Total-Body Irradiation With or Without Fludarabine Phosphate Followed By Donor Stem Cell Transplant in Treating Patients With Hematologic Cancer

A Multi-center Phase III Study Comparing Nonmyeloablative Conditioning With TBI Versus Fludarabine/TBI for HLA-matched Related Hematopoietic Cell Transplantation for Treatment of Hematologic Malignancies

This randomized phase III trial is studying total-body irradiation (TBI) and fludarabine phosphate to see how it works compared with TBI alone followed by donor stem cell transplant in treating patients with hematologic cancer. Giving low doses of chemotherapy, such as fludarabine phosphate, and radiation therapy before a donor stem cell transplant helps stop the growth of cancer cells. It also stops the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune system 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 cyclosporine and mycophenolate mofetil after transplant may stop this from happening. It is not yet known whether TBI followed by donor stem cell transplant is more effective with or without fludarabine phosphate in treating hematologic cancer.

Study Overview

• Status: Completed
• Conditions: Hematopoietic and Lymphoid Cell Neoplasm; Diffuse Large B-Cell Lymphoma; Refractory Hodgkin Lymphoma; Waldenstrom Macroglobulinemia; Mantle Cell Lymphoma; Plasma Cell Myeloma; Refractory Chronic Lymphocytic Leukemia; Myelodysplastic/Myeloproliferative Neoplasm; Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Aggressive Non-Hodgkin Lymphoma; Indolent Non-Hodgkin Lymphoma; Acute Myeloid Leukemia in Remission; Acute Lymphoblastic Leukemia in Remission
• Intervention / Treatment: Drug: Mycophenolate Mofetil; Drug: Fludarabine Phosphate; Drug: Cyclosporine; Procedure: Peripheral Blood Stem Cell Transplantation; Procedure: Total-Body Irradiation

Detailed Description

PRIMARY OBJECTIVES:

I. To compare overall survival at 3 years after conditioning with 200 cGy TBI alone vs. fludarabine (fludarabine phosphate)/200 cGy TBI in heavily pretreated patients with hematologic malignancies at low/moderate risk for graft rejection.

SECONDARY OBJECTIVES:

I. To compare the non-relapse mortality 1-year after conditioning in patients who received TBI alone vs. fludarabine/TBI.

II. To compare the incidences of graft rejection in patients who received TBI alone vs. fludarabine/TBI.

III. To compare the incidences of grades II-IV acute graft-versus-host disease (GVHD) and chronic extensive GVHD.

IV. To compare rates of disease progression and/or relapse-related mortality.

V. To compare the immune reconstitution and the risks of infections.

OUTLINE:

NONMYELOABLATIVE CONDITIONING REGIMEN: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive fludarabine phosphate intravenously (IV) on days -4 to -2. Patients then undergo low-dose TBI on day 0.

ARM II: Patients undergo low-dose TBI on day 0.

ALLOGENEIC PERIPHERAL BLOOD STEM CELL TRANSPLANTATION (PBSCT): After TBI, patients undergo PBSCT on day 0.

IMMUNOSUPPRESSION: Patients receive cyclosporine orally (PO) twice daily (BID) on days -3 to 56 in the absence of GVHD. Patients with no evidence of GVHD at day 56 begin a cyclosporine taper and continue the taper until day 180. Patients with evidence of disease progression and no evidence of GVHD prior to day 56 receive tapered doses of cyclosporine for 2 weeks. Patients also receive mycophenolate mofetil (MMF) PO BID on days 0-28 in the absence of GVHD. If treatment for GVHD is required before day 28, MMF is continued until a steroid taper begins.

Patients are followed up periodically for 1.5 years and then annually for 5 years post-transplantation.

• Study Type: Interventional
• Enrollment (Actual): 87
• Phase: Phase 3

Contacts and Locations

Study Locations

• Germany
  • Koln, Germany, 50924
    • Medizinische Univ Klinik Koln
  • Leipzig, Germany, D-04103
    • Universitaet Leipzig
  • Tuebingen, Germany, D-72076
    • University of Tuebingen-Germany
• Italy
  • Torino, Italy, 10126
    • University of Torino
• United States
  • Oregon
    • Medford, Oregon, United States, 97504
      • OHSU Cancer Institute-Southern Region
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Huntsman Cancer Institute/University of Utah
    • Salt Lake City, Utah, United States, 84143
      • LDS Hospital
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
    • Seattle, Washington, United States, 98101
      • VA Puget Sound Health Care System
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Froedtert and the Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 75 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients must be not eligible for conventional allogeneic hematopoietic cell transplantation (HCT) and must have disease expected to be stable for at least 100 days without chemotherapy
• An autograft immediately prior (less than 6 months) to nonmyeloablative HCT (tandem approach) is not permitted
• Patients with hematologic malignancies treatable with HCT or with a B cell malignancy except those curable with autologous transplant will be included
• Aggressive non-Hodgkin lymphomas (NHLs) and other histologies such as diffuse large B cell NHL: patients are eligible IF they are not eligible for autologous hematopoietic stem cell transplantation (HSCT), not eligible for conventional myeloablative HSCT, or have failed an autologous HSCT
• Low grade NHL with < 6 month duration of complete remission (CR) between courses of conventional therapy
• Mantle cell NHL; may be treated in first CR

• Chronic lymphocytic leukemia (CLL) must have either:

  • Failed to meet National Cancer Institute (NCI) Working Group criteria for complete or partial response after therapy with a regimen containing fludarabine phosphate (FLU) (or another nucleoside analog, e.g. cladribine [2-CDA], pentostatin) or experience disease relapse within 12 months after completing therapy with a regimen containing FLU (or another nucleoside analog)
  • Failed FLU-cyclophosphamide [CY]-rituximab (FCR) combination chemotherapy at any time point
  • Have "17p deletion" cytogenetic abnormality; patients should have received induction chemotherapy but could be transplanted in 1st CR
  • Or patients with a diagnosis of CLL (or small lymphocytic lymphoma) or diagnosis of CLL that progresses to prolymphocytic leukemia (PLL), or T-cell CLL or PLL
• Hodgkin lymphoma (HL): must have received and failed frontline therapy; patients must have failed or were not eligible for autologous transplant
• Multiple myeloma (MM): must have chemosensitive disease after failed autografting (an autografting immediately prior [within 6 months] to nonmyeloablative HCT [tandem approach] is not permitted)
• Acute myeloid leukemia (AML): must have < 5% marrow blasts at the time of transplant and be beyond first CR
• Acute lymphocytic leukemia (ALL): must have < 5% marrow blasts at the time of transplant and be beyond first CR
• Chronic myelogenous leukemia (CML): patients will be accepted in chronic phase (CP) beyond CP1 if they have received previous myelosuppressive chemotherapy or HCT, < 5% marrow blasts at time of transplant
• Myelodysplastic syndromes (MDS)/myeloproliferative disorders (MPD): must have received previous myelosuppressive chemotherapy or HCT, < 5% marrow blasts at time of transplant
• Waldenstroms Macroglobulinemia: must have failed 2 courses of therapy
• Patients will not be allowed to receive myelosuppressive chemotherapy for three weeks prior to conditioning
• Patients < 12 years old must be approved by both the participating institutions' patient review committee such as the Patient Care Conference (PCC) at the Fred Hutchinson Cancer Research Center (FHCRC) and the FHCRC principal investigator
• Patients who refused to be treated on a conventional HCT protocol; for this inclusion criterion, transplants must be approved by both the participating institution's patient review committee such as the Patient Care Conference (PCC) at the FHCRC and the FHCRC principal investigator
• Patients with human leukocyte antigen (HLA)-matched related donors
• DONOR: Related donor who is HLA genotypically identical at least at one haplotype and may be phenotypically or genotypically identical at the allele level at HLA-A, -B, -C, -DRB1, and -DQB1
• 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)
• DONOR: For females of child bearing age, serum pregnancy qualitative (PGSTAT) within 72 hours prior to initial dose of filgrastim (G-CSF); results must be available prior to filgrastim

Exclusion Criteria:

• Eligible for a high priority curative autologous transplant
• Patients with rapidly progressive, aggressive NHL unless in minimal disease state
• Patients with chronic myelomonocytic leukemia
• Presence of circulating leukemic blasts (in the peripheral blood) detected by standard pathology for patients with AML, ALL or CML
• Life expectancy severely limited by diseases other than malignancy
• Any current central nervous system (CNS) involvement with disease refractory to intrathecal chemotherapy
• Fertile men or women unwilling to use contraceptives during and for up to 12 months post treatment
• Female patients who are pregnant or breastfeeding
• Human immunodeficiency virus (HIV) positive patients
• Patients with active non-hematological malignancies (except localized non-melanoma skin malignancies)
• Patients with a history of non-hematologic malignancies (except non-melanoma skin cancers) currently in a complete remission, who are less than 5 years from the time of complete remission, and have a > 20% risk of disease recurrence
• Fungal infections with radiological progression after receipt of amphotericin formulation or mold-active azoles for greater than 1 month
• Patients with active bacterial or fungal infections unresponsive to medical therapy
• Karnofsky score < 50 for adult patients
• Lansky-Play performance score < 50 for pediatric patients
• The addition of cytotoxic agents for "cytoreduction" with the exception of tyrosine kinase inhibitors (imatinib mesylate), cytokine therapy, hydroxyurea, low dose cytarabine, chlorambucil, or rituxan will not be allowed within three weeks of the initiation of conditioning

• Patients with the following organ dysfunction:

  • Symptomatic coronary artery disease or ejection fraction < 35% or other cardiac failure requiring therapy (required for patients with history of cardiac disease or anthracycline use); ejection fraction is required if age > 50 years or there is a history of anthracycline exposure or history of cardiac disease
  • Poorly controlled hypertension on multiple antihypertensives
  • Pulmonary: diffusion capacity of carbon monoxide (DLCO) < 30%, total lung capacity (TLC) < 30%, forced expiratory volume in one second (FEV1) < 30% and/or receiving supplementary continuous oxygen; the FHCRC study principal investigator (PI) must approve enrollment of all patients with pulmonary nodules
  • Liver function abnormalities: patients with clinical or laboratory evidence of liver disease would be evaluated for the cause of liver disease, its clinical severity in terms of liver function, bridging fibrosis, and the degree of portal hypertension; patients will be excluded if they are found to have fulminant liver failure, cirrhosis of the liver with evidence of portal hypertension, alcoholic hepatitis, esophageal varices, a history of bleeding esophageal varices, hepatic encephalopathy, uncorrectable hepatic synthetic dysfunction evinced by prolongation of the prothrombin time, ascites related to portal hypertension, bacterial or fungal liver abscess, biliary obstruction, chronic viral hepatitis with total serum bilirubin > 3 mg/dL, and symptomatic biliary disease
• DONOR: Age less than 12 years
• DONOR: Identical twin
• DONOR: Pregnancy
• DONOR: Infection with HIV
• DONOR: Known allergy to filgrastim
• DONOR: Current serious systemic illness that would result in increased risk for filgrastim mobilization and harvest of PBSC

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I (chemotherapy, TBI, transplant, GVHD prophylaxis); Patients receive fludarabine phosphate IV on days -4 to -2. Patients then undergo low-dose TBI on day 0. After TBI, patients undergo PBSCT on day 0. Patients receive cyclosporine PO BID on days -3 to 56 in the absence of GVHD. Patients with no evidence of GVHD at day 56 begin a cyclosporine taper and continue the taper until day 180. Patients with evidence of disease progression and no evidence of GVHD prior to day 56 receive tapered doses of cyclosporine for 2 weeks. Patients also receive MMF PO BID on days 0-28 in the absence of GVHD. If treatment for GVHD is required before day 28, MMF is continued until a steroid taper begins.	Drug: Mycophenolate Mofetil; Given PO; Other Names: Cellcept; MMF; Drug: Fludarabine Phosphate; Given IV; Other Names: 2-F-ara-AMP; Beneflur; SH T 586; Drug: Cyclosporine; Given PO; Other Names: 27-400; CsA; Neoral; Sandimmun; OL 27-400; Procedure: Peripheral Blood Stem Cell Transplantation; Undergo transplantation; Other Names: PBPC transplantation; Peripheral Blood Progenitor Cell Transplantation; Peripheral Stem Cell Support; Peripheral Stem Cell Transplantation; Procedure: Total-Body Irradiation; Undergo TBI; Other Names: Total Body Irradiation; TBI; Whole-Body Irradiation
Active Comparator: Arm II (TBI, transplant, GVHD prophylaxis); Patients undergo low-dose TBI on day 0. After TBI, patients undergo PBSCT on day 0. Patients receive cyclosporine PO BID on days -3 to 56 in the absence of GVHD. Patients with no evidence of GVHD at day 56 begin a cyclosporine taper and continue the taper until day 180. Patients with evidence of disease progression and no evidence of GVHD prior to day 56 receive tapered doses of cyclosporine for 2 weeks. Patients also receive MMF PO BID on days 0-28 in the absence of GVHD. If treatment for GVHD is required before day 28, MMF is continued until a steroid taper begins.	Drug: Mycophenolate Mofetil; Given PO; Other Names: Cellcept; MMF; Drug: Cyclosporine; Given PO; Other Names: 27-400; CsA; Neoral; Sandimmun; OL 27-400; Procedure: Peripheral Blood Stem Cell Transplantation; Undergo transplantation; Other Names: PBPC transplantation; Peripheral Blood Progenitor Cell Transplantation; Peripheral Stem Cell Support; Peripheral Stem Cell Transplantation; Procedure: Total-Body Irradiation; Undergo TBI; Other Names: Total Body Irradiation; TBI; Whole-Body Irradiation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	Percentage of patients surviving as estimated by Kaplan-Meier.	3 years after transplant

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Non-relapse Mortality	Percentage of NRM as estimated by cumulative incidence methods with competing risks	3 years after transplant
Incidence of Relapse/Progression	Percentage of relapse estimated by cumulative incidence methods	3 years after transplant
Incidence of Relapse-related Mortality	Percentage of death following relapse/progression, estimated by cumulative incidence methods	3 years after transplant
Incidence of Grades II-IV Acute GVHD	Percentage patients with grades II-IV GHVD, estimated by cumulative incidence methods	120 days after transplant
Incidence of Chronic Extensive GVHD	Percentage patients with chronic extensive GVHD, estimated by cumulative incidence methods	3 years after transplant
Incidence of Graft Rejection	Donor CD3 chimerism less than 5%	1 year after transplant
Progression-free Survival	Percentage of patients with progression-free survival, estimated by cumulative incidence methods	3 years after transplant

Collaborators and Investigators

• Sponsor: Fred Hutchinson Cancer Center
• Collaborators: National Cancer Institute (NCI); National Heart, Lung, and Blood Institute (NHLBI)

Publications and helpful links

General Publications

• Cooper JP, Storer BE, Granot N, Gyurkocza B, Sorror ML, Chauncey TR, Shizuru J, Franke GN, Maris MB, Boyer M, Bruno B, Sahebi F, Langston AA, Hari P, Agura ED, Lykke Petersen S, Maziarz RT, Bethge W, Asch J, Gutman JA, Olesen G, Yeager AM, Hubel K, Hogan WJ, Maloney DG, Mielcarek M, Martin PJ, Flowers MED, Georges GE, Woolfrey AE, Deeg JH, Scott BL, McDonald GB, Storb R, Sandmaier BM. Allogeneic hematopoietic cell transplantation with non-myeloablative conditioning for patients with hematologic malignancies: Improved outcomes over two decades. Haematologica. 2021 Jun 1;106(6):1599-1607. doi: 10.3324/haematol.2020.248187.
• Kornblit B, Maloney DG, Storb R, Storek J, Hari P, Vucinic V, Maziarz RT, Chauncey TR, Pulsipher MA, Bruno B, Petersen FB, Bethge WA, Hubel K, Bouvier ME, Fukuda T, Storer BE, Sandmaier BM. Fludarabine and 2-Gy TBI is superior to 2 Gy TBI as conditioning for HLA-matched related hematopoietic cell transplantation: a phase III randomized trial. Biol Blood Marrow Transplant. 2013 Sep;19(9):1340-7. doi: 10.1016/j.bbmt.2013.06.002. Epub 2013 Jun 11.

Study record dates

Study Major Dates

• Study Start: October 1, 2003
• Primary Completion (Actual): February 1, 2014
• Study Completion (Actual): February 2, 2014

Study Registration Dates

• First Submitted: January 9, 2004
• First Submitted That Met QC Criteria: January 11, 2004
• First Posted (Estimate): January 12, 2004

Study Record Updates

• Last Update Posted (Actual): May 15, 2017
• Last Update Submitted That Met QC Criteria: April 7, 2017
• Last Verified: April 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Neoplasms, Plasma Cell; Leukemia, Lymphoid; Leukemia, B-Cell; Lymphoma, B-Cell; Neoplasms; Lymphoma; Lymphoma, Large B-Cell, Diffuse; Multiple Myeloma; Leukemia; Leukemia, Myeloid; Lymphoma, Non-Hodgkin; Lymphoma, Mantle-Cell; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Waldenstrom Macroglobulinemia; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Chronic-Phase; Myeloproliferative Disorders; Myelodysplastic-Myeloproliferative Diseases; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Fludarabine; Fludarabine phosphate; Mycophenolic Acid; Cyclosporine; Cyclosporins
• Other Study ID Numbers: 1813.00 (Other Identifier: Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium); P30CA015704 (U.S. NIH Grant/Contract); P01CA078902 (U.S. NIH Grant/Contract); NCI-2009-01532 (Registry Identifier: CTRP (Clinical Trial Reporting Program))