Fludarabine Phosphate, Low-Dose Total Body Irradiation, and Donor Stem Cell Transplant in Treating Patients With Hematologic Malignancies or Kidney Cancer
Study Details
Study Description
Brief Summary
This clinical trial studies fludarabine phosphate, low-dose total body irradiation, and donor stem cell transplant in treating patients with hematologic malignancies or kidney cancer. Giving chemotherapy drugs, such as fludarabine phosphate, 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. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-versus-tumor effect). Giving an infusion of the donor's T cells (donor lymphocyte infusion) after the transplant may help increase this effect. Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving cyclosporine before the transplant and cyclosporine and mycophenolate mofetil after the transplant may stop this from happening.
Detailed Description
PRIMARY OBJECTIVES:
- To determine whether stable allogeneic engraftment from unrelated hematopoietic stem cell donors can be safely established using a non-myeloablative conditioning regimen in patients with hematologic malignancies and renal cell carcinoma.
SECONDARY OBJECTIVES:
- To evaluate whether donor lymphocyte infusion (DLI) can be safely used in patients with mixed or full donor chimerism to eliminate persistent or progressive disease.
OUTLINE:
CONDITIONING REGIMEN: Patients receive fludarabine phosphate intravenously (IV) on days -4 to -2. Patients also undergo low-dose total-body irradiation (TBI) on day 0.
TRANSPLANTATION: Patients undergo allogeneic peripheral blood stem cell (PBSC) or bone marrow transplantation 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 BID on days 0-40 with taper to day 96. Patients with mixed chimerism, persistent or progressive disease, and no evidence of graft-versus-host disease and who have been off immunosuppression for at least 2 weeks undergo DLI over 30 minutes. DLI may be repeated every 65 days for up to 3 doses.
After completion of study treatment, patients are follow-up periodically for 5 years.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Treatment (chemotherapy, TBI, HSCT) CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV on days -4 to -2. Patients also undergo low-dose TBI on day 0. TRANSPLANTATION: Patients undergo allogeneic PBSC or bone marrow transplantation on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine PO BID on days -3 to 100 with taper to day 177 and mycophenolate mofetil PO BID on days 0-40 with taper to day 96. Patients with mixed chimerism, persistent or progressive disease, and no evidence of graft-versus-host disease and who have been off immunosuppression for at least 2 weeks undergo DLI over 30 minutes. DLI may be repeated every 65 days for up to 3 doses. |
Drug: fludarabine phosphate
Given IV
Other Names:
Radiation: total-body irradiation
Undergo low-dose TBI
Other Names:
Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation
Undergo nonmyeloablative HSCT
Procedure: allogeneic bone marrow transplantation
Undergo nonmyeloablative allogeneic bone marrow transplantation
Other Names:
Procedure: peripheral blood stem cell transplantation
Undergo nonmyeloablative allogeneic PBSC transplantation
Other Names:
Biological: therapeutic allogeneic lymphocytes
Undergo DLI
Other Names:
Drug: cyclosporine
Given PO
Other Names:
Drug: mycophenolate mofetil
Given PO
Other Names:
Other: pharmacological study
Correlative studies
Other Names:
Other: laboratory biomarker analysis
Correlative studies
|
Outcome Measures
Primary Outcome Measures
- Establishment of an allograft as defined by stable mixed chimerism or full donor chimerism [At day 56]
Engraftment will be assessed separately among patients who receive bone marrow and patients who receive PBSC. Patients with low-risk and high-risk disease will be assessed separately.
Secondary Outcome Measures
- Disease-free survival [Up to 200 days]
Will be summarized.
- Relapse [Assessed up to 5 years]
Will be summarized.
- Disease-related mortality [Before day 200]
Will be summarized.
- Response of malignancy to DLI [Assessed up to 5 years]
Examined and reported in a descriptive manner and confidence intervals will be presented for all estimates. Analyses will be conducted separately among the low- and high-risk groups.
- Incidence of myelosuppression [Greater than 2 days after initial PBSC infusion]
Absolute neutrophil count (ANC) less than 500/ul for more than 2 days, platelets less than 20,000/ul for more than 2 days. Examined and reported in a descriptive manner and confidence intervals will be presented for all estimates. Analyses will be conducted separately among the low- and high-risk groups.
- Incidence of aplasia after DLI [Greater than 2 days after initial PBSC infusion]
Examined and reported in a descriptive manner and confidence intervals will be presented for all estimates. Analyses will be conducted separately among the low- and high-risk groups.
- Incidence of grades 2-4 acute GVHD after DLI [Until day 90]
Examined and reported in a descriptive manner and confidence intervals will be presented for all estimates. Analyses will be conducted separately among the low- and high-risk groups.
- Incidence of grades 2-4 acute GVHD after PBSC infusion [Up to day 177]
Examined and reported in a descriptive manner and confidence intervals will be presented for all estimates. Analyses will be conducted separately among the low- and high-risk groups.
- Incidence of grades 2-4 chronic extensive GVHD after DLI [Assessed up to 5 years]
Examined and reported in a descriptive manner and confidence intervals will be presented for all estimates. Analyses will be conducted separately among the low- and high-risk groups.
- Dose of CD3+ required to convert mixed to full lymphoid chimeras [Day 28 post-transplant]
Examined and reported in a descriptive manner and confidence intervals will be presented for all estimates. Analyses will be conducted separately among the low- and high-risk groups.
- Dose of CD3+ required to convert mixed to full lymphoid chimeras [Day 56 post-transplant]
Examined and reported in a descriptive manner and confidence intervals will be presented for all estimates. Analyses will be conducted separately among the low- and high-risk groups.
- Dose of CD3+ required to convert mixed to full lymphoid chimeras [Day 84 post-transplant]
Examined and reported in a descriptive manner and confidence intervals will be presented for all estimates. Analyses will be conducted separately among the low- and high-risk groups.
- Incidence of infections [Assessed up to 5 years]
Examined and reported in a descriptive manner and confidence intervals will be presented for all estimates. Analyses will be conducted separately among the low- and high-risk groups.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Age > 50 years with hematologic malignancies treatable by allogeneic hematopoietic stem cell transplant (HSCT) and all patients with B cell malignancies except those who may be cured by autologous stem cell transplantation (SCT)
-
Age =< 50 years of age with hematologic diseases treatable by allogeneic HSCT who through pre-existing medical conditions or prior therapy are considered to be of high risk for regimen related toxicity associated with a conventional transplant or those patients who refuse a conventional SCT; transplants must be approved for these inclusion criteria by both the participating institution's patient review committee such as the Patient Care Conference (PCC at the Fred Hutchinson Cancer Research Center [FHCRC]) and by the principal investigator
-
Patients with metastatic renal cell carcinoma with the histologic subtypes of clear cell, papillary and medullary may be accepted regardless of age
-
The following diseases will be permitted although other diagnoses can be considered if approved by PCC or the participating institution's patient review committees and the principal investigator
-
Non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), Hodgkin lymphoma (HL) - must have received and failed frontline therapy
-
Multiple myeloma - must have received prior chemotherapy; consolidation of chemotherapy by autografting prior to nonmyeloablative HSCT is permitted
-
Acute myeloid leukemia (AML)/acute lymphoblastic leukemia (ALL) - must be in complete remission and have received cytotoxic chemotherapy at some stage before transplant; patients with molecular or early relapse will be accepted providing a donor is available; patients with persistent or refractory disease will be considered on a case by case basis and transplants must be approved by the institution's patient review committees
-
Chronic myelogenous leukemia (CML) - patients will be accepted in chronic phase or accelerated phase; patients who have received prior autografts after high dose therapy or have undergone intensive chemotherapy for either peripheral blood stem cell (PBSC) mobilization or treatment of advanced CML may be enrolled provided they are in complete remission (CR), chronic phase (CP) or accelerated phase (AP)
-
Myelodysplastic syndromes (MDS) - all patients with MDS will be eligible for this protocol; however, those patients with MDS and frank AML (> 30% blasts in bone marrow aspirate by morphology or flow cytometry) will require induction chemotherapy to obtain a complete remission (marrow blasts < 5%) and remain in complete remission at time of transplant
-
Renal cell carcinoma- must have evidence of disease not amenable to surgical cure or metastatic disease by radiological and histological criteria
-
DONOR: Human leukocyte antigen (HLA) matched unrelated donor; donors should be matched for HLA -A, -B, -C, -developmentally regulated ribonucleic acid (RNA) binding protein 1(DRB)1 and -class II, DQ beta 1 (DQB) 1; HLA -A and -B loci should be matched at least to the level of resolution; HLA -C, -DRB1, and -DQB1 should be typed at the highest level of resolution available at the time of donor selection; donor must consent to either a bone marrow harvest or PBSC mobilization with filgrastim (G-CSF) arranged through the National Marrow Donor Program (NMDP) or other donor centers
Exclusion Criteria:
-
Patients with rapidly progressive intermediate or high grade NHL
-
Renal cell carcinoma patients with expected survival of less than 6 months
-
Bulky disease resulting in severely limited performance status (< 70%)
-
Any vertebral instability
-
Any active central nervous system (CNS) involvement with disease
-
Fertile men or women unwilling to use contraceptive techniques during and for 12 months following treatment
-
Females who are pregnant
-
Patients with non-hematological tumors
-
Cardiac ejection fraction < 30%
-
Diffusion capacity of the lung for carbon monoxide (DLCO) < 30% and/or receiving supplementary continuous oxygen
-
Significant elevation of bilirubin and transaminases should be discussed at participating institutions' patient review committees in a case by case basis; evidence of synthetic dysfunction or severe cirrhosis will result in patient exclusion
-
Karnofsky score < 50 (except renal cell carcinoma [RCC])
-
Patients with poorly controlled hypertension on multiple antihypertensives
-
Human immunodeficiency virus (HIV) positive patients
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | City of Hope Medical Center | Duarte | California | United States | 91010 |
| 2 | Stanford University Hospitals and Clinics | Stanford | California | United States | 94305 |
| 3 | University of Colorado | Denver | Colorado | United States | 80217-3364 |
| 4 | Baylor University Medical Center | Dallas | Texas | United States | 75246 |
| 5 | Huntsman Cancer Institute/University of Utah | Salt Lake City | Utah | United States | 84112 |
| 6 | Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium | Seattle | Washington | United States | 98109 |
| 7 | Universitaet Leipzig | Leipzig | Germany | D-04103 |
Sponsors and Collaborators
- Fred Hutchinson Cancer Center
- National Heart, Lung, and Blood Institute (NHLBI)
- National Cancer Institute (NCI)
Investigators
- Principal Investigator: Brenda Sandmaier, Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 1463.00
- NCI-2012-00667
- 1463.00
- P01CA018029
- P30CA015704