Donor Stem Cell Transplant using Alpha / Beta+ T-Cell Depletion in Treating Patients with Hematologic Malignancies
This phase II trial studies the side effects of donor stem cell transplant using allogeneic TCR alpha / beta-positive T-lymphocyte-depleted peripheral blood stem cells (alpha / beta positive [+] T-cell depletion) in treating patients with hematologic malignancies. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. The donated stem cells may also replace the patient’s immune cells and help destroy any remaining cancer cells. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells called graft-versus-host disease. Removing the T cells from the donor cells before the transplant may stop this from happening.
- 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 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 central nervous system (CNS) or other extramedullary involvement ** White blood cell count (WBC) count >= 100,000 cells/uL 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, including: *** Mutated FLT3-ITD or FLT3-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;22); BCR-ABL1 *** Inversions or translocations of chromosome 3 *** T(6;9)(p23;q34.1); DEK-NUP214 *** Somatic mutation of RUNX1, ASXL1 or TP53 ** Extramedullary involvement ** WBC count >= 100,000 cells/uL at diagnosis * Relapsed acute leukemia with =< 5% blasts in the bone marrow prior to transplantation (i.e. second complete response [CR2] or greater) * Myelodysplastic syndrome, myeloproliferative neoplasms, or MDS/myeloproliferative neoplasms (MPN) overlap syndrome with =< 10% blasts and at least one of the following: ** Revised International Prognostic Scoring System (IPSS) risk score of intermediate (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 European Group for Blood and Marrow Transplantation (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 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
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (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 diffusion lung capacity (DLCO) >= 50% of predicted
- DONOR: Partially HLA-matched unrelated volunteers (allele level matched at 6-7 of 8 HLA loci: -A, -B, -C, and -DRB1) are eligible
- DONOR: Related, haploidentical donors are eligible
- DONOR: Able to provide informed consent to the donation process
- DONOR: Meet standard criteria for donor collection as defined by the National Marrow Donor Program Guidelines
- 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 human immunodeficiency virus (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
- Patients with previous checkpoint inhibitor therapy such as PD-1/PDL-1 inhibitors cannot undergo transplantation less than 6 weeks from the last checkpoint inhibitor therapy
Locations & Contacts
Contact: Brian C. Shaffer
Trial Objectives and Outline
I. To estimate the incidence of grade 3-4 acute graft versus host disease in persons undergoing human leukocyte antigen (HLA)-mismatched allogeneic hematopoietic cell transplantation with grafts depleted of T cell receptor (TCR)-alpha/beta+ cells.
I. To estimate overall survival at one year.
II. To estimate the cumulative incidence of non-relapse mortality at one year.
III. To estimate the cumulative incidence of relapse at one year.
IV. To determine reconstitution of CD4+, CD8+ T-lymphocytes, CD19+ B-lymphocytes.
I. To determine reconstitution of TCR-alpha/beta+ T-lymphocytes after TCR-alpha/beta+ lymphocyte depleted allografts at 30, 100, 180, and 365 days post transplantation.
OUTLINE: Participants are assigned to 1 of 3 regimens.
REGIMEN A: Participants with lymphoid malignancies including acute lymphoblastic leukemia, myelodysplastic syndrome (MDS), or acute myeloid leukemia (AML) undergo total body irradiation on days -9 to -6. Participants also receive thiotepa intravenously (IV) on days -5 to -4, cyclophosphamide IV on days -3 to -2, and rabbit anti-thymocyte globulin IV on days -3 to -2 in the absence of disease progression or unacceptable toxicity.
REGIMEN B: Participants with MDS or AML receive busulfan IV over 2 hours on days -9 to -7, melphalan IV over 30 minutes on days -6 to -5, fludarabine IV over 30 minutes on days -6 to -2, and rabbit anti-thymocyte globulin IV on days -3 to -2 in the absence of disease progression or unacceptable toxicity.
REGIMEN C: Participants with lymphoid malignancies including acute lymphoblastic leukemia receive clofarabine IV over 2 hours on days -9 to -5, thiotepa IV on day -4, melphalan IV over 30 minutes on days -3 to -2, and rabbit anti-thymocyte globulin IV on days -3 to -2 in the absence of disease progression or unacceptable toxicity.
T-CELL INFUSION: Participants receive allogeneic TCR alpha/beta-positive T-lymphocyte-depleted peripheral blood stem cells via infusion on day 0.
POST-T CELL INFUSION: Participants receive tacrolimus orally (PO) or IV on -3 to 30 with taper through day 100. Participants also receive rituximab IV over 30-60 minutes on day 5 and filgrastim IV on day 7 in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, participants are followed up at 30, 60, and 100 days, and at 6, 12, and 18 months.
Trial Phase & Type
Memorial Sloan Kettering Cancer Center
Brian C. Shaffer
Secondary IDs NCI-2018-01805
Clinicaltrials.gov ID NCT03615105