Neoplasms

Symptoms and General Pathology

All Conditions

Blood and Lymph Conditions

Immune System Diseases

Diseases and Abnormalities at or Before Birth

Rare Diseases

Neoplasm Metastasis

Syndrome

Recurrence

Leukemia

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Leukemia, Lymphoid

Congenital Abnormalities

Anemia

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Graft vs Host Disease

Preleukemia

Myelodysplastic Syndromes

Anemia, Refractory, with Excess of Blasts

Anemia, Refractory

Neoplasms by Histologic Type

Hematologic Diseases

Bone Marrow Diseases

Precancerous Conditions

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Lymphoblastic Leukemia

Lymphoblastic Lymphoma

Acute Non Lymphoblastic Leukemia

Homologous Wasting Disease

Acute Graft Versus Host Disease

Childhood Acute Lymphoblastic Leukemia

Myelodysplastic Syndrome With Excess Blasts

Antineoplastic Agents

All Drugs and Chemicals

Fludarabine

Fludarabine phosphate

Tacrolimus

Thiotepa

Antimetabolites

Immunosuppressive Agents

Immunologic Factors

Calcineurin Inhibitors

Enzyme Inhibitors

Antineoplastic Agents, Alkylating

Alkylating Agents

CONDITIONING: Patients undergo total-body irradiation twice daily on days -10 to -7. Patients also receive thiotepa IV over 4 hours on days -6 and -5 and fludarabine IV over 30 minutes on days -6 to -2. TRANSPLANTATION: Patients undergo infusion of CD34+ enriched allogeneic peripheral blood stem cells (PBSC) followed by CD45RA+ T-cell-depleted allogeneic PBSC on day 0.

GRAFT-VS-HOST DISEASE PROPHYLAXIS: Cohort A: Patients receive tacrolimus IV continuously or orally twice daily beginning on day -1 and continuing until day 50 followed by standard taper in the absence of grade II-IV acute GVHD. Cohort B: Patients receive tacrolimus IV continuously or orally twice daily beginning on day -1 and continuing until day 30 followed by rapid taper in the absence of grade II-IV acute GVHD.

Fludarabine will be administered in a dose of 25 mg/m2/day IV over approximately 30 minutes for 5 consecutive days (day -6 to -2). The total dose of fludarabine will be 125 mg/m2.

Fludarabine Phosphate

Tacrolimus will be administered beginning on day -1 at a dose of 0.03 mg/kg/day by continuous IV infusion.

For the first cohort of 35 patients, if there is no evidence of grade II-IV acute GVHD on or prior to day 50, tacrolimus should then be tapered at the rate of approximately 5% of the day 50 dose each week for liquid, and 20% of the day 50 dose per month for capsules.

In the second cohort of 25 patients if there is no evidence of grade II GVHD on or prior to day 30, tacrolimus should then be tapered at the rate of approximately 8% of the day 30 dose each week for liquid, and 33% of the day 30 dose per month for capsules.

Thiotepa will be administered in a dose of 5 mg/kg/day (adjusted body weight) IV over approximately 4 hours for 2 consecutive days (day -6 and day -5).

TBI will be given as 165 cGy fractions twice per day x 4 days - total dose 1320cGy (days -10 to -7).

Total-Body Irradiation (TBI)

Magnetic Affinity Cell Sorting

Patient will undergo a PBSC transplantation

Peripheral Blood Stem Cell Transplantation

Patients who are considered appropriate candidates for allogeneic hematopoietic stem cell transplantation

Allogeneic Hematopoietic Stem Cell Transplantation

Patients who are eligible will receive a T Cell-Depleted Hematopoietic Stem Cell Transplantation

T Cell-Depleted Hematopoietic Stem Cell Transplantation

Marie Bleakley, MD

Warren Shlomchik, MD

RATIONALE: Allogeneic hematopoietic stem cell transplant (HSCT) is a treatment that can cure acute leukemia and myelodysplasia. After giving the patient chemotherapy and total body irradiation to stop the growth of cancer and remove the patient's diseased bone marrow, healthy stem cells from a donor are infused into the patient to replace the patient's bone marrow and make red and white blood cells and platelets. Unfortunately HSCT is often complicated by 'graft versus host disease' (GVHD) in which the transplanted cells from a donor can make an immune response against the body's normal cells and cause tissue damage and severe symptoms. Removing a subset of the donor T cells, called 'naive T cells', before transplant may reduce the frequency and intensity of GVHD.

PURPOSE: This phase II trial will determine whether the removal of the naive T cells from donor cells can decrease the rate and severity of graft-vs-host disease while preserving specific immunity against infections in patients with acute leukemia or advanced myelodysplastic syndromes.

OBJECTIVES:

Primary

* Estimate the probability of grades II-IV acute graft-vs-host disease (GVHD) in patients with acute leukemia or advanced myelodysplastic syndromes treated with CD45RA+ T-cell-depleted allogeneic peripheral blood stem cell transplantation and compare this to relevant historical experience.
* Estimate the probability of graft failure in these patients.

Secondary

* Evaluate immune reconstitution and pathogen-specific T-cell reconstitution in these patients.
* Estimate the probability of transplant-related mortality by day 100 in these patients.
* Estimate the probability of relapse in these patients.
* Estimate the probability and severity of chronic GVHD in these patients.

OUTLINE: This is a multicenter study.

* Myeloablative conditioning regimen: Patients undergo total body irradiation twice daily for 4 days (Days -10 to -7) Patients also receive thiotepa IV over 4 hours for 2 days (Days -6 and -5) and fludarabine phosphate IV over 30 minutes for 5 days (Days -6 to -2.)
* Transplantation: Patients receive a CD34+ enriched allogeneic peripheral blood stem cell (PBSC) product followed by a CD45RA+ T-cell-depleted allogeneic PBSC product on day 0.
* Graft-vs-host disease (GVHD) prophylaxis: Patients will receive Tacrolimus as per cohort 1. If the rate of grade II-IV acute GVHD in the first 35 patients is significantly reduced (compared to historical controls), subsequent patients are enrolled in cohort 2.

  * Cohort 1: Patients receive tacrolimus IV continuously or orally twice daily beginning on day -1 and continuing until day 50, followed by a standard taper in the absence of grade II-IV acute GVHD.
  * Cohort 2: Patients receive tacrolimus IV continuously or orally twice daily beginning on day -1 and continuing until day 30, followed by a rapid taper in the absence of grade II-IV acute GVHD.

Patients are followed actively for at least 1 year post transplant.

Selective Depletion of CD45RA+T Cells From Allogeneic Peripheral Blood Stem Cell Grafts for the Prevention of GVHD

A Multi-center Phase II Study of Selective Depletion of CD45RA+ T Cells From Allogeneic Peripheral Blood Stem Cell Grafts for the Prevention of GVHD

Number of participants with aGVHD and severity of aGVHD within the first 360 days post-transplant as graded by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. Acute GVHD is graded by standard criteria, and all suspected cases of acute GVHD will be confirmed histologically by biopsy of an affected organ. The severity of acute GVHD is determined by an assessment of the degree of involvement of the skin, liver, and gastrointestinal tract. Grade I is characterized as mild disease, Grade II as moderate, Grade III as severe (involvement of any organ system), and Grade IV as life-threatening.

Graft failure is defined as either a failure to reach an ANC of \>500/uL for 3 consecutive days by day 28 post-transplant, or an irreversible decrease in ANC \<100 after an established donor graft, unless there is a reasonable explanation such as a viral infection or drug effect that may be responsible for a reversible decrease in ANC.

Number of participants who died due to transplant-related issues within the first 100 days of transplant

Relapse is defined by the presence of malignant cells in marrow, peripheral blood, or extramedullary sites by histopathology. Testing for recurrent malignancy in the blood and bone marrow performed by monitoring the CBC and bone marrow at Day 28, 58, 80, 360, and as needed for suspected relapse.

Chronic GVHD measured by meeting NIH criteria and treated with immune suppression

National Cancer Institute (NCI)

Fred Hutchinson Cancer Center

No Serious Adverse Events reported were related to the investigational cell product, but to the transplant or other indications.

CD34+ enriched allogeneic peripheral blood stem cells (PBSC) followed by CD45RA+ T-cell-depleted allogeneic PBSC and tacrolimus for GVHD prophylaxis

Overall Study Participants

CONDITIONING: Patients receive TBI twice per day on days -10 to -7, then thiotepa IV administered over approximately 4 hours on days -6 and -5, and fludarabine IV administered over 30 minutes on days -6 to -2.

DONOR BONE MARROW TRANSPLANTATION: GCSF-mobilized CD34 enriched PBSC and CD45RA depleted cells infused on day 0.

POST-TRANSPLANT IMMUNOSUPPRESSION: Ptients receive tacrolimus beginning on day -1 by continuous IV infusion, converting to oral formulation when oral feeding is established. If there is no evidence of grade II-IV acute GVHD prior to day 50, tacrolimus is then tapered.

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Number of Participants With Acute Graft-vs-host Disease (GVHD): Grade I-IV, Including Those With no Reportable Acute GVHD

Number of Participants Who Did Not Engraft After Receiving a CD45RA+ T Cell Depleted PBSC Transplant

Transplant-related Mortality by Day 100

Number of Participants Who Have Relapsed Within 5 Years of CD45RA+ T Cell Depleted PBSC Transplant

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Selective Depletion of CD45RA+T Cells From Allogeneic Peripheral Blood Stem Cell Grafts for the Prevention of GVHD	NCT00914940	Graft Versus Ho... Leukemia Myelodysplastic...	Fludarabine Pho... Tacrolimus Thiotepa Total-Body Irra... Magnetic Affini... Peripheral Bloo... Allogeneic Hema... T Cell-Depleted...	14 Years - 55 Years	Fred Hutchinson Cancer Center
Selective Depletion of CD45RA+T Cells From Allogeneic Peripheral Blood Stem Cell Grafts for the Prevention of GVHD	NCT00914940	Graft Versus Ho... Leukemia Myelodysplastic...	Fludarabine Pho... Tacrolimus Thiotepa Total-Body Irra... Magnetic Affini... Peripheral Bloo... Allogeneic Hema... T Cell-Depleted...	14 Years - 55 Years	Fred Hutchinson Cancer Center
Selective Depletion of CD45RA+T Cells From Allogeneic Peripheral Blood Stem Cell Grafts for the Prevention of GVHD	NCT00914940	Graft Versus Ho... Leukemia Myelodysplastic...	Fludarabine Pho... Tacrolimus Thiotepa Total-Body Irra... Magnetic Affini... Peripheral Bloo... Allogeneic Hema... T Cell-Depleted...	14 Years - 55 Years	Fred Hutchinson Cancer Center

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