Clinical trial NCT00075478: Total-Body Irradiation With or Without Fludarabine Phosphate Followed By Donor Stem Cell Transplant in Treating Patients With Hematologic Cancer
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Acute Lymphoblastic Leukemia in Remission
Acute Myeloid Leukemia in Remission
Aggressive Non-Hodgkin Lymphoma
Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive
Diffuse Large B-Cell Lymphoma
Hematopoietic and Lymphoid Cell Neoplasm
Indolent Non-Hodgkin Lymphoma
Mantle Cell Lymphoma
Myelodysplastic/Myeloproliferative Neoplasm
Plasma Cell Myeloma
Refractory Chronic Lymphocytic Leukemia
Refractory Hodgkin Lymphoma
Waldenstrom Macroglobulinemia
Lead sponsor: Fred Hutchinson Cancer Center
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
name: National Cancer Institute (NCI)
First posted: 2004-01-12
Enrollment: 87
Sex: ALL
Maximum age (years): 75
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Overall Survival
timeFrame: 3 years after transplant
Secondary outcomes:
measure: Incidence of Non-relapse Mortality
timeFrame: 3 years after transplant
measure: Incidence of Relapse/Progression
timeFrame: 3 years after transplant
measure: Incidence of Relapse-related Mortality
timeFrame: 3 years after transplant
measure: Incidence of Grades II-IV Acute GVHD
timeFrame: 120 days after transplant
measure: Incidence of Chronic Extensive GVHD
timeFrame: 3 years after transplant
measure: Incidence of Graft Rejection
timeFrame: 1 year after transplant
measure: Progression-free Survival
timeFrame: 3 years after transplant
Other outcomes:
Locations:
city: Medford
country: United States
facility: OHSU Cancer Institute-Southern Region
state: Oregon
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute/University of Utah
state: Utah
city: Salt Lake City
country: United States
facility: LDS Hospital
state: Utah
city: Seattle
country: United States
facility: VA Puget Sound Health Care System
state: Washington
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
state: Washington
city: Milwaukee
country: United States
facility: Froedtert and the Medical College of Wisconsin
state: Wisconsin
city: Koln
country: Germany
facility: Medizinische Univ Klinik Koln
city: Leipzig
country: Germany
facility: Universitaet Leipzig
city: Tuebingen
country: Germany
facility: University of Tuebingen-Germany
city: Torino
country: Italy
facility: University of Torino
Study officials:
affiliation: Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
name: Brenda Sandmaier
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.