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An infusion of HLA matched unrelated bone marrow or peripheral blood stem cells.

Allogeneic Stem Cell Transplantation

Participants received a standard conditioning regimen consisting of total body irradiation, cyclophosphamide, thiotepa and ATG. GVHD prophylaxis consisted of cyclosporine and Methotrexate.

Chemotherapy and antibodies

Gregory Hale, M.D.

Childhood leukemias which cannot be cured by chemotherapy alone may be effectively treated by allogeneic bone marrow transplantation. Moreover, for patients with chronic myelogenous leukemia (CML), allogeneic hematopoietic stem cell transplantation (HSCT) is the only proven curative modality of treatment. Patients who have received hematopoietic stem cells from an HLA matched sibling donor have proven to be less at risk for disease relapse and regimen related toxicity. However, about 70% of patients in need of HSCT do not have an HLA matched sibling donor. This necessitates the search for alternative donors, which may increase the risk of a poor outcome.

The nature of the hematopoietic stem cell graft has been implicated as a primary factor determining these outcomes. The standard stem cell graft has been unmanipulated bone marrow, but recently several advantages of T-lymphocyte depleted bone marrow and mobilized peripheral blood progenitor cells (PBPC) have been demonstrated. However, T-cell depletion may increase the risk of infectious complications and leukemic recurrence while an unmanipulated stem cell graft may increase the risk of graft vs. host disease (GVHD). A key element in long range strategies in improving outcomes for patients undergoing matched unrelated donor (MUD) HSCT is to provide the optimal graft.

The primary objective of this clinical trial is to estimate the incidence of acute GVHD in pediatric patients with hematologic malignancies who receive HSCT with an unmanipulated marrow graft. The results of this study can be used as the foundation for future trials related to engineering unrelated donor graft.

Secondary outcome evaluations for this clinical study include the following:

* To estimate the overall survival in patients with high risk hematological malignancies who receive a HSCT with an unmanipulated marrow graft or a peripheral blood stem cell graft
* To estimate disease-free survival and relapse rates
* To estimate the rates of chronic GvHD and graft failure
* To estimate the incidence of non-hematologic peri-transplant regimen-related toxicity and regimen-related mortality in the first 100 days after transplantation
* To estimate the time to neutrophil and platelet engraftment after transplantation
* To determine the degree of NK cell and T-cell immune reconstitution at 30 days and 100 days post-transplant
* To estimate the incidence of EBV reactivation or post-transplant lymphoproliferative disease (PTLPD)
* To determine the pharmacokinetics of anti-thymocyte globulin (rATG) in patients receiving allogeneic transplantation and the development of rATG antibodies

Originally this study began as a randomized comparison between unmanipulated bone marrow and T-cell depleted bone marrow utilizing the investigational CliniMACS selection system. The hypothesis to be tested at the time was that the incidence of severe acute GvHD was significantly reduced in children who received HSCT with a T-cell depleted bone marrow stem cell graft as compared to those receiving an unmanipulated graft. Approximately midway through the study the evidence indicated that although the incidence of severe acute GvHD with T-cell depletion was low, it was not significantly lower than the standard treatment of unmanipulated bone marrow. Therefore the study was amended to remove the T-cell depleted arm and continue accrual to one arm providing all patients with an unmanipulated bone marrow stem cell graft. The primary objective then being to determine if the true incidence of severe acute GvHD was below 15% as reported. The observational group receiving PBPC remained open for those patients whose donors or donor centers chose to provide PBPC in lieu of bone marrow. Only one such patient was assigned to this group; therefore, no valid conclusions can be formulated.

Intervention analysis was based on those patients who received an unmanipulated stem cell product only. For this study, the investigators had requested bone marrow for all study subjects. However, the final determination of the source of the hematopoietic stem cells, bone marrow or peripheral blood, was at the discretion of the donor and the donor center. Those participants who received a peripheral blood stem cell product were followed in the observational group only. All participants, whether recipients of a bone marrow or blood stem cell product, received the same preparative conditioning regimen

Stem Cell Transplantation for Patients With Hematologic Malignancies

Hematopoietic Stem Cell Transplantation Using Matched Unrelated Donor Peripheral Blood or Bone Marrow for Patients With Hematologic Malignancies

St. Jude Children's Research Hospital

Gregory Hale, MD / Principal Investigator

Neoplasm Metastasis

Lymphoma, Non-Hodgkin

Hodgkin Disease

Precancerous Conditions

Neoplastic Processes

Hodgkin Lymphoma

Paroxysmal Nocturnal Hemoglobinuria

Fludarabine

Fludarabine phosphate

Rituximab

Melphalan

Mycophenolic Acid

Muromonab-CD3

An infusion of HLA mismatched family member donor stem cells processed through the use of the investigational Miltenyi Biotec CliniMACS device.

Stem Cell Transplantation

Miltenyi Biotec CliniMACS

Transplant recipients received a non-TBI based reduced intensity conditioning regimen consisting of OKT-3, Fludarabine Thiotepa, and Melphalan. Rituximab was administered within 24 hours of the transplant in an effort to prevent PTLPD. In addition to T-cell depletion of the haploidentical stem cell product, Mycophenolate mofetil was provided as prophylaxis for GVHD.

Systemic chemotherapy and antibodies

Relapsed disease is the most common cause of death in children with hematological malignancies. Patients who fail high-intensity conventional chemotherapeutic regimens or relapse after stem cell transplantation have a poor prognosis. Toxicity from multiple therapies and elevated leukemic/tumor burden usually make these patients ineligible for the aggressive chemotherapy regimens required for conventional stem cell transplantation. Alternative options are needed. One type of treatment being explored is called haploidentical transplant.

Conventional blood or bone marrow stem cell transplant involves destroying the patient's diseased marrow with radiation or chemotherapy. Healthy marrow from a donor is then infused into the patient where it migrates to the bone marrow space to begin generating new blood cells. The best type of donor is a sibling or unrelated donor with an identical immune system (HLA "match"). However, most patients do not have a matched sibling available and/or are unable to identify an acceptable unrelated donor through the registries in a timely manner. In addition, the aggressive treatment required to prepare the body for these types of transplants can be too toxic for these highly pretreated patients. Therefore doctors are investigating haploidentical transplant using stem cells from HLA partially matched family member donors.

Although haploidentical transplant has proven curative in many patients, this procedure has been hindered by significant complications, primarily regimen-related toxicity including graft versus host disease (GVHD), and infection due to delayed immune reconstitution. These can, in part, be due to certain white blood cells in the graft called T cells. GVHD happens when the donor T cells recognize the patient's (the host) body tissues are different and attack these cells. Although too many T cells increase the possibility of GVHD, too few may cause the recipient's immune system to reconstitute slowly or the graft to fail to grow, leaving the patient at high-risk for infection. However, the presence of T cells in the graft may offer a positive effect called graft versus malignancy or GVM. With GVM, the donor T cells recognize the patient's malignant cells as diseased and, in turn, attack these diseased cells.

For these reasons, a primary focus for researchers is to engineer the graft to provide a T cell depleted product to reduce the risk of GVHD, yet provide a sufficient number of cells to facilitate immune reconstitution, graft integrity and GVM.

In this study, patients were given a haploidentical graft engineered to with specific T cell parameter values using the CliniMACS system. A reduced intensity, preparative regimen was used to reduce regimen-related toxicity and mortality. The primary goal of this study is to evaluate overall survival in those who receive this study treatment.

Secondary objectives for this protocol are to 1) assess the kinetics of lymphohematopoietic reconstitution and 2) describe the short and long-term (up to 5 years post- transplant) toxicity of haploidentical stem cell transplantation, including GVHD, in children with refractory hematological malignancies.

Haploidentical Stem Cell Transplant for Treatment Refractory Hematological Malignancies

Haploidentical Stem Cell Transplantation Utilizing T-Cell Depletion as Therapy for Patients With Refractory Hematological Malignancies

Gregory Hale, M.D. / Principal Investigator

Amino Acids

Lenograstim

Thymoglobulin

Alemtuzumab

Mechlorethamine

Antilymphocyte Serum

Immunosuppressive Agents

Antineoplastic Agents, Alkylating

Alkylating Agents

Antineoplastic Agents, Immunological

Anti-Bacterial Agents

Antibiotics, Antitubercular

Antitubercular Agents

Enzyme Inhibitors

Phenylalanine

Participants meeting eligibility criteria undergo haploidentical stem cell transplantation along with systemic chemotherapy and antibodies, including Fludarabine, Thioplex®, L-phenylalanine mustard, mycophenolate mofetil, CellCept®, Rituxan™, Muromonab (prior to January 2010) or Alemtuzumab (after January 2010), Cyclophosphamide, Anti-thymocyte globulin (Rabbit), and G-CSF.

Grafts from suitable haploidentical donors are processed using the CliniMACS system.

Miltenyi Biotec CliniMACS stem cell selection device

CliniMACS

Stem cell transplantation

Transplant recipients will receive a conditioning regimen consisting of systemic chemotherapy and antibodies.

Thioplex®

L-phenylalanine mustard

Mycophenolate mofetil

Rituxan™

After January 2010, due to the unavailability of muromonab, transplant recipients received a conditioning regimen consisting of systemic chemotherapy and antibodies, including alemtuzumab.

Anti-thymocyte globulin (Rabbit)

G-CSF

Prior to January 2010, transplant participants received a conditioning regimen consisting of systemic chemotherapy and antibodies, including muromonab. Muromonab became unavailable from the manufacturer at that time and was replaced by alemtuzumab.

Muromonab

Brandon Triplett, MD

Blood and marrow stem cell transplant has improved the outcome for patients with high-risk hematologic malignancies. However, most patients do not have an appropriate HLA (immune type) matched sibling donor available and/or are unable to identify an acceptable unrelated HLA matched donor through the registries in a timely manner. Another option is haploidentical transplant using a partially matched family member donor.

Although haploidentical transplant has proven curative in many patients, this procedure has been hindered by significant complications, primarily regimen-related toxicity including GVHD and infection due to delayed immune reconstitution. These can, in part, be due to certain white blood cells in the graft called T cells. GVHD happens when the donor T cells recognize the body tissues of the patient (the host) are different and attack these cells. Although too many T cells increase the possibility of GVHD, too few may cause the recipient's immune system to reconstitute slowly or the graft to fail to grow, leaving the patient at high-risk for significant infection.

For these reasons, a primary focus for researchers is to engineer the graft to provide a T cell dose that will reduce the risk for GVHD, yet provide a sufficient number of cells to facilitate immune reconstitution and graft integrity. Building on prior institutional trials, this study will provide patients with a haploidentical (HAPLO) graft engineered to specific T cell target values using the CliniMACS system. A reduced intensity, preparative regimen will be used in an effort to reduce regimen-related toxicity and mortality.

The primary aim of the study is to help improve overall survival with haploidentical stem cell transplant in this high risk patient population by 1) limiting the complication of graft versus host disease (GVHD), 2) enhancing post-transplant immune reconstitution, and 3) reducing non-relapse mortality.

This study will explore the following objectives:

1. To assess if the event-free survival at one-year post-transplant for research participants with high-risk hematologic malignancies can be improved following HAPLO hematopoietic stem cell transplant (HSCT) using a graft depleted of CD3+ cells ex vivo and a reduced intensity-conditioning regimen.

Secondary objectives:

1. To estimate the one-year overall survival (OS) and disease-free survival (DFS) for research participants who receive this study treatment.
2. To estimate the cumulative incidence of relapse for research participants who receive this study treatment.
3. To estimate the rate of overall grade III-IV acute GVHD, and the rate and severity of chronic GVHD in research participants.
4. To estimate the incidence of non-hematologic regimen-related toxicity and regimen-related mortality in the first 100 days post-transplant.

Exploratory objectives:

1. To explore the biologic significance of soluble interleukin-2 receptor and immunologic state \[quantitative lymphocyte studies, V beta spectratyping, T-cell receptor excision circles (TREC) assay\] to predict the development of acute and chronic GVHD in these research participants.
2. To measure the pharmacokinetics of Campath-1H in pediatric HAPLO HSCT recipients

NOTE: This protocol originally used muromonab (OKT3) in the conditioning regimen to prepare participants for haploidentical HCT. After muromonab became unavailable from the manufacturer in 2010, muromonab was replaced by alemtuzumab (Campath-1H) for use in subsequent participants.

Mismatched Family Member Donor Transplantation for Children and Young Adults With High Risk Hematological Malignancies

A Reduced Intensity Conditioning Regimen With CD3-Depleted Hematopoietic Stem Cells to Improve Survival for Patients With Hematologic Malignancies Undergoing Haploidentical Stem Cell Transplantation

To determine if one year event-free survival can be improved in pediatric patients undergoing a haploidentical transplant by using a reduced intensity conditioning regimen and a targeted dose T cell depleted donor product. EFS is defined as time from transplantation to the occurrence of relapse or death due to any cause. Patients who are alive at the time of analysis will be censored. The estimated percentage of participants with EFS at one-year post-transplantation is reported using Kaplan-Meier analysis.

Estimate the one-year overall survival (OS) for research participants who receive this study treatment. OS is defined as time from transplantation to death due to any cause. Patient who are alive at the time of analysis will be censored. The estimated percentage of participants with OS at one-year post-transplantation is reported using Kaplan-Meier analysis.

Estimate the one-year disease-free survival (DFS) for research participants who receive this study treatment. DFS is defined as time from transplantation to the occurrence of relapse or death due to relapse. Patients who are alive at the time of analysis or die due to other causes will be censored at the time of their events. The estimated percentage of participants with DFS at one-year post-transplantation is reported using Kaplan-Meier analysis.

Estimate of the incidence of non-hematologic regimen-related toxicity and regimen-related toxicity in the first 100 days post-transplant. The percentage of participants are reported by maximum grade seen using binomial distribution. Participants were graded for toxicity using Common Terminology Criteria for Adverse Events version 3.0. In general, Grade 1 is mild, 2 is moderate toxicity but generally does not require treatment, 3 is severe enough to require treatment, 4 is life-threatening, and 5 means it was associated with death.

The incidence of regimen-related mortality in the first 100 days post-transplant is estimated based on binomial distribution.

The Cumulative Incidence of Relapse will be reported as the proportion of number of relapses since transplant to the total number of patients at risk at five years post-transplant.

The rate of Overall Grade III-IV Acute AVHD will be report as the proportion of patients who have Grade III-IV Acute GVHD to the total patients with transplant. The rate of Chronic GVHD will be report as the proportion of patients who have Chronic GVHD to the total patients with transplant. The Severity of Chronic GVHD will be reported using CTCAE grading system, as a number.

Participants meeting eligibility criteria and who underwent haploidentical stem cell transplantation with systemic chemotherapy and antibodies, including Fludarabine, Thioplex®, L-phenylalanine mustard, mycophenolate mofetil, CellCept®, Rituxan™, Muromonab (prior to January 2010) or Alemtuzumab (beginning January 2010), Cyclophosphamide, Anti-thymocyte globulin (Rabbit), and G-CSF.

High-Risk Hematologic Malignancies

Age was evaluated at the time of transplantation.

Age, Continuous

Age, Customized

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Muromonab (OKT3)

Alemtuzumab (Campath-1H)

Conditioning Drug Received

Event-free Survival (EFS)

Overall Survival (OS)

Disease-Free Survival (DFS)

Grade 1

Grade 2

Grade 3

Grade 4

Grade 5

Incidence of Non-hematologic Regimen-related Toxicities

Incidence of Regimen-related Mortality

The Cumulative Incidence of Relapse at five year p

Estimate±SE

To Estimate the Cumulative Incidence of Relapse for Research Participants Who Receive This Study Treatment.

Rate of Overall Grade III-IV Acute AVHD

Rate of limited grade Chronic GVHD

To Estimate the Rate of Overall Grade III-IV Acute GVHD, and the Rate and Severity of Chronic GVHD in Research Participants.

Overall Study

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Stem Cell Transplantation for Patients With Hematologic Malignancies	NCT00152139	Acute Lymphobla... Acute Myelocyti... Chronic Myeloid... Juvenile Myelom... Myelodysplastic... Hemoglobinuria,... Non-Hodgkin Lym...	Allogeneic Stem... Chemotherapy an...	2 Years - 21 Years	St. Jude Children's Research Hospital
Stem Cell Transplantation for Patients With Hematologic Malignancies	NCT00152139	Acute Lymphobla... Acute Myelocyti... Chronic Myeloid... Juvenile Myelom... Myelodysplastic... Hemoglobinuria,... Non-Hodgkin Lym...	Allogeneic Stem... Chemotherapy an...	2 Years - 21 Years	St. Jude Children's Research Hospital
Haploidentical Stem Cell Transplant for Treatment Refractory Hematological Malignancies	NCT00145613	Acute Lymphobla... Acute Myeloid L... Secondary AML Myelodysplastic... Secondary MDS Chronic Myeloid... Juvenile Myelom... Paroxysmal Noct... Lymphoma, Non-H... Hodgkin Disease	Stem Cell Trans... Miltenyi Biotec... Systemic chemot...	2 Years - 21 Years	St. Jude Children's Research Hospital
Mismatched Family Member Donor Transplantation for Children and Young Adults With High Risk Hematological Malignancies	NCT00566696	Leukemia, Acute... Leukemia, Myelo... Leukemia, Myelo... Juvenile Myelom... Hemoglobinuria,... Hodgkin Lymphom... Lymphoma, Non-H... Myelodysplastic...	CliniMACS Stem cell trans... Fludarabine Thioplex® L-phenylalanine... Mycophenolate m... Rituxan™ Alemtuzumab Cyclophosphamid... Anti-thymocyte ... G-CSF Muromonab	- 21 Years	St. Jude Children's Research Hospital
Mismatched Family Member Donor Transplantation for Children and Young Adults With High Risk Hematological Malignancies	NCT00566696	Leukemia, Acute... Leukemia, Myelo... Leukemia, Myelo... Juvenile Myelom... Hemoglobinuria,... Hodgkin Lymphom... Lymphoma, Non-H... Myelodysplastic...	CliniMACS Stem cell trans... Fludarabine Thioplex® L-phenylalanine... Mycophenolate m... Rituxan™ Alemtuzumab Cyclophosphamid... Anti-thymocyte ... G-CSF Muromonab	- 21 Years	St. Jude Children's Research Hospital
Haploidentical Stem Cell Transplant for Treatment Refractory Hematological Malignancies	NCT00145613	Acute Lymphobla... Acute Myeloid L... Secondary AML Myelodysplastic... Secondary MDS Chronic Myeloid... Juvenile Myelom... Paroxysmal Noct... Lymphoma, Non-H... Hodgkin Disease	Stem Cell Trans... Miltenyi Biotec... Systemic chemot...	2 Years - 21 Years	St. Jude Children's Research Hospital

Spots Global Cancer Trial Database for high risk hematologic malignancies