Newly diagnosed high-risk malignant brain tumors with leptomeningeal dissemination in young children: A final update on Head Start II Regimen A2 intensified with high-dose methotrexate

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 9552-9552
Author(s):  
S. Chi ◽  
S. Gardner ◽  
L. Y. Ji ◽  
R. Sposto ◽  
G. Dhall ◽  
...  
Keyword(s):  
High Risk ◽  
Head Start ◽  
Young Children ◽  
Brain Tumors ◽  
Response Rate ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Leptomeningeal Dissemination ◽  
Newly Diagnosed ◽  
Dose Methotrexate

9552 Background: The prognosis for young children with newly diagnosed malignant brain tumors with leptomeningeal dissemination remains poor. From Jan 1997 to Mar 2003, “Head Start II” Regimen A2, intensified with high-dose methotrexate, was offered to this high-risk population. Methods: Eligibility: patients < 10 yrs of age; confirmed diagnosis of medulloblastoma (MB), primitive neuroectodermal tumor (PNET), ependymoma and choroid plexus carcinoma (CPC); and high-risk status as determined by neuroaxis dissemination. Patients with atypical teratoid/rhabdoid tumor (ATRT), regardless of stage, were also eligible. Treatment: 5 cycles of vincristine (0.05 mg/kg/week × 3 doses), cisplatin (3.5 mg/kg), etoposide (4 mg/kg/day × 2 days), cyclophosphamide (65 mg/kg/day × 2 days), and methotrexate (400 mg/kg) with leucovorin. Children without progressive disease (PD) by the end of induction underwent a single consolidation cycle (carboplatin, etoposide, thiotepa) with autologous stem cell rescue. Reduced dose RT (2340cGy CSI and focal boost) was reserved for any with residual disease at the end of induction or for the older patient (>6 yrs of age). Results: 40 patients were enrolled (MB, 22; PNET, 6; ependymoma, 5; AT/RT, 6; CPC, 1), med age at diagnosis 38 mos (range 5 to 119 mos). Significant toxicities of this intensified regimen included GI toxicities and infections. Among the entire cohort, there were 26 CR, 6 PR, 2 with stable disease and 4 with PD (and 2 toxic deaths), for a CR +PR response rate of 82%. For disseminated MB (4 M1; 2 M2; 16 M3), the CR rate alone is 77% (17/22). The 5-year EFS and OS for disseminated MB are 45% (95% CI, 24 % to 64%) and 54% (95% CI, 31% to 72%), respectively. Of note, 6/12 MB survivors (all M3) did not receive RT and all are NED >5 years from diagnosis. In addition, there are 3 AT/RT survivors, 12, 54 and 66 mos post-diagnosis who did not receive RT. Conclusions: This intensified regimen is feasible and tolerable. For patients with disseminated MB, the majority of whom had M3 disease at diagnosis, the impressive response rate and outcomes suggest that the addition of methotrexate is justified for future studies. Long- term neuropsychological outcomes are being studied at this time. No significant financial relationships to disclose.

Combination Chemotherapy and Radiotherapy for Primary Central Nervous System Lymphoma: Radiation Therapy Oncology Group Study 93-10

2002 ◽  
Vol 20 (24) ◽  
pp. 4643-4648 ◽  
Author(s):  
Lisa M. DeAngelis ◽  
Wendy Seiferheld ◽  
S. Clifford Schold ◽  
Barbara Fisher ◽  
Christopher J. Schultz
Keyword(s):  
Combination Chemotherapy ◽  
Response Rate ◽  
Radiation Therapy Oncology Group ◽  
Primary Cns Lymphoma ◽  
Central Nervous System Lymphoma ◽  
Cranial Irradiation ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Newly Diagnosed ◽  
Dose Methotrexate

PURPOSE: Primary CNS lymphoma (PCNSL) is an aggressive primary brain tumor. Cranial irradiation alone rarely results in long-term disease control or prolonged survival. We prospectively studied the use of combination chemotherapy plus cranial irradiation in newly diagnosed patients with PCNSL. PATIENTS AND METHODS: We enrolled 102 newly diagnosed, immunocompetent patients with PCNSL; 98 were assessable. Patients first received five cycles of methotrexate 2.5 g/m2, vincristine, procarbazine, and intraventricular methotrexate (12 mg). Whole-brain radiotherapy (RT) was administered to a total dose of 45 Gy and all patients received high-dose cytarabine after RT. RESULTS: Fifty-eight percent of patients with measurable disease had a complete response to preirradiation chemotherapy and 36% had a partial (> 50%) response, for a 94% response rate. Median progression-free survival was 24.0 months and overall survival was 36.9 months. Age was an important prognostic factor; median survival was 50.4 months in patients younger than 60 and only 21.8 months in those aged 60 or older (P < .001). Fifty-three percent of patients had grade 3 or 4 toxicity during induction chemotherapy, half of which was hematologic. However, 12 patients (15%) experienced severe delayed neurologic toxicity, eight of whom died. CONCLUSION: This is the first multicenter trial demonstrating improved survival with the combination of chemotherapy plus RT compared with previous reports of RT alone. A high-dose methotrexate-based regimen produced a high response rate before RT was administered. High-dose methotrexate combined with cranial irradiation is an effective therapeutic approach to PCNSL, but neurotoxicity is a delayed risk of this approach.

Feasibility and Response to Induction Chemotherapy Intensified With High-Dose Methotrexate for Young Children With Newly Diagnosed High-Risk Disseminated Medulloblastoma

2004 ◽  
Vol 22 (24) ◽  
pp. 4881-4887 ◽  
Author(s):  
Susan N. Chi ◽  
Sharon L. Gardner ◽  
Adam S. Levy ◽  
Edmond A. Knopp ◽  
Douglas C. Miller ◽  
...  
Keyword(s):  
High Risk ◽  
Young Children ◽  
Induction Chemotherapy ◽  
Response Rate ◽  
Chemotherapy Regimen ◽  
High Response Rate ◽  
High Dose ◽  
Newly Diagnosed ◽  
Stem Cell Rescue ◽  
Myeloablative Chemotherapy

Purpose To evaluate the feasibility of and response rate to an intensified induction chemotherapy regimen for young children with newly diagnosed high-risk or disseminated medulloblastomas. Patients and Methods From January 1997 to March 2003, 21 patients with high-risk or disseminated medulloblastoma were enrolled. After maximal surgical resection, patients were treated with five cycles of vincristine (0.05 mg/kg/wk × three doses per cycle for three cycles), cisplatin (3.5 mg/kg per cycle), etoposide (4 mg/kg/d × 2 days per cycle), cyclophosphamide (65 mg/kg/d × 2 days per cycle) with mesna, and methotrexate (400 mg/kg per cycle) with leucovorin rescue. Following induction chemotherapy, eligible patients underwent a single myeloablative chemotherapy cycle with autologous stem-cell rescue. Results Significant toxicities of this intensified regimen, including gastrointestinal and infectious toxicities, are described. Among the 21 patients enrolled, there were 17 complete responses (81%), two partial responses, one stable disease, and one progressive disease. The 3-year event-free survival and overall survival are 49% (95% CI, 27% to 72%) and 60% (95% CI, 36% to 84%), respectively. Conclusion This intensified induction chemotherapy regimen is feasible and tolerable. With the majority of patients with disseminated medulloblastoma having M2 or M3 disease at diagnosis, the encouraging high response rate of this intensified induction regimen suggests that such an addition of methotrexate should be explored in future studies.

scholarly journals Preliminary Results of a Phase II Study of Methotrexate in Combination with Ibrutinib and Temozolomide (MIT) in Newly Diagnosed Primary CNS Lymphoma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2481-2481
Author(s):  
Xiaoxiao Wang ◽  
Yan Gao ◽  
Shanshan Yu ◽  
Bing Bai ◽  
Qiuxiang Ou ◽  
...  
Keyword(s):  
Response Rate ◽  
Induction Treatment ◽  
Disease Monitoring ◽  
High Dose ◽  
Hematologic Toxicity ◽  
Plasma Samples ◽  
High Dose Methotrexate ◽  
Newly Diagnosed ◽  
Dose Methotrexate

Abstract Background: Primary central nervous system lymphoma (PCNSL) is a rare and aggressive subtype of B-cell lymphoma with very 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 high-dose methotrexate as a first-line treatment was suboptimal with a short effective remission time and low response rate. We aimed to investigate the efficacy of induction treatment, high-dose methotrexate in combination with ibrutinib and temozolomide (MIT), in newly diagnosed PCNSL. Methods: Thirty-three patients were planned to be enrolled in this open-label, non-randomized, multi-center phase II prospective clinical study (NCT04514393). Between October 2020 and April 2021, nine newly diagnosed PCNSL patients were enrolled. Eligible patients are ≥18 and ≤75 years of age with adequate organ function and require at least one measurable lesion. The MIT induction treatment included six cycles of high-dose methotrexate (HD-MTX, 3.5 g/m 2, every three weeks), ibrutinib (560 mg/d, after HD-MTX clearance), and temozolomide (150 mg/m 2 d1-d5, every three weeks). After the completion of the six cycles of MIT induction treatment, ASCT consolidation (only for patients &lt; 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 objective of this study was to evaluate the overall response rate (ORR) of MIT induction treatment for PCNSL defined as the proportion of subjects with complete response (CR) or partial response (PR). The safety and toxicity of MIT treatment were also investigated. No dose reduction or delayed treatment occurred. Baseline tissue samples and sequential CSF/plasma samples were collected and underwent targeted next-generation sequencing (NGS). Results: The median age of the nine enrolled patients was 50 yr (range: 29-68) and six of them were male. Six patients have completed the six cycles of MIT treatment and the rest three had just completed two cycles. Hematologic toxicity was mild, Grade 3-4 neutropenia occurred in one patient. Other side effects such as opportunistic infections (including Aspergillus) were not observed. Eight out of the nine (88.9%) patients achieved CR. While patient #2 progressed and dropped out after two cycles of MIT treatment (Figure A). The mutational profiles of baseline tissue and/or CSF samples revealed that PIM1 and MYD88 mutations were present in 88.9% of the entire cohort followed by HISTHIE and CD78B (6/9, 66.7%). CDKN2A copy number loss was detected in four patients. Four patients with sequential CSF or plasma sampling during MIT treatment were analyzed for dynamic disease monitoring. As shown in the figure A, the clearance of ctDNA in the CSF/plasma samples was observed as early as post one cycle in three CR patients (#1,3,4) and maintained until the latest follow-up. However, the ctDNA remained detectable in the CSF sample of the PD patient (#2), which baseline genetic status shows MYD88 (M232T) mutation alone without CD79B mutations, and with CCND3, CDK4 and ERBB3 gene amplification(Figure B). After a median follow-up of 7 months, the 1-year PFS is 88.9% and the OS is 100%. Other clinical results of this ongoing study (NCT04514393) will be updated. Conclusions: The induction treatment of MIT achieved excellent responses in newly diagnosed PCNSL patients with mild hematologic toxicity. The clearance of ctDNA in CSF/plasma samples was observed during dynamic disease monitoring which was in accord with imageology-based response evaluation. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals High-dose methotrexate-based regimens and post-remission consolidation for treatment of newly diagnosed primary CNS lymphoma: meta-analysis of clinical trials

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Junyao Yu ◽  
Huaping Du ◽  
Xueshi Ye ◽  
Lifei Zhang ◽  
Haowen Xiao
Keyword(s):  
Meta Analysis ◽  
Primary Cns Lymphoma ◽  
Central Nervous System Lymphoma ◽  
Progression Free Survival ◽  
Complete Response ◽  
Cns Lymphoma ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Newly Diagnosed ◽  
Dose Methotrexate

AbstractWith the exception of high-dose methotrexate (HD-MTX), there is currently no defined standard treatment for newly diagnosed primary central nervous system lymphoma (PCNSL). This review focused on first-line induction and consolidation treatment of PCNSL and aimed to determine the optimal combination of HD-MTX and the long-term beneficial consolidation methods. A comprehensive literature search of MEDLINE identified 1407 studies, among which 31 studies met the inclusion criteria. The meta-analysis was performed by using Stata SE version 15. Forest plots were generated to report combined outcomes like the complete response rate (CRR), overall survival, and progression-free survival. We also conducted univariate regression analyses of the baseline characteristics to identify the source of heterogeneity. Pooled analysis showed a CRR of 41% across all HD-MTX-based regimens, and three- and four-drug regimens had better CRRs than HD-MTX monotherapy. In all combinations based on HD-MTX, the HD-MTX + procarbazine + vincristine (MPV) regimen showed pooled CRRs of 63% and 58% with and without rituximab, respectively, followed by the rituximab + HD-MTX + temozolomide regimen, which showed a pooled CRR of 60%. Pooled PFS and OS showed that post-remission consolidation with autologous stem cell transplantation (ASCT) was associated with the best survival outcome, with a pooled 2-year OS of 80%, a 2-year PFS of 74%, a 5-year OS of 77%, and a 5-year PFS of 63%. Next, whole-brain radiation therapy (WBRT) + chemotherapy showed a pooled 2-year OS of 72%, 2-year PFS of 56%, 5-year OS of 55%, and 5-year PFS of 41%, with no detectable CR heterogeneity throughout the entire treatment process. In HD-MTX-based therapy of newly diagnosed PCNSL, MPV with or without rituximab can be chosen as the inductive regimen, and the rituximab + HD-MTX + temozolomide regimen is also a practical choice. Based on our study, high-dose chemotherapy supported by ASCT is an efficacious approach for consolidation. Consolidation with WBRT + chemotherapy can be another feasible approach.

Pharmacodynamics of High-Dose Methotrexate in Pediatric Patients

2002 ◽  
Vol 36 (9) ◽  
pp. 1344-1350 ◽  
Author(s):  
Irene Aquerreta ◽  
Azucena Aldaz ◽  
Joaquín Giráldez ◽  
Luis Sierrasesúmaga
Keyword(s):  
High Risk ◽  
Daily Practice ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
High Dose ◽  
Hematologic Toxicity ◽  
High Dose Methotrexate ◽  
Dose Methotrexate ◽  
Nonhematologic Toxicity ◽  
The Relationship

OBJECTIVE: To establish a relationship between the pharmacokinetics of high-dose methotrexate (MTX) and toxicity in children of a pediatric oncology department and to reassess MTX concentrations at which the patients would be at high risk for toxic effects. METHODS: This study included 37 patients (227 treatment courses) who received a median dose of 4.87 g/m2 of MTX in a 4-hour infusion. The population pharmacokinetic parameters of MTX were estimated by parametric (IT2B) and nonparametric methods (NPEM). Gastrointestinal, renal, and hematologic toxicity were evaluated. The relationship between pharmacokinetic parameters and toxicity was analyzed by logistic regression and multiple linear regression. RESULTS: Equations to predict hematologic and nonhematologic toxicity were obtained. An increase of 100 μmol/L in the MTX peak concentration meant a 12% (p = 0.03) higher risk of vomiting; a significant delay in MTX elimination implied a 5.76-fold higher risk of mucositis (p < 0.001). An increase of 1 μmol/L in the MTX concentration 24 hours after the end of the infusion (Cp24h) led to a 43% increase in the risk of renal toxicity (p < 0.001). Hematologic toxicity was significantly conditioned by the baseline leukocyte count and Cp24h (p < 0.001). CONCLUSIONS: The analysis of high-dose MTX pharmacokinetic/pharmacodynamic relationship to toxicity has led to equations able to predict toxicity that are easily applicable to daily practice. Cp24h >3.5 μmol/L was confirmed as an indicator of high risk of toxicity.

Timing of high dose methotrexate CNS prophylaxis in DLBCL: a multicenter international analysis of 1,384 patients

Blood ◽  
2022 ◽  
Author(s):  
Matthew R. Wilson ◽  
Toby Andrew Eyre ◽  
Amy A Kirkwood ◽  
Nicole Wong Doo ◽  
Carole Soussain ◽  
...  
Keyword(s):  
High Risk ◽  
International Prognostic Index ◽  
Multivariable Analysis ◽  
B Cell Lymphoma ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Cns Prophylaxis ◽  
Dose Methotrexate ◽  
Cns Relapse ◽  
Increased Risk

Prophylactic high-dose methotrexate (HD-MTX) is often used for diffuse large B-cell lymphoma (DLBCL) patients at high risk of central nervous system (CNS) relapse, despite limited evidence demonstrating efficacy or the optimal delivery method. We conducted a retrospective, international analysis of 1,384 patients receiving HD-MTX CNS prophylaxis either intercalated (i-HD-MTX) (n=749) or at the end (n=635) of R-CHOP/R-CHOP-like therapy (EOT). There were 78 CNS relapses (3-year rate 5.7%), with no difference between i-HD-MTX and EOT; 5.7% vs 5.8%, p=0.98, 3-year difference: 0.04% (-2.0% to 3.1%). Conclusions were unchanged on adjusting for baseline prognostic factors or on 6-month landmark analysis (n=1,253). In patients with high CNS international prognostic index (n=600), 3-year CNS relapse rate was 9.1% with no difference between i-HD-MTX and EOT. On multivariable analysis, increasing age and renal/adrenal involvement were the only independent risk factors for CNS relapse. Concurrent intrathecal prophylaxis was not associated with reduction in CNS relapse. R-CHOP delays of ≥7 days were significantly increased with i-HD-MTX versus EOT, with 308/1573 (19.6%) i-HD-MTX treatments resulting in delay to subsequent R-CHOP (median 8 days). Increased risk of delay occurred in older patients when delivery was later than day 10 in the R-CHOP cycle. In summary, we found no evidence that EOT delivery increases CNS relapse risk versus i-HD-MTX. Findings in high-risk subgroups were unchanged. Rates of CNS relapse in this HD-MTX-treated cohort were similar to comparable cohorts receiving infrequent CNS prophylaxis. If HD-MTX is still considered for certain high-risk patients, delivery could be deferred until R-CHOP completion.

scholarly journals DA-EPOCH-R combined with high-dose methotrexate in patients with newly diagnosed stage II-IV CD5-positive diffuse large B-cell lymphoma: a single-arm, open-label, phase II study

Haematologica ◽  
2020 ◽  
Vol 105 (9) ◽  
pp. 2308-2315 ◽  
Author(s):  
Kana Miyazaki ◽  
Naoko Asano ◽  
Tomomi Yamada ◽  
Kohta Miyawaki ◽  
Rika Sakai ◽  
...  
Keyword(s):  
Response Rate ◽  
Phase Ii Study ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Stage Ii ◽  
High Dose ◽  
Newly Diagnosed ◽  
Large B Cell Lymphoma ◽  
Dose Methotrexate ◽  
Large B Cell

CD5-positive diffuse large B-cell lymphoma (CD5+ DLBCL) is characterized by poor prognosis and a high frequency of central nervous system relapse after standard immunochemotherapy. We conducted a phase II study to investigate the efficacy and safety of dose-adjusted (DA)- EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) combined with high-dose methotrexate (HD-MTX) in newly diagnosed patients with CD5+ DLBCL. Previously untreated patients with stage II to IV CD5+ DLBCL according to the 2008 World Health Organization classification were eligible. Four cycles of DA-EPOCH-R followed by two cycles of HD-MTX and four additional cycles of DAEPOCH- R (DA-EPOCH-R/HD-MTX) were planned as the protocol treatment. The primary end point was 2-year progression-free survival (PFS). Between September 25, 2012, and November 11, 2015, we enrolled 47 evaluable patients. Forty-five (96%) patients completed the protocol treatment. There were no deviations or violations in the DA-EPOCH-R dose levels. The complete response rate was 91%, and the overall response rate was 94%. At a median follow up of 3.1 years (range, 2.0-4.9 years), the 2- year PFS was 79% [95% confidence interval (CI): 64-88]. The 2-year overall survival was 89% (95%CI: 76-95). Toxicity included grade 4 neutropenia in 46 (98%) patients, grade 4 thrombocytopenia 12 (26%) patients, and febrile neutropenia in 31 (66%) patients. No treatment-related death was noted during the study. DA-EPOCH-R/HD-MTX might be a first-line therapy option for stage II-IV CD5+ DLBCL and warrants further investigation. (Trial registered at: UMIN-CTR: UMIN000008507.)

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