The investigators observed responses in all compartments of the central nervous system; however, they noted that the duration of the responses in patients who entered the study with brain lesions was short. Still, 15 patients (29%) experienced complete responses that lasted more than 12 months.

In 2 patients, the dose was reduced to 280 mg/day and 420 mg/day. The researchers identified 30 adverse events that occurred in 26 patients. Some of the serious events included 2 ventricular hemorrhages, 2 hemorrhages in the anterior chamber of the eye, 2 atrial fibrillations, and 2 cases of pulmonary aspergillosis — 1 of which had a favorable outcome and 1 of which was fatal.

The authors determined the mutation status in the BCR pathway for 18 patients. No mutation in CARD11 or concurrent mutations in MYD88 and CD79B were found. In 7 patients, the researchers identified wild-type (wt) CARD11, CD79b, and MYD88, where the best therapeutic responses were a complete response in 2 patients, partial response in 2 patients, and progressive disease in 3 patients.

Related Articles

The investigators observed a mutation in MYD88 in 9 patients, and that mutation was linked to either partial response (in 2 patients) or progressive disease (in 7 patients). Furthermore, 1 patient had a mutation in CD79b and exhibited a partial response.

The authors pointed out that their genomic findings differed from previous results. “In a series of systemic lymphomas,2  the patients with MYD88 mutations but wt CD79B were unresponsive to ibrutinib,” the researchers wrote. “We observed therapeutic responses in patients with wt CD79, and wt MYD88 and in patients with MYD88 mutations but wt CD79B.”

Anas Al-Janadi, MD, vice president and department chief of oncology for Spectrum Health Cancer Center in Grand Rapids, Michigan, who was not involved in the study, said that the authors proved that the drug was able to cross the blood-brain barrier, in a concentration that was effective.

Ruthee-Lu Bayer, MD, director of cellular therapy and stem cell transplantation at Northwell Health Cancer Institute in Lake Success, New York, who was not involved in the study, agreed with Dr Al-Janadi’s assessment. “With this disease entity, it is imperative that the treatment cross the blood brain barrier in order to have an impact on the disease,” she said. “This study confirms this with ibrutinib. More information is needed with respect to mutational analysis and ibrutinib.”

Dr Bayer added she has some experience administering ibrutinib in secondary CNS lymphoma. “I have treated, several years ago, a patient with secondary CNS lymphoma who failed both autologous and allogenic stem cell transplantation, with ibrutinib,” she said. “Her life was prolonged by this intervention and she had no significant toxicity subsequently.”

Lakshmi Nayak, MD, director of the Center for Central Nervous System (CNS) Lymphoma at Dana-Farber Cancer Institute and assistant professor of neurology at Harvard Medical School, in Boston, Massachusetts — who was also not involved in the study — noted that the authors found differences in progression-free survival depending on the presence or absence of brain involvement. For the 30 patients who had brain involvement, the progression-free survival was only about 2 months, Dr Nayak emphasized. “However, they had 6 patients that had a response that was durable for 12 months, which means there’s a small group of patients that likely benefits more from this,” she said. Still, she noted, “in the overall cohort, the durability is poor.”

“This is a great proof of concept [study],” said Haroon Ahmad, MD, an assistant professor of neurology at the University of Maryland Medical Center, Baltimore, who was not part of the research. However, he also noted that the patient response to ibrutinib was short-lived. He said he’s looking forward to seeing follow-up studies assessing the effects of combining ibrutinib with traditional methotrexate therapy.

References

  1. Soussain C, Choquet S, Blonski M. Ibrutinib monotherapy for relapse or refractory primary CNS lymphoma and primary vitreoretinal lymphoma: Final analysis of the phase II ‘proof-of-concept’ iLOC study by the Lymphoma study association (LYSA) and the French oculo-cerebral lymphoma (LOC) net. Eur J Cancer. 2019;117:121-130.
  2. Wilson WH, Young RM, Schmitz R, et al. Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma. Nat Med. 2015;21(8):922e6.