CNS Relapse in Diffuse Large B-Cell Lymphoma Patients with Oral Cavity and Bone Marrow Involvement-Experience from an Inner City Hospital

Introduction: Central nervous system (CNS) relapse in patients with Diffuse Large B-cell Lymphoma (DLBCL) is an uncommon yet serious complication with incidence reported between 2-10% depending on patient characteristics and risk factors. Recently N.Schmitz et al.(doi:10.1200/JCO.2015.65.6520) proposed and validated a robust CNS-IPI risk model that includes individual International Prognostic Index (IPI) risk factors and kidney/adrenal extra-nodal site involvement. Head & neck and bone marrow involvement were not associated with increased CNS relapse risk in the model. These two variables have long been associated with increased risk of CNS relapse. Aim of the present study was to evaluate CNS relapse in patients with DLBCL who had bone marrow and head & neck involvement at diagnosis. Methods: Retrospective chart review was carried out on patients treated for DLBCL at John H Stroger Jr.Hospital of Cook County, an inner city urban hospital in Chicago, between 2007- 2011. All patients had histologically confirmed diagnosis of DLBCL. Patients with cutaneous, CNS involvement at diagnosis and those with incomplete charts were excluded. Variables studied included age at diagnosis, stage at diagnosis, bone marrow infiltration, IPI-score at diagnosis, type of extra-nodal involvement, type of chemotherapy, initial systemic response, CNS relapse and timing of relapse. Decision regarding CNS prophylaxis was at the discretion of treating physician. CNS-IPI was calculated for each chart. Data was analyzed using descriptive statistics (frequency, mean, median), non-parametric Fischer's exact test and logistic regression analysis. Results: 120 charts met the inclusion criteria. Median follow up duration was 56 months (IQR: 24 to 72 months). Average age at diagnosis was 51yrs. 61 (52.3%) patients were stage III/IV at diagnosis. 68 (57%) had IPI score >/= 2 at diagnosis. Extra nodal involvement was seen in 52(43%) patients. Extra nodal sites involved were head & neck 22(18%), followed by stomach 10(8%), visceral involvement 10(8%), visceral lining 6(5%) and bowel involvement 6(5%). Renal involvement was seen in 2 patients. Of the 22 patients with head and neck involvement, 18(82%) had oral cavity (tonsillar, pharyngeal) and 4(18%) had orbital involvement. 12(10%) patients had bone marrow involvement. 111 (93%) patients were treated with RCHOP and 9(7%) with DA-EPOCH R. Seven(5.8%) patients received CNS prophylaxis with intrathecal methotrexate in 3-4 doses, with oral cavity involvement being the indication in 5/7 (72%) patients. 87(73%) had complete treatment response to systemic chemotherapy, rest had progressive disease. 24(27%) of the 87 patients relapsed, median time to relapse was 18months (IQR 11-24months). Three (2.5%) patients had CNS relapse at a median of 38 months(IQR 6-48months). On logistic regression analysis, increasing CNS IPI-risk score was predictive of CNS relapse (p= 0.05; OR 2.9, CI: 1.001 to 8.558).Bone marrow involvement was not significantly associated with risk of CNS relapse (p=0.273). No statistically significant difference in CNS relapse was noted between patients with oral cavity involvement that did and did not receive CNS prophylactic treatment (p=1.00). Conclusion: Bone marrow and oral cavity (tonsillar and pharyngeal) involvement by DLBCL were not associated with increased risk of CNS relapse in the studied population, hence CNS directed prophylactic treatments in these group of patients may be omitted. Data from our cohort supports the use of CNS-IPI risk model to predict risk of CNS relapse. Disclosures No relevant conflicts of interest to declare.

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Extranodal Diffuse Large B Cell Lymphoma In The Rituximab Era and The Risk of Central Nervous System (CNS) Relapse. A Single Center Experience From 2008-2012

Blood ◽

10.1182/blood.v122.21.4330.4330 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4330-4330

Author(s):

Christina Tsao ◽

Kate Fisher ◽

Ji-Hyun Lee ◽

Julio C Chavez ◽

Samir Dalia ◽

...

Keyword(s):

Bone Marrow ◽

Cell Lymphoma ◽

Bone Marrow Involvement ◽

Progression Free Survival ◽

B Cell Lymphoma ◽

Free Survival ◽

Large B Cell Lymphoma ◽

Cns Relapse ◽

Musculoskeletal Involvement

Abstract Background Diffuse large b-cell lymphoma (DLBCL) with CNS relapse or progression has a poor prognosis. Prior studies noted certain factors which increased the risk of CNS relapse: bone marrow involvement, type as well as number (1+) of extra-nodal sites, age over 60, and increasing International Prognostic Index (IPI) score. However, these were prior to the advent of rituximab (R), which has been suggested to lower CNS relapse when used in combination with CHOP therapy. To our knowledge, no one has looked at the incidence of CNS relapse with regards to extranodal disease in the rituximab era. Methods Retrospective chart review of patients with DLBCL treated with multiagent induction therapy including rituximab from July‘08 to Jan’12 at Moffitt Cancer Center. Age, stage, IPI score, extra-nodal site, number of nodal sites, and use of intrathecal prophylaxis (IT), were evaluated for their impact on the risk of developing CNS relapse. For those who had complete response to initial therapy, time to progression(TTP) for CNS relapse was measured from completion date of first set of chemo cycles to date of CNS relapse (those who did not CNS relapse were censored at last follow up). TTP was censored at 6 years. Progression free survival(PFS) was measured from date of diagnosis to date of CNS or systemic relapse or death (those who were alive without relapse were censored at last follow up). Overall survival (OS) was measure from date of diagnosis to date of death. Stratified Kaplan Meier curves(with log rank p-values) and Cox PH models(with Wald p-values) were used to explore potential risk factors associated with relapse. Results Sixty-four patients with DLBCL who received induction therapy were evaluated: median age (range) = 65 (24-93) years; male =56%; IPI scores at diagnosis: 1 (43.8%), 2(21.9%), 3(15.6%); median length of follow up from time of diagnosis = 32 months. All the patients received a regimen containing rituximab, and 92% of patients received R-Chop as treatment. IT prophylaxis with methotrexate was used in 28% of the patients. Incidence of CNS relapse in our study population= 17.3% (n=9) The risk of CNS relapse varied depending on the extranodal site. Those with bone marrow and/or musculoskeletal involvement had an increased risk, with 78% of the CNS relapses occurring in patients with one or both of these sites of involvement. The hazard ratio (HR) for CNS relapse for patients with bone marrow and musculoskeletal involvement was 2.53 and 2.74, respectively (p=0.20 and p=0.13). Other extranodal sites of disease such as visceral organs, genital urinary tract, nasopharynx, or skin did not seem to significantly contribute to the risk of CNS relapse. Patients with bone marrow involvement also had an inferior overall survival (HR=3.05, Wald p=0.02) (see figure 1). Though not statistically significant (log rank p=0.126), those receiving IT methotrexate prophylaxis appear to have longer PFS than those who did not, with 83% alive without relapse at 6 years compared to 43% (see figure 2). Conclusions Despite the addition of rituximab to multiagent chemotherapy, those with bone marrow and musculoskeletal involvement still had a significantly higher risk of CNS relapse. There is a trend which suggests intrathecal prophylaxis with methotrexate can improve progression free survival and is still possibly beneficial in high risk DLBCL patients even in the rituximab era. Larger prospective studies are needed to determine the true benefit of prophylactic IT therapy in this population. Disclosures: No relevant conflicts of interest to declare.

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Cell-of-origin and bone marrow involvement increase specificity of defining patients with diffuse large B-cell lymphoma at high risk of CNS relapse: a study of 793 patients treated with chemoimmunotherapy in Asia

Leukemia & Lymphoma ◽

10.1080/10428194.2019.1648805 ◽

2019 ◽

Vol 61 (1) ◽

pp. 225-227 ◽

Cited By ~ 1

Author(s):

Shin Yeu Ong ◽

Colin Phipps ◽

Chandramouli Nagarajan ◽

Tiffany Tang ◽

Soon Thye Lim ◽

...

Keyword(s):

Bone Marrow ◽

High Risk ◽

B Cell ◽

Cell Lymphoma ◽

Bone Marrow Involvement ◽

B Cell Lymphoma ◽

Cell Of Origin ◽

Large B Cell Lymphoma ◽

Cns Relapse ◽

Large B Cell

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Follicular large-cell lymphoma treated with intensive chemotherapy: an analysis of 89 cases included in the LNH87 trial and comparison with the outcome of diffuse large B-cell lymphoma. Groupe d'Etude des Lymphomes de l'Adulte.

Journal of Clinical Oncology ◽

10.1200/jco.1997.15.4.1654 ◽

1997 ◽

Vol 15 (4) ◽

pp. 1654-1663 ◽

Cited By ~ 48

Author(s):

D Wendum ◽

C Sebban ◽

P Gaulard ◽

B Coiffier ◽

H Tilly ◽

...

Keyword(s):

Bone Marrow ◽

Prognostic Factors ◽

B Cell ◽

Cell Lymphoma ◽

Bone Marrow Involvement ◽

B Cell Lymphoma ◽

Large Cell ◽

Intensive Chemotherapy ◽

Large B Cell Lymphoma ◽

Beta 2 Microglobulin

PURPOSE The aims of this study were as follows: (1) to analyze clinical, histopathologic characteristics, treatment outcome, and prognostic factors of patients with follicular large-cell lymphoma (FLCL); and (2) to compare them with those of patients with diffuse large B-cell lymphoma (DLCL) treated in the same therapeutic trial. PATIENTS AND METHODS Eighty-nine FLCL patients who were histologically reviewed and who received an intensive chemotherapy regimen according to the LNH 87 protocol were analyzed and compared with 1,096 B-cell DLCL patients included in the same protocol. RESULTS After intensive induction treatment, 59 patients (67%) achieved a complete remission [CR]. Estimated 5-year survival was 59%, and estimated 5-year freedom from progression (FFP) was 39%. Prognostic factors associated with shorter FFP were age greater than 60 years (P = .02), advanced clinical stage (P = .01), abnormal lactic dehydrogenase (LDH) level (P = .02), abnormal beta-2 microglobulin (P = .02), B symptoms (P = .03), bone marrow involvement (P = .04), and high expression of bcl-2 protein (P = .05). When compared with B-cell DLCL patients, FLCL patients were younger (P = .02), had a better Eastern Cooperative Oncology Group (ECOG) status (P = .05), less bulky mass (P = .04), more advanced clinical stages (P < .001), and more bone marrow involvement (P = .02). No significant difference was observed between FLCL and DLCL patients for response to therapy (67% v 67% of CR), 5-year overall survival (58% v 51%), 5-year disease-free survival (53% v 57%), or FFP survival (39% v 43%). CONCLUSION FLCL patients have a favorable response rate and survival when treated with intensive chemotherapy. Their outcome is similar to that of B-cell DLCL patients, and a long-term FFP is observed for a substantial number of patients. Some adverse prognostic factors (including those of the International Prognostic Index, bone marrow involvement, and beta-2 microglobulin) have been identified to define a subset of patients who require other therapeutic approach.

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Occult bone marrow involvement in patients with diffuse large B-cell lymphoma: results of a pilot study

Pathology ◽

10.1080/00313020701684417 ◽

2007 ◽

Vol 39 (6) ◽

pp. 580-585 ◽

Cited By ~ 14

Author(s):

Dipti Talaulikar ◽

Jane E. Dahlstrom ◽

Bruce Shadbolt ◽

Michelle McNiven ◽

Amy Broomfield ◽

...

Keyword(s):

Bone Marrow ◽

Pilot Study ◽

B Cell ◽

Cell Lymphoma ◽

Bone Marrow Involvement ◽

B Cell Lymphoma ◽

Large B Cell Lymphoma ◽

Large B Cell

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Cytomorphology and Molecular Characterization of CLTC-ALK Rearrangement in 2 Cases of ALK-Positive Diffuse Large B-cell Lymphoma with Extensive Bone Marrow Involvement

Annals of Laboratory Medicine ◽

10.3343/kjlm.2008.28.2.89 ◽

2008 ◽

Vol 28 (2) ◽

pp. 89-94 ◽

Cited By ~ 5

Author(s):

Hee-Suk Choung ◽

Hee-Jin Kim ◽

Won-Seog Kim ◽

Kihyun Kim ◽

Sun-Hee Kim

Keyword(s):

Bone Marrow ◽

B Cell ◽

Cell Lymphoma ◽

Bone Marrow Involvement ◽

B Cell Lymphoma ◽

Alk Rearrangement ◽

Large B Cell Lymphoma ◽

Alk Positive ◽

Large B Cell

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Prognostic Factors in Diffuse Large B Cell Lymphoma,A Preliminary Study.

Blood ◽

10.1182/blood.v114.22.5006.5006 ◽

2009 ◽

Vol 114 (22) ◽

pp. 5006-5006

Author(s):

Ru Feng ◽

Meng Xu ◽

Yongqiang Wei ◽

Fen Huang ◽

Tong Zhao

Keyword(s):

Bone Marrow ◽

Negative Correlation ◽

Cell Lymphoma ◽

Bone Marrow Involvement ◽

B Cell Lymphoma ◽

Single Factor ◽

Extranodal Involvement ◽

Positive Correlation ◽

Large B Cell Lymphoma ◽

Large B Cell

Abstract Abstract 5006 Diffuse large B-cell lymphoma (DLBCL) has an obvious heterogeneity for a set of morphological, immunological phenotype, genetics and clinical manifestations. We found some patients suffered in bone invovlement at early stage. However some patients are not even if many of primary lesions or at the advanced stage. Is this is a universal or accident phenomenon? Is there any regularity for the occurrence of bone invovlement? As we all know, CD44 is a important antigent in normal development of B cells, which express in post-germinal center. It has a negative contro with the expression of Bcl-6, and has a a positive control with Stat-3. CD44 is also a cell surface glycoprotein and the principle receptor for hyaluronan and have multiple splice forms, such as CD44H and CD44v6. In the immune system, CD44 is called a homing receptor. The goal of our study is to evaluate if using a panel of markers such as CD20, CD44H, CD44v6,Bcl-6, Mum-l and Stat3 by immunohistochemistry defines prognosis in patients with DLBCL. We expect to find out some effective indexes for prognosis and bone marrow involvement. Materials and Methods Results 1. Case imformation: There are male 67 cases (55.8%) and 53 cases (44.2%) of female in the 120 cases. The median age is 55 years. 77 cases of primary lymph nodes (60%) and 48 cases of primary lymph node outside (40%). The Median follow-up of 120 patient was17 months, range to 6-148 month 2. The percentage of expression for CD20, CD44H, CD44v6, Bcl-6, Stat3 and Mum-1 in the 120 cases studied were as follows: 95.0%, 66.0%, 55.8%,54.2%,41.7%,46.7%. 3. Survival for single factor and multi-factor analysis: The single factor survival analysis showed that Hans group, Bcl-6/Stat-3 group, chemotherapy ± Rituximab, age, systemic symptoms, LDH level, bone marrow involvement, IPI score, number of extranodal involvement, Bcl-6, CD44H, CD44v6 on the survival of patients with DLBCL influential. In the Cox multivariate analysis, only chemotherapy ± Rituximab, age, extranodal involvement and CD44v6 have a significant statistical significance on the survival of patients with DLBCL (P = 0.000, 0.001, 0.000 and 0.009 respectively). 4. The associativity with antigen expression and clinical factors. It showed that the expression of CD44H had a positive correlation with bone marrow involvement (P 0.022), and implied a poor effect (P 0.003). The expression of CD44v6 also had a negative correlation with effect (P 0.000) and had a positive correlation with bone marrow involvement (P 0.052). The expression of Bcl-6 had a negative correlation with age and extranodal involvement (P 0.025 A0.005);the expression of Stat-3 had a negative correlation with pathology stage (P 0.030); the expression of Mum-1 had a positive correlation with age and extranodal involvement (P 0.014 A0.023), but had a negative correlation with bone marrow involvement (P 0.028). The rest had no statistics, P>0.05. 5. The associativity with antigens expression. It showed that the expressions of CD44H and CD44v6 had a positive correlation (P 0.000); the expression of CD44v6 and Stat-3 also had a positive correlation (P 0.045); the expression of Bcl-6 with Stat-3, Mum-1 had a negative correlation (P 0.013 A0.000);the expression of Stat-3 and Mum-1 also had a positive correlation (P 0.007). 6. Bcl-6 (-) ACD44v6 (+) and Stat-3 (+) provide actively singal to choose rituximab for DLBCL patients. Conclusions ACKNOWLEDGMENTS. We thank Hilda Ye for helpes and discussions. Disclosures No relevant conflicts of interest to declare.

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Dual Translocation Is An Independent Poor Prognostic Factor in Diffuse Large B-Cell Lymphoma,

Blood ◽

10.1182/blood.v118.21.3683.3683 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3683-3683

Author(s):

Kevin Tay ◽

Gillianne Lai ◽

Elaine J Chua ◽

Whee Sze Ong ◽

Tiffany Tang ◽

...

Keyword(s):

Bone Marrow ◽

Prognostic Factor ◽

Cell Lymphoma ◽

Bone Marrow Involvement ◽

B Cell Lymphoma ◽

Survival Outcomes ◽

Poor Prognostic Factor ◽

Large B Cell Lymphoma ◽

Independent Poor Prognostic Factor ◽

Large B Cell

Abstract Abstract 3683 Background: Diffuse large B-cell lymphoma (DLBCL) is a heterogenous group of diseases, that are associated with variable survival outcomes depending on the presence of certain genetic and molecular features. Of particular interest is a subset known as the “double-hit” (DH) lymphoma. DH lymphoma (dual translocation) is defined by the presence of a chromosomal breakpoint affecting the MYC/8q24 locus with a second oncogene translocation, most commonly a BCL2 rearrangement, and less commonly involving BCL6 or CCND1 rearrangements. However, the incidence of DH lymphoma remains to be determined. These patients typically have poor prognostic factors, with a dismal outcome when treated with rituximab-CHOP (RCHOP) chemotherapy. The aim of this study was to identify any clinical defining characteristics in patients with DH lymphoma, and to compare their outcomes with that of DLBCL patients without dual translocation. Methods: 202 newly diagnosed DLBCL patients, of whom 90% received rituximab based chemotherapy, were investigated using immunohistochemistry and fluorescence in situ hybridization (FISH), using breakapart FISH probes targeting BCL2, BCL6, MYC, CCND1 and IgH genes. The clinical characteristics and survival outcomes of patients who were identified with DH lymphoma were compared to those without the dual translocation. Results: Out of the 202 patients with DLBCL, we identified 10 cases (5%) with two or more concurrent translocations involving MYC and BCL2, or MYC and BCL6. Among the 10 patients with DH lymphoma, there were 6 patients with concurrent BCL2 and MYC translocations, 1 patient with BCL6 and MYC translocations and 3 patients with all 3 abnormalities. 7 of the 10 patients were male, with a median age of 68 years (42 – 84). Patients with DH lymphoma also presented with a significantly higher incidence of high-risk clinical features, including advanced stage disease, bulky disease, extranodal disease, bone marrow involvement and a high IPI score. Interestingly, the majority of patients with DH lymphoma expressed a germinal center (GC) phenotype (8 out of 9 patients) based on the Han's criteria. These patients also demonstrated a significantly poorer overall survival (OS) when compared to patients without dual translocation (2 yr OS 33% vs 84%, p = < 0.001). On multivariate analysis, the presence of a dual translocation was found to be an independent poor prognostic factor for OS (hazard ratio 8.84, 95% CI 3.54 to 22.08). Other factors predictive of an inferior OS included age, stage, bone marrow involvement and patients treated without rituximab. Conclusions: Our findings showed that the presence of dual translocation is an independent poor prognostic factor in DLBCL. It was present in 5% of our cohort and was associated with more advanced disease. Patients with dual translocation also had a significantly poorer survival following treatment with standard chemotherapy such as RCHOP, even though most patients exhibited the GC phenotype. Therefore, the use of novel agents in combination with chemotherapy is an area that deserves further exploration in this type of lymphoma. Disclosures: No relevant conflicts of interest to declare.

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High-Grade Diffuse Large B-Cell Lymphoma in Elderly Patients: Russian Multicenter Trial Results in R-EPOCH/R-HMA Protocol

Blood ◽

10.1182/blood.v128.22.5386.5386 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5386-5386

Author(s):

Olga A. Gavrilina ◽

Eugene E. Zvonkov ◽

Elena N. Parovichnikova ◽

Nelly G. Gabeeva ◽

Vera V. Troitskaya ◽

...

Keyword(s):

Bone Marrow ◽

Elderly Patients ◽

B Cell ◽

Older Patients ◽

Cell Lymphoma ◽

Bone Marrow Involvement ◽

B Cell Lymphoma ◽

High Grade ◽

Large B Cell Lymphoma ◽

Large B Cell

Abstract Background: The number of elderly patients with diffuse large B-cell lymphoma (DLBCL) in our aging society continues to rise. Median of age for patients with diffuse large B-cell lymphoma (DLBCL) is 60. Approximately 50% of older patients with DLBCL are defined as high-grade by IPI and these forms are characterized by aggressive course and poor response to standard chemotherapy (CT). Intensive protocols cannot be performed due to their toxicity for older patients with comorbidity. Addition of R-HMA to R-DA-EPOCH favourably changes the outcome in patients with untreated high-grade diffuse large B-cell lymphoma and didn't have higher toxicity [ASH 2015 # 2708]. Aim: To evaluate the efficacy and toxicity of R-EPOCH/R-HMA protocol in older patients with untreated high-grade diffuse large B-cell lymphoma. Patients and Methods: 19 untreated older DLBCL patients from 4 centers were enrolled in a prospective study between August 2013 - July 2016; stage II-IV; ECOG 0-3; median age 66 years (60-78); age ≥70y/60<70y 21%/79%; M/F 52%/48%; IPI: 52% high-intermediate and 48% high risk; 26% with bone marrow involvement. Severe comorbidity was diagnosed in 8 (42%) patients (coronary heart disease, hypertonic disease, chronic obstructive pulmonary disease and arrhythmia). All patients underwent 4-6 courses (2-3 cycles) of chemotherapy: R-EPOCH (standard dose and scheme), R-HMA (R 375 mg/m2 d1, MTX 500 mg/m2 24 hours d 2, AraC 1000 mg/m2 q 12 hrs d 3-4). In 3 cases of DLBCL with bone marrow involvement BEAM conditioning and autologous stem cell transplantation were applied. Results: The median follow-up is 18 months (3-37). There was no mortality associated with toxicity. The main non-hematological toxicities of R-HMA were infections (mucositis, pneumonia, sepsis, enteropathy) grades 1-2 and 3-4 in 90% and 10%, respectively. Hematological toxicity grade 4 for less than 4 days we observed only after courses R-HMA. Complete remission (CR) was achieved in 18 (100%) patients and 1 patient in the treatment now. There are four failures in patients older than 60 years: three relapses (after 6 and two after 14 month CR) and one death after 7 month CR by reasons not related with DLBCL. With a median follow 18 months overall and event-free survival of 19 older patients constituted 93,8% and 75,9%, respectively (Fig.1). There is no difference in older patients according to stage, IPI, LDH level, ECOG status for OS and EFS. So the combination of R-EPOCH/R-HMA may be considered as optimal intensive approach in older patients. Conclusions: TheR-EPOCH/R-HMA protocol demonstrated acceptable toxicity and high efficacy in older patients with high-grade DLBCL. Figure 1 Overall (A) and Event-free (B) survival in elderly patients with DLBCL. Figure 1. Overall (A) and Event-free (B) survival in elderly patients with DLBCL. Disclosures No relevant conflicts of interest to declare.

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