Hematologic Malignancies
Conditions
Keywords
Allogeneic transplant, Hematologic Malignancies, Acute Leukemia, Myeloproliferative disorders, Lymphoma, Myeloma
Brief summary
In this trial, we aim to improve the outcomes of haplo cord transplant. Haplo cord transplant is a novel and promising way to improve transplant outcomes. We hypothesize that identification of a graft that is at least 5/6 matched and inherited paternal antigen (IPA) targeted (i.e., cord blood grafts share one or more IPA antigens with the prospective recipient) is more important to the outcome of haplo cord transplant than the nucleated cell dose. The identification of such a graft for a large proportion of the subjects may necessitate accepting a lower umbilical cord graft dose. In addition to a umbilical cord blood transplant, recipients will receive stem cells from a family member ( a haplo-identical donor) . After collection and prior to infusion, these cells will be purified using a device called a CliniMACS CD34 selection device. The subject will undergo a chemotherapy conditioning regimen prior to transplantation. No experimental drugs are used in this study, and the combinations of drugs that will be used in the conditioning regimen are combinations that have been used in the past.
Detailed description
This is a clinical trial for subjects with hematologic malignancies ( acute leukemia, myeloproliferative disorders, lymphoma, myeloma) who are in need of a donor stem cell transplant, and for whom an umbilical cord blood transplant is thought to be the best option. As donors for allogeneic transplant, we typically try to use related family members, such as brothers or sisters, or volunteer donors who are 'HLA matched', i.e. share similar proteins on their cells. This study is for subjects for whom such a matched sibling donor or a matched unrelated donor is not available. For such subjects a commonly used transplant procedure is to use stem cells from one or two umbilical cords (UCB) from a newborn. These umbilical cord blood grafts, despite not completely matching the recipient, cause few problems with graft vs host disease (a common complication of transplant). But they tend to grow very slowly and subjects often have very prolonged hospital stays and are at high risk for complications due to low blood counts. Umbilical cord blood transplant will be the standard arm for this protocol. This study uses a new method of bone marrow transplantation called combined haplo-identical cord (haplo-cord) transplantation. In this procedure, cells from a related donor who shares half of the HLA proteins ( haplo-identical) are collected from the blood, as well as cells from an umbilical cord, and then both are transplanted. It is hoped that by using cells from a haplo-identical relative, subjects will have a faster recovery and require fewer transfusions. Over time the haplo-identical cells from the relative are replaced by the cells from the cord blood. The combined transplantation of haplo-identical stem cells and cord blood has previously been used in approximately 60 subjects with very encouraging results. Traditionally it has been felt that the most important determinant of outcome of an UCB stem cell transplant is the cord blood cell dose. The second determinant is the degree of matching between donor and recipient. Many times, we have difficulty identifying UCB units of sufficient cell dose that are well matched. Of interest,in our prior study of haplo-cord SCT indicated outcomes seemed independent of the UCB cell dose. If this preliminary observation is correct, we may be able to improve the outcomes of haplo cord transplant further by accepting lower threshold UCB doses and rather focusing on optimal matching (including matching for HLA and another characteristic called IPA). This is the primary objective of this study.
Interventions
The stem cells from the haplo-identical donor will be purified by a procedure called CD34 selection before they are given to the subject. A special device called the CliniMACS® CD34 Reagent System, which is not FDA approved, will be used for this purpose. The manufacturer of the device, Miltenyi Biotec, is providing the researchers access to the device for use in this research study. Because the stem cells from the haplo-identical donor are treated using the CliniMACS CD34 selection device, they cells are considered investigational.
DRUGFludarabine
Administer 30 mg/m2 /day intravenously x 5 days (Day -7 to Day -3) of a total dose of 150 mg/m2. Fludarabine will be dosed according to actual body weight.
DRUGMelphalan
Administer 70mg/m2/day intravenously x 2 days. Melphalan will be dosed according to actual body weight. Cryotherapy with ice chips will be administered to prevent mucositis
Administer 1.5 mg/kg/day intravenously x 3 days, total 4.5 mg/kg. ATG will be dosed according to actual body weight. The first dose will be infused over at least six hours, and subsequent doses over at least 4 hours. Pre-medications include acetaminophen 650 mg by mouth, diphenhydramine 25-50 mg by mouth or intravenously, and methylprednisolone 2 mg/kg (1 mg/ kg at the initiation and 1 mg/kg half-way through anti-thymocyte globulin administration).
DRUGRituximab
Administer one dose of 375 mg/m2 prior to or upon admission for all patients not previously exposed to rituximab or who have not received rituximab in the six months prior to transplant.
RADIATIONTotal Body Irradiation
Patients at high risk of CNS relapse (e.g. ALL or Burkitt's lymphoma) or patients at high risk for graft rejection (i.e., donor-specific HLA antibodies, patients with severe aplastic anemia, or hemoglobinopathies) may receive 2 doses of TBI as part of the conditioning.
DRUGMycophenolate Mofetil
Will be started on Day -2 and given at a dose of 1000 mg every 8 hours until Day 28. Mycophenolae Mofetil can be given orally or intravenously. Infection, toxicity, very low patient weight (\<50 kilograms) may prompt earlier discontinuation or adjustment of doses.
DRUGTacrolimus
Administered 0.03/mg/kg/day intravenous continious infusion (CI) over 24 hours from 4pm Day -2 until engraftment or when subject is able to take orally, then tacrolimus approximately 0.09 mg/kg orally in 2 divided doses. Tacrolimus should be given at full dose to maintain levels of 5-15 ng/mL through Day 180, tapered by 20% every week thereafter. Infection, toxicity or other clinical circumstances may prompt earlier discontinuation or adjustment of doses. In the presence of Graft versus Host Disease, a clinical decision by the attending physician will determine if tacrolimus can be tapered or should be continued. Oral tacrolimus can be used when intravenous access for CI tacrolimus is unavailable.
Sponsors
Weill Medical College of Cornell University
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subject must have a confirmed diagnosis of: 1. Previously Relapsed or refractory acute leukemia (myeloid or lymphoid) 2. Acute leukemia in first remission at high-risk for recurrence 3. Chronic myelogenous leukemia in chronic, accelerated phase or blast-crisis 4. Recurrent or refractory malignant lymphoma or Hodgkin lymphoma 5. Chronic lymphocytic leukemia, relapsed or with poor prognostic features 6. Multiple myeloma 7. Myelodysplastic syndrome 8. Chronic myeloproliferative disease 9. Hemoglobinopathies 10. Aplastic anemia 11. Other hematological disorder in need of allogeneic transplant (e.g. blastoid dendritic cell neoplasm) * Age ≥ 18 years * Likely to benefit from allogeneic transplant in the opinion of the transplant physician * An HLA-identical related or unrelated donor cannot be identified within an appropriate time frame. * Karnofsky (KPS) Performance status of \>= 70% * Acceptable organ function as defined below: Serum bilirubin: \< 2.0mg/dL ALT(SGPT): \< 3 X upper limit of normal Creatinine Clearance: \> 50 mL/min/1.73m2 (as estimated by the modified MDRD equation) * Ability to understand and the willingness to sign a written informed consent document
Exclusion criteria
* Life expectancy is severely limited by concomitant illness or uncontrolled infection * Severely decreased Left Ventricular Ejection Fraction (LVEF) or impaired pulmonary function tests (PFT's) * Evidence of chronic active hepatitis or cirrhosis * Uncontrolled HIV disease * Pregnant or lactating
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects Who Achieved Engraftment With De-Escalating Umbilical Cord Total Nucleated Cell (TNC) Dose | 100 days | We aim to identify the lowest threshold of umbilical cord total nucleated cell (TNC) dose that can be utilized assure durable umbilical cord blood engraftment in the haplo-cord transplants. The threshold will be defined as the lowest dose which assures cord blood engraftment occurs in at least 80% of subjects. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Long-term Survival of Subjects Undergoing Haplo-cord Transplants | 5 years after transplant | Evaluate the long term outcome of subjects undergoing haplo cord transplants using an optimally matched umbilical cord blood (UCB) graft (i.e. Survival, profession-free survival (PFS), Relapse, transplant-related mortality (TRM), toxicities, infections and GVHD) |
| Impact of IPA Targeting on Transplant Outcome | 5 years from transplantation | As much as possible, UCB units will be chosen to be IPA targeted. This is not always possible. We will therefore also retrospectively analyze transplant outcomes and correlate with IPA status. |
| Impact of NIMA Matching on Transplant Outcome | 5 years from transplantation | As much as possible, UCB units will be chosen to be NIMA matched. This is not always possible. We will therefore also retrospectively analyze transplant outcomes and correlate with NIMA status. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 - Minimum Cell Dose 2 x 10^7 TNC/kg All subjects in this cohort will receive a minimal cell dose of 2 x 10\^7 total nucleated cells (TNC)/kilogram (kg) for the umbilical cord blood unit.
Haplo-cord transplantation:
All subjects will receive a conditioning regimen of chemotherapy prior to stem cell transplantation. No experimental drugs are used in this study, and the combinations of drugs that will be used in the conditioning regimen are combinations that have been used in the past.
For the transplant component of treatment, subject will receive umbilical cord blood. The study involves transplantation of unlicensed units of cord blood. Therefore, these are considered investigational products.
In addition to the umbilical cord blood unit, recipients will receive stem cells from a family member ( a haplo-identical donor). After collection and prior to infusion, these cells will be purified using a device called a CliniMACS CD34 selection device. | 15 |
| Cohort 2 - Minimum Cell Dose 1 x 10^7 TNC/kg All subjects in this cohort will receive a minimal cell dose of 1 x 10\^7 total nucleated cells (TNC)/kilogram (kg) for the umbilical cord blood unit.
Haplo-cord transplantation:
All subjects will receive a conditioning regimen of chemotherapy prior to stem cell transplantation. No experimental drugs are used in this study, and the combinations of drugs that will be used in the conditioning regimen are combinations that have been used in the past.
For the transplant component of treatment, subject will receive umbilical cord blood. The study involves transplantation of unlicensed units of cord blood. Therefore, these are considered investigational products.
In addition to the umbilical cord blood unit, recipients will receive stem cells from a family member ( a haplo-identical donor). After collection and prior to infusion, these cells will be purified using a device called a CliniMACS CD34 selection device. | 20 |
| Cohort 3 - Minimum Cell Dose 0.5 x 10^7 TNC/kg All subjects in this cohort will receive a minimal cell dose of 0.5 x 10\^7 total nucleated cells (TNC)/kilogram (kg) for the umbilical cord blood unit.
Haplo-cord transplantation:
All subjects will receive a conditioning regimen of chemotherapy prior to stem cell transplantation. No experimental drugs are used in this study, and the combinations of drugs that will be used in the conditioning regimen are combinations that have been used in the past.
For the transplant component of treatment, subject will receive umbilical cord blood. The study involves transplantation of unlicensed units of cord blood. Therefore, these are considered investigational products.
In addition to the umbilical cord blood unit, recipients will receive stem cells from a family member ( a haplo-identical donor). After collection and prior to infusion, these cells will be purified using a device called a CliniMACS CD34 selection device. | 25 |
| Cohort 4 All subjects in this cohort will receive the minimum required cell dose that is determined following the dose de-escalation portion of the study (cohorts 1 through 3)
Haplo-cord transplantation:
All subjects will receive a conditioning regimen of chemotherapy prior to stem cell transplantation. No experimental drugs are used in this study, and the combinations of drugs that will be used in the conditioning regimen are combinations that have been used in the past.
For the transplant component of treatment, subject will receive umbilical cord blood. The study involves transplantation of unlicensed units of cord blood. Therefore, these are considered investigational products.
In addition to the umbilical cord blood unit, recipients will receive stem cells from a family member ( a haplo-identical donor). After collection and prior to infusion, these cells will be purified using a device called a CliniMACS CD34 selection device. | 210 |
| Total | 270 |
Baseline characteristics
| Characteristic | Cohort 4 | Total | Cohort 1 - Minimum Cell Dose 2 x 10^7 TNC/kg | Cohort 2 - Minimum Cell Dose 1 x 10^7 TNC/kg | Cohort 3 - Minimum Cell Dose 0.5 x 10^7 TNC/kg |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 46 Participants | 67 Participants | 4 Participants | 7 Participants | 10 Participants |
| Age, Categorical Between 18 and 65 years | 164 Participants | 203 Participants | 11 Participants | 13 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 16 Participants | 20 Participants | 0 Participants | 1 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 124 Participants | 159 Participants | 8 Participants | 14 Participants | 13 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 70 Participants | 91 Participants | 7 Participants | 5 Participants | 9 Participants |
| Primary Disease Acute Lymphoblastic Leukemia | 17 Participants | 23 Participants | 1 Participants | 3 Participants | 2 Participants |
| Primary Disease Acute Myeloid Leukemia | 109 Participants | 144 Participants | 9 Participants | 10 Participants | 16 Participants |
| Primary Disease Chronic Myelogenous Leukemia | 5 Participants | 5 Participants | 0 Participants | 0 Participants | 0 Participants |
| Primary Disease Hodgkin's Lymphoma | 5 Participants | 7 Participants | 0 Participants | 2 Participants | 0 Participants |
| Primary Disease Myelodysplastic Syndrome | 44 Participants | 50 Participants | 2 Participants | 1 Participants | 3 Participants |
| Primary Disease Myeloproliferative Neoplasm | 5 Participants | 5 Participants | 0 Participants | 0 Participants | 0 Participants |
| Primary Disease Non-Hodgkin's Lymphoma | 19 Participants | 28 Participants | 3 Participants | 2 Participants | 4 Participants |
| Primary Disease Other Acute Leukemia | 3 Participants | 3 Participants | 0 Participants | 0 Participants | 0 Participants |
| Primary Disease Other Leukemia (including Chronic Lymphocytic Leukemia) | 2 Participants | 3 Participants | 0 Participants | 1 Participants | 0 Participants |
| Primary Disease Severe Aplastic Anemia | 1 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 30 Participants | 34 Participants | 1 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 37 Participants | 45 Participants | 4 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 64 Participants | 84 Participants | 3 Participants | 6 Participants | 11 Participants |
| Race (NIH/OMB) White | 79 Participants | 106 Participants | 7 Participants | 11 Participants | 9 Participants |
| Region of Enrollment United States | 210 Participants | 270 Participants | 15 Participants | 20 Participants | 25 Participants |
| Sex: Female, Male Female | 94 Participants | 119 Participants | 7 Participants | 7 Participants | 11 Participants |
| Sex: Female, Male Male | 116 Participants | 151 Participants | 8 Participants | 13 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 6 / 15 | 6 / 20 | 11 / 25 | 79 / 210 |
| other Total, other adverse events | 6 / 15 | 6 / 20 | 12 / 25 | 93 / 210 |
| serious Total, serious adverse events | 7 / 15 | 9 / 20 | 14 / 25 | 156 / 210 |
Outcome results
Primary
Number of Subjects Who Achieved Engraftment With De-Escalating Umbilical Cord Total Nucleated Cell (TNC) Dose
We aim to identify the lowest threshold of umbilical cord total nucleated cell (TNC) dose that can be utilized assure durable umbilical cord blood engraftment in the haplo-cord transplants. The threshold will be defined as the lowest dose which assures cord blood engraftment occurs in at least 80% of subjects.
Time frame: 100 days
Population: A subset of participants were assessed to analyze the lowest threshold of umbilical cord total nucleated cell (TNC) dose. Once the lowest threshold was established, the remaining participants on study were treated based on that threshold.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| All Patients | Number of Subjects Who Achieved Engraftment With De-Escalating Umbilical Cord Total Nucleated Cell (TNC) Dose | Participants Achieving Engraftment with Minimum TNC of 2 x 10^5/kg | 15 participants |
| All Patients | Number of Subjects Who Achieved Engraftment With De-Escalating Umbilical Cord Total Nucleated Cell (TNC) Dose | Participants Achieving Engraftment with Minimum TNC of 1 x 10^5/kg in umbilical cord blood unit | 18 participants |
| All Patients | Number of Subjects Who Achieved Engraftment With De-Escalating Umbilical Cord Total Nucleated Cell (TNC) Dose | Participants Achieving Engraftment with Minimum TNC of 0.5 x 10^5/kg | 20 participants |
Secondary
Impact of IPA Targeting on Transplant Outcome
As much as possible, UCB units will be chosen to be IPA targeted. This is not always possible. We will therefore also retrospectively analyze transplant outcomes and correlate with IPA status.
Time frame: 5 years from transplantation
Secondary
Impact of NIMA Matching on Transplant Outcome
As much as possible, UCB units will be chosen to be NIMA matched. This is not always possible. We will therefore also retrospectively analyze transplant outcomes and correlate with NIMA status.
Time frame: 5 years from transplantation
Secondary
Long-term Survival of Subjects Undergoing Haplo-cord Transplants
Evaluate the long term outcome of subjects undergoing haplo cord transplants using an optimally matched umbilical cord blood (UCB) graft (i.e. Survival, profession-free survival (PFS), Relapse, transplant-related mortality (TRM), toxicities, infections and GVHD)
Time frame: 5 years after transplant