Ibrutinib suppression of chronic lymphocytic leukemia endures in second year

Disease progression halted in 76 percent of patients at 30 months, side effects decline

MD Anderson News Release 12/09/13

The targeted therapy ibrutinib continues to stifle relapsed or resistant chronic lymphocytic leukemia for patients in an extended clinical trial while treatment side effects decline in frequency and severity over time, researchers reported at the 55th American Society of Hematology (ASH) Annual Meeting and Exposition.

Out of 140 patients in the phase II trial, 86 percent of those who were previously untreated had a partial or complete response to the oral drug while 88 percent of those with relapsed or treatment-resistant CLL also responded to ibrutinib. Watch video on Ibrutinib keeps CLL in check. 

“Progression-free survival at 30 months was about 76 percent, which in previously untreated patients is good, but you could achieve that with other treatment regimens,” said Susan O’Brien, M.D., professor of Leukemia at The University of Texas MD Anderson Cancer Center, who presented the updated results.

“Among patients with relapsed or refractory CLL, it’s really amazing that so many people would still be responding and on the drug well out over two years,” O’Brien said. “This is a very exciting drug.”

Ibrutinib continues to be well-tolerated, with most patients staying on the drug until disease progression, O’Brien noted, rather than having to quit due to side effects or other complications.

The median duration of response – the point where half of patients remain on the drug – had not been reached at a median follow-up of 27 months. Ibrutinib does not cure CLL but tamps the disease down to low levels, stalling progression and improving quality of life, O’Brien said.

No new side effects emerge

“When you have a new drug, you always want to be on the lookout for late effects of treatment,” O’Brien said. “We did not see any late, unknown effects after two years and, in fact, the early effects remain early and over time you don’t have as many adverse events.”

CLL is a malignancy of immune system B cells, white blood cells that craft antibodies against infection. Ibrutinib blocks Bruton’s tyrosine kinase (BTK), a vital component of B cell receptor signaling.  CLL is the most common adult leukemia. The American Cancer Society estimates about 15,680 new cases will be diagnosed in 2013 and about 4,580 people will die from the disease.

The U.S. Food and Drug Administration approved the drug, known commercially as IMBRUVICA, for treatment of mantle cell lymphoma last month under its breakthrough therapy designation.  A similar application for CLL by Pharmacyclics, Inc., the drug’s developer, is pending at the FDA.

Chemotherapy and antibody combinations cause remissions in many CLL patients, however, they are at increased risk of developing secondary cancers related to treatment, mainly acute myeloid leukemia and myelodysplastic syndromes.

The most common side effect from the drug is diarrhea, which resolves over time, O’Brien said.

Adverse events decline during second year

Ibrutinib does not contribute to two common, potentially life-threatening complications of CLL – suppression of creation of blood cells in the bone marrow, or myelosuppression, and infections.

Both CLL and chemotherapy cause myelosuppression, which lowers levels of red blood cells, platelets and white blood cells, exposing patients to anemia, bleeding or infections.

“Ibrutinib is not myelosuppressive,” O’Brien said, “And infections we see mainly are related to extensive prior therapy and those decline in incidence as the disease improves with treatment.”

O’Brien was senior author on a New England Journal of Medicine paper earlier this year that reported ibrutinib clinical trial results for the first 85 patients.  Updated findings presented Monday include:

  •  A decline in the overall  incidence of grade 3 or 4 adverse events from 43 percent of patients in the first year to 32 percent in the second year. (Grade 3 events are significant but not immediately life-threatening, grade 4 events are life-threatening.)
  • Drug-related grade 3 and 4 events occurred in 24 percent and 8 percent of patients in the first year, then fell to 7 percent and zero in the second year.
  • Overall, 62 percent of those with relapsed or resistant CLL experienced a grade 3 or higher adverse event, compared with 29 percent among those treated for the first time.
  • Adverse events pushed 12 patients off the trial in the first year and six during the second year.

The higher rate of events in the relapsed/resistant group likely reflects the more advanced disease state and previous treatment of those patients rather than the drug, O’Brien noted. The median number of previous treatments was four.
The most common grade 3 or higher events, regardless of cause, were:

  • Pneumonia (16.9 percent)
  • Hypertension (13.5 percent)
  • Low white blood cell count (11.5 percent)
  • Low platelet count (7.4 percent)
  • Diarrhea (5.4 percent).

Overall response rate of 93 percent

Initial treatment with ibrutinib elevates levels of white blood cells, including CLL cells, which at first appeared to be a sign of disease progression in the phase I trial.  However, at the same time, patients experienced sharp shrinkage in their lymph nodes, where CLL cells accumulate, O’Brien said.

Research by Jan Burger, M.D., Ph.D., associate professor of Leukemia, connected these two events. Ibrutinib attacks chemokines, hormonal regulators that allow CLL cells to cling to their hiding places in the lymph nodes and bone marrow, where they evade treatment and draw nourishment.

Flushing the cells into the blood stream makes them more vulnerable to treatment.  And the increased white cell counts – called lymphocytosis – decline over time.  When patients who are responding to ibrutinib but still have lymphocytosis are included, the overall response rate jumps to 93 percent.

Clinical trials are under way at MD Anderson that combine ibrutinib with rituximab, an antibody that targets CLL cells, to improve response.  Burger is presenting an update of one trial (abstract 675) at ASH.
Pharmacyclics funds this clinical trial.  O’Brien receives research funding from the company, Burger serves in an unpaid scientific advisory capacity for a different clinical trial.  

Co-authors with O’Brien and Berger are William Wierda, M.D., Ph.D., professor of Leukemia, and Nathan Fowler, M.D., associate professor of Lymphoma/Myeloma at MD Anderson; Richard Furman, M.D., of Weill Cornell Medical College; Steven Coutre, M.D., and Ranjana Advani, M.D., of Stanford University School of Medicine; Jeff Sharman, M.D.,  of Willamette Valley Cancer Institute and Research Center in Eugene, Ore.; Kristie Blum, M.D.,  Jeffrey Jones, M.D., and John Byrd, M.D., of The Ohio State University; Emiliano Mugnaini, M.D., of Vermont Cancer Center; Ian Flinn, M.D., Ph.D., of Sarah Cannon Research Institute in Nashville, Tenn.; Kathryn Kolibaba, M.D., of Northwest Cancer Specialists in Vancouver, Wash., and Yun Shaw, Fong Clow, ScD., and Danelle James, M.D., all of Pharmacyclics.