Rituximab in Preventing Acute Graft-Versus-Host Disease in a Donor Stem Cell Transplant for Hematologic Cancer

Phase 2

Terminated

Conditions: Adult Acute Lymphoblastic Leukemia in Remission
Adult Acute Myeloid Leukemia in Remission
Contiguous Stage II Mantle Cell Lymphoma
Adult Nasal Type Extranodal NK/T-cell Lymphoma
Blastic Phase Chronic Myelogenous Leukemia
Contiguous Stage II Grade 1 Follicular Lymphoma
Contiguous Stage II Grade 3 Follicular Lymphoma
Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma
Noncontiguous Stage II Adult Lymphoblastic Lymphoma
Noncontiguous Stage II Mantle Cell Lymphoma

Interventions: Drug: rituximab
Drug: mycophenolate mofetil
Drug: tacrolimus
Drug: anti-thymocyte globulin
Procedure: allogeneic hematopoietic stem cell transplantation
Other: laboratory biomarker analysis
Biological: graft versus host disease prophylaxis/therapy
Drug: cyclophosphamide
Drug: fludarabine phosphate
Drug: busulfan
Radiation: total-body irradiation
Biological: graft-versus-tumor induction therapy
Biological: immunosuppressive therapy

Registration Number: NCT01044745

Lead Sponsor: University of Nebraska

Brief Summary: This phase II trial is studying how well rituximab works in preventing acute graft-versus-host disease (GVHD) in patients undergoing a donor stem cell transplant for hematologic cancer. Giving chemotherapy and total-body irradiation before a donor stem cell transplant helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune 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 a monoclonal antibody, rituximab, together with anti-thymocyte globulin, tacrolimus, and mycophenolate mofetil before and after the transplant may stop this from happening

Detailed Description: PRIMARY OBJECTIVES:

I. To determine the incidence of grade II-IV acute GVHD at day 100 after matched unrelated donor allogeneic hematopoietic cell transplantation (HCT) when incorporating rituximab in the conditioning regimen.

SECONDARY OBJECTIVES:

I. To determine the day 100 transplant related mortality after matched unrelated donor allogeneic HCT when incorporating rituximab in the conditioning regimen.

II. To determine overall survival (OS) and disease-free survival (DFS) after matched unrelated donor allogeneic HCT when incorporating rituximab in the conditioning regimen.

III. To determine the cumulative incidence of infectious complications at day 100 after matched unrelated donor HCT when incorporating rituximab in the conditioning regimen.

IV. To determine the effect of rituximab addition to the conditioning regimen on recovery of T regulatory (T-reg) cells, and to determine the effect of T-cell, including T-reg, number in the stem cell product and at day 30 on the incidence of grade II-IV acute GVHD (aGVHD) and the cumulative infectious complications at day 100.

V. To determine the effect of rituximab addition to the conditioning regimen on antigen presenting myeloid cell recovery, and to determine the effect of dendritic cell subset DC1, DC2 and myeloid-derived suppressor cells (MDSC), number in the stem cell graft and at day +30 on the incidence of acute GVHD grade II-IV and the cumulative incidence of infectious complications at day 100.

OUTLINE:

CONDITIONING REGIMEN: Patients receive one of the following conditioning regimens as per the transplant physician: cyclophosphamide and total-body irradiation (TBI); targeted busulfan and fludarabine; reduced-dose busulfan and fludarabine; or fludarabine and TBI.

GRAFT-VERSUS-HOST DISEASE PROPHYLAXIS: Patients receive rituximab intravenously (IV) on days -6, 1, 8, and 15 and anti-thymocyte globulin IV over 6-8 hours on days -3 to -1. Patients also receive tacrolimus IV continuously and then orally (PO) beginning on day -1 and continuing until day 150 followed by a taper until day 180 and mycophenolate mofetil PO or IV twice daily on days -1 to 60.

TRANSPLANTATION: Patients undergo allogeneic hematopoietic stem cell transplantation on day 0.

Patients are followed up periodically for 100 days after transplant.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 20

Inclusion Criteria

Diagnosis of acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML) in accelerated phase or blast crisis, chronic lymphocytic leukemia (CLL), Non-Hodgkin lymphoma (NHL), myelodysplastic syndromes (MDS) (intermediate-2 or high-risk disease by International Pelvic Pain Society [IPPS])
Patients with AML, ALL, or MDS scheduled for myeloablative conditioning should have =< 10% blasts in bone marrow or peripheral blood at the start of conditioning
Patients with AML, ALL, or CML scheduled for reduced intensity conditioning or non-myeloablative conditioning should be in complete morphologic remission at the start of conditioning (residual disease by flow cytometry or cytogenetics and/or incomplete recovery of neutrophil or platelet count are acceptable)
Patients with CLL or NHL scheduled for reduced intensity or non-myeloablative conditioning should have no evidence of bulky disease (> 50% bone marrow involvement or masses > 10 cm) at the start of conditioning
Fulfills all pulmonary, cardiac, renal, and hepatic criteria for standard-of-care matched unrelated donor (MUD) allogeneic HCT
Men and women of reproductive potential must agree to use an acceptable method of birth control during treatment and for twelve months after stem cell transplantation
Adequately matched unrelated donor available
Written informed consent; written informed consent of the unrelated donor is required to participate in the optional studies

Exclusion Criteria

Patient or donor infected with human immunodeficiency virus (HIV)
Patient or donor with history of hepatitis B or C and/or positive serology consistent with previous hepatitis B or C infection (patients and/or donor who received Hepatitis B vaccination are acceptable)
Patient or donor with active hepatitis B or C and/or detectable viral ribonucleic acid (RNA)
More than 20,000 circulating CD20+ cells/uL
Treatment with rituximab for any reason in the 12 months preceding HCT
Patient scheduled for cord blood transplantation
Presence of active uncontrolled infection at start of conditioning
Presence of active central nervous system (CNS) disease (history of adequately treated CNS disease is acceptable)
Presence of uncontrolled psychiatric disorder
Patient unable to give informed consent
Unrelated donor products received from the Deutsche Knochenmarkspenderdatei (DKMS) Registry are not eligible for the optional study

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (Rituximab and allogeneic HCT transplant)	mycophenolate mofetil	CONDITIONING REGIMEN: Patients receive one of the following conditioning regimens as per the transplant physician: cyclophosphamide and TBI; targeted busulfan and fludarabine; reduced-dose busulfan and fludarabine; or fludarabine and TBI. GRAFT-VERSUS-HOST DISEASE PROPHYLAXIS: Patients receive rituximab IV on days -6, 1, 8, and 15 and anti-thymocyte globulin IV over 6-8 hours on days -3 to -1. Patients also receive tacrolimus IV continuously and then PO beginning on day -1 and continuing until day 150 followed by a taper until day 180 and mycophenolate mofetil PO or IV twice daily on days -1 to 60. TRANSPLANTATION: Patients undergo allogeneic hematopoietic stem cell transplantation on day 0.
Treatment (Rituximab and allogeneic HCT transplant)	total-body irradiation	CONDITIONING REGIMEN: Patients receive one of the following conditioning regimens as per the transplant physician: cyclophosphamide and TBI; targeted busulfan and fludarabine; reduced-dose busulfan and fludarabine; or fludarabine and TBI. GRAFT-VERSUS-HOST DISEASE PROPHYLAXIS: Patients receive rituximab IV on days -6, 1, 8, and 15 and anti-thymocyte globulin IV over 6-8 hours on days -3 to -1. Patients also receive tacrolimus IV continuously and then PO beginning on day -1 and continuing until day 150 followed by a taper until day 180 and mycophenolate mofetil PO or IV twice daily on days -1 to 60. TRANSPLANTATION: Patients undergo allogeneic hematopoietic stem cell transplantation on day 0.
Treatment (Rituximab and allogeneic HCT transplant)	immunosuppressive therapy	CONDITIONING REGIMEN: Patients receive one of the following conditioning regimens as per the transplant physician: cyclophosphamide and TBI; targeted busulfan and fludarabine; reduced-dose busulfan and fludarabine; or fludarabine and TBI. GRAFT-VERSUS-HOST DISEASE PROPHYLAXIS: Patients receive rituximab IV on days -6, 1, 8, and 15 and anti-thymocyte globulin IV over 6-8 hours on days -3 to -1. Patients also receive tacrolimus IV continuously and then PO beginning on day -1 and continuing until day 150 followed by a taper until day 180 and mycophenolate mofetil PO or IV twice daily on days -1 to 60. TRANSPLANTATION: Patients undergo allogeneic hematopoietic stem cell transplantation on day 0.
Treatment (Rituximab and allogeneic HCT transplant)	laboratory biomarker analysis	CONDITIONING REGIMEN: Patients receive one of the following conditioning regimens as per the transplant physician: cyclophosphamide and TBI; targeted busulfan and fludarabine; reduced-dose busulfan and fludarabine; or fludarabine and TBI. GRAFT-VERSUS-HOST DISEASE PROPHYLAXIS: Patients receive rituximab IV on days -6, 1, 8, and 15 and anti-thymocyte globulin IV over 6-8 hours on days -3 to -1. Patients also receive tacrolimus IV continuously and then PO beginning on day -1 and continuing until day 150 followed by a taper until day 180 and mycophenolate mofetil PO or IV twice daily on days -1 to 60. TRANSPLANTATION: Patients undergo allogeneic hematopoietic stem cell transplantation on day 0.
Treatment (Rituximab and allogeneic HCT transplant)	allogeneic hematopoietic stem cell transplantation	CONDITIONING REGIMEN: Patients receive one of the following conditioning regimens as per the transplant physician: cyclophosphamide and TBI; targeted busulfan and fludarabine; reduced-dose busulfan and fludarabine; or fludarabine and TBI. GRAFT-VERSUS-HOST DISEASE PROPHYLAXIS: Patients receive rituximab IV on days -6, 1, 8, and 15 and anti-thymocyte globulin IV over 6-8 hours on days -3 to -1. Patients also receive tacrolimus IV continuously and then PO beginning on day -1 and continuing until day 150 followed by a taper until day 180 and mycophenolate mofetil PO or IV twice daily on days -1 to 60. TRANSPLANTATION: Patients undergo allogeneic hematopoietic stem cell transplantation on day 0.
Treatment (Rituximab and allogeneic HCT transplant)	graft versus host disease prophylaxis/therapy	CONDITIONING REGIMEN: Patients receive one of the following conditioning regimens as per the transplant physician: cyclophosphamide and TBI; targeted busulfan and fludarabine; reduced-dose busulfan and fludarabine; or fludarabine and TBI. GRAFT-VERSUS-HOST DISEASE PROPHYLAXIS: Patients receive rituximab IV on days -6, 1, 8, and 15 and anti-thymocyte globulin IV over 6-8 hours on days -3 to -1. Patients also receive tacrolimus IV continuously and then PO beginning on day -1 and continuing until day 150 followed by a taper until day 180 and mycophenolate mofetil PO or IV twice daily on days -1 to 60. TRANSPLANTATION: Patients undergo allogeneic hematopoietic stem cell transplantation on day 0.
Treatment (Rituximab and allogeneic HCT transplant)	graft-versus-tumor induction therapy	CONDITIONING REGIMEN: Patients receive one of the following conditioning regimens as per the transplant physician: cyclophosphamide and TBI; targeted busulfan and fludarabine; reduced-dose busulfan and fludarabine; or fludarabine and TBI. GRAFT-VERSUS-HOST DISEASE PROPHYLAXIS: Patients receive rituximab IV on days -6, 1, 8, and 15 and anti-thymocyte globulin IV over 6-8 hours on days -3 to -1. Patients also receive tacrolimus IV continuously and then PO beginning on day -1 and continuing until day 150 followed by a taper until day 180 and mycophenolate mofetil PO or IV twice daily on days -1 to 60. TRANSPLANTATION: Patients undergo allogeneic hematopoietic stem cell transplantation on day 0.
Treatment (Rituximab and allogeneic HCT transplant)	anti-thymocyte globulin	CONDITIONING REGIMEN: Patients receive one of the following conditioning regimens as per the transplant physician: cyclophosphamide and TBI; targeted busulfan and fludarabine; reduced-dose busulfan and fludarabine; or fludarabine and TBI. GRAFT-VERSUS-HOST DISEASE PROPHYLAXIS: Patients receive rituximab IV on days -6, 1, 8, and 15 and anti-thymocyte globulin IV over 6-8 hours on days -3 to -1. Patients also receive tacrolimus IV continuously and then PO beginning on day -1 and continuing until day 150 followed by a taper until day 180 and mycophenolate mofetil PO or IV twice daily on days -1 to 60. TRANSPLANTATION: Patients undergo allogeneic hematopoietic stem cell transplantation on day 0.
Treatment (Rituximab and allogeneic HCT transplant)	rituximab	CONDITIONING REGIMEN: Patients receive one of the following conditioning regimens as per the transplant physician: cyclophosphamide and TBI; targeted busulfan and fludarabine; reduced-dose busulfan and fludarabine; or fludarabine and TBI. GRAFT-VERSUS-HOST DISEASE PROPHYLAXIS: Patients receive rituximab IV on days -6, 1, 8, and 15 and anti-thymocyte globulin IV over 6-8 hours on days -3 to -1. Patients also receive tacrolimus IV continuously and then PO beginning on day -1 and continuing until day 150 followed by a taper until day 180 and mycophenolate mofetil PO or IV twice daily on days -1 to 60. TRANSPLANTATION: Patients undergo allogeneic hematopoietic stem cell transplantation on day 0.
Treatment (Rituximab and allogeneic HCT transplant)	tacrolimus	CONDITIONING REGIMEN: Patients receive one of the following conditioning regimens as per the transplant physician: cyclophosphamide and TBI; targeted busulfan and fludarabine; reduced-dose busulfan and fludarabine; or fludarabine and TBI. GRAFT-VERSUS-HOST DISEASE PROPHYLAXIS: Patients receive rituximab IV on days -6, 1, 8, and 15 and anti-thymocyte globulin IV over 6-8 hours on days -3 to -1. Patients also receive tacrolimus IV continuously and then PO beginning on day -1 and continuing until day 150 followed by a taper until day 180 and mycophenolate mofetil PO or IV twice daily on days -1 to 60. TRANSPLANTATION: Patients undergo allogeneic hematopoietic stem cell transplantation on day 0.
Treatment (Rituximab and allogeneic HCT transplant)	cyclophosphamide	CONDITIONING REGIMEN: Patients receive one of the following conditioning regimens as per the transplant physician: cyclophosphamide and TBI; targeted busulfan and fludarabine; reduced-dose busulfan and fludarabine; or fludarabine and TBI. GRAFT-VERSUS-HOST DISEASE PROPHYLAXIS: Patients receive rituximab IV on days -6, 1, 8, and 15 and anti-thymocyte globulin IV over 6-8 hours on days -3 to -1. Patients also receive tacrolimus IV continuously and then PO beginning on day -1 and continuing until day 150 followed by a taper until day 180 and mycophenolate mofetil PO or IV twice daily on days -1 to 60. TRANSPLANTATION: Patients undergo allogeneic hematopoietic stem cell transplantation on day 0.
Treatment (Rituximab and allogeneic HCT transplant)	fludarabine phosphate	CONDITIONING REGIMEN: Patients receive one of the following conditioning regimens as per the transplant physician: cyclophosphamide and TBI; targeted busulfan and fludarabine; reduced-dose busulfan and fludarabine; or fludarabine and TBI. GRAFT-VERSUS-HOST DISEASE PROPHYLAXIS: Patients receive rituximab IV on days -6, 1, 8, and 15 and anti-thymocyte globulin IV over 6-8 hours on days -3 to -1. Patients also receive tacrolimus IV continuously and then PO beginning on day -1 and continuing until day 150 followed by a taper until day 180 and mycophenolate mofetil PO or IV twice daily on days -1 to 60. TRANSPLANTATION: Patients undergo allogeneic hematopoietic stem cell transplantation on day 0.
Treatment (Rituximab and allogeneic HCT transplant)	busulfan	CONDITIONING REGIMEN: Patients receive one of the following conditioning regimens as per the transplant physician: cyclophosphamide and TBI; targeted busulfan and fludarabine; reduced-dose busulfan and fludarabine; or fludarabine and TBI. GRAFT-VERSUS-HOST DISEASE PROPHYLAXIS: Patients receive rituximab IV on days -6, 1, 8, and 15 and anti-thymocyte globulin IV over 6-8 hours on days -3 to -1. Patients also receive tacrolimus IV continuously and then PO beginning on day -1 and continuing until day 150 followed by a taper until day 180 and mycophenolate mofetil PO or IV twice daily on days -1 to 60. TRANSPLANTATION: Patients undergo allogeneic hematopoietic stem cell transplantation on day 0.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Grades II-IV Acute GVHD	At day 100	Determined with death as a competing risk. Defined and staged using the 1994 consensus conference modifications of the Glucksberg criteria.

Secondary Outcome Measures

Name	Time	Method
Event-free Survival	From the date of transplant with relapse/progression or death as censored events, up to 2 years	Estimated using Kaplan-Meier estimator.
Overall Survival	From the date of transplant with death from any cause as a censored event, up to 2 years	Estimated using Kaplan-Meier estimator.
Transplant-related Mortality (TRM)	At day 100	Transplant-related mortality (TRM) defined as any mortality after transplantation except mortality from relapsed disease - Reported as a simple percentage.