High-dose Intravenous Methotrexate Research Articles

Efficacy of intravenous high-dose methotrexate in preventing relapse to the central nervous system in R-CHOP(-like)-treated, high-risk, diffuse large B-cell lymphoma patients and its effect on mortality: a systematic review and meta-analysis.

To evaluate: 1) whether addition of prophylactic intravenous HD-MTX reduces the risk of CNS relapse in high-risk DLBCL patients treated with R-CHOP or similar and 2) whether HD-MTX prophylaxis confers an overall survival benefit, irrespective of CNS relapse. A systematic search of MEDLINE/PubMed and EMBASE on DLBCL patients at high risk of CNS relapse treated with R-CHOP or similar receiving HD-MTX as intervention and a comparator arm receiving no prophylaxis and/or IT prophylaxis. Risk of Bias was estimated using the ROBINS-I tool and the quality of the evidence by the GRADE approach. Finally, a meta-analysis based on the systematic review was conducted. A total of 1812 studies were screened. No RCT's were identified. Seven observational studies comprising 1661 patients met inclusion criteria. We found a statistically non-significant relative risk of 0.54 [0.27-1.07, 95% CI] of CNS relapse for patients receiving HD-MTX vs. controls. The meta-analysis investigating mortality demonstrated a relative risk of death of 0.70 [0.44-1.11, 95% CI] for HD-MTX treated vs. controls. The overall risk of bias was adjudged as "serious" and the quality of the evidence was rated as low. Our data indicate that HD-MTX does not prevent, or at best, only slightly reduces the risk of CNS relapse and confers no survival benefit.

The Management of Children with Pre-School Medulloblastoma – A Review of Four Decades of Multi-Disciplinary and Multi-Institutional Collaboration.

Background: The management and consequent survival and quality of survival for young children with medulloblastoma have undergone substantial improvement over the last four decades. While many of these changes reflect improvements in pediatric neurosurgical, neuro- imaging and radiation oncologic technology and training, as well as in supportive care experience and expertise, this review will focus particularly upon improvements in chemotherapeutic approaches. Methods: This review focuses only upon prospective clinical trials conducted in young children with newly-diagnosed medulloblastoma since the 1980s. The upper age limits for these trials varied from under three to up to six years of age at diagnosis. Results: Certain but not all trials endeavoring to improve outcomes for young children with now- recognized pathological and molecular low-risk characteristics, specifically the Sonic Hedgehog (SHH) sub-type, representing some 50-60% of young children with medulloblastoma, have reaped substantial gains in event-free and overall survival, irradiation-free survival as well as neuropsychological outcomes. Those successful trials utilized either induction including intravenous high-dose methotrexate and intraventricular (intra-Ommaya) methotrexate without consolidation by marrow-ablative chemotherapy with autologous hematopoietic progenitor cell rescue (AuHPCR), or induction with or without intravenous high-dose methotrexate (but not intra-ventricular methotrexate) followed by consolidation with marrow-ablative chemotherapy with AuHPCR. These two approaches have consistently produced superior outcomes compared with other trials. For children with molecularly-characterized Groups 3 or 4 medulloblastoma, representing those at high-risk of relapse, some modest improvements have been made over the years, but much room for improvement remains, especially for those presenting with the highest- risk molecular characteristics (CMYC-amplified Group 3 medulloblastoma) as well as for children with metastatic disease at initial diagnosis. Conclusions: Substantial gains in improving outcomes for young children with medulloblastoma have been achieved with acceptable short- and long-term morbidities of treatment. However, the inclusion of intra-ventricular therapies (conventional chemotherapeutic, radio-labeled monoclonal antibody or adaptive cellular immunotherapeutic approaches) as well as the identification of targeted systemic therapies (biological and/or immunological) and their incorporation into prospective multi-center clinical trials, must be investigated prospectively if we are to improve outcomes for those children at high-risk for relapse, even with the inclusion of refined irradiation therapeutic approaches.

Primary central nervous system lymphoma.

Primary central nervous system lymphoma (PCNSL) is a rare type of non-Hodgkin lymphoma (NHL) manifesting in the brain, spinal cord, cerebrospinal fluid and/or eyes, in the absence of systemic manifestations. With an increasing incidence and a 30% 5-year overall survival if promptly treated, timely diagnosis and subsequent treatment is paramount. The typical MRI appearance for PCNSL is a solitary or multiple T2-hypointense, homogeneous gadolinium-enhancing lesion with restricted diffusion. Dexamethasone treatment might compromise and delay the diagnosis. Hallmark of treatment is induction with intravenous high-dose methotrexate consisting polychemotherapy followed by consolidation treatment. Consolidation treatment consists of either whole brain radiotherapy (WBRT) or autologous stem cell transplantation (ASCT). Given the (cognitive) side effects of WBRT, ASCT is increasingly being used as the first choice of treatment.

Diffuse Large B-Cell Lymphoma CNS Relapse Prophylaxis with Intrathecal or High-Dose Intravenous Methotrexate

Introduction: Central nervous system (CNS) relapse is a relatively infrequent but often fatal complication of the most common subtype of non-Hodgkin lymphoma, diffuse large B-cell lymphoma (DLBCL). Median overall survival (OS) after DLBCL relapse in the CNS is about 4 months. Despite identifying patients at high risk of developing CNS relapse using the CNS international prognostic index (CNS-IPI) score, it has been difficult to validate any specific strategy. Various chemotherapies and administration methods have been tested. Thus far, only the addition of rituximab to chemotherapy has yielded significant results. Our objective is to determine if administering prophylactic chemotherapy is efficacious in preventing DLBCL relapse in the CNS. Methodology: We collected retrospective data for patients with newly diagnosed DLBCL treated with rituximab and anthracycline-based chemotherapy from 2010 to 2020 in the Northwell Health system to determine the efficacy of CNS prophylaxis. Patients with CNS disease at diagnosis, primary testicular lymphoma, primary mediastinal large B-cell lymphoma, and HIV-associated lymphoma were excluded from this study. CNS prophylaxis was defined as receiving at least two doses of prophylactic chemotherapy, whether intravenous or intrathecal. Follow up for at least one year after diagnosis was required for inclusion. Overall survival (OS) was defined as the time difference between the date of definitive diagnosis to death or last date of contact. Other potential prognostic factors including double hit status and cell of origin, germinal center B-cell (GCB) vs. non-germinal center B-cell (non-GCB), were also evaluated. Pearson's chi-square analysis was used to compare the rate of DLBCL relapse in the CNS based on whether patients received CNS prophylaxis. Low risk was defined as CNS-IPI score 0 to 3 and high risk as CNS-IPI score 4 to 6. Kaplan-Meier analysis with log-rank (Mantel-Cox) testing was used to determine if any significant OS benefit was observed for the low and high-risk groups based on CNS-IPI score. Results: Of the 437 charts reviewed, 127 were eligible for inclusion. Most patients were male (56.7%). Median age was 69 years and median Eastern Cooperative Oncology Group (ECOG) performance status was 1. Most cases were non-GCB (44.9%, as 25% of cases were missing data) and not double hit (85%). Of the 35 patients at high risk for CNS relapse, 27 (77%) received prophylaxis. Intrathecal methotrexate (IT MTX) was given to 26 patients (96%) and high dose intravenous methotrexate (HD MTX) was given to 1 patient. CNS relapse occurred in 6 patients, of which 5 had a low-risk CNS-IPI score. One of the five patients in the low-risk group and the one patient in the high-risk group that had CNS relapse received prophylaxis. No significant difference in overall relapse rates were observed based on whether prophylaxis was given, X 2 (1, N = 127) = 0.30, p = .59. Kaplan-Meier analysis showed no difference in OS after stratification of patients by CNS-IPI score into the high-risk ( p = .50) and low-risk ( p = .24) groups. HD MTX was not administered frequently enough to determine its efficacy. Neither cell of origin (X 2 (1, N = 95) = 2.95, p = .086) nor double hit status (X 2 (1, N = 127) = 1.512, p = .22) had any significant effect on OS. Conclusions: We did not observe any clear benefit for administering IT MTX to prevent DLBCL relapse in the CNS. Most of the CNS relapse events occurred in the low-risk group, even though 8 patients in the high-risk group did not receive any CNS prophylaxis. This study did not have sufficient power to make a definitive conclusion. As CNS relapse is a rare event, a much larger sample size is required to determine the true efficacy of CNS prophylaxis. Non-GCB cell origin and positive double hit status are not included in the CNS-IPI score but their potential association with risk of DLBCL relapse in the CNS is understudied. Future studies should build upon these findings.

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.

Efficacy and safety of first-line combination therapy versus monotherapy for vitreoretinal lymphoma: a systematic review and meta-analysis

BackgroundVitreoretinal lymphoma (VRL) is usually treated with a combination of intraocular methotrexate (ioMTX), high-dose intravenous methotrexate (HD-MTX), or local radiotherapy (RT) as the first options. The effectiveness and safety of monotherapy like bruton’s tyrosine kinase inhibitors (BTKi) for PVRL remain uncertain.MethodsA systematic review and meta-analysis of clinical trial data and conference abstracts in VRL patients treated with first-line combination therapy or monotherapy were conducted through a search of PubMed, Embase, and Scopus databases until December 2022. A total of 24 studies comprising 517 patients were included, and survival data were extracted from 279 patients due to inconsistent units across studies.ResultsThe combined treatment group used ioMTX + chemotherapy (in 4 studies), RT + chemotherapy (in 2 studies), ioMTX/HD-MTX based regimen (in 2 studies), ioMTX + RT + chemotherapy (in 2 studies), ioMTX + lenalidomide/BTKi (in 2 studies) and combination of multiple therapies (in 7 studies). The monotherapy group was mainly treated with oral monotherapies such as BTKi. The combination therapy had a higher overall response rate (ORR) and complete response rate (CRR) than monotherapy (ORR: 96% vs. 72%, CRR: 92% vs. 63%). Combination therapy also resulted in a longer median progression-free survival (28.8 months vs. 13 months, p = 0.012). However, the combination therapy group had more severe side effects (grade 3/4 toxicity) than the monotherapy group (45% vs. 8%).ConclusionThe study showed combination therapy had better OR and CR rates, longer survival, and more toxicity than monotherapy. While BTK inhibitors were well-tolerated, long-term effectiveness needs confirmation from prospective studies. In addition, given the small number of studies of monotherapy for VRL, more studies are needed to validate its effects.Trial registrationCRD42023400305.

Model for Predicting Central Nervous System Relapse in Diffuse Large B-Cell Lymphoma and Discussion of Prophylaxis Measures

Relapse of the central nervous system (CNS) is a rare but fatal complication in diffuse large B-cell lymphoma (DLBCL). The purpose of this study is to learn how to identify high-risk patients and take effective preventive measures. We retrospectively analyzed 1,290 adult patients with DLBCL at Peking University Cancer Hospital and Shanxi Bethune Hospital between 2010 and 2020. There were 55 patients with CNS relapse who had a median follow-up of 5 years. The risk of CNS relapse was 1.58% in the low-risk group, 5.66% in the moderate-risk group, and 11.67% in the high-risk group based on CNS International Prognostic Index (CNS-IPI). We found that CNS-IPI and testicular involvement were risk factors for CNS relapse, with OR 1.913 (95% CI: 1.036∼3.531; P=0.038) vs OR 3.526 (95% CI: 1.335∼9.313; P=0.011), respectively. Intrathecal MTX and/or cytarabine prophylaxis was used in 166 patients (13.94%), intravenous high-dose methotrexate (HD-MTX) prophylaxis in 8 patients (0.67%), and intrathecal plus intravenous prophylaxis in 15 patients (1.26%). There was no significant difference in CNS relapse risk between IT, HD-MTX, and no prophylaxis recipients (12.7% vs 0% vs 23.6%, respectively, P= 0.170). The risk of CNS relapse was similar whether or not patients accepted prophylaxis (5-year risk 4.1% vs 2.2%, P=0.140). CNS relapse is associated with high risk CNS-IPI and testicular involvement. Therefore, it is necessary to pursue novel prophylactic strategies for CNS relapse.

CPC11 Immune checkpoint inhibitor-associated eosinophilic fasciitis: a case report

Abstract A 67-year-old man presented with a 3-month history of skin tightness associated with shooting, burning pains and numbness on both his upper and lower limbs. The patient had a background of metastatic bladder cancer, treated with six cycles of gemcitabine and cisplatin therapy from September 2019 to January 2020. Following this, he also had radical radiotherapy to the bladder, and in August 2020, he started pembrolizumab therapy. Pembrolizumab was paused in February 2022 due to the development of immunotherapy-related myositis. On examination, the patient had visibly shiny and thickened skin bilaterally involving the upper and lower limbs. Symptoms significantly limited the patient’s mobility and daily activities. A skin biopsy showed marked reduction in elastin fibres and mild fibromuscular thickening around the blood vessels, suggestive of scleroderma. Following a joint rheumatology and dermatology multidisciplinary meeting, a diagnosis of eosinophilic fasciitis (EF) secondary to the checkpoint inhibitor pembrolizumab was made. This was further supported by lower limb magnetic resonance imaging, which demonstrated evidence of bilateral oedema of the soleus muscle tendinous junction. Eosinophilic fasciitis is characterized by inflammatory infiltration, thickening and fibrosis involving the fascia. Unlike scleroderma, patients, such as in our case, with EF do not have sclerodactyly, Raynaud phenomenon, telangiectasias or nailfold capillary changes. Clinical manifestations of EF involve sudden onset, and pain and erythema (usually bilaterally) of the affected extremities. Patients have also been known to develop joint contractures, morphoea-like lesions and inflammatory polyarthritis. The reported triggers and causative agents of EF include trauma, autoimmune disorders and drugs. Only 13 cases have been reported secondary to pembrolizumab therapy, and the median time of symptom onset is 12 months following the commencement of checkpoint inhibitor treatment. According to the literature, there may be an underlying diagnosis of a solid tumour, haematological disorder or autoimmune disease. High-dose prednisolone is the primary treatment of choice, followed by methotrexate. However, some patients have shown spontaneous recovery. Our patient has now started a treatment course of high-dose intravenous methylprednisolone and methotrexate. While the therapeutic outcome is too early to report, he has already noticed improvements in skin tightening of the lower limbs.

Longitudinal associations between peripheral neuropathy and neurocognitive decline in long-term survivors of pediatric cancer treated without central nervous system (CNS) directed therapy.

10054 Background: Survivors of pediatric cancer treated without CNS-directed therapy are at risk of neurocognitive impairment and peripheral neuropathies. Using the St. Jude Lifetime Cohort, we investigated longitudinal associations with neuropathy to inform contributors to long-term cancer-related neurocognitive decline. Methods: Survivors of pediatric cancer (N=899 mean age 32 [SD 12], 24[10] years from diagnosis) treated without CNS-directed therapy completed neurocognitive testing and medical assessments at two timepoints (T1, T2 4.4[2.3] years apart). Peripheral sensory and motor neuropathy subscales combined with functional tasks were severity graded using a modified CTCAE (no neuropathy = none or grade 1 at T1 and T2; new onset = new grade 2 or 3 at T2; persistent = grade 2 or 3 at T1 & T2). Linear regression models estimated change in neurocognitive Z-score associated with neuropathy groups, adjusted for diagnosis age, time between visits, sex, race/ethnicity, high-dose intravenous methotrexate & baseline neurocognitive Z-score. Results: New onset sensory (n=33, 3.6%) and motor (n=35, 3.9%) neuropathy was associated with a 0.33 standard deviation (SD) decline in visual-motor processing speed (Table). New onset motor neuropathy was associated with a 0.50 SD decline in sustained attention as well as significant declines in verbal recall, working memory, and cognitive flexibility (p’s<0.05). Persistent sensory neuropathy (n=25, 2.8%) was associated with large declines in focused attention and cognitive flexibility (p’s<0.05). Persistent motor neuropathy (n=18, 2.0%) was associated with a 0.50 SD decline in sustained attention, verbal recall, and working memory (p’s<0.05). Conclusions: Peripheral neuropathies are associated with future neurocognitive decline in adult survivors of pediatric cancer. Research is needed to understand shared mechanisms (e.g. pain, inflammation) to inform targeted interventions to improve neuropathic symptoms and neurocognitive function. [Table: see text]

CNS RELAPSE OF DIFFUSE LARGE B‐CELL LYMPHOMA AND ROLE OF UPFRONT PROPHYLAXIS: A 10‐YEAR SINGLE CENTER EXPERIENCE

Introduction: Central nervous system (CNS) relapse of diffuse large B-cell lymphoma (DLBCL) is a rare event, occurring in about 5% of patients (pts) and correlating with a very dismal prognosis. Much debate has surrounded the use of strategies to avert CNS disease recurrence. Nowadays, CNS prophylaxis is mostly based on high-dose intravenous (iv) methotrexate (HD-MTX), but its effectiveness is controversial. Our study focuses on pts with CNS relapse of DLBCL in order to evaluate their clinical and biological features, the validity of known prognostic scores, the efficacy of CNS prophylaxis, prognosis and treatment at the time of relapse. Methods: All pts with DLBCL diagnosed between January 2010 and December 2021 at AOU Città della Salute e della Scienza di Torino and treated with curative intent were selected: 498 cases with at least 12 months of follow-up were identified. Pts with primary mediastinal lymphoma, primary testicular lymphoma or CNS disease at diagnosis were excluded. Results: The case series included 406 pts. Mean age was 67 years, 56/400 had ECOG PS ≥ 2 (14%), 231/400 elevated LDH levels (58%), 251/404 were stage IV (62%), 192/374 IPI score ≥ 3 (51%), 189/373 CNS-IPI 2–3 (51%), 91/373 CNS-IPI 4–6 (24%). 95/397 pts received CNS prophylaxis (24%): 59 by intrathecal (IT) route only (15%) (n 26 CNS-IPI 2-3; n 29 CNS-IPI 4-6), 25 by iv MTX only (6%) (n 17 HD-MTX ≥3 g/mq; n 6 CNS-IPI 2-3; n 16 CNS-IPI 4-6), and 11 by combined route (3%) (n 5 CNS-IPI 2-3, n 6 CNS-IPI 3–6). 12 pts experienced CNS relapse; 8/12 exclusively CNS and 4/12 along with systemic recurrence. The cumulative incidence at 3 years was 2.8%. In univariate analysis CNS relapse risk was significantly influenced by ECOG PS and elevated LDH levels, while the use of prophylaxis was not shown to impact the risk of CNS recurrence. However, none of the pts who received systemic MTX prophylaxis had subsequent CNS disease, while 2/59 pts who received exclusive IT prophylaxis had CNS relapse with an incidence superimposable to the whole cohort (3.3%). In multivariate analysis, only ECOG PS confirmed significant correlation with the risk of such disease recurrence (Figure 1). With a mean follow-up of 36 months, the 3-year overall survival for pts with SNC recurrence was 30%. Encore Abstract—previously submitted to EHA 2023 Keyword: aggressive B-cell non-Hodgkin lymphoma No conflicts of interests pertinent to the abstract.

Diffuse large B-cell lymphoma at risk of secondary CNS involvement: The inefficacy of intravenous high-dose methotrexate CNS prophylaxis and the importance of baseline cerebrospinal fluid analysis.

High-dose intravenous methotrexate (HD-MTX) CNS prophylaxis in high-risk diffuse large B cell lymphoma (DLBCL) remains controversial. We describe real-world CNS relapse incidence following baseline cerebrospinal fluid (CSF) analysis to exclude asymptomatic leptomeningeal involvement in newly diagnosed high-risk DLBCL patients with versus without single-route HD-MTX CNS prophylaxis. Consecutively diagnosed high-risk systemic DLBCL patients without leptomeningeal involvement by CSF analysis (noCNS) were identified retrospectively. Five-year CNS relapse incidence and survival outcomes were examined, as stratified by receipt of HD-MTX prophylaxis. Secondary analysis of survival outcomes in patients with synchronous leptomeningeal involvement (CNSinv) by CSF analysis at diagnosis were compared with the noCNS group. No significant difference in 5-year CNS relapse incidence was observed following HD-MTX prophylaxis versus no prophylaxis (total n = 445) despite similar CNS-IPI risk; 6.2% versus 5.6%, adjusted HR 1.08 (95% CI 0.41-2.85), p = .88; nor in 5-year progression free survival (PFS) or overall survival (OS) risk. Of CNSinv patients, 93.3% had ≥1 extranodal site. Increased CNS relapse/progression risk (5-year risk; HR 10.7 [95% CI 5.35-21.37], p < .0001) and inferior PFS and OS were observed in CNSinv versus all noCNS patients. The CNSinv group had superior OS compared with noCNS patients who later experienced CNS relapse (HR 0.55, p = .052). HD-MTX prophylaxis does not reduce CNS relapse risk in high-risk systemic DLBCL without leptomeningeal involvement by CSF analysis at diagnosis. Asymptomatic patients with synchronous leptomeningeal involvement on baseline CSF examination are at increased risk of further CNS disease events and inferior survival compared to patients without CSF involvement.

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.

Prognostic Factors of the Primary Central Nervous System Lymphoma: Clinical Experience from a Tertiary Care Center in the Middle East.

Aim  Primary central nervous system lymphoma (PCNSL) is a rare extra nodal non-Hodgkin's lymphoma. The optimal treatment for PCNSL is still unclear. In this study, we present our experience with management of PCNSL in a tertiary care center in Iran. Methods  In this retrospective study, 58 patients with tissue diagnosis of PCNSL were studied. All patients were treated with chemotherapy including intravenous high-dose methotrexate, rituximab and temozolomide and radiotherapy by the same oncologist. Statistical analysis was performed using SPSS. Results  The mean overall survival (OS) in this study was 37.4 ± 13.6 months and the mean progression free survival (PFS) was 35.1 ± 9.8 months. The mean time to progression was 15.2 ± 8.79 months among 8 patients who experienced progression in this series. Finding of a positive CSF cytology was not linked with disease progression, while HIV infection and multifocal involvement at initial presentation were strongly linked to a lower PFS. The single most important factor affecting the OS was the histopathologic type of the PCNSL; two of the three patients who died from their disease in this series had non-B cell PCNSL, whereas only one patient with DLBCL died because of brainstem involvement. Conclusion  The results of this study show a lower rate of HIV-infection in patients with PCNSL as compared to the series from the western countries. Non-B cell histopathology and HIV-infection were found to be associated with the dismal prognosis.

Methotrexate Drug Monitoring From Central Access: Can Blood Sample Collection From Central Venous Access Replace Peripheral Venipuncture in Adults?

Intravenous high-dose methotrexate (MTX ≥ 1 g/m 2 ) is frequently used in patients with cerebral lymphoma or other malignancies. In addition to its potent efficacy, it is known to have pronounced toxicity and life-threatening side effects. Regular-level monitoring at short and defined intervals is mandatory. This study aimed to evaluate the possibility of replacing peripheral blood sampling with blood samples from central venous catheters for therapeutic monitoring of MTX in adults. A total of 6 patients and 7 cycles of chemotherapy (6 females; 5 with cerebral non-Hodgkin lymphoma and 1 with osteosarcoma, median age 51 years; range 33-62 years) were included. An immunoassay was used for quantitative analysis of MTX levels. The measurement points were obtained in the time intervals of 24, 42, 48, and 72 hours, and afterward, every 24 hours until the level was below <0.1 µmol/L. After flushing with 10 mL of saline solution and discarding 10 mL of venous blood, blood was drawn from the central venous access through which MTX had previously been administered. Simultaneously, MTX levels were obtained from peripheral venipuncture. Methotrexate levels from central venous access and MTX levels from peripheral venipuncture showed a significant correlation (r = 0.998; P < 0.01; n = 35). During withdrawal from the central access group, 17 values showed a lower MTX level, 10 showed a higher level, and 8 showed no difference. However, the MTX level difference was not significant ( P = 0.997, linear mixed model). No increase in the dose of calcium folinate was necessary based on the collected MTX levels. In adults, MTX monitoring from central venous access is not inferior to monitoring from peripheral venipuncture. Repeated venipuncture to measure MTX levels can be replaced after establishing standardized instructions for proper sampling by a central venous catheter.

プロテオーム解析とゲノム薬理学を応用した薬剤性中枢神経障害の病態解明

Neurocognitive complications such as leukoencephalopathy after high-dose intravenous methotrexate therapy （HD‒MTX） are important for childhood cancer survivors, because these neurocognitive complications affect the quality of life of patients. We identified Protein A in cerebrospinal fluid （CSF） as an MTX-related neurotoxicity-associated protein by proteomics analysis. In a series of CSF samples obtained during MTX-containing chemotherapy of 17 pediatric patients with hematological malignancy, Protein A was elevated at onset and just before onset of neurocognitive complications associated with HD‒MTX or intrathecal MTX therapy in the patients. The concentration of MTX in CSF was higher in the 5 g/m2 HD‒MTX group than the 2 g/m2 HD‒MTX group. We will evaluate the significance of Protein A in CSF as a biomarker for leukoencephalopathy in a larger cohort. We will also study the association between Protein A and MTX in CSF and leukoencephalopathy by pharmacogenetic approach.

Is CD19-directed chimeric antigen receptor T cell therapy a smart strategy to combat central nervous system lymphoma?

Primary central nervous system lymphoma (PCNSL) is a rare form and aggressive type of diffuse large B-cell lymphoma (DLBCL) that occurs in both immunocompetent and immunocompromised adults. While adding rituximab to chemotherapeutic regimens resulted in dramatic improvement in both progression-free survival and overall survival in patients with non-central nervous system (CNS) DLBCL, the outcomes of PCNSL are generally poor due to the immune-privileged tumor microenvironment or suboptimal delivery of systemic agents into tumor tissues. Therefore, more effective therapy for PCNSL generally requires systemic therapy with sufficient CNS penetration, including high-dose intravenous methotrexate with rituximab or high-dose chemotherapy followed by autologous stem cell transplantation. However, overall survival is usually inferior in comparison to non-CNS lymphomas, and treatment options are limited for elderly patients or patients with relapsed/refractory disease. Chimeric antigen receptor T (CAR-T) cell therapy has emerged as a cutting-edge cancer therapy, which led to recent FDA approvals for patients with B-cell malignancies and multiple myeloma. Although CAR-T cell therapy in patients with PCNSL demonstrated promising results without significant toxicities in some small cohorts, most cases of PCNSL are excluded from the pivotal CAR-T cell trials due to the concerns of neurotoxicity after CAR-T cell infusion. In this review, we will provide an overview of PCNSL and highlight current approaches, resistance mechanisms, and future perspectives of CAR-T cell therapy in patients with PCNSL.

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.

648TiP Reduction of methotrexate (MTX) levels after glucarpidase in patients with diffuse large b cell lymphoma (DLBCL) at risk of central nervous system (CNS) involvement who receive cycles of HDMTX: An open-label, interventional, non-randomized, phase II, pilot, multicenter study

CNS relapse in patients with Diffuse Large B Cell Lymphoma (DLBCL) is usually an early complication and with poor prognosis. R-CHOP, the standard treatment for DLBCL plays a minimal role preventing leptomeningeal and/or brain parenchyma relapse. Risk factors have been previously identified for this complication and high dose intravenous methotrexate (HDMTX) has been suggested as an effective strategy to prevent CNS lymphoma relapse (GELTAMO guidelines Haematologica 2017 and British guidelines BJAEM 2020).

P1217: INTRATHECAL METHOTREXATE PROPHYLAXIS AND CENTRAL NERVOUS SYSTEM RELAPSE IN PATIENTS WITH DIFFUSE LARGE B-CELL LYMPHOMA TREATED WITH INTENSIFIED R-ACVBP STRATEGY

Background: Central nervous system (CNS) relapse of diffuse large B-cell lymphoma is relatively uncommon (2-5%) and remains catastrophic with a median survival of 2 to 5 months. Intrathecal (IT) or intravenous high-dose methotrexate (HD MTX) have limited if any prophylactic impact on CNS relapse. We recently demonstrated in a cohort of 2203 patients included in multicenter clinical trials conducted by LYSA and GLA/ DSHNHL, that only 4 (1.6%) CNS relapses were seen with the R-ACVBP strategy in pts with aaIPI 2, 3 (and intermediate/high CNS-IPI), while 15 (3.9%) relapses did occur after R-(Mega)CHO(E)P. Aims: To address the role of IT in this intensified strategy R-ACVBP, we took the advantage of real world data of patients treated in four centers, and compared CNS relapses occurring in patients treated with R-ACVBP strategy with or without IT. Methods: The LYSA R-ACVBP strategy include four cycles of R-ACVBP (75 mg/m2 doxorubicin, and 1200 mg/m2 cyclophosphamide; 2 mg/m2 vindesine and 10 mg bleomycin on days 1 and 5) with four IT, two cycles of high dose methotrexate (3g/m2), four cycles of R-etoposide (300 mg/m2) and ifosfamide (1500 mg/m2) and 2 cycles of cytarabine(100 mg/m2) given sub cutaneously for 4 days. 233 patients with previously untreated diffuse large B-cell lymphoma (DLBCL) aged 18 to 59 years old received this intensified strategy between 2010 and 2020. We excluded 30 patients who received ASCT in first line and 10 others who received less than four cycles of R-ACVBP. We assessed the risk for of relapse and CNS-relapse. We also assesed the impact of the 2 courses of subcutaneous aracytine on overall survival (OS) and progression free survival (PFS). Results: A total of 193 pts were included. Median age was 44.4 years (IQR, 30.8-53, range: 17-62). Distribution of CNS IPI was not significantly different comparing IT (n=132) vs non-IT (n=61) groups within aaIPI categories (Table 1). 92 patients did not receive the two courses of subcutaneous Aracytine (no AraC group) for consolidation and 101 patients received the two courses (AraC group). With a median follow-up at 57.2 months, the 3 year OS and 3 year PFS of the whole cohort was 93.6% and 86.2%, respectively, without significant difference between IT and non IT groups in terms of OS (3yr-OS, = 92.3% versus 95.1%, HR= 1.29 (95%CI, 0.41 to 4.04, p=0.67) and PFS (3yr-PFS, 84.4% versus 90.1%, HR= 1.26 (95%CI, 0.59 to 2.72, p=0.55). The 3y-cumulative incidence of CNS relapse for pts treated IT group was 3.2% (95%CI, 1.0 to 7.4), and 3.3% (95%CI, 0.6 to 10.2) in the non-IT group (p= 0.93). In pts with aaIPI 1, two patients experienced a CNS relapse, one in the IT group and one in the non-IT group. In pts with aaIPI 2,3 and intermediate/high CNS IPI, 4 patients experienced a CNS relapse, three out of four in the IT group. 92 patients did not receive the two courses of subcutaneous Aracytine (no AraC group) for consolidation and 101 patients received the two courses (AraC group). Receiving or not AraC did not have any impact on the CNS relapse with a risk of CNS relapse at 4.1% (95%CI, 1.3 to 9.5) for patients receiving AraC and 2.2% (95%CI, 0.4 to 6.9) for patients not receiving AraC (p= 0.48). Image:Summary/Conclusion: CNS relapse was rare in younger DLBCL treated with this intensified strategy. Only 6 CNS relapses were observed without difference between IT and non-IT groups. The results presented at the EHA will included the total cohort of more than 600 patients.

Toxicity associated with high-dose intravenous methotrexate for hematological malignancies

Intravenous high-dose methotrexate (HD-MTX) is a critical chemotherapeutic agent in hematological malignancies, however, data are lacking on how to predict and prevent toxicities such as kidney injury. We retrospectively analyzed 539 episodes of HD-MTX (≥1 g/m2) delivered to 144 patients for treatment of prophylaxis of CNS hematological malignancy across three Australian institutions and correlated risk factors with toxicity. Clinically relevant (CTCAE v4.03 grade 2–4) nephrotoxicity occurred on 36 (7%) occasions and was mostly grade 2. Multivariate analysis revealed that doses ≥6 g/m2 (HR 5.02, 95%CI 1.46–17.2, p = 0.01) and interacting/nephrotoxic drugs (HR: 7.15, 91%CI: 2.18–23.512, p = 0.001) were the only factors associated with nephrotoxicity. 48-hour methotrexate level, hypoalbuminemia and increasing age were associated with prolonged clearance but not nephrotoxicity. Mucositis, liver dysfunction and cytopenias were transient and mild in most cases. We have demonstrated that the most common risk factors for nephrotoxicity are modifiable which may assist clinical decision-making when administering this important drug.