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Reduced Intensity Chemotherapy and Total Body Irradiation before TCR-alpha / beta+ T-lymphocytes Donor Transplant in Treating Participants with High-Risk Myeloid Diseases

Trial Status: Active

This phase I trial studies how well reduced intensity chemotherapy and total-body irradiation before allogeneic TCR alpha / beta-positive T-lymphocyte-depleted peripheral blood stem cells (TCR-alpha / beta+ T-lymphocytes donor transplant) works in treating participants with high-risk myeloid diseases. Giving chemotherapy such as anti-thymocyte globulin and fludarabine phosphate, as well as total-body irradiation before a donor peripheral blood stem cell transplant helps stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. It may also stop the participant's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the participant they may help the participant's bone marrow make stem cells, red blood cells, white blood cells, and platelets. 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.

Inclusion Criteria

  • Patients with one of the high risk myeloid diseases as outlined below. Patients must have =< 5% blasts on the last bone marrow (BM) evaluation prior to starting the conditioning regimen. Diseases included on this protocol include: * Acute myeloid leukemia (AML) in first complete remission (CR1) with intermediate or high risk features as defined below: ** Cytogenetic abnormalities which are not considered “good risk” cytogenetic features (i.e. t(8:21), t(15:17), inv 16 without c-kit mutations. And/or ** Therapy related AML with history of antineoplastic therapy (radiation and/or chemotherapy) And/or ** Normal karyotype with mutations of FLT3, RUNX1, TP53 mutation, ASXL1 or any others that are considered to be high risk * AML in >= 2nd remission * Myelodysplastic syndrome, myeloproliferative neoplasms, or MDS/myeloproliferative neoplasms (MPN) overlap syndrome with: ** International prognostic scoring system risk score intermediate-2 (INT-2) or high risk at the time of transplant evaluation. And/or ** Any risk category if life-threatening cytopenia exists And/or ** 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. * Chronic myelomonocytic leukemia (CMML). * Chronic myeloid leukemia (CML) with the following features: ** Patients who have failed or are intolerant to BCR-ABL tyrosine kinase inhibitors. And/or ** CML with BCR-ABL mutation consistent with poor response to tyrosine kinase inhibition (e.g. T351l mutation) * Patients with severe aplastic anemia.
  • Chronic lymphocytic leukemia (CLL) with high risk disease as defined by the European Society for Blood and Marrow Transplantation (EBMT) consensus criteria
  • 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.
  • Multiple Myeloma with disease in the following categories: * Patients with relapsed multiple myeloma following autologous stem cell transplantation who have achieved at least partial response following additional chemotherapy * Patients with high risk cytogenetics at diagnosis must have achieved at least a partial response following autologous stem cell transplantation. Patients must have complex karyotype, del17p, t4;14, and/or t14;16 by fluorescence in situ hybridization (FISH) and/or del13 by karyotyping.
  • Each patient must be willing to participate as a research participant and must sign an informed consent form.
  • Patients must have a Karnofsky (adult) or performance status >= 70%.
  • Cardiac: Asymptomatic or if symptomatic, then left ventricular ejection fraction (LVEF) at rest must be >= 40% and must improve with exercise.
  • Hepatic: < 5 x upper limit of normal (ULN) alanine aminotransferase (ALT).
  • Hepatic: < 2 x ULN total serum bilirubin, unless there is congenital benign hyperbilirubinemia.
  • Renal: Creatinine clearance (CrCl) >= 30 ml/min (measured or calculated/estimated).
  • Pulmonary: Asymptomatic or if symptomatic, diffusion capacity of the lung for carbon monoxide (DLCO) > 50% of predicted (corrected for hemoglobin).
  • DONOR: Must be a 10/10 human leukocyte antigen (HLA) genotypically match related or unrelated donor at all A, B, C, DRB1, and DQB1 loci, as tested by deoxyribonucleic acid (DNA) analysis.
  • DONOR: Able to provide informed consent for the donation process per institutional standards.
  • DONOR: Meet standard criteria for donor collection as defined by the National Marrow Donor Program Guidelines.

Exclusion Criteria

  • Prior allogenic hematopoietic stem cell transplantation.
  • Prior radiation therapy with 400 cGY or more of TBI.
  • BM with increased fibrosis (reticulin stain > 1/3).
  • Active and uncontrolled infection at time of transplantation.
  • Human immunodeficiency virus (HIV) infection.
  • Seropositivity for human T-lymphotrophic virus (HTLV)-1.
  • Inadequate performance status/organ function.
  • Pregnancy or breast feeding.
  • Patient or guardian unable to give informed consent or unable to comply with the treatment protocol including appropriate supportive care, follow-up, and research tests.

New Jersey

Middletown
Memorial Sloan Kettering Monmouth
Status: ACTIVE
Contact: Roni Tamari
Phone: 646-608-3738

New York

New York
Memorial Sloan Kettering Cancer Center
Status: ACTIVE
Contact: Roni Tamari
Phone: 646-608-3738

PRIMARY OBJECTIVE:

I. To assess the ability to achieve a sustained full donor myeloid engraftment after using a T cell depleted graft from matched related or unrelated donor and a reduced intensity conditioning regimen in patients with myeloid malignancies.

SECONDARY OBJECTIVES:

I. Subset chimerism at days +30, +60 +100, +180 and at 1, 1.5 and 2 years post-hematopoietic cell transplantation (HCT).

II. Counts recovery (platelet [PLT] > 20,000 and hemoglobin [Hb] > 8) at days 30 and 100 post-HCT.

III. Overall survival at 2 years post-transplant.

IV. Incidence of relapse at 2 years post-transplant.

V. Incidence of non-relapsed mortality at 2 years post-transplant.

VI. Incidence of viral infection and disease at day 100 and at 1 year post-transplant (specifically cytomegalovirus [CMV] reactivation and disease and Epstein-Barr virus [EBV] reactivation and EBV-post-transplant lymphoproliferative disease [PTLD]).

VII. Incidence and severity of chronic graft versus host disease (GVHD) at 2 year post-transplant.

VIII. Incidence and severity of acute GVHD at 100 days and at 1 year post-transplant.

IX. Immune recovery after transplant at days 100, 180 and at 1 year post-transplant.

X. Assess toxicities early (first 100 days) and late (> 100 days) post-transplant.

CORRELATIVE OBJECTIVES:

I. Assess T cell response to viruses that are commonly reactivated post allo-HSCT, i.e. CMV, EBV and adenovirus.

II. Assess reconstitution of TCR-alpha/beta+ T-lymphocytes after T-cell receptor (TCR)-alpha/beta+ lymphocyte depleted allografts at days +100, +180 and at 1 year post transplantation.

III. Assess for residual disease post allo-HSCT by using a panel of aberrantly expressed cell surface proteins that are highly specific and sensitive for the detection of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML).

OUTLINE:

REDUCED INTENSITY CONDITIONING: Participants receive anti-thymocyte globulin intravenously (IV) over 30 minutes once daily (QD) on days -8 to -6, fludarabine phosphate IV over 30 minutes on days -5 to -2, and undergo total body irradiation (TBI) over 20-30 minutes on days -2 and -1.

TRANSPLANT: Participants receive allogeneic TCR alpha/beta-positive T-lymphocyte-depleted peripheral blood stem cells on days 0.

POST-TRANSPLANT: Participants receive cyclophosphamide IV over 30 minutes on days 3-4 and rituximab IV over 90 minutes on day 5.

After completion of transplant, participants are followed up at 30, 60, and 100 days, at 6, 9, 12, 18, and 24 months, and then yearly for 5 years.

Trial Phase Phase I

Trial Type Treatment

Lead Organization
Memorial Sloan Kettering Cancer Center

Principal Investigator
Roni Tamari

  • Primary ID 17-639
  • Secondary IDs NCI-2018-01149
  • Clinicaltrials.gov ID NCT03531736