A Phase II Study of Allo-HCT for B-Cell NHL Using Zevalin, Fludarabine and Melphalan

PRIMARY OBJECTIVES: I. To evaluate the safety and efficacy of a preparative regimen of Yttrium-90 (90^Y)- labeled anti-cluster of differentiation (CD)20 monoclonal antibody (MAb) (yttrium Y 90 ibritumomab tiuxetan) in combination with fludarabine (fludarabine phosphate) and melphalan followed by allogeneic hematopoietic stem cell transplant (APBSCT) for treatment of patients with B-cell low-grade non-Hodgkin lymphoma (LG NHL), intermediate-grade non-Hodgkin lymphoma (IG NHL) and mantle cell lymphoma (MCL). II. To evaluate the short- and long-term complications of this new preparative regimen, including rates of engraftment, acute and chronic graft-versus-host-disease (GVHD) and infectious complications. III. To estimate the disease response rate, disease relapse (progression) rate, and non-relapse mortality rate. IV. To perform exploratory studies that seek to measure/characterize the expression of costimulatory molecules and impact of these molecules on the natural killer (NK) and T cells of a subset of lymphoma patients pre- post- allogeneic stem cell transplant (ASCT) and the stem cell product from a portion of sibling donors.

OUTLINE: REDUCED-INTENSITY CONDITIONING: Patients receive rituximab intravenously (IV) followed by indium In-111 ibritumomab tiuxetan IV over 10 minutes on day -21 and rituximab IV followed by yttrium Y 90 ibritumomab tiuxetan IV over 10 minutes on day -14. Patients also receive fludarabine phosphate IV on days -9 to -5 and melphalan IV on day -4.

STEM CELL TRANSPLANTATION: Patients undergo APBSCT on day 0.

GVHD PROPHYLAXIS: Patients receive tacrolimus IV or orally (PO) and sirolimus PO beginning on day -3 and continuing for up to 6 months with taper.

After completion of study treatment, patients are followed up every 3 months for 1 year and then every 6 months for up to 5 years.

Inclusion criteria

• 6/6/human leukocyte antigen (HLA) matched sibling donor or related donor, or acceptable matched unrelated donor
• Biopsy (Bx) proven diagnosis of LG (including small lymphocytic lymphoma [SLL]/chronic lymphocytic leukemia [CLL], lymphoplasmacytic lymphoma, marginal zone, mucosa-associated lymphoid tissue [MALT] lymphoma and follicular lymphoma [FL] grade 1 and 2), IG (FL grade 3 and DLCL) or MCL NHL
• Prior demonstrated monoclonal CD20+ malignant B-Cell population in lymph nodes and/or BM Bx specimen
• LG NHL; must have relapsed after achieving a complete response (CR) or partial response (PR) to prior therapy or have never responded to prior therapy, including chemotherapy and/or MAb therapy
• MCL NHL in any disease state
• Other aggressive B-cell lymphomas (excluding Burkitt lymphoma or Burkitt-like lymphoma) having had at least one relapse or having been refractory to chemotherapy
• Bone marrow (BM) aspiration and Bx ( =< 42 days prior to imaging dose) which show < 25% lymphomatous involvement of total cellularity; in CLL, peripheral lymphocyte count < 5000/mm^3
• Salvage chemotherapy/MAbs to reduce BM lymphomatous involvement and reduce disease bulk allowed
• Normal renal function test with serum creatinine of =< 1.5 mg/dl, or a creatinine clearance of >= 60 ml/min
• Adequate pulmonary function as measured by forced expiratory volume in one second (FEV1) > 65% of predicted measured, or a diffusing capacity of carbon monoxide (DLCO) >= 50% of predicted measured
• Cardiac Ejection fraction of > 50% by Echocardiogram (ECHO) or multi gated acquisition (MUGA)
• Adequate liver function tests with a bilirubin of =< 1.5 x normal and serum glutamic oxaloacetic transaminase (SGOT) or serum glutamic pyruvic transaminase (SGPT) =< 2 x normal
• Negative Human Immunodeficiency Virus (HIV) antibody
• Karnofsky Performance Status (KPS) > 80
• No active Central Nervous System (CNS) disease or prior history of CNS disease
• Involved field External Beam Therapy (EBT) to area excluding lung, heat, liver, and kidney allowed, but evaluated on a case-by-case basis
• Recovery from last therapy and therapy dose (Y-90 Zevalin) must be >= 4 weeks from prior systemic chemotherapy
• DONOR: Age < 75 years
• DONOR: HLA genotypically identical related donor or acceptable matched unrelated donor
• DONOR: Must consent to G-CSF administration and leukapheresis for matched sibling donor, but for unrelated donor, the donor will sign a standard consent for donation at their designated donor or collection center
• DONOR: Must have adequate veins for leukapheresis or agree to placement of a Central Venous Catheter (CVC [femoral, subclavian])

Exclusion criteria

• Presence of Human Anti-Zevalin Antibody (HAZA)
• Prior radioimmunotherapy (RIT)
• Prior AHSCT; but prior aHSCT is allowed; prior fractionated total body irradiation (FTBI) in the conditioning regimen will be evaluated on an individual basis
• Prior malignancy, except for: adequately treated basal cell or squamous cell skin cancer; adequately treated noninvasive carcinomas; or other cancer from which the patient has been disease-free for at least 5 years; myelodysplastic syndromes (MDS) is excluded from this criterion
• Active evidence of Hepatitis B or C infection; hepatitis B surface antigen positive
• Total peripheral lymphocyte count > 5,000/mm^3 if SLL/CLL
• Burkitt lymphoma or Burkitt-like lymphoma
• DONOR: Age < 12 years
• DONOR: Identical twin
• DONOR: Pregnancy
• DONOR: HIV infection
• DONOR: Inability to achieve adequate venous access
• DONOR: Known allergy to G-CSF
• DONOR: Current serious systemic illness or any disease that may preclude the use of G-CSF (eg, recent thromboembolic event); for unrelated donors, considered ineligible by National Marrow Donor Program (NMDP) donor evaluation center