Combination Therapy With Remdesivir, Dexamethasone, and Tocilizumab in Patients With Severe Corona Virus Disease 2019 in Clinical Practice

2020 ◽  
Author(s):  
Takehiro Izumo ◽  
Minoru Inomata ◽  
Naoyuk Kuse ◽  
Nobuyasu Awano ◽  
Mari Tone ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Mortality Rate ◽  
Combination Therapy ◽  
Adverse Events ◽  
Combination Treatment ◽  
Virus Disease ◽  
Medical Center ◽  
Single Agent ◽  
Red Cross ◽  
Control Group

Abstract BackgroundThe use of several promising drugs for coronavirus disease 2019 (COVID-19) has emerged. However, considering the pathophysiology of COVID-19, the effect of a single agent is limited. Hence, the current study aimed to compare the clinical outcomes between patients who received combination treatment with remdesivir, dexamethasone, and tocilizumab (RDT) and those who did not.MethodsPatients who received combination therapy with RDT at Japanese Red Cross Medical Center were included in the RDT group, and those who did not in the control group. The mortality rate and presence of severe adverse events were compared between the two groups.ResultsIn total, 46 patients (n = 29, control group and n = 17, RDT group) with severe COVID-19 were enrolled in this study. The 28-day mortality rate was significantly lower in the RDT group than in the control group, with 1 (6%) and 9 (31%) deaths recorded, respectively (P = 0.04). Further, both groups did not present with severe adverse events.ConclusionsInformation on the outcomes of combination therapy with RDT was considered useful for the treatment of severe COVID-19.

scholarly journals In Vitro Synergy and In Vivo Activity of Tigecycline-Ciprofloxacin Combination Therapy against Vibrio vulnificus Sepsis

2019 ◽  
Vol 63 (10) ◽  
Author(s):  
Seong Eun Kim ◽  
Hee Kyung Kim ◽  
Su-Mi Choi ◽  
Yohan Yu ◽  
Uh Jin Kim ◽  
...  
Keyword(s):  
Survival Rate ◽  
Mortality Rate ◽  
Combination Therapy ◽  
Combination Treatment ◽  
Vibrio Vulnificus ◽  
Antibiotic Regimen ◽  
Content Type ◽  
Time Kill

ABSTRACT The mortality rate associated with Vibrio vulnificus sepsis remains high. An in vitro time-kill assay revealed synergism between tigecycline and ciprofloxacin. The survival rate was significantly higher in mice treated with tigecycline plus ciprofloxacin than in mice treated with cefotaxime plus minocycline. Thus, combination treatment with tigecycline-ciprofloxacin may be an effective novel antibiotic regimen for V. vulnificus sepsis.

scholarly journals Combination therapy with beraprost sodium and aspirin for acute ischemic stroke: a single-center retrospective study

2019 ◽  
Vol 47 (7) ◽  
pp. 3014-3024 ◽  
Author(s):  
De Cai ◽  
Xiao-Pu Chen ◽  
Dun-Can Wei ◽  
Qian Zhang ◽  
Si-Qia Chen ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Retrospective Study ◽  
Combination Therapy ◽  
Adverse Events ◽  
Acute Ischemic Stroke ◽  
Blood Coagulation ◽  
Control Group ◽  
Single Center ◽  
Beraprost Sodium ◽  
Significant Difference

Objectives To evaluate the effectiveness and safety of the combination of beraprost sodium (BPS) and aspirin in patients with acute ischemic stroke (AIS). Methods There were 384 patients with AIS enrolled in this single-center, retrospective study. The BPS group comprised patients who received combination therapy with BPS and aspirin, and the control group comprised those who received only aspirin. Primary measurements were glomerular filtration rate (GFR), cystatin-c (Cys-C), National Institute of Health Stroke Scale (NIHSS) score, modified activities of daily living index (MBI), modified Rankin scale (mRS), and blood coagulation indexes. Recurrence and adverse events were recorded. Results There were no significant differences in patient characteristics at baseline between the two groups. GFR and Cys-C levels increased in the BPS group compared with the control group. After treatment, the NIHSS and mRS score were significantly lower in the BPS group compared with the control group, whereas the MBI scores were significantly higher in the BPS group compared with the control group. There was no significant difference in blood coagulation between the two groups. There were no serious adverse events in either group. Conclusions Combination therapy with BPS and aspirin may be a safe and effective treatment for AIS.

scholarly journals 1% ivermectin in combination therapy regimens for rosacea

2020 ◽  
pp. 17-23
Author(s):  
E. A. Khlystova ◽  
A. L. Savastenko
Keyword(s):  
Quality Of Life ◽  
Comparative Analysis ◽  
Combination Therapy ◽  
Combination Treatment ◽  
Clinical Manifestations ◽  
Life Quality ◽  
Clinical Results ◽  
Control Group ◽  
Before And After

Introduction. The article provides latest data on modern methods of treating rosacea. The results of own clinical observations of patients with moderate to severe papulopustular rosacea receiving combination treatment and a comparative analysis of the efficacy of various therapy regimens are presented.Objective of the study. The aim of the study was to conduct a comparative analysis of the therapeutic efficacy of combination therapy using the ivermectin 1% topical drug combined with systemic therapy drugs (doxycycline, minocycline, isotretinoin).Materials and methods. We observed 37 patients with moderate to severe papulo-pustular rosacea subtype. The patients were divided into 4 groups (A, B, C, D). Patients in the control group received monotherapy with 1% ivemectin topical drug, patients in the other groups received combination therapy (1% ivermectin combined with low-dose doxycycline, minocycline and isotretinoin). The efficacy of the therapy was evaluated by measuring rosacea severity on the Scale for Diagnostic Assessment of Rosacea (SDAR), clinical manifestations according to the IGA (Investigator Global Assessment) criteria, and by assessing the patients' quality of life using the DLQI (Dermatology Life Quality Index) questionnaire before and after 3-month treatment.Results. The comparative analysis of changes in severity indicators of the skin process and quality of life in patients with moderate to severe papulopustular rosacea after topical and combination therapy showed that the results of the treatment in patients receiving combination therapy were more significant than those in the group receiving monotherapy.Conclusion. The concomitant use of 1% ivermectin and systemic drugs is most effective in patients with severe papulopustular rosacea subtype. The combination treatment tailored to the clinical forms and severity of rosacea allows to optimize the clinical results of the therapy, which significantly affects the patients' quality of life and opens up potential for an individual approach in the algorithms for the treatment of rosacea.

Safety and efficacy of combination of etanercept and methotrexate compared to treatment with etanercept only in patients with juvenile idiopathic arthritis (JIA): preliminary data from the German JIA Registry

2008 ◽  
Vol 68 (4) ◽  
pp. 519-525 ◽  
Author(s):  
G Horneff ◽  
F De Bock ◽  
I Foeldvari ◽  
H J Girschick ◽  
H Michels ◽  
...  
Keyword(s):  
Juvenile Idiopathic Arthritis ◽  
Combination Therapy ◽  
Adverse Events ◽  
Control Group ◽  
Monotherapy Group ◽  
Serious Adverse Events ◽  
Safety And Efficacy ◽  
Randomised Study ◽  
Treatment Groups ◽  
American College Of Rheumatology

Objective:Etanercept monotherapy has been studied and approved for treatment of polyarticular juvenile idiopathic arthritis (JIA). The following study evaluates the safety and efficacy of combination therapy of etanercept and methotrexate compared to etanercept monotherapy in JIA.Methods:We perfomed an open, non-randomised study on patients who had previously failed to respond to at least one disease-modifying antirheumatic drug (DMARD). A total of 722 patients with JIA in whom at least 1 item of follow-up data was recorded were identified; of these, 118 patients treated with further slow acting drugs were excluded. In all, 504 patients were treated with a combination of etanercept and methotrexate. A total of 100 patients treated with etanercept only were in the control group. Efficacy was calculated using the American College of Rheumatology paediatric scores for 30, 50 and 70% improvement (PedACR30/50/70). Adverse events (AEs) and serious adverse events (SAEs) were reported.Results:After 12 months 55 patients in the monotherapy group and 376 patients in the etanercept and methotrexate group were available for comparison. For the intention to treat analysis, 65 patients discontinuing treatment prematurely were included. All activity parameters decreased significantly in both treatment groups. After 12 months 81%/74%/62% of patients of the etanercept and methotrexate group and 70%/63%/45% of patients of the etanercept monotherapy group achieved PedACR30/50/70 scores, respectively (p<0.05 for PedACR30, p<0.01 for PedACR70). The likelihood of achieving a PedACR70 increased with combination therapy with an odds ratio of 2.1 (95% CI 1.2 to 3.5). In total, 25 infectious and 23 non-infectious SAEs including 3 malignancies occurred in the etanercept and methotrexate group, and 1 infectious and 3 non-infectious SAEs occurred in the single etanercept group.Conclusions:The patients’ disease activity improved during etanercept monotherapy and etanercept and methotrexate combination therapy. Tolerability in both treatment groups was comparable.

658 Toxicities of single agent and combination immune checkpoint inhibitors in patients with pre-existing autoimmune diseases

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A695-A695
Author(s):  
Sabina Sandigursky ◽  
Safa Houssein ◽  
Xerxes Pundole ◽  
Elizaveta Efuni ◽  
Samuel Cytryn ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Adverse Events ◽  
Autoimmune Diseases ◽  
Immune Checkpoint ◽  
Single Agent ◽  
Group Versus ◽  
Cancer Center ◽  
Combination Group ◽  
Safety And Efficacy ◽  
Increased Risk

BackgroundAutoimmunity is associated with increased risk of malignancy. However, patients with pre-existing autoimmune diseases (AIDs) were excluded from immune checkpoint inhibitor (ICI) trials as these agents can cause immune-related adverse events (irAEs). Data are limited on the safety and efficacy of combination immunotherapy in this at-risk population.MethodsWe conducted a multi-center retrospective study to evaluate the safety and efficacy of ICI therapy in patients with pre-existing AID treated at NYU and at MD Anderson Cancer Center. Primary endpoints were occurrence of irAEs and AID flares. Secondary endpoints were time to treatment failure (TTF) and overall survival (OS).ResultsOf 121 patients identified from our institutional databases, 53% received single-agent anti-PD-1 therapy, and 47% received ICI combination. Over half of malignancies were lung cancer (34%) and melanoma (20%). Preexisting AIDs included: rheumatologic (58%), gastrointestinal (12%), endocrine (16%) and neurologic (4%). Overall, 94% had asymptomatic AID, and 21% were receiving systemic immunomodulatory drugs at ICI initiation. Median duration of follow up after ICI initiation was 9 (0.4–41.9) months in patients receiving ICI combination and 8 (0.2–47.3) months in patients receiving anti-PD-1 monotherapy. Combination therapy was associated with higher rates of irAEs compared with anti-PD-1 monotherapy (56% versus 28%). Grade 3/4 irAEs were equivalent in both groups: combination (38%) and anti-PD-1 group (39%). Treatment related deaths were not observed in any group. AID flares occurred in 36% of the anti-PD-1 group versus 29% of combination group. Adverse events (irAEs and/or flares) required systemic immunomodulatory therapies more frequently in the combination group (84%) versus the anti-PD-1 group (59%), and permanent ICI discontinuation was reported in 19% of patients in the combination group versus 11% in the anti-PD-1 group. Tumor progression was observed in 49% of patients on combination ICI and TTF was 14.5 months (95% CI 0.000–31.5), while progression was observed in 64% of patients on anti-PD-1 monotherapy and TTF was 6.4 months (95% CI 4.01–8.9) (p=0.019). Median OS in the combination therapy group was not reached whereas it was 27.3 months in the anti-PD-1 monotherapy group.ConclusionsOur novel findings suggest that high rates of adverse events were observed in patients with pre-existing AIDs treated with ICI combination therapy. However, they were manageable and rarely required permanent ICI discontinuation. Taken together, these data show that ICIs should be offered, albeit with caution in patients with AIDs, to achieve durable cancer remission. Prospective clinical data are needed to guide these complex decisions.Ethics ApprovalThe study was approved by NYU Langone’s Ethics Board, approval number i18-01657 and MD Anderson’s Ethics Board, approval number PA19-0089

scholarly journals Efficacy and Toxicity Profile of Elotuzumab for Multiple Myeloma: A Systematic Review and Meta-Analysis

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5640-5640
Author(s):  
Faiza Jamil ◽  
Madeeha Shafqat ◽  
Sharoon Samuel ◽  
Zunairah Shah ◽  
Ceren Durer ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Adverse Events ◽  
Meta Analysis ◽  
Single Agent ◽  
Random Effect Model ◽  
Drug Regimen ◽  
Pooled Analysis ◽  
Cochrane Library ◽  
Control Group

Abstract Background: Elotuzumab (elo) is a humanized monoclonal antibody, which has been approved by the FDA for use in combination with lenalidomide (lena) and dexamethasone (dexa) in patients (pts) with relapsed and refractory multiple myeloma (RRMM). Elotuzumab is effective as a single agent, as well as in combination for multiple myeloma treatments, supporting the use of elo in pts with RRMM and newly diagnosed multiple myeloma (NDMM) pts. Method: After review of literature using database searches was done on 6/27/18 (Pubmed, Embase, Cochrane Library, Web of Science and Clinical Trials.gov), 9 prospective and 1 retrospective study with 1128 enrolled pts met the inclusion criteria to date in RRMM and 2 clinical trials including 123 pts in NDMM (Table 1). CMA software v.3 was used for meta-analysis. A random-effect model was applied. Result: Regimens used in RRMM: Based on pooled analysis (95% CI), an overall response rate (ORR) of 66% (54-76.2) was calculated in 685 evaluable pts treated with elo based regimens in RRMM (Figure 1). Most common grade (G) ≥ 3 hematological adverse events (HAE) and non-hematological adverse events (NHAE) based on regimen were calculated using pooled analysis in RRMM pts (Table 2). Anemia was noted in 12.1% ( 7.7-18.6) in 559 pts, while neutropenia in 14.5% (7.5-26.4) out of 591 pts and thrombocytopenia (tcp) in 11.9% (7.9-17.4) in 198 evaluable pts. Diarrhea 5.5% (3.6-8.3), pyrexia 2.4% (1.5-4), peripheral neuropathy (PN) 8.4% (3.8-17.8) were measured in 626, 668 and 143 pts respectively. Elotuzumab as monotherapy: 1 study (n=34) evaluated the efficacy of elo as single agent in RRMM. The median age, time from diagnosis and number of prior therapies were 64.5 years (y) (46-87), 4.4 y (0.9-12.8) and 4.5 y (2-10) respectively. It produced an ORR of 1.4% (0.1-19.1 95% CI) in 34 evaluable pts. Adverse events recorded were pyrexia and fatigue in 17.6% and 8.8% pts respectively. Elotuzumab in two drug regimen: In RRMM, 2 clinical trials (n=49) evaluated the efficacy (95% CI) of elo, ORR of 25% (4.1-72.3) was calculated. The best PFS (progression free survival) produced was in combination of elo 20 mg with bortezumib (bort) 1.3mg/m2 of 9.46 months as compared to 1.8 months when elo10mg/kg + dexamethasone (dexa) 28mg was used. In our analysis for safety, common G≥ 3 HAE calculated were, thrombocytopenia 8.7% (3.3-21.1) n=49, neutropenia 10.7 % (3.5-28.4) n=28 pts and anemia 7.1% (1.8-24.5) n=28 pts. NHAE included diarrhea 1.7% (0.1-22.3), PN 10.7% (3.5-28.4), pyrexia 1.7% (0.1-22.3) in 28 evaluable pts each. Elotuzumab in three drug regimen: In RRMM, 10 clinical trials including 602 pts evaluated the efficacy of elo as a part of triple drug regimen, producing an ORR of 72.2% (54-76.2). The best results were produced with the combination of elo 10-20mg/kg + lenalidomide (lena) 25mg + dexa 40mg producing a PFS of 32.2 mo and 28.62 mo in its phase I and II cohorts respectively. Based on pooled analysis (95% CI) common HAE calculated were neutropenia 17.5% (7.6-35.4) in n=563, thrombocytopenia 12.7% (8.2-19.4) in n=149 and anemia 13% (8-20.5) in n=531 pts. Common G ≥ 3 NHAE estimated were diarrhea 5.7% (3.7-8.6), PN 6.6% (2-19.2), pyrexia 2.5% (1.5-4.1) in 598, 115 and 640 pts respectively. Elotuzumab based regimen in NDMM: A currently ongoing clinical trial NCT02272803 has produced promising results in NDMM pts. As a part of three drug regimen with dose of elo 10mg/kg-20mg/kg, lena 25mg, dexa 20mg in 40 pts produced an ORR of 87.5% (73.2-95.8) versus control group of lena 25mg plus dexa 40mg in 42 pts with an ORR of 73.8% (58-86.1). The PFS rate recorded at 1 year was 93% (79-98%) and 91% (73-97%) respectively. The HAE G ≥ 3 included, neutropenia 18% and leukopenia 15%. In another study with 41 pts, elo was used in combination with lena, bort and dexa producing an ORR of 100% and greater than grade 3 adverse events including Tcp 15%, PN 2%. Conclusion: Results produced in our study suggest that elotuzumab is highly effective when used in pts with RRMM and NDMM. Combination regimens for elo produces an ORR ranging from 79-83% with elo + lena+ dexa, proving that the best results were produced by three drug regimens. Large prospective studies are required to evaluate efficacy and safety of elotuzumab in combination therapies. Disclosures No relevant conflicts of interest to declare.

Continued high activity of figitumumab (CP-751,871) combination therapy in squamous lung cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 8072-8072
Author(s):  
D. D. Karp ◽  
S. Novello ◽  
F. Cardenal ◽  
P. Haluska ◽  
L. J. Blakely ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Adverse Events ◽  
High Activity ◽  
Tumor Size ◽  
Single Agent ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Small Data ◽  
Type I ◽  
Data Set

8072 Background: Figitumumab (CP-751,871) is a fully human, IgG2monoclonal antibody against the insulin-like growth factor type I receptor (IGF-IR). We reported in a randomized phase II study (ASCO 2008), preliminary evidence of high activity of the combination of paclitaxel (T), carboplatin (C) and figitumumab (F) in advanced treatment-naïve NSCLC of squamous cell histology (n=11 pts). A single arm trial extension cohort was conducted to confirm those findings. Methods: Fifty-six pts with non-adenocarcinoma NSCLC were enrolled. Pts received T (200 mg/m2), C (AUC of 6) and F (20 mg/kg) q3weeks for up to 6 cycles; pts with response (PR) or stable disease were eligible to continue F as single agent until disease progression. Statistical hypotheses were 30% (null) versus 50% (response of interest). Protein expression of the IGF-IR in core tumor biopsies was quantified using automated quantitative analysis (AQUA) technology. Results: Pts were 72% male, 28% >70 years old and 91% stage IV. Median number of treatment cycles was 4, with 46% of pts receiving single agent F beyond cycle 4. TCF was well tolerated. The most common all-causality grade 3, 4 CTCAE adverse events were neutropenia (21%), hyperglycemia (14%) and fatigue (14%). Hyperglycemia adverse events almost always occurred within the first treatment cycle and were manageable with standard measures. Responses in squamous pts are currently 25 out of 40 pts according to RECIST, with final response assessment still pending for 7 additional pts (≥53%, p<0.001). One complete response and 7 striking PRs (50–80% tumor size reduction at cycle 2) were observed. Tumor size reductions with F maintenance treatment were also seen in 2 pts. Median progression free survival has not been yet reached at 4 months follow up. A trend (p=0.1) for higher IGF-IR expression in patients responding to TCF was observed in a small data set (n=12). Median tumor IGF-IR expression in pts responding to TCF therapy and non-responders were respectively 6287 and 4131 AQUA scores. Analysis of IGF-IR and other members of the IGF-IR pathway continues. Conclusions: These data further support the activity of figitumumab combination therapy in pts with squamous NSCLC. [Table: see text]

Combination therapy with lenvatinib and anti-PD-1 antibodies for unresectable or advanced hepatocellular carcinoma: A real-world study.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16610-e16610
Author(s):  
Hui-Chuan Sun ◽  
Xiao-Dong Zhu ◽  
Cheng Huang ◽  
Ying-Hao Shen ◽  
Ning-Ling Ge ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Combination Therapy ◽  
Adverse Events ◽  
Combination Treatment ◽  
Tumor Regression ◽  
R0 Resection ◽  
Advanced Hepatocellular Carcinoma ◽  
First Line ◽  
Angiogenic Therapy ◽  
First Line Therapy

e16610 Background: Combination therapy of anti-angiogenic therapy and anti-PD-1 antibody had shown promising anti-tumor effects for advanced hepatocellular carcinoma (HCC) in clinical trials. Here we report the effectiveness and safety of the combination therapy of lenvatinib and anti-PD-1 antibodies in a cohort of unresectable or advanced HCC pts. Methods: From Sep 2018 to Jan 2020, 77 consecutive pts received a combination treatment of lenvatinib and an anti-PD-1 antibody. Lenvatinib was given 8 mg/d regardless of patient body weight and anti-PD-1 antibody was used either q2wk (nivolumab or camrelizumab) or q3wk (pembrolizumab, sintilimab or toripalimab). pts who completed at least one efficacy and safety assessment were eligible for this study. Tumor response were evaluated with abdominal contrast-enhanced MRI/CT and/or chest CT every 2 mo (± 1 wk). Laboratory tests were monitored every 2-3 wk. Results: 59 pts were eligible for this study. Of them, 1 (1.7%) were BCLC stage A, 10 (16.9%) were BCLC stage B, 48 (81.4%) were BCLC stage C (including 20 pts in China Liver Cancer [CNLC] stage IIIa and 28 in CNLC stage IIIb). 43 (72.9%) pts were treated as first-line therapy. The table below shows efficacy results. R0 resection was performed in 6 (10.2%) pts due to tumor regression. By the data cut-off date, 13 pts died, and mOS was not mature. Overall, the combination treatment was well tolerated. 28 (47.5%) pts had at least one ≥ grade 3 treatment-emergent adverse event. 3 (5.1%) pts died from immune-related adverse events, 2 of them died from immune-related adverse events after hepatectomy. Conclusions: The combination of lenvatinib + anti-PD-1 antibody is effective and well-tolerated in pts with HCC as first-line or second-line treatment. It is also noted that initially unresectable HCC may be converted to resectable HCC following this combination treatment. [Table: see text]

scholarly journals Prescreening and treatment of aortic dissection through an analysis of infinite-dimension data

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Peng Qiu ◽  
Yixuan Li ◽  
Kai Liu ◽  
Jinbao Qin ◽  
Kaichuang Ye ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Mortality Rate ◽  
Adverse Events ◽  
Aortic Dissection ◽  
Predictive Accuracy ◽  
Morphological Changes ◽  
Hospital Treatment ◽  
Control Group ◽  
Optimal Timing

Abstract Background Aortic dissection (AD) is one of the most catastrophic aortic diseases associated with a high mortality rate. In contrast to the advances in most cardiovascular diseases, both the incidence and in-hospital mortality rate of AD have experienced deviant increases over the past 20 years, highlighting the need for fresh prospects on the prescreening and in-hospital treatment strategies. Methods Through two cross-sectional studies, we adopt image recognition techniques to identify pre-disease aortic morphology for prior diagnoses; assuming that AD has occurred, we employ functional data analysis to determine the optimal timing for BP and HR interventions to offer the highest possible survival rate. Results Compared with the healthy control group, the aortic centerline is significantly more slumped for the AD group. Further, controlling patients’ blood pressure and heart rate according to the likelihood of adverse events can offer the highest possible survival probability. Conclusions The degree of slumpness is introduced to depict aortic morphological changes comprehensively. The morphology-based prediction model is associated with an improvement in the predictive accuracy of the prescreening of AD. The dynamic model reveals that blood pressure and heart rate variations have a strong predictive power for adverse events, confirming this model’s ability to improve AD management.

scholarly journals Combination chemotherapy versus temozolomide for patients with methylated MGMT (m-MGMT) glioblastoma: results of computational biological modeling to predict the magnitude of treatment benefit

2021 ◽  
Author(s):  
Michael Castro ◽  
Anusha Pampana ◽  
Aftab Alam ◽  
Rajan Parashar ◽  
Swaminathan Rajagopalan ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Combination Chemotherapy ◽  
Combination Treatment ◽  
Drug Response ◽  
Single Agent ◽  
Genomic Analysis ◽  
Treatment Benefit ◽  
Disease Heterogeneity ◽  
Disease Behavior ◽  
Copy Number Changes

Abstract Background A randomized trial in glioblastoma patients with methylated-MGMT (m-MGMT) found an improvement in median survival of 16.7 months for combination therapy with temozolomide (TMZ) and lomustine, however the approach remains controversial and relatively under-utilized. Therefore, we sought to determine whether comprehensive genomic analysis can predict which patients would derive large, intermediate, or negligible benefits from the combination compared to single agent chemotherapy. Methods Comprehensive genomic information from 274 newly diagnosed patients with methylated-MGMT glioblastoma (GBM) was downloaded from TCGA. Mutation and copy number changes were input into a computational biologic model to create an avatar of disease behavior and the malignant phenotypes representing hallmark behavior of cancers. In silico responses to TMZ, lomustine, and combination treatment were biosimulated. Efficacy scores representing the effect of treatment for each treatment strategy were generated and compared to each other to ascertain the differential benefit in drug response. Results Differential benefits for each drug were identified, including strong, modest-intermediate, negligible, and deleterious (harmful) effects for subgroups of patients. Similarly, the benefits of combination therapy ranged from synergy, little or negligible benefit, and deleterious effects compared to single agent approaches. Conclusions The benefit of combination chemotherapy is predicted to vary widely in the population. Biosimulation appears to be a useful tool to address the disease heterogeneity, drug response, and the relevance of particular clinical trials observations to individual patients. Biosimulation has potential to spare some patients the experience of over-treatment while identifying patients uniquely situated to benefit from combination treatment. Validation of this new artificial intelligence tool is needed.

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