Pharmacological Research 157 (2020) 104866

Contents lists available at ScienceDirect

Pharmacological Research
journal homepage: www.elsevier.com/locate/yphrs

The CoV-2 outbreak: how hematologists could help to fight Covid-19 T

a, ,1 a,1 b a a
Sara Galimberti * , Chiara Baldini , Claudia Baratè , Federica Ricci , Serena Balducci ,
Susanna Grassia, Francesco Ferroa, Gabriele Budaa, Edoardo Benedettib, Rita Fazzib,
Laura Bagliettoa, Ersilia Lucentefortea, Antonello Di Paoloa, Mario Petrinia
a
Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
b
AOUP, Pisa, Italy

ARTICLE INFO ABSTRACT

Keywords: COVID-19 is a medical emergency, with 20 % of patients presenting with severe clinical manifestations. From
COVID-19 the pathogenetic point of view, COVID-19 mimics two other well-known diseases characterized by cytokine
Ruxolitinib storm and hyper-activation of the immune response, with consequent organ damage: acute graft-versus-host
TKIs disease (aGVHD) and macrophage activation syndrome (MAS). Hematologists are confident with these situations
Begelomab
requiring a prompt therapeutic approach for switching off the uncontrolled cytokine release; here, we discuss
Baricitinib
Tocilizumab
pros and cons of drugs that are already employed in hematology in the light of their possible application in
GVHD COVID-19. The most promising drugs might be: Ruxolitinib, a JAK1/2 inhibitor, with a rapid and powerful anti-
MAS cytokine effect, tyrosine kinase inhibitors (TKIs), with their good anti-inflammatory properties, and perhaps the
anti-Cd26 antibody Begelomab. We also present immunological data from gene expression experiments where
TKIs resulted effective anti-inflammatory and pro-immune drugs. A possible combined treatment algorithm for
COVID-19 is here proposed.

1. Introduction SARS-CoV-2-positive passenger; these authors estimated that 17.9 % of

all infected cases remained asymptomatic during quarantine [1]. An-
Coronavirus disease 2019 (COVID-19), sustained by the new other group estimated that the rate of symptomatic cases was 101/
Coronavirus SARS-CoV-2, started in China in December 2019 in the 10,000, after a median incubation time of 14 days [2]. Moreover, the
province of Hubei and then rapidly overspread over the world, be- Italian COVID-19 Surveillance Group, during the peak of infection, re-
coming a “pandemic”. The 22 April 2020, the European Centre for ported 460 deaths on 85,308 infected individuals (9.9 %), with an
Disease Prevention and Control reported 2,520,522 infected subjects overall case-fatality rate around 7.2 %, substantially higher than in
around the world, with 176,786 deaths [https://www.ecdc.europa.eu/ China (2.3 %), thus highlighting the compelling need for more effective
en/geographical-distribution-2019-ncov-cases]; 1,101,681 people were approaches. The median age of infected subjects was 62 years, 85 % of
infected in Europe and 825,041 in USA, with 107,453 and 45,063 deaths occurring in patients between 70 and 89 years. Moreover, only
deaths, in Europe and USA, respectively [https://www.cdc.gov/ 1.2 % of infected patients presented at the hospitalization without co-
coronavirus/2019-ncov/cases-updates/cases-in-us.html]. morbidities, while 23.5 % had one, 26.6 % two, and 48.6 % three or
This great number of infected subjects is requiring an enormous more comorbidities. The most frequent concomitant diseases resulted:
worldwide effort for hospitalizing and caring all patients who have to previous ischemic heart attack or stroke, atrial fibrillation, hyperten-
receive firstly an adequate diagnostic approach (chest X-ray or CT, viral sion, diabetes, dementia, a recent history of cancer, chronic liver dis-
genome identification and quantitation, serology), then the best pos- ease or renal failure. Only 7.5 % of patients did not present any
sible therapies that might avoid the more severe phase of disease. From symptom at the hospital admission, 12.7 % were pauci-symptomatic,
the clinical point of view, the majority of patients remains asympto- 37.9 % and 19.6 % manifested mild and severe symptoms, respectively,
matic or presents mild symptoms; Mizumoto et al. conducted an epi- while 4.4 % were critical [https://www.epicentro.iss.it/coronavirus/].
demiologic study on the 3711 people who remained on board of the In the international scenario, the most frequent clinical manifestations
Diamond Princess cruise ship, blocked in Japan after identification of a were fever and dyspnea, whilst cough, diarrhea and hemoptysis were

⁎
Corresponding author at: Hematology, Ospedale S. Chiara, Edificio 11, 56126 Pisa, Italy.
E-mail address: [email protected] (S. Galimberti).
1
First co-authors.

https://doi.org/10.1016/j.phrs.2020.104866
Received 3 April 2020; Received in revised form 24 April 2020; Accepted 26 April 2020
Available online 06 May 2020
1043-6618/ © 2020 Elsevier Ltd. All rights reserved.
S. Galimberti, et al. Pharmacological Research 157 (2020) 104866

less common; acute respiratory distress syndrome (ARDS) was observed the hyper-inflammation caused by the new Coronavirus: the graft-
in 96 % of severe cases, followed by acute renal failure in one third of versus-host disease, in its acute (aGVHD) and chronic forms (cGVHD).
them; super-infections were documented in 8.5 % of critical cases GVHD, which interests about half of transplanted patients, can appear
where septic shock and the macrophage activation syndrome (MAS) by or after 100 days from the allogeneic stem cell infusion, with a
were the most frequent cause of death [3,4]. From the early stages of prevalence that ranges from 35 % to 55 %, according to donor type,
infection patients develop lymphopenia and neutrophilia; in the more conditioning regimen, disease status at transplant and prophylactic
advanced cases, lymphocyte further reduce, liver failure appears with approach [20,21]. GVHD is the consequence of a misleading attack by
hypoalbuminemia, and the hyper-inflammatory status, characterized by donor T lymphocytes of several recipient’s antigens recognized as out-
high levels of reactive protein C, ferritin, D-dimer, LDH, troponin and N- siders, with consequent damage of his/her liver, lungs, gastrointestinal
terminal fragment of the B-type natriuretic peptide (NT-proBNP), is tract, eyes, vagina, muscles and joints. Allogeneic T and B lymphocytes
demonstrable [5,6]. sustain this hyper-inflammation that causes tissue damage and fibrosis,
The pathogenesis of this “hyper-inflammation” have been recently both by increasing production of inflammatory cytokines (IL-1, IL-2R,
revised: chemokines, such as MCP-1, IL2, IL-7, IL-10, G-CSF, IP-10, MIP- IL-6, TNF alpha) and by the deposition of immune complexes. The in-
1A and IL6 are highly expressed, whereas TNF-alpha seems to be only testinal epithelium damage releases bacteria and modifies the gut mi-
moderately up-regulated. Cytotoxic CD8+ and exhausted T cells, to- crobiome, further increasing the immune response: T CD8+ lympho-
gether with an abnormal balance between Th1 and Th2 lymphocytes, cytes are especially activated by the recipient hematopoietic antigen-
mirror the onset of a severe immune dysfunction [7]. Consequently, presenting cells (APC), whereas donor T CD4+ cells can be activated by
several approaches able to switch off inflammation by maintaining at other APC types, principally in the gut. The participation of other im-
the same time the host’s antiviral immunocompetence have been ra- munocompetent cells, such as NK, macrophages, monocytes and neu-
pidly designed and tempted: Chloroquine, already employed in rheu- trophils, makes GVHD a hyper-inflammatory dangerous condition that
matological diseases, inhibiting the attack of the SARS-CoV-2 to the well recapitulates what occurs in COVID-19, where the rapid Cor-
ACE2 receptors (that represent one of the two virus receptors) resulted onavirus replication impairs the IFN-induced immune response, with
quite effective [8], alone or in combination with azithromycin [9]. rapid increase of M1-oriented macrophages and pro-inflammatory cy-
Tocilizumab, an anti-IL6 antibody, already used both in rheumatoid tokines [7]. Moreover, clinical manifestations, especially of the aGVHD,
arthritis [10,11] and in the cytokines release syndrome after infusion of are similar to those observed in COVID-19: skin rash, diarrhea, elevated
CAR-T in patients affected by acute lymphoblastic leukemia or ag- bilirubin, infections, pulmonary leak syndrome, eye and mouth damage
gressive lymphomas [12,13], has been employed with success in and, in the chronic form, also fasciitis, myositis and fibrosis that mimic
COVID-19. Recently, an Italian group proposed a new treatment algo- the systemic scleroderma [22,23].
rithm whose backbone is represented by Chloroquine; Tocilizumab is Another COVID-19-like condition that hematologists and rheuma-
used precociously in all patients with high levels of IL6 and D-dimer, tologists have to deal with is the Macrophage activation syndrome
including those, especially the elderly cases, with hypoxemia without (MAS), an acute hyper-inflammatory condition characterized by acti-
severe dyspnea [14]. Other possible options from the “rheumatological” vation and expansion of T cells and hemophagocytic macrophages, with
background are the anti-IL1 monoclonal antibody Anakinra, already the consequent cytokine storm, with increased levels of proin-
effective in the MAS [15], and the JAK1/2 inhibitors, such as Bar- flammatory cytokines, such as IL-1, IL-6, IL-18, TNF alpha, and IFN
icitinib, already employed in rheumatoid arthritis [16], used alone or gamma [24]. MAS is reported to interest about 4% of patients with
in combination with intravenous Immunoglobulins [14]. In 22 April juvenile idiopathic arthritis and systemic lupus erythematosus, but it
2020 a clinical trial aimed to assess the Baricitinib effectiveness in se- can also represent a complication of hematological neoplasms or in-
vere COVID-19 has been authorized by the Italian Drug Agency (AIFA) fections, with a mortality higher than 40 %, that makes MAS a real
[https://www.aifa.gov.it/sperimentazioni-cliniche-covid-19]. Finally, medical emergency [25]. From the diagnostic point of view, MAS is a
anti-TNF alpha antibodies, such as Adalimumab, prescribed for the febrile condition characterized by hyperferritinemia, multilineage cy-
treatment of psoriasis [17] and Behcet’s disease [18], have been pro- topenia, coagulopathy, transaminitis, high levels of triglycerides, hy-
posed as possible furher therapeutic tools for COVID-19 pandemic [7]. pofibrinogenemia and splenomegaly. Classically, MAS is treated with
In this apocalyptic scenario, some authors already observed that this high steroid doses and etoposide [26], but in the era of new biological
“rheumatological” approach, notwithstanding a clear fast and positive drugs promising results derived from the use of anti-IL1 and anti-IL6
anti-inflammatory effect, could impair the immunological control of antibodies, like Anakinra, Canakinumab, Rilonacept and Tocilizumab
neoplasms in patients receiving chemotherapy or immunotherapy for [27].
cancer. Indeed, cancer patients showed a higher rate of severe events
after SARS-CoV-2 infection in comparison with patients without cancer 3. The hematological approach to COVID-19: pros and cons
(39 % vs 8%) [19]. This epidemiological observation, in addition to the
consideration that the majority of reported comorbidities in patients Hematologists are already confident with GVHD and MAS, that re-
with critical COVID-19 were diseases characterized by a pro-in- quire a rapid intervention for switching off the cytokine storm and
flammatory profile, underlines once again the need of identifying fur- controlling the exaggerated immune response. In the following, we’ll
ther drugs exerting a significant anti-inflammatory action but without discuss positive and negative aspects of drugs employed for treating
losing their anti-tumor effect. On the basis of these considerations, we GVHD and MAS, in the light of their possible employ in the COVID-19
decided to review literature and what hematologists know about the war.
relationship between hematological drugs, inflammation and im-
munity, in order to help the scientific community to definitively fight 3.1. Immunosuppressive agents
the COVID-19.
In aGVHD, treatment includes topic or systemic corticosteroids,
2. COVID-19 challenge: what hematologists learnt from anti-thymocyte immunoglobulins, cyclosporine, mycophenolate mofetil
hematological diseases for appropriate management of acute phase. Novel approaches also
include mesenchymal stem cells, etanercept and infliximab (anti-TNF
2.1. Two good “hematological” COVID-19-like models: the graft-versus-host alfa), daclizumab (anti-IL2) or vedolizumab (anti-a4b7), but results are
disease and the MAS still very preliminary and not worth to be considered for translating the
experience deriving from the aGVHD “new era” directly to the COVID-
In hematology, we have a well-known similar condition that mimics 19 [28]. About cGVHD as “inspirating source”, also in this case the first

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line approach is represented by immunosuppressive agents [29] that mice [39]. In cGVHD, Ibrutinib, switching off the cytokine storm,
seems to be not really effective in COVID-19 [7]. was successful in two third of cases, with 21 % of complete and 45 %
of partial responses [40], with a significant improvement of patients’
3.2. Monoclonal antibodies quality of life [41]. Unfortunately, this treatment is characterized by
adverse events that cause treatment discontinuation in 30 % of pa-
Tocilizumab, anti-IL6 monoclonal antibody, has been used also for tients; in particular, pneumonitis, fatigue and diarrhea of grade ≥3
treating aGVHD, with 70 % of partial remissions (PR). Nevertheless, in occur in 71 % of patients in the first year and in 25 % in the second
a series of 11 patients, 2 developed a bacterial sepsis, one of whom died year, inducing therapy discontinuation in 40 % of cases [38]. In
[30]. Until today, 23 trials have been registered in the “clinical agreement with these results, the experience in CLL reported high
trials.gov” website, thus supporting the promising use of this drug in infection rates: in a cohort of 378 patients, serious infections were
COVID-19. Rituximab has been also used as therapeutic tool in GVHD, observed in 11.4 % of cases, especially bacterial and fungal [42]. At
with 60 % of overall response rate (ORR); however, as reported by the the moment, no clinical trials using Ibrutinib in COVID-19 have been
Italian cooperative group (GITMO), 3/38 treated patients died for in- registered in the “clinical trials.gov” website; nevertheless, Treon
fections [31], and in a meta-analysis involving 111 cGVHD patients, and coworkers in the last days published in Blood an interesting
one third of them presented pneumonitis and Herpes virus reactivation report concerning the low rate of COVID-19 occurrence in patients
[32]. No studies involving this monoclonal antibody have still regis- with Waldenstrom’s macroglobulinemia (only 6 out of 300 in-
tered in the “clinical trials.gov” website. In our opinion, the use of Ri- dividuals). All patients experienced cough and fever as prodromal
tuximab in the COVID19 could be not considered, either for the high rate of symptoms; the 5 patients on Ibrutinib 420 mg/day experienced no
infections reported in the hematological context, or because Rituximab re- dyspnea and did not require hospitalization, with a shorter disease
quires a too long time to be efficacious. course in comparison with the one patient receiving lower Ibrutinib
Begelomab, a monoclonal anti-CD26 antibody, has been recently dose, who, on the contrary, required the administration of Tocili-
reported to be efficacious in treatment of 69 steroid-refractory aGVHD zumab and i.v. immunoglobulins [43].
patients. In the compassionate use, Begelomab was administered at
In our opinion, Ibrutinib, might be a potential candidate for fighting the
3 mg/m2/day for 5 days, followed by six additional doses of 3 mg/m2 at
CoV-2, but probably if used for a short time, due to the high number of
day +10, +14, +17, +21, and +24. The overall response rate at one
infections and treatment discontinuations that usually characterize its
month was 75 % in the prospective studies and 61 % in the compas-
use in the hematological scenario. Clinical trials are needed to conclude if
sionate use, with complete response rates of 11 and 12 %, respectively.
the balance weighs more on the side of efficacy or toxicity.
Response in grade-III GVHD was higher than 70 %, and response in
grade-IV GVHD cases about 60 %, with higher response rates described
for skin, liver, and gut. The tolerability of treatment was good, with the
most common adverse events being diarrhea, cytomegalovirus re- 3.4. JAK2 inhibitors
activation, infections, probably more linked to the GVHD and the pre-
vious steroid treatment than to the antibody itself. In the 8 complete The other drug licensed by FDA and EMA for treatment of GVHD is
responders there was only one late death due to infections; in the 38 Ruxolitinib, already successfully employed for reducing spleen di-
partial responders, the infection rate was 10.5 % [33]. Recently, the mension and improving quality of life and survival of patients affected
DPP4/CD26 glycoprotein has been reported to be one of the two re- by myelofibrosis [44]. Ruxolitinib, a JAK1/2-inhibitor, decreases the
ceptors for the spike S1 SARS-CoV2 surface protein, together with the activity of Th1 lymphocytes, and, through modulation of the STAT
angiotensin converting enzyme (ACE2) [34]. Once activated by SARS- pathway, the secretion of pro-inflammatory cytokines, such as TNF
CoV-2, this protease helps virus 1) to reduce autophagy, the process alpha, IL1, IL6, and IFN gamma [45]. Ruxolitinib is effective both in
physiologically aimed to eliminate external microorganisms from the acute and in chronic GVHD: in 71 cases of steroid-refractory aGVHD,
host cells, 2) to sustain the hyper-inflammatory status and 3) to reduce Ruxolitinib offered 55 % of ORR and 27 % of CR, especially in skin,
the host anti-viral immune response [35]. The hypothesis of destroying gastrointestinal tract, and liver. Median duration of response was 345
this strict link by the anti-CD26 antibodies or the DPP4 inhibitors, al- days and the overall survival (OS) at 6 months 51.0 %. Cytopenias
ready employed in the diabetic patients, seems really interesting [36]. occurred in half of cases, peripheral edema in 45 %, but no significant
DPP4 inhibitors have been already demonstrated to be efficacious in infective toxicity has been reported [46]. In another cohort, Rux-
several in vitro models of SARS [34] and, considering the 80 % of olitinib, at a dose of 20 mg/day, offered 57.1 % of ORR; reported
homology between old and new Coronavirus, DPP4 inhibitors might be adverse events were anemia, thrombocytopenia, neutropenia, infec-
useful also in the COVID-19 pandemic [37]. Nevertheless, no studies tions, edema, bleeding, and transaminitis [47]. In the cGVHD, Rux-
with Begelomab have still been registered in the “clinical trials.gov” olitinib has been reported to be effective in 80 % of patients; never-
website. Considering these novel findings about the possibility of destroying theless, reactivation of CMV occurred in 15 % of patients [48]. In a
the CD26 axis connecting Coronavirus and inflammation/perturbed host meta-analysis including 414 patients with cGVHD, during treatment
immunity, in our opinion, the use of Begelomab, probably for a short time with Ruxolitinib infections occurred in 20 % of patients, more fre-
course, might be considered an interesting approach, worth to be tested in the quently sustained by bacteria (55 %) and CMV (39 %) [49]. The pro-
COVID19. infective aspect of Ruxolitinib is also evident in myelofibrosis, where
cases of hepatitis B [50] and tuberculosis (in 1.4 % of cases) [51]
3.3. BTK inhibitors reactivation, in addition to pneumonitis sustained by Pneumocystis
jiroveci [52], have been reported. In the last weeks, 8 clinical trials
In the last two years, FDA and EMA licensed Ibrutinib as treat- with Ruxolitinib in COVID-19 started, with dose ranging from 10 to
ment for steroid-refractory cGVHD. Ibrutinib, already effective in 20 mg/day. The first 11 cases treated in Italy avoided the incoming
high risk chronic lymphocytic leukemia (CLL) [34], in addition to the intubation, so confirming in the real life the anti-inflammatory power
Bruton Kinase, also inhibits another kinase, the interleukin-2–in- of this JAK1/2 inhibitor.
ducible T-cell kinase (ITK), that is involved in the selective activation In our opinion, Ruxolitinib could represent a very good candidate
of T-cells that drive immune reactivity toward healthy tissues [38], against COVID-19 for its well-known powerful and fast anti-in-
and a SRC kinase, HCK, whose over-expression, in a murine model, flammatory effect; nevertheless, the high rate of viral and microbial
has been reported to be responsible for extensive pulmonary in- reactivation observed in the hematological setting might represent a
flammation and enhanced immune response, particularly in older caveat in its prolonged use in the COVID-19.

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S. Galimberti, et al. Pharmacological Research 157 (2020) 104866

3.5. Tyrosine kinase inhibitors pathway) [68]. In another murine model of intra-cerebral hemorrhage
with brain injury caused by post-bleeding inflammation, Bosutinib once
Another class of drugs already employed in the treatment of GVHD more showed its anti-inflammatory action: inhibiting SIK-2, it activates
that could help to win the COVID-19 challenge are the tyrosine kinase CREB and IkB, so blocking the NF-kB-derived inflammation. Moreover,
inhibitors (TKIs), already successfully employed in treatment of chronic Bosutinib shifted the macrophagic response from M1 to M2, and de-
myeloid leukemia (CML), Philadelphia-positive acute lymphoblastic creased pro-inflammatory cytokines production [69]. Bosutinib and
leukemia and stromal gastro-intestinal tumor (GIST) [53]. Imatinib has Nilotinib were also used and compared in a murine model of Alzhei-
been the first TKI licensed for CML treatment, followed by Nilotinib, mer’s disease (where brain plaques are considered a consequence of
Dasatinib, Bosutinib (second generation TKIs) and Ponatinib (third hyper-inflammation). In this context, both TKIs decreased inflammation
generation TKI). All TKIs, and especially those of second and third by reducing TNF alpha, IL4, IL6, IL3, and IL2 levels and increasing IL10
generation, in CML offer high rates of complete hematological, cyto- and CX3CL1, but, in comparison with Nilotinib, Bosutinib increased IL-
genetic and molecular responses [53], necessary key for treatment 10 and CX3CL1 also in the peripheral blood [70]. Thus, the anti-in-
discontinuation (TFR), that has success in about 40 % of patients [54]. flammatory profile of Bosutinib is evident. About its safety, in the BE-
Different studies focused on TFR explored the impact of TKIs on the FORE trial, where Bosutinib and Imatinib were compared in 536 CML
immunological response, showing that this class of drugs play a positive patients in first line, grade 3/4 infection rate was 3.4 % in the Bosutinib
effect on NK cells whose number and activated status is fundamental for versus 4.9 % in the Imatinib arm, with only 0.4 % of upper respiratory
maintaining deep molecular response without treatment [55,56]. tract infections in the cohort treated with Bosutinib [71]. All these data
Moreover, TKIs are able to restore the immunocompromised status suggest that Bosutinib might have a relevant anti-inflammatory effect,
observed in CML patients at diagnosis by reducing myeloid-derived with a good safety profile; at the moment, no studies with Bosutinib
suppressor cells, re-activating T and NK cells, and reducing the ex- have been registered in the “clinical trials.gov” website. Nevertheless, in
pression of PD-1 on T and NK lymphocytes and of PD-L1 on the mi- our opinion, Bosutinib could be considered a possible effective drug in the
croenvironment and on neoplastic clone [57]. Imatinib has been em- COVID-19. Nevertheless, no experience with this drug has been done in
ployed with success also in GVHD, but mainly in its chronic form, GVHD or MAS.
where it was successful in about 60 % of cases [58]. From the safety Nilotinib is a valid second-generation TKI approved for treatment
point of view, in a series of 19 cases only one pneumonitis and one CNS of CML in first or subsequent lines [72]. Nilotinib is now in experi-
infection by JCV have been reported [59]. In another cohort with mentation also in GVHD, on the basis of data from the preclinical stu-
sclerodermic GVHD Imatinib was compared to Dasatinib: one of the 4 dies that clearly demonstrated its anti-inflammatory power. Indeed,
patients receiving Imatinib had pneumonitis versus 2 of the 5 cases Nilotinib significantly reduced production of pro-inflammatory cyto-
treated with Dasatinib [60]. Two trials proposing Imatinib in COVID-19 kines (IL-2, IFN-gamma, TNF alpha, IL-17, TGF beta), without losing
have been already registered in the “clinical trials.gov” website the lymphocyte immunocompetence [73,74]. Nevertheless, no defini-
(NCT04357613, NCT04356495), both involving elderly patients. In a tive data on Nilotinib safety in GVHD are still available; consequently,
third study, Imatinib will be compared to hidroxicloroquine, Lopinavir/ safety profile must be derived from the experience in CML. In the EN-
ritonavir, and Baricitinib (NCT04346147). ESTnd trial, comparing Nilotinib and Imatinib in 564 CML patients in
first line, all grade infection rate was 17 % in the Nilotinib versus 14 %
In our opinion, Imatinib might represent a good therapeutic possibility in
in the Imatinib arm, with grade 3/4 infections rate in the Nilotinib
the COVID-19 for its demonstrated anti-inflammatory activity added to a
cohort less then 1% [75]. In conclusion, Nilotinib seems to be an anti-
good safety profile, but a caveat has to be done about the delayed onset
inflammatory agent with a good infective safe profile; these features
of its positive therapeutic effects.
could make it, in our opinion, a good candidate in the COVID-19 set-
Dasatinib has not been further used in GVHD, but the toxicities that ting; nevertheless, we have to consider its high rate of cardiovascular
it causes in CML might contraindicate its use in the COVID-19. In fact, complications seen in CML [76,77] that could be the consequence of the
about 25 % of CML patients develop pleural effusion during Dasatinib inflammatory endothelial damage, as shown by higher IL6 and lower
treatment [61]. Several mechanisms have been explored, from the in- IL10 levels in CML patients presenting cardiovascular events [78]. At
hibition of PDGFR beta to increased T lymphocytes in pleural fluid the moment, no studies with Nilotinib in COVID-19 have been regis-
[62]. In multivariate analysis, a previous skin rash or history of auto- tered in the “clinical trials.gov” website. In our opinion, this pro-
immune disease resulted as significant factors predicting pleural effu- atherogenic aspect might made Nilotinib a sub-optimal candidate in the
sion [63]. About infective risk during Dasatinib administration, the COVID-19 context.
incidence of grade 3/4 infections resulted 11 % [64]; in the DASISION
trial, which compared Dasatinib with Imatinib as first-line treatment, 3.6. Interferons
4.5 % of patients in the Dasatinib and lessa than 1% in the Imatinib
cohort died for infections, so sustaining the high infective risk of Da- Interferons (IFNs) are old, but at the same time “evergreen” drugs,
satinib in comparison to Imatinib [65]. At the moment, no studies with for many years used for treating different hematological diseases, from
Dasatinib in COVID-19 have been registered in the “clinical trials.gov” CML and Philadelphia-negative chronic myeloproliferative neoplasms
website. On the basis of available data, in our opinion, Dasatinib might be (MPNs) to lymphomas and myeloma, due to their potent immune en-
not a valid candidate for the COVID-19 treatment. hancing capacity that allows recognition and elimination of neoplastic
On the contrary, different promising suggestions come from some in cells by the patient’s immune system. In CML, Interferon has been used
vitro and in vivo models that would support the use of Bosutinib as a until the introduction of TKIs; its offered hematological and cytogene-
powerful anti-inflammatory agent. This TKI is today indicated for tical, but very few molecular responses. Nevertheless, for many years it
treatment of CML Imatinib-intolerant or resistant patients [66]. Dif- represented an advantageous treatment in respect of hydroxyurea [79].
fering from Dasatinib, whose pro-inflammatory action is supported by In MPNs, IFNs are still successfully employed, especially in younger
the high rate of pleural effusion, Bosutinib resolved this adverse event people, where their discontinuation after long-term treatment may be
in 17/20 cases presenting effusion during treatment with Dasatinib. followed by several years with normal cell counts and low-JAK2V617 F
Moreover, the safety of Bosutinib from the immunological point of view burden, that once again supports the concept that IFN-alpha is able to
is supported by the quite total absence of infective adverse events [67]. modulate and enhance the immune system-mediated defense against
Moreover, in a model of membranous glomerulonephritis, Bosutinib cancer [80]. In lymphomas, IFN is still the first line of treatment of
was able to ameliorate renal damage by reducing expression of IL2R, hairy cell leukemia [81] and, with less fortune, has been employed as
IL4R, and by inhibiting JAK2/JAK3 (that sustain the inflammatory maintenance therapy in indolent lymphomas, especially after

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S. Galimberti, et al. Pharmacological Research 157 (2020) 104866

autologous transplantation [82]. In multiple myeloma, IFN has been

demonstrated to reduce plasmacells growth by down-regulating the IL6
production, with a synergic action with melphalan and corticosteroids
in reducing the monoclonal component. IFN has also been used as
maintenance after autologous transplantation before introduction in the
clinical practice of lenalidomide and bortezomib, but with doubt fa-
vorable prognostic impact [83]. Moving from the hematological context
to the SARS, during the outbreak of 2002 IFNs were also tried; a meta-
analysis including 54 studies with IFN was performed in 2006, with
discordant results. Indeed, while the in vitro studies showed a good anti-
viral power of IFNs (with IFN beta being more effective than alpha), the
in vivo studies were inconclusive, with a doubtful prognostic advantage
in respect of steroids [84]. At the moment, 6 studies, aimed to under-
stand if IFNs might be useful in COVID-19, have been registered in the
“clinical trials.gov” website, trying either IFN alpha/beta or lambda
(NCT04344600, NCT04350671, NCT04343768, NCT04343976,
NCT04254874, NCT04320238). Interestingly, one of these studies is
employing the IFN alpha via aeresol, probably in order to avoid the
systemic adverse events (flu-like syndrome, fatigue, hypothyroidism,
creatinine increase) that frequently lead to the drug discontinuation in
the hematological patients [85]. The use of IFN lambda (type III IFN),
seems interesting, based on different action mechanisms that char-
acterize tipe I and III IFNs. Indeed, for decades, type I IFNs (IFN alpha
and beta) have been explored as mediators of rapid, innate antiviral
protection. In 2003, a novel group of three cytokines, now known as
type III IFNs (IFN lambda), have been discovered. The distinctive ac-
tions of type I and type III IFNs depend on the engagement of different
receptors: type I IFNs trigger pro-inflammatory responses via the re-
cruitment and activation of immune cells, promoting an anti-viral state
in the host, while type III IFNs signal is restricted to epithelial cells and
neutrophils. Therefore, type III IFN administration as a prophylactic
treatment or at an early stage of COVID-19 might result in a good an-
tiviral response localized to epithelial cells, reducing side effects and
inflammation associated with the systemic action of type I IFNs [86] In
our opinion, considering the actual availability of different clinical options,
because of their poor tolerability, IFNs might be not good candidate in the
COVID-19 therapy.

4. Our personal contribution to the COVID-19 war: the analysis of

the immune transcriptome

After this analysis, we became convinced that, in addition to

Ruxolitinib, Imatinib and Bosutinib would represent possible inter-
esting therapeutic tools in the COVID-19 war. Thus, we decided to
contribute to the COVID-19 challenge by confirming ex vivo the anti-
inflammatory power of Imatinib and if and how it could modify the
immunological profile of our patients. Thus, we used the Nanostring
technology (Nanostring, Seattle, USA) for analyzing the immune tran-
scriptome profile of 5 patients affected by CML, at diagnosis and after 6
months of treatment with Imatinib. The tested RNAs have been already
stocked in our laboratory as leftovers that the respective patients do-
nated to us for further non-profit researches after routine diagnostics.
We employed the “Human nCounter Myeloid Innate Immunity panel”
that measures the expression value of 770 genes involved in 19 dif-
ferent pathways fundamental for the innate immune response. Results
were analyzed by the nCounter Advanced Analysis 2.0 software. In
Fig. 1 we represented some of the up- (red squares) and down-regulated
(green squares) genes by volcano plots, and in the Table 1 are listed all
down- (in green) or up- (in red) regulated genes and the pathways
where they are involved. In Table 2 we better detailed all genes that
resulted significantly deregulated after Imatinib, their respective phy-
siological role and their possible contribution to inflammation and (caption on next page)
immunological infection control. Overall, 40 genes resulted down- and
18 up-regulated by Imatinib; 35 of these down-regulated genes may
sustain the inflammation in different autoimmune diseases, whilst 5 are
anti-inflammatory. After Imatinib-induced gene expression down-

5
S. Galimberti, et al. Pharmacological Research 157 (2020) 104866

Fig. 1. CML: Volcano plots of some pathways de-regulated by 6 months of Table 2

treatment with Imatinib. CML gene expression profiling.
Some of the up- (red squares) and down- (green squares) genes de-regulated
GENE ID function output on ref
during treatment of CML patients with Imatinib are represented by volcano
plots. Statistical significance (at 0.05 and 0.01) are indicated with dotted and inflammation/
continuous lines, respectively. In a) the Antigen presentation pathway, in b) the immune resp
Cytokines pathway, in c) the FCR signaling pathway is represented. ANXA4 high in Sjogren anti infl [87]
ARG1 immunosuppressive pro immun [97]
BTK sustains GVHD anti infl [38]
Table 1 C3AR1 neutrophils chemotaxis antagonist pro immun [98]
CAMP increased in inflammation anti infl [126]
CML gene expression profiling.
CASP10 increased in Chron anti infl [88]
Gene Id Pathway Gene Id Pathway CDC20 increased in the adiposity inflamm anti infl [127]
model
ANXA4 Ag present GRN pat resp CEACAM1 inhibits T lynf pro immun [99]
ARG1 metabolism GSN pat resp CEACAM8 high in arthritis anti infl [89]
BTK BCR IL18 cytokines CLEC5A high in neurogen shock anti infl [92]
C3AR1 complement ITGAM migration COL17A1 induce IL7 that sustains T & B lynf anti immun [128]
CAMP pat respo LTA4H metabolism CTSG high in rheumatic arthritis anti infl [90]
CASP10 cytokines MAP2K1 angiogenesis CXCL2 high in Alzheimer anti infl [70]
CDC20 Ag present MMP8 ECM CXCL3 sustain adipogenesis anti infl [129]
CEACAM1 migration MMP9 ECM CYBB increased in inflammation anti infl [130]
CEACAM8 migration MPO pat resp DAGLB sustains production of arachidonic acid anti infl [131]
CLEC5A ly activation NECTIN1 migration ELANE high in LPS inflammation anti infl [132]
COL17A1 ECM OLR1 migration EPX high in asthma anti infl [133]
CTSG Ag present PGLYRP1 pat resp FGFR1 high in prostatic inflammation anti infl [134]
CXCL2 chemokines PLAU complement FUT4 increased in bacterial infections anti infl [135]
CXCL3 chemokines PRG2 pat resp
CYBB Ag present PTX3 pat resp GENE ID function output on ref
DAGLB metabolism RNASE2 pat resp
ELANE ECM RNASE3 pat resp inflammation
EPX pat resp SPTBN1 cytokines GRN high in dementhia anti [94]
FGFR1 cytokines TM7SF3 cytokines GSN increases NK apoptosis pro immun [100]
FUT4 metabolism TNFAIP8 cytokines IL18 high in arthritis anti [91]
ITGAM high in psoriasis anti [95]
Gene Id Pathway LTA4H high after trauma anti [113]
MAP2K1 high in sinusitis anti [114]
CCL5 chemokines MMP8 high in intra-amniotic infections anti [115]
CCR4 chemokines MMP9 high in skin healing anti [116]
CCR5 chemokines MPO high in neutrophils anti [117]
CD28 migration NECTIN1 high in Chlamidial infection pro imm [101]
CD74 Ag presentation OLR1 NFkB activator anti [118]
CX3CR1 chemokines PGLYRP1 high in gengivitis anti [96]
CXCL16 chemokines PLAU high after thrombosis anti [119]
CXCR3 chemokines PRG2 eosinophils basic protein anti [120]
FYN Ag presentation PTX3 increased by IL6 anti [121]
HAVCR2 cytokines RNASE2 high in inflamm, anti-viral anti anti-imm [125]
IFNG Ag presentation RNASE3 anti viral anti imm [125]
JAK3 chemokines SPTBN1 reduces TGFb pro [122]
NFATC2 Ag presentation TM7SF3 reduces nitric oxid pro [123]
PDE4A metabolism TNFAIP8 high in inflamm anti [124]
SERPINB9 pat resp
SOCS3 Ag presentation GENE ID function output on ref
STAT5A cytokines
TLR3 pat resp inflammation

Table represents all genes that, among the 770 genes whose expression CCL5 activates NK pro immun [138]
had been tested by the Nanostring “Human nCounter Myeloid Innate CCR4 high in asthma pro [137]
Immunity” panel, resulted up- (in red) and down- (in green) regulated CCR5 activates NK pro immun [136]
after 6 months of treatment with Imatinib. The adopted Nanostring CD28 inactivated by PD1 pro immun [139]
panel allows to classify genes in 19 different pathways. The Table re- CD74 increases MCHII expression pro immun [140]
CX3CR1 high in antifungal resp pro immun [141]
ports for each gene its respective pathway of belonging.
CXCL16 high in anti-viral resp pro-immun [105]
CXCR3 high in T effector pro immun [142]
regulation, the final effect was a significant reduction of pro-in- FYN high in inflamm/sustains NK pro pro imm [143]
flammatory cytokines and chemokines mRNAs. Unfortunately, these HAVCR2 high in anti-viral resp pro-immun [106]
data are not completed by the quantification of cytokines in the serum, IFNG antiviral pro immun [107]
JAK3 shift from M1 to M2 resp anti [102]
because of the retrospective nature of the study. On the other hand,
NFATC2 increases T memory pro immun [144]
among the 18 genes those expressions increased after Imatinib, 15 PDE4A low in sepsis anti [145]
support the physiological innate immune response. More in detail, SERPINB9 activates CD8 pro immun [146]
among the down-regulated ones, we found some genes that are highly SOCS3 low in arthritis anti [103]
STAT5A high in colon inflamm pro [147]
expressed in autoimmune diseases: ANX4A, high in the Sjogren’s syn-
TLR3 anti-viral/anti-inflamm anti pro imm [104]
drome [87], CASP10, high the Crohn's disease [88], while CEACAM8
[89], CTSG [90], and IL18 [91] are overexpressed in arthritis. More- Table represents all genes that resulted Up- (in red) and down- (in green)
over, CLEC5A, increased after neurogenic shock [92], CXCL2 and GRN regulated after 6 months of treatment with Imatinib, as listed in Table 1.
are highly expressed in the Alzheimer’s disease [93,94], ITGAM was Table 2 in addition for each gene reports the respective physiological function
(with correspondent literature references) and the final effect resulting from
elevated in psoriasis [95], and PGLYRP1 had high levels in chronic
mRNA de-regulation made by 6 months of Imatinib, with focus on the in-
flammation and on the immunological infection control.
6
S. Galimberti, et al. Pharmacological Research 157 (2020) 104866

gingivitis [96]. All these genes were down-regulated by Imatinib, as a further consideration has to be done about the costs of these possible
demonstration of its anti-inflammatory action. At the same time, the new treatments: in 2018, a group of researchers from the Mayo Clinic
anti-inflammatory effect exerted by Imatinib was also sustained by the performed a cost/effectiveness analysis on 1047 patients treated for
reduced expression of the genes that identified the mast cells (Fig. 2). cGVHD. Among the drugs that can be used against COVID-19, in that
Our Nanostring analysis also demonstrated that, while Imatinib re- study on cGVHD the cheapest resulted chloroquine (9181 US$), fol-
duced inflammation, the patient’s immunocompetence was not lost. lowed by Imatinib (43,965 US$), and Ruxolitinib (97,807 US$) [111].
Indeed, Imatinib down-regulated several genes that physiologically In our opinion, the final list of the “hematological” drugs that could
impair the T- and NK-cell response, such as ARG1 [97], C3AR1 [98], represent promising options in the COVID-19 war might include also
CEACAM1 [99], GSN [100] and NECTIN1 [101]. On the contrary, this Ruxolitinib, Bosutinib, Imatinib and Begelomab. Ruxolitinib probably is
TKI up-regulated some genes that usually support the immune response, the fastest and more powerful agent in the switching off the cytokine
such as JAK3, able to switch the macrophagic response from M1 (pro- storm, as already shown in aGVHD and also in the first COVID-19 cases
inflammatory) to M2 (anti-inflammatory) [102], SOCS3, which had a treated with this JAK1/2 inhibitor. Nevertheless, its doubtful safety
low expression in arthritis [103], while TLR3 displayed low levels in from the infective point of view probably might impose at least the need
inflammation and during viral infections [104]. Interestingly, Imatinib of a careful observation of the immunocompetence in COVID-19 pa-
on the other hand also increased expression of some genes relevant for tients, also considering that super-infections have been documented in
the antiviral response: CXCL16 [105], HAVCR2 [106], IFNG [107], 8.5 % of them. TKIs could be tried as further options: in different
RNASE2 and RNASE3 [108,109]. Finally, during Imatinib treatment, an models of inflammations, Bosutinib showed optimal anti-inflammatory
increase in T cytotoxic and activated NK cells has been observed properties, already demonstrated by its ability of reverting the pro-in-
(Fig. 2). flammatory effects of Dasatinib. In addition, data coming from the
In conclusion, even if preliminary, our findings agree with data al- experience in CML sustain its good safety profile and sustain the hy-
ready published by Alves et al. that reported an increased number of NK pothesis of a rapid efficacy also. Imatinib displays a good anti-in-
cells and lower IL21 levels during treatment with TKIs and IFN [110], flammatory effect, its use is characterized by a low infection rate; it is
and support the hypothesis that Imatinib might be a very good candidate to worth to remember also that Imatinib remain the cheapest drug and
fight COVID-19 due to its anti-inflammatory action in a context of a con- probably the TKI most frequently available worldwide. Begelomab,
served and efficient immunological infection control (Fig. 3). probably for a short period of time, might also be an interesting option
for its capacity of destroying the strict negative link between Cor-
onavirus and inflammation actors.
5. Conclusions
Thus, all considered, in a hypothetical “hematological-driven” al-
gorithm (see graphical abstract), we could imagine using Begelomab for
In Table 3 we resumed characteristics, pros and cons of drugs that,
blocking the first steps of infection, Ruxolitinib to rapidly switch off the
on the basis of above reported considerations, might be translated from
cytokine storm in the severe/hyperacute phase, and, then to sustain
the hematological scenario to the CoV-2 pandemic. Nevertheless, a

Fig. 2. CML: Box plots representing some cellular types de-regulated by 6 months of treatment with Imatinib.
Changes of mRNAs identifying different cellular populations after Imatinib treatment are here reported. In a) cytotoxic cells (defined as GZMA+, NKG7+, CD94+),
whose mRNAs resulted increased by Imatinib; in b) NK cells (CD56 bright), that increased after Imatinib treatment; in c) mast cells (defined as CPA3+, tryptase+,
MSGA2+, CCL22+), whose RNAs were decreased by Imatinib; in d) RNAs characterizing neutrophils (defined as FPR1+, SIGLEC5+, CSF3R+, FCAR+), that
remained unchanged in respect of diagnosis.

7
S. Galimberti, et al. Pharmacological Research 157 (2020) 104866

Fig. 3. A possible therapeutic algorithm for

COVID-19.
A possible “hematological-based” integrated
algorithm for COVID-19 treatment, based on
different disease phases, is here represented. In
the early stage of SARS-CoV2 infection, chlor-
oquine, imatinib or begelomab might be useful
for blocking the attack of the viral S protein to
the CD26 virus receptors, for modifying the
lysosome pH or for restoring the anti-microbial
autophagy. During an eventual mild COVID-19
phase, the anti-viral host reaction might be
sustained by imatinib or ibrutinib, that at the
same time might exert also an useful anti-in-
flammatory action, even if moderate. In the
more severe phases of COVID-19, the anti-
JAK1/2 inhibitors might be useful, alone or in
combination with anti-cytokine monoclonal
antibodies, such as Tocilizumab.

Table 3
Table reports the comparison of several features (hematological indication, safety, cost) in different hematological drugs that might have a role in the COVID-19.
Abbreviations: MPN = chronic myeloproliferative neoplasms; MAS = macrophage activation syndrome; CML = chronic myeloid leukemia; ALL = acute lympho-
blastic leukemia; GIST = stromal gastro-intestinal tumor; GVHD = graft-versus-host disease; LNH = non Hodgkin’s lymphoma; MM = multiple myeloma.
Ruxolitinib Imatinib Dasatinib Nilotinib Bosutinib Ibrutinib Begelomab IFN

Drug os os os os os os IV os
formulation
Clinical use in
GVHD XX X X X – XX XX –
Use in MPNs CML CML CML CML CLL GVHD CML
hematological MAS ALL ALL ALL MCL MPN
diseases GIST LNH
MM
Infection rate 20 % 5% 11 % 17 % 4% 71 % 10 % na
Estimated ++ + + + + +++ +++ +
costs

immunity (that Ruxolitinib is not able to do) and the required long-term References
anti-inflammatory effect by TKIs. On the other hand, the combination
of Ruxolitinib with Nilotinib has already been adopted in a phase-I [1] E. Nicastri, A. D’Abramo, G. Faggioni, R. De Santis, A. Mariano, L. Lepore, et al.,
study in CML patients with unsatisfactory molecular response, without Coronavirus disease (COVID-19) in a paucisymptomatic patient: epidemiological
and clinical challenge in settings with limited community transmission, Italy,
significant infections occurrence [112]. In the last few weeks many 2020, Euro Surveill. 25 (11) (2020), https://doi.org/10.2807/1560-7917.
trials with some of the above mentioned drugs started and will gave us [2] S.A. Lauer, K.H. Grantz, Q. Bi, F.K. Jones, Q. Zheng, H.R. Meredith, et al., The
soon fundamental information; indeed, the war against SARS-CoV-2 has incubation period of coronavirus disease 2019 (COVID-19) from publicly reported
confirmed cases: estimation and application, Ann. Intern. Med. (2020), https://
to be continued: rethinking drugs use with a multidisciplinary approach doi.org/10.7326/M20-0504.
could be a possible improvement for the final victory. [3] B.E. Young, Kalimuddin S. Ong SWX, J.G. Low, S.Y. Tan, J. Loh, et al.,
Epidemiologic features and clinical course of patients infected with SARS-CoV-2 in
Singapore, JAMA. (2020), https://doi.org/10.1001/jama.2020.3204.
Author contribution [4] Y. Wang, Y. Wang, Y. Chen, Q. Qin, Unique epidemiological and clinical features
of the emerging 2019 novel coronavirus pneumonia (COVID-19) implicate special
S. Galimberti and C. Baldini wrote the manuscript; all authors re- control measures, J. Med. Virol. (2020), https://doi.org/10.1002/jmv.25748.
[5] COVID-19 National Emergency Response Center, Epidemiology and Case
vised and approved it. Management Team, Korea Centers for Disease Control and Prevention. Early
Epidemiological and Clinical Characteristics of 28 Cases of Coronavirus Disease in
South Korea. Osong Public Health Res Perspect. 11(1) (2020) 8-14. doi: 10.24171/
Declaration of Competing Interest j.phrp.2020.11.1.03.
[6] F. Shi, Q. Yu, W. Huang, C. Tan, Novel coronavirus (COVID-19) pneumonia with
Hemoptysis as the initial symptom: CT and clinical features, Korean J. Radiol.
S. Galimberti, C. Baratè and M. Petrini were speakers in the events 2020 (2019), https://doi.org/10.3348/kjr.2020.0181.
supported by Novartis, Pfizer, Celgene/BMS, Janssen, Roche, Incyte [7] P. Sarzi-Puttini, V. Giorgi, S. Sirotti, D. Marotto, S. Ardizzone, G. Rizzardini, et al.,
and members of advisory boards for Novartis and Janssen; A. Di Paolo COVID-19, cytokines and immunosuppression: what can we learn from severe
acute respiratory syndrome? Clin. Exp. Rheumatol. 38 (2) (2020) 337–342 Epub
was a speaker for Medac GmbH, Novartis, Roche, Incyte, and was an
2020 Mar 22.
advisory board member for Novartis; C. Baldini and F. Ferro do not [8] Y.J. Duan, Q. Liu, S.Q. Zhao, F. Huang, L. Ren, L. Liu, Y.W. Zhou, The trial of
have any conflict of interest. chloroquine in the treatment of corona virus disease 2019 (COVID-19) and its
research progress in forensic toxicology, Fa Yi Xue Za Zhi 36 (2) (2020), https://
doi.org/10.12116/j.issn.1004-5619.2020.02.001.
Acknowledgments [9] P. Gautret, J.C. Lagier, P. Parola, V.T. Hoang, L. Meddeb, Morgane Maihle, et al.,
Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an
open-label non-randomized clinical trial, Int. J. Antimicrob. Agents (2020)
The experimental part of the work has been supported by University 105949, , https://doi.org/10.1016/j.ijantimicag.2020.105949.
of Pisa with PRA 2018 grant (PI, Prof. Petrini). This article is dedicated [10] L.J. Scott, Tocilizumab: a review in rheumatoid arthritis, Drugs 77 (17) (2017)
to all patients and all physicians that every day have to fight COVID-19 1865–1879, https://doi.org/10.1007/s40265-017-0829-7.
[11] M. Biggioggero, C. Crotti, A. Becciolini, Eg. Favalli, Tocilizumab in the treatment
and to all people that died during the pandemic.

8
S. Galimberti, et al. Pharmacological Research 157 (2020) 104866

of rheumatoid arthritis: an evidence-based review and patient selection, Drug Des. [38] D. Miklos, C.S. Cutler, M. Arora, E.K. Waller, M. Jagasia, I. Pusic, et al., Ibrutinib
Devel. Ther. 13 (2018) 57–70, https://doi.org/10.2147/DDDT.S150580. for chronic graft-versus-host disease after failure of prior therapy, Blood 130 (21)
[12] K.A. Hay, Cytokine release syndrome and neurotoxicity after CD19 chimeric an- (2017) 2243–2250, https://doi.org/10.1182/blood-2017-07-793786.
tigen receptor-modified (CAR-) T cell therapy, Br. J. Haematol. 183 (3) (2018) [39] M. Ernst, M. Inglese, G.M. Scholz, K.W. Harder, F.J. Clay, S. Bozinovski, et al.,
364–374, https://doi.org/10.1111/bjh.15644. Constitutive activation of the SRC family kinase Hck results in spontaneous pul-
[13] C. Kotch, D. Barrett, D.T. Teachey, Tocilizumab for the treatment of chimeric monary inflammation and an enhanced innate immune response, J. Exp. Med. 196
antigen receptor T cell-induced cytokine release syndrome, Expert Rev. Clin. (5) (2002) 589–604 PMID:12208875.
Immunol. (8) (2019) 813–822, https://doi.org/10.1080/1744666X.2019. [40] E.K. Waller, D. Miklos, C. Cutler, M. Arora, M.H. Jagasia, I. Pusic, et al., Ibrutinib
1629904. for chronic graft-versus-Host disease after failure of prior therapy: 1-Year update
[14] F. Ferro, E. Elefante, C. Baldini, E. Bartoloni, I. Puxeddu, R. Talarico, et al., COVID- of a phase 1b/2 study, Biol. Blood Marrow Transplant. 25 (10) (2019) 2002–2007,
19: the new challenge for rheumatologists, Clin. Exp. Rheumatol. 38 (2) (2020) https://doi.org/10.1016/j.bbmt.2019.06.023.
175–180. [41] B.L. King-Kallimanis, T. Wroblewski, V. Kwitkowski, R.A. De Claro, T. Gwise,
[15] M. Lind-Holst, U.B. Hartling, A.E. Christensen, High-dose anakinra as treatment V. Bhatnagar, et al., FDA review summary of patient-reported outcome results for
for macrophage activation syndrome caused by refractory Kawasaki disease in an ibrutinib in the treatment of chronic graft versus host disease, Qual. Life Res.
infant, BMJ Case Rep. 12 (8) (2019), https://doi.org/10.1136/bcr-2019-229708 (2020), https://doi.org/10.1007/s11136-020-02448-y.
pii: e229708. [42] T. Varughese, Y. Taur, N. Cohen, M.L. Palomba, S.K. Seo, T.M. Hohl, G. Redelman-
[16] Z.T. Al-Salama, L.J. Scott, Baricitinib: a review in rheumatoid arthritis, Drugs 78 Sidi, Serious infections in patients receiving ibrutinib for treatment of lymphoid
(7) (2018) 761–772, https://doi.org/10.1007/s40265-018-0908-4. Cancer, Clin. Infect. Dis. 67 (5) (2018) 687–692, https://doi.org/10.1093/cid/
[17] A. Blauvelt, N. Shi, R. Burge, Wn Malatestinic, Cy Lin, Cr Lew, et al., Comparison ciy175.
of real-world treatment patterns among psoriasis patients treated with ixekizumab [43] S.P. Treon, J. Castillo, A.P. Skarbnik, J.D. Soumerai, I.M. Ghobrial, M.L. Guerrera,
or adalimumab, Patient Prefer. Adherence 14 (2020) 517–527, https://doi.org/10. et al., The BTK-inhibitor ibrutinib may protect against pulmonary injury in
2147/PPA.S233993. COVID-19 infected patients, Blood (2020), https://doi.org/10.1182/blood.
[18] T. Ono, T. Iwasaki, Y. Terada, K. Abe, J. Lee, M. Mochizuki, K. Miyata, Serum KL-6 2020006288 pii: blood.2020006288.
elevation in a uveitis patient with Behçet’s disease treated with adalimumab, Am. [44] S. Verstovsek, J. Gotlib, R.A. Mesa, A.M. Vannucchi, J.J. Kiladjian, F. Cervantes,
J. Ophthalmol. Case Rep. 18 (2020), https://doi.org/10.1016/j.ajoc.2020.100660 et al., Long-term survival in patients treated with ruxolitinib for myelofibrosis:
100660. COMFORT-I and -II pooled analyses, J. Hematol. Oncol. 10 (1) (2017) 156,
[19] M. Bersanelli, Controversies about COVID-19 and anticancer treatment with im- https://doi.org/10.1186/s13045-017-0527-7.
mune checkpoint inhibitors, Immunotherapy. (2020), https://doi.org/10.2217/ [45] S. Albeituni, K.C. Verbist, P.E. Tedrick, H. Tillman, J. Picarsic, R. Bassett,
imt-2020-0067. K.E. Nichols, Mechanisms of action of ruxolitinib in murine models of hemopha-
[20] S. Nassereddine, H. Rafei, E. Elbahesh, Tabbara I. Acute graft versus host disease: a gocytic lymphohistiocytosis, Blood 134 (2) (2019) 147–159, https://doi.org/10.
comprehensive review, Anticancer Res. 37 (4) (2017) 1547–1555. 1182/blood.2019000761.
[21] A.Z. Kerep, J. Broome, F. Pirsl, L.M. Curtis, S.M. Steinberg, S.A. Mitchell, et al., [46] M. Jagasia, M.A. Perales, M.A. Schroeder, H. Ali, N.N. Shah, Y.B. Chen, et al.,
Impact of the 2014 NIH chronic graft-versus-host disease scoring criteria mod- Ruxolitinib for the treatment of steroid-refractory acute GVHD (REACH1): a
ifications assessed in a large cohort of severely affected patients, Bone Marrow multicenter, open-label, phase 2 trial, Blood. (2020), https://doi.org/10.1182/
Transplant. 54 (1) (2019) 76–84, https://doi.org/10.1038/s41409-018-0224-3. blood.2020004823 pii: blood.2020004823.
[22] K.P. MacDonald, B.R. Blazar, G.R. Hill, Cytokine mediators of chronic graft-versus- [47] L. Hui, L. Qi, H. Guoyu, S. Xuliang, T. Meiao, Ruxolitinib for treatment of steroid-
host disease, J. Clin. Invest. 127 (7) (2017) 2452–2463, https://doi.org/10.1172/ refractory graft-versus-host disease in adults: a systematic review and meta-ana-
JCI90593. lysis, Expert Rev. Hematol. (2020) 1–11, https://doi.org/10.1080/17474086.
[23] W. McManigle, A. Youssef, S. Sarantopoulos, B cells in chronic graft-versus-host 2020.1738214.
disease, Hum. Immunol. 80 (6) (2019) 393–399, https://doi.org/10.1016/j. [48] R. Zeiser, A. Burchert, C. Lengerke, M. Verbeek, K. Maas-Bauer, S.K. Metzelder,
humimm.2019.03.003. et al., Ruxolitinib in corticosteroid-refractory graft-versus-host disease after allo-
[24] G.S. Schulert, A.A. Grom, Pathogenesis of macrophage activation syndrome and geneic stem cell transplantation: a multicenter survey, Leukemia 29 (10) (2015)
potential for cytokine- directed therapies, Annu. Rev. Med. 66 (2015) 145–159, 2062–2068, https://doi.org/10.1038/leu.2015.212.
https://doi.org/10.1146/annurev-med-061813-012806. [49] L. Hui, L. Qi, H. Guoyu, S. Xuliang, T. Meiao, Ruxolitinib for treatment of steroid-
[25] M.H. Moradinejad, V. Ziaee, The incidence of macrophage activation syndrome in refractory graft-versus-host disease in adults: a systematic review and meta-ana-
children with rheumatic disorders, Minerva Pediatr. 63 (6) (2011) 459–466. lysis, Expert Rev. Hematol. (2020) 1–11, https://doi.org/10.1080/17474086.
[26] H. Yildiz, E. Van Den Neste, J.P. Defour, E. Danse, J.C. Yombi, Adult haemopha- 2020.1738214.
gocytic lymphohistiocytosis: a Review, QJM (2020), https://doi.org/10.1093/ [50] G. Caocci, F. Murgia, L. Podda, A. Solinas, S. Atzeni, G. La Nasa, Reactivation of
qjmed/hcaa011 pii: hcaa011. hepatitis B virus infection following ruxolitinib treatment in a patient with mye-
[27] A.A. Grom, A. Horne, F. De Benedetti, Macrophage activation syndrome in the era lofibrosis, Leukemia 28 (1) (2014) 225–227, https://doi.org/10.1038/leu.2013.
of biologic therapy, Nat. Rev. Rheumatol. 12 (5) (2016) 259–268, https://doi.org/ 235.
10.1038/nrrheum.2015.179. [51] F. Khalid, M. Damlaj, M. AlZahrani, K.A. Abuelgasim, G.E. Gmati, Reactivation of
[28] S. Nassereddine, H. Rafei, E. Elbahesh, Tabbara I. Acute graft versus host disease: a tuberculosis following ruxolitinib therapy for primary myelofibrosis: case series
comprehensive review, Anticancer Res. 37 (4) (2017) 1547–1555. and literature review, Hematol. Stem Cell Ther. (2020), https://doi.org/10.1016/
[29] S. Sarantopoulos, A.R. Cardones, K.M. Sullivan, How I treat refractory chronic j.hemonc.2020.02.003 pii: S1658-3876(20)30032-30037.
graft-versus-host disease, Blood. 133 (11) (2019) 1191–1200, https://doi.org/10. [52] S.C. Lee, J. Feenstra, P.R. Georghiou, Pneumocystis jiroveci pneumonitis compli-
1182/blood-2018-04-785899. cating ruxolitinib therapy, BMJ Case Rep. (2014), https://doi.org/10.1136/bcr-
[30] A.S. Kattner, E. Holler, B. Holler, S. Klobuch, D. Weber, D. Martinovic, et al., IL6- 2014-204950 pii: bcr2014204950.
receptor antibody tocilizumab as salvage therapy in severe chronic graft-versus- [53] P. Jain, H. Kantarjian, J. Cortes, Chronic myeloid leukemia: overview of new
host disease after allogeneic hematopoietic stem cell transplantation: a retro- agents and comparative analysis, Curr. Treat. Options Oncol. 14 (2) (2013)
spective analysis, Ann. Hematol. 99 (4) (2020) 847–853, https://doi.org/10. 127–143, https://doi.org/10.1007/s11864-013-0234-8.
1007/s00277-020-03968-w. [54] C. Fava, G. Rege-Cambrin, I. Dogliotti, M. Cerrano, P. Berchialla, M. Dragani,
[31] F. Zaja, A. Bacigalupo, F. Patriarca, M. Stanzani, M.T. Van Lint, C. Filì, et al., et al., Observational study of chronic myeloid leukemia Italian patients who dis-
Treatment of refractory chronic GVHD with rituximab: a GITMO study, Bone continued tyrosine kinase inhibitors in clinical practice, Haematologica. 20104 (8)
Marrow Transplant. 40 (3) (2007) 273–277. (2019) 1589–1596, https://doi.org/10.3324/haematol.2018.205054.
[32] M.A. Kharfan-Dabaja, A.R. Mhaskar, B. Djulbegovic, C. Cutler, M. Mohty, [55] P.Y. Dumas, E. Bérard, C. Bréal, S. Dulucq, D. Réa, F. Nicolini, et al., Killer im-
A. Kumar, Efficacy of rituximab in the setting of steroid-refractory chronic graft- munoglobulin-like receptor genotypes and chronic myeloid leukemia outcomes
versus-host disease: a systematic review and meta-analysis, Biol. Blood Marrow after imatinib cessation for treatment-free remission, Cancer Med. 8 (11) (2019)
Transplant. 15 (9) (2009), https://doi.org/10.1016/j.bbmt.2009.04.003 1005-13. 4976–4985, https://doi.org/10.1002/cam4.2371.
[33] A. Bacigalupo, E. Angelucci, A.M. Raiola, R. Varaldo, C. Di Grazia, F. Gualandi, [56] G. Caocci, B. Martino, M. Greco, E. Abruzzese, M.M. Trawinska, S. Lai, et al., Killer
et al., Treatment of steroid resistant acute graft versus host disease with an anti- immunoglobulin-like receptors can predict TKI treatment-free remission in chronic
CD26 monoclonal antibody-Begelomab, Bone Marrow Transplant. (2020), https:// myeloid leukemia patients, Exp. Hematol. 43 (12) (2015) 1015–1018, https://doi.
doi.org/10.1038/s41409-020-0855-z. org/10.1016/j.exphem.2015.08.004 e1.
[34] N. Vankadari, J.A. Wilce, Emerging WuHan (COVID-19) coronavirus: glycan [57] A. Hughes, A.S.M. Yong, Immune effector recovery in chronic myeloid leukemia
shield and structure prediction of spike glycoprotein and its interaction with and treatment-free remission, Front. Immunol. 8 (2017) 469, https://doi.org/10.
human CD26, Emerg. Microbes Infect. 9 (1) (2020) 601–604, https://doi.org/10. 3389/fimmu.2017.00469.
1080/22221751.2020.173956. [58] T. Alsuliman, L. Magro, V. Coiteux, J. Gauthier, M. Srour, A. Lionet, et al., The
[35] V. Deretic, B. Levine, Autophagy balances inflammation in innate immunity, concurrent administration of imatinib with extracorporeal photopheresis leads to
Autophagy. 14 (2) (2018) 243–251, https://doi.org/10.1080/15548627.2017. complete and durable responses in patients with refractory sclerotic type chronic
1402992. graft-versus-host disease, Curr. Res. Transl. Med. (2019), https://doi.org/10.
[36] D.J. Drucker, Coronavirus infections and type 2 diabetes-shared pathways with 1016/j.retram.2019.10.001 pii: S2452-3186(19)30041-30048.
therapeutic implications, Endocr. Rev. (2020), https://doi.org/10.1210/endrev/ [59] A. Olivieri, F. Locatelli, M. Zecca, A. Sanna, M. Cimminiello, R. Raimondi, et al.,
bnaa011 pii: bnaa011. Imatinib for refractory chronic graft-versus-host disease with fibrotic features,
[37] G. Iacobellis, COVID-19 and diabetes: Can DPP4 inhibition play a role? Diabetes Blood 114 (3) (2009) 709–718, https://doi.org/10.1182/blood-2009-02-204156.
Res. Clin. Pract. 162 (2020), https://doi.org/10.1016/j.diabres.2020.108125 [60] I. Sánchez-Ortega, R. Parody, O. Servitje, C. Muniesa, M. Arnan, B. Patino, et al.,
108125. Imatinib and dasatinib as salvage therapy for sclerotic chronic graft-vs-host

9
S. Galimberti, et al. Pharmacological Research 157 (2020) 104866

disease, Croat. Med. J. 57 (3) (2016) 247–254. and interferon-α induces prolonged clinical and molecular remissions in patients
[61] A. Iurlo, S. Galimberti, E. Abruzzese, M. Annunziata, M. Bonifacio, R. Latagliata, with follicular lymphoma, Br. J. Haematol. 184 (3) (2019) 469–472, https://doi.
et al., Pleural effusion and molecular response in dasatinib-treated chronic mye- org/10.1111/bjh.15118.
loid leukemia patients in a real-life Italian multicenter series, Ann. Hematol. 97 (1) [83] D.E. Joshua, S. MacCallum, J. Gibson, Role of alpha interferon in multiple mye-
(2018) 95–100, https://doi.org/10.1007/s00277-017-3144-1. loma, Blood Rev. 11 (4) (1997) 191–200 PMID: 9481449.
[62] A. Bergeron, D. Réa, V. Levy, C. Picard, V. Meignin, J. Tamburini, et al., Lung [84] L.J. Stockman, R. Bellamy, P. Garner, SARS: systematic review of treatment ef-
abnormalities after dasatinib treatment for chronic myeloid leukemia: a case fects, PLoS Med. 3 (9) (2006) e343 PMID:16968120.
series, Am. J. Respir. Crit. Care Med. 176 (8) (2007) 814–818. [85] P. Raanani, I. Ben-Bassat, Immune-mediated complications during interferon
[63] H. de Lavallade, S. Punnialingam, D. Milojkovic, M. Bua, J.S. Khorashad, therapy in hematological patients, Acta Haematol. 107 (3) (2002) 133–144
I.H. Gabriel, et al., Pleural effusions in patients with chronic myeloid leukaemia PMID:11978934.
treated with dasatinib may have an immune-mediated pathogenesis, Br. J. [86] L. Prokunina-Olsson, N. Alphonse, R.E. Dickenson, J.E. Durbin, J.S. Glenn,
Haematol. 141 (5) (2008) 745–747, https://doi.org/10.1111/j.1365-2141.2008. R. Hartmann, et al., COVID-19 and emerging viral infections: the case for inter-
07108.x. feron lambda, J. Exp. Med. 217 (5) (2020), https://doi.org/10.1084/jem.
[64] A. Maiti, J.E. Cortes, K.P. Patel, L. Masarova, G. Borthakur, F. Ravandi, et al., 20200653 pii: e20200653.
Long-term results of frontline dasatinib in chronic myeloid leukemia, Cancer 126 [87] W.L.A. Cai, H.K. Galtung, E.M. Guerreiro, R. Øvstebø, B. Thiede, T.P. Utheim,
(7) (2020) 1502–1511, https://doi.org/10.1002/cncr.32627. et al., Proteomic and histopathological characterisation of sicca subjects and pri-
[65] J.E. Cortes, G. Saglio, H.M. Kantarjian, M. Baccarani, J. Mayer, C. Boqué, et al., mary Sjögren’s syndrome patients reveals promising tear, saliva and extracellular
Final 5-Year study results of DASISION: the dasatinib versus imatinib study in vesicle disease biomarkers, Arthritis Res. Ther. 21 (1) (2019) 181, https://doi.org/
treatment-naïve chronic myeloid leukemia patients trial, J. Clin. Oncol. 34 (20) 10.1186/s13075-019-1961-4.
(2016) 2333–2340, https://doi.org/10.1200/JCO.2015.64.8899. [88] N. Li, Shi RH. lncRNACNN3-206 activates intestinal epithelial cell apoptosis and
[66] S. Isfort, M. Crysandt, D. Gezer, S. Koschmieder, T.H. Brümmendorf, Wolf D. invasion by sponging miR-212, an implication for Crohn’s disease, World J.
Bosutinib: a potent second-generation tyrosine kinase inhibitor, Recent Results Gastroenterol. 26 (5) (2020) 478–498, https://doi.org/10.3748/wjg.v26.i5.478.
Cancer Res. 212 (2018) 87–108, https://doi.org/10.1007/978-3-319-91439-8_4. [89] M. Ribon, J. Mussard, L. Semerano, B.B. Singer, P. Decker, Extracellular chromatin
[67] M. Tiribelli, E. Abruzzese, I. Capodanno, F. Sorà, E. Trabacchi, A. Iurlo, et al., triggers release of soluble CEACAM8 upon activation of neutrophils, Front.
Efficacy and safety of bosutinib in chronic phase CML patients developing pleural Immunol. 10 (2019) 1346, https://doi.org/10.3389/fimmu.2019.01346.
effusion under dasatinib therapy, Ann. Hematol. 98 (11) (2019) 2609–2611, [90] D. Trzybulska, A. Olewicz-Gawlik, K. Graniczna, K. Kisiel, M. Moskal, D. Cieślak,
https://doi.org/10.1007/s00277-019-03802-y. et al., Quantitative analysis of elastase and cathepsin G mRNA levels in peripheral
[68] C. Zhang, L. Leng, Z. Li, Y. Zhao, J. Jiao, Identification of biomarkers and drug blood CD14(+) cells from patients with rheumatoid arthritis, Cell. Immunol. 292
repurposing candidates based on an immune-, inflammation- and membranous (1-2) (2014) 40–44, https://doi.org/10.1016/j.cellimm.2014.08.009.
glomerulonephritis-associated triplets network for membranous glomerulone- [91] J. Bao, Z. Chen, L. Xu, L. Wu, Y. Xiong, Rapamycin protects chondrocytes against
phritis, BMC Med. Genomics 13 (1) (2020) 5, https://doi.org/10.1186/s12920- IL-18-induced apoptosis and ameliorates rat osteoarthritis, Aging (Albany NY).
019-0655-8. (2020) 12, https://doi.org/10.18632/aging.102937.
[69] L. Ma, A. Manaenko, Y.B. Ou, A.W. Shao, S.X. Yang, J.H. Zhang, Bosutinib at- [92] P.S. Sung, W.C. Chang, S.L. Hsieh, CLEC5A: a promiscuous pattern recognition
tenuates inflammation via inhibiting salt-inducible kinases in experimental model receptor to microbes and beyond, Adv. Exp. Med. Biol. 1204 (2020) 57–73,
of intracerebral hemorrhage on mice, Stroke 48 (11) (2017) 3108–3116, https:// https://doi.org/10.1007/978-981-15-1580-4_3.
doi.org/10.1161/STROKEAHA.117.017681. [93] A. Cattaneo, N. Cattaneo, S. Galluzzi, S. Provasi, N. Lopizzo, et al., INDIA-FBP
[70] I. Lonskaya, M.L. Hebron, S.T. Selby, R.S. Turner, C.E. Moussa, Nilotinib and Group. Association of brain amyloidosis with pro-inflammatory gut bacterial taxa
bosutinib modulate pre-plaque alterations of blood immune markers and neuro- and peripheral inflammation markers in cognitively impaired elderly, Neurobiol.
inflammation in Alzheimer’s disease models, Neuroscience. 304 (2015) 316–327, Aging 49 (2017) 60–68, https://doi.org/10.1016/j.neurobiolaging.2016.08.019.
https://doi.org/10.1016/j.neuroscience.2015.07.070. [94] J. Marschallinger, T. Iram, M. Zardeneta, S.E. Lee, B. Lehallier, M.S. Haney, et al.,
[71] J.E. Cortes, C. Gambacorti-Passerini, M.W. Deininger, M.J. Mauro, C. Chuah, Lipid-droplet-accumulating microglia represent a dysfunctional and proin-
D.W. Kim, et al., Bosutinib versus imatinib for newly diagnosed chronic myeloid flammatory state in the aging brain, Nat. Neurosci. 23 (2) (2020) 194–208,
leukemia: results from the randomized BFORE trial, J. Clin. Oncol. 36 (3) (2018) https://doi.org/10.1038/s41593-019-0566-1.
231–237, https://doi.org/10.1200/JCO.2017.74.7162. [95] P. Hruska, D. Kuruczova, V. Vasku, J. Bienertova-Vasku, MiR-21 binding site SNP
[72] T. Sacha, G. Saglio, Nilotinib in the treatment of chronic myeloid leukemia, Future within ITGAM associated with psoriasis susceptibility in women, PLoS One 14 (6)
Oncol. 15 (9) (2019) 953–965, https://doi.org/10.2217/fon-2018-0468. (2019), https://doi.org/10.1371/journal.pone.0218323 e0218323.
[73] E. Marinelli Busilacchi, A. Costantini, N. Viola, B. Costantini, J. Olivieri, L. Butini, [96] A. Silbereisen, A.K. Hallak, G.G. Nascimento, T. Sorsa, G.N. Belibasakis, R. Lopez,
et al., Immunomodulatory effects of tyrosine kinase inhibitor in vitro and in vivo N. Bostanci, Regulation of PGLYRP1 and TREM-1 during progression and resolu-
study, Biol. Blood Marrow Transplant. 24 (2) (2018) 267–275, https://doi.org/10. tion of gingival inflammation, JDR Clin. Trans. Res. 4 (4) (2019) 352–359, https://
1016/j.bbmt.2017.10.039. doi.org/10.1177/2380084419844937.
[74] E. Marinelli Busilacchi, A. Costantini, G. Mancini, G. Tossetta, J. Olivieri, [97] W. Cai, X. Dai, J. Chen, J. Zhao, M. Xu, L. Zhang, B. Yang, et al., STAT6/Arg1
A. Poloni, et al., Nilotinib Treatment of Patients Affected by Chronic Graft-versus- promotes microglia/macrophage efferocytosis and inflammation resolution in
Host Disease Reduces Collagen Production and Skin Fibrosis by Downmodulating stroke mice, JCI Insight 4 (20) (2019), https://doi.org/10.1172/jci.insight.131355
the TGF-β and p-SMAD Pathway, Biol. Blood Marrow Transplant. (2020), https:// pii: 131355.
doi.org/10.1016/j.bbmt.2020.01.014 pii: S1083-8791(20)30046-X. [98] F.H. Brennan, T. Jogia, E.R. Gillespie, L.V. Blomster, X.X. Li, B. Nowlan, et al.,
[75] A. Hochhaus, G. Saglio, T.P. Hughes, R.A. Larson, D.W. Kim, S. Issaragrisil, et al., Complement receptor C3aR1 controls neutrophil mobilization following spinal
Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid cord injury through physiological antagonism of CXCR2, JCI Insight 4 (9) (2019),
leukemia in chronic phase: 5-year update of the randomized ENESTnd trial, https://doi.org/10.1172/jci.insight.98254 pii: 98254.
Leukemia 30 (5) (2016) 1044–1054, https://doi.org/10.1038/leu.2016.5. [99] T. Nagaishi, L. Pao, S.H. Lin, H. Iijima, A. Kaser, S.W. Qiao, et al., SHP1 phos-
[76] G. Caocci, O. Mulas, M. Annunziata, L. Luciano, E. Abruzzese, M. Bonifacio, et al., phatase-dependent T cell inhibition by CEACAM1 adhesion molecule isoforms,
Long-term mortality rate for cardiovascular disease in 656 chronic myeloid leu- Immunity 25 (5) (2006) 769–781.
kaemia patients treated with second- and third-generation tyrosine kinase in- [100] M. Wątek, U. Wnorowska, T. Wollny, B. Durnaś, P. Wolak, S. Kościołek-Zgódka,
hibitors, Int. J. Cardiol. 301 (2020) 163–166, https://doi.org/10.1016/j.ijcard. et al., Hypogelsolinemia in patients diagnosed with acute myeloid leukemia at
2019.10.036. initial stage of Sepsis, Med. Sci. Monit. 25 (2019) 1452–1458, https://doi.org/10.
[77] G. Caocci, O. Mulas, M. Annunziata, L. Luciano, M. Bonifacio, E.M. Orlandi, et al., 12659/MSM.911904.
Cardiovascular toxicity in patients with chronic myeloid leukemia treated with [101] J.A. Slade, J.V. Hall, J. Kintner, R. Phillips-Campbell, R.V. Schoborg, Host Nectin-1
second-generation tyrosine kinase inhibitors in the real-life practice: Identification promotes chlamydial infection in the female mouse genital tract, but is not re-
of risk factors and the role of prophylaxis, Am. J. Hematol. 93 (7) (2018) quired for infection in a novel male murine rectal infection model, PLoS One 11
E159–E161, https://doi.org/10.1002/ajh.25102. (8) (2016), https://doi.org/10.1371/journal.pone.0160511 e0160511.
[78] M. Bocchia, S. Galimberti, L. Aprile, A. Sicuranza, A. Gozzini, F. Santilli, et al., [102] L. Quero, A.N. Tiaden, E. Hanser, J. Roux, A. Laski, J. Hall, Kyburz D. miR-221-3p
Genetic predisposition and induced pro-inflammatory/pro-oxidative status may drives the shift of M2-Macrophages to a pro-inflammatory function by suppressing
play a role in increased atherothrombotic events in nilotinib treated chronic JAK3/STAT3 activation, Front. Immunol. 10 (2020) 3087, https://doi.org/10.
myeloid leukemia patients, Oncotarget 7 (44) (2016) 72311–72321, https://doi. 3389/fimmu.2019.03087.
org/10.18632/oncotarget.11100. [103] T. Gui, B.S. He, Q. Gan, C. Yang, Enhanced SOCS3 in osteoarthiritis may limit both
[79] R.P. Gale, R. Hehlmann, M.J. Zhang, J. Hasford, J.M. Goldman, H. Heimpel, et al., proliferation and inflammation, Biotech. Histochem. 92 (2) (2017) 107–114,
Survival with bone marrow transplantation versus hydroxyurea or interferon for https://doi.org/10.1080/10520295.2017.1278792.
chronic myelogenous leukemia, The German CML Study Group. Blood. 91 (5) [104] S. Ribes, C. Arcilla, M. Ott, S. Schütze, U.K. Hanisch, S. Nessler, R. Nau, Pre-
(1998) 1810–1819. treatment with the viral Toll-like receptor 3 agonist poly(I:C) modulates innate
[80] H.C. Hasselbalch, M.O. Holmström, Perspectives on interferon-alpha in the immunity and protects neutropenic mice infected intracerebrally with Escherichia
treatment of polycythemia vera and related myeloproliferative neoplasms: coli, J. Neuroinflammation 17 (1) (2020) 24, https://doi.org/10.1186/s12974-
minimal residual disease and cure? Semin. Immunopathol. 41 (1) (2019) 5–19, 020-1700-4.
https://doi.org/10.1007/s00281-018-0700-2. [105] O. Touzelet, L. Broadbent, S.D. Armstrong, W. Aljabr, E. Cloutman-Green,
[81] P.A. Thompson, F. Ravandi, How I manage patients with hairy cell leukaemia, Br. U.F. Power, J.A. Hiscox, The secretome profiling of a pediatric airway epithelium
J. Haematol. 177 (4) (2017) 543–556, https://doi.org/10.1111/bjh.14524]. infected with hRSV identified aberrant apical/basolateral trafficking and novel
[82] L. Smyth, R. Buckstein, N. Pennell, R. Weerasinghe, M.C. Cheung, K. Imrie, et al., immune modulating (CXCL6, CXCL16, CSF3) and antiviral (CEACAM1) proteins,
Autologous stem cell transplant and combination immunotherapy of rituximab Mol. Cell Proteomics (2020), https://doi.org/10.1074/mcp.RA119.001546 pii:

10
S. Galimberti, et al. Pharmacological Research 157 (2020) 104866

mcp.RA119.001546. [126] C. Ratcliffe, B. Wandschneider, S. Baxendale, P. Thompson, M.J. Koepp,

[106] S. Liong, R. Lim, G. Barker, M. Lappas, Hepatitis A virus cellular receptor 2 L. Caciagli, Cognitive function in genetic generalized epilepsies: insights from
(HAVCR2) is decreased with viral infection and regulates pro-labour mediators neuropsychology and neuroimaging, Front. Neurol. 11 (2020) 144, https://doi.
OA, Am J Reprod Immunol. 78 (1) (2017), https://doi.org/10.1111/aji.12696. org/10.3389/fneur.2020.00144.
[107] P. Gao, L. Fan, H. Du, B. Xiang, Y. Li, M. Sun, et al., Recombinant duck interferon [127] Z. Merhi, A.J. Polotsky, A.P. Bradford, E. Buyuk, J. Chosich, T. Phang, et al.,
gamma inhibits H5N1 influenza virus replication in vitro and in vivo, J. Interferon Adiposity alters genes important in inflammation and cell cycle division in human
Cytokine Res. 38 (7) (2018) 290–297, https://doi.org/10.1089/jir.2018.0034. cumulus granulosa cell, Reprod. Sci. 22 (10) (2015) 1220–1228, https://doi.org/
[108] H.F. Rosenberg, Eosinophil-derived neurotoxin (EDN/RNase 2) and the mouse 10.1177/1933719115572484.
eosinophil-associated RNases (mEars): expanding roles in promoting host defense, [128] M. Krześniak, A. Zajkowicz, A. Gdowicz-Kłosok, M. Głowala-Kosińska, B. Łasut-
Int. J. Mol. Sci. 16 (7) (2015) 15442–15455, https://doi.org/10.3390/ Szyszka, M. Rusin, Synergistic activation of p53 by actinomycin D and nutlin-3a is
ijms160715442. associated with the upregulation of crucial regulators and effectors of innate im-
[109] L. Cao, X.M. Wu, P. Nie, M.X. Chang, The negative regulation of piscine CD44c in munity, Cell. Signal. 69 (2020) 109552, , https://doi.org/10.1016/j.cellsig.2020.
viral and bacterial infection, Dev. Comp. Immunol. 96 (2019) 135–143, https:// 109552.
doi.org/10.1016/j.dci.2019.03.005. [129] J. Kusuyama, A. Komorizono, K. Bandow, T. Ohnishi, T. Matsuguchi, CXCL3 po-
[110] R. Alves, S.E.B. McArdle, J. Vadakekolathu, A.C. Gonçalves, P. Freitas-Tavares, sitively regulates adipogenic differentiation, J. Lipid Res. 57 (10) (2016)
A. Pereira, et al., Flow cytometry and targeted immune transcriptomics identify 806–1820.
distinct profiles in patients with chronic myeloid leukemia receiving tyrosine ki- [130] S. Kröller-Schön, A. Daiber, S. Steven, M. Oelze, K. Frenis, S. Kalinovic, et al.,
nase inhibitors with or without interferon-α, J. Transl. Med. 18 (1) (2020) 2, Crucial role for Nox2 and sleep deprivation in aircraft noise-induced vascular and
https://doi.org/10.1186/s12967-019-02194-x. cerebral oxidative stress, inflammation, and gene regulation, Eur. Heart J. 39 (38)
[111] F.F. Yalniz, M.H. Murad, S.J. Lee, S.Z. Pavletic, N. Khera, N.D. Shah, S.K. Hashmi, (2018) 3528–3539, https://doi.org/10.1093/eurheartj/ehy333.
Steroid refractory chronic graft-versus-Host disease: cost-effectiveness analysis, [131] K.L. Hsu, K. Tsuboi, A. Adibekian, H. Pugh, K. Masuda, B.F. Cravatt, DAGLβ in-
Biol. Blood Marrow Transplant. 24 (9) (2018) 1920–1927, https://doi.org/10. hibition perturbs a lipid network involved in macrophage inflammatory responses,
1016/j.bbmt.2018.03.008. Nat. Chem. Biol. 8 (12) (2012) 999–1007, https://doi.org/10.1038/nchembio.
[112] K. Sweet, L. Hazlehurst, E. Sahakian, J. Powers, L. Nodzon, F. Kayali, K. Hyland, 1105.
et al., A phase I clinical trial of ruxolitinib in combination with nilotinib in chronic [132] W. Gu, D. Wen, H. Lu, A. Zhang, H. Wang, J. Du, et al., MiR-608 exerts anti-
myeloid leukemia patients with molecular evidence of disease, Leuk. Res. 74 inflammatory effects by targeting ELANE in monocytes, J. Clin. Immunol. 40 (1)
(2018) 89–96, https://doi.org/10.1016/j.leukres.2018.10.002. (2020) 147–157, https://doi.org/10.1007/s10875-019-00702-8.
[113] Y. Cheng, M. Pereira, N.P. Raukar, J.L. Reagan, M. Quesenberry, L. Goldberg, [133] A. Cardenas, J.E. Sordillo, S.L. Rifas-Shiman, W. Chung, L. Liang, B.A. Coull, et al.,
et al., Inflammation-related gene expression profiles of salivary extracellular ve- The nasal methylome as a biomarker of asthma and airway inflammation in
sicles in patients with head trauma, Neural Regen. Res. 15 (4) (2020) 676–681, children, Nat. Commun. 10 (1) (2019) 3095, https://doi.org/10.1038/s41467-
https://doi.org/10.4103/1673-5374.266924. 019-11058-3.
[114] Y.A. Tsou, Y.T. Tung, T.F. Wu, G.R. Chang, H.C. Chen, C.D. Lin, et al., Lactoferrin [134] C. Wang, Y. Ke, S. Liu, S. Pan, Z. Liu, H. Zhang, et al., Ectopic fibroblast growth
interacts with SPLUNC1 to attenuate lipopolysaccharide-induced inflammation of factor receptor 1 promotes inflammation by promoting nuclear factor-κB signaling
human nasal epithelial cells via down-regulated MEK1/2-MAPK signaling, in prostate cancer cells, J. Biol. Chem. 293 (38) (2018) 14839–14849, https://doi.
Biochem. Cell Biol. 95 (3) (2017) 394–399, https://doi.org/10.1139/bcb-2016- org/10.1074/jbc.RA118.002907.
0047. [135] J. Markic, A. Jeroncic, D. Polancec, N. Bosnjak, A. Markotic, J. Mestrovic,
[115] B.H. Yoon, R. Romero, J.Y. Park, K.J. Oh, J. Lee, A. Conde-Agudelo, J.S. Hong, V.C. Culic, CD15s is a potential biomarker of serious bacterial infection in infants
Antibiotic administration can eradicate intra-amniotic infection or intra-amniotic admitted to hospital, Eur. J. Pediatr. 172 (10) (2013) 1363–1369, https://doi.org/
inflammation in a subset of patients with preterm labor and intact membranes, 10.1007/s00431-013-2047-y.
Am. J. Obstet. Gynecol. 221 (2) (2019) 142, https://doi.org/10.1016/j.ajog.2019. [136] F. Li, Y. Sheng, W. Hou, P. Sampath, D. Byrd, S. Thorne, Y. Zhang, CCL5-armed
03.018 e1-142.e22. oncolytic virus augments CCR5-engineered NK cell infiltration and antitumor ef-
[116] N. Funel, V. Dini, A. Janowska, B. Loggini, M. Minale, F. Grieco, et al., Triticum ficiency, J. Immunother. Cancer 8 (1) (2020), https://doi.org/10.1136/jitc-2019-
vulgare extract modulates protein-kinase B and matrix metalloproteinases 9 pro- 000131 pii: e000131.
tein expression in BV-2 cells: bioactivity on inflammatory pathway associated with [137] K. Matsuo, D. Nagakubo, Y. Komori, S. Fujisato, N. Takeda, M. Kitamatsu, et al.,
molecular mechanism wound healing, Mediators Inflamm. 2020 (2020) 2851949, CCR4 is critically involved in skin allergic inflammation of BALB/c mice, J. Invest.
, https://doi.org/10.1155/2020/2851949. Dermatol. 138 (8) (2018) 1764–1773, https://doi.org/10.1016/j.jid.2018.02.027.
[117] Aratani Y. Myeloperoxidase, Its role for host defense, inflammation, and neu- [138] F. Li, Y. Sheng, W. Hou, P. Sampath, D. Byrd, S. Thorne, Y. Zhang, CCL5-armed
trophil function, Arch. Biochem. Biophys. 640 (2018) 47–52, https://doi.org/10. oncolytic virus augments CCR5-engineered NK cell infiltration and antitumor ef-
1016/j.abb.2018.01.004. ficiency, J. Immunother. Cancer 8 (1) (2020), https://doi.org/10.1136/jitc-2019-
[118] O.J. Lara-Guzmán, Á Gil-Izquierdo, S. Medina, E. Osorio, R. Álvarez-Quintero, 000131 pii: e000131.
N. Zuluaga, et al., Oxidized LDL triggers changes in oxidative stress and in- [139] E. Hui, J. Cheung, J. Zhu, X. Su, M.J. Taylor, H.A. Wallweber, et al., T cell cost-
flammatory biomarkers in human macrophages, Redox Biol. 15 (2018) 1–11, imulatory receptor CD28 is a primary target for PD-1-mediated inhibition, Science.
https://doi.org/10.1016/j.redox.2017.11.017. 355 (6332) (2017) 1428–1433, https://doi.org/10.1126/science.aaf1292.
[119] Y. Shi, Z. Zhang, D. Cai, J. Kuang, S. Jin, C. Zhu, et al., Urokinase attenuates [140] Z.Q. Wang, K. Milne, J.R. Webb, P.H. Watson, CD74 and intratumoral immune
pulmonary thromboembolism in an animal model by inhibition of inflammatory response in breast cancer, Oncotarget. 8 (8) (2017) 12664–12674, https://doi.
response, J. Immunol. Res. 2018 (2018), https://doi.org/10.1155/2018/6941368 org/10.18632/oncotarget.8610.
6941368. [141] I. Leonardi, X. Li, A. Semon, D. Li, I. Doron, G. Putzel, et al.,
[120] Y. Yun, A. Kanda, Y. Kobayashi, D. Van Bui, K. Suzuki, S. Sawada, et al., Increased CX3CR1+mononuclear phagocytes control immunity to intestinal fungi, Science.
CD69 expression on activated eosinophils in eosinophilic chronic rhinosinusitis 359 (6372) (2018) 232–236, https://doi.org/10.1126/science.aao1503.
correlates with clinical findings, Allergol. Int. (2020), https://doi.org/10.1016/j. [142] J.R. Groom, A.D. Luster, CXCR3 in T cell function, Exp. Cell Res. 317 (5) (2011)
alit.2019.11.002 pii: S1323-8930(19)30194-30197. 620–631, https://doi.org/10.1016/j.yexcr.2010.12.017.
[121] B. Bottazzi, A. Inforzato, M. Messa, M. Barbagallo, E. Magrini, C. Garlanda, [143] D. Bahal, T. Hashem, K.E. Nichols, Das R. SLAM-SAP-Fyn, Old players with new
A. Mantovani, The pentraxins PTX3 and SAP in innate immunity, regulation of roles in iNKT cell development and function, Int. J. Mol. Sci. 20 (19) (2019),
inflammation and tissue remodelling, J. Hepatol. 64 (6) (2016) 1416–1427, https://doi.org/10.3390/ijms20194797 pii: E4797.
https://doi.org/10.1016/j.jhep.2016.02.029. [144] T. Xu, A. Keller, G.J. Martinez, NFAT1 and NFAT2 differentially regulate CTL
[122] K. Kitisin, N. Ganesan, Y. Tang, W. Jogunoori, E.A. Volpe, S.S. Kim, et al., differentiation upon acute viral infection, Front. Immunol. 10 (2019) 184, https://
Disruption of transforming growth factor-beta signaling through beta-spectrin ELF doi.org/10.3389/fimmu.2019.00184.
leads to hepatocellular cancer through cyclin D1 activation, Oncogene 26 (50) [145] C. Lelubre, H. Medfai, I. Akl, J. Leentjens, M. Kox, P. Pickkers, et al., Leukocyte
(2007) 7103–7110. phosphodiesterase expression after lipopolysaccharide and during sepsis and its
[123] R. Isaac, I. Goldstein, N. Furth, N. Zilber, S. Streim, S. Boura-Halfon, et al., relationship with HLA-DR expression, J. Leukoc. Biol. 101 (6) (2017) 1419–1426,
TM7SF3, a novel p53-regulated homeostatic factor, attenuates cellular stress and https://doi.org/10.1189/jlb.5A0516-240R.
the subsequent induction of the unfolded protein response, Cell Death Differ. 24 [146] M.S. Mangan, C.R. Melo-Silva, J. Luu, C.H. Bird, A. Koskinen, A. Rizzitelli, et al., A
(1) (2017) 132–143, https://doi.org/10.1038/cdd.2016.108. pro-survival role for the intracellular granzyme B inhibitor Serpinb9 in natural
[124] S. Niture, J. Moore, D. Kumar, TNFAIP8: inflammation, immunity and human killer cells during poxvirus infection, Immunol. Cell Biol. 95 (10) (2017) 884–894,
diseases, J. Mol. Cell. Immunol. 1 (2) (2019) 29–34. https://doi.org/10.1038/icb.2017.59.
[125] T. Ostendorf, T. Zillinger, K. Andryka, T.M. Schlee-Guimaraes, S. Schmitz, S. Marx, [147] H. Li, C. Fan, C. Feng, Y. Wu, H. Lu, P. He, X. Yang, et al., Inhibition of phos-
et al., Immune sensing of synthetic, bacterial, and protozoan RNA by toll-like phodiesterase-4 attenuates murine ulcerative colitis through interference with
receptor 8 requires coordinated processing by RNase T2 and RNase 2, Immunity. mucosal immunity, Br. J. Pharmacol. 176 (13) (2019) 2209–2226, https://doi.
52 (4) (2020) 591–605, https://doi.org/10.1016/j.immuni.2020.03.009 e6. org/10.1111/bph.14667.

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