High-dose Methotrexate Chemotherapy Research Articles

Prognostic analysis of childhood T-lymphoblastic lymphoma treated with leukemia regimen

To investigate the prognosis of childhood T-lymphoblastic lymphoma (T-LBL) treated with acute lymphoblastic leukemia (ALL) regimen and related influencing factors. A retrospective analysis was performed for the prognostic characteristics of 29 children with T-LBL who were treated with ALL regimen (ALL-2009 or CCCG-ALL-2015 regimen) from May 2010 to May 2022. The 29 children with T-LBL had a 5-year overall survival (OS) rate of 84%±7% and an event-free survival (EFS) rate of 81%±8%. The children with B systemic symptoms (unexplained fever >38°C for more than 3 days; night sweats; weight loss >10% within 6 months) at initial diagnosis had a lower 5-year EFS rate compared to the children without B symptoms (P<0.05). The children with platelet count >400×109/L and involvement of both mediastinum and lymph nodes at initial diagnosis had lower 5-year OS rates (P<0.05). There were no significant differences in 5-year OS and EFS rates between the children treated with CCCG-ALL-2015 regimen and those treated with ALL-2009 regimen (P>0.05). Compared with the ALL-2009 regimen, the CCCG-ALL-2015 regimen reduced the frequency of high-dose methotrexate chemotherapy and the incidence rate of severe infections (P<0.05). The ALL regimen is safe and effective in children with T-LBL. Children with B systemic symptoms, platelet count >400×109/L, and involvement of both mediastinum and lymph nodes at initial diagnosis tend to have a poor prognosis. Reduction in the frequency of high-dose methotrexate chemotherapy can reduce the incidence rate of severe infections, but it does not affect prognosis.

Could Cerebral Inflammatory Lesions be the Cellular Origin of Primary Central Nervous System Lymphoma?

Primary central nervous system lymphoma (PCNSL) presents a diagnostic enigma due to the inherent absence of lymphoid tissue in the central nervous system (CNS). The hypothesis posits that lymphocytes infiltrating the CNS during inflammatory responses could represent a cellular source for PCNSL, challenging traditional understandings of its etiology. In 2 illustrative cases, patients presented with neurological symptoms initially misdiagnosed as encephalitis and demyelinating disease, respectively. These diagnoses were established based on clinical assessments and initial biopsy findings. Subsequent biopsies, conducted months after the first signs of disease, confirmed the diagnosis of PCNSL in both patients. Identifying CD20-positive tumor cells was pivotal, indicating a B-cell lymphoma origin. Treatment strategies included high-dose methotrexate chemotherapy for both patients. In addition, the second patient underwent adjuvant whole-brain radiotherapy after the chemotherapy regimen. The therapeutic approach significantly reduced tumor size in both cases, with no evidence of recurrence observed during the follow-up period. This outcome underscores the potential efficacy of the chosen interventions. In response to inflammatory lesions, lymphocyte infiltration into the CNS may serve as a pivotal origin for tumor cells in PCNSL. These cases highlight the complexity of diagnosing CNS disorders and suggest that various forms of encephalitis in the early stages could influence the prognosis of lymphoma. This insight into the cellular origins and treatment responses of PCNSL contributes to a broader understanding of its pathophysiology and management.

Factors influencing delayed high-dose methotrexate excretion and its correlation with adverse reactions after treatment in children with malignant hematological tumors.

High-dose methotrexate (HDMTX) is crucial in treating pediatric malignant hematological tumors. However, its use is often complicated by delayed excretion and associated adverse reactions, which can significantly affect treatment outcomes and patient safety. Identifying risk factors is essential for safer, more effective therapy. This study aimed to investigate the influencing factors for delayed excretion and their correlation with adverse reactions in children with malignant hematological tumors after receiving HDMTX chemotherapy. From April to October 2021, the clinical information of children who had undergone HDMTX chemotherapy and had their blood tested for drug concentration was gathered by the Department of Hematology and Oncology at Shanghai Children's Medical Center. Via univariate and multivariate logistic regression, the factors affecting the delayed excretion of HDMTX were examined, and the relationship between delayed excretion and unfavorable effects in children was determined. This study included 99 patients comprising 199 courses of HDMTX. The occurrence rate of HDMTX delayed excretion was 20.1%. Age ≥9 years and a 24-hour methotrexate (MTX) concentration of 64 µmol/L were independent risk factors for delayed MTX excretion according to multivariate logistic regression analysis (P<0.05). Negative side effects, such as fever, infection, mucositis, gastrointestinal response, and decreased platelet count in children with delayed excretion were statistically significant when compared to those of children with normal excretion. White blood cell reduction, hemoglobin levels below 65 g/L, MTX excretion delay, and concomitant etoposide treatment were all independent risk factors for infection in children. To estimate the risk of delayed MTX excretion during HDMTX therapy, patient laboratory data should be scrutinized, especially for patients ≥9 years or those with a 24-hour MTX concentration of greater than 64 µmol/L.

18F-FACBC and 18F-FDG PET/MRI in the evaluation of 3 patients with primary central nervous system lymphoma: a pilot study

BackgroundThis PET/MRI study compared contrast-enhanced MRI, 18F-FACBC-, and 18F-FDG-PET in the detection of primary central nervous system lymphomas (PCNSL) in patients before and after high-dose methotrexate chemotherapy. Three immunocompetent PCNSL patients with diffuse large B-cell lymphoma received dynamic 18F-FACBC- and 18F-FDG-PET/MRI at baseline and response assessment. Lesion detection was defined by clinical evaluation of contrast enhanced T1 MRI (ce-MRI) and visual PET tracer uptake. SUVs and tumor-to-background ratios (TBRs) (for 18F-FACBC and 18F-FDG) and time-activity curves (for 18F-FACBC) were assessed.ResultsAt baseline, seven ce-MRI detected lesions were also detected with 18F-FACBC with high SUVs and TBRs (SUVmax:mean, 4.73, TBRmax: mean, 9.32, SUVpeak: mean, 3.21, TBRpeak:mean: 6.30). High TBR values of 18F-FACBC detected lesions were attributed to low SUVbackground. Baseline 18F-FDG detected six lesions with high SUVs (SUVmax: mean, 13.88). In response scans, two lesions were detected with ce-MRI, while only one was detected with 18F-FACBC. The lesion not detected with 18F-FACBC was a small atypical MRI detected lesion, which may indicate no residual disease, as this patient was still in complete remission 12 months after initial diagnosis. No lesions were detected with 18F-FDG in the response scans.Conclusions18F-FACBC provided high tumor contrast, outperforming 18F-FDG in lesion detection at both baseline and in response assessment. 18F-FACBC may be a useful supplement to ce-MRI in PCNSL detection and response assessment, but further studies are required to validate these findings.Trial registration ClinicalTrials.gov. Registered 15th of June 2017 (Identifier: NCT03188354, https://clinicaltrials.gov/study/NCT03188354).

Addition of High-Dose Methotrexate to Initial Chemotherapy Improved Treatment Outcome of Patients with Newly Diagnosed Intravascular Large B-Cell Lymphoma: A Multicenter, Retrospective Study

[Introduction] Intravascular large B-cell lymphoma (IVLBCL) is a rare subtype of diffuse large B-cell lymphoma characterized by selective growth of lymphoma cells in the lumina of small vessels. Although the clinical outcomes of IVLBCL before rituximab era were dismal, a retrospective analysis published in 2008 showed improved outcomes for patients treated with rituximab-containing chemotherapy (R-chemo). Furthermore, a recent multicenter, single-arm, phase II trial conducted in Japan (PRIMEUR-IVL study) supports the usage of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone combined with high-dose methotrexate (HD-MTX) and intrathecal chemotherapy (IT), with a 2-year Overall survival (OS) of 92% and 2-year progression-free survival (PFS) of 76% in a selected population with newly diagnosed IVLBCL. However, this trial did not include a control arm, making it difficult to evaluate whether the addition of HD-MTX improves the treatment outcome. Thus, with the largest cohort (we already reported at ASH 2022), we retrospectively evaluated the efficacy of the HD-MTX in real-world settings. [Methods] Patients with histopathologically proven newly diagnosed IVLBCL according to the 2008 World Health Organization criteria between January 2010 through February 2022 from hospitals participating in the North Japan Hematology Study Group were included. Survival analysis was limited to patients with serum creatinine &amp;lt; 2.0 mg/dL and aged 20-79 years, following the eligibility criteria of the PRIMEUR-IVL study. PFS was defined as the time from the start of treatment to the first of progression, relapse, or death from any cause. Patients undergoing upfront autologous stem-cell transplantation (auto-SCT) were censored at the time of transplantation. [Results] A total of 110 IVLBCL cases were identified. Eighty-six patients with serum creatinine &amp;lt; 2.0 mg/dL, aged 20-79 years, received chemotherapy. Eighty-five of 86 patients (98.8%) received R-chemo. Thirty-six of 86 patients (41.9%) received HD-MTX during the initial therapy (w HD-MTX group), and 50 patients (58.1%) did not (w/o HD-MTX group). Fifty-six patients (65.1%) received IT. Six patients (7.0%) received upfront auto-SCT. Complete response (CR), no change (NC), and primary refractory disease were noted after initial therapy by 62 (72.1%), 11 (12.8%), and 11 (12.8%) patients, respectively. The disease progression after achieving NC was noted in 3 patients (3.5%). Fourteen patients (16.3%) experienced a relapse after achieving CR. Eight of 28 recurrences (progressions or relapses) were neurolymphomatosis forms, and 7 were central nervous system (CNS) recurrences. Twenty-five patients (29.1%) died, and 21 were due to disease progression. Compared clinical characteristics of the w HD-MTX group with the w/o HD-MTX group, the proportion of patients older than 60 years, male sex, poor performance status (ECOG PS &amp;gt; 1), elevated serum LDH, Ann Arbor stage III-IV and 2 or more extra-nodal lesions were not significantly different. The number of patients who received IT was significantly higher in the w HD-MTX group (77.8% vs. 56.0%, P = 0.042). Median follow-up duration for censored cases was 47.1 months (range, 7.4-130.7 months) in w HD-MTX group and 33.0 months (range, 1.78-140.5 months) in w/o HD-MTX group. Two-year PFS and OS were 73.1% (95% CI, 54.5-85.0) and 85.0% (95% CI, 67.5-93.5), respectively, in the w HD-MTX group and 54.7% (95% CI, 38.6-68.3) and 69.2% (95% CI, 53.2-80.6), respectively, in the w/o HD-MTX group (log-rank test, P = 0.016 and P = 0.005, respectively; Fig. a, b). The w HD-MTX group and the w/o HD-MTX group showed no significant difference in the cumulative incidence of CNS recurrence at 2 years (8.7%; 95% CI, 2.2-21.0 vs. 6.6%; 95% CI, 1.7-16.5, Gray test, P = 0.98). In univariate analysis, male gender, the addition of IT, and the addition of HD-MTX were significantly associated with PFS and OS ( Table). Multivariate analysis demonstrated that the addition of HD-MTX was independently associated with both PFS and OS. No HD-MTX-related deaths occurred in the w HD-MTX group. Adverse events related to HD-MTX were observed in 24 of 36 patients (66.7%), with grade 3 or 4 non-hematological adverse events in 3 patients (8.3%). [Conclusion] In conclusion, this largest retrospective study showed that the addition of HD-MTX to initial chemotherapy improved the treatment outcome of patients with newly diagnosed IVLBCL.

Reagentless impedimetric immunosensor for monitoring of methotrexate in human blood serum using multiwalled carbon nanotube@polypyrrole/polytyramine film electrode

Ensuring effective monitoring of methotrexate (MTX) levels in the bloodstream of cancer patients undergoing high-dose methotrexate chemotherapy is crucial to prevent potentially harmful side effects. However, the absence of portable analytical devices suitable for point-of-care bedside monitoring has presented a significant obstacle to achieving real-time MTX monitoring. In this study, we developed an impedimetric immunosensor that doesn't require reagents for measuring MTX levels in undiluted human blood serum. This reagentless approach simplifies the assay process, enabling rapid and straightforward MTX quantification. The immunosensor transducer was fabricated by electrodepositing conductive network of porous multiwalled carbon nanotube@polypyrrole/polytyramine on screen-printed gold microchip electrode (SP–Au/MWCNT70@PPy-PTA). Polyclonal anti-MTX antibodies were immobilized on the film, acting as the immunorecognition element. Non-specific binding was prevented by blocking the transducer interface with denatured bovine serum albumin (dBSA) fibrils, resulting in SP-Au/MWCNT70@PPy-PTA/anti-MTXAb|dBSA film electrode. When MTX binds to the SP-Au/MWCNT70@PPy-PTA/anti-MTXAb|dBSA interface, the film conductance and electron transfer resistance changes. This conductivity attenuation allows for electrochemical impedimetric signal transduction without a redox-probe solution. The electrochemical impedance spectroscopy (EIS) results showed increased charge transfer resistance and phase angle as MTX concentrations increased. The SP-Au/MWCNT70@PPy-PTA/anti-MTXAb|dBSA demonstrated high sensitivity, with a linear response from 0.02 to 20.0 μM and a detection limit of 1.93 nM. The detection limit was 50 times lower than the intended safe level of MTX in human serum. The immunosensor exhibited minimal cross-reactivity with endogenous MTX analogs and serum proteins. The SP-Au/MWCNT70@PPy-PTA/anti-MTXAb|dBSA immunosensor presents a simple and rapid method for therapeutic drug monitoring compared to traditional immunoassay systems.

PRELIMINARY FINDINGS OF A PHASE II STUDY OF CHEMO‐FREE COMBINATION OF POMALIDOMIDE, ORELABRUTINIB, RITUXIMAB WITH SEQUENTIAL HIGH‐DOSE METHOREXATE IN NEWLY DIAGNOSED PRIMARY CNS LYMPHOMA

Background: High-dose methotrexate (HD-MTX) is widely used as front-line treatment in patients with primary central nervous system lymphoma (PCNSL). Both preclinical models and clinical data suggested pomalidmide and orelabrutinib were effective in PCNSL and the combination of them may have synergy in DLBCL. Aims: We aimed to evaluate the tolerability and efficacy of pomalidomide, orelabrutinib and rituximab (POR) with the sequential addition of HD-MTX chemotherapy in newly diagnosed PCNSL. Methods: This is an investigator-initiated, single-arm phase II study, and immunocompetent patients with untreated PCNSL were enrolled. Patients were treated with pomalidomide 4 mg once per day on days 1-14, orelabrutinib 150 mg once daily continuously, and rituximab 375 mg/m2 intravenous once on day 1 of each 21-day cycle. After four cycles, HD-MTX chemotherapy was sequentially added for two additional cycles. The primary endpoint was overall response rate (ORR) at the end of four cycles of POR. Circulating tumor DNA detection of cerebrospinal fluid was performed. This trial was registered at www.clinicaltrials.gov (#NCT 05390749). Findings: The data cut-off date was 15 February 2023, and thirteen patients were enrolled in this study. The median age was 58 years (range 34-79 years). Four patients had eye involvement and one patient had leptomeninges involvement. Eight patients performed ctDNA analysis and all had MYD88 l265p mutation. One patient discontinued the experimental treatment due to treatment-related adverse events (TRAE) and eleven patients finished four cycles of POR and were evaluable. The ORR after four cycles of POR was 90.1% and the complete response rate was 36.4%. Twelve patients who finished at least 1 cycle were evaluated for safety analysis. The most common grade 3 or 4 AEs were neutropenia (G3, n = 1; G4, n = 2), thrombocytopenia (G3, n = 2), rash (G3 n = 1, G4 n = 1), ALT increased (G3, n = 1) and anemia (G3, n = 1). With a median follow-up of 4 months, one patient relapsed and died of PCNSL. Conclusion: This is the first study to treat newly diagnosed PCNSL with a targeted therapy combination before chemotherapy. POR produced a high ORR with good tolerance. This suggested the potential of noncytotoxic first-line therapies for PCNSL. Encore Abstract—previously submitted to EHA 2023 The research was funded by: CAMS Innovation Fund for Medical Sciences (CIFMS) 2021-I2M-C&T-B-005. Keywords: aggressive B-cell non-Hodgkin lymphoma, immunotherapy, molecular targeted therapies No conflicts of interests pertinent to the abstract.

Correlation between methylation level of the SLC19A1 promoter region and methotrexate metabolism in adult acute lymphoblastic leukemia.

Aims: To analyze the methylation level in the promoter region of SLC19A1 in adult acute lymphoblastic leukemia (ALL) patients, and explore the relationship between methotrexate (MTX) drug metabolism and SLC19A1 methylation. Methods: The methylation levels of the SLC19A1 promoter region in 52 adult ALL patients who received high-dose MTX chemotherapy were retrospectively analyzed in combination with clinical indicators and plasma MTX concentration. Results: Methylation levels of 17 CpG units were differently correlated with clinical parameters of ALL patients including gender, age, immunophenotype and Philadelphia chromosome status. Patients with delayed MTX drug excretion had higher methylation levels in the SLC19A1 promoter region. Conclusion: The methylation may affect the MTX plasma level and adverse reactions, which may predict patients at risk of adverse reactions after high-dose MTX therapy.

Acute Kidney Injury with SARS-CoV-2 Infection in Pediatric Patients Receiving High-Dose Methotrexate Chemotherapy: A Report of Three Cases

Methotrexate is renally excreted. HDMTX (high dose-methotrexate)-induced acute kidney injury (AKI) is a non-oliguric decrease in glomerular filtration rate (GFR) heralded by an acute rise in serum creatinine. Moreover, AKI is also a frequent complication of COVID-19. Among our patients treated with HDMTX, some of these developed AKI during SARS-CoV-2 infection. Therefore, we wondered whether our patients' kidney failure might have been triggered by their underlying SARS-CoV-2 positivity. Data were collected from the database at the Pediatric Oncology Unit of the Istituto Nazionale dei Tumori in Milan (Italy) regarding patients who matched the following selective criteria: (a) treatment with HDMTX during the pandemic period; (b) SARS-CoV-2 infection during the treatment; (c) development of AKI during HDMTX treatment and SARS-CoV-2 infection. From March 2020 to March 2022, a total of 23 patients were treated with HDMTX; 3 patients were treated with HDMTX during SARS-CoV-2 infection and all 3 developed AKI. Clinical manifestations associated with this virus are many, so we are not yet able to lower our guard and rule out this infection as a cause of clinical manifestations with any certainty.

Relationship between methylenetetrahydrofolate reductase gene polymorphisms and methotrexate drug metabolism and toxicity.

Acute lymphoblastic leukemia (ALL) is the most common malignancy in children, and methotrexate (MTX) is the key drug for ALL. Studies on the relationship between High-Dose methotrexate (HD-MTX) toxicity and methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C genes have drawn different conclusions. This study aimed to investigate the relationship between the polymorphism of MTHFR C677T and A1298C genes and the toxicity responses of MTX. The MTHFR C677T and A1298C genotypes of 271 children with ALL who received HD-MTX chemotherapy in southern China from September 2017 to June 2021 were analyzed, and the toxicity of HD-MTX was evaluated and analyzed according to Common Terminology Criteria for Adverse Events (CTCAE) 5.0. The MTHFR C677T and A1298C gene polymorphisms were not correlated with the 48-hour MTX blood concentrations (P>0.05). Unconditional logistic regression model analysis also revealed that the risk of liver function impairment [odds ratio (OR) =1.656, 95% confidence interval (CI): 1.179-2.324, P<0.05] and mucosal damage (OR =1.508, 95% CI: 1.042-2.183, P<0.05) were 1.656 and 1.508 times higher for the heterozygous mutant (CT), and homozygous mutant (TT) mutant type than for the wild-type (CC), wild-type, respectively. The risk of neutropenia and liver function impairment were 0.498 (OR =0.498, 95% CI: 0.251-0.989, P<0.05) and 6.067 (OR =6.067, 95% CI: 1.183-31.102, P<0.05) times higher in low-risk children with CT+TT mutant genotypes than in those with CC wild genotypes, respectively. Furthermore, the risk of mucosal damage was 1.906 times higher in high-risk children with the CT+TT genotype than in those with the CC genotype (OR =1.906, 95% CI: 1.033-3.518, P<0.05). The MTHFR A1298C genotypes differed in the incidence of liver function damage and gastrointestinal toxic reactions in children with ALL. Nonetheless, no increased risk of liver function impairment nor gastrointestinal reactions in children with the heterozygous mutant (AC)+CC mutation was observed. Advancements in MTHFR genotype testing in children with ALL and the introduction of personalised treatments based on genotype results during HD-MTX chemotherapy will help to predict, prevent, and reduce the occurrence of adverse MTX-related toxic reactions.

Renal function features in pediatric acute lymphoblastic leukemia during high-dose methotrexate chemotherapy

Introduction: High-dose Methotrexate (HD-MTX), a chemotherapy agent for acute lymphoblastic leukemia, is a cytotoxic agent for some organs, including kidneys. One of the most important toxicities due to HD-MTX is acute kidney injury due to Methotrexate crystallization in renal tubules. The prevalence of Acute kidney injury due to HD-MTX administration in pediatric ALL in dr. Soetomo General Hospital was unknown. The study aims to analyze renal function features in pediatric ALL during HD-MTX chemotherapy. Methods: An analytical observational study with a prospective approach was conducted at Dr. Soetomo General Hospital Surabaya from December 2021 - July 2022. The subjects were ALL children aged 1-18 years who met inclusion and exclusion criteria. High-dose Methotrexate chemotherapy was given 3 times every 2 weeks during the consolidation phase. Laboratory examinations were performed before and after HD-MTX chemotherapy. Laboratory results were recorded to determine the GFR value. The difference test was performed using Wilcoxon signed rank test and the Friedman test with a significance value of p&lt;0.05. Results: A total of 20 subjects, the median age was 78 months old, and boys and girls were equal. Standard Risk of ALL was in 55% of subjects, and 45% were at high risk. There was no significant difference in laboratory parameters between before and after HD-MTX chemotherapy in all cycles with a p-value &gt;0.05. The median value of GFR in each cycle is 257.5; 243.5; 228.5. Minimal GFR was 119 ml/min/1.73 m2, and maximum GFR was 638 ml/min/1.73 m2. It showed a median value of GFR in all cycles was &gt;175 ml/min/m2 (hyperfiltration). Conclusions: We concluded there was no AKI due to HD-MTX chemotherapy in pediatric ALL. It may be caused by providing adequate hydration, urine alkalinization, and leucovorin rescue.

Cranial Radiation Therapy as Salvage in the Treatment of Relapsed Primary CNS Lymphoma.

Primary central nervous system lymphoma (PCNSL) is a rare malignancy. Standard of care is upfront high-dose methotrexate (HD-MTX) chemotherapy, while cranial radiation is more commonly used in the salvage setting. In this retrospective study, we aimed to investigate the safety and efficacy of salvage cranial radiation in PCNSL. PCNSL patients who received upfront HD-MTX chemotherapy and salvage cranial radiation after treatment failure between 1995 and 2018 were selected. Radiological response to cranial radiation was assessed as per Response Assessment in Neuro-Oncology Criteria. Twenty one patients were selected (median age 59.9 years), with median follow-up of 19.9 months. Fourteen patients (66.7%) received a boost to the gross tumour volume (GTV). Four patients (19.0%) sustained grade ≥2 treatment-related neurotoxicity post-completion of cranial radiation. Of the 19 patients who had requisite MRI with gadolinium imaging available for Response Assessment in Neuro-Oncology (RANO) criteria assessment, 47.4% achieved complete response, 47.4% achieved partial response, and 5.3% of patients exhibited stable disease. Higher dose to the whole brain (&gt;30 Gy) was associated with higher rate of complete response (63.6%) than lower dose (≤30 Gy, 37.5%), while boost dose to the gross disease was also associated with higher rate of complete response (61.5%) compared with no boost dose (33.3%). Median overall survival was 20.0 months. PCNSL patients who relapsed following upfront chemotherapy showed a high rate of response to salvage cranial radiation, especially in those receiving greater than 30 Gy to the whole brain and boost to gross disease.

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

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

Evaluation of kidney dysfunction in childhood cancer survivors

BackgroundThe major increase in the survival rate among children with cancer is due to improvement in the diagnosis and treatment. Despite this increase, childhood cancer survivors (CCS) are at high risk of developing late complications such as nephrotoxicity due to chemotherapy. So, we aimed to detect early subclinical kidney dysfunction among CCS.MethodsThis cross-sectional study was implemented on 52 survivors of childhood cancer recruited from Pediatric Oncology Unit, Menoufia University. Laboratory evaluations for each participant, including complete blood count, serum urea, creatinine, urinary protein, urinary calcium, uric acid, and serum cystatin C and urinary Neutrophil Gelatinase Associated Lipocalin (UrNGAL) by ELISA were obtained.ResultsEstimated GFR was decreased in 23.1% of cases, with elevated serum cystatin C, UrNGAL and UrNGAL/Cr. There was a significant increase of Uprotein/Cr, UCa/Cr, UACR (p = 0.02), UrNGAL and UrNGAL/Cr (P < 0.001) in patients with tubular dysfunction compared without tubular dysfunction. There was a significant difference between two groups regarding cisplatin (P = 0.03) and high-dose methotrexate chemotherapy (p = 0.04). The AUCs for detecting kidney tubular dysfunction by UrNGAL and UrNGAL/Cr were 0.807 and 0.747.ConclusionA significant tubular dysfunction among childhood cancer survivors receiving chemotherapy as cisplatin and high-dose methotrexate.ImpactDetection of kidney dysfunction mainly tubular in childhood cancer survivors after finishing chemotherapy.Urinary NGAL is a good predictor for detection of tubular dysfunction in childhood cancer survivors after finishing chemotherapy.

Ibrutinib Monotherapy as Bridge-to-Transplant for Relapsed/Refractory Primary Oculo-Cerebral Lymphoma.

Introduction. Primary central nervous system lymphoma is an uncommon form of extranodal non-Hodgkin’s lymphoma, with increasing incidence, a relatively aggressive course and a poor 5-year survival. Because of its localization, the therapeutic compounds used in this disease must be able to pass through the blood-brain barrier. Chemotherapy regimens based on high-dose methotrexate are currently the standard of care for all patients who can tolerate such drugs. Autologous stem cell transplantation is indicated for malignant lymphomas in the relapsed/refractory setting. Methods. Three patients, with a median age of 60 years, range 53–64, were diagnosed with primary CNS lymphoma, and treated with ibrutinib monotherapy in the Department of Hematology, Ion Chiricuta Clinical Cancer Center, Cluj-Napoca, Romania, between September 2018 and November 2020 All the patients were relapsed–refractory following high-dose methotrexate chemotherapy. We present our experience using ibrutinib monotherapy-based treatment as a bridge-to-transplant option on a single-center case series and a review of the literature in this field. Results. Two of the patients were given ibrutinib as a second line therapy, both achieving complete remission and being eligible for an autologous stem cell transplantation. The third patient achieved a short remission using six cycles of systemic chemotherapy, but was started on ibrutinib monotherapy, with limited results. Conclusion. Our data is limited, and these results should be confirmed by multicentric clinical trials and should be regarded as a single-center case series, with all its limitations. Still, it brings forward a new therapeutic option for this rare subtype of malignant lymphomas, which if left untreated has a dismal prognosis.

Current progress and future perspectives of research on intravascular large B-cell lymphoma.

Intravascular large B‐cell lymphoma is a rare disease of the large B cells characterized by selective growth in the lumina of small vessels in systemic organs. Since first reported in 1959, the difficulty of obtaining sufficient tumor cells from biopsy specimens has hampered the elucidation of its underlying biology. Recent progress using xenograft models and plasma cell‐free DNA has uncovered genetic features that are similar to those of activated B‐cell type diffuse large B‐cell lymphoma, including MYD88 and CD79B mutations and frequent alterations in immune check point‐related genes such as PD‐L1 and PD‐L2. Given the improvement in clinical outcomes and a higher risk of secondary central nervous system (CNS) involvement in the rituximab era, a phase 2 trial of R‐CHOP combined with high‐dose methotrexate and intrathecal chemotherapy as a CNS‐oriented therapy has been conducted. This trial, the PRIMEUR‐IVL study, has displayed good progression‐free survival and a low cumulative incidence of secondary CNS involvement. Long‐term follow‐up within this trial is still ongoing. Further understanding of the pathophysiology of the disease and improvements in clinical outcomes are still needed.

Primary vitreoretinal lymphoma: short review of the literature, results of a European survey and French guidelines of the LOC network for diagnosis, treatment and follow-up.

The aim of this study was to highlight the diagnostic and management challenges of primary vitreoretinal lymphoma (PVRL) through a review of the literature and a European survey on real-life practices for PVRL. The care of PVRL patients is heterogeneous between specialists and countries. Upfront systemic treatment based on high-dose methotrexate chemotherapy, with or without local treatment, might reduce or delay the risk of brain relapse.Ibrutinib, lenalidomide with or without rituximab, and temozolomide are effective for patients with relapsed/refractory PVRL and should be tested as first-line treatments. The prognosis of PVRL remains dismal. No firm conclusion regarding optimal treatment can yet be drawn. The risk of brain relapse remains high. Diagnostic procedures and assessment of therapeutic responses need to be homogenized. Collaboration between specialists involved in PVRL and multicentric prospective therapeutic studies are strongly needed. The recommendations of the French group for primary oculocerebral lymphoma (LOC network) are provided, as a basis for further European collaborative work.

Outcome of patients with newly diagnosed primary CNS lymphoma after high-dose methotrexate followed by consolidation whole-brain radiotherapy and cytarabine: an 8-year cohort study.

Addition of cytarabine to high-dose methotrexate (HD-MTX) chemotherapy improves outcome of primary CNS lymphoma (PCNSL); however, the combination therapy increases toxicity. Sequential chemotherapy and cranial radiation may decrease toxicity without altering efficacy. This was a single-center, retrospective cohort study of consecutive newly diagnosed immunocompetent PCNSL patients treated with HD-MTX (5 cycles of 3g/m2 every 2weeks) followed by consolidation whole-brain radiotherapy (WBRT) and cytarabine (2 cycles of 3g/m2/d for 2days every 3weeks) from January 2013 to December 2020. Initial WBRT before HD-MTX was allowed in patients with significant disability or brain edema at presentation. Primary outcome was progression-free survival (PFS). Key secondary outcomes were response rate, treatment-related toxicity, and overall survival (OS). Of 41 patients, 25 patients had a complete response (CR) and ten patients had a partial response, inferring an overall response rate (ORR) of 85.4% and a CR rate of 60.9%. More than 90% of patients were able to tolerate and complete the HD-MTX. The incidence of ≥ grade 3 hematologic and non-hematologic toxicities were 4.8% and 17.1%, respectively. Treatment-related mortality rate was 2.4%. There was no difference in toxicity between patients with age < 60 and ≥ 60years. At the median follow-up duration of 39.8months, the median PFS was 35.2months (95% CI 12.4-69.3) and median OS was 46.5months (95% CI 21.8-NR). High-dose methotrexate followed by consolidation whole-brain radiotherapy and cytarabine has acceptable efficacy, great tolerability, and low toxicity in newly diagnosed PCNSL patients.

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

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

Current achievements and future perspectives in the research on intravascular large B-cell lymphoma

Intravascular large B-cell lymphoma is a rare disease entity of extranodal large B-cell lymphoma and is characterized by selective growth of tumor cells in the lumina of small vessels in systemic organs. The challenge in obtaining sufficient tumor cells from biopsy specimens has hampered the elucidation of underlying biology. Recent advances in xenograft models and plasma cell-free DNA have revealed that the intravascular large B-cell lymphoma has genetic features similar to those of activated B-cell-like diffuse large B-cell lymphoma and frequent genetic alterations in immune-check point related genes. In terms of clinical aspects, considering the improvement in the clinical outcomes and higher risk of secondary central nervous system (CNS) involvement in the rituximab era, phase 2 trial of R-CHOP therapy combined with high-dose methotrexate and intrathecal chemotherapy as CNS-oriented therapy was conducted. The trial, named the PRIMEUR-IVL study, displayed good progression-free survival and low cumulative incidence of secondary CNS involvement. Further research is necessary to enable a deeper understanding of the pathophysiology of the disease and further improve the clinical outcomes.