Neoplasms

Blood and Lymph Conditions

All Conditions

Immune System Diseases

Rare Diseases

Leukemia

Lymphoma

Hematologic Neoplasms

Hematologic Diseases

Lymphosarcoma

Antineoplastic Agents

Antirheumatic Agents

All Drugs and Chemicals

Anti-Infective Agents

Amino Acids

Cyclophosphamide

Fludarabine

Fludarabine phosphate

Melphalan

Lenograstim

Mycophenolic Acid

Thiotepa

Mechlorethamine

Mesna

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

Anti-Bacterial Agents

Antibiotics, Antitubercular

Antitubercular Agents

Enzyme Inhibitors

Adjuvants, Immunologic

Phenylalanine

Participants undergo a preparative regimen of total lymphoid irradiation, fludarabine, cyclophosphamide, fludarabine, thiotepa, melphalan, and mycophenolate mofetil, followed by HPC,A infusion and TC-NK infusion. They also receive G-CSF and mesna.

Cells for infusion are prepared using the CliniMACS System.

Participants receive total lymphoid irradiation over four doses.

Total Lymphoid Irradiation

Participants received infusions of HPC,A (CD34+ selected) and HPC,A (CD45RA depleted).

HPC,A Infusion

TC-NK Infusion

Participants receive G-CSF subcutaneously or intravenously.

Donors receive G-CSF subcutaneously during cell mobilization.

G-CSF

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.

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

Mycophenolate mofetil

Brandon M. 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) or matched unrelated donor (MUD) identified, will receive a haploidentical donor HCT with additional natural killer (NK) cells.

The investigators anticipate enrollment of 75 donors and 75 recipients.

PRIMARY OBJECTIVE:

* To estimate the rate of successful engraftment at day +42 post-transplant in patients who receive haploidentical donor stem cell plus NK cell transplantation with TLI based conditioning regimen for high risk hematologic malignancy.

SECONDARY OBJECTIVES:

* Estimate the incidence of malignant relapse, event-free survival, and overall survival at one-year post-transplantation.
* Estimate incidence and severity of acute and chronic (GVHD).
* Estimate the rate of transplant related mortality (TRM) in the first 100 days after transplantation.

Donors will undergo G-CSF mobilization of peripheral blood stem cells (PBSC) prior to undergoing two apheresis collections of hematopoietic progenitor cells (HPC,A) and one apheresis collection of therapeutic cell product of purified natural killer cells (TC-NK).

The HPC products will be T-cell depleted (TCD) using the investigational CliniMACS device. CD34+ enrichment and CD45RA depletion will be utilized on sequential HPC grafts.

Participants will undergo a preparative regimen of total lymphoid irradiation, fludarabine, cyclophosphamide, granulocyte colony stimulating factor (G-CSF), thiotepa, and melphalan. This is followed by infusions of donor cells that have been prepared using the CliniMACS system: HPC,A (CD34+ selected), HPC,A (CD45RA depleted), and TC-NK.

Haploidentical Donor Hematopoietic Progenitor Cell and NK Cell Transplantation for Hematologic Malignancy

Haploidentical Donor Hematopoietic Progenitor Cell and Natural Killer Cell Transplantation With a TLI Based Conditioning Regimen in Patients With Hematologic Malignancies

Neutrophil engraftment will be determined using the parameters put forth by the Center for International Blood and Marrow Registry. Assessments will be made upon review of daily complete blood count and serial chimerism studies. Successful engraftment for the purposes of this objective will be patients who do not experience graft failure.

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.

The one-year event free survival is defined by the patient who has neither experienced relapse nor death within one year after post transplantation. And the rate is calculated by computing the ratio between total number of one year event free survival patients and the total number of patients.

The one-year survival is defined by the patient who has not died within one year after post transplantation. And the rate is calculated by computing the ratio between total number of one year survival patients and the total number of patients.

Acute and chronic graft-vs.-host disease will be evaluated using the standard grading criteria. The estimate will be the number of recipients who experienced GVHD divided by the total number of patients considered in this group.

Estimate the proportion of patients died within 100 days after the transplantation who has not experienced a relapse. The estimate will be the number of TRM divides the total number of patients considered in this group.

Ongoing assessment of toxicity will be done using the NCI CTCAE version 3.0. Acute and chronic graft-vs.-host disease will be evaluated using the standard grading criteria. The severity of acute GvHD and chronic GvHD will be described. The analysis for this objective will be performed when the last evaluable participant has been followed for 100 days post transplant. Acute GvHD is graded from 1-4 with 4 being the worst outcome.

Ongoing assessment of toxicity will be done using the NCI CTCAE version 3.0. Acute and chronic graft-vs.-host disease will be evaluated using the standard grading criteria. The severity of acute GvHD and chronic GvHD will be described. The analysis for this objective will be performed when the last evaluable participant has been followed for 1 year post-transplant. Chronic GvHD is graded as "mild", "moderate" or "severe" with "severe" being the worst outcome.

Assisi Foundation

St. Jude Children's Research Hospital

Recipient participants were followed for all NCI Grade III-V adverse events from the start of conditioning through the first-year post HCT, regardless of their relationship to the treatment given. Clinically significant NCI Grade I-II adverse events that are judged to be related/possibly related may be collected per the discretion and judgment of the PI. Adverse events that affected more than 5 participants are included in this description.

Participants meeting eligibility criteria and who completed study therapy: haploidentical stem cell transplantation with additional natural killer (NK) cells and total lymphoid irradiation (TLI) based conditioning regimen. Participants who received a therapeutic variance (maraviroc) are included.

Experimental: Transplant Recipients

Participants meeting eligibility criteria and who completed study therapy: haploidentical stem cell transplantation with additional natural killer (NK) cells and total lymphoid irradiation (TLI) based conditioning regimen. Participants who received a therapeutic variance (maraviroc) are excluded.

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Donor relationship to patient: Father, Mother, Sibling, Other.

Age was evaluated at the time of transplantation.

Number of Transplant Recipients With Successful Engraftment

Number of Transplant Recipients With Malignant Relapse

Event-free Survival

Overall Survival

Number of Transplant Recipients With Acute Graft Versus Host Disease (aGVHD)

Number of Transplant Recipients With Chronic Graft Versus Host Disease (cGVHD)

Number of Transplant Recipients With Acute and/or Chronic Graft Versus Host Disease (GVHD)

Number of Transplant Recipients With Transplant-related Mortality (TRM)

Ongoing assessment of toxicity will be done using the NCI CTCAE version 3.0. Acute and chronic graft-vs.-host disease will be evaluated using the standard grading criteria. The severity of acute GvHD and chronic GvHD will be described. The analysis for this objective will be performed when the last evaluable participant has been followed for 100 days post-transplant.

Severity of Acute Graft Versus Host Disease (aGVHD)

Severity of Chronic Graft Versus Host Disease (cGVHD)

Participants undergo a preparative regimen of total lymphoid irradiation, fludarabine, cyclophosphamide, fludarabine, thiotepa, melphalan, and mycophenolate mofetil, followed by HPC,A infusion and TC-NK infusion. They also receive G-CSF and mesna.

Cells for infusion are prepared using the CliniMACS System. Total Lymphoid Irradiation: Participants receive total lymphoid irradiation over four doses. Fludarabine: Given IV.

Cyclophosphamide: Given IV. Thiotepa: Given IV. Melphalan: Given IV. HPC,A Infusion: Participants received infusions of HPC,A (CD34+ selected) and HPC,A (CD45RA depleted). TC-NK Infusion: Participants receive infusions of TC-NK.

G-CSF: Participants receive G-CSF subcutaneously or intravenously. Donors receive G-CSF subcutaneously during cell mobilization.

Mesna: 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.

CliniMACS: 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.

Mycophenolate mofetil: Given intravenously or orally.

Transplant Recipients

Overall Study

Symptoms and General Pathology

Syndrome

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Preleukemia

Leukemia, Myelomonocytic, Juvenile

Myelodysplastic Syndromes

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Leukemia, Lymphoid

Sarcoma

Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Sarcoma, Myeloid

Lymphoma, Non-Hodgkin

Neoplasms by Histologic Type

Neoplasms, Connective and Soft Tissue

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Bone Marrow Diseases

Precancerous Conditions

Myeloproliferative Disorders

Chronic Disease

Disease Attributes

Myelodysplastic-Myeloproliferative Diseases

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Chronic Myelomonocytic Leukemia

Juvenile Myelomonocytic Leukemia

Acute Lymphoblastic Leukemia

Lymphoblastic Lymphoma

Chronic Graft Versus Host Disease

Soft Tissue Sarcoma

Chronic Myeloid Leukemia

Acute Graft Versus Host Disease

Myeloid Sarcoma

Chronic Myeloproliferative Disorders

Myelodysplastic/myeloproliferative Disease

Blinatumomab

Tacrolimus

Rituximab

Thymoglobulin

Sirolimus

Antilymphocyte Serum

Temsirolimus

MTOR Inhibitors

Antineoplastic Agents, Immunological

Calcineurin Inhibitors

Clotrimazole

Miconazole

Antifungal Agents

Participants receive a conditioning regimen of antithymocyte globulin (rabbit), cyclophosphamide, mesna, fludarabine, thiotepa, tacrolimus (first 5 participants enrolled), sirolimus (used beginning with 6th enrolled participant), melphalan, rituximab. This is followed by HPC,A infusion (transplant), then by G-CSF and blinatumomab.

Cells for infusion are prepared using the CliniMACS System.

Given intravenous (IV) prior to transplant on Days -14, -13, -12.

Anti-thymocyte globulin (rabbit)

Given by continuous IV infusion at least 2 weeks post-engraftment. Blinatumomab will be given only to patients with CD19+ malignancies.

Given by IV infusion prior to transplant on Day -9.

Given IV prior to transplant on Days -8, -7, -6, -5, and -4.

Given IV or subcutaneous (SQ) following transplant on Days 6 and 7.

Given IV prior to transplant on Days -2 and -1.

Given IV prior to cyclophosphamide administration and at approximately 3, 6, and 9 hours after cyclophosphamide infusion.

Given oral (PO) or IV beginning prior to transplant on Day -2. The dose will begin to taper at approximately day +60 after transplant in the absence of GVHD. Tacrolimus was used for the first 5 participants enrolled on study. Subsequent participants receive sirolimus.

Hematopoietic Progenitor Cell, Apheresis (HPC,A) infusion of TCRɑβ+ depleted cells on day of transplant (Day 0) and HPC,A infusion of CD45RA+ depleted cells on Day +1 following transplant.

Given orally (PO) starting Day 0. The dose will be tapered off over two weeks starting on Day +42 in the absence of GVHD.

Brandon Triplett, MD

This study seeks to examine treatment therapy that will reduced regimen-related toxicity and relapse while promoting rapid immune reconstitution with limited serious graft-versus-host-disease (GVHD) and also improve disease-free survival and quality of life. The investigators propose to evaluate the safety and efficacy of selective naive T-cell depleted (by TCRɑβ and CD45RA depletion, respectively) haploidentical hematopoietic cell transplant (HCT) following reduced intensity conditioning regimen that avoids radiation in patients with hematologic malignancies that have relapsed or are refractory following prior allogeneic transplantation.

PRIMARY OBJECTIVE:

* To estimate engraftment by day +30 post-transplant in patients who receive TCRɑβ-depleted and CD45RA-depleted haploidentical donor progenitor cell transplantation following reduced intensity conditioning regimen without radiation.

SECONDARY OBJECTIVES:

* Assess the safety and feasibility of the addition of Blinatumomab in the early post-engraftment period in patients with CD19+ malignancy.
* Estimate the incidence of malignant relapse, event-free survival, and overall survival at one-year post-transplantation.
* Estimate incidence and severity of acute and chronic (GVHD).
* Estimate the rate of transplant related mortality (TRM) in the first 100 days after transplantation.

Blood progenitor cells will be obtained from a partially matched adult family member (donor). After processing and filtration using the CliniMACS device, cells will be infused into participants meeting eligibility criteria.

Prior to transplant, participants will receive a conditioning treatment of rabbit ATG, cyclophosphamide, fludarabine, thiotepa, melphalan, and rituximab. Mesna will be given to help prevent side effects of cyclophosphamide. Tacrolimus will be given to help reduce the risk of GVHD. G-CSF will be given after transplant to help the donor progenitor cells make white blood cells faster so that the immune system is better able to fight infection.

Blood progenitor cells will be given in two infusions on Day 0 and Day +1. Progenitor cells then move through the blood stream to the bone marrow space where they should begin to grow. Participant blood will be monitored for 100 days to assure that the progenitor cells begin to grow. If the growth is low, additional progenitor cells may be given.

Blood tests will be monitored for up to one year to observe how well the donor cells grow and their effect on the infection-fighting system.

Provision of TCRγδ T Cells and Memory T Cells Plus Selected Use of Blinatumomab in Naïve T-cell Depleted Haploidentical Donor Hematopoietic Cell Transplantation for Hematologic Malignancies Relapsed or Refractory Despite Prior Transplantation

ANC engraftment is defined as the first of 3 consecutive tests performed on different days of an ANC ≥ 500/mm\^3 with evidence of donor cell engraftment.

If the drug is held for more than 2 weeks due to toxicity, it will be permanently discontinued.

The estimate of cumulative incidence of relapse will be estimated using Kalbfleisch-Prentice method. Death is the competing risk event. The Kaplan-Meier estimates of overall survival (OS) and event-free survival (EFS) along with their standard errors will be calculated.

OS is defined as time from transplantation to death or last follow-up, whichever comes first. EFS is defined as time from transplantation to events including relapse, graft failure, death due to any cause and last follow-up whichever comes first. The participants surviving at the time of analysis without events will be censored.

The cumulative incidence of acute and chronic GVHD will be estimated using Kalbfleisch-Prentice method. Death is the competing risk event. GVHD will be reported separately for participants receiving tacrolimus and those receiving sirolimus.

The severity of acute GVHD and chronic GVHD will be described.

The cumulative incidence of transplant related mortality will be estimated using Kalbfleisch-Prentice method. Deaths before day 100 because of other reasons are the competing risk events.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Haploidentical Donor Hematopoietic Progenitor Cell and NK Cell Transplantation for Hematologic Malignancy	NCT01807611	Leukemia Lymphoma	Total Lymphoid ... Fludarabine Cyclophosphamid... Thiotepa Melphalan HPC,A Infusion TC-NK Infusion G-CSF Mesna CliniMACS Mycophenolate m...	- 21 Years	St. Jude Children's Research Hospital
Provision of TCRγδ T Cells and Memory T Cells Plus Selected Use of Blinatumomab in Naïve T-cell Depleted Haploidentical Donor Hematopoietic Cell Transplantation for Hematologic Malignancies Relapsed or Refractory Despite Prior Transplantation	NCT02790515	Acute Lymphobla... Acute Myeloid L... Myeloid Sarcoma Chronic Myeloid... Juvenile Myelom... Myelodysplastic... Non-Hodgkin Lym...	Anti-thymocyte ... Blinatumomab Cyclophosphamid... Fludarabine G-CSF Melphalan Mesna Rituximab Tacrolimus Thiotepa HPC,A Infusion CliniMACS Sirolimus	- 21 Years	St. Jude Children's Research Hospital

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