Acute Myeloid Leukemia, Chronic Lymphocytic Leukemia, Chronic Myeloid Leukemia, Myelodysplasia, Myeloproliferative Disorder, Myelofibrosis, Lymphoma, Lymphoma, Non-Hodgkin, Plasma Cell Disorder
Conditions
Keywords
haploidentical, transplant, peripheral blood, allogeneic
Brief summary
The standard Johns Hopkins' regimen will be used in study subjects, with the use of donor peripheral blood stem cells, rather than marrow. Clinical outcomes will be defined while focusing efforts on immune reconstitution focusing on immune checkpoint regulators after a related haploidentical stem cell transplant.
Detailed description
We propose a clinical trial to define clinical endpoints, including engraftment, 100-day survival and one year survival (Objective #1). We will characterize the incidence, prevalence and function of immune checkpoint regulators in patients' blood and bone marrow following transplantation (Objective #2). We will correlate these laboratory results with clinical outcomes and the incidence of GVHD. As an exploratory aim, in those patients experiencing GVHD and requiring treatment, we will define the frequency/expression of checkpoint regulator expression and correlate these results with the patient's response to GVHD therapy.
Interventions
DRUGCyclophosphamide
14.5 mg/kg for 2 days (days -6, -5) and then 50 mg/kg for two days (days 3, 4)
DRUGFludarabine
30 mg/m2 daily for 5 days
RADIATIONTotal Body Irradiation
200 centigray (cGy) for one day (day -1)
DRUGTacrolimus
1 mg IV daily, (or the oral equivalent) adjusted to achieve a level between 5 and 15 ng/ml. If there is no evidence of GVHD, discontinue Tacrolimus by Day 180.
DRUGcellcept
dose at 15 mg/kg po three times per day (maximum dose of 3 grams/day). Stop Cellcept at Day 35 following transplantation.
DRUGg-csf
5 mcg/kg/d starting day 5 and continue until Absolute Neutrophil Count (ANC) \> 1000/mcL for 3 days.
PROCEDUREPeripheral Blood Transplant
cell dose goal: \< 5 x 106 Hematopoietic progenitor cell antigen CD34+ cells/kg recipient weight
Sponsors
Dartmouth-Hitchcock Medical Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
Yes
Inclusion criteria
* Age: less than 75 years * The patient must be approved for transplant by the treating transplant physician. This includes completion of their pre-transplant workup, as directed by standard Dartmouth-Hitchcock Medical Center (DHMC) Standard Operating Procedure (SOP) (DHMC SOP - Pre-transplant Evaluation of allogeneic recipient (Appendix). * The patient must have a disease (listed below) with treatment-responsiveness that the treating transplant physician believes will benefit from an allogeneic stem cell transplant. The diseases include: * Acute leukemia - Acute Myeloid Leukemia, Acute Lymphocytic Leukemia * Chronic leukemia - Chronic Myeloid Leukemia, Chronic Lymphocytic Leukemia * Myelodysplasia * Myeloproliferative disorder * Myelofibrosis * Lymphoma - Non-Hodgkin's Lymphoma or Hodgkin's disease * Plasma cell disorder, including myeloma, Waldenstrom's Macroglobulinemia * Donor availability- the patient must have an identified RELATED haplo-identical donor * No Human Immunodeficiency Virus infection or active hepatitis B or C * Eastern Cooperative Oncology Group performance status: 0-2 * Diffusing capacity of carbon monoxide (DLCO) greater than or equal to 40 % predicted * Left ventricular ejection fraction greater than or equal to 40% * Serum bilirubin \< 2x upper limit of normal; transaminases \< 3x normal at the time of transplant * No active or uncontrollable infection * In female, a negative pregnancy test if experiencing menstrual periods * No major organ dysfunction precluding transplantation * No evidence of an active malignancy that would limit the patient's survival to less than 2 years. (If there is any question, the PI can make a decision).
Exclusion criteria
* Psychiatric disorder or a mental deficiency of the patient that is sufficiently severe to make compliance with the treatment unlikely, and making informed consent impossible. * Major anticipated illness or organ failure incompatible with survival from bone marrow transplant. * History of refractory systemic infection DONOR ELIGIBILITY * Human leukocyte antigen (HLA) haplo-identical matched related. * The donor must be healthy and must be willing to serve as a donor, based on standard National Marrow Donor Program (NMDP) guidelines and DHMC SOP - Donor Evaluation (Appendix) * The donor must have no significant co-morbidities that would put the donor at marked increased risk * There is no age restriction for the donor * Informed consent must be signed by donor DONOR
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Survived to 100-Days Post-transplant | 100 days post date of peripheral blood transplant | Define 100-day survival of subjects |
| Number of Participants Who Survived to One Year Post-Transplant. | One year post date of peripheral blood transplant | Define one year survival of subjects |
| Number of Participants Who Experienced a Successful Engraftment | Post-peripheral blood transplant | Define number of subjects who experience a successful engraftment: Defined as absolute neutrophil count \> 500/mm3 and platelets \> 20,000/mcl for three consecutive days (count first day as engraftment) |
| Number of Participants Who Achieved a Response to Treatment at 100 Days | 100 days post-peripheral blood transplant | Define response to treatment at 100 days post-peripheral blood transplant. The Standard International Criteria for responses for each disease will be used, based on CIBMTR (Center for International Blood and Marrow Transplant Research) criteria. |
| Number of Participants Who Achieved a Response to Treatment at One Year | One year post-peripheral blood transplant | Define response to treatment at one year post-peripheral blood transplant. The Standard International Criteria for responses for each disease will be used, based on CIBMTR (Center for International Blood and Marrow Transplant Research) criteria. |
| Number of Participants Who Experienced Toxicities Associated With This Treatment Regimen | Post-peripheral blood transplant | Define subjects who experienced toxicities associated with this treatment regimen |
| Number of Participants Who Had Incidence of Acute GVHD | Post-peripheral blood transplant | Define subjects who had incidence of acute GVHD |
| Number of Participants Who Had Incidence of Chronic GVHD | Post-peripheral blood transplant | Define subjects who had incidence of chronic GVHD |
| Number of Participants Who Experienced Donor-Recipient Chimerism Following Transplant at Days 30, 60, and 90. | Days 30, 60, and 90 post-peripheral blood transplant | Define subjects who experience donor-recipient chimerism following transplant at days 30, 60 and 90. All patients were assessed for donor-recipient chimerism at days 30, 60, and 90, but only one patient experienced chimerism. Day 90 for this patient is reported. |
| Number of Participants Who Experienced Treatment-Related Mortality Within the First 100 Days | 100 days post-peripheral blood transplant | Define subjects who experienced treatment-related mortality within the first 100 days post-peripheral blood transplant |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Immune Checkpoint Regulators - Incidence | Days 30, 60, and 90 post-transplant | To characterize the incidence of immune checkpoint regulators (V-domain Ig Suppressor of T-cell Activation, cytotoxic T-lymphocyte-associated protein 4 \[CTLA\], Programmed cell death protein 1 \[PD-1\]) during early immune recovery following an allogeneic stem cell transplant. |
| Myeloid-derived Suppressor Cells (MDSCs) After Graft vs. Host Disease (GVHD) Diagnosis - Checkpoint Regulator Expression | Post-transplant through study completion or death, assessed up to 3 years post-transplant | In those patients experiencing GVHD, the study team will define the checkpoint regulator expression on MDSCs |
| MDSCs After GVHD Diagnosis - Peripheral Blood Mononuclear Cells | Post-transplant through study completion or death, assessed up to 3 years post-transplant | In those patients experiencing GVHD, the study team will define the peripheral blood mononuclear cells and myeloid subsets. |
| MDSCs After GVHD Diagnosis - Myeloid Subsets Using Flow Cytometry | Post-transplant through study completion or death, assessed up to 3 years post-transplant | In those patients experiencing GVHD, the study team will define the myeloid subsets. |
| MDSCs After GVHD Diagnosis - Frequency | Post-transplant through study completion or death, assessed up to 3 years post-transplant | In those patients experiencing GVHD, the study team will define the MDSCs frequency. |
| Immune Checkpoint Regulators - Prevalence | Days 30, 60, and 90 post-transplant | To characterize the prevalence of immune checkpoint regulators (VISTA, CTLA-4, PD-1) during early immune recovery following an allogeneic stem cell transplant. |
| Immune Checkpoint Regulators - Function | Days 30, 60, and 90 post-transplant | Flow cytometry will be used to characterize the function of immune checkpoint regulators (VISTA, CTLA-4, PD-1) during early immune recovery following an allogeneic stem cell transplant. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORKenneth Meehan, MD
Dartmouth-Hitchcock Medical Center
Participant flow
Recruitment details
21 individuals signed consent. 1 individual was deemed ineligible during screening. Therefore 20 individuals were evaluated for the primary endpoint.
Participants by arm
| Arm | Count |
|---|---|
| Johns Hopkins' Conditioning Regimen Cyclophosphamide, fludarabine, total body irradiation, immune suppression including tacrolimus and cellcept, Granulocyte colony-stimulating factor (G-CSF), and peripheral blood transplant
Cyclophosphamide: 14.5 mg/kg for 2 days (days -6, -5) and then 50 mg/kg for two days (days 3, 4)
Fludarabine: 30 mg/m2 daily for 5 days
Total Body Irradiation: 200 centigray (cGy) for one day (day -1)
Tacrolimus: 1 mg IV daily, (or the oral equivalent) adjusted to achieve a level between 5 and 15 ng/ml. If there is no evidence of GVHD, discontinue Tacrolimus by Day 180.
cellcept: dose at 15 mg/kg po three times per day (maximum dose of 3 grams/day). Stop Cellcept at Day 35 following transplantation.
g-csf: 5 mcg/kg/d starting day 5 and continue until Absolute Neutrophil Count (ANC) \> 1000/mcL for 3 days.
Peripheral Blood Transplant: cell dose goal: \< 5 x 106 Hematopoietic progenitor cell antigen CD34+ cells/kg recipient weight | 20 |
| Total | 20 |
Baseline characteristics
| Characteristic | Johns Hopkins' Conditioning Regimen |
|---|---|
| Age, Categorical <=18 years | 1 Participants |
| Age, Categorical >=65 years | 10 Participants |
| Age, Categorical Between 18 and 65 years | 9 Participants |
| Age, Continuous | 59.55 Years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 20 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Number of Evaluable Participants | 20 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 20 Participants |
| Region of Enrollment United States | 20 participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 5 / 20 |
| other Total, other adverse events | 16 / 20 |
| serious Total, serious adverse events | 3 / 20 |
Outcome results
Primary
Number of Participants Who Achieved a Response to Treatment at 100 Days
Define response to treatment at 100 days post-peripheral blood transplant. The Standard International Criteria for responses for each disease will be used, based on CIBMTR (Center for International Blood and Marrow Transplant Research) criteria.
Time frame: 100 days post-peripheral blood transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Johns Hopkins' Conditioning Regimen | Number of Participants Who Achieved a Response to Treatment at 100 Days | 16 Participants |
Primary
Number of Participants Who Achieved a Response to Treatment at One Year
Define response to treatment at one year post-peripheral blood transplant. The Standard International Criteria for responses for each disease will be used, based on CIBMTR (Center for International Blood and Marrow Transplant Research) criteria.
Time frame: One year post-peripheral blood transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Johns Hopkins' Conditioning Regimen | Number of Participants Who Achieved a Response to Treatment at One Year | 13 Participants |
Primary
Number of Participants Who Experienced a Successful Engraftment
Define number of subjects who experience a successful engraftment: Defined as absolute neutrophil count \> 500/mm3 and platelets \> 20,000/mcl for three consecutive days (count first day as engraftment)
Time frame: Post-peripheral blood transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Johns Hopkins' Conditioning Regimen | Number of Participants Who Experienced a Successful Engraftment | 18 Participants |
Primary
Number of Participants Who Experienced Donor-Recipient Chimerism Following Transplant at Days 30, 60, and 90.
Define subjects who experience donor-recipient chimerism following transplant at days 30, 60 and 90. All patients were assessed for donor-recipient chimerism at days 30, 60, and 90, but only one patient experienced chimerism. Day 90 for this patient is reported.
Time frame: Days 30, 60, and 90 post-peripheral blood transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Johns Hopkins' Conditioning Regimen | Number of Participants Who Experienced Donor-Recipient Chimerism Following Transplant at Days 30, 60, and 90. | 1 Participants |
Primary
Number of Participants Who Experienced Toxicities Associated With This Treatment Regimen
Define subjects who experienced toxicities associated with this treatment regimen
Time frame: Post-peripheral blood transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Johns Hopkins' Conditioning Regimen | Number of Participants Who Experienced Toxicities Associated With This Treatment Regimen | 16 Participants |
Primary
Number of Participants Who Experienced Treatment-Related Mortality Within the First 100 Days
Define subjects who experienced treatment-related mortality within the first 100 days post-peripheral blood transplant
Time frame: 100 days post-peripheral blood transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Johns Hopkins' Conditioning Regimen | Number of Participants Who Experienced Treatment-Related Mortality Within the First 100 Days | 2 Participants |
Primary
Number of Participants Who Had Incidence of Acute GVHD
Define subjects who had incidence of acute GVHD
Time frame: Post-peripheral blood transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Johns Hopkins' Conditioning Regimen | Number of Participants Who Had Incidence of Acute GVHD | 3 Participants |
Primary
Number of Participants Who Had Incidence of Chronic GVHD
Define subjects who had incidence of chronic GVHD
Time frame: Post-peripheral blood transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Johns Hopkins' Conditioning Regimen | Number of Participants Who Had Incidence of Chronic GVHD | 9 Participants |
Primary
Number of Participants Who Survived to 100-Days Post-transplant
Define 100-day survival of subjects
Time frame: 100 days post date of peripheral blood transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Johns Hopkins' Conditioning Regimen | Number of Participants Who Survived to 100-Days Post-transplant | 18 Participants |
Primary
Number of Participants Who Survived to One Year Post-Transplant.
Define one year survival of subjects
Time frame: One year post date of peripheral blood transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Johns Hopkins' Conditioning Regimen | Number of Participants Who Survived to One Year Post-Transplant. | 16 Participants |
Secondary
Immune Checkpoint Regulators - Function
Flow cytometry will be used to characterize the function of immune checkpoint regulators (VISTA, CTLA-4, PD-1) during early immune recovery following an allogeneic stem cell transplant.
Time frame: Days 30, 60, and 90 post-transplant
Population: Blood samples were collected, however laboratory analysis was not performed due to lack of funding. There are no plans to potentially analyze the samples in the future, therefore these samples were not, and will not be, analyzed.
Secondary
Immune Checkpoint Regulators - Incidence
To characterize the incidence of immune checkpoint regulators (V-domain Ig Suppressor of T-cell Activation, cytotoxic T-lymphocyte-associated protein 4 \[CTLA\], Programmed cell death protein 1 \[PD-1\]) during early immune recovery following an allogeneic stem cell transplant.
Time frame: Days 30, 60, and 90 post-transplant
Population: Blood samples were collected, however laboratory analysis was not performed due to lack of funding. There are no plans to potentially analyze the samples in the future, therefore these samples were not, and will not be, analyzed.
Secondary
Immune Checkpoint Regulators - Prevalence
To characterize the prevalence of immune checkpoint regulators (VISTA, CTLA-4, PD-1) during early immune recovery following an allogeneic stem cell transplant.
Time frame: Days 30, 60, and 90 post-transplant
Population: Blood samples were collected, however laboratory analysis was not performed due to lack of funding. There are no plans to potentially analyze the samples in the future, therefore these samples were not, and will not be, analyzed.
Secondary
MDSCs After GVHD Diagnosis - Frequency
In those patients experiencing GVHD, the study team will define the MDSCs frequency.
Time frame: Post-transplant through study completion or death, assessed up to 3 years post-transplant
Population: Blood samples were collected, however laboratory analysis was not performed due to lack of funding. There are no plans to potentially analyze the samples in the future, therefore these samples were not, and will not be, analyzed.
Secondary
MDSCs After GVHD Diagnosis - Myeloid Subsets Using Flow Cytometry
In those patients experiencing GVHD, the study team will define the myeloid subsets.
Time frame: Post-transplant through study completion or death, assessed up to 3 years post-transplant
Population: Blood samples were collected, however laboratory analysis was not performed due to lack of funding. There are no plans to potentially analyze the samples in the future, therefore these samples were not, and will not be, analyzed.
Secondary
MDSCs After GVHD Diagnosis - Peripheral Blood Mononuclear Cells
In those patients experiencing GVHD, the study team will define the peripheral blood mononuclear cells and myeloid subsets.
Time frame: Post-transplant through study completion or death, assessed up to 3 years post-transplant
Population: Blood samples were collected, however laboratory analysis was not performed due to lack of funding. There are no plans to potentially analyze the samples in the future, therefore these samples were not, and will not be, analyzed.
Secondary
Myeloid-derived Suppressor Cells (MDSCs) After Graft vs. Host Disease (GVHD) Diagnosis - Checkpoint Regulator Expression
In those patients experiencing GVHD, the study team will define the checkpoint regulator expression on MDSCs
Time frame: Post-transplant through study completion or death, assessed up to 3 years post-transplant
Population: Blood samples were collected, however laboratory analysis was not performed due to lack of funding. There are no plans to potentially analyze the samples in the future, therefore these samples were not, and will not be, analyzed.