Blood Cancer Journal volume 13, Article number: 65 (2023)
Introduction
The coronavirus disease 2019 (Covid19) pandemic caused by the spreading of the coronavirus SARS-CoV-2 has led to substantial mortality in patients with hematological diseases [1]. During the first wave of pandemic, patients with Philadelphia-negative chronic myeloproliferative neoplasms (MPN) including essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF) were reported at higher risk of acquiring SARS-CoV-2 and of having a poor outcome after infection, with a mortality rate of about 30%, increasing to 48% in MF patients [2].
Ruxolitinib is a JAK1/2 inhibitor that is widely used both in MF and PV [3]. It may affect immunological response by decreasing the production of pro-inflammatory cytokines and by altering the function of several immune cells, including macrophages and B/T-lymphocytes [4]. Its use and discontinuation have been identified as risk factors for SARS-CoV-2 infection and Covid19-related death [5] Additionally, ruxolitinib-treated patients show lower serological response to anti-SARS-CoV-2 vaccination [6, 7].
Previous studies on Covid19 in MPN patients have included patients regardless of treatment type, with few patients treated with ruxolitinib at the time of the pandemic. Here, we explored features associated with Covid19 disease and survival after Covid19 in a large cohort of ruxolitinib-treated PV and MF patients.
This analysis could provide useful information for identifying those ruxolitinib-treated patients that are at higher risk of SARS-CoV-2 infection and assessing prognostic factors for survival in a homogeneously treated cohort. The final objective is to provide decision-support tools for viral therapy and/or hospitalization.
Methods
Study setting
The observational retrospective cohort studies “RUX-MF and “PV-ARC” were promoted by the IRCCS Azienda Ospedaliero-Universitaria S. Orsola-Malpighi, Bologna, Italy. The PV-ARC study involves 934 PV patients, while the “RUX-MF” study collects 886 MF patients in chronic phase who received ruxolitinib outside clinical trials. Details of protocol design, list of participating Centres and operational procedures have already been reported [8, 9]. For the purposes of this analysis, data concerning MF/PV and characteristics related to first Covid19 infections during ruxolitinib therapy were recorded. The data cut-off date was January 2022.
Waves of the Covid19 pandemic were divided into three periods, according to the type of predominant circulating variants in Europe: first (wild-type variant, February–June 2020); second (alpha/beta/gamma variants, July 2020–June 2021) and third (delta variant, July 2021–January 2022).
Covid19 severity was categorized according to the NIH Guidelines [10].
Statistical analysis
Statistical analysis was carried out at the biostatistics laboratory of the MPN Unit at the Institute of Hematology “L. and A. Seràgnoli”, IRCCS Azienda Ospedaliero-Universitaria, Bologna.
Continuous variables have been summarized by their median and range, and categorical variables by count and relative frequency (%) of each category. Comparisons of quantitative variables between groups were carried out by Wilcoxon–Mann–Whitney rank-sum test; association between categorical variables was tested by the χ2 test. By Receiver Operating Characteristic (ROC) curve, the optimal cut-off for neutrophil to lymphocyte ratio (NLR) was found at 5.5 (AUC: 0.66) for hospitalization and at 6.8 (AUC: 0.71) for death.
Using Cox proportional hazard model, association with COVID-19 hospitalization and Covid19-related survival was evaluated for the following variables: age ≥ 70 years, sex, presence of at least one comorbidity, MPN type, NLR ≥ 5.5 (hospitalization), NLR ≥ 6.8, vaccination, wave, previous thrombosis, and platelet count/hemoglobin at infection. The same factors were evaluated using a logistic regression model for PV and MF patients (adding DIPSS and spleen response at Covid19 infection in the latter). The association between thromboses that occurred during the pandemic and Covid19 infection, MPN type and NLR was also investigated.
For all analyses, the starting time was February 2020, corresponding to the pandemic start.
Overall survival was calculated by Kaplan–Meier analysis, starting from the date of Covid19 infection and considering only Covid19-related deaths.
Pearson’s test was used to measure the collinearity of covariates.
Akaike’s Information Criterion (AIC) and Schwarz’s Bayesian Information Criterion (BIC) were used to choose the model that best fits the data.
For all tested hypotheses, two-tailed p-values < 0.05 were considered significant. Statistical analyses were performed using STATA Software, 15.1 (StataCorp LP, College Station TX, USA).
Results
Study cohort
Overall, 886 MF and 172 PV patients treated with ruxolitinib outside clinical trials have been registered in the RUX-MF and in the PV-ARC databases, respectively. At pandemic start, 560 patients (413 MF and 147 PV) were receiving ruxolitinib and were included in this analysis. Ruxolitinib dose was evaluable in 135 and 409 PV and MF patients, respectively. Median dose at pandemic start was 5–10 mg BID in all PV and 189 (46.2%) MF patients, 15 mg BID and 20 mg BID in 114 (27.9%) and 106 (25.9%) MF patients.
From February 2020 to January 2022, 83 (14.2%) patients acquired the Covid19 disease (PV n = 16, 10.8%; MF n = 67, 16.2%; p = 0.12), with an overall incidence rate of 10.5 per 100 patient-years. Overall, 15, 41, and 27 infections were observed during the first, second, and third pandemic wave, with incidence rates of 6.5, 7.8, and 7.3 per 100 patient-years in the three waves, respectively (p = 0.75).
Infection was asymptomatic/mild in 21 patients (25.3%), moderate in 17 (20.5%), severe in 18 (21.7%), critical in 6 (7.2%) and fatal in 21 (25.3%) patients (Supplementary Fig. 1).
Characteristics associated with Covid19 infection and hospitalization
Differences between non-Covid19 and Covid19 ruxolitinib-treated patients are summarized in Table 1. Overall, 371/467 evaluable patients (79.4%) received ≥ 1 dose of anti-SARS-CoV2 vaccine. All but one patient received an mRNA vaccine (BioNTech/Pfizer n = 327 [88.1%], Moderna n = 43 [11.6%]).
Compared to Covid19 patients, those who did not acquire the infection had more frequently received ≥ 1 dose of anti-SARS-Cov2 vaccine (p < 0.001). The protective effect of vaccination was confirmed also in the MF and in the PV population separately (39.5% and 56.3% of vaccinated patients vs. 82.5% and 86.8% of unvaccinated patients with Covid19 infection in MF and PV, p < 0.001 and p = 0.003, respectively).
All the 45 (54.2%) patients with severe, critical, fatal infections were hospitalized. The frequency of hospitalization in the first and second waves (66 and 68%) was higher compared to the third one (26%), (p = 0.002). Compared to outpatients, those admitted to hospital were more likely to be ≥ 70 years (p = 0.05), had a significantly lower median platelet counts (150 vs. 226 × 109/L, p = 0.02) and higher neutrophil counts (7.2 vs. 4.2 × 109/L, p = 0.04), with a significant increase of neutrophil to lymphocyte ratio (NLR) (5.6 vs. 3.5, p = 0.04). At Covid19 diagnosis, ruxolitinib was reduced in 11 (13.3%) patients. Ruxolitinib discontinuation occurred in 9 patients (10.8%) in the 1st, 2nd and 3 wave in 4, 4 and 1 patients, respectively, and comparably in MF and PV. The cause of discontinuation was severe Covid19 infection in all cases, together with severe thrombocytopenia (platelet < 50 × 109/l) in 2 cases.