Impressive Zevalin Data Highlighted at 53^rd Annual Meeting of the ASH; Spectrum to Increase Clinical Efforts to Expand Zevalin Indications

Spectrum Pharmaceuticals announced results from several clinical trials further expanding the body of evidence supporting the safety and efficacy of Zevalin (ibritumomab tiuxetan) injection for intravenous use. Data were presented at the 53rd Annual Meeting of the American Society of Hematology (ASH), held in December 2011 in San Diego, California. Results from multiple studies of Zevalin were presented in 19 abstracts. Encouraging data were reported in diverse patient groups, including those with newly diagnosed follicular lymphoma, relapsed/refractory follicular lymphoma, marginal zone lymphoma, and patients who had received autologous or allogeneic transplantation.

Following are summaries of the key Zevalin abstracts presented at the ASH:
Abstract #99: Phase II Study with R-FND Followed by Zevalin and Rituximab Maintenance for Untreated High-risk Follicular Lymphoma: 49 patients were enrolled and 47 received treatment between October 2004 and April 2009. Following R-FND (rituximab, fludarabine, mitoxantrone, and dexamethasone), the complete (CR+CRu) and partial response rates were 87% and 13%, respectively. With RIT consolidation, the CR rate increased to 91%. At a median follow-up of 50 months, the projected 5-year OS and PFS rates were 93% and 74%, respectively. Toxicity was mainly hematologic. Grade ≥3 neutropenia and thrombocytopenia occurred in 57% and 35% of patients, respectively. Thirty-seven patients required growth factors and 17 required transfusions. The median time to hematologic recovery following RIT was 10 weeks. The most common non-hematologic adverse events (≥grade 3) were fatigue (17%), dyspnea (13%), and myalgia (11%). There were three cases of myelodysplasia (MDS), one in a patient who did not receive FIT. The combination of R-FND followed by RIT intensification and rituximab maintenance resulted in OS and PFS outcomes that are better than traditional combinations in this high-risk population.

Abstract #100: Safety and Efficacy of 90-Y Zevalin for Untreated Follicular Non-Hodgkin’s Lymphoma Patients, an Italian Cooperative Study: 50 patients, with a median age of 59 years (range 35-81 years), were treated; 48% had bone marrow involvement (<25%) and 14% had an elevated LDH level. Thirty-four percent of patients had high-risk FLIPI. The ORR was 93% (45/48) with a CR rate of 82% (41/48). Twenty-six patients, who were PCR-positive at diagnosis, were assessed at week 14; 20 of which became PCR-negative. After a median follow-up of 24 months, the 2-year EFS for all patients was 85%. Moreover, 15 patients (55%) who were PCR-positive at diagnosis maintained PCR negativity. As expected, the main toxicity was moderate myelosuppression, with 30% and 26% of patients developing grade 3/4 neutropenia and thrombocytopenia, respectively. Very few patients required platelets transfusion (4%) or growth factor use (6%). None of the patients experienced grade 3/4 non-hematologic toxicity. In conclusion, Zevalin is a highly effective and safe treatment for newly diagnosed follicular lymphoma patients.

Abstract #101: A Systematic Review and Meta-analysis of Radioimmunotherapy Consolidation for Untreated Patients with Follicular Lymphoma: More than 1,136 records were reviewed; 8 studies met inclusion criteria, totaling 556 patients. Between 1998 and 2007, patients were accrued at multiple sites. Median ages ranged from 49 to 57 years; among the studies reporting gender, 41% to 61% subjects were male. A weighted average of 97.2% patients had stage 3/4 disease with 73% to 98% patients having grade 1/2 disease, among those studies reporting histology. Among studies reporting this information, 19% to 44% of patients had abnormal LDH values, and 25% to 100% had bulky lymph nodes. CR rates ranged from 51% to 97%; 2-year PFS ranged from 65% to 86%; and 5-year PFS ranged from 38% to 67%. The pooled estimates of the CR and OR rates following consolidative RIT were 78% (95% CI: 66%–87%) and 98% (95% CI: 92.9%–99.5%), respectively. The pooled estimates for the 2-year and 5-year PFS were 77.0% (95% CI: 70.5%–82.4%) and 56.0% (95% CI: 41.9%–69.2%), respectively. This analysis suggests that consolidative RIT is beneficial to patients with previously untreated follicular lymphoma with meaningful CR rates and 5-year PFS. In addition, consolidative RIT compares favorably to maintenance therapy with rituximab given after chemotherapy (ECOG 1496) in both 2-year PFS (77.0% vs. 73.5%) and 5-year PFS (56.0% vs. 46.4%) and needs to be compared with maintenance R following R-chemotherapy induction.

Abstract #102: Fractionated 90y Zevalin Radioimmunotherapy as an Initial Therapy of Follicular Lymphoma: 74 patients with a median age of 61 years (range 28-80 years) – including 58 (78%) with stage 3/4 stage, 23 (31%) with intermediate-risk FLIPI, and 34 (46%) with high-risk FLIPI – were included between June 2007 and June 2010 in seven centers. The second infusion of RIT was withheld secondary to hematologic toxicity with first infusion (n = 12, 17%) or human anti-murine antibodies positive testing (n = 4; 5.6%), or other (n = 1; 1.4%). Two out of 72 patients did not have recorded response data and the EOR was 95.7% (67/70) with CR/CRu of 57.1% (40/71). Six patients subsequently improved response, making an ORR of 97.1% (68/70) (95% CI: 90.0% – 99.7%), and CR/CRu of 64.3% (45/70) (95% CI: 51.9% – 75.4%). For the subset of 17 patients who received only a single Zevalin infusion, ORR (CR/CRu) was 100% (76.5%). At a median follow-up of 1.52 years (range 0.13–3.69 years), the PFS was 67%; 20 patients progressed, and 12 of these required further treatment (8 chemotherapy, 2 radiotherapy, 2 other). Updated data with median follow-up of more than 2 years were presented. Ten patients experienced at least one SAE during the treatment period, with three related to study treatment (one case of rigors associated with the first infusion of rituximab and two cases of neutropenic sepsis associated with the second RIT dose). The most common toxicity was hematologic: after the first Zevalin dose, related grade 3/4 hematological AEs were transient neutropenia (20.8%, median duration 18 days) and thrombocytopenia (20.8%; median duration 20 days). After the second Zevalin dose, related grade 3/4 hematological AEs increased to 36.4% for neutropenia (median duration 31 days), 14% for anemia (8/55 required transfusion), and 56.4% for thrombocytopenia (median duration 40 days). One case of MDS was reported diagnosed 26 months after treatment and one death due to metastatic breast cancer diagnosed 9 months post-last dose of Zevalin.

Abstract #3078: Z-BEAM Followed by ASCT Significantly Improves OS after Rituximab-containing Induction Therapy in Patients with High-risk Aggressive B-cell NHL: 43 patients received Z-BEAM and 42 patients received BEAM conditioning. Median ages were 56 and 52 years, respectively. No significant differences in disease characteristics were reported. Median follow-up (range) was 15 months (6–54 months) and 39 months (0–112 months), respectively. OS was significantly better in the Z-BEAM group compared with the BEAM group (P = 0.02) with an estimated 2-year OS of 90% vs. 65%. In the first 2 years of follow-up, 7 patients in the Z-BEAM group relapsed compared with 11 in the BEAM group; this did not reach significance (P = 0.09). Median time to recovery of neutrophils and thrombocytes was not significantly different. Moreover, there was no significant difference in TRM (no TRM in the Z-BEAM group vs. two patients in the BEAM group). Patients who relapsed in both groups were able to receive re-induction chemotherapy and, if indicated, allogeneic SCT without being compromised by decreased bone marrow reserve or non-hematological toxicities.

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Source: Spectrum Pharma; ASH 2011: Abstract No. 99, Abstract No. 100, Abstract No. 101, Abstract No. 102, Abstract No. 3078

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