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

NCT01231412 | Completed Phase 3 Results DMC

• 4 other identifiers: 2448.00NCI-2010-02035P01CA018029P30CA015704
• Study Type: interventional
• Target: 174
• Locations: 3 countries
• Sites: 11

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.

Conditions

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

Outcome Measures

Primary Outcomes (1)

• Number of Patients With Grades II-IV Acute GVHD

  Number of patients with grades II-IV acute GVHD aGVHD Stages Skin: 1. a maculopapular eruption involving \< 25% BSA 2. a maculopapular eruption involving 25 - 50% BSA 3. generalized erythroderma 4. generalized erythroderma w/ bullous formation and often w/ desquamation Liver: 1. bilirubin 2.0 - 3.0 mg/100 mL 2. bilirubin 3 - 5.9 mg/100 mL 3. bilirubin 6 - 14.9 mg/100 mL 4. bilirubin \> 15 mg/100 mL Gut: Diarrhea is graded 1 - 4 in severity. Nausea and vomiting and/or anorexia caused by GVHD is assigned as 1 in severity. The severity of gut involvement is assigned to the most severe involvement noted. Patients w/ visible bloody diarrhea are at least stage 2 gut and grade 3 overall. aGVHD Grades Grade II: Stage 1 - 2 skin w/ no gut/liver involvement Grade III: Stage 2 - 4 gut involvement and/or stage 2 - 4 liver involvement Grade IV: Pattern and severity of GVHD similar to grade 3 w/ extreme constitutional symptoms or death

  At day 100 post-transplant

Secondary Outcomes (5)

• Number of Patients With Chronic Extensive GVHD

  Up to 1 year

• Number of Patients With Grades III-IV Acute GVHD

  Up to 100 days

• Number of Non-Relapse Mortalities

  Up to 1 year

• Number of of Participants Surviving Overall

  Up to 1 year

• Number of Participants With Relapse/Progression

  Up to 1 year

Study Arms (3)

Arm I (MMF and CSP)

ACTIVE COMPARATOR

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.

Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Drug: Cyclosporine; Drug: Fludarabine Phosphate; Drug: Mycophenolate Mofetil; Procedure: Peripheral Blood Stem Cell Transplantation; Radiation: Total-Body Irradiation

Arm II (MMF, CSP, and Sirolimus)

EXPERIMENTAL

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.

Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Drug: Cyclosporine; Drug: Fludarabine Phosphate; Drug: Mycophenolate Mofetil; Procedure: Peripheral Blood Stem Cell Transplantation; Drug: Sirolimus; Radiation: Total-Body Irradiation

Arm 0 (CSP and Sirolimus)

EXPERIMENTAL

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

Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Drug: Cyclosporine; Drug: Fludarabine Phosphate; Procedure: Peripheral Blood Stem Cell Transplantation; Drug: Sirolimus; Radiation: Total-Body Irradiation

Interventions

Allogeneic Hematopoietic Stem Cell Transplantation PROCEDURE

Undergo allogeneic PBSCT

Also known as: allogeneic stem cell transplantation, HSC, HSCT

Arm 0 (CSP and Sirolimus); Arm I (MMF and CSP); Arm II (MMF, CSP, and Sirolimus)

Cyclosporine DRUG

Given PO or IV

Also known as: 27-400, Ciclosporin, CsA, Cyclosporin, Cyclosporin A, Gengraf, Neoral, OL 27-400, Sandimmun, Sandimmune, SangCya

Arm 0 (CSP and Sirolimus); Arm I (MMF and CSP); Arm II (MMF, CSP, and Sirolimus)

Fludarabine Phosphate DRUG

Given IV

Also known as: 2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, SH T 586

Arm 0 (CSP and Sirolimus); Arm I (MMF and CSP); Arm II (MMF, CSP, and Sirolimus)

Mycophenolate Mofetil DRUG

Given PO

Also known as: Cellcept, MMF

Arm I (MMF and CSP); Arm II (MMF, CSP, and Sirolimus)

Peripheral Blood Stem Cell Transplantation PROCEDURE

Undergo allogeneic PBSCT

Also known as: PBPC transplantation, Peripheral Blood Progenitor Cell Transplantation, Peripheral Stem Cell Support, Peripheral Stem Cell Transplantation

Arm 0 (CSP and Sirolimus); Arm I (MMF and CSP); Arm II (MMF, CSP, and Sirolimus)

Sirolimus DRUG

Given PO

Also known as: AY 22989, RAPA, Rapamune, RAPAMYCIN, SILA 9268A, WY-090217

Arm 0 (CSP and Sirolimus); Arm II (MMF, CSP, and Sirolimus)

Total-Body Irradiation RADIATION

Undergo TBI

Also known as: TOTAL BODY IRRADIATION, Whole-Body Irradiation

Arm 0 (CSP and Sirolimus); Arm I (MMF and CSP); Arm II (MMF, CSP, and Sirolimus)

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• Fred Hutchinson Cancer Center: lead
• National Cancer Institute (NCI): collaborator

Study Sites (11)

University of Colorado

Denver, Colorado, 80217-3364, United States

Location

Presbyterian - Saint Lukes Medical Center - Health One

Denver, Colorado, 80218, United States

Location

Emory University/Winship Cancer Institute

Atlanta, Georgia, 30322, United States

Location

Huntsman Cancer Institute/University of Utah

Salt Lake City, Utah, 84112, United States

Location

VA Puget Sound Health Care System

Seattle, Washington, 98101, United States

Location

Fred Hutch/University of Washington Cancer Consortium

Seattle, Washington, 98109, United States

Location

Aarhus University Hospital

Aarhus, 8200, Denmark

Location

Rigshospitalet University Hospital

Copenhagen, 2100, Denmark

Location

Medizinische Univ Klinik Koln

Cologne, 50924, Germany

Location

Universitaet Leipzig

Leipzig, D-04103, Germany

Location

University of Tuebingen-Germany

Tübingen, D-72076, Germany

Location

Related Publications (2)

• 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.

  PMID: 32499241 DERIVED

• 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.

  PMID: 31248843 DERIVED

MeSH Terms

Conditions

Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Myeloid, Acute; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Large B-Cell, Diffuse; Hematologic Neoplasms; Lymphoma, Mantle-Cell; Myelodysplastic Syndromes; Myeloproliferative Disorders; Leukemia, Prolymphocytic; Multiple Myeloma; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Hodgkin Disease; Leukemia, Prolymphocytic, T-Cell; Waldenstrom Macroglobulinemia

Interventions

Cyclosporine; Cyclosporins; fludarabine phosphate; Mycophenolic Acid; Peripheral Blood Stem Cell Transplantation; Sirolimus; Whole-Body Irradiation

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Leukemia, Myeloid; Leukemia, B-Cell; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms by Site; Bone Marrow Diseases; Neoplasms, Plasma Cell; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hemorrhagic Disorders; Leukemia, T-Cell

Intervention Hierarchy (Ancestors)

Peptides, Cyclic; Macrocyclic Compounds; Polycyclic Compounds; Peptides; Amino Acids, Peptides, and Proteins; Caproates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Fatty Acids; Lipids; Hematopoietic Stem Cell Transplantation; Stem Cell Transplantation; Cell Transplantation; Cell- and Tissue-Based Therapy; Biological Therapy; Therapeutics; Transplantation; Surgical Procedures, Operative; Macrolides; Lactones; Radiotherapy; Investigative Techniques

Results Point of Contact

• Title: Dr. Brenda M. Sandmaier
• Organization: Fred Hutchinson Cancer Research Center

bsandmai@fhcrc.org

(206) 667-4961

Study Officials

• Brenda Sandmaier

  Fred Hutch/University of Washington Cancer Consortium

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: October 28, 2010
• First Posted: November 1, 2010
• Study Start: November 1, 2010
• Primary Completion: October 8, 2016
• Study Completion: June 30, 2017
• Last Updated: April 30, 2026
• Results First Posted: December 4, 2017

Record last verified: 2019-10

Locations

DK (2); US (6); DE (3)