Activity of ibrutinib in mantle cell lymphoma patients with central nervous system relapse

Mantle cell lymphoma (MCL) is a rare lymphoma, accounting for 5% of non-Hodgkin lymphomas.¹  Central nervous system (CNS) dissemination occurs in 4.1% of these patients during the course of the disease.²  Median survival after diagnosis of CNS involvement is 3.7 months.² 

Ibrutinib, an oral Bruton tyrosine kinase (BTK) inhibitor, acts by blocking B-cell antigen receptor signaling, thereby reducing malignant proliferation of B cells and inducing apoptosis.³  Ibrutinib is a highly active novel agent with durable single-agent activity in relapsed and refractory MCL, giving a 68% response rate in a cohort of patients with relapsed/refractory MCL.^4,5 

We report here the clinical observation of 3 MCL patients with CNS relapse treated with ibrutinib. All 3 patients presented with symptomatic CNS disease. Neuroimaging confirmed MCL infiltration in the cerebral parenchyma or the spinal cord, and cerebrospinal fluid (CSF) analysis was positive in 1 patient. We observed rapid responses in all 3 patients without any significant toxicity.

Three MCL patients with CNS relapse presented for treatment in our unit between April 2014 and May 2015. MCL diagnosis was confirmed with cyclin D1 overexpression at diagnostic biopsy for the 3 patients. All patients had received at least one line of prior treatment, two having R-BEAM high-dose therapy followed by autologous stem cell transplant. All 3 patients presented with refractory or early relapsing MCL and measurable CNS disease (retro-orbital lesion, CSF infiltration, temporal mass, transverse myelitis). Patients and disease characteristics at ibrutinib initiation and responses to treatment are summarized in Table 1. Ibrutinib treatment was administered at a standard dose (560 mg/d) as a single agent. Patients were assessed for response (clinical examination, CSF, magnetic resonance imaging [MRI], fluorodeoxyglucose-positron emission tomography [FDG-PET] scan, Cheson criteria) and toxicity. Response assessment was specific to each patient, adapted for initial CNS lesion. Plasma and CSF pharmacokinetics analyses were performed (patients 2 and 3 only). Blood samples for plasma pharmacokinetics were collected on day 8 at pre-dose and 1, 2, 4, 6, and 8 hours post-dose. CSF collection was performed 2 to 4 hours post-dose. Ibrutinib quantification in plasma and CSF was performed using a liquid chromatography coupled with mass tandem spectrometry (Thermo Quantum Ultra TQD) validated according to the bioanalytical method validation guidelines.^6,7  Maximal concentration (Cmax) was determined and area under the plasma concentration vs time curve (AUC_0–t) was calculated according the trapezoidal rule.

At 3 months, impressive responses had been obtained for all 3 patients (Figure 1). The first patient presented a complete response (CR) for cerebral and extracerebral lesions according to Lugano classification criteria⁸  at 3 months, which was maintained at 6 months, with a normal computed tomography (CT) scan and a negative FDG-PET scan of the CNS retro-ocular lesion. The follow-up for this patient is currently at 1 year and he is still in CR as seen on FDG-PET, cerebral MRI, and CT scan. The second patient showed very early improvement in his neurologic exam (within 3 days). In parallel, we observed a reduction of CNS lesion on MRI at day 8, with a CR at 1 month on cerebral MRI, medullar MRI, and FDG-PET. At 6 months, the CR was confirmed at both sites on cerebral and medullar MRI. The third patient presented a partial response (PR) in CSF (decrease from 900 to 76 cells/mL) and retro-orbital lesion evaluation (cerebral MRI) with recovery of walking, decreased pain, and improved performance status. All 3 responses occurred within 3 to 8 days of treatment initiation, with a significant improvement in the clinical examination. Response was confirmed in all cases by biological analysis and imaging. Only 2 cases (patients 2 and 3) were evaluated for CSF infiltration, and one of them was positive. Patients obtained a clinical response in the 3 cases, with no consideration of CNS relapse site and CSF infiltration. We did not observe any secondary effect in terms of bleeding or hematoma when performing lumbar puncture under ibrutinib.

Treatment was well tolerated by all 3 patients, including heavily pretreated patients, with no severe toxicity. Patient 2 had higher ibrutinib plasma exposure on day 8 (AUC_0-24h 3119 ng*h/mL; C_max 729 ng*mL−1) compared with published data,^9,10  and ibrutinib CSF concentrations reached 50 ng/mL (equivalent to 113. 5 nmol/L). Patient 3 had ibrutinib plasma exposure on day 8, consistent with published data (AUC_0-24h 1002 ng*h/mL; C_max 188 ng/mL), and ibrutinib CSF concentrations reached 2 ng/mL (equivalent to 4.5 nmol/L), which was well above ibrutinib IC50 (0.46 nmol/L).

CNS relapse is probably the most dramatic complication in B-cell malignancies. Although infrequent, it has rapidly fatal consequences with a poor median survival.²  CNS relapse in MCL is a significant unmet medical need and its very poor prognosis with current treatment options¹¹  highlights the urgent need for alternative therapeutic approaches. This is the first report describing the efficacy of ibrutinib in MCL patients with CNS relapse. The highly active therapeutic activity for these patients after single oral agent ibrutinib therapy, with clinical and objective responses within 3 months, seems to be very promising. Survival after CNS relapse diagnosis for these patients is already substantially higher than the median 3.7 months reported,²  and for two of them, follow-up at 1 year and at 9 months showed a persisting CR, confirming the efficacy of ibrutinib.

In the relapse setting, numerous phase 2 studies have proven the efficacy of ibrutinib monotherapy in B-cell malignancies,¹²  not only in MCL and in chronic lymphocytic leukemia, where Food and Drug Administration approval has already been obtained after an accelerated process (in November 2013 and February 2014, respectively), but also in follicular lymphoma, Waldenström disease, and diffuse large B-cell lymphoma.^9,13,14 

In the first-line setting, ibrutinib is currently being evaluated in phase 1b trials in combination with standard first line treatment in diffuse large B-cell lymphoma.¹⁵  Based on this observation, we postulate that this association opens new perspectives in terms of CNS relapse prevention in B-cell malignancies. Moreover, the safety and simplicity of daily oral treatment with ibrutinib offers greater comfort to patients compared with intrathecal injections.¹⁶ 

We have shown that a low CSF-to-plasma ibrutinib concentration ratio (ranging from 1%-7%) was observed. Ibrutinib CSF distribution may rely on an active influx transport across the blood-brain barrier or a simple diffusion limited by the high plasma protein binding of ibrutinib.¹⁷  Further preclinical studies are needed to determine precisely the mechanism involved.

In conclusion, ibrutinib is emerging as a promising targeted therapy approach for MCL patients with CNS relapse, whatever the form of CNS relapse. Our clinical, biological, and pharmacokinetic results confirm the ability of ibrutinib to cross the blood-brain barrier. The use of ibrutinib to manage CNS relapses of MCL likely constitutes an efficient solution for this unmet medical need and should be considered for other B-cell malignancies. Based on these data, one may speculate on the potential of a prophylactic activity on CNS relapse for ibrutinib in B-cell malignancies at diagnosis, by considering the proprieties of each of these entities. This observation about 3 patients opens new perspectives in the utility of ibrutinib in MCL disease but needs to be confirmed with other studies.

This study was supported in part by the Nelia and Amadeus Barletta Foundation (C.T.).

Contribution: S.B. and C.T. designed the research; all authors analyzed data; S.B. and C.T. wrote the paper; and L.G., S.A., P.B., J.B., E.d.K., S.M., and H.S. reviewed the manuscript.

Conflict-of-interest disclosure: C.T. has participated on advisory committees for Gilead, Janssen, and Roche. P.B. has participated on advisory committees for Takeda. The remaining authors declare no competing financial interests.

Correspondence: Catherine Thieblemont, Hemato-Oncology Department, Saint-Louis University Hospital, 1, Avenue Claude Vellefaux, 75010 Paris, France; e-mail: catherine.thieblemont@aphp.fr.