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

Phase 2

Completed

Conditions: Graft Versus Host Disease
Leukemia
Lymphoma

Interventions: Biological: rituximab
Drug: fludarabine phosphate
Drug: melphalan
Drug: sirolimus
Drug: tacrolimus
Procedure: allogeneic hematopoietic stem cell transplantation
Radiation: indium In 111 ibritumomab tiuxetan
Radiation: yttrium Y 90 ibritumomab tiuxetan
Other: laboratory biomarker analysis

Registration Number: NCT00577278

Lead Sponsor: City of Hope Medical Center

Brief Summary: RATIONALE: Giving monoclonal antibody therapy, radioimmunotherapy, and chemotherapy before a donor stem cell transplant helps stop the growth of cancer cells and helps stop the patient's immune system from rejecting the donor's stem cells. When the stem cells from a related donor that do not exactly match the patient's blood, are infused into the patient, they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving tacrolimus and sirolimus before and after transplant may stop this from happening.

PURPOSE: This phase II trial is studying the side effects and how well giving indium In 111 ibritumomab tiuxetan and yttrium y 90 ibritumomab tiuxetan together with rituximab, fludarabine, melphalan, and donor stem cell transplant works in treating patients with B-cell non-Hodgkin lymphoma.

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 41

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (chemo, monoclonal antibody therapy, transplant)	rituximab	REDUCED-INTENSITY CONDITIONING: Patients receive rituximab 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 PO and sirolimus PO beginning on day -3 and continuing for up to 6 months with taper.
Treatment (chemo, monoclonal antibody therapy, transplant)	allogeneic hematopoietic stem cell transplantation	REDUCED-INTENSITY CONDITIONING: Patients receive rituximab 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 PO and sirolimus PO beginning on day -3 and continuing for up to 6 months with taper.
Treatment (chemo, monoclonal antibody therapy, transplant)	indium In 111 ibritumomab tiuxetan	REDUCED-INTENSITY CONDITIONING: Patients receive rituximab 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 PO and sirolimus PO beginning on day -3 and continuing for up to 6 months with taper.
Treatment (chemo, monoclonal antibody therapy, transplant)	yttrium Y 90 ibritumomab tiuxetan	REDUCED-INTENSITY CONDITIONING: Patients receive rituximab 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 PO and sirolimus PO beginning on day -3 and continuing for up to 6 months with taper.
Treatment (chemo, monoclonal antibody therapy, transplant)	sirolimus	REDUCED-INTENSITY CONDITIONING: Patients receive rituximab 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 PO and sirolimus PO beginning on day -3 and continuing for up to 6 months with taper.
Treatment (chemo, monoclonal antibody therapy, transplant)	tacrolimus	REDUCED-INTENSITY CONDITIONING: Patients receive rituximab 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 PO and sirolimus PO beginning on day -3 and continuing for up to 6 months with taper.
Treatment (chemo, monoclonal antibody therapy, transplant)	laboratory biomarker analysis	REDUCED-INTENSITY CONDITIONING: Patients receive rituximab 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 PO and sirolimus PO beginning on day -3 and continuing for up to 6 months with taper.
Treatment (chemo, monoclonal antibody therapy, transplant)	fludarabine phosphate	REDUCED-INTENSITY CONDITIONING: Patients receive rituximab 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 PO and sirolimus PO beginning on day -3 and continuing for up to 6 months with taper.
Treatment (chemo, monoclonal antibody therapy, transplant)	melphalan	REDUCED-INTENSITY CONDITIONING: Patients receive rituximab 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 PO and sirolimus PO beginning on day -3 and continuing for up to 6 months with taper.

Primary Outcome Measures

Name	Time	Method
Relapse/Progression Rate at Two Years	From the initial treatment to the last disease assessment, up to two years	The primary endpoint was 2-year cumulative incidence of relapse/progression (RP), defined as time from alloHCT to disease recurrence or progression. Cumulative incidences for RP was generated in a competing-risk setting, given that death events were competing events.

Secondary Outcome Measures

Name	Time	Method
Overall Survival at Two Years	From the initial treatment to the last disease assessment, up to two years	Overall survival (OS) was measured from initial treatment to death from any cause. It was estimated using the Kaplan-Meier method; the 95% confidence interval was calculated using Greenwood's formula.
Progression-free Survival at Two Years	From the initial treatment to the last disease assessment, up to two years	Progression-free survival (PFS) was measured from initial treatment to disease progression or death from any cause, whichever came first. It was estimated using the Kaplan-Meier method; the 95% confidence interval was calculated using Greenwood's formula.