Background In this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation. Methods This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein ≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg–800 mg (depending on weight) given intravenously. A second dose could be given 12–24 h later if the patient's condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov ( NCT04381936 ). Findings Between April 23, 2020, and Jan 24, 2021, 4116 adults of 21 550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76–0·94; p=0·0028). Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12–1·33; p<0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; risk ratio 0·84; 95% CI 0·77–0·92; p<0·0001). Interpretation In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids. Funding UK Research and Innovation (Medical Research Council) and National Institute of Health Research.

The TEL (ETV6)؊AML1 (CBFA2) gene fusion is the most common reciprocal chromosomal rearrangement in childhood cancer occurring in Ϸ25% of the most predominant subtype of leukemia-common acute lymphoblastic leukemia. The TEL-AML1 genomic sequence has been characterized in a pair of monozygotic twins diagnosed at ages 3 years, 6 months and 4 years, 10 months with common acute lymphoblastic leukemia. The twin leukemic DNA shared the same unique (or clonotypic) but nonconstitutive TEL-AML1 fusion sequence. The most plausible explanation for this finding is a single cell origin of the TEL-AML fusion in one fetus in utero, probably as a leukemia-initiating mutation, followed by intraplacental metastasis of clonal progeny to the other twin. Clonal identity is further supported by the finding that the leukemic cells in the two twins shared an identical rearranged IGH allele. These data have implications for the etiology and natural history of childhood leukemia.An extraordinary diversity of chromosomal molecular abnormalities has been identified in hematopoietic malignancies (1, 2). Among the most prominent are reciprocal chromosomal translocations that produce, via genetic recombination, inframe fusion genes and hybrid proteins (3, 4). Although details of the mechanisms involved remain to be elucidated, many of these genes encode transcription factors; their novel products are thought to endow clonal advantage via the imposition of an altered pattern of gene regulation (3, 4). One of the most frequent gene fusions so far described is that between TEL (or ETV6) and AML1 (or CBFA2). This rearrangement, although cryptic at the level of chromosome karyotype, occurs in approximately 25% of the predominant subtype of pediatric cancer and leukemia-common acute lymphoblastic leukemia (cALL)-in children diagnosed between the ages of 2 and 10 years (5, 6). The translocation t(12;21)(p13;q22) in ALL consistently involves the fusion of the protein dimerization encoding 5Ј region of the ETS-like gene TEL with almost the entire AML1 gene including its DNA binding region (with homology to Drosophila runt) and transactivation domain (reviewed in ref. 5). The chromosome 12 breakpoints cluster within a single intron of the TEL gene whereas AML1 breaks occur within the large and currently unsized first two introns of the AML1 gene on chromosome 21 (5-7). As with other fusion genes in leukemia, each patient's intronic breakpoints and subsequent fusion sequence are unique, providing a stable genomic marker of the derivative clone of cells. In the context of the etiology and natural history of childhood ALL, a key issue is when and how the TEL-AML1 fusion gene is generated and whether this is an early or initiating event. We report here a molecular analysis of the genomic fusion region of TEL-AML1 in the unusual situation of concordant leukemia in monozygotic twins. This analysis provides unequivocal evidence that this genetic lesion can be acquired during fetal hematopoiesis in utero.

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