Neoplasms

Blood and Lymph Conditions

All Conditions

Hematologic Neoplasms

Hematologic Diseases

Antineoplastic Agents

Antirheumatic Agents

All Drugs and Chemicals

Anti-Infective Agents

Cyclophosphamide

Mycophenolic Acid

Tacrolimus

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

Calcineurin Inhibitors

Enzyme Inhibitors

Anti-Bacterial Agents

Antibiotics, Antitubercular

Antitubercular Agents

Patients undergoing hematopoietic stem cell transplant from a partially matched related donor

TBI twice daily days 6-9 prior to transplant (HSCT)

Total Body Irradiation (TBI)

DLI given 6 days prior to transplant (HSCT).

Donor Lymphocyte Infusion (DLI)

Cyclophosphamide given once daily at 60 mg/kg on days 2 and 3 prior to transplant (HSCT).

Cyclophosphamide (CY)

Tacrolimus given one day prior to transplant (HSCT).

MMF given one day prior to transplant (HSCT).

Mycophenolate Mofetil (MMF)

CD34+ selected Hematopoietic Stem Cell Transplant (HSCT) is performed. This is the day of transplantation.

Hematopoietic Stem Cell Transplant (HSCT)

Neal Flomenberg, MD

The purpose of this study is to develop a way of treating patients who do not have a completely matched family donor or a readily available unrelated donor with bone marrow transplant by using a partially-matched family donor. Patients receiving this type of transplant will receive chemotherapy and/or radiation to treat their disease. They will also receive their donor's cells in 2 parts. During the first part, the donor's lymphocytes will be exposed to one of the chemotherapy agents to help the patient become tolerant to the lymphocytes. In the second part of the transplant, the patient will receive their donor's stem cells to help recover their peripheral blood counts and establish long-term engraftment. The hypothesis of this study is that in partially-matched allogeneic transplant, there is a defined number of donor T-cells that can be treated and given to the recipient to avoid post-transplant infection without causing severe graft-versus-host disease.

Haploidentical hematopoietic stem cell transplant is a life-saving therapy for patients who are without well matched donors. This type of therapy has been associated with poor outcomes in the past due to complications such as infection. The Jefferson 2 Step approach was designed to allow the infusion of an exact dose of tolerized lymphocytes in haploidentical transplant in order to allow for immune reconstitution post transplant to avoid infectious complications while still having acceptable rates of GVHD. In this approach, patients with high-risk hematological malignancies undergo 8 fractions of TBI (12 Gy) followed by an exact dose of donor lymphocytes. The phase I portion of the study determined the optimal dose of lymphocytes. Two days after receiving the donor lymphocytes, the patients receive 2 daily doses of cyclophosphamide. One day after receiving cyclophosphamide, the patients receive stem cell from their donor. Tacrolimus and mycophenylate mofetil are used as GVHD prophylaxis.

A Two-Step Approach to Bone Marrow Transplant Using Cells From A Partially-Matched Relative

A Two Step Approach To Allogeneic Hematopoietic Stem Cell Transplantation for Hematologic Malignancies From HLA Partially-Matched Related Donors

To determine overall survival at 6 months post-transplant.

To determine the optimal dose of CD3+ donor lymphocytes required for consistent engraftment without the development of grade III/IV GVHD.

Measured as CD3+ donor lymphocytes given as n x 10\^8/kg.

"n" was found to be 2 and was found to be the optimal dose and was the only dose given.

To assess hematopoietic engraftment rates.

To assess the pace of lymphoid recovery in this patient population.

To determine the incidence and severity of GVHD in these patients using a combination of cyclophosphamide, tacrolimus and mycophenolate mofetil (MMF) as GVHD prophylaxis.'

Severity was graded using CTCAE 3.0 (1=mild, 2=moderate, 3=severe, 4=life threatening/disabling, 5=death)

Sidney Kimmel Cancer Center at Thomas Jefferson University

Haploidentical Allogeneic Transplantation

Age, Categorical

Age, Continuous

Sex: Female, Male

United States

Region of Enrollment

Limitations of the trial include small sample size and single institution

27 Patients undergoing haploidentical transplant at Thomas Jefferson University

Overall Survival of Participants

Two patients died prior to expected day of engraftment

Optimal Dose of CD3+ Donor Lymphocytes (T-cells) for Consistent Engraftment Without GVHD

Two patients died prior to expected engraftment day

Engraftment Rates

Two patients did not engraft, two patients died prior to expected day of engraftment

Lymphoid Recovery

Two patients died prior to expected engraftment. Two patients who rejected were retransplanted and were evaluable for GVHD.

Incidence of Grades III-IV GVHD

Overall Study

Symptoms and General Pathology

Immune System Diseases

Rare Diseases

Syndrome

Leukemia

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Preleukemia

Myelodysplastic Syndromes

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Leukemia, Lymphoid

Lymphoma

Leukemia, Lymphocytic, Chronic, B-Cell

Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Hodgkin Disease

Bone Marrow Failure Disorders

Pancytopenia

Neoplasms by Histologic Type

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Bone Marrow Diseases

Leukemia, B-Cell

Chronic Disease

Disease Attributes

Myeloproliferative Disorders

Cytopenia

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Acute Lymphoblastic Leukemia

Lymphoblastic Lymphoma

Chronic Graft Versus Host Disease

Lymphosarcoma

Chronic Lymphocytic Leukemia

Chronic Myeloid Leukemia

Hodgkin Lymphoma

Acute Graft Versus Host Disease

Chronic Myeloproliferative Disorders

Fludarabine

Fludarabine phosphate

Fludarabine 30mg/m2 IV days -6 to -2 Cyclophosphamide 14.5 mg/kg IV days -6 and -5 Total body irradiation 2Gy day -1 Stem cell transplant: day 0 Cyclophosphamide 50mg/kg days +3 \& +4

Total body irradiation 12Gy in 8 fractions days -9 to -6 Donor lymphocyte infusion day -6 Cyclophosphamide 60mg/kg IV days -3 \& -2 Stem cell transplant day 0

Reduced intensity haplodentical stem cell transplant

Myeloablative haploidentical stem cell transplant

Dr Kavita Raj

This trial investigates stem cell transplants from partially mismatched donors in patients with blood and bone marrow cancers. The trial will test two kinds of transplants - a full intensity transplant using a high dose of radiotherapy and chemotherapy, and a reduced intensity transplant with lower doses of chemotherapy and radiotherapy. Patients will be entered for the treatment pathway that is most appropriate for their level of health and fitness

Trial of Haploidentical Stem Cell Transplantation for Haematological Cancers

A UK Multicentre Study of Haploidentical Stem Cell Transplantation in Patients With Haematological Malignancies

Bloodwise

University College, London

Histiocytosis

Antibodies

Melphalan

Immunomodulating Agents

Immunoglobulins

Thiotepa

Muromonab-CD3

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

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

St. Jude Children's Research Hospital

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

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

CD3 Lymphocyte

CD3 Gamma Delta

Data was not available for analysis for all patients at all time points.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Two-Step Approach to Bone Marrow Transplant Using Cells From A Partially-Matched Relative	NCT00429143	Hematologic Mal...	Total Body Irra... Donor Lymphocyt... Cyclophosphamid... Tacrolimus Mycophenolate M... Hematopoietic S...	18 Years -	Thomas Jefferson University
Trial of Haploidentical Stem Cell Transplantation for Haematological Cancers	NCT01597219	Hodgkin's Lymph... Non-Hodgkin's L... Acute Myeloid L... Acute Lymphobla... Myelodysplastic... Chronic Myeloid... Chronic Lymphoc... Acquired Bone M... Other Haematolo...	Reduced intensi... Myeloablative h...	16 Years - 70 Years	University College, London
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
Partially HLA Mismatched (Haploidentical) Allogeneic Bone Marrow Transplantation	NCT01749293	Hematologic Mal...	Haploidentical ... Fludarabine Busulfan Total Body Irra... Cyclophosphamid...	10 Years - 75 Years	University of Illinois at Chicago

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