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Antineoplastic Agents

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REDUCED-INTENSITY CONDITIONING: Patients receive fludarabine phosphate IV on days -4, -3, and -2 and undergo TBI on day 0.

TRANSPLANT: Patients undergo allogeneic PBSCT on day 0.

IMMUNOSUPPRESSION: Patients receive cyclosporine PO BID on days -3 to 100 with taper to day 177 and mycophenolate mofetil PO every 8 hours on days 0-40 with taper to day 96.

Fludarabine Phosphate

Total-Body Irradiation

Peripheral Blood Stem Cell Transplantation

Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation

Mycophenolate Mofetil

Brenda Sandmaier

This phase I/II trial studies whether a new kind of blood stem cell (bone marrow) transplant, that may be less toxic, is able to treat underlying blood cancer. Stem cells are "seed cells" necessary to make blood cells. Researchers want to see if using less radiation and less chemotherapy with new immune suppressing drugs will enable a stem cell transplant to work. Researchers are hoping to see a mixture of recipient and donor stem cells after transplant. This mixture of donor and recipient stem cells is called "mixed-chimerism". Researchers hope to see these donor cells eliminate tumor cells. This is called a "graft-versus-leukemia" response.

PRIMARY OBJECTIVES:

I. To determine whether stable unrelated peripheral blood stem cell (PBSC) grafts can be safely established using nonmyeloablative pretransplant conditioning with intensified post-grafting immunosuppression and with every (q) 8 hours (hr) and possibly q 6 hr mycophenolate mofetil (MMF) dosing in patients with hematologic malignancies and renal cell carcinoma.

II. To determine if the incidence and severity of acute grades II-IV graft-versus-host disease (GVHD) can be reduced in patients with sustained engraftment with the use of q 8 hr MMF dosing.

SECONDARY OBJECTIVES:

I. To determine if engraftment can be maintained in patients with low chimerism and high risk of rejection with the use of a single dose of fludarabine (fludarabine phosphate) followed by donor lymphocyte infusion (DLI) on continued MMF/cyclosporine (CSP).

II. To compare survival and disease free survival to those achieved under protocol 1463.

OUTLINE:

REDUCED-INTENSITY CONDITIONING: Patients receive fludarabine phosphate intravenously (IV) on days -4, -3, and -2 and undergo total-body irradiation (TBI) on day 0.

TRANSPLANT: Patients undergo allogeneic peripheral blood stem cell transplant (PBSCT) on day 0.

IMMUNOSUPPRESSION: Patients receive cyclosporine orally (PO) twice daily (BID) on days -3 to 100 with taper to day 177 and mycophenolate mofetil PO every 8 hours on days 0-40 with taper to day 96.

After completion of study treatment, patients are followed up at 6 months, 1 year, 1.5 years, 2 years, and then annually thereafter.

Total-Body Irradiation and Fludarabine Phosphate Followed by Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Hematologic Malignancies or Kidney Cancer

Low-Dose TBI and Fludarabine Followed by Nonmyeloablative Unrelated Donor Peripheral Blood Stem Cell Transplantation Using Enhanced Postgrafting Immunosuppression for Patients With Hematologic Malignancies and Renal Cell Carcinoma - A Multi-center Trial

The goal is to reduce the risk in patients without preceding chemotherapy to \< 20% and with preceding chemotherapy to \< 10%.

The goal is to reduce the incidence of grades II-IV acute GVHD from 50% to less than 35% in patients with sustained engraftment by increasing the dosing of MMF to every 8 hours. The impact of the enhanced post-grafting immunosuppression on objective measures of GVHD will be described. These include doses and duration of immunosuppression (in particular corticosteroids) and number of GVHD treatment regimens used within the first year. These parameters will be compared to the results of protocol 1463.

The secondary objective of reversing pending graft rejection with fludarabine phosphate and DLI will be evaluated in the context of overall engraftment. The number of patients given DLI in this context is expected to be small. The response to DLI will be followed and reported in a descriptive manner. The effect of this intervention on adverse outcomes will be followed.

National Heart, Lung, and Blood Institute (NHLBI)

National Cancer Institute (NCI)

Fred Hutchinson Cancer Center

Leukemia, Prolymphocytic

Leukemia, Prolymphocytic, T-Cell

Waldenstrom Macroglobulinemia

Leukemia, Prolymphocytic, B-Cell

Leukemia, T-Cell

T-cell Prolymphocytic Leukemia

B Cell Prolymphocytic Leukemia

Amino Acids

Etoposide

Cytarabine

Cyclophosphamide

Melphalan

Tacrolimus

Etoposide phosphate

Podophyllotoxin

Carmustine

Mechlorethamine

Nitrogen Mustard Compounds

Antineoplastic Agents, Alkylating

Alkylating Agents

Antiviral Agents

Keratolytic Agents

Tubulin Modulators

Antimitotic Agents

Phenylalanine

Alanine

Allogeneic Bone Marrow Transplantation

Allogeneic Hematopoietic Stem Cell Transplantation

Autologous Hematopoietic Stem Cell Transplantation

Autologous-Allogeneic Tandem Hematopoietic Stem Cell Transplantation

Laboratory Biomarker Analysis

Mohamed Sorror

This phase II trial studies autologous peripheral blood stem cell transplant followed by donor bone marrow transplant in treating patients with high-risk Hodgkin lymphoma, non-Hodgkin lymphoma, multiple myeloma, or chronic lymphocytic leukemia. Autologous stem cell transplantation uses the patient's stem cells and does not cause graft versus host disease (GVHD) and has a very low risk of death, while minimizing the number of cancer cells. Peripheral blood stem cell (PBSC) transplant uses stem cells from the patient or a donor and may be able to replace immune cells that were destroyed by chemotherapy. These donated stem cells may help destroy cancer cells. Bone marrow transplant known as a nonmyeloablative transplant uses stem cells from a haploidentical family donor. Autologous peripheral blood stem cell transplant followed by donor bone marrow transplant may work better in treating patients with high-risk Hodgkin lymphoma, non-Hodgkin lymphoma, multiple myeloma, or chronic lymphocytic leukemia.

PRIMARY OBJECTIVES:

I. Event-free survival (EFS) at 1-year after autograft.

SECONDARY OBJECTIVES:

I. Relapse rates at 1-year after autograft.

II. Overall survival (OS) at 1-year after autograft.

III. Incidence of grades II-IV acute GVHD and chronic extensive GVHD.

IV. Non-relapse mortality (NRM) at 200 days and 1 year after allograft.

V. Donor engraftment at day +84.

VI. Incidence of infections.

OUTLINE:

CONDITIONING REGIMEN 1 (lymphoma, Waldenstrom macroglobulinemia, or chronic lymphocytic leukemia \[CLL\] with no dose limiting radiation or significant comorbidities: Patients receive cyclophosphamide intravenously (IV) on days -6 and -5. Patients undergo high-dose total body irradiation (TBI) twice daily (BID) on days -3 to -1.

CONDITIONING REGIMEN 2 (lymphoma, Waldenstrom Macroglobulinemia, CLL, with prior dose-limiting radiation, or significant comorbidities): Patients receive carmustine IV on day -7, etoposide IV BID on days -6 to -3, cytarabine IV BID on days -6 to -3, and melphalan IV on day -2.

CONDITIONING REGIMEN 3 (multiple myeloma or plasma cell leukemia, with no significant renal insufficiency or other significant comorbidities): Patients receive high-dose melphalan IV on day -2.

CONDITIONING REGIMEN 4 (multiple myeloma or plasma cell leukemia, with significant renal insufficiency or other significant comorbidities): Patients receive lessened dose of melphalan IV on day -2.

PBSC TRANSPLANTATION: All patients undergo autologous PBSC transplantation on day 0.

WAITING INTERVAL: Between 40 and 120 days.

NONMYELOABLATIVE CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV once daily (QD) on days -6 to -2 and cyclophosphamide IV QD on days -6 to -5 and day 3. Patients infused with donor's peripheral blood stem cells will additionally receive cyclophosphamide IV on day 4. Patients undergo low-dose TBI on day -1.

ALLOGENEIC BONE MARROW TRANSPLANTATION: Patients undergo donor bone marrow transplantation on day 0.

GRAFT VERSUS HOST DISEASE PROPHYLAXIS: Beginning on day 4, patients receive tacrolimus orally (PO) or IV and taper beginning on day 86 if no graft-versus-host disease. Patients also receive mycophenolate mofetil PO thrice daily (TID) on days 4 - 35.

PERIPHERAL BLOOD COUNT SUPPORT: Patients receive filgrastim (G-CSF) IV or subcutaneously (SC) beginning from day 4 and continue till blood counts recover.

ALLOGENEIC PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMC) TRANSPLANTATION: Patients undergo donor PBMC transplantation on day 0.

GRAFT VERSUS HOST DISEASE PROPHYLAXIS: Beginning on day 5, patients receive tacrolimus orally (PO) or IV and taper beginning on day 86 if no graft-versus-host disease. Patients also receive mycophenolate mofetil PO thrice daily (TID) on days 5 - 35.

PERIPHERAL BLOOD COUNT SUPPORT: Patients receive filgrastim IV or SC beginning from day 5 and continue till blood counts recover.

After completion of study treatment, patients are followed up annually for 5 years.

Autologous Peripheral Blood Stem Cell Transplant Followed by Donor Bone Marrow Transplant in Treating Patients With High-Risk Hodgkin Lymphoma, Non-Hodgkin Lymphoma, Multiple Myeloma, or Chronic Lymphocytic Leukemia

Sequential Autologous HCT / Nonmyeloablative Allogeneic HCT Using Related, HLA-Haploidentical Donors for Patients With High-Risk Lymphoma, Multiple Myeloma, or Chronic Lymphocytic Leukemia

Number of patients surviving without relapsed/progressive disease

Relapse/Progression defined as:

Nodes, liver, and/or spleen ≥50% increased or new by physical exam / imaging studies.

Circulating lymphocytes ≥50% increased by morphology and/or flow cytometry. Richter's transformation by lymph node biopsy .

Number of patients surviving one year post-autograft

aGVHD The diagnosis of aGVHD is identified through various stages and grading of the disease related to Skin (Rash), Gut (Diarrhea, Nausea/vomiting and/or anorexia) and the liver (Bilirubin) assessed by severity and grading scale outlined in the section Grafts vs Hosts by Sullivan (1999).

GVHD Grades Grade I: 1-2 Skin Rash; No gut or liver involvement Grade II: Stage 1-3 Skin rash; Stage 1 gut and/or stage 1 liver involvement Grade III: Stage 2-4 gut involvement and/or stage 2-4 liver involvement with or without rash Grade IV: Pattern and severity of GVHD similar to grade 3 with extreme constitutional symptoms or death

CGVHD The diagnosis of cGVHD requires at least one manifestation that is distinctive for chronic GVHD as opposed to acute GVHD. In all cases, infection and others causes must be ruled out in the differential diagnosis of chronic GVHD.

Number of patients with non-relapse mortalities.

Number of patients with donor engraftment.

Allogeneic Bone Marrow Transplantation: Undergo donor HCT

Allogeneic Hematopoietic Stem Cell Transplantation: Undergo donor HCT

Autologous Hematopoietic Stem Cell Transplantation: Undergo autologous PBSC transplant

Autologous-Allogeneic Tandem Hematopoietic Stem Cell Transplantation: Undergo autologous-donor tandem HCT

Carmustine: Given IV

Cyclophosphamide: Given IV

Cytarabine: Given IV

Etoposide: Given IV

Fludarabine Phosphate: Given IV

Laboratory Biomarker Analysis: Correlative study

Melphalan: Given IV

Mycophenolate Mofetil: Given PO

Peripheral Blood Stem Cell Transplantation: Undergo donor HCT

Tacrolimus: Given IV or PO

Total-Body Irradiation: Undergo TBI

Treatment (Autologous HCT, Donor HCT)

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Dr. Mohamed L. Sorror

Event-Free Survival (EFS)

Number of Patients With Relapsed/Progressive Disease

Overall Survival

Acute Graft-versus-Host-Disease

Chronic extensive Graft-versus-Host-Disease

Two patients are not evaluable for Graft-versus-Host-Disease due to disease progression; they failed the study and did not receive the allogeneic transplantation.

Number of Patients With Grade II-IV Acute Graft-versus-Host-Disease and/or Chronic Extensive Graft-versus-Host-Disease

200 days

1 Year

Two patients are not evaluable for GVHD due to disease progression; they failed the study and did not receive the allogeneic transplantation.

Non-relapse Mortality (NRM)

Number of Patients Who Engrafted

Number of Patients Who Had Infections

Overall Study

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Total-Body Irradiation and Fludarabine Phosphate Followed by Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Hematologic Malignancies or Kidney Cancer	NCT00027820	Adult Acute Mye... Childhood Acute... Childhood Acute... Childhood Myelo... Childhood Renal... Chronic Myelomo... Clear Cell Rena... de Novo Myelody... Metastatic Rena... Previously Trea... Progression of ... Recurrent Adult... Recurrent Adult... Recurrent Adult... Recurrent Adult... Recurrent Adult... Recurrent Child... Recurrent Child... Recurrent Child... Recurrent Child... Refractory Anem... Refractory Anem... Refractory Chil... Refractory Chro... Renal Medullary... Type 1 Papillar... Type 2 Papillar... Untreated Adult... Untreated Adult... Untreated Child...	Fludarabine Pho... Total-Body Irra... Peripheral Bloo... Nonmyeloablativ... Cyclosporine Mycophenolate M...	-	Fred Hutchinson Cancer Center
Autologous Peripheral Blood Stem Cell Transplant Followed by Donor Bone Marrow Transplant in Treating Patients With High-Risk Hodgkin Lymphoma, Non-Hodgkin Lymphoma, Multiple Myeloma, or Chronic Lymphocytic Leukemia	NCT01008462	B-Cell Prolymph... Hypodiploidy Loss of Chromos... Plasma Cell Leu... Progression of ... Recurrent Adult... Recurrent Adult... Recurrent Child... Recurrent Child... Recurrent Chron... Recurrent Plasm... Recurrent Small... Refractory Chil... Refractory Chro... Refractory Non-... Refractory Plas... Refractory Smal... t(14;16) t(4;14) T-Cell Prolymph... Waldenstrom Mac...	Allogeneic Bone... Allogeneic Hema... Autologous Hema... Autologous-Allo... Carmustine Cyclophosphamid... Cytarabine Etoposide Fludarabine Pho... Laboratory Biom... Melphalan Mycophenolate M... Peripheral Bloo... Tacrolimus Total-Body Irra...	- 75 Years	Fred Hutchinson Cancer Center

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