Non-Hodgkin's Lymphoma, Hodgkin's Lymphoma, Multiple Myeloma, Chronic Lymphocytic Leukemia, Acute Myelogenous Leukemia
Conditions
Keywords
NHL, lymphoma, leukemia, myelodysplastic disorder, aplastic anemia
Brief summary
This trial will use two cord blood units for transplantation using a reduced intensity regimen rather than using intense doses of chemotherapy and radiation therapy. Two cord blood units (double cord blood) are being used, as the numbers of blood cells in one unit are too few to allow successful growth of these cells. Because the risk of infection, particularly virus infection, is high after double cord blood transplant, this study seeks to reduce the rise of virus infection by using a reduced intensity regimen without a medicine called antithymocyte globulin (ATG), as used in prior cord blood transplants. Subjects will receive two chemotherapy drugs, melphalan and fludarabine, and low dose of total body radiation (one treatment) instead of the ATG. The number of patients with virus infections in this study will be compared to our prior experience using the ATG.
Detailed description
Subjects will receive their transplants as in-patients. * IV-Catheter * one or two IV catheters will be placed on the day of hospital admission * Conditioning * Fludarabine IV six days before transplant (days -7, -6, -5. -4, -3, -2) * Melphalan IV (day -1) * Total body radiation on day 0 (same day as transplant) * Immunosuppressive Therapy * Tacrolimus and sirolimus beginning day -3, daily for 6-9 months post-transplant. Given IV as in-patient, orally as out-patient * Infusion of Cord Blood units * 2 cord blood units IV on Day 0 Routine post-transplant supportive care will be provided
Interventions
DRUGFludarabine
30 mg/m2/day IV x 6 days
DRUGMelphalan
100 mg/m2/day IV x 1 day
RADIATIONTotal Body Radiation
200 cGy on Day 0
BIOLOGICALCord Blood
2 cord blood units IV
Sponsors
Massachusetts General Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Hematologic malignancy for whom allogeneic stem cell transplantation is deemed clinically appropriate * Appropriate candidate for reduced intensity regimen, according to the treating physician * Lack of 6/6/ or 5/6 HLA-matched related, 8/8/ HLA-matched unrelated donor, or unrelated donor not available with a time frame necessary to perform a potentially curative stem cell transplant * Able to comply with the requirements for care after allogeneic stem cell transplantation
Exclusion criteria
* Cardiac disease: symptomatic congestive heart failure or evidence of left ventricular dysfunction * Pulmonary disease: symptomatic chronic obstructive lung disease, symptomatic restrictive lung disease * Renal disease * Hepatic disease * Neurologic disease: symptomatic leukoencephalopathy, active CNS malignancy or other neuropsychiatric abnormalities believed to preclude transplantation * HIV-positive * Uncontrolled infection * Pregnant or breast-feeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With a Clinically Significant Infection | 1 Year | The one year significant infection rate (infections requiring medical intervention) after double umbilical cord blood transplant using a novel conditioning regimen of fludarabine/melphalan/low dose total body radiation. The data is shown as the number of significant infections participants experienced during the first year, measured from the start of treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Median Time to Platelet Engraftment | From the time of transplantation, until the time of platelet engraftment, median duration of 52 days | The time to platelet engraftment is measured from the time of transplantation until the time of first documented platelet engraftment. Platelet engraftment is defined as a platelet count ≥ 20,000/µL for three consecutive measurements over three or more days. The first of the three days will be designated the day of platelet engraftment. Subjects must not have had platelet transfusions during the preceding 3 days or in the following 7 days after the day of engraftment, unless the platelet transfusion is being given specifically to achieve a platelet threshold to allow an elective invasive procedure, such as a central catheter removal. |
| Number of Participants With Primary Graft Failure | From the time of transplantation until 42 days post transplantation | Primary graft failure is defined as the failure to achieve an absolute neutrophil count (ANC) \>500/ µL by day 42, in the absence of relapse. |
| Rates of Grade II-IV and Grade III-IV Acute Graft Versus Host Disease (GVHD) at 100 Days | 100 Days | Acute GVHD is assessed using Consensus Criteria: Organ Classifications: * 0: No rash due to GVHD; Bilirubin \< 2 mg/dL; \< 500 mL diarrhea/ day * 1: Maculopapular rash \< 25% of body surface; Bilirubin 2-3 mg/dL; 500 to 999 mL diarrhea/ day or persistent nausea with histologic evidence of GVHD in stomach/ duodenum * 2: Maculopapular rash 25-50% of body surface; Bilirubin 3.1-6 mg/dL; 1,000 to 1,499 mL diarrhea/ day * 3: Maculopapular rash \> 50% of body surface; Bilirubin 6.1-15 mg/dL; 1,500 or more mL diarrhea/ day * 4: Generalized erythroderma with bullous formation; Bilirubin \> 15 mg/dL; Severe abdominal pain with or without ileus Overall Clinical Grade: * 0: No Stage 1-4 of any organ * I: Stage 1-2 rash and no liver or gut involvement * II: Stage 3 rash, or Stage 1 liver involvement, or Stage 1 gut involvement * III: None to Stage 3 skin rash with Stage 2-3 liver involvement, or Stage 2-4 gut involvement * IV: Stage 4 skin rash, or Stage 4 liver involvement |
| The Rate of Chronic GVHD | From the time of transplantation until the time of chronic GVHD onset, up to 1 year | Chronic Graft Versus Host Disease (GVHD) is assessed using the National Institutes of Health (NIH) consensus criteria. |
| 100-day Treatment Related Mortality | 100 Days | The percentage of treatment related participant deaths within 100 days of receiving umbilical cord blood transplantation. All deaths in the absence of relapse of the primary malignancy will be considered treatment related mortality. |
| Median Time to Neutrophil Engraftment | From the time of transplantation, until the time of neutrophil engraftment, median duration of 24 days | The median number of days measured from the time of transplantation, until the first documented neutrophil engraftment. neutrophil engraftment is defined as the first of 3 consecutive days of absolute neutrophil count \> 500 neutrophils per microliter of blood. |
| Relapse-free Survival | 2 years | The percentage of participants that have not died or had disease progression by two years. Relapse is defined by either morphological or cytogenetic evidence of the original malignancy consistent with pre-transplant features. |
| Overall Survival | 2 years | The percentage of participants alive at two years |
| 1 Year Relapse Rate | 1 year | The percentage of participants that relapsed within 12 months. Relapse is defined by either morphological or cytogenetic evidence of the original malignancy consistent with pre-transplant features. |
| Rate of Post-transplant Lymphoma | 2.5 years | The number of participants that were found to have lymphoma post-transplant. |
| Median Thrombopoietin Levels After Transplant | 30 Days | — |
| Immune Reconstitution - Median CD4 Count at 12 Months | 1 Year | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Fludarabine/Melphalan/TBI All patients receive same therapy
Fludarabine: 30 mg/m2/day IV x 6 days
Melphalan: 100 mg/m2/day IV x 1 day
Total Body Radiation: 200 cGy on Day 0
Cord Blood: 2 cord blood units IV | 31 |
| Total | 31 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Ineligible after consent/ registration | 2 |
Baseline characteristics
| Characteristic | Fludarabine/Melphalan/TBI | — |
|---|---|---|
| Age, Continuous | 57 years | — |
| Disease Acute Lymphoblastic Leukemia (ALL) | 2 Participants | — |
| Disease Acute Myeloid Leukemia (AML) | 11 Participants | — |
| Disease Hodgkin's Disease (HD) | 1 Participants | — |
| Disease Myelodysplastic Syndromes (MDS) | 8 Participants | — |
| Disease Myeloproliferative Disorder (MPD) | 2 Participants | — |
| Disease Non-Hodgkin Lymphoma (NHL) | 7 Participants | — |
| Performance Status 0 | 10 Participants | — |
| Performance Status 1 | 19 Participants | — |
| Performance Status 2 | 2 Participants | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Region of Enrollment United States | 31 Participants | — |
| Sex: Female, Male Female | 9 Participants | — |
| Sex: Female, Male Male | 22 Participants | — |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 31 |
| other Total, other adverse events | 26 / 31 |
| serious Total, serious adverse events | 10 / 31 |
Outcome results
Primary
Number of Participants With a Clinically Significant Infection
The one year significant infection rate (infections requiring medical intervention) after double umbilical cord blood transplant using a novel conditioning regimen of fludarabine/melphalan/low dose total body radiation. The data is shown as the number of significant infections participants experienced during the first year, measured from the start of treatment.
Time frame: 1 Year
Population: The two participants found to be ineligible after being consented and registered were excluded from the analysis.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Fludarabine/Melphalan/TBI | Number of Participants With a Clinically Significant Infection | 0 Infections | 12 Participants |
| Fludarabine/Melphalan/TBI | Number of Participants With a Clinically Significant Infection | 1 Infection | 14 Participants |
| Fludarabine/Melphalan/TBI | Number of Participants With a Clinically Significant Infection | 2 Infections | 5 Participants |
Secondary
100-day Treatment Related Mortality
The percentage of treatment related participant deaths within 100 days of receiving umbilical cord blood transplantation. All deaths in the absence of relapse of the primary malignancy will be considered treatment related mortality.
Time frame: 100 Days
Population: The two participants found to be ineligible after being consented and registered were excluded from the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fludarabine/Melphalan/TBI | 100-day Treatment Related Mortality | 9.7 percentage of participants |
Secondary
1 Year Relapse Rate
The percentage of participants that relapsed within 12 months. Relapse is defined by either morphological or cytogenetic evidence of the original malignancy consistent with pre-transplant features.
Time frame: 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fludarabine/Melphalan/TBI | 1 Year Relapse Rate | 20 percentage |
Secondary
Immune Reconstitution - Median CD4 Count at 12 Months
Time frame: 1 Year
Population: CD4 counts were only available for 11 participants at the 12 months time point
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fludarabine/Melphalan/TBI | Immune Reconstitution - Median CD4 Count at 12 Months | 362.4 cells/mm3 |
Secondary
Median Thrombopoietin Levels After Transplant
Time frame: 30 Days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fludarabine/Melphalan/TBI | Median Thrombopoietin Levels After Transplant | 2500 pg/mL |
Secondary
Median Time to Neutrophil Engraftment
The median number of days measured from the time of transplantation, until the first documented neutrophil engraftment. neutrophil engraftment is defined as the first of 3 consecutive days of absolute neutrophil count \> 500 neutrophils per microliter of blood.
Time frame: From the time of transplantation, until the time of neutrophil engraftment, median duration of 24 days
Population: The two participants found to be ineligible after being consented and registered were excluded from the analysis. In addition to those two participants, the 8 participants that did not achieve engraftment were not included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fludarabine/Melphalan/TBI | Median Time to Neutrophil Engraftment | 24 Days |
Secondary
Median Time to Platelet Engraftment
The time to platelet engraftment is measured from the time of transplantation until the time of first documented platelet engraftment. Platelet engraftment is defined as a platelet count ≥ 20,000/µL for three consecutive measurements over three or more days. The first of the three days will be designated the day of platelet engraftment. Subjects must not have had platelet transfusions during the preceding 3 days or in the following 7 days after the day of engraftment, unless the platelet transfusion is being given specifically to achieve a platelet threshold to allow an elective invasive procedure, such as a central catheter removal.
Time frame: From the time of transplantation, until the time of platelet engraftment, median duration of 52 days
Population: The two participants found to be ineligible after being consented and registered were excluded from the analysis. In addition to those two participants, the 10 participants that did not achieve engraftment were not included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fludarabine/Melphalan/TBI | Median Time to Platelet Engraftment | 52 Days |
Secondary
Number of Participants With Primary Graft Failure
Primary graft failure is defined as the failure to achieve an absolute neutrophil count (ANC) \>500/ µL by day 42, in the absence of relapse.
Time frame: From the time of transplantation until 42 days post transplantation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Fludarabine/Melphalan/TBI | Number of Participants With Primary Graft Failure | 8 Participants |
Secondary
Overall Survival
The percentage of participants alive at two years
Time frame: 2 years
Population: The two participants found to be ineligible after being consented and registered were excluded from the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fludarabine/Melphalan/TBI | Overall Survival | 55 percentage of participants |
Secondary
Rate of Post-transplant Lymphoma
The number of participants that were found to have lymphoma post-transplant.
Time frame: 2.5 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Fludarabine/Melphalan/TBI | Rate of Post-transplant Lymphoma | 0 Participants |
Secondary
Rates of Grade II-IV and Grade III-IV Acute Graft Versus Host Disease (GVHD) at 100 Days
Acute GVHD is assessed using Consensus Criteria: Organ Classifications: * 0: No rash due to GVHD; Bilirubin \< 2 mg/dL; \< 500 mL diarrhea/ day * 1: Maculopapular rash \< 25% of body surface; Bilirubin 2-3 mg/dL; 500 to 999 mL diarrhea/ day or persistent nausea with histologic evidence of GVHD in stomach/ duodenum * 2: Maculopapular rash 25-50% of body surface; Bilirubin 3.1-6 mg/dL; 1,000 to 1,499 mL diarrhea/ day * 3: Maculopapular rash \> 50% of body surface; Bilirubin 6.1-15 mg/dL; 1,500 or more mL diarrhea/ day * 4: Generalized erythroderma with bullous formation; Bilirubin \> 15 mg/dL; Severe abdominal pain with or without ileus Overall Clinical Grade: * 0: No Stage 1-4 of any organ * I: Stage 1-2 rash and no liver or gut involvement * II: Stage 3 rash, or Stage 1 liver involvement, or Stage 1 gut involvement * III: None to Stage 3 skin rash with Stage 2-3 liver involvement, or Stage 2-4 gut involvement * IV: Stage 4 skin rash, or Stage 4 liver involvement
Time frame: 100 Days
Population: The two participants found to be ineligible after being consented and registered were excluded from the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fludarabine/Melphalan/TBI | Rates of Grade II-IV and Grade III-IV Acute Graft Versus Host Disease (GVHD) at 100 Days | 16 percentage of participants |
Secondary
Relapse-free Survival
The percentage of participants that have not died or had disease progression by two years. Relapse is defined by either morphological or cytogenetic evidence of the original malignancy consistent with pre-transplant features.
Time frame: 2 years
Population: The two participants found to be ineligible after being consented and registered were excluded from the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fludarabine/Melphalan/TBI | Relapse-free Survival | 49 percentage of participants |
Secondary
The Rate of Chronic GVHD
Chronic Graft Versus Host Disease (GVHD) is assessed using the National Institutes of Health (NIH) consensus criteria.
Time frame: From the time of transplantation until the time of chronic GVHD onset, up to 1 year
Population: The two participants found to be ineligible after being consented and registered were excluded from the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fludarabine/Melphalan/TBI | The Rate of Chronic GVHD | 21 percentage of participants |