Yttrium Y 90 Ibritumomab Tiuxetan, Etoposide, Cyclophosphamide, and an AHSCT in Non-Hodgkin's Lymphoma Patients

OBJECTIVES:

• To evaluate the safety and efficacy of a new preparative regimen of yttrium Y 90 ibritumomab tiuxetan in combination with high-dose etoposide and cyclophosphamide followed by autologous stem cell transplantation (ASCT) for treatment of patients with poor-risk, relapsed, or refractory non-Hodgkin lymphoma (NHL).
• To determine the maximum tolerated dose of yttrium Y 90 ibritumomab tiuxetan which can be given with high-dose etoposide and high-dose cyclophosphamide followed by ASCT in patients with NHL.
• To perform dosimetry study to estimate the radiation dose delivered to the tumor and normal organs.
• To evaluate the short-term and long-term complications of this new preparative regimen.

OUTLINE: This is a phase I does-escalation study of yttrium Y 90 ibritumomab tiuxetan followed by an open-label phase II study.

• Preparation for transplantation: Peripheral blood stem cells (PBSCs) are collected via leukapheresis. Samples are analyzed by cytogenetic studies, immunophenotyping, and gene rearrangement. Patients with an adequate number of collected CD34-positive cells (≥ 3 times 10^6 /kg) proceed to radioimmunotherapy.
• Radioimmunotherapy: Patients receive yttrium Y 90 ibritumomab tiuxetan IV on days -21 and -14. Patients undergo bone marrow biopsy and dose estimation on day -7.
• Chemotherapy: Patients receive etoposide IV on day -4 and cyclophosphamide IV over 2 hours on day -2.
• Transplantation: Patients undergo reinfusion of PBSCs on day 1.
• Growth factor therapy: Patients receive filgrastim (G-CSF) IV beginning on day 1 and continuing until blood counts recover.

Treatment continues in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed periodically.

DISEASE CHARACTERISTICS:

• Biopsy proven diagnosis of low- or intermediate-grade* non-Hodgkin lymphoma (NHL) including any of the following:

• Follicular small cleaved
• Follicular mixed
• Follicular large cell
• Diffuse small cleaved
• Diffuse mixed
• Diffuse large cell
• Immunoblastic (working formulation B, C, D, E, F, G and H) NOTE: *A new classification scheme for adult non-Hodgkin 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.
• Mantle cell and transformed low-grade lymphomas allowed
• Demonstrated monoclonal CD20-positive B-cell population in lymph nodes and/or bone marrow
• Favorable biodistribution on imaging dose
• Patient either relapsed after achieving a complete (CR) or partial response (PR) to prior therapy, never responded to prior therapy, or has poor-risk disease

• Sensitivity of disease based on 1 of the following:

• Induction failure: patients who did not achieve a CR or PR from induction chemotherapy
• Resistant relapse: patients who did not achieve a CR or PR from the most recent standard salvage chemotherapy
• Sensitive relapse: patients who did achieve a CR or PR from the most recent standard salvage chemotherapy
• Poor-risk disease defined as any of the following:

• Age-adjusted International Prognostic Index (IPI) High- (3 risk factors) or High-Intermediate (2 risk factors) based on the following risk factors:

• Stage III-IV disease
• Elevated serum lactate dehydrogenase level
• ECOG performance status 2-4
• Patients with aggressive NHL including mantle cell lymphoma and who required 2 different induction chemotherapy regimens to achieve a CR/PR
• Patients with B-cell NHL and who failed to achieve a CR after adequate induction chemotherapy regimen(s)
• Patients must have bone marrow aspiration and biopsy within 42 days before salvage chemotherapy or stem cell collection which show ≤ 10% lymphomatous involvement of total cellularity
• Normal cytogenetic study on bone marrow (prior to salvage chemotherapy or stem cell collection)

• Cytogenetic study on peripheral blood is acceptable if bone marrow biopsy has already been done and shows no sign of myelodysplastic syndrome (MDS) or lymphoma and a repeat bone marrow is deemed unnecessary by attending physician
• No active or prior history of CNS diseases
• No human anti-mouse antibody (HAMA) or human anti-chimeric antibody

PATIENT CHARACTERISTICS:

• ECOG performance status (PS) 0-1 or Karnofsky PS 80-100%
• Platelet count normal
• Serum creatinine ≤ 1.5 mg/dL or creatinine clearance ≥ 60 mL/min
• FEV_1 > 65% of predicted or DLCO ≥ 50% of predicted
• LVEF > 50% by ECHO or MUGA scan
• Bilirubin ≤ 1.5 times normal
• SGOT or SGPT ≤ 2 times normal
• HIV antibody-negative
• No prior malignancy except for adequately treated basal cell or squamous cell skin cancer, adequately treated noninvasive carcinoma, or other cancer from which the patient has been disease-free for at least five years
• No active evidence of hepatitis B or C infection
• No hepatitis B surface antigen positivity
• No history of alcohol abuse
• Body weight ≤ 250 pounds

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• Patients who have received involved field external beam therapy to area excluding lung, heart, liver and kidney are allowed, but will be evaluated on a case-by-case basis
• Patients must have recovered from last therapy and should be at least four weeks from prior radiation or chemotherapy
• No prior radioimmunotherapy
• No prior bone marrow transplantation