Selective Depletion of CD45RA+ T Cells From Allogeneic Peripheral Blood Stem Cell Grafts in Preventing GVHD in Children

Phase 2

Completed

Conditions: Accelerated Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive
Acute Biphenotypic Leukemia
Acute Undifferentiated Leukemia
Adult Acute Lymphoblastic Leukemia in Remission
Blast Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive
Recurrent Adult Acute Lymphoblastic Leukemia
Refractory Childhood Acute Lymphoblastic Leukemia
Acute Leukemia of Ambiguous Lineage
Adult Acute Myeloid Leukemia in Remission
Childhood Acute Lymphoblastic Leukemia in Remission

Interventions: Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
Drug: Fludarabine Phosphate
Other: Laboratory Biomarker Analysis
Drug: Methotrexate
Procedure: Peripheral Blood Stem Cell Transplantation
Biological: T Cell-Depleted Hematopoietic Stem Cell Transplantation
Drug: Tacrolimus
Drug: Thiotepa
Radiation: Total-Body Irradiation

Registration Number: NCT01858740

Lead Sponsor: Fred Hutchinson Cancer Center

Brief Summary: This phase II trial studies how well T cell depleted donor peripheral blood stem cell transplant works in preventing graft-versus-host disease in younger patients with high risk hematologic malignancies. Giving chemotherapy and total-body irradiation before a donor peripheral blood stem cell transplant helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Removing a subset of the T cells from the donor cells before transplant may stop this from happening.

Detailed Description: OUTLINE:

CONDITIONING REGIMEN: Patients undergo total body irradiation (TBI) twice daily (BID) on days -10 to -7, receive thiotepa intravenously (IV) over 4 hours on days -6 and -5 and fludarabine phosphate IV over 30 minutes on days -6 to -2.

TRANSPLANT: Patients undergo CD34+ enriched, CD45RA+ T cell-depleted allogeneic PBSCT on day 0.

POST-TRANSPLANT IMMUNOSUPPRESSION: Patients receive tacrolimus IV continuously or orally (PO) every 12 hours beginning on day -1 and continuing through day 50 with taper. Patients also receive methotrexate IV on days 1, 3, 6, and 11.

After completion of study treatment, patients are followed up for up to 5 years.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 20

Inclusion Criteria

Patients who are considered appropriate candidates for allogeneic hematopoietic stem cell transplantation and have one of the following diagnoses:
- Acute lymphocytic leukemia in first or subsequent remission
- Acute myeloid leukemia in first or subsequent remission
- Acute lymphocytic leukemia in relapse or primary refractory disease with a circulating blast count of no more than 10,000/mm^3
- Acute myeloid leukemia in relapse or primary refractory disease with a circulating blast count of no more than 10,000/mm^3
- Refractory anemia with excess blasts (RAEB-1 and RAEB-2)
- Chronic myelogenous leukemia with a history of accelerated phase or blast crisis
- Other acute leukemia (including but not limited to 'biphenotypic', 'undifferentiated' or 'ambiguous lineage' acute leukemia)
Patient with a human leukocyte antigen (HLA)-identical (HLA-A, B, C, and ribonucleic acid [RNA] binding motif protein 45 [DRB1] molecularly matched) unrelated donor or related donor capable of donating PBSC
DONOR: HLA-matched unrelated donors (HLA-A, B, C, and DRB1 matched based on high-resolution typing) capable and willing to donate PBSC
DONOR: HLA-matched related donors >= 18 years and capable and willing to donate PBSC

Exclusion Criteria

Patients with central nervous system (CNS) involvement refractory to intrathecal chemotherapy and/or standard cranial-spinal radiation
Patients on other experimental protocols for prevention of acute GVHD
Patients who weigh >= 70 kg must be discussed with the principal investigator prior to enrolling on the protocol
Patients who are human immunodeficiency virus positive (HIV+)
Patients with uncontrolled infections for whom myeloablative hematopoietic stem cell transplant (HCT) is considered contraindicated by the consulting infectious disease physician (upper respiratory tract viral infection does not constitute an uncontrolled infection in this context)
Creatinine > 1.5 mg/dl
Cardiac ejection fraction < 45%
Patients who can perform pulmonary function tests will be excluded if they have a diffusing capacity of the lung for carbon monoxide (DLCO) (corrected for hemoglobin) of < 60% predicted; patients who are unable to perform pulmonary function tests (for example, due to young age and/or developmental status) will be excluded if the oxygen (O2) saturation is < 92% on room air
Patients who have liver function test (LFTs) (including total bilirubin, aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) >= twice the upper limit of normal should be evaluated by a gastrointestinal (GI) physician unless there is a clear precipitating factor (such as an azole, methotrexate, Bactrim or another drug); if the GI physician considers that HCT on protocol 2660 is contraindicated for that patient the patient will be excluded from the protocol; patients with Gilbert's syndrome and no other known liver function abnormality and patients with reversible drug-related transaminitis do not necessarily require GI consultation and may be included on the protocol
Patients with a life expectancy < 3 months from co-existing disease other than the leukemia or RAEB
Patients who are pregnant or breast-feeding
Fertile patients of child bearing age unwilling to use contraception during and for 12 months post-transplant
Patients with a significant other medical conditions that would make them unsuitable for transplant
Patients with a known hypersensitivity to tacrolimus
DONOR: Donors who are HIV-1, HIV-2, human T-lymphotropic virus (HTLV)-1, HTLV-2 seropositive or with active hepatitis B or hepatitis C virus infection
DONOR: Donors who fail eligibility requirements for donation of cells or tissue per section 21 Code of Federal Regulations (CFR) 1271 for donation of a HCT/product (P) will be excluded unless use of the cells complies with 21 CFR 1271.65(b)(iii) (urgent medical need) or with 21 CFR 1271.65(b)(i) (allogeneic use in a first-degree or second-degree relative)
DONOR: Unrelated donors donating outside of the United States of America (USA) or Germany

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (CD45RA+ T cell depleted PBSCT)	Laboratory Biomarker Analysis	CONDITIONING REGIMEN: Patients undergo TBI BID on days -10 to -7, receive thiotepa IV over 4 hours on days -6 and -5 and fludarabine phosphate IV over 30 minutes on days -6 to -2. TRANSPLANT: Patients undergo CD34+ enriched, CD45RA+ T cell-depleted allogeneic PBSCT on day 0. POST-TRANSPLANT IMMUNOSUPPRESSION: Patients receive tacrolimus IV continuously or PO every 12 hours beginning on day -1 and continuing through day 50 with taper. Patients also receive methotrexate IV on days 1, 3, 6, and 11.
Treatment (CD45RA+ T cell depleted PBSCT)	T Cell-Depleted Hematopoietic Stem Cell Transplantation	CONDITIONING REGIMEN: Patients undergo TBI BID on days -10 to -7, receive thiotepa IV over 4 hours on days -6 and -5 and fludarabine phosphate IV over 30 minutes on days -6 to -2. TRANSPLANT: Patients undergo CD34+ enriched, CD45RA+ T cell-depleted allogeneic PBSCT on day 0. POST-TRANSPLANT IMMUNOSUPPRESSION: Patients receive tacrolimus IV continuously or PO every 12 hours beginning on day -1 and continuing through day 50 with taper. Patients also receive methotrexate IV on days 1, 3, 6, and 11.
Treatment (CD45RA+ T cell depleted PBSCT)	Allogeneic Hematopoietic Stem Cell Transplantation	CONDITIONING REGIMEN: Patients undergo TBI BID on days -10 to -7, receive thiotepa IV over 4 hours on days -6 and -5 and fludarabine phosphate IV over 30 minutes on days -6 to -2. TRANSPLANT: Patients undergo CD34+ enriched, CD45RA+ T cell-depleted allogeneic PBSCT on day 0. POST-TRANSPLANT IMMUNOSUPPRESSION: Patients receive tacrolimus IV continuously or PO every 12 hours beginning on day -1 and continuing through day 50 with taper. Patients also receive methotrexate IV on days 1, 3, 6, and 11.
Treatment (CD45RA+ T cell depleted PBSCT)	Fludarabine Phosphate	CONDITIONING REGIMEN: Patients undergo TBI BID on days -10 to -7, receive thiotepa IV over 4 hours on days -6 and -5 and fludarabine phosphate IV over 30 minutes on days -6 to -2. TRANSPLANT: Patients undergo CD34+ enriched, CD45RA+ T cell-depleted allogeneic PBSCT on day 0. POST-TRANSPLANT IMMUNOSUPPRESSION: Patients receive tacrolimus IV continuously or PO every 12 hours beginning on day -1 and continuing through day 50 with taper. Patients also receive methotrexate IV on days 1, 3, 6, and 11.
Treatment (CD45RA+ T cell depleted PBSCT)	Peripheral Blood Stem Cell Transplantation	CONDITIONING REGIMEN: Patients undergo TBI BID on days -10 to -7, receive thiotepa IV over 4 hours on days -6 and -5 and fludarabine phosphate IV over 30 minutes on days -6 to -2. TRANSPLANT: Patients undergo CD34+ enriched, CD45RA+ T cell-depleted allogeneic PBSCT on day 0. POST-TRANSPLANT IMMUNOSUPPRESSION: Patients receive tacrolimus IV continuously or PO every 12 hours beginning on day -1 and continuing through day 50 with taper. Patients also receive methotrexate IV on days 1, 3, 6, and 11.
Treatment (CD45RA+ T cell depleted PBSCT)	Tacrolimus	CONDITIONING REGIMEN: Patients undergo TBI BID on days -10 to -7, receive thiotepa IV over 4 hours on days -6 and -5 and fludarabine phosphate IV over 30 minutes on days -6 to -2. TRANSPLANT: Patients undergo CD34+ enriched, CD45RA+ T cell-depleted allogeneic PBSCT on day 0. POST-TRANSPLANT IMMUNOSUPPRESSION: Patients receive tacrolimus IV continuously or PO every 12 hours beginning on day -1 and continuing through day 50 with taper. Patients also receive methotrexate IV on days 1, 3, 6, and 11.
Treatment (CD45RA+ T cell depleted PBSCT)	Total-Body Irradiation	CONDITIONING REGIMEN: Patients undergo TBI BID on days -10 to -7, receive thiotepa IV over 4 hours on days -6 and -5 and fludarabine phosphate IV over 30 minutes on days -6 to -2. TRANSPLANT: Patients undergo CD34+ enriched, CD45RA+ T cell-depleted allogeneic PBSCT on day 0. POST-TRANSPLANT IMMUNOSUPPRESSION: Patients receive tacrolimus IV continuously or PO every 12 hours beginning on day -1 and continuing through day 50 with taper. Patients also receive methotrexate IV on days 1, 3, 6, and 11.
Treatment (CD45RA+ T cell depleted PBSCT)	Methotrexate	CONDITIONING REGIMEN: Patients undergo TBI BID on days -10 to -7, receive thiotepa IV over 4 hours on days -6 and -5 and fludarabine phosphate IV over 30 minutes on days -6 to -2. TRANSPLANT: Patients undergo CD34+ enriched, CD45RA+ T cell-depleted allogeneic PBSCT on day 0. POST-TRANSPLANT IMMUNOSUPPRESSION: Patients receive tacrolimus IV continuously or PO every 12 hours beginning on day -1 and continuing through day 50 with taper. Patients also receive methotrexate IV on days 1, 3, 6, and 11.
Treatment (CD45RA+ T cell depleted PBSCT)	Thiotepa	CONDITIONING REGIMEN: Patients undergo TBI BID on days -10 to -7, receive thiotepa IV over 4 hours on days -6 and -5 and fludarabine phosphate IV over 30 minutes on days -6 to -2. TRANSPLANT: Patients undergo CD34+ enriched, CD45RA+ T cell-depleted allogeneic PBSCT on day 0. POST-TRANSPLANT IMMUNOSUPPRESSION: Patients receive tacrolimus IV continuously or PO every 12 hours beginning on day -1 and continuing through day 50 with taper. Patients also receive methotrexate IV on days 1, 3, 6, and 11.

Primary Outcome Measures

Name	Time	Method
Time to Discontinuation of Systemic Immunosuppression	5 years post transplant	Measure the number of days to discontinuation of systemic immunosuppression (both including and excluding calcineurin inhibitors) in pediatric recipients of CD45RA+ T cell-depleted PBSCT. Possible outcomes range from no systemic immunosuppression (best outcome) to 5 years on immunosuppression (poor outcome)
Graft Failure	Up to 5 years	Graft failure defined as failure to reach ANC of \>500/uL for 3 consecutive days by day 28, or irreversible decrease in ANC to \<100 after an established donor graft. A reduction in ANC as result of relapse is not considered graft failure

Secondary Outcome Measures

Name	Time	Method
Acute GVHD Grade III-IV	Up to day 100	Number of patients with acute GVHD grade III-IV
Acute GVHD Grades II-IV	Up to day 100	Number of patients with acute GVHD grades II-IV
Time to Platelet Count > 50,000/uL for 3 Days Without Transfusion	Up to 5 years	Number of days post-transplant without transfusion where platelet count is \>50,000/uL. Measured as the first of three days
Relapse Post-transplant	Up to 5 years	Relapse defined by the presence of malignant cells in marrow, peripheral blood, or extramedullary sites by histopathology
Use of Additional Immune Suppressive Agents to Treat Chronic GVHD	Up to 5 years	Use of additional immune suppressive agents to treat chronic GVHD other than first line therapy. First line therapy is considered prednisone and tacrolimus/cyclosporin.
Steroid Refractory Acute GVHD	Up to day 100	Presence of steroid refractory acute GVHD within the first 100 days post transplant
Time to Platelet Count > 20,000/uL for 3 Days Without Transfusion	Up to 5 years	Number of days post transplant until platelet count is \>20,000/uL for three consecutive days without transfusion, counted as the first of three days
Time to ANC of > 1,000/uL	Up to 5 years	Time (in days) to ANC of \> 1,000/uL, counted as the first of three consecutive days post-transplant
Time to ANC of > 500/uL	Up to 5 years	Time (in days) to ANC of \> 500/uL, counted as the first of three consecutive days post-transplant
Occurrence of Chronic GHVD Meeting NIH Criteria and Requiring Systemic Pharmacological Immunosuppression	Up to 5 years	Number of patients with chronic GVHD defined using NIH criteria. Incidents requiring only calcineurin inhibitors will not be counted. If patients do not develop cGVHD after transplant but then relapse and then receive a donor lymphocyte infusion or antigen specific T cells as treatment, they will no longer be evaluable for the cGVHD endpoint.
Transplant Related Mortality	Up to 5 years	Transplant related mortality defined as mortality in any patient for whom there has not been a diagnosis of relapse