Previously untreated follicular NHL who achieve a partial or complete response to first-line chemotherapy.¹

The efficacy of ZEVALIN as part of the first-line setting was established in a 414-patient Phase III trial.

 

  

A multicenter, randomized, open-label clinical study evaluated the safety and efficacy of the ZEVALIN therapeutic regimen in patients with follicular NHL who had achieved a partial (PR) or complete response (CR/CRu) to first-line chemotherapy. Key eligibility criteria included < 25% lymphoma involvement in the bone marrow, no prior external-beam radiation or myeloablative therapy, and recovery of platelets to normal levels. The primary efficacy endpoint was progression-free survival (PFS) as assessed by study investigators using the 1999 International Workshop to Standardize Response Criteria for NHL.¹

PFS was significantly prolonged among ZEVALIN-treated patients compared with those receiving no further treatment: median PFS 38 months versus 18 months, respectively (HR = 0.46 [95% CI: 0.35,0.60]); P < 0.0001).¹

Registrational Phase III Study in Previously Untreated Follicular NHL (n=414)

 

  

The ZEVALIN therapeutic regimen decreased the risk of disease progression by 54% when used after response to first-line chemotherapy in patients with follicular lymphoma. PFS was significantly prolonged among ZEVALIN-treated patients compared to those receiving no further treatment [median PFS 38 months vs. 18 months; HR 0.46 (95% CI: 0.35, 0.60); P < 0.0001)].¹

Study Safety Information

When administered following first-line chemotherapy, grade 3/4 adverse reactions of ZEVALIN include prolonged and severe cytopenias (thrombocytopenia [51%], neutropenia [41%], leukopenia [36%], lymphopenia [18%], and anemia [5%]) and secondary malignancies. Cytopenias were more severe and more prolonged among eleven (5%) patients who received ZEVALIN after first-line fludarabine or a fludarabine-containing chemotherapy regimen as compared to patients receiving non–fludarabine-containing regimens. Grade 3/4 infections occurred in 8% of ZEVALIN-treated patients and in 2% of controls and included neutropenic sepsis (1%), bronchitis, catheter sepsis, diverticulitis, herpes zoster, influenza, lower respiratory tract infection, sinusitis, and upper respiratory tract infection.

Among 204 patients receiving Y-90-ZEVALIN following first-line chemotherapy, two patients (1%) were diagnosed with AML within 3 years of receiving ZEVALIN.

Study References

• Morschhauser F, Radford J, Van Hoof A, et al. Phase III trial of consolidation therapy with yttrium-90-ibritumomab with no additional therapy after first remission in advanced follicular lymphoma. Journal of Clinical Oncology. 2008;26:5156-5164.

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Relapsed/Refractory, Low-grade or Follicular Non-Hodgkin's Lymphoma

Relapsed or refractory, low-grade or follicular B-cell Non-Hodgkin's Lymphoma (NHL).¹

The efficacy of ZEVALIN in the Relapsed/Refractory setting was determined in 3 separate registrational studies.

Study 1

A single-arm clinical study evaluated the ZEVALIN therapeutic regimen in patients with follicular NHL who were refractory to rituximab therapy (n = 54). Patients had < 25% lymphoma involvement in the bone marrow, a WHO performance status of 0-2, no prior bone marrow transplantation, and acceptable hematologic, renal, and hepatic function. Patients were considered refractory to rituximab if their last rituximab therapy did not result in a CR or PR or if time-to-disease-progression (TTP) was less than 6 months. The primary efficacy endpoint was overall response rate (ORR) using the International Workshop Response Criteria. Other efficacy endpoints included TTP and duration of response (DR).¹

The ZEVALIN therapeutic regimen produced an ORR of 74% with a 15% CR rate. The estimated median DR was 6.4 months [0.5-49.9+], with an estimated median TTP of 6.8 months [1.1-50.9+]. A summary of the efficacy data from this study is presented below.

Study References

• Witzig TE, Flinn IW, Gordon LI, et al. Treatment with ibritumomab tiuxetan radioimmunotherapy in patients with rituximab refractory follicular Non-Hodgkin's Lymphoma. Journal of Clinical Oncology. 2002;20: 3262-3269.

Study 2

A multicenter, randomized, open-label clinical study compared the efficacy of the ZEVALIN therapeutic regimen versus rituximab in patients with relapsed or refractory low-grade or follicular NHL (n = 130). Eligibility criteria included histologically confirmed NHL requiring therapy, < 25% lymphoma involvement in the bone marrow, a WHO performance status of 0-2, no prior bone marrow transplantation, and acceptable hematologic function. None of the patients had received prior therapy with rituximab. The primary efficacy endpoint was ORR using International Workshop Response Criteria.¹

The ZEVALIN therapeutic regimen produced an ORR of 83% with a 38% CR rate. The estimated median DR was 14.3 months [1.8-47.6+]^*, with an estimated median TTP of 12.1 months [2.1-49.0+]^*. A summary of the efficacy data from this study is presented below.

^*Not statistically significant

Study References

• 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. Journal of Clinical Oncology. 2002;20:2453-2463.

Study 3

Study 3 was a single arm study of 30 patients of whom 27 had relapsed or refractory low-grade, follicular NHL and a platelet count 100,000 to 149,000/mm³. Patients with ≥ 25% lymphomatous marrow involvement, prior myeloablative therapy with stem cell support, prior external beam radiation to > 25% of active marrow or neutrophil count < 1,500/mm³ were ineligible for Study 3. All patients received Y-90 ZEVALIN [0.3 mCi per kg (11.1 MBq per kg)]. Objective, durable clinical responses were observed [89% ORR (95% CI: 70-97%) with a median duration of response of 11.6 months (range: 1.0-42.4+ months)].

Study References

• Witzig, TE, White CA, Gordon, LI, et al. Safety of yttrium-90 ibribumomab tiuxetan radioimmunotherapy for relapsed low-grade, follicular, or transformed Non-Hodgkin's Lymphoma. Journal of Clinical Oncology. 2003;21:1263-1270.

Relapsed/Refractory Safety Information

Grade 3/4 adverse reactions of ZEVALIN in relapsed or refractory NHL patients include prolonged and severe cytopenias (thrombocytopenia [63%], neutropenia [60%], anemia [17%], and ecchymosis [<1%]) and secondary malignancies. Serious infections occurred in 3% of patients (urinary tract infection, febrile neutropenia, sepsis, pneumonia, cellulitis, colitis, diarrhea, osteomyelitis, and upper respiratory tract infection). Life-threatening infections were reported in 2% of patients (sepsis, empyema, pneumonia, febrile neutropenia, fever, and biliary stent-associated cholangitis).

Myelodysplastic syndrome (MDS) and/or acute myelogenous leukemia (AML) were reported in 5.2% (11/211) of patients with relapsed or refractory NHL enrolled in clinical studies and 1.5% (8/535) of patients included in the expanded-access trial, with median follow-up of 6.5 and 4.4 years, respectively. Among the 19 reported cases, the median time to diagnosis of MDS or AML was 1.9 years following treatment with the ZEVALIN therapeutic regimen; however, the cumulative incidence continues to increase.

References

1. ZEVALIN [package insert]. Irvine, CA: Spectrum Pharmaceuticals, Inc.; 2011.

 

View Indication and Important Safety Information

ZEVALIN^® (ibritumomab tiuxetan) is a CD20-directed radiotherapeutic antibody administered as part of the ZEVALIN therapeutic regimen indicated for the treatment of patients with:

• Relapsed or refractory, low-grade or follicular B-cell non-Hodgkin's lymphoma (NHL)
• Previously untreated follicular NHL who achieve a partial or complete response to first-line chemotherapy

WARNING: SERIOUS INFUSION REACTIONS, PROLONGED AND SEVERE CYTOPENIAS, and SEVERE CUTANEOUS AND MUCOCUTANEOUS REACTIONS Serious Infusion Reactions: Deaths have occurred within 24 hours of rituximab infusion, an essential component of the ZEVALIN therapeutic regimen. These fatalities were associated with hypoxia, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, or cardiogenic shock. Most (80%) fatalities occurred with the first rituximab infusion. Discontinue rituximab and Y-90 ZEVALIN infusions in patients who develop severe infusion reactions. Prolonged and Severe Cytopenias: Y-90 ZEVALIN administration results in severe and prolonged cytopenias in most patients. Do not administer Y-90 ZEVALIN to patients with ≥25% lymphoma marrow involvement and/or impaired bone marrow reserve. Severe Cutaneous and Mucocutaneous Reactions: Severe cutaneous and mucocutaneous reactions, some fatal, can occur with the ZEVALIN therapeutic regimen. Discontinue rituximab and Y-90 ZEVALIN infusions in patients experiencing severe cutaneous or mucocutaneous reactions. Dosing: The dose of Y-90 ZEVALIN should not exceed 32.0 mCi (1184 MBq).

ADDITIONAL IMPORTANT SAFETY INFORMATION

Leukemia and Myelodysplastic Syndrome: Among 204 patients receiving Y-90-ZEVALIN following first-line chemotherapy, two patients (1%) were diagnosed with AML within 3 years of receiving ZEVALIN.

Myelodysplastic syndrome (MDS) and/or acute myelogenous leukemia (AML) were reported in 5.2% (11/211) of patients with relapsed or refractory NHL enrolled in clinical studies and 1.5% (8/535) of patients included in the expanded-access trial, with median follow-up of 6.5 and 4.4 years, respectively. Among the 19 reported cases, the median time to diagnosis of MDS or AML was 1.9 years following treatment with the ZEVALIN therapeutic regimen; however, the cumulative incidence continues to increase.

Embryo-fetal Toxicity: May cause fetal harm if given during pregnancy.

Extravasation: Monitor for extravasation and terminate infusion if it occurs. Resume infusion in another limb.

Immunization: Do not administer live viral vaccines to patients who recently received ZEVALIN.

Laboratory Monitoring: Obtain complete blood counts (CBC) and platelet counts at least weekly.

Radionuclide Precautions: During and after radiolabeling ZEVALIN with Y-90, minimize radiation exposure to patients and to medical personnel, consistent with institutional good radiation safety practices and patient management procedures.

Creutzfeldt-Jakob Disease (CJD): The ZEVALIN therapeutic regimen contains albumin, a derivative of human blood. Based on effective donor screening and product manufacturing processes, ZEVALIN carries an extremely remote risk for transmission of viral diseases. A theoretical risk for transmission of CJD also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin.

Impairment of Fertility: There is a potential risk that the ZEVALIN therapeutic regimen could cause toxic effects on the male and female gonads. Effective contraceptive methods should be used during treatment and for up to 12 months following the ZEVALIN therapeutic regimen.

Nursing Mothers: Patients should be advised to discontinue nursing during and after ZEVALIN treatment.

Adverse Reactions: The most common adverse reactions of ZEVALIN are cytopenias, fatigue, abdominal pain, nausea, nasopharyngitis, asthenia, diarrhea, cough, and pyrexia. Common adverse reactions (≥40%) in clinical trials were: neutropenia, leukopenia, thrombocytopenia, anemia, infection, asthenia, musculoskeletal symptoms, and gastrointestinal symptoms. The most serious adverse reactions of ZEVALIN are prolonged and severe cytopenias (thrombocytopenia, anemia, lymphopenia, neutropenia) and secondary malignancies.

When administered following first-line chemotherapy, grade 3/4 adverse reactions of ZEVALIN include prolonged and severe cytopenias (thrombocytopenia [51%], neutropenia [41%], leukopenia [36%], lymphopenia [18%], and anemia [5%]) and secondary malignancies. Cytopenias were more severe and more prolonged among eleven (5%) patients who received ZEVALIN after first-line fludarabine or a fludarabine-containing chemotherapy regimen as compared to patients receiving non–fludarabine-containing regimens. Grade 3/4 infections occurred in 8% of ZEVALIN-treated patients and in 2% of controls and included neutropenic sepsis (1%), bronchitis, catheter sepsis, diverticulitis, herpes zoster, influenza, lower respiratory tract infection, sinusitis, and upper respiratory tract infection.

Grade 3/4 adverse reactions of ZEVALIN in relapsed or refractory NHL patients include prolonged and severe cytopenias (thrombocytopenia [63%], neutropenia [60%], anemia [17%], and ecchymosis [<1%]) and secondary malignancies. Serious infections occurred in 3% of patients (urinary tract infection, febrile neutropenia, sepsis, pneumonia, cellulitis, colitis, diarrhea, osteomyelitis, and upper respiratory tract infection). Life-threatening infections were reported in 2% of patients (sepsis, empyema, pneumonia, febrile neutropenia, fever, and biliary stent-associated cholangitis).

Please click here to read full Prescribing Information, including BOXED WARNINGS, for ZEVALIN. Because the ZEVALIN therapeutic regimen includes the use of rituximab, please also consult prescribing information for rituximab.