | Event of Chronic Graft-verses-host-disease (cGVHD) | Extensive cGVHD | 44 events |
| Regimen A: High-dose TBI + Fludarabine + Cyclophosphamide; Double-cord Transplant | Event of Chronic Graft-verses-host-disease (cGVHD) | Limited cGVHD | 11 events |
| Regimen B: Middle-intensity TBI + Fludarabine + Cyclophosphamide + Thiotepa; Double-cord Transplant | Event of Chronic Graft-verses-host-disease (cGVHD) | Extensive cGVHD | 2 events |
| Regimen B: Middle-intensity TBI + Fludarabine + Cyclophosphamide + Thiotepa; Double-cord Transplant | Event of Chronic Graft-verses-host-disease (cGVHD) | Limited cGVHD | 5 events |
Secondary
Event of Clinically Significant Infections
Each event of infection will be assessed to determine whether or not it is clinically significant. An infection is defined as clinically significant when it is scored as ≥ grade 3 (where worse outcomes are associated with higher grading) in accordance with the CTCAE version 3.0/protocol Appendix VI, and constitutes a Serious Adverse Event (SAE). Monitoring will take place separately for the single and double UCBT cohorts.
Time frame: Up to 2 years post-transplant
Population: Participants who received UCBT on study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Regimen A: High-dose TBI + Fludarabine + Cyclophosphamide; Single-cord Transplant | Event of Clinically Significant Infections | 2 events |
| Regimen B: Middle-intensity TBI + Fludarabine + Cyclophosphamide + Thiotepa; Single-cord Transplant | Event of Clinically Significant Infections | 0 events |
| Regimen A: High-dose TBI + Fludarabine + Cyclophosphamide; Double-cord Transplant | Event of Clinically Significant Infections | 21 events |
| Regimen B: Middle-intensity TBI + Fludarabine + Cyclophosphamide + Thiotepa; Double-cord Transplant | Event of Clinically Significant Infections | 1 events |
Secondary
Event of Grade II-IV and III-IV Acute Graft-versus-host Disease (aGVHD)
Each event of aGVHD will be assigned an overall aGVHD score based on extent of skin rash, volume of diarrhea, and maximum bilirubin level, per protocol Appendix I, GVHD Staging and Grading. Scores reported range from most mild at 2, to worse at 4. Monitoring will take place separately for the single and double UCBT cohorts.
Time frame: Up to day 100 post-transplant
Population: Participants who received UCBT on study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Regimen A: High-dose TBI + Fludarabine + Cyclophosphamide; Single-cord Transplant | Event of Grade II-IV and III-IV Acute Graft-versus-host Disease (aGVHD) | Grade III-IV aGVHD | 7 events |
| Regimen A: High-dose TBI + Fludarabine + Cyclophosphamide; Single-cord Transplant | Event of Grade II-IV and III-IV Acute Graft-versus-host Disease (aGVHD) | Grade II-IV aGVHD | 29 events |
| Regimen B: Middle-intensity TBI + Fludarabine + Cyclophosphamide + Thiotepa; Single-cord Transplant | Event of Grade II-IV and III-IV Acute Graft-versus-host Disease (aGVHD) | Grade III-IV aGVHD | 2 events |
| Regimen B: Middle-intensity TBI + Fludarabine + Cyclophosphamide + Thiotepa; Single-cord Transplant | Event of Grade II-IV and III-IV Acute Graft-versus-host Disease (aGVHD) | Grade II-IV aGVHD | 14 events |
| Regimen A: High-dose TBI + Fludarabine + Cyclophosphamide; Double-cord Transplant | Event of Grade II-IV and III-IV Acute Graft-versus-host Disease (aGVHD) | Grade II-IV aGVHD | 51 events |
| Regimen A: High-dose TBI + Fludarabine + Cyclophosphamide; Double-cord Transplant | Event of Grade II-IV and III-IV Acute Graft-versus-host Disease (aGVHD) | Grade III-IV aGVHD | 17 events |
| Regimen B: Middle-intensity TBI + Fludarabine + Cyclophosphamide + Thiotepa; Double-cord Transplant | Event of Grade II-IV and III-IV Acute Graft-versus-host Disease (aGVHD) | Grade III-IV aGVHD | 1 events |
| Regimen B: Middle-intensity TBI + Fludarabine + Cyclophosphamide + Thiotepa; Double-cord Transplant | Event of Grade II-IV and III-IV Acute Graft-versus-host Disease (aGVHD) | Grade II-IV aGVHD | 5 events |
Secondary
Incidence of Relapse
Relapse is defined as post-transplant disease recurrence in participants who had initially recovered or improved, with incidence measured from Day 0 to 1 year post-transplant, and from 1 year post-transplant to 2 years post-transplant. Monitoring will take place separately for the single and double UCBT cohorts.
Time frame: At 1 and 2 years post-transplant
Population: Analysis population is all patients who underwent UCB transplant on study.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Regimen A: High-dose TBI + Fludarabine + Cyclophosphamide; Single-cord Transplant | Incidence of Relapse | Relapse at 2 year | 0 Participants |
| Regimen A: High-dose TBI + Fludarabine + Cyclophosphamide; Single-cord Transplant | Incidence of Relapse | Relapse at 1 year | 2 Participants |
| Regimen A: High-dose TBI + Fludarabine + Cyclophosphamide; Single-cord Transplant | Incidence of Relapse | No relapse while on study | 31 Participants |
| Regimen B: Middle-intensity TBI + Fludarabine + Cyclophosphamide + Thiotepa; Single-cord Transplant | Incidence of Relapse | Relapse at 2 year | 0 Participants |
| Regimen B: Middle-intensity TBI + Fludarabine + Cyclophosphamide + Thiotepa; Single-cord Transplant | Incidence of Relapse | Relapse at 1 year | 4 Participants |
| Regimen B: Middle-intensity TBI + Fludarabine + Cyclophosphamide + Thiotepa; Single-cord Transplant | Incidence of Relapse | No relapse while on study | 13 Participants |
| Regimen A: High-dose TBI + Fludarabine + Cyclophosphamide; Double-cord Transplant | Incidence of Relapse | Relapse at 2 year | 0 Participants |
| Regimen A: High-dose TBI + Fludarabine + Cyclophosphamide; Double-cord Transplant | Incidence of Relapse | No relapse while on study | 61 Participants |
| Regimen A: High-dose TBI + Fludarabine + Cyclophosphamide; Double-cord Transplant | Incidence of Relapse | Relapse at 1 year | 11 Participants |
| Regimen B: Middle-intensity TBI + Fludarabine + Cyclophosphamide + Thiotepa; Double-cord Transplant | Incidence of Relapse | Relapse at 2 year | 1 Participants |
| Regimen B: Middle-intensity TBI + Fludarabine + Cyclophosphamide + Thiotepa; Double-cord Transplant | Incidence of Relapse | No relapse while on study | 9 Participants |
| Regimen B: Middle-intensity TBI + Fludarabine + Cyclophosphamide + Thiotepa; Double-cord Transplant | Incidence of Relapse | Relapse at 1 year | 0 Participants |
Secondary
Incidence of Transplant-related Mortality (TRM)
Defined as death due to complication (other than relapse) within 6 months following UCBT. Monitoring will take place separately for the single and double UCBT cohorts.
Time frame: At 6 months post-transplant
Population: Analysis population is all patients who underwent UCB transplant on study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Regimen A: High-dose TBI + Fludarabine + Cyclophosphamide; Single-cord Transplant | Incidence of Transplant-related Mortality (TRM) | 2 Participants |
| Regimen B: Middle-intensity TBI + Fludarabine + Cyclophosphamide + Thiotepa; Single-cord Transplant | Incidence of Transplant-related Mortality (TRM) | 1 Participants |
| Regimen A: High-dose TBI + Fludarabine + Cyclophosphamide; Double-cord Transplant | Incidence of Transplant-related Mortality (TRM) | 9 Participants |
| Regimen B: Middle-intensity TBI + Fludarabine + Cyclophosphamide + Thiotepa; Double-cord Transplant | Incidence of Transplant-related Mortality (TRM) | 1 Participants |
Secondary
Neutrophil Engraftment
Neutrophil engraftment after UCBT is defined as the first day of absolute neutrophil count (ANC) ≥ 5 x 10⁸/L for 3 consecutive measures. Monitoring will take place separately for the single and double UCBT cohorts.
Time frame: Up to day 42 post-transplant
Population: Analysis population is all patients who underwent UCB transplant and experienced ANC engraftment by day 42 post-transplant on study. 4 patients did engraft ANC after day 42 post-transplant, but are not included in this analysis due to protocol definition of engraftment period.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Regimen A: High-dose TBI + Fludarabine + Cyclophosphamide; Single-cord Transplant | Neutrophil Engraftment | 19 Days post-transplant |
| Regimen B: Middle-intensity TBI + Fludarabine + Cyclophosphamide + Thiotepa; Single-cord Transplant | Neutrophil Engraftment | 19 Days post-transplant |
| Regimen A: High-dose TBI + Fludarabine + Cyclophosphamide; Double-cord Transplant | Neutrophil Engraftment | 22 Days post-transplant |
| Regimen B: Middle-intensity TBI + Fludarabine + Cyclophosphamide + Thiotepa; Double-cord Transplant | Neutrophil Engraftment | 20 Days post-transplant |
Secondary
Platelet Engraftment
Platelet (PLT) engraftment after UCBT is defined as the first day of platelet count \> 20,000/μl without subsequent transfusions for 7 days. Monitoring will take place separately for the single and double UCBT cohorts.
Time frame: Up to 6 months post-transplant
Population: Analysis population is all patients who underwent UCB transplant and experienced PLT engraftment by 6 months post-transplant on study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Regimen A: High-dose TBI + Fludarabine + Cyclophosphamide; Single-cord Transplant | Platelet Engraftment | 34 Days post-transplant |
| Regimen B: Middle-intensity TBI + Fludarabine + Cyclophosphamide + Thiotepa; Single-cord Transplant | Platelet Engraftment | 35 Days post-transplant |
| Regimen A: High-dose TBI + Fludarabine + Cyclophosphamide; Double-cord Transplant | Platelet Engraftment | 41 Days post-transplant |
| Regimen B: Middle-intensity TBI + Fludarabine + Cyclophosphamide + Thiotepa; Double-cord Transplant | Platelet Engraftment | 37 Days post-transplant |
Secondary
Progression-free Survival (PFS)
PFS is defined as the time (in days) from UCBT until the disease progresses or the patient dies from any cause, with incidence measured up to 2 years post-transplant. Monitoring will take place separately for the single and double UCBT cohorts. Measure will be reported as the median amount of days from full minimum and maximum range.
Time frame: Up to 2 years post-transplant
Population: Analysis population is all patients who underwent UCB transplant on study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Regimen A: High-dose TBI + Fludarabine + Cyclophosphamide; Single-cord Transplant | Progression-free Survival (PFS) | 167 Days post-transplant |
| Regimen B: Middle-intensity TBI + Fludarabine + Cyclophosphamide + Thiotepa; Single-cord Transplant | Progression-free Survival (PFS) | 155 Days post-transplant |
| Regimen A: High-dose TBI + Fludarabine + Cyclophosphamide; Double-cord Transplant | Progression-free Survival (PFS) | 112 Days post-transplant |
| Regimen B: Middle-intensity TBI + Fludarabine + Cyclophosphamide + Thiotepa; Double-cord Transplant | Progression-free Survival (PFS) | 317 Days post-transplant |