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

Bernard, Sophie; Goldwirt, Lauriane; Amorim, Sandy; Brice, Pauline; Brière, Josette; Kerviler, É. de; Mourah, Samia; Sauvageon, Hélène; Thiéblemont, Catherine

doi:10.1182/blood-2015-05-647834

Cited by 132 publications

(98 citation statements)

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“…2,85 New agents like ibrutinib and lenalidomide, which cross the brain barrier, are being explored, and the impact on CNS relapse risk in DLBCL remains to be established. 86,87 Systemic prophylaxis with HD-cytarabine in a small sample of DLBCL patients was found to have no clear beneficial role in preventing CNS disease. 2,85 New agents like ibrutinib and lenalidomide, which cross the brain barrier, are being explored and the impact on CNS relapse risk in DLBCL remains to be established.…”

Section: Systemic Prophylaxismentioning

confidence: 99%

“…2,85 New agents like ibrutinib and lenalidomide, which cross the brain barrier, are being explored and the impact on CNS relapse risk in DLBCL remains to be established. 86,87 Which prophylactic strategy should be chosen?…”

Section: Systemic Prophylaxismentioning

confidence: 99%

“…102 Hopefully, new molecules that cross the BBB, like ibrutinib or lenalidomide, might further improve the outcome of these patients. 86,87 To our understanding, current treatments for this condition should incorporate multifaceted approaches, such as multi-drug regimens with non-cross resistance and CNS activity, rituximab to improve systemic lymphoma control, IT therapy, and treatment intensification with ASCT.…”

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confidence: 99%

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Guidelines for diagnosis, prevention and management of central nervous system involvement in diffuse large B-cell lymphoma patients by the Spanish Lymphoma Group (GELTAMO)

et al. 2016

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Several factors hinder the identification of risk factors for central nervous system (CNS) involvement in diffuse large B-cell lymphoma (DLBCL), including the retrospective nature of most studies, the relatively low frequency of CNS relapse in DLBCL, and the heterogeneity of CNS prophylaxis methods used in these studies. Moreover, the impact of newly developed diagnostic tools (such as multiparameter flow cytometry [FCM]) and new treatments introduced in the last decade, in particular rituximab, has still not been fully clarified.Several studies 4,5,[7][8][9][10] and a recent meta-analysis 1 have described a decrease in rates D iffuse large B-cell lymphoma patients have a 5% overall risk of central nervous system events (relapse or progression), which account for high morbidity and frequently fatal outcomes, 1 and shortened overall survival of <6 months.2 Early diagnosis of central nervous system events is critical for successful treatment and improved prognosis. Identification of patients at risk of central nervous system disease is critical to accurately identify candidates for central nervous system prophylaxis vs. therapy. [3][4][5] This report by the Spanish Lymphoma Group (GELTAMO) aims to provide useful guidelines and recommendations for the prevention, diagnosis, and treatment of central nervous system diffuse large B-cell lymphoma patients with, or at risk of, leptomeningeal and/or brain parenchyma lymphoma relapse. A panel of lymphoma experts working on behalf of GELTAMO reviewed all data published on these topics available in PubMed up to May 2016. Recommendations were classified according to the Grading of Recommendations Assessment Development and Evaluation (GRADE) approach. 6 A practical algorithm based on the proposed recommendations was then developed (Figure 1 have concluded that the incidence of CNS relapse decreased after the introduction of rituximab (Table 1). The identification of risk factors has been the major goal of many studies of CNS involvement. Several large retrospective studies conducted in the pre-rituximab era [12][13][14][15] reported higher rates of CNS relapse in patients with increased serum lactate dehydrogenase (LDH) levels and/or involvement of >1 extranodal site, although these factors failed to predict CNS relapse in more than half of all cases.12 In addition to the involvement of >1 extranodal site and increased LDH, International Prognostic Index (IPI) score was also identified as an independent predictor for CNS relapse in other studies.13,16 A post-rituximab era study of 399 DLBCL patients, randomized to R-CHOP or CHOP chemotherapy, 3 identified an age-adjusted IPI (aaIPI) >1 as the only risk factor for CNS involvement, although a high aaIPI score was recorded for more than 60% of the patients. When aaIPI was excluded from the analysis, elevated LDH and a poor performance status (PS >1) were identified as independent predictive factors for CNS relapse. Similarly, in the randomized RICOVER-60 trial, 4 the combination of increased LDH levels, the involvement of >1 ex...

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Section: Systemic Prophylaxismentioning

confidence: 99%

Section: Systemic Prophylaxismentioning

confidence: 99%

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confidence: 99%

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Guidelines for diagnosis, prevention and management of central nervous system involvement in diffuse large B-cell lymphoma patients by the Spanish Lymphoma Group (GELTAMO)

et al. 2016

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“…However, most patients with MCL at our institution are offered participation in investigational protocols incorporating Bruton tyrosine kinase inhibitors; there are data suggesting the first-in-class agent, ibrutinib, penetrates the CNS 66 and may be effective in MCL with CNS involvement. 67 We have not observed any CNS relapses in our MCL patients treated with Bruton tyrosine kinase inhibitors (C.Y.C., pooled analysis of patients with MCL treated on phase 1-3 studies with BTK inhibitors as single agents or in combination with chemotherapy, unpublished data). However, larger datasets are required to confirm this observation.…”

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confidence: 99%

“…This highlights the need for further studies to better identify high-risk patients; better prophylactic strategies are needed as well. Novel agents such as ibrutinib and lenalidomide cross the blood-brain barrier 67,86 and are active in both systemic ABC DLBCL 87,88 and CNS lymphomas. [89][90][91] In a recent pooled analysis of 2 prospective studies…”

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How I treat patients with aggressive lymphoma at high risk of CNS relapse

Chin

Cheah

2017

Blood

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Central nervous system (CNS) relapses are an uncommon yet devastating complication of non-Hodgkin lymphomas. The identification of patients at high risk of secondary CNS relapse is therefore paramount. Retrospective data indicate prophylactic CNS-directed therapies may reduce the risk of CNS involvement; however, no consensus exists about dose, timing, or route of therapy. In addition, prophylaxis is not without risk of treatment-related complications and morbidity. Here, we present a series of case vignettes highlighting our approach to common dilemmas encountered in routine clinical practice. We review the method of assessing CNS relapse risk, factors that increase the likelihood of relapse including histologic subtype, MYC rearrangement, protein expression, and extranodal involvement, and review our clinical practice based on available evidence in administering CNS-directed prophylaxis. (Blood. 2017;130(7):867-874) IntroductionNon-Hodgkin lymphomas are biologically and clinically diverse hematological malignancies. Treatment is influenced by patient fitness, disease biology, and tumor burden. Identifying patients at high risk of central nervous system (CNS) relapse is important as the outcome of secondary CNS lymphoma is poor. [1][2][3][4] Risk of CNS progression is influenced by histologic subtype and subtype-specific clinicopathologic features (eg, site of involvement, protein expression, or gene rearrangements). Patients with highly aggressive lymphomas (eg, lymphoblastic, Burkitt lymphoma) are at high risk and frontline protocols include CNS-directed prophylaxis. In contrast, indolent lymphomas rarely involve the CNS and CNS prophylaxis is not required. Between these extremes fall diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma (HGBL) with MYC and BCL2 or BCL6 rearrangements, so-called "double-hit" lymphomas (HGBL-DH), and (nodal) peripheral T-cell lymphomas (PTCLs). The addition of rituximab has slightly reduced CNS relapse in DLBCL, probably through superior systemic control as there is negligible CNS penetration of the drug across the intact blood-brain barrier. 1,5 However, ;4% of unselected patients with DLBCL treated with prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (R-CHOP) experience CNS relapse, 6,7 and considerable efforts have been made to identify those at greatest risk. In this review, we will summarize our approach to this problem with case vignettes drawn from our practice. How I identify patients at increased risk for CNS relapseMany investigators have examined risk factors for CNS relapse, but studies have yielded inconsistent results, due to heterogeneity in patient populations, treatment, and/or limited sample size. [8][9][10][11][12][13][14][15][16] To address some of these limitations, Schmitz et al developed a 6-point score from 2164 patients treated on prospective German studies and validated in 1597 patients with DLBCL treated with R-CHOP in the British Columbia Cancer Agency (BCCA) Lymphoid Malignancies Database. 6 The components of the s...

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Efficacy of ibrutinib in the treatment of Bing–Neel syndrome

et al. 2016

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

Abstract: Key Points Ibrutinib induces a rapid, dramatic, and sustained response in MCL patient with symptomatic CNS relapse. Ibrutinib penetration through the blood-brain barrier was confirmed using plasma and cerebrospinal fluid pharmacokinetic analyses.

Cited by 132 publications

References 13 publications

Guidelines for diagnosis, prevention and management of central nervous system involvement in diffuse large B-cell lymphoma patients by the Spanish Lymphoma Group (GELTAMO)

Guidelines for diagnosis, prevention and management of central nervous system involvement in diffuse large B-cell lymphoma patients by the Spanish Lymphoma Group (GELTAMO)

How I treat patients with aggressive lymphoma at high risk of CNS relapse

Efficacy of ibrutinib in the treatment of Bing–Neel syndrome

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