Optimized Donor Selection, Nonmyeloablative BMT for B-cell Lymphomas With Post-transplantation Cy and Rituximab

Nonmyeloablative BMT With Post-transplant Cyclophosphamide, Rituximab and Optimized Donor Selection for B-cell Lymphomas

This phase II trial is studying how well giving fludarabine and cyclophosphamide together with total-body irradiation and rituximab works in treating patients with B-cell lymphoma or chronic lymphocytic leukemia who are undergoing an allogeneic (donor) bone marrow transplant. The type of bone marrow transplant is a less intensive or "mini" transplant using a relative as the bone marrow donor. The donated bone marrow stem cells may replace the patient's immune system cells and help destroy any remaining cancer (graft-versus-tumor effect). Patients undergoing this type of transplant often have more than one relative who could be a donor. The trial is also studying a new way of choosing amongst possible donors which might improve how the rituximab works.

Study Overview

• Status: Terminated
• Conditions: Lymphoma; B-cell Lymphoma; Chronic Lymphocytic Leukemia; Non Hodgkin Lymphoma
• Intervention / Treatment: Drug: Fludarabine; Radiation: Total body irradiation; Drug: Cyclophosphamide; Drug: Tacrolimus; Drug: Mycophenolate Mofetil; Drug: Rituximab; Biological: Allogeneic Bone Marrow Transplant (BMT)

Detailed Description

This phase II for relapsed or refractory B-cell malignancies builds on the platform of nonmyeloablative, related-donor, HLA (human leukocyte antigen)-matched or HLA-haploidentical BMT with post-transplantation high-dose cyclosphosphamide administered for prophylaxis of graft-versus-host disease and graft rejection. Rituximab is added to the transplant regimen with the goal of augmenting anti-tumor activity. In patients with B-cell lymphomas, specific polymorphisms in the immunoglobulin Fc receptor have been associated with greater sensitivity to rituximab or rituximab-based therapies, translating in some series into higher response rates and improved progression-free survival. This raises the possibility of selecting donors who carry this permissive polymorphism. This trial identifies and selects donors who have the favorable polymorphism at FcgammaR3A-158, thereby potentially conferring greater sensitivity to rituximab in the host after BMT.

• Study Type: Interventional
• Enrollment (Actual): 135
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21231
      • Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 75 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Poor-risk CD20+, B-cell lymphoma, as follows:

  • Low grade B-cell lymphoma that has failed at least two prior therapies (excluding single agent rituximab), or undergone histologic conversion (if histologic conversion, PR or CR is required):

    1. Follicular grade 1 or 2 lymphoma
    2. Follicular lymphoma not otherwise specified
    3. Marginal zone (or MALT) lymphoma
    4. Lymphoplasmacytic lymphoma / Waldenstrom's macroglobulinemia
    5. Hairy cell leukemia
    6. Small lymphocytic lymphoma / chronic lymphocytic leukemia (SLL/CLL)
    7. Low grade B-cell lymphoma, unspecified
    8. Nodular lymphocyte-predominant Hodgkin lymphoma
• Poor-risk small lymphocytic lymphoma or chronic lymphocytic leukemia, defined by a 17p deletion, 11q deletion, or histologic conversion (if histologic conversion, PR or CR is required)

• Aggressive B-cell non-Hodgkin's lymphoma that has failed at least one prior regimen of multiagent chemotherapy, is in PR (partial remission) or CR (complete remission), and patient is either ineligible for autologous hematopoietic BMT or autologous BMT is not recommended:

  1. Follicular grade 3 lymphoma
  2. Histoconversion of low-grade B-cell lymphoma (including SLL/CLL) to aggressive B-cell non-Hodgkin's lymphoma
  3. Mantle cell lymphoma
  4. Diffuse large B-cell lymphoma (excluding primary CNS [central nervous system] lymphoma)
  5. "Gray zone" or composite lymphomas with combined features of primary mediastinal large B-cell and Hodgkin's lymphoma
  6. Burkitt's lymphoma/leukemia
  7. Atypical Burkitt's lymphoma/leukemia (high grade B-cell lymphoma, unclassified, including that with features intermediate between Burkitt's and diffuse large B-cell lymphoma)
• Must have a related donor who is at least HLA haploidentical
• Any previous BMT must have occurred at least 3 months prior
• Left ventricular ejection fraction at least 35%
• Bilirubin no more than 3.0 mg/dL (unless due to Gilbert's syndrome), and ALT (alanine aminotransferase) and AST (aspartate aminotransferase) no more than 5 x upper limit of normal
• FEV1 (forced expiratory volume in one second) and FVC (forced vital capacity) at least 40% of predicted
• Absence of uncontrolled infection

Exclusion Criteria:

• More than 20% involvement of bone marrow by chronic lymphocytic leukemia
• Active central nervous system lymphoma
• ECOG (Eastern Cooperative Oncology Group) performance status greater than 1 (2,3, and 4)
• HIV positive
• Pregnant or breastfeeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Transplant; Non-myeloablative allogeneic bone marrow transplant (BMT) with a fludarabine (Flu), cyclophosphamide (Cy), total body irradiation (TBI) preparative regimen and post-transplant Cy, mycophenolate mofetil (MMF), and tacrolimus as GVHD (graft vs host disease) prophylaxis. Rituximab will be given as post-transplant maintenance.

Drug: Fludarabine; Days -6 through -2: 30 mg/m^2 IV daily; Other Names: Fludara; Radiation: Total body irradiation; Day -1: 200 centigray (cGy) in a single fraction; Other Names: TBI; Drug: Cyclophosphamide; Days -6 and -5: 14.5 mg/kg IV daily; Days 3 and 4: 50 mg/kg IV daily; Other Names: Cytoxan; CTX; Cy; Drug: Tacrolimus; Start on Day 5 through Day 180; Other Names: Prograf; FK506; FK-506; Drug: Mycophenolate Mofetil; Days 5 through 35: 15 mg/kg PO three times daily (max 3 g/day); Other Names: CellCept; MMF; Drug: Rituximab; Day 30 and every week after for 8 total doses: 375 mg/m^2 IV; Other Names: Rituxan; Biological: Allogeneic Bone Marrow Transplant (BMT); Day 0: Donor bone marrow infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival	Percentage of participants alive and without relapse or disease progression.	1 year post-intervention

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Graft Failure	Percentage of participants who failed to engraft.	Day 60
Progression-free Survival	Percentage of participants alive with and without relapse.	2 years post-intervention
Overall Survival	Percentage of participants alive.	1 year post intervention
Overall Survival	Percentage of participants alive.	2 years post intervention
Relapse	Percentage of participants alive with relapse or disease progression.	1 year post intervention
Relapse	Percentage of participants alive with relapse or disease progression.	2 years post intervention
Non-relapse Mortality	Percentage of participants who died due to BMT-related reasons.	1 year post intervention
Incidence of Grades II-IV Acute Graft-versus-Host-Disease (GVHD)	Percentage of participants who experienced grade II, III, or IV acute GVHD. Acute GVHD is graded using the Przepiorka criteria.	1 year post intervention
Incidence of Grades III-IV Acute GVHD	Percentage of participants who experienced grade II, III, or IV acute GVHD. Acute GVHD is graded using the Przepiorka criteria.	1 year post intervention
Incidence of Chronic GVHD	Percentage of participants who experienced chronic GVHD. Chronic GVHD is graded using NIH consensus criteria and Seattle criteria.	1 year post intervention
Engraftment	Percentage of patients who engrafted neutrophils and platelets.	Day 60

Collaborators and Investigators

• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Investigators: Principal Investigator: Yvette L Kasamon, MD, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Publications and helpful links

General Publications

• Kanakry JA, Gocke CD, Bolanos-Meade J, Gladstone DE, Swinnen LJ, Blackford AL, Fuchs EJ, Huff CA, Borrello I, Matsui WH, Brodsky RA, Rosner GL, Shanbhag S, Luznik L, Jones RJ, Ambinder RF, Kasamon YL. Phase II Study of Nonmyeloablative Allogeneic Bone Marrow Transplantation for B Cell Lymphoma with Post-Transplantation Rituximab and Donor Selection Based First on Non-HLA Factors. Biol Blood Marrow Transplant. 2015 Dec;21(12):2115-2122. doi: 10.1016/j.bbmt.2015.07.012. Epub 2015 Jul 14.

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2009
• Primary Completion (Actual): July 1, 2013
• Study Completion (Actual): July 17, 2013

Study Registration Dates

• First Submitted: July 21, 2009
• First Submitted That Met QC Criteria: July 22, 2009
• First Posted (Estimate): July 24, 2009

Study Record Updates

• Last Update Posted (Actual): August 27, 2018
• Last Update Submitted That Met QC Criteria: July 26, 2018
• Last Verified: July 1, 2018

More Information

Terms related to this study

• Keywords: lymphoma; rituximab; cyclophosphamide; bone marrow transplantation; allogeneic; nonmyeloablative; non hodgkin lymphoma
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Leukemia, Lymphoid; Leukemia; Leukemia, B-Cell; Lymphoma; Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Leukemia, Lymphocytic, Chronic, B-Cell; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Immunological; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Cyclophosphamide; Rituximab; Fludarabine; Tacrolimus; Mycophenolic Acid
• Other Study ID Numbers: J0941; NA_00025589 (Other Identifier: Johns Hopkins Medicine Institutional Review Board)