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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

Neoplasm Metastasis

Hodgkin Disease

Neoplastic Processes

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Chronic Myeloid Leukemia

Hodgkin Lymphoma

Paroxysmal Nocturnal Hemoglobinuria

Fludarabine

Fludarabine phosphate

Melphalan

Mycophenolic Acid

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

Gregory Hale, M.D.

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

Histiocytosis

Immunomodulating Agents

Immunosuppressive Agents

Antineoplastic Agents, Alkylating

Alkylating Agents

Participants who meet the eligibility criteria for this study. Donor cells will be obtained using the Miltenyi Biotec CliniMACS device.

Interventions: Chemotherapy and antibodies, allogeneic stem cell transplantation.

Study participants will receive a non-TBI based preparative regimen consisting of Cyclophosphamide, fludarabine, thiotepa, melphalan, and muromonab-CD3 (OKT3) followed by an infusion of a T-lymphocyte depleted haploidentical hematopoietic stem cell graft. Seven days posttransplant, participants will receive an infusion of additional donor derived cells called NK cells.

Chemotherapy and antibodies

Allogeneic natural killer (NK)cell infusion

Allogeneic stem cell transplantation

Brandon Triplett, MD

Recent studies of conventional chemotherapy for infants with high-risk hematologic malignancies show that the long-term disease-free survival is low. Although blood and marrow stem cell transplantation using an HLA identical sibling has improved the outcome for these children, less than 25% have this donor source available. Another option is haploidentical transplantation using a partially matched family member donor (i.e. parental donor).

Although haploidentical transplantation has proven curative for some patients, this procedure has been hindered by significant complications, primarily regimen-related toxicity including infection and graft versus host disease (GVHD). Building on prior institutional trials, this study will provide patients a haploidentical graft depleted of T lymphocytes using the investigational device, CliniMACS selection system. One week after the transplant procedure, patients will also receive an infusion of additional donor derived white blood cells called Natural Killer (NK) cells in an effort to decrease risks for rejection of the graft, disease relapse, and regimen related toxicity. The primary objective of the study is to evaluate 1 year survival in infants with high risk hematologic malignancies who receive this study treatment.

Secondary objectives for this study include the following:

* To estimate the incidence of three transplant-related adverse outcomes (i.e., regimen-related mortality, engraftment failure, and fatal acute GVHD) in the first 100 days after transplantation.
* To estimate the incidence of chronic graft-versus-host disease.
* To evaluate those factors that affect one-year survival.
* To assess the kinetics of lymphohematopoietic reconstitution.
* To assess the frequency and clinical relevance of minimal residual disease (MRD) before and after transplantation.
* To evaluate the incidence of and risk factors for long-term neurocognitive deficit and organ dysfunction.

HLA-Nonidentical Stem Cell and Natural Killer Cell Transplantation for Children Less the Two Years of Age With Hematologic Malignancies

The one-year survival of infants with high-risk hematologic malignancies who receive a haploidentical transplant procedure using a total body irradiation (TBI)-excluding conditioning regimen followed by an HLA-nonidentical family donor hematopoietic stem cell (HSC) graft depleted of T cells ex vivo using the CliniMACS CD34+ selection system, with a subsequent infusion of donor NK cells purified ex vivo using the CliniMACS CD3+ depletion and CD56+ enrichment system.

The Kaplan-Meier estimate for one-year survival is reported.

The cumulative incidences of regimen-related mortality will be estimated using method of Kalbfleisch and Prentice.

Engraftment failure is defined as \<10% donor cell chimerism at any time point between 28 and 100 days after transplant with no evidence of disease relapse or requiring stem cell boost.

The cumulative incidence estimate for occurrence of fatal acute GVHD by the end of the first 100 days post-transplant was calculated using method of Kalbfleisch and Prentice.

Chronic GVHD was graded according to Seattle Criteria: limited or extensive. Limited is defined as localized skin and/or hepatic dysfunction. Extensive is defined as one or more of the following:

* generalized skin involvement
* liver histology showing chronic aggressive hepatitis, bridging necrosis or cirrhosis
* eye dryness with Schirmer's test \<5 mm wetting
* oral: involvement of salivary glands or oral mucosa
* other: another target organ involvement

Due to small sample size (n=14) and total number of events (n=7), the analysis to check the various factors that affect the one-year survival was not performed (using logistic and cox model).

HLA typing determined the degree of match by looking at 6 different HLA loci. The results indicate the number of the 6 loci that matched for each participant. Due to small sample size (n=14) and total number of events (n=7), the analysis to check the various factors that affect the one-year survival was not performed (using logistic and cox model).

Detection of leukemia blasts in bone marrow by flow cytometry

The organ dysfunction will be summarized using summary statistics and assessed in a longitudinal manner and analyzed accordingly.

The long-term neurocognitive deficit will be summarized using summary statistics and assessed in a longitudinal manner and analyzed accordingly.

The presence or absence of MRD before and after the bone marrow transplant (BMT) and its frequency distribution will be obtained for each time point separately.

The lymphohematopoietic reconstitution will be summarized using summary statistics and assessed in a longitudinal manner and analyzed accordingly.

Assisi Foundation

Study participants received a non-TBI based preparative regimen consisting of Cyclophosphamide, fludarabine, thiotepa, melphalan, and muromonab-CD3 (OKT3) followed by an infusion of a T-lymphocyte depleted haploidentical hematopoietic stem cell graft. Seven days post-transplant, participants received an infusion of additional donor derived cells called natural killer (NK) cells.

Stem cells were obtained from donors using the Miltenyi Biotec CliniMACS stem cell selection device.

Study Participants

Group of participants who survived to at least one year post HSCT.

Study participants received a non-TBI based preparative regimen consisting of Cyclophosphamide, fludarabine, thiotepa, melphalan, and muromonab-CD3 (OKT3) followed by an infusion of a T-lymphocyte depleted haploidentical hematopoietic stem cell graft. Seven days posttransplant, participants received an infusion of additional donor derived cells called natural killer (NK) cells.

Stem cells were obtained from donors using the Miltenyi Biotec CliniMACS stem cell selection device.

Alive

Those participants who did not survive to at least one year post HSCT.

Study participants received a non-TBI based preparative regimen consisting of Cyclophosphamide, fludarabine, thiotepa, melphalan, and muromonab-CD3 (OKT3) followed by an infusion of a T-lymphocyte depleted haploidentical hematopoietic stem cell graft. Seven days posttransplant, participants received an infusion of additional donor derived cells called natural killer (NK) cells.

Stem cells were obtained from donors using the Miltenyi Biotec CliniMACS stem cell selection device.

Expired

Total

Age, Continuous

Sex: Female, Male

Black

Other

White

Race/Ethnicity, Customized

The study was limited due to the unavailability of the study drug OKT3 beginning in June 2011. The study was temporarily closed to accrual. Because OKT3 is still unavailable, the study was formally closed to accrual in March 2015.

Study participants received a non-TBI based preparative regimen consisting of Cyclophosphamide, fludarabine, thiotepa, melphalan, and muromonab-CD3 (OKT3) followed by an infusion of a T-lymphocyte depleted haploidentical hematopoietic stem cell graft. Seven days posttransplant, participants received an infusion of additional donor derived cells called natural killer (NK) cells.

Stem cells were obtained from donors using the Miltenyi Biotec CliniMACS stem cell selection device.

One-year Survival

Number of Transplant-Related Adverse Outcomes: Regimen-Related Mortality

Number of Transplant-Related Adverse Outcomes: Engraftment Failure

Number of Transplant-Related Adverse Outcomes: Fatal Acute Graft-Versus Host Disease (GVHD)

Number of Incidences of Chronic GVHD.

Group of participants who survived to at least one year post HSCT.

Those participants who did not survive to at least one year post HSCT.

Fourteen study participants were evaluable for the outcome measures. Study participants received a non-TBI based preparative regimen consisting of Cyclophosphamide, fludarabine, thiotepa, melphalan, and muromonab-CD3 (OKT3) followed by an infusion of a T-lymphocyte depleted haploidentical hematopoietic stem cell graft. Seven days posttransplant, participants received an infusion of additional donor derived cells called natural killer (NK) cells.

Stem cells were obtained from donors using the Miltenyi Biotec CliniMACS stem cell selection device.

Factors Affecting One-year Survival: Median Age of Donor at HSCT

Factors Affecting One-year Survival: Median Dose of CD34

Factors Affecting One-year Survival: Median Dose of NK Cells

Active Disease

Complete Remission-1

Complete Remission-2

Progressive Disease

Relapse

Factors Affecting One-year Survival: Disease Status at HSCT

Father

Mother

Uncle

Factors Affecting One-year Survival: Donor Type

3/6 HLA Loci

4/6 HLA Loci

Factors Affecting One-year Survival: Match N/6 HLA Loci

Negative for MRD

Positive for MRD

MRD data were collected on four study participants. Study participants received a non-TBI based preparative regimen consisting of Cyclophosphamide, fludarabine, thiotepa, melphalan, and muromonab-CD3 (OKT3) followed by an infusion of a T-lymphocyte depleted haploidentical hematopoietic stem cell graft. Seven days posttransplant, participants received an infusion of additional donor derived cells called natural killer (NK) cells.

Stem cells were obtained from donors using the Miltenyi Biotec CliniMACS stem cell selection device.

Only four of the 14 participants had MRD measured at the one-year time point.

Factors Affecting One-year Survival: Minimal Residual Disease (MRD)

There was not enough data available after 1 year post-transplant to evaluate long term outcomes on this study.

Incidence of and Risk Factors for Organ Dysfunction.

Incidence of and Risk Factors for Long-term Neurocognitive Deficit.

Patient 1

Patient 2

Patient 3

Patient 4

All study participants as previously described.

Study Participants: Before HSCT

Study Participants: 1 Year Post HSCT

Study Participants: 5 Years Post HSCT

MRD data was collected on only four participants during at least one time point.

Frequency of and Clinical Relevance of Minimal Residual Disease (MRD) Before and After Transplantation

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
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
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
HLA-Nonidentical Stem Cell and Natural Killer Cell Transplantation for Children Less the Two Years of Age With Hematologic Malignancies	NCT00145626	Acute Myeloid L... Acute Lymphocyt... Myelodysplasia Chronic Myeloid... Histiocytosis	Chemotherapy an... Miltenyi Biotec... Allogeneic stem...	- 24 Months	St. Jude Children's Research Hospital

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