Cycles Of High-dose Methotrexate Research Articles

Efficacy and safety of first-line high-dose cytarabine in patients with primary CNS lymphoma ineligible for high-dose methotrexate: a case series

Abstract Introduction Despite recent significant advances, the treatment of elderly patients with primary central nervous system lymphoma (PCNSL) is still challenging due to comorbidities, poor baseline performance status (PS), and drug toxicities. There are proposals to use high-dose cytarabine (HD-araC) in these patients. Results Our retrospective study aimed to assess the efficacy and toxicity of HD-araC as an upfront treatment for patients with PCNSL who are ineligible for high-dose methotrexate (HD-MTX). Methods We identified 12 consecutive patients with newly diagnosed PCNSL (out of a total of 68) who received first-line treatment with HD-araC, with or without rituximab (R). Most of them had poor PS and relevant comorbidities. Six patients received this treatment upfront, while the other six received it after discontinuing HD-MTX-(based) therapy. Treatment with HD-araC resulted in poor outcome, limited response, and severe hematological and infectious complications. Patients who had previously received at least one cycle of HD-MTX appeared to have slightly better outcomes, highlighting the importance of HD-MTX in the treatment of PCNSL. Conclusion Our case series showed limited efficacy and substantial toxicity of (R)-HD-araC in patients with PCNSL ineligible for HD-MTX. This treatment should be omitted in elderly/frail patients to avoid further compromising their quality of life.

Development of a novel nomogram for predicting delayed methotrexate excretion following high-dose methotrexate in adult patients with hematologic malignancies.

High-dose methotrexate (HDMTX) is integral in treating hematologic malignancies but carries risks of severe toxicities due to prolonged MTX exposure. However, knowledge of delayed MTX excretion is primarily derived from pediatric and adolescent cohorts, with the reported predictors being presented as rough dichotomous values. This study aimed to identify risk factors for delayed MTX excretion exclusively in adult patients with hematologic malignancies and develop a more applicable predictive nomogram based on continuous clinical and laboratory variables. 517 HDMTX cycles in 194 patients were retrospectively analyzed. Delayed MTX excretion was defined as either MTX concentration ≥ 1.0 µmol/L at 48h or ≥ 0.1 µmol/L at 72h after HDMTX initiation. Multivariate logistic regression analysis was used to construct the nomogram internally validated with the bootstrap method. Delayed MTX excretion was observed in 24.0% of cycles. Six significant predictors were identified: relapsed/refractory disease (Odds ratio [OR] 2.03), fewer HDMTX cycles (OR 0.771), treatment intent (OR 2.13), lower albumin (OR 0.563) and creatinine clearance levels (OR 0.993), and increased γ-glutamyl transpeptidase levels (OR 1.004, all P < 0.05). These were incorporated into a web-based nomogram as continuous variables with good prediction accuracy (area under the curve, 0.73) and without significant overfitting. Delayed MTX excretion increased risks of developing acute kidney injury, even solely at the 72h timepoint (OR 2.57, P = 0.025), without providing any benefit of clinical outcomes. This study comprehensively characterized MTX elimination failure following HDMTX in adult patients and could pave the way for individualized risk prediction.

Impact of Prophylactic Trimethoprim-Sulfamethoxazole on Clearance of High-Dose Methotrexate in Adult Patients.

High-dose methotrexate (HDMTX) is an antineoplastic dosing strategy used to treat various cancers including primary central nervous system lymphoma. Trimethoprim-sulfamethoxazole (TMP/SMX) is commonly used for antibiotic prophylaxis against Pneumocystis pneumonia infections in this patient population. Significant drug-drug interactions between TMP/SMX and methotrexate (MTX) leading to adverse outcomes have been documented, primarily in adult patients taking MTX for rheumatologic conditions. This study is a single-center, retrospective, cohort study comparing outcomes in patients where TMP/SMX was held during HDMTX and patients who received concurrent prophylactic TMP/SMX during treatment. The primary end point was mean MTX level at 24, 48, and 72 hours. Secondary end points included rate of nonhematologic toxicity, rate of hematologic toxicity, median days to MTX clearance, and frequency of glucarpidase utilization. In total, 248 cycles of HDMTX were analyzed from 221 individual patients. One hundred ninety-one cycles were administered without prophylactic TMP/SMX, and 57 were administered with TMP/SMX. The median MTX level at 24, 48, and 72 hours in those without versus with prophylactic TMP/SMX was 4.30 versus 4.30, 0.29 versus 0.30, and 0.14 versus 0.15, respectively. Similarly, rates of hematologic and nonhematologic toxicities did not differ significantly between groups with the exception of neutropenia; however, there was no corresponding increased rate of neutropenic fever. Only one patient received glucarpidase and had not received TMP/SMX. Prophylactic TMP/SMX had minimal interaction with HDMTX and does not lead to increased time to clearance or clinically relevant toxicities. Prophylactic TMP/SMX can be safely administered with HDMTX in adult patients.

A Retrospective Study on Outcomes of Secondary CNS Lymphoma: Pattern of Relapse, Prognostic Factors, and Role of Consolidation Therapy

Introduction Secondary CNS lymphoma (SCNSL) remains a treatment challenge in patients (pts) with aggressive lymphoma. Outcome of SCNSL is poor. Pts are often treated with high dose Methotrexate (HD-MTX) based regimens followed by autologous stem cell transplant (auto SCT). However, the benefit of consolidation therapy is not well established. There is limited data on the treatments and outcomes of SCNSL. In this single institution study, we aim to analyze the role of consolidation therapy and potential prognostic factors of outcomes in SCNSL. Method All pts with a diagnosis SCNSL who presented to Moffitt Cancer Center, FL, USA between 2017 and 2022 were included. The hazard ratios (HRs) were evaluated in the univariate and multivariate analysis using the cox proportional hazard mode. All analyses were done using SAS 9.4. Results A total of 60 pts with SCNSL were identified. The median age was 63 years (range 26-83 years); 27 (45%) were female; 13 (21.7%) had Eastern cooperative oncology group performance status (ECOG) ≥2. Entire cohort was divided in 3 subgroups: pts with concurrent CNS involvement at the time of initial diagnosis with systemic lymphoma (Sys-CNS) [22 (36.7%)]; pts with isolated CNS relapse (R-SCNS) [30 (50.0%)]; and pts with simultaneous CNS and systemic relapse (R-Sys-CNS) [8 (13.3%)]. 31 (51.7%) pts had brain parenchymal involvement, 24 (40%) had leptomeningeal disease, 4 (6.7%) had both leptomeningeal and parenchymal involvement, and 1 (1.7%) had ocular disease. 58(96.6%) pts had diffuse large B cell lymphoma (DLBCL) histology; 9 (15%) had DLBCL with MYC and BCL2 rearrangement; 10 (16.7%) had DLBCL MYC and BCL2 expression. For induction therapy of SCNSL, 53 (88.3%) of pts received HD MTX-based chemotherapy; 2 (3.3%) received Bruton tyrosine kinase inhibitor (BTKi), and 5 (8.3%) with meningeal disease alone received IT chemotherapy and/or rituximab(R). Sys-CNS pts also received R-CHOP or DA-R-EPOCH while R-Sys-CNS pts received R-Polatuzumab or Polatuzumab-R-Bendamustine. 20 (33.3%) received consolidation either by WBRT [13 (21.7%)] or auto SCT [4 (6.7%)]; 3 (5.0%) proceeded with chimeric antigen receptor (CAR-T) therapy. The overall response rate (ORR) for entire cohort was 55.2% (34.5% complete response CR and 20.7% partial response PR). However, improved ORR and CR were observed with 14(73.68%) and 9 (47.37%) respectively in pts who received consolidation. ORR and CR for pts with Sys-CNS, R-SCNS, R-Sys-CNS were 13 (61.9%)/ 10 (47.6%), 14 (48.3%)/9 (31%) and 2 (25%)/ 2 (25%), respectively. After a median follow up of 33.6 months, median OS was 8.3 months with a 2-year survival probability of 33.8% (95% CI: 21.7-46.3%); the PFS was 6.5 months with a 2-year PFS probability of 32.9% (95% CI: 20.7-45.6%). Consolidation therapy with either auto SCT or WBRT had significant survival benefit. In this subgroup, median OS is not reached (NR) and the 2-year OS probability was 59.6% (95% CI: 32.9-78.7%); median PFS was 25.6 months and 2-year PFS probability was 53.3% (95% CI: 27.5-73.6%). After the first-line therapy for CNS disease, 21(35%) pts experienced relapsed. However, relapse rate in consolidation group [7 (36.8%)] was almost similar to those who did not receive consolidation [14 (34.2%)] (table 1). 39 (65%) pts died; 29 (48.33%) from disease progression, 3 (5%) from therapy related side effect and 7(11.7%) from other causes. In the univariate analysis, ECOG PS ≥2 [HR 3.60 (CI:1.80-7.20), p&amp;lt;0.001], lack of consolidation therapy [2.45 (CI:1.12-5.36), p=0.024], &amp;lt;3 cycles of HD-MTX containing regimen [2.85 (CI: 1.47-5.520), p=0.002] and double hit lymphoma [2.27 (CI: 1.02-5.06), p=0.045] were associated with worse OS. In the multivariate analysis, R-SYS-CNS, &amp;lt;3 cycles of HD-MTX, ECOG ≥2 and lack of consolidation remained significant. Lack of consolidation and receiving &amp;lt;3 cycles of HD-MTX were associated with inferior PFS in both univariate and multivariate analysis (figure 1). Conclusion Outcomes of aggressive B cell lymphoma with CNS involvement remain poor. The median OS was 8.3 months in our cohort. After adjusting for confounding factors, receiving &amp;gt;3 cycles of HD-MTX based regimen and consolidation with either WBRT or auto SCT were associated with improved outcomes. Pts with simultaneous CNS and systemic relapse had worse OS. Prospective studies are needed to evaluate optimal treatment for SCNSL.

CNSC-37. THE ASSOCIATION BETWEEN THE NUMBER OF HIGH-DOSE METHOTREXATE CYCLES AND LONGER REMISSION PERIODS IN PATIENTS WITH PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA: A RETROSPECTIVE REVIEW

Abstract Representing 3-4% of newly diagnosed central nervous system tumors, primary central nervous system lymphomas (PCNSL) are rare, extra-nodal non-Hodgkin lymphomas with an overall survival (OS) of 91.9 months. Though patients can achieve a complete response (CR) after first-line therapy, PCNSL typically recurs within two years. Standard treatment involves high-dose methotrexate (HD-MTX)-based polychemotherapy, but the ideal number of HD-MTX cycles that achieves and maintains a CR is unclear. To address this question, we conducted a retrospective review of PCNSL patients. The primary outcome was median OS. Secondary outcomes included the OS of recurrent PCNSL patients (rOS), number of HD-MTX cycles before the first recurrence or CR, and adverse events (AE). Survival analysis was performed using the Kaplan-Meier estimate. Forty-one patients (23 males; median age: 66) were identified. The median OS is 114 months (95% CI 44.9, NA). Twenty-nine patients achieved CR after first-line therapy with a median of five cycles. Eleven patients experienced PCNSL recurrence (rPCNSL), with five patients previously achieving a CR. The median rOS before the first recurrence was 60.4 months (95% CI 6.3, NA). The median number of cycles of HD-MTX before recurrence was three cycles, and the cumulative total of HD-MTX was five cycles. Among the 24 patients without recurrence and with CR, the median OS was not reached, but the median number of HD-MTX cycles before CR was six cycles and cumulatively was six cycles. Complete results of AEs will be updated at the meeting, but they currently include grade III hypokalemia (45.8%), grade III anemia (45.8%), and grade III acute kidney injury (25.0%). Despite the limitations of a retrospective review, our findings suggest that a higher number of HD-MTX cycles is associated with prolonged duration of remission. Future studies are warranted to determine an ideal number of HD-MTX to maintain remission state in PCNSL patients.

High-Dose Methotrexate, Ibrutinib and Temozolomide (MIT) for the Treatment of Newly Diagnosed Primary Central Nervous System Lymphoma: A Multi-Center Prospective Phase II Study

Abstract Background: Primary central nervous system lymphoma (PCNSL) is a rare and aggressive subtype of B-cell lymphoma with poor survival. Genetic alterations often occur in the chronic active B-cell receptor signaling which mediate the response to BTK inhibition (BTKi) in PCNSL. However, the efficacy of traditional high-dose methotrexate-based regimen as a first-line treatment was suboptimal with a short effective remission time and low response rate. Therefore, we initiated this phase II trial to investigate the efficacy of novel induction combination of high-dose methotrexate (HD-MTX) plus ibrutinib and temozolomide (MIT), in the treatment of newly diagnosed PCNSL for the first time (ClinicalTrials.gov identifier: NCT04514393). Methods: Patients aged 18-75 years, newly diagnosed PCNSL and at least one measurable or evaluable lesion were enrolled. The MIT induction treatment included six cycles of HD-MTX (3.5 g/m 2, every three weeks), ibrutinib (560 mg/d, after HD-MTX clearance), and temozolomide (150 mg/m2 d1-d5, every three weeks). After the completion of the six cycles of MIT induction treatment, ASCT consolidation (only for patients &amp;lt; 65 years) or daily ibrutinib maintenance (560 mg/d) were administered up to two years, or until disease progression, intolerable toxicity, or death. Treatment response was evaluated by brain MRI and FDG-PET and/or cerebrospinal fluid (CSF) examination every two cycles of MIT treatment. The primary objective of this study was to evaluate the overall response rate (ORR) of MIT induction treatment. The safety profile of MIT was also investigated. At the same time, next generation sequencing (NGS) of baseline tissues and dynamic monitoring with CSF/ plasma ctDNA were performed by Nanjing Geneseeq Technology Inc. Results: Between July 2021 and October 2022, thirty-three patients were enrolled in this open-label, multi-center phase II prospective clinical study. The median age was 56 years (range: 27-75) and 17 of them were male. Eye involvement occurred in 5 patients (15%). Twenty-five patients (76%) had multiple cerebral lesions. The best ORR was 94% and complete response rate was 73%. The median follow-up was 17.5 months (range: 5.8-21.3 months) for survivors. Twenty-three patients underwent ibrutinib maintenance after 6 cycles of induction therapy. The swimmer plot of the 33 patients was shown in Figure 1. The 1-year progression-free survival was 66.4% (95%CI: 58.1-74.7%) and overall survival was 90.5% (95%CI: 85.2-95.8%) (Figure 2). Treatment-related toxicities were acceptable, with grade 3-4 neutropenia occurring in 9%, thrombocytopenia in 6%, subdural hematoma (SH) in 6%, and atrial fibrillation in 3%. The 2 patients with SH recovered following discontinuation of ibrutinib. No fungal infections and treatment-related deaths were observed. NGS of Tissue/CSF was tested in 30 patients, 19 (63%) of whom were classified as MCD subtype, 2 (7%) as BN2 subtype. The mutational profiles of baseline tissue and/or CSF samples revealed that PIM1 and MYD88 mutations were present in 75.9% and 65.5% of the entire cohort followed by BTG2 (55.2%) and CD79B (51.7%). Patients with dynamic CSF ctDNA monitoring during MIT treatment were analyzed (Figure 1). The consistence of ctDNA clearance in CSF/plasma samples and imaging complete remission was observed. Patients with clearance of ctDNA in the CSF after 2 cycles of MIT treatment achieved better PFS. Conclusions: The novel induction treatment of MIT achieved encouraging responses in newly diagnosed PCNSL patients with acceptable toxicities. The early clearance of ctDNA in CSF may be related to favorable survival. Disclosures No relevant conflicts of interest to declare.

Impact of microRNA polymorphisms on high-dose methotrexate-related hematological toxicities in pediatric acute lymphoblastic leukemia.

It is well known that transporter and enzyme genes could be regulated by microRNA (miRNA) at the post-transcriptional level, and single-nucleotide polymorphisms (SNPs) in miRNA, which are involved in the miRNA production and structure, may impact the miRNA expression level and then influence drug transport and metabolism. In this study, we aim to evaluate the association between miRNA polymorphisms and high-dose methotrexate (HD-MTX) hematological toxicities in Chinese pediatric patients with acute lymphoblastic leukemia (ALL). A total of 181 children with ALL were administered with 654 evaluable cycles of HD-MTX. Their hematological toxicities were evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events v5. The association between 15 candidate SNPs of miRNA and hematological toxicities (leukopenia, anemia, and thrombocytopenia) was analyzed using Fisher's exact test. Further multiple backward logistic regression analysis was used to explore the independent risk factors for grade 3/4 hematological toxicities. Rs2114358 G>A in pre-hsa-miR-1206 was related to HD-MTX-related grade 3/4 leukopenia after multiple logistic regression [GA + AA vs. GG: odds ratio (OR): 2.308, 95% CI: 1.219-4.372, P = 0.010], and rs56103835 T > C in pre-hsa-mir-323b was associated with HD-MTX-related grade 3/4 anemia (TT + TC vs. CC: OR: 0.360, 95% CI: 0.239-0.541, P = 0.000); none of the SNPs were significantly associated with grade 3/4 thrombocytopenia. Bioinformatics tools predicted that rs2114358 G>A and rs56103835 T>C would impact the secondary structure of pre-miR-1206 and pre-miR-323b, respectively, and then probably influence the expression level of mature miRNAs and their target genes. Rs2114358 G>A and rs56103835 T>C polymorphism may potentially influence HD-MTX-related hematological toxicities, which may serve as candidate clinical biomarkers to predict grade 3/4 hematological toxicities in pediatric patients with ALL.

Methotrexate concentrations and associated variability factors in high dose therapy of children with acute lymphoblastic leukemia and non-Hodgkin lymphoma

Monitoring and optimization procedures improved high dose methotrexate (HDMTX) treatment outcomes. However, there are still some concerns regarding unexplained concentration variability. The objective of this study was to evaluate drug concentrations and associated variability factors in pediatric patients with acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL) on HDMTX. Fifty patients (aged 1–18 years), receiving in total 184 HDMTX cycles of 3 or 5 g/m2/24 h infusion, were included in the study. Comparisons of MTX concentrations and concentrations to dose ratio between two dosing groups were conducted by Mann-Whitney U test. Regression analysis was performed with transformed data to assess relationship between MTX concentration to dose ratio and patient characteristics, biochemical analysis and therapy data. Statistically significant difference in concentrations between 3 and 5 g/m2 dosing groups was detected only at 24 h after the start of infusion (p < 0.001), but not at 48 and 72 h (p > 0.05). There was no difference between dose-normalized concentrations. Regression analysis showed that 73.9% of variability in dependent variable can be explained by included variables: time since dose, creatinine clearance (CrCl), hemoglobin and certain concomitant therapy. Our results highlight the importance of not only renal function and concomitant therapy, but also hemoglobin in reducing the variation in MTX concentrations. Therefore, monitoring of aforementioned biochemical parameters during HDMTX is important not only to assess toxicity, but also in predicting their impact on drug level.

Clinical Outcomes and Treatment Patterns of Primary Central Nervous System Lymphoma: Multicenter Retrospective Analysis

Objectives: Primary central nervous system lymphoma (PCNSL) is a rare malignant disease with poor prognosis. Its low incidence leads to challenges in decision-making for treatment. As a matter of fact, there is still no consensus on the appropriate treatment modalities. In this context, the objective of this study is to investigate and comparatively assess the efficacies of several treatment modalities in the treatment of PCNSL. Methods: Thirty-four patients diagnosed with PCNSL at 5 different hematology centers between 2007 and 2021 were included in the study. Patients’ data from all five centers were collected retrospectively. Since ibrutinib is not approved for this indication in Turkey, consent for off-label use of ibrutinib is obtained from each patient. Ethics committee approval was obtained on June 9, 2021 with decision number 2021/18-05. Results: The median age of the patients was 59 (min.: 22, max.: 78) years. The male-to-female ratio was 1.26/1. Nineteen (55.9%) patients had Eastern Cooperative Oncology Group (ECOG) performance score of ?2. Fifteen (44.1%) patients had normal lactate dehydrogenase (LDH) levels and only 14.7% of the patients had B symptoms at the time of diagnosis. Magnetic resonance imaging (MRI) revealed a single mass lesion in 14 (41.2%) patients. As an induction therapy, methotrexate-based regimen was administered in 29 (85.3%) patients. Only 14 of the 34 patients received 4 or more cycles of high-dose methotrexate (MTX). About 32.4% of the patients received radiation therapy (RT) during follow-up as a part of induction therapy. Five patients received only RT due to poor performance status. Ibrutinib was administered in 5 patients for refractory disease. It was determined that four or more cycles of MTX treatment increased progression-free survival (PFS) (p=0.031) and overall survival (OS) (p=0.012). Moreover, RT improved PFS (p=0.023). Considering that the complete response achieved by induction therapy influences long-term survival, achievement of the best response to the treatment regimens administered in combination with new agents may prolong survival (PFS: p=0.01, OS: p=0.023). Conclusion: The findings of this study indicate that the initial response to treatment is crucial. Additionally, it was found that high-dose MTX treatment should be administered for 4 cycles or more in order to achieve the best results. Furthermore, it was determined that ibrutinib monotherapy was well-tolerated in our patients with relapsed/refractory disease, with excellent clinical benefits. In conclusion, a combination therapy consisting of high-dose MTX, ibrutinib, and rituximab appears to be a promising initial treatment approach in appropriate patients. Keywords: PCNSL, methotrexate, radiotherapy, ibrutinib

Consolidation Improves Survival in Primary Central Nervous System Lymphoma without Preference for Type of High-Dose Methotrexate-Based Induction Treatment Regimen

Introduction Primary central nervous system lymphoma (PCNSL) is a rare non-Hodgkin lymphoma with a median overall survival (OS) of 3 years. The current treatment strategies of PCNSL are governed by high-dose methotrexate (HD-MTX)-based (immuno)chemotherapies, and in young and fit patients combined with high-dose cytarabine (HD-AraC). These (immuno)polychemotherapies are preferably consolidated with whole brain radiotherapy (WBRT) or autologous stem cell transplantation (autoSCT). The aim of this large, retrospective multicenter study was to evaluate the outcome of PCNSL patients treated with several HD-MTX-based (immuno)polychemotherapeutic induction regimens with and without consolidation. Methods A total of 250 consecutive, newly diagnosed PCNSL patients between 2008 and 2021 from 11 Dutch and Belgian hospitals were included. All patients were treated with ≥1 cycle of HD-MTX ≥3g/m2 per cycle, with an intended cumulative dose of ≥12g/m2. HD-AraC was defined as 2g/m2 per cycle with an intended cumulative dose of ≥8g/m2. Patients treated with three different standard first-line regimens with intended cumulative doses of ≥12g/m2 HD-MTX and ≥8g/m2 HD-AraC were allocated to the 'intense' treatment group (Figure 1). Patients receiving two other combination regimens of HD-MTX (intended ≥12g/m2)with procarbazine or teniposide and carmustine as standard first-line therapeutic strategy were assigned to the 'moderate' treatment group. WBRT with a cumulative dose of 40 Gy and autoSCT (from 2012 onward) were evaluated as sequential consolidation if received within 8 weeks after good response to (immuno)polychemotherapy. Primary end points were best objective response rate (ORR) at any time and 5-year OS. Results Of the 250 patients, 142 (57%) were male and the median age at diagnosis was 67 years (range 28-86). In total, 113 (45%) received 'intense' treatment and 137 (55%) 'moderate' treatment. Considering ORR, 122 patients achieved complete response (CR, 49%), 88 partial response (PR, 35%), 29 stable/progressive disease (SD/PD, 12%) and 11 unknown response (4%). During follow-up, 117 (47%) patients experienced progression or relapse and 119 (48%) patients died, of which 97 (82%) were lymphoma-related deaths. Median PFS and OS were 2.4 and 3.5 years, respectively. No significant OS difference was found between the 'intense' and 'moderate' treatment regimens (OS p=0.14) or between any of the HD-MTX-based (immuno)polychemotherapeutic treatment regimens (Figure 1, p=0.54). In total, 83 (33%) patients received subsequent consolidation therapy of whom 52 (63%) WBRT and 31 (37%) autoSCT. No OS differences between WBRT and autoSCT were observed (Figure 2, p=0.67). Patients receiving consolidation demonstrated a superior OS (p<0.0001) and a significantly better best ORR (p<0.01) compared to unconsolidated patients. All baseline characteristics were comparable between the consolidated and unconsolidated group, except for age (p<0.01) which was higher in the unconsolidated group. To correct for immortal time bias for the consolidation group, landmark (LM) analyses were performed. The significant effect of consolidation was confirmed at LM 5 months (OS p=0.03) and LM 9 months (OS p=0.03) whereas 80% and 98% of the cohort received consolidation, respectively. To evaluate possible confounders, multivariable analysis was performed and confirmed that older age (HR 1.03, CI 1.01-1.05), WHO performance status ≥2 (HR 1.84, CI 1.31-2.57) and elevated LDH (HR 1.78, CI 1.18-2.69) at diagnosis (all p<0.01) have an adverse effect on risk of mortality and consolidation significantly reduced the risk of mortality (HR 0.44, CI 0.30-0.64), in contrast to treatment intensity (HR 0.96, CI 0.67-1.37). Conclusion This multicenter study evaluated several first-line HD-MTX-based regimens in a large cohort of PCNSL patients. Sequential consolidation with WBRT or autoSCT was significantly associated with improved OS, regardless of type of HD-MTX-based induction regimens. Disregarding assessment of toxicity, these results together with other studies call for induction therapy with HD-MTX-based (immuno)polychemotherapy irrespective of type of regimen and sequential consolidation therapy with either WBRT or autoSCT, thereby shaping next treatment algorithms. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Assessing the Safety of Discharging Patients Receiving High-Dose Methotrexate with Levels Greater Than 0.1 Umol/L

Introduction: High-dose methotrexate (HD-MTX) remains a backbone therapy in a number of malignancies and is defined as a dose of greater than 500 mg/m2. HD-MTX requires supportive measures to minimize toxicity, particularly nephrotoxicity. MTX levels are followed to ensure adequate clearance of drug. Historically, patients were discharged with a MTX level of ≤0.05 umol/L. However, many single-center studies have shown that liberalizing the discharge level to <0.1 umol/L is safe and allows earlier hospital discharge. At NYU Langone Health (NYULH), many patients with stable renal function are discharged with a level of >0.1 umol/L, with supportive medications including oral leucovorin with or without sodium bicarbonate. The aim of our study is to confirm the safety of discharging patients with a MTX level of >0.1 umol/L. Methods/Results: This was a single center, retrospective, institutional-review board approved study of all adult patients who received HD-MTX in the inpatient setting, between January 1, 2017 and February 20, 2021. The primary endpoint was the incidence of renal injury post discharge from the HD-MTX admission. Outcomes were analyzed among three MTX level categories at discharge (>0.2 umol/L, 0.1-0.2 umol/L, <0.1 umol/L). If patients received more than one cycle of HD-MTX, each cycle was reported as an individual event. Baseline characteristics were reported based on the first infusion of each unique individual. Baseline renal insufficiency was defined as a creatinine clearance (CrCl) of less than 30 mL/min. Renal injury was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE, version 5.0). The first outpatient serum creatinine (SCr) documented in the patient chart post HD-MTX hospitalization was utilized to analyze renal injury. The study included 108 patients who received a total of 336 HD-MTX infusions. The primary indication for HD-MTX was central nervous system prophylaxis for diffuse large b-cell lymphoma or acute lymphoblastic leukemia. The most common HD-MTX doses were between 1,001-3,500 mg/m2 compared to 500-1,000mg/m2 and >3,500mg/m2 (p=0.0006). Four patients (4%) had baseline renal insufficiency. Of the 336 infusions, 49 (15%) infusions were categorized into MTX discharge level >0.2 umol/L, 145 (43%) into MTX 0.1-0.2 umol/L, and 142 (42%) into MTX <0.1 umol/L. Within the discharge category >0.2 umol/L, the median level was 0.28 umol/L (IQR, 0.22 - 0.37). The highest level was 1.04 umol/L at discharge. Patients were more likely to be discharged with oral leucovorin if they were discharged with a MTX level >0.1 umol/L (p<0.001). Similarly, patients were more frequently prescribed oral sodium bicarbonate if discharged with a MTX level >0.2 umol/L (p<0.001). There were 28 (8%) renal injury events, with no significant difference in renal injury occurring among the three MTX discharge level ranges. The renal injury events were primarily Grade 1. The median LOS in our study was statistically longer in the MTX <0.1 umol/L category (4 days, IQR 3-12) compared to the MTX 0.1-0.2 umol/L and >0.2 umol/L categories, 3 days (IQR 3-4) and 3.4 days, (IQR 3-4), respectively (p=0.023). There were 14 readmissions post HD-MTX hospitalization discharge. Two patients were admitted on two separate encounters after HD-MTX administration, leaving 12 unique patients. The primary reason for readmission was for myelosuppression, although all of these patients received other cytotoxic chemotherapy as part of the hyper-CVAD regimen. Two readmissions were after a MTX discharge level of >0.2 umol/L and 6 readmissions for both MTX discharge level of 0.1- 0.2 umol/L and <0.1 umol/L. Conclusion: Our study demonstrates that it is safe to discharge patients with a MTX level of >0.1 umol/L, with no difference in renal injury, and supporting shortened length of stay. Our data also suggest that it is safe to discharge a patient with a MTX level up to 0.4 umol/L, as our upper 75th quartile range was 0.37 umol/L, acknowledging supportive medications are prescribed. Limitations of this study include the retrospective nature of the study and heterogenous population. The length of stay data are confounded by other factors as well including multiday chemotherapy regimens, infections, and newly diagnosed malignancies. Our plan is to create an institutional protocol to outline the supportive care to support an early discharge of patients receiving HD-MTX. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Prospective Study of Methotrexate in Combination with Ibrutinib and Temozolomide (MIT) in Newly Diagnosed Primary CNS Lymphoma

Background: Primary central nervous system lymphoma (PCNSL) is a rare non-Hodgkin lymphoma ,High-dose methotrexate (HD-MTX) systemic chemotherapy is considered as the first-line standard therapy for PCNSL, but the ORR of HD-MTX-based chemotherapy was 60%~70%.The activation of the B-cell receptor pathway has been identified as a key mechanism of PCNSL and BTK inhibitor is a promising agent. Here we aimed to investigate the safety and efficacy of induction treatment, high-dose methotrexate in combination with ibrutinib and temozolomide (MIT) in newly diagnosed PCNSL. Methods: This open-label， single-arm, multi-center phase II prospective study(NCT04514393) was designed to enroll 33 patients , and 25 patients have response (approx 75%), the MIT treatment would be considered effective. Eligible patients were ≥18 and ≤75 years of age with adequate organ function, with at least one measurable lesion. The MIT induction treatment included six cycles of high-dose methotrexate (HD-MTX, 3.5 g/m2, every three weeks), ibrutinib (560 mg/d, after HD-MTX clearance), and temozolomide (150 mg/m2 d1-d5, every three weeks). After the completion of the six cycles of MIT induction treatment, ASCT consolidation (only for patients < 65 yr) and daily ibrutinib (560 mg/d) were administered up to two years, or until disease progression, intolerable toxicity, or death. Treatment response was evaluated by brain MRI and FDG-PET and/or cerebrospinal fluid (CSF) examination every two cycles of the induction MIT treatment. The primary endpoint was the overall response rate (ORR) of the 6 cycles of MIT induction treatment for PCNSL evaluated by investigator. The safety of the treatment were also investigated. Baseline and sequential CSF/plasma samples were collected and underwent targeted next-generation sequencing (NGS). Results: Between July 2021 and July 2022, thirty-one newly diagnosed PCNSL patients with no prior therapy were enrolled and 28 patients accepted at least 2 cycles of MIT treatment. The median age of the patients was 53 yr (range: 27-75) and15/28 (53.6%) were male. By data cutoff, 12/28 (42.9%) patients had completed six cycles of treatment, 9/28 had completed 4 cycles of treatment, and 7/28 had completed 2 cycles of treatment. The ORR was 92.9% (26/28), and CR rate was 67.9% (19/28). Among 12 patients had completed 6 cycles of treatment, 11/12 (91.7%) patients achieved CR, 1 patient achived PR. Among 9 patients had completed 4 cycles of treatment, 4 (44.4%) achived CR, 3/9 (33.3%) achived PR. Among 7 patients had completed 2 cycles of treatment, 4 (57.1%) patients achieved CR and 3 (42.8%) pateints achived PR. The mutation profiles of dynamic CFS and plasma ctDNA were collected and analyzed. The most commonly mutated genes in CSF were PIM1, MYD88, BTG2, CD79B, IRF4, and ETS1. The Cerebrospinal fluid protein (CSF-TP) and CSF cfDNA concentration (ng/ml), ctDNA MAF, and ctDNA concentration (hGe/ml), MAF,and hGe/ml were positively correlated. We compared gene profiles of patients in response and no response. KMT2D gene mutations were more commonly detected in patients with progression disease compared to patients responding to treatment (P=0.03). Interestingly, detectable baseline plasma ctDNA and post-treatment CSF ctDNA were significant associated with progression disease (P=0.03, P=0.004, respectively). This clinical trial is still on going. Conclusions: The MIT induction treatment could achieve higher responses compared with HD-MTX-based chemotherapy in newly diagnosed PCNSL patients and the adverse events are manageable.

High-Dose Chemotherapy and Autologous Stem Cell Transplant in Elderly and Fit Primary CNS Lymphoma Patients - a Multicenter Study By the Cooperative PCNSL Study Group (MARTA study)

Introduction: High-dose methotrexate (HD-MTX) based induction chemo-immunotherapy followed by high-dose chemotherapy and autologous stem cell transplantation (HCT-ASCT) has been shown to be feasible and effective in younger and in selected elderly PCNSL patients. We aimed to investigate this treatment approach in patients > 65 years with newly diagnosed PCNSL in a multicentre study. Methods: This open-label, multicentre, single arm phase II study was conducted at 15 German centres (DRKS 00011932). Main eligibility criteria included newly diagnosed PCNSL, immunocompetence, age > 65 years, Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤ 2, and adequate organ function. Induction treatment consisted of two 21-day cycles of HD-MTX 3.5 g/m² (day 1), cytarabine 2 g/m² twice daily (days 2, 3) and rituximab 375 mg/m² before and after each chemotherapy with stem cell harvest after the 1st cycle. Patients not suffering disease progression subsequently received consolidation treatment with HCT-ASCT with rituximab 375 mg/m² (day -8), busulfan 3.2 mg/kg (days -7, -6), thiotepa 5 mg/kg/d (days -5, -4) and reinfusion of stem cells (day 0). Primary endpoint was progression-free survival (PFS) at 1 year by intention-to-treat (ITT). Secondary endpoints included overall survival (OS), treatment response and toxicities. Results: Between Nov 2017 and Sept 2020, we registered 57 patients. Five patients were excluded because of systemic lymphoma manifestation, absence of measurable radiologic lesion(s), inadequate renal function, ECOG PS >2 and deterioration before the start of study treatment. Finally, 52 eligible patients were included in the ITT population. Mean age was 72 years (range 65-80 years), 27/52 (51.9%) patients initially presented with an ECOG PS > 1. All patients started induction chemo-immunotherapy, 45 of 52 (86.5%) patients completed induction treatment. Thirty-seven of 52 (71.2%) patients proceeded to HCT-ASCT. Most common serious adverse events were infections, renal failure and (cerebro)vascular events, which mainly occurred during induction treatment. Overall, 22 (42.3%) patients died, 12 of whom (23.1%) without evidence of disease progression or relapse. Three (5.8%) patients died because of treatment-related complications, all of them during induction treatment. An additional patient died within 30 days after HCT-ASCT due to fatal viral pneumonia, main other non treatment-related causes of deaths were late infections and (cerebro)vascular events. Forty-one of 52 (78.8%) patients responded to induction treatment; 23 (44.2%) patients achieved a (unconfirmed) complete response and 11 (21.2%) patients a partial response 30 days after HCT-ASCT. After an estimated median follow-up of 23 months, PFS at 12 and 24 months was 57.7% (95% CI 43.2-69.7%) and 54.8% (40-67.4%), respectively; median PFS was 41.1 months (95% CI 6.7 to not calculable). Overall survival at 12 and 24 months was 63.1% (95% CI 48.4-74.7%) and 60.5% (95% CI 45.5-72.5%), respectively; median OS was 41.1 months (95% CI 10.3 to not calculable). Of those 37 patients undergoing HCT-ASCT, 2-year PFS and OS rates were 71.7% (95% CI 53.4-83.8%) and 80.8% (95% CI 63.8-90.3%), respectively. Conclusions: Feasibility and efficacy of HCT-ASCT in selected elderly patients with newly diagnosed PCNSL are confirmed in a multicenter setting with survival rates comparable to those of younger cohorts. Nevertheless, non-relapse mortality remains a major challenge in this vulnerable patient population emphasizing that standardized assessment of eligibility for intensive treatment is of utmost importance. This will be addressed in the upcoming randomized phase III PRIMA-CNS trial (DRKS00022768). Final data analysis is currently ongoing and will be presented in detail at the meeting.

Patterns of Treatment Failure in PCNSL

<h3>Purpose/Objective(s)</h3> Primary CNS Lymphoma (PCNSL) is a rare and often fatal disease. Despite varied combinations of therapy with a backbone of high-dose methotrexate (HD-MTX), there remains no clear standard of care and treatment failure is a persistent challenge. This analysis evaluates factors that affect local disease control and patterns of failure. <h3>Materials/Methods</h3> Retrospective review of 95 consecutive patients with PCNSL pathologically confirmed from 2002 and 2021. The primary endpoints were Local Failure (LF) and pattern of first failure (distant only vs local). Univariate (UVA) and multivariate analyses (MVA) with backward selection at alpha of 0.2, Log-rank test and Cox proportional hazard models were used for time to event endpoints and associations with age, Karnofsky performance status (KPS; ≥70 vs <70), use of upfront WBRT, number of cycles of HD-MTX (≥6 vs 0-5), 1^st line chemo agents, type of surgery, and size of contrast-enhancing lesion(s) (≥14cc vs <14 cc). <h3>Results</h3> Most patients had KPS ≥70 (64.2%), were HIV negative (89.5%), and had no history of solid organ transplant (95.8%). Diagnosis was made by biopsy (73.7%) or resection (26.3%). 54.3% had <14 cc contrast-enhancing tumor volume (overall median 12.6 cc, range 0.5 - 67.8 cc). Of the 62 patients treated first line with at least 1 cycle of HD-MTX, 61.3% had HD-MTX + Rituximab (R). Of the 60 patients with evaluable CSF, 30.0% had positive cytology. IT chemotherapy (ITc) was administered to 12 patients (cytology positive for 5, negative for 4, and unknown for 3). WBRT for consolidation after chemotherapy used for 3 patients and as monotherapy for 9 patients with poor KPS. At 2-years, OS was 50%, PFS was 39%, and LF was 27%. For patients with progression (n=29), 7 had distant only progression while 5 had local and distant progression and 17 had local only progression. LF was numerically higher in patients with ≥14 cc tumors (2-yr LF 26% vs 42%, p=0.43). On MVA, hazard of LF was significantly associated with age (HR 1.08 per yr, 95% CI: 1.02-1.16, p=0.02), KPS (HR 0.10, 95% CI: 0.01-0.65, p=0.016), completion of at least 6 cycles HD-MTX (HR 0.10, 95% CI 0.03-0.34, p<0.01), and use of ITc (HR 0.03, 95% CI: 0.00-0.32, p<0.01). There were no significant associations with upfront WBRT (p=0.37), use of HD-MTX + R (p = 0.12), or type of surgery (p=0.94). On UVA, distant first failure trended to be significantly associated with age (p=0.06), ITc use (p=0.07), and size of lesion(s) (p=0.08). On MVA, distant only first failure was significantly associated with age (OR 0.91 per year, 95% CI: 0.83-0.99, p=0.04). <h3>Conclusion</h3> The majority of treatment failures were local only. LF of PCNSL was associated with not completing induction HD-MTX and not using ITc. There was no association with LF or type of first failure and use of WBRT or more aggressive surgery. Larger tumors trended to fail locally warranting further investigation as local disease can be devastating.

ABCL-421 Demographics, Pattern of Care, and Outcomes of Primary CNS Lymphoma-Experience from a Tertiary Care Cancer Center in India

Primary central nervous system (CNS) lymphoma (PCNSL) is a rare subtype of non-Hodgkin lymphoma with the worst outcomes amongst all extranodal lymphomas. This study analyzed the demographic patterns, risk stratification, treatment regimens used, and outcomes of patients treated at Tata Memorial Center Mumbai, India. This is a retrospective analysis of 142 patients with newly diagnosed primary CNS lymphoma from January 2013 to December 2019. Out of 142 patients, 43 (30.2%) were excluded, and 99 patients were included in the final analysis. Among these 99 patients, 72 (72.7%) were <60 years, 70 (70.7%) had Eastern cooperative oncology group (ECOG) performance status (PS) < 2. Diffuse large B-cell lymphoma (DLBCL) was the most common histology in 86.4% cases and only 1 patient was positive for HIV serology. Multiple intracranial lesions were found in 59.5% and surgical resection was performed in 28.4% of patients. International extranodal lymphoma study group (IELSG) score is available for 63 patients; 34 (54%) high-risk disease. As per Memorial Sloan Kettering Cancer Center (MSKCC) risk grouping, patients were almost equally distributed in all the risk groups. High dose methotrexate (HD-MTX) based regimens were administered to 92 (92.9%) patients, and 72.8% of these patients received rituximab. Of these 92 patients, 59 (64.1 %) patients could complete induction, and 52 patients received consolidation. Majority of patients received high dose cytarabine as consolidation (31 patients) followed by Whole Brain Radiotherapy (19 patients). Thus only 52 patients completed entire course of induction with consolidation therapy. Post completion of consolidation, 49 (94.2 %) patients had a complete response. With a median follow-up duration of 39.2 months, the median progression-free survival (PFS) and the median overall survival (OS) of the patients taken into the analysis (N=99) were 21 and 37 months respectively. On multivariate analysis, age < 60 yrs, ≥5 HD-MTX cycles received & the use of rituximab predicted better OS. Outcomes of patients with PCNSL treated with HD-MTX based therapy are comparable to reported literature however a large proportion of patients do not undergo required treatment despite the curable nature of disease.

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.

Impact of systemic therapy regimen on survival of PCNSL.

2070 Background: Primary CNS Lymphoma (PCNSL) is a rare and often fatal disease. Treatment includes multi-agent systemic therapy with a backbone of high-dose methotrexate (HD-MTX). Despite multiple drug and radiotherapy combinations for induction and consolidation treatment there remains no clear standard of care. The purpose of this analysis is to evaluate how varying treatment approaches impacted clinical outcomes at our institution. Methods: Data retrospectively collected for 95 consecutive patients with PCNSL pathologically confirmed from 2002 to 2021. Primary endpoint was OS with secondary endpoints of PFS and LC. Progression based on RANO criteria. Kaplan-Meier analyses, Log-rank test and Cox proportional hazard models used for time to event endpoints. MVA by backward selection applying an alpha of 0.2 for associations with 1st line chemo agents, number of cycles of HD-MTX (&gt;6 or 0-5), size of enhancing tumor at presentation, CSF cytology, type of surgery (biopsy, STR, or GTR), and use of WBRT. Results: Most patients had KPS &gt;70 (64.2%), were HIV negative (89.5%), and had no history of solid organ transplant (95.8%). Diagnosis was made by biopsy (73.7%) or resection (GTR 13.7%, STR 12.6%). 54.3% had &lt;14 cc contrast-enhancing tumor volume (median 12.6 cc, range 0.5 - 67.8 cc) and 48.6% had single enhancing lesion. Of the 62 patients treated first line with at least 1 cycle of HD-MTX, 61.3% were treated with HD-MTX + Rituximab (R) and 33.9% with HD-MTX + R + temozolomide (TMZ). With or after induction HD-MTX, 1-3 patients received one or a combination of cytarabine, thiotepa, procarbazine, vincristine, carmustine, or ASCT. Of the 60 patients with evaluable CSF, 30.0% had positive cytology. IT chemotherapy (ITc) was administered to 12 patients (5 with + cytology, 4 with - cytology, 3 with unknown cytology). WBRT for consolidation after chemotherapy used for 3 patients and as monotherapy for 9 patients. 2-year OS and PFS rate was 50.1% (95% CI 38.6%-60.5%) and 38.5% (95% CI 27.9%-49.0%). On MVA, &gt; 6 cycles of MTX was associated with superior OS, PFS, and LC. For patients receiving any chemotherapy, addition of R was associated with inferior OS while ITc was associated with improved OS, PFS, and LC (Table). There was no OS association on MVA with TMZ, GTR, consolidation WBRT, or size or number of initial lesions (p&gt;0.05). Conclusions: Completion of induction HD-MTX and use of ITc was associated with better outcomes in this population. Incorporation of R into 1st line therapy was associated with worse OS. Survival remained poor throughout the study period, underscoring importance of further innovation. [Table: see text]

Hypoalbuminemia and not undernutrition predicts high-dose methotrexate-induced nephrotoxicity in children with acute lymphoblastic leukemia in resource-constrained centers.

The standard practice to mitigate high-dose methotrexate (HD-MTX)-induced nephrotoxicity (HMN) in acute lymphoblastic leukemia (ALL) is to monitor levels until serum MTX falls below a predefined threshold. It is not feasible in most resource-constrained centers. Literature on the various factors affecting HMN in these centers is limited, retrospective, and heterogeneous. Though hypoalbuminemia has been postulated as a risk factor for HMN, the relationship of undernutrition with HMN has not been studied. This prospective observational study consecutively enrolled children<12 years old with ALL receiving HD-MTX. Children with preexisting renal disease and exposed to nephrotoxic drugs two weeks preceding HD-MTX infusion were excluded. HD-MTX was administered over 24 hours (BFM-2009 protocol) with 12 hours of prehydration. Solitary MTX levels at 36 hours (MTX36) were outsourced, and 6-8 doses of leucovorin were given six-hourly. Hydration was continued till last dose of leucovorin. Various factors affecting HMN (rise in creatinine to 1.5 times baseline) were recorded: age, sex, type of ALL, risk group of ALL, first dose of MTX, dose of MTX, undernourishment, serum protein, and albumin along with C-reactive protein and MTX36 levels. Forty-four children who received 150 HD-MTX cycles were analyzed. HMN was seen in 14% of cycles. On univariate analysis, undernourishment, MTX36 levels, hypoproteinemia, and hypoalbuminemia were significantly associated with HMN. On multivariate analysis, hypoalbuminemia and MTX36 levels significantly predicted the development of HMN with odds ratios of 4.71 and 1.45. Hypoalbuminemia and solitary serum MTX levels predict HMN in centers where serial MTX level monitoring is not feasible.

Is hypoalbuminemia a risk factor for high-dose methotrexate toxicity in children with acute lymphoblastic leukemia?

BackgroundRepeated high-dose methotrexate (HDMTX) is a critical component of contemporary childhood acute lymphoblastic leukemia (ALL) treatment regimens. Serum albumin is considered a carrier of methotrexate (MTX) in the blood. Hypoalbuminemia is not a rare finding in children with leukemia. This study aimed to investigate the relationship between pre-infusion serum albumin and possible HDMTX toxicities.MethodsThirty Egyptian children with ALL were consecutively enrolled in the study between May 2018 and July 2020. They were prospectively followed up while receiving HDMTX during the consolidation phase of the TOTAL study XV protocol. HDMTX was administered intravenously as a 24-h infusion every 2 weeks. Doses of 2.5 g/m2 were used for low-risk patients and 5 g/m2 for standard/high-risk patients. The Common Terminology Criteria for Adverse Events (V.4.03) was used to report the observed toxicities after HDMTX cycles. Plasma MTX levels were estimated at 24 h (MTX24) from the beginning of HDMTX infusion in the first consolidation cycle. Serum albumin level was determined before HDMTX administration, and pre-infusion hypoalbuminemia was defined when serum albumin was <3.5 g/dL.ResultsThe patients’ age ranged from 2.3 to 13.3 years at diagnosis, and most of them had B cell ALL (86.7%). Overall, 120 HDMTX cycles were analyzed, equally distributed between low and standard/high risk. Grade 3–4 anemia, grades 3–4 thrombocytopenia, febrile neutropenia, and oral mucositis were significantly more frequent in HDMTX cycles with pre-infusion hypoalbuminemia than those with normal pre-infusion albumin (p=0.003, p=0.007, p=0.006, and p=0.001, respectively). In addition, pre-infusion hypoalbuminemia was significantly associated with additional hospitalization due to HDMTX toxicity (p=0.031). Most HDMTX toxicities were comparable irrespective of the MTX dose. Oral mucositis was more frequently encountered in the 2.5 g/m2 than the 5 g/m2 HDMTX cycles (46.7 vs. 26.7%, p=0.023). A significantly longer hospitalization (due to HDMTX toxicity) was observed in the 5 g/m2 HDMTX cycles (median= 7 days vs. 4 days, p=0.012).ConclusionsSerum albumin levels should be checked before starting HDMTX cycles, especially in resource-limited settings where malnutrition is common, and serum MTX monitoring may not be available. Optimizing serum albumin levels before HDMTX may help decrease the possibility of HDMTX toxicities.

Feasibility of high-dose methotrexate administered on day 1 of (R)CHOP in aggressive non-Hodgkin lymphomas

AbstractThe optimal timing for administering high-dose methotrexate (HDMTX) when combined with (R)CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone, with/without rituximab) is unclear. Recent data showed that the administration of prophylactic HDMTX before day 10 of R- CHOP may lead to fewer treatment delays. Herein, we report our experience with HDMTX administered on day 1 of (R)CHOP in patients with aggressive non-Hodgkin lymphoma (NHL). We identified 140 patients treated with ≥1 cycle of HDMTX combined with (R)CHOP for prophylaxis against (n = 84) or treatment of (n = 56) central nervous system (CNS) involvement. Overall, (R)CHOP treatment delays ≥7 days (4% of cycles, 13% of patients), doxorubicin, and/or cyclophosphamide dose reductions (1% of cycles, 6% of patients) or (R)CHOP discontinuations due to toxicity (4% of patients) were uncommon. Neutropenic fever (NF) occurred in 7% of cycles and 24% of patients and was more common during HDMTX-containing cycles. Acute kidney injury (AKI) occurred in 19% of cycles but was mostly grade ≤2. Grade ≥3 hepatotoxicity and mucositis were uncommon (each 2% of cycles). In the prophylaxis cohort, the rates of NF and grade ≥2 AKI were lower in patients who initiated HDMTX with cycle 2 or later (11% vs 30%, P = .03 and 16% vs 39%, P = .03, respectively). Our data show that HDMTX administration on day 1 of (R)CHOP may improve the deliverability of (R)CHOP and the overall safety of the regimen compared with historical data of HDMTX administration on day 10 or later of R-CHOP. Delaying prophylactic HDMTX beyond cycle 1 of (R)CHOP may reduce the risk of NF and AKI.