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Miltenyi Biotec CliniMACS

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

Stem Cell Transplantation

Transplant recipients received a myeloablative conditioning regimen consisting of total body irradiation, thiotepa, cyclophosphamide, ATG, and OKT3. Rituximab was provided prior to transplant for PTLPD prophylaxis. In addition to T cell depletion of the donor product, cyclosporine was administered for GVHD prophylaxis.

TBI, systemic chemotherapy and antibodies as follows:

Gregory A. Hale, M.D.

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 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 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.

This research project will investigate the use of particular pre-transplant conditioning regimen (chemotherapy, antibodies and total body irradiation) followed by a stem cell infusion from a "mismatched" family member donor. Once these stem cells are obtained they will be highly purified in an effort to remove T cells using the investigational CliniMACS stem cell selection device. The primary goal of this study will be to determine the rate of neutrophil and platelet engraftment, as well as the degree and rate of immune reconstitution in the first 100 days posttransplant for patients who receive this study treatment. Researchers will also study ways to decrease complications that may occur with a transplant from a genetically mismatched family donor.

Secondary outcome evaluations for this clinical study include the following:

* To estimate overall survival, disease free survival and event free survival for these patients
* To estimate the incidence of grade 2 to 4 acute GvHD in these patients
* To estimate the incidence of chronic GvHD and graft failure in these patients
* To estimate the incidence of non-hematologic peri-transplant regimen-related toxicity and regimen-related mortality in the first 100 days after transplantation in these patients
* To estimate the number of patients who require donor lymphocyte infusions and/or stem cell boosts after transplantation in this group of patients and evaluate its impact on immune reconstitution and engraftment
* To estimate the number of patients who develop evidence of EBV reactivation or post transplant lymphoproliferative disease (PTLPD) post transplant in this group of patients
* Describe the pharmacokinetics of rabbit anti-thymocyte globulin (rATG) in patients receiving allogeneic transplantation and determine the frequency of rATG antibody development
* Explore dose and patient characteristics as determinants of active rATG pharmacokinetic parameters

Originally this study began as a randomized comparison of two methods of stem cell selection utilizing the CliniMACS device. Both arms provided a purified product of CD34+ hematopoietic cells that was depleted of T-lymphocytes. One arm utilized a positive selection methodology using an anti-CD34 antibody and the other arm utilized negative selection with the anti-CD3 antibody OKT-3. There were no toxicities noted that would have required the study to be interrupted early, however, due to low accrual, it was decided to redesign the study. The new design focused on the standard arm utilizing negative selection, and all subsequent participants were treated in that manner. The patients who were treated on the positive selection arm are continuing to be monitored as specified in the original protocol, but will be reported in a descriptive manner only. The primary and secondary objectives of the current version of this study will be answered only by those patients receiving a haploidentical stem cell transplant utilizing a negative selection methodology.

Haploidentical Stem Cell Transplantation for Patients With Hematologic Malignancies

Haploidentical Stem Cell Transplantation Utilizing Purified CD34+ Hematopoietic Cells for Patients With Hematologic Malignancies

St. Jude Children's Research Hospital

G. Hale, MD, Principal Investigator

Hodgkin Disease

Hodgkin Lymphoma

Amino Acids

Fludarabine

Fludarabine phosphate

Melphalan

Lenograstim

Mycophenolic Acid

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

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Chronic Myeloid Leukemia

Paroxysmal Nocturnal Hemoglobinuria

Immunomodulating Agents

Systemic chemotherapy and antibodies as follows:

Transplant recipients received a reduced intensity conditioning regimen consisting of OKT-3, fludarabine, thiotepa, and melphalan followed by an infusion of a T-cell depleted haploidentical hematopoietic stem cell graft. The antibody Rituximab was administered within 24 hours of the infusion in an effort to prevent PTLPD. In addition to T -cell depletion of the donor product, Mycophenylate mofetil was provided over several months as prophylaxis for GVHD

Systematic chemotherapy and antibodies

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

Allogeneic stem cell transplantation

Miltenyi CliniMACS

Gregory Hale, M.D.

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 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.

Two groups of patients were enrolled on this study. One group included those with high-risk hematologic malignancies and the second group included participants with refractory hematologic malignancies or undergoing a second transplant. The primary aim of the study was to estimate the relapse rate in the one group of research participants with refractory hematologic malignancies or those undergoing second allogeneic transplant. Both groups will be followed and analyzed separately in regards to the secondary objectives.

This study was closed to accrual on April 2006 as it met the specific safety stopping rules regarding occurrence of severe graft vs. host disease. Although this study is no longer open to accrual, the treated participants continue to be followed as directed by the protocol.

Secondary outcome evaluations for this clinical study included the following:

* To estimate one-year overall survival for research participants with high risk malignancies who receive a haploidentical HSCT
* To compare overall survival and cumulative incidence of relapse for the two groups of patients with their corresponding historical controls
* To estimate disease-free survival and event-free survival in participants with hematologic malignancies who receive a haploidentical HSCT
* To estimate the incidence of overall grade 3-4 acute GvHD in research participants with hematologic malignancies who receive a haploidentical HSCT
* To estimate the incidence of chronic GvHD and graft failure in research participants with hematologic malignancies who receive a haploidentical HSCT
* To estimate the incidence of non-hematologic regimen-related toxicity and regimen-related mortality in the first 100 days post-transplant in research participants with hematologic malignancies who receive a haploidentical HSCT
* To estimate the number of research participants who develop evidence of EBV reactivation or post-transplant lymphoproliferative disease (PTLPD)
* To describe disease-free survival, GvHD and engraftment in research participants receiving grafts from Killer immunoglobulin-like receptor (KIR) mismatched and KIR matched haploidentical donors

Stem Cell Transplantation as Immunotherapy for Hematologic Malignancies

Haploidentical Hematopoietic Stem Cell Transplantation Utilizing Partial T-Cell Depletion as Immunotherapy for Hematologic Malignancies

G. Hale, Principal Investigator

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Haploidentical Stem Cell Transplantation for Patients With Hematologic Malignancies	NCT00186823	Leukemia, Acute... Leukemia, Myelo... Leukemia, Myelo... Juvenile Myelom... Hemoglobinuria,... Lymphoma, Non-H... Myelodysplastic...	Miltenyi Biotec... Stem Cell Trans... TBI, systemic c...	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
Stem Cell Transplantation as Immunotherapy for Hematologic Malignancies	NCT00143559	Leukemia Acute Lymphobla... Acute Myeloid L... Chronic Myeloid... Juvenile Myelom... Myelodysplastic... Paroxysmal Noct... Hodgkin's Lymph... Non-Hodgkin Lym...	Systematic chem... Allogeneic stem... Miltenyi CliniM...	2 Years - 21 Years	St. Jude Children's Research Hospital

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