Abstract Background: Patients with HR-positive, HER2-negative breast cancer respond poorly to neoadjuvant chemotherapy. The phase 3 DAWNA-1 and DAWNA-2 studies have proved that adding dalpiciclib (a CDK4/6 inhibitor) to endocrine therapy can significantly improve progression-free survival in patients with hormone receptor (HR)-positive, HER2-negative advanced breast cancer. However, the evidence of dalpiciclib in the neoadjuvant setting is limited. This study aimed to explore the efficacy and safety of dalpiciclib plus letrozole as neoadjuvant therapy in in patients with HR-positive, HER2-negative stage II-III breast cancer. Methods: In this multicenter, single-arm exploratory trial (NCT05512780), adult postmenopausal women with HR-positive (estrogen receptor >10%), HER2-negative stage II-III invasive breast cancer were enrolled. Patients received oral dalpiciclib (150 mg on days 1-21 of each 28-day cycle) and oral letrozole (2.5 mg once daily) for 4 cycles, followed by surgery. The primary endpoint was objective response rate (ORR), assessed by investigator according to the Response Evaluation Criteria In Solid Tumors version 1.1. Secondary endpoints included complete cell cycle arrest (CCCA, defined as Ki-67 < 2.7% on day 15 of the first cycle) rate, total pathological complete response (tpCR; ypT0/is ypN0) rate, residual cancer burden (RCB) 0-I rate, and safety. Results: Between June 2022 and January 2023, 41 patients were screened at 9 sites, and 35 patients were enrolled and received at least one dose of study drug. The median age was 66 years (range, 52-83), and the median baseline Ki-67 level was 20% (range, 4%-40%). The majority of patients had T2 disease (65.7%), lymph node-positive disease (88.6%), and stage II disease (IIA: 45.7%; IIB: 40.0%). The ORR was 35.5% (11/31) at 8 weeks and 51.7% (15/29) at 16 weeks in patients with evaluable response. The CCCA rate was 70.0% (21/30) in patients with available data. Four patients refused surgery and chose to continue the drug therapy. Of 27 patients who had undergone surgery, one (3.7%) patient had tpCR and RCB 0. Of 35 patients, the most common adverse events were neutrophil count decreased (74.3%), white blood cell decreased (68.6%), anemia (34.3%), and fatigue (31.4%). The most common grade 3 or higher adverse event was neutrophil count decreased (45.7%). No febrile neutropenia or treatment-related deaths occurred. Conclusions: This is the first prospective study of neoadjuvant dalpiciclib in patients with HR-positive, HER2-negative breast cancer. The findings suggest the promising tumor response to neoadjuvant dalpiciclib plus letrozole in postmenopausal patients with HR-positive, HER2-negative breast cancer, with a manageable safety profile. This combination can effectively suppress the tumor cell proliferation, as reflected by change in Ki-67 level. Citation Format: Lina Zhang, Chao Yang, Jie Ma, Yuntao Li, Ruizhen Luo, Jianjun Han, Xiaochun Wang, Zhisheng Zhang, Li Ma, Haifeng Cai, Xiangshun Kong, Zunyi Wang, Xinping Zhou, Yueping Liu, JiaJie Shi, Yanshou Zhang, Meiqi Wang, Jiaxing Wang, Cuizhi Geng. CDK4/6 inhibitor dalpiciclib combined with letrozole as neoadjuvant therapy in postmenopausal patients with hormone receptor-positive, HER2-negative stage II-III breast cancer: a single-arm exploratory trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-02-05.
Abstract In hematologic malignancies (HM) patients, COVID-19 infections carry a significant risk of mortality due to disease status, treatment, and other factors.The risk factors of the severity and persistence of COVID-19 infections remains unclear. A study observed adults with HM diagnosed with COVID-19 from November 2022 to February 2023. Patient blood samples yielded biochemical data, with COVID-19 confirmed via RNA or antigen testing. In the examined cohort, 133 individuals diagnosed with HM and concomitantly infected with COVID-19 were scrutinized. Using advanced multivariate logistic regression, high C-reactive protein levels (≥100mg/L) significantly increased the risk of severe/critical conditions in HM patients with COVID-19 (OR: 3.415, 95% CI: 1.294-9.012; p=0.013). Patients enduring Omicron infection beyond 30 days were deemed persistent, in contrast to those achieving infection control within this duration. The research indicated that taking ＜2 vaccine doses (OR: 0.202, 95% CI: 0.048-0.857; p=0.030), having low IgG levels (＜1000 mg/dl) (OR: 0.129, 95% CI: 0.027-0.607; p=0.010), and increased interleukin-6 levels (≥12pg/ml) (OR: 5.098, 95% CI: 1.118-23.243; p=0.035) were key indicators of ongoing infection. A significant difference in survival rates was observed between patients with persistent and non-persistent infections, with the latter showing better survival outcomes (P<0.001). In conclusion, increased C-reactive protein levels had a higher likelihood of severe health outcomes for HM patients with COVID-19 infection. Persistent infections tended to be more prevalent in those with lower vaccine dosages, diminished IgG levels, and escalated interleukin-6 levels.
Molecular-clinical prognostic models for Myelodysplastic syndromes (MDS) offer more accurate prognosis predictions, yet existing models often overlook the heterogeneity of mutational profiles against the cytogenetic background. Moreover, how to apply these models in regions where large panel NGS is unaffordable remains a significant challenge to be addressed. A total of 237 NK MDS patients from our center were used as the training set to screen for key variables and develop a prognostic model with overall survival (OS) as the endpoint. The C-index was used as the main evaluation metric to assess the model's performance. The IWG-PM cohort (n = 691) was used as an external independent validation set to evaluate the generalizability of the model. We developed a seven-parameter molecular-clinical prognostic model, the Molecular Prognostic Scoring System for NK MDS (NK-PSS-M), which only incorporates three gene mutations as parameters. The NK-PSS-M can reliably predict OS and leukemia-free survival (LFS). The performance of NK-PSS-M was comparable to that of the Molecular International Prognostic Scoring System (IPSS-M), and it significantly outperformed the Revised International Prognostic Scoring System for MDS (IPSS-R). The NK-PSS-M model improved the risk stratification of non-molecular models and provided a reliable alternative to the IPSS-M. This strategy provides insights into how resource-scarce regions can apply molecular-clinical models.
Abstract Aim The aim of this study was to evaluate the clinical and molecular characteristics of myelodysplastic syndrome (MDS) patients with monosomal karyotype (MK). Methods Eighty MDS patients with MK diagnosed between January 2010 and December 2018 were included in the retrospective study. Seventy‐three had complex karyotype (CK) and 46 had very CK (vCK, ≥ 5 abnormalities). Clinical information was collected, and a panel of 37 genes, on which mutations have been previously reported to be associated with MDS patients, was analyzed by next‐generation sequencing. Genetic and biological features and their association with survival were evaluated. Results Monosomy 5, 7, and 17 were the most frequent and mainly occurred in patients with vCK. While median overall survival (OS) for all patients was 12.8 months with 95% CI 9.1‐16.5, patients with vCK had shorter OS (8.4 months with 95% CI 3.9‐12.8) than those with non‐vCK (16.1 months with 95% CI 11.5‐20.8) ( P = .02). At least one gene mutation was detected in 76 patients (95%), TP53 mutations were detected in 57 patients, and their median OS was significantly shorter than those without TP53 mutations (9.5 months with 95% CI 7.5‐11.5 vs 26.1 months with 95% CI 8.0‐44.2, P < .01). In 34 patients who received treatment with decitabine, 25 with TP53 mutations had higher overall response rate than those with wild‐type TP53 (60% vs 22.2%, P = .03). However, OS was still significantly shorter in those with TP53 mutations (10.1 vs 26.1 months, P = .03). Multivariate analysis confirmed that TP53 mutations was an independent poor prognostic factor on OS. Conclusions CK and vCK overlap in most of the MDS patients with MK. TP53 mutations occur more frequently in MDS patients with vCK, and both TP53 mutations and vCK are adverse prognostic factors.
Abstract Background Trisomy 8 positivity myelodysplastic syndrome with Behçet's disease is rare. Isolated trisomy 8 is a frequent cytogenetic abnormality in the MDS, but the characteristic of trisomy 8 and the association between trisomy 8 positivity myelodysplastic syndrome and Behçet's disease is unclear. Case presentation Here, we reported a 63‐year‐old man, who presented with fever, abdominal pain and hematochezia. Imaging studies revealed bowel wall thickening and mural hyperenhancement of terminal ileum and cecum. Colonoscopy found multiple round ulcers in terminal ileum, ileocecal valve and multiple yellow dotted pseudomembranous attachments throughout the colon. Capsule endoscopy also revealed multiple irregular ulcers in lower ileum. Serum C-reactive protein levels and fecal calprotectin were abnormally high. The clostridium difficile toxin A and B was positive. However, the patient's intestinal ulcers did not resolve after two weeks course of vancomycin. Considered that the patient was diagnosed as MDS-RAEB2 with a karyotype of 47 XX, + 8. And detailed inquiry of medical history revealed epifolliculitis and frequently recurrent oral ulcers 2 months before admission. A diagnosis of trisomy 8 positivity MDS with BD was made. Then he received glucocorticoid along with the 5th course of azacytidine. The follow-up endoscopy showed significantly improved intestinal ulcer 2 months after treatment. we report a rare disease and provide the diagnose and treatment ideas. Conclusions We highlight the challenges and the process of thinking about of the diagnosis. This may provide a new idea for the diagnosis of intestinal ulcers.
Abstract Common variable immunodeficiency (CVID) was a kind of primary immunodeficiency disorders with heterogeneous phenotype and genotype. Lipopolysaccharide-responsive and beige-like anchor (LRBA) mutation was identified as disease associated in CVID, advanced genetic method will help to detect atypical cases. We report a case of adult patient manifested as hemophagocytic lymphohistiocytosis (HLH), bone marrow examination suggested prosperity to MDS, manifested as increased immature myeloid cells and dysplastic hematopoiesis. Whole exome sequencing (WES) identified a novel heterogeneous c.1876T > C (p.W626R) mutation in LRBA and four somatic mutations: ASXL1 (c.1967dupA); PTPN11 (c.226G > A), U2AF1 (c.101C > T and c.470A > G), among which ASXL1 was a high-risk marker of clonal hematopoiesis. Combined with her recurrent severe infections and immune abnormalities such as hypoimmunoglobulinemia, the patient was diagnosed with CVID. Subsequent hematopoietic stem cell transplantation saved her from severe cytopenia and immune deficiency. This case report highlights the great promise of utilization of WES for diagnosing rare disease with atypical manifestations and guiding further treatment.
Purpose: To explore the efficacy and safety of lower-dose decitabine in patients with lower-risk MDS, a prospective multicenter phase II study was conducted to compare decitabine with the best supportive care (BSC).Methods: Patients diagnosed with lower-risk MDS from September 2013 to August 2018 were assigned to the decitabine group or the BSC group.Decitabine (12 mg/m 2 /day) was administered over 1 hour/day for 5 consecutive days in a 4-week cycle.BSC, including growth factors, transfusion, thalidomide, lenalidomide, and immunosuppressive agents were given consecutively.The endpoints included the proportion of patients who achieved overall response (OR) in the first 2 or 3 courses, event-free survival (EFS), and overall survival (OS).Results: A total of recruited 82 patients were analyzed.In the decitabine group, 65.9% (27/41) achieved OR after 2 or 3 cycles of treatment, compared with 22.0% (9/41) in the BSC group (p <0.01).Besides, 44.0% (11/25) in the decitabine group became independent of RBC/Platelets transfusion, compared with 27.8% (5/18) in the BSC group.Patients with gene mutation and treated with decitabine achieved a higher OR rate, compared with those without gene mutation [72.0%(18/25) vs 11.5% (3/26), p <0.01].There was no significant difference in the median EFS between the decitabine and BSC groups (20.6 vs 14.3 months respectively, p = 0.665).In the decitabine group, the most significant adverse events were infections of any grades or neutropenic fever (46.3%, 19/41) and one patient (4.2%) died of acute cerebral infarction within 6 weeks of treatment.Conclusion: Lower-dose decitabine demonstrated promising clinical response with acceptable toxicity profiles in patients with low-and intermediate 1-risk MDS.A higher response rate to decitabine was observed in patients with mutated genes.Therefore, lower-dose decitabine can be advocated for patients with low-risk MDS and mutated genes.
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