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Amino Acids

Cyclophosphamide

Fludarabine

Fludarabine phosphate

Melphalan

Prednisolone

Lenograstim

Mycophenolic Acid

Tacrolimus

Methylprednisolone

Thiotepa

Methylprednisolone Acetate

Methylprednisolone Hemisuccinate

Prednisolone acetate

Prednisolone hemisuccinate

Prednisolone phosphate

Mechlorethamine

Mesna

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Alkylating Agents

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Phenylalanine

Interventions: cyclophosphamide, thiotepa, fludarabine, melphalan, mesna, granulocyte colony-stimulating factor (G-CSF), mycophenolate mofetil, tacrolimus, methylprednisolone, total lymphoid irradiation, and lymphocyte infusions.

Cells for infusion are prepared using the CliniMACS System.

Given by intravenous infusion as part of the preparative regimen.

Mesna is generally dosed at approximately 25% of the cyclophosphamide dose. It is generally given intravenously prior to and again at 3, 6 and 9 hours following each dose of cyclophosphamide.

Given either by intravenous infusion or subcutaneously daily until absolute neutrophil count (ANC) \>2000 for 3 consecutive days.

G-CSF

Given either orally or by intravenous infusion as part of the post-transplantation immunosuppression.

Mycophenolate mofetil

Given either intravenously or orally, if needed to treat graft-versus-host-disease (GVHD).

TLI will be administered in divided fractions given at a minimum of 6 hours apart.

Total lymphoid irradiation

Donors will undergo haploidentical mobilization with G-CSF. Cells will be collected by leukapheresis over two days, then processed using the investigational CliniMACS device and CD34 Microbead reagent as directed by the manufacturer.

Lymphocyte infusions

The mechanism of action of the CliniMACS Cell Selection System is based on magnetic-activated cell sorting (MACS). The CliniMACS device is a powerful tool for the isolation of many cell types from heterogeneous cell mixtures, (e.g. apheresis products). These can then be separated in a magnetic field using an immunomagnetic label specific for the cell type of interest, such as CD3+ human T cells.

CliniMACS

Brandon Triplett, MD

In this study, participants with high-risk hematologic malignancies undergoing hematopoietic cell transplantation (HCT), who do not have a suitable human leukocyte antigen (HLA)-matched related/sibling donor (MSD), matched unrelated donor (MURD) or killer-immunoglobulin receptors (KIR) ligand mismatched haploidentical donor identified, will receive a combined T cell depleted (TCD) haploidentical peripheral blood stem cell (PBSC) and unrelated umbilical cord blood transplantation (UCBT) using a total lymphoid irradiation (TLI) based preparative regimen.

Primary objective:

* To estimate the incidence of donor derived neutrophil engraftment by day +42 post-transplant for participants with high-risk hematologic malignancies undergoing a total lymphoid irradiation (TLI)-based hematopoietic cell transplantation (HCT) using a T cell depleted (TCI) haploidentical donor peripheral blood stem cell (PBSC) donor combined with an unrelated umbilical cord blood (UCB) donor.

Secondary objectives:

* Estimate the incidence of malignant relapse, event-free survival (EFS), and overall survival (OS) at one-year post-transplantation.
* Estimate the incidence and severity of acute and chronic graft versus host disease (GVHD) in the first 100 days after transplantation.
* Estimate the incidence of secondary graft failure transplant related mortality (TRM) and transplant related morbidity in the first 100 days after HCT.

Prior to stem cell infusion, participants will receive a preparative regimen of total lymphoid irradiation (TLI), fludarabine, cyclophosphamide, melphalan, and thiotepa to prepare their bone marrow. Thereafter, they will receive a hematopoietic cell graft from a haploidentical donor and an unrelated umbilical cord blood donor. Post-transplantation immunosuppressive treatment will include tacrolimus and mycophenolate mofetil.

Combined T Cell Depleted Haploidentical Peripheral Blood Stem Cell and Unrelated Umbilical Cord Blood Transplantation in Patients With Hematologic Malignancies Using a Total Lymphoid Irradiation Based Preparative Regimen

Neutrophil engraftment is defined as absolute neutrophil count (ANC) recovery of ≥ 0.5 x 10\^9/L (500/mm\^3) for three consecutive laboratory values obtained on different days (derived from either donor). Date of engraftment is the date of the first of the three consecutive laboratory values. The number of patients engrafted by day +42 post-transplant is provided.

Relapse was evaluated using standard World Health Organization (WHO) criteria for each disease. The estimate of cumulative incidence of relapse will be estimated using Kalbfleisch-Prentice method. Relapse defined as the recurrence of original disease. Death is the competing risk event. The analysis will be implemented using Statistical Analysis System (SAS) macro (bmacro252-Excel2007\\cin).

Due to the early close of the study, a small number of patients were enrolled. Subsequently, the number of patients who experienced malignant relapse is provided

The Kaplan-Meier estimate of EFS with relapse, death due to any cause and graft failure as events along with their standard errors will be calculated using the SAS macro (bmacro251-Excel2007\\kme) available in the Department of Biostatistics at St. Jude, where EFS = min (date of last follow-up, date of relapse, date of graft failure, date of death due to any cause) - date of transplant, and all participants surviving at the time of analysis without events will be censored. The number of participants who did not experience any of these events through one year post-transplant is given.

Due to the early close of the study, a small number of patients were enrolled. Subsequently, the number of patients who did not experience any events defined above is provided.

The Kaplan-Meier estimate of OS with relapse, death due to any cause and graft failure as events along with their standard errors will be calculated using the SAS macro (bmacro251-Excel2007\\kme) available in the Department of Biostatistics at St. Jude, where OS = min (date of last follow-up, date of death) - date of hematopoietic cell transplantation (HCT) and all participants surviving after 1 year post-transplant will be considered as censored.

Due to the early close of the study, a small number of patients were enrolled. Subsequently, the number of patients who did not die at 1 year post-transplant is provided.

Cumulative incidence of acute GVHD was estimated using Kalbfleisch-Prentice method. Death is the competing risk event. SAS macro (bmacro252-Excel2007\\cin) available at St. Jude was used for analysis. Severity of GVHD and stage were determined using the Clinical Oncology Group (COG) Stem Cell Committee Consensus Guidelines for establishing organ stage and overall grade of acute GVHD. Participants are graded on a scale from I to IV, with I being mild and IV being severe.

Overall Clinical Grade (based on the highest stage obtained):

Grade 0: No stage 1-4 of any organ. Grade I: Stage 1-2 skin and no liver or gut involvement. Grade II: Stage 3 skin, or Stage I liver involvement, or Stage 1 gastrointestinal (GI).

Grade III: Stage 0-3 skin, with Stage 2-3 liver, or Stage 2-3 GI. Grade IV: Stage 4 skin, liver or GI involvement.

Due to early close of study, a small number of patients were enrolled. The number of patients who experienced acute GVHD is provided.

Cumulative incidence of acute and chronic GVHD was estimated using Kalbfleisch-Prentice method. Death is competing risk event. SAS macro (bmacro252-Excel2007\\cin) available St. Jude was used for such analysis. Severity of chronic GVHD was evaluated using National Institutes of Health (NIH) Consensus Global Severity Scoring. Mild is considered a better outcome with severe being the worst.

Criteria for grading chronic GVHD:

Mild: 1-2 organs/sites, maximum organ score of 1, and lung score of 1. Moderate: 3 or more organs/sites and maximum organ score of 1 and lung score of 1, OR at least 1 organ/site and maximum organ score of 2 and lung score of 1. Severe: At least 1 organ/site and maximum organ score of 3 and lung score of 2-3.

Due to the early close of the study, a small number of patients were enrolled. Subsequently, the number of patients who experienced chronic GVHD is provided.

The cumulative incidence of secondary graft failure will be estimated using the Kalbfleisch-Prentice method. Deaths due to toxicity and relapse before day 100 are the competing events.

Secondary graft failure or graft rejection will be defined as no evidence of donor chimerism by umbilical cord blood (UCB) and/or haploidentical donor (\<10%), or too few cells to perform adequate chimerism analysis, in research participants with prior neutrophil engraftment.

Due to the early close of the study, a small number of patients were enrolled. Subsequently, the number of patients who experienced secondary graft failure is provided.

TRM is any death in remission and related to protocol therapy. The cumulative incidence of TRM was estimated using the Kalbfleisch-Prentice method. Deaths before day 100 because of other reasons are the completing events.

Due to the early close of the study, a small number of patients were enrolled. Subsequently, the number of patients who experienced TRM is provided.

Any patient who had adverse events listed either as probable or definite in the first 100 days post-transplant are counted as transplant-related morbidity. The cumulative incidence of transplant-related morbidity will be estimated using the Kalbfleisch-Prentice method. Deaths before day 100 are the competing risk events.

Due to the early close of the study, a small number of patients were enrolled. Subsequently, the number of patients who experienced at least one-transplant-related morbidity is provided.

St. Jude Children's Research Hospital

Adverse events were monitored for donors beginning with the on-study date through one year post-transplantation.

Interventions: cyclophosphamide, thiotepa, fludarabine, melphalan, mesna, G-CSF, mycophenolate mofetil, tacrolimus, methylprednisolone, total lymphoid irradiation, and lymphocyte infusions.

Cells for infusion are prepared using the CliniMACS System.

Prior to stem cell infusion, participants receive a preparative regimen of total lymphoid irradiation (TLI), fludarabine, cyclophosphamide, melphalan, and thiotepa to prepare their bone marrow. Thereafter, they will receive a hematopoietic cell graft from a haploidentical donor and an unrelated umbilical cord blood donor. Post-transplantation immunosuppressive treatment will include tacrolimus and mycophenolate mofetil.

Treatment

Blood donors were enrolled on the study to provide cells for transplantation used in the Treatment Arm.

Blood Donors

Age, Continuous

Sex: Female, Male

Ethnicity

Race/Ethnicity, Customized

Race

Diagnosis

Complete remission (CR) defined as less than 5 percent leukemia blasts in a bone marrow with evidence of hematopoietic recovery. Relapse is defined as return of 5 percent leukemia blasts or more in a bone marrow after previous achieving CR. Refractory is defined as never achieving CR despite therapy, also known as induction failure. The disease status worsens going down the list with CR1 indicating the best prognosis and Relapse 2 the worst prognosis.

Disease Status at HSCT

The study was halted early due to slow accrual.

Number of Participants With Neutrophil Engraftment

Number of Participants With Malignant Relapse

Number of Participants With Event-free Survival (EFS)

Number of Participants With Overall Survival (OS)

No Acute GVHD

Grade I

Grade II

Grade III

Grade IV

Number of Participants by Severity With Acute Graft Versus Host Disease (GVHD) in the First 100 Days After HCT

No Chronic GVHD

Mild

Moderate

Severe

Number of Participants by Severity With Chronic Graft Versus Host Disease (GVHD) in the First 100 Days After HCT

Number of Participants With Secondary Graft Failure

Number of Participants With Transplant-related Mortality (TRM)

Number of Participants With Transplant-related Morbidity

Interventions: cyclophosphamide, thiotepa, fludarabine, melphalan, mesna, granulocyte colony-stimulating factor (G-CSF), mycophenolate mofetil, tacrolimus, methylprednisolone, total lymphoid irradiation, and lymphocyte infusions.

Cells for infusion are prepared using the CliniMACS System.

Prior to stem cell infusion, participants receive a preparative regimen of total lymphoid irradiation (TLI), fludarabine, cyclophosphamide, melphalan, and thiotepa to prepare their bone marrow. Thereafter, they will receive a hematopoietic cell graft from a haploidentical donor and an unrelated umbilical cord blood donor. Post-transplantation immunosuppressive treatment will include tacrolimus and mycophenolate mofetil.

Spots Global Cancer Trial Database for lymphocyte infusions