A Phase I/II Study of Autologous Stem Cell Transplantation Followed by Nonmyeloablative Allogeneic Stem Cell Transplantation for Patients With Relapsed or Refractory Lymphoma - A Multi-center Trial
Overview
- Phase
- Phase 1
- Intervention
- Autologous Hematopoietic Stem Cell Transplantation
- Conditions
- Prolymphocytic Leukemia
- Sponsor
- Fred Hutchinson Cancer Center
- Enrollment
- 76
- Locations
- 5
- Primary Endpoint
- Engraftment of HLA Identical PBSC Allografts
- Status
- Completed
- Last Updated
- 6 years ago
Overview
Brief Summary
This phase I/II trial studies how well autologous stem cell transplant followed by donor stem cell transplant works in treating patients with lymphoma that has returned or does not respond to treatment. Peripheral blood stem cell transplant using stem cells from the patient or a donor may be able to replace immune cells that were destroyed by chemotherapy used to kill cancer cells. The donated stem cells may also help destroy any remaining cancer cells (graft-versus-tumor effect).
Detailed Description
PRIMARY OBJECTIVES: I. To evaluate engraftment of human leukocyte antibody (HLA) identical peripheral blood stem cell (PBSC) allografts given after conditioning with total-body irradiation (TBI) (200cGy) +/- fludarabine (fludarabine phosphate), 90 mg/m\^2 and post-grafting immunosuppression with cyclosporine (CSP)/mycophenolate mofetil (MMF) in refractory or relapsed lymphoma patients following an initial autologous peripheral blood stem cell transplant (PBSCT) for disease cytoreduction. II. To determine the non-relapse mortality at day 100 post-non-myeloablative allografting following mobilization and high-dose chemotherapy with autografting. SECONDARY OBJECTIVES: I. To determine the disease free survival and overall survival of non-myeloablative allografting following autologous PBSCT. OUTLINE: CONDITIONING REGIMEN: Patients with matched, related stem cell donors receive cyclophosphamide intravenously (IV) on days -6 and -5 and undergo TBI twice daily (BID) on days -3 to -1. Patients with matched, unrelated stem cell donors receive carmustine IV over 3 hours on day -7, etoposide IV over 2 hours BID on days -6 to -3, and cytarabine IV over 3 hours BID on days -6 to -3, and melphalan IV over 30 minutes on day -2. TRANSPLANTATION: All patients undergo autologous PBSCT on day 0. NON-MYELOABLATIVE CONDITIONING: Beginning 40-120 days following PBSC transplant, patients with related donors undergo TBI on day 0. Patients with unrelated donors receive fludarabine phosphate IV over 30 minutes on days -4 to -2 and undergo TBI on day 0. TRANSPLANTATION: Patients undergo non-myeloablative allogeneic PBSCT on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine orally (PO) BID on days -3 to 56 (patients with related donors) or 100 (patients with unrelated donors) followed by taper to day 180. Patients also receive mycophenolate mofetil PO BID on days 0-27 (patients with related donors) or thrice daily (TID) on days 0-27, then BID on days 28-40 followed by taper to day 96 (patients with unrelated donors). Some patients may undergo donor lymphocyte infusion if there is evidence of disease progression and no evidence of graft-vs-host disease (GVHD). After completion of study treatment, patients are followed up at day 180, 1 year, 1.5 years, 2 years, 3 years, and then annually thereafter.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patients with lymphoma (non-Hodgkin lymphoma \[NHL\], chronic lymphocytic leukemia/small lymphocytic lymphoma \[CLL/SLL\] or Hodgkin's lymphoma) with primary refractory or relapsed disease after standard chemotherapy at high risk of relapse with conventional autografting; patients with a diagnosis of CLL (or small lymphocytic lymphoma) or diagnosis of CLL that progresses to prolymphocytic leukemia (PLL), or T-cell CLL or PLL
- •Must have an HLA genotypically or phenotypically identical related donor or, at a minimum, a high likelihood of identifying an HLA-matched unrelated donor; the determination of availability of a suitable unrelated donor may be based on a World-Book search
- •Cross-over to other tandem autologous-allogeneic research protocol (#2241) will be allowed if the patient loses the suitable HLA-matched related or unrelated donor but has an available HLA-haploidentical donor before receiving the allogeneic transplantation and if the patient meets the eligibility criteria of the subsequent study
- •Cross-over from other tandem autologous-allogeneic research protocol (#2241) will be allowed if a suitable HLA-matched related or unrelated donor is identified before receiving the allogeneic transplantation and if the patient meets the eligibility criteria of the subsequent study
- •Signed informed consent
- •Detectable tumor on radiographic studies or bone marrow biopsy prior to mobilization regimen
- •Expected survival \>= 3 months from study entry
- •DONOR: HLA genotypically or phenotypically identical related donor
- •DONOR: Must consent to granulocyte-colony stimulating factor (G-CSF) (filgrastim) administration and leukapheresis for both PBSC allograft and subsequent donor lymphocyte infusion (DLI)
- •DONOR: Must have adequate veins for leukapheresis or agree to placement of central venous catheter (femoral or subclavian)
Exclusion Criteria
- •Life expectancy severely limited by disease other than lymphoma
- •Prior autologous hematopoietic stem cell transplant
- •Patients at high risk of veno-occlusive disease of the liver (criteria not yet rigorously defined but includes bilirubin \> 2.0 mg and serum glutamic oxaloacetic transaminase \[SGOT\] or serum glutamate pyruvate transaminase \[SGPT\] \> 2 x normal); patients may be accepted outside of this range if cleared by gastrointestinal (GI) consult
- •Cardiac ejection fraction (EF) \< 40% on multi-gated acquisition (MUGA) scan or cardiac echocardiogram (echo) (or if unable to obtain ejection fraction, shortening fraction of \< 26%); patients with active or a history of cardiac disease should be evaluated with appropriate cardiac studies and/or consult; ejection fraction is required if age \> 50 years or there is a history of anthracyclines or history of cardiac disease; patients with a shortening fraction \< 26% may be enrolled if approved by a cardiologist
- •Baseline serum-creatinine \> 2.0 mg/dl and a calculated or measured creatinine clearance of \< 50 ml/minute
- •Seropositive for the human immunodeficiency virus (HIV)
- •Pulmonary dysfunction as measured by a corrected diffusing capacity of the lung for carbon monoxide (DLCO) \< 50% of predicted total lung capacity (TLC) \< 30%, forced expiratory volume in 1 second (FEV1) \< 30% and/or receiving supplementary continuous oxygen; the FHCRC principal investigator (PI) of the study must approve enrollment of all patients with pulmonary nodules
- •Pregnancy or breast-feeding
- •Patients with poorly controlled hypertension despite hypertensive medication
- •Karnofsky score less than 60; pediatric criteria: Lansky Play-Performance Score \< 40
Arms & Interventions
Treatment (tandem transplantation)
See Detailed Description
Intervention: Autologous Hematopoietic Stem Cell Transplantation
Treatment (tandem transplantation)
See Detailed Description
Intervention: Autologous-Allogeneic Tandem Hematopoietic Stem Cell Transplantation
Treatment (tandem transplantation)
See Detailed Description
Intervention: Carmustine
Treatment (tandem transplantation)
See Detailed Description
Intervention: Cyclophosphamide
Treatment (tandem transplantation)
See Detailed Description
Intervention: Cyclosporine
Treatment (tandem transplantation)
See Detailed Description
Intervention: Cytarabine
Treatment (tandem transplantation)
See Detailed Description
Intervention: Etoposide
Treatment (tandem transplantation)
See Detailed Description
Intervention: Fludarabine Phosphate
Treatment (tandem transplantation)
See Detailed Description
Intervention: Laboratory Biomarker Analysis
Treatment (tandem transplantation)
See Detailed Description
Intervention: Melphalan
Treatment (tandem transplantation)
See Detailed Description
Intervention: Mycophenolate Mofetil
Treatment (tandem transplantation)
See Detailed Description
Intervention: Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation
Treatment (tandem transplantation)
See Detailed Description
Intervention: Peripheral Blood Stem Cell Transplantation
Treatment (tandem transplantation)
See Detailed Description
Intervention: Therapeutic Autologous Lymphocytes
Treatment (tandem transplantation)
See Detailed Description
Intervention: Total-Body Irradiation
Outcomes
Primary Outcomes
Engraftment of HLA Identical PBSC Allografts
Time Frame: Day 56
Number of patients who engrafted by Day 56 post allogeneic transplant. Failure to engraft is defined as the absence of detectable donor cells in the marrow. The rates and accompanying confidence intervals associated with failure of engraftment at day +56 will be calculated after every 5th patient is enrolled on the study. If the lower limit to the appropriate one-sided 80% confidence interval exceeds 25%, this will be considered sufficient evidence of an excess "failure" rate and the study will be stopped. For these purposes, all patients will be evaluated together (patients with chemosensitive and chemoresistant disease).
Non-Relapse Mortality
Time Frame: Day 100 post-non-myeloablative allografting following mobilization and high-dose chemotherapy with autografting
The rates and accompanying confidence intervals associated with transplant-related mortality will be calculated after every 5th patient is enrolled on the study. If the lower limit to the appropriate one-sided 80% confidence interval exceeds 25%, this will be considered sufficient evidence of an excess "failure" rate and the study will be stopped. For these purposes, all patients will be evaluated together (patients with chemosensitive and chemoresistant disease).
Secondary Outcomes
- Overall Survival (OS)(From the date of autologous transplant until the time of death, assessed up to 3 years)
- Progression Free-survival (PFS)(From the date of autologous transplant until the time of progression, relapse, death, or the date the patient was last known to be in remission, assessed up to 3 years)