AUDIENCE: Hematology, Family Medicine
KEY FINDINGS: D-dimer levels at ALL diagnosis are associated with venous or arterial thrombosis at 100 days. Future studies should include D-dimer collated with other known risk factors to build a risk assessment model for thrombosis in patients with newly diagnosed ALL.
BACKGROUND: Patients with acute lymphoblastic leukemia (ALL) are at increased risk of thrombotic and/or bleeding events during early chemotherapy, especially when receiving asparaginase.
DETAILS: D-dimer is a marker of fibrinolysis that has been associated with thrombotic risk in solid cancers and acute myeloid leukemia; however, to date, no ALL-based study has assessed D-dimer level and risk for thrombosis. Sought to examine D-dimer as a biomarker for risk of thrombosis or bleeding during ALL treatment in a retrospective cohort study at The University of Chicago. Identified 61 consecutive adult patients with ALL, gathering demographic characteristics, treatment regimens, initial biomarkers including D-dimer, and assessing occurrence of venous or arterial thrombosis and bleeding in the first 100 days after diagnosis (index). The 100-day cumulative incidence (95% confidence interval [CI]) of venous or arterial thrombosis in patients with high D-dimer (>=4 µg/mL) was 52.9% (95% CI, 26.4-73.8) compared with 13.8% (95% CI, 5.5-25.7) in patients with low to moderate D-dimer (<4 µg/mL), corresponding with a hazard ratio of 5.04 (95% CI, 1.79-14.22). When testing for potential confounders in a series of bivariate logistic regression models, the association between D-dimer and thrombosis remained after adjusting for body mass index, age, sex, asparaginase treatment, disseminated intravascular coagulation score, initial platelet level, and ALL phenotype.
Copyright © The American Society of Hematology. All rights reserved.
Source: Anderson, D. R., Stock, W., Karrison, T. G., et al. (2022). D-Dimer and Risk for Thrombosis In Adults with Newly Diagnosed Acute Lymphoblastic Leukemia. Blood Adv. 2022; 6(17): 5146-5151. Published: September 13, 2022. DOI: 10.1182/bloodadvances.2022007699.
A Nationwide Emulation Trial
AUDIENCE: Internal Medicine, Oncology, Ob/Gyn
KEY FINDINGS: Continuation of anti-TNF after 24 weeks of pregnancy appears beneficial regarding IBD activity and prematurity, while not affecting neonatal outcomes and serious infections in the offspring.
BACKGROUND: Continuation of biologics for inflammatory disorders during pregnancy is still a difficult decision. Many women with inflammatory bowel diseases (IBDs) stop anti-tumor necrosis factor (anti-TNF) treatment after 24 weeks.
DETAILS: Occurrence of maternal IBD relapse up to 6 months after pregnancy, adverse pregnancy outcomes, and serious infections in the offspring during the first 5 years of life was compared according to anti-TNF continuation after 24 weeks of pregnancy using inverse probability-weighted marginal models. A total of 5293 pregnancies were included; among them, anti-TNF treatment was discontinued before 24 weeks for 2890 and continued beyond 24 weeks for 2403. Continuation of anti-TNF was associated with decreased frequencies of maternal IBD relapse (35.8% vs. 39.0%; adjusted risk ratio [aRR], 0.93 [95% CI, 0.86 to 0.99]) and prematurity (7.6% vs. 8.9%; aRR, 0.82 [CI, 0.68 to 0.99]). No difference according to anti-TNF continuation was found regarding stillbirths (0.4% vs. 0.2%; aRR, 2.16 [CI, 0.64 to 7.81]), small weight for gestational age births (13.1% vs. 12.9%; aRR, 1.01 [CI, 0.88 to 1.17]), and serious infections in the offspring (54.2 vs. 50.2 per 1000 person-years; adjusted hazard ratio, 1.08 [CI, 0.94 to 1.25]).
Copyright © American College of Physicians. All Rights Reserved.
Source: Meyer, A., Neumann, A., Drouin, J., et al. (2022). Benefits and Risks Associated With Continuation of Anti-Tumor Necrosis Factor After 24 Weeks of Pregnancy in Women With Inflammatory Bowel Disease. Annals of Internal Medicine. Published: September 27, 2022. DOI: 10.7326/M22-0819.
AUDIENCE: Gastroenterology, Oncology, Internal Medicine
KEY FINDINGS: The large-sample multiomics data suggest that altered microbiome–metabolome interplay helps explain the pathogenesis of EO-CRC and LO-CRC. The potential of microbiome-derived biomarkers as promising non-invasive tools could be used for the accurate detection and distinction of individuals with EO-CRC.
BACKGROUND: The incidence of early-onset colorectal cancer (EO-CRC) is steadily increasing. Here, we aimed to characterise the interactions between gut microbiome, metabolites and microbial enzymes in EO-CRC patients and evaluate their potential as non-invasive biomarkers for EO-CRC.
DETAILS: Metagenomic and metabolomic analyses was performed, identified multiomics markers and constructed CRC classifiers for the discovery cohort with 130 late-onset CRC (LO-CRC), 114 EO-CRC subjects and age-matched healthy controls (97 LO-Control and 100 EO-Control). An independent cohort of 38 LO-CRC, 24 EO-CRC, 22 LO-Controls and 24 EO-Controls was analysed to validate the results. Compared with controls, reduced alpha-diversity was apparent in both, LO-CRC and EO-CRC subjects. Although common variations existed, integrative analyses identified distinct microbiome–metabolome associations in LO-CRC and EO-CRC. Fusobacterium nucleatum enrichment and short-chain fatty acid depletion, including reduced microbial GABA biosynthesis and a shift in acetate/acetaldehyde metabolism towards acetyl-CoA production characterises LO-CRC. In comparison, multiomics signatures of EO-CRC tended to be associated with enriched Flavonifractor plauti and increased tryptophan, bile acid and choline metabolism. Notably, elevated red meat intake-related species, choline metabolites and KEGG orthology (KO) pldB and cbh gene axis may be potential tumour stimulators in EO-CRC. The predictive model based on metagenomic, metabolomic and KO gene markers achieved a powerful classification performance for distinguishing EO-CRC from controls.
Copyright © BMJ Publishing Group Ltd & British Society of Gastroenterology. All rights reserved.
Source: Kong C., Liang L., Liu G., et al. (2022). Integrated Metagenomic and Metabolomic Analysis Reveals Distinct Gut-Microbiome-Derived Phenotypes In Early-Onset Colorectal Cancer. Gut. Published: August 11, 2022. DOI: 10.1136/gutjnl-2022-327156.
Actionable Tumor Alterations and Treatment Protocol Enrollment of Pediatric and Young Adult Patients With Refractory Cancers in the National Cancer Institute-Children's Oncology Group Pediatric MATCH Trial.
AUDIENCE: Oncology, Pediatric
KEY FINDINGS: The Pediatric MATCH trial has proven the feasibility of a nationwide screening Protocol for identification of actionable genetic alterations and assignment of pediatric and young adult patients with refractory cancers to trials of molecularly targeted therapies. These data support the early use of tumor molecular screening for childhood patients with cancer whose tumors have not responded to standard treatments.
BACKGROUND: The National Cancer Institute-Children's Oncology Group Pediatric MATCH trial aimed to facilitate evaluation of molecular-targeted therapies in biomarker-selected cohorts of childhood and young adult patients with cancer by screening tumors for actionable alterations.
DETAILS: Tumors from patients age 1-21 years with refractory solid tumors, lymphomas, or histiocytic disorders were subjected to cancer gene panel sequencing and limited immunohistochemistry to identify actionable alterations for assignment to phase II treatment arms. The rates of treatment arm assignment and enrollment were compared between clinical and demographic groups. Testing was completed for 94.7% of tumors submitted. Actionable alterations were detected in 31.5% of the first 1,000 tumors screened, with treatment arm assignment and enrollment occurring in 28.4% and 13.1% of patients, respectively. Assignment rates varied by tumor histology and were higher for patients with CNS tumors or enrolled at Pediatric Early Phase Clinical Trials Network sites. A reported history of prior clinical molecular testing was associated with higher assignment and enrollment rates. Actionable alterations in the mitogen-activated protein kinase signaling pathway were most frequent (11.2%). The most common reasons provided for not enrolling on treatment arms were patients receiving other treatment or poor clinical status.
Copyright © American Society of Clinical Oncology. All rights reserved.
Source: Parsons, D. W., Janeway, K. A., Patton, D. R., et al. (2022). Actionable Tumor Alterations and Treatment Protocol Enrollment of Pediatric and Young Adult Patients With Refractory Cancers in the National Cancer Institute-Children's Oncology Group Pediatric MATCH Trial. Journal of Clinical Oncology. 2022; 40(20): 2224-2234. Published: July 10, 2022. DOI: 10.1200/JCO.21.02838.
AUDIENCE: Hematology, Ob/Gyn, Family Medicine
KEY FINDINGS: Despite these limitations, this pilot study suggests that metformin is safe and well tolerated in FA and may afford clinical benefit in a subset of patients. Development of a subsequent multicenter efficacy study may provide greater clarity regarding metformin's role in the treatment of FA. Given the historical experience of treating FA-associated cytopenias with androgens, combination treatment of androgens with metformin could also be explored. Future efficacy end points should study the utility of metformin as both a prophylactic agent aimed at curtailing progression of bone marrow failure and as a chemo preventive agent aimed at reducing cancer risk in FA.
BACKGROUND: Fanconi anemia (FA), a genetic DNA repair disorder characterized by marrow failure and cancer susceptibility. In FA mice, metformin improves blood counts and delays tumor development.
DETAILS: A single institution study of metformin in nondiabetic patients with FA was conducted to determine feasibility and tolerability of metformin treatment and to assess for improvement in blood counts. Fourteen of 15 patients with at least 1 cytopenia (hemoglobin < 10 g/dL; platelet count < 100,000 cells/µL; or an absolute neutrophil count < 1000 cells/µL) were eligible to receive metformin for 6 months. Median patient age was 9.4 years (range 6.0-26.5 ). Thirteen of 14 subjects (93%) tolerated maximal dosing for age; 1 subject had dose reduction for grade 2 gastrointestinal symptoms. No subjects developed hypoglycemia or metabolic acidosis. No subjects had dose interruptions caused by toxicity, and no grade 3 or higher adverse events attributed to metformin were observed. Hematologic response based on modified Myelodysplastic Syndrome International Working Group criteria was observed in 4 of 13 evaluable patients (30.8%; 90% confidence interval, 11.3-57.3). Median time to response was 84.5 days (range 71-128 days). Responses were noted in neutrophils (n = 3), platelets (n = 1), and red blood cells (n = 1). No subjects met criteria for disease progression or relapse during treatment. Correlative studies explored potential mechanisms of metformin activity in FA. Plasma proteomics showed reduction in inflammatory pathways with metformin. Metformin is safe and tolerable in nondiabetic patients with FA and may provide therapeutic benefit.
Copyright © The American Society of Hematology. All rights reserved.
Source: Addo, O. W., Mei, Z., Hod, E. A., et al. (2022). Physiologically Based Serum Ferritin Thresholds for Iron Deficiency in Women of Reproductive Age Who Are Blood Donors. Blood Adv.. 2022; 6(12): 3803-3811. Published: June 28, 2022. DOI: 10.1182/bloodadvances.2021006490.
A Multicentre, Open-Label Phase 2 Trial
AUDIENCE: Family Medicine, Oncology
KEY FINDINGS: Patients aged at least 65 years, with advanced oesophageal squamous cell carcinoma might benefit from combined nivolumab and ipilimumab therapy in second-line treatment.
BACKGROUND: The overall survival of patients with advanced and refractory oesophageal squamous cell carcinoma, mostly aged 65 years and older, is poor. Treatment with PD-1 antibodies showed improved progression-free survival and overall survival. Assessed the safety and efficacy of combined nivolumab and ipilimumab therapy in this population.
DETAILS: This multicentre, open-label, phase 2 trial done in 32 sites in Germany included patients aged 65 years and older with oesophageal squamous cell carcinoma and disease progression or recurrence following first-line therapy. Patients were treated with nivolumab (240 mg fixed dose once every 2 weeks, intravenously) in the safety run-in phase and continued with nivolumab and ipilimumab (nivolumab 240 mg fixed dose once every 2 weeks and ipilimumab 1 mg/kg once every 6 weeks, intravenously). The primary endpoint was overall survival, which was compared with a historical cohort receiving standard chemotherapy in the intention-to-treat population. Between March 2, 2018, and Aug 20, 2020, we screened 75 patients with advanced oesophageal squamous cell carcinoma. We enrolled 66 patients (50 [76%] men and 16 [24%] women; median age 70.5 years [IQR 67.0-76.0]), 44 (67%) of whom received combined nivolumab and ipilimumab therapy and 22 (33%) received nivolumab alone. Median overall survival time at the prespecified data cutoff was 7.2 months (95% CI 5.7-12.4) and significantly higher than in a historical cohort receiving standard chemotherapy (p=0.0063). The most common treatment-related adverse events were fatigue (12 [29%] of 42), nausea (11 [26%]), and diarrhoea (ten [24%]). Grade 3-5 treatment-related adverse events occurred in 13 (20%) of 66 patients. Treatment-related death occurred in one patient with bronchiolitis obliterans while on nivolumab and ipilimumab treatment.
Copyright © Elsevier Ltd. All rights reserved.
Source: Ebert, M. P., Meindl-Beinker, N. M., Gutting, T., et al. (2022). Second-line Therapy With Nivolumab Plus Ipilimumab For Older Patients With Oesophageal Squamous Cell Cancer (RAMONA): A Multicentre, Open-Label Phase 2 Trial. The Lancet. 2022; 3(6): 417-427. Published: June 1, 2022. DOI: 10.1016/S2666-7568(22)00116-7.