A Randomized Phase III Study to Determine the Most Promising Postgrafting Immunosuppression for Prevention of Acute GVHD After Unrelated Donor Hematopoietic Cell Transplantation Using Nonmyeloablative Conditioning for Patients With Hematologic Malignancies: A Multi-center Trial
Overview
- Phase
- Phase 3
- Status
- Completed
- Enrollment
- 174
- Locations
- 11
- Primary Endpoint
- Number of Patients With Grades II-IV Acute GVHD
Overview
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.
Detailed Description
PRIMARY OBJECTIVES:
I. To compare the effectiveness of 2 GVHD prophylaxis regimens in preventing acute grades II-IV GVHD.
SECONDARY OBJECTIVES:
I. Compare non-relapse mortality in the 2 arms.
II. Compare survival and progression-free survivals in the 2 arms.
OUTLINE: Patients are randomized to 1 of 2 treatment arms.
All patients receive FLU intravenously (IV) over 30 minutes on days -4 to -2 followed by 2-3 Gy TBI on day 0.
ARM 0: 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
ARM I: Patients receive CSP orally (PO) twice daily (BID) on days -3 to 96 with taper to day 150 and MMF PO three times daily (TID) on days 0-29 and then BID on days 30-150 with taper to day 180.
ARM II: Patients receive CSP as in Arm I and sirolimus PO once daily (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.
TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0 following the TBI.
After completion of study treatment, patients are followed up periodically.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Ages \> 50 years with hematologic malignancies treatable by unrelated hematopoietic cell transplant (HCT)
- •Ages =\< 50 years of age with hematologic diseases treatable by allogeneic HCT who through pre-existing medical conditions or prior therapy are considered to be at high risk for regimen related toxicity associated with a high dose transplant (\> 40% risk of transplant related mortality \[TRM\]); this criterion can include patients with a HCT-comorbidity index (CI) score of \>= 1; transplants should be approved for these inclusion criteria by the principal investigators at the collaborating centers and at the Fred Hutchinson Cancer Research Center (FHCRC); all children \< 12 years must be discussed with the FHCRC principal investigator (PI) prior to registration
- •Ages =\< 50 years of age with chronic lymphocytic leukemia (CLL)
- •Ages =\< 50 years of age with hematologic diseases treatable by allogeneic HCT who refuse a high-dose HCT; transplants must be approved for these inclusion criteria by the principal investigators at the collaborating centers and at FHCRC
- •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);
Exclusion Criteria
- •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
- •Patients with active non-hematological malignancies (except non-melanoma skin cancers) or those with non-hematological malignancies (except non-melanoma skin cancers) who have been rendered with no evidence of disease, but have a greater than 20% chance of having disease recurrence within 5 years; this exclusion does not apply to patients with non-hematologic malignancies that do not require therapy
- •Fungal infections with radiological progression after receipt of amphotericin B or active triazole for greater than 1 month
Arms & Interventions
Arm I (MMF and CSP)
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.
Intervention: Allogeneic Hematopoietic Stem Cell Transplantation (Procedure)
Arm I (MMF and CSP)
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.
Intervention: Cyclosporine (Drug)
Arm I (MMF and CSP)
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.
Intervention: Fludarabine Phosphate (Drug)
Arm I (MMF and CSP)
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.
Intervention: Mycophenolate Mofetil (Drug)
Arm I (MMF and CSP)
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.
Intervention: Peripheral Blood Stem Cell Transplantation (Procedure)
Arm I (MMF and CSP)
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.
Intervention: Total-Body Irradiation (Radiation)
Arm II (MMF, CSP, and Sirolimus)
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.
Intervention: Allogeneic Hematopoietic Stem Cell Transplantation (Procedure)
Arm II (MMF, CSP, and Sirolimus)
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.
Intervention: Cyclosporine (Drug)
Arm II (MMF, CSP, and Sirolimus)
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.
Intervention: Fludarabine Phosphate (Drug)
Arm II (MMF, CSP, and Sirolimus)
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.
Intervention: Mycophenolate Mofetil (Drug)
Arm II (MMF, CSP, and Sirolimus)
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.
Intervention: Peripheral Blood Stem Cell Transplantation (Procedure)
Arm II (MMF, CSP, and Sirolimus)
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.
Intervention: Sirolimus (Drug)
Arm II (MMF, CSP, and Sirolimus)
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.
Intervention: Total-Body Irradiation (Radiation)
Arm 0 (CSP and Sirolimus)
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
Intervention: Allogeneic Hematopoietic Stem Cell Transplantation (Procedure)
Arm 0 (CSP and Sirolimus)
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
Intervention: Cyclosporine (Drug)
Arm 0 (CSP and Sirolimus)
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
Intervention: Fludarabine Phosphate (Drug)
Arm 0 (CSP and Sirolimus)
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
Intervention: Peripheral Blood Stem Cell Transplantation (Procedure)
Arm 0 (CSP and Sirolimus)
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
Intervention: Sirolimus (Drug)
Arm 0 (CSP and Sirolimus)
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
Intervention: Total-Body Irradiation (Radiation)
Outcomes
Primary Outcomes
Number of Patients With Grades II-IV Acute GVHD
Time Frame: At day 100 post-transplant
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
Secondary Outcomes
- Number of Non-Relapse Mortalities(Up to 1 year)
- Number of Participants With Relapse/Progression(Up to 1 year)
- Number of of Participants Surviving Overall(Up to 1 year)
- Number of Patients With Chronic Extensive GVHD(Up to 1 year)
- Number of Patients With Grades III-IV Acute GVHD(Up to 100 days)
Investigators
Brenda Sandmaier
Principal Investigator
Fred Hutchinson Cancer Center