Use of ruxolitinib in patients with severe COVID-19

Ruxolitinib is a Janus kinase (JAK)1 and JAK2 inhibitor that has a good safety profile and is currently approved for the treatment of myelofibrosis, polycythemia vera, and acute graft-versus-host disease, which are all characterized by hyperinflammation. Due to ruxolitinib’s anti-inflammatory and immunomodulatory properties, it is currently being assessed as a potential therapeutic option for severe COVID-19. COVID-19 is caused by the SARS-CoV-2 virus and displays symptoms which vary from mild to very severe, depending on the extent of inflammatory response that is induced upon viral replication.

MPN Hub Steering Committee member, Alessandro Vannucchi and colleagues from the RUXO-COVID Study Group have recently published the findings of a prospective observational study in Leukemia, in which they assessed response to ruxolitinib treatment in 34 patients with COVID-19-induced severe pulmonary disease.¹

Study design

Patients were included who had:

• A positive SARS-CoV-2 polymerase chain reaction (PCR) test,
• Severe COVID-19 disease, defined by the presence of pulmonary infiltrates, reduced oxygen saturation (≤ 93%), and/or a reduced P/F ratio (arterial oxygen partial pressure (PaO2)/fraction of inspired oxygen (FiO2); ≤ 300 mmHg), and
• No evidence of impaired renal function, who did not require mechanical ventilation and could comply with treatment directions.

Ruxolitinib was given at a dose of 5 mg twice a day, increasing to 10 mg twice a day after 1−2 days, and to 25 mg daily after a further 2 days if there was no response. Treatment continued for up to 28 days. The study had an adaptive approach to enable patients to receive other therapies that were available.

Patients were categorized using a modified Ordinary Scale for Clinical Improvement (recommended by the WHO R&D Blueprint on novel coronavirus²) at baseline, and then daily. Clinical improvement was defined as a decrease of ≥ 2 points on the ordinal scale. The seven categories are:

1. Not hospitalized, recovery of normal activities
2. Not hospitalized, residual limitations of normal activities
3. Hospitalized, oxygen therapy not required
4. Hospitalized, low-flow oxygen therapy
5. Hospitalized, high-flow oxygen therapy or non-invasive ventilation
6. Hospitalized, intubation and mechanical ventilation or ventilation with organ support or extracorporeal membrane oxygenation
7. Death

Results

A total of 29 patients (85%) were discharged by the end of the 28-day follow up period. Baseline characteristics are detailed in Table 1.

Of the 29 discharged patients, two sets of 14 patients each met the characteristics of categories 4 and 5, and the symptoms of one patient were defined as category 3. Two patients died, one from bacterial sepsis and the other from cardiorespiratory failure. Three patients did not show clinical improvement and were still in hospital at the end of the follow-up period.

Overall, the cumulative incidence of clinical improvement was 82.4% (95% CI, 71–93) and clinical improvement seemed to be independent of the need for high-flow oxygen support. These improvements were starting to be visible 5 days after initiation of ruxolitinib and reached their maximum after around 25 days.

Severe respiratory impairment (P/F < 300 mmHg) was correlated with a reduced likelihood of clinical improvement, with a hazard ratio of 0.31 (95% CI, 0.1–1.0) in patients with P/F between < 300 and ≥ 200, and hazard ratio 0.20 (95% CI, 0.06–0.67) for those with a P/F of < 200.

Table 1. Baseline characteristics of patients included in the study¹

The study team reported a PCR-negative SARS-CoV-2 viral status in 23 patients (67.6%) after a median 21 days (interquartile range [IQR], 17–26) of treatment with ruxolitinib. They also report that serum cytokine levels were significantly increased at baseline, especially for IL-6, interferon gamma-induced protein-10, and MCP1, and that by Day 14 of treatment with ruxolitinib these were close to normal levels.

In terms of safety, the study team found that over the median duration of 13 days of ruxolitinib exposure (IQR, 7.3–16.8), adverse events (AEs) of any grade were recorded in 82.3% of patients, 38.2% of patients reported Grade 3 AEs, but these were not the cause of drug discontinuation in any of the patients. The most common AEs were anemia (55.9%), urinary tract infection (29.4%), an increase in creatinine (23.5%), thrombocytopenia (14.7%), and an increase in aminotransferases (14.7%).

Case reports on ruxolitinib use in patients with COVID-19

In a case report published in the European Journal of Haematology, MPN Hub Steering Committee member Steffen Koschmieder and colleagues reported on a 55-year-old man with myelofibrosis managed with ruxolitinib who developed COVID-19.³ The patient had significant comorbidities including chronic kidney disease, arterial hypertension, and obesity, which put him at high risk for acute respiratory distress syndrome (ARDS) and death from SARS-CoV-2 infection. He was admitted to the intensive care unit with hypotension, tachycardia, and hypoxia despite oxygen supplementation. Ruxolitinib treatment was continued to avoid development of discontinuation syndrome. During the entire hospital stay, the patient did not require mechanical ventilation, antihypotensive treatment, or antibiotics and was moved out of the intensive care unit after 7 days. According to the authors, the disease course was less severe than would be expected in a man with multiple risk factors, and ruxolitinib was indicated as a factor contributing to the benign course of the infection.

A note of caution, however, is warranted, as Valeria Gaspari recently detailed two cases of patients with SARS-CoV-2 infection who were treated with ruxolitinib and developed novel side effects in the International Journal of Antimicrobial Agents.⁴ Both patients, 74 and 63 years old, had received enoxaparin, lopinavir/ritonavir, and hydroxychloroquine prior to starting ruxolitinib. One patient developed purpuric lesions on the skin of the upper and dorsal limbs with a simultaneous decrease in platelet levels in 5 days and a deep tissue infection of the left arm. The other patient experienced erythrodermic rash and a drop in hemoglobin.

Other studies using ruxolitinib for COVID-19 treatment

Yang Cao et al. described the results of a multicenter, prospective, single-blind randomized phase II trial involving 43 patients with severe COVID-19 disease in The Journal of Allergy and Clinical Immunology.⁵ In this study, 22 patients received ruxolitinib and 21 were given a placebo based on the current standard of care. Numerically, a faster clinical improvement was seen with the patients treated with ruxolitinib which was not statistically significant. Nevertheless, significantly more patients in the ruxolitinib group showed computed tomography improvement (p = 0.495). In the control group, three patients died of respiratory failure, whereas the mortality rate in the ruxolitinib group was zero with no new safety signals recorded.

A study by Felicitas La Rosée and colleagues, published in Leukemia, describes the creation of a comprehensive COVID-19 Inflammation Score (CIS) involving chest X-ray, laboratory markers of inflammation, and coagulation parameters, to identify patients that would benefit from ruxolitinib treatment.⁶ Out of the 105 patients tested, 14 were selected for treatment with ruxolitinib and 86% of these patients achieved a significant reduction in CIS by Day 7, with maintained clinical improvements in 79% without short term indicators of ruxolitinib toxicity.

In response to the La Rosée paper, Alessandro Gozetti and colleagues investigated the treatment of 18 COVID-19 patients with higher doses of ruxolitinib using the novel CIS for disease assessment, which they presented in a letter to the editor of Leukemia.⁷ Patients were treated with 20 mg ruxolitinib twice daily for 2 days then a two-step dose de-escalation was performed at 10 mg and 5 mg over a maximum of 2 weeks. The median age of the patients included was 62.5 years (range, 28−86 years; 12 male and 6 female). Out of these patients, 14 could be evaluated for CIS and 12 of 14 had a CIS > 10. All 18 patients had progressive ARDS and were assessed as in need of mechanical ventilation at the start of ruxolitinib treatment. Following treatment however, 16 out of 18 patients showed a notable improvement in respiratory response within 48 hours and did not require mechanical ventilation. By the end of 2 weeks, they had regained complete respiratory function. There were no fatalities in the group treated with ruxolitinib.

COVID-19 in Philadelphia chromosome-negative MPN

Massimo Breccia et al. reported on the results of the GIMEMA cross-sectional study of Philadelphia chromosome-negative MPN patients in Italy, also published in Leukemia.⁸ A total of 13,248 patients were identified across 34 centers. Of these, 1,095 were being treated with ruxolitinib (75.5% for myelofibrosis and 24.3% for polycythemia vera). Between the end of February to the start of April 2020, 36 patients were found to be positive for COVID-19. Out of these patients, 36% were asymptomatic, 36% had only flu-like symptoms, and 27.8% had COVID-19 associated pneumonia. During the time period of interest, eight patients died, two required non-invasive ventilation, while four received mechanical ventilation. However, overall incidence of SARS-CoV-2 infection in these patients was low and insufficient to assess if ruxolitinib played a protective role.

Conclusion

Several publications have now reported on clinical improvements using ruxolitinib in patients with severe manifestations of COVID-19, especially those with high-risk comorbidities. The recent study initiated by the RUXO-COVID Study Group indicated that compassionate use of ruxolitinib in these patients was well tolerated and resulted in clinical improvement in > 80% of the patients.

While there are positive signals associated with the treatment of COVID-19 with ruxolitinib, the picture is far from clear. Clinicians must be aware of the potential risks and caveats when using this drug for the treatment of these patients. Encouraging findings from preliminary studies and case reports support the need for definitive controlled trials to further understand the role of ruxolitinib in the treatment of COVID-19.

The global pandemic highlights the need for sharing medical knowledge and information through case reports and clinical studies, in order to better manage the disease and reduce patient morbidity and mortality.