Busulfan, Melphalan, and Thiotepa in Treating Patients Who Are Undergoing an Autologous Stem Cell Transplant for Hodgkin's or Non-Hodgkin's Lymphoma

Study Overview
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Brief Summary
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RATIONALE: Chemotherapy, such as busulfan, melphalan, and thiotepa, may destroy cancerous blood-forming cells (stem cells) in the blood and bone marrow. Giving the patient their healthy stem cells will help their bone marrow make new stem cells that become red blood cells, white blood cells, and platelets. PURPOSE: This phase II trial is studying how well busulfan, melphalan, and thiotepa work in treating patients who are undergoing an autologous stem cell transplant for Hodgkin's or non-Hodgkin's lymphoma.

Detailed Description
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OBJECTIVES: Determine the therapeutic efficacy of a myeloablative preparative regimen comprising busulfan, melphalan, and thiotepa followed by autologous peripheral blood stem cell (PBSC) transplantation in patients with Hodgkin's or non-Hodgkin's lymphoma. Determine the toxic effects of this preparative regimen in these patients. OUTLINE: Myeloablative preparative regimen: Patients receive busulfan IV over 3 hours on days -8 to -6, melphalan IV over 15-30 minutes on days -5 and -4, and thiotepa IV over 2 hours on days -3 and -2. Peripheral blood stem cell (PBSC) transplantation: Patients undergo PBSC transplantation on day 0 followed by filgrastim (G-CSF) IV over 30 minutes beginning on day 5 and continuing until blood counts recover. Intrathecal chemotherapy: Patients with a history of treated Central Nervous System (CNS) disease or at high-risk for CNS relapse receive methotrexate and cytarabine intrathecally (IT) for 2 doses each within 10 days prior to transplantation and 4-6 doses each beginning on day 32 post-transplantation. Consolidation therapy: Patients with residual bulk disease at 80-100 days post-transplantation that is > 2.5 cm by CT scan may undergo local radiotherapy to residual scar/disease provided it can be encompassed in a single radiation port and the volume of lung to be irradiated is ≤ 20%. After completion of study treatment, patients are followed weekly for 1 month, monthly for 6 months, every 3 months for 6 months, every 6 months for 1 year, and then annually thereafter. PROJECTED ACCRUAL: A total of 30 patients will be accrued for this study.

Official Title
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A Phase II Study to Evaluate the Safety and Efficacy of IV Busulfan, Melphalan, and Thiotepa (BuMelTT) Followed By Autologous PBSC Infusion for Patients With Hodgkin's Disease and Non-Hodgkin's Lymphoma

Conditions
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Lymphoma

Intervention / Treatment
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* Biological: filgrastim
* Drug: busulfan
* Drug: melphalan
* Drug: thiotepa
* Procedure: bone marrow ablation with stem cell support
* Procedure: peripheral blood stem cell transplantation


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Diagnosis of 1 of the following: Intermediate- or high-grade non-Hodgkin's lymphoma (NHL), meeting 1 of the following criteria: In first complete remission (CR) AND at high-risk for relapse, as defined by all of the following criteria: High age-adjusted International Prognostic Index category AND meets the following criteria at diagnosis: Stage III or IV disease Lactic dehydrogenase abnormal Eastern Cooperative Oncology Group (ECOG) score 0-2 Mantle cell histology Primary refractory disease Beyond first CR Low-grade NHL Beyond second relapse Hodgkin's lymphoma Primary refractory disease OR beyond first CR Must have an adequate number of stored autologous peripheral blood stem cells (PBSCs) (i.e., 2.0 x 10^6 hematopoietic progenitor cell antigen (CD34)-positive cells/kg) Patients who are not able to mobilize a sufficient number of PBSCs may use bone marrow instead No active CNS disease NOTE: A new classification scheme for adult non-Hodgkin's lymphoma has been adopted by PDQ. The terminology of indolent or aggressive lymphoma will replace the former terminology of low, intermediate, or high grade lymphoma. However, this protocol uses the former terminology. PATIENT CHARACTERISTICS: Age 0 to 70 Performance status ECOG 0-2 Life expectancy Not specified Hematopoietic Not specified Hepatic Bilirubin < 2 times upper limit of normal (ULN) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 times ULN Renal Creatinine ≤ 2.0 mg/dL Creatinine clearance ≥ 50 mL/min Pulmonary No significant pulmonary dysfunction, defined as Diffusing Capacity the Lung for Carbon monoxide (DLCO) < 60% of predicted Other Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception for ≥ 2 months before and during study participation HIV negative No significant active infection that would preclude PBSC transplantation PRIOR CONCURRENT THERAPY: Biologic therapy No prior transplantation No other concurrent blood products during PBSC transplantation Chemotherapy Not specified Endocrine therapy Not specified Radiotherapy More than 60 days since prior local or regional radiotherapy Surgery Not specified Other More than 30 days since prior investigational drugs No concurrent amphotericin

Ages Eligible for Study
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Maximum Age: 70 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: Filgrastim/Melphalan/Thiotepa<br>Biological/Vaccine: filgrastim 5mcg/kg intravenous piggyback (IVPB) will be administered beginning on day +5 and continued until absolute neutrophil count (ANC) > 1500 for 2 consecutive days. Drug: busulfan 3.2mg/kg/day for 3 days starting on day -8. Each dose of intravenous busulfan will be mixed in a concentration of 0.54 mg/ml of 0.9% saline and infused over 3 hours. Drug: melphalan 50mg/m2/day/iv, infused over 30 minutes on days -5 and -4. The reconstituted melphalan is diluted in 250cc normal saline to a concentration not greater than 0.4 mg/ml. Drug: thiotepa 250 mg/m2/day/iv on days -3 and -2 Procedure/Surgery: bone marrow ablation with stem cell support The transplant therapy should begin within 2 weeks of registration, but no sooner then 30 days after the last dose of chemotherapy. Procedure/Surgery: peripheral blood stem cell transplantation Performed 36-48 hours following last chemotherapy dose. | Biological: filgrastim<br>* 5mcg/kg IVPB will be administered beginning on day +5 and continued until ANC> 1500 for 2 consecutive days.<br>Drug: busulfan<br>* 3.2mg/kg/day for 3 days starting on day -8. Each dose of intravenous busulfan will be mixed in a concentration of 0.54 mg/ml of 0.9% saline and infused over 3 hours.<br>Drug: melphalan<br>* 50mg/m2/day/iv, infused over 30 minutes on days -5 and -4. The reconstituted melphalan is diluted in 250cc normal saline to a concentration not greater than 0.4 mg/ml.<br>Drug: thiotepa<br>* 250 mg/m2/day/iv on days -3 and -2<br>Procedure: bone marrow ablation with stem cell support<br>* The transplant therapy should begin within 2 weeks of registration, but no sooner then 30 days after the last dose of chemotherapy.<br>Procedure: peripheral blood stem cell transplantation<br>* Performed 36-48 hours following last chemotherapy dose.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease-Free Survival | The data presented below represents the total number of subjects (out of 36) that reached disease-free survival status during Months 3, 6, 9, 12, 18, and 24 time points. | 3, 6, 9, 12, 18, and 24 months post transplantation | 
| Therapy-Related Toxicities | The table presented below reflects how many participants (out of 36 total) presented an adverse event related to the treatment regimen within each toxicity category. To review specific adverse events, both related and unrelated to study treatment, please refer to Adverse Events Section. | Through 24 months post transplantation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent adult Hodgkin lymphoma, recurrent adult diffuse small cleaved cell lymphoma, stage III adult diffuse small cleaved cell lymphoma, stage IV adult diffuse small cleaved cell lymphoma, recurrent grade 3 follicular lymphoma, stage III grade 3 follicular lymphoma, stage IV grade 3 follicular lymphoma, recurrent adult diffuse mixed cell lymphoma, stage III adult diffuse mixed cell lymphoma, stage IV adult diffuse mixed cell lymphoma, recurrent adult diffuse large cell lymphoma, stage III adult diffuse large cell lymphoma, stage IV adult diffuse large cell lymphoma, recurrent adult immunoblastic large cell lymphoma, stage III adult immunoblastic large cell lymphoma, stage IV adult immunoblastic large cell lymphoma, recurrent adult lymphoblastic lymphoma, stage III adult lymphoblastic lymphoma, stage IV adult lymphoblastic lymphoma, recurrent adult Burkitt lymphoma, stage III adult Burkitt lymphoma, stage IV adult Burkitt lymphoma, recurrent mantle cell lymphoma, stage III mantle cell lymphoma, stage IV mantle cell lymphoma, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue, nodal marginal zone B-cell lymphoma, recurrent marginal zone lymphoma, splenic marginal zone lymphoma, recurrent small lymphocytic lymphoma, recurrent grade 1 follicular lymphoma, recurrent grade 2 follicular lymphoma, recurrent/refractory childhood Hodgkin lymphoma, stage III childhood Hodgkin lymphoma, stage IV childhood Hodgkin lymphoma, recurrent childhood anaplastic large cell lymphoma, stage III childhood anaplastic large cell lymphoma, stage IV childhood anaplastic large cell lymphoma, childhood grade III lymphomatoid granulomatosis, recurrent childhood large cell lymphoma, stage III childhood large cell lymphoma, stage IV childhood large cell lymphoma, recurrent childhood lymphoblastic lymphoma, stage III childhood lymphoblastic lymphoma, stage IV childhood lymphoblastic lymphoma, recurrent childhood small noncleaved cell lymphoma, stage III childhood small noncleaved cell lymphoma, stage IV childhood small noncleaved cell lymphoma, recurrent cutaneous T-cell non-Hodgkin lymphoma, stage III cutaneous T-cell non-Hodgkin lymphoma, stage IV cutaneous T-cell non-Hodgkin lymphoma