COVID-19 in Philadelphia-negative myeloproliferative disorders: a GIMEMA survey

Breccia, Massimo; Piciocchi, Alfonso; Stefano, Valerio De; Finazzi, Guido; Iurlo, Alessandra; Fazi, Paola; Soddu, Silvia; Martino, Bruno; Palandri, Francesca; Siragusa, Sergio; Albano, Francesco; Passamonti, Francesco; Vignetti, Marco; Vannucchi, Alessandro M.

doi:10.1038/s41375-020-01032-0

Cited by 16 publications

(17 citation statements)

References 12 publications

(14 reference statements)

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“…This infection has spread to Europe in February 2020 and, since then, thousands of studies addressing various aspects of COVID-19 have started and numerous clinical trials have been registered on ClinicalTrials.gov. However, there is limited information describing the presenting characteristics and outcomes of COVID-19 patients with myeloproliferative neoplasms (MPN), including essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF) [4,5]. Natural history of MPN is marked by a high incidence of thrombosis and hemorrhagic complications and by a natural propensity to transform into overt MF and acute leukemia.…”

Section: Introductionmentioning

confidence: 99%

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: Introductionmentioning

confidence: 99%

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

et al. 2021

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“…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. Ruxolitinib-related side effects, when present, could be managed and resolved through a fruitful and humble cooperation between oncohematologists familiar to the drug ( 130 – 133 ) and clinicians from infectious disease, lung and intensive care units ( 118 , 123 – 125 , 127 , 130 , 134 ), without being misled by false convictions, lack of personal experience, overestimated toxicity ( 134 ) or by unethical conflicts of interests. In line with what recently highlighted in Lancet ( 135 ) and by La Rosée and colleagues ( 127 ), in this sad and difficult historical moment, patients deserve the best possible care and kind evaluation of new agents, communicating positive results immediately and promptly to the whole scientific community and translating new observational findings into structured (randomized) and methodologically correct clinical trials.…”

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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“…In regard to MPN, the guidelines for treating COVID-19 infection among others note that ruxolitinib may predispose the patients to severe COVID-19 infection [ 177 ]. For reasons given above, we believe that ruxolitinib may actually benefit MPN-patients with COVID-19 infection, reducing their risk of developing a cytokine storm and accordingly severe and critical disease [ 178 ]. Furthermore, by dampening the hyperinflammatory state in MPN-patients, ruxolitinib may also reduce the increased risk of thromboembolism, elicited by the COVID-19 infection per se [ [10] , [11] , [12] , [13] , [14] , [15] , [16] , [17] , [18] , [19] , [20] , [21] , [22] , [23] , [24] ] and adding to the inherent risk of thrombosis associated with MPN.…”

Section: Urgent Questions On the Role Of Treatment With Interferon-almentioning

confidence: 99%

COVID-19 as a mediator of interferon deficiency and hyperinflammation: Rationale for the use of JAK1/2 inhibitors in combination with interferon

Hasselbalch

Skov

Kjær

et al. 2021

Cytokine & Growth Factor Reviews

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COVID-19 in Philadelphia-negative myeloproliferative disorders: a GIMEMA survey

Cited by 16 publications

References 12 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

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

COVID-19 as a mediator of interferon deficiency and hyperinflammation: Rationale for the use of JAK1/2 inhibitors in combination with interferon

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