Autologous Stem Cell Transplant Followed by Donor Stem Cell Transplant in Treating Patients With Relapsed or Refractory Lymphoma

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Prolymphocytic Leukemia, Recurrent Adult Hodgkin Lymphoma, Recurrent Childhood Hodgkin Lymphoma, Recurrent Childhood Non-Hodgkin Lymphoma, Recurrent Chronic Lymphocytic Leukemia, Recurrent Non-Hodgkin Lymphoma, Recurrent Small Lymphocytic Lymphoma, Refractory Childhood Hodgkin Lymphoma, Refractory Chronic Lymphocytic Leukemia, Refractory Hodgkin Lymphoma, Refractory Non-Hodgkin Lymphoma, Refractory Small Lymphocytic Lymphoma, T-Cell Chronic Lymphocytic Leukemia, T-Cell Prolymphocytic Leukemia

Intervention / Treatment
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* Procedure: Autologous Hematopoietic Stem Cell Transplantation
* Procedure: Autologous-Allogeneic Tandem Hematopoietic Stem Cell Transplantation
* Drug: Carmustine
* Drug: Cyclophosphamide
* Drug: Cyclosporine
* Drug: Cytarabine
* Drug: Etoposide
* Drug: Fludarabine Phosphate
* Other: Laboratory Biomarker Analysis
* Drug: Melphalan
* Drug: Mycophenolate Mofetil
* Procedure: Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation
* Procedure: Peripheral Blood Stem Cell Transplantation
* Biological: Therapeutic Autologous Lymphocytes
* Radiation: Total-Body Irradiation


Participation Criteria
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Eligibility Criteria
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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) DONOR: Age < 75 years (yrs), older donors may be considered after review at Patient Care Conference DONOR: Fred Hutchinson Cancer Research Center (FHCRC) matching allowed will be grades 1.0 to 2.1; unrelated donors who are prospectively: matched for HLA-A, B, C, DRB1 and DQB1 by high resolution typing; only a single allele disparity will be allowed for HLA-A, B, or C as defined by high resolution typing DONOR: Donors are excluded when preexisting immunoreactivity is identified that would jeopardize donor hematopoietic cell engraftment; this determination is based on the standard practice of the individual institution; the recommended procedure for patients with 10 of 10 HLA allele level (phenotypic) match is to obtain a panel reactive antibody (PRA) screens to class I and class II antigens for all patients before HCT; if the PRA shows > 10% activity, then flow cytometric or B and T cell cytotoxic cross matches should be obtained; the donor should be excluded if any of the cytotoxic cross match assays are positive; for those patients with an HLA class I allele mismatch, flow cytometric or B and T cell cytotoxic cross matches should be obtained regardless of the PRA results; a positive anti-donor cytotoxic crossmatch is an absolute donor exclusion DONOR: Patient and donor pairs homozygous at a mismatched allele in the graft rejection vector are considered a two-allele mismatch, i.e., the patient is A*0101 and the donor is A*0102, and this type of mismatch is not allowed DONOR: Only G-CSF mobilized peripheral blood mononuclear cells (PBMC) only will be permitted as a hematopoietic stem cell (HSC) source on this protocol 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 Patients with cluster of differentiation (CD)34 selected auto grafts Patients with active non-hematologic malignancies (except non-melanoma skin cancers); this exclusion does not apply to patients with non-hematologic malignancies that do not require therapy Patients with a history of non-hematologic malignancies (except non-melanoma skin cancers) currently in a complete remission, who are less than 5 years from the time of complete remission, and have a > 20% risk of disease recurrence; this exclusion does not apply to patients with non-hematologic malignancies that do not require therapy DONOR: Identical twin DONOR: Age less than 12 years DONOR: Pregnancy DONOR: Human immunodeficiency virus (HIV) seropositivity DONOR: Inability to achieve adequate venous access DONOR: Known allergy to G-CSF DONOR: Current serious systemic illness DONOR: Failure to meet FHCRC criteria for stem cell donation DONOR: Donor (or centers) who will exclusively donate marrow

Ages Eligible for Study
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Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (tandem transplantation)<br>See Detailed Description | Procedure: Autologous Hematopoietic Stem Cell Transplantation<br>* Undergo autologous transplantation<br>* Other names: Autologous Stem Cell Transplantation;Procedure: Autologous-Allogeneic Tandem Hematopoietic Stem Cell Transplantation<br>* Undergo autologous-allogeneic tandem hematopoietic stem cell transplantation<br>* Other names: auto-allo HCT;Drug: Carmustine<br>* Given IV<br>* Other names: WR-139021;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Drug: Cyclosporine<br>* Given PO<br>* Other names: SangCya;Drug: Cytarabine<br>* Given IV<br>* Other names: WR-28453;Drug: Etoposide<br>* Given IV<br>* Other names: VP-16-213;Drug: Fludarabine Phosphate<br>* Given IV<br>* Other names: SH T 586;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Melphalan<br>* Given IV<br>* Other names: WR-19813;Drug: Mycophenolate Mofetil<br>* Given PO<br>* Other names: MMF;Procedure: Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation<br>* Undergo allogeneic transplantation<br>* Other names: NST;Procedure: Peripheral Blood Stem Cell Transplantation<br>* Undergo allogeneic transplantation<br>* Other names: Peripheral Stem Cell Transplantation;Biological: Therapeutic Autologous Lymphocytes<br>* IV donor lymphocyte infusion<br>* Other names: Autologous T-cells;Radiation: Total-Body Irradiation<br>* Undergo radiotherapy<br>* Other names: Whole-Body Irradiation;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Engraftment of HLA Identical PBSC Allografts | 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). | Day 56 | 
| Non-Relapse Mortality | 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). | Day 100 post-non-myeloablative allografting following mobilization and high-dose chemotherapy with autografting | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Number of patients surviving by interval. Chemosensitive and chemoresistant subjects will be analyzed separately. | From the date of autologous transplant until the time of death, assessed up to 3 years | 
| Progression Free-survival (PFS) | Number of patients surviving without disease by interval. Chemosensitive and chemoresistant subjects will be analyzed separately. | 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 |