Ibritumomab Tiuxetan (Zevalin)

Number: 0659

Table Of Contents

Applicable CPT / HCPCS / ICD-10 Codes


Scope of Policy

This Clinical Policy Bulletin addresses ibritumomab tiuxetan (Zevalin) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

  1. Criteria for Initial Approval

    1. Relapsed or Refractory, Low-grade or Follicular Non-Hodgkin’s Lymphoma (NHL)

      Aetna considers ibritumomab tiuxetan (Zevalin) medically necessary for treatment of relapsed or refractory, low-grade or follicular B-cell non-Hodgkin’s lymphoma (NHL).

    2. Previously Untreated Follicular NHL

      Aetna considers ibritumomab tiuxetan (Zevalin) medically necessary for previously untreated follicular NHL in members who have achieved a partial or complete response to first-line chemotherapy.

    Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).

  2. Continuation of Therapy

    See Dosage and Administration information.

Dosage and Administration

Ibritumomab tiuxetan (Zevalin) is available for injection as 3.2 mg ibritumomab tiuxetan per 2 mL as a clear, colorless solution, that may contain translucent particles, in a single-dose vial for intravenous use.

Relapsed or Refractory, Low-grade or Follicular B-cell Non-Hodgkin's Lymphoma (NHL) or Previously Untreated Follicular NHL

The Zevalin therapeutic regimen consists of two distinct steps; step 1 involves an infusion of rituximab and step 2, 7 to 9 days later, consists of a second infusion of rituximab followed by yttrium‐90 (Y-90) ibritumomab tiuxetan.

  • Day 1: Administer rituximab 250 mg/m2 intravenous infusion.
  • Day 7, 8, or 9: Administer rituximab 250 mg/m2 intravenous infusion:

    • If platelets at least 150,000/mm3: within 4 hours after rituximab infusion, administer 0.4 mCi/kg (14.8 MBq per kg) Y-90 Zevalin intravenous infusion;
    • If platelets 100,000 to 149,000/mm3 in relapsed or refractory persons: within 4 hours after rituximab infusion, administer 0.3 mCi/kg (11.1 MBq per kg) Y-90 Zevalin intravenous infusion.
  • Initiate the Zevalin therapeutic regimen following recovery of platelet counts to 150,000/mm3 or more at least 6 weeks, but no more than 12 weeks, following the last dose of first-line chemotherapy.
  • Only administer Rituxan/Zevalin in facilities where immediate access to resuscitative measures is available.
  • Do not administer Zevalin regimen to members with platelet counts less than 100,000 cells/mm3.
  • The maximum allowable dose of Y-90 Zevalin is 32.0 mCi (1184) MBq regardless of the member's body weight.

Source: Acrotech, 2019

Experimental and Investigational or Not Medically Necessary

Aetna considers ibritumomab tiuxetan (Zevalin) not medically necessary when given as a repeat course of treatment.

Aetna considers the ibritumomab tiuxetan (Zevalin) therapeutic regimen experimental and investigational for the treatment of all other indications including the following (not an all-inclusive list) because its effectiveness for these indications has not been established:

  • Burkitt lymphoma
  • Chronic lymphocytic leukemia
  • Gastric MALT lymphoma
  • Hepatocellular carcinoma
  • Mantle cell lymphoma
  • Nodal marginal zone lymphoma
  • Nongastric MALT lymphoma
  • Post-transplantation lymphoproliferative disorders
  • Splenic marginal zone lymphoma.


CPT Codes/ HCPCS Codes / ICD-10 Codes

Code Code Description

CPT codes covered if selection criteria are met:

79403 Radiopharmaceutical therapy, radiolabeled monoclonal antibody by intravenous infusion

Other CPT codes related to the CPB:

78800 - 78804 Radiopharmaceutical localization of tumor or distribution of radiopharmaceutical agent(s)
85032 Blood count; manual cell count (erythrocyte, leukocyte, or platelet), each
85049     platelet, automated
96401 - 96450 Chemotherapy administration

Ibritumomab Tiuxetan (Zevalin):

HCPCS codes covered if selection criteria are met:

A9543 Yttrium Y-90 ibritumomab tiuxetan, therapeutic, per treatment dose, up to 40 millicuries

Other HCPCS codes related to the CPB:

A9542 Indium In-111 ibritumomab tiuxetan, diagnostic, per study dose, up to 5 millicuries

ICD-10 codes covered if selection criteria are met:

C82.00 - C82.99 Follicular lymphoma [relapsed or refractory, ‘low-grade or follicular B-cell non-Hodgkin’s lymphoma']
C83.00 - C83.09, C83.30 - C83.39, C83.90 - C83.99, C86.5 - C86.6 Lymphosarcoma and reticulosarcoma, other named variants
C84.a0 - C84.99 Cutaneous T-cell and mature T/NK-cell lymphomas

ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):

C22.0 Liver cell carcinoma
C83.80 - C83.89 Other lymphomas [diffuse large B-cell non-Hodgkin lymphoma]
C83.10 - C83.19 Mantle cell lymphoma
C83.70 - C83.79 Burkitt lymphoma
C88.4 Marginal zone lymphoma [gastric/nongastric MALT, primary cutaneous B-cell lymphoma]
C91.10 - C91.12, C91.90 - C91.92 Chronic lymphoid leukemia [chronic lymphocytic]
D47.Z1 Post-transplant lymphoproliferative disorder (PTLD)


U.S. Food and Drug Administration (FDA)-Approved Indications

  • Relapsed or Refractory, Low-grade or Follicular NHL

    Zevalin is indicated for the treatment of adult patients with relapsed or refractory, low-grade or follicular B-cell non-Hodgkin’s lymphoma (NHL).

  • Previously Untreated Follicular NHL

    Zevalin is indicated for the treatment of previously untreated follicular NHL in adult patients who achieve a partial or complete response to first-line chemotherapy.

Ibritumomab tiuxetan is available as Zevalin (Acrotech Biopharma LLC) is a CD20-directed radiotherapeutic antibody administered as part of the Zevalin therapeutic regimen and is FDA approved for the treatment of adult patients with relapsed or refractory, low-grade or follicular B-cell non-Hodgkin's lymphoma (NHL), or previously untreated follicular NHL who achieve a partial or complete response to first-line chemotherapy Zevalin consists of a monoclonal antibody linked to the radioactive isotope yttrium-90.  After infusion into a patient, the monoclonal antibody targets the CD20 antigen, which is found on the surface of mature B cells and B-cell tumors. The CD20 antigen is expressed on more than 90 % of B-cell non-Hodgkin’s lymphomas. In this manner, cytotoxic radiation is delivered directly to malignant cells (Acrotech, 2019).

Ibritumomab tiuxetan (Zevalin) is the immunoconjugate resulting from a stable thiourea covalent bond between the monoclonal antibody ibritumomab and the linker‐chelator tiuxetan [N‐[2‐bis(carboxymethyl)amino]‐3‐(pisothiocyanatophenyl)‐propyl]‐[N‐[2‐bis(carboxymethyl)amino]‐2‐(methyl)‐ethyl] glycine. This linker‐chelator provides a high affinity, conformationally restricted chelation site for Indium‐111 or Yttrium‐90. The antibody moiety of Zevalin is ibritumomab, a murine IgG1 kappa monoclonal antibody directed Against the CD20 antigen. Regions of ibritumomab bind to the CD20 antigen on B lymphocytes and induce apoptosis (programmed cell death) in CD20+ B‐cell lines in vitro. Tiuxetan (chelator) tightly binds In‐111 or Y‐90. The chelator complex covalently links to the amino acids of exposed lysines and arginines contained within the antibody (ibritumomab). Beta emission from Y‐90 induces cellular damage by the formation of free radicals in the target and neighboring cells (Acrotech, 2019). 

Ibritumomab tiuxetan must be used along with rituximab (Rituxan), another monoclonal antibody that targets malignant B-lymphocytes and has been approved for treatment of low-grade B-cell non‐Hodgkin’ lymphoma (NHL).  Ibritumomab tiuxetan is approved by the FDA for patients who have not responded to standard chemotherapy treatments or to the use of rituximab alone (Acrotech, 2019).

According to the prescribing information, ibritumomab tiuxetan (Zevalin) carries the following warnings and precautions:

  • Serious infusion reactons (black box warning)
  • Prolonged and severe cytopenias (black box warning)
  • Severe cutaneous and mucocutaneous reactions (black box warning)
  • Development of leukemia and myelodysplastic syndrome
  • Extravasation
  • Immunization
  • Embryo-fetal toxicity.

Per the prescribing information, common adverse reactions (> 10%) in clinical trials included: cytopenias, fatigue, nasopharyngitis, nausea, abdominal pain, asthenia, cough, diarrhea, and pyrexia.

Otte (2008) noted that treatment of follicular NHL with yttrium-90 labeled Zevalin has become an efficacious asset in standard treatment concepts of this disease. The author stated that a pre-diagnostic imaging or dosimetry is not necessary as an additional mandatory safety measure to confirm the expected biodistribution.

Two multi-center trials were conducted to demonstrate the safety and effectiveness of the Zevalin therapeutic regimen.  In the first trial, 54 patients who were no longer responding to chemotherapy or rituximab received the Zevalin therapeutic regimen.  The overall response rate was 74 %.

The second study was a randomized, controlled phase III trial that included 143 subjects with relapsed or refractory, low-grade or follicular NHL or transformed B-cell NHL.  An overall response rate of 80 % was obtained in subjects receiving the Zevalin therapeutic regimen (73 subjects), compared to 56 % for the subjects receiving rituximab alone (70 subjects).  Thirty percent of Zevalin-treated subjects experienced a complete response, compared to a 16 % complete response rate for rituximab-treated subjects.  The duration of response was approximately 2 months longer with the Zevalin therapeutic regimen, although it has not been determined whether Zevalin improves overall survival.

The Zevalin treatment regimen is more toxic than treatment with rituximab. More than 50 % of the patients in the clinical trials experienced serious leukopenia or thromocytopenia lasting for 3 to 4 weeks. Hemorrhages, some fatal, and life-threatening infections occurred in a small number of patients.  Because of these concerns, the Zevalin therapeutic regimen is only approved by the FDA for patients who have failed other treatments.  In addition, the development of myeloid malignancies and dysplasias have been reported with Zevalin.

In a phase-II clinical trial, Krishnan and colleagues (2008) assessed the safety and effectiveness of combining yttrium-90 (90Y) Zevalin with high-dose carmustine, cytarabine, etoposide, and melphalan (BEAM) and autologous stem-cell transplantation (ASCT) in patients with NHL who were ineligible for total-body irradiation because of older age or prior radiotherapy.  A total of 41 patients with received standard-dose 90Y Zevalin (14.8 MBq/kg [0.4 mCi/kg]) followed by high-dose BEAM.  The median age was 60 years (range of 19 to 78 years), and the median number of previous therapies was 2 (range of 1 to 6).  Disease histologies were diffuse large B-cell (n = 20), mantle cell (n = 13), follicular (n = 4), and transformed lymphoma (n = 4).  With a median follow-up of 18.4 months (range of 5.5 to 53.3 months), the estimated 2-year overall survival (OS) and progression-free survival (PFS) were 88.9 % (95 % confidence interval [CI]: 75.3 % to 95.2 %) and 69.8 % (95 % CI: 56.4 % to 79.7 %), respectively.  The median time to white blood cell engraftment was 11 days (range of 9 to 26 days) and time to platelet engraftment was 12 days (range of 3 to 107 days).  Adverse events were similar to those seen historically with high-dose BEAM alone, and included grade 3 or 4 pulmonary toxicity in 10 patients.  The authors concluded that adding 90Y Zevalin to high-dose BEAM with ASCT is feasible and has a toxicity and tolerability profile similar to that observed with BEAM alone.  They noted that rates of PFS seen in these patients are promising and warrant additional study.

Allogeneic SCT is an effective therapy for lymphoma.  Reduced-intensity conditioning (RIC) reduces non-relapse mortality associated with myeloablative conditioning but relapse rates are high when performed in active disease.  Shimoni et al (2008) examined the safety and outcome of Zevalin combined with RIC in patients with advanced lymphoma.  The study included 12 patients, median age 54 years (37 to 62), with a median of 4 prior treatments (2 to 6) and active disease documented on positron emission tomography-computed tomography (PET-CT).  Zevalin 0.4 mCi/kg was given on day-14 and fludarabine combined with busulfan (n = 6) or melphalan (n = 6) was started on day-6.  Graft-versus-host disease (GVHD) prevention was tapered 3 months after SCT to augment the graft-versus-lymphoma effect.  All patients engrafted at a median of 14 days after SCT.  Eighty-three percent achieved complete response/partial response.  With a median follow-up of 21 months (12 to 37), 2-year PFS was 33 %.  Only 3 patients relapsed; cumulative incidence was 25 %.  Non-relapse mortality was 42 %, predominantly due to acute GVHD.  Zevalin-RIC is feasible with consistent engraftment, acceptable organ toxicity, but high rates of acute GVHD.  The low incidence of relapse suggested augmented anti-lymphoma effect.  The authors stated that Zevalin-RIC merits further study.  Better results may be achieved in patients earlier in disease course and with longer duration of immune-suppression.

In a pilot study, Maza et al (2008) evaluated the outcome and assessed complications of (90)Y ibritumomab tiuxetan (IT) therapy in patients with primary cutaneous B-cell lymphomas (PCBCL).  A total of 10 patients, all but 1, with relapsed PCBCL were included and treated with rituximab (250 mg m(-2)/body surface) on days 1 and 8 followed by a single dose of (90)Y IT (11-15 MBq kg(-1)).  The overall response rate was 100 %.  The complete response rate was 100 %.  The median time to relapse was 12 months.  Ongoing remissions were achieved in 4 patients (median follow-up of 19 months).  Transient and reversible myelosuppression (grade 3 to 4) was the most frequent adverse event.  Radioimmunotherapy with (90)Y IT is an effective treatment in relapsed primary cutaneous follicle center lymphomas and diffuse large B-cell lymphoma leg-type.  The authors stated that further investigations in controlled randomized clinical trials evaluating the role of (90)Y IT versus rituximab in PCBCL are needed.

Jain et al (2009) stated that radioimmunotherapy (RIT) with radio-labeled monoclonal antibodies to CD20 produce a high response rate in patients with relapsed lymphoma. Use of this modality in patients with chronic lymphocytic leukemia (CLL) has been hampered by the extensive marrow involvement seen in patients with CLL, which would produce a high risk for marrow aplasia after treatment with RIT. Patients with lymphoma and marrow involvement have been treated with RIT if involved marrow was less than 25 % of the total marrow.  Thus, these investigators adapted this approach as consolidation therapy in patients with CLL responding to chemoimmunotherapy.  A total of 14 patients with relapsed CLL either in partial remission or in complete remission but with disease documented by flow cytometry were treated with (90)Y IT.  One patient responded and achieved a complete remission but with residual disease detected by flow cytometry.  Of note was that grade 3 or 4 hematologic toxicity was seen in 12 of the 13 (92 %) evaluable patients, with grade 3 or 4 thrombocytopenia noted in 11 (85 %) of the patients.  In addition, myelosuppression was prolonged with a median duration of grade 3 or 4 thrombocytopenia of 37 days.  Five patients had persistent thrombocytopenia 3 months post-therapy.  The authors concluded that even in patients with CLL and limited marrow involvement, the use of RIT results in unacceptable hematologic toxicity.

Koechli et al (2015) noted that the addition of anti-CD20 antibodies to high intensity poly-chemotherapy regimens has improved response and survival rates in newly diagnosed patients with Burkitt lymphoma (BL). However, the role of additional anti-CD20 directed RIT for consolidation of first remission (CR1) has not been reported so far in BL patients receiving rituximab during first-line treatment. These researchers compared 5 BL patients receiving Y-90-IT RIT consolidation in CR1 to 22 consecutive BL patients without consolidation. They observed that Y-90-IT treatment was associated with clinically relevant myelosuppression. After a median follow-up of 50 months, none of the patients with Y-90-IT treatment relapsed, and no patient died. In contrast, 1 patient (4.5 %) in the non-Y-90-IT group relapsed (50 months-PFS 95.5 %; p = 0.6336), and 1 patient died (50 months-OS 95.5 %; p = 0.6171). The authors concluded that these findings suggested that survival rates are excellent and equal in rituximab pre-treated BL patients with or without Y-90-IT consolidation in first remission.

Rossignol et al (2015) stated that post-transplantation lymphoproliferative disorders (PTLDs) are life-threatening complications after solid organ and hematopoietic stem cell transplantation. Only 50 % of CD20-positive PTLDs respond to rituximab monotherapy, and outcomes remain poor for patients with relapsed/refractory disease, especially those who do not qualify for an anthracycline-containing regimen due to frailty or co-morbidities. Radioimmunotherapy might be an option in this particular setting. These investigators reported a panel of 8 patients with rituximab refractory/relapsed CD20-positive PTLDs including 3 ineligible for subsequent CHOP-like chemotherapy who received (90) Y-ibritumomab tiuxetan as a single agent (n = 7) or combined to chemotherapy (n = 1). Five out of 8 patients were kidney transplant recipients, while 2/8 had a liver transplant and 1/8 had a heart transplant. Patients received a median of 2 previous therapies. Overall response rate was 62.5 %. Importantly, all responders achieved CR. At a median follow-up of 37 months, CR was ongoing in 4 patients. Toxicity was predominantly hematological and easily manageable. No graft rejection was noticed concomitantly or following RIT administration despite immunosuppression reduction after diagnosis of PTLDs. The authors concluded that this report emphasized the potential efficiency of salvage RIT for early rituximab refractory PTLDs without any unexpected toxicity.

Diffuse Large B-Cell Lymphoma

Lugtenburg et al (2019) stated that patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) after, or ineligible for, autologous stem cell transplantation (ASCT) have a dismal prognosis. In a phase-II clinical trial, these researchers examined treatment with R-PECC (rituximab, prednisolone, etoposide, chlorambucil, lomustine), every 28 days for 4 cycles in 62 patients, followed by radio-immunotherapy consolidation with 90 Y-ibritumomab tiuxetan in responsive patients. Primary endpoints were FFS and incidence of grade-3 or higher AEs from start of 90 Y-ibritumomab tiuxetan. The ORR after R-PECC was 50 %; 29 of 31 responsive patients proceeded to 90 Y-ibritumomab tiuxetan; 5 out of 15 PR patients converted to CR after 90 Y-ibritumomab tiuxetan. One-year FFS and OS from start of 90 Y-ibritumomab tiuxetan was 52 % (95 % CI: 33 % to 68 %) and 62 % (95 % CI: 42 % to 77 %), respectively. One-year FFS and OS from start of R-PECC was 28 % (95 % CI: 17 % to 39 %) and 49 % (95 % CI: 36 % to 61 %), respectively. Toxicities of R-PECC and 90 Y-ibritumomab tiuxetan were mainly hematological. The authors concluded that for relapsed DLBCL patients the largely oral R-PECC regimen achieved promising response rates, combined with an acceptable safety profile. Consolidation with 90 Y-ibritumomab tiuxetan resulted in long-term response durations in approximately 1/3 of the patients who received it.

Chow et al (2022) noted that allogeneic hematopoietic cell transplantation (allo-HCT) can be curative for relapsed or refractory B-cell lymphomas (BCLs; for which DLBCL comprises the majority of these patients), although outcomes are worse in aggressive disease, and most patients will still experience relapse. Radioimmunotherapy using 90Y-ibritumomab tiuxetan can induce disease control across lymphoma subtypes in a dose-dependent fashion. These researchers hypothesized that mega-doses of 90Y-ibritumomab tiuxetan with RIC could safely produce deeper remissions in aggressive BCL further maintained with the immunologic effect of allo-HCT. In a phase-II clinical trial, CD20+ BCL patients received outpatient 90Y-ibritumomab tiuxetan (1.5 mCi/kg; maximum of 120 mCi), fludarabine, and then 2 Gy total body irradiation (TBI) before HLA-matched allo-HCT. A total of 20 patients were enrolled after a median of 4.5 prior lines of therapy, including 14 with prior ASCT and 4 with prior anti-CD19 chimeric T-cellular therapy. A median 90Y-ibritumomab tiuxetan activity of 113.6 mCi (range of 71.2 to 129.2 mCi) was administered, delivering a median of 552 cGy to the liver (range of 499 to 2,411 cGy). The estimated 1- and 5-year PFS was 55 % (95 % CI: 31 % to 73 %) and 50 % (95 % CI: 27 % to 69 %) with a median PFS (mPFS) of 1.57 years. The estimated 1- and 5-year OS was 80 % (95 % CI: 54 % to 92 %) and 63 % (95 % CI: 38 % to 81 %) with a median OS of 6.45 years. A total of 16 patients (80 %) experienced grade-3 or higher toxicities, although non-relapse mortality was 10 % at 1 year. No patients developed secondary acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS). The authors concluded that mega-dose 90Y-ibritumomab tiuxetan, fludarabine, and low-dose TBI followed by an HLA-matched allo-HCT was feasible, safe, and effective in treating aggressive BCL, exceeding the pre-specified endpoint while producing non-hematologic toxicities comparable to those of standard RIC regimens.

Marginal Zone Lymphomas

Moustafa et al (2022) noted that yttrium-90 ibritumomab tiuxetan [(90)Y-IT] is a CD20-targeted radioimmuno-conjugate. Clinical trials of (90)Y-IT as a 1st-line stand-alone treatment in follicular lymphoma (FL) and/or marginal zone lymphoma (MZL) showed high efficacy; however, long-term survival outcomes and toxicities are not well-defined. In a retrospective study, these researchers examined the use of (90)Y-IT in previously untreated low grade (LG)-FL and MZL at Mayo Clinic Cancer Center between January 2000 and October 2019. They selected patients with LG-FL and MZL who received standard-dose (90)Y-IT as a single agent in the 1st-line setting. The cohort (n = 51) consists of previously untreated LG-FL (n = 41) or MZL (n = 10). Median follow-up was 5.3 years (95 % CI: 4.2 to 6.2); ORR was 100 % with complete response (CR) rate of 94 %. Continuous CR was observed in 59 % patients who had more than 2 years of follow-up. Long-term CR (more than 7 years) was observed in 25 % of patients; mPFS for the whole cohort was not reached (NR) (95 % CI: 4.9, NR). Bulky disease was associated with shorter median PFS of 3.5 years (95 % CI: 0.8 to 4.9) compared to non-bulky disease NR (95 % CI: 5.8, NR; p = 0.02). The incidence of grade-3 or higher thrombocytopenia, neutropenia and anemia were 47 %, 37 %, and 4 %, respectively. No therapy-related MDS or AML were observed. The authors concluded that long real-life follow-up showed that single-agent (90)Y-IT was highly effective with durable long-term survival in previously untreated LG-FL and MZL without significant risk for secondary malignancies.

Ibritumomab Tiuxetan for Consolidation After Induction Chemotherapy in Indolent non-Hodgkin Lymphoma

Iino and colleagues (2019) indolent B-cell NHLs (iNHLs) are considered incurable.  Rituximab maintenance and yttrium-90 ibritumomab tiuxetan (90Y-IT) consolidation are promising post-remission therapies.  However, only 1 randomized, phase-II clinical trial has compared their efficacies and adverse effects.  These researchers compared the safety and efficacy of 90Y-IT consolidation and rituximab maintenance in iNHL patients.  They retrospectively examined 75 iNHL patients with CR or PR after initial chemotherapy between January 2008 and December 2018.  A total of 27 patients received 90Y-IT consolidation and 48 received rituximab maintenance (every 2 months for 2 years); PFS, OS, and time to next treatment (TTNT) were estimated from the start of the treatment, and adverse effects were evaluated.  After a median 3.6-year follow-up, the 5-year PFS of the 90Y-IT consolidation and rituximab maintenance groups were 75.5 % and 82.4 %, respectively (log-rank test, p = 0.839), and the 5-year OS were 100 % and 97.8 %, respectively (log-rank test, p = 0.465).  The corresponding median TTNTs were not reached (log-rank test, p = 0.804).  The commonest adverse effect with 90Y-IT consolidation was hematotoxicity; lower rates and grades of cytopenia were observed in patients who received rituximab maintenance.  Secondary malignancies were observed in 1 patient (4 %) who received 90Y-IT consolidation and 2 patients (4.2 %) who received rituximab maintenance (Fisher's exact test, p > 0.99).  The authors concluded that 90Y-IT consolidation and rituximab maintenance were similar with respect to PFS, OS, and TTNT.  However, the features and grades of adverse effects significantly differed.  Patient-specific characteristics should be considered when deciding post-remission treatments.

The authors stated that this study had several drawbacks.  It was non-randomized, retrospective, and based on a small number of patients with heterogeneous histopathological iNHL.  Because of the indolent nature of iNHL, long-term follow-up is needed to confirm prognosis and adverse effects, including the potential for secondary malignancies in patients who received 90Y-IT consolidation treatment.  These researchers stated that large, randomized studies are needed to confirm these findings.

Ibritumomab Tiuxetan for Consolidation in Relapsed or Refractory DLBCL Patients Who Are Ineligible for or Have Failed Autologous Stem Cell Transplantation

Lugtenburg and colleagues (2019) noted that patients with relapsed/refractory DLBCL after, or ineligible for, ASCT have a dismal prognosis.  In a phase-II clinical trial, these researchers evxamined treatment with R-PECC (rituximab, prednisolone, etoposide, chlorambucil, lomustine), every 28 days for 4 cycles in 62 patients, followed by consolidation with 90Y-IT in responsive patients. Primary end-points were failure-free survival (FFS) and incidence of grade greater than or equal to 3 AEs from start of 90Y-IT.  The overall response rate (ORR) after R-PECC was 50 %; 29 of 31 responsive patients proceeded to 90Y-IT; 5 out of 15 PR patients converted to CR after 90Y-IT; 1-year FFS and OS from start of 90Y-IT was 52 % (95 % CI: 33 to 68 %) and 62 % (95 % CI: 42 to 77 %), respectively; 1-year FFS and OS from start of R-PECC was 28 % (95 % CI: 17 to 39 %) and 49 % (95 % CI: 36 to 61 %), respectively.  Toxicities of R-PECC and 90Y-IT were mainly hematological.  The authors concluded that for relapsed DLBCL patients the largely oral R-PECC regimen achieved promising response rates, combined with an acceptable safety profile.  Consolidation with 90Y-IT resulted in long-term response durations in approximately 1/3 of the patients that received it.

Ibritumomab Tiuxetan for Diffuse Large B-Cell Lymphoma

In a phase II clinical trial, Witzig and colleagues (2015) studied patients with early stage diffuse large B-cell lymphoma (DLBCL) who received RCHOP (rituximab cyclophosphamide, doxorubicin, vincristine, prednisone) alone or with involved field radiotherapy (IFRT). Anti-CD20 RIT delivers radiation to microscopic sites outside of known disease. This study aimed to achieve a functional CR rate of greater than or equal to 75 % to RCHOP and 90 Yttrium-ibritumomab tiuxetan RIT. Patients with stages I/II DLBCL received 4 to 6 cycles of RCHOP followed by RIT [14.8 MBq/kg (0.4 mCi/kg)]; patients with positron emission tomography-positive sites of disease after RCHOP/RIT received 30 Gy IFRT. Of the 62 patients enrolled; 53 were eligible – 42 % (22/53) had stage I/IE; 58 % (31/53) stage II/IIE. After RCHOP, 79 % (42/53) were in CR/unconfirmed CR; and 48 patients proceeded to RIT. One partial responder after RIT received IFRT and achieved a CR. The best response after RCHOP + RIT in all 53 patients was a functional CR rate of 89 % (47/53; 95 % CI: 77 to 96 %). With a median follow-up of 5.9 years, 7 (13 %) patients have progressed and 4 (8 %) have died (2 with DLBCL). At 5 years, 78 % of patients remain in remission and 94 % are alive. The authors concluded that chemoimmunotherapy and RIT is an active regimen for early stage DLBCL patients; 89 % of patients achieved functional CR without the requirement of IFRT. They stated that this regimen is worthy of further study for early stage DLBCL in a phase III trial.

In an open-label, single-center, phase II clinical trial, Karmali and associates (2017) evaluated the safety and effectiveness of dose-dense CHOP-R-14 followed by 90Y-ibritumomab RIT in patients with previously untreated DLBCL.  A total of 20 patients, the majority presenting with high-risk characteristics, were enrolled to receive dose-dense cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab every 14 days (CHOP-R-14), followed by 90Y-ibritumomab tiuxetan consolidation; 16 patients completed RIT consolidation (rituximab 250 mg/m2 on day 1 and day 7, 8, or 9, followed by a single injection of 90Y-ibritumomab); CR rates of 75 and 95 % were observed after treatment with CHOP-R-14 and RIT, respectively; 4 of the 5 patients who achieved a partial response (PR) after CHOP-R-14 converted to CR following treatment with RIT.  With a median follow-up of 89.7 months, the PFS and OS rates for the cohort were 75 % and 85 %, respectively.  Hematological adverse events (AEs) were common following CHOP-R-14 and RIT, but they were manageable with treatment interruption.  The authors concluded that this regimen achieved promising survival outcomes in high-risk DLBCL on long term follow-up, with manageable toxicity.  They noted that this study had several drawbacks, including the small sample size (n = 16 for completion of RIT consolidation) and incomplete accrual; thus, these findings on effectiveness must be interpreted with caution.  Additionally, this trial pre-dated the PET era.  Nonetheless, the long-term follow-up provided a reliable measure of response, with evidence of benefit in patients with high-risk characteristics.  They noted that in an era of targeted therapies, closer investigation of RIT consolidation should not be entirely abandoned as a potential therapeutic option in DLBCL.

In a prospective multi-center. Phase-II clinical trial, Hertzberg and co-workers (2017) examined if treatment intensification with R-ICE (rituximab, ifosfamide, carboplatin, and etoposide) chemotherapy followed by 90YIT-BEAM (BCNU, etoposide, cytarabine, and melphalan) for high-risk DLBCL patients who are positive on interim PET scan after 4 cycles of R-CHOP-14 (rituximab, cyclophosphamide, doxorubicin, and prednisone) can improve 2-year PFS from a historically unfavorable rate of 40 % to a rate of 65 %.  Patients received 4 cycles of R-CHOP-14, followed by a centrally-reviewed PET performed at day 17 to 20 of cycle 4 and assessed according to International Harmonisation Project criteria.  Median age of the 151 evaluable patients was 57 years, with 79 % stages 3 to 4, 54 % bulk, and 54 % International Prognostic Index 3 to 5.  Among the 143 patients undergoing interim PET, 101 (71 %) were PET-negative (96 of whom completed R-CHOP), 42 (29 %) were PET-positive (32 of whom completed R-ICE and 90YIT -BEAM).  At a median follow up of 35 months, the 2-year PFS for PET-positive patients was 67 %, a rate similar to that for PET-negative patients treated with R-CHOP-14 (74 %, p = 0.11); OS was 78 % and 88 % (p = 0.11), respectively.  In an exploratory analysis, PFS and OS were markedly superior for PET-positive Deauville score 4 versus score 5 (p = 0.0002 and p = 0.001, respectively).  The authors concluded that DLBCL patients who were PET-positive after 4 cycles of R-CHOP-14 and who switched to R-ICE and 90YIT-BEAM achieved favorable survival outcomes similar to those for PET-negative R-CHOP-14-treated patients.  Moreover, they stated that further studies are needed to confirm these promising results.

Chahoud and colleagues (2018) examined the effect on long-term survival of adding rituximab (R) to BEAM (carmustine, etoposide, cytarabine, and melphalan) conditioning with or without yttrium-90 ibritumomab tiuxetan (90YIT) in patients with relapsed DLBCL undergoing ASCT.  Patients were enrolled on 3 consecutive phase-II clinical trials.  Patients received 2 doses of rituximab (375 and 1,000 mg/m2) during mobilization of stem cells, followed by 1,000 mg/m2 on days +1 and +8 after ASCT with R-BEAM or 90YIT-R-BEAM (90YIT dose of 0.4 mCi/kg) conditioning.  A total of 113 patients were enrolled, with 73 receiving R-BEAM and 40 receiving 90YIT-R-BEAM.  All patients had a prior exposure to rituximab.  The median follow-up intervals for survivors were 11.8, 8.1, and 4.2 years in the 3 trials, respectively.  The 5-year disease-free survival (DFS) rates were 62 % for R-BEAM and 65 % for 90YIT-R-BEAM (p = 0.82).  The 5-year OS rates were 73 % and 77 %, respectively (p = 0.65).  In patients with de-novo DLBCL, survival outcomes of the germinal center/activated b-cell histologic subtypes were similar with 5-year OS rates (p = 0.52) and DFS rates (p = 0.64), irrespective of their time of relapse (less than 1 versus greater than 1 year) after initial induction chemotherapy (p = 0.97).  The authors concluded that administering ASCT with rituximab during stem cell collection and immediately after transplantation induced long-term disease remission and abolished the negative prognostic impact of cell-of-origin in patients with relapsed DLBCL.  Moreover, they stated that the addition of 90YIT did not confer a further survival benefit.

Ibritumomab Tiuxetan for Diffuse Mantle Cell Lymphoma

In a phase II clinical trial, Wang et al (2009) evaluated the safety and effectiveness of (90)Y-IT in patients with relapsed or refractory mantle cell lymphoma (MCL).  Patients were eligible for the study if they had adequate major organ function and performance status.  Those with central nervous system disease, pleural effusion, circulating lymphoma cells greater than or equal to 5,000/microL, or history of stem-cell transplant were ineligible.  Patients with a platelet count greater than or equal to 150,000/microL received a dose of 0.4 mCi/kg of (90)Y-IT, whereas those with a platelet count less than 150,000/microL received a dose of 0.3 mCi/kg.  A total of 34 patients with a median age of 68 years (range of 52 to 79 years) received the therapeutic dose.  The patients had received a median of 3 prior treatment regimens (range of 1 to 6 treatment regimens), including those that contained rituximab (n = 32) and bortezomib (n = 7).  Of the 32 patients with measurable disease, 10 (31 %) achieved complete or partial remission.  After a median follow-up of 22 months (range of 2 to 72+ months), an intent-to-treat analysis revealed a median event-free survival (EFS) duration of 6 months and an OS duration of 21 months.  The median EFS for those who achieved partial or complete remission was 28 months, while it was 3 months for those whose disease did not respond (p < 0.0001); it was 9 months for patients whose tumor measured less than 5 cm in the largest diameter before treatment and 3 months for those whose tumor measured greater than or equal to 5 cm (p = 0.015).  The authors concluded that the single-agent activity of (90)Y-IT and its favorable safety profile warrant its further development for the treatment of MCL.

Mondello and co-workers (2016) MCL is an aggressive lymphoma with a dismal prognosis because of numerous relapses.  Because the most promising results have been obtained with immunochemotherapy followed by ASCT, these investigators evaluated the effectiveness of (90)Y-IT consolidation after such an intensive treatment.  They retrospectively assessed 57 patients affected by intermediate or high-risk MCL in CR or partial remission (PR) after 3 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin [hydroxydaunorubicin], vincristine [Oncovin], prednisolone) plus 3 cycles of R-DHAP (dexamethasone, cytarabine [Ara-C], cisplatin [platinum]) followed by ASCT and additional consolidation treatment with (90)Y-IT in 28 cases.  All patients underwent 2 years of rituximab maintenance.  After ASCT, 94 % achieved CR and 4 % achieved PR.  The median follow-up was 6.2 years (range of 1.8 to 9.7 years).  Treatment intensification was well-tolerated and led to a significantly longer response duration in comparison to standard treatment.  In contrast to the historical cohort, the addition of (90)Y-IT appeared to overcome important risk factors such as Mantle Cell Lymphoma International Prognostic Index (MIPI) score and bone marrow infiltration.  The authors concluded that in the present retrospective analysis, immunochemotherapy followed by ASCT resulted in a very high response rate, and subsequent (90)Y-IT consolidation significantly reduced the number of relapses and increased survival, suggesting that (90)Y-IT consolidation might be a valid option in 1st-line treatment.  Moreover, they stated that a prospective confirmatory trial is needed.

Jurczak and colleagues (2019) noted that the Polish Lymphoma Research Group performed a phase-II clinical trial to examine if 90Y ibritumomab tiuxetan radioimmunotherapy (Y90) may constitute an alternative consolidation for MCL patients unfit for high-dose therapy.  A total of 46 patients were consolidated with Y90 following response to the 1st (n = 34) or 2nd line (n = 12) immuno-chemotheray.  Majority of the patients had advanced disease (stage IV and presence of B-symptoms in 85 % and 70 %, respectively) and high MIPI (5.8, range of 4 to 7).  Consolidation with Y90 increased the CR rate obtained by the 1st line therapy from 41 % to 91 % and allowed for median PFS of 3.3 and OS of 6.5 years.  In the 1st relapse, CR rate increased from 16 % to 75 %, while median PFS and OS totaled 2.2 and 6.5 years, respectively.  At 8 years, 30 % of patients, consolidated in the 1st line CR were alive, without relapse.  Toxicity associated with Y90 was manageable, more severe after fludarabine-based regimens.

Ibritumomab Tiuxetan for Hepatocellular Carcinoma

An UpToDate review on "Overview of treatment approaches for hepatocellular carcinoma" (Abdalla, Stuart, and Singal, 2023) does not mention ibritumomab tiuxetan as a therapeutic option.

Primary Gastrointestinal Follicular Lymphoma

Desai and colleagues (2021) noted that primary gastro-intestinal follicular lymphoma (PGIFL) is characterized by localized involvement of the GI tract. PGIFL usually runs an indolent course. External beam radiation therapy (EBRT) is curative in a substantial proportion of localized follicular lymphomas; however, GI toxicities may discourage its use in PGIFL. Ibritumomab tiuxetan radioimmunotherapy (RIT) is a radioimmunoconjugate of anti-CD20 monoclonal antibody linked to chelator tiuxetan and radioisotope. RIT delivers confined high-intensity radiation with short path length specifically targeting lymphoma cells and sparing normal tissue. In this case-series study, these researchers described the findings of 6 patients with PGIFL who were treated with RIT. All patients had low-risk, localized, and non-bulky disease. They responded completely and were relapse-free for the duration of follow-up. Hematologic toxicities were observed, but none was serious. The authors concluded that RIT is a potentially curative therapeutic option in PGIFL with a tolerable toxicity profile. These researchers stated that this was, to their knowledge, the 1st report of successful treatment of PGIFL with RIT. Moreover, they stated that RIT is not approved by the FDA for the front-line treatment of PGIFL. This was a small case-series (n = 6) report of efficacy of RIT for this entity, and large, prospective studies are needed to confirm these findings.


The above policy is based on the following references:

  1. Abdalla EK, Stuart KE, Singal AG. Overview of treatment approaches for hepatocellular carcinoma. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed July 2023.
  2. Acrotech Biopharma LLC. Zevalin (ibritumomab tiuxetan) injection, for intravenous use. Prescribing Information. East Windsor,NJ: Acrotech; revised September 2019.
  3. Ansell SM, Armitage J. Non-Hodgkin lymphoma: Diagnosis and treatment. Mayo Clin Proc. 2005;80(8):1087-1097.
  4. Arranz R, García-Noblejas A, Grande C, et al. First-line treatment with rituximab-hyperCVAD alternating with rituximab-methotrexate-cytarabine and followed by consolidation with 90Y-ibritumomab-tiuxetan in patients with mantle cell lymphoma. Results of a multicenter, phase 2 pilot trial from the GELTAMO group. Haematologica. 2013;98(10):1563-1570.
  5. Center for Medicare & Medicaid Services (CMS). Decision memo for radioimmunotherapy for non-Hodgkin's lymphoma (CAG-00163N). Medicare Coverage Database. Baltimore, MD: CMS; July 25, 2005. 
  6. Chahoud J, Sui D, Erwin WD, et al. Updated results of rituximab pre- and post-BEAM with or without 90yttrium ibritumomab tiuxetan during autologous transplant for diffuse large B-cell lymphoma. Clin Cancer Res. 2018;24(10):2304-2311.
  7. Cheson BD. Radioimmunotherapy of non-Hodgkin lymphomas. Blood. 2003;101(2):391-298.
  8. Chow VA, Cassaday RD, Gooley TA, et al. Megadose 90Y-ibritumomab tiuxetan prior to allogeneic transplantation is effective for aggressive large B-cell lymphoma. Blood Adv. 2022;6(1):37-45.
  9. Cullen M, Dixon A, Goldstone AH, et al.; British Committee for Standards in Haematology, Haematology-Oncology Task Force. Nodal non-Hodgkin's lymphoma. Guidelines on Diagnosis and Therapy. London, UK: British Committee for Standards in Haematology; August 2002.
  10. Desai S, Moustafa MA, Wiseman G, Witzig T. Ibritumomab tiuxetan radioimmunotherapy for primary gastrointestinal follicular lymphoma. Oncologist. 2021;26:1-3.
  11. Gibson AD. Updated results of a phase III trial comparing Ibritumomab tiuxetan with rituximab in previously treated patients with non-Hodgkin's lymphoma. Clin Lymphoma. 2002;3(2):87-89.
  12. Gopal AK, Gooley TA, Maloney DG, et al. High-dose radioimmunotherapy versus conventional high-dose therapy and autologous hematopoietic stem cell transplantation for relapsed follicular non-Hodgkin's lymphoma: A multivariable cohort analysis. Blood. 2003;102(7):2351-2357.
  13. Hertzberg M, Gandhi MK, Trotman J, et al; Australasian Leukaemia Lymphoma Group (ALLG). Early treatment intensification with R-ICE and 90Y-ibritumomab tiuxetan (Zevalin)-BEAM stem cell transplantation in patients with high-risk diffuse large B-cell lymphoma patients and positive interim PET after 4 cycles of R-CHOP-14. Haematologica. 2017;102(2):356-363.
  14. IDEC Pharmaceuticals. Zevalin (ibritumomab tiuxetan) prescribing information. San Diego, CA: IDEC; January 2002. 
  15. Iino M, Sakamoto Y, Sato T. Yttrium-90 ibritumomab tiuxetan consolidation versus rituximab maintenance therapy after induction chemotherapy in patients with indolent non-Hodgkin lymphoma: A single-institution experience. Hematology. 2019;24(1):623-630.
  16. Jacene HA, Filice R, Kasecamp W, Wahl RL. Comparison of 90Y-ibritumomab tiuxetan and 131I-tositumomab in clinical practice. J Nucl Med. 2007;48(11):1767-1176.
  17. Jain N, Wierda W, Ferrajoli A, et al. A phase 2 study of yttrium-90 ibritumomab tiuxetan (Zevalin) in patients with chronic lymphocytic leukemia. Cancer. 2009;115(19):4533-4539.
  18. Jurczak W, M Gruszka A, Sowa Staszczak A, et al. Consolidation with 90Y ibritumomab tiuxetan radioimmunotherapy in mantle cell lymphoma patients ineligible for high dose therapy: Results of the phase II multicentre Polish Lymphoma Research Group trial, after 8-year long follow-up. Leuk Lymphoma. 2019;60(11):2689-2696.
  19. Karmali R, Larson ML, Shammo JM, et al. Phase 2 study of CHOP-R-14 followed by 90Y-ibritumomab tiuxetan in patients with previously untreated diffuse large B-cell lymphoma. Mol Clin Oncol. 2017;6(4):627-633.
  20. Koechli V, Klaeser B, Banz Y, et al. Consolidation of first remission using radioimmunotherapy with yttrium-90-ibritumomab-tiuxetan in adult patients with Burkitt lymphoma. Leuk Res. 2015;39(3):307-310.
  21. Kolstad A, Laurell A, Jerkeman M, et al; Nordic Lymphoma Group. Nordic MCL3 study: 90Y-ibritumomab-tiuxetan added to BEAM/C in non-CR patients before transplant in mantle cell lymphoma. Blood. 2014;123(19):2953-2959.
  22. Krishnan A, Nademanee A, Fung HC, et al. Phase II trial of a transplantation regimen of yttrium-90 ibritumomab tiuxetan and high-dose chemotherapy in patients with non-Hodgkin's lymphoma. J Clin Oncol. 2008;26(1):90-95.
  23. Lugtenburg PJ, Zijlstra JM, Doorduijn JK, et al; Dutch HOVON group. Rituximab-PECC induction followed by (90) Y-ibritumomab tiuxetan consolidation in relapsed or refractory DLBCL patients who are ineligible for or have failed ASCT: Results from a phase II HOVON study. Br J Haematol. 2019;187(3):347-355.
  24. Maza S, Gellrich S, Assaf C, et al. Yttrium-90 ibritumomab tiuxetan radioimmunotherapy in primary cutaneous B-cell lymphomas: First results of a prospective, monocentre study. Leuk Lymphoma. 2008;49(9):1702-1709.
  25. Mei M, Palmer J, Tsai NNC, et al. Results of a phase II trial of allogeneic hematopoietic stem cell transplantation using 90Y-ibritumomab tiuxetan (Zevalin) in combination with fludarabine and melphalan in patients with high-risk B-cell non-Hodgkin's lymphoma. Clin Lymphoma Myeloma Leuk. 2023 May 23 [Online ahead of print].
  26. Mondello P, Steiner N, Willenbacher W, et al. 90Y-ibritumomab-tiuxetan consolidation therapy for advanced-stage mantle cell lymphoma after first-line autologous stem cell transplantation: Is it time for a step forward? Clin Lymphoma Myeloma Leuk. 2016;16(2):82-88.
  27. Morschhauser F, Radford J, Van Hoof A, et al. Phase III trial of consolidation therapy with yttrium-90-ibritumomab tiuxetan compared with no additional therapy after first remission in advanced follicular lymphoma. J Clin Oncol. 2008;26(32):5156-5164.
  28. Moustafa MA, Borah BJ, Moriarty JP, et al. Yttrium-90 ibritumomab tiuxetan is cost-effective compared to bendamustine + rituximab in low-grade lymphomas. Clin Lymphoma Myeloma Leuk. 2023;23(4):259-265.
  29. Moustafa MA, Peterson J, Hoppe BS, et al. Real world long-term follow-up experience with yttrium-90 ibritumomab tiuxetan in previously untreated patients with low-grade follicular lymphoma and marginal zone lymphoma. Clin Lymphoma Myeloma Leuk. 2022;22(8):618-625.
  30. Nachtnebel A. Ibritumomab tiuxetan (Zevalin) as consolidation therapy after first remission in patients with follicular lymphoma. Decision Support Document: Horizon Scanning in Oncology Vol. 5. Vienna, Austria: Ludwig Boltzmann Institut fuer Health Technology Assessment (LBI-HTA); 2009.
  31. National Comprehensive Cancer Network (NCCN). Ibritumomab tiuxetan. NCCN Drugs & Biologics Compendium. Plymouth Meeting, PA: NCCN; February 2023.
  32. National Horizon Scanning Centre (NHSC). Ibritumomab tiuxetan for NHL -- horizon scanning review. New and Emerging Technology Briefing. Birmingham, UK: National Horizon Scanning Centre (NHSC); 2002.
  33. No authors listed. Ibritumomab tiuxetan (Zevalin) for non-Hodgkin's lymphoma. Med Lett Drugs Ther. 2002;44(1144):101-102.
  34. Otte A. Diagnostic imaging prior to 90Y-ibritumomab tiuxetan (Zevalin) treatment in follicular non-Hodgkin's lymphoma. Hell J Nucl Med. 2008;11(1):12-15.
  35. Pandit-Taskar N, Hamlin PA, Reyes S, et al. New Strategies in radioimmunotherapy for lymphoma. Curr Oncol Rep. 2003;5(5):364-371.
  36. Pohar R, Clark M, Nkansah E. Radioimmunotherapies for non-Hodgkin lymphoma: Systematic review of clinical effectiveness, cost-effectiveness, and guidelines. Health Technology Assessment Rapid Review. Ottawa, ON: Canadian Agency for Drugs and Technologies in Health (CADTH); 2009. 
  37. Pouget JP, Navarro-Teulon I, Bardies M, et al. Clinical radioimmunotherapy -- the role of radiobiology. Nat Rev Clin Oncol. 2011;8(12):720-734.
  38. Rossignol J, Terriou L, Robu D, et al. Radioimmunotherapy ((90) Y-ibritumomab tiuxetan) for posttransplant lymphoproliferative disorders after prior exposure to rituximab. Am J Transplant. 2015;15(7):1976-1981.
  39. Sgouros G, Squeri S, Ballangrud AM, et al. Patient-specific, 3-dimensional dosimetry in non-Hodgkin's lymphoma patients treated with 131I-anti-B1 antibody: Assessment of tumor dose-response. J Nucl Med. 2003;44(2):260-268.
  40. Shimoni A, Zwas ST, Oksman Y, et al. Ibritumomab tiuxetan (Zevalin) combined with reduced-intensity conditioning and allogeneic stem-cell transplantation (SCT) in patients with chemorefractory non-Hodgkin's lymphoma. Bone Marrow Transplant. 2008;41(4):355-361.
  41. Song H, Sgouros G. Radioimmunotherapy of solid tumors: Searching for the right target. Curr Drug Deliv. 2011;8(1):26-44.
  42. Spectrum Pharmaceuticals, Inc. Zevalin (ibritumomab tiuxetan) injection for intravenous use. Prescribing Information. Irvine, CA: Spectrum Pharmaceuticals, revised August 2013.
  43. Tennvall J, Fischer M, Bischof Delaloye A, et al; Therapy Committee, EANM; Oncology Committee, EANM; Dosimetry Committee, EANM. EANM procedure guideline for radio-immunotherapy for B-cell lymphoma with 90Y-radiolabelled ibritumomab tiuxetan (Zevalin). Eur J Nucl Med Mol Imaging. 2007;34(4):616-622.
  44. U.S. Food and Drug Administration, Office of Public Affairs. FDA approves first radiopharmaceutical product to treat non-Hodgkin's lymphoma. T02-11. FDA Talk Paper. Rockville, MD: FDA; February 19, 2002. 
  45. Vaklavas C, Meredith RF, Shen S, et al. Phase I study of a modified regimen of 90-Yttrium-ibritumomab tiuxetan for relapsed or refractory follicular or transformed CD20+ non-Hodgkin lymphoma. Cancer Biother Radiopharm. 2013;28(5):370-379.
  46. Wang M, Oki Y, Pro B, et al. Phase II study of yttrium-90-ibritumomab tiuxetan in patients with relapsed or refractory mantle cell lymphoma. J Clin Oncol. 2009;27(31):5213-5218.
  47. Wiseman GA, Gordon LI, Multani PS, et al. Ibritumomab tiuxetan radioimmunotherapy for patients with relapsed or refractory non-Hodgkin lymphoma and mild thrombocytopenia: A phase II multicenter trial. Blood. 2002;99(12):4336-4342.
  48. Wiseman GA, Kornmehl E, Leigh B, et al. Radiation dosimetry results and safety correlations from 90Y-ibritumomab tiuxetan radioimmunotherapy for relapsed or refractory non-Hodgkin's lymphoma: Combined data from 4 clinical trials. J Nucl Med. 2003;44(3):465-474.
  49. Wiseman GA, Leigh BR, Erwin WD, et al. Radiation dosimetry results from a phase II trial of ibritumomab tiuxetan (Zevalin trade mark) radioimmunotherapy for patients with non-Hodgkin's lymphoma and mild thrombocytopenia. Cancer Biother Radiopharm. 2003;18(2):165-178.
  50. Wiseman GA, White CA, Sparks RB, et al. Biodistribution and dosimetry results from a phase III prospectively randomized controlled trial of Zevalin radioimmunotherapy for low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma. Crit Rev Oncol Hematol. 2001;39(1-2):181-194.
  51. Wiseman GA, White CA, Stabin M, et al. Phase I/II 90Y-Zevalin (yttrium-90 ibritumomab tiuxetan, IDEC-Y2B8) radioimmunotherapy dosimetry results in relapsed or refractory non-Hodgkin's lymphoma. Eur J Nucl Med. 2000;27(7):766-777.
  52. Witzig TE, Flinn IW, Gordon LI, et al. Treatment with ibritumomab tiuxetan radioimmunotherapy in patients with rituximab-refractory follicular non-Hodgkin's lymphoma. J Clin Oncol. 2002;20(15):3262-3269.
  53. Witzig TE, Gordon LI, Cabanillas F, et al. Randomized controlled trial of yttrium-90-labeled ibritumomab tiuxetan radioimmunotherapy versus rituximab immunotherapy for patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma. J Clin Oncol. 2002;20(10):2453-2463.
  54. Witzig TE, Hong F, Micallef IN, et al. A phase II trial of RCHOP followed by radioimmunotherapy for early stage (stages I/II) diffuse large B-cell non-Hodgkin lymphoma: ECOG3402. Br J Haematol. 2015;170(5):679-686.
  55. Witzig TE, Molina A, Gordon LI, et al. Long-term responses in patients with recurring or refractory B-cell non-Hodgkin lymphoma treated with yttrium 90 ibritumomab tiuxetan. Cancer. 2007;109(9):1804-1810.
  56. Witzig TE, White CA, Gordon LI, et al. Safety of yttrium-90 ibritumomab tiuxetan radioimmunotherapy for relapsed low-grade, follicular, or transformed non-Hodgkin's lymphoma. J Clin Oncol. 2003;21(7):1263-1270.
  57. Witzig TE, White CA, Wiseman GA, et al. Phase I/II trial of IDEC-Y2B8 radioimmunotherapy for treatment of relapsed or refractory CD20(+) B-cell non-Hodgkin's lymphoma. J Clin Oncol. 1999;17(12):3793-3803.
  58. Witzig TE, Wiseman GA, Maurer MJ, et al. A phase I trial of immunostimulatory CpG 7909 oligodeoxynucleotide and 90 yttrium ibritumomab tiuxetan radioimmunotherapy for relapsed B-cell non-Hodgkin lymphoma. Am J Hematol. 2013;88(7):589-593.
  59. Zinzani PL, d'Amore F, Bombardieri E, et al. Consensus conference: Implementing treatment recommendations on yttrium-90 immunotherapy in clinical practice - report of a European workshop. Eur J Cancer. 2008;44(3):366-373.