Compassionate use of JAK1/2 inhibitor ruxolitinib for severe COVID-19: a prospective observational study

Vannucchi, Alessandro M.; Sordi, Benedetta; Morettini, A; Nozzoli, Carlo; Poggesi, Loredana; Pieralli, Filippo; Bartoloni, Alessandro; Atanasio, Alessandro; Miselli, Filippo; Paoli, Chiara; Loscocco, Giuseppe Gaetano; Fanelli, Andrea; Para, Ombretta; Berni, Andrea; Tassinari, Irene; Zammarchi, Lorenzo; Maggi, Laura; Mazzoni, Alessio; Scotti, Valentina Rita; Falchetti, Giorgia; Malandrino, Danilo; Luise, Fabio; Millotti, Giovanni; Bencini, Sara; Capone, Manuela; Piccinni, Marie‐Pierre; Annunziato, Francesco; Guglielmelli, Paola; Mannelli, Francesco; Coltro, Giacomo; Fantoni, Duccio; Borella, Miriam; Ravenda, Enrica; Peruzzi, Benedetta; Caporale, Roberto; Cosmi, Lorenzo; Liotta, Francesco; Lombardelli, Letizia; Logiodice, Federica; Vanni, Anna; Salvati, Lorenzo; Lazzeri, Chiara; Bonizzoli, Manuela; Peris, Adriano; Cianchi, Giovanni; Bosi, Alberto; Pucatti, Michela; Fontanari, Paolo; Benemei, Silvia; Cerinic, Marco Matucci; Turco, Lucia

doi:10.1038/s41375-020-01018-y

Cited by 67 publications

(72 citation statements)

References 63 publications

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“…Of note, MF was the most represented among the MPNs (34%) and HU was the most common treatment (45.1%). Ruxo was used in 25% of cases, a figure that is consistent with recent reports on real-world clinical treatment of MPNs [8,9] and in agreement with the high prevalence of MF in our cohort. All the 135 hospitalized patients and 20 (50%) of those treated at home had COVID-19 diagnosis confirmed by a positive result on polymerase chain reaction testing of a nasopharyngeal sample; the remaining 20 patients managed at home were diagnosed based on highly suggestive symptomatology.…”

Section: Discussionsupporting

confidence: 92%

High mortality rate in COVID-19 patients with myeloproliferative neoplasms after abrupt withdrawal of ruxolitinib

et al. 2021

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We report the clinical presentation and risk factors for survival in 175 patients with myeloproliferative neoplasms (MPN) and COVID-19, diagnosed between February and June 2020. After a median follow-up of 50 days, mortality was higher than in the general population and reached 48% in myelofibrosis (MF). Univariate analysis, showed a significant relationship between death and age, male gender, decreased lymphocyte counts, need for respiratory support, comorbidities and diagnosis of MF, while no association with essential thrombocythemia (ET), polycythemia vera (PV), and prefibrotic-PMF (pre-PMF) was found. Regarding MPN-directed therapy ongoing at the time of COVID-19 diagnosis, Ruxolitinib (Ruxo) was significantly more frequent in patients who died in comparison with survivors (p = 0.006). Conversely, multivariable analysis found no effect of Ruxo alone on mortality, but highlighted an increased risk of death in the 11 out of 45 patients who discontinued treatment. These findings were also confirmed in a propensity score matching analysis. In conclusion, we found a high risk of mortality during COVID-19 infection among MPN patients, especially in MF patients and/or discontinuing Ruxo at COVID-19 diagnosis. These findings call for deeper investigation on the role of Ruxo treatment and its interruption, in affecting mortality in MPN patients with COVID-19.

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Section: Discussionsupporting

confidence: 92%

High mortality rate in COVID-19 patients with myeloproliferative neoplasms after abrupt withdrawal of ruxolitinib

et al. 2021

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“…Other three single arm not randomized studies were published so far about the use of Ruxolitinib in Covid-19 . All confirm a fast effect of the drug reducing markers on infection and improving signs of respiratory distress [21][22][23] The important role of lung hyperinflammation in Covid-19 19 is again supported by the present study.…”

Section: Accepted Articlesupporting

confidence: 85%

Compassionate use of ruxolitinib in patients with SARS‐Cov‐2 infection not on mechanical ventilation: Short‐term effects on inflammation and ventilation

Mortara

Mazzetti

Margonato

et al. 2021

Clinical Translational Sci

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Ruxolitinib is an anti‐inflammatory drug that inhibits the Janus kinase‐signal transducer (JAK‐STAT) pathway on the surface of immune cells. The potential targeting of this pathway using JAK inhibitors is a promising approach in patients affected by coronavirus disease 2019 (COVID‐19). Ruxolitinib was provided as a compassionate use in patients consecutively admitted to our institution for severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2) infection. Inclusion criteria were oxygen saturation less than or equal to 92%, signs of interstitial pneumonia, and no need of mechanical ventilation. Patients received 5 mg b.i.d. of ruxolitinib for 15 days, data were collected at baseline and on days 4, 7, and 15 during treatment. Two main targets were identified, C‐reactive protein (CRP) and PaO2/FiO2 ratio. In the 31 patients who received ruxolitinib, symptoms improved (dyspnea scale) on day 7 in 25 of 31 patients (80.6%); CRP decreased progressively from baseline (79.1 ± 73.4 mg/dl) to day 15 (18.6 ± 33.2, p = 0.022). In parallel with CRP, PO2/FiO2 ratio increased progressively during the 3 steps from 183 ± 95 to 361 ± 144 mmHg (p < 0.001). In those patients with a reduction of polymerase chain reaction less than or equal to 80%, delta increase of the PO2/FiO2 ratio was significantly more pronounced (129 ± 118 vs. 45 ± 35 mmHg, p = 0.02). No adverse side effects were recorded during treatment. In patients hospitalized for COVID‐19, compassionate‐use of ruxolitinib determined a significant reduction of biomarkers of inflammation, which was associated with a more effective ventilation and reduced need for oxygen support. Data on ruxolitinib reinforces the hypothesis that targeting the hyperinflammation state, may be of prognostic benefit in patients with SARS‐CoV‐2 infection. WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Some evidence suggest that patients affected by coronavirus disease 2019 (COVID‐19) present an exuberant inflammatory response represented by a massive production of type I interferons and different pro‐inflammatory cytokines. Nonetheless, as for the present, there are no proven therapeutic agents for COVID‐19, in particular anti‐inflammatory and antiviral, with a significant and reproducible positive clinical response. WHAT QUESTION DID THIS STUDY ADDRESS? Targeted therapeutic management of pro‐inflammatory pathways appears to be a promising strategy against COVID‐19, and ruxolitinib, due to its established broad and fast anti‐inflammatory effect, appears to be a promising candidate worthy of focused investigations in this field. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? Ruxolitinib rapidly reduces the systemic inflammation, which accompanies the disease, thereby improving respiratory function and the need of oxygen support. This effect may contribute to avoid progression of the disease and the use of invasive ventilation. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? Data on ruxolitinib contributes the reinforcement of the hypothesis that it is crucial to...

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“…On the bases of all biological premises (62,115,(118)(119)(120)(121)(122)(123)(124)(125)(126)(127)(128)(129), and of our preliminary results, we firmly believe that ruxolitinib presents a strong potential in overcoming lung and systemic complications caused by JAK/STAT-mediated immune hyperactivation during COVID-19 disease. Indeed, while recent works in this field (123)(124)(125)127) demonstrated a promising activity of ruxolitinib in avoiding respiratory worsening and progression to mechanical ventilation in hyperinflamed patients at imminent risk to be admitted to ICU (by using different treatment schedules, including a dose escalation in case of not-responding patients), here we presented a case-report documenting the potential activity of the drug (with a slightly different 20-days schedule which include a preplanned dose intensification followed by a decalage phase) in patients already under mechanical ventilation, thus extending the possibility of using this drug in critical patients (our patient was indeed quickly intubated after treatment beginning and received ruxolitinib through a nasogastric tube). Anyway, while using different timings and schedules, all the studies reported a clinical benefit within few days from treatment starts without major signs of ruxolitinib-associated toxicities (mainly due to the short treatment courses) underscoring the need of larger studies (phase 3 studies are ongoing) to confirm the activity of the drug in hyperinflamed COVID-19 patients regardless of the respiratory support they need.…”

Section: Discussionmentioning

confidence: 60%

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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Compassionate use of JAK1/2 inhibitor ruxolitinib for severe COVID-19: a prospective observational study

Cited by 67 publications

References 63 publications

High mortality rate in COVID-19 patients with myeloproliferative neoplasms after abrupt withdrawal of ruxolitinib

High mortality rate in COVID-19 patients with myeloproliferative neoplasms after abrupt withdrawal of ruxolitinib

Compassionate use of ruxolitinib in patients with SARS‐Cov‐2 infection not on mechanical ventilation: Short‐term effects on inflammation and ventilation

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

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