Graft-Versus-Host Disease Prophylaxis in Treating Patients With Hematologic Malignancies Undergoing Unrelated Donor Peripheral Blood Stem Cell Transplant

NCT ID: NCT01231412

Last Updated: 2019-10-24

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 174 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-11-30
• Study Completion Date: 2017-06-30

Brief Summary

This randomized phase III trial studies how well graft-vs-host disease (GVHD) prophylaxis works in treating patients with hematologic malignancies undergoing unrelated donor peripheral blood stem cell transplant. Giving chemotherapy and total-body irradiation before a donor peripheral blood stem cell transplant (PBSCT) 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 (TBI) together with fludarabine phosphate (FLU), cyclosporine (CSP), mycophenolate mofetil (MMF), or sirolimus before transplant may stop this from happening.

Detailed Description

PRIMARY OBJECTIVES:

I. To compare the effectiveness of 2 GVHD prophylaxis regimens in preventing acute grades II-IV GVHD.

SECONDARY OBJECTIVES:

I. Compare non-relapse mortality in the 2 arms.

II. Compare survival and progression-free survivals in the 2 arms.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

All patients receive FLU intravenously (IV) over 30 minutes on days -4 to -2 followed by 2-3 Gy TBI on day 0.

ARM 0: Patients receive CSP orally (PO) twice daily (BID) on days -3 to 96 with taper to day 150 and and sirolimus PO once daily (QD) on days -3 to 150 with taper to day 180. Arm removed as of 14-Sep-2011

ARM I: Patients receive CSP orally (PO) twice daily (BID) on days -3 to 96 with taper to day 150 and MMF PO three times daily (TID) on days 0-29 and then BID on days 30-150 with taper to day 180.

ARM II: Patients receive CSP as in Arm I and sirolimus PO once daily (QD) on days -3 to 150 with taper to day 180. Patients also receive MMF PO TID on days 0-29 and then BID on days 30-40. MMF will then be discontinued without taper unless GVHD or disease relapse/progression occurs.

TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0 following the TBI.

After completion of study treatment, patients are followed up periodically.

Conditions

Acute Lymphoblastic Leukemia; Acute Myeloid Leukemia; Aggressive Non-Hodgkin Lymphoma; Chronic Lymphocytic Leukemia; Diffuse Large B-Cell Lymphoma; Hematopoietic and Lymphoid Cell Neoplasm; Indolent Non-Hodgkin Lymphoma; Mantle Cell Lymphoma; Myelodysplastic Syndrome; Myeloproliferative Neoplasm; Prolymphocytic Leukemia; Recurrent Chronic Lymphocytic Leukemia; Recurrent Plasma Cell Myeloma; Refractory Chronic Lymphocytic Leukemia; Refractory Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Refractory Hodgkin Lymphoma; Small Lymphocytic Lymphoma; T-Cell Chronic Lymphocytic Leukemia; Waldenstrom Macroglobulinemia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Arm I (MMF and CSP)

Patients receive FLU IV over 30 minutes on days -4 to -2. Patients also receive CSP PO BID on days -3 to 96 with taper to day 150 and MMF PO TID daily on days 0-29 and then BID on days 30-150 with taper to day 180. Patients undergo allogeneic PBSCT on day 0 following the TBI.

Group Type: ACTIVE_COMPARATOR

Allogeneic Hematopoietic Stem Cell Transplantation

Intervention Type: PROCEDURE

Undergo allogeneic PBSCT

Cyclosporine

Intervention Type: DRUG

Given PO or IV

Fludarabine Phosphate

Intervention Type: DRUG

Given IV

Mycophenolate Mofetil

Intervention Type: DRUG

Given PO

Peripheral Blood Stem Cell Transplantation

Intervention Type: PROCEDURE

Undergo allogeneic PBSCT

Total-Body Irradiation

Intervention Type: RADIATION

Undergo TBI

Arm II (MMF, CSP, and Sirolimus)

Patients receive FLU and CSP as in Arm I and sirolimus PO QD on days -3 to 150 with taper to day 180. Patients also receive MMF PO TID on days 0-29 and then BID on days 30-40. MMF will then be discontinued without taper unless GVHD or disease relapse/progression occurs. Patients undergo allogeneic PBSCT on day 0 following the TBI.

Group Type: EXPERIMENTAL

Allogeneic Hematopoietic Stem Cell Transplantation

Intervention Type: PROCEDURE

Undergo allogeneic PBSCT

Cyclosporine

Intervention Type: DRUG

Given PO or IV

Fludarabine Phosphate

Intervention Type: DRUG

Given IV

Mycophenolate Mofetil

Intervention Type: DRUG

Given PO

Peripheral Blood Stem Cell Transplantation

Intervention Type: PROCEDURE

Undergo allogeneic PBSCT

Sirolimus

Intervention Type: DRUG

Given PO

Total-Body Irradiation

Intervention Type: RADIATION

Undergo TBI

Arm 0 (CSP and Sirolimus)

Patients receive CSP orally (PO) twice daily (BID) on days -3 to 96 with taper to day 150 and and sirolimus PO once daily (QD) on days -3 to 150 with taper to day 180. Arm removed as of 14-Sep-2011

Group Type: EXPERIMENTAL

Allogeneic Hematopoietic Stem Cell Transplantation

Intervention Type: PROCEDURE

Undergo allogeneic PBSCT

Cyclosporine

Intervention Type: DRUG

Given PO or IV

Fludarabine Phosphate

Intervention Type: DRUG

Given IV

Peripheral Blood Stem Cell Transplantation

Intervention Type: PROCEDURE

Undergo allogeneic PBSCT

Sirolimus

Intervention Type: DRUG

Given PO

Total-Body Irradiation

Intervention Type: RADIATION

Undergo TBI

Interventions

Allogeneic Hematopoietic Stem Cell Transplantation

Undergo allogeneic PBSCT

Intervention Type: PROCEDURE

Cyclosporine

Given PO or IV

Intervention Type: DRUG

Fludarabine Phosphate

Given IV

Intervention Type: DRUG

Mycophenolate Mofetil

Given PO

Intervention Type: DRUG

Peripheral Blood Stem Cell Transplantation

Undergo allogeneic PBSCT

Intervention Type: PROCEDURE

Sirolimus

Given PO

Intervention Type: DRUG

Total-Body Irradiation

Undergo TBI

Intervention Type: RADIATION

Other Intervention Names

allogeneic stem cell transplantation; HSC; HSCT; 27-400; Ciclosporin; CsA; Cyclosporin; Cyclosporin A; Gengraf; Neoral; OL 27-400; Sandimmun; Sandimmune; SangCya; 2-F-ara-AMP; 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-; Beneflur; Fludara; SH T 586; Cellcept; MMF; PBPC transplantation; Peripheral Blood Progenitor Cell Transplantation; Peripheral Stem Cell Support; Peripheral Stem Cell Transplantation; AY 22989; RAPA; Rapamune; RAPAMYCIN; SILA 9268A; WY-090217; TOTAL BODY IRRADIATION; Whole-Body Irradiation

Eligibility Criteria

Inclusion Criteria

• Ages > 50 years with hematologic malignancies treatable by unrelated hematopoietic cell transplant (HCT)
• Ages =< 50 years of age with chronic lymphocytic leukemia (CLL)
• The following diseases will be permitted although other diagnoses can be considered if approved by Patient Care Conference (PCC) or the participating institutions' patient review committees and the principal investigators

• Aggressive non-Hodgkin lymphomas (NHL) and other histologies such as diffuse large B cell NHL: not eligible for autologous HCT, not eligible for high-dose allogeneic HCT, or after failed autologous HCT
• Mantle cell NHL: may be treated in first complete remission (CR); (diagnostic lumbar puncture [LP] required pre-transplant)
• Low grade NHL: with < 6 month duration of CR between courses of conventional therapy
• 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 FLU (or another nucleoside analog, e.g. 2-Chlorodeoxyadenosine [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; or
• 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: must have received and failed frontline therapy
• Multiple myeloma: must have received prior chemotherapy; consolidation of chemotherapy by autografting prior to nonmyeloablative HCT is permitted
• Acute myeloid leukemia (AML): must have < 5% marrow blasts at the time of transplant
• Acute lymphocytic leukemia (ALL): must have < 5% marrow blasts at the time of transplant
• Chronic myeloid leukemia (CML): patients in 1st chronic phase (CP1) must have failed or be intolerant of tyrosine-kinase inhibitors (TKI); patients beyond CP1 will be accepted if they have < 5% marrow blasts at time of transplant
• Myelodysplasia (MDS)/myeloproliferative syndrome (MPS): patients must have < 5% marrow blasts at time of transplant
• Waldenstrom's macroglobulinemia: must have failed 2 courses of therapy
• DONOR: FHCRC matching allowed will be grades 1.0 to 2.1: Unrelated donors who are prospectively:

• Matched for human leukocyte antigen (HLA)-A, B, C, DRB1 and DQB1 by high resolution typing
• Only a single allele disparity will be allowed for HLA-A, B, or C as defined by high resolution typing
• DONOR: Donors are excluded when preexisting immunoreactivity is identified that would jeopardize donor hematopoietic cell engraftment; this determination is based on the standard practice of the individual institution; the recommended procedure for patients with 10 of 10 HLA allele level (phenotypic) match is to obtain a panel reactive antibody (PRA) screens to class I and class II antigens for all patients before HCT; if the PRA shows > 10% activity, then flow cytometric or B and T cell cytotoxic cross matches should be obtained; the donor should be excluded if any of the cytotoxic cross match assays are positive; for those patients with an HLA class I allele mismatch, flow cytometric or B and T cell cytotoxic cross matches should be obtained regardless of the PRA results; a positive anti-donor cytotoxic crossmatch is an absolute donor exclusion
• DONOR: Patient and donor pairs homozygous at a mismatched allele in the graft rejection vector are considered a two-allele mismatch, i.e., the patient is A*0101 and the donor is A*0102, and this type of mismatch is not allowed
• DONOR: Only filgrastim (G-CSF) mobilized PBSC only will be permitted as a hematopoietic stem cell (HSC) source on this protocol

Exclusion Criteria

• Patients with rapidly progressive intermediate or high grade NHL
• Patients with a diagnosis of chronic myelomonocytic leukemia (CMML)
• Patients with refractory anemia with excess blasts (RAEB) who have not received myelosuppressive chemotherapy i.e. induction chemotherapy
• Central nervous system (CNS) involvement with disease refractory to intrathecal chemotherapy
• Presence of circulating leukemic blasts (in the peripheral blood) detected by standard pathology for patients with AML, ALL or CML
• Presence of >= 5% circulating leukemic blasts (in the peripheral blood) detected by standard pathology for patients with MDS/MPS
• Fertile men or women unwilling to use contraceptive techniques during and for 12 months following treatment
• Females who are pregnant or breast-feeding
• Patients with active non-hematological malignancies (except non-melanoma skin cancers) or those with non-hematological malignancies (except non-melanoma skin cancers) who have been rendered with no evidence of disease, but have a greater than 20% chance of having disease recurrence within 5 years; this exclusion does not apply to patients with non-hematologic malignancies that do not require therapy
• Fungal infections with radiological progression after receipt of amphotericin B or active triazole for greater than 1 month
• Cardiac ejection fraction < 35% (or, if unable to obtain ejection fraction, shortening fraction of < 26%); ejection fraction is required if age > 50 years or there is a history of anthracycline exposure or history of cardiac disease; patients with a shortening fraction < 26% may be enrolled if approved by a cardiologist
• Diffusing capacity of the lung for carbon monoxide (DLCO) < 40%, total lung capacity (TLC) < 40%, forced expiratory volume in one second (FEV1) < 40% and/or receiving supplementary continuous oxygen
• The FHCRC PI of the study must approve of enrollment of all patients with pulmonary nodules
• 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, 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, bridging fibrosis, bacterial or fungal liver abscess, biliary obstruction, chronic viral hepatitis with total serum bilirubin > 3 mg/dL, or symptomatic biliary disease
• Karnofsky scores < 60 or Lansky Score < 50
• Patient has poorly controlled hypertension and on multiple antihypertensives
• Human immunodeficiency virus (HIV) positive patients
• Active bacterial or fungal infections unresponsive to medical therapy
• All patients receiving antifungal therapy voriconazole, posaconazole, or fluconazole and who are then randomized to ARM 2 must have sirolimus reduced according to the Standard Practice Antifungal Therapy Guidelines
• The addition of cytotoxic agents for "cytoreduction" with the exception of tyrosine kinase inhibitors (such as imatinib), cytokine therapy, hydroxyurea, low dose cytarabine, chlorambucil, or Rituxan will not be allowed within three weeks of the initiation of conditioning
• DONOR: Donor (or centers) who will exclusively donate marrow
• DONOR: Donors who are HIV-positive and/or, medical conditions that would result in increased risk for G-CSF mobilization and harvest of PBSC

• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

Fred Hutchinson Cancer Center

OTHER

Sponsor Role: lead

Responsible Party

Brenda Sandmaier

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Brenda Sandmaier

Role: PRINCIPAL_INVESTIGATOR

Fred Hutch/University of Washington Cancer Consortium

Locations

University of Colorado

Denver, Colorado, United States

Presbyterian - Saint Lukes Medical Center - Health One

Denver, Colorado, United States

Emory University/Winship Cancer Institute

Atlanta, Georgia, United States

Huntsman Cancer Institute/University of Utah

Salt Lake City, Utah, United States

VA Puget Sound Health Care System

Seattle, Washington, United States

Fred Hutch/University of Washington Cancer Consortium

Seattle, Washington, United States

Aarhus University Hospital

Aarhus, , Denmark

Rigshospitalet University Hospital

Copenhagen, , Denmark

Medizinische Univ Klinik Koln

Cologne, , Germany

Universitaet Leipzig

Leipzig, , Germany

University of Tuebingen-Germany

Tübingen, , Germany

Countries

United States; Denmark; Germany

References

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.

Reference Type: DERIVED

PMID: 32499241 (View on PubMed)

Sandmaier BM, Kornblit B, Storer BE, Olesen G, Maris MB, Langston AA, Gutman JA, Petersen SL, Chauncey TR, Bethge WA, Pulsipher MA, Woolfrey AE, Mielcarek M, Martin PJ, Appelbaum FR, Flowers MED, Maloney DG, Storb R. Addition of sirolimus to standard cyclosporine plus mycophenolate mofetil-based graft-versus-host disease prophylaxis for patients after unrelated non-myeloablative haemopoietic stem cell transplantation: a multicentre, randomised, phase 3 trial. Lancet Haematol. 2019 Aug;6(8):e409-e418. doi: 10.1016/S2352-3026(19)30088-2. Epub 2019 Jun 24.

Reference Type: DERIVED

PMID: 31248843 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

NCI-2010-02035

Identifier Type: REGISTRY

Identifier Source: secondary_id

2448.00

Identifier Type: OTHER

Identifier Source: secondary_id

P01CA018029

Identifier Type: NIH

Identifier Source: secondary_id

View Link

P30CA015704

Identifier Type: NIH

Identifier Source: secondary_id

View Link

2448.00

Identifier Type: -

Identifier Source: org_study_id