Ibritumomab Tiuxetan (Zevalin)

Number: 0659


  1. Aetna considers radioimmunotherapy with ibritumomab tiuxetan (Zevalin) medically necessary for the following subtypes of Non-Hodgkin's lymphoma (NHL): 

    1. Follicular lymphoma: as second-line or subsequent therapy of refractory or progressive follicular B-cell NHL in members who are not elderly or infirm; or

    2. Histologic transformation to diffuse large B-cell lymphoma (DLBCL): for treatment when the member meets either of the following criteria:
      1. Member has received minimal or no chemotherapy prior to histologic transformation to DLBCL and has had a partial response, no response, or progressive disease after chemoimmunotherapy; or
      2. Member has received multiple prior therapies including 2 or more lines of chemoimmunotherapy for indolent or transformed disease; or
    3. Primary cutaneous diffuse large B-cell lymphoma: as second-line or subsequent treatment of relapsed or refractory primary cutaneous diffuse large B-cell lymphoma (leg type); or
  2. Aetna considers continuation of ibritumomab tiuxetan (Zevalin) medically necessary for treatment in members with the following subtypes of NHL: follicular lymphoma, histologic transormation to diffuse large B-cell lymphoma, or primary cutaneous diffuse large B-cell lymphoma, and have not experienced disease progress or an unacceptable toxicity.

  3. Aetna considers the Zevalin therapeutic regimen experimental and investigational for all other indications (not an all-inclusive list) because its effectiveness for these indications has not been established.

    1. Burkitt lymphoma
    2. Chronic lymphocytic leukemia
    3. Gastric MALT lymphoma
    4. Hepatocellular carcinoma
    5. Mantle cell lymphoma
    6. Nodal marginal zone lymphoma
    7. Nongastric MALT lymphoma
    8. Post-transplantation lymphoproliferative disorders
    9. Splenic marginal zone lymphoma.

Dosing Recommendations

  • 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 ibritumomab tiuxetan.

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

      • If platelets ≥ 150,000/mm3 : Within 4 hours after rituximab infusion, administer 0.4 mCi/kg (14.8 MBq per kg) Y-90 Zevalin intravenous
      • If platelets ≥ 100,000 but ≤ 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

  • Initiate the Zevalin therapeutic regimen following recovery of platelet counts to ≥150,000/mm3 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/mm(3).
  • The maximum allowable dose of Y-90 Zevalin is 32.0 mCi (1184) MBq regardless of the member's body weight.

Source: Spectrum Pharmaceuticals, 2013


This policy is consistent with the Food and Drug Administration (FDA)-approved indications for ibritumomab tiuxetan (Zevalin) (Spectrum Pharmaceuticals, Irvine, CA) and is adapted from the National Comprehensive Cancer Network (NCCN) Drugs & Biologics Compendium.

Ibritumomab Tiuxetan (Zevalin)

Ibritumomab tiuxetan (Zevalin) (Spectrum Pharmaceuticals, Irvine, CA) 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.

Zevalin (ibritumomab tiuxetan) 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. 

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 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.

Zevalin (ibritumomab tiuxetan) is FDA approved for patients with relapsed or refractory, low‐grade or follicular B‐cell non‐Hodgkin’ lymphoma (NHL), and patients with previously untreated follicular NHL who achieve a partial or complete response to first‐line chemotherapy.

The Zevalin therapeutic regimen is administered in 2 parts.  Patients first receive acetaminophen and rituximab (day 1). On day 7, 8, or 9, patients receive acetaminophen and rituximab again with a form of Zevalin that has a different radioactive chemical, Yttrium-90, that can provide a treatment benefit.

Common adverse reactions (> 10%) in clinical trials were: cytopenias, fatigue, nasopharyngitis, nausea, abdominal pain, asthenia, cough, diarrhea, and pyrexia.

Zevalin (ibritumomab tiuxetan) should not be utilized in the following:

  • Pediatric members <18 years old
  • Women who are pregnant (FDA category D) or breast feeding and have not been apprised of the risks of therapy
  • Prior hypersensitivity to ibritumomab tiuxetan or any component of the product
  • Do not administer Y‐90 Zevalin (ibritumomab tiuxetan) to members with altered biodistribution
  • Do not exceed 32 mCi (1184 MBq) of Y‐90 Zevalin (ibritumomab tiuxetan)
  • Do not administer Zevalin (ibritumomab tiuxetan) to members with 25% or more lymphoma marrow involvement or impaired bone marrow reserve
  • Members with platelet counts <100,000 cells/mm3 or neutrophil counts <1,500 cells/mm3

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.

Zevalin 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.

Zevalin 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.

Zevalin for Hepatocellular Carcinoma

An UpToDate review on “Nonsurgical therapies for localized hepatocellular carcinoma: Transarterial embolization, radiotherapy, and radioembolization” (Curley et al, 2017) does not mention ibritumomab as a therapeutic option.

National Comprehensive Cancer Network (NCCN)

The National Comprehensive Cancer Network Drugs & Biologics Compendium (NCCN, 2019) provide the following recommendations for ibritumomab tiuxetan (Zevalin):

  • B-Cell Lymphomas

    Follicular lymphoma (grade 1-2):

    • Treatment of histologic transformation to diffuse large B-cell lymphoma (DLBCL) in patients who have received (Category 2A)

      • minimal or no chemotherapy prior to histologic transformation to DLBCL (without translocations of MYC and BCL2 and/or BCL6) and have partial response, no response, or progressive disease after chemoimmunotherapy
      • multiple prior therapies including ≥2 lines of chemoimmunotherapy for indolent or transformed disease

    • Used as single-agent therapyFootnotes* (Category 2A for second-line or subsequent therapy in patients who are not elderly or infirm; 2B for all others)

      • first-line therapy in elderly or infirm patients with stage I (≥7 cm), contiguous stage II (≥7 cm), non-contiguous stage II disease, or for stage III or IV disease
      • optional first-line consolidation therapy or extended dosing
      • second-line or subsequent therapy (if not previously given as first-line) for refractory or progressive disease
      • Footnotes*Selection of patients requires adequate marrow cellularity >15% and <25% involvement of lymphoma in bone marrow, and platelets >100,000

    • Considered as maintenance therapy for patients with histologic transformation to diffuse large B-cell lymphoma that is coexisting with extensive follicular lymphoma who achieve a complete response to chemoimmunotherapy (Category 2B)

  • Gastric MALT lymphoma: (Category 2B)

    Used in patients with indications for treatment as:

    • first-line therapy for stage IIE, or II2, or stage IV disease (distant nodal, advanced stage)
    • additional therapy for stage I1, or I2, or stage II1 H. pylori positive disease if repeat endoscopy shows no response or recurrence after antibiotic therapy and involved site radiation therapy (ISRT)
    • additional therapy after ISRT or rituximab alone for stage I1, or I2, or stage II1 disease that is lymphoma positive after restaging with endoscopy
    • second-line or subsequent therapy for recurrent or progressive disease

  • Nongastric MALT lymphoma: (Category 2B)

    Used in patients with indications for treatment as:

    • first-line therapy for stage IV disease or recurrent stage I-II disease in patients with indications for treatment
    • second-line or subsequent therapy

  • Diffuse large B-cell lymphoma

    Second-line or subsequent therapy for relapsed or refractory primary cutaneous diffuse large B-cell lymphoma, leg type (Category 2A)

  • Nodal marginal zone lymphoma: (Category 2B)

    Used in patients with indications for treatment as:

    • first-line therapy for stage I (≥7 cm), contiguous stage II (≥7 cm), non-contiguous stage II, or stage III, IV disease
    • second-line or subsequent therapy

  • Histologic transformation of marginal zone lymphoma to diffuse large B-cell lymphoma (Category 2A)

    Treatment of patients who have received

    • minimal or no chemotherapy prior to histologic transformation to DLBCL and have partial response, no response, or progressive disease after chemoimmunotherapy
    • multiple prior therapies including ≥2 lines of chemoimmunotherapy for indolent or transformed disease

  • Splenic marginal zone lymphoma (Category 2B)

    Used in patients with indications for treatment as:

    • first-line therapy for disease recurrence following initial treatment for splenomegaly
    • second-line (if prior treatment with rituximab) or subsequent therapy.
Table: CPT Codes/ HCPCS Codes / ICD-10 Codes
Code Code Description

Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":

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
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)

The above policy is based on the following references:

  1. 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. 
  2. No authors listed. Ibritumomab tiuxetan (Zevalin) for non-Hodgkin's lymphoma. Med Lett Drugs Ther. 2002;44(1144):101-102.
  3. 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.
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. 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.
  9. 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.
  10. IDEC Pharmaceuticals. Zevalin (ibritumomab tiuxetan) prescribing information. San Diego, CA: IDEC; January 2002. 
  11. 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.
  12. 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.
  13. 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.
  14. 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.
  15. 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.
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  17. 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.
  18. Pandit-Taskar N, Hamlin PA, Reyes S, et al. New Strategies in radioimmunotherapy for lymphoma. Curr Oncol Rep. 2003;5(5):364-371.
  19. 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.
  20. 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. 
  21. Ansell SM, Armitage J. Non-Hodgkin lymphoma: Diagnosis and treatment. Mayo Clin Proc. 2005;80(8):1087-1097.
  22. 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.
  23. 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.
  24. 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.
  25. 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.
  26. 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.
  27. 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.
  28. 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.
  29. 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.
  30. 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.
  31. 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. 
  32. 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.
  33. 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.
  34. 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.
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  38. 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.
  39. 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.
  40. 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.
  41. 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.
  42. 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.
  43. 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.
  44. 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.
  45. 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.
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  49. 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.
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