High-dose Intravenous Methotrexate Research Articles

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.

Optimization of high-dose methotrexate prophylaxis for central nervous system relapse in diffuse large B-cell lymphoma: a multicenter analysis.

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

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

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

High-Dose Methotrexate Is Not Associated with Reduction in CNS Relapse in Patients with Aggressive B-Cell Lymphoma: An International Retrospective Study of 2300 High-Risk Patients

High-Dose Methotrexate Is Not Associated with Reduction in CNS Relapse in Patients with Aggressive B-Cell Lymphoma: An International Retrospective Study of 2300 High-Risk Patients

Retrospective Review of the Safety and Efficacy of High-Dose Methotrexate for Prevention of CNS Relapse in Diffuse Large B-Cell Lymphoma at Kaiser Permanente- Northern California (Jan 2015 - June 2019)

Retrospective review of the safety and efficacy of high-dose methotrexate for prevention of CNS relapse in diffuse large B-cell lymphoma at Kaiser Permanente- Northern California (Jan 2015 - June 2019)Background: Central nervous system (CNS) relapse occurs in 10-12% of high-risk diffuse large B-cell lymphoma (DLBCL) patients. Prophylactic intravenous high-dose methotrexate (HD-MTX) is recommended by international guidelines to reduce this risk despite limited evidence to support such practice. Recent retrospective studies have cast doubt on the clinical benefit of such treatment. There is limited data on safety and efficacy of such treatment in a community oncology setting.Methods: We conducted a retrospective analysis of adults ≥ 18 years diagnosed with DLBCL treated with systemic therapy and HD-MTX as CNS prophylaxis at Kaiser Permanente Northern California from 1/2015 - 6/2019. We abstracted patient demographics, clinical information, treatment, toxicity, and health care utilization from the electronic health record. Descriptive statistics were used to evaluate patients' outcomes.Results: Of 33 patients (median age: 61; range: 23 - 81; age ≥ 60: 57.5%), most had stage IV disease (78.7%) and an ECOG performance status of 0 or 1 (66.5%). Patients with CNS-IPI score of 2-3 (intermediate-risk) was 30.3%, while higher CNS-IPI scores of 4-6 (high-risk) was 51.5%. Other patient characteristics include double hit lymphoma (12.1%), kidney/adrenal gland involvement (33%), and/or epidural involvement (24.2%). Most common therapies were R-CHOP (51.5%) and R-EPOCH (27.2%). The median number of HD-MTX doses was 3 (range 1-4). The median cumulative dose was 7 gm/m2 (range 3-10.5). With regards to the treatment schedule, 63.6% received HD-MTX intercalated with systemic chemotherapy and 36.4% received HD-MTX after completion of preplanned treatment. Overall, renal toxicity was the most common adverse side effect. The rates of grade 1, 2 and 3 renal toxicity were 12.1%, 9% and 6%, respectively. Other notable side effects experienced were neutropenic fever requiring hospitalization (27.2%) and grade 3 transaminitis (6%). No patients experienced grade 3 mucositis. The median duration of hospital stay was 12 days (range 4-37) and 12.1% required suspension of future HD-MTX. With a median follow up of 31.3 months (range: 0.79 - 58.4) 69.6% are alive and 15.1% had CNS relapse despite prophylactic HD-MTX.Conclusions:In this community oncology setting, patients with DLBCL who were deemed high risk for CNS relapse and received HD-MTX for prophylaxis experienced similar CNS relapse rate compared to those who did not in previous studies. Our findings are in line with recent retrospective reviews, which further support the lack of benefit of such prophylactic treatment. This study underscores the need for further research to prevent CNS disease and improved patient selection criteria for prophylactic treatment among high risk DLBCL patients. DisclosuresNo relevant conflicts of interest to declare.

Long-term remission of AIDS-related primary central nervous system lymphoma in a patient under antiretroviral therapy: a case report and review of the literature

BackgroundAIDS-related primary central nervous system lymphoma (AR-PCNSL) is an AIDS-defining disease that usually occurs when the CD4 count is less than 50 cells/μl. The frequency of the disease has substantially decreased in the era of highly active antiretroviral therapy (HAART). Prognosis is poor with rapid progression leading to death within 2–3 months if left untreated.Case descriptionA 65 years old male presented to medical attention with gait disturbance, weight loss and slight left-sided hemiparesis. Human immunodeficiency virus infection was diagnosed with an initial CD4 count of 116 cells/µl and a viral load of 260,000 copies/ml. Magnetic resonance imaging of the brain revealed three brain lesions involving the right frontal lobe and the left parietal lobe, which on biopsy led to a diagnosis of AR-PCNSL. HAART was initiated with whole-brain radiotherapy (WBRT), and the patient declined systemic chemotherapy. Due to poor performance status, he was transferred to palliative care. Under HAART, he slowly recovered with normalization of CD4 count and undetectable viral load. Medical imaging showed complete remission (CR) of the brain lesions. At 3-year follow-up, the patient remains in CR, but presented mild neurocognitive dysfunction possibly secondary to WBRT.ConclusionNowadays, treatment paradigm parallels that of primary central nervous system lymphoma in the immunocompetent population based on systemic chemotherapy (primarily high-dose intravenous methotrexate and steroids) in association with HAART. The role of WBRT is questionable because of late neurotoxic effects.

Chemotherapy strategies for young children newly diagnosed with desmoplastic/extensive nodular medulloblastoma up to the era of molecular profiling – a comparative outcomes analysis of prospective multi-center European and North American trials.

Abstract Aims Survival has been poor in several multi-center/national trials since the 1980s, either delaying, avoiding or minimizing brain irradiation in young children with medulloblastoma. The introduction of German regimens supplementing “standard” chemotherapy with both intravenous high-dose (HD-MTX) and intraventricular (IVENT-MTX) methotrexate, and North American regimens incorporating marrow-ablative chemotherapy with autologous hematopoietic cell rescue (HDCx+AuHCR), have reported encouraging outcomes. We performed a comparative outcomes analysis of these differing strategies for young children with desmoplastic/extensive nodular medulloblastoma. Method Data from 12 trials reported between 2005 and 2020 for children <six-years-old with desmoplastic/extensive nodular medulloblastoma were reviewed; event-free (EFS) survival+/-standard errors were compared. Results The German HIT-SKK’92 and HIT-SKK’00 trials incorporating HD-MTX and IVENT-MTX reported 85+/-8% and 95+/-5% 5-10-year EFS respectively; a third trial (ACNS1221) incorporating HIT-SKK therapy but without IVENT-MTX reported only 49+/-10% EFS. Three trials (Head Start I and II combined and CCG-99703) employing induction chemotherapy without HD-MTX, followed by one or three HDCx+AuHCR cycles, reported 3-5-year EFS of 67+/-16% and 79+/-11%. Two trials employing HD-MTX-containing induction chemotherapy (Head Start III and ACNS0334), followed by one or three HDCx+AuHCR cycles, reported 3-5-year EFS of 89+/-6% and 100%, respectively. Finally, four trials utilizing neither IVENT-MTX nor HDCx+AuHCR (UK-CNS-9204, CCG-9921, COG-P9934 and SJYC07) reported 2-5 year EFS of 35+/-11%, 77+/-9%, 58+/-8% and 53+/-9% respectively. Conclusion A trend towards better EFS for young children with desmoplastic/extensive nodular medulloblastoma is observed in trials including eitherHD-MTX and IVENT-MTX or including HD-MTX-containing induction chemotherapy and HDCx+AuHCR. Trials excluding HD-MTX, IVENT-MTX and HDCx+AuHCR have poorer outcomes.

ABCL-241: Comparing Efficacy of Intrathecal Chemotherapy versus High-Dose Methotrexate for Central Nervous System Prophylaxis in High-Grade B-Cell Lymphomas

Context Outcomes of patients with high-grade B-cell lymphomas have improved with chemoimmunotherapy. However, some patients are at an increased risk of developing secondary central nervous system (CNS) relapse, associated with increased morbidity. Objective The objective of this study was to analyze the efficacy of intrathecal chemotherapy versus high-dose methotrexate for the prevention of secondary CNS relapse in high-grade B-cell lymphoma patients. Design This was a single-institution, retrospective cohort study. A report was created via electronic health records to identify patients that received CNS prophylaxis with a confirmed diagnosis of high-grade B-cell lymphoma from January 2017 to September 2020. Setting This study took place at a general community hospital. Patients or Other Participants Inclusion criteria included age > 18 years, histologically confirmed high-grade B-cell lymphoma, either R-CHOP or DA-R-EPOCH as the primary chemoimmunotherapy regimen, and no CNS involvement at the time of diagnosis. Interventions Arm A included 11 patients that received intrathecal chemotherapy, and arm B included 11 patients that received intravenous high-dose methotrexate for prophylaxis. Main Outcome Measures The primary outcome of this retrospective study was to assess rates of CNS relapse, with a median follow-up of 1 year since diagnosis. Secondary outcomes included progression-free survival (PFS), overall survival (OS), toxicity, cost of care, and delays in therapy between both arms. Results Development of secondary CNS relapse occurred in 2 (18.2%) of the patients in arm A and 2 (18.2%) in arm B, which was not statistically significant by Chi-square analysis with Yates correction (p=.58042). PFS was consistent between both arms at 72.7%. One-year OS for each arm was 90.9% vs 72.7%, (p=.0887). Toxicity developed in 36% of high-dose methotrexate patients. Two patients needed a dose reduction of high-dose methotrexate, and two had delays in further cycles of primary chemoimmunotherapy regimen. High-dose methotrexate was associated with a significantly higher cost on average per cycle. Conclusions There was no statistically significant difference in the development of secondary CNS relapse between intrathecal chemotherapy and high-dose methotrexate. Further prospective, randomized studies are needed to assess if CNS prophylaxis improves outcomes and which method of prophylaxis is more efficacious.

CNS relapse in DLBCL patients below 60 years treated with R-ACVBP, R-CHOEP, or R-CHOP: A joint analysis of LYSA and GLA/DSHNHL.

7543 Background: Central nervous system (CNS) relapse occurs in 2-6% of DLBCL patients (pts) increasing to 10% or more in high-risk groups. Intrathecal (IT) or intravenous high-dose methotrexate (HD MTX) have limited if any prophylactic impact on CNS relapse. To address the role of systemic first-line therapy in pts tolerating intensified strategies (R-ACVBP, R-(Mega)CHOEP, R-CHO(E)P), we compared CNS relapses occurring in a large cohort of pts ≤60 years. Methods: We conducted a retrospective analysis including previously untreated pts with DLBCL by central review, age 18-60 years, from multicenter clinical trials conducted by LYSA and GLA/DSHNHL (Table). We assessed the risk of CNS relapse in matched cohorts based on the aaIPI. Results: A total of 2203 pts were included. Median age was 47 years (18-60). 455 pts were treated with R-ACVBP, 444 with R-(Mega)CHOEP, 1304 with R-CHOP. Distribution of CNS IPI was not significantly different comparing R-ACVBP to R-CHO(E)P groups within aaIPI categories (Table). PFS and OS were comparable according to treatment within aaIPI groups, also adjusted for prognostic factors. No CNS events occured during observation time of 3 years in pts with aaIPI 0. In pts with aaIPI 1, no CNS event occured in the R-ACVPB arm, the 3y-cumulative incidence of CNS relapse for pts treated with R-CHO(E)P group was 1.0% (95%CI 0.3-1.7). In pts with aaIPI 2,3 and intermediate/high CNS IPI, four (1.6%) treated with R-ACVBP experienced relapse in the CNS compared to 15 (3.9%) pts treated with R-(Mega)CHO(E)P (3y-cumulative incidence 1.6% (95%CI 0-3.2) vs. 4.0% (95%CI 2.0-6.0). Conclusions: CNS relapse was extremely rare in younger DLBCL pts with aaIPI 0 or 1; prophylactic measures are not warranted. In pts with aaIPI 2,3 (and intermediate/high CNS-IPI), only 4 (1.6%) CNS relapses were seen with the R-ACVBP while 15 (3.9%) relapses did occur after R-(Mega)CHO(E)P. This analysis underlines the important role of the systemic therapy in controling CNS relapse.[Table: see text]

Effectiveness of intravenous high-dose methotrexate for prevention of relapse in patients with DLBCL.

e19562 Background: Central nervous system (CNS) relapse develops in 2-10% of patients with diffuse large B cell lymphoma (DLBCL) and has an adverse prognosis. Tools like IPI and CNS-IPI scores identify patients at high risk of systemic or CNS relapse based on the presence of established risk factors ( Schmitz et al. JCO 2016). International guidelines propose prophylactic intravenous high-dose methotrexate (HD-MTX) for patients at high risk of CNS relapse; however, limited data is backing this approach. Methods: We conducted a retrospective review of newly diagnosed DLBCL patients aged 18-75 years treated with curative intent at large academic medical centers in Riyadh, Saudi Arabia, between 2015-2018. Patients who were planned for CNS HD-MTX after cycles 2, 4, and 6 of R-CHOP and received at least one HD-MTX cycle were included. Results: We identified 35 DLBCL patients who received at least one R-CHOP cycle with one cycle of HD-MTX. The median IPI and CNS-IPI score were 3, (range = 0-4) and 3, (range = 0-5), respectively. The median number of R-CHOP cycles received was 6 (range 3-6) and HD-MTX 3 (range 1-6). The overall response rate was 91%, with 3 (9%) primary refractory patients per interim evaluation on cycle 3 of R-CHOP. Achieving complete remission after six cycles of RCHOP was noted in 80%, with four additional patients showed residual disease at the end of treatment evaluation. The entire cohort's overall survival was not reached, and five years estimated survival is 75%. With a median follow-up duration of 37.3 months, none of the patients relapsed after achieving CR at the end of treatment evaluation. The risk of systemic or CNS relapse in our cohort was 0%. In restricting the analysis to CNS-IPI of ≥ 4, a total of 13 patients with a median follow-up of 42 months were included; four patients did not achieve CR by the end of treatment, while nine patients continue to be in CR without any evidence of relapsed disease. Conclusions: High-dose methotrexate with high-intensity chemoimmunotherapy (R-CHOP) seems to be associated with an improvement in the expected rate of CNS relapse. Our data set is small, and a more extensive study evaluating HD-MTX's effectiveness in high-risk DLBCL is warranted.[Table: see text]

Intravenous high‐dose methotrexate based systemic therapy in the treatment of isolated primary vitreoretinal lymphoma: An LOC network study

The treatment of primary vitreoretinal lymphoma (PVRL) remains controversial regarding the use of local, systemic, or combined treatments. The aim of this study was to analyze the efficacy and toxicity of intravenous high-dose methotrexate (IV HD-MTX) based systemic therapy in a uniformly treated population of PVRL patients. From a nationwide French database, we retrospectively selected 59 patients (median age: 70 years, median Karnofsky Performance Status: 90%) with isolated PVRL at diagnosis who received first-line treatment with HD-MTX between 2011 and 2018. 8/59 patients also received a local treatment. No deaths or premature discontinuations of MTX due to toxicity were reported. A complete response was obtained in 40/57 patients after chemotherapy. Before treatment, IL-10 was elevated in the aqueous humor (AH) or in the vitreous in 89% of patients. After treatment, AH IL-10 was undetectable in 87% of patients with a CR/uCR/PR and detectable in 92% of patients with PD/SD. After a median follow-up of 61 months, 42/59 (71%) patients had relapsed, including 29 isolated ocular relapses as the first relapse and a total of 22 brain relapses. The median overall survival, progression-free survival, ocular-free survival and brain-free survival were 75, 18, 29 and 73 months, respectively. IV HD-MTX based systemic therapy as a first-line treatment for isolated PVRL is feasible, with acceptable toxicity, even in an elderly population. This strategy seems efficient to prevent brain relapse with prolonged overall survival. However, the ocular relapse rate remains high. New approaches are needed to improve local control of this disease, and ocular assessment could be completed by monitoring AH IL-10.

Ineffectiveness of high-dose methotrexate for prevention of CNS relapse in diffuse large B-cell lymphoma.

Central nervous system (CNS) relapse affects 5% of diffuse large B-cell lymphoma (DLBCL) patients and portends a poor prognosis. Prophylactic intravenous high-dose methotrexate (HD-MTX) is frequently employed to reduce this risk, but there is limited evidence supporting this practice. We conducted a multicenter retrospective study to determine the CNS relapse risk with HD-MTX in DLBCL patients aged 18-70 years treated in Alberta, Canada between 2012 and 2019. Provincial guidelines recommended HD-MTX for patients at high-risk of CNS relapse based upon CNS-IPI score, double-hit lymphoma, or testicular involvement. Among 906 patients with median follow-up 35.3 months (range 0.29-105.7), CNS relapse occurred in 1.9% with CNS-IPI 0-1, 4.9% with CNS-IPI 2-3, and 12.2% with CNS-IPI 4-6 (p < .001). HD-MTX was administered to 115/326 (35.3%) high-risk patients, of whom 96 (83.5%) had CNS-IPI score 4-6, 45 (39.1%) had double-hit lymphoma, and four (3.5%) had testicular lymphoma. The median number of HD-MTX doses was two (range 1-3). Central nervous system relapse risk was similar with versus without HD-MTX (11.2% vs. 12.2%, p = .82) and comparable to previous reports of high-risk patients who did not receive CNS prophylaxis (10-12%). In multivariate and propensity score analyses, HD-MTX demonstrated no association with CNS relapse, progression-free survival, or overall survival. This study did not demonstrate a benefit of prophylactic HD-MTX in this high-risk patient population. Further study is required to determine the optimal strategy to prevent CNS relapse in DLBCL.

An intrathecal limited postoperative chemotherapy regimen for the treatment of young children with nodular/desmoplastic medulloblastoma and medulloblastoma with extensive nodularity

Therapy for medulloblastoma in patients < 4years old omits radiotherapy due to anticipated neurocognitive deficits. The German Pediatric Brain Tumor Study Group described a chemotherapy regimen (HIT-SKK' 92 and HIT-SKK 2000) without radiation which yielded a 5-year progression-free survival (PFS) rate of 85% in children with nodular/desmoplastic medulloblastoma (NDMB) and medulloblastoma with extensive nodularity (MBEN). We modified the HIT-SKK regimen to reduce the total number of intrathecal methotrexate (IT MTX) doses from 12 to 2 doses/cycle and obviate Ommaya reservoir implantation through the use of lumbar administration. We report the outcomes of five patients treated with our approach. IT MTX was eliminated altogether on weeks when high-dose intravenous methotrexate was administered. On weeks when no systemic methotrexate was administered, a single dose of lumbar-administered IT MTX was substituted in place of multiple intra-Ommaya doses. Cumulative dosing of MTX was 16-24mg/cycle (age-based) compared to 24mg/cycle in the HIT-SKK regimen. Following chemotherapy, patients were monitored with interval imaging, observation for acute and late effects, and survival. Four children remained in remission 3, 5, 9, and 10years post-treatment respectively, without observed learning difficulties. One child had recurrent tumor and metastasis 6months post-treatment. She failed the attempted salvage regimen and continued to deteriorate, dying of disease at 3years old. Review of existing literature supported our modifications well. While this report is limited by the small number of children treated, we believe there is encouraging evidence that our approach warrants further evaluation in a larger population of young children with NDMB and MBEN.

ETMR-07. ETANTR: A RARE TUMOR IN A RESOURCE-LIMITED SETTING

INTRODUCTIONEmbryonal tumor with abundant neuropil and true rosettes (ETANTR) is a rare aggressive brain tumor with low survival rates. There are about 80 cases reported in literature since 2000 when it was first described. There is no standard treatment scheme for ETANTR yet. CASE REPORT: A 2 years old boy presented with a month-long of headache and inability to hold his head. CT scan and MRI revealed a large mass in the right frontal lobe with midline shift. Subtotal tumor resection was done. Histological and immunohistochemical analyses was consistent with ETANTR in one laboratory and PNET in another. The second opinion suggested by the Center of Pediatric Oncology, Hematology and Immunology in Moscow the diagnosis ETANTR was confirmed. Taking into account certain similarities with medulloblastoma was decided to provide treatment according to HIT-2014 protocol. Control MRI done after 2 cycles of Block SKK Carboplatin/Etoposide found tumor progression and for that reason patient underwent second surgical resection. Considering the age of the child radiation therapy was not expedient and the decision was to continue treatment with HIT 2014 intensified regimen, which includes Cisplatin, Vincristine, Etoposide, Cyclophosphamide and intravenous High dose Methotrexate with intrathecal Methotrexate. Aiming to evaluate the effectiveness of treatment we are planning to perform MRI after this 2nd cycle of intensified regimen.DISCUSSIONThere are difficulties in diagnosis of rare types of cancers in Armenia. Since there is no approved treatment for ETANTR, there is a need for ongoing research to improve its prognosis.

MBCL-19. CHEMOTHERAPY STRATEGIES FOR YOUNG CHILDREN NEWLY DIAGNOSED WITH DESMOPLASTIC/EXTENSIVE NODULAR MEDULLOBLASTOMA UP TO THE ERA OF MOLECULAR PROFILING – A COMPARATIVE OUTCOMES ANALYSIS OF PROSPECTIVE MULTI-CENTER EUROPEAN AND NORTH AMERICAN TRIALS

BACKGROUND/OBJECTIVESurvival has been poor in several multi-center/national trials since the 1980s, either delaying, avoiding or minimizing brain irradiation in young children with medulloblastoma. The introduction of German regimens incorporating both intravenous high-dose (HD-MTX) and intraventricular (IVENT-MTX) methotrexate, and North American regimens utilizing marrow-ablative chemotherapy with autologous hematopoietic cell rescue (HDCx+AuHCR), have reported encouraging outcomes. We performed a comparative outcomes analysis of these strategies for young children with desmoplastic/extensive nodular medulloblastoma (D/ENMB).DESIGN/METHODSData from 12 trials reported between 2005 and 2019 for children <six-years-old with D/ENMB were reviewed; event-free (EFS) with standard errors were compared.RESULTSThe German HIT-SKK’92 and HIT-SKK’00 trials incorporating HD-MTX and IVENT-MTX reported 85+/-8% and 95+/-5% 5-10-year EFS respectively; a third trial (ACNS1221) incorporating HIT-SKK therapy but without IVENT-MTX reported 49+/-10% EFS. Three trials (Head Start I/II combined and CCG-99703) employing induction chemotherapy without HD-MTX, followed by 1/3 HDCx+AuHCR cycles, reported 3-5-year EFS of 67+/-16% and 79+/-11%. Two trials employing HD-MTX-containing induction chemotherapy (Head Start III and ACNS0334), followed by 1/3 HDCx+AuHCR cycles, reported 3-5-year EFS of 89+/-6% and 100%, respectively. Finally, four trials utilizing neither IVENT-MTX nor HDCx+AuHCR (UK-CNS-9204, CCG-9921, COG-P9934 and SJYC07) reported 2-5-year EFS of 35+/-11%, 77+/-9%, 58+/-8% and 53+/-9%.CONCLUSIONSA trend towards better EFS for young children with D/ENMB is observed in trials including either HD-MTX as well as IVENT-MTX or including HD-MTX-containing induction chemotherapy and HDCx+AuHCR. Trials excluding HD-MTX, IVENT-MTX and HDCx+AuHCR have poorer outcomes.

MBCL-37. CHEMOTHERAPY STRATEGIES FOR YOUNG CHILDREN NEWLY DIAGNOSED WITH CLASSIC (CLMB) OR ANAPLASTIC/LARGE CELL (A/LCMB) MEDULLOBLASTOMA UP TO THE ERA OF MOLECULAR PROFILING – A COMPARATIVE OUTCOMES ANALYSIS

BACKGROUND/OBJECTIVEThe introduction of German regimens, supplementing “standard” chemotherapy with both intravenous high-dose (HD-MTX) and intraventricular (IVENT-MTX) methotrexate, and North American regimens incorporating marrow-ablative chemotherapy with autologous hematopoietic cell rescue (HDCx+AuHCR), report encouraging outcomes for young children with medulloblastoma. We performed a comparative outcomes analysis of treatment strategies for young children with ClMB or A/LCMB. DESIGN/METHODSData from 12 prospective multi-center trials published between 2005 and 2019 for children <six-years-old with ClMB or A/LCMB were reviewed; survivals were compared.RESULTSCOG-9921, UKCCSG-CNS9204, COG-P9934 and SJYCO7 employing standard chemotherapy with either no or risk-based irradiation, reported 3-5-year event-free survival (EFS) of 17+/-5%, 33+/-28% (ClMB), 14+/-7% and 13.8+/-9% (ClMB) respectively, with reported EFS of 0% for A/LCMB in UKCCSG-CNS9204 and SJYCO7. HIT-SKK’87, HIT-SKK’92 and HIT-SKK’00 incorporating HD-MTX and IVENT-MTX reported 2-10-year EFS of 30–34+/-10–11% for ClMB and 33+/-27% (HIT-SSK’00) for A/LCMB. Head Start HS-I-II combined, CCG-99703 and HS-III employing induction chemotherapy, with or without HD-MTX, followed by single or tandem HDCx+AuHCR reported 3-5-year EFS of 42+/-14%, 50+/-11% and 27+/-6% for ClMB, with EFS for A/LCMB of 38+/-13% (HS-III). Finally, 5-year overall survivals for ACNS0334, without or with induction HD-MTX, are 39% and 69% respectively for ClMB and A/LCMB combined.CONCLUSIONSA trend towards better outcomes for young children with ClMB and A/LCMB is observed in trials including either HD-MTX and IVENT-MTX or including HD-MTX-containing induction chemotherapy and HDCx+AuHCR. Trials excluding HD-MTX, IVENT-MTX and HDCx+AuHCR have poorer outcomes.

Management and Outcomes of Testicular Lymphoma in the Rituximab Era at an Australian Tertiary Centre

INTRODUCTION Testicular lymphoma accounts for &amp;lt;5% of all testicular neoplasms and 1-2% of non-Hodgkin's lymphoma (NHL). Historically, outcomes for testicular lymphoma have generally been inferior to systemic diffuse large B cell lymphoma (DLBCL) with a higher incidence of central nervous system (CNS) relapse. Although intrathecal methotrexate is currently considered standard of care for testicular lymphoma, there has been significant debate about its efficacy in preventing CNS relapse. Due to the rarity of testicular lymphoma, prospective data in this field is lacking. Our study aims to examine treatment practices and outcomes for all newly diagnosed patients with testicular lymphoma in a large tertiary centre in Australia since the introduction of rituximab. METHODS We conducted a retrospective review of all patients diagnosed with primary testicular lymphoma (PTL) between 2003 and 2019 at the Princess Alexandra Hospital, Brisbane, Queensland, Australia (Human Research Ethics Approval: LNR/2019/QMS/56644). RESULTS During this period, 18 patients were diagnosed with PTL; all patients had DLBCL histology. The median follow-up period for living patients was 6.5 years (range 1.3-13.4 years). The median age was 61.3 years (interquartile range: 58.3 - 71.1 years). All patients were HIV negative. The majority of patients had an Eastern Cooperative Oncology Group (ECOG) score of zero (n = 13; 72.2%) with no B symptoms (n = 14; 77.7%) and a normal LDH (n = 11; 61.1%). 50% of patients had Stage IV disease (Table 1). 17 patients (94.4%) underwent an orchidectomy (unilateral: 16, bilateral: 1) at diagnosis. Following on, as first-line systemic therapy, 14 patients (77.7%) received R-CHOP chemotherapy. Other regimens used were CHOP (n=1), modified HyperCVAD (n=1), R-HyperCVAD (n=1) and R-CVP (n=1). 17 patients (94.4%) received CNS prophylaxis with intrathecal chemotherapy; one patient declined intrathecal therapy and was given high dose intravenous methotrexate instead. 15 (83.3%) patients received loco-regional radiation therapy. Outcomes to first-line treatment were: 13 patients (72.2%) achieved complete remission (CR); one patient (5.5%) achieved partial remission (PR) (Deauville score 4 on interim PET assessment, prompting escalation to salvage therapy); three patients (16.6%) had progressive disease (and were subsequently managed with salvage chemotherapy) and one patient elected for palliation after a single cycle of R-CVP. Among the four patients who received salvage therapy, two patients (50%) achieved CR and two patients had progressive disease and were palliated. Among the 15 patients who achieved CR (n=13 R-CHOP; n=2 salvage chemotherapy), two patients relapsed, and both had CNS involvement (n=1 CNS only relapse; n=1 CNS and systemic relapse). Despite intrathecal prophylaxis, the CNS relapse rate was 12% (n=2/17). Of note, the patient who did not receive intrathecal chemotherapy remained in CR at the date of last follow-up. In total, there were seven deaths. The causes of death were: lymphoma (n=4), treatment-related mortality (n=2) and other (n=1; due to aspiration pneumonia after stroke). The 2-year and 5-year progression free survival (PFS) rates were 77.8% and 52.4%, respectively (Figure 1A). The 2-year and 5-year overall survival (OS) rates were 83.3% and 56.8%, respectively (Figure 1B). CONCLUSION With the practice of R-CHOP, intrathecal prophylaxis for CNS disease and loco-regional radiation therapy, our outcomes are comparable to the literature (5y OS ~50%). Despite intrathecal prophylaxis, our CNS relapse rate was 12%. Better strategies are required to improve the control of systemic disease and reduce the incidence of CNS relapse in patients with testicular lymphoma. Disclosures Mollee: Janssen:Membership on an entity's Board of Directors or advisory committees, Research Funding;BMS/Celgene:Membership on an entity's Board of Directors or advisory committees;Amgen:Membership on an entity's Board of Directors or advisory committees;Takeda:Membership on an entity's Board of Directors or advisory committees;Pfizer:Membership on an entity's Board of Directors or advisory committees;Caelum:Membership on an entity's Board of Directors or advisory committees.

Lack of Effectiveness of Intravenous High-Dose Methotrexate for Prevention of CNS Relapse in Patients with High-Risk DLBCL: A Retrospective Analysis from Alberta, Canada

Introduction: Central nervous system (CNS) relapse occurs in 2-10% of patients with diffuse large B cell lymphoma (DLBCL) and carries a poor prognosis. The CNS-IPI score identifies patients at high-risk (10-12%) of CNS relapse based on the presence of 4-6 risk factors: age &amp;gt;60 years, ECOG performance status &amp;gt;1, elevated LDH, stage III to IV, &amp;gt;1 extranodal site, and renal or adrenal involvement. International guidelines recommend prophylactic intravenous high-dose methotrexate (HD-MTX) for patients at high-risk of CNS relapse. However, there is limited evidence supporting this practice, and prophylactic HD-MTX requires hospital admission and increases the risk of treatment-related toxicity. Therefore, we conducted a real-world study to determine the effectiveness of HD-MTX for prevention of CNS relapse in high-risk DLBCL. Methods: We performed retrospective chart reviews of patients aged 18-70 years with DLBCL treated with curative intent at two academic medical centers in Alberta, Canada between 2012-2019. Since 2015, the Alberta Provincial Lymphoma Clinical Practice Guideline (APLCPG) has recommended CNS prophylaxis with HD-MTX 3.5g/m2 IV after cycles 2, 4, and 6 of R-CHOP for patients with the following high-risk criteria: CNS-IPI 4-6, double hit lymphoma, or testicular involvement. Between 2012-2015, HD-MTX was recommended for patients with elevated LDH, ECOG &amp;gt;1, and &amp;gt;1 extranodal site. In addition, eligible patients at risk of poor outcomes (e.g. double hit lymphoma or IPI score 4-5) could be offered higher intensity chemoimmunotherapy (e.g. da-EPOCH-R or R-CODOXM/R-IVAC) or R-CHOP followed by consolidative autotransplant. The log-rank test was applied to determine risk of CNS relapse and the Cox proportional-hazards model was used to determine factors associated with CNS relapse, progression-free survival (PFS), and overall survival (OS). Analyses were performed using SPSS version 25 and GraphPad Prism 8 statistical software. Results: We included 906 patients with a median follow-up time of 35.3 months (range 0.29-105.7). Risk of CNS relapse was 1.9% (95% C.I. 0.0-30.7%) for patients with CNS-IPI 0-1, 4.9% (95% C.I. 0.5-18.0%) for CNS-IPI 2-3, and 12.2% (95% C.I. 4.0-25.2%) for CNS-IPI 4-6 (p&amp;lt;0.0001). Risk factors for CNS relapse included APLCPG high-risk criteria (HR 4.69, 95% C.I. 2.51-8.76), CNS-IPI score 4-6 (HR 4.26, 95% C.I. 2.22-8.16), and testicular involvement (HR 3.45, 95% C.I. 0.43-27.34). Among the 326 patients meeting APLCPG high-risk criteria, median CNS-IPI was 4 (range 0-6), 67 (20.6%) had double hit lymphoma, and 17 (5.2%) had testicular involvement. Risk of CNS relapse was significantly increased for patients meeting APLCPG high-risk criteria (11.8% vs 3.0%, p&amp;lt;0.0001). Prophylactic HD-MTX was administered to 115 (35.3%) high-risk patients; median number of doses given was 2 (range 1-3). The risk of CNS relapse was 11.2% (95% C.I. 2.1-28.9%) for patients who received HD-MTX versus 12.2% (95% C.I. 2.8-28.8%) for those who did not (p=0.82). Patients who underwent higher intensity chemoimmunotherapy (n=35) or consolidative autotransplant (n=68) tended to have a lower risk of CNS relapse than patients treated with conventional R-CHOP (6.0% vs. 14.6%, p=0.09). In multivariate analyses, HD-MTX and higher intensity chemoimmunotherapy demonstrated no significant association with CNS relapse, PFS, or OS; however, consolidative autotransplant was associated with a tendency toward lower risk of CNS relapse (HR 0.30, 95% C.I. 0.09-1.01) and a significantly improved PFS (HR 0.41, 95% C.I. 0.24-0.71) and OS (HR 0.56, 95% C.I. 0.32-0.98). Conclusion: The APLCPG high-risk criteria of CNS-IPI 4-6, double hit lymphoma, or testicular involvement identify patients with DLBCL at significantly increased risk of CNS relapse. The risk of CNS relapse was similar for all high-risk patients (11.8%) and those who received prophylactic HD-MTX (11.2%) in our study relative to previously published data for patients who did not receive CNS prophylaxis (10-12%). Based on this analysis, we could not demonstrate a benefit to the current practice of prophylactic HD-MTX. However, the lower rate of CNS relapse and improved PFS and OS in patients who received consolidative autotransplant in our study suggests that optimizing frontline therapy to achieve better systemic disease control may be a more effective strategy to reduce the risk of CNS relapse than prophylactic HD-MTX alone. Disclosures Stewart: Teva: Honoraria; Sandoz: Honoraria; Novartis: Honoraria; AstraZeneca: Honoraria; Amgen: Honoraria; Roche: Honoraria; Janssen: Honoraria; Abbvie: Honoraria; Gilead: Honoraria; Celgene: Honoraria.

Intrathecal (IT) Chemotherapy for Central Nervous System (CNS) Prophylaxis in Diffuse Large B-Cell Lymphoma (DLBCL): A Single Centre Retrospective Observational Study

Introduction: CNS relapse of DLBCL is associated with poor prognosis. Estimated incidence varies between 1.9 and 8.4%1. The CNS-International prognostic index (IPI)2 help risk stratify and estimate the 2-year risk of CNS relapse in DLBCL patients treated with R-CHOP chemotherapy. CNS prophylaxis is indicated in patients with a high risk of CNS relapse (a score of ≥4 equated to a 10.2% risk). High-risk DLBCL patients outside the CNS-IPI system include double/triple-hit (MYC/BCL-2/BCL-6 translocations) lymphoma, HIV lymphoma, testicular lymphoma, primary cutaneous lymphoma-leg type, stage IE breast lymphoma3. IT methotrexate or cytarabine administered during the course of systemic chemotherapy has been the most widely employed method of CNS prophylaxis but there is paucity of data validating its efficacy. Aim: The primary aim of the study was to evaluate the CNS relapse rates in DLBCL patients who received CNS prophylaxis. Patients and Methods: This was a single-centre retrospective observational study conducted in a district general hospital. Data was extracted from the regional (Dorset Cancer Network) DLBCL database and laboratory reports for CSF analysis at the time of the first intrathecal chemotherapy. Medical records of patients with DLBCL who received CNS prophylaxis were evaluated for the following patient-related and disease-related demographics: age at diagnosis, gender, stage, systemic treatment, CNS prophylaxis, treatment response, remission duration, systemic relapse rates, CNS relapse rates and survival. CNS-IPI scores were retrospectively calculated and additional indications evaluated for patients who received CNS prophylaxis. Results: Between 2013 and 2018, 178 patients were diagnosed with DLBCL. All patients were treated with RCHOP chemo-immunotherapy. CNS prophylaxis was administered in 47 (26%) patients. Median age was 69 years (range 20-86 years) and 62% were males. All 47 patients (100%) received IT methotrexate as CNS prophylaxis, with 43 (91%) receiving all of the planned 4 doses of IT methotrexate 12.5 mg each. A CNS-IPI score of ³4 was present in 31 (66%) patients, and a score of 2-3 in 9 (19%) patients. Additional risk factors identified included testicular lymphoma in 3 patients, breast lymphoma in 2 patients and oropharyngeal lymphoma in 2 patients. Ten (21%) patients received their treatment at the outset with courses 1-4 of R-CHOP. Of the 47 patients who received CNS prophylaxis, 5 (10%) relapsed; all had isolated CNS lymphoma at relapse. Median time to CNS relapse was 25 months (range 12-36 months) from initial diagnosis of DLBCL. Median survival after CNS relapse was 5 months (range 2-9 months). Of the remaining 141 patients, 2 patients relapsed with isolated CNS lymphoma. Conclusion: Although the overall incidence was low (4%), CNS relapse was observed in 10% of high-risk patients all of whom received CNS prophylaxis with IT methotrexate. The efficacy of CNS prophylaxis with IT chemotherapy remains unproven. There is no randomised study to show that IT prophylaxis alone is effective. Current British guidelines recommend high-dose intravenous methotrexate over IT methotrexate if patient's physiological fitness and renal function are acceptable4. The median age in our cohort was 69 years which makes it challenging to deliver dose-intensive systemic therapy concurrently with intravenous high-dose methotrexate. The role of CNS prophylaxis in high-risk patients including its efficacy and safety in older patients need further evaluation in prospective randomised studies. References Eyre T et al.Efficacy of central nervous system prophylaxis with stand-alone intrathecal chemotherapy in diffuse large B-cell lymphoma patients treated with anthracycline-based chemotherapy in the rituximab era: a systematic review. Hematologica. 2019;105(7):1914-1924.Norbert Schmitz et al.CNS International prognostic Index: A risk model for CNS relapse in patients with diffuse large B-cell lymphoma treated with R-CHOPJ Clin Oncol 2016; 34:3150-3156.Andrew D Zelenetz et al.National Comprehensive Cancer Network (NCCN) Guidelines: B-Cell Lymphomas.Version 2.2020.Pamela McKay et al.The prevention of central nervous system relapse in diffuse large B-cell lymphoma: a British Society for Haematology good practice paper. Onlinelibrary.wiley.com. 2020. Available from: https://onlinelibrary.wiley.com/doi/epdf/10.1111/bjh.16866 Disclosures Hall: Janssen:Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: sponsored for educational meetings;Karyopharm:Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: sponsored for educational meetings;Takeda:Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: sponsored for educational meetings;Celgene:Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: sponsored for educational meetings.Killick:Celgene:Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending educational meetings;Jazz Pharmaceuticals:Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending educational meetings;Novartis:Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending educational meetings;Gilead:Honoraria, Other: Support for attending education meetings.McCarthy:Janssen:Honoraria;Abbvie:Membership on an entity's Board of Directors or advisory committees.Walewska:AbbVie:Other: sponsored for educational meetings, Speakers Bureau;Janssen:Other: sponsored for educational meetings, Speakers Bureau;Gilead:Speakers Bureau;Astra Zeneca:Membership on an entity's Board of Directors or advisory committees.Chacko:Astellas:Honoraria;Daiichi-Sankyo:Honoraria;Novartis:Honoraria, Other: Travel Grants;Gilead:Other: Travel grants;Jazz Pharmaceuticals:Other: Travel grants;Celgene:Other: Travel grants.

Patterns and Risk of CNS Recurrence after R-EPOCH Treatment for Double/Triple Hit Lymphoma

Patterns and Risk of CNS Recurrence after R-EPOCH Treatment for Double/Triple Hit Lymphoma