Ibrutinib Well Tolerated in Patients With Central Nervous System Lymphoma

CHICAGO–With few treatment options available for central nervous system lymphoma (CNSL), patients with recurrent/refractory disease typically have poor outcomes, with response rates ranging between 30 and 60 percent and progression-free survival ranging between two and six months.

Results from a small, phase I trial presented at the 2016 ASCO Annual Meeting show that the Bruton tyrosine kinase (BTK) inhibitor ibrutinib is well tolerated in patients with recurrent/refractory primary (PCNSL) and secondary CNSL (SCNSL).

“Targeted agents [like ibrutinib] might be an alternative therapeutic approach to be investigated for recurrent/refractory CNSL patients,” lead author Christian Grommes, MD, from Memorial Sloan Kettering Cancer Center in New York, noted in his presentation of the study results.

Ibrutinib, Dr. Grommes and authors noted, has shown promising clinical response in certain B-cell malignancies, including mantle cell lymphoma and chronic lymphocytic leukemia. Based on these data, researchers evaluated the safety of ibrutinib in adults with recurrent/refractory CNSL.

Patients were included in the study if they had a Karnofsky performance score (a measure of functional impairment) of 50-100 and normal end-organ function. There were no restrictions on the number and type of prior therapies received; in patients with SCNSL, systemic disease needed to be absent.

Ten patients (median age = 70 years; age range = 21-80 years) were enrolled; seven patients had PCNSL and three had SCNSL. Six patients had parenchymal disease, three had isolated cerebrospinal fluid (CSF) involvement, and one had both.

Overall, patients were highly pretreated: two SCNSL patients had prior hematopoietic cell transplantation and three patients (2 PCNSL, 1 SCNSL) had prior radiation therapy. The median number of prior CNS-directed therapies was two – all of which were methotrexate regimens.

Ibrutinib was evaluated at two doses: 560 mg (n=3) and 840 mg (n=7).

Two patients withdrew from the trial, “despite clinical and radiographic response,” the authors observed. “Treatment has been well tolerated, with two grade 4 toxicities (neutropenia and lymphopenia) that resolved after the drug was held.”

The most common toxicities observed were hyperglycemia, hypercholesteremia, and thrombocytopenia.

After a median follow-up of 150 days, the overall response rate was 78 percent in the nine patients who were evaluated for response:

  • 4 patients experienced CR (3 in CSF; 1 in the parenchyma)
  • 3 patients experienced PR
  • 2 patients had progressive disease

The median time to first response was 28 days, and the median progression-free survival was six months.

The authors observed a higher drug concentration in CSF in patients who received the higher ibrutinib dose (840 mg), and “continued enrollment is ongoing at 840 mg in an expansion cohort.”

The small enrollment in this early-phase trial means that results will need to be confirmed in larger studies. Molecular testing to determine if there is an association between genomic alterations and outcome is also ongoing.

Reference

Grommes C, Kaley TJ, Nolan C, et al. Phase I study of single agent ibrutinib in recurrent/refractory primary (PCNSL) and secondary CNS lymphoma (SCNSL). Abstract #2046. Presented at the 2016 ASCO Annual Meeting, June 4, 2016; Chicago, IL.

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