1. Indications
   1. Radioimmunotherapy (RIT) with Zevalin® is considered medically necessary for an individual with any of the following:
      1. Relapsed low grade B-cell CD20-positive follicular Non-Hodgkin's lymphomas (NHLs).
      2. Refractory low grade B-cell CD20-positive follicular NHLs.
      3. Newly diagnosed (consolidation after chemotherapy) low grade B-cell CD20-positive NHLs after at least a partial response (PR) to therapy.
      4. Newly diagnosed (initial treatment) low grade B-cell CD20-positive follicular NHLs for the elderly or infirm when no other option is expected to be tolerated.
      5. Transformed B-cell follicular NHLs that are CD20-positive.

[RATIONALE:

1. Agent

Currently, there is one Food and Drug Association (FDA) approved RIT agent in the United States (US), ⁹⁰Y ibritumomab tiuxetan (Zevalin^®). Tositumomab (Bexxar™) was withdrawn permanently from the US market in February 2014. Zevalin^® has FDA approval for relapsed or refractory CD20 positive follicular NHL and as a frontline adjuvant agent for CD20 positive follicular NHL achieving a complete response (CR) or partial response (PR) to induction chemotherapy (consolidation after chemotherapy). It contains murine Immunoglobulin-G (IgG) monoclonal antibodies (mAbs) that target the CD20 surface antigen on CD20 positive follicular NHL.

Zevalin^® utilizes ⁹⁰Y, a pure β-particle emitter with a physical half-life of 2.7 days. The β-particle has an energy of 2.3 megaelectronvolts (MeV) and a maximum tissue penetration of approximately 12.0 mm (R₉₀ = 5.2 mm). As such, physical contact with loved ones after administration is not limited except that sexual intercourse and kissing should be avoided in the first 24 hours. Tiuxetan is a DTPA-type chelate that attaches ⁹⁰Y to the mAb, ibritumomab. Because there is no gamma emission in the spectrum of this isotope, it is not visualized by gamma camera scans. As a result, a biodistribution assessment cannot be performed. Therefore, a surrogate imaging radionuclide that emits gamma radiation (¹¹¹In) is required.

The treatment is delivered over 1 to 2 weeks. On day 1, an infusion of nonradioactive (cold) rituximab is delivered. This is designed to saturate the CD20 antigen sink (depletion of peripheral B-cells and the binding of nonspecific sites in the liver and spleen) and provide antibody mass, which improves biodistribution and tumor targeting.

The administered activity for Zevalin^® is based on weight (0.4 mCi/kg for a platelet count ≥ 150,000; 0.3 mCi/kg for a platelet count of 100,000 to 149,000; maximum of 32 mCi). A single gamma scan (¹¹¹In ibritumomab tiuxetan) is used to confirm a normal biodistribution on days 3 to 4. A review of the Zevalin^® imaging registry reveals that only 0.6% of scans exhibited an altered biodistribution. An eligible individual is also required to have an absolute neutrophil count (ANC) ≥ 1,500 and a bone marrow biopsy that reveals <25% involvement with lymphoma.

A. Relapsed or refractory setting

There is no standard therapy for an individual with relapsed or refractory FL, and practice varies widely; as such, an individual should be encouraged to participate in clinical trials whenever possible.

The main treatment options for an individual with relapsed or refractory FL include:

1. Clinical trials of new agents or new combinations of existing agents

2. Immunotherapy either with single agent rituximab or rituximab plus chemotherapy

3. RIT with radiolabeled antibodies

4. Re-challenge of original therapy

5. High dose chemotherapy with autologous hematopoietic cell transplantation (HCT) rescue

6. Allogeneic HCT

RIT has demonstrated response rates of approximately 60% to 80%. However, RIT is not recommended for an individual with poor bone marrow reserve or high tumor burden in the bone marrow and requires coordination with physicians trained in the safe use of radionucleotides.

Prospective trials of RIT demonstrate response rates of 60% to 80% in previously treated disease ((Buchegger et al., 2006; Davies et al., 2004; Davis et al., 2004; Fisher et al., 2005; Horning et al, 2005; Leahy et al., 2006; Vose et al., 2000; Wiseman et al., 2002). Median progression-free survival (PFS) is less than one year, but an individual who achieves a complete response has a median time to progression of close to 4 years (Gordon et al., 2004; Witzig et al., 2007).

A phase III study comparing Zevalin^® versus rituximab for patients with relapsed or refractory low-grade follicular B-cell NHL or transformed NHL was performed (Witzig, et al., 2002). Patients were randomized to either a single intravenous (IV) dose of Zevalin^® 0.4 mCi/kg (n = 73) or IV rituximab 375 mg/m² weekly for 4 doses (n = 70). The RIT group was pre-treated with 2 rituximab doses (250 mg/m²) to improve biodistribution and tumor targeting. After the first rituximab dose on day 1, ¹¹¹In ibritumomab tiuxetan was administered to assess biodistribution and to aide in dosimetry. No patients received the therapeutic dose of Zevalin^® if > 20 Gy or 3 Gy was calculated to any non-tumor organ or the red marrow, respectively. Zevalin^® was administered after the second rituximab dose approximately 1 week (days 7 to 9) after the first dose of rituximab and ¹¹¹In ibritumomab tiuxetan. The administered activity of Zevalin^® was capped at 32 mCi. Patients in both arms of the study received 2 prior chemotherapy regimens. The overall response rate (ORR) was 80% for Zevalin^® and 56% for rituximab (p = 0.002). The CR rates were 30% and 16% (p = 0.04), respectively, in the Zevalin^® and rituximab group. Durable responses ≥ 6 months were 64% versus 47% (p = 0.030) for Zevalin^® versus rituximab. The conclusion of the study was that RIT with Zevalin^® was well tolerated and resulted in statistically significant and clinically significant higher ORRs and CRs than rituximab alone.

In a pivotal, nonrandomized, phase III multicenter trial (Kaminski et al., 2001), patients with relapsed, refractory, or transformed follicular B-cell NHL were treated with Bexxar™ (n = 60). A single dose resulted in an overall response rate of 65% (20% CR). Eligible patients were required to have been treated with at least two prior protocol-specific chemotherapy regimens (median of four regimens in the study) and to either have not responded or progressed within 6 months of therapy. A PR or CR was observed in 39 patients (65%) after Bexxar™ compared to 17 patients (28%) after last qualifying chemotherapy (LQC) (p <0.001). The median duration of response was 6.5 months for Bexxar™ and 3.5 months for the LQC group (p <0.001). The CR rate was 20% for Bexxar™ and 3% for the LQC group (p <0.001). The conclusion of the study was that a single dose of Bexxar™ was significantly more efficacious than the LQC received by heavily pre-treated patients with relapse or refractory follicular B-cell NHL.

Early evidence suggests that an individual relapsing following treatment with RIT may tolerate other treatment approaches including chemotherapy, external beam radiation therapy (EBRT) with photons and/or electrons, and autologous HCT.


B. Frontline therapy

Seventy to 85 percent of individuals present with advanced stage disease. Individuals with advanced stage disease are usually not cured with conventional treatment. While remissions can be attained, repeated relapses are common. Treatment focuses on the alleviation of symptoms, reversal of cytopenias, and improvement of quality of life. The disease course is variable with some individuals demonstrating stable disease for years and others progressing more rapidly. Rarely, individuals may have spontaneous remissions lasting longer than one year.

Considering the concerns about RIT for treating large bulky tumors (tumor penetration, overall required dose, non-uniform dose distribution), it would appear that bringing RIT into a frontline therapeutic setting after induction chemotherapy and maximum cyto-reduction would be the next logical direction.

A phase III first-line indolent trial (FIT) of consolidation with Zevalin^® compared to no additional therapy after first remission was reported for follicular B-cell NHL (Morschhauser et al., 2013; Morschhauser et al., 2008).

Patients with CD20+ stage III/IV follicular B-cell NHL who achieved a PR or CR to induction chemotherapy were randomized to Zevalin^® (n = 208) or to the control arm, representing no further treatment (n = 206). After a median follow-up of 7.3 years, consolidation with Zevalin^® resulted in an estimated 8-year PFS advantage of 41% versus 22% in the control arm (p <0.0001). The median PFS was 4.1 years vs. 1.1 years, respectively (p <0.001). No significant difference in overall survival (84% vs. 81%) was observed between treatment arms. The incidence of secondary malignancies was higher in the RIT arm but the difference was not statistically significant (13% vs. 7%). Incidence of MDS/AML was significantly higher in RIT arm with an actuarial 8-year incidence rate of 4.2% vs. 0.6% (p <0.042). Only 14% of patients in this study received rituximab in combination with chemotherapy as induction. The estimated 8-year PFS advantage was 56% versus 45% in the control arm. The median PFS was 7.9 years vs. 4.9 years, respectively. The difference in PFS outcomes was not significant in this subgroup; however, the trial was not statistically powered to detect differences in subgroups based on induction therapies. Since only a small portion of patients enrolled in the FIT trial received rituximab-containing induction therapy, the effects of RIT consolidation following rituximab-containing regimens cannot be fully evaluated.

The phase III randomized intergroup study by the SWOG/CALGB (S0016) evaluated the role of RIT consolidation following R-CHOP. In this study, 554 patients with newly diagnosed FL were randomly assigned to chemoimmunotherapy alone (RCHOP for 6 cycles) or to chemotherapy plus a radioimmunoconjugate (CHOP for 6 cycles followed by ¹³¹I. When compared with R-CHOP, CHOP plus Bexxar™ resulted in similar rates of overall (84% each) and complete (45% vs. 40%) remissions. Severe (grade 3/4) thrombocytopenia was greater (18% vs. 2%) among those who received a radioimmunoconjugate. At a median follow-up of 4.9 years, chemoimmunotherapy alone resulted in similar rates of PFS (76% vs. 80%) and OS (97% vs. 93%) at 2 years.

These trials suggest that consolidation with a radioimmunoconjugate may be able to improve the quality of remission by converting PRs into CRs. Indication of RIT in relapsed or refractory disease as well as consolidation in frontline therapy when chemotherapy alone has been used for induction is well supported in literature. However, it is not known whether the addition of an anti-CD20 radioimmunoconjugate improves outcomes of an individual already receiving chemoimmunotherapy. The role in the frontline setting is under investigation.

National Comprehensive Cancer Guidelines (NCCN) Guidelines^® (Follicular Lymphoma [grade 1-2], FOLL-B 1of 3, First-line Consolidation or Extended Dosing [optional]) consider RIT after induction with chemotherapy or chemoimmunotherapy a category 1 recommendation but adds the following footnotes:

• “f First-line consolidation with radioimmunotherapy or extended dosing of rituximab after bendamustine + rituximab has not been studied.”
• “g The full impact of an induction regimen containing rituximab on RIT consolidation is unknown.”
In frontline setting, RIT is also indicated for the elderly or infirm when no other option is expected to be tolerated.

C. Off-label use of radioimmunoconjugates as single-agent therapy for the management of previously untreated disease

Nonrandomized trials support use of radioimmunoconjugates as single-agent therapy for the management of previously untreated disease. While initial reports suggest good response rates and tolerability, long-term follow-up of such an approach is limited. The following describes the largest phase II trials evaluating RIT for initial management of advanced stage FL:

In an international phase II trial (Scholz et al., 2013) of 59 older patients (> 50) with stage II to IV FL, Zevalin^® was used as first line therapy and resulted in an ORR of 87% at 6 months with 56% of patients achieving a CR. After a median follow-up of 31 months, the median PFS was 26 months and the median overall survival had not been reached. Rates of PFS at 1 and 2 years were 77% and 54%, respectively. Severe (grade 3/4) thrombocytopenia, leukopenia, neutropenia, and lymphopenia were seen in approximately 48%, 34%, 32%, and 20%. Non-hematologic toxicities were mostly mild to moderate and included infections (20%) and gastrointestinal toxicities (10 %).

In an international phase II trial (Illidge et al., 2014), 74 patients with previously untreated FL (78% advanced stage) received 2 cycles of Zevalin^®. Patients with > 20% bone marrow infiltration were pretreated with four cycles of rituximab. The overall response rate was 94% (CR/complete response unconfirmed [CRu] 58%). At a median follow-up of 3 years, the estimated rates of PFS and OS at three years were 58% and 95%, respectively. Median PFS was 40 months. Toxicity was mild with the most common side effects being lethargy and gastrointestinal side effects.

In another phase II trial evaluating Bexxar™ (Kaminski et al., 2005) in 76 patients with stage III or IV FL requiring therapy, the ORR was 95% with 75% CRs. The median PFS was 6 years and the 10-year PFS rate was 40%. One patient developed MDS 8 years after treatment.


D. Histologic transformation of follicular lymphoma

The most commonly employed treatment regimens for an individual with histologic transformation (HT) includes conventional chemotherapy with immunotherapy (e.g.-CHOP), RIT, and high-dose therapy followed by autologous HCT. An individual who is not candidates for HCT may be considered for RIT.

An individual with HT of FL who is resistant to initial therapy or who relapses following initial therapy, is expected to do poorly. Available treatment options include enrollment in a clinical trial, use of chemotherapy regimens similar to that employed in relapsed/resistant diffuse large B cell lymphoma (DLBCL), or RIT. An individual with disease that responds to treatment may be a candidate for autologous or allogeneic HCT.

There are no prospective trials evaluating the use of RIT as consolidation in individuals with chemotherapy sensitive HT or DLBCL. Some clinicians offer the off-label use of RIT as consolidation in individuals with chemotherapy sensitive HT who have received extensive prior therapy and who are not candidates for autologous HCT. Given the paucity of data regarding this approach, RIT should be used in the context of a clinical trial.

NCCN Guidelines^® consider RIT an option for an individual with multiple prior therapies and for an individual with minimal or no prior chemotherapy with progression of disease, no response, or partial response to chemotherapy +/- rituximab +/- RT.


E. Preparative regimens for HCT – (Investigational])

The maximally tolerated dose of total body irradiation (TBI) is approximately 15 Gy. A randomized trial comparing 12 and 16 Gy found that the higher dose was associated with a lower relapse rate (12% vs. 35% at three years in patients with acute myeloid leukemia) (Clift, et al., 1991). One approach to achieving this goal has been the administration of mAbs radiolabeled with high energy emitting radioisotope. This would permit targeting of the radiation dose to the tumor cells and marrow with potential reduction in dose to other organs, such as the liver, lungs and kidneys.

RIT has been added to standard preparative regiments in the autologous setting for the treatment of patients with B cell NHL, with encouraging preliminary results and tolerable toxicity profiles (Gopal et al., 2007, Gopal et al., 2011; Krishnan et al., 2008). A randomized trial comparing Bexxar™-BEAM with BEAM has been conducted by the Bone Marrow Transplantation Clinical Trials Network (BMT-CTN 0401). Patient accrual has been completed but results have not yet been released.


F. Toxicities

The most profound side effects of RIT are potentially prolonged and significant cytopenias with cell count nadirs ranging from four to nine weeks post-therapy with recovery one to four weeks post-nadir. The most common cytopenias are leucopenia and thrombocytopenia, which are easily managed in the majority of individuals. RIT causes a transient depletion of B cells for approximately 6 to 9 months, but has not been associated with significant increases in severe infections or hospitalizations. RIT can be associated with an infusion reaction similar to that seen with other monoclonal antibodies.

Although initial reports suggested a possible risk of treatment-related MDS (t-MDS) and acute myeloid leukemia (t-AML), the rate of t-MDS and t-AML does not appear to be increased. An evaluation of 746 patients treated for NHL with Zevalin^® found that the rates of t-MDS and t-AML were not increased compared with historic rates in those who had received multiple chemotherapeutic regimes (Czuczman et al., 2007).

A bilateral bone marrow biopsy is required prior to the initiation of RIT to assess bone marrow involvement. RIT is not recommended in an individual with inadequate marrow reserve (i.e., platelet count < 100,000/microL, absolute neutrophil count < 1,500/microL, bone marrow cellularity < 15%), lymphoma bone marrow involvement > 25%, or previous radiation to > 25% of active marrow sites. Due to the risk of delayed hematologic toxicity, an individual should have blood count monitoring at least weekly following treatment until hematologic recovery.


G. NCCN Guidelines^™ consider RIT an option:

1. In primary cutaneous diffuse large B-cell Lymphoma, LEG type (T3, generalized disease only with either PR or relapse after R-CHOP +/- local RT)

2. For stage III/IV non-gastric MALT lymphoma with extranodal disease and multiple nodal sites as well as post RT recurrent gastric MALT lymphoma [through follicular lymphoma (FL) pathway]

3. For progressive splenic marginal zone lymphoma (through FL pathway)

4. In an individual with transformed B-cell FLs who has received multiple prior therapies, and

5. In an individual with minimal or no prior chemotherapy with progression of disease, no response, or partial response to chemotherapy +/- rituximab +/- RT

A. Poor bone marrow reserve (platelet count < 100,000/microL, absolute neutrophil count < 1,500/microL, bone marrow cellularity < 15%)

B. High tumor burden in the bone marrow (lymphoma bone marrow involvement > 25%) Bilateral cores are recommended and the pathologist should provide the percent of cellular elements involved in the marrow. Cytogenetics +/- fluorescence in situ hybridization (FISH) for known Myelodysplastic syndrome (MDS) markers. A trend towards an increased risk of MDS with RIT has been suggested

C. Previous radiation to > 25% of active marrow sites

D. In an individual with prior autologous stem cell rescue, referral to a tertiary care center is highly recommended.

E. An individual who is pregnant

A. Newly diagnosed (consolidation after chemoimmunotherapy)

1. It is not known whether the addition of RIT improves outcome of individual receiving chemoimmunotherapy. The role in the frontline setting is under investigation. NCCN Guidelines^™ on FL (grade 1-2) consider radioimmunotherapy after induction with chemotherapy or chemoimmunotherapy a category 1 recommendation but adds the following footnotes:

a. “f First-line consolidation with radioimmunotherapy or extended dosing of rituximab after bendamustine + rituximab has not been studied.”

b. “g The full impact of an induction regimen containing rituximab on RIT consolidation is unknown.”

B. RIT as single-agent (initial therapy/previously untreated disease)

C. Preparative regimens for hematopoietic cell transplantation (HCT)

D. Any type of NHL other than mentioned above

E. Solid tumors

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Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

CPT*

A9542
A9543
A9545