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CONDITIONING: Patients receive fludarabine phosphate IV over 30 minutes on days -4 to -2. Patients also undergo total-body irradiation on day 0.

TRANSPLANTATION: Patients undergo allogeneic peripheral blood stem cell transplantation.

IMMUNOSUPPRESSION: Patients receive sirolimus PO QD on days -3 to 180 with taper to day 365; cyclosporine PO BID on days -3 to 150 with taper to day 180; and mycophenolate mofetil PO TID on days 0-30 and then BID to day 100 with taper to day 150.

Undergo allogeneic peripheral blood stem cell transplant

Allogeneic Hematopoietic Stem Cell Transplantation

Fludarabine Phosphate

Laboratory Biomarker Analysis

Mycophenolate Mofetil

Peripheral Blood Stem Cell Transplantation

Total-Body Irradiation

Brenda Sandmaier

This phase II trial studies how well sirolimus, cyclosporine and mycophenolate mofetil works in preventing graft-vs-host disease (GVHD) in patients with blood cancer undergoing donor peripheral blood stem cell (PBSC) transplant. Giving chemotherapy and total-body irradiation before a donor peripheral blood 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. 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 together with sirolimus, cyclosporine, and mycophenolate mofetil before and after transplant may stop this from happening.

PRIMARY OBJECTIVES:

I. To determine whether the incidence of acute GVHD grades II-IV can be reduced to less than the historical rate of 70% with the triple-immunosuppressant combination of cyclosporine (CSP)/mycophenolate mofetil (MMF) with sirolimus in human leukocyte antigens (HLA) class I or class II mismatched related or unrelated donor hematopoietic cell transplantation (HCT) using nonmyeloablative conditioning. The evaluation will be carried out separately among class I and class II mismatched patients.

SECONDARY OBJECTIVES:

I. To evaluate the incidence of non-relapse mortality before day 100.

II. To evaluate the incidences of grades III-IV acute GVHD.

OUTLINE:

CONDITIONING: Patients receive fludarabine phosphate intravenously (IV) over 30 minutes on days -4 to -2. Patients also undergo total-body irradiation on day 0.

TRANSPLANTATION: Patients undergo allogeneic peripheral blood stem cell transplantation.

IMMUNOSUPPRESSION: Patients receive sirolimus orally (PO) once daily (QD) on days -3 to 180 with taper to day 365; cyclosporine PO twice daily (BID) on days -3 to 150 with taper to day 180; and mycophenolate mofetil PO thrice daily (TID) on days 0-30 and then BID to day 100 with taper to day 150.

After completion of study treatment, patients are followed up at 6 months and every year thereafter.

Sirolimus, Cyclosporine, and Mycophenolate Mofetil in Preventing Graft-versus-Host Disease in Treating Patients With Blood Cancer Undergoing Donor Peripheral Blood Stem Cell Transplant

A Phase II Study to Assess Immunosuppression With Sirolimus Combined With Cyclosporine (CSP) and Mycophenolate Mofetil (MMF) for Prevention of Acute GVHD After Non-Myeloablative HLA Class I or II Mismatched Donor Hematopoietic Cell Transplantation- A Multi-Center Trial

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

Number of patients expired without disease progression/relapse.

Number of patients with grades III-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

National Cancer Institute (NCI)

Fred Hutchinson Cancer Center

CONDITIONING: Patients receive fludarabine phosphate IV over 30 minutes on days -4 to -2. Patients also undergo total-body irradiation on day 0.

TRANSPLANTATION: Patients undergo allogeneic peripheral blood stem cell transplantation.

IMMUNOSUPPRESSION: Patients receive sirolimus PO QD on days -3 to 180 with taper to day 365; cyclosporine PO BID on days -3 to 150 with taper to day 180; and mycophenolate mofetil PO TID on days 0-30 and then BID to day 100 with taper to day 150.

Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplant

Cyclosporine: Given PO or IV

Fludarabine Phosphate: Given IV

Laboratory Biomarker Analysis: Correlative studies

Mycophenolate Mofetil: Given PO

Peripheral Blood Stem Cell Transplantation: Undergo allogeneic peripheral blood stem cell transplant

Sirolimus: Given PO

Total-Body Irradiation: Undergo total-body irradiation

Treatment (Fludarabine, Transplant, Immunosuppression)

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Denmark

Region of Enrollment

Dr. Brenda M. Sandmaier

Patients 1) mismatched at antigen level for any single class I locus (HLA-A, -B, -C) +/- an additional class mismatch at the allele level, or 2) mismatched at the allele level for any 2 class I loci.

Class I Mismatch

Patients mismatched at the antigen or allele level for class II loci HLA-DRB1 and/or DQB1. Must be matched for at least one DRB1 allele and one DQB1 allele.

Class II Mismatch

Number of Patients With Grade II-IV Acute Graft Versus Host Disease (GVHD)

One subject aborted transplant during conditioning and was counted towards accrual but not evaluated with respect to outcome measures.

Number of Non-Relapse Mortalities

Number of Patients With Grade III-IV Acute GVHD

Overall Study

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Sirolimus, Cyclosporine, and Mycophenolate Mofetil in Preventing Graft-versus-Host Disease in Treating Patients With Blood Cancer Undergoing Donor Peripheral Blood Stem Cell Transplant	NCT01251575	Adult Acute Lym... Adult Acute Mye... Adult Diffuse L... Adult Myelodysp... Adult Non-Hodgk... Aggressive Non-... Childhood Acute... Childhood Acute... Childhood Diffu... Childhood Myelo... Childhood Non-H... Chronic Lymphoc... Chronic Lymphoc... Chronic Phase C... Hematopoietic a... Mantle Cell Lym... Plasma Cell Mye... Prolymphocytic ... Recurrent Chron... Refractory Chro... T-Cell Prolymph... Waldenstrom Mac... Recurrent Diffu... Recurrent Hodgk...	Allogeneic Hema... Cyclosporine Fludarabine Pho... Laboratory Biom... Mycophenolate M... Peripheral Bloo... Sirolimus Total-Body Irra...	-	Fred Hutchinson Cancer Center
Sirolimus, Cyclosporine, and Mycophenolate Mofetil in Preventing Graft-versus-Host Disease in Treating Patients With Blood Cancer Undergoing Donor Peripheral Blood Stem Cell Transplant	NCT01251575	Adult Acute Lym... Adult Acute Mye... Adult Diffuse L... Adult Myelodysp... Adult Non-Hodgk... Aggressive Non-... Childhood Acute... Childhood Acute... Childhood Diffu... Childhood Myelo... Childhood Non-H... Chronic Lymphoc... Chronic Lymphoc... Chronic Phase C... Hematopoietic a... Mantle Cell Lym... Plasma Cell Mye... Prolymphocytic ... Recurrent Chron... Refractory Chro... T-Cell Prolymph... Waldenstrom Mac... Recurrent Diffu... Recurrent Hodgk...	Allogeneic Hema... Cyclosporine Fludarabine Pho... Laboratory Biom... Mycophenolate M... Peripheral Bloo... Sirolimus Total-Body Irra...	-	Fred Hutchinson Cancer Center

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