Patients With Relapsed/Refractory CLL That Progresses Early on Ibrutinib Have Poor Outcomes

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Most patients with relapsed/refractory chronic lymphocytic leukemia (CLL) who discontinued ibrutinib (Imbruvica) early “were difficult to treat and had poor outcomes,” according to a study of patients enrolled in four different clinical trials of ibrutinib, with or without rituximab (Rituxan), at The University of Texas MD Anderson Cancer Center. Among the 127 total patients, 33 patients (26%) discontinued ibrutinib. Few salvage treatment options are available for these patients, Preetesh Jain, MD, and colleagues reported in Blood.

Ibrutinib is a Bruton’s tyrosine kinase inhibitor approved for the treatment of patients with relapsed/refractory-CLL. “Response rates with ibrutinib are high; however, some patients develop progressive CLL or transform when receiving ibrutinib,” the researchers wrote.

The majority of patients discontinuing ibrutinib in the four trials “had high-risk features: 94% with unmutated immunoglobulin heavy chain variable gene rearrangement, 58% with del(17p) by fluorescence in situ hybridization, and 54% with a complex karyotype,” the investigators noted.

Causes of treatment discontinuation were adverse events in 11 patients and serious adverse events/deaths in 3 additional patients, disease transformation in 7 patients and progressive CLL in another 7 patients, stem cell transplantation in 3 patients, and miscellaneous reasons in 2 patients. “There does not appear to be any significant difference in reasons for discontinuation between patients enrolled on studies with rituximab vs those without,” the researchers stated.

The median age of the patients was 61 years old. The median number of therapies received prior to ibrutinib was two, and 45% of patients received three or more prior therapies. The median duration of ibrutinib therapy before treatment discontinuation was 13 months. The median overall survival after ibrutnib discontinuation was 3.1 months, and 25 patients (76%) died after discontinuing ibrutinib.

The “foremost” take-home lesson from this study is “the very poor prognosis and overall survival of CLL patients who discontinued the drug regardless of the reason,” according to an accompanying commentary, which was written by Javier Pinilla-Ibarz, MD, PhD, and Julio Chavez, MD, of Moffitt Cancer Center in Tampa, Florida.

“Definitely, ibrutinib has dramatically changed the landscape of [relapsed/refractory] CLL treatment and constitutes an important paradigm in the molecularly targeted approach of this disease, with excellent efficacy and tolerability,” the commentators added. “However, patients who discontinue treatment represent a challenge to the practicing oncologist, and treatment options are very limited. In the near future, early identification of very high-risk patients treated with ibrutinib should be the target of new combinatorial therapies that can improve the outcomes in this population. This report highlights that the road toward a cure (or effective disease control) of CLL has not ended and that, instead, we might be facing a new unmet need in this disease.” ■

Jain P, et al: Blood 125:2062-2067, 2015.

Pinilla-Ibarz J, Chavez JC: Blood 125:2013-2014, 2015.