Sirolimus, Tacrolimus, and Antithymocyte Globulin in Preventing Graft-Versus-Host Disease in Patients With Hematologic Cancer Who Are Undergoing Donor Stem Cell Transplant

Barbara Ann Karmanos Cancer Institute

Status and phase

Completed

Phase 2

Conditions

Multiple Myeloma and Plasma Cell Neoplasm

Chronic Myeloproliferative Disorders

Lymphoma

Leukemia

Myelodysplastic Syndromes

Myelodysplastic/Myeloproliferative Neoplasms

Treatments

Drug: carmustine

Drug: busulfan

Drug: melphalan

Radiation: total body irradiation (TBI)

Drug: anti-thymocyte globulin IV

Drug: etoposide

Biological: rituximab

Drug: cytarabine

Drug: cyclophosphamide

Drug: fludarabine phosphate

Study type

Interventional

Funder types

Other

NIH

Identifiers

NCT00691015

P30CA022453 (U.S. NIH Grant/Contract)

2007-127 (Other Identifier)

GENZ-WSU-2007-127

Details and patient eligibility

About

RATIONALE: Giving low doses of chemotherapy, monoclonal antibodies, and radiation therapy 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. Giving tacrolimus, sirolimus, and antithymocyte globulin before and after transplant may stop this from happening.

PURPOSE: This phase II trial is studying the side effects of giving sirolimus together with tacrolimus and antithymocyte globulin and to see how well it works in preventing graft-versus-host disease in patients with hematologic cancer who are undergoing donor stem cell transplant.

Full description

OBJECTIVES:

Primary

To determine the incidence and severity of acute graft-versus-host disease (GVHD) after HLA-matched or -mismatched unrelated donor peripheral blood stem cell transplantation (PBSCT) in patients with hematologic malignancies treated with immunosuppressive therapy comprising sirolimus, tacrolimus, and anti-thymocyte globulin as GVHD prophylaxis.
To determine the safety of this regimen in these patients at 6 months after PBSCT.

Secondary

To determine the time to engraftment (i.e., platelet and absolute neutrophil recovery) in patients treated with this regimen.
To determine the length of hospital stay of these patients within 100 days after PBSCT.
To determine the incidence of infections, including CMV and EBV reactivation and post-transplant lymphoproliferative disorders, in patients treated with this regimen.
To determine the incidence of thrombotic microangiopathy and veno-occlusive disease in patients treated with this regimen.
To determine the incidence of chronic GVHD in patients treated with this regimen.
To determine the overall and disease-free survival of these patients at 2 years after PBSCT.
To determine the Karnofsky performance status of these patients at baseline and at various time points after PBSCT.
To conduct immunocorrelative studies prior to and at various time points after PBSCT.

OUTLINE:

Conditioning regimen: Patients receive 1 of 6 conditioning regimens (standard of care treatment) between days -9 and -3, based on diagnosis and the treating physician's preference regarding regimen intensity.
- Regimen I: Patients receive fludarabine phosphate IV and busulfan IV.
- Regimen II: Patients undergo total body irradiation (TBI) twice daily for 8 fractions and receive etoposide IV.
- Regimen III: Patients undergo TBI once or twice daily for 11 fractions and receive cyclophosphamide IV.
- Regimen IV: Patients undergo TBI and receive fludarabine phosphate IV and busulfan IV.
- Regimen V: Patients receive carmustine IV, etoposide IV, cytarabine IV, and melphalan IV. Some patients also receive rituximab IV.
- Regimen VI: Patients receive fludarabine phosphate IV and melphalan IV. Some patients also undergo TBI.
Allogeneic peripheral blood stem cell transplantation: Patients undergo filgrastim (G-CSF)-mobilized allogeneic peripheral blood stem cell transplantation on day 0.
Graft-versus-host disease prophylaxis (GVHD): Patients receive tacrolimus IV continuously over 24 hours or orally and sirolimus orally beginning on day -3 and continuing until day 30 or day 90, followed by a taper in the absence of GVHD. Patients also receive anti-thymocyte globulin IV over 4-8 hours on days -3 to -1.

Blood samples are obtained at baseline and periodically during study for correlative biomarker studies. Samples are analyzed by T-cell immunophenotyping, absolute subset number quantification, and multi-parameter flow cytometry for evaluation of immune reconstitution, T-cell differentiation status, NK-cell recovery, allo-reactivity of donor T-cells after transplantation, and regulatory T-cell reconstitution.

After completion of study therapy, patients are followed periodically for up to 2 years.

Enrollment

48 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion criteria

DISEASE CHARACTERISTICS:

Diagnosis of a hematological malignancy, including any of the following:
- Non-Hodgkin lymphoma in complete remission (CR) or partial remission (PR)
- Hodgkin lymphoma in CR or PR
- Acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) meeting either of the following criteria:
  - In CR
  - Not in CR and meets the following criteria:
    - Bone marrow blast < 20% within 4 weeks of transplantation
    - Peripheral blood absolute blast count < 500 per microliter on the day of initiating conditioning therapy
- Myelodysplastic syndromes, treated or untreated
- Chronic myeloid leukemia in chronic phase or accelerated phase
- Multiple myeloma in CR or PR
- Chronic lymphocytic leukemia in second or greater CR or PR
- Myelofibrosis or other myeloproliferative disorders meeting the following criteria:
  - Bone marrow blasts < 20% within 4 weeks of transplantation
  - Peripheral blood absolute blast count < 500 per microliter on the day of initiating conditioning therapy
  - Patients with ascites not allowed
No prior bone marrow or ex vivo engineered or processed graft (i.e., CD34+ enrichment, T-cell depletion, etc)
Scheduled to undergo peripheral blood stem cell transplantation from a suitable HLA-matched or -mismatched unrelated donor, as determined by treating physician
- High resolution molecular HLA typing is required for HLA class I and II
- No more than one antigen or allele mismatch
No documented uncontrolled CNS disease

PATIENT CHARACTERISTICS:

ECOG performance status (PS) 0-2
Karnofsky PS 60-100%
Creatinine clearance > 50 mL/min
Bilirubin < 3 times upper limit of normal (ULN)
ALT and AST < 3 times ULN
LVEF > 50%
FVC, FEV_1, or DLCO > 50% predicted
- Patients on home oxygen not allowed
Able to cooperate with oral medication intake
HIV negative
No active hepatitis B or hepatitis C
No known contraindication to sirolimus, tacrolimus, or anti-thymocyte globulin

PRIOR CONCURRENT THERAPY:

See Disease Characteristics

Trial design

Primary purpose

Supportive Care

Allocation

N/A

Interventional model

Single Group Assignment

Masking

None (Open label)

48 participants in 1 patient group

Chemotherapy or chemotherapy + total body irradiation

Experimental group

Description:

Standard of care (SOC) chemotherapy or ( SOC) chemotherapy + total body irradiation (TBI) of one of the following regimens: Regimen I: Patients receive fludarabine phosphate IV and busulfan IV; anti-thymocyte globulin IV. Regimen II: Patients undergo total body irradiation (TBI) twice daily for 8 fractions and receive etoposide IV;anti-thymocyte globulin IV. Regimen III: Patients undergo TBI once or twice daily for 11 fractions and receive cyclophosphamide IV; anti-thymocyte globulin IV. Regimen IV: Patients undergo TBI and receive fludarabine phosphate IV and busulfan IV; anti-thymocyte globulin IV. Regimen V: Patients receive carmustine IV, etoposide IV, cytarabine IV, and melphalan IV. Some patients also receive rituximab IV; anti-thymocyte globulin IV. Regimen VI: Patients receive fludarabine phosphate IV and melphalan IV. Some patients also undergo TBI; anti-thymocyte globulin IV.

Treatment: