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Bruton's tyrosine kinase inhibitors (BTKi) exhibit superior efficacy in relapsed/refractory primary central nervous system lymphoma (PCNSL), but few studies have evaluated patients with newly diagnosed PCNSL, and even fewer studies have evaluated differences in efficacy between treatment with BTKi and traditional chemotherapy. This study retrospectively analyzed the clinical characteristics of 86 patients with PCNSL and identified predictors of poor prognosis for overall survival (OS). After excluding patients who only received palliative care, 82 patients were evaluated for efficacy and survival. According to the induction regimen, patients were divided into the traditional chemotherapy, BTKi combination therapy, and radiotherapy groups; the objective response rates (ORR) of the three groups were 71.4%, 96.2%, and 71.4% (P = 0.037), respectively. Both median progression-free survival and median duration of remission showed statistically significant differences (P = 0.019 and P = 0.030, respectively). The median OS of the BTKi-containing therapy group was also longer than that of the traditional chemotherapy group (not reached versus 47.8 (32.5–63.1) months, P = 0.038).Seventy-one patients who achieved an ORR were further analyzed, and achieved an ORR after four cycles of treatment and maintenance therapy had prolonged OS (P = 0.003 and P = 0.043, respectively). In conclusion, survival, and prognosis of patients with newly diagnosed PCNSL are influenced by the treatment regimen, with the BTKi-containing regimen showing great potential. [ABSTRACT FROM AUTHOR]

Central nervous system (CNS) relapse of diffuse large B-cell lymphoma (DLBCL) is a rare but devastating event. Intravenous high-dose methotrexate (HD-MTX) is recommended as CNS prophylaxis, but the optimal timing and dose has not been elucidated. Here, we report a multicenter analysis of prophylactic HD-MTX administration for DLBCL. Two hundred eighty-four patients receiving HD-MTX either concurrent with each induction chemotherapy cycle (n = 221) or at the end of induction therapy (EOI, n = 63) were included. Patients with CNS-IPI scoring 4–6, and/or testicular involvement, and/or double/triple hit lymphoma, were stratified into the high-risk group and the others into the moderate-risk group. Concurrent HD-MTX was associated with increased risk of grade 3/4 treatment-related toxicity (OR,1.49; P = 0.006) and subsequent chemotherapy delays (OR, 1.87; P = 0.003) in multivariate analysis. With a median follow-up of 36.0 months, no significant difference in CNS relapse rate was identified between the concurrent and EOI groups (3.2% vs 4.8%, P = 0.34), even in the high-risk group. Analysis on systemic MTX dose suggested that high-dose MTX (≥ 2 g/m2) was associated with better CNS relapse control only in the high-risk group, but not in the moderate-risk group. This study may elucidate the superiority of EOI HD-MTX to some extent. High MTX dose (≥ 2 g/m2) may not be necessary for the moderate-risk patients. [ABSTRACT FROM AUTHOR]

High-dose methotrexate (HD-MTX) at 3 g/m2 is one of the strategies for central nervous system (CNS) prophylaxis in the first-line treatment of aggressive lymphomas, especially in diffuse large B cell lymphoma patients with high-risk CNS-International Prognostic Index. The objective of our study was to retrospectively analyze the safety of 2 cycles of systemic HD-MTX administered as an ambulatory regimen. Between January 2013 and December 2016, 103 patients were carefully selected on 6 criteria, including age < 60, albumin > 34, performance status 0 or 1, normal renal and hepatic functions, good understanding of practical medical guidance, and no loss of weight. Strict procedures of HD-MTX infusion were observed including alkalinization, urine pH monitoring, and leucovorin rescue. Renal and hepatic functions were monitored at days 2 and 7. MTX clearance was not monitored. Toxicities and grades of toxicity were collected according to the NCI-CTCAE (version 4.0). Among the 103 selected patients, 92 (89%) patients successfully completed the planned 2 cycles of HD-MTX on an outpatient basis. Eleven patients completed only 1 cycle, 3 because of lymphoma progression and 8 because of toxicity including 3 grade II hepatotoxicity, 2 grade I/II renal toxicity, 1 grade III neutropenia, 1 active herpetic infection, and 1 grade III ileus reflex. Reported adverse events (AE) included 92 (84%) grade I/II and 18 (16%) grade III/IV. Grade III hepatotoxicity, mostly cytolysis, was the most frequent AE observed with 8 (8%) events. Grade III/IV hematologic toxicities concerned 9 patients with 8 grade III/IV neutropenia and 1 thrombocytopenia. Renal toxicity was rare, mild, and transient, observed with 4 (4%) grade I/II events. Ambulatory administration of HD-MTX at 3 g/m2 without MTX clearance monitoring is safe with strict medical guidance. It requires careful selection of patients before administration, and a renal and hepatic monitoring after the administration. [ABSTRACT FROM AUTHOR]

Although overall survival in diffuse large B cell lymphomas (DLBCL) has improved, central nervous system (CNS) relapse is still a fatal complication of DLBCL. For this reason, CNS prophylaxis is recommended for patients at high risk of CNS disease. However, no consensus exists on definition of high-risk patient and optimal CNS prophylaxis. Systemic high-dose methotrexate in combination with R-CHOP has been suggested as a potential prophylactic method, since methotrexate penetrates the blood-brain barrier and achieves high concentration in the CNS. In this retrospective analysis, we report treatment outcome of 95 high-risk DLBCL/FL grade 3B patients treated with R-CHOP or its derivatives with (N = 57) or without (N = 38) CNS prophylaxis. At a median follow-up time (51 months), CNS relapses were detected in twelve patients (12.6%). Ten out of twelve (83%) of CNS events were confined to CNS system only. Median overall survival after CNS relapse was 9 months. Five-year isolated CNS relapse rates were 5% in the prophylaxis group and 26% in the group without prophylaxis. These findings suggest that high-dose methotrexate-containing prophylaxis decreases the risk of CNS failure. [ABSTRACT FROM AUTHOR]

Primary central nervous system lymphomas (PCNSL) are non-Hodgkin lymphomas strictly localized to the CNS, occurring mainly in elderly patients with comorbidities. Current treatment in fit patients relies on high-dose methotrexate and high-dose cytarabine. The aim of this study was to evaluate the efficacy and feasibility of this treatment in elderly patients and to assess potential prognostic factors associated with survival. We conducted a retrospective study in two centers between January 2008 and September 2015 including 35 elderly immunocompetent patients who received first-line treatment with high-dose methotrexate. With a median follow-up of 19.8 months (range: 1.7-73.4 months), median overall survival (OS) was 39.5 months (95% confidence interval (95% CI): 18.3-60.7) and median progression-free survival (PFS) was 25.8 months (95% CI: 5.2-46.4). In univariate analysis, administration of high-dose cytarabine and achieving a relative dose intensity for methotrexate > 75% were associated with increased OS (p = 0.006 and p = 0.003, respectively) and PFS (p = 0.003 and p = 0.04, respectively) whereas comorbidities, defined by a CIRS-G score ≥ 8, were associated with decreased OS and PFS (p = 0.02 and p = 0.04, respectively). A high MSKCC score was associated with decreased OS (p = 0.02). In multivariate analysis, administration of high-dose cytarabine was associated with increased OS and PFS (p = 0.02 and p = 0.007, respectively). Comorbidities and relative dose intensity for methotrexate are important for the prognosis of elderly patients with PCNSL. These results must be confirmed in prospective trials. [ABSTRACT FROM AUTHOR]

Optimal treatment strategies for primary central nervous system lymphoma (PCNSL) have not been established. In this study, we investigated the treatment outcomes and prognostic factors of high-dose methotrexate, vincristine, and procarbazine (MVP) chemotherapy followed by an interim response-adapted intensification strategy in immunocompetent patients with PCNSL. We evaluated the evidence of infection with Epstein-Barr virus (EBV) in both brain tumor tissue and whole blood. Forty patients were retrospectively reviewed. Ten (25 %) patients who achieved complete response (CR) in the interim analysis did not receive any additional consolidation treatment after completion of planned high-dose MVP chemotherapy. Additional radiotherapy ( n = 9) or autologous stem cell transplantation (ASCT) ( n = 7) was performed in patients who did not achieve CR in the interim analysis. The median age was 55 years. The overall CR rate was 62.5 % ( n = 25), and the objective response rate was 75.0 %. Two-year overall survival (OS) was 59.8 %, and 2-year progression-free survival was 47.1 %. Grade 3 or 4 neutropenia and thrombocytopenia occurred in 47.5 and 32.5 % of patients, respectively. Treatment-related mortality was 15.0 % ( n = 6), and four patients developed delayed neurotoxicity. There was no evidence of EBV-encoded RNA expression in brain tumor tissue. Ten (29.4 %) of 34 patients showed detectable EBV-DNA in whole blood. Poor performance status and EBV-DNA positivity in whole blood were significantly associated with inferior OS ( p = 0.032, p = 0.023, respectively). We suggest that high-dose MVP chemotherapy followed by an early response-adapted intensification strategy may be effective and minimize the number of patients who receive radiotherapy or ASCT in the early course of treatment. [ABSTRACT FROM AUTHOR]

Sustained elevation of serum methotrexate (MTX) concentrations (>1.0 μM) for 48 h (48-h value) has been found to have predictive significance for the development of toxicity. However, we sometimes experience severe adverse events during high-dose (HD) MTX therapy even if serum MTX concentrations comply with recommended values. We performed a retrospective study to identify predictors for occurrence of adverse events and examined whether only the 48-h value is a statistically significant predictor for clinical adverse events during HD MTX therapy. The subjects were 32 hematological patients ( n = 58 episodes) treated with MTX at Kyoto Prefectural University of Medicine between February 2003 and July 2007. Ordered logistic regression analysis was used to identify predictors for occurrence of adverse events. The predictive factors identified were: 24-h continuous infusion therapy (24-h C-IV) (long infusion time) [odds ratio (OR) = 2.890, confidence interval (CI) =1.493-5.594; P = 0.0016] for fatigue, higher dose [OR = 2.282, CI = 1.287-4.046; P = 0.0048] and combination chemotherapy [OR = 2.177, CI = 1.059-4.477; P = 0.0344] for stomatitis, and 24-h C-IV [OR = 2.573, CI = 1.101-6.016; P = 0.0291] for neutropenia. We found that only the 48-h value was not a predictor for clinical adverse events for HD MTX therapy. A major limitation of the present study was the small number of participants. However, our findings suggest that there is evidence that a long infusion time is a significant predictor for general fatigue and neutropenia, while a higher dose and combination chemotherapy are predictors for stomatitis. [ABSTRACT FROM AUTHOR]

Primary mediastinal large B cell lymphomas (MLCL) differ from other diffuse large cell lymphomas, leading to a description as a separate entity in the current World Health Organization classification. Dose intensification improves long-term results, but no standard therapy has been established so far. We investigated the use of a high-dose methotrexate-based alternating chemotherapy regimen (B-ALL protocol of the German ALL study group) followed by consolidative mediastinal radiotherapy first as a single-center trial, then later as a prospective multicenter trial in 44 patients with a median age of 33 years. Response rates exceeded 90% with an overall survival rate of 80% in the single-center group (8.6 years median follow-up) and 82% in the multicenter group (2.5 years follow-up).Short-term toxicity was manageable, but required hospitalization: the rates of grade 3 or 4 toxicity were 20% (for mucositis), 42% (for neutropenia), 29% (for thrombocytopenia), and 9% (for neutropenic fever). No relapse occurred more than 2 years after diagnosis and initiation of treatment, but unfortunately, no patient with overt progression or relapse within these 2 years could be salvaged. Future directions in the treatment of MLCL will not focus on further dose intensification, but rather on the incorporation of (radio)immunotherapy as a therapeutic tool and gene expression profiling as well as positron emission tomography–computed tomography as stratifying tools. [ABSTRACT FROM AUTHOR]