bluuebunny/crossref_metadata_2025 huggingface dataset:
Comprehensive analysis of predictive factors for efficacy in concurrent chemo-radiotherapy for locally advanced non-small cell lung cancer, utilizing individual patient data from the Japan lung cancer society integrated clinical trial database: Is there room for further improvement?
Authors: Ozawa Yuichi , Yamamoto Kouji , Sugawara Shunichi , Niho Seiji , Ohe Yuichiro , Okamoto Hiroaki , Hotta Katsuyuki , Ikeda Norihiko , Yamamoto Nobuyuki
Published: June 2024

8043

Background: The standard treatment for unresectable, locally advanced NSCLC is concurrent chemoradiotherapy followed by durvalumab. While the effectiveness of chemoradiotherapy is pivotal, the exploration into predictive factors of the efficacy is notably limited. Methods: The Japanese Lung Cancer Society (JLCS) integrated eight randomized Phase II/III trials (JCOG9812, JCOG0301, NJLCG0601, OLCSG0007, SPECTRA, TORG1018, WJOG5008L, WJTOG0105) concerning chemoradiotherapy for locally advanced NSCLC, constructing the JLCS Integrated Clinical Trial Database (JIDB), with individual data of 1288 patients. This study analyzed 1162 patients who underwent concurrent chemoradiotherapy, focusing on factors impacting PFS. A logistic regression with the least absolute shrinkage and selection operator (LASSO) analyses for 3-yr PFS were performed, and the five most related factors were further evaluated using the Kaplan-Meier method and log-rank tests. The impact of pneumonitis and esophagitis on PFS was also explored. Results: Age [median (Q1;Q3)]; 64 (57;71), male/female; 961/201, Ad/Sq/Oth; 580/446/134, PS 0/1/2; 562/578/5, stage IIIA/IIIB; 468/694, T factor 4/3/2/1/0; 436/158/341/156/3, N factor 3/2/1/0; 300/692/44/62, PS 0/1/2; 562/578/5, primary site; upper, middle/lower lobe; 599/161, BMI; 21.8 (19.7;24.0), weight loss (≥5% within 6m) yes/no; 135/644, LDH (IU/l); 203 (175;276), CRP (mg/dl); 0.70 (0.20;2.60), irradiated dose (Gy); 60 (60;60), combined regimen; platinum/taxane 303, CDDP/mitomycin/vindesine; 254, CDDP/5-FU-based; 196, CDDP/vinorelbine 87, CDDP/pemetrexed 50, others 272. The median PFS in all patients was 9.72m (95% CI; 9.33 – 10.38), with 3-yr, 5-yr, and 10-yr PFS rates of 19.7, 14.3, 10.1%. LASSO logistic regression identified Sq, lower lobe primary, age, pack-years, and weight loss as the top negative influencers. The PFS curve was significantly shorter in patients with lower lobe primary (median of 8.15 vs. 9.46m, p = 0.023) and weight loss (median of 7.29 vs. 9.72m, p < 0.0001). Pneumonitis occurred in 50.9% (grade≥3 in 6.7%) and esophagitis in 41.9% (grade≥3 in 3.9%). Grade≥2 pneumonitis shortened PFS (8.2 vs. 10.2m, p = 0.00015), while, unexpectedly, grade≥1 esophagitis was associated with longer PFS (12.9 vs. 8.6m, p < 0.0001). Conclusions: The efficacy of concurrent chemoradiotherapy varies significantly based on the primary site. Weight loss is a significant predictor of efficacy, as is in metastatic disease. The impact of pneumonitis and esophagitis suggest that modifying lung and esophageal irradiation might enhance treatment efficacy. Further research in this area is still certainly warranted.
Biomarker testing in early-stage NSCLC: Results from the MYLUNG Consortium.
Authors: Evangelist Makenzi Colleen , Butrynski James Edward , Paschold John C. , Ward Patrick J. , Waterhouse David Michael , Spira Alexander I. , Ali Kashif , Hakimian David , Jotte Robert M. , Larson Timothy , Meshad Michael W. , Owera Rami , Richards Donald A. , Neubauer Marcus A. , Robert Nicholas J , Yori Jennifer L. , Pant Manoj , Coleman Robert L. , Spigel David R.
Published: June 2024

8047

Background: The Molecularly Informed Lung Cancer Treatment in a Community Cancer Network: A Pragmatic Consortium (MYLUNG) program seeks to identify and resolve barriers to biomarker testing in patients (pts) with non-small-cell lung cancer (NSCLC). We previously reported prospectively collected molecular testing data in pts with Stage IB-IV NSCLC (Evangelist et al. 2023). Herein we report additional data on molecular testing rates and patterns in the cohort of pts with early-stage (ES) NSCLC. Methods: Pts were enrolled from 12/20-9/22 at 18 community practices (76 sites) across the US Oncology Network. Analyses performed in the ES cohort include rates of molecular testing for targets with approved (PD-L1 , EGFR) or emerging ( ALK) therapies for ES NSCLC and next-generation sequencing (NGS); reasons for not testing; and treatment (Tx) received, including targeted therapy and immunotherapy (IO). Analyses are preliminary as data collection continues over 5-year follow-up. Results: Included in this analysis were 284 pts with newly diagnosed Stage IB-IIIA NSCLC: median age 68y (range 32, 92); 50% female; 54% ECOG 0-1; 61% adenocarcinoma, 36% squamous cell carcinoma. In total, 76% of pts (82% of pts with adenocarcinoma vs 67% with squamous cell carcinoma) had molecular testing ordered prior to or within 12 weeks of initiating first systemic therapy. Rates of testing (either alone or inclusive of other tests) were PD-L1 ,74%; EGFR,71%; ALK, 62%; EGFR + PD-L1, 61%. In total, 52% of pts had NGS testing; overall, 16% received no molecular testing. The most common reasons for not testing were patient and/or provider attitude/perception (34%) and insufficient tumor tissue (25%). Conclusions: New therapeutic options provide a catalyst to increase molecular testing in ES NSCLC. EGFR and PD-L1 testing are now standard for the management of these pts, with other biomarkers emerging. In this study, 54% of pts received testing for PD-L1, EGFR, and ALK, with additional therapy being offered in pts with biomarker-positive tumors; however, 16% still received no molecular testing at all. For pts with EGFRwt/PD-L1+ tumors, prescription of IO increased 1.8-fold post-adjuvant FDA approval. Data from this and future analyses will be used to implement interventions to improve molecular testing rates in NSCLC. [Table: see text]
Outcomes of combined immunotherapy and palliative radiotherapy in patients with recurrent/metastatic head and neck cancers.
Authors: Cheng Yanshuang , Wang Juan , Sun Ji , Zhong Yahua , Wu Qiuji
Published: June 2024

e18002

Background: Immunotherapy has revolutionized the treatment for recurrent/metastatic head and neck cancers (R/M HNC). It is uncertain whether the combination of immunotherapy and radiotherapy can provide survival benefits for R/M HNC. Methods: This study included patients with R/M HNC who underwent immunotherapy in our institute from November 2018 to October 2022. All patients received intravenous PD-1 inhibitors every 3 weeks. Palliative radiotherapy was administered to localized lesions for symptomatic treatment purposes in addition to systemic therapies. Tumor response was evaluated using RECIST1.1 criteria. The primary outcome measures were progression-free survival (PFS) and overall survival (OS). Other outcome measures were disease control rate (DCR) and objective response rate (ORR). The Kaplan-Meier method was utilized for survival analysis, and univariate and multivariate Cox regression analysis was conducted to identify prognostic factors associated with PFS and OS. Results: We included 129 R/M HNC patients. The median follow-up time was 14.0 months. The median number of immunotherapy courses received was 4 (range: 1-60). During immunotherapy, 43 patients received palliative radiotherapy, targeting primary tumors, lymph nodes, metastasis in liver, lung, bone, and other sites. Following the treatments, 16 (12.4%) patients achieved complete response (CR), 44 (34.1%) achieved partial response (PR), 35 (27.1%) had stable disease (SD), and 34 (26.4%) had progressive disease (PD). The ORR was 46.5% and the DCR was 73.6%. The group receiving immunotherapy combined with palliative radiotherapy had higher ORR (65.1% vs 37.2%, p = 0.005) and DCR (90.7% vs 65.1%, p = 0.004) than those without palliative radiotherapy. The PFS (15.0 months vs 4.0 months, p = 0.0027) and OS (not reached vs 26.0 months, p = 0.036) were improved in patients receiving palliative radiotherapy compared to those not. Patients who had received prior radiotherapy (n = 81) had a shorter PFS (4.0 months vs 14.0 months, p = 0.014), while there was no difference in OS (p = 0.16). We further showed that patients had better PFS (20.0 months vs 2.0 months; p < 0.0001) and OS (43 months vs 17 months; p = 0.0043) when they received more than 4 cycles of immunotherapy. At the same time, our findings demonstrated that immunotherapy combined with nanoparticle albumin‐bound (nab-) paclitaxel-based regimens may prolong PFS (14.0 months vs 4.0months vs 2.5months, p = 0.0055) than gemcitabine-based regimens and other regimens. Conclusions: In patients with R/M HNC, the combination of immunotherapy and palliative radiotherapy demonstrates a synergistic effect, resulting in survival benefits. Prior radiotherapy might compromise patients’ PFS. Increasing the number of immunotherapy cycles and combining with nab-paclitaxel chemotherapy may improve patient survival.
Real-world evaluation of nivolumab in patients with non-nasopharyngeal recurrent or metastatic head and neck cancer: A retrospective multi-center study by the Turkish Oncology Group (TOG).
Authors: Akyildiz Arif , Guven Deniz Can , Koksal Baris , Karaoğlan Beliz Bahar , Kivrak Salim Derya , Sütcüoğlu Osman , Erciyestepe Mert , Alan Ozkan , Taban Hakan , Yildirim Nilgun , Sakalar Teoman , Yazilitas Dogan , Ismayilov Rashad , On Sercan , Aslan Ferit , Demirci Nebi Serkan , Kemal Yasemin , Diker Omer , Gullu Ibrahim Halil , Aksoy Sercan
Published: June 2024

e18004

Background: Head and neck cancers (HNCs) represent a significant global health concern due to high morbidity and mortality rates. The prognosis for advanced or recurrent cases remains challenging. Nivolumab obtained approval for recurrent or metastatic HNC based on the Phase III CheckMate 141 trial. This study aimed to evaluate the real-world outcomes of nivolumab in patients with non-nasopharyngeal HNC. Methods: In this multicenter retrospective study, we analyzed 124 patients with recurrent or metastatic non-nasopharyngeal HNC who received nivolumab in the second-line setting and beyond. Data were collected from 22 different cancer centers across Turkey. The effectiveness and safety of the treatment and survival outcomes were evaluated. Results: The median follow-up duration was 7.5 months (3-66.1 months). Overall survival (OS) and progression-free survival (PFS) were determined to be 11.8 and 3.8 months, respectively. Nivolumab exhibited clinical responses, yielding an objective response rate (ORR) of 29.9% and a disease control rate (DCR) of 55.7%. Safety assessments consistently revealed a well-tolerated profile, with no reported instances of treatment discontinuation or mortality attributed to adverse side effects. Notably, several factors, including performance status, neutrophil-to-lymphocyte ratio, tumor location, and p16 positivity, emerged as prognostic indicators significantly associated with OS. Conclusions: Nivolumab is an effective and safe treatment option for patient with recurrent or metastatic non-nasopharyngeal HNC in real-world setting. [Table: see text]
Prevalence and risk factors associated with chronic pain among survivors of head and neck cancer.
Authors: Jiang Rong , Chen Meng , White Melissa Christina , Ramos Katherine , Corbett Cheyenne , Watts Tammara L , Graboyes Evan Michael , Osazuwa-Peters Nosayaba
Published: June 2024

e18016

Background: There are over 500,000 survivors of head and neck cancer (HNC) in the United States. Pain is one of the most common symptoms of HNC due to disease anatomy, treatment and post-treatment toxicities. While opioid treatment is a mainstay in HNC care, factors associated with chronic pain are not properly understood. Methods: We built a retrospective cohort of adult patients with a history of HNC using the National Health Interview Survey (NHIS) from 2010 to 2021 that collected through personal household interviews ( n = 353). Chronic pain was defined using the question: In the past three months, how often did you have pain? Would you say never, some days, most days, or every day? Chronic pain was coded as “yes” if the response was most or every day, and “no” if it was never or some days. Using weighted logistic regression analysis adjusting for age and sex, we examined the association between chronic pain and sociodemographic (race, insurance, education, income, employment and smoking history) and clinical (depression, and self-rated health status) factors. Results: Among individuals with a history of HNC, 149 (adjusted Prevalence Rate = 43.2%; 95% CI: 36.6%, 49.8%) had experienced chronic pain in the past three months. There were significant associations with clinical factors, as individuals with poor self-rated health (aOR = 6.42; 95% CI: 3.25, 12.70) and those with depression (aOR = 3.25; 95% CI: 1.73, 6.11) had increased odds of reporting chronic pain. Among sociodemographic factors White race (aOR = 2.52, 95% CI: 1.04, 6.10) and Medicaid insurance (aOR = 3.76, 95% CI: 1.40, 10.10) were associated with and increased odds of reporting chronic pain. There was no significant association of education, income, employment or smoking history with chronic pain among the study HNC survivors. Conclusions: Over 40% of individuals with a history of HNC may be living with chronic pain, unequally distributed based on race, payor status and comorbid depression. Given the current opioid crisis in the United States, and the poor outcomes associated mental health in cancer survivors, our findings highlight clinical and social determinants of health factors that should be taken into the consideration for management of chronic pain among survivors of HNC patients.
Prognostic impact of caspase-8 mutation in oral cavity squamous cell carcinoma: A real-world cohort study.
Authors: Lu Hsueh-Ju , Wu Ming-Fang , Yang Sung-Fa
Published: June 2024

e18029

Background: Identifying the drive genes and inhibiting its significant signals were persistently the main concept in cancer treatment. However, for oral cavity squamous cell carcinoma (OCSCC), the most influential genes for overall survival (OS) remain unclear. Methods: A total of 120 OCSCC patients, with corresponding pathologic specimens at initial diagnosis, were collected in Taiwan. After excluding eligible patients, 95 patients were enrolled for analysis. Whole-exome sequencing was done and the prognostic impact of each gene was analyzed. The Cancer Genome Atlas (TCGA) database was used to validate. Results: The incidences of caspase-8 mutation were 22.1% and 10.9% in the Taiwan and TCGA cohort, respectively. In the Taiwan cohort, caspase-8 mutation was the most significant independent for OS with an adjusted hazard ratio (HR) [95% confidence interval (CI)]: 3.83[1.84-7.99]). It was validated by the TCGA database (HR [95% CI]: 1.51[1.00-2.29]). The 5-year OSs of the patients with or without caspase-8 mutation were 38.1% vs. 75.3% ( P < 0.001) (HR [95% CI]: 3.264[1.645-6.438]) in the Taiwan cohort, and 26.1% vs. 49.0% ( P = 0.048) (1.513[1.001-2.288]) in the TCGA cohorts, respectively. Caspase-8 mutation was also individually associated with poor prognosis for TNM stage I/II/III/IV, respectively. L81F, R127*, R472*, R494*, S174*, and T528I were the intersected point mutations of caspase-8. Most of these intersected point mutations were pathologic/likely pathologic variants in the published bioinformatic databases. Conclusions: In conclusion, caspase-8 mutation was the most significant genetic alteration impacting prognosis. Novel agent development could be considered for this candidate.
Differential gene expression and methylation of upper aerodigestive tract and lung squamous cell carcinoma between European ancestry (EA) and African ancestry (AA) patients.
Authors: Thomas Hannah , Mukhina Vera , Saxena Anirudh , Mehra Ranee , Gaykalova Daria
Published: June 2024

e18031

Background: Pan-cancer analysis of cancer disparities revealed both head and neck and lung cancer are among the top cancers with significant disparities in overall survival outcomes between EA and AA patients. Analysis of The Cancer Genome Atlas (TCGA) for all cancer in EA and AA found genetic signatures associated with noted disparities, such as somatic copy number alterations, TP53 mutations, CCNE1 amplification, and overexpression of genes correlated with chromosomal instability. To inform whether epigenetic and transcriptomic factors could be driving the disparities seen in squamous cell carcinoma (SCC) of the upper aerodigestive tract (UADT) and lung, we sought to analyze genomic data to identify differentially methylated and expressed genes between EA and AA patients and determine whether these affected survival. Methods: TCGA was queried to extract data from self-identified EA and AA patients with head and neck, esophageal, and lung SCC. Literature suggests that SCC tumors share genetic and epigenetic signatures and can be analyzed as a group. Human papillomavirus positive patients were excluded. Patients were separated into EA and AA groups matched for age, stage, and smoking to account for clinical biases of biological analysis. DNA methylation (Epic array) and gene expression (RNA-Seq) profiles were compared between tumor tissue samples in EA patients, tumors in AA patients, and normal tissue. The genes that were identified to be differentially methylated were then analyzed to compare overall survival between hypomethylation and hypermethylation of each identified gene, with and without subgrouping by race. Differentially expressed genes were similarly analyzed between high and low expression. Overall survival was estimated by the Kaplan-Meier method and compared using the log-rank test. Results: A comparison of DNA methylation profiles found 79 genes that were differentially methylated when comparing EA tumor, AA tumor, and normal tissue samples. Survival analysis was performed on top 21 of the differentially methylated genes. Of these, 9 were found to have significant differences in overall survival when stratifying by race and methylation status. Differentially methylated genes included MAD1L1 (Mitotic Arrest Deficient 1 Like 1), which is known for its role in the spindle assembly checkpoint in mitosis and tumor suppression. Similar analysis revealed 404 genes that were differentially expressed comparing EA tumor, AA tumor, and normal tissue. Candidate genes based on expression level will be discussed. Conclusions: Differential DNA methylation and gene expression were noted between EA and AA groups with lung and UADT SCC. This difference may contribute to the disparity in overall survival seen between these groups that persists even when controlling for variables commonly associated with worse survival.
Racial and gender disparities in the incidence of thyroid cancer using Nationwide Inpatient Database.
Authors: Frasier Kelly , Javaid Saad , Li Vivian , Vinagolu-Baur Julia , Ortega Yaguachi Nataly , Rodriguez Evadne , Del Castillo Olivia , Batista Raquel , Jonas Kenlee , Palma Laura
Published: June 2024

e18066

Background: This study aimed to conduct a comprehensive evaluation of the ethnic and gender disparities that exist in thyroid cancer. Despite the significant amount of research that has been conducted on the complex and multifaceted differences between races and genders in various forms of cancer, there is still a noticeable gap in the data available in patients with thyroid cancer. Therefore, this study comprehensively assessed these disparities and their potential impact on the risk of developing Thyroid cancer. Methods: Using the National Inpatient Sample 2020, we identified patients with Thyroid cancer as the primary diagnosis (local/regional and advanced metastatic). We analyzed baseline characteristics such as age, gender, insurance, and income status, and several comorbidities to assess the risk associated with Thyroid cancer. Log Binomial regression model was used to calculate the Risk ratios after adjusting for confounding variables. Results: A total of 6,471,165 patients were analyzed, and it was found that 7520 of them (0.1%) had Thyroid cancer. Among these patients, 44.8% were male, and 55.1% were female, p<0.001. Female patients demonstrated a higher risk of developing thyroid cancer as compared to males (RR= 1.41(1.27-1.57); p<0.001). Compared to white females, white males, black males and females exhibited a decreased risk of bladder cancer (RR=0.66(0.58-0.76),p<0.001; RR= 0.24(0.16-0.36),p<0.001 and RR= 0.53(0.40-0.68), p<0.001, respectively). Hispanic females (RR=2.67(2.26-3.16);p<0.001) and females of other races (RR=1.69(1.20-2.37); p=0.002) had increased risk of Thyroid cancer, while no difference in risk was noted in Asian males (RR= 0.38(0.09-1.56); p=0.18), females (RR= 0.94(0.39-2.28); p=0.90) and males of other races (RR=0.81(0.51-1.29); p=0.38). Compared to lower income group patients, patients with high incomes had an increased risk of thyroid cancer ($65,000-$85,999: RR=1.18(1.01-1.38), p=0.03 ; >$86,000: RR=1.30(1.10-1.52), p=0.001). The risk of thyroid cancer decreased with increasing age (36-45:RR=0.59(0.48-0.72),p<0.001; 46-64: RR= 0.25(0.21-0.29),p<0.001; >65: RR =0.24(0.19-0.30), p<0.001). Patients with Diabetes had decreased risk (RR= 0.31(0.27-0.36); p<0.001), while patients with Hypertension had increased risk of thyroid cancer (RR=1.30(1.16-1.47); p<0.001). Conclusions: The disparities in healthcare access and the unique challenges faced by high-risk groups have a profound impact on patients with thyroid cancer. A more comprehensive understanding of these disparities is essential to effectively support this vulnerable patient population and to identify preventive measures that can reduce the incidence of bladder cancer among high-risk demographic segments.
Real-world analysis of HyperCVAD + TKI for untreated Ph+ ALL.
Authors: Rakiewicz Tara , Keiffer Gina , Palecki Julia , Bernstein Andrew , Wilde Lindsay , Kasner Margaret T.
Published: June 2024

e18500

Background: Tyrosine kinase inhibitors (TKI) have revolutionized the treatment of acute lymphoblastic leukemia (ALL) with t(9;22) (Ph+). A single-center, single-arm, phase II study published in 2017 reported excellent outcomes in adult patients (pts) treated with ponatinib + HyperCVAD alternating with high-dose methotrexate and cytarabine (HyperCVAD). Complete remission (CR) rate was 100% with 78% of pts achieving complete molecular response (CMR). 2-year (yr) event free survival (EFS) was 81% and overall survival (OS) was 80% with 9/37 pts undergoing allogeneic stem cell transplantation (SCT). This treatment's success changed standard of care for patients with Ph+ ALL; however validation of these findings is needed. Methods: We performed a real-world, retrospective analysis of adult patients with previously untreated Ph+ ALL treated with at least 1 cycle of HyperCVAD + ponatinib or an alternate TKI, at our institution between 2016 and 2023. The primary endpoint was 2-yr EFS. Kaplan-Meier method was used to estimate all time-to-event endpoints and proportions were estimated along with 95% confidence intervals. Results: 19 patients with a median age of 46 yr were analyzed. 18 pts were newly diagnosed; 1 pt had relapsed Ph+ ALL. Median follow up was 29.4 months (m). Baseline characteristics are in the table. All evaluable patients achieved a response (18/18). 1 pt died from septic shock within 4 weeks of treatment start (5.3%). All evaluable pts achieved CMR, defined as undetectable BCR/ABL1 transcript (17/17; 1 missing). Median time to CMR was 3.83 m [1.67, 9.30]. Of the 9 pts who underwent SCT, 5 (55.6%) received ponatinib and 4 (44.4%) received an alternate TKI (p=0.350). SCT was planned in 5 pts, but performed for molecular relapse (MR) in 4 pts. No pts had clinical relapse, but incidence of MR was 40.1%. 2-yr cEFS (defined as clinical relapse or death) was 89.2% [63.1%, 97.2%]. Median cEFS was greater than 32.6 m [32.6, ∞], but when defined as death or any relapse, it decreased to 18.40 m [7.27, ∞]. 2-yr OS was 89.2% [63.1%, 97.2%]. Conclusions: While 2-yr OS and EFS are similar in our cohort to published data, a surprisingly large number of patients experienced molecular relapse, which was not reported in the original trial. While our sample size was small, there was no significant difference in CR or transplant status for patients treated with Hyper CVAD + ponatinib versus alternate TKI. [Table: see text]
RNA expression-based risk stratification of de novo acute myeloid leukemia.
Authors: Kim Donghyun , Yu Yeonhwa
Published: June 2024

e18503

Background: Prognostication of acute myeloid leukemia (AML) at initial diagnosis relies on the identification of certain underlying genetic abnormalities as proposed by the European LeukemiaNet (ELN) risk classification. However, AML is highly heterogenous at the molecular level and standard guidelines are often not straightforwardly applicable. In this study, we explored gene expression-based risk stratification strategies and found that FLT3 and NPM1 transcript level profiles can predict overall survival in de novo AML. Methods: The Cancer Genome Atlas AML (TCGA-LAML) project’s normalized RNA-Seq transcriptome profile (n=158) published in 2013 was analyzed with MATLAB software. "High” or “low” level of each gene was determined by the median RPKM of the cohort used as cutoff. P-values were obtained from Cox proportional hazards regression model. Results: The low-FLT3 level group was associated with superior median OS (mOS) compared to high-FLT3 group (24 vs. 16 months; p = 0.02), whereas high-NPM1 level group was associated with superior mOS compared to low-NPM1 group (26 vs. 12 months; p = 0.03). The mOS for high-FLT3/low-NPM1 and low-FLT3/high-NPM1 groups were 9 months and 27 months, respectively (p = 0.001). In high-FLT3/low-NPM1 and low-FLT3/high-NPM1 groups, composition of Cancer and Leukemia Group B (CALGB) cytogenetic risk category [favorable, intermediate, adverse] was [9%, 73%, 18%] and [32%, 49%, 19%], respectively; composition of French-American-British (FAB) classification [M0, M1, M2, M3, M4, M5, M6, M7] was [15%, 27%, 3%, 6%, 24%, 24%, 0%, 0%] and [3%, 14%, 41%, 19%, 22%, 0%, 0%, 3%], respectively; composition of FLT3/NPM1c mutations [ wt/wt, mut/wt, wt/mut, mut/mut, NOS] was [45%, 18%, 18%, 18%, 0%] and [61%, 14%, 7%, 14%, 2%], respectively. Conclusions: We demonstrate a de novo AML risk categorization method solely based on FLT3 and NPM1 RNA-Seq transcript levels. The mOS of high-FLT3/low-NPM1 group resembled that of ELN "adverse" risk group, whereas the mOS of low-FLT3/high-NPM1 group resembled that of ELN "favorable" risk group. High-FLT3/low-NPM1 group was composed of fewer "favorable” but more “intermediate” CALGB risk categories compared to low-FLT3/high-NPM1 group. Notably, considerably more FAB M0, M1 and M5 but fewer M2 and M3 classes were enriched in high-FLT3/low-NPM1 group compared to low-FLT3/high-NPM1 group. We also note approximately half of the cases analyzed were FLT3 and NPM1 wild-types and speculate FLT3 and NPM1 transcript profiles may represent a global oncogenic state regardless of the underlying FLT3 or NPM1 mutations. This is also supported by the previously reported FLT3 mutation-like transcriptomic profiles observed in FLT3 wild-type AML cases1). Reference: 1) Mosquera Orgueira A, et al. Gene expression profiling identifies FLT3 mutation-like cases in wild-type FLT3 acute myeloid leukemia. PLoS One. 2021 Feb 16;16(2):e0247093
Co-mutation landscape and its prognostic impact on newly diagnosed adult patients with NPM1 mutated de novo acute myeloid leukemia.
Authors: Yao Yiyi , Zhuo Nanfang , Zhou Yile , Mao Liping , Yang Min , Lou Yinjun , Tong Hongyan , Jin Jie , Wang Huafeng
Published: June 2024

e18505

Background: 25-35% of adult patients with acute myeloid leukemia (AML) carries NPM1 mutation, characterized by aberrant cytoplasmic dislocation of NPM1 protein, which is generally associated with a favorable outcome in the absence of FLT3-ITD mutation. Indeed, for NPM1-mutated AML patients with different co-mutation profiles, identification of specific co-mutation combinations other than FLT3-ITD mutation is necessary for accurate risk stratification and contributes to identify the optimal population who may benefit from allogeneic hematopoietic stem cell transplantation (allo-HSCT) during post-remission therapy. Methods: Eligible patients included newly diagnosed adult patients (≥18 years old) with NPM1 mutated de novo AML (M3 excluded) treated at the First Affiliated Hospital of Zhejiang University School of Medicine for at least one complete course of induction therapy from October 2018 to December 2022. All patients received next generation sequencing (NGS) detection for diagnosis before treatment. Response was evaluated within two courses of induction chemotherapy. Overall survival (OS), event-free survival (EFS), and disease-free survival (DFS) were collected for endpoint analysis. Results: 178 patients were analyzed. Median age was 59 years old (IQR, 51-68). The co-mutated genes with a detection rate of ≥ 10% included FLT3, DNMT3A, TET2, IDH2, IDH1, PTPN11, NRAS, and WT1. The median follow-up was 26.2 months. Our results showed that in NPM1 mutated AML, co-mutations of IDH1, IDH2, and PTPN11-PTP domain were associated with favorable prognosis, while co-mutations of FLT3-ITD and DNMT3A were associated with poor prognosis. Interestingly, the adverse outcome trends brought by FLT3-ITD and DNMT3A co-mutations could be reversed by IDH mutation and PTPN11 mutations, respectively (Table). Besides, for NPM1 mutated AML patients combined with FLT3-ITD/ DNMT3A mutations, allo-HSCT after remission could significantly improve outcome ( P < 0.05), while similar results were not found in FLT3-ITD/ DNMT3A wild type patients. Conclusions: This study demonstrated that NPM1-mutated AML with different co-mutation profiles led to heterogeneous outcomes. For NPM1-mutated AML patients with adverse prognosis-related co-mutation combinations, allo-HSCT after remission may be a recommended strategy to improve outcome. [Table: see text]
A propensity score–matched comparison of cytoreductive strategies in patients with acute myeloid leukemia presenting with hyperleukocytosis.
Authors: Avetian George , Ho Thuy , Lee Hyun , Bouligny Ian Michael , Maher Keri Renee
Published: June 2024

e18509

Background: Hyperleukocytosis (white blood cell (WBC) count greater than 100x109), which may lead to the clinical entity of leukostasis, is a hematologic emergency present at diagnosis in 18% of patients with acute myeloid leukemia (AML). There is controversy regarding the appropriate cytoreductive strategy, which may include cytoreductive chemotherapy, hydroxyurea, and/or leukapheresis. The American society for apheresis (ASFA) released guidelines in 2023 making leukapheresis a Category III recommendation, however significant heterogeneity and methodologic flaws exist in the evidence used to make these recommendations. Methods: Retrospective analysis of 58 patients at Massey Comprehensive Cancer Center between 2017 and 2023 who received either hydroxyurea alone (n=35) or both hydroxyurea and leukapheresis (n=23) for hyperleukocytosis at time of presentation for AML diagnosis was performed. Baseline characteristics including age, sex, Charlson Comorbidity Index (CCI), European LeukemiaNet (ELN) risk stratification, and WBC count prior to cytoreduction were collected. Comparisons of complete remission rates (CR/CRi), 30- and 60-day mortality, median overall survival (OS), and rates of therapy-induced tumor lysis syndrome (TLS) and disseminated intravascular coagulation (DIC) were analyzed using Kaplan-Meier, Fisher’s exact, Mann-Whitney tests, respectively on a propensity score matched cohort to account for differing initial WBC counts between the treatment groups. Results: PSM was used to match presenting WBC counts between the two cohorts. Other baseline characteristics including median age (65y v. 60y), median CCI (5 v. 4), ELN adverse risk rate (31.53% v. 26.1%) did not differ after PSM. No significant difference was found between the hydroxyurea group compared to the hydroxyurea and leukapheresis group, respectively, when analyzing for rate of CR/CRi (36.5% v. 43.5%), 30-day mortality (10.5% v. 17.3%), 60-day mortality (10.5% v. 34.8%), median OS (7.77 mo. v. 8.07 mo.), or rates of DIC (10.5% vs. 8.7%) and therapy induced TLS (0% v. 0%). Conclusions: Patients who received hydroxyurea alone had similar outcomes when compared to the combined treatment group with respect to median OS, CR/CRi, and mortality rates. These results are notable given that leukapheresis is not available at many medical centers and is a resource-heavy procedure, and especially so in light of new ASFA guideline changes. However, these results reflect the laboratory entity of hyperleukocytosis rather than the clinical entity of leukostasis. Further work is ongoing to assess impact of cytoreductive strategies in leukostasis in AML, and among different cytogenetic and molecular subtypes. Decisions for leukapheresis or other cytoreductive strategies should be made on a case-by-case decision at an experienced center when possible.
Predictors of disseminated intravascular coagulation in patients with acute myeloid leukemia with severe sepsis and septic shock.
Authors: Adla Jala Saisree Reddy , Gadhiya Dhruvkumar , Ramphul Yogeshwaree , Mal Madho , Tummala Nayanika , Dhaliwal Kanwar Bir Singh , Sakthivel Hemamalini , Dandwani Mehndi , Ramphul Kamleshun , Chennapragada Suma Sri
Published: June 2024

e18511

Background: Multiple pathophysiological pathways predispose Acute Myeloid Leukemia (AML) patients to Disseminated Intravascular Coagulation (DIC). As sepsis can also trigger DIC, we aim to evaluate the predictors of DIC among AML patients with severe sepsis and septic shock. Methods: We queried adults with a diagnosis of AML and severe sepsis with septic shock admitted between 2016 and 2020 in the United States via the National Inpatient Sample(NIS). Patients ages <18 years were excluded from our sample. Multivariate regression models were used to estimate the impact of multiple factors on events of DIC among these patients. Results: Our sample consisted of 19545 cases of severe sepsis with septic shock in AML adults that matched our selection criteria. It included 1705(8.7%) patients who also experienced DIC during hospitalization. Several factors, such as medium (aOR 2.174, p<0.01) and high frailty risk (aOR 1.788, p<0.01, vs. Low frailty risk), history of nutritional anemia (aOR 1.580, p<0.01), cirrhosis (aOR 2.316, p<0.01), chronic kidney disease (CKD) (aOR 1.319, p<0.01), systemic lupus erythematosus (SLE) (aOR 1.845, p=0.040), Females (vs. Males, aOR 1.169, p<0.01), and patients covered by Medicaid (vs. Medicare, aOR 1.325, p<0.01) showed higher odds of DIC. In addition, those ages ≥60 years were less likely to experience an event of DIC (aOR 0.699, p<0.01), as DIC patients were younger (mean age 58.85 years vs. 62.43 years, p<0.01). Patients with obesity (aOR 0.605, p<0.01), smoking (aOR 0.772, p<0.01), and cachexia (aOR 0.738, p=0.038) also showed fewer events of DIC. However, no racial differences were found between Blacks(aOR 0.928, p=0.404) or Hispanics (aOR 1.019, p=0.831)(vs. Whites). DIC patients who died were also older (mean age 59.99 years vs. 56.19 years, p<0.01). Finally, we were also able to confirm that events of DIC led to poorer prognosis with a higher rate of all-cause mortality (70.1% vs. 47.6%, aOR 2.169, p<0.01). Conclusions: Factors increasing the risk of DIC in patients with AML and severe sepsis with septic shock included anemia, cirrhosis, CKD, SLE, medium and high frailty risk, female sex, and Medicare insurance. While we noted lower odds of DIC among patients who are ≥60 years old, obese, cachectic, and smokers, further hospital-based studies to evaluate the severity of their illnesses along with other variables that could be analyzed via the NIS should be encouraged.
Venetoclax combined with hypomethylating agents for favorable risk acute myeloid leukemia: A single center experience.
Authors: Bajwa Shammas , Parkin Brian , Gayle Arlene A. , Patel Rushang D. , Mori Shahram , Pancari Philip , Socola Francisco Andres
Published: June 2024

e18514

Background: Favorable risk acute myeloid leukemia (FR-AML) is typically treated with intensive induction chemotherapy followed by high dose consolidative cytarabine. However, a subgroup of FR-AML are not candidates for high intensity induction because of advanced age, comorbidities, or poor performance status. For these patients, hypomethylating agents (HMA) combined with venetoclax (HMA-Ven) is inferred as the standard of care based upon results of the VIALE-A trial; however, that trial enrolled only intermediate or poor risk AML. The efficacy of HMA-Ven in FR-AML is unclear. Here we present a single center experience of this regimen in FR-AML. Methods: In this retrospective single center case series, we collected data from all patients >18 years old with newly diagnosed FR-AML between January 2018 to December 2022 at AdventHealth Orlando who were treated with HMA-Ven. Patient with relapsed/refractory disease or a diagnosis of acute promyelocytic leukemia were excluded. FR-AML was defined using ELN 2022 guidelines based on the results of genomic testing of the initial bone marrow aspirate. The primary endpoints were the complete remission (CR) rate and 1-year overall survival (OS). Statistical analyses were performed using the R survminer package. Results: Newly diagnosed FR-AML who received HMA-Ven were identified (n=12). The median age was 67.5 years. 3 (25%) cases had inversion of chromosome 16 and 9 (75%) had NPM1 mutations without FLT3-ITD mutations. 11 (92%) patients received decitabine and venetoclax. Patients received a median of 2.5 cycles of HMA-Ven, and all 12 patients achieved CR after one cycle of treatment. 6 (50%) patients were consolidated with intermediate-dose cytarabine (IDAC), 3 (25%) continued HMA-Ven, 2 (17%) underwent allogeneic stem cell transplant, and 1 (8%) received enasidenib. The 1-year OS was 80% (CI 0.59-1), and the median OS was not reached. 1 patient died due to chemotherapy toxicity with IDAC, and 1 patient died due to heart complications. 2 patients relapsed, 1 after IDAC and 1 after intolerance to further treatment after 6 cycles of HMA-Ven. Conclusions: Our findings suggest that HMA-Ven is an effective treatment for newly diagnosed favorable risk AML. All patients achieved CR with one cycle of treatment with most surviving more than one year. Large multicenter studies are needed to further validate these promising results.
Patients with relapsed/refractory mIDH1 AML who proceeded to transplant after olutasidenib treatment.
Authors: De Botton Stéphane , Watts Justin M. , Jonas Brian Andrew , Chao Mwe Mwe , Cortes Jorge E.
Published: June 2024

e18516

Background: Hematopoietic stem cell transplantation (HSCT) in post-remission AML is potentially curative and can improve survival for patients at high risk of relapse. However, achieving remission in patients with relapsed/refractory (R/R) AML is difficult, and therapies that enable previously ineligible patients to proceed to HSCT are highly desired. Olutasidenib (OLU) is FDA-approved for treatment of R/R mIDH1 AML. In the pivotal cohort of the registrational, Ph2, open-label, multicenter trial of olutasidenib, 35% of patients achieved complete remission (CR) or CR with partial hematologic recovery (CRh) with a 25.9 mos duration of response. Here we report the characteristics and outcomes of patients treated with olutasidenib who then underwent HSCT. Methods: In the Phase 2 trial, the pivotal cohort enrolled adults with R/R m IDH1 AML. OLU was administered at 150 mg BID in continuous 28-day cycles. The primary efficacy endpoint was the CR/CRh rate. Patients who achieved remission and met criteria for transplant could proceed to HSCT with discontinuation of OLU. Data cutoff: June 18, 2021. Results: 153 patients with m IDH1 R/R AML received OLU monotherapy, and 16 (11%) proceeded to HSCT. In these 16 patients, median age was 61 (40, 67), 50% were male, and median BMI was 24 (18, 38). Baseline bone marrow blast count was 24% (6% - 60%). At baseline, 15/16 (94%) had intermediate cytogenetic risk and 1 was unknown. Time since diagnosis was 8.2 mos (1.5, 116.8). 8 (50%) were refractory and 8 were relapsed (2 for >12 months). Median number of prior regimens was 2 (range 1-7). All 16 had prior induction, 2 (13%) had prior HMA, 3 (19%) had prior HSCT, and 94% (15/16) had prior intensive chemotherapy (IC), 50% (n=8) of whom were IC-refractory. Response rates to OLU in the 16 patients prior to proceeding to HSCT were 75% CR/CRh (69% CR), 19% patients CRi and 6% stable disease (see Table). All 16 patients were alive at 100 days. Median survival from start of OLU treatment has not been reached. Overall survival probability was 94% (95%CI: 63, 99) at 12 months and 61% (95% CI: 32, 80) at 24 months. The safety profile of this subpopulation was consistent with the rest of the cohort. No deaths due to an adverse event occurred. Conclusions: Olutasidenib was effective in achieving remission in patients with mIDH1 R/R AML, thus enabling patients R/R to or ineligible for intensive chemotherapy at study entry to proceed to potentially curative HSCT. Clinical trial information: NCT02719574 . [Table: see text]
The effects of substituting cladribine for fludarabine on outcomes of a reduced intensity conditioning regimen.
Authors: Sahin Ugur , Urlu Selin Merih , Gokmen Ayla , Arslan Onder , Ozcan Muhit
Published: June 2024

e18518

Background: Drug shortages may be encountered especially in times of pandemics and war. The extrapolation of data focusing on different diseases may provide clinical clues for substituting two chemotherapeutic drugs of the same class. The substitution of cladribine for fludarabine in a reduced intensity conditioning (RIC) regimen composed of fludarabine, melphalan and total body irradiation (TBI) may yield similar side effect profile and outcomes. Methods: Consecutive patients undergoing an allogeneic stem cell transplant in our center between November 2019 to December 2022 were included. Within this period cladribine had to be substituted for fludarabine during a drug shortage. All patients received intravenous melphalan 75 mg/m2/day on day -2, and 200 cGy TBI on day -1. The regimen included either subcutaneous cladribine 10 mg/m2/day on days -5 to -2, or intravenous fludarabine 40 mg/m2/day on days -5 to -2. Graft versus host disease (GvHD) prophylaxis included a calcineurin inhibitor (CNI) + mycophenolate mofetil (MMF) for matched related donor transplants; and post-transplant cyclophosphamide + CNI + MMF for matched unrelated (MUD) and haploidentical donors. The distributions and medians of studied parameters in two cohorts were compared with non-parametric methods. Overall survival (OS), progression-free survival (PFS) and transplant-related mortality (TRM) were estimated by the Kaplan-Meier Method. The cut-off for statistical significance was defined as p<0.05. Results: A total of 70 patients (27 in cladribine and 43 in fludarabine cohort) were included. Median age was 59 (22 to 76) and 64.3% constituted males. Median follow-up was 10.2 months (0.1 to 44.7). Acute leukemia diagnosis, intermediate to high disease risk index (DRI) and intermediate to high Charlson comorbidity index (CCI) constituted 45.7%, 60.0% and 58.1% respectively. Haploidentical donors were used in 28.6%. The distribution of gender, diagnosis, DRI and CCI scores, donor type, total CD34 dose given, panel reactive antibody (PRA) positivity were similar. Median days to neutrophil engraftment was shorter with fludarabine (19 vs 16, p=0.01), however, median duration of in-unit stay was similar (27 vs 28 days, p=0.73). TRM, nausea and acute GvHD frequency was lower with cladribine (p=0.35, p=0.001 and p=0.02, respectively). Typhilitis and perianal infections were more common with cladribine (p=0.07 and p=0.04, respectively). OS and PFS were similar (p=0.81 and p=0.66, respectively). When cladribine was compared to fludarabine on day +90, OS was 78,0% (95% CI: 62.3-93.7) vs 65,0% (95% CI: 51.3-78.7); PFS was 70.0% (95% CI: 52.4-87.6) vs 65.0% (95% CI: 51.3-78.7); TRM was 19.0% (95% CI: 3.3-34.7) vs 24.0% (95% CI: 10.3-37.7). Conclusions: Cladribine may be safely constituted for cladribine in a RIC regimen and may yield similar, even some favorable, outcomes when compared to fludarabine.
ASC4REAL: Efficacy and tolerability comparison between ASCEMBL study, a phase 3 randomized clinical trial (RCT), and consolidated real-world (RW) experience with asciminib (ASC) in patients with CML beyond two TKIs.
Authors: Khanna Anchit , Small Hannah , Lutchman Dhamend , Schofield Peter
Published: June 2024

e18519

Background: Despite advances in the management of chronic myeloid leukemia (CML), effective treatment options in later lines are limited. Treatment failure rates increase with each line of treatment and sequential tyrosine kinase inhibitor (TKI) therapy is associated with increased resistance. Importantly, almost all TKIs in the clinics target the ATP-binding site potentially resulting in off-target effects and long-term tolerability issues. Although data for ASC, a novel allosteric TKI targeting the myristoyl pocket, is emerging in the RW setting, low patient numbers in ASC RW studies hinders a robust comparison with the larger phase 3 RCT study. Methods: Post systematic literature search, data from 9 published or publicly presented RW studies was extracted. 319 CML patients that received ASC beyond 2 TKIs were included in this analysis. RW studies that had less than 10 patients were excluded. The results were then compared to estimates from the ASCEMBL study. Results: Compared to the RCT, RW studies showed similar or higher efficacy based on major molecular response (MMR) and deep molecular response (DMR) rates, achieved in shorter time. Rate of discontinuation of ASC was also lower in the RW setting. Similarly, some adverse events, specifically thrombocytopenia and arterial occlusive events (AOE) were lower, while some such as myalgia were higher in the RW setting when compared with the RCT. Conclusions: This analysis demonstrates ASC as an effective TKI for CML patients in the RW setting, supporting the results from the ASCEMBL RCT. [Table: see text]
Epidemiology of mast cell leukemia: A must!
Authors: Ali Hassan , Thirumaran Rajesh , Desai Krishna
Published: June 2024

e18537

Background: Mast Cell Leukemia (MCL) is one of the rarest encountered malignancies. It is an aggressive oncologic subtype of systemic mastocytosis (SM) and accounts for <1% of total cases. To make the diagnosis of MCL, in addition to the diagnostic criteria for SM (enlisted in the table), ≥ 20% atypical mast cells should be present in the marrow or ≥ 10% in the peripheral blood. However, an aleukemic form also exists. It can either occur as a de novo mutation or follow mastocytosis. The aim of this epidemiologic study is to aid better understanding of this lesser known aggressive malignancy. Methods: The data was collected from Surveillance, Epidemiology and End Result database Research Plus Data, 17 Registries, Nov 2022 Sub (2000-2020). We extracted Systemic Mastocytosis and Mast Cell Leukemia cases diagnosed after 20 years of age, using the ICD Code 9741/3 (SM) and 9742/3 Mast Cell Leukemia (MCL). The analysis was stratified for MCL based on age, sex, race, and treatment modality used. Results: A total of 795 cases of SM were identified, which were diagnosed between 2000 and 2020. Of which, only 35 cases were attributed to MCL over the last two decades. Of these 35 cases, 60% patients were males, and 40% were females. ~82.85% were Caucasians, ~11.42% were African-Americans, ~2.85% belonged to Asians and Pacific Islanders, and ~2.85% belonged to the Hispanic population. No reported cases were found amongst Alaskan Natives. Further analysis based on survival, gender and races was not done, due to small sample size. Conclusions: MCL accounts for only about 4% of total SM cases. Only 35 cases were identified in the past twenty years, making it one of the rarest encountered malignancies. From the reported data, it was slightly inclined to have male predilection, and Caucasians were the most commonly impacted individuals. Given its extremely low incidence, more research and analysis is warranted to understand this lesser known malignancy. [Table: see text]