1. Ibritumomab tiuxetan (Zevalin)

   Aetna considers radioimmunotherapy with ibritumomab tiuxetan (Zevalin) medically necessary for the following types of non-Hodgkin's lymphoma: follicular lymphoma, gastric MALT lymphoma, non-gastric MALT lymphoma, primary cutaneous B-cell lymphoma, and splenic marginal zone lymphoma. 

   Aetna considers the Zevalin therapeutic regimen experimental and investigational for all other indications (e.g., chronic lymphocytic leukemia, and mantle cell lymphoma) because its effectiveness for these indications has not been estanlished.

   A single course of treatment with Zevalin therapeutic regimen is considered medically necessary.  The U.S. Food and Drug Administration (FDA) has stated that the safety of multiple courses of the Zevalin therapeutic regimen, or combination of this regimen with other forms of irradiation, has not been evaluated.  

2. Tositumomab (Bexxar)

   Aetna considers radioimmunotherapy with tositumomab (Bexxar) medically necessary for the following types of non-Hodgkin's lymphoma: follicular lymphoma, gastric MALT lymphoma, non-gastric MALT lymphoma, primary cutaneous B-cell lymphoma, and splenic marginal zone lymphoma. 

   Aetna considers the Bexxar therapeutic regimen experimental and investigational for all other indications (e.g., thyroid cancer and other solid tumors) because its effectiveness for these indications has not been estanlished.

   A single course of treatment with Bexxar therapeutic regimen is considered medically necessary.  The FDA has stated that the safety of multiple courses of the Bexxar therapeutic regimen, or combination of this regimen with other forms of irradiation or chemotherapy, has not been evaluated.

This policy is consistent with the Food and Drug Adminsitration (FDA)-approved indications for ibritumomab tiuxetan (Zevalin) (IDEC Pharmaceuticals, San Diego, CA) and for tositumomab (Bexxar) (Corixa Corporation, Seattle, WA).

Ibritumomab tiuxetan 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.

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.

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.

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.

The FDA-approved labeling of Zevalin states that it should not be administered to patients with 25 % or more lymphoma marrow involvement or impaired bone marrow reserve, e.g., prior myeloablative therapies; platelet count less than 100,000 cells/mm3; neutrophil count less than 1,500 cells/mm3; hypocellular bone marrow.

Guidelines from the National Comprehensive Cancer Network (2012) state that ibritumomab tiuxetan radioimmunotherapy alone is indicated in follicular lymphoma, gastric MALT lymphoma, non-gastric MALT lymphoma, or primary cutaneous B-cell lymphoma.  For these indications, tositumomab is indicated following chemotherapy or as second-line radioimmunotherapy or refractory or progressive disease, or as first-line therapy for persons with comorbidities, including the elderly or infirm, where tolerability of combination chemotherapy is a concern.

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.

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.

Bexxar consists of a monoclonal antibody, tositumomab, linked to the radioactive isotope iodine iodine-131.  The monoclonal antibody targets the CD20 antigen, which is found on the surface of mature B cells and B cell tumors. 

The Bexxar therapeutic regimen is administered in 2 steps: (i) the dosimetric and (ii) therapeutic steps.  Each step consists of a sequential infusion of tositumomab followed by iodine-131 (I-131) tositumomab.  The therapeutic step is administered 7 to 14 days after the dosimetric step.

The purpose of the dosimetric step is to provide a consistent radiation dose by adjusting for the individual patient’s rate of clearance of the drug.  Clinical studies found that patients with high tumor burden, splenomegaly, or bone marrow involvement have a faster clearance, shorter terminal half-life, and larger volume of distribution.  Patient-specific dosing, based on total body clearance, has been found to provide a consistent radiation dose, despite variable pharmacokinetics, by allowing each patient’s administered activity to be adjusted for individual patient variables.

The efficacy of the Bexxar therapeutic regimen was evaluated in a multi-center, single-arm study in 40 patients with low-grade or transformed low-grade or follicular large-cell lymphoma whose disease had not responded to or had progressed after rituximab therapy.  Determination of clinical benefit of the Bexxar therapeutic regimen was based on evidence of durable responses.  All patients in the study were required to have received prior treatment with at least four doses of rituximab without an objective response, or to have progressed following treatment.

Overall response rate was 68 %, with a median duration of response of 16 months.  One-third of patients demonstrated a complete response.  Among a subset of patients who were refractory to rituximab, overall response rate was 63 %, with a median duration of response of 25 months.  Twenty-nine percent of patients who were refractory to rituximab exhibited a complete response to the Bexxar therapeutic regimen.

The results of this study were supported by demonstration of durable objective responses in 4 single-arm studies enrolling 190 patients evaluable for efficacy with rituximab-naïve, follicular non-Hodgkin lymphoma (NHL) with or without transformation, who had relapsed following or were refractory to chemotherapy.  In these studies, the overall response rates ranged from 47 % to 64 % and the median durations of response ranged from 12 to 18 months.  It is not known whether the Bexxar therapeutic regimen improves OS.

The most common adverse reactions associated with the Bexxar therapeutic regimen were severe or life-threatening cytopenias, which occurred among 71 % of patients enrolled in clinical studies.  These severe or life-threatening cytopenias consisted primarily of severe thrombocytopenia (53 %) and severe neutropenia (63 %).  Sequelae of severe cytopenias observed in clinical studies included infections (45 % of patients), hemorrhage (12 %), a requirement for growth factors (12 % hematopoietic colony stimulating factors; 7 % erythropoietin) and blood product support (15 % platelet transfusions; 16 % red blood cell transfusions).  Myelodysplastic syndrome or acute leukemia was reported in 8 % of subjects enrolled in clinical studies.

According to the FDA, the safety of the Bexxar therapeutic regimen has not been established in patients with greater than 25 % lymphoma marrow involvement, platelet count less than 100,000 cells/mm3 or neutrophil count less than 1,500 cells/mm3.

The FDA-approved labeling of Bexxar states that I-131 tositumomab is contraindicated for use in women who are pregnant.  The labeling states that I-131 may cause harm to the fetal thyroid gland when administered to pregnant women, and that transplacental passage of radioiodide may cause severe, and possibly irreversible, hypothyroidism in neonates.  The FDA recommends that the use of the Bexxar therapeutic regimen in women of child-bearing age should be deferred until the possibility of pregnancy has been ruled out.  If the patient becomes pregnant while being treated with the Bexxar therapeutic regimen, the patient should be apprised of the potential hazard to the fetus.

The FDA-approved labeling states that the Bexxar therapeutic regimen may result in hypothyroidism.  The labeling states that thyroid-blocking medications should be initiated at least 24 hours before receiving the dosimetric dose and continued until 14 days after the therapeutic dose.  The FDA-approved labeling states that persons who are unable to tolerate thyroid blocking agents should not receive Bexxar.

Guidelines from the National Comprehensive Cancer Network (2012) state that tositumomab radioimmunotherapy alone is indicated in follicular lymphoma, gastric MALT lymphoma, non-gastric MALT lymphoma, or primary cutaneous B-cell lymphoma.  For these indications, tositumomab is indicated following chemotherapy or as second-line radioimmunotherapy or refractory or progressive disease, or as first-line therapy for persons with co-morbidities, including the elderly or infirm, where tolerability of combination chemotherapy is a concern.

Song and Sgouros (2011) stated that radioimmunotherapy of solid tumors remains a challenge despite the tremendous success of 90Y-ibritumomab (Zevalin) and I-131 tositumomab (Bexxar) in treating non-Hodgkin's lymphoma.  For a variety of reasons, clinical trials of radio-labeled antibodies against solid tumors have not led to responses equivalent to those seen against lymphoma.  In contrast, promising responses have been observed with unlabeled antibodies that target solid tumor receptors associated with cellular signaling pathways.  These observations suggest that anti-tumor efficacy of the carrier antibody might be critical to achieving clinical responses.

On February 20, 2014, GlaxoSmithKline announced that it will discontinue the manufacture and sale of the BEXXAR® therapeutic regimen (tositumomab and iodine I 131 tositumomab). 

Vaklavas et al (2013) stated that radioimmunotherapy (RIT) capitalizes on the radio-sensitivity of NHL and the targeted nature of monoclonal antibodies.  In an attempt to reverse bone marrow infiltration with B-cells and optimize the bio-distribution of 90 (90)Y-ibritumomab tiuxetan, these researchers conducted a phase I study combining a single course of (90)Y-ibritumomab tiuxetan after a 4-weekly course of rituximab in relapsed or refractory low-grade or transformed CD20+ B-cell NHLs with less than 25 % marrow involvement.  The 0.4 mCi/kg dose was associated with 80 % grade-4 cytopenias.  Dose escalation was held, and 6 patients were enrolled at a 0.3 mCi/kg cohort.  As the 0.3 mCi/kg dose was well-tolerated, the 0.4 mCi/kg cohort was expanded to 6 additional patients.  In the expansion cohort, grade-4 cytopenia developed in 33 %.  Further dose escalation was held, and the maximum tolerated dose was determined at 0.4 mCi/kg.  With this regimen, marrow involvement decreased in all patients with complete clearance in 50 %.  The overall response rate (ORR) was 82 %.  With a median follow-up of 31.7 months, the median PFS and time to next treatment were 12.3 and 10.9 months, respectively.  The authors concluded that although this regimen was associated with a high response rate, the hematologic toxicity was higher than with the standard (90)Y-ibritumomab tiuxetan regimen.

Witzig and associates (2013) noted that RIT for relapsed indolent NHL produces ORR of 80 % with mostly partial remissions.  Synthetic CpG oligonucleotides change the phenotype of malignant B-cells, are immuno-stimulatory, and can produce responses when injected intra-tumorally and combined with conventional radiation.  In a phase I clinical trial, these researchers tested systemic administration of both CpG and RIT.  Eligible patients had biopsy-proven previously treated CD20+ B-cell NHL and met criteria for RIT.  Patients received rituximab 250 mg/m(2) days 1,8, and 15; (111) In-ibritumomab tiuxetan days 1, 8; CpG 7909 days 6, 13, 20, 27; and 0.4 mCi/kg of (90) Y-ibritumomab tiuxetan day 15.  The doses of CpG 7909 tested were 0.08, 0.16, 0.32 (6 patients each) and 0.48 mg/kg (12 patients) IV over 2 hours without dose limiting toxicity.  The ORR was 93 % (28/30) with 63 % (19/30) complete remission (CR); median PFS of 42.7 months (95 % CI: 18 to NR); and median duration of response (DR) of 35 months (4.6 to 76+).  Correlative studies demonstrated a decrease in IL10 and TNFα, and an increase in IL1β, in response to therapy.  The authors concluded that CpG 7909 at a dose of 0.48 mg/kg is safe with standard RIT and produces a high CR rate and long DR; moreover, they state that these results warrant confirmation.

In a multi-center, phase II, pilot trial, Arranz et al (2013) evaluated the feasibility, safety and effectiveness of rituximab-hyperCVAD alternating with rituximab-methotrexate-cytarabine followed by consolidation with (90)Y-ibritumomab tiuxetan in patients with MCL.  Patients received 6 cycles followed by a single dose of (90)Y-ibritumomab tiuxetan.  A total of 30 patients were enrolled; their median age was 59 years.  Twenty-four patients finished the induction treatment, 23 achieved CR (77 %, 95 % CI: 60 to 93) and 1 patient had progressive disease (3 %).  Eighteen patients (60 %), all in CR, received consolidation therapy.  In the intent-to-treat population, failure-free, PFS and OS rates at 4 years were 40 % (95 % CI: 20.4 to 59.6), 52 % (95 % CI: 32.4 to 71.6) and 81 % (95 % CI: 67.28 to 94.72), respectively.  For patients who received consolidation, failure-free and OS rates were 55 % (95 % CI: 31.48 to 78.52) and 87 % (95 % CI: 70 to 100), respectively.  Hematologic toxicity was significant during induction and responsible for 1 death (3.3 %).  After consolidation, grade 3 to 4 neutropenia and thrombocytopenia were observed in 72 % and 83 % of patients, with a median duration of 5 and 12 weeks, respectively.  Six (20 %) patients died, 3 due to secondary malignancies (myelodysplastic syndrome and bladder and rectum carcinomas).  The authors concluded that rituximab-hyperCVAD alternated with rituximab-methotrexate-cytarabine and followed by consolidation with (90)Y-ibritumomab tiuxetan was effective although less feasible than expected.  Moreover, they stated that unacceptable toxicity observed, especially secondary malignancies, advised against the use of this strategy.

Kolstad and colleagues (2014) noted that the main objective of the MCL3 study was to improve outcome for patients with MCL not in CR before transplant by adding (90)Y-ibritumomab-tiuxetan (Zevalin) to the high-dose regimen.  A total of 160 untreated, stage II to IV MCL patients less than 66 years received rituximab (R)-maxi-CHOP (cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone) alternating with R-high-dose cytarabine (6 cycles total), followed by high-dose BEAM/C (bis-chloroethylnitrosourea, etoposide, cytarabine, and melphalan or cyclophosphamide) and autologous stem cell transplantation from 2005 to 2009.  Zevalin (0.4 mCi/kg) was given to responders not in CR before transplant.  Overall response rate pre-transplant was 97 %.  The outcome did not differ from that of the historic control: the MCL2 trial with similar treatment except for Zevalin.  Overall survival, EFS, and PFS at 4 years were 78 %, 62 %, and 71 %, respectively.  For responding non-CR patients who received Zevalin, DR was shorter than for the CR group.  Inferior PFS, EFS, and OS were predicted by PET positivity pre-transplant and detectable minimal residual disease (MRD) after transplant.  The authors concluded that positive PET and MRD were strong predictors of outcome.  Intensification with Zevalin may be too late to improve the outcome of patients not in CR before transplant.

Appendix

NCCN guidelines indicate Zevalin and Bexxar for the following indications:

Follicular Lymphoma - First-line radioimmunotherapy alone in elderly or infirm patients with the indications for treatment in the setting of comorbidities where tolerability of combination chemotherapy is a concern, or following chemotherapy or as second-line radioimmunotherapy for refractory or progressive disease in patients with the indications for treatment.

Gastric MALT Lymphoma - First-line radioimmunotherapy alone in elderly or infirm patients with the indications for treatment in the setting of comorbidities where tolerability of combination chemotherapy is a concern, or following chemotherapy for stage IIIE-IV disease or as second-line radioimmunotherapy for recurrent or progressive disease in patients with the indications for treatment.

Nongastric MALT Lymphoma - First-line radioimmunotherapy alone in elderly or infirm patients with the indications for treatment in the setting of comorbidities where tolerability of combination chemotherapy is a concern, or following chemotherapy for stage III-IV disease or second-line radioimmunotherapy for recurrent stage I-II disease or for progressive disease in patients with the indications for treatment.

Primary Cutaneous B-Cell Lymphoma - Radioimmunotherapy alone, including in elderly or infirm patients with the indications for treatment in the setting of comorbidities where tolerability of combination chemotherapy is a concern, or following chemotherapy for refractory generalized cutaneous or newly diagnosed generalized extracutaneous primary cutaneous marginal zone or follicle center lymphoma or as second-line radioimmunotherapy for refractory generalized cutaneous disease or relapsed generalized extracutaneous disease in patients with the indications for treatment.

Splenic Marginal Zone Lymphoma - For progessive disease following initial treatment for splenomegaly in patients with the indications for treatment as:

• first-line radioimmunotherapy alone in elderly or infirm patients with the indications for treatment in the setting of comorbidities where tolerability of combination chemotherapy is a concern, or following chemotherapy
• second-line radioimmunotherapy.