Rituximab in Preventing Acute Graft-Versus-Host Disease in Patients Undergoing a Donor Stem Cell Transplant for Hematologic Cancer
Study Details
Study Description
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:
- 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:
-
To determine the day 100 transplant related mortality after matched unrelated donor allogeneic HCT when incorporating rituximab in the conditioning regimen.
-
To determine overall survival (OS) and disease-free survival (DFS) after matched unrelated donor allogeneic HCT when incorporating rituximab in the conditioning regimen.
-
To determine the cumulative incidence of infectious complications at day 100 after matched unrelated donor HCT when incorporating rituximab in the conditioning regimen.
-
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.
-
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Treatment (Rituximab and allogeneic HCT transplant) 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. |
Drug: rituximab
Given IV
Other Names:
Drug: mycophenolate mofetil
Given IV or PO
Other Names:
Drug: tacrolimus
Given IV
Other Names:
Drug: anti-thymocyte globulin
Given IV
Other Names:
Procedure: allogeneic hematopoietic stem cell transplantation
Stem cell transplant
Other: laboratory biomarker analysis
Correlative studies
Biological: graft versus host disease prophylaxis/therapy
Undergo graft versus host disease prophylaxis/therapy
Other Names:
Drug: cyclophosphamide
Given PO or IV
Other Names:
Drug: fludarabine phosphate
Given IV
Other Names:
Drug: busulfan
Given IV
Other Names:
Radiation: total-body irradiation
Undergo TBI
Other Names:
Biological: graft-versus-tumor induction therapy
Undergo graft-versus-tumor induction therapy
Other Names:
Biological: immunosuppressive therapy
Undergo immunosuppressive therapy
Other Names:
|
Outcome Measures
Primary Outcome Measures
- 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
- 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.
Eligibility Criteria
Criteria
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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of Nebraska Medical Center | Omaha | Nebraska | United States | 68198-7830 |
Sponsors and Collaborators
- University of Nebraska
- National Cancer Institute (NCI)
Investigators
- Principal Investigator: Robert Bociek, University of Nebraska
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 083-09
- NCI-2009-01552
- P30CA036727
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Treatment (Rituximab and Allogeneic HCT Transplant) |
|---|---|
| Arm/Group Description | CONDITIONING REGIMEN: Cyclophosphamide and TBI; targeted busulfan and fludarabine; reduced-dose busulfan and fludarabine; or fludarabine and TBI. GRAFT-VERSUS-HOST DISEASE PROPHYLAXIS: Rituximab IV days -6, 1, 8, and 15 and anti-thymocyte globulin IV over 6-8 hours on days -3 to -1. 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: Allogeneic hematopoietic stem cell transplantation on day 0. laboratory biomarker analysis: Correlative studies graft versus host disease prophylaxis/therapy: Undergo graft versus host disease prophylaxis/therapy cyclophosphamide: Given PO or IV fludarabine phosphate: Given IV busulfan: Given IV total-body irradiation: Undergo TBI graft-versus-tumor induction therapy: Undergo graft-versus-tumor induction therapy immunosuppressive therapy: Undergo immunosuppressive therapy |
| Period Title: Overall Study | |
| STARTED | 20 |
| COMPLETED | 18 |
| NOT COMPLETED | 2 |
Baseline Characteristics
| Arm/Group Title | Treatment (Rituximab and Allogeneic HCT Transplant) |
|---|---|
| Arm/Group Description | CONDITIONING REGIMEN: Cyclophosphamide and TBI; targeted busulfan and fludarabine; reduced-dose busulfan and fludarabine; or fludarabine and TBI. GRAFT-VERSUS-HOST DISEASE PROPHYLAXIS: Rituximab IV days -6, 1, 8, and 15 and anti-thymocyte globulin IV over 6-8 hours on days -3 to -1. 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: Allogeneic hematopoietic stem cell transplantation on day 0. laboratory biomarker analysis: Correlative studies graft versus host disease prophylaxis/therapy: Undergo graft versus host disease prophylaxis/therapy cyclophosphamide: Given PO or IV fludarabine phosphate: Given IV busulfan: Given IV total-body irradiation: Undergo TBI graft-versus-tumor induction therapy: Undergo graft-versus-tumor induction therapy immunosuppressive therapy: Undergo immunosuppressive therapy |
| Overall Participants | 20 |
| Age (years) [Median (Full Range) ] | |
| Median (Full Range) [years] |
39
|
| Sex: Female, Male (Count of Participants) | |
| Female |
11
55%
|
| Male |
9
45%
|
| Region of Enrollment (participants) [Number] | |
| United States |
20
100%
|
Outcome Measures
| Title | Number of Participants With Grades II-IV Acute GVHD |
|---|---|
| Description | Determined with death as a competing risk. Defined and staged using the 1994 consensus conference modifications of the Glucksberg criteria. |
| Time Frame | At day 100 |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Treatment (Rituximab and Allogeneic HCT Transplant) |
|---|---|
| Arm/Group Description | CONDITIONING REGIMEN: Cyclophosphamide and TBI; targeted busulfan and fludarabine; reduced-dose busulfan and fludarabine; or fludarabine and TBI. GRAFT-VERSUS-HOST DISEASE PROPHYLAXIS: Rituximab IV days -6, 1, 8, and 15 and anti-thymocyte globulin IV over 6-8 hours on days -3 to -1. 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: Allogeneic hematopoietic stem cell transplantation on day 0. laboratory biomarker analysis: Correlative studies graft versus host disease prophylaxis/therapy: Undergo graft versus host disease prophylaxis/therapy cyclophosphamide: Given PO or IV fludarabine phosphate: Given IV busulfan: Given IV total-body irradiation: Undergo TBI graft-versus-tumor induction therapy: Undergo graft-versus-tumor induction therapy immunosuppressive therapy: Undergo immunosuppressive therapy |
| Measure Participants | 20 |
| Count of Participants [Participants] |
16
80%
|
| Title | Event-free Survival |
|---|---|
| Description | Estimated using Kaplan-Meier estimator. |
| Time Frame | From the date of transplant with relapse/progression or death as censored events, up to 2 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Treatment (Rituximab and Allogeneic HCT Transplant) |
|---|---|
| Arm/Group Description | CONDITIONING REGIMEN: Cyclophosphamide and TBI; targeted busulfan and fludarabine; reduced-dose busulfan and fludarabine; or fludarabine and TBI. GRAFT-VERSUS-HOST DISEASE PROPHYLAXIS: Rituximab IV days -6, 1, 8, and 15 and anti-thymocyte globulin IV over 6-8 hours on days -3 to -1. 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: Allogeneic hematopoietic stem cell transplantation on day 0. laboratory biomarker analysis: Correlative studies graft versus host disease prophylaxis/therapy: Undergo graft versus host disease prophylaxis/therapy cyclophosphamide: Given PO or IV fludarabine phosphate: Given IV busulfan: Given IV total-body irradiation: Undergo TBI graft-versus-tumor induction therapy: Undergo graft-versus-tumor induction therapy immunosuppressive therapy: Undergo immunosuppressive therapy |
| Measure Participants | 18 |
| Median (Full Range) [months] |
12
|
| Title | Overall Survival |
|---|---|
| Description | Estimated using Kaplan-Meier estimator. |
| Time Frame | From the date of transplant with death from any cause as a censored event, up to 2 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Treatment (Rituximab and Allogeneic HCT Transplant) |
|---|---|
| Arm/Group Description | CONDITIONING REGIMEN: Cyclophosphamide and TBI; targeted busulfan and fludarabine; reduced-dose busulfan and fludarabine; or fludarabine and TBI. GRAFT-VERSUS-HOST DISEASE PROPHYLAXIS: Rituximab IV days -6, 1, 8, and 15 and anti-thymocyte globulin IV over 6-8 hours on days -3 to -1. 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: Allogeneic hematopoietic stem cell transplantation on day 0. laboratory biomarker analysis: Correlative studies graft versus host disease prophylaxis/therapy: Undergo graft versus host disease prophylaxis/therapy cyclophosphamide: Given PO or IV fludarabine phosphate: Given IV busulfan: Given IV total-body irradiation: Undergo TBI graft-versus-tumor induction therapy: Undergo graft-versus-tumor induction therapy immunosuppressive therapy: Undergo immunosuppressive therapy |
| Measure Participants | 18 |
| Median (Full Range) [months] |
12
|
| Title | Transplant-related Mortality (TRM) |
|---|---|
| Description | Transplant-related mortality (TRM) defined as any mortality after transplantation except mortality from relapsed disease - Reported as a simple percentage. |
| Time Frame | At day 100 |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Treatment (Rituximab and Allogeneic HCT Transplant) |
|---|---|
| Arm/Group Description | 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. rituximab: Given IV mycophenolate mofetil: Given IV or PO tacrolimus: Given IV anti-thymocyte globulin: Given IV allogeneic hematopoietic stem cell transplantation laboratory biomarker analysis: Correlative studies graft versus host disease prophyla |
| Measure Participants | 18 |
| Count of Participants [Participants] |
0
0%
|
Adverse Events
| Time Frame | ||
|---|---|---|
| Adverse Event Reporting Description | ||
| Arm/Group Title | Treatment (Rituximab and Allogeneic HCT Transplant) | |
| Arm/Group Description | CONDITIONING REGIMEN: Cyclophosphamide and TBI; targeted busulfan and fludarabine; reduced-dose busulfan and fludarabine; or fludarabine and TBI. GRAFT-VERSUS-HOST DISEASE PROPHYLAXIS: Rituximab IV days -6, 1, 8, and 15 and anti-thymocyte globulin IV over 6-8 hours on days -3 to -1. 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: Allogeneic hematopoietic stem cell transplantation on day 0. laboratory biomarker analysis: Correlative studies graft versus host disease prophylaxis/therapy: Undergo graft versus host disease prophylaxis/therapy cyclophosphamide: Given PO or IV fludarabine phosphate: Given IV busulfan: Given IV total-body irradiation: Undergo TBI graft-versus-tumor induction therapy: Undergo graft-versus-tumor induction therapy immunosuppressive therapy: Undergo immunosuppressive therapy | |
All Cause Mortality |
||
| Treatment (Rituximab and Allogeneic HCT Transplant) | ||
| Affected / at Risk (%) | # Events | |
| Total | 5/20 (25%) | |
Serious Adverse Events |
||
| Treatment (Rituximab and Allogeneic HCT Transplant) | ||
| Affected / at Risk (%) | # Events | |
| Total | 10/20 (50%) | |
| Gastrointestinal disorders | ||
| Diarrhea | 3/20 (15%) | 3 |
| vomiting | 1/20 (5%) | 1 |
| anorexia | 1/20 (5%) | 1 |
| mucositis oral | 1/20 (5%) | 1 |
| ileus | 1/20 (5%) | 1 |
| dehydration | 1/20 (5%) | 1 |
| Hepatobiliary disorders | ||
| thrombotic event | 1/20 (5%) | 1 |
| Immune system disorders | ||
| Immune system disorders-other | 2/20 (10%) | 2 |
| Infections and infestations | ||
| pneumonitis | 3/20 (15%) | 3 |
| sepsis | 3/20 (15%) | 3 |
| urinary tract infection | 1/20 (5%) | 1 |
| cystitis | 3/20 (15%) | 3 |
| Renal and urinary disorders | ||
| acute kidney injury | 3/20 (15%) | 3 |
| hematuria | 1/20 (5%) | 1 |
Other (Not Including Serious) Adverse Events |
||
| Treatment (Rituximab and Allogeneic HCT Transplant) | ||
| Affected / at Risk (%) | # Events | |
| Total | 16/20 (80%) | |
| Blood and lymphatic system disorders | ||
| Febrile Neutropenia | 3/20 (15%) | 3 |
| Gastrointestinal disorders | ||
| Ascites | 1/20 (5%) | 1 |
| Mucositis - oral | 3/20 (15%) | 3 |
| Diarrhea | 1/20 (5%) | 1 |
| Nausea | 1/20 (5%) | 1 |
| General disorders | ||
| Altered mental status | 1/20 (5%) | 1 |
| Immune system disorders | ||
| Immune-system disorders- Other | 2/20 (10%) | 3 |
| Infections and infestations | ||
| Rash | 2/20 (10%) | 2 |
| Infection and infestation - Other | 1/20 (5%) | 1 |
| Sepsis | 5/20 (25%) | 8 |
| Skin infection | 1/20 (5%) | 1 |
| sinusitis | 1/20 (5%) | 1 |
| Lung infection | 2/20 (10%) | 2 |
| Urinary tract infection | 1/20 (5%) | 1 |
| Bladder infection | 1/20 (5%) | 1 |
| Investigations | ||
| creatinine increased | 1/20 (5%) | 1 |
| Weight loss | 1/20 (5%) | 1 |
| blood bilirubin increased | 2/20 (10%) | 2 |
| Alanin amintransferase increased | 1/20 (5%) | 1 |
| Aspartate aminotransferase | 1/20 (5%) | 1 |
| Metabolism and nutrition disorders | ||
| Hypokalemia | 7/20 (35%) | 15 |
| Hyponatremia | 5/20 (25%) | 6 |
| Hyperglycemia | 8/20 (40%) | 14 |
| Hypophosphatemia | 4/20 (20%) | 6 |
| dehydration | 1/20 (5%) | 1 |
| Anorexia | 3/20 (15%) | 3 |
| Hypoalbuminemia | 4/20 (20%) | 8 |
| Hypocalcemia | 2/20 (10%) | 13 |
| Musculoskeletal and connective tissue disorders | ||
| Muscle weakness | 1/20 (5%) | 1 |
| Skin and subcutaneous tissue disorders | ||
| Palmar-plantar erythrodysesthesia syndrome | 1/20 (5%) | 1 |
| Vascular disorders | ||
| Thromboembolic event | 2/20 (10%) | 2 |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | R. Gregory Bociek, MD |
|---|---|
| Organization | University of Nebraska Medical Center |
| Phone | 402-559-5388 |
| rgbociek@unmc.edu |
- 083-09
- NCI-2009-01552
- P30CA036727