Donor Stem Cell Transplant, Pentostatin, and Total-Body Irradiation in Treating Patients With Hematological Cancer

Sponsor

University of Nebraska (Other)

Overall Status

Withdrawn

CT.gov ID

NCT00816413

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Location

Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

RATIONALE: Giving low doses of 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. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Removing the T cells from the donor cells before transplant and giving cyclosporine and mycophenolate mofetil after transplant may stop this from happening.

PURPOSE: This phase I/II trial is studying the side effects of giving a donor stem cell transplant after pentostatin and total-body irradiation and to see how well it works in treating patients with hematological cancer.

Condition or Disease	Intervention/Treatment	Phase
Chronic Myeloproliferative Disorders Leukemia Lymphoma Myelodysplastic Syndromes Nonmalignant Neoplasm	Drug: cyclosporine Drug: mycophenolate mofetil Drug: pentostatin Genetic: cytogenetic analysis Genetic: fluorescence in situ hybridization Genetic: protein analysis Other: flow cytometry Other: immunoenzyme technique Other: laboratory biomarker analysis Other: reduced-intensity transplant conditioning procedure Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation Procedure: peripheral blood stem cell transplantation (PBSC) Radiation: total-body irradiation	Phase 1/Phase 2

Detailed Description

OBJECTIVES:

Primary

To determine the safety of pentostatin and low-dose total body irradiation followed by T-cell-reduced unrelated donor peripheral blood stem cell transplantation, in terms of regimen-related toxicity, in patients with hematological malignancies.
To evaluate the efficacy of this regimen, measured as engraftment rate and establishment of donor hematopoietic chimerism, in these patients.

Secondary

To determine the incidence of acute and chronic graft-versus-host disease in patients treated with this regimen.

OUTLINE:

Reduced-intensity preparative regimen: Patients receive pentostatin IV over 30 minutes once daily on days -10 to -8 and undergo low-dose total-body irradiation on day -1.
Unrelated donor peripheral blood stem cell transplantation (PBSCT): Patients undergo T-cell-reduced donor PBSCT on day 0.
Graft-versus-host disease (GVHD) prophylaxis: Patients receive cyclosporine IV over 2 hours twice daily on days -1, 0, and 1 and then orally twice daily on days 2-70 followed by a taper in the absence of GVHD. Patients also receive oral mycophenolate mofetil twice daily on days 0-27 followed by a taper.

Patients undergo bone marrow aspirate and biopsies and blood sample collection periodically for laboratory studies. Samples are analyzed for cytokines (i.e., IL-6, TNF-γ, IL-1β, and IL-10) by ELISA; phenotypic, molecular, and functional analysis of immunologic reconstitution markers (i.e., PHA, IL-2, IL-4, IL-10, IL-12, Fas, FasL, TNF, TGF-β, and IFN-γ) by flow cytometry; and cytogenetics by FISH.

After completion of study treatment, patients are followed periodically.

Study Design

Study Type:

Interventional

Actual Enrollment :

0 participants

Allocation:

Non-Randomized

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

T Cell-Reduced Unrelated Donor Allogeneic Peripheral Blood Stem Cell Transplantation With Pentostatin and Low-Dose Total Body Irradiation

Study Start Date :

Sep 1, 2008

Actual Primary Completion Date :

Feb 1, 2010

Actual Study Completion Date :

Feb 1, 2010

Outcome Measures

Primary Outcome Measures

Severe transplant-related toxicity (grade III-IV adverse events) as assessed by NCI CTCAE v2.0 [before day 100]
Stable donor engraftment [by day 70]
Mortality [at day 100]

Secondary Outcome Measures

Incidence of grade III-IV acute graft-versus-host disease [at day 100]
An interim analysis will be performed after the accrual of each five patients (i.e., three interim analyses and 1 final analysis) has reached day 100.

Eligibility Criteria

Criteria

Ages Eligible for Study:

19 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

DISEASE CHARACTERISTICS:

Diagnosis of a confirmed hematological malignancy that has relapsed or is at high risk for relapsing, including any of the following:
Acute myeloid leukemia (AML) meeting any of the following criteria:
Antecedent hematologic disorder
Therapy related
Primary induction failure
In first complete remission (CR1) with poor-risk cytogenetics, as defined by the following:
del(5q)/-5
del(7q)/-7
abn(3q)
t(6;9)
del(20q)
del(17p)
+13
Complex karyotype
t(9;22) = 11q23 rearrangement
In second complete remission (CR2) or greater
Acute lymphoblastic leukemia meeting any of the following criteria:
In CR1 with WBC > 50,000/mm³ at diagnosis
In CR1 with poor-risk cytogenetics (i.e., t[9;22], t[1;19], t[4;11]) AND meets at least 1 of the following criteria:

= 19-75 years of age AND received prior high-dose chemotherapy, total-body irradiation (TBI), or a radiation dose that precludes administration of 12 Gy of TBI = 50-75 years of age = 19-75 years of age with hematopoietic stem cell transplantation (HSCT) comorbidity index ≥ 3

CNS or testicular involvement at diagnosis
No CR within 4 weeks of initial treatment
Primary induction failure
In CR2 or greater
Myelodysplastic syndromes meeting the following criteria:
Intermediate-2 or high-risk category as determined by International Prognostic Scoring System
Not considered a candidate for intensive or standard chemotherapy or HSCT
Chronic myelogenous leukemia meeting any of the following criteria:
First chronic phase AND < 40 years of age
First chronic phase AND no hematologic response after 3 months of imatinib mesylate therapy
First chronic phase AND never achieved a complete cytogenetic response during imatinib mesylate therapy
First chronic phase AND loss of previously documented response
Accelerated phase
Blast crisis phase
Chronic myeloproliferative disorder (i.e., polycythemia vera, essential thrombocythemia, myelofibrosis)
Bone marrow blasts > 5% and/or other evidence of progression to acute leukemia
Chronic myelomonocytic leukemia
Severe aplastic anemia
Failed prior antithymocyte globulin and cyclosporine immunosuppressive therapy
Mantle cell lymphoma meeting any of the following criteria:
In CR1
In first partial remission (PR1)
In CR 2 or greater
In second PR (PR2) or greater
Indolent non-Hodgkin lymphoma OR chronic lymphocytic leukemia meeting either of the following criteria:
In CR 2 or greater
In PR 2 or greater
Lymphoblastic lymphoma
In CR1 or greater
Must have minimal residual disease as defined by either of the following:
No more than 5% blasts in blood and/or bone marrow (in patients with acute leukemia/MDS)
No bulky adenopathy (> 5 cm masses) and/or < 20% bone marrow involvement by lymphoma (in patients with lymphoma)
No progressive disease within 8 weeks of most recent prior therapy OR within 12 weeks of prior autologous HSCT
No active CNS malignancy (i.e., known positive CSF cytology or parenchymal lesions visible by CT scan or MRI)
HLA-matched unrelated peripheral blood stem cell donor available
Meets the University of Nebraska Medical Center's or the National Marrow Donor Program's criteria for donors
Matched at 7/8 or 8/8 HLA-A, B, C, or DRβ1 loci by molecular typing
If match is not at allele level, suitability for donation requires discussion with and approval by the principal investigator
Not an identical twin

PATIENT CHARACTERISTICS:

Karnofsky performance status 60-100%
Creatinine clearance ≥ 55 mL/min
Total bilirubin ≤ 2 times upper limit of normal (ULN) (unless due to Gilbert's disease or malignancy)
ALT and AST ≤ 4 times ULN
DLCO ≥ 40%
FEV1/FVC ratio ≥ 50% of predicted
Cardiac ejection fraction ≥ 40%
Not pregnant or nursing
Fertile patients must use effective contraception
Not receiving supplementary continuous oxygen
No NYHA grade II-IV cardiac disease
HIV negative
No evidence of active hepatitis B (i.e., positive HBsAg and/or positive HBeAg or high copy number on quantitative RNA testing) or hepatitis C
No active uncontrolled infection or immediate life-threatening condition
No uncontrolled medical illnesses (e.g., uncontrolled systemic hypertension or diabetes)

PRIOR CONCURRENT THERAPY:

See Disease Characteristics
Prior cytoreductive chemotherapy or irradiation to areas of bulky disease allowed, as determined by the primary physician in consultation with the study investigators
No other concurrent anti-tumor therapy