Ibrutinib in patients with relapsed/refractory central nervous system lymphoma: A retrospective single‐centre analysis

Abstract

Central nervous system lymphomas (CNSL) including primary CNSL (PCNSL) and isolated secondary CNSL (iSCNSL) are rare diseases predominantly classified as diffuse large B-cell lymphomas (DLBCL). Clinical prognosis of patients with primary refractory disease or relapse after initial response (relapsed/refractory CNSL, rrCNSL) is poor and the optimal salvage treatment strategy has not been developed yet.1 CNSLs are characterized by gain-of-function mutations affecting genes involved in the B-cell receptor (BCR) signalling pathway and the Toll-like receptor adaptor protein MYD88, with MYD88 L265P mutations representing the genetic hallmark of CNSL.2 The accumulation of these genetic aberrations suggests that CNSL may be addicted to BCR signalling.3 Ibrutinib irreversibly inhibits Bruton's tyrosine kinase (BTK) downstream of BCR signalling and has shown clinical activity in phase I and II trials, both as single agent or in combination with rituximab and chemotherapy.4-7 In this single-centre case series, we report the results of a retrospective real-world analysis of rrCNSL patients treated with either off-label ibrutinib monotherapy or ibrutinib-based combination therapy. Patients selected for this analysis were treated at University Medical Center Freiburg (Germany) between December 2017 and January 2020. All patients provided written informed consent approved by the institutional ethics committee and in accordance with the Declaration of Helsinki. Response to therapy was assessed by routine magnetic resonance imaging (MRI) according to the International Primary CNS Lymphoma Collaborative Group criteria.8 Progression-free survival (PFS) was defined as time from initiation of ibrutinib to disease progression, death from any cause, or last follow-up. Overall survival (OS) was defined as time from initiation of ibrutinib to death from any cause or last follow-up. DLBCL cell-of-origin (COO) was assessed following the Hans classification criteria.9 MYD88 L265P mutation status of tumour or cerebrospinal fluid was assessed by digital droplet polymerase chain reaction (ddPCR). Nine eligible patients with rrCNSL (five PCNSL, four iSCNSL) were included in the analysis (two female, seven male). Median age was 63 years (range: 53–82) and median Eastern Cooperative Oncology Group (ECOG) score was 2 (range: 0–3). All patients were heavily pretreated (median of two prior treatment regimens), with 100% of patients receiving high-dose cytarabine (HD-AraC) and/or methotrexate (HD-MTX) and five patients (56%) undergoing high-dose chemotherapy and autologous stem cell transplantation before ibrutinib initiation. Six patients required steroid treatment at enrolment to control neurologic symptoms. Steroids were discontinued in all six cases between 2 and 9 weeks after the start of ibrutinib. In 78% (n = 7) of cases, CNSL histology was DLBCL, with all cases being classified as non-GCB (germinal centre B-cell-like) subtype. One patient was diagnosed with isolated CNS involvement of lymphoplasmacytic lymphoma (LPL, Bing–Neel syndrome), one with chronic lymphocytic leukaemia (CLL) (Table I). Radiation Dosage (Gy) No. of sites 25/5 1 30/ 3 2 25/ 5 1 Treatment regimens were heterogeneous. One third of patients (n = 3) received either ibrutinib monotherapy or focal radiation followed by ibrutinib maintenance. Two patients obtained ibrutinib in combination with either rituximab alone (monthly) or rituximab plus HD-MTX according to a recently published phase Ib trial.5 Immunohistopathological staining of one patient's brain tumour at relapse (classified as DLBCL) was negative for CD20 but positive for CD38 antigens. Thus, this patient received ibrutinib in combination with CD38 antibody daratumumab (every three weeks; Table I). MYD88 L265P mutations were identified in all DLBCL tumour samples (7/7) at allele frequencies between 1·8 and 45·8%, while one patient with CLL did not harbour this aberration (Table S1). Median follow-up was 427 days (range: 75–711). Best clinical responses included six complete remissions (CR) and three stable diseases (SD) with an overall response rate (ORR) of 66%. ORR in relapsed/refractory PCNSL was 60% (3/5) and 75% (3/4) in iSCNSL (Fig 1A). CRs were observed in all patients receiving focal radiation followed by ibrutinib maintenance (3/3), in all patients with ibrutinib–antibody combination therapy (2/2), and in one patient receiving ibrutinib monotherapy (1/3). No response was seen in a patient with rrPCNSL who obtained ibrutinib with rituximab/HD-MTX. This patient did not complete immunochemotherapy due to disease progression after cycle 2 (LYFR069; Fig 1B). Median PFS for all patients was 275 days (95% CI, range 110–428 days), with five patients developing disease progression during treatment and four remaining disease-free on ibrutinib therapy (Fig 1B, Figure S1). Notably, two out of three patients undergoing focal radiation and ibrutinib maintenance showed a durable response, remaining disease-free after 427 and 670 days respectively. On the other hand, response to ibrutinib monotherapy was rather incomplete, with all patients developing CNSL progression after 110, 282, and 482 days respectively. Both patients obtaining ibrutinib plus antibody treatment remained disease-free after a follow-up of 75 and 275 days (Fig 1B). Median OS was not reached, with 7/9 (77·8%) patients being alive at time of the analysis. Two patients deceased immediately after disease progression following ibrutinib treatment and one patient was lost to follow-up after PD (Table SI, Figure S1). The value of retrospective studies for the assessment of adverse events (AEs) is rather limited. However, we did not observe any bleeding complications or fungal infections (e.g., aspergillosis of the lung or CNS), a phenomenon that has frequently been reported before.10 Most common AEs were anaemia, electrolyte imbalances, and elevation of liver enzymes. In summary, we demonstrate clinical activity of ibrutinib monotherapy and ibrutinib-based combinations in routine management of heavily pretreated rrCNSL patients. While the majority of patients receiving ibrutinib focal radiation followed by ibrutinib maintenance or ibrutinib–antibody combination therapy had durable responses, ibrutinib activity as single agent was rather transient and short, with all patients eventually showing disease progression or relapse. These observations indicate that ibrutinib activity in combination with other agents might be superior over ibrutinib monotherapy, as suggested before.5, 6 Our study is inherently limited by its retrospective nature and the heterogeneity of patient cohorts and treatment strategies. However, it might serve as a stimulus report for future prospective clinical trials further evaluating the role of ibrutinib-based combinations as a treatment strategy for patients with rrCNSL. None This work was supported by the Else Kröner-Fresenius-Stiftung (2018_A38, to FS), the Deutsche Gesellschaft für Innere Medizin Clinician Scientist Program (to FS), and the Fördergesellschaft Forschung Tumorbiologie (to FS). PCR has received research support from the Fraunhofer-Gesellschaft and personal fees, travel support, and honoraria from Boston Scientific, Brainlab, and Inomed. JD-A has received travel support from Sobi and Gilead, and honoraria from Roche. EML and FS developed the concept, designed the molecular experiments, analyzed the data, and wrote the manuscript. EML and MB performed tumour volume analyses. MW, JM, and SB performed molecular experiments and analyzed ddPCR data. JD-A, JD, RM, GI, JF, ES, and FS provided patient specimens and/or clinical data. All authors commented on the manuscript at all stages. Table SI. MYD88 L265P digital droplet PCR (ddPCR) results. Fig S1. Progression-free survival and overall survival. Kaplan–Meier analysis of (A) progression-free survival (PFS) and (B) overall survival (OS). Dashed lines in (A) highlight median PFS. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

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