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AbbVie leukemia treatment ADT-199 scores 84 percent overall response rate in chronic lymphocytic leukemia
SAN ANTONIO, Tex.—The relevant segment in the official release of the American Society of Hematology (ASH) begins with the authoritative, if convoluted, statement that “Bcl-2 Inhibitor ABT-199 (GDC-0199) Monotherapy Shows Anti-Tumor Activity Including Complete Remissions in High-Risk Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL) .” The news lead, buried in the second paragraph, states that “The preliminary study results show encouraging drug activity, as evidenced by an 84 percent overall response rate and a 21 percent complete response rate in the study population.”
AbbVie itself, perhaps out of a sense of caution based on a single death of a study participant early in the trial, issued no press release on ABT-199 at the San Antonio event. But reports were rife that the experimental AbbVie drug for leukemia controlled or eliminated signs of the disease in more than 80 percent of patients who had failed to benefit from previous treatments, an unprecedented finding that could spur use of the medicine for other cancers, researchers said.
The AbbVie drug works by blocking a protein called BCL-2 that allows cancer cells to avoid apoptosis, programmed cell death, in which the body kills off defective or cancerous cells.
Some 84 percent of patients who took ABT-199 strongly responded to the drug, with at least a 50 percent reduction in signs of the disease. And 23 percent had complete remissions.
"To achieve that magnitude of complete remission is extraordinarily promising and unprecedented in this particular type of leukemia, among patients with otherwise resistant disease," said Dr. John Seymour, MBBS, Ph.D., a researcher with the Peter MacCallum Cancer Centre in Melbourne, Australia
In the ongoing study, 72 percent of patients remain on the drug and are well at or beyond 12 months of treatment, Seymour said. Seymour said patients with chronic lymphocytic leukemia that have failed to respond to therapy typically only live another 12 to 18 months. He said it was too early to say how patients in his trial would fare.
Commenting on the one patient in the trial who died from a complication of treatment, called tumor lysis syndrome, Seymour said dosages of the drug are now slowly increased during the first few weeks of treatment, a change that has markedly decreased the lysis risk. Otherwise, he said ABT-199 was very well tolerated, with generally mild side effects such as nausea and diarrhea.
"For decades BCL-2 has been a sought-after target, but up until now no other drugs have had the potency and precision of ABT-199," Seymour said. "This compound has that potential, but we're still at the very early stages of testing it," Seymour said. "We're crawling, but we're looking forward to where we may be running in the future."
The development of CLL and other hematologic malignancies is often associated with the dysfunction of certain proteins that regulate cell death (apoptosis), known as B-cell lymphoma-2 (BCL-2) proteins, which allow cancerous cells to live longer and replicate in the body. Using these proteins as a treatment target, researchers developed ABT-199, that may be able to help trigger cell death in these tumors.
To determine the maximum tolerated dose of ABT-199, researchers enrolled 56 patients with relapsed or treatment-resistant CLL or small lymphocytic lymphoma in an ongoing Phase I study. Patients were divided into several cohorts to receive different doses of the drug (ranging from 150 to 1200 mg). The preliminary study results show encouraging drug activity, as evidenced by an 84 percent overall response rate and a 21 percent complete response rate in the study population. Early in the treatment period, some patients experienced tumor lysis syndrome (TLS), a treatment toxicity that occurs when contents of tumor cells that have been rapidly destroyed by effective therapy are released into the blood, potentially causing organ damage. Investigators therefore reduced the initial dose and instituted a progressive, slow increase in dose over the first several weeks of ABT-199 treatment, which helped to prevent and control TLS during the remainder of the treatment period.
“We are very encouraged by these early results and in particular, by the high rate of complete response among patients with treatment- resistant or relapsed CLL,” said Seymour. “Our ongoing work will seek to improve the efficacy of this drug while carefully monitoring toxicities to deliver the maximum benefit to high-risk patients where conventional chemotherapy has proven inadequate.”
The American Society of Hematology (ASH) (www.hematology.org) is the world’s largest professional society of hematologists dedicated to furthering the understanding, diagnosis, treatment, and prevention of disorders affecting the blood. For more than 50 years, the Society has led the development of hematology as a discipline by promoting research, patient care, education, training, and advocacy in hematology. The official journal of ASH is Blood (www.bloodjournal.org), the most cited peer-reviewed publication in the field, which is available weekly in print and online.