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227 citation(s) found for "Islam, M".

A systematic review and network meta-analysis evaluating neoadjuvant treatments in muscle-invasive bladder cancer.
Ikram, Waleed, Naqvi, Syed Arsalan Ahmed , Fatima, Ezza, Islam, Mahnoor, Asghar, Noureen, Khakwani, Kaneez Zahra Rubab, Khan, Ahsan Masood , Sonpavde, Guru , Siddiqi, Rabbia , Xu, Wenxin Vincent , Hussain, Syed A. , Bryce, Alan H. , Riaz, Irbaz Bin , Singh, Parminder Pal

Journal of Clinical Oncology | February 16, 2022 | Volume: 40 | Issue: 6_suppl | Pages: 518-518

10.1200/jco.2022.40.6_suppl.518 Get It

518 Background: Cisplatin (C) based neoadjuvant chemotherapy (NAC) has been the mainstay treatment for muscle invasive bladder cancer (MIBC). However, the optimal choice of NAC is not well-established. We therefore conducted a network-meta-analysis (NMA) to assess comparative efficacy of different treatment options. Methods: Several electronic databases (MEDLINE, and EMBASE) and conference proceedings were systematically used to identify randomized trials evaluating first-line treatments in neoadjuvant MIBC. Outcomes of interest included overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and pathologic complete response (pCR). DerSimonian-Laird random-effects meta-analysis was used to compute direct comparisons between NAC and local therapy (LT) only. Fixed effect NMA was conducted within the frequentist framework for mixed treatment comparisons. P-scores were used to assess relative treatment rankings. All statistical analyses were conducted in R (v 4.1.1). Results: This systematic review included 23 trials (25 references) with a total of 5313 patients with 10 unique treatments. Direct comparisons showed significant benefit in PFS (HR: 0.82; 95% CI: 0.71-0.94), and in OS (HR: 0.85; 95% CI: 0.78-0.92) with NAC when compared to LT only. However, the likelihood of achieving an objective response (RR: 1.18; 95% CI: 0.72-1.95: I2: 85%) or CR (RR: 1.51; 95% CI: 0.87-2.61; I2: 79%) was not different between the two arms. Data available in 15 trials contributed to the network for PFS outcome while only eight trials contributed to OS outcome. Mixed treatment comparisons showed significantly improved PFS with nintedanib-gemcitabine-cisplatin (NinGC; HR: 0.42; 95% CI: 0.20-0.87) and dose-dense-methotrexate-vinblastine-doxorubicin-cisplatin (ddMVAC; HR: 0.61; 95% CI: 0.43-0.88) compared to LT only. Consistent benefit was observed when NinGC (HR: 0.48; 95% CI: 0.24-0.97) and ddMVAC (HR: 0.70; 95% CI: 0.51-0.96) were compared to GC only. However, no significant differences were observed between NinGC (rank 1) and ddMVAC (rank 2) or among other mixed treatment comparisons. Similarly, OS was significantly improved with NinGC (rank 1) relative to MVAC (HR: 0.41; 95% CI: 0.17-0.97), MVC (HR: 0.37; 95% CI: 0.16-0.88), MC (HR: 0.38; 95% CI: 0.16-0.92), AC (HR: 0.36; 95% CI: 0.15-0.91), and GC (HR: 0.39; 95% CI: 0.17-0.90). While similar results were observed with ddMVAC (rank 2) when compared to MVC (HR: 0.63; 95% CI: 0.42-0.94), MC (HR: 0.64; 95% CI: 0.42-0.98), and GC (HR: 0.66; 95% CI: 0.47-0.92), no significant differences were observed with ddMVAC when compared to MVAC (HR: 0.62; 95% CI: 0.38-1.01) and NinGC (HR: 1.70; 95% CI: 0.69-4.19). Conclusions: Current evidence shows improved PFS and OS with the use of neoadjuvant ddMVAC and Nin-GC in patients with MIBC relative to other treatment options.
Quantifying absolute benefit of adjuvant treatments in renal cell carcinoma: A systematic review and network-meta-analysis.
Sipra, Qurat Ul Ain Riaz , Naqvi, Syed Arsalan Ahmed , Islam, Mahnoor, Asghar, Noureen, Ikram, Waleed, Siddiqi, Rabbia , Singh, Parminder Pal , Xu, Wenxin Vincent , Ho, Thai H. , Bryce, Alan H. , Riaz, Irbaz Bin

Journal of Clinical Oncology | February 16, 2022 | Volume: 40 | Issue: 6_suppl | Pages: 360-360

10.1200/jco.2022.40.6_suppl.360 Get It

360 Background: Pembrolizumab has been established as an effective treatment option in adjuvant renal cell carcinoma after the publication of KEYNOTE-564. However, the magnitude of benefit based on different risk categories is not well defined. Methods: We included full-text publications of phase II/III randomized controlled trials (RCTs) evaluating immune checkpoint inhibitors or tyrosine kinase inhibitors (TKIs) in adjuvant renal cell carcinoma after a systematic search. The outcomes of interest included disease free survival (DFS), overall survival (OS), all grade or grade ≥3 treatment related, and all cause adverse events. Mixed treatment comparisons were computed through a fixed-effect multivariate meta-regression within the frequent framework. Relative treatment rankings were assessed using P-scores. We used stratified baseline risks of disease progression from observational data and at 5, 10, 15 years from the Leibovich risk stratification system (based on risk scores ranging from 0 to ≥15). Corresponding intervention risks (CIRs) were then approximated using relative effect estimates (from NMA) and baseline risks. The difference between CIRs and baseline risks were calculated to present absolute risk differences in each baseline category. Results: This NMA included six RCTs with a total of 7525 participants and five unique treatment options. Mixed treatment comparisons showed significant DFS and OS benefit with pembrolizumab (rank 1) when compared against sunitinib (DFS HR 0.74 [0.55-0.99]; OS HR 0.51 [0.27-0.94]). However, there were no significant differences with pembrolizumab compared to pazopanib (DFS HR 0.81 [0.60- 1.09]; OS HR 0.54[0.29-1.01]) and axitinib (DFS HR 0.78 [0.54-1.14]; OS HR 0.52 [0.24-1.16]). The safety profiles were comparable. Absolute benefit of TKIs in adjuvant setting was minimal whereas this benefit increased with higher T and N patients in patients treated with pembrolizumab (Table). Similarly, the treatment benefit increased with higher Leibovich’s risk scores at 5, 10 and 15 years of follow up. Conclusions: The current analysis suggests that a risk adapted approach may be useful when considering adjuvant pembrolizumab in RCC patients.[Table: see text]
Triplet therapy in metastatic castration-sensitive prostate cancer: A systematic review and meta-analysis.
Naqvi, Syed Arsalan Ahmed , Riaz, Zaryab Bin, Riaz, Anum, Islam, Mahnoor, Ikram, Waleed, Jafar, Muhammad Ali, Ravi, Praful , Siddiqi, Rabbia , Singh, Parminder Pal , Riaz, Irbaz Bin , Bryce, Alan H.

Journal of Clinical Oncology | February 16, 2022 | Volume: 40 | Issue: 6_suppl | Pages: 136-136

10.1200/jco.2022.40.6_suppl.136 Get It

136 Background: Intensification of initial treatment of in patients with metastatic castration-sensitive prostate cancer (mCSPC) with androgen pathway inhibition (API) in addition to docetaxel (DOC) and androgen deprivation therapy (ADT) has shown promise to improve clinical outcomes. Thus, we synthesize the data from modern clinical trials to estimate overall estimates of progression and survival outcomes. Methods: A systematic search of electronic databases (MEDLINE and EMBASE) was conducted to include phase III randomized controlled trials (RCTs) evaluating triplet therapy (API+DOC+ADT) against doublet therapy (DOC+ADT) in mCSPC. Outcomes of interest included overall survival (OS) and radiographic progression-free survival (rPFS). A DerSimonian-Laird random-effects meta-analysis was performed to pool precomputed hazard ratios (HRs) and confidence intervals (CIs) after logarithmic transformation using inverse-variance weighting approach. Cochran’s Q statistical test was used to assess statistically significant heterogeneity not explained by chance, while I2 statistical test was used to quantify the total observed variability, due to between-study heterogeneity. I2 values >50% indicated substantial heterogeneity. A summary of findings table was constructed to translate relative estimates to absolute risks. Results: A total of 1,531 patients in four RCTs with direct comparative data between triplet and doublet therapies, were included in this meta-analysis. PEACE-1 was the only RCT directly assessing this question (AAP+DOC+ADT). ENZA+DOC+ADT was evaluated as a subgroup in two RCTs (ENZAMET; ARCHES), APA+DOC+ADT was evaluated as a subgroup in one (TITAN). To be able to pool studies, the relative efficacy of control arm in ENZAMET (first generation bicalutamide + ADT) was considered equivalent to ADT based on prior literature. A total of 672 rPFS events were observed (34%; 261 events in triplet therapy, 54%; 411 events in doublet therapy). The difference was statistically significant (HR: 0.49; 95% CI: 0.42-0.58; I2: 0%). Similarly, 469 OS events were observed (28%; 217 events in triplet therapy, 33%; 252 events in doublet therapy). The difference was statistically significant (HR: 0.80; 95% CI: 0.67-0.96; I2: 0%). The summary of findings is outlined in the table. Conclusions: The results of this meta-analysis support an improvement in rPFS and OS in favor of triplet therapy over doublet therapy for mCRPC. However, comparative effectiveness of different triplet regimens may be different and needs further exploration.[Table: see text]
Differential efficacy of PARP inhibitors in metastatic castration-resistant prostate cancer with DNA repair defects: A systematic review and meta-analysis.
Naqvi, Syed Arsalan Ahmed , Zafar, Muhammad Daim Bin , Islam, Mahnoor, Ikram, Waleed, Raina, Ammad, Singh, Parminder Pal , Riaz, Irbaz Bin , Bryce, Alan H.

Journal of Clinical Oncology | February 16, 2022 | Volume: 40 | Issue: 6_suppl | Pages: 134-134

10.1200/jco.2022.40.6_suppl.134 Get It

134 Background: Recent trials have suggested poly ADP-ribose polymerase inhibitors (PARPi) sensitivity in patients with treatment-refractory metastatic castration-resistant prostate cancer (mCRPC) harboring mutations in DNA damage and response repair genes (DDR). However, the efficacy profile might differ with different genes and is still being explored in multiple studies. Methods: We systematically searched several electronic databases (MEDLINE, EMBASE), and conference proceedings to include abstracts and full-text publications of phase II/III trials evaluating PARPi in treatment-refractory mCRPC with DDR gene alterations. Outcomes of interest included objective response rate (ORR), complete response (CR), prostate specific antigen (PSA) 50% response, circulating tumor cells conversion (CTCc) from ≥ 5 to < 5 cells, composite response (CoR) and risk of progression. Data was pooled using Inverse-variance approach. A DerSimonian and Laird random-effect meta-analysis was conducted to estimate pooled proportion (PP) of events using the Freeman-Tukey transformation in each gene. Clopper-Pearson method was used to estimate the associated 95% confidence intervals (CI). Results: This systematic review and meta-analysis included five unique trials with 648 patients and four PARPi (niraparib, olaparib, rucaparib, talazoparib). Objective response to PARPi was observed in 44.7% of patients with mutations in either BRCA1 or 2 or both (95% CI: 36.0%-53.6%; I2: 0%), 23.5% with ATM (95% CI: 3.91%-51.0%; I2: 65%), 25.0% with CDK12 (95% CI: 8.66%-49.1%), and 45.3% with PALB2 alterations (95% CI: 14.8%-77.5%; I2: 0%). Consistent results were observed for CR outcome. PSA50% response to PARPi was observed in 60.3% of patients with BRCA1/2 mutations (95% CI: 50.3%-70.0%; I2: 57%), 5.54% (95% CI: 0.01-16.6; I2: 0%) with ATM, and 70.1% (95% CI: 35.6%-96.6%; I2: 0%) with PALB2 mutations while no PSA 50% response was observed in patients with CDK12 mutations (PP: 0.00%; 95% CI: 0%-16.84%). Moreover, CTCc was observed in 68.3% of patients with BRCA1/2 mutations (95% CI: 45.0%-87.8%; I2: 77), 34.2% (95% CI: 11.2-61.3%; I2: 45%) with ATM, 41.7% (95% CI: 15.2%-72.3%) with CDK12, and 48.5% (95% CI: 6.39%-92.9%; I2: 49%) with PALB2. CoR was observed in 76.5% patients with BRCA1/2 mutations (95% CI: 65.4%-86.1%; I2: 22%), 30.4% (95% CI: 16.0%-46.9%) with ATM, 25% (95% CI: 8.66%-49.1%) with CDK12, and 63.9% (95% CI: 31.0%-91.8%; I2: 0%) with PALB2 mutations. Similarly, the risk of progression was 50.9% in patients with BRCA1/2 mutations (95% CI: 37.7%-63.9%), 70.9% (95% CI: 60.0%-80.40%; I2: 0%) with ATM, and 75% (95% CI: 19.4-99.3%) with PALB2. Conclusions: Current evidence is sparse regarding efficacy by specific genes. Limited data favors the use of PARPi in mCRPC patients harboring mutations in BRCA1/2 and PALB2 genes.
A quantitative synthesis of disparities in the inclusion of racial/ethnic minorities and older adults in prostate cancer clinical trials over the last three decades.
Islam, Mahnoor, Ikram, Waleed, Naqvi, Syed Arsalan Ahmed , Riaz, Anum, Ravi, Praful , Odedina, Folakemi T., Duma, Narjust , Riaz, Irbaz Bin , Maqsood, Hamza , Saleem, Yusra, Hussain, Syed A. , Warner, Jeremy L. , Singh, Parminder Pal , Bryce, Alan H.

Journal of Clinical Oncology | February 16, 2022 | Volume: 40 | Issue: 6_suppl | Pages: 26-26

10.1200/jco.2022.40.6_suppl.026 Get It

26 Background: The underrepresentation of minority populations in clinical trials negatively impacts cancer and widens inequities. We aimed to quantify the enrollment disparities in prostate cancer (PC) clinical trials over the last three decades. Methods: MEDLINE and Embase were searched to identify primary reports of prostate cancer RCTs (1989-2020). Data for trial characteristics, the proportion of trials reporting race, ethnicity and age, and the proportion of patients by race, ethnicity and age enrolled in trials were summarized using descriptive statistics. Enrollment incidence ratios (EIR), which compare trial enrollment against global estimates of incidence in age-related subgroups (acquired from the Global Burden of Disease database) and U.S. population-based estimates of racial/ethnic subgroups (acquired from the SEER 18 incidence database) were calculated. Individual trial EIRs were pooled using random-effects meta-analyses to account for the substantial heterogeneity between trials. Multivariable meta-regression was used to explore associations between key trial characteristics and EIR. Annual percentage changes (APC) over the last three decades in enrollment disparities were analyzed using the Joinpoint Regression Analysis. Results: 281 trials from 1989 to 2020 with 99,588 patients were included in this analysis. 107 trials reported race (38%), of which only 25 trials (9%) reported data on all 5 U.S. racial categories (Black, White, Asian, Pacific Islander and Native American. 255 (91%) trials reported mean or median but only 71 trials (25%) specifically reported the enrollment proportion of older adults (age > 65 years). Clinical outcomes by race and age were reported in 9 (8%) and 37 (14%) trials, respectively. Results from meta-analyses showed that Black patients (summary EIR: 0.42 [95% CI: 0.35 - 0.51]), Hispanics (summary EIR: 0.50 [95% CI: 0.37 - 0.68]) and older adults (summary EIR: 0.95 [95% CI: 0.91 - 0.99]) were underrepresented in trials relative to their population estimates. Significantly fewer Black participants (EIR for Black patients = 0.42, EIR for White patients = 0.99; p < 0.0001), Hispanic participants (EIR for Hispanics = 0.50, EIR for non-Hispanics = 1.00; p = 0.001) and older adults (EIR for older adults = 0.95, EIR for younger adults = 1.06; p = 0.037) were enrolled. Representation of Black patients decreased significantly from 1989-2019 (APC: -4.25), while Hispanic representation increased significantly from 2000-2020 (APC: 5.89). Meta-regression showed Black patients were particularly underrepresented in larger-size trials (p < 0.0001). Conclusions: Black representation in PC clinical trials is less than 50% of their expected share based on cancer incidence and it has consistently decreased over last three decades, contributing to the disparities experienced by the population.
In reply: ‘multiple etiologies explain the association between sarcoidosis and diabetes mellitus’
El‐Qushayri, Amr Ehab , Ghozy, Sherief , Islam, Sheikh Mohammed Shariful , Islam, Sheikh Mohammed Shariful , Ghozy, Sherief

Expert Review of Respiratory Medicine | February 2, 2022 | Volume: 16 | Issue: 3 | Pages: 369-370

10.1080/17476348.2022.2035221 | PMID 35108145 Get It

Physical activity level and stroke risk in US population: A matched case–control study of 102,578 individuals
Ghozy, Sherief , Zayan, Ahmad Helmy , El‐Qushayri, Amr Ehab , Varney, Joseph , Morsy, Sara , Abbas, Alzhraa Salah , Diestro, Jose Danilo Bengzon , Dmytriw, Adam A. , Shah, Jaffer , Islam, Sheikh Mohammed Shariful , Parker, Kate Elizabeth , Varney, Joseph , Kallmes, Kevin M , Morsy, Sara , Abbas, Alzhraa Salah , Diestro, Jose Danilo B , Dmytriw, Adam A , Shah, Jaffer , Hassan, Ameer E , Islam, Sheikh Mohammed Shariful , Ghozy, Sherief , Hassan, Ameer E

Annals of Clinical and Translational Neurology | January 30, 2022 | Volume: 9 | Issue: 3 | Pages: 264-275

10.1002/acn3.51511 | PMID 35094505 Get It

AbstractBackgroundStroke has been linked to a lack of physical activity; however, the extent of the association between inactive lifestyles and stroke risk has yet to be characterized across large populations.PurposeThis study aimed to explore the association between activity‐related behaviors and stroke incidence.MethodsData from 1999 to 2018 waves of the concurrent cross‐sectional National Health and Nutrition Examination Survey (NHANES) were extracted. We analyzed participants characteristics and outcomes for all participants with data on whether they had a stroke or not and assessed how different forms of physical activity affect the incidence of disease.ResultsOf the 102,578 individuals included, 3851 had a history of stroke. A range of activity‐related behaviors was protective against stroke, including engaging in moderate‐intensity work over the last 30 days (OR = 0.8, 95% CI = 0.7–0.9; P = 0.001) and vigorous‐intensity work activities over the last 30 days (OR = 0.6, 95% CI = 0.5–0.8; P < 0.001), and muscle‐strengthening exercises (OR = 0.6, 95% CI = 0.5–0.8; P < 0.001). Conversely, more than 4 h of daily TV, video, or computer use was positively associated with the likelihood of stroke (OR = 11.7, 95% CI = 2.1–219.2; P = 0.022).ConclusionDifferent types, frequencies, and intensities of physical activity were associated with reduced stroke incidence, implying that there is an option for everyone. Daily or every other day activities are more critical in reducing stroke than reducing sedentary behavior duration.
Association of Accuracy, Conclusions, and Reporting Completeness With Acceptance by Radiology Conferences and Journals
Frank, Robert , Hallgrimson, Zachary , Korevaar, Daniël A. , Cohen, Jérémie F. , McInnes, Matthew D. F. , Treanor, Lee , McGrath, Trevor A. , Sharifabadi, Anahita Dehmoobad , Atyani, Almohannad , Kazi, Sakib , Choo‐Foo, Jade , Asraoui, Nabil, Ha, Winston , Prager, Ross , Rooprai, Paul, Pozdnyakov, Alex , John, Susan , Osman, Heba, Islam, Nayaar , Li, Nicole , Gauthier, Isabelle , Absi, Marissa , Kraaijpoel, Noémie , Ebrahimzadeh, Sanam , Stoker, Jaap , Frank, Robert A , McInnes, Matthew D F , McGrath, Trevor A , Alabousi, Mostafa , Stoker, Jaap , Fabiano, Nicholas , Bossuyt, Patrick M. , Leeflang, Mariska , Moher, David , Salameh, Jean‐Paul , Port, John D. , Klein, Jeffrey S. , Schweitzer, Mark

Journal of Magnetic Resonance Imaging | January 8, 2022 | Volume: 56 | Issue: 2 | Pages: 380-390

10.1002/jmri.28046 | PMID 34997786 Get It

BackgroundPreferential publication of studies with positive findings can lead to overestimation of diagnostic test accuracy (i.e. publication bias). Understanding the contribution of the editorial process to publication bias could inform interventions to optimize the evidence guiding clinical decisions.Purpose/HypothesisTo evaluate whether accuracy estimates, abstract conclusion positivity, and completeness of abstract reporting are associated with acceptance to radiology conferences and journals.Study TypeMeta‐research.PopulationAbstracts submitted to radiology conferences (European Society of Gastrointestinal and Abdominal Radiology (ESGAR) and International Society for Magnetic Resonance in Medicine (ISMRM)) from 2008 to 2018 and manuscripts submitted to radiology journals (Radiology, Journal of Magnetic Resonance Imaging [JMRI]) from 2017 to 2018. Primary clinical studies evaluating sensitivity and specificity of a diagnostic imaging test in humans with available editorial decisions were included.AssessmentPrimary variables (Youden's index [YI > 0.8 vs. <0.8], abstract conclusion positivity [positive vs. neutral/negative], number of reported items on the Standards for Reporting of Diagnostic Accuracy Studies [STARD] for Abstract guideline) and confounding variables (prospective vs. retrospective/unreported, sample size, study duration, interobserver agreement assessment, subspecialty, modality) were extracted.Statistical TestsMultivariable logistic regression to obtain adjusted odds ratio (OR) as a measure of the association between the primary variables and acceptance by radiology conferences and journals; 95% confidence intervals (CIs) and P‐values were obtained; the threshold for statistical significance was P < 0.05.ResultsA total of 1000 conference abstracts (500 ESGAR and 500 ISMRM) and 1000 journal manuscripts (505 Radiology and 495 JMRI) were included. Conference abstract acceptance was not significantly associated with YI (adjusted OR = 0.97 for YI > 0.8; CI = 0.70–1.35), conclusion positivity (OR = 1.21 for positive conclusions; CI = 0.75–1.90) or STARD for Abstracts adherence (OR = 0.96 per unit increase in reported items; CI = 0.82–1.18). Manuscripts with positive abstract conclusions were less likely to be accepted by radiology journals (OR = 0.45; CI = 0.24–0.86), while YI (OR = 0.85; CI = 0.56–1.29) and STARD for Abstracts adherence (OR = 1.06; CI = 0.87–1.30) showed no significant association. Positive conclusions were present in 86.7% of submitted conference abstracts and 90.2% of journal manuscripts.Data ConclusionDiagnostic test accuracy studies with positive findings were not preferentially accepted by the evaluated radiology conferences or journals.Evidence Level3Technical EfficacyStage 2.
Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life Years for 29 Cancer Groups From 2010 to 2019
Kocarnik, Jonathan , Compton, Kelly, Dean, Frances , Fu, Weijia , Gaw, Brian, Harvey, James , Henrikson, Hannah , Lu, Dan , Pennini, Alyssa, Xu, Rixing, Ababneh, Emad , Abbasi‐Kangevari, Mohsen , Abbastabar, Hedayat , Abd‐Elsalam, Sherief , Abedi, Aidin , Abidi, Hassan , Abolhassani, Hassan , Adedeji, Isaac Akinkunmi , Advani, Shailesh M, Aghaali, Mohammad , Ahmad, Tauseef , Rashid, Tarik A. , Salih, Yusra Ahmed , Aklilu, Addis , Akram, Tayyaba , Akunna, Chisom Joyqueenet , Hamad, Hanadi Al , Alahdab, Fares , Alimohamadi, Yousef, Alipour, Vahid, Alkhayyat, Motasem , Almasri, Nihad A. , Al‐Maweri, Sadeq Ali , Almustanyir, Sami , Alonso, Nivaldo , Alvis‐Guzmán, Nelson , Amu, Hubert , Ansari, Fereshteh, Antwi, Maxwell Hubert , Anvari, Davood , Anyasodor, Anayochukwu Edward , Aqeel, Muhammad , Arabloo, Jalal , Aremu, Olatunde , Ariffin, Hany , Aripov, Timur , Arshad, Muhammad , Artaman, Al, Arulappan, Judie , Jafarabadi, Mohammad Asghari , Ashraf, Tahira , Atorkey, Prince , Ausloos, Marcel , Awedew, Atalel Fentahun , Quintanilla, Beatriz Paulina Ayala , Ayenew, Temesgen , Azab, Mohammed A. , Azadnajafabad, Sina , Jafari, Amirhossein Azari , Azarian, Ghasem , Badiye, Ashish , Bahadory, Saeed , Baig, Atif Amin , Baker, Jennifer L. , Balakrishnan, Senthilkumar , Bärnighausen, Till , Barone‐Adesi, Francesco , Barrow, Amadou , Belgaumi, Uzma , Bezabhe, Woldesellassie, Bezabih, Yihienew Mequanint , Bhagat, Devidas S. , Bhagavathula, Akshaya Srikanth , Bhardwaj, Nikha , Bhaskar, Sonu , Bhojaraja, Vijayalakshmi S, Bibi, Sadia , Bijani, Ali , Bisignano, Catherine, Bolarinwa, Obasanjo Afolabi , Bolla, Srinivasa Rao , Braithwaite, Dejana , Brar, Amanpreet , Brenner, Hermann , Bustamante-Teixeira, Maria Teresa , Butt, Nadeem Shafique , Butt, Zahid A , Santos, Florentino Luciano Caetano dos , Cao, Yin , Carreras, Giulia , Catalá-López, Ferrán , Cembranel, Francieli , Cerin, Ester , Cernigliaro, Achille , Chakinala, Raja Chandra , Chattu, Soosanna Kumary , Chattu, Vijay Kumar , Chaturvedi, Pankaj, Chimed‐Ochir, Odgerel , Cho, Daniel , Chu, Dinh‐Toi , Conde, João , Cortés, Sandra , Cortesi, Paolo Angelo, Costa, Vera Marisa , Cunha, Amanda Ramos da , Dadras, Omid , Dagnew, Amare Belachew , Dandona, Lalit , Dandona, Rakhi , Hoz, Fernando de la , Dhamnetiya, Deepak , Dhimal, Mandira Lamichhane , Díaz, Daniel , Djalalinia, Shirin , Doaei, Saeid , Dorostkar, Fariba, Driscoll, Tim , Ebrahimi, Hedyeh , Eftekharzadeh, Sahar , Tantawi, Maha El , El‐Abid, Hassan , Elbarazi, Iffat , Elhabashy, Hala Rashad , Elhadi, Muhammed , Eshrati, Babak, Esmaeilzadeh, Firooz , Etemadi, Arash , Ezzikouri, Sayeh , Faisaluddin, Mohammed, Fares, Jawad , Farzadfar, Farshad , Feroze, Abdullah , Desideri, Lorenzo Ferro , Fischer, Florian , Fisher, James L. , Fukumoto, Takeshi , Gad, Mohamed M. , Fonseca, Mariana Gaspar, Obsa, Abera Getachew, Ghafourifard, Mansour , Ghashghaee, Ahmad , Ghith, Nermin , Gholamalizadeh, Maryam , Gilani, Syed Amir , Gizaw, Abraham Tamirat , Glasbey, James , Golechha, Mahaveer , Goleij, Pouya , Gopalani, Sameer Vali , Gorini, Giuseppe , Goudarzi, Houman , Gubari, Mohammed Ibrahim Mohialdeen , Guerra, Maximiliano Ribeiro, Guha, Avirup , Gunasekera, Sanjeeva , Gupta, Bhawna , Gupta, Vivek , Gutiérrez, Reyna Alma, Hafezi‐Nejad, Nima , Haider, Mohammad Rifat , Hameed, Sajid , Hanif, Asif , Haque, Shafiul , Harlianto, Netanja I. , Hasaballah, Ahmed I , Hay, Simon I , Heidari, Golnaz , Herrera-Serna, Brenda Yuliana , Herţeliu, Claudiu , Hezam, Kamal , Hossain, Mohammad Bellal , Hosseini, Mohammad‐Salar , Hosseini, Mostafa, Hosseinzadeh, Mehdi , Hostiuc, Mihaela , Househ, Mowafa , Hsaïri, Mohamed, Huang, Junjie , Hugo, Fernando Neves , Hussain, Rabia , Hussein, Nawfal R , Hwang, Bing‐Fang , Ibitoye, Segun Emmanuel , Ida, Fidelia , Ikuta, Kevin S , Ilić, Irena , Irham, Lalu Muhammad , Islam, Jessica Y. , Islam, Sheikh Mohammed Shariful , Ismail, Nahlah Elkudssiah , Isola, Gaetano , Iwagami, Masao , Jacob, Louis , Jain, Vardhmaan , Jakovljević, Mihajlo, Javaheri, Tahereh , Jayaram, Shubha, Jha, Ravi Prakash , Jonas, Jost B, Joó, Tamás , Joseph, Nitin , Joukar, Farahnaz, Jürisson, Mikk , Kalankesh, Leila R , Kalhor, Rohollah , Kalkonde, Yogeshwar , Kamath, Ashwin , Al-Salihi, Nawzad Kameran, Kandel, Himal , Kapoor, Neeti , Kasa, Ayele Semachew , Keshavarz, Pedram , Keykhaei, Mohammad , Khader, Yousef , Khalilov, Rovshan , Khan, Maseer , Khan, Md Nuruzzaman , Khan, Moien AB , Khang, Young-Ho, Khater, Amir M, Kısa, Adnan , Kısa, Sezer , Kopec, Jacek A , Koteeswaran, Rajasekaran , Koul, Parvaiz A , Laxminarayana, Sindhura Lakshmi Koulmane , Biçer, Burcu Küçük , Kugbey, Nuworza , Kumar, G Anil , Kurmi, Om , Kutluk, Tezer, Lami, Faris Hasan, Lee, Yo Han , Leigh, James , Leong, Elvynna , Li, Ming‐Chieh , Liu, Xuefeng , Loureiro, Joana A. , Lunevičius, Raimundas , Razek, Muhammed Magdy Abd El, Majeed, Azeem , Makki, Alaa, Male, Shilpa, Malik, Ahmad Azam , Martini, Santi , Masoumi, Seyedeh Zahra , Mehrotra, Ravi , Mendoza, Walter, 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JAMA Oncology | December 30, 2021 | Volume: 8 | Issue: 3 | Pages: 420

10.1001/jamaoncol.2021.6987 | PMID 34967848 Get It

Sabatolimab (MBG453) Combination Treatment Regimens for Patients (Pts) with Higher-Risk Myelodysplastic Syndromes (HR-MDS): The MDS Studies in the Stimulus Immuno-Myeloid Clinical Trial Program
Al‐Kali, Aref , Borate, Uma , Cluzeau, Thomas , Kobata, Krissy, Lyons, Roger M. , Sallman, David A. , Xiao, Zhijian , Hoef, Marlies Van, Nourry-Boulot, Claire, Sadek, Islam , Bengoudifa, Bourras‐Rezki, Sachs, Carolin, Sabo, John , Garcia‐Manero, Guillermo , Zeidan, Amer M. , Dezern, Amy Elizabeth , Esteve, Jordi , Giagounidis, Aristoteles , Platzbecker, Uwe , Santini, Valeria , Sanz, Guillermo , Sekeres, Mikkael A. , Wei, Andrew H.

Blood | November 23, 2021 | Volume: 138 | Issue: Supplement 1 | Pages: 4669-4669

10.1182/blood-2021-145626 Get It

Abstract Background: Pts with HR-MDS unfit for hematopoietic stem cell transplant (HSCT) have poor outcomes and limited survival with single-agent hypomethylating agent (HMA) therapy. Novel treatments that provide durable responses and clinically meaningful survival benefit for pts with HR-MDS are needed. TIM-3 is a promising target in myeloid malignancies as it regulates innate and adaptive immune cells and is expressed on leukemic stem cells (LSCs) and blasts but not normal hematopoietic stem cells. Sabatolimab (MBG453) is a novel immuno-myeloid therapy that binds to TIM-3 on immune cells, facilitating antileukemic immune activation and phagocytic killing of leukemic cells. Sabatolimab also binds to TIM-3 on leukemic cells, potentially impeding self-renewal of LSCs via inhibition of TIM3-galectin-9. In an early phase (ph) trial (NCT03066648) sabatolimab + HMA therapy showed a durable clinical benefit and was well tolerated in pts with HR-MDS (Wei, EHA 2021). Study Design and Methods: The STIMULUS immuno-myeloid clinical trial program is investigating the safety, efficacy, and durability of multiple sabatolimab-based combination therapies in pts with myeloid malignancies. Additional exploration of the mechanism of action of sabatolimab and identification of potential biomarkers predictive of response is planned. This abstract summarizes the design of the 4 ongoing STIMULUS trials in previously untreated adult pts with HR-MDS who are not eligible for intensive chemotherapy (IC) or HSCT. STIMULUS-MDS1 (NCT03946670) is an international, randomized, double-blind, placebo-controlled Ph II trial evaluating sabatolimab + HMA therapy in pts with very-high, high-, or intermediate-risk (vH/H/IR)-MDS which has completed enrollment (N=127). The primary endpoints of STIMULUS-MDS1 are complete response (CR) and progression-free survival (PFS). STIMULUS-MDS2 (NCT04266301) is an ongoing, international, randomized, double-blind, placebo-controlled, Ph III trial of sabatolimab + azacitidine (AZA) in pts with vH/H/IR-MDS or chronic myelomonocytic leukemia-2. Target enrollment is ~500 pts. The primary endpoint in this trial is overall survival (OS). Key secondary endpoints are time to definitive deterioration of fatigue; duration of RBC transfusion-free interval; and improvement of fatigue, physical functioning, and emotional functioning. Other endpoints include CR, marrow CR (mCR), partial remission (PR), PFS, and leukemia-free survival (LFS). STIMULUS-MDS2 is a trial that aims to determine if sabatolimab + HMA has a statistically significant and clinically meaningful benefit in OS and quality of life vs HMA alone. STIMULUS MDS-US (NCT04878432) is a US-based, open-label, single-arm, Ph II trial investigating sabatolimab + HMAs of investigators' choice (AZA intravenous [IV] or subcutaneous, decitabine IV or oral decitabine) in pts with vH/H/IR-MDS. Target enrollment is 90 pts. Primary endpoint is safety, which will be evaluated via incidence and severity of adverse events (AEs) and serious AEs. Secondary endpoints include CR, PFS, LFS, and OS. This trial will provide further understanding of sabatolimab + HMA therapy with additional insight into the safety and efficacy of sabatolimab + oral HMA. STIMULUS-MDS3 (NCT04812548) is an international, open-label, single-arm, Ph II trial that explores triplet therapy of sabatolimab combined with AZA and the BCL-2 inhibitor venetoclax (VEN) in pts with vH/HR-MDS. Part 1 of this trial is a safety run-in comprising 2 safety cohorts with ~6 pts receiving sabatolimab 400 mg + AZA + VEN and ~12 pts receiving sabatolimab 800 mg + AZA + VEN. Primary endpoint of part 1 is safety (dose-limiting toxicities between cycle 1 day 8 and end of cycle 2). If (both 400 and 800 mg) sabatolimab + AZA and VEN are safe, the trial will progress to an expansion cohort (~58 pts) of sabatolimab 800 mg Q4W + AZA + VEN. The primary endpoint is CR. Secondary endpoints include CR + mCR rate, overall response rate (CR + mCR + PR + hematologic improvement), OS, PFS, LFS, and event-free survival. The STIMULUS immuno-myeloid clinical trial program is investigating the efficacy, safety, and improved quality of life of multiple sabatolimab-based combination therapies in pts with myeloid malignancies. The goal of ongoing STIMULUS-MDS trials is to gain insight into the promising durable benefit of sabatolimab combination therapies in pts with HR-MDS. Figure 1 Figure 1. Disclosures Zeidan: Jazz: Consultancy; Jasper: Consultancy; Pfizer: Other: Travel support, Research Funding; AstraZeneca: Consultancy; Janssen: Consultancy; Novartis: Consultancy, Other: Clinical Trial Committees, Travel support, Research Funding; Loxo Oncology: Consultancy, Other: Clinical Trial Committees; Ionis: Consultancy; Kura: Consultancy, Other: Clinical Trial Committees; Incyte: Consultancy, Research Funding; Gilead: Consultancy, Other: Clinical Trial Committees; Genentech: Consultancy; Epizyme: Consultancy; Daiichi Sankyo: Consultancy; Geron: Other: Clinical Trial Committees; BMS: Consultancy, Other: Clinical Trial Committees, Research Funding; Cardiff Oncology: Consultancy, Other: Travel support, Research Funding; Boehringer Ingelheim: Consultancy, Research Funding; BioCryst: Other: Clinical Trial Committees; BeyondSpring: Consultancy; Astex: Research Funding; Astellas: Consultancy; Aprea: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Agios: Consultancy; ADC Therapeutics: Research Funding; Acceleron: Consultancy, Research Funding; AbbVie: Consultancy, Other: Clinical Trial Committees, Research Funding. Al-Kali: Astex: Other: Research support to institution; Novartis: Research Funding. Borate: Takeda: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharma: Research Funding; Blueprint Medicine: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees; incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Rampal: Membership on an entity's Board of Directors or advisory committees; Galecto, Inc.: Consultancy; Promedior: Consultancy. Cluzeau: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses, Speakers Bureau; Abbvie: Consultancy, Honoraria, Speakers Bureau; Agios: Honoraria; Amgen: Speakers Bureau; Jazz Pharma: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Astellas: Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Speakers Bureau; Pfizer: Other: travel, accommodations, expenses; Takeda: Other: travel, accommodations, expenses. DeZern: Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees. Esteve: Jazz: Consultancy; Novartis: Consultancy, Research Funding; Astellas: Consultancy; Abbvie: Consultancy; Bristol Myers Squibb/Celgene: Consultancy; Pfizer: Consultancy; Novartis: Research Funding. Giagounidis: Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Platzbecker: Celgene/BMS: Honoraria; Novartis: Honoraria; Janssen: Honoraria; Geron: Honoraria; AbbVie: Honoraria; Takeda: Honoraria. Sallman: Kite: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau; Syndax: Membership on an entity's Board of Directors or advisory committees; Intellia: Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Magenta: Consultancy. Santini: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Menarini: Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Geron: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Astex: Membership on an entity's Board of Directors or advisory committees. Sanz: Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses, Speakers Bureau; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Helsinn Healthcare: Consultancy, Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Other: Travel, accommodations, and expenses. Sekeres: Novartis: Membership on an entity's Board of Directors or advisory committees; Takeda/Millenium: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Wei: Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Membership on an entity's Board of Directors or advisory committees, Research Funding; Macrogenics: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Van Hoef: Novartis Pharma: Current Employment. Nourry-Boulot: Novartis: Current Employment. Sadek: Novartis: Current Employment. Bengoudifa: Novartis Pharma AG: Current Employment. Sachs: Novartis Pharma AG: Current Employment. Sabo: Novartis: Current Employment, Current holder of stock options in a privately-held company. OffLabel Disclosure: Sabatolimab is a novel immuno-myeloid therapy targeting TIM-3 and is under investigation for the treatment of patients with myeloid malignancies