Clinical trial NCT00914940: Selective Depletion of CD45RA+T Cells From Allogeneic Peripheral Blood Stem Cell Grafts for the Prevention of GVHD
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Graft Versus Host Disease
Leukemia
Myelodysplastic Syndromes
Keywords: graft versus host disease
adult acute lymphoblastic leukemia in remission
recurrent adult acute lymphoblastic leukemia
childhood acute lymphoblastic leukemia in remission
recurrent childhood acute lymphoblastic leukemia
adult acute myeloid leukemia in remission
recurrent adult acute myeloid leukemia
adult acute myeloid leukemia with 11q23 (MLL) abnormalities
adult acute myeloid leukemia with inv(16)(p13;q22)
adult acute myeloid leukemia with t(15;17)(q22;q12)
adult acute myeloid leukemia with t(16;16)(p13;q22)
adult acute myeloid leukemia with t(8;21)(q22;q22)
childhood acute myeloid leukemia in remission
recurrent childhood acute myeloid leukemia
childhood myelodysplastic syndromes
previously treated myelodysplastic syndromes
refractory anemia with excess blasts
de novo myelodysplastic syndromes
secondary myelodysplastic syndromes
Lead sponsor: Fred Hutchinson Cancer Center
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2009-06-05
Enrollment: 41
Sex: ALL
Minimum age (years): 14
Maximum age (years): 55
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Diagnosis of 1 of the following:

  * Acute lymphocytic leukemia (ALL) or acute myeloid leukemia (AML) in first or subsequent remission
  * ALL or AML in relapse or primary refractory ALL or AML with a circulating blast count ≤ 10,000/mm\^3
  * Refractory anemia with excess blasts (RAEB) (RAEB-1 or RAEB-2) if the patient has received induction chemotherapy within the past 60 days
* Appropriate candidate for allogeneic hematopoietic stem cell transplantation (HSCT)
* No CNS involvement refractory to intrathecal chemotherapy and/or standard cranial-spinal radiotherapy

PATIENT CHARACTERISTICS:

* Age 14-55
* Creatinine \< 1.5 mg/dL
* Cardiac ejection fraction \> 45%
* DLCO corrected \> 60% of predicted
* Total bilirubin \< 2 times upper limit of normal (ULN) (unless attributed to Gilbert syndrome)
* AST and ALT \< 2 times ULN
* Not pregnant or nursing
* Fertile patients must use effective contraception during and for 12 months after transplantation
* HIV negative
* No co-existing disease (other than leukemia or RAEB) that would limit life expectancy to \< 3 months
* No uncontrolled infection that, in the opinion of the consulting infectious disease physician, would contraindicate myeloablative HSCT
* No other medical condition that would contraindicate HSCT
* No known hypersensitivity to tacrolimus

PRIOR CONCURRENT THERAPY:

* See Disease Characteristics
* No prior HSCT
* No concurrent participation in other experimental studies for the prevention of graft-vs-host disease

DONOR CHARACTERISTICS:

* Genotypic or phenotypic HLA-identical related donor
* Able to donate peripheral blood stem cells
* Age \> 14 years
* Applicable to male patients only: No female donors who have previously given birth to a male child or have had a pregnancy beyond the first trimester miscarriage or termination of pregnancy or nursing
* No donors who have received blood transfusions
* No CD45 Mutation with aberrant CD45RA isoform expression

Primary outcomes:
measure: Number of Participants With Acute Graft-vs-host Disease (GVHD): Grade I-IV, Including Those With no Reportable Acute GVHD
timeFrame: Within 360 days of transplant
measure: Number of Participants Who Did Not Engraft After Receiving a CD45RA+ T Cell Depleted PBSC Transplant
timeFrame: Up to 5 years post transplant
Secondary outcomes:
measure: Transplant-related Mortality by Day 100
timeFrame: Transplant to day 100
measure: Number of Participants Who Have Relapsed Within 5 Years of CD45RA+ T Cell Depleted PBSC Transplant
timeFrame: Up to 5 years post transplant
measure: Number of Participants With Chronic GVHD
timeFrame: Up to 5 years post transplant
Other outcomes:
Locations:
city: New Haven
country: United States
facility: Yale University School of Medicine/Yale New Haven Hospital
state: Connecticut
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center
state: Washington
Study officials:
affiliation: Fred Hutchinson Cancer Center
name: Marie Bleakley, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Yale University School of Medicine/Yale New Haven Hospital
name: Warren Shlomchik, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Bleakley M, Sehgal A, Seropian S, Biernacki MA, Krakow EF, Dahlberg A, Persinger H, Hilzinger B, Martin PJ, Carpenter PA, Flowers ME, Voutsinas J, Gooley TA, Loeb K, Wood BL, Heimfeld S, Riddell SR, Shlomchik WD. Naive T-Cell Depletion to Prevent Chronic Graft-Versus-Host Disease. J Clin Oncol. 2022 Apr 10;40(11):1174-1185. doi: 10.1200/JCO.21.01755. Epub 2022 Jan 10.
citation: Bleakley M, Heimfeld S, Loeb KR, Jones LA, Chaney C, Seropian S, Gooley TA, Sommermeyer F, Riddell SR, Shlomchik WD. Outcomes of acute leukemia patients transplanted with naive T cell-depleted stem cell grafts. J Clin Invest. 2015 Jul 1;125(7):2677-89. doi: 10.1172/JCI81229. Epub 2015 Jun 8.