Disorder Related to Transplantation, Hematologic Malignancies, Hematopoietic Malignancy
Conditions
Keywords
Hematologic Malignancies, Umbilical Cord Blood transplantation, Hematopoietic Cell Transplantation
Brief summary
In this study, participants with high-risk hematologic malignancies undergoing hematopoietic cell transplantation (HCT), who do not have a suitable human leukocyte antigen (HLA)-matched related/sibling donor (MSD), matched unrelated donor (MURD) or killer-immunoglobulin receptors (KIR) ligand mismatched haploidentical donor identified, will receive an umbilical cord blood transplantation (UCBT) using a myeloablative preparative regimen. The preparative regimen includes fludarabine (75 mg/m2), fractionated total body irradiation (TBI) (10.0 Gy), and cyclophosphamide (120mg/kg) with mesna. Fludarabine will be given once a day at 25 mg/m2 for three days on day -10 to day -8, TBI will be given twice a day at 150 cGy for four days on day -7 to day -4, and cyclophosphamide will be given once a day for at 60mg/kg for two days on day -3 and day -2. Post-transplantation immunosuppression with cyclosporine and MMF will begin on day -3. Cord Blood infusion will occur on day 0 and G-CSF will start on day +1.
Detailed description
The primary objectives is to estimate the event-free survival (EFS) at one-year post-transplant for research participants with high-risk hematologic malignancies undergoing hematopoietic cell transplantation (HCT) using single unit umbilical cord blood (UCB). Secondary objectives are: * Describe the clinical outcome of patients undergoing a double unit UCBT. * Estimate the incidence and severity of acute and chronic graft versus host disease (GVHD) of patients enrolled in the research arm. * Estimate the incidence and time to neutrophil and platelet engraftment among patients enrolled in the research arm. * Estimate the incidence of transplant related mortality (TRM) and transplant related morbidity in the first 100 days after transplantation among patients enrolled in the research Exploratory Objectives are: * Assess the relationship between pre-transplant minimal residual disease (MRD) with transplant outcomes. * Record immune reconstitution parameters, including chimerism analysis, quantitative lymphocyte subsets, T cell receptor excision circle (TREC) and spectratyping. Immunophenotyping and functional assays of T, B and NK cells and lymphocytes will also be evaluated. * Evaluate the determinants of engraftment.
Interventions
Fludarabine (75 mg/m2), fractionated total body irradiation (TBI) (12.0 Gy), and cyclophosphamide (120mg/kg) with mesna. Fludarabine will be given once a day at 25 mg/m2 for three days on day -10 to day -8, TBI will be given twice a day at 150 cGy for four days on day -7 to day -4, and cyclophosphamide will be given once a day for at 60mg/kg for two days on day -3 and day -2. Post-transplantation immunosuppression with cyclosporine and MMF will begin on day -3. Cord Blood infusion will occur on day 0 and G-CSF will start on day +1.
Sponsors
The Hartwell Foundation
Assisi Foundation
St. Jude Children's Research Hospital
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 21 Years
Healthy volunteers
No
Inclusion criteria
* Age less than or equal to 21 years old. * Has a partially HLA-matched single or double UCB product * High-risk hematologic malignancy. * High risk ALL in CR1, ALL in High risk CR2, ALL in CR3 or subsequent. * AML in high risk CR1, AML in CR2 or subsequent * AML in first relapse with \< 25% blasts in BM * Therapy related AML, with prior malignancy in CR \> 12mo * MDS, primary or secondary * NK cell, biphenotypic, or undifferentiated leukemia in CR1 or subsequent. * CML in accelerated phase, or in chronic phase with persistent molecular positivity or intolerance to tyrosine kinase inhibitor. * Hodgkin lymphoma in CR2 or subsequent after failure of prior autologous HCT, or unable to mobilize stem cells for autologous HCT. * Non-Hodgkin lymphoma in CR2 or subsequent after failure of prior autologous HCT, or unable to mobilize stem cells for autologous HCT. * JMML * All patients with evidence of CNS leukemia must be treated and be in CNS CR to be eligible for study. Patient must fulfill pre-transplant evaluation: * Cardiac shortening fraction ≥ 26%. * Creatinine clearance ≥ 70 ml/min/1.73m2. * Forced vital capacity (FVC) ≥ 50% of predicted value or pulse oximetry ≥ 92% on room air. * Karnofsky (≥ 16 years) or Lansky (\<16 years) performance score ≥ 70 * Bilirubin ≤ 2.5 mg/dL. * Alanine aminotransferase (ALT) ≤ 5 times the upper limit of normal for age. * Aspartate aminotransferase (AST) ≤ 5 times the upper limit of normal for age.
Exclusion criteria
* Patient has a suitable MSD, volunteer MURD, or KIR mismatched haploidentical donor available in the necessary time for stem cell donation. * Patient has any other active malignancy other than the one for which HCT is indicated. * Patient had a prior allogeneic HCT * Patient had an autologous HCT within the previous 12 months. * Patient is pregnant as confirmed by positive serum or urine pregnancy test within 14 days prior to enrollment. * Patient is lactating * Patient has Down Syndrome * Patient has a current uncontrolled bacterial, fungal, or viral infection per the judgment of the PI.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Event Free Survival (EFS) for Research Participants | 1 year post-transplant | Estimate EFS for research participants at one-year post transplant by using single unit umbilical cord blood. The event is defined as relapse, graft failure, death due to any cause. The number of participants who did not experience any of those events (relapse, graft failure, death due to any cause) at year 1 post-transplant was given. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Observational Arm Patients Who Relapsed | 1 year | The number of observational arm patients who relapsed was given. |
| Number of Deaths of Observational Arm Patients | 1 year | The number of observational arm patients who died was given. |
| Number of Observational Arm Patients With Transplant-related Mortality (TRM) | First 100 days | The number of patients with TRM within the first 100 days post transplant was given. |
| Number of Participants With Acute GVHD | 1 year | The number of participants with incidence of acute GVHD by grade was given. Participants are graded on a scale from 1 to 4, with 1 being mild and 4 being severe. |
| Number of Observational Arm Participants Engrafted | 1 year | For patients enrolled in the observational arm (undergoing a double unit UCBT), the number of patients engrafted was given. |
| Time to Engraftment of Research Arm Participants | first 100 days post transplant | Platelet engraftment was defined as platelet count ≥20,000/mm\^3 for 3 consecutive tests performed on different days with no platelet transfusions in the preceding 7 days. Neutrophil engraftment will be defined as achieving ANC ≥ 500/mm3 for 3 consecutive tests performed on different days with evidence of donor cell engraftment. Descriptive statistics are provided. |
| Incidence of Transplant-related Mortality (TRM) | first 100 days post transplant | TRM is death occurring in patients in continuous complete remission. The numbers of patients with TRM was given. |
| The Number of Participants With Transplant-related Morbidity | first 100 days post transplant | Any patient who had adverse events listed either as probable or definite in the first 100 days post-transplant are counted as transplant related morbidity. The number of patients with transplant-related morbidity was given. |
| Number of Participants With Chronic GVHD | 1 year | Due to the small sample size, cumulative incidence analysis was not done. The incidence of chronic GVHD was evaluated using NIH Consensus Global Severity Scoring. The number of patients with incidence of chronic GVHD by severity was provided. |
Countries
United States
Participant flow
Recruitment details
Fourteen patients were enrolled at St. Jude Children's Research Hospital between September 2011 and April 2014.
Participants by arm
| Arm | Count |
|---|---|
| Research Arm Participant with high-risk hematologic malignancies undergoing Hematopoietic Cell Transplantation, who do not have a suitable Human Leukocyte Antigen -matched related/sibling donor, Matched Unrelated Donor or Killer immunoglobulin receptors ligand mismatched haploidentical donor identified, will receive a single UCB unit.
Intervention: Preparative Regimen
Preparative Regimen: Fludarabine (75 mg/m2), fractionated total body irradiation (TBI) (12.0 Gy), and cyclophosphamide (120mg/kg) with mesna. Fludarabine will be given once a day at 25 mg/m2 for three days on day -10 to day -8, TBI will be given twice a day at 150 cGy for four days on day -7 to day -4, and cyclophosphamide will be given once a day for at 60mg/kg for two days on day -3 and day -2.
Post-transplantation immunosuppression with cyclosporine and MMF will begin on day -3. Cord Blood infusion will occur on day 0 and G-CSF will start on day +1. | 9 |
| Observational Arm Patients requiring two UCB units will be eligible for UCBT01 on the observational arm.
Intervention: Preparative Regimen
Preparative Regimen: Fludarabine (75 mg/m2), fractionated total body irradiation (TBI) (12.0 Gy), and cyclophosphamide (120mg/kg) with mesna. Fludarabine will be given once a day at 25 mg/m2 for three days on day -10 to day -8, TBI will be given twice a day at 150 cGy for four days on day -7 to day -4, and cyclophosphamide will be given once a day for at 60mg/kg for two days on day -3 and day -2.
Post-transplantation immunosuppression with cyclosporine and MMF will begin on day -3. Cord Blood infusion will occur on day 0 and G-CSF will start on day +1. | 4 |
| Total | 13 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Significant Change in Health Status | 1 | 0 |
Baseline characteristics
| Characteristic | Research Arm | Observational Arm | Total |
|---|---|---|---|
| Age, Continuous | 3.40 years STANDARD_DEVIATION 2.54 | 14.3 years STANDARD_DEVIATION 2.98 | 6.76 years STANDARD_DEVIATION 5.83 |
| Race/Ethnicity, Customized Declined to respond | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Mexican/Chicano | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Non Spanish speaking, Non Hispanic | 3 Participants | 2 Participants | 5 Participants |
| Race/Ethnicity, Customized NOS Spanish, Hispanic, latino | 2 Participants | 2 Participants | 4 Participants |
| Race/Ethnicity, Customized Puerto Rican | 2 Participants | 0 Participants | 2 Participants |
| Sex: Female, Male Female | 5 Participants | 2 Participants | 7 Participants |
| Sex: Female, Male Male | 4 Participants | 2 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 4 / 9 | 2 / 4 |
| other Total, other adverse events | 9 / 9 | 4 / 4 |
| serious Total, serious adverse events | 7 / 9 | 3 / 4 |
Outcome results
Primary
Event Free Survival (EFS) for Research Participants
Estimate EFS for research participants at one-year post transplant by using single unit umbilical cord blood. The event is defined as relapse, graft failure, death due to any cause. The number of participants who did not experience any of those events (relapse, graft failure, death due to any cause) at year 1 post-transplant was given.
Time frame: 1 year post-transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Research Arm | Event Free Survival (EFS) for Research Participants | 4 Participants |
Secondary
Incidence of Transplant-related Mortality (TRM)
TRM is death occurring in patients in continuous complete remission. The numbers of patients with TRM was given.
Time frame: first 100 days post transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Research Arm | Incidence of Transplant-related Mortality (TRM) | 0 Participants |
| Observational Arm | Incidence of Transplant-related Mortality (TRM) | 1 Participants |
Secondary
Number of Deaths of Observational Arm Patients
The number of observational arm patients who died was given.
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Research Arm | Number of Deaths of Observational Arm Patients | 2 Participants |
Secondary
Number of Observational Arm Participants Engrafted
For patients enrolled in the observational arm (undergoing a double unit UCBT), the number of patients engrafted was given.
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Research Arm | Number of Observational Arm Participants Engrafted | 3 Participants |
Secondary
Number of Observational Arm Patients Who Relapsed
The number of observational arm patients who relapsed was given.
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Research Arm | Number of Observational Arm Patients Who Relapsed | 1 Participants |
Secondary
Number of Observational Arm Patients With Transplant-related Mortality (TRM)
The number of patients with TRM within the first 100 days post transplant was given.
Time frame: First 100 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Research Arm | Number of Observational Arm Patients With Transplant-related Mortality (TRM) | 1 Participants |
Secondary
Number of Participants With Acute GVHD
The number of participants with incidence of acute GVHD by grade was given. Participants are graded on a scale from 1 to 4, with 1 being mild and 4 being severe.
Time frame: 1 year
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Research Arm | Number of Participants With Acute GVHD | Grade 1 | 2 Participants |
| Research Arm | Number of Participants With Acute GVHD | Grade 4 | 0 Participants |
| Research Arm | Number of Participants With Acute GVHD | Grade 2 | 1 Participants |
| Research Arm | Number of Participants With Acute GVHD | No Acute GVHD | 5 Participants |
| Research Arm | Number of Participants With Acute GVHD | Grade 3 | 1 Participants |
| Observational Arm | Number of Participants With Acute GVHD | No Acute GVHD | 3 Participants |
| Observational Arm | Number of Participants With Acute GVHD | Grade 4 | 0 Participants |
| Observational Arm | Number of Participants With Acute GVHD | Grade 2 | 0 Participants |
| Observational Arm | Number of Participants With Acute GVHD | Grade 1 | 0 Participants |
| Observational Arm | Number of Participants With Acute GVHD | Grade 3 | 1 Participants |
Secondary
Number of Participants With Chronic GVHD
Due to the small sample size, cumulative incidence analysis was not done. The incidence of chronic GVHD was evaluated using NIH Consensus Global Severity Scoring. The number of patients with incidence of chronic GVHD by severity was provided.
Time frame: 1 year
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Research Arm | Number of Participants With Chronic GVHD | Mild | 0 Participants |
| Research Arm | Number of Participants With Chronic GVHD | Moderate | 0 Participants |
| Research Arm | Number of Participants With Chronic GVHD | Severe | 0 Participants |
| Research Arm | Number of Participants With Chronic GVHD | No Chronic GVHD | 9 Participants |
| Observational Arm | Number of Participants With Chronic GVHD | No Chronic GVHD | 4 Participants |
| Observational Arm | Number of Participants With Chronic GVHD | Mild | 0 Participants |
| Observational Arm | Number of Participants With Chronic GVHD | Severe | 0 Participants |
| Observational Arm | Number of Participants With Chronic GVHD | Moderate | 0 Participants |
Secondary
The Number of Participants With Transplant-related Morbidity
Any patient who had adverse events listed either as probable or definite in the first 100 days post-transplant are counted as transplant related morbidity. The number of patients with transplant-related morbidity was given.
Time frame: first 100 days post transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Research Arm | The Number of Participants With Transplant-related Morbidity | 8 Participants |
| Observational Arm | The Number of Participants With Transplant-related Morbidity | 3 Participants |
Secondary
Time to Engraftment of Research Arm Participants
Platelet engraftment was defined as platelet count ≥20,000/mm\^3 for 3 consecutive tests performed on different days with no platelet transfusions in the preceding 7 days. Neutrophil engraftment will be defined as achieving ANC ≥ 500/mm3 for 3 consecutive tests performed on different days with evidence of donor cell engraftment. Descriptive statistics are provided.
Time frame: first 100 days post transplant
Population: Those patients who did not reach engraftment are not included in the results provided below.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Research Arm | Time to Engraftment of Research Arm Participants | Days to Platelets ≥20,000 | 42.67 Days | Standard Deviation 8.8 |
| Research Arm | Time to Engraftment of Research Arm Participants | Days to ANC ≥500 | 17.11 Days | Standard Deviation 5.93 |