Articles de revues : « Caleb T »

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Whitlark, Jason. « Listen, Understand, Obey : Essays on Hebrews in Honor of Gareth Lee Cockerill ed. by Caleb T. Friedman ». Catholic Biblical Quarterly 82, n^o 1 (2020) : 164–65. http://dx.doi.org/10.1353/cbq.2020.0040.

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Borker, Parth, Yi Bao, Yuanyuan Qiao, Arul Chinnaiyan, Jae Eun Choi, Yuping Zhang, Rahul Mannan et al. « Abstract 7479 : Targeting the lipid kinase PIKfyve upregulates surface expression of MHC class I to augment cancer immunotherapy ». Cancer Research 84, n^o 6_Supplement (22 mars 2024) : 7479. http://dx.doi.org/10.1158/1538-7445.am2024-7479.

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Abstract The widespread success of cancer immunotherapies suggests a promising future - but has been subverted by unresponsiveness and resistance. Current research has furthered the understanding of immunotherapy resistance through the findings of “hot” (responsive) and “cold” (unresponsive) tumors. Here, we focus on the genetic and pharmacological inhibition of PIKfyve, a lipid kinase regulator of autophagic flux and lysosomal biogenesis. We find that inhibition of PIKfyve results in the upregulation of major histocompatibility complex class I (MHC-I) surface expression in cancer cells (through inhibition of autophagic flux), resulting in increased CD8+ T cell-mediated cancer cell death. These findings were corroborated in multiple syngeneic mouse models, which also displayed increased intratumoral functional CD8+ T cells. In addition, the Pikfyve-depletion antitumor responses are CD8+ T cell and MHC-I dependent - as CD8+ T cell and B2m knockout rescued tumor growth - resulting in improved response to immune checkpoint blockable (ICB), adoptive cell therapy, and a therapeutic vaccine. Further, high PIKfyve expression predicts poor ICB response and is prognostic of poor survival in ICB-treated cohorts. Ultimately, these findings collectively suggest PIKfyve as an effective target to enhance immunotherapies through elevation of MHC-I surface expression in cancer cells, and accordingly, PIKfyve inhibitors have novel potential to increase immunotherapy response in cancer patients. Citation Format: Parth Borker, Yi Bao, Yuanyuan Qiao, Arul Chinnaiyan, Jae Eun Choi, Yuping Zhang, Rahul Mannan, Caleb Cheng, Tongchen He, Yang Zheng, Jiali Yu, Mahnoor Gondal, Gabriel Cruz, Sara Sara Grove, Xuhong Cao, Fengyun Su, Rui Wang, Yu Chang, Ilona Kryczek, Marcin Cieslik, Michael D. Green, Weiping Zou. Targeting the lipid kinase PIKfyve upregulates surface expression of MHC class I to augment cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7479.

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Liu, Vincent, Katalin Sandor, Bence Daniel, Lionel Berthoin, Shan Sabri, Sofia Panagiotopoulou, Yajie Yin et al. « Abstract 1701 : Single-cell multi-omic profiling and clonal tracing of the human gynecological tumor microenvironment ». Cancer Research 82, n^o 12_Supplement (15 juin 2022) : 1701. http://dx.doi.org/10.1158/1538-7445.am2022-1701.

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Abstract Tumor initiation and progression are the result of a close interplay between malignant cells and immune cells. While single-cell genomics has enabled the molecular dissection of the cellular heterogeneity underlying complex cancers, many facets of tumor microenvironments remain unresolved. In particular, the ontogeny of myeloid cells have not been fully understood in human tumors, although the source and expansion of macrophages have been suggested to underlie tumor development and metastasis in mice. In an effort to comprehensively characterize these tumor microenvironments, we profiled endometrial, ovarian, and metastatic tumors from 16 patients using CITE-seq (an atlas of 258,810 cells) and mitochondrial single-cell ATAC-seq (mtscATAC-seq; consisting of 173,820 cells). Our multi-omic analyses reveal the heterogeneity of tumor-infiltrating immune cells at clonal, epigenetic, transcriptomic, and proteomic levels. Notably, all tumor types harbored diverse exhausted T cell subsets, including terminal and precursor exhausted T cells, and gamma/delta T cells. Clonal somatic variant analysis between tumor tissues and peripheral blood mononuclear cells identified blood-derived monocytes, rather than embryonically derived cells, as the origin of macrophages within gynecological tumors. Further, our analyses show that macrophages expand minimally within the tumor microenvironment, suggesting that they may be continuously replenished by blood, an observation that may facilitate new approaches for cancer immunotherapy. In total, our dataset represents the first multi-modal single cell atlas of gynecologic tumors and reveals distinct features of T cell heterogeneity and myeloid expansions in complex tumor microenvironments. Citation Format: Vincent Liu, Katalin Sandor, Bence Daniel, Lionel Berthoin, Shan Sabri, Sofia Panagiotopoulou, Yajie Yin, Kamir Hiam-Galvez, Rene Sit, Zi Fan, Brendan Galvin, Omar Khan, Natalie Bezman, Jane Grogan, Brooke Howitt, Grace Zheng, Caleb Lareau, Ansuman Satpathy. Single-cell multi-omic profiling and clonal tracing of the human gynecological tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1701.

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Hurvitz, Sara, Sung-Bae Kim, Wei-Pang Chung, Seock-Ah Im, Yeon Hee Park, Roberto Hegg, Min-Hwan Kim et al. « Abstract GS3-01 : Trastuzumab deruxtecan (T-DXd ; DS-8201a) vs. trastuzumab emtansine (T-DM1) in patients (pts) with HER2+ metastatic breast cancer (mBC) : subgroup analyses from the randomized phase 3 study DESTINY-Breast03 ». Cancer Research 82, n^o 4_Supplement (15 février 2022) : GS3–01—GS3–01. http://dx.doi.org/10.1158/1538-7445.sabcs21-gs3-01.

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Abstract Background: T-DXd is a HER2-targeting antibody-drug conjugate approved for the treatment of pts with advanced HER2+ mBC based on the DESTINY-Breast01 study (NCT03248492). DESTINY-Breast03 (NCT03529110) isa randomized, multicenter, open-label, phase 3 study assessing the efficacy and safety of T-DXd vs. T-DM1 in pts with HER2+ mBC previously treated with trastuzumab and taxane. In the primary analysis, T-DXd demonstrated a clinically meaningful and statistically significant improvement in PFS vs. T-DM1 (Corteset al, ESMO 2021). In this exploratory analysis, we provide additional efficacy and safety data in subgroups, including in pts with brain metastases (BMs). Methods: Pts were randomly assigned 1:1 to receive 5.4 mg/kg T-DXd or 3.6 mg/kg T-DM1 Q3W. Pts with clinically stable BMs were eligible. Lesions were measured per modified Response Evaluation Criteria in Solid Tumors version 1.1. The primary endpoint was progression-free survival (PFS) determined by blinded independent central review (BICR). PFS and overall response rate (ORR) were analyzed for subgroups.Sites of progression and post-end-of-study therapies were also investigated. Results: At data cutoff (May 21, 2021), 524 pts were randomly assigned to T-DXd (n=261) orT-DM1 (n=263). T-DXd demonstrated superior PFS by BICR vs. T-DM1 (HR, 0.28 [95%CI, 0.22-0.37]; P=7.8 x 10-22); median (m) PFS by BICR was not reached (95% CI, 18.5-NE) for T-DXd compared with 6.8 mo (95% CI, 5.6-8.2) forT-DM1. For pts with stable BMs at baseline (n=82), mPFS was 15.0 mo (95% CI,12.5-22.2) for T-DXd vs. 3.0 mo (95% CI, 2.8-5.8) for T-DM1 (HR, 0.25 [95% CI,0.31-0.45)]. Overall, confirmed ORR for T-DXd was 79.7% vs. 34.2% for T-DM1.For patients with stable BMs at baseline, ORR was 67.4% for T-DXd vs. 20.5% forT-DM1. Consistent PFS and ORR benefit was also observed across other subgroups(Table 1). At data cutoff, 84 (32.2%) pts treated with T-DXd had progressive disease (PD) versus 155 (58.9%) with T-DM1. In pts with stable BMs in the T-DXd arm, 48.8% of pts (21/43) had PD. In pts with stable BMs in the T-DM1 arm, 69.2%of pts (27/39) had PD. Data on sites of progression will be presented. Further analyses are underway and will be presented. Overall, the safety profile of T-DXd was manageable and comparable with its known safety profile. Adjudicated drug-related interstitial lung disease/pneumonitis was reported in 27 (10.5%) pts treated with T-DXd and 5 (1.9%) pts treated with T-DM1 overall, with no grade 4 or 5 events. Additional new safety data will be presented. Conclusion: DESTINY-Breast03,the first-reported randomized phase 3 trial comparing T-DXd to standard of care, met the primary endpoint with T-DXd demonstrating superior PFS vs. T-DM1and T-DXd had a manageable safety profile. In this exploratory analysis, consistent PFS and ORR benefit with T-DXd vs. T-DM1 was observed across subgroups in pts with HER2+ mBC previously treated with trastuzumab and taxane, including in pts with BMs. Table 1.Subgroup Analyses forPFS and ORR of T-DXd versus T-DM1PFS by BICR HR (95% CI)Absolute ORR Difference (T-DXd-T-DM1) (95% CI)All patients (N=524)0.28 (0.22-0.37)45.5 (37.6-53.4)Hormone receptorPositive (n=272)0.32 (0.22-0.46)47.3 (36.1-58.4)Negative (n=248)0.30 (0.20-0.44)43.2 (31.5-55.0)Prior pertuzumabYes (n=320)0.31 (0.22-0.43)46.7 (36.5-56.9)No (n=204)0.30 (0.19-0.47)43.6 (30.5-56.7)Prior lines of therapya0-1 (n=258)0.33 (0.23-0.48)39.3 (27.3-51.2)≥2 (n=266)0.28 (0.19-0.41)51.6 (40.9-62.4)Visceral disease Yes (n=384)0.28 (0.21-0.38)48.3 (39.1-57.6)No (n=140)0.32 (0.17-0.58)39.1 (23.6-54.6)Brain metastases at baseline Yes (n=82)0.25 (0.13-0.45)46.9 (25.6-68.3)No (n=442)0.30 (0.22-0.40)45.5 (36.9-54.1) Citation Format: Sara Hurvitz, Sung-Bae Kim, Wei-Pang Chung, Seock-Ah Im, Yeon Hee Park, Roberto Hegg, Min-Hwan Kim, Ling-Ming Tseng, Vanessa Petry, Chi-Feng Chung, Hiroji Iwata, Erika Hamilton, Giuseppe Curigliano, Binghe Xu, Caleb Lee, Yali Liu, Jillian Cathcart, Emarjola Bako, Sunil Verma, Javier Cortés. Trastuzumab deruxtecan (T-DXd; DS-8201a) vs. trastuzumab emtansine (T-DM1) in patients (pts) with HER2+ metastatic breast cancer (mBC): subgroup analyses from the randomized phase 3 study DESTINY-Breast03 [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS3-01.

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Fan, Zenghua, David Y. Oh, Anthony Wong, Katsuto Shinohara, Hao Nguyen, Caleb Hwang, Hewitt Chang et al. « Abstract 4988 : Responders to combination radiation and PD-1 blockade demonstrate reduced myeloid immunosuppression and enhanced interferon signaling in oligometastatic prostate cancer patients ». Cancer Research 84, n^o 6_Supplement (22 mars 2024) : 4988. http://dx.doi.org/10.1158/1538-7445.am2024-4988.

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Abstract Background: Prostate cancer is unresponsive to current immunotherapies such as checkpoint inhibitors. Overcoming this “cold” environment requires rational combination of therapeutic modalities that can prime anti-tumor immunity. Radiation is a potential candidate; however it remains unclear how it should be most productively combined with immunotherapies. Methods: We completed an investigator-initiated clinical trial of newly diagnosed men with oligometastatic, hormone-sensitive prostate cancer (mHSPC, NCT03007732). Patients were randomized to receive anti-PD-1 x 13 cycles (pembrolizumab, Arm 1, n=12), or anti-PD-1 with intraprostatic injections of TLR9 agonist SD-101 (Arm 2, n=11). All patients received SBRT to the prostate tumor during cycle 1, and concomitant hormonal therapy with a GnRH agonist and abiraterone. Response was assessed as PSA < nadir + 2 ng/mL at 15 months after ceasing all cancer therapies. For unbiased correlative immune interrogation of these patients, fresh paired biopsies of primary prostate tumor and PBMCs both before and after radiation and immunotherapy were analyzed by multi-omic single-cell genomics to assess changes with treatment, including T cell repertoire changes. Results: Fourteen of 21 evaluable patients responded by PSA criteria with 3 patients not yet reaching 15 months of post-treatment follow-up. Adverse events included expected IRAEs from anti-PD-1, and flu-like symptoms from SD-101, with no unexpected AEs. Single-cell analysis of tumor biopsies reveals treatment-induced decreases in cytotoxic T cell populations and increases in both immunostimulatory LAMP3+ dendritic cells and immunosuppressive SPP1+ myeloid populations. Treatment increased interferon (IFN) signaling in most myeloid subsets while strongest in LAMP3+ DCs. Compared to non-responders, responders showed less immunosuppression at baseline with depletion of myeloid cells and enhanced IFN activity on LAMP3+ DCs, and treatment-induced IFN activity on cytotoxic T cells. TLR9 agonism also specifically enhanced IFN responses, persistence of cytotoxic T cell clonotypes, and enhanced antigen presentation in tumor cells. Circulating T cells in blood detected shared clones with tissue showing enrichment in cytotoxic phenotype and association with responders. Conclusions: Responders to combination radiation and anti-PD-1 blockade have decreased myeloid immunosuppression and enhanced IFN activity prior to treatment in oligometastatic prostate cancer. This may identify patients likely to respond, and baseline immune setpoints that can be enhanced with improved immunotherapy strategies. Acknowledgements: This work was supported by the Prostate Cancer Foundation and Merck. Merck Sharp & Dohme LLC, Rahway, NJ, USA provided drug and financial support for the study. Citation Format: Zenghua Fan, David Y. Oh, Anthony Wong, Katsuto Shinohara, Hao Nguyen, Caleb Hwang, Hewitt Chang, Alec Starzinski, Tony Li, Christopher De Leon, Marissa Gin, Eliezer Van Allen, Li Zhang, Rahaul R. Aggarwal, Terence W. Friedlander, Eric J. Small, Felix Y. Feng, Lawrence Fong. Responders to combination radiation and PD-1 blockade demonstrate reduced myeloid immunosuppression and enhanced interferon signaling in oligometastatic prostate cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4988.

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Lafargue, Audrey M., Hailun Wang, Sivarajan T. Chettiar, Rajendra P. Gajula, Amol C. Shetty, Yang Song, Brian W. Simons et al. « Abstract 2968 : TWIST1-induced suppression of oncogene-induced senescence in non-small cell lung cancer requires the transactivation domain of TWIST1 ». Cancer Research 84, n^o 6_Supplement (22 mars 2024) : 2968. http://dx.doi.org/10.1158/1538-7445.am2024-2968.

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Abstract Non-small cell lung carcinoma (NSCLC) is a major cause of cancer mortality. High expression of the epithelial-to-mesenchymal transition transcription factor TWIST1 is strongly associated with metastatic cancers and treatment resistance. Additionally, TWIST1 can upregulate O-GlcNAcylation which (1) is required to suppress fail-safe programs such as oncogene (KRasG12D)-induced senescence (OIS) to accelerate tumorigenesis in primary NSCLC tumors, and (2) is a potential modulator of DNA repair/radiation response. To decipher the domains and transcriptional targets required for tumorigenicity and radioresistance, we created a novel genetically engineered mouse model (GEMM) allowing tetracycline-inducible expression in the lung epithelium (via lung specific CCSP-reverse tetracycline transactivator (C)) of KRasG12D (R) with Twist1wt (T) or with Twist1F191G transactivation-null mutant (F). CRT mice had shorter tumor-free survival and more aggressive tumors compared to CR/CRF mice indicating that the Twist1 transactivation domain is required for Twist1-dependent tumorigenesis acceleration. Also, Twist1wt expression promoted radioresistance in cell lines and GEMMs. Contrary to CRT, CRF showed a progressive loss of Twist1F191G expression over time suggesting no functionality/no selective advantage. CRT lung tumors had higher proliferation (Ki67) and lower cell-cycle arrest (p16) compared to CR/CRF suggesting that the transactivation domain of Twist1 is important for the suppression of OIS. Supporting these data, we observed in non-cancer Human Bronchial Epithelial Cell (HBEC) that the co-expression of human TWIST1wt (HBEC-TWIST1wt) could suppress HRasG12V-induced senescence while the transactivation-null TWIST1F187G mutant (HBEC-TWIST1F187G) could not. Additionally, HBEC expressing HRasG12V-TWIST1wt had enhanced tumorigenic/invasive programs. Interestingly, we observed that the inhibition of O-GlcNAcylation rescued OIS in HBEC-HRasG12V-TWIST1wt while the stimulation of O-GlcNAcylation in HBEC-HRasG12V-TWIST1F187G suppressed OIS. Furthermore, TWIST1wt expression with HRasG12V modulated MYC downstream targets and the inhibition of MYC activity using the novel MYC inhibitor MYCi975 in HBEC-HRasG12V-TWIST1wt also rescued OIS induction. Altogether, these results suggest that TWIST1 may suppress OIS via MYC signaling and nominate MYCi975 as a means to activate latent OIS programs. In this context, MYC inhibiting strategies could serve as a therapeutic sensitizer for TWIST1-positive NSCLC. This work and our future studies on TWIST1 toward the control of OIS, O-GlcNAcylation and of mechanisms of radioresistance may help to identify new potential NSCLC therapeutic strategies. Citation Format: Audrey M. Lafargue, Hailun Wang, Sivarajan T. Chettiar, Rajendra P. Gajula, Amol C. Shetty, Yang Song, Brian W. Simons, Triet Nguyen, Christine Lam, Francesca A. Carrieri, Caleb Smack, Nick Connis, Dipanwita Dutta Chowdhury, Jinhee Chang, Danielle Council, Katriana Nugent, Ismaeel Siddiqui, Kekoa Taparra, Mohammad Rezaee, Natasha Zachara, Zachary S. Morris, Christopher McFarland, Sarki Abba Abdulkadir, Christine L. Hann, Phuoc T. Tran. TWIST1-induced suppression of oncogene-induced senescence in non-small cell lung cancer requires the transactivation domain of TWIST1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2968.

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Tien, Jean C., Yu Chang, Yuping Zhang, Jonathan Chou, Yunhui Cheng, Xiaoju Wang, Jianzhang Yang et al. « Abstract PR010 : CDK12 loss promotes prostate cancer development while exposing vulnerabilities to paralog-based synthetic lethality ». Molecular Cancer Therapeutics 23, n^o 6_Supplement (10 juin 2024) : PR010. http://dx.doi.org/10.1158/1538-8514.synthleth24-pr010.

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Abstract Biallelic loss of cyclin-dependent kinase 12 (CDK12) defines a unique molecular subtype of metastatic castration-resistant prostate cancer (mCRPC). It remains unclear, however, whether CDK12 loss per se is sufficient to drive prostate cancer development—either alone, or in the context of other genetic alterations—and whether CDK12-mutant tumors exhibit sensitivity to specific pharmacotherapies. Here, we demonstrate that tissue-specific Cdk12 ablation is sufficient to induce preneoplastic lesions and robust T cell infiltration in the mouse prostate. Allograft-based CRISPR screening demonstrated that Cdk12 loss is positively associated with Trp53 inactivation but negatively associated with Pten inactivation—akin to what is observed in human mCRPC. Consistent with this, ablation of Cdk12 in prostate organoids with concurrent Trp53 loss promotes their proliferation and ability to form tumors in mice, while Cdk12knockout in the Pten-null prostate cancer mouse model abrogates tumor growth. Bigenic Cdk12 and Trp53 loss allografts represent a new syngeneic model for the study of androgen receptor (AR)-positive, luminal prostate cancer. Notably, Cdk12/Trp53 loss prostate tumors are sensitive to immune checkpoint blockade. Cdk12-null organoids (either with or without Trp53 co-ablation) and patient-derived xenografts from tumors with CDK12 inactivation are highly sensitive to inhibition or degradation of its paralog kinase, CDK13. Together, these data identify CDK12 as a bona fidetumor suppressor gene with impact on tumor progression and lends support to paralog-based synthetic lethality as a promising strategy for treating CDK12-mutant mCRPC. Citation Format: Jean C. Tien, Yu Chang, Yuping Zhang, Jonathan Chou, Yunhui Cheng, Xiaoju Wang, Jianzhang Yang, Rahul Mannan, Palak Shah, Xiao-Ming Wang, Abbey Todd, Sanjana Eyunni, Caleb Cheng, Xuhong Cao, Yi Bao, James Neiswender, Rachel Brough, Stephen Pettitt, Estefania Labanca, Yuzhuo Wang, Marcin Cieslik, Christopher J. Lord, Ke Ding, Arul M. Chinnaiyan. CDK12 loss promotes prostate cancer development while exposing vulnerabilities to paralog-based synthetic lethality [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr PR010.

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Dai, Chaobin, Bin Zhang, Yunyang Liao, Qicai Liu, Feiguang Wu, Xiaoting Lv, Kai Zeng et Xiaofeng Zhu. « CALCB rs3829222 T/T Genotype and Low Expression of CALCB Are High-Risk Factors for Adenoid Cystic Carcinoma of Salivary Gland ». Disease Markers 2021 (12 juin 2021) : 1–5. http://dx.doi.org/10.1155/2021/5546858.

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Objectives. To investigate the relationship between polymorphisms of calcitonin-related peptide gene II (beta-calcitonin gene-related peptide (βCGRP), CALCB) and serum CGRP levels in salivary adenoid cystic carcinoma. Materials and Methods. Using the polymerase chain reaction (PCR) technique, the full-length amplification and genotype analysis of CALCB genes were performed in 39 patients with adenoid cystic carcinoma of salivary gland and 158 normal controls. The gene frequencies of major genotype of CALCB in adenoid cystic carcinoma of salivary gland and normal control group were analyzed. Enzyme-linked immunosorbent assay (ELISA) was used to evaluate serum calcitonin gene-related peptide (CGRP) and its concentration of alpha and beta subtypes. Results. Univariate logistic regression analysis showed that the CALCB rs2839222 T/T genotype was closely related to the occurrence of salivary adenoid cystic carcinoma, with a correlation coefficient of 3.89. Conclusions. The serum CGRP concentration in the salivary adenoid cystic carcinoma group was 1.56 times that of the normal control group. The αCGRP subtype was significant, which was 3.02 times that of the normal control. The polymorphism of βCGRP gene is associated with genetic susceptibility to salivary adenoid cystic carcinoma, and serum CGRP and βCGRP can be used as novel markers of salivary adenoid cystic carcinoma.

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BUENO, VINICIUS R., MORGAN R. GOSTEL et GUSTAVO HEIDEN. « The spiraling story of Tyleropappus and a new name for Calea (Asteraceae : Neurolaeneae) from Venezuela ». Phytotaxa 622, n^o 1 (24 octobre 2023) : 75–84. http://dx.doi.org/10.11646/phytotaxa.622.1.5.

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Tyleropappus was described in 1931 by Greenman and is characterized by its spiral, alternate leaves and epaleaceous receptacle. Throughout its taxonomic history, the genus was placed into the tribes Helenieae and Neurolaeneae, often treated as the sister genus of Geissopappus, which is currently a synonym of Calea. Later, Tyleropappus was synonymized with Calea; however, when its synonymization was proposed, the sole species in the genus, T. dichotomus, had not been synonymized under a previously described species nor properly transferred to Calea. Ongoing taxonomic studies in Neurolaeneae have provided opportunities to clarify the challenging taxonomic history of this monotypic genus. We confirm the synonymy of Tyleropappus in Calea; however, we recognize T. dichotomus as a distinct species that should be accepted in Calea. Nonetheless, the name C. dichotoma already exists, and is a synonym of C. ternifolia. Therefore, we propose the new name C. spiralis to accommodate this species, which is morphologically similar to C. linearifolia. The former can be distinguished from the latter by the spiral, alternate (vs. decussate) arrangement of leaves, receptacle epaleaceous (vs. oligopaleaceous) and cypselae hirsute (vs. glabrous). We also provide a detailed description of the species, the first map of its geographic occurrence, an illustration with diagnostic characters, and the first taxonomic key for the Nana clade of Calea.

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Alkashgari, Hossam, Cornelia Stoian, Caleb Ruiz-Jimenez, Jacqueline Coats, Carlos A. Casiano, Sinisa Dovat et Kimberly J. Payne. « Abstract 1528 : Molecular mechanisms of TSLP as a therapy for CRLF2 B-Cell acute lymphoblastic leukemia ». Cancer Research 82, n^o 12_Supplement (15 juin 2022) : 1528. http://dx.doi.org/10.1158/1538-7445.am2022-1528.

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Abstract B-cell acute lymphoblastic leukemia (B-ALL) is the most common type of leukemia in children. B-ALL characterized by cytokine receptor-like factor 2 (CRLF2) overexpression (CRLF2 B-ALL) has a survival rate of <30% and is the highest risk sub-group of B-ALL in both adults and children. CRLF2 is a receptor component for the cytokine thymic stromal lymphopoietin (TSLP). TSLP plays a role in the survival and proliferation of B-cell precursors, thus explaining the oncogenic role of increased CRLF2 signaling in CRLF2 B-ALL. To our surprise, we found that high-levels of TSLP eliminated leukemia cells in patient-derived xenograft (PDX) models of CRLF2 B-ALL. CRLF2 and IL-7 receptor-alpha (IL-7Ra) form the heterodimer type-I cytokine receptor for TSLP cytokine. Binding of TSLP to its CRLF2 receptor complex induces JAK-STAT5 and PI3K-AKT pathway signals. TSLP shares the IL-7Ra with Interleukin 7 (IL-7) which has a heterodimer receptor consisting of IL-7Ra and the common gamma chain. High-levels of IL-7 (50 ng/ml) have been shown to induce IL-7Ra internalization and degradation in T-cells. We hypothesize that high-level TSLP induces internalization and degradation of IL-7Ra leading to CRLF2 signal inhibition, death of CRLF2 B-ALL cells and the anti-leukemia effects that we have observed in PDX mice. To test this hypothesis, we treated CRLF2 B-ALL cell lines with different TSLP concentrations to observe the effect of TSLP on its receptor and CRLF2 signaling. Flow cytometry data showed that continuous or a pulse of high-dose TSLP induced a loss of surface IL-7Ra expression for up to 24 hours. Phosphorylation assays showed that cells cultured with high-dose TSLP were unresponsive to subsequent TSLP-induced phosphorylation events (pSTAT5 and pRPS6), indicating CRLF2 signal inhibition. In conclusion, high-dose TSLP induces loss of (IL-7Ra) and inhibition of CRLF2 signaling. These results suggest that TSLP exerts its anti-leukemia effects by shutting down CRLF2-mediated signals possibly via the loss of the IL-7Ra receptor component. Citation Format: Hossam Alkashgari, Cornelia Stoian, Caleb Ruiz-Jimenez, Jacqueline Coats, Carlos A. Casiano, Sinisa Dovat, Kimberly J. Payne. Molecular mechanisms of TSLP as a therapy for CRLF2 B-Cell acute lymphoblastic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1528.

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Muffly, Lori, Jun Yin, Sawyer Jacobson, Anna Wall, Elisa Quiroz, Anjali S. Advani, Selina M. Luger et al. « Disparities in trial enrollment and outcomes of Hispanic adolescent and young adult acute lymphoblastic leukemia ». Blood Advances 6, n^o 14 (15 juillet 2022) : 4085–92. http://dx.doi.org/10.1182/bloodadvances.2022007197.

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Abstract In this secondary analysis of Hispanic adolescents and young adults (AYA) with acute lymphoblastic leukemia (ALL) treated on Cancer and Leukemia Group B (CALGB) 10403, we evaluated outcomes and geographic enrollment patterns relative to US population data. We used demographic, clinical, and survival data on AYAs enrolled on CALGB 10403 (N = 295, 2007-2012). Surveillance, Epidemiology, and End Results registries provided overall survival (OS) for US AYA ALL by ethnicity/race. North American Association of Cancer Registries provided AYA ALL incidence overall and proportion among Hispanics by US state. Of AYAs enrolled on CALGB 10403, 263 (89%) reported ethnicity/race: 45 (17%) Hispanic, 172 (65%) non-Hispanic White (NHW), 25 (10%) non-Hispanic Black (NHB), and 21 (8%) other. Compared with NHWs, Hispanic and NHB patients had lower household income, and Hispanic patients were more likely to harbor high-risk CRLF2 aberrations. Relative to US estimates, where Hispanic patients represented 46% of newly diagnosed AYA ALL patients and experienced inferior OS compared with NHW (P < .001), Hispanic AYAs on CALGB 10403 did as well as NHW patients (3 year OS, 75% vs 74%; P = NS). Hispanic patients also had higher rates of protocol completion (P = .05). Enrollments on CALGB 10403 differed relative to the distribution of Hispanic AYA ALL in the United States: enrollment was highest in the Midwest; t and only 15% of enrollees were from states with a high proportion of Hispanic AYA ALL patients. In summary, Hispanic patients treated on CALGB 10403 did as well as NHWs and better than population estimates. Geographical misalignment between trial sites and disease epidemiology may partially explain the lower-than-expected enrollment of Hispanic AYA ALL patients.

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Eston, Roger G., Gaynor Parfitt, Laura Campbell et Kevin L. Lamb. « Reliability of Effort Perception for Regulating Exercise Intensity in Children Using the Cart and Load Effort Rating (CALER) Scale ». Pediatric Exercise Science 12, n^o 4 (novembre 2000) : 388–97. http://dx.doi.org/10.1123/pes.12.4.388.

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The purpose of this study was to assess whether young children could reliability regulate exercise intensity production after several practice trials, without reference to objective feedback measures. The study used a new 10-point scale (Cart and Load Effort Rating [CALER] Scale), which depicts a child on a bicycle, at various stages of exertion, towing a cart in which the load increases progressively. After warm-up, 20 children, aged 7–10 years, performed an intermittent, effort production protocol at CALER 2, 5, and 8 on a cycle ergometer. This was repeated on three further occasions in the next 4 weeks. An increase in PO across trials (44, 65, and 79 W at CALER 2, 5, and 8, respectively) confirmed that the children understood the scale. A Bland and Altman limits of agreement (LoA) analysis and an intraclass correlation analysis (ICC) between trials (T) indicated that reliability improved with practice. Intertrial comparisons of overall reliability from T1 to T2 and from T3 to T4 ranged from 0.76 to 0.97 and an improvement in the overall bias ± 95% limits of agreement from −12 ± 19 W to 0 ± 10 W. This study is the first to apply more than two repeated effort production trials in young children and provides strong evidence that practice improves the reliability of effort perception in children. The data also provide preliminary evidence for the validity of the CALER Scale in children aged 7–10 years.

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Kaufman, P. A., G. Broadwater, K. Lezon-Geyda, L. G. Dressler, D. Berry, P. Friedman, E. P. Winer et al. « CALGB 150002 : Correlation of HER2 and chromosome 17 (ch17) copy number with trastuzumab (T) efficacy in CALGB 9840, paclitaxel (P) with or without T in HER2+ and HER2- metastatic breast cancer (MBC) ». Journal of Clinical Oncology 25, n^o 18_suppl (20 juin 2007) : 1009. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.1009.

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1009 Background: Accurate assessment of HER-2 is critical in MBC and predicts benefit from T. We have previously shown low level amplification of HER-2 associated with ch17 polysomy is common in IHC 2+ cases that are FISH(-). However, the clinical relevance of this is unknown. Methods: CALGB 150002, a correlative companion to 9840, was designed to assess the predictive role of HER-2 in MBC pts treated with weekly vs q 3W P ± T. Pts HER-2(-) locally were randomized to ±T. 585 pts were enrolled in 9840; 304 blocks were available for central analysis with DAKO HercepTest (IHC) and Pathvysion (FISH). Logistic regression was used to test HER-2:ch17 ratio and HER-2 copy # as predictor of response rate (RR) to T in HER-2(+) pts. 1-sided Fisher’s Exact Test was used to compare RR of P vs P+T in pts with ch17 polysomy on central testing (>2.2 copies ch17/cell), but defined as HER-2(-) locally and randomized to T. Results: In pts HER-2(+) locally, FISH is a significant predictor of RR to P+T. A higher HER-2:ch17 ratio is associated with a higher RR by logistic regression (p=0.033, n=95). No interaction is seen between HER-2 and P schedule, p=0.71. On central testing of cases IHC(-) locally, 16/140 (11%) were IHC 3+ and 5/133 (4%) HER-2 amplified. In 21 HER-2(-) cases reclassified as HER-2 3+ or FISH (+) centrally, we do not find a difference in RR to P vs P+T. However among 133 cases HER-2(-) locally and central FISH(-) we find 32 with ch17 polysomy (copy # ch17 = 2.2); 12 treated with P alone, and 19 with P+T (see table for RR). Conclusions: These data suggest a higher RR to P+T in HER-2(+) pts with a higher HER-2:ch17 ratio, consistent with a relationship between RR to T and HER-2 copy #. In FISH(-) cases we note an increased RR to P+T vs P in cases with ch17 polysomy, typically reported clinically as HER-2(-). This analysis suggests that T might be effective in a subpopulation of breast cancer conventionally defined as HER-2(-), but in fact displaying low level HER-2 amplification. [Table: see text] [Table: see text]

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Hayes, D. F., A. Thor, L. Dressler, D. Weaver, G. Broadwater, L. Goldstein, S. Martino, J. Ingle, I. C. Henderson et D. Berry. « HER2 predicts benefit from adjuvant paclitaxel after AC in node-positive breast cancer : CALGB 9344 ». Journal of Clinical Oncology 24, n^o 18_suppl (20 juin 2006) : 510. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.510.

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510 Background: CALGB 9344 showed 4 cycles of paclitaxel (T) after 4 cycles of doxorubicin/cyclophosphamide (AC) improved disease-free (DFS) and overall survival (OS) compared to 4 cycles of AC. Higher dose of A had no benefit (Henderson JCO ’03). Prior studies suggest HER2 is associated with benefit from standard vs low dose of C&A (Dressler JCO ’05). We hypothesized that HER2 might predict benefit from higher dose of A or from T, and that HER2 might refine the observed negative interaction of T with estrogen receptor (ER). Methods: 3121 node + women in CALGB 9344 received 4 q3wk cycles of AC (A: 60, 75, or 90 mg/m2) and then 4 cycles of T (175 mg/m2 q3wk) or no T. Blocks were collected from ∼2800 subjects. 2 sets of 750 patients each were randomly selected from these cases: Set 1 to develop hypotheses; Set 2 for validation. Tissue specimens were available from 643 (set1) and 679 (set2) cases (20% & 22% total enrolled in 9344 respectively). HER2 was evaluated by FISH and by IHC (by antibody cb11 and by Herceptest). Statistical analyses used Cox proportional hazards models, including interaction terms, and Kaplan-Meier estimates for comparing 5-yr DFS by treatment group. Results: In Set 1, all 3 assays suggested that T improved DFS for HER2+ but not for HER2-. For this single set the interaction was not statistically significant. There appeared to be an interaction of HER2, T and ER. IHC using cb11 was applied to Set 2, revealing nearly identical results. In the two sets combined (n=1322), the interaction between HER2 and T was statistically significant (p=0.013). The 3-way interaction of HER2, ER and T was hypothesis-generating and not tested statistically. Differences in 5-yr DFS rates (95% CI) for T vs. no T by HER2 and ER (both sets combined) There was no interaction between HER2 and dose of A. Conclusions: These results suggest that the benefit of adding T to AC is greater for HER2+ tumors, even if ER+, while T was of no apparent benefit in the ER+, HER2- group. Further validation is needed from remaining cases in 9344 and from other trials involving T. [Table: see text] [Table: see text]

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Mrózek, Krzysztof, Andrew J. Carroll, Kati Maharry, Kathleen W. Rao, Shivanand R. Patil, Mark J. Pettenati, Michael S. Watson et al. « Central Review of Cytogenetics Is Essential for Cooperative Group Clinical and Correlative Studies of Acute Leukemia : The Cancer and Leukemia Group B (CALGB) 8461 Experience. » Blood 104, n^o 11 (16 novembre 2004) : 1081. http://dx.doi.org/10.1182/blood.v104.11.1081.1081.

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Abstract Cytogenetic analysis has become an integral part of diagnosis and prognostication of acute myeloid (AML) and acute lymphoblastic leukemia (ALL). Consequently, CALGB mandates cytogenetic analyses for adult AML and ALL first-line treatment trials and many correlative studies. It is thus imperative that cytogenetic data are accurate. To this end, CALGB has performed central review of karyotypes (CRK) submitted by CALGB approved institutional cytogenetics laboratories since 1985. In this study, we have evaluated the role of CRK in ensuring that high quality cytogenetic data are available to CALGB researchers using two criteria: 1) the proportion of specimens deemed on CRK to be of sufficient vs insufficient quality to be included in the CALGB database (ie, accepted vs rejected according to the criteria published by Byrd et al, Blood2002;100:4325–4336), and 2) among the accepted cases, the proportion of submitted karyotypes whose interpretation was changed during CRK. In our analyses, we excluded samples studied cytogenetically during complete remission, because they differ from pretreatment and relapse samples in that they rarely contain leukemic cells and usually are karyotypically normal. Overall, 18% of AML and 35% of ALL karyotypes submitted were not accepted (Table). The most common reason for rejecting a karyotype on CRK was inadequate banding quality, which accounted for rejection in 41% of AML and 34% of ALL inadequate cases. Disease All Specimens 1986 CRK 2001-2003 CRK P-value* * A comparison of the rejection rates between the 1986 and 2001–2003 CRKs using Chi-square test; † % of the accepted specimens AML No. of specimens reviewed 4169 269 795 <0.0001 % rejected on CRK 18% 30% 12% % revised on CRK† 26% ALL No. of specimens reviewed 996 92 65 0.004 % rejected on CRK 35% 49% 26% % revised on CRK† 25% The quality of the submitted karyotypes, measured by the proportion of rejected cases, has improved significantly in both AML and ALL since 1986. However, CRK in 2001–2003 still found 12% of AML and 26% of ALL samples inadequate. Among karyotypes deemed adequate, we analyzed in detail revisions made during the 2001–2003 CRK. Changes in karyotype interpretation were made in 26% of AML and 25% of ALL cases. The revisions included identification or reinterpretation, other than reassignment of breakpoints, of the chromosome abnormality (seen in 52% of samples with karyotype errors), a misidentified or upside down chromosome(s) (34%), reassignment of breakpoints in structural aberrations recognized by the submitting laboratory (28%) and correction of errors in the ISCN (1995) nomenclature (15%). Examples of clinically relevant changes in karyotype interpretation included revisions of a normal karyotype to an abnormal one that harbored inv(3)(q21q26), t(9;11)(p22;q23), t(11;19)(q23;p13.1), or inv(16)(p13q22), change from del(11)(q23) to t(6;11)(q27;q23), etc. Overall, 35% of AML and 45% of ALL samples submitted were either rejected or revised on CRK. We conclude that although we observed an improvement in quality of cytogenetic analyses over time, central review of karyotypes still plays a vital role in ensuring the success of the clinical trials and correlative studies conducted by cooperative groups.

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Gajewski, T. F., D. Niedzwiecki, J. Johnson, G. Linette, C. Bucher, M. Blaskovich, S. Sebti et F. Haluska. « Phase II study of the farnesyltransferase inhibitor R115777 in advanced melanoma : CALGB 500104 ». Journal of Clinical Oncology 24, n^o 18_suppl (20 juin 2006) : 8014. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.8014.

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8014 Background: Ras-based signaling is thought to be critical in the genesis of melanoma. Farneslytransferase (FT) inhibitors (FTIs) have been developed as a pharmacologic strategy to inhibit Ras function. Additional farnesylated proteins are also important for the malignant process, and FTIs inhibit melanoma cell line proliferation in vitro. These considerations motivated the development of a phase II trial of the FTI R115777 in patients with melanoma. Farnesylated proteins are also important for T cell activation. The interest in future combinations of targeted agents and immunotherapeutics in this disease prompted analysis of T cell function ex vivo. Methods: A 3-stage design was pursued with a maximum of 40 patients planned and early stopping if there were no responders in the first 14, or fewer than 2 responders in the first 28 patients. Eligibility included intact organ function, PS≤1, no prior chemotherapy, at most 1 prior immunotherapy, no brain metastases, and presence of at least 2 cutaneous lesions amenable to excisional biopsy. R115777 (300 mg orally) was administered twice per day for 21 days of a 28-day cycle. Patients were evaluated every 2 cycles by RECIST criteria. Blood was obtained pre-treatment and during week 7 for analysis of HDJ-2 farnesylation and for T cell IFN-γ production in response to SEA. In addition, tumor biopsies were performed pre- and post-treatment when feasible to directly measure FT activity. Results: 14 patients were enrolled. 2 patients had grade 3 toxicities, which included myelosuppression, nausea/vomiting, elevated BUN, and anorexia. There were no clinical responses, and only 4 patients went on to a second course of treatment. All analyzed patients showed HDJ-2 gel shift in peripheral blood cells, as well as marked inhibition of FT activity (by 85–98%) in tumor tissue. T cell production of IFN-γ was also suppressed. Conclusions: Despite potent target inhibition, the FTI R115777 showed no evidence for clinical activity as a single agent in this cohort of 14 metastatic melanoma patients. Inhibition of T cell function has implications for future combination therapies and suggests the possibility for FTIs as candidate immunosuppressive agents. New therapeutic approaches for melanoma, or logically selected combination therapies, are needed. [Table: see text]

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Lozanski, Gerard, Ben Sanford, Krzysztof Mrozek, Colin Edwards, Rebecca Pearson, Clara D. Bloomfield, Richard A. Larson et Wendy Stock. « Quantitative Measurement of CD52 Expression and Alemtuzumab Binding in Adult Acute Lymphoblastic Leukemia (ALL) : Correlation with Immunophenotype and Cytogenetics in Patients (Pts) Enrolled on a Phase I/II Trial from the Cancer and Leukemia Group B (CALGB 10102). » Blood 110, n^o 11 (16 novembre 2007) : 2386. http://dx.doi.org/10.1182/blood.v110.11.2386.2386.

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Abstract The feasibility of incorporating Alemtuzumab (A) into frontline therapy of adult ALL pts was evaluated in a recently completed Phase I/II clinical trial, CALGB 10102. Pts were considered CD52+ and eligible to receive A during post-remission therapy if at least 10% of lymphoblasts had detectable expression of CD52 as measured by qualitative flow cytometry analysis in a CALGB reference laboratory. Using this qualitative assay, we have determined that 212 of 302 (70%) pts were CD52+ and eligible to receive A. Interestingly, 40/40(100%) pts with t(9;22) were CD52+. To better characterize CD52 expression level on lymphoblasts at the time of diagnosis and to obtain insights into subset specific therapies in adults with ALL, we developed a quantitative flow cytometry method to measure CD52 antigen expression and A binding using custom conjugated clinical grade A antibody. Results of this quantitative assay are expressed in arbitrary units of Antibody Bound per Cell (ABC). To determine whether ABC correlated with immunophenotype and specific cytogenetic subsets of adult ALL, we assessed ABC in a randomly selected subset of 88 untreated pts entered onto CALGB 10102. Seventy-two (81%) pts had precursor-B cell (pre-B) ALL and 16 (19%) had precursor T-cell (pre-T) ALL. The median ABC for pre-B cases was 37,178 (range: 1,545–228,247) and was significantly higher than the median ABC of 15,585 (range: 5,231–53,409) for pre-T cases (p=0.01). Interestingly, ABC on both pre-B and pre-T lymphoblasts was significantly lower than the median ABC on residual normal B-lymphocytes of 135,047 (range: 30,277–1,214,141), and on residual normal T -lymphocytes with a median of 70,139 (range: 20,621–557,859) that were present in the diagnostic bone marrow specimen (p<0.001). ABC by cytogenetic subset was also evaluated with results tabulated below for some of the commonly recurring abnormalities: ABC on lymphoblasts differed significantly across the cytogenetic subsets examined (p<0.001). The highest ABC levels were present in pts with del 9p and the lowest ABC levels were detected in pts with t(4;11). In conclusion, CD52 expression and A binding are significantly higher in pts with pre-B ALL than those with pre-T ALL. However, overall CD52 expression and A binding is significantly lower on lymphoblasts in comparison with normal residual lymphocytes present in the diagnostic bone marrows. We also demonstrate for the first time that differential CD52 expression and A binding occurs in specific cytogenetic subsets of adults with ALL. Quantitative PCR analysis of minimal residual disease following A treatment is being performed to determine whether pretreatment ABC levels identify pts who benefit from A therapy. CD52 ABC in Common Cytogenetic Subsets Cytogenetic Subsets CD52 ABC on Blasts Total number of cases studies (n=39 N (%) Median Range * 5 patients had del(9p), 1 patient had i(9)(q10) ** including 1 patient with t(11;19)(q23;p13.3) Loss of 9p* 6 14 67,323.5 (13,702–206,952) t(9;22)(q34;q11.2) 14 32 37,558.5 (11,771–135,085) Normal karyotype 12 27 36,127.5 (5,829–111,443) t(4;11)(q21;q23)** 7 16 3,826 (1,685–4,950)

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Giordano, S. H., Z. Duan, Y. F. Kuo, G. N. Hortobagyi, J. Freeman et J. S. Goodwin. « The impact of CALGB 9344 on adjuvant taxane (T) Use for breast cancer (BC) ». Journal of Clinical Oncology 23, n^o 16_suppl (juin 2005) : 669. http://dx.doi.org/10.1200/jco.2005.23.16_suppl.669.

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Woyach, Jennifer A., Amy S. Ruppert, Nyla A. Heerema, Bercedis L. Peterson, John G. Gribben, Vicki A. Morrison, Kanti R. Rai, Richard A. Larson et John C. Byrd. « Chemoimmunotherapy With Fludarabine and Rituximab Produces Extended Overall Survival and Progression-Free Survival in Chronic Lymphocytic Leukemia : Long-Term Follow-Up of CALGB Study 9712 ». Journal of Clinical Oncology 29, n^o 10 (1 avril 2011) : 1349–55. http://dx.doi.org/10.1200/jco.2010.31.1811.

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Purpose The addition of rituximab to fludarabine-based regimens in chronic lymphocytic leukemia (CLL) has been shown to produce high response rates with extended remissions. The long-term follow-up of these regimens with respect to progression, survival, risk of secondary leukemia, and impact of genomic risk factors has been limited. Methods We report the long-term follow-up of the chemoimmunotherapy trial CALGB 9712 from the Cancer and Leukemia Group B, for which treatment regimen was previously reported, to examine end points of progression-free survival (PFS), overall survival (OS), impact of genomic features, and risk of therapy-related myeloid neoplasm (t-MN). Results A total of 104 patients were enrolled on this study and now have a median follow-up of 117 months (range, 66 to 131 months). The median OS was 85 months, and 71% of patients were alive at 5 years. The median PFS was 42 months, and 27% were progression free at 5 years. An estimated 13% remained free of progression at almost 10 years of follow-up. Multivariable models of PFS and OS showed that immunoglobulin heavy chain variable region mutational status was significant for both, whereas cytogenetic abnormalities were significant only for OS. No patient developed t-MN before relapse. Conclusion Long-term follow-up of CALGB 9712 demonstrates extended OS and PFS with fludarabine plus rituximab. Patients treated with fludarabine plus rituximab administered concurrently or sequentially have a low risk of t-MN. These long-term data support fludarabine plus rituximab as one acceptable first-line treatment for symptomatic patients with CLL.

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Stradomska, Dominika, Monika Heba, Aleksandra Czernek, Nikodem Kuźnik, Danuta Gillner, Katarzyna Maresz, Wojciech Pudło, Andrzej Jarzębski et Katarzyna Szymańska. « Lipase Immobilized on MCFs as Biocatalysts for Kinetic and Dynamic Kinetic Resolution of sec-Alcohols ». Catalysts 11, n^o 4 (20 avril 2021) : 518. http://dx.doi.org/10.3390/catal11040518.

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Dynamic kinetic resolution (DKR) is one of the most attractive methods for enantioselective synthesis. In the reported studies, lipase B from Candida antarctica (CALB) immobilized on siliceous mesoporous cellular foams (MCF) functionalized with different hydrophobic groups, and two ruthenium complexes with substituted cyclopentadienyl ligands were investigated as catalysts for the chemoenzymatic DKR of (rac)-1-phenylethanol, using Novozym 435 as a benchmark biocatalyst. Studies on the (rac)-1-phenylethanol transesterification reaction showed that CALB supported on MCFs grafted with methyl groups is a promising biocatalyst and isopropenyl acetate is a preferable acylation agent. Both Ru-complexes activated by K3PO4 or t-BuOK, proved to be effective catalysts of the racemization reaction. The final DKR experiments using all catalysts combinations singled out, gave 96% conversion, and (R)-1-phenylethyl acetate enantiomeric excess of 98% in 8 h using K3PO4 activator.

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Miura, D., Y. Saitoh, T. Iwatani, H. Kawabata et N. Inoshita. « Chromosome enumeration probe 17 (CEP) ratio to predict chemosensitivity in HER-2 overexpressing breast cancer ». Journal of Clinical Oncology 27, n^o 15_suppl (20 mai 2009) : e11600-e11600. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e11600.

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e11600 Background: Precise assessment of HER-2 is critical in breast cancers and predicts benefit of trastuzumab (T). Although subset analysis of CALGB 9840 suggests benefit in FISH-negative patients with chromosome 17 polysomy (C17), clinical significance of C17 in FISH-positive patients is still less known. To analyze the epidemiologic feature of C17 in Japanese patients, consecutive operable breast cancer patients during 05–07 treated in single institution were studied. Methods: HER-2 status of consecutive 307 patients excluding DCIS and whose specimens were poor quality for study, were analyzed with Pathvysion (FISH). We defined HER- 2 (+) and C17 as HER-2/chromosome 17 ratio ≥ 2.2 and CEP ratio ≥ 2.2, respectively. Pathological response following neoadjuvant chemotherapy (NACT) was assigned according to the Japanese Breast Cancer Society (G3; no invasive or in situ residual tumor in the breast, G2; up to two thirds of primary cancer cells having pathologically severe changes or disappearance, G1; up to one third to two thirds of primary cancer cells having pathologically severe changes or disappearance). Results: HER-2 (+) was found in 22% (67/307) and C17 in 25% (77/307). Twenty-four of 67(36%) in HER-2 (+) had C17 and 53 of 240 (22%) in HER-2 (-) did C17. Among HER-2 (+), 23 cases received T-contained regimens as NACT (FEC/EC followed by PAC+T in 18 and DOC+CPA+T in 5). Six of 9 (67%) with C17 had G3 and 2 of 14 (14%) with non-C17 did G3. CEP ratio significantly predicts to have G3 (p=0.02) but HER-2/chromosome 17 ratio by logistic regression analysis. Conclusions: C17 was found in 25% of Japanese operable breast cancer patients of which was similar to that of CALGB. CEP ratio is a good predictive marker for chemo- sensitivity in HER-2 (+) subset. No significant financial relationships to disclose.

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Czuczman, Myron S., Pierluigi Porcu, Jeffrey Johnson, Donna Niedzwiecki, Michael Kelly, Eric D. Hsi, James R. Cook, George Canellos, Bruce D. Cheson et For the Cancer and Leukemia Group B. « Results of a phase II study of 506U78 in cutaneous T-cell lymphoma and peripheral T-cell lymphoma : CALGB 59901 ». Leukemia & ; Lymphoma 48, n^o 1 (janvier 2007) : 97–103. http://dx.doi.org/10.1080/10428190600961058.

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Raychaudhuri, Suravi, Ilana Yurkiewicz, Gabriel N. Mannis, Bruno C. Medeiros, Steve E. Coutre, Lori S. Muffly et Michaela Liedtke. « Event free survival in adults with relapsed ALL who underwent front-line therapy with CALGB 10403. » Journal of Clinical Oncology 39, n^o 15_suppl (20 mai 2021) : e19005-e19005. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e19005.

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e19005 Background: CALGB 10403 is a pediatric-inspired ALL regimen that has recently been shown to have improved survival rates in adolescents and young adults with ALL when compared to historical outcomes with traditional adult ALL regimens (Stock et. al, 2019). Methods: This is a retrospective cohort study of ALL patients who received induction CALGB 10403 at Stanford University (both on and off trial), achieved CR1, and subsequently relapsed. Primary outcome of interest was event free survival from time of diagnosis. Events were defined as relapse or death. Secondary outcomes were overall survival and event free survival from first relapse. Patients were censored at time of last clinical follow up. Results: 25 patients met inclusion criteria and received front-line CALGB 10403 from April 2010 to September 2018. At the time of initial diagnosis median age was 30 years (range 18 – 39 years). 68% of patients were male. 48% of patients were overweight and 40% were obese. 76% of patients had precursor B cell ALL while 24% had T cell ALL. 12% had CNS disease at diagnosis. 36% of patients had WBC greater than 30k. 12% of patients had CRLF2 rearrangement. 12% of patients were MRD positive after first induction. 20% of patients received rituximab. Median event free survival time from diagnosis was 20 months (range 3 – 79 months) and median overall survival time was 53 months. Blinatumomab was the most common salvage therapy after 1st relapse, followed by inotuzumab. 15 patients (60%) achieved CR2, of which 4 (27%) were MRD positive after 2nd induction. 15 patients (60%) went to HSCT. Of the patients who achieved CR2, 8 relapsed for a second time. Median event free survival time after first relapse was 23 months. Survival 1 year after relapse was 60%. 11 of the 25 patients were alive at last follow up. Median follow up time of survivors was 6 years. Conclusions: This is a descriptive retrospective cohort study of adult patients in a real world setting who received CALGB 10403 induction and subsequently relapsed. Compared to other studies of relapsed ALL patients who were induced with traditional chemotherapy (Fielding et. al, 2007), survival 1 year after relapse was much higher (60% vs. 22%). As CALGB 10403 becomes an increasingly common induction regimen for AYA and adults with ALL, further outcomes study is required.[Table: see text]

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Baer, Maria R., Carleton C. Stewart, David Lawrence, Diane C. Arthur, John C. Byrd, Frederick R. Davey, Charles A. Schiffer et Clara D. Bloomfield. « Expression of the Neural Cell Adhesion Molecule CD56 Is Associated With Short Remission Duration and Survival in Acute Myeloid Leukemia With t(8 ; 21)(q22 ; q22) ». Blood 90, n^o 4 (15 août 1997) : 1643–48. http://dx.doi.org/10.1182/blood.v90.4.1643.

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Abstract Although acute myeloid leukemia (AML) with t(8; 21) (q22; q22) is associated with a high complete remission (CR) rate and prolonged disease-free survival, treatment outcome is not universally favorable. Identifying factors that predict for treatment outcome might allow therapy to be optimized based on risk. AML with t(8; 21) has a distinctive immunophenotype, characterized by expression of the myeloid and stem cell antigens CD13, CD15, CD34, and HLADr, and frequent expression of the B-cell antigen CD19 and the neural cell adhesion molecule CD56, a natural killer cell/stem cell antigen. Because CD56 expression has been associated with both extramedullary leukemia and multidrug resistance, we sought to correlate CD56 expression with treatment outcome in AML with t(8; 21). Pretreatment leukemia cells from 29 adult de novo AML patients with t(8; 21) treated on Cancer and Leukemia Group B (CALGB) protocols were immunophenotyped by multiparameter flow cytometry as part of a prospective immunophenotyping study of adult AML (CALGB 8361). CD56 was expressed in 16 cases (55%). There was no correlation between CD56 expression and age, sex, white blood cell count, granulocyte count, the presence of additional cytogenetic abnormalities, or the presence of extramedullary disease at diagnosis. The CR rate to standard-dose cytarabine and daunorubicin was similar for cases with and without CD56 expression (88% v 92%; P = 1.0). Post-CR therapy included at least one course of high-dose cytarabine in 24 of 26 patients who achieved CR; numbers of courses administered were similar in cases with and without CD56 expression. Although post-CR therapy did not differ, CR duration was significantly shorter in cases with CD56 expression compared with those without (median, 8.7 months v not reached; P = .01), as was survival (median, 16.5 months v not reached; P = .008). We conclude that CD56 expression in AML with t(8; 21) is associated with significantly shorter CR duration and survival. Our results suggest that CD56 expression may be useful in stratifying therapy for this subtype of AML.

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Baer, Maria R., Carleton C. Stewart, David Lawrence, Diane C. Arthur, John C. Byrd, Frederick R. Davey, Charles A. Schiffer et Clara D. Bloomfield. « Expression of the Neural Cell Adhesion Molecule CD56 Is Associated With Short Remission Duration and Survival in Acute Myeloid Leukemia With t(8 ; 21)(q22 ; q22) ». Blood 90, n^o 4 (15 août 1997) : 1643–48. http://dx.doi.org/10.1182/blood.v90.4.1643.1643_1643_1648.

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Although acute myeloid leukemia (AML) with t(8; 21) (q22; q22) is associated with a high complete remission (CR) rate and prolonged disease-free survival, treatment outcome is not universally favorable. Identifying factors that predict for treatment outcome might allow therapy to be optimized based on risk. AML with t(8; 21) has a distinctive immunophenotype, characterized by expression of the myeloid and stem cell antigens CD13, CD15, CD34, and HLADr, and frequent expression of the B-cell antigen CD19 and the neural cell adhesion molecule CD56, a natural killer cell/stem cell antigen. Because CD56 expression has been associated with both extramedullary leukemia and multidrug resistance, we sought to correlate CD56 expression with treatment outcome in AML with t(8; 21). Pretreatment leukemia cells from 29 adult de novo AML patients with t(8; 21) treated on Cancer and Leukemia Group B (CALGB) protocols were immunophenotyped by multiparameter flow cytometry as part of a prospective immunophenotyping study of adult AML (CALGB 8361). CD56 was expressed in 16 cases (55%). There was no correlation between CD56 expression and age, sex, white blood cell count, granulocyte count, the presence of additional cytogenetic abnormalities, or the presence of extramedullary disease at diagnosis. The CR rate to standard-dose cytarabine and daunorubicin was similar for cases with and without CD56 expression (88% v 92%; P = 1.0). Post-CR therapy included at least one course of high-dose cytarabine in 24 of 26 patients who achieved CR; numbers of courses administered were similar in cases with and without CD56 expression. Although post-CR therapy did not differ, CR duration was significantly shorter in cases with CD56 expression compared with those without (median, 8.7 months v not reached; P = .01), as was survival (median, 16.5 months v not reached; P = .008). We conclude that CD56 expression in AML with t(8; 21) is associated with significantly shorter CR duration and survival. Our results suggest that CD56 expression may be useful in stratifying therapy for this subtype of AML.

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Woyach, Jennifer A., Amy S. Ruppert, Nyla A. Heerema, Bercedis Peterson, John G. Gribben, Vicki A. Morrison, Kanti R. Rai, Richard A. Larson et John C. Byrd. « Treatment with Fludarabine and Rituximab Produces Extended Overall Survival (OS) and Progression-Free Survival (PFS) in Chronic Lymphocytic Leukemia (CLL) without Increased Risk of Second Malignancy : Long-Term Follow up of CALGB Study 9712. » Blood 114, n^o 22 (20 novembre 2009) : 539. http://dx.doi.org/10.1182/blood.v114.22.539.539.

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Abstract Abstract 539 Introduction: The addition of rituximab to fludarabine-based regimens in CLL has been shown to produce high response rates with extended remissions. The long-term follow-up of these regimens with respect to progression, survival, and development of secondary malignancies has been limited. Patients and Methods: We report the long-term follow up of the chemoimmunotherapy trial CALGB 9712 (Blood 2003;101:6-14). This trial randomized 104 untreated, symptomatic patients to receive either 6 monthly cycles of fludarabine plus rituximab (FR) followed 2 months later by 4 weekly doses of rituximab (concurrent arm) or 6 monthly cycles of single agent fludarabine followed by rituximab consolidation using 4 weekly doses (sequential arm). With a median follow up of 92 months (range: 60-107), we analyzed the updated CALGB database and flow sheets submitted by treating physicians. Results: The overall response rate (ORR) was 84% (95% CI: 77%-91%), with a 90% ORR in the concurrent group (95% CI: 82%-98%) and a 77% ORR in the sequential group (95% CI: 66%-89%). Complete response (CR) was seen in 38% of patients (95% CI: 30%-45%), and partial response (PR) in 46% (95% CI: 38%-54%). The median OS was 85 months (95% CI: 71-95), with 71% of patients alive at 5 years (95% CI: 61%-79%). The median PFS was 37 months (95% CI: 27-45), with 27% progression-free at 5 years (95% CI: 19%-36%). With long-term follow up, the estimated median OS and PFS for the concurrent group were 84 months (95% CI: 57-100) and 32 months (95% CI: 23-55), respectively; the median OS and PFS for the sequential group were 91 months (95% CI: 71-110) and 40 months (95% CI: 23-50), respectively. Patients with del(17p13.1)/del(11q22.3)(18 patients) and unmutated IgVH(43 patients) continue to have an inferior OS (P=0.01 and P=0.04, respectively) and PFS (P=0.03 and P=0.04, respectively) compared to those without these abnormalities. We next assessed the frequency of therapy-related myeloid neoplasms (t-MN) and other cancers occurring after this chemoimmunotherapy regimen. No patient has developed MDS or AML prior to relapse. One patient (1%) developed t-MDS following relapse and receipt of FCR 41 months after completing trial therapy; t-MDS was diagnosed 9 months later. Richter's transformation was noted in three (3%) of the CALGB 9712 patients with large cell (n=2) or Hodgkin lymphoma (n=1). Second malignancies have included localized basal cell or squamous cell skin cancer in 12 (12%) patients whereas 11 (11%) have developed other epithelial malignancies including 4 GI, 3 lung, 3 melanomas, and 1 prostate cancer. Conclusions: Long-term follow up of patients enrolled on CALGB 9712 demonstrates extended OS and PFS with fludarabine plus rituximab, given either concurrently or sequentially, with an estimated 17%(95% CI: 9%-27%) of responders still in remission 8 years later. Looking at other published data, patients treated with FR administered concurrently or sequentially do not appear to have an increased risk of t-MN or second cancers. These long-term data reaffirm that FR is one of several acceptable frontline treatments for symptomatic patients with CLL. Disclosures: Morrison: Genentech: Speakers Bureau.

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Czuczman, Myron S., Pierluigi Porcu, Jeff Johnson, Donna Niedzwiecki, George P. Canellos et Bruce D. Cheson. « CALGB 59901 : Results of a Phase II Study of 506U78 in CTCL and PTCL. » Blood 104, n^o 11 (16 novembre 2004) : 2486. http://dx.doi.org/10.1182/blood.v104.11.2486.2486.

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Abstract T-cell lymphoma comprises approximately 10% to 15% of all lymphomas seen in the Western hemisphere and may be broadly categorized into 2 main groups: the various histologies of peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma (CTCL). Overall, PTCL patients (pts) are believed to have a worse prognosis than pts with B-cell lymphoma. Except for the favorable subset of ALK-1-positive anaplastic large cell lymphoma, most PTCL are incurable with standard therapy. Salvage chemotherapy is often ineffective in relapsed PTCL or in pts with advanced CTCL no longer responding to agents that modulate T-cell function (e.g. retinoids, interferons, antibodies). New agents are needed for these pts. 506U78 is a pro-drug of ara-G, a deoxyguanosine analogue. Ara-G itself is difficult to synthesize and poorly water soluble. 506U78 is 10 X more water soluble than ara-G and is rapidly demethoxylated in blood to ara-G, which has been shown to be toxic to T-cells at even micromolar concentrations. Based on positive preliminary data with 506U78 in pediatric pts with recurrent/refractory precursor T-lymphoblastic lymphoma or leukemia (PTLL), we activated CALGB protocol 59901, a Phase II study of 506U78 in pts with systemically untreated CTCL or refractory/relapsed PTCL. Objectives were to determine response rate, remission duration, and safety associated with 506U78 given at 1.5 g/m2/day on Days 1, 3, and 5 as an IV infusion q 21 days for a minimum of 2 cycles and/or to continue for 2 cycles after CR (up to max of 8 cycles). Eligibility included: diagnosis of PTCL or CTCL; measurable disease; no CNS lymphoma; no history of seizure disorder or significant (>grade 1) neurologic dysfunction; age <70; PS 0–2; adequate renal and hepatic function; CTCL pts were originally not permitted to have received systemic chemo, but the protocol was amended on 2/15/02 to allow therapy with one prior course of single-agent chemotherapy in an attempt to increase accrual. Nineteen pts were enrolled between 5-15-00 and 3-15-04: 11 CTCL and 8 PTCL pts. Five of 11 CTCL pts had received no prior therapy and 7 of 7 evaluable PTCL pts had received prior chemo and 2 prior BMT. Adverse event (AE) data are available for 18 pts. Grade 3 or 4 AEs were documented in 50% and 28% of pts, respectively. Thirty-three percent of pts experienced Grade 3 or 4 neurologic toxicities which included: ataxia, vertigo, peripheral neuropathy, confusion, and/or depressed consciousness. There were 2 treatment-related deaths, 1 due to infection and 1 due to CNS hemorrhage (both in pts with CTCL). There were 2 PRs to therapy, one each in the PTCL and CTCL groups, with disease progression at 3m and 5.5m, respectively. The overall response rate is 10.5% (1.3% – 33.1%; 95% CI). Fifteen of 19 pts have died. Median EFS was 1.2m (1.0, 1.6 m; 95% CI) and median OS was 3 months (1.4, 9.8m; 95% CI). Due to lack of efficacy and excessive toxicity the protocol was closed on 3/15/04. In contrast to the favorable results seen in pediatric pts with recurrent PTLL, our data demonstrate that 506U78 has low efficacy, is unacceptably toxic and is not recommended as monotherapy in adult pts with CTCL and PTCL.

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Fobare, Sydney, Jessica Kohlschmidt, Hatice Gulcin Ozer, Krzysztof Mrózek, Deedra Nicolet, Alice S. Mims, Ramiro Garzon et al. « Molecular, clinical, and prognostic implications of PTPN11 mutations in acute myeloid leukemia ». Blood Advances 6, n^o 5 (25 février 2022) : 1371–80. http://dx.doi.org/10.1182/bloodadvances.2021006242.

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Abstract Prognostic factors associated with chemotherapy outcomes in patients with acute myeloid leukemia (AML) are extensively reported, and one gene whose mutation is recognized as conferring resistance to several newer targeted therapies is protein tyrosine phosphatase non-receptor type 11 (PTPN11). The broader clinical implications of PTPN11 mutations in AML are still not well understood. The objective of this study was to determine which cytogenetic abnormalities and gene mutations co-occur with PTPN11 mutations and how PTPN11 mutations affect outcomes of patients treated with intensive chemotherapy. We studied 1725 patients newly diagnosed with AML (excluding acute promyelocytic leukemia) enrolled onto the Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology trials. In 140 PTPN11-mutated patient samples, PTPN11 most commonly co-occurred with mutations in NPM1, DNMT3A, and TET2. PTPN11 mutations were relatively common in patients with an inv(3)(q21q26)/t(3;3)(q21;q26) and a normal karyotype but were very rare in patients with typical complex karyotype and core-binding factor AML. Mutations in the N-terminal SH2 domain of PTPN11 were associated with a higher early death rate than those in the phosphatase domain. PTPN11 mutations did not affect outcomes of NPM1-mutated patients, but these patients were less likely to have co-occurring kinase mutations (ie, FLT3-ITD), suggesting activation of overlapping signaling pathways. However, in AML patients with wild-type NPM1, PTPN11 mutations were associated with adverse patient outcomes, providing a rationale to study the biology and treatment approaches in this molecular group. This trial was registered at www.clinicaltrials.gov as #NCT00048958 (CALGB 8461), #NCT00899223 (CALGB 9665), and #NCT00900224 (CALGB 20202).

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Peñaloza De La Torre, Ulises, et Gabriela Condori Condori. « Efecto antibacteriano del paramonoclorofenol alcanforado vs la asociación de hidróxido de calcioparamonoclorofenol alcanforado, sobre el cultivo in vitro de enterococcus faecalis ». Revista Médica Basadrina 10, n^o 1 (8 mai 2019) : 16–19. http://dx.doi.org/10.33326/26176068.2016.1.590.

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INTRODUCCIÓN: El presente estudio se realizó en el laboratorio de la escuela de biología-microbiología de la UNJBG, con el objetivo de establecer el efecto antibacteriano del Paramonoclorofenol Alcanforado vs la asociación de Hidróxido de Calcio-Paramonoclorofenol Alcanforado (CALEN PMCC) sobre el cultivo in vitro de Enterococcusfaecalis. Para probar su efecto se realizó un estudio laboratorial, cuasiexperimental y de corte transversal. MATERIAL Y MÉTODO: Se analizó in-vitro una cepa de Enterococcusfaecalis, en soluciones que contenían, el antiséptico, medio de cultivo y la bacteria activa; se incubaron y para determinar la acción de los antisépticos estudiados, se utilizó la técnica de recuento en placa a los 3, 7, 14 y 21 días para observar si hubo o no crecimiento bacteriano. RESULTADOS: Mostraron que la asociación de Calen PMCC fue efectivo a los 14 y 21 días; mientras que el Paramonoclorofenol Alcanforado tuvo un efecto bactericida a partir del 3er día. Se utilizó la prueba estadística de Levene y la prueba t de student, obteniendo una diferencia estadísticamente significativa (p=0,001<=0,05); Conclusión: Se concluye que el Paramonoclorofenol alcanforado tiene una acción más rápida ya que ejerce su acción bactericida desde el 3er día.

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Hylton, N., J. Blume, C. Gatsonis, R. Gomez, W. Bernreuter, E. Pisano, M. Rosen, H. Marques, L. Esserman et M. Schnall. « MRI tumor volume for predicting response to neoadjuvant chemotherapy in locally advanced breast cancer : Findings from ACRIN 6657/CALGB 150007 ». Journal of Clinical Oncology 27, n^o 15_suppl (20 mai 2009) : 529. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.529.

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529 Background: American College of Radiology Imaging Network (ACRIN) trial 6657, the imaging component of the I-SPY trial (CALGB 150007/150012), is testing MRI for predicting response to treatment and stratifying risk-of-recurrence in patients with locally-advanced breast cancer. We report preliminary results evaluating MRI for prediction of pathologic response. Methods: Women with ≥3 cm invasive breast cancer receiving neoadjuvant chemotherapy (NACT) with anthracycline-cyclophosphamide (AC) followed by a taxane (T) were enrolled from May 2002 to March 2006. MRI was performed prior to NACT (t1), after 1 cycle AC (t2), between AC and T (t3), and following T prior to surgery (t4). MRI tumor size assessments included longest diameter (MRLD) and tumor volume (MRVol). Clinical size (clinsize) and mammographic longest diameter (MGLD) were also recorded. Linear dimension was measured by the radiologist for MGLD and MRLD; MRVol was calculated by computer using signal enhancement ratio (SER) thresholds. Change in clinical and MRI variables at t2 were compared for ability to predict pathologic complete response (pCR). Results: 237 patients were enrolled at 9 institutions. 216 patients with complete imaging were analyzed. Of tumor size measurements at t4, MRVol showed the strongest correlation with pathsize among clinsize (r = 0.44), MGLD (ns), MRLD (r = 0.28) and MRVol (r = 0.61). Early change in MRVol measured at t2 was the only variable predictive of pCR among clinsize (p = 0.14, 0.15), MRLD (p = 0.40, 0.07), MRVol (p = 0.02, 0.01) and peak SER (p = 0.53, 0.72) in univariate and multivariate logistic regression, respectively. Conclusions: Tumor response measured volumetrically by MRI is a stronger and earlier predictor of pathologic response after NACT than clinical exam or tumor diameter. This work is funded by NIH/ACRIN U01 CA79778; CALGB CA31946, CA33601; NCI SPORE CA58207. [Table: see text]

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Venook, Alan P., Donna Niedzwiecki, Margarita Lopatin, Xing Ye, Mark Lee, Paula N. Friedman, Wendy Frankel et al. « Biologic Determinants of Tumor Recurrence in Stage II Colon Cancer : Validation Study of the 12-Gene Recurrence Score in Cancer and Leukemia Group B (CALGB) 9581 ». Journal of Clinical Oncology 31, n^o 14 (10 mai 2013) : 1775–81. http://dx.doi.org/10.1200/jco.2012.45.1096.

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Purpose A greater understanding of the biology of tumor recurrence should improve adjuvant treatment decision making. We conducted a validation study of the 12-gene recurrence score (RS), a quantitative assay integrating stromal response and cell cycle gene expression, in tumor specimens from patients enrolled onto Cancer and Leukemia Group B (CALGB) 9581. Patients and Methods CALGB 9581 randomly assigned 1,713 patients with stage II colon cancer to treatment with edrecolomab or observation and found no survival difference. The analysis reported here included all patients with available tissue and recurrence (n = 162) and a random (approximately 1:3) selection of nonrecurring patients. RS was assessed in 690 formalin-fixed paraffin-embedded tumor samples with quantitative reverse transcriptase polymerase chain reaction by using prespecified genes and a previously validated algorithm. Association of RS and recurrence was analyzed by weighted Cox proportional hazards regression. Results Continuous RS was significantly associated with risk of recurrence (P = .013) as was mismatch repair (MMR) gene deficiency (P = .044). In multivariate analyses, RS was the strongest predictor of recurrence (P = .004), independent of T stage, MMR, number of nodes examined, grade, and lymphovascular invasion. In T3 MMR-intact (MMR-I) patients, prespecified low and high RS groups had average 5-year recurrence risks of 13% (95% CI, 10% to 16%) and 21% (95% CI, 16% to 26%), respectively. Conclusion The 12-gene RS predicts recurrence in stage II colon cancer in CALGB 9581. This is consistent with the importance of stromal response and cell cycle gene expression in colon tumor recurrence. RS appears to be most discerning for patients with T3 MMR-I tumors, although markers such as grade and lymphovascular invasion did not add value in this subset of patients.

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Nurhablisyah, Nurhablisyah, et Khikmah Susanti. « Analisis Pesan Visual pada Media Kampanye Luar Ruang Caleg 2019 ». Magenta | Official Journal STMK Trisakti 3, n^o 02 (26 juillet 2019) : 478–86. http://dx.doi.org/10.61344/magenta.v3i02.49.

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Campaign moment in Indonesia means every place near the road or meeting point was covered by legislative campaignâ€™s banner (out of home media). In 2019, this campaign media was overloaded which could covered others belonging from different party. Not only roads, trees, homeâ€™s gate and wall was becoming a random target for placing the media. Another phenomenon that was caught by eyes was too many message attributes which applied into the media by using AIDA Model (attention, interest, desire, action), therefore riders and pedestrian could not see the meaning clearly. Those visual message consists of texts, illustration (photos), color, layout etc. This descriptive research is trying to analyze visual message in legislative out of home media campaign 2019 in East Jakarta and Depok. Analysis method is using out of home principals messages. The result of this research showed, mostly legislative candidates didnâ€™tâ€™ applied the ideals principals about out of home media characters. Designing message for out of home media should base on this principals; (1) out of home provide a very limited information space, therefor choose the most important message and conduct mission and vision,(2) pedestrian and riders donâ€™t have enough time to read all the information, choose the readable and clear text, illustration and color, (3) the frequency and size of the media is also influence the attention, (4) media was not only to attract people but also to influence to people around it.

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Rodrigues, William Costa, et Paulo Cesar Rodrigues Cassino. « Parasitóides Associados a Cochonilhas e Aleirodídeos (Sternorrhyncha) de Plantas Cítricas no Estado do Rio de Janeiro ». EntomoBrasilis 5, n^o 1 (21 mars 2012) : 33–36. http://dx.doi.org/10.12741/ebrasilis.v5i1.177.

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Com o propósito de conhecer os parasitóides de cochonilhas e aleirodídeos, associados às plantas cítricas no Estado do Rio de Janeiro, foram realizadas coletas de folhas contendo os fitoparasitos: Aleurothrixus floccosus (Maskell), Tetraleurodes (=Aleurotrachelus) cruzi (Cassino), Paraleyrodes bondari Peracchi, Coccus viridis (Green), Crysomphalus ficus (Ashmead), Orthezia praelonga (Douglas) e Pinnaspis aspidistrae (Signoret), sendo estas limpas, em seguida procedia-se a eliminação dos organismo que eram objeto de estudo (cada folha permanecia com um única espécie de fitoparasito, para que os parasitóides que surgissem fossem mesmo associados àquela espécie). Após este procedimento as folhas foram incubadas por um período de 25 dias, onde foi observado somente o parasitismo de A. floccosus, P. aspidistrae, C. viridis e T. cruzi, sendo que os parasitóides deste dois últimos, não foram identificados, pois o número de espécimes obtidos foi muito reduzido. Parasitando A. floccosus observou-se: Arrhenophagus sp., Cales sp., Encarsia sp (1), Eretmocerus sp., Signiphora sp. (1), Signiphora sp. (2), Signiphora sp. (3) e uma espécie da família Platygasteridae. Parasitando P. aspidistrae observou-se: Arrhenophagus sp., Cales sp., Encarsia sp (2) e Pteroptrix sp. Algumas espécies estão associadas tanto A. floccosus quanto P. aspidistrae. Através dos resultados verificou-se que o parasitismo de Arrhenophagus sp. e a espécie da família Platygasteridae em A. floccosus e o parasitismo de Arrhenophagus sp. e Pteroptrix sp. em P. aspidistrae, são novos registros de ocorrência para o Estado do Rio de Janeiro. Parasitoids Associated to Scales and Whiteflies (Sternorrhyncha) of Citrus Plants in Rio de Janeiro State Abstract. With the purpose of knowing parasitids of scales and whiteflies, associates to the citrus plants in Rio de Janeiro State, they were accomplished leaves collected contend fitoparasits: Aleurothrixus floccosus (Maskell), Tetraleurodes (=Aleurotrachelus) cruzi (Cassino), Paraleyrodes bondari Peracchi, Coccus viridis (Green), Crysomphalus ficus (Ashmead), Orthezia praelonga (Douglas) and Pinnaspis aspidistrae (Signoret), being this ones clean, it soon after proceded the organism elimination that was study object (each leaf remained with an only species of fitoparasite, so that parasitoids that had arisen had gone same associate to that species). After this procedure the leaves were incubate for a period of 25 days, when it was observed only parasitism in A. floccosus, P. aspidistrae, C. viridis and T. cruzi, and parasitoids of this the latter, not identified because the number specimens was very reduced. It was parasiting A. floccosus it observed: Arrhenophagus sp., Cales sp., Encarsia sp. (1), Eretmocerus sp., Signiphora sp. (1), Signiphora sp. (2), Signiphora sp. (3) and a species of the family Platygasteridae. Parasiting P. aspidistrae it was observed: Arrhenophagus sp., Cales sp., Encarsia sp. (2) and Pteroptrix sp. Some species are associated either to A. floccosus or to P. aspidistrae. By the results it was verified that Arrhenophagus sp. the parasitism and the species of the family Platygasteridae in A. floccosus and parasitism of Arrhenophagus sp. and Pteroptrix sp. in P. aspidistrae, they are occurrence new record for do Rio de Janeiro State

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Silverman, Lewis R., David R. McKenzie, Bercedis L. Peterson, Richard M. Stone, Bayard L. Powell, Christy Mayo, Jay T. Backstrom et Richard A. Larson. « Response Rates in Patients with Acute Myeloid Leukemia (AML), Treated with Azacitidine, Using WHO and International Working Group (IWG) Criteria for Myelodysplastic Syndrome (MDS). » Blood 106, n^o 11 (16 novembre 2005) : 1848. http://dx.doi.org/10.1182/blood.v106.11.1848.1848.

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Abstract The CALGB conducted a series of clinical trials with azacitidine (Vidaza®) administered subcutaneously or intravenously in patients with MDS using the FAB classification (JCO2002;20:2429). Since completion of these CALGB studies (8421, 8921, 9221), a new classification system was developed by the WHO that distinguishes MDS from AML (blasts > 20%). Although studies with azacitidine in patients with AML had previously shown activity, the 75 mg/m2/day dose in the CALGB studies was lower than previously studied. Using the WHO system, the diagnosis for CALGB study patients was redefined and patients with AML were analyzed separately. Most of the 105 patients were previously considered refractory anemia with excess blasts in transformation (RAEB-T). Also, new treatment response criteria for MDS were published by the IWG (Blood2000; 96:3671). Using IWG response criteria, azacitidine patients with WHO AML in studies 8421, 8921, or 9221 had an overall response rate (CR+PR+HI) of 48% (12/25), 32% (9/28), and 37% (10/27), respectively. Best Response using IWG Response Criteria for WHO AML Patients in Studies 8421, 8921, and 9221 Median duration of any response (CR, PR or HI) in the 33 azacitidine-treated responders was 279 days (range: 61 to 724 days). The median duration of CR in the 8 azacitidine-treated responders was not achieved; however, the 25th percentile was 115 days (range: 92 to 274+ days). In Study 9221, the median duration of transfusion independence (defined as ≥56 days) in patients independent at baseline was significantly longer in the azacitidine group compared with supportive care for red blood cells (azacitidine [n=8]: 411 days vs. supportive care [n=9]: 133 days, p=0.02) and platelets (azacitidine [n=13]: 363 days vs. supportive care [n=18]: 125 days, p=0.004). In the azacitidine group, 22% (6/27) of patients had a hemoglobin improvement to >11 g/dL that was maintained for ≥56 days compared with 8% (2/25) in the supportive care group (p=0.2). The proportions of patients with ANC >1500/m3 and platelets >100,000/mm3 lasting for ≥56 days were similar between the treatment arms. Azacitidine patients with WHO AML had a longer median survival (19.3 months) compared with the supportive care group (12.9 months) (p=0.2). Further studies investigating azacitidine in patients with AML with dysplasia are warranted.

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Stock, Wendy, Jeffrey Johnson, Daohai Yu, Diane Bennett, Dorie Sher, Richard M. Stone, Jonathan E. Kolitz et al. « Daunorubicin Dose Intensification during Treatment of Adult Acute Lymphoblastic Leukemia (ALL) : Final Results from Cancer and Leukemia Group B Study 19802. » Blood 106, n^o 11 (16 novembre 2005) : 1833. http://dx.doi.org/10.1182/blood.v106.11.1833.1833.

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Abstract For the past decade, survival (S) for adults with ALL has remained at 30–40% despite achieving high complete remission (CR) rates of 70–90%. CALGB 19802 was designed to test the hypothesis that dose intensification of daunorubicin (D) and cytarabine (Ara-C) could improve disease-free survival (DFS) and that aggressive high dose intravenous (IV), oral (PO) and intrathecal (IT) methotrexate (MTX) could replace cranial irradiation (RT) for central nervous system (CNS) prophylaxis. Treatment consisted of 6 monthly courses of intensive therapy followed by 18 mos of maintenance. In pts < 60 yrs, the D dose during induction and in post-remission therapy was increased in cohorts from 45 mg/m2 on days 1–3 (used in prior CALGB ALL studies) to 60 and then to 80 mg/m2/day X 3. In pts ≥ 60 yrs, D was increased from 30 to 60 mg/m2/day X 3. High-dose Ara-C and CNS prophylaxis with IV, PO, and IT MTX were given in post-remission modules for all pts with a goal of targeting serum methotrexate levels to be 1–2 μM at 30 hours following the IV MTX infusion. No cranial RT was given. From 1/99–1/01, 163 adults with untreated ALL were enrolled. Median age was 40 yrs (range, 16–82) and 33 (20%) were ≥ 60 yrs old; 61% were male. Of 127 centrally reviewed cases, 100 (79%) were precusor B-cell; 19 (15%) precursor T-cell; and 8 (7%) were bilineal or biphenotypic. A large proportion, 46 (46%) of 100 centrally reviewed and evaluable cases, had poor risk cytogenetics as defined in prior CALGB studies: 31 with t(9;22), 7 with t(4;11), 6 with −7 and 2 with +8. With a median follow-up of 4.4 years, the S and, especially DFS, for pts < 60 yrs was improved for those who received D at 80 mg/m2 vs 60 mg/m2. The outcome of all 163 evaluable pts is summarized below: CR (%) 3 yr DFS [95% CI] 3 yr S [95% CI] OVERALL 128 (78.5) 32% [24–41] 36% [29–44] AGE/ D DOSE < 60/ 60 mg/m2 36 (92%) 24% [11–39] 35% [20–50] <60/ 80 mg/m2 72 (79%) 43% [31–54] 46% [35–56] 60+/ 60 mg/m2 20 (61%) 10% [2–27] 8% [2–21] Disease progression during treatment occurred in 43 (26%) and 20 (12%) were removed for alternative therapies including 16 pts who received allo-SCT in CR1. Relapses have occurred in 84 (66%) pts; of these, 10 (8%) were isolated CNS relapses. CNS relapses tended to occur more frequently in pts with hour 30 serum MTX levels of < 1μM during CNS prophylaxis. Age ≥ 60 was significantly associated with worse DFS and S. DFS was longer for precursor T-ALL (median S at 3 years not reached). Interestingly, neither WBC > 30,000/μl nor adverse cytogenetics were significantly associated with worse outcomes. Higher levels of minimal residual disease (MRD) using quantitative clone specific PCR following induction therapy was predictive of inferior DFS (p = .02). In conclusion, omission of CNS irradiation did not result in higher CNS relapse rates than what has been reported in prior CALGB studies; furthermore, adjustment of MTX dosing to achieve targeted serum MTX levels may reduce the risk of CNS relapse. Younger pts who received 80 mg/m2 D had improved DFS and S. However, in contrast to other reports, the differences were not statistically significant. Thus, risk-adapted approaches to eradication of MRD using new agents and/or biologically targeted therapies should be incorporated into front-line treatment of ALL.

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Marcucci, Guido, Susan Geyer, Kristina Laumann, Weiqiang Zhao, Donna Bucci, Geoffrey L. Uy, William Blum et al. « Combination of dasatinib with chemotherapy in previously untreated core binding factor acute myeloid leukemia : CALGB 10801 ». Blood Advances 4, n^o 4 (24 février 2020) : 696–705. http://dx.doi.org/10.1182/bloodadvances.2019000492.

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Abstract Acute myeloid leukemia (AML) with either t(8;21)(q22;q22) or inv(16)(p13q22)/t(16;16)(p13;q22) is referred to as core binding factor (CBF) AML. Although categorized as favorable risk, long-term survival for these patients is only ∼50% to 60%. Mutated (mut) or overexpressed KIT, a gene encoding a receptor tyrosine kinase, has been found almost exclusively in CBF AML and may increase the risk of disease relapse. We tested the safety and clinical activity of dasatinib, a multi-kinase inhibitor, in combination with chemotherapy. Sixty-one adult patients with AML and CBF fusion transcripts (RUNX1/RUNX1T1 or CBFB/MYH11) were enrolled on Cancer and Leukemia Group B (CALGB) 10801. Patients received cytarabine/daunorubicin induction on days 1 to 7 and oral dasatinib 100 mg/d on days 8 to 21. Upon achieving complete remission, patients received consolidation with high-dose cytarabine followed by dasatinib 100 mg/d on days 6 to 26 for 4 courses, followed by dasatinib 100 mg/d for 12 months. Fifteen (25%) patients were older (aged ≥60 years); 67% were CBFB/MYH11–positive, and 19% harbored KITmut. There were no unexpected or dose-limiting toxicities. Fifty-five (90%) patients achieved complete remission. With a median follow-up of 45 months, only 16% have relapsed. The 3-year disease-free survival and overall survival rates were 75% and 77% (79% and 85% for younger patients [aged <60 years], and 60% and 51% for older patients). Patients with KITmut had comparable outcome to those with wild-type KIT (3-year rates: disease-free survival, 67% vs 75%; overall survival, 73% vs 76%), thereby raising the question of whether dasatinib may overcome the negative impact of these genetic lesions. CALGB 10801 was registered at www.clinicaltrials.gov as #NCT01238211.

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Battaglin, Francesca, Yasmine Baca, Joshua Millstein, Yan Yang, Joanne Xiu, Hiroyuki Arai, Jingyuan Wang et al. « CCR5andCCL5gene expression in colorectal cancer : comprehensive profiling and clinical value ». Journal for ImmunoTherapy of Cancer 12, n^o 1 (janvier 2024) : e007939. http://dx.doi.org/10.1136/jitc-2023-007939.

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BackgroundThe C-C motif chemokine receptor 5 (CCR5)/C-C motif chemokine ligand 5 (CCL5) axis plays a major role in colorectal cancer (CRC). We aimed to characterize the molecular features associated withCCR5/CCL5expression in CRC and to determine whetherCCR5/CCL5levels could impact treatment outcomes.Methods7604 CRCs tested with NextGen Sequencing on DNA and RNA were analyzed. Molecular features were evaluated according toCCR5andCCL5tumor gene expression quartiles. The impact on treatment outcomes was assessed in two cohorts, including 6341 real-world patients and 429 patients from the Cancer and Leukemia Group B (CALGB)/SWOG 80405 trial.ResultsCCR5/CCL5expression was higher in right-sided versus left-sided tumors, and positively associated with consensus molecular subtypes 1 and 4. HigherCCR5/CCL5expression was associated with higher tumor mutational burden, deficiency in mismatch repair and programmed cell death ligand 1 (PD-L1) levels. Additionally, highCCR5/CCL5were associated with higher immune cell infiltration in the tumor microenvironment (TME) of MMR proficient tumors. Ingenuity pathway analysis revealed upregulation of the programmed cell death protein 1 (PD-1)/PD-L1 cancer immunotherapy pathway, phosphatase and tensin homolog (PTEN) and peroxisome proliferator-activated receptors (PPAR) signaling, and cytotoxic T-lymphocyte antigen 4 (CTLA-4) signaling in cytotoxic T lymphocytes, whereas several inflammation-related pathways were downregulated. LowCCR5/CCL5expression was associated with increased benefit from cetuximab-FOLFOX treatment in the CALGB/SWOG 80405 trial, where significant treatment interaction was observed with biologic agents and chemotherapy backbone.ConclusionsOur data show a strong association betweenCCR5/CCL5gene expression and distinct molecular features, gene expression profiles, TME cell infiltration, and treatment benefit in CRC. Targeting the CCR5/CCL5 axis may have clinical applications in selected CRC subgroups and may play a key role in developing and deploying strategies to modulate the immune TME for CRC treatment.

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Blum, William, Ben Sanford, Rebecca B. Klisovic, Daniel J. DeAngelo, Geoffrey Uy, Bayard L. Powell, Wendy Stock et al. « Maintenance Therapy with Decitabine in Younger Adults with Acute Myeloid Leukemia (AML) in First Remission : A Phase II Cancer and Leukemia Group B Study (CALGB 10503, Alliance) ». Blood 120, n^o 21 (16 novembre 2012) : 44. http://dx.doi.org/10.1182/blood.v120.21.44.44.

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Abstract Abstract 44 CALGB (now part of the Alliance for Clinical Trials in Oncology) performed a non-randomized phase II study testing one year (yr) of investigational maintenance therapy with decitabine for newly diagnosed adult AML patients (pts) <60 yrs of age (CALGB 10503, Alliance). The study included induction followed by molecular and cytogenetic risk-adapted consolidation identical to that given in the prior CALGB study for younger AML pts (19808). Induction used daunorubicin 90 mg/m2 for 3 days, etoposide 100 mg/m2 for 3 days, and cytarabine 100 mg/m2 for 7 days (3+3+7). Reinduction (2+2+5) was given for residual disease on day 14. Favorable risk pts [defined here as t(8;21), inv(16), or t(16;16)] in complete remission (CR) received 3 cycles of high dose cytarabine (HiDAC); all other pts received two-step consolidation with chemo-mobilization and autologous transplantation (autoHCT) if eligible, or HiDAC-based consolidation if not. However, removal from study for alloHCT in 1st CR, instead of the two-step autoHCT, was permitted for non-favorable risk pts. Maintenance decitabine began as soon as possible after recovery from consolidation; pts had to have CR with neutrophils >1 × 109/L, platelets >75 × 109/L, and be within 90 days after day 1 of the final consolidation. Decitabine 20mg/m2 was given IV over 1 hour for 4–5 days, every 6 weeks, for 8 cycles. 546 pts enrolled with a median age of 48 yrs (range, 17–60) and median presenting white blood count (WBC) of 12.6 × 109/L (range, 0.3–380 × 109/L). 75% achieved CR (412/546). Reasons for CR pts not receiving maintenance were mainly early relapse, alloHCT in 1st CR, inadequate count recovery, and patient refusal (Blum et al. ASH 2011). 33% of CR pts (134/412) received investigational maintenance. Of these, 46 (34%) were favorable risk; among the remaining 88 pts, 73 were consolidated with autoHCT, and 15 received HiDAC-based consolidation. The median time from initial study registration to initiation of maintenance therapy was 6.3 months. Pts receiving decitabine had a median age of 45 yrs (range, 18–60) and presenting WBC of 13.5 × 109/L (range, 0.4–221 × 109/L). Treatment with decitabine maintenance was feasible and reasonably well tolerated; the primary toxicity was myelosuppression. Preplanned dose reduction criteria for neutropenia were met after the first 20 pts had been treated. After this early timepoint, all subsequent pts who had been consolidated with autoHCT received only 4 days of decitabine per cycle (HiDAC consolidated pts continued to receive 5 days per cycle). The median number of cycles of decitabine received was 7 (range, 1–8); 46% of pts (62/134) received all 8 cycles, and 75% completed at least 4 cycles. Reasons for discontinuation of decitabine before completing 8 cycles included relapse (28%, 38/134), pt refusal (13%), adverse events (4%), and others. In this selected cohort of pts who received post-CR maintenance with decitabine, 1-yr and 3-yr overall survival (OS) were 96% and 66%; 1-yr and 3-yr disease-free survival (DFS) were 80% and 53%. 1-yr “failure-free survival” calculated from the time of registration to decitabine was 68% (70% for favorable risk, 68% for others). These results are similar to the outcomes for comparable pts enrolled on our prior CALGB study 19808 who received identical chemotherapy for induction and consolidation and then were randomized to observation or maintenance with interleukin-2 (3-yr OS 61% and 68%, 3-yr DFS 45% and 56%, for observation and IL-2 respectively). Post-consolidation maintenance with decitabine appears to provide only modest, if any, benefit overall. Correlative studies for CALGB 10503 are ongoing, including investigations into the impact of decitabine in unique molecular and cytogenetic subsets of disease, the prognostic/predictive value of aberrant methylation and other molecular markers, and assessment of minimal residual disease. Supported by CA33601 and CA128377. Disclosures: No relevant conflicts of interest to declare.

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Marcucci, Guido, K. Mrózek, A. S. Ruppert, K. Maharry, J. E. Kolitz, R. J. Mayer, M. J. Pettenati et al. « t(8;21) Acute Myeloid Leukemia (AML) Differs from inv(16) AML in Pretreatment Characteristics, Outcome and Prognostic Factors Predicting Outcome : A Cancer and Leukemia Group B (CALGB) Study. » Blood 104, n^o 11 (16 novembre 2004) : 2017. http://dx.doi.org/10.1182/blood.v104.11.2017.2017.

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Abstract Since t(8;21) and inv(16) disrupt core binding factor in AML and confer a favorable prognosis, these cytogenetic groups are often treated similarly, but hitherto have not been compared in a large study. We compared 144 adult AML patients (pts) with t(8;21) with 168 with inv(16) enrolled on the cytogenetic study CALGB 8461. t(8;21) pts were less frequently white (P=.01), had lower hemoglobin levels (P=.03), WBC (P<.001) and % blood (P<.001) and BM blasts (P=.005), and had more frequently secondary chromosome aberrations (P<.001) than inv(16) pts, who more often had extramedullary disease (P<.001). Pts were induced with cytarabine/daunorubicin (AD) or cytarabine/daunorubicin/etoposide ±PSC833(ADE±P). Complete remission (CR) was achieved by 89% of t(8;21) and 87% of inv(16) pts. Upon multivariable analysis (MVA), non-white race (P=.006), lower platelets (P=.01) and higher BM blasts (P=.004) predicted negatively for CR in t(8;21), and lower platelets (P=.009) and hepatomegaly (P=.04) in inv(16) pts. Non-whites with t(8;21) had 5.7 times the odds of not achieving CR as whites. For the entire group (median follow-up 6.4 yrs), the estimated 5-yr overall survival (OS) and cumulative incidence of relapse (CIR) were 51% and 53%, respectively. Pts with t(8;21) showed a trend for shorter OS (46% vs 54%; P=.17) but no difference in CIR compared with inv(16) pts. Upon MVA, t(8;21) pts had worse OS than inv(16) pts (HR 1.5; P=.04), once adjusting for age, platelets, and WBC. Following first relapse, the 5-yr survival of t(8;21) pts (n=58) was shorter than that of inv(16) pts (n=74) (14% vs 36%; P=.01); in an age-adjusted model, the risk of death was 1.8 times higher for t(8;21) pts (P=.005). In a subanalysis of pts <60 yrs, consolidation therapy with multi-course high-dose cytarabine (HDAC x3 or 4) significantly decreased CIR compared to single-course HDAC (x1) in t(8;21) (5-yr CIR, 35% vs 64%; P=.005) and inv(16) (5-yr CIR, 44% vs 70%; P =.03) pts. Upon MVA, consolidation with multi-course HDAC reduced CIR for both t(8;21) and inv(16), but other prognostic factors differed (see Table). For t(8;21), induction with ADE±P and higher platelets increased risk of relapse. However, relatively few pts received ADE±P so its prognostic impact requires confirmation. For inv(16), +22 and other secondary cytogenetic aberrations, and male sex were favorable prognostic factors. Multivariable analysis (MVA) for CIR in pts <60 yrs achieving CR on CALGB 8221, 8525, 9022, 9222, 9621 Variable t(8;21) HR (95% CI); P inv(16) HR (95% CI); P HR=Hazard Ratio, CI=confidence intervals —, not included in final model Consolidation:Single vs multi-course HDAC 4.5 (2.1-9.4); <.001 3.4 (1.7-6.6); <.001 Induction:ADE±P vs AD 2.6 (1.1-5.9); .02 1.4 (0.6-3.2); .41 log(platelets) 1.8 (1.2-2.9); .007 — Secondary cytogenetics — 0.2 (<0.1-0.5); .002 Male vs Female — 0.5 (0.3-0.9); .03 In summary, once pretreatment factors and therapy are considered, the outcome of t(8;21) AML appears inferior to that of inv(16). Although these data should be confirmed prospectively, our analysis suggests that future studies should report the outcomes of pts with t(8;21) and inv(16) separately, and seek to identify and target therapeutically leukemogenic mechanisms accountable for these clinical differences.

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Lozanski, Gerard, Ben Sanford, Daohai Yu, Rebecca Pearson, Colin Edwards, John C. Byrd, Richard A. Larson, Clara D. Bloomfield et Wendy Stock. « CD52 Expression in Adult Acute Lymphoblastic Leukemia (ALL) : Quantitative Flow Cytometry Provides New Insights. » Blood 108, n^o 11 (1 novembre 2006) : 2293. http://dx.doi.org/10.1182/blood.v108.11.2293.2293.

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Abstract We recently tested the feasibility of incorporating Alemtuzumab, a humanized anti-CD52 monoclonal antibody, into frontline therapy of adult ALL (CALGB 10102) in an attempt to eradicate minimal residual disease (MRD). We have previously reported that CD52 expression occurs in 68% of newly diagnosed ALL. This assessment was based upon the use of a qualitative flow cytometric assay performed on all pre-treatment cases in a central CALGB reference laboratory. Cases with > 10% CD52 expression on lymphoblasts relative to an isotype control were considered CD52 positive and eligible to receive Alemtuzumab during post-remission therapy. To better characterize the CD52 expression level on lymphoblasts and to obtain insights for the design of future subset specific therapies in adult ALL, we developed a quantitative assay to measure CD52 antigen density on lymphoblasts using custom PE conjugated clinical grade Alemtuzumab on 29 cases of precursor B-cell (pre-B) ALL and 9 cases of precursor T-cell (pre-T) ALL. In this assay, CD52 is expressed in arbitrary units of antibody bound per cell (ABC). We also measured CD52 levels on residual normal B and T lymphocytes in every specimen to calculate a normalized ratio (NR) of lymphoblast CD52ABC/ normal lymphocytes CD52 ABC. The results are tabulated below: CD52 Expression Cell Type Precursor B-Cell ALL (n=29) median (range) Precursor T Cell ALL (n=9) median (range) CD52 ABC units Blasts 27658 (2042–206952) 10222 (3784–35337) CD52 ABC units Normal B Lymphocytes 125475 (59872–282245) 146478 (68098–291878) CD52 ABC units Normal T Lymphocytes 64142 (27406–141635) 78720 (22412–144350) CD52 NR Blasts/Normal B Lymphocytes 0.19 (0.02–0.88) 0.06 (0.02–0.16) CD52 NR Blasts/Normal T Lymphocytes 0.38 (0.04–2.16) 0.12 (0.07–0.26) Pre-B lymphoblasts express significantly lower levels of CD52 antigen than normal B lymphocytes (p<0.0001). Similarly, Pre-T lymphoblasts express significantly lower levels of CD52 antigen than the normal T lymphocytes (p<0.0001). Moreover, lymphoblasts in pre-T ALL show a near-significant lower expression of CD52 than pre-B lymphoblasts (two-sided p=0.05). Calculation of the NR confirms these observations. We have also begun to investigate CD52 expression by cytogenetic subset. Of note, we have determined that Philadelphia chromosome positive (Ph+) lymphoblasts were CD52+ in 26/28 (93%) cases studied; quantification of CD52 expression in Ph+ cases and in other common cytogenetic subsets is in progress. Correlation of CD52 expression with Alemtuzumab plasma levels and with development of opportunistic infections is underway. In conclusion, these data are the first to demonstrate that lymphoblasts from patients with untreated ALL express lower levels of CD52 antigen than residual normal lymphocytes present at the time of diagnosis. These findings may lead to improved selection of patients most likely to benefit from administration of Alemtuzumab and may have important implications for optimizing dosing and scheduling of Alemtuzumab during ALL therapy.

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Wilson, E., J. Crown, J. Ballot, D. McDonnell, E. Sheehan et J. Healy. « Estimating the real cost of adjuvant (A) trastuxumab (T) in patients(pts) with HER-2+ (H+) early stage breast cancer (ESBC) ». Journal of Clinical Oncology 24, n^o 18_suppl (20 juin 2006) : 6081. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.6081.

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6081 Background: Pts with H+ metastatic (M) ESBC have a high risk of relapse. T has been reported to reduce the risk of relapse for pts with H+ESBC by approximately 50% when combined with A chemotherapy (CT). We attempted to study the real cost of AT in the context of current use of T in MBC (MT), and of the predicted reduction in the risk of relapse. Methods: We conducted a retrospective analysis of the mean per pt cost of AT and MT, and standard ACT in St. Vincent’s Hospital. The costs/pt for AT and MT were €34k, and €47k respectively, and for the listed agents in standard A: docetaxel(D)-8.8k, paclitaxel(P)-7.4 k, filgrastim(G)-9.3 k. Based on published/presented data (BCIRG 001), we assumed a 35% risk for relapse at five years for pts with H+BC receiving conventional A, and a 50% risk reduction (RR) for AT, giving an absolute benefit of 17.5%. We then devised an equation to calculate the Crp for AT: Crp=[a-M(NRA/104)]/[NRA/104] where a = cost per pt for treatment (Tx) with AT, M = cost per pt for Tx with T in MBC, N = % of pts relapsing after standard A, RA = % reduction in the risk of relapse after Tx with AT (over standard A). Results: The corresponding real T costs/100 pts for the following reductions in relapse rate would be:25%-€3.4m 50%-€2.6m-, 80%-€2.1m, 100%-€1.8m. The Crp for AT with a 50% reduction in relapse rate is €147k. With a 100% reduction in the RR we estimate the Crp to be €50k. We studied D (D-BCIRG 001), P (P-CALGB 9344) and G (G-CALGB 9741 dose-dense), and noted the following published absolute relapse reductions for these tx: D-7%, P-5% and G-4%. The following costs per relapse prevented were calculated: P-148 k; G-231k; D-126k. Conclusions: Using the equation, the real cost per relapse prevented of AT can be calculated, and comparisons made with the cost-effectiveness of other accepted A. Assuming no re-treatment with MT, AT appears to be a relatively cost-efficient means of reducing relapses. Reports of the efficacy of short AT regimens suggest the possibility of even greater cost-effectiveness. This equation could possibly be used to calculate the cost effectiveness of other novel A molecular therapies. [Table: see text]

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Demichelis, Roberta, Karla Adriana Espinosa, Juan Rangel-Patiño, Emmanuel Almanza et Ana Cooke. « Pediatric-Inspired Regimens Are Associated with Better Outcomes When Compared with Hypercvad in Hispanic Adolescents and Young Adults with Acute Lymphoblastic Leukemia ». Blood 134, Supplement_1 (13 novembre 2019) : 3877. http://dx.doi.org/10.1182/blood-2019-125370.

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Background Acute lymphoblastic leukemia (ALL) is frequent in Mexico, representing 51% of acute leukemia in adults. Hispanic ethnicity is associated with high-risk features and poor outcomes. We previously reported a multicenter experience in Mexico, where the majority of our ALL-patients (67%) were adolescents and young adults (AYA), mostly treated with HyperCVAD and with poor outcomes: 3-year overall survival (OS) of 25.7%. Many groups have demonstrated better outcomes with pediatric-inspired regimens (PIR) in the AYA-group, with long term OS > 60%. In 2016-2017 we changed the standard of care from HyperCVAD to PIR in two of the centers from the previously mentioned study. Methods We included AYA-patients with the diagnosis of Philadelphia-negative ALL treated with PIR (ALL-BFM 90 or CALGB 10403) between March 2016 and June 2019 in two centers in Mexico City. Both regimens were modified from the original: we used E. Coli asparaginase instead of pegaspargase and mercaptopurine instead of thioguanine. We compared these patients with our common historic database of patients with the same characteristics diagnosed between February 2009 and June 2015, treated with HyperCVAD. Hyperleukocytosis was defined as a white blood cell count > 30 x103/mcL for B-cell ALL and > 100 x103/mcL for T-cell ALL. Patients with t(v;11q23), hypodyploid or complex karyotype were considered high-risk. Baseline characteristics of both groups were compared with Chi-square or Mann-Whitney U test. We estimate OS by Kaplan-Meier method and compared groups by log-rank test. Multivariate Cox proportional hazards regression was used to evaluate independent prognostic factors associated with OS. Results We compared 73 patients treated with PIR with a control group of 137 patients treated with HyperCVAD. The patients treated with PIR received either ALL-BFM 90 (N=46) or CALGB 10403(N=27). The median follow-up was 49.8, 23.3 and 12.7 months for HyperCVAD, ALL-BFM 90 and CALGB 10403 respectively. Patients treated with PIR were slightly older than those in the control group (median 24 vs. 20 years, p=0.005) and presented with high-risk karyotype more frequently (31.9% vs. 12.2%, p=0.042). Most of the patients were B-cell ALL (91.8% for PIR and 95.6% for HyperCVAD; p=0.349). Comparing PIR vs. HyperCVAD, there were no differences in the proportion of patients with hyperleukocytosis (33.3% vs. 25.0%, p=0.128) or obesity (24.7% vs. 16.4%, p=0.192). The induction related mortality was 5.7% for the entire group with a trend that favors PIR (1.4% vs. 8.0%, p=0.061). In patients treated with PIR, the 4-week complete remission (CR) rate was higher (79.5% vs. 64.2%, p=0.027) and the relapse rate was lower (41.5% vs. 60.0%, p=0.027). Patients treated with PIR were more frequently treated with allogeneic stem-cell transplant (alloSCT) in first CR: 19.2% vs. 7.3%, p=0.017. The median OS was significantly higher with PIR than with HyperCVAD, with a median of 19.0 months (3.3-25.4 months) vs. 11.1 months (7.3-14.8 months), and a 18-month OS of 53% vs. 33%, p=0.017. When comparing the two different PIR (ALL-BFM 90 vs. CALGB 10403), the patients treated with ALL-BFM 90 had more frequently high-risk karyotypes (46% vs. 10.5%, p=0.012). Both regimens were associated with similar 4-week CR rate (78.3% vs. 81.5%, p=1). OS was higher with the CALGB 10403 with an 18 month-OS of 79% vs. 42% with the ALL-BFM 90 (p=0.044). When adjusted for high-risk karyotype, the benefit on OS was no longer significant. In the multivariate analysis for OS, the independent significant prognostic factors were: treatment with a PIR (HR 0.428, 95% CI 0.221-0.826, p=0.011), alloSCT in first CR (HR 0.316, 95% CI 0.106-0.938, p=0.038) and high-risk karyotype (HR 2.695 95% CI 1.272-5.560, p=0.009). Discussion Although different groups have shown the benefit of PIR in the AYA-patients, the MD Anderson group couldn´t found any benefit from using the augmented BFM when compared to HyperCVAD. In our experience, the outcomes with HyperCVAD are poor in this group. In this report, the treatment with PIR was associated with a higher CR rate, lower relapse rate and better OS when compared with our historical HyperCVAD in AYA-patients. The benefit on survival was independent of other risk factors or alloHSCT. The main limitation of the study is the comparison with a historical group. However, given the general trend to treat these patients with RIP, a prospective randomized study in this regard is unlikely. Disclosures Demichelis: Abbvie: Speakers Bureau; AMGEN: Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Shire: Speakers Bureau.

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Harpole, D. H., R. Petersen, S. Mukherjee, A. Bild, H. Dressman, R. Kratzke, M. J. Kelley et al. « A genomic strategy to refine prognosis in early stage non-small cell lung carcinoma (NSCLC) ». Journal of Clinical Oncology 24, n^o 18_suppl (20 juin 2006) : 7026. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.7026.

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7026 Background. Although stage-specific classification identifies appropriate populations for adjuvant chemotherapy, this is likely an imprecise predictor for the individual patient with early stage NSCLC. Methods. Using previously-described methodologies that employ DNA microarray data, multiple gene expression profiles (‘metagenes’) that predict risk of recurrence in patients with stage I disease were identified. This analysis used an initial ‘test’ cohort of patients with NSCLC (n = 89) that represented an equal mix of squamous cell and adenocarcinoma. Also, each histologic subset had equal number of patients who survived more than 5 years and those who died within 2.5 years of initial diagnosis. The performance of the metagene-based model generated on the training cohort was then evaluated in independent ‘validation’ sets, including two multi-center cooperative group studies (ACOSOG Z0030 and CALGB 9761). Importantly, the CALGB validation was performed in a blinded fashion. Results. Classification tree analyses that sample multiple gene expression profiles were used to develop a model of recurrence, termed the Lung Metagene Model, that accurately assesses prognosis (risk of recurrence and survival), performing significantly (p<0.001, odds ratio: 16.1, multivariate analysis) better than pathologic stage, T-size, nodal status, age, gender, histologic subtype and smoking history. The accuracy of prognosis using the Lung Metagene Model exceeded 90% (leave-one-out cross validation) in the initial training set (n = 89), 72% in the ACOSOG (n = 25), and 81% in the CALGB (n = 84) datasets. The prognostic accuracy was consistent across histologic subtypes and stages of NSCLC. Importantly, this provides an opportunity to re-classify stage IA patients to identify a subset of ‘high risk’ patients that may benefit from adjuvant chemotherapy. Further, stage IB and II patients identified as ‘low risk’ for recurrence, and who present co-morbidities, could potentially be candidates for observation, and those patients predicted to be at ‘high risk’ may benefit from novel therapeutic trials. Conclusions. The Lung Metagene Model provides a mechanism to refine the estimation of an individual patient’s risk for disease recurrence and thus guide the use of adjuvant chemotherapy in NSCLC. No significant financial relationships to disclose.

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Bashey, Asad, Kouros Owzar, Jeffrey L. Johnson, Steven M. Devine, Richard K. Shadduck, Thomas C. Shea et Charles Linker. « Reduced-Intensity Allogeneic Transplantation after Failure of Autologous Transplantation : A Prospective Multi-Center CALGB Study. » Blood 108, n^o 11 (16 novembre 2006) : 3122. http://dx.doi.org/10.1182/blood.v108.11.3122.3122.

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Abstract Relapse of malignancy (RM) remains the most important cause of treatment failure following high-dose chemotherapy and autologous hematopoietic transplantation (AHCT). Allogeneic transplantation (allo-HCT) can salvage some patients who relapse or develop MDS following AHCT. However, myeloablative allo-HCT has been associated with a prohibitive transplant-related mortality (TRM) in such patients. CALGB study 100002 prospectively assessed the safety of reduced-intensity allo-HCT (RICT) in patients who failed prior AHCT. Eligibility required the development of RM or MDS > 6 months following AHCT for a hematologic malignancy and an available HLA-identical sibling (MSD) or 9/10 locus matched related donor, or a 10/10 matched unrelated donor. Between Dec 02 and Mar 06, 82 patients were registered from 11 CALGB centers. Patient characteristics: median age = 51 (17–70); male-63%; diagnoses - NHL 30%, HD 26%, MM 18%, MDS 16%, AML 8%, CLL 2%; donor - MSD 43%, MUD 55%, 9/10 MRD 2%. Median time between AHCT and RICT was 2.6 yrs (0.6–5.7 yrs). Preparative regimen for patients with MSD was fludarabine 30 mg/m2/d x 5 d, busulfan (i.v.) 3.2 mg/kg/d x 2 d. For patients without MSD rabbit ATG (Thymoglobulin ®) 2.5mg/kg/d x 4 d was added. PBSC 2–8 x 106 CD34+ cells/kg was used as the graft. GVHD prophylaxis consisted of tacrolimus tapering at d +90 and methotrexate 5 mg/m2 x 3 doses for MSD patients. For non-MSD patients, tacrolimus was tapered starting d +180, a fourth dose of methotrexate and MMF (d 0 to d +60) were added. Primary endpoint was TRM at 6 months. For 56 patients with > 6 months post-RICT follow-up (median follow-up 1.3 yrs), 6 month TRM was 8.7% (MSD patients 4.2%, non-MSD patients 9.3%). Total cumulative TRM was 14.3% (MSD 16.7%, non-MSD 12.5%). Reported cumulative rates of II–IV and III–IV acute GVHD are 28.2% and 11.8% respectively. Chimerism studies were performed centrally on peripheral blood (PB) specimens. The percentage of patients from MSD patients who achieved full (> 90%) donor T-cell (CD3) chimerism in PB on day 30, 60, 90 and 180 post transplant are 15, 40, 47, 57 and 60% respectively. In contrast, for non-MSD patients the corresponding rates are 78, 68, 86 and 91 % respectively. Both MSD and non-MSD patients achieved full (>90%) donor chimerism in myeloid cells by d 30 in > 80% of patients. This study observed a <10% 6-month TRM for RICT following AHCT failure in the multi-center, co-operative group setting. Also, the use of a more potent GVHD prophylaxis regimen seems to enable TRM rates for non-MSD patients to approximate those seen for MSD patients. MSD patients achieve slower onset of full-donor chimerism in T-cells with this regimen. A successor study will assess means of increasing early T-cell chimerism in the MSD patients.

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Muffly, Lori, Jun Yin, Sawyer Jacobson, Anjali Advani, Selina M. Luger, Martin S. Tallman, Mark R. Litzow et al. « Enrollment Characteristics and Outcomes of Hispanic and Black AYA ALL Patients Enrolled on a U.S. Intergroup Clinical Trial : A Comparison of the CALGB 10403 (Alliance) Cohort with U.S. Population-Level Data ». Blood 138, Supplement 1 (5 novembre 2021) : 337. http://dx.doi.org/10.1182/blood-2021-148804.

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Abstract Introduction According to population-based Surveillance, Epidemiology and End Results (SEER) cancer registry data, approximately 40% of adolescents and young adults (AYA) with acute lymphoblastic leukemia (ALL) in the United States (U.S.) are Hispanic and 7% are Black and both Hispanic and Black patients have significantly inferior outcomes relative to non-Hispanic Whites (NHW). CALGB 10403, a prospective Phase II clinical trial conducted by the U.S. Intergroup, demonstrated the feasibility of delivering a pediatric-inspired ALL regimen to newly diagnosed AYA ALL patients and found this approach to be superior to historical adult regimens (Stock et al. Blood 2019). In the current analysis, we evaluate enrollment patterns of Hispanic and Black AYAs on CALGB 10403 and compare survival relative to SEER estimates. Methods Demographics on AYAs (18-40 yrs) enrolled on CALGB 10403 (N=295 from 2007-2012) were supplemented with patient-reported education and socioeconomic status (SES) information. Data from the North American Association of Cancer Registries (NAACCR; 2013-2017) were used to evaluate U.S. country-wide ALL incidence (20-49 yrs) overall and among Hispanics, reported per U.S. state. SEER registries (2008-2012) provided racial/ethnic distribution and overall survival (OS) of AYA ALL (15-39 yrs). The distribution of OS was estimated using the Kaplan-Meier method and compared across racial/ethnic groups using log-rank tests. Results Relative to the U.S. AYA ALL population, CALGB 10403 included proportionally fewer Hispanics (41.7% vs. 16.3%, P < 0.001); the distribution of blacks was similar (6.4% vs. 8.5%, P = 0.174). Demographics and ALL characteristics among CALGB 10403 enrollees demonstrated no significant differences in age, sex, cytogenetics, or BMI by race/ethnicity; however, Black AYAs were more likely to have T-ALL, and Hispanic patients were more likely to have Ph-like B-ALL and rearrangements in CRLF2. Hispanic and Black patients reported lower household yearly income, and Black patients had less educational attainment. In order to explore reasons for disproportionately low Hispanic enrollment on CALGB 10403, we calculated the proportion of Hispanic AYAs with ALL relative to the AYA ALL incidence across U.S. states using NAACCR data and compared this with the geographical distribution of CALGB 10403 enrollments. The incidence of AYA ALL across U.S. states is represented in Fig 1A and the proportion of Hispanic AYA ALL patients in Fig 1B. The states with highest proportion of Hispanic patients included CA, TX, and NM, followed by AZ, CO, FL, and NJ. Although CALGB 10403 enrolled patients in 31 U.S. states, the trial did not open in TX or FL. The enrollments numbers were highest across the Mid-Western U.S., with only 47/295 (15.9%) of enrollments coming from the seven states with a high proportion of Hispanic AYA ALL patients (Fig 1C). The 3-yr event-free survival (EFS) and OS for the total CALGB 10403 cohort were 59.1% (53.1%, 65.75%) and 73.5% (68.1%, 79.4%), respectively. Per protocol completion of therapy was highest in Hispanics (75%), relative to Black (64%) and NHW patients (56%), P=0.049. Overall survival among CALGB 10403 participants differed significantly across race/ethnicity (Fig 2), with superior OS experienced by Hispanic patients and inferior OS by Black patients (P= 0.021). These clinical trial results differ from SEER estimates, where both Hispanic and Black patients experience worse OS relative to NHW (Fig 2). Conclusions This in-depth analysis of racial/ethnic enrollments and outcomes on CALGB 10403 uncovered findings that may translate across clinical trials beyond AYA ALL. Importantly, our data suggest that closer matching of trial site selection to geographical racial/ethnic disease incidence may improve minority enrollments on multi-center clinical trials. Relative to NHW, Hispanic patients had superior survival despite having higher rates of Ph-like ALL, indicating that clinical trial participation may mitigate racial/ethnic survival disparities seen in population-based data. Finally, we saw no improvement in trial outcomes among Black AYAs; a deeper understanding of the biological leukemia underpinnings and barriers to successful outcomes would aid future efforts at improving survival across racial/ethnic groups. Figure 1 Figure 1. Disclosures Muffly: Pfizer, Amgen, Jazz, Medexus, Pfizer: Consultancy; Astellas, Jasper, Adaptive, Baxalta: Research Funding; Adaptive: Honoraria, Other: fees for non-CME/CE services: , Research Funding. Advani: Abbvie: Research Funding; Macrogenics: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Glycomimetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Immunogen: Research Funding; Pfizer: Honoraria, Research Funding; OBI: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Luger: Syros: Honoraria; Agios: Honoraria; Daiichi Sankyo: Honoraria; Jazz Pharmaceuticals: Honoraria; Brystol Myers Squibb: Honoraria; Acceleron: Honoraria; Astellas: Honoraria; Pfizer: Honoraria; Onconova: Research Funding; Celgene: Research Funding; Biosight: Research Funding; Hoffman LaRoche: Research Funding; Kura: Research Funding. Tallman: NYU Grand Rounds: Honoraria; Syros: Membership on an entity's Board of Directors or advisory committees; Kura: Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Biosight: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Oncolyze: Membership on an entity's Board of Directors or advisory committees; KAHR: Membership on an entity's Board of Directors or advisory committees; Orsenix: 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; Amgen: Research Funding; Rafael Pharmaceuticals: Research Funding; Glycomimetics: Research Funding; Biosight: Research Funding; Orsenix: Research Funding; Abbvie: Research Funding; Mayo Clinic: Honoraria; UC DAVIS: Honoraria; Northwell Grand Rounds: Honoraria; NYU Grand Rounds: Honoraria; Danbury Hospital Tumor Board: Honoraria; Acute Leukemia Forum: Honoraria; Miami Leukemia Symposium: Honoraria; New Orleans Cancer Symposium: Honoraria; ASH: Honoraria; NCCN: Honoraria. Litzow: Omeros: Other: Advisory Board; Jazz: Other: Advisory Board; Pluristem: Research Funding; Actinium: Research Funding; Amgen: Research Funding; AbbVie: Research Funding; Astellas: Research Funding; Biosight: Other: Data monitoring committee. Foster: Macrogenics: Research Funding; Rafael Pharmaceuticals: Research Funding; Macrogenics: Consultancy; Daiichi Sankyo: Consultancy; Agios: Consultancy; Bellicum Pharmaceuticals: Research Funding. Larson: Gilead: Research Funding; Epizyme: Consultancy; Astellas: Consultancy, Research Funding; Rafael Pharmaceuticals: Research Funding; CVS/Caremark: Consultancy; Takeda: Research Funding; Novartis: Research Funding; Cellectis: Research Funding.

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Ryan, Charles J., Sandipan Dutta, William Kevin Kelly, Rob Middleberg, Carly Russell, Eric Jay Small, Michael J. Morris, Mary-Ellen Taplin et Susan Halabi. « Serum androgens and survival in metastatic castration resistant prostate cancer (mCRPC) patients treated with docetaxel and prednisone : Results from CALGB 90401 (Alliance). » Journal of Clinical Oncology 35, n^o 15_suppl (20 mai 2017) : 5067. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.5067.

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5067 Background: Higher baseline androgens have been previously shown to be associated with an improved overall survival (OS) in mCRPC patients treated with the androgen synthesis inhibitors, ketoconazole or abiraterone. The purpose of this analysis was to determine whether baseline serum androgen levels (Testosterone (T), Androstenedione (A) and DHEA (D) are associated with OS in mCRPC patients treated with docetaxel-based chemotherapy. Methods: Data from 1,050 men treated on CALGB 90401 with docetaxel, prednisone and either bevacizumab or placebo were used. Eligibility required progressive mCRPC and no prior chemotherapy. Pre-treatment serum assays for T, A and D were performed via tandem Liquid Chromatography-Mass Spectrometry (LC-MS/MS) at NMS labs. The proportional hazards model was used to assess the prognostic significance of T, A, and D in predicting OS adjusting for known prognostic factors. Results: Median values for T, A, and, D were 1.00, 13.00 and 8.12, ng/dL respectively.Values above the median were defined as low, above as high. Median OS for low vs high levels was 22.7 and 23.1 month for T, 22.4 and 21.7 month for A and 21.8 and 24.0 month for D, respectively, all NS. In multivariable analysis adjusting for 10 known prognostic values and prior keto use in mCRPC (Halabi JCO 2014), A (p-value = 0.013) levels were associated with OS. The HR for A was = 0.99 (95% CI = 0.98-0.99). Conclusions: In multivariate analysis, baseline androstenedione levels are prognostic factors for OS in mCRPC patients receiving chemotherapy. Low or undetectable levels of other androgens are associated with shorter OS, consistent with prior results in androgen synthesis inhibitor treated pts in both the chemotherapy naive and post chemotherapy settings. This relationship may reflect more aggressive tumor biology that evolves in an extreme androgen deprived milieu. Clinical trial information: NCT00110214.

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Malnassy, Greg, Susan Geyer, Noreen Fulton, Greg Koval, Donna Niedzwiecki, Victoria Carlton, Li Weng et al. « Comparison Of Deep Sequencing and Allele-Specific Oligonucleotide PCR Methods For MRD Quantitation In Acute Lymphoblastic Leukemia and Mantle Cell Lymphoma : CALGB 10403 and CALGB 59909 (Alliance) ». Blood 122, n^o 21 (15 novembre 2013) : 2547. http://dx.doi.org/10.1182/blood.v122.21.2547.2547.

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Abstract Background The assessment of minimal residual disease (MRD) is a key component of prognosis and monitoring in acute lymphoblastic leukemia (ALL) and mantle cell lymphoma (MCL). Allele-specific oligonucleotide (ASO)-PCR can be used to assess MRD; however, this technique requires preparation of clonotype-specific primers for each patient, which is laborious and time-consuming. We demonstrated the utility of sequencing-based MRD assessment in ALL (Faham et al., Blood 2012). This quantitative approach relies on amplification and sequencing of immunoglobulin and T-cell receptor gene segments using consensus primers and can address some of the limitations associated with traditional MRD detection. Here we compared the ability of the sequencing and ASO-PCR methods to identify clonal cancer gene rearrangements at diagnosis and evaluated the concordance of MRD detection in bone marrow (BM) or blood samples from 37 patients (pts) with ALL and 22 pts with MCL entered onto prospective CALGB treatment trials, 10403 and 59909 (Alliance), respectively . Methods Using the quantitative ASO-PCR and sequencing assays, we analyzed diagnostic blood and BM samples from ALL pts for clonal rearrangements of immunoglobulin (IGH-VDJ, IGH-DJ, IGK) and T cell receptor (TRB, TRD, TRG) genes. We then assessed MRD at the IGH and/or TRG locus in 84 follow-up samples from ALL pts. Similarly, we analyzed samples from 22 MCL pts for immunoglobulin (IGH-VDJ, IGH-DJ, IGK) clonal gene rearrangements and measured MRD at the IGH and/or IGK locus in 114 follow-up samples. Sensitivity of the ASO-PCR vs sequencing was 1 X 10 4-5 vs 1 X 106, respectively. Concordance between sequencing and ASO-PCR MRD assessment on serial samples collected during and post-treatment was evaluated across all pts and within disease groups using concordance correlation coefficients for repeated measures (CCC-RM). Concordance in identification of detectable vs. undetectable MRD by both methods was also evaluated using Kappa statistics. Results Using the sequencing platform, high frequency clonal rearrangements were observed in at least two receptors in 97% and 95% of pts with ALL and MCL, respectively. Selected ALL samples were known to have IGH-VDJ or TRG clonal rearrangements by ASO-PCR; however, sequencing revealed additional clonal rearrangements in 36/37 (97%) pts with ALL. Good concordance was observed with identification of MRD positive vs. negative between the methods (K=0.62; p<0.0001), where better agreement was observed within the ALL (K=0.63) than within the MCL (K=0.59) cohorts. Across both diseases, the sequencing method proved a more sensitive measure and CCC-RM was 0.82, reflecting the fact that 28 pts with undetectable MRD by ASO-PCR methods had low detectable MRD measures by the sequencing approach. The sequencing platform also provided new insights into kinetics of relapse. In one ALL case (Fig 1), we observed three high frequency IGH-VDJ clones, two of which are related based on VDJ replacement model. Dramatic reduction in frequency of one clone (clone 3, Fig 1) was observed following initial induction chemotherapy in both BM and blood. Only this single clone was monitored using ASO-PCR, and the patient appeared to be in molecular remission. However, the other two high frequency clones were chemo-resistant, and sequencing MRD monitoring revealed no reduction in clone frequency in either the BM or blood. The patient experienced early relapse at day 56, which may have resulted from the expansion of a clone carrying one or both of the clonal sequences that was not monitored by ASO-PCR. Thus, the sequencing method can be used to monitor response to treatment at the individual clone level. Conclusions This study demonstrates concordance between identification of detectable MRD in ALL and MCL by sequencing and ASO-PCR Methods. The sequencing approach offers improvements over ASO-PCR including the ability to monitor multiple clonal sequences, faster turnaround time (results in 1 week), and greater sensitivity. The clinical significance of this greater sensitivity remains to be tested prospectively and must be correlated with clinical results. Nevertheless, the sequencing method represents an alternative approach for clinical MRD monitoring which could fundamentally improve the ability to monitor disease progression and recurrence in patients with lymphoid malignancies. Disclosures: Carlton: Sequenta, Inc.: Employment, Equity Ownership. Weng:Sequenta, Inc.: Employment, Equity Ownership. Faham:Sequenta, Inc.: Employment, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees.

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Paschka, P., M. D. Radmacher, G. Marcucci, A. S. Ruppert, T. Vukosavljevic, S. P. Whitman, K. Mrózek, C. Liu, R. A. Larson et C. D. Bloomfield. « Outcome prediction in adult core binding factor (CBF) acute myeloid leukemia (AML) with gene expression profiling : A Cancer and Leukemia Group B (CALGB) study ». Journal of Clinical Oncology 25, n^o 18_suppl (20 juin 2007) : 7011. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.7011.

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7011 Background: In CBF AML with t(8;21)(q22;q22) or inv(16)(p13q22)/t(16;16)(p13;q22) [abbreviated inv(16)], KIT mutations (mutKIT) and, in inv(16), trisomy 22 predict outcome and may guide the development of novel risk-adapted therapies. However, prognosis of patients (pts) lacking the aforementioned markers is less clear. Therefore, we profiled gene expression in t(8;21) (n=22) or sole inv(16) (n=25) pts who lacked mutKIT to identify signatures predictive of outcome. All pts were treated on CALGB trials incorporating consolidation therapy with multiple courses of higher dose cytarabine. Methods: Gene expression profiling was performed using Affymetrix U133 plus 2.0 arrays on diagnostic samples. As differences in gene expression distinguished all t(8;21) pts from all inv(16) pts, indicating two different biological entities, we pursued outcome prediction separately for each cytogenetic group. Gene expression-based outcome predictors for event-free survival (EFS) were constructed using a cross-validated prediction algorithm. Results: Among t(8;21) pts, EFS for predicted good (n=13) and poor (n=9) outcome groups differed strikingly (P=0.005; estimated 3-year EFS rates: 69% v 11%). Prediction was correct for 77% of pts. Among sole inv(16) pts, EFS for predicted good (n=18) and poor (n=7) outcome groups also differed (P=0.08; 3-year EFS rates: 78% v 29%). Prediction was correct for 76% of pts. FLT3 mutations appeared not to account for differences in EFS between the predicted groups; only the predicted outcome groups were associated with EFS (all baseline clinical characteristics at P>0.10). Pts with predicted poor outcome had higher expression of genes with leukemogenic potential such as WT1 [t(8;21) and inv(16)], CCNA1 [t(8;21)] and the oncogene MYCN [inv(16)]. Conclusions: Gene expression profiling improves outcome prediction in CBF AML pts lacking the known prognostic markers. Future studies should explore the clinical usefulness of targeting products of over- expressed genes, such as WT1 encoding a potential target for immunotherapy in AML. No significant financial relationships to disclose.

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Silverman, Lewis R., David R. McKenzie, Bercedis L. Peterson, Erin P. Demakos, Neil T. Malone, James F. Holland et Richard A. Larson. « Azacitidine Prolongs Survival and Time to AML Transformation in High-Risk Myelodysplastic Syndrome (MDS) Patients ≥ 65 Years of Age. » Blood 106, n^o 11 (16 novembre 2005) : 2524. http://dx.doi.org/10.1182/blood.v106.11.2524.2524.

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Abstract The prognosis for patients with refractory anemia with excess blasts (RAEB) or RAEB in transformation (RAEB-T) ≥ 65 years of age has been poor. These high-risk patients are often not eligible for intensive induction/transplantation regimens or combination chemotherapies, leaving few treatment options besides supportive or palliative care. In the publication of the CALGB trial by Silverman et al (JCO2002;20:2429), no age- and/or risk- related subgroup analyses for azacitidine (Vidaza®) were presented. To assess the treatment effect of azacitidine versus supportive care on survival and time to AML transformation in a homogeneous sample of high-risk patients with MDS, we performed a subgroup analysis on the 191 patients included in the CALGB trial. All patients with a baseline diagnosis of RAEB or RAEB-T who were ≥ 65 years of age were included in the comparative analysis, using intent-to-treat (ITT) principles based on randomization to azacitidine or supportive care. Efficacy was analyzed using three survival endpoints: overall survival, time to death or AML transformation, and time to AML transformation. In all, 31 azacitidine patients and 37 supportive care patients met the criteria for this high-risk subgroup analysis. No significant differences in demographics or disease characteristics between the two groups were observed. For all three survival analyses, a statistically significant difference was observed for patients in the azacitidine group compared with those in the supportive care group. (Table) Median time to transformation to AML, in particular, was prolonged for 24 months in azacitidine patients compared with patients in the supportive care group. A sensitivity analysis of the overall survival results was conducted by performing 10 additional subgroup analyses based on ages ≥ 60 through ≥ 70 years in increments of one year with all overall survival results remaining significant (p < 0.05, except for 2 subgroup analyses based on ages ≥ 60 and ≥ 66 where both p-values were 0.051). The sensitivity results demonstrated robust patient benefit in the subgroup ≥ 65 years of age. The most common adverse event observed with azacitidine was myelosuppression, which decreased in frequency as therapy continued. Azacitidine provided clear treatment effect and patient benefit to this difficult-to-treat, high-risk group of RAEB and RAEB-T patients ≥ 65 years of age by significantly prolonging overall survival and time to AML transformation. Time of Even Analysis

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Khan, Abdul Moiz, Kyle Kondrat, Aditi Sharma et Jay Yang. « A Single Center, 10-Year Experience of CALGB-10403 Regimen in AYA Population with Philadelphia-Chromosome Negative Acute Lymphoblastic Leukemia ». Blood 142, Supplement 1 (28 novembre 2023) : 5822. http://dx.doi.org/10.1182/blood-2023-186830.

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INTRODUCTION: The use of pediatric-inspired regimens for the treatment of acute lymphoblastic leukemia (ALL) has now become the standard of care in adolescents and adults (AYA). One such regimen, CALGB 10403, had higher rates of event free survival (EFS) and overall survival (OS) compared with historical controls using adult ALL regimens. It was shown to be feasible and efficacious in fit patients up to the age of 40 (Wendy Stock et al., Blood 2019). In 2012, based on emerging data on the improved efficacy of pediatric-inspired regimens in AYA patients, CALGB 10403 was adopted as the standard-of-care regimen in this population at Karmanos Cancer Institute (KCI), an adult cancer treatment center. Here we report our single center, real world experience of using this regimen in a Philadelphia chromosome negative (Ph-) AYA population, approximately 10 years after its adoption. METHODS: We conducted a retrospective chart review of consecutive AYA (ages 18-39) patients with Ph- ALL treated with CALGB 10403 regimen between January 2012 and June 2023 at KCI. Patients who received alternative regimens due to distance from KCI were excluded. Baseline demographic, clinical and molecular characteristics were noted. High-risk cytogenetics were defined as KMT2A rearrangements, hypodiploidy with a chromosome number ≤43, and complex karyotype. Testing for Ph-like ALL was not available in most patients. Beginning in 2019, clonoSEQ assay was used to test for minimal residual disease (MRD), with MRD negativity defined at a threshold of less than 10 -4. Incidence of adverse effects and treatment related mortality were reported to describe safety. Complete response (CR) rate, OS and PFS were used as efficacy outcomes. Kaplan-Meier curves were used to estimate OS and PFS. RESULTS: A total of 17 Ph- AYA patients were treated at KCI with a median age at diagnosis of 25 years (range 18-34). Males and females had a near equal representation (47% and 53%). The patients were predominantly White (64%). The majority of patients had a good ECOG performance status of 0 or 1 (88%). The diagnosis was B-ALL in 9 (53%) and T-ALL in 8 (47%) patients. High risk cytogenetics were present in 3 (80%) of the evaluable patients. None of the patients had CNS involvement at diagnosis. Baseline laboratory parameters expressed as medians were bone marrow blast percentage 80%, WBC count 9.2 x1000/mm 3, hemoglobin 8.4 g/dL, platelets 109 x1000/mm 3, and LDH 480. The median duration of follow-up was 54 months. 15 (88%) patients had CR with induction, and MRD was negative in 4 (57%) of the 7 evaluable patients. 2 (12%) patients had primary refractory disease. One of the patients with refractory disease underwent further therapy with blinatumomab, inotuzumab, CAR-T and allogeneic stem cell transplantation and is alive at 16 months from diagnosis. Another underwent salvage with hyper-CVAD and allogeneic stem cell transplant, and is currently alive at 88 months from diagnosis. Two additional patients were MRD positive after induction (course I) but subsequently attained MRD negativity. One of these eventually relapsed 7.5 months from diagnosis with a mixed phenotypic (T/myeloid) leukemia and died at 10 months, while the other is currently under treatment. An additional patient with CR1 and unknown MRD status had CNS relapse at 35 months, underwent successful hyper-CVAD, reintroduction of intrathecal chemotherapy and allo-HSCT salvage and is alive at 122 months. The 5-year PFS and OS were 74.5% and 94% respectively and the medians were not reached for both. Noteworthy adverse effects include neutropenic fever (65%), liver function tests (LFT) abnormalities (70%), and neuropathy from vincristine (70%). Peg-asparaginase administration was associated with pancreatitis in 12%, thromboembolism in 30% and hypersensitivity reactions in 24% requiring switching to alternative forms of asparaginase products (erwinia and Rylaze). These toxicities were manageable and there were no treatment-related deaths in our cohort. CONCLUSIONS: The pediatric-inspired regimen CALGB 10403 was safe and efficacious in our AYA Ph- ALL population with no deaths due to treatment and a 5-year overall survival of 94%. Toxicities, especially from peg-asparaginase, should be closely monitored. While most patients will attain durable remission/cure, the minority with refractory or relapsed disease can still be successfully salvaged to achieve long term survival.

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