High-dose Methotrexate Regimen Research Articles

Improving measured health-related quality of life with outpatient high-dose methotrexate regimen among oncology patients with intracranial metastases: A systematic assessment

Intracranial metastases including leptomeningeal disease are not uncommon in patients with metastatic solid tumor cancers, such as breast and sarcoma. Treatment options are limited with disease progression on standard-of-care therapies, and high-dose Methotrexate (MTX) is offered for patients with well-preserved performance status. However, standard high-dose MTX treatment entails a lengthy hospitalization and close monitoring which can limit Quality of Life (QoL) for patients who already have multiple provider visits. The impact of high-dose MTX on patients’ daily lives has not yet been qualitatively examined. As a quality improvement project, our team designed an outpatient high-dose protocol for patients who tolerated at least one cycle of inpatient high-dose MTX, and herein we describe the protocol and a quality survey with patients’ feedback. The purpose of this study is to explore and compare the influence of high-dose MTX treatments in two different settings – inpatient and ambulatory – on patients’ QoL. Second, we aim to identify recurrent themes defining patients’ perceived QoL and healthcare experiences. This study identified key QoL impacts that high-dose MTX treatments have on metastatic breast and sarcoma patients. Patients experienced decreased health-related burdens and improved social and psychosocial well-being associated with high-dose MTX treatment compared to standard inpatient treatment. This study provides an opportunity to identify recurrent thematic domains defining QoL in women with metastatic breast cancer.

A Phase II Study of the Efficacy and Safety of the Srmt (Sintilimab, Rituximab, Methotrexate, and Temozolomide) Regimen in Newly Diagnosed Primary Central Nervous System Lymphoma

BACKGROUND Primary central nervous system lymphoma (PCNSL) is a rare and aggressive subtype of lymphoma with poor prognosis. One potential therapeutic approach could involve targeting the programmed death-1 (PD-1) immune checkpoint pathway, as these tumors often express PD-L1. However, the efficacy of this strategy using sintilimab in combination with immunochemotherapy as frontline therapy for patients with newly diagnosed PCNSL remains uncertain. METHODS In this phase II trial with a safety run-in, we enrolled treatment-naive PCNSL patients between the ages of 18 and 70, who had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. All patients were given sintilimab combined with rituximab, high-dose methotrexate and temozolomide (SRMT) regimen (six cycles every 21 days): sintilimab (200 mg, i.v., Day-0), rituximab (375 mg/m 2, i.v., Day-0), methotrexate (3.0 g/m 2, i.v., Day-1 or 1.0 g/m 2 for patients aged ≥65 years, and temozolamide (150 mg/m 2/d, p.o., Days 1-5). The primary outcome was overall response rate (ORR), with secondary outcomes including duration of response (DOR), progression-free survival (PFS), overall survival (OS), safety, and potential biomarkers. RESULTS Between 3 April 2020 and 23 August 2022, a total of 28 patients were enrolled. No dose-limiting toxicities were observed during the safety run-in period. Among 27 evaluable patients, the primary outcome was met with an impressive ORR of 96.3% (95% CI: 81-99.9%). In detail, 25 patients (92.6%) achieved a complete response and one (3.7%) exhibited a partial response. As of 7 April 2023, the median follow-up was 20.8 months. The Medians for DOR, PFS, and OS were not reached. Remarkably, 2-year PFS and 2-year OS were 65.4% (48.1-88.8%) and 88.5% (74.1-100%), respectively. The most common grade 3-4 treatment-related toxicities were increased levels of alanine aminotransferase (18.5%) and aspartate aminotransferase (14.8%). Additionally, the receiver operating characteristic analysis revealed that the baseline IL10/IL6 ratio in cerebrospinal fluid exhibited promising performance in predicting PFS, achieving an area under curve of 0.91 at 2 years. CONCLUSIONS The SRMT regimen as frontline treatment for PCNSL is highly efficacious and well tolerated. (Chinese Clinical Trial Registry number: ChiCTR1900027433).

A meta-analysis of the efficacy and safety of first-line chemotherapeutic agents for osteosarcoma.

Osteosarcoma is a pleomorphic cancer that frequently affects children and teenagers. Although several chemotherapy regimens have been utilized for many years, the best therapeutic option for the treatment of osteosarcoma has not yet been determined. This meta-analysis was designed to assess the clinical efficacy of a high-dose methotrexate, doxorubicin and cisplatin (MAP) regimen and compare its survival outcomes with those of other chemotherapy strategies in patients diagnosed with osteosarcoma. We systematically searched databases, namely Embase, the Cochrane Library and PubMed, up to August 2022, for relevant studies investigating the impact of the MAP chemotherapy protocol on survival among patients with osteosarcoma. The odds ratio (OR) pooled estimates and their 95% confidence intervals (95% CIs) were calculated. Twelve studies including 4102 patients were eligible for analysis in this study. The estimated pooled ORs of the 3-year overall survival (OS) and event-free survival (EFS) were OR = 1.08 (95% CI: 0.72-1.62, p = 0.70) and OR = 1.04 (95% CI: 0.81-1.32, p = 0.78, respectively). The 5-year OS and EFS were OR = 0.87 (95% CI: 0.62-1.23, p = 0.42) and OR = 1.13 (95% CI: 0.76-1.68, p = 0.54), respectively, with no statistical differences. The subgroup analysis of MAP compared to a 2-drug regimen (doxorubicin and cisplatin) revealed a significant difference between the 2 chemotherapy strategy groups in 3-year OS rates (OR = 0.72 (95% CI: 0.56-0.92, p = 0.009)) and 5-year EFS rates (OR = 0.57 (95% CI: 0.43-0.76, p < 0.001)). The MAP chemotherapy strategy for osteosarcoma showed superiority over other regimens, especially over the 2-drug regimen (doxorubicin/cisplatin), in terms of better prognosis and safety.

Abstract P5-07-05: Improving Health-Related Quality of Life with Outpatient High-Dose Methotrexate Regimen Among Solid Tumor Oncology Patients with Intracranial Metastases: A Qualitative Study

Abstract Introduction: Breast cancer patients with intracranial (IC) metastases including leptomeningeal metastasis (LM) confer poor prognosis. Upon disease progression with standard lines of therapy, high-dose intravenous methotrexate (HD IV MTX) is offered to patients given its effective CNS penetrance. HD IV MTX is commonly administered inpatient, requiring extended hospitalization, rigorous leucovorin rescue, IV hydration, and urine alkalinization. Currently, quality of life (QoL) aspects of inpatient v. outpatient regimens remain unknown. Methods: An outpatient MTX protocol with daily visits to outpatient infusion centers was institutionally developed. Study eligibility criteria included solid tumor diagnoses with IC±LM metastasis, disease progression on standard of care treatment, and transition from inpatient to outpatient regimen within the past 12 months. For eligible patients upon consent, qualitative semi-structured phone interviews were conducted with focus on physical functioning and symptom burden. Thematic analysis was utilized. Results: Of the 10 patients who were screened, three (breast=2, sarcoma=1) were eligible. Patient demographics included 2 Caucasians, 1 African American, mean age of 52 years, and s/p prior whole brain radiation. Among QoL measures, no differences in functional status were reported between the two regimens. Single sarcoma patient reported less nausea and emesis with the outpatient regimen. All patients agreed on convenience, autonomy, greater personal and family time, and stronger emotional support while undergoing the outpatient protocol. Despite honorable mentions of inpatient onsite staff and services, all patients reported higher QoL experienced with outpatient MTX protocol vs. inpatient. Conclusions: Interview analysis determined that patient autonomy and nonobligatory hospitalization are key outpatient MTX treatment hallmarks that greatly enhanced patient QoL. Despite the small preliminary patient pool, this study delineates the feasibility in development of an institutionalized patient-centered outpatient MTX protocol. Future clinical trials will additionally be dedicated in conducting a cost-effective analysis comparing both MTX regimens. Citation Format: Heun Min, Elizabeth Weil, Maggie Nelson, John Charlson, Meghan Conroy, Miracle Powell, Yee Chung Cheng, Lubna N. Chaudhary, John Burfeind, Janet Retseck, Deepika Sriram, Sailaja Kamaraju. Improving Health-Related Quality of Life with Outpatient High-Dose Methotrexate Regimen Among Solid Tumor Oncology Patients with Intracranial Metastases: A Qualitative Study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-07-05.

Iatrogenic immunodeficiency-associated lymphoproliferative disorders of the central nervous system: a treatment paradox.

Primary central nervous system lymphomas (PCNSLs) have historically had dismal survival rates until the advent of high-dose methotrexate (HD-MTX) based chemotherapy regimens. With increasing prevalence of autoimmune disease and development of new immunosuppressants, a genetically distinct entity known as iatrogenic immunodeficiency-associated lymphoproliferative disorder (LPD) has emerged. Many of these cases arise following methotrexate use, challenging feasibility of standard HD-MTX regimens. The aim of this study was to further characterize this disorder and determine the optimal management strategy. We describe a case of a 76-year-old female with iatrogenic immunodeficiency-associated PCNSL successfully treated with surgical resection followed by an antiviral and rituximab based regimen. We then performed a systematic literature review and identified 58 cases of non-transplant iatrogenic immunodeficiency-associated LPD involving the CNS. We used a linear probability statistical model to determine correlations with outcome. Natalizumab was associated with EBV negative tumors (P=.023), and EBV positive tumors were associated with improved outcomes (P=.016). Surgical resection was associated with improved outcomes (P=.032), although limited by potential confounding effect. Antiviral treatment (P=.095), rituximab (P=.111), and stem cell transplant (SCT) (P=.198) showed a trend toward improved outcomes. The remaining treatments including methotrexate showed no improvement. We propose that surgical resection, rituximab, and antiviral treatment may be considered as an alternative to standard HD-MTX based regimens when managing iatrogenic immunodeficiency-associated LPD of the CNS. Further study through prospective cohort studies or randomized clinical trials is warranted.

EPID-18. IATROGENIC IMMUNODEFICIENCY ASSOCIATED LYMPHOPROLIFERATIVE DISORDERS OF THE CENTRAL NERVOUS SYSTEM: A TREATMENT PARADOX

Abstract BACKGROUND Primary central nervous system lymphomas (PCNSLs) have historically had dismal survival rates until the advent of high-dose methotrexate (HD-MTX) based chemotherapy regimens. With increasing prevalence of autoimmune disease and development of new immunosuppressants, a genetically distinct entity known as iatrogenic immunodeficiency associated lymphoproliferative disorder (LPD) has emerged. Many of these cases arise following methotrexate use, challenging feasibility of standard HD-MTX regimens. The aim of this study was to further characterize this disorder and determine the optimal management strategy. METHODS We describe a case of a 76-year-old female with iatrogenic immunodeficiency associated PCNSL successfully treated with surgical resection followed by an antiviral and rituximab based regimen. We then performed a systematic literature review and identified 58 cases of non-transplant iatrogenic immunodeficiency associated LPD involving the CNS. We used a linear probability statistical model to determine correlations with outcome. RESULTS Natalizumab was associated with EBV negative tumors (p = 0.023), and EBV positive tumors were associated with improved outcomes (p = 0.016). Surgical resection was associated with improved outcomes (p = 0.032), although limited by potential confounding effect. Antiviral treatment (p = 0.095), rituximab (p = 0.111), and SCT (p = 0.198) showed a trend toward improved outcomes. The remaining treatments including methotrexate showed no improvement. CONCLUSION We propose that surgical resection, rituximab, and antiviral treatment may be considered as an alternative to standard HD-MTX based regimens when managing iatrogenic immunodeficiency associated LPD of the CNS. Further study through prospective cohort studies or randomized clinical trials is warranted.

Dose-individualization Efficiently Maintains Sufficient Exposure to Methotrexate without Additional Toxicity in High-dose Methotrexate Regimens for Pediatric Acute Lymphoblastic Leukemia.

Methotrexate (MTX) can be safely administered to most patients but may cause severe toxicity in others. This study aimed to summarize the characteristics of high-dose methotrexate (HD-MTX) chemotherapy and to evaluate whether the modified dose-adjustment program was able to improve the maintenance of sufficient MTX exposure levels while minimizing toxicities. We evaluated 1172 cycles of high-dose MTX chemotherapy from 294 patients who were treated according to the CCCG-ALL-2015 protocol (clinical trial number: ChiCTR-IPR-14005706) and analyzed the data of actual MTX dosage, MTX concentration, toxicity, and prognosis. We compared data between the dose-adjustment Program 1 (fixed 20% reduction in dose) and the dose-adjustment Program 2 (dose-individualization based on reassessment of the creatine clearance rate and the MTX concentration-monitoring point at 16 h), which were applied if the MTX clearance was delayed in the previous cycle. The patients who used Program 2 had higher actual MTX infusion doses and infusion rates and were able to better maintain the MTX concentration at 44 h at the established target value than those on Program 1 (P<0.001). No significant differences in toxicities were found between these two programs except that abnormal serum potassium levels and prolonged myelosuppression in intermediate-risk/high-risk patients were more frequently observed in patients using Program 2 (P<0.001). No significant correlations were observed between the MTX dose, dose-adjustment programs, or MTX concentrations and relapse-free survival. Adjusting the MTX dose using Program 2 is more efficient for maintaining sufficient MTX exposure without significantly increasing the toxicity.

High-dose methotrexate and rituximab induction regimen in immunocompetent patients with primary CNS lymphoma: a retrospective single-center study of survival predictors.

Primary Central Nervous System Lymphoma (PCNSL) is an aggressive tumor that is confined to the CNS. Although the provision of high-dose methotrexate (HD-MTX) has remarkably improved outcomes in PCNSL patients, the optimal treatment regimens and standard MTX dose for induction therapy have been largely controversial. Herein, we sought to explore the impact of adjuvant rituximab and different dosages of induction HD-MTX on survival outcomes of immunocompetent patients with PCNSL. In this study, we examined patients with PCNSL treated at a single NCI-designated comprehensive cancer center to evaluate their survival outcomes. We conducted a retrospective analysis of 51 immunocompetent patients with PCNSL who received their induction chemotherapy at the University of Alabama at Birmingham (UAB) between 2001 and 2019. Only adult patients with a confirmed diagnosis of PCNSL who had either HD-MTX alone or in combination with rituximab were included. Patients' demographics, clinical characteristics, and survival data were collected and analyzed. There is no significant difference in survival among patients who received MTX alone versus MTX plus rituximab (HR = 0.996 (95% CI: 0.398-2.493), p = 0.994). Lower doses of MTX were associated with worse survival outcomes (HR = 0.680 (95% CI: 0.530-0.872), p = 0.002); however, this difference in survival was not significant when adjusted to age (HR = 0.797 (95% CI: 0.584-1.088), p = 0.153). Our experience challenges the role of rituximab in PCNSL during induction therapy. Our study also highlights the shorter survival in elderly patients with PCNSL which can be related, to some extent, to the relatively lower doses of HD-MTX. There is an unmet need to establish a consensus on the most effective upfront regimen in PCNSL through prospective studies.

Association between SLCO1B1 polymorphism and methotrexate-induced hepatotoxicity: a systematic review and meta-analysis.

Reports on the association between the solute carrier organic anion transporter 1B1 (SLCO1B1) T521C polymorphism and methotrexate-induced hepatotoxicity in patients with malignancies are inconsistent. This meta-analysis evaluated the association between the SLCO1B1 T521C polymorphism and methotrexate-induced hepatotoxicity. We performed a systematic review of previous reports from the PubMed, Web of Science, and EMBASE databases, and a meta-analysis was conducted. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated to evaluate the effect of the SLCO1B1 T521C polymorphism on the occurrence of methotrexate-induced hepatotoxicity. In total, data from five studies including 465 patients were analyzed. Patients had received a high-dose methotrexate regimen (1-5 g/m2). The SLCO1B1 variant allele (C allele) carriers had a 1.9-fold higher risk of hepatotoxicity than wild-type homozygote carriers (TT; OR, 1.94; 95% CI, 1.14-3.31). This meta-analysis demonstrated that C allele carriers of the SLCO1B1 polymorphism had a higher risk of hepatotoxicity than patients with the TT genotype. The SLCO1B1 T521C polymorphism may be a useful predictor for methotrexate-induced hepatotoxicity in patients with malignancies.

Characteristics, Management and Outcome of DLBCL Patients Presenting with Simultaneous Systemic and CNS Disease at Diagnosis - a Retrospective Multicenter Study

▪Background: The incidence of lymphoma concurrently involving the central nervous system (CNS) and systemic organs is very rare. Data regarding this clinical setting are based on case reports and relatively small retrospective series, precluding the establishment of solid recommendation regarding prognosis and treatment.Objectives: The current retrospective multi-center study investigated the characteristics, treatment protocols and outcome of patients with B cell non-Hodgkin lymphoma (B-NHL), diagnosed with concomitant systemic and CNS involvement, between the years 2004 to 2017.Results: All consecutive patients with B- NHL, presenting with concomitant systemic and CNS involvement at diagnosis were reviewed. Thirty five patients were included (24 male; 11 females). Median age at diagnosis was 59 years (34-86). Histological subtype was diffuse large B-cell lymphoma in almost all patients (n=34; 97%). The International prognostic index was greater than 2 in 70% of the patients (n=24). The median number of extra nodal sites was 1 (range: 0-4), with bone being the most common extra nodal site (n=14).Concurrent indolent and aggressive lymphoma were reported in 2 out of 30 patients for which these data were available (6.7%). Twenty two patients had paranchymal involvement (63%). Eight patients had meningeal involvement per imaging (23%) and 4 had spinal disease. Cerebrospinal fluid (CSF) involvement, defined by a positive CSF cytology or immunophenotyping, was detected in 59% (13/22 patients).The most common induction chemotherapy was anthracycline-based (RCHOP / RCHOP like regimen) in combination with high-dose methotrexate (MTX), with or without cytarabine (23 of 35 patients, 66%). Seven patients were ineligible for intensive chemotherapy due to poor performance status. Overall, 14 patients died from the disease (40%). Six of them during induction and 8 due to relapsed/refractory disease. 2 patients died from other causes.Overall response rate following induction treatment was 80%, including 60% complete remissions (CRs) and 20% partial remissions (PRs). Most patients achieved CNS and systemic CR (evaluated by nervous system MRI/CT and PET/CT).14 patients were treated with high dose chemotherapy followed by autologous stem cell transplantation (ASCT) (12 in CR and 2 in PR). ASCT did not improve depth of response in any of the patients transplanted in less than CR.Nine patients (33.3%) relapsed within less than 2 years from diagnosis. Disease-free survival (DFS) and overall survival (OS) of the entire cohort were 50.4% and 70.2%, respectively (Figure 1), similar to patients receiving anthracycline-based / high-dose MTX regimen (47.8% and 79.2% respectively). ASCT did not improve the outcome of patients treated with anthracycline-based / high-dose MTX chemotherapy (figure 2). Paravertebral mass (HR=14.8, p=0.002) rather than brain disease (parenchyma, intraventricular or both), meningeal or cranial nerve involvement and an increased LDH level (HRfor100unit=1.11, p=0.006) were found to be associated with shorter OS.Restricted analysis, including patients receiving anthracycline-based / high-dose MTX regimen only , found paravertebral mass (HR=38.265, p=0.011) and meningeal disease (HR=10.463, p=0.059) to be associated with an increased risk of relapse. Of note, brain involvement (HR=0.08, p=0.036) was associated with a decrease risk of relapse.Conclusion: Combination therapy with RCHOP-HD MTX provides encouraging outcome in DLBCL patients presenting with systemic and CNS disease, with half remain free of disease at 2 years post diagnosis. Patients presenting with brain involvement had better survival than patients diagnosed with paravertebral involvement. Our study did not demonstrate clear survival benefit for patients undergoing ASCT, and given the relatively good outcome of our cohort, the benefit of ASCT in this group of patients needs to be further validated in prospective studies. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Prophylaxis with intrathecal or high-dose methotrexate in diffuse large B-cell lymphoma and high risk of CNS relapse

Although methotrexate (MTX) is the most widely used therapy for central nervous system (CNS) prophylaxis in patients with diffuse large B-cell lymphoma (DLBCL), the optimal regimen remains unclear. We examined the efficacy of different prophylactic regimens in 585 patients with newly diagnosed DLBCL and high-risk for CNS relapse, treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or R-CHOP-like regimens from 2001 to 2017, of whom 295 (50%) received prophylaxis. Intrathecal (IT) MTX was given to 253 (86%) and high-dose MTX (HD-MTX) to 42 (14%). After a median follow-up of 6.8 years, 36 of 585 patients relapsed in the CNS, of whom 14 had received prophylaxis. The CNS relapse risk at 1 year was lower for patients who received prophylaxis than patients who did not: 2% vs. 7.1%. However, the difference became less significant over time (5-year risk 5.6% vs. 7.5%), indicating prophylaxis tended to delay CNS relapse rather than prevent it. Furthermore, the CNS relapse risk was similar in patients who received IT and HD-MTX (5-year risk 5.6% vs. 5.2%). Collectively, our data indicate the benefit of MTX for CNS prophylaxis is transient, highlighting the need for more effective prophylactic regimens. In addition, our results failed to demonstrate a clinical advantage for the HD-MTX regimen.

Prognostic Role of Blood Markers in Primary Central Nervous System Lymphoma Patients Treated With High-Dose Methotrexate-Based Therapy.

Purpose: Primary central nervous system lymphoma (PCNSL) is a rare type of extra-nodal non-Hodgkin lymphoma, but the prognostic value of blood parameters indicating systemic inflammation and nutritional status remains unknown. We aim to explore the prognostic role of blood parameters in PCNSL.Methods: All PCNSL patients diagnosed at West China Hospital between February 2011 and February 2020 were retrospectively screened. For patients who were initially treated with high-dose methotrexate (HD-MTX)-based therapy, clinical data were collected. Survival analyses were performed using the Kaplan–Meier method and multivariable Cox proportional regression. The accuracies of different multivariate models were assessed by Harrell's C statistical analysis (C-index).Results: Sixty patients were included. Median overall survival (OS) was 4.8 ± 3.7 years, and median progression-free survival (PFS) was 1.9 ± 1.3 years. In the multivariate analysis, hemoglobin (Hb) (HR 3.940, p = 0.013), neutrophil–lymphocyte ratio (NLR) (HR 10.548, p = 0.034), and total bilirubin (TBIL) (HR 3.429, p = 0.004) had independent prognostic values for PFS, while lymphocyte–monocyte ratio (LMR) (HR 6.195, p = 0.039), systemic immune-inflammation index (SII) (HR 5.144, p = 0.012), and TBIL (HR 3.892, p = 0.009) were independently related to OS. The C-index of the Memorial Sloan-Kettering Cancer Center (MSKCC) score increased from 0.57 to 0.72 when SII and TBIL were combined.Conclusions: Our study indicated that pretreatment Hb, NLR, SII, LMR, and TBIL were convenient prognostic factors in PCNSL. Adding SII and TBIL to the MSKCC score can better predict the survival of PCNSL based on HD-MTX regimens.

Evaluation of Hepatic Complications for High Dose Methotrexate in Children: 10 Years after Treatment of Malignancy

Background Methotrexate is a chemotherapy drug used in high doses to treat malignancies that can lead to serious liver damage, especially cirrhosis in a dose-dependent manner. We aimed to evaluate the hepatic complications, 10 years after treating children with hematologic malignancies by high-dose Methotrexate regimen. Materials and Methods: In a descriptive-analytical study, all children with hematologic malignancies who received high-dose methotrexate for treating cancer and who were hospitalized in Tabriz Children’s Hospital, Tabriz, Iran, from 2008 to 2009 were included. Demographic data were extracted from medical records. Liver enzyme tests, ultrasonography, as well as a Doppler ultrasound of the portal vein were performed for all participants in the Tabriz Children’s Hospital. Data were analyzed using descriptive statistics. The Chi-Square test was used to examine the relationship between variables using SPSS software version 22.0. Results: Out of 30 patients, 18 cases (60%) were boys and 23 (76.67%) of patients had Acute Lymphoblastic Leukemia. ALT, Total BILL, and Direct BILL levels were increased by 13.33%, 13.33%, and 10% of cases, respectively. AST, PT, and PTT levels were normal in all patients. The liver and spleen spans were larger than normal in 26.67% and 40% of cases, respectively and 5 patients (16.67%) had grade 1 fatty liver. Port vein diameter was normal in all patients. Conclusion Based on the results of the study, it is possible to consider the long-term safety of high dose Methotrexate in terms of the development of severe liver disease following treating malignancies in children. However, patient follow-up is recommended to identify complications for years after discontinuing treatment.

R-split-EPOCH plus high dose methotrexate in untreated diffuse large B cell lymphoma with MYC rearrangement or double expression of MYC and BCL-2.

Purpose: Diffuse large B cell lymphoma (DLBCL) with MYC rearrangement or double expression of MYC and BCL-2 (DE DLBCL) has a relatively poor prognosis and does not respond well to standard R-CHOP. In the current study, we aimed to investigate the efficacy and safety of R-split-EPOCH plus high dose methotrexate (HD-MTX) in the particular patient population.Methods: A total of 28 patients diagnosed with DE DLBCL or DLBCL with MYC rearrangement between January 2015 and December 2018 were included and retrospectively analyzed. All the participants underwent R-split-EPOCH plus HD-MTX as introduction therapy, with split infusion of etoposide, doxorubicin, and vincristine for 48 hours on D1-2 and D10-11, respectively.Results: The overall objective response (ORR) rate was 100%, with 24 (85.7%) complete response (CR) and 4 (14.3%) partial response (PR). The CR rate was 76.9% and 93.3% for DLBCL patients with MYC rearrangement and DE DLBCL patients, respectively. The 1- and 3-year PFS rate was 100% and 74.9%, respectively. The 1- and 3-year OS rate was 100% and 92.9%, respectively. Grade 3/4 non-hematological toxicity and grade 3/4 hematological toxicity occurred in 50% and 85.7% of patients, respectively. No treatment-related death was reported.Conclusions: R-split-EPOCH plus HD-MTX regimen is an effective and feasible treatment option for DE DLBCL and DLBCL with MYC rearrangement.

Increased Health Resource Utilization with the Introduction of Matrix for First-Line Treatment of Primary Central Nervous System Lymphoma

Introduction: Prior to 2016, Primary Central Nervous System Lymphoma (PCNSL) was treated using High-Dose Methotrexate (HD-MTX) +/- Cytarabine. Since 2016, the MATRix regimen (HD-MTX, Cytarabine, Thiotepa, Rituximab) was adopted based on the IELSG32 study (Ferreri et al. Lancet 2016). Information on health resource utilization (HRU) for the MATRix regimen compared to prior standards of care is limited. We sought to investigate HRU in PCNSL patients treated with the MATRix regimen compared to other HD-MTX regimens at a single institution. Methods: Adults (≥18years) with a diagnosis of PCNSL between January 1, 2009 and December 31, 2018 and treated with a HD-MTX regimen were included. All patients were treated in Hamilton, ON, Canada and had complete treatment data available. Patient characteristics, including age, sex, malignancy type, chemotherapy regimen, length and number of hospitalizations, and transfusion data were obtained through electronic health records. Patients treated for relapsed/refractory disease were excluded. Patients were categorized based on the treatment regimen received. Results: Fifty-one patients [20 (39.2%) female] were included. Median age was 69.0 [range, 41 to 87]. 17 (33.3%) patients were treated with MATRix, 14 (27.5%) with HD-MTX + Cytarabine, and 18 (35.3%) with HD-MTX only. 2 (3.9%) patients were treated with other drug regimens and excluded from analysis. The mean overall length of stay (LOS) was 92.6 days [95%CI, 48.9 to 136.3] in the MATRix group, 70.5 days [95%CI, 37.4 to 103.6] in the HD-MTX + Cytarabine group, and 40.6 days [95%CI, 25.6 to 55.5] in the HD-MTX group. Mean LOS was significantly shorter in the HD-MTX group compared to MATRix group (P = 0.04), all other comparisons for LOS were not statistically significant. The mean number of red blood cell units transfused per patient was 11.5 [95%CI, 8.4 to 14.5] in the MATRix group, 10.6 [95%CI, 3.5 to 17.8] in the HD-MTX + Cytarabine group, and 1.9 [95%CI, 0.7 to 3.2] in the HD-MTX group. There were significantly more red blood cell units transfused per patient with MATRix compared to HD-MTX (RR 1.54, 95%CI, 1.05 to 2.27, P = 0.03) but not HD-MTX + Cytarabine compared to HD-MTX (RR 1.40, 95%CI, 0.92 to 2.15, P = 0.12) or HD-MTX + Cytarabine compared to MATRix (RR 1.10, 95%CI, 0.86 to 1.40, P = 0.45). The mean number of pooled platelet units transfused was 8.1 [95%CI 4.0 to 12.1] for the MATRix group, 5.3 [95%CI, 0.9 to 9.7] for the HD-MTX + Cytarabine group, and 0.7 [95%CI, 0 to 1.5] for the HD-MTX group. There were significantly more platelet blood cell units transfused per patient in the MATRix group compared to the HD-MTX group (RR 2.47, 95%CI, 1.24 to 4.92, P = 0.01), all other comparisons were not significant. Conclusion: Our institution observed that the HRU, assessed through LOS, and number of red blood cell and platelet transfusions, in PCNSL patients was significantly higher for patients treated with a MATRix regimen in comparison to a HD-MTX only regimen but not a HD-MTX + Cytarabine regimen. These findings highlight important implications for assessing the impact to patients and systems when a new standard of care is adopted. Additionally, beyond drug acquisition costs these considerations may make the adoption of regimes such as MATRix prohibitive for resource limited settings. Disclosures Hillis: Roche: Honoraria.

Central Nervous System Lymphoma: Approach to Diagnosis and Treatment.

Central nervous system lymphoma (CNSL) is a rare form of extranodal non-Hodgkin lymphoma. Central nervous system lymphoma can be primary (isolated to the central nervous space) or secondary in the setting of systemic disease. Treatment of CNSL has improved since the introduction of high-dose methotrexate and aggressive consolidation regimens. However, results after treatment are durable in only half of patients, and long-term survivors may experience late neurotoxicity, impacting quality of life. Given the rarity of this disease, few randomized prospective trials exist. This leaves many questions unanswered regarding optimal first-line and salvage treatments. Recent advances in the knowledge of pathophysiology of CNSL will hopefully help the development of future treatments. This review gives an overview of the epidemiology, pathophysiology, clinical presentation, diagnosis, and treatment of immunocompetent patients with CNSL.

The Predictors and Prevention of the Central Nervous System Relapse in Patients with Extranodal NK/T Cell Lymphoma, Nasal Type

Background: The incidence of central nervous system (CNS) involvement is rare ranging from 0 to 6% in patients with extranodal NK/T cell lymphoma, nasal type. A few studies have suggested that CNS prophylaxis should be considered in the high PINK group, but it is unclear because of relatively small numbers of patients. However, non-anthracycline-based chemotherapy with L-asparaginase improved the survival outcome, and the frequency of CNS relapse is expected to increase. Therefore, we aimed to identify the incidence and risk factors for CNS relapse and to evaluate the need for CNS prophylaxis with high-dose methotrexate (HD MTX) regimens. Patients and methods: We retrospectively reviewed 399 patients who had diagnosed with extranodal NK/T-cell lymphoma, nasal type, and received non-anthracycline based chemotherapy from January 2000 to January 2019 at multicenter in Korea. The CNS relapse was defined as a brain parenchymal or leptomeningeal involvement confirmed either by MRI or CSF study during chemotherapy or follow-up period. For subgroup analysis, we used the prognostic index of natural killer lymphoma (PINK), and the prognostic index of natural killer lymphoma with Epstein-Barr virus DNA (PINK-E), which includes age, Ann Arbor stage, lymph node involvement, and EBV DNA. Patients were divided into two groups, according to whether the chemotherapy regimen included HD-MTX. Results: Twenty-seven patients (6.8%, 27/399) experienced CNS relapse during chemotherapy or follow-up period. The median overall survival of all patients was 93.7 months [95% confidence interval (CI) 72.53-114.95], and the median time to CNS relapse of 27 patients was 10.1 months (range 0.0-42.0). The clinical variables associated with CNS relapse were BM involvement (HR 4.026, p=0.002), extranodal involvement≥2 (HR 8.198, p&lt;0.001), EBV DNA (HR 3.90, p=0.013), Ann Arbor stage III/IV (HR 9.397, p&lt;0.001), PINK [intermediate (HR 4.700, p=0.009), high (HR 9.554, p&lt;0.001)], and PINK-E [intermediate (HR 6.032, p=0.001), high (HR 6.775, p&lt;0.001)]. In multivariate analysis, PINK was the powerful predictor of CNS relapse (HR 3.486, p=0.019). The cumulative incidence of CNS relapse was significantly different between groups of Ann Arbor stage (p&lt;0.001), PINK (p=0.004), or PINK-E (p=0.002). The incidence of CNS relapse in patients with/without HD-MTX regimens was six patients (6/101, 5.9%) and 21 patients (21/298, 7.0%). Although there was no significant difference between both treatment groups in all patients, the patients who received chemotherapy with HD MTX regimens had a lower incidence of CNS relapse than those who received other regimens in Ann Arbor stage III/IV (p=0.033). Conclusions: We demonstrate the strong predictability of PINK and PINK-E for CNS relapse in patients with extranodal NK/T-cell lymphoma, nasal type. HD MTX regimens reduced the incidence of CNS relapse in Ann Arbor stage III/IV groups, and CNS prophylaxis should be considered for these patients. Disclosures Kim: F. Hoffmann-La Roche Ltd: Research Funding; Celltrion: Research Funding; Novartis: Research Funding; Donga: Research Funding; Kyowa-Kirin: Research Funding; Novartis: Research Funding; J + J: Research Funding.

CLINICAL FEATURES, TREATMENT AND OUTCOME OF NEUROLYMPHOMATOSIS: SINGLE INSTITUTION EXPERIENCE

Introduction: Neurolymphomatosis (NL) is a highly rare disorder defined as infiltration of peripheral nervous system by a lymphoproliferative neoplasm, both presented as the first manifestation of the malignancy (primary NL) or as a site of disease progression or relapse (secondary NL). Clinical features of NL and best approach are still widely unknown. Methods: We retrospectively reviewed clinical records of all histologically confirmed-NL, diagnosed and treated at the Hematology Department of Mayo Clinic in Rochester MN between January 2002 and December 2018. Results: Over a 16-year period 40 patients were diagnosed with NL. Primary and secondary NL were 18 (45%) and 22 (55%) respectively, with a median age of 60.5 years (range 37-83) and male sex 24/40 (60%). The majority had B-cell lymphomas (39/40 patients): 27/40 (60%) with diffuse large B-cell lymphoma (DLBCL) and only 1 case of T-cell lymphoma. The affected structures included peripheral nerves in 16/40 cases, spinal nerves (12/40), neural plexus (14/40), cranial nerves (4/40), cauda equine (6/40); multiple sites were involved in 13/40. 4/40 cases had brain involvement and cerebrospinal fluid (CSF) was positive in 7/29. NL clinical manifestations included muscular weakness (33/40 patients), sensory deficit (32/40), pain (28/40) and autonomic dysfunction (3/40). Magnetic resonance imaging (MRI) detected neural abnormalities in 35/36 cases (97%), CT imaging identified disease in 3/8 (37%) and FDG-PET scan was positive in 22/31 (71%); electromyography showed some grade of neuropathy in 28/29 cases. Treatment included systemic chemotherapy in 38/40 patients, containing high dose methotrexate (HD-MTX) in 26/40(65%) and rituximab in 20/40 (50%); 11/39 (28%) patients underwent consolidative autologous stem cell transplant; 4/40 received consolidative radiotherapy (RT) and 1/40 was managed with RT alone; intrathecal chemotherapy was infused in 1/40 cases; one patient with solely great auricular nerve NL involvement was cured with surgery only. Treatment efficacy evaluated by imaging and clinical improvement consisted with an overall response rate of 73% (27/37) with a 51% (19/37) rate of complete remission (CR); the rates of CR reached with HD-MTX regimens and other systemic treatments were 56% (13/24) and 42% (5/13) respectively. The median overall survival (OS) was 137.8 months with a 48-months OS 73%. A trend of longer survival rate for primary NL, although no statistically significance, was observed, with a 48-month OS of 94% vs 56% for secondary NL (p 0.134). (Figure 1) Keywords: extranodal lymphomas; immunochemotherapy; non-Hodgkin lymphoma (NHL).

Primary Central Nervous System Lymphoma: An Experience of a Regional Cancer Center from India

Background: Primary central nervous system lymphoma (PCNSL) is a rare malignant non-Hodgkin's lymphoma and it accounts for 1% of all intracranial tumors. Only a few PCNSL studies have been reported from India, and hence, we conducted the retrospective study in our institute to analyze the main clinical features at diagnosis and the treatment results in PCNSL. Materials and Methods: We retrospectively reviewed the medical records of 32 patients with PCNSL who were treated from 2003 to 2014. A complete history was recorded, and the physical examination included neurological assessment. Baseline investigations such as complete blood count, blood biochemistry, chest X-ray, HIV serology, and two-dimensional echocardiography were also done. Contrast-enhanced computed tomography (CT) of the brain or magnetic resonance imaging, positron-emission tomography (if affordable), cerebrospinal fluid (CSF) analysis for cytology, histopathological diagnosis (following stereotactic or open biopsy), CT of the thorax and abdomen, and bone marrow biopsy were done. All patients received whole-brain radiotherapy (WBRT) (36–50 Gy) followed by cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) regimen for six cycles. Clinical features and the treatment results were analyzed. Results: A total of 32 patients with PCNSL were studied. The median age was 50 years (range: 32–70 years). Male: female ratio was 2.5:1. All the 32 patients were histologically diffuse large B-cell lymphoma. The most common presenting symptom was headache in 20 (62.5%) patients. The area of involvement was mainly cerebral hemispheres in 22 (68.8%) patients. Multifocal involvement was seen in 22 (68.8%) patients. CSF cytology was negative in all patients. All patients received WBRT (36–50 Gy) followed by CHOP regimen for six cycles. All patients were compliant to radiation as well as chemotherapy. On a median follow-up of 18 months, the median overall survival was 14 months (range: 1–80). Conclusions: Breaking the blood–brain barrier with radiotherapy followed by CHOP chemotherapy results in reasonable outcome in patients of PCNSL, especially in the Indian setting where general built and tolerance is low- to high-dose methotrexate regimens. Newer chemotherapy regimens or targeted therapies need to be evaluated to further improve the survival.

Addition of Rituximab to High-Dose Methotrexate Regimens Improves Complete Response Rates and Median Overall Survival in Non-Germinal Center Primary CNS Lymphoma

Background:Primary central nervous system lymphoma (PCNSL) is a rare type of extranodal non-Hodgkin lymphoma (NHL). Most cases occur in the immunocompetent population. Despite advances in therapy, the prognosis of PCNSL remains poor, with 5-year overall survival (OS) rates at 30-50% (Ferreri 2011). The standard of care treatment regimen includes high-dose methotrexate (HD-MTX), often in combination with other multiagent CNS penetrating chemotherapies. Although the addition of rituximab in systemic aggressive B-cell NHLs has shown improvement in OS, the benefit of this agent in PCNSL has not been confirmed in a prospective dataset (Bromberg 2017). The majority of PCNSLs are classified as diffuse large B-cell lymphomas (DLBCL), and the outcomes based on treatment and cell of origin (germinal center B-cell (GCB) vs. non-GCB subtype) have yet to be fully elucidated. In this review, we report our findings from a series of PCNSL patients based on treatment regimen and cell of origin.Methods:This is a retrospective study of patients with PCNSL diagnosed and treated at the University of Colorado Hospital from 1995 to 2017. Chart abstraction included demographics, DLBCL subtype by Hans algorithm (Hans 2004), treatment details, and outcomes. OS was examined using Kaplan Meier methods, while bootstrap resampling and a z-test was used to compare median survival times across strata. Fisher's exact test was used to determine whether treatment responses were different between those that received treatment withHD-MTX and rituximab versus HD-MTX without rituximab. A significance level of 0.05 was used for all tests. When assessing differences by subtype, treatment type, relapse, and treatment response the data was subset to include only patients without a prior HIV diagnosis.Results:71 patients with PCNSL were identified. 13 patients were HIV positive (the HIV status of 1 patient was unknown). Of the remaining 57 immunocompetent patients, 39 patients were treated with HD-MTX, of which 29 patients received rituximab in combination therapy. The most commonly received regimen was rituximab with methotrexate, procarbazine, and vincristine (R-MPV) (43.6%, 17 of 39). Median age in the HD-MTX subgroup was 65 years, with 83% of patients with KPS>70 at diagnosis. EBV positivity was noted in only 4 of 39 samples (10.2%), while 25 of 39 (64.1%) tested negative; the remaining patients' data was not available.Median OS was 29.9 months for all 71 patients (Figure 1). There was no significant difference in median OS between those with and without HIV (p=0.127).22 of 29 (75.9%) patients in the HD-MTX with rituximab group achieved a complete response (CR) while no patients (0%; 0 of 10) in the HD-MTX without rituximab group achieved a CR. The number of patients with a CR was significantly higher for those that received HD-MTX with rituximab compared to those that received HD-MTX without rituximab (p<0.001).Median OS for HIV negative patients treated with HD-MTX without rituximab (N = 10) was 32.6 months whereas median OS for HIV negative patients treated with HD-MTX with rituximab (N = 29) has not been reached at a median follow up of 33.4 months (range 1.5 - 116.9 months) (Figure 2)Subtyping was available for 23 patients without HIV treated with HD-MTX with or without additional agents. 6 patients had GCB subtype and 16 had non-GCB subtype. Median OS for GCB subtype has not yet been reached, while median OS for non-GCB subtype was 33.4 months (Figure 3). When analyzing data for patients who received HD-MTX and rituximab, median OS for GCB has not been reached, while median OS for non-GCB was 43.8 months (Figure 4).Conclusions:Our review of patients with PCNSL suggests that the addition of rituximab to a high dose MTX-based regimen improves survival although numbers are too small to determine any overarching statistical conclusion. CR rates were significantly higher in patients receiving rituximab in addition to HD-MTX compared to HD-MTX without rituximab. Patients with non-GCB subtype treated with HD-MTX and rituximab had increased median OS compared to median OS of non-GCB patients treated with HD-MTX without rituximab. However, in line with previous data we demonstrated worse outcomes associated with non-GCB subtype compared to GCB subtype. Future research is needed to focus on the characteristics of this subtype of PCNSL to improve outcomes with novel therapeutics. [Display omitted] DisclosuresKamdar:Genentech: Consultancy; Seattle Genetics: Speakers Bureau. Haverkos:Viracta Therapeutics: Membership on an entity's Board of Directors or advisory committees.