Ruxolitinib for tocilizumab‐refractory severe COVID‐19 infection

Innes, Andrew; Cook, Lucy; Marks, Sasha; Bataillard, Edward; Crossette‐Thambiah, Christina; Sivasubramaniam, Gayathiri; Apperley, Jane F.; Milojković, Dragana

doi:10.1111/bjh.16979

Cited by 37 publications

(42 citation statements)

References 9 publications

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“…Strikingly, in the latter study, tocilizumab decreases hospital-related mortality (HR: 0.64, 95%CI 0.47-0.87; p = 0.040). Conversely, reports of tocilizumab failure for COVID-19 have also been reported [28][29][30], and, in another study of 21 patients (matched to a historical control group using propensity score matching), such beneficial effect of tocilizumab was not outlined [31]. Yet, it should be emphasized that in the latter study, all patients received high-dose methylprednisolone -which might have skewed the study results-and the levels of oxygen therapy were not specified.…”

Section: Discussionmentioning

confidence: 97%

Tocilizumab for Severe Worsening COVID-19 Pneumonia: a Propensity Score Analysis

et al. 2020

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Background High levels of serum interleukin-6 (IL-6) correlate with disease severity in COVID-19. We hypothesized that tocilizumab (a recombinant humanized anti-IL-6 receptor) could improve outcomes in selected patients with severe worsening COVID-19 pneumonia and high inflammatory parameters. Methods The TOCICOVID study included a prospective cohort of patients aged 16–80 years with severe (requiring > 6 L/min of oxygen therapy to obtain Sp02 > 94%) rapidly deteriorating (increase by ≥ 3 L/min of oxygen flow within the previous 12 h) COVID-19 pneumonia with ≥ 5 days of symptoms and C-reactive protein levels > 40 mg/L. They entered a compassionate use program of treatment with intravenous tocilizumab (8 mg/kg with a maximum of 800 mg per infusion; and if needed a second infusion 24 to 72 h later). A control group was retrospectively selected with the same inclusion criteria. Outcomes were assessed at D28 using inverse probability of treatment weighted (IPTW) methodology. Results Among the 96 patients included (81% male, mean (SD) age: 60 (12.5) years), underlying conditions, baseline disease severity, and concomitant medications were broadly similar between the tocilizumab ( n = 49) and the control ( n = 47) groups. In the IPTW analysis, treatment with tocilizumab was associated with a reduced need for overall ventilatory support (49 vs. 89%, wHR: 0.39 [0.25–0.56]; p < 0.001). Albeit lacking statistical significance, there was a substantial trend towards a reduction of mechanical ventilation (31% vs. 45%; wHR: 0.58 [0.36–0.94]; p = 0.026). However, tocilizumab did not improve overall survival (wHR = 0.68 [0.31–1.748], p = 0.338). Among the 85 (89%) patients still alive at D28, patients treated with tocilizumab had a higher rate of oxygen withdrawal (82% vs. 73.5%, wHR = 1.66 [1.17–2.37], p = 0.005), with a shorter delay before being weaned of oxygen therapy (mean 11 vs. 16 days; p < 0.001). At D28, the rate of patients discharged from hospital was higher in the tocilizumab group (70% vs. 40%, wHR = 1.82 [1.22–2.75]; p = 0.003). The levels of CRP and fibrinogen post therapy ( p < 0.001 for both variables) were significantly lower in the tocilizumab group (interaction test, mixed model). Rates of neutropenia (35% vs. 0%; p < 0.001) were higher in the tocilizumab group, yet rates of infections (22% vs. 38%, p = 0.089) including ventilator-acquired pneumonia (8% vs. 26%, p = 0.022) were higher in the control group. Conclusion These data could be helpful for the design of future trials aiming to counter COVID-19-induced inflammation, especially before patients require admission to the intensive ca...

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Section: Discussionmentioning

confidence: 97%

Tocilizumab for Severe Worsening COVID-19 Pneumonia: a Propensity Score Analysis

et al. 2020

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“…Almost 20 years after the approval of imatinib, oral anticancer therapy has become an integral part in the treatment regimens of various malignancies [1] and other diseases such as graft versus host disease (GvHD) [2] and even COVID-19 [3]. One group of oral anticancer drugs comprises so-called kinase inhibitors (KI) such as osimertinib and afatinib which share a similar mechanism of action by inhibiting protein kinases in malignant cells.…”

Section: Introductionmentioning

confidence: 99%

Development and validation of a sensitive liquid chromatography tandem mass spectrometry assay for the simultaneous determination of ten kinase inhibitors in human serum and plasma

et al. 2020

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A liquid chromatography tandem mass spectrometry method for the analysis of ten kinase inhibitors (afatinib, axitinib, bosutinib, cabozantinib, dabrafenib, lenvatinib, nilotinib, osimertinib, ruxolitinib, and trametinib) in human serum and plasma for the application in daily clinical routine has been developed and validated according to the US Food and Drug Administration and European Medicines Agency validation guidelines for bioanalytical methods. After protein precipitation of plasma samples with acetonitrile, chromatographic separation was performed at ambient temperature using a Waters XBridge® Phenyl 3.5 μm (2.1 × 50 mm) column. The mobile phases consisted of water-methanol (9:1, v/v) with 10 mM ammonium bicarbonate as phase A and methanol-water (9:1, v/v) with 10 mM ammonium bicarbonate as phase B. Gradient elution was applied at a flow rate of 400 μL/min. Analytes were detected and quantified using multiple reaction monitoring in electrospray ionization positive mode. Stable isotopically labeled compounds of each kinase inhibitor were used as internal standards. The acquisition time was 7.0 min per run. All analytes and internal standards eluted within 3.0 min. The calibration curves were linear over the range of 2–500 ng/mL for afatinib, axitinib, bosutinib, lenvatinib, ruxolitinib, and trametinib, and 6–1500 ng/mL for cabozantinib, dabrafenib, nilotinib, and osimertinib (coefficients of correlation ≥ 0.99). Validation assays for accuracy and precision, matrix effect, recovery, carryover, and stability were appropriate according to regulatory agencies. The rapid and sensitive assay ensures high throughput and was successfully applied to monitor concentrations of kinase inhibitors in patients.

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“…Indeed, in addition to significantly reducing the serum levels of IL-6 and C-reactive protein (CRP) ( 77 , 112 ), ruxolitinib could influence the regulation of several inflammatory cytokines (including IL-2, IL-5, and IL-10) ( 36 , 113 ), and consequently reduce hyperferritinemia. The observed rapidity of action obtainable in just 2 h from administration ( 114 ) in modulation of the cytokine-induced STAT3 phosphorylation signal, and the possibility of administration by nasogastric tube, could make the drug definitely suitable for a therapeutic approach of emergency in serious ICU patients even in patients refractory to anti-IL-6 agents ( 115 ).…”

Section: Discussionmentioning

confidence: 99%

COVID-19: High-JAKing of the Inflammatory “Flight” by Ruxolitinib to Avoid the Cytokine Storm

et al. 2021

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Since SARS-CoV-2 outbreak in December 2019, world health-system has been severely impacted with increased hospitalization, Intensive-Care-Unit (ICU) access and high mortality rates, mostly due to severe acute respiratory failure and multi-organ failure. Excessive and uncontrolled release of proinflammatory cytokines (cytokine release/storm syndrome, CRS) have been linked to the development of these events. The recent advancements of immunotherapy for the treatment of hematologic and solid tumors shed light on many of the molecular mechanisms underlying this phenomenon, thus rendering desirable a multidisciplinary approach to improve COVID-19 patients’ outcome. Indeed, currently available therapeutic-strategies to overcome CRS, should be urgently evaluated for their capability of reducing COVID-19 mortality. Notably, COVID-19 shares different pathogenic aspects with acute graft-versus-host-disease (aGVHD), hemophagocytic-lymphohistiocytosis (HLH), myelofibrosis, and CAR-T-associated CRS. Specifically, similarly to aGVHD, an induced tissue damage (caused by the virus) leads to increased cytokine release (TNFα and IL-6) which in turn leads to exaggerated dendritic cells, macrophages (like in HLH) and lymphocytes (as in CAR-T) activation, immune-cells migration, and tissue-damage (including late-stage fibrosis, similar to myelofibrosis). Janus Kinase (JAK) signaling represents a molecular hub linking all these events, rendering JAK-inhibitors suitable to limit deleterious effects of an overwhelming inflammatory-response. Accordingly, ruxolitinib is the only selective JAK1 and JAK2-inhibitor approved for the treatment of myelofibrosis and aGVHD. Here, we discuss, from a molecular and hematological point of view, the rationale for targeting JAK signaling in the management of COVID-19 patients and report the clinical results of a patient admitted to ICU among the firsts to be treated with ruxolitinib in Italy.

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Ruxolitinib for tocilizumab‐refractory severe COVID‐19 infection

Cited by 37 publications

References 9 publications

Tocilizumab for Severe Worsening COVID-19 Pneumonia: a Propensity Score Analysis

Tocilizumab for Severe Worsening COVID-19 Pneumonia: a Propensity Score Analysis

Development and validation of a sensitive liquid chromatography tandem mass spectrometry assay for the simultaneous determination of ten kinase inhibitors in human serum and plasma

COVID-19: High-JAKing of the Inflammatory “Flight” by Ruxolitinib to Avoid the Cytokine Storm

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