Comparison of standardized prophylactic high-dose and intrathecal methotrexate for DLBCL with a high risk of CNS relapse.

The efficacy of high-dose methotrexate (HD-MTX) for central nervous system (CNS) relapse prophylaxis in patients with high-risk diffuse large B-cell lymphoma (DLBCL) is controversial. We compared the prophylactic effects of HD-MTX and intrathecal methotrexate (IT-MTX) on CNS relapse in high-risk DLBCL, in a multicenter retrospective study. A total of 132 patients with DLBCL at high risk of CNS relapse who received frontline chemotherapy and IT-MTX from 2003 to 2013 (n = 34) or HD-MTX from 2014 to 2020 (n = 98) were included. After a median follow-up of 52 months (range: 9-174), 11 patients had isolated CNS relapse: six (6.1%) in the HD-MTX group and five (14.7%) in the IT-MTX group. The median time until CNS relapse was 38 months (range: 11-122), and the cumulative incidence of CNS relapse at 3 years was 3.9% in the HD-MTX group and 6.1% in the IT-MTX group (P = 0.93). Similar results were obtained after adjusting for background factors using propensity score-matched analysis (4.5% HD-MTX vs. 7.6% IT-MTX, P = 0.84). The CNS relapse rate in HD-MTX-treated patients was equivalent to that in IT-MTX patients, demonstrating that HD-MTX was not superior to IT-MTX in preventing CNS relapse.

High-Dose Methotrexate as CNS Prophylaxis in High-Risk Aggressive B-Cell Lymphoma.

PURPOSE: CNS progression or relapse is an uncommon but devastating complication of aggressive B-cell lymphoma. There is no consensus regarding the optimal approach to CNS prophylaxis. This study was designed to determine whether high-dose methotrexate (HD-MTX) is effective at preventing CNS progression in patients at high risk of this complication. PATIENTS AND METHODS: Patients age 18-80 years with aggressive B-cell lymphoma and high risk of CNS progression, treated with curative-intent anti-CD20-based chemoimmunotherapy, were included in this international, retrospective, observational study. Cause-specific hazard ratios (HRs) and cumulative risks of CNS progression were calculated according to use of HD-MTX, with time to CNS progression calculated from diagnosis for all patients (all-pts) and from completion of frontline systemic lymphoma induction therapy, for patients in complete response at completion of chemoimmunotherapy (CR-pts). RESULTS: Two thousand four hundred eighteen all-pts (HD-MTX; n = 425) and 1,616 CR-pts (HD-MTX; n = 356) were included. CNS International Prognostic Index was 4-6 in 83.4% all-pts. Patients treated with HD-MTX had a lower risk of CNS progression (adjusted HR, 0.59 [95% CI, 0.38 to 0.90]; P = .014), but significance was not retained when confined to CR-pts (adjusted HR, 0.74 [95% CI, 0.42 to 1.30]; P = .29), with 5-year adjusted risk difference of 1.6% (95% CI, -1.5 to 4.4; all-pts) and 1.4% (95% CI, -1.5 to 4.1; CR-pts). Subgroups were underpowered to draw definitive conclusions regarding the efficacy of HD-MTX in individual high-risk clinical scenarios; however, there was no clear reduction in CNS progression risk with HD-MTX in any high-risk subgroup. CONCLUSION: In this large study, high-risk patients receiving HD-MTX had a 7.2% 2-year risk of CNS progression, consistent with the progression risk in previously reported high-risk cohorts. Use of HD-MTX was not associated with a clinically meaningful reduction in risk of CNS progression.

Central Nervous System Relapse in T and NK cell Lymphomas.

PURPOSE OF REVIEW: T and NK cell lymphomas are relatively rare and heterogeneous forms of non-Hodgkin lymphoma that are associated with high rates of mortality. Central nervous system relapse carries significant morbidity, though management is largely extrapolated from literature in B cell neoplasms. As such, outcomes for central nervous system involvement in T/NK cell lymphomas are dismal with no standard of care. In this review, we discuss the epidemiology of central nervous system relapse in T/NK cell lymphomas and critically analyze available literature regarding prophylaxis and treatment. RECENT FINDINGS: Retrospective studies of central nervous system involvement in T/NK cell lymphomas have been limited by small sample sizes and heterogeneity of subtypes, though sites of extranodal involvement and disease subtypes are consistently reported as risk factors. Compelling evidence for the use of central nervous system-directed prophylactic therapy has not yet been established, though recent reports of central nervous system activity with novel agents may suggest promising therapeutic options. The overall rarity of T and NK cell lymphomas has precluded adequate study of prophylaxis and treatment of central nervous system relapse. Collaborative efforts are needed to better define strategies to address CNS disease in T/NK cell lymphomas. These should involve the use of targeted agents, which may hold an advantage over traditional cytotoxic drugs.

Controversies in central nervous system prophylaxis of high-risk diffuse large B-cell lymphoma.

PURPOSE OF REVIEW: Central nervous system (CNS) relapse in patients with diffuse large B-cell lymphoma (DLBCL) is an uncommon but devastating complication with an overall survival of less than 6 months. This article will review the recent updates on CNS prophylaxis including new potential advances in the identification of high-risk patients. RECENT FINDINGS: The identification of patients at a high risk of CNS relapse is based on clinical and biological features has improved over recent years; however, the of different CNS prophylaxis strategies including intrathecal chemotherapy and high-dose methotrexate have been recently questioned in several large retrospective studies. The analysis of cell-free circulating tumor DNA (ctDNA) in the cerebrospinal fluid has been shown to identify patients with a high risk of CNS involvement and work is ongoing to identify how this can be used as a prognostic biomarker. SUMMARY: Recent clinical retrospective data have questioned the effectiveness of intrathecal and high-dose methotrexate in the prevention of CNS relapse in high-risk DLBCL patients. The role of more sensitive methods to detect CNS involvement and the benefit of novel therapies in CNS relapse prevention are currently under evaluation.

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.

[Risk assessment and prophylactic treatment strategies for central nervous system relapse of diffuse large B-cell lymphoma].

Rituximab treatment significantly improved the outcomes of diffuse large B-cell lymphoma (DLBCL). A central nervous system (CNS) relapse remains a serious and fatal event for patients with DLBCL; therefore, the clinical question of the optimal treatment regimen for reducing the risk of CNS relapse remains unknown. The CNS-International Prognostic Index was identified as a predictive model for CNS relapse. No factors can completely predict CNS relapse although several reports regarding high-risk factors for CNS relapse have been reported. In practice, intrathecal methotrexate (MTX) and high-dose MTX therapy have been used for CNS prophylaxis. Unfortunately, evidence of the optimal therapy for CNS prophylaxis in patients with DLBCL remains lacking. This study aimed to review CNS relapse assessment and discuss study results with clinical impacts on CNS prophylaxis treatment strategies in DLBCL.

Management of primary and secondary CNS lymphoma.

Central nervous system (CNS) lymphoma has traditionally had very poor outcomes however advances in management have seen dramatic improvements and long-term survival of patients. In primary CNS lymphoma there are now randomised trial data to inform practice, however secondary CNS lymphoma has a lack of randomised trial data and CNS prophylaxis remains a contentious area. We describe treatment strategies in these aggressive disorders. Dynamic assessment of patient fitness and frailty is key throughout treatment alongside delivery of CNS-bioavailable therapy and enrolment in clinical trials. Intensive high-dose methotrexate-containing induction followed by autologous stem cell transplantation is preferred for patients who are fit. Less intensive chemoimmunotherapy, whole brain radiotherapy and novel therapies may be reserved for patients unfit or chemoresistant. It is essential to better define patients at increased risk of CNS relapse, as well as effective prophylactic strategies to prevent it. Future prospective studies incorporating novel agents are key.

Central nervous system prophylaxis in diffuse large B-cell lymphoma: What does the evidence tell us?

Secondary involvement of the central nervous system (CNS) by diffuse large b-cell lymphoma (DLBCL) is a rare yet often catastrophic event for DLBCL patients. As standard first-line therapy for DLBCL with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) does not cross the blood-brain barrier, one approach to lessen the risk of CNS relapse has been to include additional agents, primarily methotrexate, directed at the CNS with standard R-CHOP although the timing, dose, and mode of administration differs widely across treating physicians. This practice derives from decades of non-randomized, often retrospective data with inconsistent outcomes. The current available tools and risk models are imprecise in their ability to predict which patients are truly at risk of secondary CNS relapse and more recent, large-scale real-world analyses call into question these longstanding practices. In a field lacking any prospective, randomized studies, this review synthesizes the available data investigating the utility of CNS prophylaxis in patients with DLBCL receiving 1st line therapy.

Impact of triple intrathecal prophylaxis in acute lymphoblastic leukemia adults receiving HyperCVAD: A COVID-19 practice change.

Treatment of acute lymphoblastic leukemia (ALL) requires both systemically and locally directed therapies to prevent central nervous system (CNS) recurrence. In response to restrictions brought on by the COVID-19 pandemic, our institution adopted triple intrathecal (IT) chemotherapy for CNS prophylaxis during HyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine). We retrospectively reviewed records of newly diagnosed adult all patients who were consecutively treated with HyperCVAD between January 2011 and July 2022. Outcomes of patients who received triple IT chemotherapy and standard of care (SOC) CNS prophylaxis were compared. The primary endpoint was CNS relapse-free survival (RFS) while secondary endpoints included cumulative incidence of relapse, overall survival, number of outpatient, and total ITs per patient, and CNS treatment-related toxicities. A total of 37 patients including 21 in the triple IT and 16 in the SOC cohorts were evaluated. There were no differences between the triple IT and SOC cohorts with respect to CNS-RFS (89.6% vs. 80.4%; HR, 1.55; 95% CI, 0.45-5.39; p = .49), cumulative incidence of relapse (8.9% vs. 19.6%; HR, 1.14; 95% CI, 0.3-5.3; p = .87), and overall survival (89.6% vs. 85.7%; HR, 0.91; 95% CI, 0.20-4.21; p = .90) at 2-years. Significantly fewer IT doses were administered in the triple IT cohort (p = .011) and the number of additional outpatient appointments to administer IT chemotherapy were markedly reduced as 98.6% of IT doses were administered during scheduled admissions compared to 76.8% (p < .001). The adoption of triple IT chemotherapy did not increase CNS treatment-related toxicities but rather, the inverse was observed. Triple IT chemotherapy during HyperCVAD represents a feasible alternative to SOC CNS prophylaxis, especially during times of resource restriction and when minimization of patient exposures is desired.

Diagnosis, treatment, and prognosis of primary intraocular lymphoma: Single-center real-world clinical experience.

BACKGROUND: The diagnosis and management of primary intraocular lymphoma (PIOL) remain challenging. This study identified factors indicative of PIOL, described treatment outcomes, and determined modalities to prevent relapse. METHODS: We included 21 PIOL-diagnosed patients, seven via cytology, 12 via genetic evaluation, and two via interleukin (IL) level measurements, who underwent vitrectomy and received local intravitreal methotrexate (IV-MTX) injection. Clinical outcomes, including treatment response and relapse, were compared between patients receiving IV-MTX alone (n = 13) or IV-MTX with systemic high-dose methotrexate (HD-MTX) as prophylaxis (n = 8). RESULTS: Twelve ophthalmologic and eight central nervous system (CNS) relapse cases within a median of 20.3 and 11.6 months were shown, regardless of the treatment modalities, with a median progression-free survival of 21.3 (95% confidence interval, 9.5-36.7) months. There was no difference in demographic characteristics between the two groups, except with the poorer performance status in patients in the HD-MTX prophylaxis group. Furthermore, patients demonstrated rapid elevations in the vitreous fluid IL-10/IL-6 cytokine ratio before ophthalmologic and CNS relapse. Therefore, diagnosis should be based on clinical signs and assisted by vitrectomy, cytologic, molecular, and cytokine studies. CONCLUSION: For PIOL, aggressive systemic treatment equivalent to that of primary CNS lymphoma (PCNSL) is recommended because solely HD-MTX did not prevent or delay CNS relapse. To prevent PIOL relapse in the CNS efficiently, prospective trials with large numbers of patients and advanced therapeutic regimens are necessary. Furthermore, regular clinical follow-up is crucial, and the IL-10/IL-6 ratio can help evaluate relapse promptly.

How I prevent and treat central nervous system disease in adults with acute lymphoblastic leukemia.

The central nervous system (CNS) is the most important site of extramedullary disease in adults with acute lymphoblastic leukemia (ALL). Although CNS disease is identified only in a minority of patients at the time of diagnosis, subsequent CNS relapses (either isolated or concurrent with other sites) occur in some patients even after the delivery of prophylactic therapy targeted to the CNS. Historically, prophylaxis against CNS disease has included intrathecal (IT) chemotherapy and radiotherapy (RT), although the latter is being used with decreasing frequency. Treatment of a CNS relapse usually involves intensive systemic therapy and cranial or craniospinal RT along with IT therapy and consideration of allogeneic hematopoietic cell transplant. However, short- and long-term toxicities can make these interventions prohibitively risky, particularly for older adults. As new antibody-based immunotherapy agents have been approved for relapsed/refractory B-cell ALL, their use specifically for patients with CNS disease is an area of keen interest not only because of the potential for efficacy but also concerns of unique toxicity to the CNS. In this review, we discuss data-driven approaches for these common and challenging clinical scenarios as well as highlight how recent findings potentially support the use of novel immunotherapeutic strategies for CNS disease.

Prevention and management of secondary central nervous system lymphoma.

Secondary central nervous system (CNS) lymphoma (SCNSL) is defined by the involvement of the CNS, either at the time of initial diagnosis of systemic lymphoma or in the setting of relapse, and can be either isolated or with synchronous systemic disease. The risk of CNS involvement in patients with diffuse large B-cell lymphoma is approximately 5%; however, certain clinical and biological features have been associated with a risk of up to 15%. There has been growing interest in improving the definition of patients at increased risk of CNS relapse, as well as identifying effective prophylactic strategies to prevent it. SCNSL often occurs within months of the initial diagnosis of lymphoma, suggesting the presence of occult disease at diagnosis in many cases. The differing presentations of SCNSL create the therapeutic challenge of controlling both the systemic disease and the CNS disease, which uniquely requires agents that penetrate the blood-brain barrier. Outcomes are generally poor with a median overall survival of approximately 6 months in retrospective series, particularly in those patients presenting with SCNSL after prior therapy. Prospective studies of intensive chemotherapy regimens containing high-dose methotrexate, followed by hematopoietic stem cell transplantation have shown the most favorable outcomes, especially for patients receiving thiotepa-based conditioning regimens. However, a proportion of patients will not respond to induction therapies or will subsequently relapse, indicating the need for more effective treatment strategies. In this review we focus on the identification of high-risk patients, prophylactic strategies and recent treatment approaches for SCNSL. The incorporation of novel agents in immunochemotherapy deserves further study in prospective trials.

CNS prophylaxis in aggressive B-cell lymphoma.

The prevention of central nervous system (CNS) relapse in diffuse large B-cell lymphoma (DLBCL) continues to be one of the most contentious areas of lymphoma management. Outcomes for patients with secondary CNS lymphoma (SCNSL) have historically been very poor. However, in recent years improved responses have been reported with intensive immunochemotherapy approaches, and there is a growing interest in potential novel/cellular therapies. Traditional methods for selecting patients for CNS prophylaxis, including the CNS International Prognostic Index, are hampered by a lack of specificity, and there is accumulating evidence to question the efficacy of widely employed prophylactic interventions, including intrathecal and high-dose methotrexate (HD-MTX). Given the potential toxicity of HD-MTX in particular and the ongoing need to prioritize systemic disease control in high-risk patients, there is an urgent need to develop more robust methods for identifying patients at highest risk of CNS relapse, as well as investigating prophylactic interventions with greater efficacy. Here we review new evidence in this field from the last 5 years, focusing on the potential use of molecular diagnostics to improve the identification of high-risk patients, recent large data sets questioning the efficacy of HD-MTX, and the current approach to management of patients with SCNSL. We provide a suggested algorithm for approaching this very challenging clinical scenario.

Central Nervous System Prophylaxis and Treatment in Acute Leukemias.

OPINION STATEMENT: Improvements in systemic therapy in the treatment of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) have improved patient outcomes and reduced the incidence of CNS relapse. However, management of patients with CNS disease remains challenging, and relapses in the CNS can be difficult to salvage. In addition to treatment with CNS-penetrant systemic therapy (high-dose methotrexate and cytarabine), intrathecal prophylaxis is indicated in all patients with ALL, however is not uniformly administered in patients with AML without high-risk features. There is a limited role for radiation treatment in CNS prophylaxis; however, radiation should be considered for consolidative treatment in patients with CNS disease, or as an option for palliation of symptoms. Re-examining the role of established treatment paradigms and investigating the role of radiation as bridging therapy in the era of cellular therapy, particularly in chemotherapy refractory patients, is warranted.

Prophylaxis strategies containing high dose intravenous methotrexate on preventing CNS relapse for patients with diffuse large B-cell lymphoma at intermediate to high risk: A study based on 12 cohorts in the rituximab era.

During the Rituximab era, high dose intravenous methotrexate (HD) and intrathecal methotrexate (IT) are recommended prophylaxis in preventing central nervous system (CNS) relapse of diffuse large B-cell lymphoma (DLBCL) patients. However, the optimal CNS prophylaxis strategies remained uncertain. This meta-analysis research explored the findings of previous studies and highlighted the efficacy of HD and/or IT on CNS prophylaxis of DLBCL patients at intermediate to high risk. Specifically, it aims to answer the following research questions: (1) Is there a difference on CNS relapse rate between HD and IT cohorts? (2) Is there a correlation between CNS prophylaxis and survival? This meta-analysis research performed an in-depth examination of pertinent studies available in PubMed, Embase, and Cochrane databases. The primary endpoints included: CNS relapse rate and 2-year or 3-year survival rate. The findings of the qualified studies were reviewed and analyzed using 5.3 version of the Review Manager software. After thorough analysis of 12 studies involving 5950 DLBCL patients, it was revealed that in comparison with IT alone, HD with or without additional IT (HD ± IT) significantly reduced the risk of CNS relapse (Risk Ratio (RR)= 0.41, 95 % CI (0.24-0.68), P = 0.0007). Besides, the efficacy of HD alone was comparable to HD + IT (RR = 1.08, 95 % CI (0.19-6.32), P = 0.93), which was also considered to be more optimal than IT alone on CNS prophylaxis (RR = 0.39, 95 % CI (0.15-1.06), P = 0.06).Based on these results, IT alone or no-prophylaxis were viewed as a group of inadequate prophylaxis. Comparing to HD ± IT, the 3-year survival rate of inadequate prophylaxis group was lower (RR = 1.17, 95 % CI (1.03-1.32), P = 0.01). The results of this study reveals that in the Rituximab Era, prophylaxis strategies containing HD is better than IT alone or no-prophylaxis on preventing CNS relapse of DLBCL patients with intermediate to high risk.

CNS prophylaxis for diffuse large B-cell lymphoma.

CNS relapse in the brain parenchyma, eyes, or leptomeninges is an uncommon but devastating complication of diffuse large B-cell lymphoma. CNS prophylaxis strategies, typically involving intrathecal or high-dose antimetabolites, have been developed in the front-line treatment setting with the aim to reduce this subsequent risk. Clinical and biological features associated with elevated risk are increasingly well defined and are discussed in this Review. This Review summarises both the historical and current developments in this challenging field, provides a nuanced discussion regarding current reasons for and against standard prophylactic measures, outlines evidence for the timing of prophylactic measures when delivered, and reflects on possible future developments.

Secondary Central Nervous System Lymphoma: Updates in Treatment and Prophylaxis Strategies.

OPINION STATEMENT: Referring to any central nervous system (CNS) involvement with preceding or concurrent systemic disease, secondary CNS lymphoma (SCNSL) lacks a clear standard of care and historically carries a very poor prognosis. Aggressive histologies predominate, most notably diffuse large B cell lymphoma (DLBCL), with higher relative frequency in Burkitt lymphoma but lower absolute incidence. Therapeutic strategies commonly feature intensive CNS-penetrant chemotherapy, including methotrexate, cytarabine, and others. Combination regimens, novel targeted agents, and cellular therapy considerations are reviewed, noting that patients with SCNSL are often excluded from clinical trials and dedicated SCNSL studies are historically limited. Given these challenges, there has been renewed attention on CNS prophylaxis as well as strategies for early CNS detection. Prophylaxis is standard of care in Burkitt lymphoma, whereas its role in DLBCL and related histologies is increasingly unclear.

SOHO State of the Art Updates and Next Questions: Prophylaxis and Management of Secondary CNS Lymphoma.

Secondary CNS lymphoma (SCNSL) is a rare but frequently fatal complication of systemic lymphoma. There is no standard treatment for SCNSL, and patients who develop SCNSL at diagnosis or after frontline therapy often receive highly intensive chemotherapy regimens that are inactive against primary chemorefractory disease and too toxic for older, frail patients to tolerate. Because the prognosis of SCNSL is so poor, management has historically emphasized prevention, but the current methods of CNS prophylaxis are not universally effective. To improve both the prevention and management of SCNSL, better characterization of the molecular determinants of CNS invasion is needed. Novel treatments that are currently being studied in SCNSL include targeted pathway inhibitors and cellular therapy, but SCNSL patients are often excluded from clinical trials of promising new therapies.