Fludarabine Phosphate and Total-Body Radiation Followed by Donor Peripheral Blood Stem Cell Transplant and Immunosuppression in Treating Patients With Hematologic Malignancies

Not Applicable

Completed

• Conditions: Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Childhood Myelodysplastic Syndromes; Childhood Nasal Type Extranodal NK/T-cell Lymphoma; Acute Myeloid Leukemia/Transient Myeloproliferative Disorder; Adult Nasal Type Extranodal NK/T-cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Myeloid Leukemia in Remission; Acute Undifferentiated Leukemia
• Interventions: Drug: fludarabine phosphate; Radiation: total-body irradiation; Procedure: peripheral blood stem cell transplantation; Procedure: allogeneic hematopoietic stem cell transplantation; Drug: cyclosporine; Drug: mycophenolate mofetil; Other: laboratory biomarker analysis

• Registration Number: NCT00014235
• Lead Sponsor: Fred Hutchinson Cancer Center

Brief Summary

This clinical trial studies fludarabine phosphate and total-body radiation followed by donor peripheral blood stem cell transplant and immunosuppression in treating patients with 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. Giving total-body irradiation together with fludarabine phosphate, cyclosporine, and mycophenolate mofetil before transplant may stop this from happening.

Detailed Description

PRIMARY OBJECTIVES:

I. To estimate the rate of grade III/IV graft-versus-host disease (GVHD) in patients treated with low-dose total body irradiation (TBI), fludarabine (fludarabine phosphate), PBSC infusion and immunosuppression with mycophenolate mofetil and a disease risk-based cyclosporine taper.

II. To estimate the risk of graft rejection, GVHD, disease response, non-relapse mortality and the incidence and severity of infectious complications using this treatment strategy.

OUTLINE: Patients are assigned to 1 of 2 treatment groups.

ARM I (indolent disease):

CONDITIONING REGIMEN: Patients receive fludarabine phosphate intravenously (IV) on days -4 to -2 and undergo TBI on day 0.

TRANSPLANTATION: Patients undergo donor peripheral blood stem cell transplantation (PBSCT) on day 0.

IMMUNOSUPPRESSION: Patients receive cyclosporine orally (PO) twice daily (BID) or IV every 8-12 hours on days -3 to 56 with a taper to day 180 and mycophenolate mofetil PO BID or IV every 8-12 hours on days 0 to 27.

ARM II (aggressive disease):

CONDITIONING REGIMEN: Patients receive fludarabine phosphate and undergo TBI as in Arm I.

TRANSPLANTATION: Patients undergo donor PBSCT on day 0.

IMMUNOSUPPRESSION: Patients receive cyclosporine PO BID or IV every 8-12 hours on days -3 to 56 with a taper to day 70 and mycophenolate mofetil as in Arm I.

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

Study Timeline

• Study Start: 2000-12
• Study First Submitted: 2001-04-10
• Study First Submitted QC: 2003-01-26
• Study First Posted: 2003-01-27
• Primary Completion: 2005-02
• Status Verified: 2020-01
• Last Update Submitted: 2020-01-17
• Last Update Posted: 2020-01-21

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 160

Inclusion Criteria

• Patients with non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL) or multiple myeloma who are not eligible for a curative autologous transplantation or who have received a prior autologous transplantation; patients with NHL or CLL must have failed prior therapy with an alkylating agent and/or fludarabine, or be at high risk of relapse; patients with multiple myeloma must have stage II or III disease and received prior chemotherapy

• Patients < 50 years of age with NHL, Hodgkin's disease (HD), CLL or multiple myeloma at high risk of regimen related toxicity through prior autologous transplant or through pre-existing medical conditions

• Patients < 75 years of age with other malignant diseases treatable by allogeneic bone marrow transplant (BMT) whom through pre-existing chronic disease affecting kidneys, liver, lungs, and heart are considered to be at high risk for regimen related toxicity using standard high dose regimens; the following diseases are the likely candidates

  • Myelodysplastic syndromes
  • Myeloproliferative syndromes
  • Acute Leukemia with < 10% blasts
  • Amyloidosis
  • Hodgkin's disease

• The Fred Hutchinson Cancer Research Center (FHCRC) Patient Care Conference (PCC) may approve patients with other malignancies or patients declining standard allografts for transplant following presentation and approval; centers outside the FHCRC that have a PCC or equivalent should obtain their Institutional approval; if there is not a comparable group at the Institution, please contact the FHCRC Principal Investigator for FHCRC approval through PCC

• DONOR: Human leukocyte antigen (HLA) genotypically or phenotypically identical related donor

• DONOR: Donor must consent to filgrastim (G-CSF) administration and leukapheresis

• DONOR: Donor must have adequate veins for leukapheresis or agree to placement of central venous catheter (femoral, subclavian)

Exclusion Criteria

• Eligible for a high-priority curative autologous transplant
• Patients with rapidly progressive aggressive NHL unless in minimal disease state
• Any current central nervous system (CNS) involvement with disease
• Fertile men or women unwilling to use contraceptive techniques during and for 12 months following treatment
• Females who are pregnant
• Patients who are human immunodeficiency virus (HIV) positive
• Cardiac ejection fraction < 40%; ejection fraction is required if the patient has a history of anthracyclines or history of cardiac disease
• Receiving supplementary continuous oxygen
• Diffusing capacity of the lung for carbon monoxide (DLCO) < 30%
• Total lung capacity (TLC) < 30%
• Forced expiratory volume in one second (FEV1) < 30%
• Total bilirubin > 2x the upper limit of normal
• Serum glutamate pyruvate transaminase (SGPT) and serum glutamic oxaloacetic transaminase (SGOT) 4x the upper limit of normal
• Karnofsky score < 50
• Patients with poorly controlled hypertension who are unable to have blood pressure kept below 150/90 on standard medication
• Patients with renal failure are eligible, however patients with renal compromise (serum creatinine greater than 2.0) will likely have further compromise in renal function and may require hemodialysis (which may be permanent) due to the need to maintain adequate serum cyclosporine levels
• The addition of cytotoxic agents for "cytoreduction" with the exception of hydroxyurea and imatinib mesylate will not be allowed within two weeks of the initiation of conditioning
• DONOR: Identical twin
• DONOR: Age less than 12 years
• DONOR: Pregnancy
• DONOR: Infection with HIV
• DONOR: Inability to achieve adequate venous access
• DONOR: Known allergy to G-CSF
• DONOR: Current serious systemic illness

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm I (indolent disease)	total-body irradiation	CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI on day 0. TRANSPLANTATION: Patients undergo donor PBSCT on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine PO BID or IV every 8-12 hours on days -3 to 56 with a taper to day 180 and mycophenolate mofetil PO BID or IV every 8-12 hours on days 0 to 27.
Arm I (indolent disease)	allogeneic hematopoietic stem cell transplantation	CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI on day 0. TRANSPLANTATION: Patients undergo donor PBSCT on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine PO BID or IV every 8-12 hours on days -3 to 56 with a taper to day 180 and mycophenolate mofetil PO BID or IV every 8-12 hours on days 0 to 27.
Arm II (aggressive disease)	peripheral blood stem cell transplantation	CONDITIONING REGIMEN: Patients receive fludarabine phosphate and undergo TBI as in Arm I. TRANSPLANTATION: Patients undergo donor PBSCT on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine PO BID or IV every 8-12 hours on days -3 to 56 with a taper to day 70 and mycophenolate mofetil as in Arm I.
Arm II (aggressive disease)	total-body irradiation	CONDITIONING REGIMEN: Patients receive fludarabine phosphate and undergo TBI as in Arm I. TRANSPLANTATION: Patients undergo donor PBSCT on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine PO BID or IV every 8-12 hours on days -3 to 56 with a taper to day 70 and mycophenolate mofetil as in Arm I.
Arm II (aggressive disease)	allogeneic hematopoietic stem cell transplantation	CONDITIONING REGIMEN: Patients receive fludarabine phosphate and undergo TBI as in Arm I. TRANSPLANTATION: Patients undergo donor PBSCT on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine PO BID or IV every 8-12 hours on days -3 to 56 with a taper to day 70 and mycophenolate mofetil as in Arm I.
Arm II (aggressive disease)	laboratory biomarker analysis	CONDITIONING REGIMEN: Patients receive fludarabine phosphate and undergo TBI as in Arm I. TRANSPLANTATION: Patients undergo donor PBSCT on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine PO BID or IV every 8-12 hours on days -3 to 56 with a taper to day 70 and mycophenolate mofetil as in Arm I.
Arm I (indolent disease)	peripheral blood stem cell transplantation	CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI on day 0. TRANSPLANTATION: Patients undergo donor PBSCT on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine PO BID or IV every 8-12 hours on days -3 to 56 with a taper to day 180 and mycophenolate mofetil PO BID or IV every 8-12 hours on days 0 to 27.
Arm I (indolent disease)	laboratory biomarker analysis	CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI on day 0. TRANSPLANTATION: Patients undergo donor PBSCT on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine PO BID or IV every 8-12 hours on days -3 to 56 with a taper to day 180 and mycophenolate mofetil PO BID or IV every 8-12 hours on days 0 to 27.
Arm I (indolent disease)	fludarabine phosphate	CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI on day 0. TRANSPLANTATION: Patients undergo donor PBSCT on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine PO BID or IV every 8-12 hours on days -3 to 56 with a taper to day 180 and mycophenolate mofetil PO BID or IV every 8-12 hours on days 0 to 27.
Arm I (indolent disease)	cyclosporine	CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI on day 0. TRANSPLANTATION: Patients undergo donor PBSCT on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine PO BID or IV every 8-12 hours on days -3 to 56 with a taper to day 180 and mycophenolate mofetil PO BID or IV every 8-12 hours on days 0 to 27.
Arm I (indolent disease)	mycophenolate mofetil	CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI on day 0. TRANSPLANTATION: Patients undergo donor PBSCT on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine PO BID or IV every 8-12 hours on days -3 to 56 with a taper to day 180 and mycophenolate mofetil PO BID or IV every 8-12 hours on days 0 to 27.
Arm II (aggressive disease)	fludarabine phosphate	CONDITIONING REGIMEN: Patients receive fludarabine phosphate and undergo TBI as in Arm I. TRANSPLANTATION: Patients undergo donor PBSCT on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine PO BID or IV every 8-12 hours on days -3 to 56 with a taper to day 70 and mycophenolate mofetil as in Arm I.
Arm II (aggressive disease)	mycophenolate mofetil	CONDITIONING REGIMEN: Patients receive fludarabine phosphate and undergo TBI as in Arm I. TRANSPLANTATION: Patients undergo donor PBSCT on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine PO BID or IV every 8-12 hours on days -3 to 56 with a taper to day 70 and mycophenolate mofetil as in Arm I.
Arm II (aggressive disease)	cyclosporine	CONDITIONING REGIMEN: Patients receive fludarabine phosphate and undergo TBI as in Arm I. TRANSPLANTATION: Patients undergo donor PBSCT on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine PO BID or IV every 8-12 hours on days -3 to 56 with a taper to day 70 and mycophenolate mofetil as in Arm I.

Primary Outcome Measures

Name	Time	Method
Probability of severe (grade III/IV) GVHD in each arm	Up to 5 years	95% confidence intervals will be calculated.

Secondary Outcome Measures

Name	Time	Method
Incidence of graft rejection	Day 365	Chimerism analysis by FISH or VNTR. Examined and reported in a descriptive manner. Confidence intervals will be presented.
Incidence of non-relapse mortality	Up to 5 years	Examined and reported in a descriptive manner. Confidence intervals will be presented.
Incidence of infectious complications	Up to 5 years	Examined and reported in a descriptive manner. Confidence intervals will be presented.
Severity of infectious complications	Up to 5 years	Examined and reported in a descriptive manner. Confidence intervals will be presented.

Trial Locations

Locations (11)

University of Arizona Health Sciences Center; 🇺🇸 Tucson, Arizona, United States

Baylor University Medical Center; 🇺🇸 Dallas, Texas, United States

OHSU Knight Cancer Institute; 🇺🇸 Portland, Oregon, United States

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium; 🇺🇸 Seattle, Washington, United States

Universitaet Leipzig; 🇩🇪 Leipzig, Germany

University of Torino; 🇮🇹 Torino, Italy

City of Hope Medical Center; 🇺🇸 Duarte, California, United States

Stanford University Hospitals and Clinics; 🇺🇸 Stanford, California, United States

LDS Hospital; 🇺🇸 Salt Lake City, Utah, United States

Huntsman Cancer Institute/University of Utah; 🇺🇸 Salt Lake City, Utah, United States

Froedtert Hospital; 🇺🇸 Milwaukee, Wisconsin, United States