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American Society of Hematology: Eculizumab (Soliris) and Paroxysmal Nocturnal Hemolysis

Presenter: Peter Hillmen, MD, Consulting Hematologist, Leeds General Infirmary, Leeds, United Kingdom

“Eculizumab is the first treatment that targets intravascular hemolysis, the primary clinical manifestation of PNH (paroxysmal nocturnal hemolysis),” stated Dr. Hillmen.

Eculizumab (Soliris, Alexion) is a monoclonal antibody with activity against complement protein C5, a protein that blocks terminal complement activation on red blood cells in PNH. PNH results from an acquired genetic mutation in hemato-poietic stem cells that allows terminal complement-mediated cell lysis. Thromboembolism, the most feared complication, accounts for about 45% of PNH deaths. Although a causal link between hemolysis and thrombosis has not been established, thrombosis is temporally associated with increasing hemoly-sis.

In clinical trial experience with eculizumab to date (including about 250 years of treatment among 195 patients), the agent has reduced intravascular hemolysis significantly and has improved PNH symptoms.
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In Dr. Hillmen’s analysis of all the eculizumab trials, the pre treatment rate of major adverse vascular events (MAVEs) per 100 patient-years was 7.37 over a total of 1,683.4 patient-years. These trials included a pilot study plus an extension trial. TRIUMPH was a single, pivotal double-blind, randomized, multicenter, placebo-controlled phase 3 efficacy study. SHEPHERD was an open-label nonrandomized, non-placebo-controlled, multicenter safety study.

For eculizumab-treated patients (three events in 281.03 patient-years), the MAVE rate was 1.07 (P < 0.001), an 85°% reduction in thrombosis. In a further sensitivity analysis, the MAVE rate in the 12 months prior to treatment was 17.21, compared with 1.07 for eculizumab treatment (a 94% reduction; P = 0.0002). The pretreatment MAVE rate for patients receiving antithrombotic therapy was 14.00; the rate for these patients with eculizumab treatment was 0.62 (P < 0.001), a 96% reduction in thrombosis.

Similarly, the MAVE rate with eculizumab for patients with prior thrombosis compared favorably with pretreatment rates at 2.27, versus the pretreatment MAVE rate of 21.42 (P < 0.001), an 89% reduction. Intravascular hemolysis was reduced by 86%, and clinical thrombosis by an extremely highly significant (P < 0.000000001) 85%.

Although only three thrombotic events occurred in eculizumab-treated patients, two of them occurred early at the sites of prior thromboses. The author suggested that these events might have been pre-existing.

Dr. Hillmen characterized the eculizumab effect as “robust” and noted that with treatment continuing for more than four years, patients have remained well and transfusion-independent. He concluded that long-term treatment with this agent should have a beneficial impact on survival in patients with PNH. Eculizumab was approved by the FDA on March 19, 2007.

Zoledronic Acid (Zometa) and Pamidronate (Aredia) in Multiple Myeloma

Presenter: James R. Berenson, MD, Medical and Scientific Director of the Institute for Myeloma and Bone Cancer Research, Los Angeles, California

Preclinical data suggest that zoledronic acid (Zometa, Novartis), a calcium modifier, has an anti-myeloma effect, but clinical evidence has been largely anecdotal.

Dr. Berenson conducted a retrospective analysis of a large international clinical trial comparing the effects of pamidronate 90 mg (Aredia, Novartis) and zoledronic acid 4 mg on bone complications. The purpose of this exploratory subset analysis, however, was to investigate whether zoledronic acid produced a survival benefit, compared with pamidronate, among patients with MM. Zoledronic acid is 100 to 1,000 times as potent as pamidronate.

The patients were stratified according to their bone-specificalkaline phosphatase (bone ALP) levels at the baseline evaluation. Bone ALP is a marker of osteoblast-mediated bone formation, and elevated levels of this marker in patients with malignant bone disease from solid tumors or myeloma correlate significantly with the risk of skeleton-related events and shorter survival, Dr. Berenson said.

The trial included 353 patients with MM. The analysis included the trial’s 212 MM patients who were assessed for bone ALP They were classified as having “high” levels (146 IU/liter or greater) or low levels (below 146 IU/liter) of baseline bone ALP. The 25-month survival levels were higher for all bone ALP-assessed patients receiving zoledronic acid (76% vs. 63%, or a 43% reduction; P = 0.026), but were similar for 123 patients with low bone ALP levels (73% for zoledronic acid, 71% for pamidronate).
Among 89 patients with high bone ALP levels, the survival rates were 82% with zoledronic acid and 53% with pamidronate, or a 57% reduction (P = 0.041).
Overall survival was significantly longer in patients with high baseline bone ALP levels (P = 0.04).
Dr. Berenson listed several mechanisms of zoledronic acid’s anti-myeloma effects:

• immunostimulation of the effects on gamma-delta T cells
• inhibition of angiogenesis
• promotion of tumor cell apoptosis
• reduction of cytokines (e.g., interleukin-6)

Among adverse events, he said that the main concerns with bisphosphonates in MM patients were osteonecrosis of the jaw and impaired renal function. These need to be monitored, he advised.
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“Zoledronic acid significantly improved survival compared with pamidronate in the subset of patients with multiple myeloma and high baseline BALP,” the author concluded. The benefit needs to be corroborated in a prospective study, he added.

Category: Disease

Tags: American Society, Hematology

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