From OncoLog, September 2011, Vol. 56, No. 9
New Targeted Therapy Offers Hope in Relapsed Hodgkin and Anaplastic Large-Cell Lymphoma
By Bryan Tutt
The U.S. Food and Drug Administration (FDA) has approved the first new drug for Hodgkin lymphoma since 1977.
In August, the FDA granted accelerated approval for brentuximab vedotin to treat patients with Hodgkin lymphoma whose disease has recurred after stem cell transplantation and patients with relapsed or treatment-resistant systemic anaplastic large-cell lymphoma (ALCL).
Most patients with Hodgkin lymphoma can be cured with standard chemotherapy and/or radiation therapy, but those who cannot face a grim prognosis. “In all, 20%–30% of patients with Hodgkin lymphoma require second-line therapy, and this percentage may be a little higher for patients with ALCL,” said Anas Younes, M.D., a professor and the director of clinical and translational research in the Department of Lymphoma and Myeloma at The University of Texas MD Anderson Cancer Center.
Autologous stem cell transplantation is effective as a second-line therapy in about half of those with Hodgkin lymphoma who do not attain a longterm remission with conventional therapy, but for patients whose disease relapses after transplantation, the overall survival rate is 55% at 2 years and only 32% at 5 years.
Patients with relapsed ALCL have a poor prognosis. They typically receive additional chemotherapy, and once a second remission is achieved, an autologous stem cell transplant is recommended. “Patients with ALCL have high rates of disease progression or relapse after front-line chemotherapy,” said Michelle Fanale, M.D., an assistant professor in the Department of Lymphoma and Myeloma. She added that patients whose tumors do not express the ALK gene have the highest rates of disease progression or relapse (40%–65%) after front-line chemotherapy. “Thus there has been a great need to develop effective targeted therapies for ALCL,” she said.
The recommendation for FDA approval of brentuximab vedotin was made on the basis of two pivotal studies—one in patients with Hodgkin lymphoma and the other in patients with ALCL—conducted at MD Anderson and other institutions. In both studies, brentuximab vedotin was given as a single agent by 30-minute intravenous infusion every 3 weeks for up to 16 doses.
In the Hodgkin lymphoma trial, patients had undergone a median of four previous chemotherapy regimens; Dr. Younes, who served as MD Anderson’s principal investigator for the trial, said some had undergone as many as 13 previous regimens. In addition, all patients had undergone an autologous stem cell transplant that had failed. The objective rate of response to brentuximab vedotin was 75%, with approximately one-third of patients experiencing complete remissions.
In the ALCL study, brentuximab vedotin was given to 58 patients with relapsed or treatment-refractory ALCL. All patients had previously undergone one or more multi-agent chemotherapy regimens with curative intent. Most patients had not undergone stem cell transplantation. The objective response rate was 86%, with 57% of patients experiencing complete remission. Some of these patients went on to receive stem cell transplantation.
Dr. Fanale, MD Anderson’s principal investigator for the ALCL trial, said that patients whose tumors did not express the ALK gene—a group that typically does not respond well to chemotherapy—had the same response rate as those whose tumors did express ALK.
“I think this agent has had a profound impact on the lives of our patients with Hodgkin lymphoma and ALCL,” Dr. Fanale said. “We have seen significant positive responses to outpatient treatment with brentuximab vedotin, and our patients have been able to return to many of their normal daily activities at work, school, and home.”
Mechanism of action
Brentuximab vedotin targets the tumor necrosis factor receptor CD30, which is expressed on the surface of ALCL and Hodgkin lymphoma cells. Brentuximab vedotin comprises the CD30-specific monoclonal antibody cAC10 and the antitubulin agent monomethyl auristatin E, which are attached by a protease-cleavable linker.
The antibody-drug conjugate binds to CD30 on the surface of lymphoma cells and is rapidly internalized. Inside the cell, the linker is selectively cleaved and the monomethyl auristatin E binds tubulin, prompting cell cycle arrest and apoptosis.
Other types of lymphoma sometimes express CD30, although this expression occurs in fewer patients and at lower levels in other lymphomas than in Hodgkin lymphoma or ALCL. “Given the activity of brentuximab vedotin in Hodgkin lymphoma and ALCL, it’s reasonable for us to test it against other types of lymphoma,” said Yasuhiro Oki, M.D., an assistant professor in the Department of Lymphoma and Myeloma.
Dr. Oki will be the principal investigator at MD Anderson for a multi-institutional phase II trial of brentuximab vedotin in patients with CD30-positive non-Hodgkin lymphoma that has relapsed or is treatment-refractory. “We’re hoping this agent will provide another option for these patients,” he said. The trial is expected to begin recruiting patients later this fall.
Even as studies of brentuximab vedotin in patients with treatment-resistant disease continue, Dr. Fanale, Dr. Younes, and other researchers are testing its use in front-line regimens for treatment-naïve patients.
Two of these trials are already under way at MD Anderson. In patients with Hodgkin lymphoma, brentuximab vedotin is being given with the standard chemotherapy regimen of doxorubicin, bleomycin, vinblastine, and dacarbazine. In patients with ALCL, it is being given with the standard regimen of cyclophosphamide, doxorubicin, vincristine, and prednisone.
Dr. Younes is optimistic about the addition of brentuximab vedotin to front-line therapy regimens. “Hopefully, we will change the standard of care and improve the cure rate for patients with these diseases,” he said.
For more information, contact Dr. Yasuhiro Oki at 713-792-2860, Dr. Michelle Fanale at 713-792-2860, or Dr. Anas Younes at 713-792-2860.