Clinical trial NCT00816413: Donor Stem Cell Transplant, Pentostatin, and Total-Body Irradiation in Treating Patients With Hematological Cancer
Official title: T Cell-Reduced Unrelated Donor Allogeneic Peripheral Blood Stem Cell Transplantation With Pentostatin and Low-Dose Total Body Irradiation
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE1
PHASE2
Conditions: Chronic Myeloproliferative Disorders
Leukemia
Lymphoma
Myelodysplastic Syndromes
Nonmalignant Neoplasm
Keywords: 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)
adult acute myeloid leukemia in remission
recurrent adult acute myeloid leukemia
secondary acute myeloid leukemia
adult acute lymphoblastic leukemia in remission
recurrent adult acute lymphoblastic leukemia
accelerated phase chronic myelogenous leukemia
blastic phase chronic myelogenous leukemia
chronic phase chronic myelogenous leukemia
relapsing chronic myelogenous leukemia
chronic myelomonocytic leukemia
de novo myelodysplastic syndromes
previously treated myelodysplastic syndromes
secondary myelodysplastic syndromes
essential thrombocythemia
polycythemia vera
primary myelofibrosis
stage III mantle cell lymphoma
stage IV mantle cell lymphoma
marginal zone B-cell lymphoma of mucosal lymphoid tissue
nodal marginal zone B-cell lymphoma
splenic marginal zone lymphoma
stage III adult lymphoblastic lymphoma
stage IV adult lymphoblastic lymphoma
aplastic anemia
chronic eosinophilic leukemia
chronic neutrophilic leukemia
contiguous st II adult diffuse small cleaved cell lymphoma
noncontig stage II adult diffuse small cleaved cell lymphoma
stage I adult diffuse small cleaved cell lymphoma
stage III adult diffuse small cleaved cell lymphoma
stage IV adult diffuse small cleaved cell lymphoma
contiguous stage II grade 1 follicular lymphoma
contiguous stage II grade 2 follicular lymphoma
noncontiguous stage II grade 1 follicular lymphoma
noncontiguous stage II grade 2 follicular lymphoma
stage I grade 1 follicular lymphoma
stage I grade 2 follicular lymphoma
stage III grade 1 follicular lymphoma
stage III grade 2 follicular lymphoma
stage IV grade 1 follicular lymphoma
stage IV grade 2 follicular lymphoma
contiguous stage II marginal zone lymphoma
noncontiguous stage II marginal zone lymphoma
stage I marginal zone lymphoma
stage III marginal zone lymphoma
stage IV marginal zone lymphoma
contiguous stage II small lymphocytic lymphoma
noncontiguous stage II small lymphocytic lymphoma
stage I small lymphocytic lymphoma
stage III small lymphocytic lymphoma
stage IV small lymphocytic lymphoma
contiguous stage II mantle cell lymphoma
noncontiguous stage II mantle cell lymphoma
stage I mantle cell lymphoma
contiguous stage II adult lymphoblastic lymphoma
noncontiguous stage II adult lymphoblastic lymphoma
stage I adult lymphoblastic lymphoma
stage I chronic lymphocytic leukemia
stage II chronic lymphocytic leukemia
stage III chronic lymphocytic leukemia
stage IV chronic lymphocytic leukemia
Lead sponsor: University of Nebraska
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2009-01-01
Enrollment: 0
Sex: ALL
Minimum age (years): 19
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: Inclusion Criteria • 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 CR2 or greater In second PR (PR2) or greater

Indolent non-Hodgkin lymphoma OR chronic lymphocytic leukemia meeting either of the following criteria:

In CR2 or greater In PR2 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 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%Prior cytoreductive chemotherapy or irradiation to areas of bulky disease allowed, as determined by the primary physician in consultation with the study investigators

Exclusion Criteria No CR within 4 weeks of initial treatment No other concurrent anti-tumor therapy Not pregnant or nursing (fertile patients must use effective contraception) Not receiving supplementary continuous oxygen No NYHA grade II-IV cardiac disease HIV positive Active hepatitis B (i.e., positive HBsAg and/or positive HBeAg or high copy number on quantitative RNA testing) or hepatitis C Active uncontrolled infection or immediate life-threatening condition Uncontrolled medical illnesses (e.g., uncontrolled systemic hypertension or diabetes)

Primary outcomes:
measure: Severe transplant-related toxicity
timeFrame: before day 100
measure: Stable donor engraftment
timeFrame: by day 70
measure: Mortality
timeFrame: at day 100
Secondary outcomes:
measure: Incidence of grade III-IV acute graft-versus-host disease
timeFrame: at day 100
Other outcomes:
Locations:
Study officials:
affiliation: University of Nebraska
name: Robert Bociek, MD
role: PRINCIPAL_INVESTIGATOR
References: