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Haplo-cord transplantation:

All subjects will receive a conditioning regimen of chemotherapy prior to stem cell transplantation. No experimental drugs are used in this study, and the combinations of drugs that will be used in the conditioning regimen are combinations that have been used in the past.

For the transplant component of treatment, subject will receive umbilical cord blood. The study involves transplantation of unlicensed units of cord blood. Therefore, these are considered investigational products.

In addition to the umbilical cord blood unit, recipients will receive stem cells from a family member ( a haplo-identical donor). After collection and prior to infusion, these cells will be purified using a device called a CliniMACS CD34 selection device.

The stem cells from the haplo-identical donor will be purified by a procedure called CD34 selection before they are given to the subject. A special device called the CliniMACS® CD34 Reagent System, which is not FDA approved, will be used for this purpose. The manufacturer of the device, Miltenyi Biotec, is providing the researchers access to the device for use in this research study. Because the stem cells from the haplo-identical donor are treated using the CliniMACS CD34 selection device, they cells are considered investigational.

CliniMACS® CD34 Reagent System

Administer 30 mg/m2 /day intravenously x 5 days (Day -7 to Day -3) of a total dose of 150 mg/m2. Fludarabine will be dosed according to actual body weight.

Administer 70mg/m2/day intravenously x 2 days. Melphalan will be dosed according to actual body weight. Cryotherapy with ice chips will be administered to prevent mucositis

Administer 1.5 mg/kg/day intravenously x 3 days, total 4.5 mg/kg. ATG will be dosed according to actual body weight. The first dose will be infused over at least six hours, and subsequent doses over at least 4 hours. Pre-medications include acetaminophen 650 mg by mouth, diphenhydramine 25-50 mg by mouth or intravenously, and methylprednisolone 2 mg/kg (1 mg/ kg at the initiation and 1 mg/kg half-way through anti-thymocyte globulin administration).

anti-thymocyte globulin (rabbit)

Administer one dose of 375 mg/m2 prior to or upon admission for all patients not previously exposed to rituximab or who have not received rituximab in the six months prior to transplant.

Patients at high risk of CNS relapse (e.g. ALL or Burkitt's lymphoma) or patients at high risk for graft rejection (i.e., donor-specific HLA antibodies, patients with severe aplastic anemia, or hemoglobinopathies) may receive 2 doses of TBI as part of the conditioning.

Total Body Irradiation

Will be started on Day -2 and given at a dose of 1000 mg every 8 hours until Day 28. Mycophenolae Mofetil can be given orally or intravenously. Infection, toxicity, very low patient weight (\<50 kilograms) may prompt earlier discontinuation or adjustment of doses.

Mycophenolate Mofetil

Administered 0.03/mg/kg/day intravenous continious infusion (CI) over 24 hours from 4pm Day -2 until engraftment or when subject is able to take orally, then tacrolimus approximately 0.09 mg/kg orally in 2 divided doses. Tacrolimus should be given at full dose to maintain levels of 5-15 ng/mL through Day 180, tapered by 20% every week thereafter. Infection, toxicity or other clinical circumstances may prompt earlier discontinuation or adjustment of doses. In the presence of Graft versus Host Disease, a clinical decision by the attending physician will determine if tacrolimus can be tapered or should be continued. Oral tacrolimus can be used when intravenous access for CI tacrolimus is unavailable.

Alexandra Gomez Arteaga, MD

In this trial, we aim to improve the outcomes of haplo cord transplant. Haplo cord transplant is a novel and promising way to improve transplant outcomes. We hypothesize that identification of a graft that is at least 5/6 matched and inherited paternal antigen (IPA) targeted (i.e., cord blood grafts share one or more IPA antigens with the prospective recipient) is more important to the outcome of haplo cord transplant than the nucleated cell dose. The identification of such a graft for a large proportion of the subjects may necessitate accepting a lower umbilical cord graft dose.

In addition to a umbilical cord blood transplant, recipients will receive stem cells from a family member ( a haplo-identical donor) . After collection and prior to infusion, these cells will be purified using a device called a CliniMACS CD34 selection device. The subject will undergo a chemotherapy conditioning regimen prior to transplantation. No experimental drugs are used in this study, and the combinations of drugs that will be used in the conditioning regimen are combinations that have been used in the past.

This is a clinical trial for subjects with hematologic malignancies ( acute leukemia, myeloproliferative disorders, lymphoma, myeloma) who are in need of a donor stem cell transplant, and for whom an umbilical cord blood transplant is thought to be the best option. As donors for allogeneic transplant, we typically try to use related family members, such as brothers or sisters, or volunteer donors who are 'HLA matched', i.e. share similar proteins on their cells. This study is for subjects for whom such a matched sibling donor or a matched unrelated donor is not available.

For such subjects a commonly used transplant procedure is to use stem cells from one or two umbilical cords (UCB) from a newborn. These umbilical cord blood grafts, despite not completely matching the recipient, cause few problems with graft vs host disease (a common complication of transplant). But they tend to grow very slowly and subjects often have very prolonged hospital stays and are at high risk for complications due to low blood counts. Umbilical cord blood transplant will be the standard arm for this protocol.

This study uses a new method of bone marrow transplantation called combined haplo-identical cord (haplo-cord) transplantation. In this procedure, cells from a related donor who shares half of the HLA proteins ( haplo-identical) are collected from the blood, as well as cells from an umbilical cord, and then both are transplanted. It is hoped that by using cells from a haplo-identical relative, subjects will have a faster recovery and require fewer transfusions. Over time the haplo-identical cells from the relative are replaced by the cells from the cord blood. The combined transplantation of haplo-identical stem cells and cord blood has previously been used in approximately 60 subjects with very encouraging results.

Traditionally it has been felt that the most important determinant of outcome of an UCB stem cell transplant is the cord blood cell dose. The second determinant is the degree of matching between donor and recipient. Many times, we have difficulty identifying UCB units of sufficient cell dose that are well matched. Of interest,in our prior study of haplo-cord SCT indicated outcomes seemed independent of the UCB cell dose. If this preliminary observation is correct, we may be able to improve the outcomes of haplo cord transplant further by accepting lower threshold UCB doses and rather focusing on optimal matching (including matching for HLA and another characteristic called IPA). This is the primary objective of this study.

Targeting the IPA and Matching for the Non-Inherited Maternal Antigen for Haplo-Cord Transplantation

A Prospective Study of Optimal Cord Selection for Haplo-Cord Transplantation: Targeting the Inherited Paternal Antigen (IPA) and Matching for the Non-Inherited Maternal Antigen (NIMA)

We aim to identify the lowest threshold of umbilical cord nucleated cell dose that can be utilized assure durable umbilical cord blood engraftment in the haplo-cord transplants. The threshold will be defined as the lowest dose which assures cord blood engraftment occurs in at least 80% of subjects.

Evaluate the long term outcome of subjects undergoing haplo cord transplants using an optimally matched umbilical cord blood (UCB) graft (i.e. Survival, profession-free survival (PFS), Relapse, transplant-related mortality (TRM), toxicities, infections and GVHD)

As much as possible, UCB units will be chosen to be IPA targeted. This is not always possible. We will therefore also retrospectively analyze transplant outcomes and correlate with IPA status.

As much as possible, UCB units will be chosen to be NIMA matched. This is not always possible. We will therefore also retrospectively analyze transplant outcomes and correlate with NIMA status.

Weill Medical College of Cornell University

Symptoms and General Pathology

Syndrome

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Preleukemia

Myelodysplastic Syndromes

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Leukemia, Lymphoid

Hodgkin Disease

Neoplasms by Histologic Type

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Bone Marrow Diseases

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Acute Lymphoblastic Leukemia

Lymphoblastic Lymphoma

Hodgkin Lymphoma

Imidacloprid

The UCB unit must supply a minimum of 1.0 x107/kg pre-cryopreserved nucleated cell dose. The unit must match at a minimum of 4 of 6 at HLA-A, -B, -DRB1 loci with the recipient. This may include 0-2 antigen mismatches at each A or B (at the antigen level) or DRB1 (at the allele level) loci. All typing will be done using molecular typing. Though molecular level typing will be available, a match is defined at intermediate resolution for HLA-A and -B and at high resolution for -DRB1

For the standard arm, UCB units will be selected using the Minnesota strategy and the strategy followed in a recent CTN study.17;19Each unit must supply a minimum of 1.5 x107/kg pre-cryopreserved nucleated cell dose. Subjects must have two partially HLA-matched UCB units. Each unit must match at a minimum of 4 of 6 at HLA-A, -B, -DRB1 loci with the recipient. This may include 0-2 antigen mismatches at each A or B (at the antigen level) or DRB1 (at the allele level) loci. All typing will be done using molecular typing. Though molecular level typing will be available, a match is defined at intermediate resolution for HLA-A and -B and at high resolution for -DRB1

If a subject is randomized to the haplo-cord transplant group, their family member will undergo a stem cell collection. The stem cells from the haplo-identical donor will be purified by a procedure called CD34 selection before they are given to the subject. A special device called the CliniMACS® CD34 Reagent System, which is not FDA approved, will be used for this purpose. The manufacturer of the device, Miltenyi Biotec, is providing the researchers access to the device for use in this research study. Because the stem cells from the haplo-identical donor are treated using the CliniMACS CD34 selection device, they cells are considered investigational.

Fludarabine: 30 mg/m2 /day intravenously x 5 days total dose 150 mg/m2. Fludarabine will be dosed according to actual body weight

Melphalan: 70mg/m2/day intravenously x 2 days. Melphalan will be dosed according to actual body weight. Cryotherapy with ice chips will be administered to prevent mucositis.

Rabbit ATG (rATG): 1.5 mg/kg/day intravenously x 4 days, total 6 mg/kg. ATG will be dosed according to actual body weight. The first dose will be infused over at least six hours, and subsequent doses over at least 4 hours. Pre-medications include acetaminophen 650 mg by mouth, diphenhydramine 25-50 mg by mouth or intravenously, and methylprednisolone 2 mg/kg (1 mg/ kg at the initiation and 1 mg/kg half-way through anti-thymocyte globulin administration).

Rabbit ATG

All subjects will receive an UCB dose of \> 3 x107/kg nucleated blood cells. It is expected that this will require co-infusion of two UCB in the large majority of cases. If two UCB are required, they will be at least 4/5 matched to the recipient.

Double Umbilical Cord Blood Transplantation

If randomized to the haplo-cord group, a family member will undergo a stem cell collection. In both arms, subjects will receive a "conditioning regimen" prior to transplantation. The conditioning regimen utilized in this study incorporates fludarabine-Melphalan and antithymocyte globulin (ATG). This regimen has the advantage of being nearly identical to the regimen utilized for our haplo-cord regimen is based on the experience of the Dana-Farber/Mass-General regimen.

Haplo-Identical Cord Transplantation

Koen van Besien, MD, PhD

The purpose of this study is compare the efficacy of haplo-cord transplant (investigational arm) with that of a more commonly used procedure in which only the cells contained in one or two umbilical cords are infused (standard arm).

We hypothesize that reduced intensity conditioning and haplo-cord transplant results in fast engraftment of neutrophils and platelets, low incidences of acute and chronic graft versus host disease, low frequency of delayed opportunistic infections, reduced transfusion requirements, shortened length of hospital stay and promising long term outcomes. We also hypothesize that umbilical cord blood selection can prioritize matching and better matched donors can be identified rapidly for most subjects.

This is a clinical trial for subjects with hematologic malignancies ( acute myelogenous leukemia, acute lymphocytic leukemia, Hodgkin's or Non-Hodgkin's lymphoma, or myelodysplastic syndrome) who are in need of a donor stem cell transplant, and for whom an umbilical cord blood transplant is thought to be the best option. For allogeneic transplant donors, we typically try to use related family members, such as brothers or sisters, or volunteer donors who are 'HLA matched', i.e. share similar proteins on their cells. This study is for subjects for whom such a matched sibling donor or a matched unrelated donor is not available.

This study tests a new method of bone marrow transplantation called combined haplo-identical cord (haplo-cord) transplantation. In this procedure, cells from a related donor who shares half of the HLA proteins ( haplo-identical)are collected from the blood, as well as cells from an umbilical cord, and then both are transplanted. It is hoped that by using cells from a haplo-identical relative, subjects will have a faster recovery and require fewer transfusions. Over time the haplo-identical cells from the relative are replaced by the cells from the cord blood. The combined transplantation of haplo-identical stem cells and cord blood has previously been used in approximately 60 subjects with very encouraging results.

The purpose of this study is to compare the efficacy of haplo-cord transplant ( "investigational" arm) with the more commonly used procedure in which only the cells contained in one or two umbilical cords are infused ("standard" arm). Subjects will be randomly assigned into either the haplo-cord group or the umbilical cord group.

If randomized to the haplo-cord group, a family member will undergo a stem cell collection. In both arms, subjects will receive a "conditioning regimen" prior to transplantation. The conditioning regimen consists of chemotherapy, which is meant to destroy the cancer cells and suppress the immune system to allow the transplanted cells to grow. Subjects will remain in the hospital until the stem cells are fully recovered, which is usually 4 to 6 weeks after the transplant. Subjects will have bone marrow aspiration and biopsy at 3 weeks, 4 weeks, 2 months, 6 months and 1 year after the transplant and then yearly thereafter. Participation in the study will continue for up to 5 years after transplantation.

Randomized HaploCord Blood Transplantation vs. Double Umbilical Cord Blood Transplantation for Hematologic Malignancies

A Randomized Study of Combined Haplo-identical Umbilical Cord Blood Transplantation vs. Double Umbilical Cord Blood Transplantation in Patients With Hematologic Malignancies

No patients completed this study and are therefore inevaluable. Subject data not evaluable for the outcome measure time frame. Subject data only evaluable up to month 3.

No patients completed this study and are therefore inevaluable

The UCB unit must supply a minimum of 1.0 x107/kg pre-cryopreserved nucleated cell dose. The unit must match at a minimum of 4 of 6 at HLA-A, -B, -DRB1 loci with the recipient. This may include 0-2 antigen mismatches at each A or B (at the antigen level) or DRB1 (at the allele level) loci. All typing will be done using molecular typing. Though molecular level typing will be available, a match is defined at intermediate resolution for HLA-A and -B and at high resolution for -DRB1.

Haplo-Cord SCT

For the standard arm, UCB units will be selected using the Minnesota strategy and the strategy followed in a recent CTN study.17;19Each unit must supply a minimum of 1.5 x107/kg pre-cryopreserved nucleated cell dose. Subjects must have two partially HLA-matched UCB units. Each unit must match at a minimum of 4 of 6 at HLA-A, -B, -DRB1 loci with the recipient. This may include 0-2 antigen mismatches at each A or B (at the antigen level) or DRB1 (at the allele level) loci. All typing will be done using molecular typing. Though molecular level typing will be available, a match is defined at intermediate resolution for HLA-A and -B and at high resolution for -DRB1.

UCB SCT

Total

Age, Categorical

Sex: Female, Male

United States

Region of Enrollment

Koen van Besien, MD

Rate of Neutrophil Engraftment After Combined Haplo-identical Cord With That of Umbilical Cord Blood Transplantation.

The UCB unit must supply a minimum of 1.0 x107/kg pre-cryopreserved nucleated cell dose. The unit must match at a minimum of 4 of 6 at HLA-A, -B, -DRB1 loci with the recipient. This may include 0-2 antigen mismatches at each A or B (at the antigen level) or DRB1 (at the allele level) loci. All typing will be done using molecular typing. Though molecular level typing will be available, a match is defined at intermediate resolution for HLA-A and -B and at high resolution for -DRB1

CliniMACS® CD34 Reagent System: If a subject is randomized to the haplo-cord transplant group, their family member will undergo a stem cell collection. The stem cells from the haplo-identical donor will be purified by a procedure called CD34 selection before they are given to the subject. A special device called the CliniMACS® CD34 Reagent System, which is not FDA approved, will be used for this purpose. The manufacturer of the device, Miltenyi Biotec, is providing the researchers access to the device for

For the standard arm, UCB units will be selected using the Minnesota strategy and the strategy followed in a recent CTN study.17;19Each unit must supply a minimum of 1.5 x107/kg pre-cryopreserved nucleated cell dose. Subjects must have two partially HLA-matched UCB units. Each unit must match at a minimum of 4 of 6 at HLA-A, -B, -DRB1 loci with the recipient. This may include 0-2 antigen mismatches at each A or B (at the antigen level) or DRB1 (at the allele level) loci. All typing will be done using molecular typing. Though molecular level typing will be available, a match is defined at intermediate resolution for HLA-A and -B and at high resolution for -DRB1

Fludarabine: Fludarabine: 30 mg/m2 /day intravenously x 5 days total dose 150 mg/m2. Fludarabine will be dosed according to actual body weight

Melphalan: Melphalan: 70mg/m2/day intravenously x 2 days. Melphalan will be dosed according to actual body weight. Cryotherapy with ice chips will be administered to prevent mucosit

Platelet Recovery After Transplant Regimens

Transfusion Requirements After Haplo-identical Umbilical Cord Blood Transplant Versus Double Umbilical Cord Blood Transplant

Transplant-related Mortality (TRM), Relapse Rate, Survival and Progression Free Survival

Incidence of Acute and Chronic GVHD

Severity of Opportunistic Infections

The UCB unit must supply a minimum of 1.0 x107/kg pre-cryopreserved nucleated cell dose. The unit must match at a minimum of 4 of 6 at HLA-A, -B, -DRB1 loci with the recipient. This may include 0-2 antigen mismatches at each A or B (at the antigen level) or DRB1 (at the allele level) loci. All typing will be done using molecular typing. Though molecular level typing will be available, a match is defined at intermediate resolution for HLA-A and -B and at high resolution for -DRB1

CliniMACS® CD34 Reagent System: If a subject is randomized to the haplo-cord transplant group, their family member will undergo a stem cell collection. The stem cells from the haplo-identical donor will be purified by a procedure called CD34 selection before they are given to the subject. A special device called the CliniMACS® CD34 Reagent System, which is not FDA approved, will be used for this purpose.

For the standard arm, UCB units will be selected using the Minnesota strategy and the strategy followed in a recent CTN study.17;19Each unit must supply a minimum of 1.5 x107/kg pre-cryopreserved nucleated cell dose. Subjects must have two partially HLA-matched UCB units. Each unit must match at a minimum of 4 of 6 at HLA-A, -B, -DRB1 loci with the recipient. This may include 0-2 antigen mismatches at each A or B (at the antigen level) or DRB1 (at the allele level) loci. All typing will be done using molecular typing. Though molecular level typing will be available, a match is defined at intermediate resolution for HLA-A and -B and at high resolution for -DRB1 Fludarabine: Fludarabine: 30 mg/m2 /day intravenously x 5 days total dose 150 mg/m2. Fludarabine will be dosed according to actual body weight Melphalan: Melphalan: 70mg/m2/day intravenously x 2 days. Melphalan will be dosed according to actual body weight.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Targeting the IPA and Matching for the Non-Inherited Maternal Antigen for Haplo-Cord Transplantation	NCT01810588	Hematologic Mal...	CliniMACS® CD34... Fludarabine Melphalan anti-thymocyte ... Rituximab Total Body Irra... Mycophenolate M... Tacrolimus	18 Years -	Weill Medical College of Cornell University
Randomized HaploCord Blood Transplantation vs. Double Umbilical Cord Blood Transplantation for Hematologic Malignancies	NCT01745913	Acute Myelogeno... Myelodysplastic... Acute Lymphocyt... Hodgkin's Lymph... Non-Hodgkin's L...	CliniMACS® CD34... Fludarabine Melphalan Rabbit ATG Double Umbilica... Haplo-Identical...	18 Years -	Weill Medical College of Cornell University
Randomized HaploCord Blood Transplantation vs. Double Umbilical Cord Blood Transplantation for Hematologic Malignancies	NCT01745913	Acute Myelogeno... Myelodysplastic... Acute Lymphocyt... Hodgkin's Lymph... Non-Hodgkin's L...	CliniMACS® CD34... Fludarabine Melphalan Rabbit ATG Double Umbilica... Haplo-Identical...	18 Years -	Weill Medical College of Cornell University

Spots Global Cancer Trial Database for clinimacs® cd34 reagent system