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IntroductionWe have reported that thiopurine induced myelosuppression is associated with variants in NUDT15 in patients with IBD of European ancestry. However, because we used a retrospective phenotype-first approach our findings were limited by ascertainment and recall bias. Before clinical implementation, further work is needed to define the penetrance, expressivity, and variant pathogenicity of NUDT15 carriage. We used a reverse-phenotyping retrospective cohort design to investigate the six-month risk of myelosuppression in patients with NUDT15 variants.MethodsWe screened whole exome data and identified 451/23082 patients with a loss of function NUDT15 variant (*2, *3, *4, *5, *6 &*9) from the IBD BioResource. We matched these patients, based on ethnicity, to 916 participants without NUDT15 or TPMT variants who were treated with a thiopurine.Myelosuppression was defined as a white cell count (WCC) <3.5x109/L or a neutrophil count <2.0x109/L that occurred within six months of achieving the maximum thiopurine dose, or in the absence of blood test results, a decision to dose reduce or withdraw the thiopurine due to myelosuppression. Severe myelosuppression was defined as a WCC <2.5x109/L or neutrophil count <1.0x109/L and a decision to either reduce or withdraw the thiopurine.ResultsNUDT15 variants were more commonly seen in individuals of East and South Asian ancestry (East Asian 21.7% [10/46], South Asian 13.6% [151/962], African 1.6% [5/322], European 1.3% [271/21304], other 6.8% [20/296], p <0.001). Overall, 239/457 patients who carried a NUDT15 variant allele were treated with a thiopurine. There were no differences in the median-weight drug-adjusted doses (1.79 mg/kg/day vs 1.87 mg/kg/day, p=0.2) amongst patients with and without NUDT15.Amongst patients with wild-type NUDT15 and TPMT 13.7% had an episode of myelosuppression, but severe myelosuppression and hospitalisations were uncommon. The time to myelosuppression was shorter in patients with NUDT15 variants. Rates of myelosuppression, severe myelosuppression, and hospitalisations were greater in patients with NUDT15 variants. Carriage of *3, *6, *9 were all associated with a shorter time to myelosuppression compared to wild-type NUDT15 (p=0.047). Carriage of *3, was associated with a shorter time to myelosuppression than *6 and *9 (p=0.032). The number needed to genotype to prevent a single case of myelosuppression in European participants was 786 (95%CI 451–3045) and in South Asians was 26 (95%CI 19–42).ConclusionAbout a third of patients in the UK who carry an NUDT15 variant have myelosuppression when treated with a thiopurine. Further work to define the cost-effectiveness of pharmacogenetic testing to prevent myelosuppression and to permit suspension of blood test monitoring in patients without a TPMT or NUDT15 variant is underway.Abstract O24 Figure 1Cumulative hazard of developing myelosuppression from the start of the thiopurine exposure to date of myelosuppression in days and the odds ratio and frequency of developing myelosuppression.[Figure omitted. See PDF]Abstract O24 Table 1NUDT15 Genotype Myelosuppression (WCC <3.5x109/L OR Neutrophil <2.0x109/L) Severe myelosuppression (WCC <2.5x109/L OR Neutrophil <1.0x109/L) Myelosuppression related hospitalisation Wild-Type 13.7% (115/840) 0.7% (6/840) 0.1% (1/840) Carriage of any NUDT variant 32.6% (78/239) OR 3.05 (2.18–4.26, p<0.001) 10.4% (25/239) OR 9.19 (3.70–26.38, p<0.001) 2.9% (7/239) OR 7.00 (1.00–142.57, p=0.09) *3 40% (54/135) OR 4.20 (2.82–6.24, p<0.001) 12.6% (17/135) OR 9.75 (3.64–29.50, p<0.001) 4.4% (6/135) OR 8.25 (1.11–172.60, p=0.07) *6 26.8% (12/56) OR 1.72 (0.85–3.25, p=0.11) 8.9% (5/56) OR 10.24 (2.44–43.60, p=0.001) 0% 0/56 - *9 25% (10/40) OR 2.10 (0.95–4.27, p=0.05) 5% (2/40) OR 4.10 (0.53–22.14, p=0.12) 2.5% (1/40) -

In this trial, progression-free survival was more than twice as high among patients with advanced melanoma who received tumor-infiltrating lymphocytes plus interleukin-2 as among those who received ipilimumab.

Treatment options for highly drug-resistant tuberculosis are limited. In this study in South Africa, a new agent, pretomanid, was combined with bedaquiline and linezolid for a 26-week course to treat extensively drug-resistant and complicated multidrug-resistant pulmonary TB. Although there were toxic effects, 90% of patients had favorable outcomes.

In 101 patients with refractory large B-cell lymphoma, anti-CD19 chimeric antigen receptor (CAR) T-cell therapy (axicabtagene ciloleucel) resulted in an overall response rate of 82%, with a 52% survival at 18 months, despite serious toxic effects.

Approved systemic treatments for malignant pleural mesothelioma (MPM) have been limited to chemotherapy regimens that have moderate survival benefit with poor outcomes. Nivolumab plus ipilimumab has shown clinical benefit in other tumour types, including first-line non-small-cell lung cancer. We hypothesised that this regimen would improve overall survival in MPM. This open-label, randomised, phase 3 study (CheckMate 743) was run at 103 hospitals across 21 countries. Eligible individuals were aged 18 years and older, with previously untreated, histologically confirmed unresectable MPM, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible participants were randomly assigned (1:1) to nivolumab (3 mg/kg intravenously once every 2 weeks) plus ipilimumab (1 mg/kg intravenously once every 6 weeks) for up to 2 years, or platinum plus pemetrexed chemotherapy (pemetrexed [500 mg/m2 intravenously] plus cisplatin [75 mg/m2 intravenously] or carboplatin [area under the concentration-time curve 5 mg/mL per min intravenously]) once every 3 weeks for up to six cycles. The primary endpoint was overall survival among all participants randomly assigned to treatment, and safety was assessed in all participants who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT02899299, and is closed to accrual. Between Nov 29, 2016, and April 28, 2018, 713 patients were enrolled, of whom 605 were randomly assigned to either nivolumab plus ipilimumab (n=303) or chemotherapy (n=302). 467 (77%) of 605 participants were male and median age was 69 years (IQR 64–75). At the prespecified interim analysis (database lock April 3, 2020; median follow-up of 29·7 months [IQR 26·7–32·9]), nivolumab plus ipilimumab significantly extended overall survival versus chemotherapy (median overall survival 18·1 months [95% CI 16·8–21·4] vs 14·1 months [12·4–16·2]; hazard ratio 0·74 [96·6% CI 0·60–0·91]; p=0·0020). 2-year overall survival rates were 41% (95% CI 35·1–46·5) in the nivolumab plus ipilimumab group and 27% (21·9–32·4) in the chemotherapy group. Grade 3–4 treatment-related adverse events were reported in 91 (30%) of 300 patients treated with nivolumab plus ipilimumab and 91 (32%) of 284 treated with chemotherapy. Three (1%) treatment-related deaths occurred in the nivolumab plus ipilimumab group (pneumonitis, encephalitis, and heart failure) and one (<1%) in the chemotherapy group (myelosuppression). Nivolumab plus ipilimumab provided significant and clinically meaningful improvements in overall survival versus standard-of-care chemotherapy, supporting the use of this first-in-class regimen that has been approved in the USA as of October, 2020, for previously untreated unresectable MPM. Bristol Myers Squibb.

A randomized trial of bedaquiline–pretomanid–linezolid for highly drug-resistant tuberculosis assessed the use of linezolid at 600 or 1200 mg for 9 or 26 weeks; the 600-mg dose for 26 weeks had a favorable profile.

The development and approval of cyclin-dependent kinase (CDK) 4 and 6 inhibitors for hormone receptor-positive and human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer represents a major milestone in cancer therapeutics. Three different oral CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, have significantly improved progression-free survival by a number of months when combined with endocrine therapy. More recently, improvement in overall survival has been reported with ribociclib and abemaciclib. The toxicity profile of all three drugs is well described and generally easily manageable with dose reductions when indicated. More myelotoxicity is observed with palbociclib and ribociclib, but more gastrointestinal toxicity is observed with abemaciclib. Emerging data is shedding light on the resistance mechanisms associated with CDK4/6 inhibitors, including cell cycle alterations and activation of upstream tyrosine kinase receptors. A number of clinical trials are exploring several important questions regarding treatment sequencing, combinatorial strategies, and the use of CDK4/6 inhibitors in the adjuvant and neoadjuvant settings, thereby further expanding and refining the clinical application of CDK4/6 inhibitors for patients with breast cancer.

In patients with midgut neuroendocrine tumors that progressed during octreotide analogue therapy, the addition of 177 Lu-Dotatate to octreotide resulted in an 18% response rate and a significantly higher rate of progression-free survival at 20 months than high-dose octreotide alone. Neuroendocrine tumors of the midgut (which is defined as the jejunoileum and the proximal colon) commonly metastasize to the mesentery, peritoneum, and liver and are frequently associated with the carcinoid syndrome. 1 , 2 Neuroendocrine tumors of the midgut represent the most common type of malignant gastrointestinal neuroendocrine tumors and are associated with 5-year survival rates of less than 50% among persons with metastatic disease. 3 , 4 First-line systemic therapy usually consists of a somatostatin analogue for control of both hormonal secretion and tumor growth. 5 – 7 With the exception of everolimus for the treatment of nonfunctional neuroendocrine tumors, 8 no standard second-line systemic treatment . . .

Patients with metastatic triple-negative breast cancer were treated with standard chemotherapy or the anti–Trop-2 antibody–drug conjugate sacituzumab govitecan. Patients receiving the drug conjugate had significantly longer progression-free and overall survival as well as more frequent myelotoxic effects and diarrhea.

Background Existing evidence indicates that germline BRCA mutation (gBRCA‐m) may increase chemotherapy sensitivity and toxicity. However, its role in chemotherapy‐induced myelosuppression (CIM) remains unclear. We conducted this study to investigate the influence of gBRCA‐m on CIM incidence and severity in patients with epithelial ovarian carcinoma (EOC). Methods Patients with EOC treated at the First Affiliated Hospital of Nanjing Medical University from January 2018 to August 2023 were classified into two groups: gBRCA‐m and gBRCA wild‐type. Chemotherapy regimen and myelosuppression data were retrospectively reviewed. Multivariate analysis assessed the association between gBRCA‐m and CIM incidence and severity in patients with EOC receiving first‐line chemotherapy. Results Sixty six (27%) of 242 included patients were gBRCA‐m carriers. The median times to myelosuppression onset and the most severe occurrence were significantly shorter for patients with gBRCA‐m (6.0 vs. 27.0 days, p < 0.001; 73.5 vs. 121.0 days, p < 0.001). Patients with gBRCA‐m had a greater likelihood of Grade IV (GIV) myelosuppression at onset (aOR = 5.585, 95% CI = 1.621–19.241). During the most severe myelosuppression, patients with gBRCA‐m experienced more pronounced decreases in white blood cells (1.83 × 109 vs. 2.33*109 cells/L, p = 0.002), neutrophils (0.73 × 109 vs. 1.08 × 109 cells/L, p = 0.001), haemoglobin levels (90.41 vs. 94.14 g/L, p = 0.017) and platelets (81.62 × 109 vs. 97.63 × 109 cells/L, p = 0.001) and were more prone to febrile GIV myelosuppression (aOR = 2.882, 95% CI = 1.071–7.754). The incidences of chemotherapy dose reduction (aOR = 4.322, 95% CI = 2.048–9.124) and delay (aOR = 6.045, 95% CI = 2.266–16.126) were significantly greater in patients with gBRCA‐m. An analysis across all chemotherapy cycles indicated that patients with gBRCA‐m had greater risks of GIII (aOR = 2.356, 95% CI = 1.770–3.137), GIV (aOR = 2.324, 95% CI = 1.685–3.207) myelosuppression and GIV myelosuppression with fever (aOR = 2.097, 95% CI = 1.077–4.083), as well as a greater incidence of chemotherapy dose reduction (aOR = 2.606, 95% CI = 1.785–3.805) and delay (aOR = 4.118, 95% CI = 2.213–7.663). Conclusions EOC patients with gBRCA‐m experienced earlier and more severe CIM, highlighting the need for careful monitoring and tailored management.