Hematologic Malignancy, Myeloid Malignancy
Conditions
Brief summary
The participants are being asked to take part in this clinical trial because the participant have a lymphoid or myeloid based cancer diagnosis that requires a bone marrow transplant. Primary Objectives To estimate the incidence of severe acute GVHD (saGVHD) using a prophylaxis regimen with no calcineurin inhibitors after day +60 post first allogeneic Human Leukocyte antigen (HLA)-matched sibling or unrelated donor HCT for hematological malignancies. Secondary objective Determine the cumulative incidence of relapse, NRM, chronic GVHD, and OS in study participants at one year post-transplant. Exploratory objectives * To evaluate the pharmacokinetic/pharmacodynamic (PK/PD) profiles of ruxolitinib, fludarabine, and rATG. * To assess immune reconstitution in study participants within the first year post-HCT.
Detailed description
The investigator propose to employ two preparative regimens based on the underlying hematological malignancy. For hematological malignancies of the lymphoid lineage we will use a standard preparative regimen consisting of Total Body Irradiation and cyclophosphamide (TBI/Cy), unless TBI is contraindicated. For myeloid malignancies we will use thiotepa, busulfan, and fludarabine (TBF), a preparative regimen that has been associated with a reduced risk of relapse and trend for improved survival with comparable NRM in comparison to busulfan and cyclophosphamide (BuCy), our current regimen. All HCT recipients will receive cyclosporine in combination with methotrexate and ruxolitinib as GVHD prophylaxis. Recipients of MUD HCT will receive rATG for additional immunosuppression as is standard for unrelated donor transplants
Interventions
DRUGRuxolitinib
Day +40 Dosage and Route of Administration-Ruxolitinib tablets should be administered orally BID, approximately every 12 hours, continuously, Oral
DRUGMesna
Days -3 and -2 Dosage and Route of Administration-Mesna is dosed based on the cyclophosphamide dose and generally administered in fractionated doses at approximately 20% of the total cyclophosphamide dose, Intravenous.
Days -3, -2 and -1 Dosage and Route of Administration-(7 mg/kg total dose); intravenous.
DRUGCyclosporine
Day -1 Dosage and Route of Administration-3 mg/kg; dose will be adjusted to maintain a steady concentration between 250-350 ng/mL or trough concentration between 175-250 ng/mL when transitioned to intermittent dosing.
DRUGCyclophosphamide
Days -3 and -2 Dosage and Route of Administration-60 mg/kg for 2 consecutive days, (120 mg/kg total dose); intravenous.
DRUGFludarabine
Days -4, -3 and -2 Dosage and Route of Administration-50 mg/m2 daily for 3 consecutive days (150 mg/m2 total dose) intravenous
DRUGMethotrexate
Days +1, +3, +6 and +11 Dosage and Route of Administration-10 mg/m2/dose, intravenous
RADIATIONTotal Body Irradiation (radiation treatment)
Days -7, -6, -5 and -4 6.2.3 Target Dose 1200 cGy total dose delivered 150 cGy per treatment fraction delivered BID over 4 days with 6 MV photons. Dose rate should be \< 10 cGy/min in patients treated at extended SSD (450-500 cm) in the TBI couch and will be less than 15 cGy/min in young children and infants treated at extended SSD (200-220 cm) on the floor. Intra-fraction interval should be 6 hours. Custom posteriorly placed (PA only) partial transmission lung shields (blocks) will be used to reduce the average dose to the lung to approximately 1000 cGy total dose. An additional 400 cGy supplemental testicular radiation delivered in 2 fractions of 200 cGy delivered for males with lymphoid lineage leukemia.
Day 0
DRUGBusulfan
Days -4, -3 and -2 Dosage and Route of Administration-3.2 mg/kg/day; intravenous.
DRUGThiotepa
Days -6 and -5 Dosage and Route of Administration-(10 mg/kg total dose); intravenous
Sponsors
St. Jude Children's Research Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Diagnosis: * Patients with high risk acute lymphoblastic leukemia in first remission. Examples include, but are not limited to, patients with certain leukemic cell cytogenetic findings (e.g. t(9;22) or t(4;11)); delayed response to induction chemotherapy; re-emergence of leukemic blasts by MRD (at any level) in patients previously MRD negative; persistently detectable MRD at lower levels; early T-cell precursor (ETP) ALL. * Patients with acute lymphoblastic leukemia beyond first remission. * Patients with Hodgkin's disease beyond first remission or with refractory disease. * Patients with chronic myelogenous leukemia. * Patients with primary or secondary myelodysplastic syndrome. * Patients with Non-Hodgkin's lymphoma beyond first remission or with refractory disease. * Patients with de novo acute myeloid leukemia in or beyond first remission or with relapsed or refractory disease, or myeloid sarcoma (extra-medullary AML). * Patients with secondary acute myeloid leukemia. * NK cell lymphoblastic leukemia in any CR. * Biphenotypic, bilineage, or undifferentiated leukemia. * Juvenile Myelomonocytic Leukemia (JMML) * All patients with prior evidence of CNS leukemia must be treated and be in CNS CR. Patients must have a related or unrelated donor matched at 12 of 12 HLA alleles. Patient must have a Karnofsky/Lansky score of 70 or higher. Patients must be 12 years of age or older. Patients must have a shortening fraction \>26% or left ventricular ejection fraction \>40%. Patients must have bilirubin less than or equal to 2.5 mg/dL and alanine aminotransferase (ALT) less than or equal to 5 times the upper limit of normal. Patients must have creatinine clearance, or a glomerular filtration rate (GFR), greater than 70 mL/min/1.73m2. Patients must be free of severe infection that upon determination of principal investigator precludes BMT. Patients must have FVC \>50% predicted OR, if unable to perform pulmonary function testing, must maintain pulse oximetry oxygen saturation \>92% on room air. Female patients of childbearing age must have a negative pregnancy test.
Exclusion criteria
* Patients who have undergone prior HCT. * Patients who have a peripheral blood stem cell graft source. * Patients who have a non-permissive mismatch at the DPB1 allele. * Patients who are HIV positive. * Patients positive for Hepatitis B surface antigen (HBsAg). * Patients positive for Hepatitis C. * Patients with latent tuberculosis with positive TB IFN gamma release assay.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of saGVHD Using a ProphylaxisRegimen With no Calcineurin Inhibitors After Day 100 Post First Allogeneic HLA-Matched Sibling or Unrelated Donor HCT for Hematological Malignancies. | 100 days post transplant | Development of Severe Acute GVHD (saGVHD) at or before Day 100 post transplant is considered as an event. Severe acute GVHD is defined as grade II-IVGVHD. Acute graft-vs-host disease will be evaluated using the standard grading criteria. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cumulative Incidence of Overall Survival (OS) | One-year post-transplantation. | The one-year survival is defined by the participant who has not died within one year after post transplantation. The rate is calculated by computing the ratio between total number of one year survival patients and the total number of patients. |
| Cumulative Incidence of Relapse | One-year post-transplantation. | Bone marrow studies for disease status evaluation will be performed at 1-year post-transplant. Testing will include a research evaluation for minimal residual disease. |
| Cumulative Incidence of Non Relapse Mortality (NRM) | One-year post-transplantation. | Non-relapse mortality is death without evidence of disease relapse or progression. The rate is calculated by computing the ratio between total number of NRM patients and the total number of patients. |
| Cumulative Incidence of Chronic GVHD | One-year post-transplantation. | Chronic graft-vs-host disease will be evaluated using the standard grading criteria. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Total Body Irradiation (TBI)/Cyclophosphamide (Cy) Patients with lymphoid malignancies will receive Total Body Irradiation (TBI)/Cyclophosphamide (Cy).
Bone marrow grafts will be used. HLA-identical sibling donors will be considered first followed by histocompatible relatives or unrelated donors. Permissive DPB1 mismatched grafts will be included. Unrelated grafts will be obtained through NMDP or other registries.
Participants receive 8 doses TBI. Cyclophosphamide, IV. Rabbit ATG, IV. Males with lymphoid lineage leukemia will receive an additional testicular boost concurrent with TBI.
Patients who receive a bone marrow product from MSD will not receive rATG.
G-CSF: Use of GCSF is not recommended except after day +21 when a single dose not exceeding 2.5mcg/kg may be given after rounding off if APC is \>500 cells/mm3, and ANC is\<500 cells/mm3 to mobilize cells.
Mesna: Mesna will be given IV approximately 15 minutes prior to each dose of cyclophosphamide and approximately 3, 6, 9, and 12 hours after each dose of cyclophosphamide.
GVHD prophylaxis: Cyclosporine, IV. Methotrexate, IV. Ruxolitinib, Oral or NG. | 2 |
| Thiotepa, Busulfan, and Fludarabine (TBF) Patients with myeloid, bi-phenotypic, bilineage or undifferentiated leukemia will receive thiotepa, busulfan, and fludarabine (TBF). Patients will receive TBF regimen when TBI is not appropriate.
Bone marrow grafts will be used. HLA-identical sibling donors will be considered first followed by histocompatible relatives or unrelated donors. Permissive DPB1 mismatched grafts will be included. Unrelated grafts will be obtained through NMDP or other registries.
Participants receive Thiotepa, IV. Busulfan, IV. Fludarabine, IV. Rabbit ATG, IV.
Patients who receive a bone marrow product from MSD will not receive rATG.
G-CSF: Use of GCSF is not recommended except after day +21 when a single dose not exceeding 2.5mcg/kg may be given after rounding off if APC is \>500 cells/mm3, and ANC is\<500 cells/mm3 to mobilize cells.
Levetiracetam IV will be prescribed as seizure prophylaxis for recipients receiving busulfan.
GVHD prophylaxis: Cyclosporine, IV. Methotrexate, IV. Ruxolitinib, Oral or NG. | 1 |
| Total | 3 |
Baseline characteristics
| Characteristic | Thiotepa, Busulfan, and Fludarabine (TBF) | Total | Total Body Irradiation (TBI)/Cyclophosphamide (Cy) |
|---|---|---|---|
| Age, Continuous | 17 years STANDARD_DEVIATION 0 | 16.25 years STANDARD_DEVIATION 3.6 | 15.5 years STANDARD_DEVIATION 4.95 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 1 Participants | 3 Participants | 2 Participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 1 Participants |
| Sex: Female, Male Male | 0 Participants | 1 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 2 | 0 / 1 |
| other Total, other adverse events | 2 / 2 | 1 / 1 |
| serious Total, serious adverse events | 2 / 2 | 1 / 1 |
Outcome results
Primary
Proportion of saGVHD Using a ProphylaxisRegimen With no Calcineurin Inhibitors After Day 100 Post First Allogeneic HLA-Matched Sibling or Unrelated Donor HCT for Hematological Malignancies.
Development of Severe Acute GVHD (saGVHD) at or before Day 100 post transplant is considered as an event. Severe acute GVHD is defined as grade II-IVGVHD. Acute graft-vs-host disease will be evaluated using the standard grading criteria.
Time frame: 100 days post transplant
Population: None of the 3 participants had saGVHD.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Total Body Irradiation (TBI)/Cyclophosphamide (Cy) | Proportion of saGVHD Using a ProphylaxisRegimen With no Calcineurin Inhibitors After Day 100 Post First Allogeneic HLA-Matched Sibling or Unrelated Donor HCT for Hematological Malignancies. | 0 Participants |
| Thiotepa, Busulfan, and Fludarabine (TBF) | Proportion of saGVHD Using a ProphylaxisRegimen With no Calcineurin Inhibitors After Day 100 Post First Allogeneic HLA-Matched Sibling or Unrelated Donor HCT for Hematological Malignancies. | 0 Participants |
Secondary
Cumulative Incidence of Chronic GVHD
Chronic graft-vs-host disease will be evaluated using the standard grading criteria.
Time frame: One-year post-transplantation.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Total Body Irradiation (TBI)/Cyclophosphamide (Cy) | Cumulative Incidence of Chronic GVHD | 0 Participants |
| Thiotepa, Busulfan, and Fludarabine (TBF) | Cumulative Incidence of Chronic GVHD | 0 Participants |
Secondary
Cumulative Incidence of Non Relapse Mortality (NRM)
Non-relapse mortality is death without evidence of disease relapse or progression. The rate is calculated by computing the ratio between total number of NRM patients and the total number of patients.
Time frame: One-year post-transplantation.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Total Body Irradiation (TBI)/Cyclophosphamide (Cy) | Cumulative Incidence of Non Relapse Mortality (NRM) | 0 Participants |
| Thiotepa, Busulfan, and Fludarabine (TBF) | Cumulative Incidence of Non Relapse Mortality (NRM) | 0 Participants |
Secondary
Cumulative Incidence of Overall Survival (OS)
The one-year survival is defined by the participant who has not died within one year after post transplantation. The rate is calculated by computing the ratio between total number of one year survival patients and the total number of patients.
Time frame: One-year post-transplantation.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Total Body Irradiation (TBI)/Cyclophosphamide (Cy) | Cumulative Incidence of Overall Survival (OS) | 1 Participants |
| Thiotepa, Busulfan, and Fludarabine (TBF) | Cumulative Incidence of Overall Survival (OS) | 1 Participants |
Secondary
Cumulative Incidence of Relapse
Bone marrow studies for disease status evaluation will be performed at 1-year post-transplant. Testing will include a research evaluation for minimal residual disease.
Time frame: One-year post-transplantation.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Total Body Irradiation (TBI)/Cyclophosphamide (Cy) | Cumulative Incidence of Relapse | 0 Participants |
| Thiotepa, Busulfan, and Fludarabine (TBF) | Cumulative Incidence of Relapse | 0 Participants |