Hodgkin lymphoma (HL) is characterized by the presence of Reed-Sternberg tumor cells that express a tumor marker called CD30. Brentuximab vedotin (BV) is a novel anti-CD30 antibody linked to an antimicrotubule agent, monomethyl auristatin E (MMAE).
These new types of treatment for cancers are called antibody-drug conjugates (ADCs) and consist of cytotoxic agents or toxins chemically conjugated to monoclonal antibodies. ADCs potentially represent an advantage over treatment with chemotherapy because they are designed to deliver the cytotoxic agent specifically to tumor cells, thereby resulting in an improved safety profile.
The U.S. Food and Drug Administration recently approved BV for Hodgkin lymphoma patients who have failed many different treatments, because in large clinical trials nearly 90 percent of the patients had their lymph nodes decrease in size. (1)
Memorial Sloan Kettering has participated in many of the clinical trials with BV and has led the effort to evaluate this agent in a variety of settings. We currently have four important studies combining BV with other agents in the management of HL:
We have designed a small pilot study for patients with newly diagnosed early-stage Hodgkin lymphoma. Patients will receive four cycles of AVD chemotherapy in conjunction with BV, followed by involved-site radiotherapy. Involved-site radiation is a specialized radiation treatment that reduces the radiation therapy field and targets only the diseased lymph nodes in an attempt to spare normal tissue from the radiation. This type of radiation therapy was pioneered at Memorial Sloan Kettering.
We are participating in a large randomized phase III clinical trial to determine if substituting BV for bleomycin in the ABVD regimen will cure more patients with stage III or IV disease.
Pre-autologous stem cell transplant (ASCT) or salvage therapy
Over the past two decades we have focused our research on patients with relapsed or refractory HL who are eligible for ASCT. We designed the most common chemotherapy program, ICE (ifosfamide, carboplatin, and etoposide), as a pretransplant regimen to shrink lymphoma prior to a stem cell transplant.In a trial currently enrolling patients, subjects receive six doses of weekly BV and then undergo evaluation with fluorodeoxyglucose-positron emission tomography (FDG-PET). Patients with a negative FDG-PET scan can avoid the ICE chemotherapy and proceed directly to transplant. Patients with positive FDG-PET will receive two cycles of ICE chemotherapy followed by repeat FDG-PET prior to ASCT. To date, 40 patients have been treated in this study, and 80 percent have achieved a negative FDG-PET scan after BV alone or BV and ICE. These are some of the most promising results we have seen in the past two decades.
Combinations with other novel agents
Inhibitors of the mammalian target of rapamycin (mTOR), such as everolimus and temsirolimus, are effective as single agents in patients with Hodgkin lymphoma and demonstrate synergy with BV in HL cell lines and animal models. We will be initiating a phase I study to evaluate the combination of temsirolimus and BV in patients with relapsed or refractory HL. Provided the combination of BV and temsirolimus is found to be safe and effective, future studies will test this combination in the pre-ASCT salvage setting.
For more information on these trials or to refer a patient, contact Dr. Moskowitz at 212-639-2696.