Central Nervous System Relapse Rate Research Articles

Patterns and prognostic impact of CNS infiltration in adults with newly diagnosed acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is highly associated with central nervous system (CNS) infiltration and can be associated with higher risk of relapse. Conventional cytology (CC) is the traditional method for diagnosing CNS infiltration, although the use of immunophenotyping by flow cytometry (FC) has gained prominence in recent years due to its higher sensitivity. Also, some authors have proposed that CSF contamination by a traumatic lumbar puncture (TLP) could have a clinical impact. This retrospective study accessed the impact of CNS infiltration by CC or FC on overall survival, event-free survival, and relapse rate. In a cohort of 105 newly diagnosed ALL patients, CNS1, CNS2, and CNS3 status were found in 84%, 14%, and 2%, respectively. We found that extramedullary disease at the diagnosis, higher leukocyte counts, and higher blast percentage were associated with a positive CC. Sensitivity and specificity of CC were 53% and 98%, respectively. Three-year overall survival was 42.5%. Conversely, TLP was not associated with a positive CC nor had an impact on relapse rates. In multivariate analysis, a positive CC was associated with an increased relapse rate (HR 2.074, p = 0.037), while its detection by FC did not associate with this endpoint. Survival rates seem to be increasing over the last years by the adoption of a stratified CNS prophylaxis risk strategy. CSF contamination does not represent a major concern according to our report, as it did not increase CNS involvement or relapse rates.

Incidence of Central Nervous System Relapse in Patients with Primary Mediastinal Large B-Cell Lymphoma: A Retrospective Study

Background Primary mediastinal large B-cell lymphoma (PMBCL) is an uncommon type of non-Hodgkin lymphoma. Clinicopathologic features are distinct from diffuse large B cell lymphoma, but it shares some clinical and biologic features with Nodular sclerosis classic Hodgkin lymphoma. Central nervous system (CNS) relapse appears to be rare in patients with PMBCL, with limited literature reporting a rate of approximately 1.5% to 4%. We examined the incidence of CNS relapse, treatment approaches and survival outcomes in patients with PMBCL. Methods Patients with newly diagnosed PMBCL seen at Mayo Clinic between 2002 and 2022 were identified using the prospective Mayo Clinic Lymphoma Database. Clinical features, treatment details and outcomes were abstracted from the medical record. Cumulative incidence of CNS relapse was analyzed with death as a competing risk. The association of CNS-IPI, systemic treatment, and CNS prophylaxis approach with CNS relapse rate was analyzed using competing risk models and descriptively. Event-free survival (EFS) for the cohort was defined as time from PMBCL diagnosis to first recorded CNS and/or systemic relapse or death from any cause. Overall survival (OS) was defined as time from PMBCL diagnosis (or CNS relapse) to death from any cause. Survival analysis was performed using the Kaplan-Meier method. Results A total of 124 PMBCL cases were identified. The median age at diagnosis was 37 years and 61% were female. The distribution of CNS-IPI was low-risk in 67 (61%), intermediate-risk in 41 (37%), and high-risk in 2 (2%). 64 patients (52%) received R-CHOP and 54 patients (44%) received R-DA-EPOCH as frontline therapy. High-dose methotrexate (HD-MTX) for CNS prophylaxis was administered to 6 patients (5%), 5 with R-CHOP and 1 with R-DA-EPOCH. 16 patients received intrathecal (IT) chemotherapy (methotrexate and/or cytarabine) for CNS prophylaxis, 3 with R-CHOP and 13 with R-DA-EPOCH. The median follow-up was 56.0 months. The 5-year EFS rate was 75.1% and the 5-year OS rate was 90.7% for the entire cohort. 20 patients had systemic relapse only and 3 had CNS relapse. The cumulative incidence of CNS relapse was 1.84% (95% CI 0.46%-7.17%) at 2 years and 2.92% (95% CI 0.50%-8.84%) at 5 years (Figure 1). No statistically significant association of CNS-IPI, systemic therapy or CNS prophylaxis regimen with CNS relapse rate was found in competing risk models; however, this analysis was limited by a small event number (n=3). Among the 3 patients with CNS relapse, 1 had high-risk CNS-IPI and 2 had intermediate risk. All 3 patients were treated initially with R-CHOP. Two patients did not receive any CNS prophylaxis and 1 patient received IT CNS prophylaxis. All three patients who had CNS relapse were female. Patient #1 was diagnosed at age 48 and had simultaneous CNS and systemic relapse 6 months later. The patient was treated with HD-MTX, temozolomide and rituximab for CNS relapse, and subsequently received multiple therapies for systemic disease including R-DHAP, R-ICE, and died 17 months after CNS relapse. Patient #2 was diagnosed at age 22 and had CNS relapse after 8.7 months, followed by systemic relapse 2 months later. The patient received HD-MTX, temozolomide and rituximab for CNS relapse, followed by systemic and whole-brain radiation therapy (RT) for both systemic and CNS relapse. Subsequently the patient received salvage chemotherapy, autologous and allogeneic stem cell transplant for systemic relapse. The patient died 26.8 months after CNS relapse. Patient #3 was diagnosed at age 24 and had systemic relapse after 20.7 months, followed by CNS relapse 5.4 months later. The patient received methotrexate and whole-brain RT following CNS relapse and died 1.2 months after CNS relapse. Besides these 3 patients, we identified 6 PMBCL patients with CNS relapse who were diagnosed at other medical centers and subsequently referred to our institution for management of refractory disease. The survival after CNS relapse was poor, with a median OS of 10.4 months (95% CI 5.6-15.2). Conclusion Our study showed that the CNS relapse rate (1.84% at 2 years and 2.92% at 5 years) was overall low in patients with PMBCL, consistent with previous reports. CNS relapse was associated with poor survival despite aggressive treatment approaches. Novel approaches utilizing biological risk factors for CNS relapse, such as circulating tumor DNA, are needed to identify patients with CNS relapse.

Survival and CNS Relapse in Patients with CD5-Positive Diffuse Large B-Cell Lymphoma: A Multi-Institutional Observational Study in Japan

Background: CD5-positive diffuse large B-cell lymphoma (CD5+ DLBCL) is usually characterized by activated B-cell type, poor prognosis, and frequent central nervous system (CNS) relapse. A sandwich therapy of dose-adjusted (DA)-EPOCH-R combined with high-dose methotrexate (HD-MTX) (DA-EPOCH-R/HD-MTX) showed excellent efficacy in a phase II study for newly diagnosed stage II-IV CD5+ DLBCL, including 2-year (yr) overall survival (OS), progression-free survival (PFS), and CNS relapse rates of 89%, 79%, and 9%, respectively (Miyazaki K, et al. Haematologica, 2020). It has been introduced in practice in Japan; however, the current status of treatment and the prognosis in patients with CD5+ DLBCL are unclear. Methods: We retrospectively analyzed the prognosis and CNS relapse rate of consecutive patients with untreated CD5+ DLBCL who were diagnosed at 30 hospitals in Japan from January 2016 to December 2021. Patients who were diagnosed with double-/triple-hit lymphoma, those with CNS involvement at diagnosis, and those who had not received any anthracycline-containing chemotherapy with rituximab (R-chemo) were excluded. We identified risk factors for OS using Cox proportional hazards method. The outcomes in the stage II-IV patients who received DA-EPOCH-R/HD-MTX were compared with those of the phase II study. To evaluate the efficacy of CNS prophylaxis, we divided patients into four groups: HD-MTX alone, intrathecal administration of MTX alone (IT MTX), both HD-MTX and IT MTX (HD/IT MTX), and no CNS prophylaxis. Results: Among the413 enrolled patients, 20 were excluded due to ineligible diagnosis or insufficient clinical information, 18 had CNS involvement at diagnosis, and 27 did not receive R-chemo. As a result, 348 patients were eligible and showed the following features: median age, 71 yrs (range, 23-92); male sex, 54%; stage II-IV, 90%; stage III or IV, 73%; ECOG performance status (PS) > 1, 30%; > 1 extranodal site, 42%; elevated serum lactate dehydrogenase (sLDH) level, 71%; high-intermediate or high International Prognostic Index (IPI), 63%; high CNS-IPI, 41%; and B symptoms, 29%. According to Hans's criteria, the nongerminal center B-cell type accounted for 67% of the 276 cases examined. Among the 348 patients, 62 (18%) received DA-EPOCH-R/HD-MTX, and 286 (82%) were treated with other R-chemo, such as R-CHOP (n = 254). The median age was 63.5 yrs (range, 29-75) in the DA-EPOCH-R/HD-MTX group and 72 yrs (range, 23-92) in the other R-chemo group. The DA-EPOCH-R/HD-MTX group included significantly more patients aged ≤ 60 yrs ( P < 0.001), although it tended to have more patients with ECOG PS > 1 than the other R-chemo group ( P = 0.069). Patients who received IT MTX made up 16% of the DA-EPOCH-R/HD-MTX group and 31% in the other R-chemo group. HD-MTX was used in 100% of patients in the DA-EPOCH-R/HD-MTX group and 17% of patients in the other R-chemo group. Details of CNS prophylaxis were HD-MTX alone in 84 patients (24%), IT MTX alone in 70 (20%), both HD/IT MTX in 28 (8%), and no CNS prophylaxis in 166 (48%). At a median follow-up of 43 months, the 2-yr OS, PFS, and CNS relapse rates of patients with stage II-IV disease in the DA-EPOCH-R/HD-MTX group were 87% (95% CI, 73-94%), 78% (95% CI, 63-87%), and 7.3% (95% CI, 2.8-18.2%), respectively. There were no significant differences in OS or PFS between stage I and stage II-IV patients in the DA-EPOCH-R/HD-MTX group. In all 348 patients with stage I-IV, both the OS ( P = 0.044) and PFS ( P = 0.043) in the DA-EPOCH-R/HD-MTX group were longer than those in the other R-chemo group. The 2-yr OS in these groups were 89% and 78%, and their 2-yr PFS were 78% and 64%, respectively. Multivariate analysis identified elevated sLDH ( P = 0.005), > 1 extranodal involvement ( P < 0.001), no IT MTX ( P = 0.005), and no DA-EPOCH-R/HD-MTX ( P = 0.005) as independent risk factors for OS. The 2-yr CNS relapse rate was 6.5% in the DA-EPOCH-R/HD-MTX group (n = 4) and 10.0% in the other R-chemo group. There were no significant differences in the CNS relapse rate between the two groups ( P = 0.54). The 2-yr CNS relapse rates of HD-MTX, IT MTX alone, both HD/IT MTX, and no prophylaxis were 9.8%, 9.1%, 3.7% (n = 1), and 10.3%, respectively. Conclusions: Our results confirmed favorable survival in the phase II study of DA-EPOCH-R/HD-MTX in clinical settings. DA-EPOCH-R/HD-MTX and IT MTX were associated with longer OS of patients with CD5+ DLBCL in our study cohort, warranting further investigation.

Differences in Characteristics and Outcomes of Central Nervous System Versus Systemic Relapse after First Line Therapy in DLBCL Patients: A Veterans Health Administration (VHA) Study

Introduction Around 30%-40% of patients with diffuse large B-cell lymphoma (DLBCL) will experience disease progression or relapse after first line (1L) chemoimmunotherapy with most patients relapsing within the first 12 months. Relapse may be systemic, isolated to the central nervous system (CNS), or both with CNS relapse occurring in 2-5% of patients. The purpose of this study is to evaluate the characteristics and outcome differences of Veterans diagnosed with DLBCL within the VHA who experienced systemic relapse, isolated CNS relapse or both. Methods A retrospective chart review of 6,266 lymphoma patients seen in the VHA nationwide between 01/01/2011 and 12/31/2021 was performed by trained abstractors. Patients diagnosed with DLBCL were included. Patients were excluded if they had a diagnosis other than DLBCL, had incomplete records or were diagnosed and treated outside the VHA, had baseline CNS involvement, did not receive treatment, or died before receiving a scan to assess response to 1L therapy. Outcomes including response to 1L treatment, time to relapse and overall survival (OS) defined as time from diagnosis to death were evaluated. Early relapse was defined as having primary refractory disease (stable or progressive disease (SD or PD) as best response to 1L therapy) or disease progression in ≤12 months in patients achieving a complete response (CR) or partial response (PR). Late relapse was defined as disease progression >12 months. Results A total of 2,658 patients met inclusion criteria for analysis with 97% of the population being male, 65% with stage III-IV disease, and 90% with an ECOG performance status of 0-2. Of the total cohort, 74% of patients received a CHOP-based regimen, 74% had an intermediate- or high-risk CNS International Prognostic Index (CNS-IPI) score, 81% did not receive a baseline diagnostic lumbar puncture (LP) and 86% did not receive any CNS prophylaxis. The median follow-up time for subjects in this study was 54 months. Relapse occurred in 29% of the total cohort with systemic only relapse occurring in 27% of patients, isolated CNS in 1%, and CNS + systemic in 1%. Of the 761 patients who experienced relapse, 77% had an early relapse with a median time to relapse of 4.4 months (IQR 2.8-6.7). For the 23% of patients with late relapse, the median time to relapse was 25 months (IQR 18-41). The characteristics of patients who experienced relapse were similar regardless of type of relapse or time to relapse (table 1). A higher percentage of patients with early relapse had a high-risk CNS-IPI score, bone marrow involvement, and renal or adrenal involvement. Autologous stem cell transplant was performed in 11% of patients, predominately in those with systemic only relapse. The median OS (mOS) was similar between relapse types with systemic, isolated CNS, and CNS + systemic having a mOS of 23.5 months (95% CI: 21-27), 30.6 months (95% CI: 15-71), and 29.6 months (95% CI: 20-45), respectively (p=0.75). Figure 1 describes mOS by relapse type and time to relapse. Overall, patients with early relapse had a poorer prognosis regardless of relapse type with a mOS of 17 months (95% CI: 15-18) compared to a mOS of 68 months (95% CI: 59-88) in patients with late relapse (p<0.001). The 24-month survival rate of those with early versus late relapse was 37% and 78%, respectively. Patients with a late systemic relapse had the longest mOS of 74 months (95% CI: 60-90). Conclusion This is the largest study reporting outcomes of Veterans who experienced relapsed DLBCL within the VHA. Although earlier data suggests specific features may correlate with early versus late relapse, all characteristics were similar in our population across relapse types regardless of time to relapse. The rate of relapse in the total cohort and the rates of CNS relapse were lower than previously reported, adding to recent data suggesting the use of CNS prophylaxis may have limited benefit. Patients with early relapse performed poorly and may benefit from novel therapies including chimeric antigen receptor T-cell therapy, which could not be evaluated with this study. The retrospective nature of this analysis, and a predominately male veteran population may limit external application.

Prognosis of Patients with Diffuse Large B Cell Lymphoma with Central Nervous System Relapse: USC Experience

Introduction: Diffuse large B cell lymphoma (DLBCL) is the most common form of lymphoma and a potentially curable disease with systemic immunochemotherapy regimens. Involvement of the central nervous system (CNS) in patients with DLBCL is a relatively rare event which occurs in approximately 2-5% of patients overall, but the CNS relapse rate can be as high as 10-12% in high-risk patients. Unfortunately, CNS relapse confers poor prognosis with some studies estimating median survival of 2.5 months from relapse. Our study evaluates prognostic factors and outcomes in this patient population. Methods: This study is a retrospective review of patients diagnosed with DLBCL who then developed CNS relapse and were treated at Los Angeles General Medical Center (LAGMC) and Norris Comprehensive Cancer Center (NCCC) from 2016-2023. Information regarding patient demographics, prognostic factors to calculate NCCN-IPI scores, pathologic characterization, therapy, clinical course, and survival were collected. CNS relapse was defined as pathologic or imaging diagnosis of CNS involvement after initial treatment was received. Results: A total of 29 patients with CNS relapse of DLBCL were identified with a median age of 60 (range 43-86). The median time from initial diagnosis to CNS relapse was 9 months. The patients were 72.4% male (N=21), 79.3% Hispanic (N=23), and 17.2% (N=5) HIV positive. NCCN-IPI scores were calculated for all patients and divided into NCCN-IPI risk groups. The low-risk group (NCCN-IPI 0-1) made up 10.3% (N=3), low-intermediate risk group (NCCN-IPI 2-3) 48.3% (N=14), high-intermediate risk group (NCCN-IPI 4-5) 34.5% (N=10), and high-risk group (6-8) 6.90% (N=2). Pathologic analysis revealed 41.4% (N=12) of patients had germinal center type lymphoma, 44.8% (N=13) were BCL-2/c-myc double expressors, 13.8% (N=4) were BCL-2/c-myc double hit, and 13.8% (N=4) were BCL-6/c-myc double hit (Table 1). Overall survival (OS) for the entire cohort was 18.5% at five years after CNS relapse of DLBCL with a median survival of 12 months. Patients with a low or low-intermediate NCCN-IPI score (0-3) had an OS of 57.4% at 12 months and 29.1% at five years. Patients with a high-intermediate or high NCCN-IPI score had an OS of 35.7% at 12 months and 0% by 33 months. OS at 12 months for the HIV negative group was 70.4% compared to 40.0% in the HIV positive group, but OS at 5 years was similar in both groups at 19.4% and 20.0%, respectively (Figure 1). Conclusions: CNS relapse in patients with DLBCL is a rare but devastating complication. In our largely male and Hispanic patient population, prognosis at five years was very poor for those with CNS relapse, but higher NCCN-IPI scores demonstrated a trend that conferred a higher likelihood of death at both the one year and five year time points compared to those with lower scores. Survival after CNS relapse in our cohort is longer compared to prior studies, indicating possible improvements in the prognosis of patients with CNS relapse of DLBCL. Given the overall poor prognosis of CNS relapse of DLBCL, improved prognostic stratification is of the utmost importance in this highly curable disease.

The Addition of Lenalidomide to R-CHOP Is Effective for Prevention of CNS Relapse in High-Risk Patients with Diffuse Large B-Cell Lymphoma

Central nervous system (CNS) relapse is an uncommon but devastating event in patients in diffuse large B-cell lymphoma (DLBCL). Although several prophylaxis attempts including intrathecal methotrexate and intravenous high-dose methotrexate were conducted to reduce the CNS relapse rate, the optimal management remained uncertain. Herein, we performed an open-label, multicenter trial to explore the efficacy and safety of the combination of lenalidomide and R-CHOP (R2-CHOP) for preventing the CNS relapse in the high-risk diffuse large B cell lymphoma. Eligible patients were aged 18-80 years, newly diagnosed DLBCL and high risk for CNS recurrence: CNS-IPI:4-6 or involvement of testicular, kidneys or adrenal glands. Lenalidomide orally 25 mg per day was administered on days 1 through 10 of each cycle and delivered concomitantly with standard dose R-CHOP-21 regimen. All patients received aspirin 100mg per day prophylaxis throughout. The primary endpoint was 2-year central nervous system relapse rates. The secondary endpoint were 2-year overall survival, progression-free survival, and treatment-emergent adverse events. This trial is registered with ClinicalTrials.gov, number NCT04544059. A total of 56 DLBCL patients with high-risk for CNS relapse were included in this study. The median age of the patients in this study was 57 years old (range 26-77） and 47.8% patients were female. 88.9% patients had a CNS-IPI score ≥4 and the left patients may be involved with testicular, kidneys or adrenal glands. With a median follow up of 20 months,45patients finished planned cycles of R2-CHOP treatment and only 2（4.4%） patient developed CNS relapse. The 2-year progression-free survival and overall survival were 77.8% and 79.7%, respectively. In summary, lenalidomide with R-CHOP is effective for prevention of CNS relapse in high-risk patients with diffuse large B-cell lymphoma. Keywords: Diffuse large B-cell lymphoma, central nervous system relapse, lenalidomide.

Evaluating the Impact of Prophylactic Intrathecal Chemotherapy in Diffuse Large B Cell Lymphoma (DLBCL) Patients with High Central Nervous System International Prognostic Index (CNS-IPI) Scores: A Comprehensive Review and Meta-Analysis

Introduction Diffuse large B cell lymphoma (DLBCL) with a high CNS-IPI score poses an increased risk for relapse involving the central nervous system (CNS). Despite various studies seeking to validate the use of CNS prophylaxis, including intrathecal chemotherapy, results have been equivocal. This ambiguity may be partly attributed to the lack of prospective data, patient heterogeneity, limited sample sizes, and outdated methodologies in pre-rituximab studies. Consequently, administering CNS prophylaxis with intrathecal chemotherapy is not a standardized practice, and decisions are often based on individual factors such as anatomical location, disease stage, and specific case characteristics. Methods This systematic review and meta-analysis were conducted and reported using the PRISMA guidelines. A thorough search was conducted across multiple online databases, including Google Scholar, Science Direct, PubMed, Cochrane, CINAHL, EMBASE, ProQuest Dissertation and Theses, ISI web of knowledge, PsycINFO, and Embase for articles on this topic. The date range of the articles included was between 2013-2023 and were limited to English language, peer-reviewed articles, cohort studies, retrospective studies & randomized controlled trials. The inclusion and exclusion criteria for studies helped to determine suitable studies Results Out of 179 studies retrieved from the database search and 2 from other studies' reference lists, 6 met the inclusion criteria for qualitative and quantitative analysis. Data from 2209 patients in these 6 studies was analyzed using a random-effects model to perform a subgroup analysis of the benefits and risks of prophylactic intrathecal chemotherapy for patients with DLBCL and a high CNS-IPI score. The results demonstrated a significant improvement in overall treatment success, with a difference of 0.60 (95% Confidence Interval, 0.45 to 0.93) on a 0-10 Visual Analogue Scale (VAS). The heterogeneity of the studies was determined to be significant (P=0.02), further substantiating the positive impact of prophylactic intrathecal chemotherapy on the therapy success rate for DLBCL patients with high CNS-IPI scores. Conclusion Our review elucidates that intrathecal chemotherapy as a prophylactic measure can reduce the rate of CNS relapse and enhance overall survival for patients with DLBCL possessing a high CNS-IPI score. However, it underscores the necessity to thoroughly assess each patient's unique clinical situation when determining if intrathecal chemotherapy is the appropriate therapeutic approach.

An International Multicenter Study of Primary Vitreoretinal Lymphoma from the Australasian Lymphoma Alliance and Collaborators

Background: Primary vitreoretinal lymphoma (PVRL) is a rare high-grade extranodal non-Hodgkin lymphoma characterized by frequent and often fatal central nervous system (CNS) relapse. Despite improved outcomes for patients with primary CNS lymphomas over the last decade, approaches to the diagnosis and management of PVRL remain contentious. Given limited prospective data to date, there is need to better elucidate current international practice in the modern era to optimize outcomes for this patient group. Methods: Patients with pathologically confirmed PVRL diagnosed between January 2010 and December 2022 were identified from ten sites across Australia, Singapore, Canada and the United Kingdom. Patients were aged ≥18 years, with isolated PVRL at diagnosis (i.e. no concomitant CNS involvement at baseline or secondary vitreoretinal involvement). Variables included were baseline demographic data, presenting symptoms, diagnostic procedures undertaken and sample characteristics such as cytological, immunocytochemical and flow cytometric features. Where available, molecular results and biomarkers such as IL-10 and IL-6 were also collected. Treatment approaches including local, systemic and combined local/systemic therapies were captured. Outcomes measured included response rates, patterns of relapse, progression-free (PFS) and overall survival (OS). Results: 36 patients were identified with a median age at diagnosis of 68 years (range 38-89) with a female predominance (58%). Most patients presented with bilateral involvement (72%) with decreased visual acuity being the predominant presenting symptom (53%). Most patients received a PVRL diagnosis within weeks to months of symptom onset, however a third of patients had >12 months delay to diagnosis. Ancillary diagnostic tests such as flow cytometry, molecular and cytokine measurements performed in a minority of patients only, largely due to sample viability and paucity. Concurrent CNS involvement was evaluated by brain MRI in 97% with diagnostic lumbar punctures performed in 64%. Exclusion of systemic disease was predominantly done via PET or PET/CT (69%) with the remainder via CT alone (Table 1). Upfront treatment choices were highly varied across participating sites with incorporation of systemic therapy in the majority (64%) of cases, either alone (25%) or in combination with local therapies (39%). For those who received systemic therapy, all incorporated high-dose methotrexate with the median dose delivered of 3.5g/m 2 per cycle and rituximab was incorporated in 48%. Autologous stem cell transplantation (ASCT) was part of frontline management in 19% of cases, and the median age of those receiving frontline ASCT was 55 years versus 71 years in those who did not. With median follow-up of 57 months (IQR 24-74 months), the median OS was 90 months whilst median PFS was only 23 months (Figures 1 and 2). 18 patients experienced disease relapse during follow up, only 2 of which had received frontline ASCT. The median PFS and OS of those who received frontline ASCT was not reached and 92 months respectively. Patients who had systemic treatment incorporated into frontline management had a trend toward improved OS than those who did not (Figure 3). Of those with relapsing disease, 14 (78%) had CNS involvement, and 29% of these patients experienced concurrent CNS and systemic involvement at relapse. Median OS from time of relapse was 8 months (IQR: 3-89 months). Of the 14 deaths occurring during follow up, 6 (43%) were secondary to lymphoma, 2 (14%) were related to toxicities of treatment and the rest were unknown or related to other co-morbidities. Conclusion: To our knowledge, this is the largest international multicenter cohort of patients with isolated PVRL reported in the modern era. The apparent improvement in OS compared with historical cohorts may reflect improvements in therapy in the recent decade, and incorporation of systemic therapy in frontline management demonstrated a trend to improved OS. However, high rates of CNS relapse continue to be a challenge. Delays in diagnosis and variation in diagnostic and management pathways reflect the need to develop prospective studies and international consensus guidelines for managing this rare lymphoma.

Evaluation of factors leading to poor outcomes for pediatric acute lymphoblastic leukemia in Mexico: a multi-institutional report of 2,116 patients.

Pediatric acute lymphoblastic leukemia (ALL) survival rates in low- and middle-income countries are lower due to deficiencies in multilevel factors, including access to timely diagnosis, risk-stratified therapy, and comprehensive supportive care. This retrospective study aimed to analyze outcomes for pediatric ALL at 16 centers in Mexico. Patients <18 years of age with newly diagnosed B- and T-cell ALL treated between January 2011 and December 2019 were included. Clinical and biological characteristics and their association with outcomes were examined. Overall, 2,116 patients with a median age of 6.3 years were included. B-cell immunophenotype was identified in 1,889 (89.3%) patients. The median white blood cells at diagnosis were 11.2.5 × 103/mm3. CNS-1 status was reported in 1,810 (85.5%), CNS-2 in 67 (3.2%), and CNS-3 in 61 (2.9%). A total of 1,488 patients (70.4%) were classified as high-risk at diagnosis. However, in 52.5% (991/1,889) of patients with B-cell ALL, the reported risk group did not match the calculated risk group allocation based on National Cancer Institute (NCI) criteria. Fluorescence in situ hybridization (FISH) and PCR tests were performed for 407 (19.2%) and 736 (34.8%) patients, respectively. Minimal residual disease (MRD) during induction was performed in 1,158 patients (54.7%). The median follow-up was 3.7 years. During induction, 191 patients died (9.1%), and 45 patients (2.1%) experienced induction failure. A total of 365 deaths (17.3%) occurred, including 174 deaths after remission. Six percent (176) of patients abandoned treatment. The 5-year event-free survival (EFS) was 58.9% ± 1.7% for B-cell ALL and 47.4% ± 5.9% for T-cell ALL, while the 5-year overall survival (OS) was 67.5% ± 1.6% for B-cell ALL and 54.3% ± 0.6% for T-cell ALL. The 5-year cumulative incidence of central nervous system (CNS) relapse was 5.5% ± 0.6%. For the whole cohort, significantly higher outcomes were seen for patients aged 1-10 years, with DNA index >0.9, with hyperdiploid ALL, and without substantial treatment modifications. In multivariable analyses, age and Day 15 MRD continued to have a significant effect on EFS. Outcomes in this multi-institutional cohort describe poor outcomes, influenced by incomplete and inconsistent risk stratification, early toxic death, high on-treatment mortality, and high CNS relapse rate. Adopting comprehensive risk-stratification strategies, evidence-informed de-intensification for favorable-risk patients and optimized supportive care could improve outcomes.

Central nervous system relapse in younger patients with diffuse large B-cell lymphoma: a LYSA and GLA/DSHNHL analysis.

Most patients with diffuse large B-cell lymphoma (DLBCL) can be cured with immunochemotherapy such as R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Patients with progression or relapse in the central nervous system (CNS) face dismal outcomes. The impact of more aggressive regimens used in frontline therapy has not been systematically investigated in this context. To this end, we analyzed a large cohort of 2203 younger patients with DLBCL treated on 10 German (German Lymphoma Alliance [GLA]/TheGermanHigh Grade Non-Hodgkin's LymphomaStudy Group [DSHNHL]) and French (The Lymphoma Study Association [LYSA]) prospective phase 2 and 3 trials after first-line therapy with R-CHOP, R-CHOEP (R-CHOP+ etoposide), dose-escalated R-CHOEP followed by repetitive stem cell transplantation (R-MegaCHOEP), or R-ACVBP (rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycine, and prednisone) followed by consolidation including multiple drugs crossing the blood-brain barrier (BBB). Patients with DLBCL with an age-adjusted International Prognostic Index (aaIPI) of 0 to 1 showed very low cumulative incidence rates of CNS relapse regardless of first-line therapy and CNS prophylaxis (3-year cumulative incidences 0%-1%). Younger high-risk patients with aaIPI of 2 to 3 had 3-year cumulative incidence rates of 1.6% and 4% after R-ACVBP plus consolidation or R-(Mega)CHO(E)P, respectively (hazard ratio 2.4; 95% confidence interval: 0.8-7.4; P= .118). Thus, for younger high-risk patients, frontline regimens incorporating agents crossing the BBB may reduce often fatal CNS relapse.

Defining risk of central nervous system relapse in acute myeloid leukemia following allogeneic stem cell transplantation.

e19009 Background: Relapse following allogeneic stem cell transplant (AlloSCT) for acute myeloid leukemia (AML) remains the commonest cause of death post-transplant. Central nervous system (CNS) relapse is a devastating complication. With an estimated incidence of 2-8%, defining those patients at high risk and the management following CNS relapse remains controversial. We sought to identify demographic, clinical, molecular, and laboratory risk factors that would predispose AML patients to CNS relapse. Methods: This was a single institution retrospective study at Loyola University Medical Center. Inclusion criteria were adult patients with AML undergoing first AlloSCT from January 2012 to June 2021. Diagnosis of CNS relapse following AlloSCT was defined as leukemic blasts detected in spinal fluid analysis in accordance with established criteria. Chi-square tests were used to test the association between the experiencing of relapse and the categorical variables recorded. Wilcoxon Rank Sum test were used to assess the relationship between relapse experience and each of the demographic variables. Due to the low count of patients with CNS relapse and in order to avoid a poor estimation of confidence limits of any effect size, we limited our analyses to descriptive statistics and univariable analyses. Results: 198 patients met inclusion criteria with 8 cases (4.0% total) identified with CNS relapse following AlloSCT. Our analysis initially characterized 44 variables including age, race, HCT-CI risk, and day 100 chimerism. Univariate analysis is shown in the table below. Of note, it revealed that 62.50% of patients with CNS relapse had a chimerism value ≤98% at day 100 post-transplant as compared to 22.58% of patients without CNS relapse (p-value 0.02). Additionally, 87.50% of the CNS relapse group versus 51.38% of the group without relapse had favorable to intermediate AML risk scores (p-value 0.07). Conclusions: We observed a 4.0% rate of CNS relapse, which is consistent with what has been repored in the literature. Our results suggest that day 100 chimerism and disease risk index may be predictive of CNS relapse. Since there is a 10.6% incidence (5/47) of eventual CNS relapse amongst those with ≤98% chimerism at day 100, these patients could be considered for a lumbar puncture and bone marrow biopsy to prevent full relapse. Further research in this topic would be valuable to provide additional AML guidance in managing this uncommon complication, such as which patients may benefit from prophylactic strategies. [Table: see text]

Patterns and Prognostic Impact of CNS Infiltration in Adults with Newly Diagnosed Acute Lymphoblastic Leukemia

Acute lymphoid leukemia (ALL) is a subtype of acute leukemia which portends a high risk of central nervous system (CNS) infiltration. At the diagnosis, 5-10% of ALL patients have CNS involvement, which has been demonstrated to decrease overall survival (OS). Based on pediatric trials, conventional cytology (CC) has been the standard for CNS disease assessment, although, more recently, flow cytometry (FC) has gained space across several centers. In this study, we intend to: i) access the impact of CNS involvement (defined by CC or FC) on OS, event-free survival (EFS) and relapse of ALL patients treated in a public health center; ii) find variables associated with CNS infiltration in this cohort. Methods: This retrospective study encompassed 105 cases of ALL newly diagnosed at Instituto do Cancer de Sao Paulo (ICESP). Clinical data were collected from Leukemia clinic database, already approved by Local Ethics Committee. Variables related to cerebrospinal fluid (CSF) were collected from the first lumbar puncture (LP). Traumatic LP was defined as more than 10 red blood cells/µL. CNS status was assessed through the COG's classification and divided into positive/negative for analysis purposes. Patients were treated with different regimens, but intensive intrathecal chemotherapy was given in CNS2 or 3 cases, while cranial irradiation was scheduled for CNS3 patients, only. Results: A total of 105 cases were diagnosed from 2014 to 2020. Only one was excluded (death before the first LP). Median age at diagnosis was 37 years (range, 15-79) with a male majority (58%). Most cases had a B-cell phenotype (76%), followed by T (19%) and ambiguous (5%). Philadelphia chromosome was found in 39%. Eighty-nine percent received corticosteroid at the time of LP with a median time of 7 days. Traumatic LP was reported in 50%. CSF resulted positive for disease in 15% (16/104) and 26% (19/72), by CC and FC, respectively. Among those with a positive CC, 56% (9/16) had a traumatic LP. By COG's classification, CNS1, CNS2 and CNS3 were found in 84%, 14% and 2% of cases, respectively. At the time of PL, 44% of patients presented blasts in peripheral blood. By comparing CC and FC, we noticed only one case with CCpos/FCneg whereas 9/19 with FCpos did not have CCpos. Sensitivity and specificity of CC for CNS disease were 53% and 98%. Traumatic LP and positive CC were not statistically correlated (p=0.8) and prior chemotherapy was associated to higher traumatic LP rates (56 vs 31%, p=0.019). Higher white-blood cell (WBC) counts were found in subjects with positive CC or FC (Mann-Whitney test, p=0.007 for CC). Furthermore, the blast percentage was also relevant for CNS positivity (p=0.027). Genetic subgroup, age, CD34 expression and phenotype were not correlated with CNS invasion, among others. Most patients received adapted versions of BFM (n=43), GRAAPH (n=24) and GRAALL-Elderly (n=18) regimens. Five patients received cranial irradiation. Median OS for the whole cohort was 16.4 months, with a 3y OS of 42.5% (95% CI 33.5-54). For BFM subset (Philadelhpia-negative, below 50 years-old), OS and EFS were 53.5% and 37.3%. We did not find correlation between CNS disease with OS or EFS in univariate analysis. Three-year relapse rate was 38.5% (95% CI 29-49) whereas non-relapse mortality (NRM) was 33%. In multivariate analysis, a positive CC increased relapse rate (HR= 2.3 [95% CI 1.1-4.9, p 0.029]). Initial WBC was also correlated with relapse in our cohort. Among relapses, only one was isolated in CNS, while 13 had concomitant bone marrow and CNS involvement. Eighteen patients proceeded to allo-stem cell transplantation so far. Conclusion: Several studies have demonstrated correlation between CNS infiltration and shorter OS in ALL, even though it relies on how these patients are managed and how CNS is assessed upfront. Our data showed that those who had a positive CSF cytology had a higher risk of relapse, whereas FC was not able to discriminate this risk. Survival rates seem to be increasing over the last years by the adoption of a stratified risk strategy. CSF contamination do not represent a major concern according to our report, as it did not increase CNS involvement or relapse rates. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Risk of Central Nervous System Involvement in High-Grade B-Cell Lymphoma with MYC and BCL2 Rearrangements: Analysis of a Population-Based Cohort with Routine Fluorescence in Situ Hybridization Testing in British Columbia

Introduction: Secondary central nervous system (CNS) involvement in aggressive B-cell lymphoma (SCNSL) is associated with dismal outcomes, highlighting the need to identify at-risk patients (pts). High-grade B-cell lymphoma with MYC and BCL2 rearrangements (HGBCL-DH-BCL2) is a cytogenetically-defined entity associated with poor outcomes, partly attributed to a high rate of SCNSL. However, historic estimates of SCNSL vary widely across studies, confounded by selective fluorescence in situ hybridization (FISH) testing. The CNS International Prognostic Index (CNS-IPI) is a robust model used to estimate the risk of CNS relapse in de novo diffuse large B-cell lymphoma (DLBCL). However, it has not yet been applied to HGBCL-DH-BCL2. Here we performed a population-based analysis to determine the rates of SCNSL in HGBCL-DH-BCL2 identified by non-selective FISH testing in British Columbia (BC) stratified by the CNS-IPI. Methods: All HGBCL-DH-BCL2 pts diagnosed in BC since the introduction of routine FISH testing in all de novo aggressive B-cell lymphoma biopsies and provincial guidelines implementing treatment with dose-adjusted etoposide, doxorubicin, vincristine, cyclophosphamide, prednisone and rituximab (DA-EPOCH-R) with intrathecal methotrexate (IT-MTX) CNS prophylaxis for appropriately fit HGBCL-DH-BCL2 pts aged ≤75 years (y) (DA-EPOCH-R era: 2015-2020) were included. The cohort was supplemented with HGBCL-DH-BCL2 pts from a historic province-wide cohort of aggressive B-cell lymphoma with FISH performed on all evaluable diagnostic biopsies in a research setting (R-CHOP era: 2005-2010). Time to CNS relapse was measured from the date of diagnosis accounting for the competing risk of death from other causes. Biopsies underwent institutional pathology review for consensus assignment to DLBCL or high-grade (HG) morphology. Results: 191 pts with HGBCL-DH-BCL2 were identified (DA-EPOCH-R era n =125, R-CHOP era n = 66). Median (interquartile range) follow up of alive pts was 3.3y (2.3-4.7y) in the DA-EPOCH-R era and 11.9y (11.4-13.2y) in the R-CHOP era. Baseline characteristics are shown in Table 1. Five (3%) pts had CNS involvement at diagnosis (4 DLBCL and 1 HG morphology). Excluding pts with CNS involvement at diagnosis, the 2y cumulative risk of CNS relapse in all HGBCL-DH-BCL2 pts treated with curative intent was 6% (Figure 1), and estimates were 5.5% and 11% in DLBCL and HG morphologies, respectively (p= 0.2). Leptomeningeal involvement was found in 8/10 (80%) of CNS relapses. High CNS-IPI (> 4) was observed in 44% of pts and was associated with a significantly higher rate of CNS relapse (12% high vs < 5% low/intermediate (int) CNS-IPI, p = 0.04). CNS-IPI was also predictive in those with DLBCL morphology (p=0.02). Limited by a small number of events, of the 3/27 pts with HG morphology that developed CNS relapse, 2 had high CNS-IPI and 1 had int CNS-IPI. CNS prophylaxis did not impact CNS relapse risk in either the entire group or when restricting the analysis to pts with high CNS-IPI. CNS relapse was similar in those treated with R-CHOP or DA-EPOCH-R (p = 0.6). To minimize potential bias introduced by treatment selection, we performed an era-on-era comparison in pts aged ≤75y at diagnosis to determine whether the introduction of DA-EPOCH-R with integrated IT-MTX, was associated with a decrease in CNS relapse risk. 79% of pts received R-CHOP in the R-CHOP era whereas 66% of pts received DA-EPOCH-R in the DA-EPOCH-R era. There were no significant differences in CNS-IPI distribution or morphology proportions between the two eras. Competing risk regression analysis found no significant difference in CNS relapse risk between the two eras after adjusting for morphology (hazard ratio and 95% confidence interval of DA-EPOCH-R vs R-CHOP era: 0.47 (0.12-1.84), p = 0.3). Conclusions: In the largest series to date examining SCNSL in HGBCL-DH-BCL2 identified through routine FISH testing, SCNSL rates are considerably lower than previously reported. For those with CNS relapse, leptomeningeal involvement was frequent. The CNS-IPI remains predictive of SCNSL in this entity, suggesting that the overall risk is driven by additional clinical risk factors. Further, as the CNS relapse risk is <5% in pts with low/int CNS-IPI, CNS-directed procedures and prophylaxis may not be required in this subset. Larger series are required to examine the impact of treatment regimen on CNS relapse risk. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The Role of Prophylactic Chemotherapy for the Prevention of Central Nervous System Relapse in Patients with Large B Cell Lymphoma: A Meta-Analysis

Introduction: Central nervous system (CNS) relapse in large B cell lymphoma (LBCL) is a rare, but catastrophic event associated with poor prognosis without an effective standard prophylactic strategy. Intravenous and/or intrathecal chemotherapy have been proposed for patients at high risk for CNS relapse (i.e., CNS-IPI of 4 or greater) with mixed results due to the lack of prospective trials comparing different approaches. Large retrospective cohort studies have challenged the value of CNS prophylaxis. We performed a systematic review and meta-analysis (MA) assessing the role of chemoprophylaxis in preventing CNS relapse for LBCL patients treated with chemoimmunotherapy. Methods: A systematic literature review was conducted using the major online databases, including English language studies published from 2011 until 2022. Data were pooled from the studies with a comparator group using the random effects model to report odds ratio (OR) and 95% confidence intervals (95% CI). Data from single-arm studies were pooled using the random effects model to report the pooled proportion with 95% CIs. Results: There were 16 studies included in the MA (12 retrospective and 4 prospective) assessing the role of CNS prophylaxis in a total of 11,530 patients. The incidence of CNS relapse appeared to be higher among patients who received CNS chemoprophylaxis (n=2108) compared with patients without chemoprophylaxis(n=9422) (OR 1.70, 95% CI 1.10-2.61) (figure 1). Among the single-arm studies, the pooled proportion of the incidence of CNS relapse, isolated CNS relapse and secondary CNS relapse was 5% (95% CI 4%-7%), 5% (95% CI 4%-7%), and 1% (95% CI 0%-2%), respectively. Results are confounded by the retrospective design of most studies, different types of chemoprophylaxis and heterogeneous patient population. Discussion: This systematic review and MA demonstrated consistent rates of CNS relapse as seen in prior large cohorts, and did not show evidence for the use of chemoprophylaxis in patients with LBCL to prevent CNS relapse. Given the scarcity of high quality data due to the absence of prospective trials and the lack of motivation by multiple stakeholders to develop these type of studies, the totality of evidence grouped in this MA constitutes one of the most robust datasets arguing against chemoprophylaxis for prevention of CNS relapse in patients with LBCL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

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.

Outcomes of high‑dose methotrexate for CNS prophylaxis in diffuse large B‑cell lymphoma with an intermediate or high CNS‑International Prognostic Index: A single‑center retrospective cohort study.

Central nervous system (CNS) relapse in patients with diffuse large B-cell lymphoma (DLBCL) is rare (2-5% of cases), but is a devastating complication with a poor survival rate. The administration of high-dose methotrexate (HDMTX) for CNS prophylaxis in patients with DLBCL is controversial and variable in the literature. The present study aimed to evaluate the clinical outcomes of HDMTX CNS prophylaxis in patients with intermediate and high CNS-International Prognostic Index (IPI) DLBCL using real-world data. An observational retrospective cohort study was conducted of all patients with intermediate and high CNS-IPI DLBCL treated at Princess Noorah Oncology Center (King Abdulaziz Medical City, Jeddah, Saudi Arabia) between January 2010 and December 2020. Patients were treated with HDMTX either intravenously or intrathecally, according to the physician's evaluation of the patient. Data on patient clinical characteristics, CNS relapses, risk factors and survival rates were obtained from hospital records. Data were analyzed using Student's unpaired t-test and the χ2 test to compare the two subgroups, the Kaplan-Meier survival method with log-rank test to calculate and compare the survival rates, and regression analysis to determine the risk factors for CNS relapse and death. The study included 358 patients (n=32 with HDMTX CNS prophylaxis and n=326 without CNS prophylaxis). Patients in the CNS prophylaxis group had a significantly higher CNS relapse rate than those in the non-CNS prophylaxis group (12.5% vs. 1.8%; P=0.008). Patients who received CNS prophylaxis were younger and had an advanced stage of disease, with extranodal involvement and a high serum lactate dehydrogenase level at presentation. CNS prophylaxis was significantly associated with CNS relapse, while relapsed disease was associated with the risk of death (all P<0.05). In conclusion, the present study found that patients with intermediate and high CNS-IPI who received HDMTX CNS prophylaxis did not have fewer CNS relapses; however, those without CNS relapse had higher survival rates. In addition to CNS prophylaxis, Stage of DLBCL and IPI were significantly associated with CNS relapse. Future randomized control trials are needed to evaluate the efficacy of HDMTX CNS prophylaxis in patients with DLBCL.

ABCL-455 Multicenter Retrospective Analysis of Single-Route Prophylaxis in Aggressive B-Cell Lymphomas

Relapses involving the central nervous system (CNS) are uncommon among patients with diffuse large B-cell lymphoma (DLBCL) but carry very poor prognosis. Prophylaxis is heterogeneously prescribed around the time of frontline therapy, with no clear standard of care in terms of recipient selection or route of administration. We retrospectively evaluated 1162 adult patients across 21 US academic centers with DLBCL or similar histologies who received single-route CNS prophylaxis as part of frontline chemoimmunotherapy between 2013-2019. Primary endpoint was CNS relapse rate. Secondary endpoints included PFS, OS, and treatment-related toxicities following frontline and salvage therapies. Prophylaxis was administered intrathecally (IT) in 894 (77%) and using systemic high-dose methotrexate (HD-MTX) in 236 (20%); 32 patients (3%) switched route due to toxicity and were assessed separately. By CNS-International Prognostic Index (IPI), 18% were considered low-risk, 51% moderate, and 30% high. Double-hit lymphoma (DHL) was confirmed in 243 of 866 evaluable patients (21%). Sixty-four patients (5.7 %) had CNS relapse, after median 7.1 months from diagnosis, including 15 of 64 (23%) within the first 6 months. There was no significant difference in CNS relapse between IT and HD-MTX recipients (5.4 vs 6.8%, p=0.40), including after propensity score matching to account for differences between respective recipient groups. Weighting by CNS-IPI, expected versus observed CNS relapse rates were nearly identical (5.8 vs 5.7%). Testicular involvement was associated with high risk of CNS relapse (11.3%) despite most having lower CNS-IPI scores. DHL did not significantly predict for CNS relapse after single-route prophylaxis, including with adjustment for treatment regimen and other factors. Median OS following CNS relapse was 6.2 months (IQR 2.9-24.6) and was significantly shorter among patients achieving less than CR to first salvage therapy (HR 3.39, 95% CI 1.76-6.54, p=0.0003). Additional analyses of outcomes following CNS relapse will be presented. This large study of CNS prophylaxis recipients with DLBCL found no significant difference in CNS relapse rates between routes of administration. Relapse rates among high-risk subgroups remain elevated; treatments following CNS relapse were heterogeneous, with poor outcomes for the vast majority of patients. Reconsideration of SCNSL prophylaxis and treatment strategies is of critical need.

Limited efficacy of high-dose methotrexate to prevent the central nervous system relapse in patients with IVLBCL

To evaluate the efficacy of high-dose methotrexate (HD-MTX, ≥1 g/m2) for the prevention of central nervous system (CNS) recurrence in patients with intravascular large B-cell lymphoma (IVLBCL), we reviewed 51 patients with pathologically diagnosed untreated IVLBCL. In total, there were five cases of CNS relapse (9.8%), and the 12-month CNS relapse rate was 9.2%. No statistical difference in CNS relapse rate (p = 0.86) was observed between patients with and without HD-MTX (n = 20 and 31, respectively). Furthermore, the composite endpoint defined as either CNS and/or neurolymphomatosis relapse was not significant in terms of the administration of HD-MTX (p = 0.25). No significant predictor of CNS relapse was found. In conclusion, patients with IVLBCL are at high risk of CNS recurrence; however, HD-MTX administration may not be effective for CNS recurrence prophylaxis. Key points The administration of HD-MTX for patients with untreated IVLBCL may not be effective for preventing CNS relapse.

Assessment of Cranial Radiotherapy Treatment in T-cell Lymphoblastic Lymphoma: Retrospective Study from Tertiary Care Center

Abstract Introduction Leukemia-like regimens given for acute lymphoblastic leukemia (ALL) are the cornerstone of treatment for T-cell lymphoblastic lymphoma (LBL) and can produce complete remission rates exceeding 90%. For central nervous system (CNS) prophylaxis, intrathecal chemotherapy and cranial irradiation are used to prevent future CNS recurrence. Objective The purpose of this study was to assess CNS relapse rate after cranial prophylaxis treatment given at our institute. Materials and Methods In this retrospective analysis, between July 2013 and June 2019, 149 files of lymphoblastic lymphoma were reviewed. Out of these, 53 patients received cranial irradiation. All patients were given CNS-directed therapy in the form of intrathecal methotrexate and patients with CNS-negative disease and primary tumor complete response or more than partial response after chemotherapy were given prophylactic cranial irradiation (18 Gy/10#), and in patients with upfront CNS involvement, therapeutic cranial irradiation (24 Gy/12#) was delivered. Radiotherapy was delivered as per the standard conventional protocol on a linear accelerator. Results Out of 53 patients (age range: 2–50 years, mean–16.79 years, 26 [49.1%] pediatric [&lt;14 years], 27 [50.9%] adults [&gt;14 years]), 13/53 (24.5%), and 40/53 (75.5%) patients were on MCP 841 and BFM 90 protocols, respectively. Also, 48 (90.56%) patients received prophylactic cranial irradiation (25 [52.1%] pediatric, 23 [47.9%] adults). Moreover, 3/48 (6.25%) (2 [4.16%] pediatric, 1 [2.08%] adult) patients had CNS failure after receiving prophylactic cranial irradiation. For 48 target patients, with the median follow-up of 27.27 months (26.1 months–pediatric, 28.2 months– adults), EFS (event-free survival) in the brain was 93.8% (92%: pediatric, 95.7%: adults). Also, the difference between pediatric and adult groups was not statistically significant (p-value = 0.662). Five (9.43%) patients had CNS-positive disease upfront and received therapeutic cranial irradiation. Conclusion In BFM 90/MCP 841 protocol in lymphoblastic lymphoma, prophylactic cranial irradiation and intrathecal methotrexate have been the standard of care as the CNS-directed therapy to prevent cranial infiltration. Though our results are not at par with the published world literature, further research and efforts are required to prevent CNS relapse in a selected sub-set of patients with lymphoblastic lymphoma.

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.