Central nervous system involvement in diffuse large B‐cell lymphoma

Yamamoto, Wataru; Tomita, Naoto; Watanabe, Reina; Hattori, Yukako; Nakajima, Yuki; Hyo, Rie; Hashimoto, Chizuko; Motomura, Shigeki; Ishigatsubo, Yoshiaki

doi:10.1111/j.1600-0609.2010.01438.x

Cited by 67 publications

(49 citation statements)

References 15 publications

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“…In our recent study with the same patient cohort, 4 adrenal as well as testicular involvement was extracted as a risk factor for CNS involvement by multivariate analysis, which seemed to be a cause of poorer OS for patients with either of these 2 extranodal involvements. As for the proportion of CNS prophylaxis, we 12 have reported 407 consecutive DLBCL patients in our group with respect to CNS involvement, and only 7.1% (29 of 407) of the cases received CNS prophylaxis. Although patients with CNS prophylaxis excluded from this study would not be a large population, selection bias might exist.…”

Section: Discussionmentioning

confidence: 99%

Prognostic impact of extranodal involvement in diffuse large B‐cell lymphoma in the rituximab era

Takahashi

Tomita

Yokoyama

et al. 2011

Cancer

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BACKGROUND:Extranodal involvement is considered a poor prognostic factor for patients with diffuse large B‐cell lymphoma (DLBCL); however, the prognostic impact of specific sites of involvement has not been fully elucidated.METHODS:The authors retrospectively analyzed 1221 patients treated uniformly with standard R‐CHOP therapy between 2003 and 2006. Patients with distinct forms of DLBCL such as intravascular lymphoma, primary effusion lymphoma, pyothorax‐associated lymphoma, primary central nervous system lymphoma, and intraocular lymphoma were also excluded. The authors evaluated 26 extranodal sites of involvement with respect to prognostic impact. The median age was 64 years (range, 15‐91 years).RESULTS:Univariate analysis revealed that patients with involvement of specific extranodal sites had significantly worse overall survival (OS) than did patients without such involvement; these sites included nasal cavity, paranasal sinus, lung, pleura, small intestine, peritoneum, liver, pancreas, stomach, spleen, adrenal gland, testis, bone, bone marrow, peripheral blood, skin, and subcutaneous tissue. Patients with Waldeyer ring involvement had significantly better OS. Multivariate analysis revealed that patients with the involvement of the pleura (P < .001), small intestine (P = .015), peritoneum (P = .002), adrenal gland (P < .001), testis (P = .005), bone marrow (P < .001), and peripheral blood (P = .002) had significantly worse OS, whereas those with Waldeyer ring involvement had significantly better OS (P = .038). Subgroup analysis with the nodal and/or Waldeyer patient group also showed prognostic impact of Waldeyer ring by multivariate analysis (relative risk, 0.3; P = .04).CONCLUSIONS:Extranodal involvement affects the prognosis of patients undergoing R‐CHOP therapy for DLBCL. Cancer 2012. © 2011 American Cancer Society.

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Section: Discussionmentioning

confidence: 99%

Prognostic impact of extranodal involvement in diffuse large B‐cell lymphoma in the rituximab era

Takahashi

Tomita

Yokoyama

et al. 2011

Cancer

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“…Elevated LDH levels, the involvement of >1 extranodal site, and an intermediate-high or high IPI score have also been cited as risk factors in other retrospective studies, reviews, and meta-analyses of the postrituximab era (Table 1). 1,2,7,9,17,18 Accumulated evidence from studies of extranodal involvement have shown that testicular or breast involvement (particularly as primary lymphoma, but also as secondary involvement) is clearly associated with a higher rate of CNS relapse. 5,[19][20][21] A growing body of evidence indicates a higher CNS relapse rate among patients with renal involvement by lymphoma.…”

Section: Guidelines For Diagnosis Prevention and Management Of Centrmentioning

confidence: 99%

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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“…40 Moreover, the addition of rituximab to standard therapy has not shown a definitive reduction in CNS involvement. [41][42][43][44] Thus, intravenous and/or intrathecal administration of cytotoxic agents is routinely used for prophylaxis against secondary CNS disease and is often associated with significant systemic toxicity.…”

Section: Anti-cd47 Antibody Therapy Is Effective In Preventing Nhl DImentioning

confidence: 99%

Extranodal dissemination of non-Hodgkin lymphoma requires CD47 and is inhibited by anti-CD47 antibody therapy

Chao¹,

Tang²,

Pachynski³

et al. 2011

Blood

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Non-Hodgkin lymphoma (NHL) presents as both localized and disseminated disease with spread to secondary sites carrying a worse prognosis. Although pathways driving NHL dissemination have been identified, there are few therapies capable of inhibiting them. Here, we report a novel role for the immunomodulatory protein CD47 in NHL dissemination, and we demonstrate that therapeutic targeting of CD47 can prevent such spread. We developed 2 in vivo lymphoma metastasis models using Raji cells, a human NHL cell line, and primary cells from a lymphoma patient. CD47 expression was required for Raji cell dissemination to the liver in mouse xenotransplants. Targeting of CD47 with a blocking antibody inhibited Raji cell dissemination to major organs, including the central nervous system, and inhibited hematogenous dissemination of primary lymphoma cells. We hypothesized that anti-CD47 antibodymediated elimination of circulating tumor cells occurred through phagocytosis, a previously described mechanism for blocking anti-CD47 antibodies. As predicted, inhibition of dissemination by anti-CD47 antibodies was dependent on blockade of phagocyte SIRP␣ and required macrophage effector cells. These results demonstrate that CD47 is required for NHL dissemination, which can be therapeutically targeted with a blocking anti-CD47 antibody. Ultimately, these findings are potentially applicable to the dissemination and metastasis of other solid tumors. (Blood. 2011;118(18):4890-4901) IntroductionLymphocyte trafficking is essential for the regulation of systemic immune processes, as well as lymphocyte differentiation and development. Most mature lymphocytes recirculate continuously from blood to tissue and back to the blood again. 1 This recirculation is not random but rather is guided by lymphocyte-endothelial interactions mediated by adhesion molecules (L-selectin, CD44, integrin ␣ 4 ␤ 7 , VLA-4, and LFA-1) and select chemokines. 2,3 Malignant transformation of normal lymphocytes results in lymphoma, many subtypes of which migrate and disseminate. Unlike the metastasis of other cancers, lymphoma dissemination probably reflects conserved physiologic behavior, rather than acquisition of metastatic potential. Indeed, mechanisms of normal lymphocyte homing and recirculation have been implicated in lymphoma dissemination and invasion. For example, adhesion molecules involved in normal lymphocyte trafficking have been shown to play a role in lymphoma dissemination, including LFA-1, ␣ 3 ␤ 3 , and other homing-associated integrins. [4][5][6] Furthermore, several of these adhesion molecules have been therapeutically exploited, as antibodies targeting the adhesion receptors LFA-1, integrin ␣ v ␤ 3 , and CD44 can inhibit dissemination of lymphoma in experimental models. 5,[7][8][9] CD47, also known as integrin-associated protein, has been implicated in the migration and mobilization of normal leukocytes. [10][11][12][13][14] In cancer, we recently demonstrated that CD47 regulates lymphoma pathogenesis by enabling evasion of phagocytosis through bind...

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Central nervous system involvement in diffuse large B‐cell lymphoma

Abstract: The incidence of CNS involvement does not decrease in rituximab-era.

Cited by 67 publications

References 15 publications

Prognostic impact of extranodal involvement in diffuse large B‐cell lymphoma in the rituximab era

Prognostic impact of extranodal involvement in diffuse large B‐cell lymphoma in the rituximab era

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

Extranodal dissemination of non-Hodgkin lymphoma requires CD47 and is inhibited by anti-CD47 antibody therapy

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