[Posted 11/Sep/2023]

AUDIENCE: Oncology, Cardiology

KEY FINDINGS: The present study demonstrates that the use of metformin in patients with cancer is associated with a decreased incidence of HF in the year following anthracycline chemotherapy. The findings are consistent with previous experimental studies and provide impetus to develop further randomized controlled trials investigating the benefits of metformin in anthracycline-induced cardiotoxicity.

BACKGROUND: The prevention of heart failure (HF) is an important issue in patients treated with anthracyclines. Metformin, widely used to treat diabetes mellitus (DM), protects from anthracycline-induced cardiotoxicity in vitro and in animal models. The aim of the study was to test the association of metformin with the occurrence of symptomatic HF in patients with DM receiving anthracyclines.

DETAILS: A total of 561 patients with DM received new anthracycline therapy between 2008 and 2021 in a tertiary care center; propensity score matching was used to compare patients with or without metformin treatment. The primary outcome was new onset symptomatic HF occurring within 1 year of the initiation of anthracyclines. A total of 315 patients (65 ± 11 years of age, 33.7% male) were included. Patients with and without metformin were well matched for age, sex, type of cancer, medications, and cardiovascular risk factors. Six patients treated with metformin and 17 matched patients developed HF within 1 year of anthracycline initiation. The incidence of HF in patients treated with metformin was lower than patients without metformin within 1 year after anthracyclines (cumulative incidence: 3.6% vs 10.5%; P = 0.022; HR: 0.35; 95% CI: 0.14-0.90; P = 0.029). The use of metformin (HR: 0.71; 95% CI: 0.50-1.00; P = 0.049), was also associated with lower mortality.

Copyright © American College of Cardiology Foundation. All rights reserved.

Source: Onoue, T., Kang, Y., Lefebvre, B., et al. (2023). The Association of Metformin With Heart Failure in Patients With Diabetes Mellitus Receiving Anthracycline Chemotherapy. J Am Coll Cardiol CardioOnc. Published: August 29, 2023. DOI: 10.1016/j.jaccao.2023.05.013.

[Posted 2/Sep/2024]

AUDIENCE: Hematology, Family Medicine

KEY FINDINGS: An alemtuzumab-based regimen successfully reduced the rate and severity of cGVHD after RIC allo-HSCT and resulted in a distinct immunomodulatory profile, which may have reduced cGVHD incidence and severity. However, increased infections and relapse resulted in a lack of survival benefit after long-term follow-up.

BACKGROUND: Chronic graft-versus-host disease (cGVHD) remains a significant problem for patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although in vivo lymphodepletion for cGVHD prophylaxis has been explored in the myeloablative setting, its effects after reduced-intensity conditioning (RIC) are not well described.

DETAILS: Patients (N = 83) with hematologic malignancies underwent targeted lymphodepletion chemotherapy followed by a RIC allo-HSCT using peripheral blood stem cells from unrelated donors. Patients were randomized to 2 GVHD prophylaxis arms: alemtuzumab and cyclosporine (AC; n = 44) or tacrolimus, methotrexate, and sirolimus (TMS; n = 39), with the primary end point of cumulative incidence of severe cGVHD. The incidence of severe cGVHD was lower with AC vs TMS prophylaxis at 1- and 5-years (0% vs 10.3% and 4.5% vs 28.5%; overall, P = .0002), as well as any grade (P = .003) and moderate-severe (P < .0001) cGVHD. AC was associated with higher rates of grade 3 to 4 infections (P = .02) and relapse (52% vs 21%; P = .003) with no difference in 5-year GVHD-free-, relapse-free-, or overall survival. AC severely depleted naïve T-cell reconstitution, resulting in reduced T-cell receptor repertoire diversity, smaller populations of CD4Treg and CD8Tscm, but a higher ratio of Treg to naïve T-cells at 6 months.

Copyright © The American Society of Hematology. All rights reserved.

Source: Holtzman, N. G., Curtis, L. M., Salit, R. B., et al. (2024). High-Dose Alemtuzumab and Cyclosporine vs Tacrolimus, Methotrexate, and Sirolimus for Chronic Graft-Versus-Host Disease Prevention. Blood Adv.. 2024; 8(16): 4294-4310. Published: August, 2024. DOI: 10.1182/bloodadvances.2023010973.

Results of a Large International Retrospective Cohort Study

[Posted 23/Aug/2024]

AUDIENCE: Oncology, Ob/Gyn

KEY FINDINGS: In young patients with HER2-negative BC and germline BRCA1/2 PVs, HER2-low disease was less frequent than expected and more frequently linked to BRCA2 PVs and associated with luminal-like disease. HER2-low status was associated with a modestly improved prognosis.

BACKGROUND: Breast cancer (BC) in women aged <=40 years carrying germline pathogenetic variants (PVs) in BRCA1/2 genes is infrequent but often associated with aggressive features. Human epidermal growth factor receptor 2 (HER2)-low-expressing BC has recently emerged as a novel therapeutic target but has not been characterized in this rare patient subset.

DETAILS: Women aged <=40 years with newly diagnosed early-stage HER2-negative BC (HER2-0 and HER2-low) and germline BRCA1/2 PVs from 78 health care centers worldwide were retrospectively included. Chi-square test and Student t-test were used to describe variable distribution between HER2-0 and HER2-low. Associations with HER2-low status were assessed with logistic regression. Kaplan–Meier method and Cox regression analysis were used to assess disease-free survival (DFS) and overall survival. Statistical significance was considered for p <= .05. Of 3547 included patients, 32.3% had HER2-low BC, representing 46.3% of hormone receptor–positive and 21.3% of triple-negative (TN) tumors. HER2-low vs. HER2-0 BC were more often of grade 1/2 (p < .001), hormone receptor–positive (p .001), and node-positive (p = .003). BRCA2 PVs were more often associated with HER2-low than BRCA1 PVs (p < .001). HER2-low versus HER2-0 showed better DFS (hazard ratio [HR], 0.86; 95% CI, 0.76–0.97) in the overall population and more favorable DFS (HR, 0.78; 95% CI, 0.64–0.95) and overall survival (HR, 0.65; 95% CI, 0.46–0.93) in the TN subgroup. Luminal A–like tumors in HER2-low (p = .014) and TN and luminal A-like in HER2-0 (p = .019) showed the worst DFS.

Copyright © John Wiley & Sons, Inc. All rights reserved.

Source: Schettini, F., Blondequx, E., Molinelli, C., et al. (2024). Characterization of HER2-Low Breast Cancer in Young Women With Germline BRCA1/2 Pathogenetic Variants: Results of a Large International Retrospective Cohort Study. Cancer. 2024; 130(16): 2746-2762. Published: August 15, 2024. DOI: 10.1002/cncr.35323.

[Posted 12/Aug/2024]

AUDIENCE: Gastroenterology, Oncology, Internal Medicine

KEY FINDINGS: Cabozantinib demonstrated efficacy in patients who had received prior ICI regimens; survival data for second-line cabozantinib following first-line ICI regimens provide a reference for future clinical trial design. The number of prior lines of treatment may be considered a stratification factor in randomised studies.

BACKGROUND: Prospective data on treatment after immune checkpoint inhibitor (ICI) therapy in hepatocellular carcinoma (HCC) are lacking. Authors conducted a phase II multicentre study on cabozantinib after ICI treatment in HCC.

DETAILS: This is an investigator-initiated, single-arm, clinical trial involving academic centres in Hong Kong and Korea. Key eligibility criteria included diagnosis of HCC, refractoriness to prior ICI-based treatment, and Child-Pugh A liver function. A maximum of two prior lines of therapy were allowed. All patients were commenced on cabozantinib at 60 mg/day. The primary endpoint was progression-free survival (PFS). Forty-seven patients were recruited from Oct 2020 to May 2022; 27 and 20 patients had received one and two prior therapies, respectively. Median follow-up was 11.2 months. The median PFS was 4.1 months (95% CI 3.3-5.3). The median overall survival (OS) was 9.9 months (95% CI 7.3-14.4), and the 1-year OS rate was 45.3%. Partial response and stable disease occurred in 3 (6.4%) and 36 (76.6%) patients, respectively. When used as a second-line treatment (n = 27), cabozantinib was associated with a median PFS and OS of 4.3 (95% CI 3.3-6.7) and 14.3 (95% CI 8.9-NR) months, respectively. The corresponding median PFS and OS were 4.3 (95% CI 3.3-11.0) and 14.3 (95% CI 9.0-NR) months, respectively, for those receiving ICI-based regimens with proven benefits (n = 17). The most common grade 3-4 treatment-related adverse event was thrombocytopenia (6.4%). The median dose of cabozantinib was 40 mg/day. The number of prior therapies was an independent prognosticator (one vs. two; hazard ratio = 0.37; p = 0.03). Prospective data on systemic treatment following prior immune checkpoint inhibitor (ICI) therapy for hepatocellular carcinoma (HCC) are lacking. This phase II clinical trial provides efficacy and safety data on cabozantinib in patients who had received prior ICI-based treatment. Exploratory analyses showed that the performance of cabozantinib differed significantly when used as a second- or third-line treatment. The above data could be used as a reference for clinical practice and the design of future clinical trials on subsequent treatment lines following ICIs.

Copyright © Elsevier Inc. All rights reserved.

Source: Chan, S. L., Ryoo, B., Mo, F., et al. (2024). Multicentre Phase II Trial of Cabozantinib in Patients With Hepatocellular Carcinoma After Immune Checkpoint Inhibitor Treatment. Journal of Hepatology. 2024; 81(2): 258-264. Published: August, 2024. DOI: 10.1016/j.jhep.2024.03.033.

Pooled Analysis of 5 Clinical Trials

[Posted 13/Jul/2024]

AUDIENCE: Hematology, Family Medicine

KEY FINDINGS: The safety profile of acalabrutinib-based therapy in this population was consistent with the known safety profile of acalabrutinib in a broad CLL population. The analysis demonstrates long-term benefit of acalabrutinib-based regimens in patients with higher-risk CLL, regardless of line of therapy.

BACKGROUND: Before targeted therapies, patients with higher-risk chronic lymphocytic leukemia (CLL), defined as del(17p) and/or TP53 mutation (TP53m), unmutated immunoglobulin heavy chain variable region genes (uIGHV), or complex karyotype (CK), had poorer prognosis with chemoimmunotherapy.

DETAILS: Bruton tyrosine kinase inhibitors (BTKis) have demonstrated benefit in higher-risk patient populations with CLL in individual trials. To better understand the impact of the second-generation BTKi acalabrutinib, authors pooled data from 5 prospective clinical studies of acalabrutinib as monotherapy or in combination with obinutuzumab (ACE-CL-001, ACE-CL-003, ELEVATE-TN, ELEVATE-RR, and ASCEND) in patients with higher-risk CLL in treatment-naive (TN) or relapsed/refractory (R/R) cohorts. A total of 808 patients were included (TN cohort, n = 320; R/R cohort, n = 488). Median follow-up was 59.1 months (TN cohort) and 44.3 months (R/R cohort); 51.3% and 26.8% of patients in the TN and R/R cohorts, respectively, remained on treatment at last follow-up. In the del(17p)/TP53m, uIGHV, and CK subgroups in the TN cohort, median progression-free survival (PFS) and median overall survival (OS) were not reached (NR). In the del(17p)/TP53m, uIGHV, and CK subgroups in the R/R cohort, median PFS was 38.6 months, 46.9 months, and 38.6 months, respectively, and median OS was 60.6 months, NR, and NR, respectively.

Copyright © The American Society of Hematology. All rights reserved.

Source: Davids, M. S., Sharman, J. P., Ghia, P., et al. (2024). Acalabrutinib-Based Regimens in Frontline or Relapsed/Refractory Higher-Risk CLL: Pooled Analysis of 5 Clinical Trials. Blood Advances. 2024; 8(13): 3345-3359. Published: July, 2024. DOI: 10.1182/bloodadvances.2023011307.

[Posted 11/Jul/2024]

AUDIENCE: Gastroenterology, Oncology, Internal Medicine

KEY FINDINGS: While identifying GIST or leiomyoma, the performance of CNN model was robust, which is highlighting its promising role in supporting less-experienced endoscopists and reducing interobserver agreement.

BACKGROUND: Gastrointestinal stromal tumors (GISTs) and leiomyomas are the most common submucosal tumors of the upper digestive tract, and the diagnosis of the tumors is essential for their treatment and prognosis. However, the ability of endoscopic ultrasonography (EUS) which could correctly identify the tumor types is limited and closely related to the knowledge, operational level, and experience of the endoscopists. Therefore, the convolutional neural network (CNN) is used to assist endoscopists in determining GISTs or leiomyomas with EUS.

DETAILS: A model based on CNN was constructed according to GoogLeNet architecture to distinguish GISTs or leiomyomas. All EUS images collected from this study were randomly sampled and divided into training set (n=411) and testing set (n=103) in a ratio of 4:1. The CNN model was trained by EUS images from the training set, and the testing set was utilized to evaluate the performance of the CNN model. In addition, there were some comparisons between endoscopists and CNN models. It was shown that the sensitivity and specificity in identifying leiomyoma were 95.92%, 94.44%, sensitivity and specificity in identifying GIST were 94.44%, 95.92%, and accuracy in total was 95.15% of the CNN model. It indicates that the diagnostic accuracy of the CNN model is equivalent to skilled endoscopists, or even higher than them.

Copyright © Wolters Kluwer Health, Inc. All rights reserved.

Source: Liu, J., Huang, J., Song, Y., et al. (2024). Differentiating Gastrointestinal Stromal Tumors From Leiomyomas of Upper Digestive Tract Using Convolutional Neural Network Model by Endoscopic Ultrasonography. Journal of Clinical Gastroenterology. 2024; 58(6): 574-579. Published: July, 2024. DOI: 10.1097/MCG.0000000000001907.