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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

Histiocytosis

Fludarabine

Fludarabine phosphate

Melphalan

Immunomodulating Agents

Muromonab-CD3

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.

Miltenyi Biotec CliniMACS

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.

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
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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