Secondary central nervous system relapse in diffuse large B cell lymphoma in a resource limited country: result from the Thailand nationwide multi-institutional registry.

Secondary central nervous system (CNS) relapse is a serious and fatal complication of diffuse large B cell lymphoma (DLBCL). Data on secondary CNS (SCNS) relapse were mostly obtained from western countries with limited data from developing countries. We analyzed the data of 2034 newly diagnosed DLBCL patients enrolled into the multi-center registry under Thai Lymphoma Study Group from setting. The incidence, September 2006 to December 2013 to represent outcome from a resource limited pattern, management, and outcome of SCNS relapse were described. The 2-year cumulative incidence (CI) of SCNS relapse was 2.7 %. A total of 729, 1024, and 281 patients were classified as low-, intermediate-, and high-risk CNS international prognostic index (CNS-IPI) with corresponding 2-year CI of SCNS relapse of 1.5, 3.1, and 4.6 %, respectively (p < 0.001). Univariate analysis demonstrated advance stage disease, poor performance status, elevated lactate dehydrogenase, presence of B symptoms, more than one extranodal organ involvement, high IPI, and high CNS-IPI group as predictive factors for SCNS relapse. Rituximab exposure and intrathecal chemoprophylaxis offered no protective effect against SCNS relapse. At the time of analysis, six patients were alive. Median OS in SCNS relapsed patients was significantly shorter than relapsed patients without CNS involvement (13.2 vs 22.6 months) (p < 0.001). Primary causes of death were progressive disease (n = 35, 63.6 %) and infection (n = 9, 16.7 %). In conclusion, although the incidence of SCNS relapse in our cohort was low, the prognosis was dismal. Prophylaxis for SCNS involvement was underused even in high-risk patients. Novel approaches for SCNS relapse prophylaxis and managements are warranted.

Factors Influencing Physician Discretion to Administer CNS Prophylaxis in Diffuse Large B Cell Lymphoma: A Single Institution Retrospective Study.

INTRODUCTION/BACKGROUND: Central nervous system (CNS) relapse is an infrequent but serious and challenging complication of diffuse large B-cell lymphoma (DLBCL) that carries a dismal prognosis. While several risk factors have been identified to stratify the risk for CNS relapse including the 2015 CNS internal Prognostic index (CNS-IPI), controversy still remains regarding the indication, timing, and method of CNS prophylaxis. The purpose of this study was to determine whether IT-MTX reduced the risk of CNS relapse, as well as treatment related and financial toxicity of CNS prophylaxis. PATIENTS AND METHODS: In this retrospective study, we identified 194 patients with DLBCL who received care at Loma Linda University Cancer Center between January 2010- August 2022. We evaluated the efficacy, side effect profile, and financial toxicity of IT-MTX for CNS prophylaxis in patients with DLBCL. RESULTS: In patients with intermediate to high CNS relapse risk (CNS-IPI 2-5) IT-MTX did not reduce the 1 year risk of CNS relapse (RR 1.1296, 95% CI 0.1933-6.6012, P = .08924). The median time to CNS relapse was longer in patients who had received IT-MTX (13.5 months) vs. those who did not (7 months). Thirty-eight (52.8%) patients reported adverse side effects of any kind as a result of IT-MTX administration, with 23.6% of patients developing grade 2 to 3 adverse events. The average cost for CNS-prophylaxis was estimated to be approximately $8,059.04 over a patient's treatment course, but as high as $20,140. CONCLUSIONS: These findings suggest that IT-MTX has limited and potential transient effectiveness in preventing CNS relapse. Given the high rate of side effects and significant cost of IT-MTX, we recommend that clinicians carefully consider the risks and benefits of prophylaxis before prescribing IT-MTX for CNS-prophylaxis.

Predictive impact of soluble interleukin-2 receptor and number of extranodal sites for identification of patients at very high risk of CNS relapse in diffuse large B-cell lymphoma.

There remains an unmet clinical need to identify which patients with diffuse large B-cell lymphoma (DLBCL) would benefit from central nervous system (CNS) prophylaxis, due to the low positive predictive value (PPV; 10%-15%) of the currently available predictive models. To stratify patients at high risk of developing CNS relapse, we retrospectively analyzed 182 patients with DLBCL initially treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), or a R-CHOP-like regimen. Among them, 17 patients relapsed with CNS involvement, and the 2-year rate of CNS relapse was 7.9%. Upon carrying out multivariate analysis, ≥3 extranodal sites and elevated soluble interleukin-2 receptor (sIL-2R) levels at diagnosis were identified as independent risk factors for CNS relapse. The 2-year and 3.5-year rates of CNS relapse were 57.1% and 78.6%, respectively, in patients with both elevated sIL-2R and ≥3 extranodal sites. Furthermore, combined use of these risk factors of both elevated sIL-2R and ≥3 extranodal sites resulted in a high PPV (71.4%), negative predictive value (93.1%), and overall accuracy (92.3%) for undergoing CNS relapse. In conclusion, we propose a simple and valuable tool to predict patients with DLBCL at very high risk of CNS relapse.

Central nervous system (CNS) prophylaxis in antiCD20-CHOP treated DLBCL at intermediate to high risk for CNS relapse: A systematic review and meta-analysis.

CNS prophylaxis is commonly used in Diffuse Large B-Cell Lymphoma (DLBCL) patients with risk features for CNS relapse. This systematic review and meta-analysis compares CNS relapse rates with and without CNS prophylaxis, for patients at intermediate to high CNS relapse risk. Studies reporting CNS relapse risk category and CNS outcomes with and without CNS prophylaxis for antiCD20-CHOP treated DLBCL patients were included. 10 studies with 3770 patients at intermediate to high CNS relapse risk were analyzed. No significant difference in the pooled Absolute Risk Difference (ARD 0.01, 95 % CI -0.01 to 0.02, P = 0.61) or Risk (RR 1.22, 95 % CI 0.81-1.83, P = 0.34) was noted in patients with and without CNS prophylaxis. There were also no differences within pre-specified subgroups of IV Methotrexate or IT chemotherapy. However, the quality of evidence supporting these observations was low. A meta-analysis of individual patient data will help evaluate the benefit of CNS prophylaxis strategies.

Patient selection and tolerability of high-dose methotrexate as central nervous system prophylaxis in diffuse large B-cell lymphoma.

INTRODUCTION: Central nervous system (CNS) relapse in diffuse large B-cell lymphoma (DLBCL) is usually fatal. Risk stratification of patients has historically been poorly defined, and CNS prophylaxis with high-dose methotrexate (HDMTX) can be associated with multiple toxicities. The CNS International Prognostic Index (IPI) defines three patient risk groups for CNS disease. The aims of this study were to evaluate the toxicity of HDMTX and describe outcomes in HDMTX and non-HDMTX patients according to the CNS-IPI. METHODS: 205 patients diagnosed with DLBCL between 2004 and 2014, initially treated with RCHOP-like chemotherapy and considered for HDMTX CNS prophylaxis were identified by pharmacy records at two teaching hospitals. Patient records were retrospectively reviewed for HDMTX toxicity, CNS-IPI calculation and CNS relapse. RESULTS: 28 patients with DLBCL were selected for two doses of HDMTX. Two of 28 patients received only one dose, and three had their second dose reduced due to renal impairment. 28% of patients experienced nephrotoxicity. 24 HDMTX and 122 non-HDMTX patients were evaluable for the CNS-IPI. No significant difference in the CNS-IPI distribution between the two groups was identified (p = 0.695). Five patients had CNS relapse, two who received HDMTX and three who did not. No significant difference in CNS relapse rate was identified between 24 HDMTX patients propensity-matched to 24 non-HDMTX patients. CONCLUSIONS: HDMTX was well-tolerated by patients. Application of the CNS-IPI identifies a different population of candidates for CNS prophylaxis compared to traditional criteria.

Aggressive Non-Hodgkin lymphomas: risk factors and treatment of central nervous system recurrence.

Introduction: Secondary central nervous system lymphoma (SCNSL) is a potentially fatal event in the setting of aggressive Non-Hodgkin Lymphomas. Nowadays, despite of the very poor outcome of SCNSL, several studies are going to identify the high-risk patients' subgroup that could early develop this detrimental event and in whom the central nervous system (CNS) prophylaxis could improve survival. Areas covered: Herein, the authors will review the prophylactic and treatment strategy for SCNSL, focusing on the identification of high-risk subgroup. Expert opinion: The validated CNS International Prognostic Index score lacks sensitivity. The role of prophylaxis has been suggested as an important step for selected patients. Intrathecal prophylaxis is always less consolidated, due to its doubtful efficacy, whereas systemic high-dose methotrexate is becoming the favored option to reduce CNS relapse in high-risk aggressive lymphomas. However, there is no a clear guideline to help physicians in clinical practice. The encouraging results on treatment of primary CNS lymphoma prompted new therapeutic strategies for SCNSL, although larger and randomized prospective studies are needed. Future efforts should be addressed to better clarify these open questions.

The number of extranodal sites assessed by PET/CT scan is a powerful predictor of CNS relapse for patients with diffuse large B-cell lymphoma: An international multicenter study of 1532 patients treated with chemoimmunotherapy.

PURPOSE: Development of secondary central nervous system involvement (SCNS) in patients with diffuse large B-cell lymphoma is associated with poor outcomes. The CNS International Prognostic Index (CNS-IPI) has been proposed for identifying patients at greatest risk, but the optimal model is unknown. METHODS: We retrospectively analysed patients with diffuse large B-cell lymphoma diagnosed between 2001 and 2013, staged with PET/CT and treated with R-CHOP(-like) regimens. Baseline clinicopathologic characteristics, treatments, and outcome data were collected from clinical databases and medical files. We evaluated the association between candidate prognostic factors and modelled different risk models for predicting SCNS. RESULTS: Of 1532 patients, 62 (4%) subsequently developed SCNS. By multivariate analysis, disease stage III/IV, elevated serum LDH, kidney/adrenal and uterine/testicular involvement were independently associated with SCNS. There was a strong correlation between absolute number of extranodal sites and risk of SCNS; the 144 patients (9%) with >2 extranodal sites had a 3-year cumulative incidence of SCNS of 15.2% (95% confidence interval [CI] 9.2-21.2%) compared with 2.6% (95% CI 1.7-3.5) among those with ≤2 sites (P < 0.001). The 3-year cumulative risks of SCNS for CNS-IPI defined risk groups were 11.2%, 3.1% and 0.4% for high-, intermediate- and low-risk patients, respectively. All risk models analysed had high negative predictive values, but only modest positive predictive values. CONCLUSIONS: Patients with >2 extranodal sites or high-risk disease according to the CNS-IPI should be considered for baseline CNS staging. Clinical risk prediction models suffer from limited positive predictive ability, highlighting the need for more sensitive biomarkers to identify patients at highest risk of this devastating complication.