Autologous or Donor Stem Cell Transplantation in Treating Patients With Recurrent Non-Hodgkin's Lymphoma (BMT CTN 0202)

Autologous Versus Non-Myeloablative Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for Patients With Chemosensitive Follicular Non-Hodgkin's Lymphoma Beyond First Complete Response or First Partial Response (BMT CTN #0202)

This study is designed as a Phase II/III, multi-center trial, comparing two transplant strategies to determine whether non-myeloablative allogeneic Hematopoietic Stem Cell Transplantation (HSCT) will improve long-term progression-free survival compared to autologous HSCT. Recipients will be biologically assigned to the appropriate treatment arm depending on the availability of a Human Leukocyte Antigen (HLA) matched sibling.

Study Overview

• Status: Terminated
• Conditions: Follicular Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma
• Intervention / Treatment: Drug: Cyclophosphamide and Rituximab; Drug: Filgrastim; Radiation: Chemotherapy or Radiation therapy; Procedure: Autologous transplant; Drug: Rituximab maintenance therapy; Drug: Non-myeloablative Conditioning regimen; Procedure: Allogeneic transplant; Drug: GVHD Prophylaxis

Detailed Description

BACKGROUND:

Although patients with follicular non-Hodgkin's lymphoma (NHL) typically experience a relatively indolent course, the disease is rarely curable with conventional chemotherapy. Patients with follicular NHL are usually treated only when symptoms require palliation or if bulky disease exists since no survival advantage has been shown as compared to administering conventional treatment at initial diagnosis. While most patients achieve a remission with initial chemotherapy, a continuous pattern of relapse occurs, resulting in progressively shorter remission durations. Additionally, the increased response rates conferred by anthracycline-containing regimens have not translated into improved survival and thus the median survival time of 6 to 10 years has not been significantly impacted over the last decade.

DESIGN NARRATIVE:

The overall study design is a comparison of two treatment arms determined by biologic assignment, based on the availability of an HLA-matched sibling, in patients diagnosed with relapsed follicular non-Hodgkin's lymphoma. Patients without an HLA-matched sibling will receive an autologous HSCT. Patients with an HLA-matched sibling will receive a non-myeloablative allogeneic HSCT.

The overall study design is that of biologic assignment, based on the availability of an HLA-matched sibling, to one of two strategies to improve the outcome for follicular lymphoma patients with chemosensitive disease. All patients will undergo cytoreduction with cyclophosphamide 4 gm/m^2 and rituximab 375 mg/m^2 x 2 doses. Rituximab will be given in two doses, approximately 1 week apart, with the cyclophosphamide administered the day after the first dose of rituximab. Patients assigned to the autologous arm will have their hematopoietic stem cells mobilized from this cytoreductive regimen. Patients with an HLA-matched sibling will undergo a non-myeloablative allogeneic HSCT. Pre-transplant conditioning will consist of fludarabine 30 mg/m^2/day and cyclophosphamide 750 mg/m^2/day x 3 days with rituximab 375 mg/m^2/day on Days -13 and -6 pre-HSCT and on Days +1 and +8 post-HSCT. The immunosuppressive regimen will consist of tacrolimus and methotrexate (MTX) to control graft-versus-host and host-versus-graft reactions. Patients without an HLA-matched sibling who have collected an adequate autologous hematopoietic cell graft, defined as at least 2.0 * 10^6 CD34+ cells/kg, will receive a preparative regimen of total body irradiation (TBI) 1200 cGy or Carmustine (BCNU) 15 mg/kg. In addition, VP-16 60 mg/kg and cyclophosphamide 100 mg/kg will be given for both autologous preparative regimens. Post-autologous HSCT therapy with rituximab 375 mg/m^2 weekly x 4 doses will commence between Days 42-75 post-HSCT.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010-3000
      • City of Hope National Medical Center
    • La Jolla, California, United States, 92037
      • Scripps Clinic
    • La Jolla, California, United States, 92093
      • UCSD Medical Center
    • Stanford, California, United States, 94305
      • Stanford Hospital and Clinics
  • Florida
    • Gainesville, Florida, United States, 32610-0277
      • University of Florida College of Medicine (Shands)
    • Tampa, Florida, United States, 33624
      • H. Lee Moffitt Cancer Center
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University
    • Atlanta, Georgia, United States, 30342
      • BMT Group of Georgia
    • Atlanta, Georgia, United States, 60153
      • Loyola University
  • Indiana
    • Beech Grove, Indiana, United States, 46107
      • Indiana BMT at Beech Grove
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Dana-Farber Cancer Institute
  • Michigan
    • Ann Arbor, Michigan, United States, 48105-2967
      • University of Michigan Medical Center
    • Detroit, Michigan, United States, 48201
      • Karmanos Cancer Institute/BMT
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota
  • Missouri
    • Kansas City, Missouri, United States, 64111
      • Kansas City Cancer Centers
    • Saint Louis, Missouri, United States, 63110
      • Washington University/Barnes Jewish Hospital
  • Nebraska
    • Omaha, Nebraska, United States, 68198-7680
      • University of Nebraska Medical Center
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center
  • North Carolina
    • Durham, North Carolina, United States, 27705
      • Duke University Medical Center
  • Ohio
    • Cleveland, Ohio, United States, 44106-5061
      • University Hospitals of Cleveland/Case Western
  • Oregon
    • Portland, Oregon, United States, 97213
      • Providence Portland Medical Center
    • Portland, Oregon, United States, 97239-3098
      • Oregon Health Sciences University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania Cancer Center
    • Pittsburgh, Pennsylvania, United States, 15232
      • University of Pittsburgh Cancer Institute
  • Tennessee
    • Nashville, Tennessee, United States, 37232-8210
      • Vanderbilt University
  • Texas
    • Dallas, Texas, United States, 75246
      • Baylor University Medical Center
    • Houston, Texas, United States, 77030
      • University of Texas/MD Anderson CRC
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University MCV Hospitals
  • Wisconsin
    • Madison, Wisconsin, United States, 53792-5156
      • University of Wisconsin Hospital and Clinics
    • Milwaukee, Wisconsin, United States, 53211
      • 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

Initial Patient Inclusion Criteria:

• Histologically confirmed recurrent Revised European American Lymphoma (REAL) classification follicle center lymphoma, follicular grades I and II, OR histologically confirmed World Health Organization (WHO) classification follicular lymphoma grades 1, 2, 3a or 3b; for either classification, the diffuse component or presence of large cleaved cells (if present) cannot be more than 50% of high power field; patients do not have to express t(14;18) to be eligible
• Received three or fewer prior regimens of chemotherapy; monoclonal antibody therapy and involved field radiation therapy will not be counted as a prior therapy

• Beyond first Complete Remission (CR) or first Partial Remission (PR) AND demonstrate chemosensitive disease; chemosensitive disease will be defined as less than 20% bone marrow involvement in the aspirate or core biopsy with follicular lymphoma AND lymph node size in axial diameter of less than 3 cm or a greater than 50% reduction in estimated lymph node volume to be measured as product of bi-dimensional measurements; Positron Emission Tomography (PET) scanning will not be used for staging or response purposes

  • Patients with adequate organ function as measured by:

    1. Cardiac: left ventricular ejection fraction at rest at least 45%
    2. Hepatic: bilirubin less than 2 times the upper limit of normal and alanine transaminase (ALT) and aspartate aminotransferase (AST) less than 3 times the upper limit of normal
    3. Renal: creatinine clearance greater than 40 mL/min
    4. Pulmonary: Diffusing capacity of the lung for carbon monoxide (DLCO), Forced expiratory volume in one second (FEV1), and Forced vital capacity (FVC) greater than 50% of predicted (corrected for hemoglobin)
  • If the patient is younger than 18 years of age and they have reached the age of assent, then they must have completed the local Institutional Review Board (IRB) assent process.
  • Able to receive cyclophosphamide and rituximab mobilization chemotherapy no earlier than 3 weeks from the beginning of the most recent cycle of salvage chemotherapy and no later than 6 weeks from enrollment

Patient Inclusion Criteria for Proceeding to Hematopoietic Stem Cell Transplant (HSCT):

• Collection of an autologous or allogeneic graft of at least 2.0 * 10^6 CD34+ cells/kg
• Blood count recovery defined as Absolute Neutrophil Count (ANC) greater than 1000/mm3 and platelets greater than 100 * 10^9/L

Patient Inclusion Criteria for Maintenance Therapy:

• Liver and renal function tests within the inclusion criteria for initial autograft
• Off intravenous antibiotics and off amphotericin B formulations for proven, probable or possible fungal infections
• No active Cytomegalovirus (CMV) infections or for patients with CMV infection post-autograft, treated with ganciclovir, valganciclovir, or foscarnet per institutional guidelines and CMV antigenemia negative
• Mucositis resolved and off hyperalimentation

Exclusion Criteria:

• Karnofsky performance score less than 70%
• Follicular lymphoma that show histologic evidence of transformation
• Uncontrolled hypertension
• Patients with uncontrolled bacterial, viral or fungal infection (currently taking medication and progression without clinical improvement).
• Prior malignancies except resected basal cell carcinoma or treated cervical carcinoma in situ; cancer treated with curative intent more than 5 years previously will be reviewed on a case-by-case basis by a Protocol Chair or Medical Monitor.
• Pregnant (positive Beta Human chorionic gonadotropin (β-HCG)) or breastfeeding
• Seropositive for Human immunodeficiency virus (HIV)
• Unwilling to use contraceptive techniques during treatment
• Prior autologous or allogeneic HSCT
• Known anaphylactic reaction to rituximab

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Autologous Transplant; Cyclophosphamide and Rituximab with Filgrastim conditioning and chemotherapy or radiation therapy prior to autologous Hematopoietic Stem Cell Transplant (HSCT). Rituximab maintenance therapy following HSCT.	Drug: Cyclophosphamide and Rituximab; Prior to undergoing HSCT, all patients will receive Cyclophosphamide 4 gm/m2 with Rituximab 375 mg/m2 x 2 doses and G-CSF support.; Other Names: Cytoxan® and Rituxan; Drug: Filgrastim; Autologous HSCT patients will receive 10 mcg/kg/day and allogeneic HSCT patients will receive 5 mcg/kg/day subcutaneous (SQ) or intravenous (IV) starting 2 days after the initiation of Cyclophosphamide.; Other Names: G-CSF; Radiation: Chemotherapy or Radiation therapy; Chemotherapy - BCNU 15 mg/kg IV x 1 dose to be administered over 2 hours on Day -6 pre-HSCT. VP-16 60 mg/kg IV x 1 dose to be administered over 4 hours on Day -4. Radiation - administered at a rate of < 20 cGy/min in one of the following doses; 120 cGy/fraction are administered at no less than 4-hour intervals three times/day or 2 times/day for a total of 10 doses (1200 cGy) over 4 days (Day -8, -7, -6 and -5), or doses of 150 cGy/fraction twice daily for a total of 8 doses (1200 cGy) over 4 days (Day -8, -7, -6 and -5). VP-16 60 mg/kg IV x 1 dose to be administered over 4 hours on Day -4 pre-HSCT. Cyclophosphamide 100 mg/kg IV x 1 dose to be administered over 2 hours on Day -2 pre-HSCT. G-CSF 5 mcg/kg SQ or IV to start on Day +5 post-HSCT and continue until ANC > 500/mm3 x 3 days.; Other Names: Etoposide and Carmustine; BCNU and VP-16; Procedure: Autologous transplant; Infusion of G-CSF mobilized autologous hematopoietic stem cells; Other Names: HSCT; Drug: Rituximab maintenance therapy; Patients must have sufficiently recovered from autologous HSCT in order to receive rituximab maintenance therapy as specified below: Dose #1: Day +42 post-autologous HSCT Dose #2: Day +49 post-autologous HSCT Dose #3: Day +56 post-autologous HSCT Dose #4: Day +63 post-autologous HSCT; Other Names: Rituxan
Active Comparator: Allogeneic Transplant; Non-myeloablative conditioning regimen followed by allogeneic Hematopoietic Stem Cell Transplant (HSCT). Graft-versus-Host Disease (GVHD) Prophylaxis therapy following HSCT.	Drug: Cyclophosphamide and Rituximab; Prior to undergoing HSCT, all patients will receive Cyclophosphamide 4 gm/m2 with Rituximab 375 mg/m2 x 2 doses and G-CSF support.; Other Names: Cytoxan® and Rituxan; Drug: Filgrastim; Autologous HSCT patients will receive 10 mcg/kg/day and allogeneic HSCT patients will receive 5 mcg/kg/day subcutaneous (SQ) or intravenous (IV) starting 2 days after the initiation of Cyclophosphamide.; Other Names: G-CSF; Drug: Non-myeloablative Conditioning regimen; Fludarabine 30 mg/m2 IV x 3 doses total to be administered daily over 30 minutes on Days -6, -5 and -4 pre-HSCT. Cyclophosphamide 750 mg/m IV x 3 doses total to be administered daily over 1 hour on Days -6, -5 and -4 pre-HSCT. Administer cyclophosphamide approximately 4 hours after start of fludarabine infusion. Rituximab 375 mg/m2 IV x 4 doses total to be administered on Days -13 and -6 pre HSCT and Days +1 and +8 post HSCT.; Other Names: Fludarabine, Cyclophosphamide, and Rituximab; Fludara, Cytoxan®, and Rituxan; Procedure: Allogeneic transplant; Infusion of G-CSF mobilized allogeneic hematopoietic stem cells; Other Names: HSCT; Drug: GVHD Prophylaxis; Tacrolimus 0.09 mg/kg/day PO, based on body weight formulas will start on Day -2 and continue until Day +90 post-HSCT. Tacrolimus (or cyclosporine, if applicable) will be given orally in a twice-daily divided dose. Methotrexate 5 mg/m2 Intravenous Pyelogram (IVP) will be administered on Days +1, +3 and +6 post-HSCT.; Other Names: Tacrolimus and Methotrexate; Prograf® and MTX

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Lymphoma Progression-free Survival	Three years post-Hematopoietic Stem Cell Transplant (HSCT)

Collaborators and Investigators

• Sponsor: Medical College of Wisconsin
• Collaborators: National Cancer Institute (NCI); National Heart, Lung, and Blood Institute (NHLBI); National Marrow Donor Program; Blood and Marrow Transplant Clinical Trials Network

Publications and helpful links

General Publications

• Tomblyn MR, Ewell M, Bredeson C, Kahl BS, Goodman SA, Horowitz MM, Vose JM, Negrin RS, Laport GG. Autologous versus reduced-intensity allogeneic hematopoietic cell transplantation for patients with chemosensitive follicular non-Hodgkin lymphoma beyond first complete response or first partial response. Biol Blood Marrow Transplant. 2011 Jul;17(7):1051-7. doi: 10.1016/j.bbmt.2010.11.004. Epub 2010 Nov 10.

Helpful Links

• National Marrow Donor Program
• Blood and Marrow Transplant Clinical Trials Network

Study record dates

Study Major Dates

• Study Start: August 1, 2004
• Primary Completion (Actual): March 1, 2006
• Study Completion (Actual): March 1, 2009

Study Registration Dates

• First Submitted: November 9, 2004
• First Submitted That Met QC Criteria: November 9, 2004
• First Posted (Estimate): November 10, 2004

Study Record Updates

• Last Update Posted (Actual): January 5, 2023
• Last Update Submitted That Met QC Criteria: December 7, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Disease Attributes; Lymphoma; Lymphoma, Follicular; Recurrence; Lymphoma, Non-Hodgkin; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Dermatologic Agents; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Calcineurin Inhibitors; Cyclophosphamide; Etoposide; Rituximab; Fludarabine; Methotrexate; Tacrolimus; Carmustine
• Other Study ID Numbers: BMTCTN0202; U01HL069294 (U.S. NIH Grant/Contract); 5U24CA076518 (U.S. NIH Grant/Contract); BMT CTN 0202 (Other Identifier: Blood and Marrow Transplant Clinical Trials Network)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes