Non-chemotherapy drug promising for chronic lymphocytic leukemia

14 Jun 2015

More than 80% of patients with relapsed chronic lymphocytic leukemia (CLL) responded to treatment with a chemotherapy-free combination therapy that includes an investigational apoptosis-targeting agent, results of a small clinical trial showed.

BCL-2 represents a major apoptosis escape mechanism for CLL, allowing the leukemic cells to evade normal processes that lead to programmed cell death. By inhibiting, or "turning off" BCL-2, venetoclax helps restore apoptotic mechanisms, reported Andrew W. Roberts, MD, of the Royal Melbourne Hospital in Australia.

Venetoclax previously demonstrated single-agent activity in relapsed CLL, leading to a first-ever phase 1b trial of combination therapy with rituximab.

Clinical study design, challenges and outcomes

Investigators enrolled 49 patients in the dose escalation/expansion study. The patients had a median age of 68 and had a median treatment exposure of two prior regimens, including some patients who had received as many as five prior therapies. All but four of the patients had received rituximab.

Initial dosing experience demonstrated a problem with tumor lysis syndrome (when tumor cells release their contents into the bloodstream, leading to hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia), which led to discontinuation by one patient. After lowering the starting dose of venetoclax, no further problems with tumor lysis syndrome occurred, Roberts said.


The analysis of the results showed:

  • An 84% overall response rate, including complete responses in 20 of 41 responding patients.
  • 13 of 20 patients who achieved complete response did so with minimal residual disease.
  • Three of the 41 patients have relapsed since achieving objective responses.
  • Six patients discontinued treatment after achieving complete response. Of those, one patient had disease recurrence after 24 months off therapy. The rest remain in remission.
  • A majority of patients developed neutropenia with the combination, which was grade 3/4 severity half the time, but nonetheless manageable in most cases with standard strategies, according to study author.

"The combination of venetoclax and rituximab is a highly active, non-chemotherapy treatment for patients with relapsed and refractory CLL," Roberts said. "The combination is well tolerated, as we observed no new toxicities as compared with venetoclax monotherapy.

“A step forward in chemotherapy-free regimens for a population of vulnerable, mostly elderly patients"

On the basis of the results, a phase 3 trial has begun, comparing venetoclax plus rituximab versus bendamustine (Treanda) and rituximab in patients with previously treated CLL.

The study is "an important step forward in chemotherapy-free regimens for a population of vulnerable, mostly elderly patients," said Anton Hagenbeek, MD, PhD, of the University of Amsterdam.

"The most dramatic side effect is when this drug works too well, too quickly, when you first give it," said Roberts. "That is, of course, tumor lysis syndrome, when the CLL all breaks down very quickly. Early in the study we had problems with that, and one patient died. As a consequence of that, we redesigned the study and now start with a lower dose and work up.

Source: MedPage Today

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