Acute Lymphoid Leukemia (ALL), Acute Myeloid Leukemia (AML), Chronic Myeloid Leukemia (CML), Hodgkin Lymphoma, Non-Hodgkin Lymphoma, Chronic Lymphocytic Leukemia
Conditions
Keywords
Allogeneic Hematopoietic Cell Transplantation, α/β+ T-lymphocyte, 18-224
Brief summary
This study is being done to learn whether a new method to prevent rejection between the donor immune system and the patient's body is effective.
Interventions
Hyperfractionated TBI is administered by a linear accelerator at a dose rate of \<20 cGy/minute. Doses of 125 cGy/fraction are administered at a minimum interval of 4 hours between fractions, three times/day for a total of 11 or 12 doses (1,375 or 1,500 cGy) over 4 days (days -9 through -6).
DRUGThiotepa
Thiotepa 5 mg/kg IV
DRUGCyclophosphamide
Cyclophosphamide 60 mg/kg IV
DRUGBusulfan
Busulfan (adult/ped dose)
DRUGFludarabine
Fludarabine 25 mg/m2 IV
DRUGMelphalan
Melphalan 70 mg/m2 IV
DRUGClofarabine
Clofarabine 20-30 mg/m2 IV
PROCEDUREHPC(A) stem cell allograft
All patients will receive anti-thymocyte globulin based conditioning followed by a G-CSF mobilized, peripheral blood hematopoietic progenitor cell HPC(A) product depleted of TCR-α/β+ Tlymphocytes using the CliniMACS system.
DRUGRituximab
Rituximab 200 mg IV flat dose
Rabbit antithymocyte globulin dosing per nomogram. This dynamic nomogram is based on absolute lymphocyte count at the start of conditioning and can result in either 2 or 3 day ATG administration. If a patient requires 2 day administration the subjequent chemotherapies may be moved forward by one day at the treating physician's discretion.
Sponsors
Memorial Sloan Kettering Cancer Center
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Participants will receive one of three myeloablative conditioning regimens followed by a Alpha/beta+ T-cell depleted peripheral blood stem cell product and short course tacrolimus. Donors are HLA mismatched unrelated adults or haploidentical family members.
Eligibility
Sex/Gender
ALL
Age
No minimum to 65 Years
Healthy volunteers
No
Inclusion criteria
Subject Inclusion Criteria: * Patients with any of the following hematologic malignancies who are considered to be eligible for allogeneic transplantation: * Acute lymphoid leukemia (ALL) in first complete remission (CR1) with high risk for relapse including: * Detectable minimal residual disease by either multicolor flow cytometry or by genomic assay after initial induction therapy * t(9;22) or detected BCR-ABL1 translocation by genomic methodologies * BCR-ABL1-Like B-ALL \[23\] including mutations of IKZF1 or CRLF2 * Translocations or mutations involving 11q23 (MLL) gene. * Hypodiploid karyotype * Deletion of 9p * Loss of 17p or TP53 mutation * T-lymphocyte lineage antigen expression (T-ALL) * Prior CNS or other extramedullary involvement * WBC count ≥ 100,000 cells/μL at diagnosis * Acute biphenotypic or bilineal leukemia in CR1 * Acute myeloid leukemia (AML) in CR1 with * Detectable minimal residual disease (MRD) by either multicolor flow cytometry or by genomic assay after initial induction therapy * In the absence of MRD any intermediate or high risk features according to the European LeukemiaNet 2017 guidelines indlucing: * Mutated FL T3-ITD or FL T3-TKD * Cytogenetic abnormalities not classified as favorable * Cytogenetic abnormalities associated with myelodysplastic syndrome including abnormalities of chromosome 5, 7, or 17p * Complex karyotype or monosomal karyotype * t(9;11)(p21.1;q23.3); MLL-KMT2A or other rearrangements of KMT2A * t(9;11); BCR-ABL1 * Inversions or translocations of chromosome 3 * T(6;9)(p23;q34.1); DEK-NUP214 * Somatic mutation of RUNX1, ASX1 or TP53 * Extramedullary involvement * WBC count ≥100,000 cells/μL at diagnosis * Relapsed acute leukemia with ≤ 5% blasts in the bone marrow prior to transplantation (i.e. CR2 or greater). * Myelodysplastic syndrome, myeloproliferative neoplasms, or MDS/MPN overlap syndrome with ≤ 10% blasts and at least one of the following: * Revised International Prognostic Scoring System risk score of INT, HIGH, or VERY HIGH at the time of transplant evaluation. * Life-threatening cytopenias * Karyotype or genomic changes that indicate high risk for progression to acute myelogenous leukemia, including abnormalities of chromosome 7 or 3, mutations of TP53, or complex or monosomal karyotype. * Therapy related disease or disease evolving from other malignant processes. * Chronic myelomonocytic leukemia (CMML) with ≤ 10% blasts prior to transplantation. * Chronic myeloid leukemia (CML) meeting one of the following criteria: * Failed or are intolerant to BCR-ABL tyrosine kinase inhibitors. * CML with BCR-ABL mutation consistent with poor response to tyrosine kinase inhibition (e.g. T351I mutation). * CML with accelerated or blast phase with \<10% blasts after therapy. * Chronic lymphocytic leukemia (CLL) with high risk disease as defined by the EBMT consensus criteria * Hodgkin lymphoma meeting both of the following criteria: * Responding to therapy prior to enrollment * Relapse after autologous bone marrow transplant or are ineligible for autologous bone marrow transplant. °Non-Hodgkin lymphoma meeting both of the following criteria: * Responding to therapy prior to enrollment. * Relapse after prior autologous bone marrow transplant or are ineligible for autologous bone marrow transplant. * Patients aged from birth through 65 years old are eligible. * Patients must have Karnofsky/Lanksy performance status ≥70%. * Cardiac left ventricular ejection fraction ≥50% at rest. * Serum bilirubin ≤ 2 mg/dL. Patients with Gilbert's disease or ongoing hemolytic anemia are acceptable if the direct bilirubin is ≤ 2 mg/dL. * AST and ALT ≤ 2.5 x ULN unless thought to be disease related * Estimated or measured creatinine clearance \> 50 mL/min/1.73 m\^2 body surface area. * Adult patients and pediatric patients capable of performing pulmonary function studies must have hemoglobin adjusted pulmonary DLCO ≥50% of predicted. Subject
Exclusion criteria
* Persons with a HLA matched sibling donor or a 8/8 allele level HLA-matched unrelated donor. * Female patients who are pregnant or breast-feeding. * Persons with an infection that is not responding to antimicrobial therapy. * Persons who are seropositive for HIV. * Persons with active/detectable central nervous system malignancy. * Persons who do not meet the age and organ function criteria specified above. * Presence of psychiatric or neurologic disease, or lack of social support that limits the patient's ability to comply with the treatment protocol including supportive care, followup, and research tests. * Prior allogeneic hematopoietic cell transplantation are ineligible. * Patients with history of other malignancy within 5 years of study therapy are ineligible with the following exceptions: Low grade prostate cancer (Gleason's ≤6) treated with curative intent, breast ductal carcinoma in situ treated with curative intent, or nonmelanomatous skin carcinomas. Donor Inclusion and
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| the Number of Incidences of Grade 3-4 Acute GVHD | 2 years | The intervention will be considered unpromising if the rate of GVHD is greater than 40% and promising if the rate is 20% or less. Number of participants with and without SAE will be evaluated. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Radiation, Thiotepa & Cyclophosphamide Hyperfractionated total body irradiation: Hyperfractionated TBI is administered by a linear accelerator at a dose rate of \<20 cGy/minute. Doses of 125 cGy/fraction are administered at a minimum interval of 4 hours between fractions, three times/day for a total of 11 or 12 doses (1,375 or 1,500 cGy) over 4 days (days -9 through -6).
Thiotepa: Thiotepa 5 mg/kg IV
Cyclophosphamide: Cyclophosphamide 60 mg/kg IV
HPC(A) stem cell allograft: All patients will receive anti-thymocyte globulin based conditioning followed by a G-CSF mobilized, peripheral blood hematopoietic progenitor cell HPC(A) product depleted of TCR-α/β+ Tlymphocytes using the CliniMACS system.
Rituximab: Rituximab 200 mg IV flat dose
Rabbit antithymocyte globulin: Rabbit antithymocyte globulin dosing per nomogram. This dynamic nomogram is based on absolute lymphocyte count at the start of conditioning and can result in either 2 or 3 day ATG administration. If a patient requires 2 day administration the subjequent chemotherapies may be moved forward by one day at the treating physician's discretion. | 3 |
| Busulfan, Fludarabine & Melphalan Busulfan: Busulfan (adult/ped dose)
Fludarabine: Fludarabine 25 mg/m2 IV
Melphalan: Melphalan 70 mg/m2 IV
HPC(A) stem cell allograft: All patients will receive anti-thymocyte globulin based conditioning followed by a G-CSF mobilized, peripheral blood hematopoietic progenitor cell HPC(A) product depleted of TCR-α/β+ Tlymphocytes using the CliniMACS system.
Rituximab: Rituximab 200 mg IV flat dose
Rabbit antithymocyte globulin: Rabbit antithymocyte globulin dosing per nomogram. This dynamic nomogram is based on absolute lymphocyte count at the start of conditioning and can result in either 2 or 3 day ATG administration. If a patient requires 2 day administration the subjequent chemotherapies may be moved forward by one day at the treating physician's discretion. | 5 |
| Clofarabine, Thiotepa & Melphalan Thiotepa: Thiotepa 5 mg/kg IV
Melphalan: Melphalan 70 mg/m2 IV
Clofarabine: Clofarabine 20-30 mg/m2 IV
HPC(A) stem cell allograft: All patients will receive anti-thymocyte globulin based conditioning followed by a G-CSF mobilized, peripheral blood hematopoietic progenitor cell HPC(A) product depleted of TCR-α/β+ Tlymphocytes using the CliniMACS system.
Rituximab: Rituximab 200 mg IV flat dose
Rabbit antithymocyte globulin: Rabbit antithymocyte globulin dosing per nomogram. This dynamic nomogram is based on absolute lymphocyte count at the start of conditioning and can result in either 2 or 3 day ATG administration. If a patient requires 2 day administration the subjequent chemotherapies may be moved forward by one day at the treating physician's discretion. | 1 |
| Total | 9 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 0 | 2 | 0 |
| Overall Study | Protocol Violation | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Busulfan, Fludarabine & Melphalan | Total | Radiation, Thiotepa & Cyclophosphamide | Clofarabine, Thiotepa & Melphalan |
|---|---|---|---|---|
| Age, Continuous | 31 years | 26 years | 20 years | 23 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 4 Participants | 2 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 4 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 2 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 3 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 2 Participants | 4 Participants | 2 Participants | 0 Participants |
| Region of Enrollment United States | 5 Participants | 9 Participants | 3 Participants | 1 Participants |
| Sex: Female, Male Female | 4 Participants | 6 Participants | 2 Participants | 0 Participants |
| Sex: Female, Male Male | 1 Participants | 3 Participants | 1 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 3 | 2 / 5 | 1 / 1 |
| other Total, other adverse events | 3 / 3 | 5 / 5 | 1 / 1 |
| serious Total, serious adverse events | 2 / 3 | 3 / 5 | 1 / 1 |
Outcome results
Primary
the Number of Incidences of Grade 3-4 Acute GVHD
The intervention will be considered unpromising if the rate of GVHD is greater than 40% and promising if the rate is 20% or less. Number of participants with and without SAE will be evaluated.
Time frame: 2 years
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Radiation, Thiotepa & Cyclophosphamide | the Number of Incidences of Grade 3-4 Acute GVHD | Number of participants with SAE | 2 Participants |
| Radiation, Thiotepa & Cyclophosphamide | the Number of Incidences of Grade 3-4 Acute GVHD | Number of participants without SAE | 1 Participants |
| Busulfan, Fludarabine & Melphalan | the Number of Incidences of Grade 3-4 Acute GVHD | Number of participants with SAE | 3 Participants |
| Busulfan, Fludarabine & Melphalan | the Number of Incidences of Grade 3-4 Acute GVHD | Number of participants without SAE | 2 Participants |
| Clofarabine, Thiotepa & Melphalan | the Number of Incidences of Grade 3-4 Acute GVHD | Number of participants with SAE | 1 Participants |
| Clofarabine, Thiotepa & Melphalan | the Number of Incidences of Grade 3-4 Acute GVHD | Number of participants without SAE | 0 Participants |