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Lymphoma Drug Gets Boxed Warning on Brain Infection Risk
Adcetris is an antibody-drug conjugate (ADC) directed to CD30 that was granted accelerated approval by the U.S. Food and Drug Administration (FDA) in August 2011 for two indications: (1) the treatment of patients with Hodgkin lymphoma (HL) after failure of autologous stem cell transplant (ASCT) or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates, and (2) the treatment of patients with systemic anaplastic large cell lymphoma (sALCL) after failure of at least one prior multi-agent chemotherapy regimen. The indications for Adcetris are based on response rate. There are no data available demonstrating improvement in patient-reported outcomes or survival with Adcetris.
“Our first priority is patient safety. By developing these agreed upon label updates with the FDA regarding PML and the contraindication with bleomycin, we aim to heighten awareness among healthcare professionals in order to most safely treat their patients with Adcetris. Although PML in lymphoma patients can be caused by factors such as underlying disease and prior therapies that affect the immune system, a contributory role of Adcetris cannot be excluded,” said Thomas C. Reynolds, M.D., Ph.D., Chief Medical Officer of Seattle Genetics. “The contraindication for the concomitant use of Adcetris and bleomycin is based on data suggesting an increased risk of pulmonary toxicity relative to ABVD alone that was identified in our phase I clinical trial in patients with newly diagnosed advanced Hodgkin lymphoma. We are confident that these label changes will help guide appropriate patient care while on treatment with Adcetris.”
PML is associated with a weakened immune system that can occur in patients with diseases such as lymphoma, leukemia and other hematologic malignancies. According to published literature, the risk of PML in persons with hematologic malignancies is estimated to be 0.07%, or approximately one in 1,400 (1). More than 2,000 patients worldwide have received treatment with Adcetris to date.
PML was described in the original PI for Adcetris based on a single case reported in a patient who had received four chemotherapy regimens prior to receiving Adcetris. Following the occurrence of a second case of PML, Seattle Genetics began working in conjunction with the FDA to add a boxed warning in order to heighten awareness of the potential risk of PML. There has also been a third suspected, but unconfirmed, case of PML reported in a heavily-pretreated patient receiving Adcetris.
In addition, based on data from a phase I clinical trial of Adcetris in combination with ABVD (Adriamycin, bleomycin, vinblastine and dacarbazine) for the treatment of newly diagnosed Hodgkin lymphoma patients, a contraindication for concomitant use of bleomycin and Adcetris will be added to the PI. This is based on data demonstrating that 40 percent of patients (10 out of 25) in the Adcetris plus ABVD cohorts of the trial had an event of pulmonary toxicity, compared to an overall rate of pulmonary toxicity with bleomycin-based regimens reported in published literature of 10 to 25 percent (2,3). To date, no pulmonary toxicity events have been observed in the Adcetris plus AVD cohorts of the trial. Adcetris is not approved for the front-line treatment of Hodgkin lymphoma.
When finalized, the updated PI will be posted at www.seattlegenetics.com.
PML is a rare, progressive, demyelinating disease of the central nervous system that often leads to death or severe disability. PML is caused by reactivation of the John Cunningham (JC) virus. JC virus resides in latent form in 40-80 percent of healthy adults. Reactivation of the latent infection is associated with immunocompromised conditions and may occur months following discontinuation of immunosuppressive therapy. PML has been reported in patients with Hodgkin lymphoma, HIV-positive patients, immunosuppressed cancer patients, transplantation patients and patients with autoimmune disease. There are no known interventions that can reliably prevent or adequately treat PML.
Adcetris (brentuximab vedotin) is an ADC comprising an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE), utilizing Seattle Genetics’ proprietary technology. The ADC employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-expressing tumor cells.
Source: Seattle Genetics