High-dose osimertinib for CNS progression in EGFR+ non-small cell lung cancer (NSCLC): A multi-institutional experience.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 9586-9586 ◽  
Author(s):  
Andrew Piper-Vallillo ◽  
Julia K Rotow ◽  
Jacqueline V Aredo ◽  
Khvaramza Shaverdashvili ◽  
Jia Luo ◽  
...  
Keyword(s):  
Disease Control ◽  
Dose Escalation ◽  
Leptomeningeal Disease ◽  
High Dose ◽  
Treatment Intensification ◽  
Cns Disease ◽  
Kaplan Meier ◽  
Institutional Experience ◽  
Life Threatening ◽  
Parenchymal Disease

9586 Background: High-dose osimertinib 160 mg QD (osi160) has activity in osi-naïve, EGFR+ NSCLC pts with CNS or leptomeningeal disease (LMD) per the BLOOM trial, but the role of dose-escalation for CNS progression (PD) and/or LMD that develops while on 80 mg QD (osi80) is unclear. We describe here our multi-institutional experience with osi160. Methods: 105 pts from 8 institutions with advanced EGFR+ NSCLC treated with osi160 were retrospectively reviewed. To assess the CNS efficacy of dose escalation for CNS PD, we focused on pts who escalated from osi80 to osi160 for CNS PD without the addition of chemo and/or RT during dose escalation (cohort A, 24 pts). We also examined osi escalation for CNS PD while receiving chemo and/or RT (cohort B, 34 pts) and those who started on osi160 for CNS PD as the initial osi dose without overlapping therapies (cohort C, 11 pts). Radiographic responses were clinically assessed via chart review of scan reports. Kaplan-Meier analysis was used for time-to-event endpoints. We defined median duration of CNS disease control (MedDurCNSCon) on osi160 as time from the start of osi160 to CNS PD or discontinuation of osi160. Results: Among the 105 pts, 69 (26M, 43F; median age 57) EGFR+ NSCLC pts (29 del19, 31 L858R, 9 other) received osi160 for CNS PD between 10/2013 and 1/2020. Median lines of therapy pre-osi was 1 (range 0-8). While all 69 pts had CNS PD at the start of osi160, 61 (90%) had isolated CNS/LMD PD, without systemic PD. In cohort A, osi160 monotherapy had a MedDurCNSCon of 3.8 mos (95% CI, 1.7 – 5.8). Cohort A pts with isolated LMD (11) had MedDurCNSCon 5.8 mos (95% CI, 1.7 – 9) while those with parenchymal mets only (11) had MedDurCNSCon of 2 mos (95% CI, 1 - 4.9). In cohort B, osi160 in combination with RT (22) and/or chemo (14), had a MedDurCNSCon of 5.1 mos (95% CI, 3.1 – 6.5). In cohort C, osi160 monotherapy had a MedDurCNSCon of 4.2 mos (95% CI, 1.6 – NA). Pts on osi160 had no severe or life-threatening side effects. Conclusions: In this real-world cohort of EGFR+ NSCLC pts with CNS and/or LMD PD on osi80, dose escalation to 160 provided modest benefit with median 3.8 mos added CNS disease control. Dose escalation appeared more effective in pts with LMD versus parenchymal disease (MedDurCNSCon of 5.8 vs 2 mos). Treatment intensification with osi escalation plus RT and/or chemo appeared to confer about 1 month additional CNS disease control (power for comparison limited). Osi naïve pts started at 160 for CNS PD derived similar benefit. While limited by small numbers and retrospective design, this study suggests we need improved strategies to optimally manage CNS PD arising on osi80.

scholarly journals RARE-42. INCIDENCE AND BEHAVIOR OF CENTRAL NERVOUS SYSTEM INVOLVEMENT IN PATIENTS WITH HODGKIN’S LYMPHOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi230-vi230
Author(s):  
Carlos Eduardo Silva Correia ◽  
Rachna Malani ◽  
Lisa DeAngelis ◽  
Alison Moskowitz
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Median Time ◽  
Hodgkin’S Lymphoma ◽  
Systemic Disease ◽  
Hodgkin's Lymphoma ◽  
Leptomeningeal Disease ◽  
High Dose ◽  
Cns Involvement ◽  
Cns Disease

Abstract INTRODUCTION Central nervous system (CNS) involvement from Hodgkin’s Lymphoma (HL) is rare, with a reported incidence of 0.07–0.5%. There is a paucity of data regarding its natural history and management. METHODS In this retrospective single-institution review, we analyzed all adult patients with HL for CNS involvement (parenchymal or meningeal), who were evaluated at Memorial Sloan Kettering Cancer Center from January 2008 until December 2018. RESULTS A total of 3478 patients with HL were identified, and CNS involvement was found in 10 patients (0.3%). All patients were symptomatic from CNS disease. Four patients had a synchronous presentation. The other 6 patients had a median time from systemic diagnosis to CNS involvement of 8 years (2.5–14). Two patients had radiographic evidence of leptomeningeal disease, however 4 had positive cerebrospinal fluid (CSF) cytology. At time of CNS involvement, 2 patients had confirmed transformation to Non-Hodgkin-Lymphoma on biopsy. 2 patients had EBV-positive HL. One patient died before treatment. Five patients received high-dose methotrexate (HD-MTX) for CNS disease. Of these patients, 1 died during treatment, 2 had partial responses, and 2 had complete response of both systemic and CNS disease; to date they are in remission. Three patients had varied responses to immunotherapy and cytotoxic chemotherapy. Removal of an immunosuppressive agent resolved disease in one EBV-positive patient. Median overall survival (OS) from diagnosis of HL was 10.6 years (1.1–21.2), and OS from time to CNS involvement was 6 years (0.2–15). CONCLUSION The median time from diagnosis to CNS involvement, and OS from time of CNS involvement are higher than previously reported, which may be related to newer therapies for systemic disease. Neuroimaging should be used in conjunction with CSF for diagnostic accuracy. HD-MTX can be used to treat CNS and refractory systemic disease, as historically used for the latter.

An Outcome Study On Survival and Disease Control in Patients with High-Risk Multiple Myeloma (MM) for Relapse, Treated with High-Dose Melphalan Combined with Bortezomib for Autotransplant Followed by Post-Transplant Maintenance with Bortezomib and Lenalidomide.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3404-3404
Author(s):  
Choon Kee Lee ◽  
Jeff Kaiser ◽  
Han Myint ◽  
Mary Berg ◽  
J. Fred Kolhouse ◽  
...  
Keyword(s):  
High Risk ◽  
Disease Control ◽  
High Dose ◽  
Term Survival ◽  
Post Transplant ◽  
Kaplan Meier ◽  
Number Of Patients ◽  
High Dose Melphalan

Abstract Abstract 3404 Poster Board III-292 Long-term survival and disease control following autotransplant have been known to be poor in symptomatic MM patients who were in relapse prior to transplant, had adverse cytogenetic abnormalities (CA) or high LDH (> 190 IU/mL) at diagnosis. In the study, we sought to improve the outcome of these patients by combining bortezomib with standard high-dose melphalan for autotransplant and implementing 3-year post-transplant maintenance with bortezomib, lenalidomide and dexamethasone. Between September 2006 and March 2009, 34 patients (median age 62, range 38 to 77 years) were accrued to the sequential regimens of 1) tandem autotransplant prepared by the MVD of ‘melphalan 200 mg/m2 (D-1) + bortezomib 1.3 mg/m2 × 2 (D-4, D-1) + dexamethasone 20 mg x 4 (D-4 through D-1)’; 2) the VLD of ‘bortezomib 1.3 mg/m2/day x 4 (D1, 4, 8, 11) + lenalidomide 10 mg/day x 14 (D1 through 14) + dexamethasone 20 mg/day x 4 (D1, 4, 8, 11)’ q 3 months for 2 years; 3) the LD of ‘monthly lenalidomide 10 mg/day x 14 + dexamethasone 20 mg q Monday in between of the VLD for the first 2 years, followed by a monthly course for the 3rd year. Of the 34 patients, 11 (32%) had unfavorable CA, 15 (44%) high LDH and 10 (29%) prior relapse. 16 patients (47%) had immunoglobulin (Ig) G, 10 (29%) Ig A, 6 (18%) light chain only and 2 (6%) nonsecretory MM. 14 patients (41%) received tandem transplant and 20 (59%) single transplant due to insurance reasons. 32 patients (94%) were able to maintain the treatment until the last follow-up on August 15, 2009 or until relapse or death. 19 patients achieved either a stringent complete remission (s-CR) (n = 16) or CR (n = 3), with an 1-year cumulative incidence (CI) of 46%. 2 additional patients achieved CR following the 2nd transplant. During the maintenance, 3 additional patients achieved s-CR (N = 1) or CR (n = 2), resulting in 71% of the 18-mo CI of response > CR. By the landmark analysis at the time of transplant, the estimated 3-year Kaplan-Meier survival, CI of relapse and event free survival (EFS) are 96% with 2 deaths (1 of MM, 1 of pulmonary embolism), 15% with 5 relapses and 70% with 6 events, respectively. Presence of CA impacted adversely the EFS: 61% of patients without CA vs. 39% of those with CA (Logrank p = 0.06). However, a history of prior relapse or high LDH was not associated with inferior EFS: 42% with prior relapse vs. 76% without prior relapse (p = 0.27); 45% with high LDH vs. 51% with normal LDH (p = 0.86). Although the current findings are limited by the small number of patients and the short duration of follow-up, the data suggests that additional bortezomib to the standard high-dose melphalan and implementation of long-term maintenance post-transplant with bortezomib and lenalidomide may overcome the adverse factors in high-risk MM patients for relapse. Further study is necessary to confirm the findings. Disclosures: Myint: Seattle Genetics, Inc.: Research Funding.

scholarly journals High Dose Infliximab in the Treatment of Refractory Uveitis: Does Dose Matter?

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Sukesh Sukumaran ◽  
Katherine Marzan ◽  
Bracha Shaham ◽  
Andreas Reiff
Keyword(s):  
Los Angeles ◽  
Disease Control ◽  
Dose Escalation ◽  
Chart Review ◽  
Retrospective Chart Review ◽  
High Dose ◽  
Topical Steroids ◽  
Optimal Dosing ◽  
Control Disease ◽  
Achieve Disease Control

Background. Infliximab (INF) has been shown to be beneficial in treating refractory uveitis, however, no data exist on optimal dosing and the efficacy of higher dosing. Objectives. To compare the efficacy of low-dose (LD) (<10 mg/kg), moderate-dose (MD) (≥10–15 mg/kg), and high-dose (HD) INF (≥15–20 mg/kg) in the treatment of uveitis. Methods. Retrospective chart review children with uveitis diagnosed at Childrens Hospital Los Angeles and Millers Children’s Hospital, CA, USA. Results. Of the 34 INF-treated children, 6 patients received LD, 19 received MD, and 9 received HD. Average disease duration prior to therapy was 10.6, 24.6, and 37.1 months each group, respectively. Topical steroids were discontinued after an average of 3 months, 9.5 months, and 10.2 months in the LD, MD, and HD groups, respectively. We found that 66% of patients receiving LD, 42% of MD, and 66% receiving HD INF failed therapy and required either dose escalation or alternate medication for disease control. Conclusions. INF is beneficial in the treatment of uveitis, and dose escalation up to 4 times above the approved dose is often necessary to achieve disease control in patients with uveitis. Doses < 10 mg/kg every 4 weeks may not be sufficient to control disease.

scholarly journals Radiation therapy dose and androgen deprivation therapy in localized prostate cancer: a meta-regression of 5-year outcomes in phase III randomized controlled trials

2021 ◽  
Author(s):  
Tommy Jiang ◽  
Daniela Markovic ◽  
Jay Patel ◽  
Jesus E. Juarez ◽  
Ting Martin Ma ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Radiation Therapy ◽  
Androgen Deprivation Therapy ◽  
Dose Escalation ◽  
Low Dose ◽  
Androgen Deprivation ◽  
Phase Iii ◽  
Localized Prostate Cancer ◽  
Treatment Intensification ◽  
Meta Regression

Abstract Background While multiple randomized trials have evaluated the benefit of radiation therapy (RT) dose escalation and the use and prolongation of androgen deprivation therapy (ADT) in the treatment of prostate cancer, few studies have evaluated the relative benefit of either form of treatment intensification with each other. Many trials have included treatment strategies that incorporate either high or low dose RT, or short-term or long-term ADT (STADT or LTADT), in one or more trial arms. We sought to compare different forms of treatment intensification of RT in the context of localized prostate cancer. Methods Using preferred reporting items for systemic reviews and meta-analyses (PRISMA) guidelines, we collected over 40 phases III clinical trials comparing different forms of RT for localized prostate cancer. We performed a meta-regression of 40 individual trials with 21,429 total patients to allow a comparison of the rates and cumulative proportions of 5-year overall survival (OS), prostate cancer-specific mortality (PCSM), and distant metastasis (DM) for each treatment arm of every trial. Results Dose-escalation either in the absence or presence of STADT failed to significantly improve any 5-year outcome. In contrast, adding LTADT to low dose RT significantly improved 5-year PCSM (Odds ratio [OR] 0.34, 95% confidence interval [CI] 0.22–0.54, p < 0.001) and DM (OR 0.35, 95% CI 0.20–0.63. p < 0.001) over low dose RT alone. Adding STADT also significantly improved 5-year PCSM over low dose RT alone (OR 0.55, 95% CI 0.41–0.75, p < 0.001). Conclusion While limited by between-study heterogeneity and a lack of individual patient data, this meta-analysis suggests that adding ADT, versus increasing RT dose alone, offers a more consistent improvement in clinical endpoints.

scholarly journals Mebendazole and temozolomide in patients with newly diagnosed high-grade gliomas: Results of a phase 1 clinical trial

2020 ◽  
Author(s):  
Gary L Gallia ◽  
Matthias Holdhoff ◽  
Henry Brem ◽  
Avadhut D Joshi ◽  
Christine L Hann ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Plasma Levels ◽  
Phase 1 ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
High Grade ◽  
Newly Diagnosed ◽  
Kaplan Meier ◽  
High Grade Gliomas ◽  
Expansion Cohort

Abstract Background Mebendazole is an anthelmintic drug introduced for human use in 1971 that extends survival in preclinical models of glioblastoma and other brain cancers. Methods A single center dose escalation and safety study of mebendazole in 24 patients with newly diagnosed high-grade gliomas (HGG) in combination with temozolomide was conducted. Patients received mebendazole in combination with adjuvant temozolomide after completing concurrent radiation plus temozolomide. Dose escalation levels were 25, 50, 100 and 200 mg/kg/day of oral mebendazole. A 15-patient expansion cohort was conducted at the maximum tolerated dose of 200 mg/kg/day. Trough plasma levels of mebendazole were measured at 4, 8 and 16 weeks. Results Twenty-four patients (18 glioblastoma, 6 anaplastic astrocytoma) were enrolled with median age of 49.9 years. Four patients (at 200 mg/kg) developed elevated grade 3 ALT and/or AST after one month, which reversed with lower dosing or discontinuation. Plasma levels of mebendazole were variable but generally increased with dose. Kaplan Meier analysis showed a 21-month median survival with 43% of patients alive at two years and 25% at 3 and 4 years. Median progression free survival (PFS) from the date of diagnosis for 17 patients taking more than one month of mebendazole was 13.1 months (95% Confidence Interval: 8.8 to 14.6 months) but for seven patients who received less than one month of mebendazole PFS was 9.2 months (95% CI: 5.8 -13.0 months). Conclusion Mebendazole at doses up to 200 mg/kg demonstrated long-term safety and acceptable toxicity. Further studies are needed to determine mebendazole’s efficacy in patients with HGG.

929 Not Another Abscess - A Case of Streptococcal Myositis Misdiagnosed as a Right Axillary Abscess

2021 ◽  
Vol 108 (Supplement_2) ◽  
Author(s):  
O Oyende ◽  
J Jackman
Keyword(s):  
White Cell Count ◽  
General Surgeon ◽  
High Dose ◽  
General Anaesthetic ◽  
Microbiological Analysis ◽  
Reactive Protein ◽  
Affected Tissue ◽  
Life Threatening ◽  
History Of ◽  
High Degree

Abstract Introduction Streptococcal myositis is a rare form of infectious myositis caused by Lansfield A beta-haemolytic streptococci. It is characterised by rapidly spreading inflammation that can result in severe systemic toxicity and necrosis of the affected tissue if not diagnosed and aggressively treated. Presentation We report a case of a 42-year-old male who presented with a one-week history of worsening right axillary swelling that progressed to painful swelling of his arm. Inflammatory markers were significantly elevated with a white cell count of 17 ×109/L and C-reactive protein of 212 mg/L. On examination, a fluctuant axillary swelling was appreciated, and a decision was made for incision and drainage under general anaesthetic. Intraoperative aspiration of his arm revealed copious purulent fluid prompting intraoperative orthopaedic consult and exploration of the anterior compartment in which there was extensive involvement of the biceps muscle. The microbiological analysis revealed gram-positive cocci in chains, and microbiology advice sought for tailoring of antibiotic regimen. He has recovered well. Discussion Though uncommon, the emergency general surgeon should have a high degree of suspicion when evaluating soft tissue infections to avert potentially disastrous outcomes. Conclusion Early diagnosis, aggressive management with high-dose intravenous antibiotics, and surgical debridement are principles to treat this rare, life-threatening infection.

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