tbuckley/cabot-search huggingface dataset:
In-depth analysis of responders in the phase 3 PhALLCON trial of ponatinib vs imatinib in newly diagnosed Ph+ ALL.
Authors: Elias Jabbour, Hagop M. Kantarjian, Ibrahim Aldoss, Pau Montesinos, Jessica Taft Leonard, David Gomez-Almaguer, Maria R. Baer, Carlo Gambacorti-Passerini, James K. McCloskey, Yosuke Minami, Cristina Papayannidis, Philippe Rousselot, Pankit Vachhani, Eunice S. Wang, Lin Yang, Meliessa Hennessy, Alexander Vorog, Niti Patel, Jose-Maria Ribera-Santasusana
Journal: Journal of Clinical Oncology (2024)

6533 Background: Ponatinib, a third-generation BCR::ABL TKI, has potent activity against all clinically relevant BCR::ABL1 variants, including T315I. PhALLCON (NCT03589326), a phase 3 trial comparing frontline TKIs in adults with Ph+ ALL, met its primary endpoint with a higher rate of minimum residual disease–negative (MRD-neg) complete remission (CR) at end of induction (EOI) with ponatinib vs imatinib (34.4%/16.7%; P=0.002). Here, we report response rates of MRD-neg at any time and PFS by age and BCR::ABL1 variant subgroups. Methods: Adults with newly diagnosed Ph+ ALL were randomized 2:1 to ponatinib (30 mg QD reduced to 15 mg QD upon MRD-neg CR at or after EOI) or imatinib (600 mg QD) plus 20 cycles of reduced-intensity chemotherapy (induction: 3 cycles; consolidation: 6 cycles; maintenance: 11 cycles), followed by single-agent ponatinib or imatinib until disease progression or unacceptable toxicity. Hematopoietic stem cell transplant (HSCT) was per investigator’s discretion. Post hoc analyses compared MRD-neg ( BCR:: ABL1 IS ≤0.01%; MR4) at any time and PFS (any-cause death, failure to achieve CR by EOI, relapse from CR, or failure to achieve/loss of MRD-neg) by age (&lt;/≥65 y) and BCR:: ABL1 variant (p190/p210). Data cutoff: Aug 12, 2022. Results: In the population of randomized patients (pts) with p190/p210 confirmed by central lab (n=232; 154/78 ponatinib/imatinib; median follow-up 20.1 mo), 68% vs 50% in the ponatinib vs imatinib arms were MRD-neg at any time, with similar benefit of ponatinib across age and variant subgroups (Table). Median PFS was more than twice as long with ponatinib vs imatinib across subgroups (Table). Pts achieving MRD-neg at any time were less likely to have HSCT with ponatinib vs imatinib (32%/56%). Among 107/42 pts without HSCT, exposure was &gt;2-fold longer in the ponatinib vs imatinib arms (median 12.8/5.1 mo) with comparable rates of arterial occlusive (3%/2%) and venous thromboembolic events (11%/12%), and discontinuations due to TEAEs (13%/14%). Conclusions: Ponatinib was superior to imatinib in combination with reduced-intensity chemotherapy for frontline treatment of Ph+ ALL, with higher rates of MRD-neg at any time, substantially longer PFS across age and BCR::ABL1 variant subgroups, and a safety profile comparable to imatinib. Clinical trial information: NCT03589326 . [Table: see text]
Safety and efficacy of olutasidenib treatment in elderly patients with relapsed/refractory m<i>IDH1</i> acute myeloid leukemia.
Authors: Stéphane De Botton, Brian Andrew Jonas, P. Brent Ferrell, Mwe Mwe Chao, Alice S. Mims
Journal: Journal of Clinical Oncology (2024)

6527 Background: Elderly patients with relapsed/refractory (R/R AML) are a special population that may elevate safety concerns, which must be balanced with clinical benefit. Olutasidenib (OLU), a targeted therapy for m IDH1 AML, was well tolerated in a registrational, Ph2, open-label, multicenter trial and, in the pivotal cohort, demonstrated complete remission (CR) or CR with partial hematologic recovery (CRh) in 35% of patients (age 32-87 years, y) for a median duration of 25.9 months. We evaluated safety and efficacy of OLU in the elderly subgroup (≥75y) with m IDH1 AML. Methods: In the Phase 2 trial, the pivotal cohort enrolled adults with R/R m IDH1AML. OLU was administered at 150 mg BID. Adverse events (AE) and lab values were collected at least monthly and graded based on the NCI CTCAE Version 4.03. Efficacy was based on response criteria of the International Working Group in AML (2003). Results: 153 patients received OLU monotherapy, 147 had centrally-confirmed mIDH1 AML, , and 45 were ≥75y (range 75-87) at study entry. Of the 45 elderly patients, 27 (60%) were male, 51% had ECOG=1, 16% had ECOG =2, 71% were relapsed, 29% had refractory AML, 58% had prior HMA, 11% received prior venetoclax, and none had prior stem cell transplant. Median bone marrow blasts were 43% (5-93). Genetic co-mutations included FLT3 in 9%, NPM1 in 20%, and TP53 in 2%. Grade 3 or 4 adverse events were reported in 45.8% of elderly patients; the most common were decreases in red blood cells (31%), platelets (13%) and neutrophils (10%) as well as febrile neutropenia (15%). AEs were consistent with published pivotal Phase 2 results, with no new safety signals. Deaths occurred in 19 patients due to disease progression (9), pneumonia (2), sepsis (2), GI haemorrhage (1), aortic stenosis (1), atrioventricular block (1), cardiac failure congestive (1), acute kidney injury (1) and other (1). The response to OLU therapy is summarized in the table. 31% of patients ≥75 y achieved CR/CRh; median time to CR/CRh was 1.5 mos (0.9-5.6) and median duration of CR/CRh was 25.9 mos (95%CI 7.4, not reached). Conclusions: Olutasidenib was generally well tolerated in elderly patients with R/R m IDH1AML and induced durable remissions. Despite the challenges of treating elderly patients who had already failed prior AML treatment, the results suggest that elderly patients can benefit from therapy with olutasidenib. Clinical trial information: NCT02719574 . [Table: see text]
Comprehensive germline and somatic DDR genomic profiles of Chinese patients with multiple primary lung cancer.
Authors: Yingshun Yang, Mingwei Li, Shuai Wang, Guotian Pei, Jiayue Qin, Shanbo Cao, Yuqing Huang
Journal: Journal of Clinical Oncology (2024)

e20019 Background: The number of multiple primary lung cancer (MPLC) patients has rapidly increased in recent years. Disruption of the DNA damage repair (DDR) gene is related to cancer risk, progression, and treatment selection. However, the characteristics and significance of DDR alterations remain undefined in MPLC. Methods: A total of 133 Chinese MPLC patients with 308 lesions were enrolled and 784 single-focus lung cancer (SFLC) patients were analyzed as a control in the present study. Genetic testing was performed by utilizing the next-generation sequencing (NGS) of 808 cancer-related genes including 276 DDR genes. The patients were divided into 3 groups: DDR-germline (germline variants, N = 11), DDR-somatic group (somatic variants, N = 98), and the non-DDR group (no DDR variants, N = 24). Results: The overall DDR variants were identified in 82.0% (109/133) of the patients, and a total of 283 variants were found, with almost all being somatic (254/283). The most commonly germline alterations were found in RAD50 (1.5%), WRN (1.5%) and BRCA2 (0.8%), while in the somatic mutations, TP53 (26.3%) showed the highest frequency. DDR-somatic group was more likely to have alterations in TP53, LRP1B, ERBB2 and MYC compared with DDR-germline group. Taken non-DDR group as reference, mutations in TP53 (P&lt;0.05), ALK and PIK3CA were more common in DDR-germline group, but EGFR, RBM10, TP53, LRP1B, TERT and MYC (all P&lt;0.05) in DDR-somatic group. Furthermore, the DDR-somatic group exhibits the highest median tumor mutational burden (6.56) compared with 3.55 (P&lt;0.01) in DDR-germline and 3.69 (P&lt;0.01) in non-DDR group. In addition, the copy number variation (CNV) was statistically different among the three groups (P&lt;0.001). The proportion of copy number gain patients in DDR-somatic group is the highest (28.3%) compared with 12.0% in DDR-germline group and 10.9% in non-DDR group (P&lt;0.01). DDR-somatic MPLC and SFLC patients possessed distinct somatic genomic characteristics, especially with significantly different prevalence in TP53, RBM10, KRAS, BRAF, and ALK (all P&lt;0.05). Moreover, we also found notable differences in the prevalence of TP53 and CNV (both P&lt;0.05) between DDR-germline MPLC and SFLC patients. Conclusions: MPLC patients exhibit a distinctive DDR mutations landscape. The differences in the mutation profile between the DDR-germline and DDR-somatic groups and the distinct actionable genes may indicate the different target-therapy choices for MPLC patients.
Potential role and prognostic value of Globo-H in lung cancer.
Authors: Tzer-Min Kuo, Jiann-Shiun Lai, Hui-Ting Hsu, Cheng-Yen Wei, Ming-Tain Lai
Journal: Journal of Clinical Oncology (2024)

e20037 Background: Globo-H (GH), a globo-series carbohydrate antigen highly expressed on multiple epithelial cancers, is a promising target for cancer immunotherapy. Clinical trials have been conducted to evaluate the efficacy of anti-GH vaccine Adagloxad Simolenin/OBI-821 (in Ph 3) and OBI-833/OBI-821 (in Ph 2) in cancer patients. Epidermal growth factor receptor (EGFR) mutations are well known as a frequent class of driver mutations in lung cancer (LC), which are responsible for tyrosine kinase inhibitors. Besides high expression in cancer cells, GH has been implicated in regulation of EGFR signaling pathway. Knockdown of key enzyme involved in GH biosynthesis β1,3-galactosyltransferase V (β3GalT5) induces apoptosis through disruption of EGFR-related signaling protein complex. In addition, GH is reported to associate the EGFR mutant in LC patients. This study aims to further investigate the potential role of GH in LC. Methods: Clinical study: The level of GH expression was evaluated by immunohistochemistry (IHC) using H-score in clinical samples from 141 patients with lung adenocarcinoma. In vitro study: FACS and Western blotting methods were used to measure the levels of total EGFR, phospho-EGFRs or GH in LC cell lines. Microwestern protein array (MWA) analysis was performed in LC NCI-H1975 cells. Results: Clinical study: Positive GH expression (H score≥1; 18.4%) was significantly associated with poor differentiation grade (p = 0.044) in all samples and disease specific survival in patients with metastasis and stage 4 LC (p = 0.033). In vitro study: Inhibition of EGFR by an EGFR-specific shRNA resulted in a decrease of GH expression in LC cells while overexpression of EGFR resulted in an increase of GH levels. β3GalT5 knockout cells and anti-GH-antibody-treated cells showed a reduction of cell proliferation as well as the total level of EGFR and phosphor-EGFRs expression, which is consistent with the results from previous studies. MWA analysis on LC cells with β3GalT5 knockout, GH ceramide-treated β3GalT5 knockout cells and anti-GH Ab-treated LC cells indicated a positive correlation between the level of GH and EGFR-related signaling proteins including phosphor-JNK, phosphor-c-Jun, phosphor-PP2A, phosphor-PP2A, phosphor-AKT, and Cyclin D1 proteins. In addition, JNK signaling inhibitor partially reduced GH expression in NCI-H1975 cells. These results revealed the mechanistic link between GH regulation and tumor promoting signals in LC. Conclusions: GH expression was associated with the worse survival of LC patients in clinical setting. In addition, the level of GH is positively correlated with levels of EGFR and EGFR-related signaling proteins in vitro. Expression of GH can induce the expression of EGFR and vice versa in LC cells. Furthermore, EGFR downstream JNK signaling pathway might involve in GH regulation by EGFR. Taken together, GH-targeting therapy has a potential application for the treatment of LC patients.
Factors associated with early-stage lung cancer diagnosis (ESLCD) in Brazil, 2013-2019: A multivariable analysis.
Authors: Isabel M Emmerick, Mônica Rodrigues Campos, Debora Castanheira, Tayná Sequeira Valerio, Lara Vinhal Faria, Jéssica Muzy, Aline Marques, Luisa Arueira, Mario Jorge Sobreira da Silva
Journal: Journal of Clinical Oncology (2024)

e20091 Background: Lung cancer has the highest mortality rate among the leading deadly cancers worldwide. Despite improvements in tobacco cessation and treatment over the years, disparities in access to care, timely diagnosis, and proper treatment remain prevalent. This study aims to identify the factors associated (FA) with Early-Stage Lung Cancer Diagnosis (ESLCD) in Brazil. Methods: This retrospective cohort study includes individuals diagnosed with lung cancer from January 2013 to December 2019, registered in the Brazilian hospital-based Cancer Registry (HBCR). Descriptive and bivariate analysis was performed, and T-tests and Chi-square were used to compare early vs late-stage groups. Multivariable backward stepwise logistic regression identified FA with ESLCD at a 95% confidence interval (CI). Results: The study was conducted with data on 86,558 individuals registered in the HBCR; 56.6% were men, 64 years old on average, and 54.8% were white. We found a high percentage of patients without education information (23.9%), and 70% had completed high school. As for behavioral characteristics, only 20% of the patients had never smoked; the others were current smokers (40%) or former smokers (40%). Almost half of the patients were from the Southeast region of Brazil (44.6%), 27% from the South, 19.9% from the Northeast, 3.9% from the North and 3.9% from the Midwest. The vast majority of the individuals were diagnosed at a late stage (85.6%), while 14.4% were ESLCD. In the bivariate analysis, being less than 65 years old, being female, white, never smoking, having a college degree, and living in the south or southeast regions were associated with ESLCD. In the final multivariable model the Factors Associated with ESLCD were having less than 65 years (OR=1.28 [95% CI: 1.22-1.34]), of the female gender (OR=1.26 [95% CI: 1.22-1.32]), having education greater than a college degree (OR=1.49 [95% CI: 1.38-1.61]), and living on the southeast (OR=1.22 [95% CI: 1.15-1.30]); and in the south region (OR=1.21 [95% CI: 1.18-1.32]); which are the wealthiest regions in the country. Conclusions: The education level was the most decisive factor associated with ESLCD. Geographic location played an important role in ESLCD, indicating issues related to wealth and access to health services. Improving access to lung cancer diagnosis, especially for vulnerable populations, can reduce disparities in the rates of early-stage diagnosis and improve overall survival. [Table: see text]
Country-specific differences in the lung tumour microbiome.
Authors: Amanda Stafford, Jie (James) Min Lam, Amedra Basgaran, Eva Lymberopoulos, Mohammad Tanweer, Michael Hobbs, James Arney, Dionisios Korovilas, David Delanoue, Stephen Moore, Muhannad Alomari, Nikhil Sharma
Journal: Journal of Clinical Oncology (2024)

e20044 Background: Sputum examination for the early detection of lung cancer continues to be explored ( Thunnissen 2003 ), however has so far resulted in a low diagnostic yield. An increasing number of studies have evidenced a mechanistic role of the lung microbiome in the induction of lung cancer ( Liu et al., 2020 ), and the presence of bacterial biomarkers in bronchoalveolar lavage and sputum have been proposed ( Cheng et al., 2020 ). It is currently unknown whether the sputum microbiome can appropriately capture the lung tumour microbiome. Given that the lung microbiome may vary by geography, this analysis was considered over two populations: China and Italy. Methods: Microbiome analysis was performed using BioCorteX’s industry-leading knowledge graph and integrated proprietary engines v20240126_153156. Data from 9 studies was used. In total, 461 samples from lung cancer patients in China (250 sputum, 211 tumour) and 60 from Italy (34 sputum, 26 tumour) were considered. Shannon’s diversity was used to consider within-sample diversity, and dimensional scaling based (MDS) on Bray-Curtis diversity was used to consider between-sample diversity. Results: All sample were checked to have a library size greater than 100, and more than 10 unique species. Only those species present in over 1% of samples were considered to reduce noise. In both China and Italy, tumour samples had a lower diversity than sputum samples (p = 0.00016 and p &lt; 2.2e-16, respectively). Samples from Italy had a lower diversity than samples from China (p &lt; 2.22e-16). In the MDS analysis, the tumour samples from China and Italy formed two distinct, non-overlapping clusters. A third cluster was formed from the union of sputum samples from both countries. These results were independent of any study-specific effects. Conclusions: These results indicate that the sputum microbiome is not representative of the tumour microbiome, and that the divergence of the tumour microbiome away from the sputum microbiome is country specific. The results of this analysis highlight that further work into differences in the lung tumour microbiome by country is warranted, especially in light of the growing body of evidence suggesting a causative role of the microbiome in lung cancer. It is also possible that lung cancer treatments may be impacted by the country-specific nature of the lung tumour microbiome.
Treatment of acute myeloid leukemia with Orca-T.
Authors: Jeremy Mark Pantin, Sagar S. Patel, Rawan Faramand, Arpita Gandhi, Amandeep Salhotra, Caspian Oliai, Samer Ali Srour, Bhagirathbhai R. Dholaria, Anna Pavlova, J. Scott McClellan, Irene Agodoa, Ai Li, Nathaniel Fernhoff, Mehrdad Abedi, Everett Meyer
Journal: Journal of Clinical Oncology (2024)

6552 Background: Allogeneic hematopoietic stem cell transplants (alloHSCT) offer a potential curative treatment for many hematological cancers, however, traditional alloHSCT is associated with high mortality from complications including infection, graft versus host disease (GvHD) and relapse. Orca-T is an investigational allogeneic T-cell immunotherapy that includes stem and immune cells, derived from allogeneic donors, that leverages highly purified, polyclonal donor regulatory T cells to control alloreactive immune responses. In this sub-group analysis, we evaluated the safety and efficacy of patients with acute myeloid leukemia who were treated with Orca-T. Methods: Data from 37 patients with the diagnosis of acute myeloid leukemia (AML) in CR/CRi who received myeloablative conditioning with busulfan, fludarabine, and thiotepa (BFT) followed by Orca-T by 6/30/22 as part of a multicenter phase 1b single-arm trial (NCT04013685) are reported here. Patients enrolled in the phase 1b trial who did not meet these criteria were not included in this analysis. Patients received BFT prior to Orca-T, followed by single-agent GvHD prophylaxis with tacrolimus, and had an 8/8 related or unrelated matched donor. Donors were matched via DNA-based high-resolution typing of HLA-A, -B, -C, and -DRB1. Results: Orca-T was successfully manufactured at a centralized GMP facility, distributed, and infused at study sites throughout the U.S. Vein-to-vein time (i.e. time between end of donor apheresis to start of recipient’s Orca-T infusion) was &lt; 72 hours for all patients, with the majority &lt; 60 hours. Median age was 51 years, 49% were female and 16% were of Hispanic or Latino ethnicity. Twenty-three (62%) had matched related donors and 14 (38%) had matched unrelated donors. Baseline HCT-CI score was 3 and 4 in 27% and 8% of the patients, respectively. The majority had intermediate DRI scores (89%) and 41% were MRD positive at baseline. The median duration of follow-up was 14 months. Relapse-free survival at 12 months was 81.4% (95% CI: 62.9, 91.2). Non-relapse mortality and overall survival were 0% and 100% at 12 months, respectively. Conclusions: These encouraging results suggest that investigational Orca-T could represent a reduced toxicity alternative to conventional alloHSCT. This combination of Orca-T with myeloablative BFT led to &gt; 80% RFS without treatment related mortality, and 100% overall survival in this AML patient population. These outcomes were accomplished with consistent and reliable cell manufacturing and distribution of Orca-T at a national scale. A multi-center randomized controlled phase 3 trial comparing Orca-T to SOC, utilizing BFT or TBI-based conditioning, will complete enrollment during the first half of 2024. (NCT05316701). Clinical trial information: NCT04013685 .
Impact of spleen volume on post-allogenic hematopoietic transplant outcomes in myelofibrosis: Utility of 3D volumetrics in splenomegaly.
Authors: Rafay Haseeb, Dongyun Yang, Pejman Motarjem, Monzr M. Al Malki, Ibrahim Aldoss, Idoroenyi Usua Amanam, Salman Otoukesh, Stephen J. Forman, Guido Marcucci, Syed Rahmanuddin, Haris Ali
Journal: Journal of Clinical Oncology (2024)

6558 Background: Splenomegaly is a hallmark of myelofibrosis, thought to be correlated with graft failure and worsened overall survival in transplant patients. Past studies have utilized manual spleen measurement, potentially affecting accuracy. Using 3D volume can more precisely measure spleen size. Hence, the true impact of splenomegaly on transplant outcomes remains unclear. In this retrospective study, we examined myelofibrosis patients who underwent HCT and, using 3D volumetrics, analyzed the impact of splenomegaly and volume reduction over time on post HCT outcomes. Methods: This retrospective study included 130 City of Hope myelofibrosis patients with pre HCT imaging (2004–2023). Patients were divided into pre HCT spleen volume of &gt;3000 cc and &lt;3000 cc, with &gt;3000 cc considered massive splenomegaly. Spleen volume was measured using Vitrea 3D volumetric software. For each patient, depending on imaging available, volume was measured 0-3 months pre HCT, 3-6 months, 6-9 months, and 9-12 months post HCT with corresponding volume reduction calculations. Pre HCT spleen volume was also temporally correlated with several post HCT outcomes. Results: Median age at HCT was 60 (17-75), and 95% of patients received the Fludarabine/Melphalan conditioning regimen. Median spleen volume pre HCT was 1150 cc (41-6695 cc). Sixteen patients measured &gt;3000cc, and 114 patients measured &lt;3000cc. Median spleen volume 3-6 months post HCT was 661 cc (80-1731 cc) with a median 48% volume reduction. The data suggests that majority of volume reduction occurred during this time (table). Five-year overall survival (OS) was 72.8%. Relapse was 11.0% at 1 year and 14.7% at 5 years. NRM at 5 years was 17.3%. ANC engraftment peaked at 28 days at 92.3%. Pre HCT spleen volume (&lt;1000 cc, 1000-2000 cc, &gt;2000 cc) did not have a significant impact on OS (P = 0.992), disease free survival (P = 0.783), relapse (P = 0.187), NRM (P = 0.627), or ANC Engraftment (P = 0.526). There was a statistically insignificant downward trend for platelet engraftment (P = 0.162). For patients with or without massive splenomegaly (&gt;3000cc), there was no significant effect with any of the analyzed post HCT outcomes. Conclusions: This retrospective study includes an analysis of spleen volume by 3D volumetrics, a more accurate measurement of spleen size, and whether it significantly impacts post HCT outcomes. Our data analysis demonstrates that splenomegaly, massive or not, does not significantly impact transplant outcomes for patients receiving a reduced intensity conditioning regimen.[Table: see text]