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ASH 2016 | Phase I/II trial finds single-agent ibrutinib is well tolerated in recurrent/refractory Primary and Secondary Central Nervous System Lymphomas

Dec 8, 2016

The 58 thAnnual Meeting & Expositionof the American Society of Hematology’s(ASH) took place in San Diego, CA, on December 3–6, 2016.

On Monday 5 thDecember, an oral abstract session was held between 10:30am and 12:00pm in the “Aggressive Lymphoma (Diffuse Large B-Cell and Other Aggressive B-Cell Non-Hodgkin Lymphomas)—Results from Prospective Clinical Trials Program” category. This session was moderated by Jennifer Effie Amengual, MD, from the Columbia University Medical Center, and Lapo Alinari, MD PhD, of the Ohio State University.

Abstract #783was titled “Single-Agent Ibrutinib in Recurrent/Refractory Central Nervous System Lymphoma” and was presented by Christian Grommes, MD, of the Memorial Sloan Kettering Cancer Center, New York, NY.

This phase 1/2, open-label, single-institution study included patients aged 18 years or over with R/R Primary CNS Lymphoma (PCNSL) or Secondary CNS Lymphoma (SCNSL). Patients who had received prior allogeneic stem cell transplantation were excluded. In total, 20 patients were enrolled (PCNSL n=13; SCNSL n=7) with a median age of 69 years (21–85) and a median of 2 prior therapies (1–8). MTX-based salvage therapy had failed in 75% of patients.

  • Adverse events:
    • No dose limiting toxicities were observed
    • Six patients experienced 3 grade 4 AEs: lymphopenia, sepsis and neutropenia
    • Nine patients experienced grade 3 AEs
    • The most frequently reported AEs: hyperglycemia, hypertriglyceridemia, thrombocytopenia, and anemia
    • One patient stopped treatment (aspergillosis of lung and brain)
    • One patient had dose reduced (colitis)
  • Pharmacokinetics in the Cerebrospinal Fluid (CSF)
    • Mean ibrutinib CSF concentrations = 0.77ng/mL (1.7nM) and 1.96ng/ML (4.4nM) in the 560mg and 840mg arms, respectively
    • Drug concentrations increased at steady state
    • Meaningful CSF ibrutinib concentrations were reached
  • At median follow-up of 255 days (147–532)
    • 19/20 patients were evaluated for response
    • A response was reported in 15/20 (75%) patients: 10 CR (3 in CSF only), 5 PR; PCNSL: 10/13 (76%); SCNSL 5/7 (71%)
    • Median PFS = 5.4 months (95% CI: 2.92–8.64)
    • Median OS = 15 months (13/20 still alive)

    • 10/20 (50%) required corticosteroids at enrollment; 6/10 (60%) were successfully tapered off dexamethasone after initiating ibrutinib

This abstract presentation concluded by stating that ibrutinib treatment is well tolerated in patients with Primary and Secondary CNS Lymphomas who experienced manageable AEs. A combination trial of ibrutinib plus methotrexate with or without rituximab is ongoing.


BACKGROUND:Primary Central Nervous System Lymphoma (PCNSL) is an aggressive primary brain tumor with median progression free survival (PFS) after upfront methotrexate-based chemotherapy of 2-3 years. Outcome and treatment options are poor for recurrent/refractory (r/r) disease. Response rates (ORR) range between 30-60% with a PFS of 2-5 months. Ibrutinib has shown promising clinical response in Mantel cell lymphoma, CLL, and Waldenström. This trial investigates Ibrutinib in patients with r/r PCNSL and SCNSL.

METHODS:Eligible patients had r/r PCNSL or Secondary CNS Lymphoma (SCNSL), age≥18, ECOG≤2, normal end-organ function, and unrestricted number of CNS directed prior therapies. In patients with SCNSL disease, systemic disease needed to be absent.

RESULTS:Twenty patients were enrolled (3 at 560 mg; 17 at 840 mg). Median age was 69 (range 21-85); 12 were women. Median ECOG was 1 (0: 2, 1: 12, 2: 6). 65% had PCNSL and 35% SCNSL; 70% had recurrent disease. Eleven had parenchymal disease, 3 isolated cerebrospinal fluid (CSF) involvement and 6 both. Five grade 4 adverse events were observed in 4 patients (lymphopenia (2), sepsis (1), neutropenia (2)). Ten patients developed grade 3 toxicities, including lymphopenia in 3 patients, thrombocytopenia in 2, hyperglycemia in 2, lung infection in 2, neutropenia in 1, urinary tract infection in 1, colitis in 1, and fungal encephalitis in 1. The most common toxicities were hyperglycemia, anemia, and thrombocytopenia. After a median follow-up of 193 days, 19/20 patients were evaluated for response: 8 CR, 7 PR, 1 SD and 3 PD; 75% (15/20) ORR. The median PFS is 7.29 months (95% CI: 3.80-15.43 months (longest: 15.3 months)). The mean Ibrutinib concentration in the CSF 2h post administration at day 1 and 29 is 1.75 ng/mL (3.97 nM) and 2.51 ng/mL (5.6 nM) which is above the IC50 (1nM) required in vitro to reduce growth of lymphoma cells. An additional treatment arm has been added to the trial which will evaluate adverse events of the combination of ibrutinib and high-dose methotrexate chemotherapy. Enrollment into the combination arm is ongoing and updates will be presented at the meeting.

CONCLUSION:Patients with CNS lymphoma tolerate Ibrutinib with manageable adverse events. Drug concentrations in CSF are higher at steady state (day 29) and meaningful CSF concentrations are reached. Clinical response was seen in 75% of CNS lymphoma patients. A combination arm will assess the adverse events of ibrutinib in combination with high-dose methotrexate chemotherapy.

  1. Grommes C. et al. Single-Agent Ibrutinib in Recurrent/Refractory Central Nervous System Lymphoma. 2016 December 5; Oral Abstract #783: ASH 58 thAnnual Meeting and Exposition, San Diego, CA.