Keywords
eltrombopag - romiplostim - avatrombopag
Schlüsselwörter
eltrombopag - romiplostim - avatrombopag
Introduction
Thrombocytopenia poses a common problem and may accompany various conditions, such
as hematologic malignancies (HMs), aplastic anemia (AA), chronic liver disease (CLD),
and patients with solid organ tumors (SOT) receiving chemotherapy. Moreover, immune-mediated
platelet destruction may be established abruptly, as is in the case of immune thrombocytopenia
(ITP).
Thrombopoietin (TPO) constitutes the master regulator of platelet production.[1]
[2] TPO is primarily produced in the liver and acts through binding to the extracellular
domain of partially predimerized cell surface TPO receptor (TPO-R), thus leading to
conformational changes, which initiate a cascade of signaling events, involving the
JAK/STAT, RAS/MAPK, and PI3K/AKT pathways.[1]
[2] In particular, TPO-R has no intrinsic kinase activity and mostly utilizes janus
kinase 2 (JAK2), which is phosphorylated upon TPO signaling, to transduce signals
within the target cell.[1]
[2] TPO exerts its effects in various stages of platelet differentiation, thereby augmenting
megakaryocytes proliferation and maturation, whereas more recent data highlight its
impact on hematopoietic stem cells (HSCs), where TPO plays a double role. On the one
hand, it promotes proliferation and survival of CD34+ and other early progenitor cells,
without affecting polarization toward a specific hematopoietic linage, on the other
hand it stimulates cell cycle arrest in more primitive HSCs in the osteoblastic niches,
preserving them in quiescence and thus protecting of their exhaustion, in cases of
great needs.[1]
[2] In addition, it seems that TPO may play a role in DNA repair in HSCs.[1]
[2]
In the past years, given the favorable properties of endogenous TPO, remarkable progress
has been made in the development of TPO receptor agonists (TPO-RAs). Recombinant human
thrombopoietin (rhTPO) and pegylated recombinant human megakaryocyte growth and development
factor (PEG-rHuMGDF) were the first agents to be developed but were soon abandoned
due to the appearance of anti-TPO autoantibodies, thereby leading to second-generation
TPO-RAs development, which are biochemically unrelated to endogenous TPO and eliminate
the possibility of autoantibody occurrence. Romiplostim (ROMI) is a peptibody that
antagonizes endogenous TPO for binding to extracellular domain of TPO-R but with a
25-fold lower affinity. Thus, in cases where endogenous TPO levels are elevated, such
as in acute myeloid leukemia (AML), use of ROMI may be limited.[2]
[3]
[4]
[5] In vitro and in vivo studies showed that ROMI stimulates the growth of colony-forming
unit-megakaryocyte (CFU-MK); increases the number, size, and ploidy of megakaryocytes;
and improves platelet production.[2]
[3]
[4]
[5]
Eltrombopag (EP) is an oral synthetic nonpeptide, which, unlike endogenous TPO, binds
to the transmembrane domain of TPO-R, thus having an additive rather than competitive
effect and rendering it an attractive option even in cases where TPO levels are elevated.
EP effectively augments proliferation and survival of megakaryocytes, through activation
of various downstream pathways, such as JAK/STAT, MAPK, AKT, ERK, but at a different
extent in comparison to ROMI.[6] For instance, previous in vitro studies showed that EP is capable of eliciting a
balanced activation of both AKT and ERK 1/2 pathways, both in hematopoietic progenitors
and mature megakaryocytes; besides proliferation of megakaryocytes, it probably further
prospers proplatelet formation, whereas ROMI triggers for megakaryocyte growth through
activation of AKT almost exclusively, and barely affects proplatelet formation.[6] These different activation patterns of downstream pathways may further influence
employment of these agents in different settings. Moreover, different properties of
EP and ROMI may be responsible for different adverse events. For example, neutralizing
antibodies against ROMI have been detected in ROMI-treated patients and have been
correlated with loss of response, while treatment with EP, which is a small molecule,
seems to confer no such risk.[4] Furthermore, EP contains a metal chelate group in the center that makes it a powerful
iron chelator and also displays a spectrum of off-target effects.[2]
[3]
[4]
[5]
[7] These iron chelating properties of EP seem to be responsible for a TPO-independent
effect on stimulating stem cells and megakaryocyte precursors in vivo.[4] Recent studies in ITP and AA have also demonstrated immunomodulatory and anti-inflammatory
capacities of these agents, mainly attributable to their interference with transforming
growth factor-β (TGF-β).[2]
[3]
[4]
[5]
[7] Increased TGF-β secretion is considered to be primarily accountable for augmented
reticulin bone marrow (BM) fibrosis, which is observed mostly in EP-treated ITP patients,
and although it is reversible, it tends to worsen in a time-dependent fashion.[7] Notably, myeloproliferative neoplasm (MPN)-like changes, with a tendency of megakaryocytes
to form clusters, have also been observed in the BM of EP-treated patients.[7] Nonetheless, these newly discovered properties of EP remain a subject of intensive
study and pave the way for further exploitation of this drug. Recently, three more
oral TPO-RAs, which also bind on the transmembrane TPO-R domain, were developed in
China: avatrombopag, lusutrombopag, and hetrombopag.[4]
[8]
Advent of TPO-RAs led to novel therapeutic approaches in thrombocytopenic patients,
primarily in chronic ITP.[2] EP, ROMI, and avatrombopag are currently approved for the treatment of persistent
or chronic ITP, unresponsive to previous first-line agents or splenectomy.[9] Several studies have reported overall response rates of 60 to 90% in ITP patients
receiving TPO-RAs.[9] Results of increased efficacy in ITP patients along with understanding TPO's effects
on HSCs gave rise to employment of TPO-RAs in a variety of thrombocytopenic settings.[2] EP has been shown effective in the management of thrombocytopenia related to hepatitis
C virus (HCV) infection, thus allowing initiation and maintenance of interferon-based
therapy.[1]
[2]
[3]
[4] EP has also been approved for the management of severe AA, either as first-line
treatment, combined with standard immunosuppressive therapy, or as second-line treatment
in refractory patients.[4]
[7] Recently, avatrombopag and lusutrombopag have also been approved for use in patients
with CLD that undergo surgery or invasive procedures.[4]
[10] Efficacy of both of these agents has been validated in large, randomized, phase
3 trials and results are in accordance with real-world data that report no requirement
for preoperative platelet transfusions in 65 to 93% of CLD patients receiving a TPO-RA
prior to an invasive procedure. Importantly, these agents have also been met with
a favorable safety profile and have low potential for drug-to-drug interactions.[10]
Collectively, these results have laid the basis for further exploration of TPO-RAs
in other thrombocytopenic settings. In this review, we discuss a broad spectrum of
thrombocytopenic conditions where TPO-RAs could be incorporated as a treatment option,
highlighting potent novel uses of these drugs, while we also discuss, in the context
of drug repurposing, about novel findings of use of TPO-RAs in the case of infections.
Thrombopoietin Receptor Agonists in Hematologic Malignancies
Thrombopoietin Receptor Agonists in Hematologic Malignancies
Thrombopoietin Receptor Agonists in Myelodysplastic Neoplasms
Myelodysplastic neoplasms (MDS) comprise a heterogenous group of HMs that are defined
by one or more cytopenias and uni- or multi-linage dysplasia, with a tendency to evolve
to AML.[11] Clinical presentation reflects the existing inadequate hematopoiesis, with profound
anemia being the most prevalent feature, while neutropenia is responsible for recurrent
infections.[11] Thrombocytopenia, which is observed in up to 25%, is associated with increased bleeding
risk and is predictive of early death.[12]
Management of MDS patients is individualized and depends mostly on clinical status,
MDS subtype and prognosis, and the presence of specific mutations that pose as targets
for novel treatments. Common therapeutic options include administration of growth
factors (e.g., erythropoietin [EPO] or luspatercept), hypomethylating (HMA) or immunomodulatory
agents, as well as targeted treatments, while allogeneic hematopoietic stem cell transplantation
(allo-HSCT) stands as the ideal option for fit patients. Regarding thrombocytopenia,
therapeutic choices are confined.[11] Although platelet transfusions play a primary role in patients with lifelong thrombocytopenia,
they have several drawbacks; since they are associated with short-term efficacy, they
have limited availability, and they also bear the risk of acute reactions and alloimmunization
with subsequent refractoriness to latter transfusions.[11]
[12]
Considering that TPO-RAs effectively incite for expansion of HSCs and stimulate for
bi- or tri-lineage hematopoiesis, their utility was also investigated in MDS. ROMI
was first evaluated in a prospective phase I/II trial of patients with low-risk MDS
and thrombocytopenia on supportive care only and the results showed a raise in platelet
counts in most of the patients, while a durable response was observed in 46%, who
remained transfusion free for 8 weeks.[13] At the same time, another phase II study examined ROMI's efficacy in low- or intermediate-risk
MDS patients who receive azacytidine and demonstrated a potential clinical benefit.[14] Subsequent studies investigated coadministration of ROMI with decitabine[15] and lenalidomide[16] in low- or intermediate-risk MDS and showed a decrease of clinically significant
thrombocytopenic events, which is grade 3 or 4 thrombocytopenia on day 15 of treatment
cycle or need for platelet transfusions during treatment. An additional phase II study
demonstrated that ROMI was efficacious in the same setting, achieving high platelet
counts and fewer bleeding episodes and transfusions, but terminated early due to concerns
of potential risk for progression to AML, which was associated with a ROMI-mediated
transient increase in peripheral blast cell counts; however, despite initial concerns,
follow-up study of the patients has demonstrated similar survival and AML rates between
ROMI and placebo group.[17]
Although well tolerated, results from a study showed that ROMI was responsible for
an increase in peripheral blasts in 9% of patients, that diminished after drug interruption,
thus prompting to concerns of potent clonal evolution.[13] In vitro studies demonstrated that various TPO concentrations trigger for TPO-R-mediated
expansion of specific blast cells of myeloid lineage.[3]
[13] However, recent data indicate that this expansion may be limited to patients with
preexisting leukemogenic mutations (e.g., AML1-ETO fusion) that act in synergy.[3]
[13] Moreover, just as ROMI, granulocyte colony-stimulating factor (G-CSF), which is
used in these patients for a longer period, leads to an increase in peripheral blasts.[13] In addition, it was shown later that patients of the aforementioned terminated study
were observed for 5 years and had the same risk for evolution to AML, regardless of
ROMI administration.[17]
[18] Ensuing studies and meta-analyses demonstrated same results.[19]
[20] Nevertheless, more studies need to be conducted so as to assess safety of ROMI in
this group.
In the wake of these encouraging results, EP's efficacy was also explored in MDS patients.
A phase I study showed that administration of 200 mg EP along with azacytidine in
MDS patients was safe and tolerable, while similar results were reported from subsequent
studies.[21] EQoL-MDS study demonstrated that EP was efficacious and tolerable in patients with
low- and intermediate-risk MDS and thrombocytopenia, raising platelet counts and decreasing
bleeding episodes, whereas a second phase of the study, concerning duration of platelet
response and long-term safety and tolerability, is still in progress.[22] Another recent study also reported that EP, as monotherapy in patients with low
or intermediate-1 risk patients, achieved hematologic responses in 44% of them, with
hypocellular BM, high TPO levels, and the presence of paroxysmal nocturnal hemoglobinuria
clones being predictive of response.[23] Similar outcomes were also reported during combination of EP with lenalidomide.[24] While EP's efficacy was demonstrated in low- and intermediate-risk MDS, data regarding
high-risk MDS are conflicting. ASPIRE study evaluated EP's efficacy in high-risk MDS
and AML patients and described a reduction of grade 3 or 4 bleeding events and need
for platelet transfusion in EP recipients.[25] On the contrary SUPPORT study of high-risk MDS patients, which investigated efficacy
of EP's coadministration with azacytidine versus azacytidine monotherapy, showed a
deterioration in platelet responses, more adverse events, and a tendency to AML progression
in the combination arm, thus leading to early termination of the study.[26] Similar results regarding efficacy were also reported in the more recent ELASTIC
study.[27] Modest platelet responses were also observed in post-HMA failure patients.[28]
[29]
Although tolerable, a major concern regarding the use of EP in HMs is that it could
contribute to blast proliferation and clone expansion, considering also that TPO-R
is variably expressed in leukemic cells of AML patients at ∼50% and given the increased
frequency of clonal cytogenetic abnormalities, chromosome 7 disorders included, observed
in AA patients receiving EP.[30] Further research, however, highlighted that EP probably displays antitumor properties.[31]
[32]
[33]
[34]
[35]
[36]
[37] In particular, EP suppressed leukemic cell lines and declined their survival.[31]
[32]
[33]
[35]
[36] This action was independent of TPO-R expression on leukemic cells and was not diminished
if TPO, EPO, or G-SCF was given or TPO-R was silenced and it was also observed in
mice, which lack TPO-R species-specific binding site, thus indicating that EP acts
in a TPO-R-independent way.[31]
[32]
[33]
[34]
[35]
[36]
Further investigation of the underlying mechanisms demonstrated that these effects
are mostly attributed to EP's induced iron chelation. A study previously denoted that
EP disrupts cell growth in human and murine leukemia cells, through an arrest in G(1)
phase of cell cycle, and leads to their increased differentiation and also indicated
that these EP's effects were associated in a dose-dependent way with a reduction of
intracellular iron.[35] Similar results were also described for other non-myeloid cellular lines, as is
hepatocellular carcinoma (HCC).[37] In general, leukemic and cancer cells have high metabolic needs; hence, iron deprivation
could crucially impact their growth.[35] Exceptionally, EP is also capable of binding other polyvalent cations such as copper
and zinc, which are also vital for these cells.[35] A study showed that EP rapidly decreases intracellular reactive oxygen species (ROS),
especially hydrogen peroxide (H2O2), thus generating rapid apoptosis of leukemic cells.[36] ROS are an elemental component of cells' homeostasis, regulating a variety of cellular
processes and their levels fluctuate among various cells.[36] For instance, cancer cells have elevated ROS levels that establish a permanent pro-oxidative
state. Whichever disorder in ROS levels leads to imbalance and apoptosis.[36] A recent study also showed that EP stimulates for self-renewal and proliferation
of HSCs, through an iron-mediated molecular reprogramming caused by labile iron pool
alterations, an effect independent of TPO-R, since it was not observed in TPO-R lacking
mice treated with ROMI.[38] Antitumor properties, mediated by its iron chelating ability, were also observed
in pediatric AML patients treated with cytarabine,[39] indicating a potential synergism, as well as in other cancers, such as HCC and Ewing's
sarcoma.[36]
[40] Finally, EP was also found to be an allosteric inhibitor of the METTL3–14 methyltransferase
complex, which is abundant in AML cells, thereby suppressing cell proliferation.[41]
Concisely, EP possibly exerts antiproliferative effects. Also, considering EP's low
molecular weight and lipophilicity that allow cellular uptake and high chelator efficacy,
it could represent a powerful weapon for patients with HMs, not only as a hematopoiesis
stimulator but also as an antileukemic drug, incorporated into chemotherapy regimens.
Of note, due to EP's iron chelating properties, iron-deficiency anemia may arise;
so, patients should be closely monitored.
Thrombopoietin Receptor Agonists in Acute Myeloid Leukemia
Thrombocytopenia in AML is also a frequent complication leading to increased morbidity
and is exacerbated due to underlying BM infiltration and chemotherapy-induced myelotoxicity.[42]
Even though EP is tolerable in AML patients, evidence concerning its efficacy remains
ambiguous.[42]
[43]
[44]
[45]
[46] EP proved to have a favorable safety profile in AML patients to doses up to 300 mg.[43] Additionally, although EP inhibits breast cancer resistance protein (BCRP), which
is a substrate for daunorubicin, thus implementing increased risk for cardiotoxicity,
a study denoted no cardiotoxic effects in patients receiving both EP and daunorubicin;
yet, EP's efficacy was not demonstrated.[42] A recent study in patients receiving induction chemotherapy reported that although
EP addition led to significant decrease in platelet transfusions, it did not affect
survival.[44] ASPIRE study also described a decline of clinically related thrombocytopenic events.[25] Moreover, Mukherjee et al reported that EP hastened platelet response rates and
reduced transfusions during induction chemotherapy, which is in accordance with findings
from a study of EP during consolidation chemotherapy.[45]
[46] Data regarding ROMI's use are scarce, since AML patients present with elevated TPO
levels that may prevent ROMI's action.[2]
[3]
[4]
Besides EP's newly emerged antileukemic properties, TPO-RAs are promising candidates
for treating thrombocytopenic AML patients. However, more prospective studies need
to be conducted to first prove their efficacy and then define optimal dose and schedule
of administration as well as durability of responses.
Thrombopoietin Receptor Agonists in Other Hematologic Malignancies
Several ongoing trials investigate the utility of TPO-RAs in the treatment of secondary
ITP or chemotherapy-induced thrombocytopenia (CIT) associated with HMs, such as lymphomas.
A recent study of lymphoma patients with CIT demonstrated reduced bleeding episodes
and platelet transfusions and higher platelet counts in EP and rhTPO recipients, thus
indicating a potential benefit.[47]
Another clinical trial evaluated EP's use in patients with chronic myeloid leukemia
or myelofibrosis upon treatment with tyrosine kinase inhibitors or ruxolitinib, respectively,
where thrombocytopenia frequently is an obstacle, resulting in treatment delay or
dose reduction.[48] EP managed to achieve a complete response in 30% of patients for at least 3 months
and permitted treatment continuation.[48]
Considerably, a study previously showed that EP can trigger megakaryopoiesis in BM
progenitors of patients with relapsed multiple myeloma (rMM) through stimulation of
AKT signaling pathways, without provoking myeloma cells' expansion or altering lenalidomide's
and bortezomib's apoptotic effects, thus implementing a potential use in rMM.[49]
Thrombopoietin Receptor Agonists in Chemotherapy-Induced Thrombocytopenia in Patients
with Solid Organ Tumors
Thrombopoietin Receptor Agonists in Chemotherapy-Induced Thrombocytopenia in Patients
with Solid Organ Tumors
CIT, which is frequently defined as platelet counts below 100,000/mL, constitutes
the most common cause of thrombocytopenia in SOT patients and its incidence and severity
are contingent on cancer subtype and chemotherapy regimen.[50]
[51] Besides increasing bleeding risk, CIT also acts as a limiting factor for anticoagulant
initiation or submission to surgery or invasive procedure.[50]
[51] Additionally, CIT often induces treatment interruption or reduction of chemotherapy-relative
dose intensity, thus affecting overall survival. Recombinant interleukin-11 (oprelvekin)
was efficiently used, yet serious adverse events occurred, thus leaving only platelet
transfusions as an option.[50]
[51]
Efficacy of rhTPO has been previously evaluated in SOT patients with CIT and currently
rhTPO is approved for use in this setting only in China.[52] During past years, management of CIT with second-generation TPO-RAs has also been
studied. Findings from most important studies are summarized in [Table 1].[52]
[53]
[54]
[55]
[56]
[57]
[58]
[59]
[60]
[61]
[62]
[63]
[64]
[65]
[66] Retrospective studies of ROMI's use in CIT highlighted a raise in platelet counts
in the vast majority and importantly no treatment delay or discontinuation or dose
reduction was observed.[53]
[54]
[55]
[58]
[59]
[61] In agreement, some prospective studies also indicated ROMI's efficacy and safety
in this setting, with one of them reporting sustained platelet responses.[56]
[57]
[60] It was demonstrated that BM infiltration, prior pelvic irradiation, and prior exposure
to temozolomide were predictive of non-response to ROMI, while lower TPO levels were
correlated with better responses.[58]
[59] While ROMI was mostly utilized for CIT treatment, EP was mostly tested for CIT prevention,
with available data suggesting a potential benefit.[62]
[63]
[64] Most recent studies explored avatrombopag's use for CIT management, also pointing
at a potential therapeutic use.[52]
[65]
[66]
Table 1
Studies of second-generation thrombopoietin receptor agonists in chemotherapy-induced
thrombocytopenia
|
Type of study
|
Patient population
|
TPO-RA used and dose administrated
|
Baseline PLT counts prior to TPO-RA initiation
|
Major efficacy results
|
TEE rate
|
|
Romiplostim
|
|
Parameswaran et al[53]
|
Retrospective
|
N = 20 patients with various SOTs receiving a range of treatments
|
ROMI 1–2 μg/kg weekly, dose-titrated
|
<100,000/μL (mean PLTs 58,000/mL)
|
1. Correction of PLT counts ≥ 100,000/μL: 95%
2. Chemotherapy resumption without dose reduction: 75%
|
DVT in 15%
|
|
Miao et al[54]
|
Retrospective
|
N = 42 patients with various SOTs receiving a range of treatments
|
ROMI 2 μg/kg
|
<100,000/μL
(median PLTs 71,000/μL)
|
1. Correction of PLT counts ≥ 100,000/μL: 94%
2. Chemotherapy resumption: 91.8%
|
14.3%
|
|
Al-Samkari et al[55]
|
Retrospective
|
N = 22 patients with various SOTs receiving a range of treatments
|
ROMI 3 μg/kg weekly, dose-titrated
|
74,000/μL (21,000–145,000/μL)
|
1. Correction of PLT counts ≥ 100,000/μL: 94%
2. Chemotherapy resumption for at least 2 cycles: 100%, 82% without dose reduction
|
No TEEs observed
|
|
Soff et al[56]
|
Randomized phase II trial
|
N = 60 patients with various SOTs receiving a range of treatments:
N = 15 randomly assigned on ROMI
N = 8 randomly assigned on observation
N = 37 single-arm ROMI phase
|
ROMI 2.0 μg/kg weekly, dose-titrated vs. observation
|
< 100,000/μL (mean PLT count 62,000/μL)
|
1. Correction of PLTs ≥ 100,000/μL within 3 wk:
- 93% in ROMI arm vs. 12.5% in observation arm (p < 0.01)
- 81% in single-arm ROMI phase
- 85% in all ROMI patients
2. Chemotherapy resumption for 8 wk or at least 2 cycles, without recurrent CIT:
85%, all responders to ROMI continued with maintenance ROMI without chemotherapy interruption
|
10.2%
|
|
Le Rhun et al
[57]
|
Phase II multicenter single-arm trial
|
N = 20 patients with newly diagnosed glioblastoma that were to be treated with standard
first-line concomitant TMZ/RT and maintenance TMZ for 6 cycles and were to develop
CTCAE grade 3/4 thrombocytopenia
|
ROMI 750 μg starting dose, weekly for a maximum of 6 cycles of maintenance TMZ
|
53,500/μL (6,000–59,000/μL)
|
Percentage of thrombocytopenic patients treated with ROMI that are able to complete
6 cycles of maintenance TMZ exceeds 10%
(secondary prophylaxis of TMZ-induced thrombocytopenia): 60% success rate (95% CI:
36–81%)
|
5%
|
|
Al-Samkari et al[58]
|
Retrospective
|
N = 153 patients with various SOTs receiving a range of treatments
|
ROMI median initiating dose 3 μg/kg, weekly or intracycle dosing
|
<100,000/μL
(median PLTs: 54,000/μL)
|
1. Correction of PLT counts ≥ 75 × 109/L and at least 30 × 109/L than pretreatment baseline: 71%
2. Achievement of PLT counts ≥ 100,000/μL: 85%
3. Chemotherapy resumption: 98%, 79% without dose reduction or delay
4. Need for PLT transfusions: 89% without need for PLT transfusions
|
5.2%
|
|
Song et al[59]
|
Retrospective
|
N = 63 patients with various SOTs receiving a range of treatments
|
ROMI 2–3 μg/kg dose-titrated, weekly
|
42,000/μL
(17,000–64,000/μL)
|
1. Correction of PLT counts ≥ 75 × 109/L and at least 30 × 109/L than pretreatment baseline:
85.7% overall response, 42.9% moderate response, 42.9% superior response
2. Need for PLT transfusions: 27%
|
NR
|
|
Wilkins et al[60]
|
Extended phase of the Soff et al study[56]
|
N = 21 patients who were treated with ROMI for ≥ 1 y
|
ROMI 3–5 μg/kg weekly
|
|
Prevention of chemotherapy dose reduction/delays due to CIT (PLTs < 100,000/μL): 70%
|
9.5%
|
|
Cheloff et al[61]
|
Retrospective
|
N = 5 patients with various SOTs receiving niraparib
|
ROMI 2 μg–5 μg/kg weekly
|
41,000/μL (14–97,000)
|
1. Correction of PLT counts ≥ 100,000/μL: 80%
2. Chemotherapy resumption: 100%
|
No TEEs observed
|
|
Eltrombopag
|
|
Kellum et al[62]
|
Randomized, multicenter double-blind, placebo-controlled
|
N = 183 patients with various SOTs who were to receive first-line carboplatin/paclitaxel
N = 46 randomly assigned on placebo
N = 44 randomly assigned on 50 mg EP
|
Placebo or EP 50 mg, 75 mg, or 100 mg (1:1:1:1) on day 2 through 11 of each 21-d chemotherapy
cycle
|
Mean Gi/L
Placebo: 321.8
50 mg EP: 290.6
75 mg EP: 317.7
100 mg EP: 324
|
1. Change in PLT counts from day 1 in cycle 1 to PLT nadir in cycle 2: EP did not
significantly decrease the change in PLT counts during cycle 2, compared with placebo,
although all patients in the EP arms had higher PLT counts on day 1 of cycles 2 and
3
2. Chemotherapy dose intensity: mean dose of carboplatin and paclitaxel was similar
across all patient groups
|
TEEs
Placebo: 7%
50 mg EP: 5%
75 mg EP: 5%
100 mg EP: 13%
|
|
Winer et al[63]
|
Randomized, multicenter phase I
|
N = 26 patients with various SOTs who were to receive gemcitabine/cisplatin (group
A) or gemcitabine monotherapy (group B)
Group A: EP N = 9, placebo: N = 3
Group B: EP N = 10, placebo: N = 4
|
Four dose cohorts of EP: 100 mg, 150 mg, 225 mg, 300 mg given on days -5 to -1 and
days 2 to 6 of each cycle, beginning on cycle 2
|
Mean PLT counts
Group A:
EP: 108.6 × 109/L
Placebo: 140 × 109/L
Group B:
EP: 269.2 × 109/L
Placebo: 263.7 × 109/L
|
1. Mean platelet nadirs across cycles 2–6:
Group A
EP: 115 × 109/L
Placebo: 53 × 109/L
Group B
EP 143 × 109/L
Placebo: 103 × 109/L
2. Chemotherapy dose reduction/delays across cycles 2–6:
Group A
EP: 22%
Placebo: 33%
Group B
EP: 40%
Placebo: 75%
|
DVT
Group A:
EP: 22%
Placebo: 0%
Group B:
EP: 10%
Placebo: 0%
|
|
Winer et al[64]
|
Randomized, multicenter placebo-controlled phase 2
|
N = 75 patients with various SOTs who were to receive ≥ 2 cycles of gemcitabine monotherapy
or combination chemotherapy with either carboplatin or cisplatin
Combination chemotherapy: n = 22 EP, n = 11 placebo
Gemcitabine monotherapy:
n = 30 EP, n = 12 placebo
|
EP 100 mg once daily or placebo on days -5 to -1 and days 2 to 6 of each chemotherapy
cycle, initiated at first cycle
|
Mean pre-chemotherapy PLT counts > 100,000/μL in all groups
|
1. Pre-chemotherapy (day 1) PLT counts across ≤ 6 cycles and PLT nadirs:
higher pre-chemotherapy PLT counts and higher PLT nadirs in EP-treated patients vs.
placebo in both arms
2. Frequencies of grades 3/4 thrombocytopenia:
Combination therapy arm:
EP 77 vs. 100% placebo
Monotherapy arm: EP 36% vs. 42% placebo
3. Chemotherapy dose delays/reductions:
Combination therapy arm:
EP 77% vs. 91% placebo
Monotherapy arm: EP 62% vs. 83% placebo
|
Gemcitabine monotherapy: 13% in EP arm vs. 8% in placebo arm
Combination chemotherapy: 5% in EP arm vs. 9% arm
|
|
Avatrombopag
|
|
Cui et al[52]
|
Multicenter, open-label, single-arm
|
N = 74 patients with various SOTs receiving a range of treatments
|
Avatrombopag 60 mg once daily for 5–10 d
|
< 75,000/μL
|
1. Correction of PLT counts ≥ 100 × 109/L or ≥ 75 × 109/L or increase ≥ 100% from baseline in the cycle after TPO-R initiation: 56.8, 59.5,
36.5%, respectively
2. Need for PLT transfusions: 18.9%
|
No TEEs observed
|
|
Gao et al[65]
|
Single-arm, single-center
|
N = 13 patients with various SOTs receiving a range of treatments
|
Avatrombopag 60 mg once daily for 8 wk
|
NR
|
1. Correction of PLT counts ≥ 50 × 109/L: 61.3%
2. Transfusion independence: 76.9%
|
NR
|
|
Al-Samkari et al[66]
|
Randomized, double-blind, placebo-controlled, phase 3
|
N = 122 patients with various SOTs receiving a range of treatments
N = 82 randomly assigned to avatrombopag 60 mg daily
N = 40 randomly assigned to placebo
|
Avatrombopag 60 mg once daily vs. placebo for 5 d before and after chemotherapy administration
|
31,000/μL
(16,000–42,000/μL)
|
Proportion of responders not requiring PLT transfusions or either a ≥ 15% chemotherapy
dose reduction or a ≥ 4-d chemotherapy delay:
70%, 95% CI: 58–79 in avatrombopag group vs. 73%, 95% CI: 56–85
|
2% in avatrombopag group, 3% in placebo
|
Abbreviations: CIT, chemotherapy-induced thrombocytopenia; CTCAE, common terminology
criteria for adverse events; EP, eltrombopag; PLT, platelet; ROMI, romiplostim; RT,
radiotherapy; SOTs, solid organ tumors; TEEs, thromboembolic events; TMZ, temozolomide;
TPO-RA, thrombopoietin receptor agonists.
Use of TPO-RAs in cancer patients raises concerns regarding their theoretical risk
for thrombosis or tumor proliferation; yet, TPO-R is barely expressed in cancer cells,
which makes the latter rather impossible.[51] Additionally, previous findings indicate that TPO-RAs do not increase platelet reactivity
in vitro.[51] Moreover, aforementioned studies proved TPO-RAs' safety and tolerability, whereas
thromboembolic event rates were analogous to those historically observed in cancer
patients.[52]
[53]
[54]
[55]
[56]
[57]
[58]
[59]
[60]
[61]
[62]
[63]
[64]
[65]
[66] As seen in [Table 1], available data from trials have reported different thromboembolic event (TEE) rates,
with avatrombopag yielding the lowest TEE rates.[52]
[53]
[54]
[55]
[56]
[57]
[58]
[59]
[60]
[61]
[62]
[63]
[64]
[65]
[66] It is not certain whether these differences can be solely attributed to the type
of TPO-RA that has been used; however, similar results, indicating low rates of thrombosis
with avatrombopag, have also been reported in patients with CLD.[10] Hence, based on these results, avatrombopag may seem more preferable in SOT patients.
Of note, recent guidelines by the International Society on Thrombosis and Haemostasis
(ISTH) Subcommittee on Hemostasis and Malignancy suggest the use of ROMI over other
TPO-RAs, whenever TPO-RAs are used for CIT, outside of the context of a clinical trial.[67] Nonetheless, further investigation is required for strong conclusions to be drawn.
Briefly, existing literature supports that TPO-RAs are potential candidates for either
prevention or management of CIT in SOT patients. Several trials are ongoing and further
investigation is certainly warranted to shed light on optimum TPO-RA dose, when TPO-RAs
ideally should be given during chemotherapy cycle and who are the patients that could
benefit the most.
Thrombopoietin Receptor Agonists in Allogeneic Hematopoietic Stem Cell Transplantation
Thrombopoietin Receptor Agonists in Allogeneic Hematopoietic Stem Cell Transplantation
Persisting thrombocytopenia post–allo-HSCT is a common complication with severe morbidity
and mortality and its etiology is multifactorial.[68] Available literature reports two types of thrombocytopenia after engraftment. Primary
failure of platelet recovery refers to remaining platelet counts below 20,000/μL in
the absence of graft failure, meaning a recovery of neutrophil counts, while secondary
failure of platelet recovery (SFPR) refers to platelet counts below 20,000/μL for
7 consecutive days or reappearance of need for transfusions, while previous platelet
counts were above 50,000/μL for 7 consecutive days without transfusions.[68] SFPR can be found in up to 20% of allo-HSCT patients.[68] Also, some authors report prolonged isolated thrombocytopenia (PIT) as dependence
on platelet transfusions > 90 days after allo-HSCT.[69] Recently, American Society for Transplantation and Cellular Therapy defined platelet
recovery post-allo-HSCT as the raise of platelets above 20,000/μL for the first 3
consecutive days in the absence of platelet transfusion for 7 consecutive days.[70] Also, poor graft function (PGF), a controversial entity that occurs in up to 20%
of patients, is defined as persistent cytopenias with transfusion dependency or regular
growth factor administration in the absence of other possible causes, as are drugs
or infections.[70] Notwithstanding the various definitions, thrombocytopenia in these patients is a
major problem and failure to achieve platelet counts more than 50,000/μL until 60th
day independently correlates with higher treatment-related mortality and poorer overall
survival.[71] Platelet transfusions remain the backbone of therapy, while boost doses of CD34+ cells have been used in PGF.[68]
Some retrospective studies, as seen in [Table 2], examined TPO-RA's role in this context, with reported response rates varying from
39.3 to 83.3%,[72]
[73]
[74]
[75]
[76]
[77]
[78]
[79]
[80]
[81]
[82]
[83] whereas results from few prospective studies are mostly conflicting.[84]
[85] Both ROMI and EP, and recently avatrombopag, proved to be as safe and effective
and possibly cost-effective in comparison to transfusions in thrombocytopenia after
allo-HSCT and PGF.[69]
[72]
[73]
[74]
[75]
[76]
[77]
[78]
[79]
[80]
[81]
[82]
[83]
[84] Notably, EP can elicit multilineage responses and along with its immunomodulatory
and anti-inflammatory effects can induce enhancement of impaired hematopoiesis in
allo-HSCT patients with PGF.[69]
[74]
[75]
[78]
[79]
[80]
[81] EP-induced iron chelation is also beneficial in these patients, which are characterized
by high ferritin levels and iron overload, since iron decrease could result in BM
microenvironment reconstitution.[78] Moreover, newly discovered antiviral properties of EP could contribute to impediment
of cytomegalovirus (CMV) reactivation, which is a major cause of PGF.[86] Given the retrospective nature of most of the studies, prospective trials, which
are currently conducted, will hopefully shed light on TPO-RA's efficacy in this scenario.
Table 2
Retrospective studies of thrombopoietin receptor agonists' use in post-allogeneic
stem cell transplant
|
Patients (n)
|
Posttransplant thrombocytopenia
|
TPO-RA
|
Response definition
|
Response rates
|
Time from start of TPO-RA to PLT response
|
Predictive factors of response
|
|
Hartranft et al[72]
|
n = 13
|
PFPR (n = 4) and SFPR (n = 9)
|
ROMI 1–10 μg/kg
|
PLT ≥ 50 × 109/L for 7 consecutive days without PLT transfusion
|
R: 53.8%
|
35 (14–56) d to response
|
Inclusion of an antilymphocyte agent (ATG or alemtuzumab) was more common among the
nonresponders
|
|
Bosch-Vilaseca et al[73]
|
n = 20
|
PFPR (n = 2) and SFPR (n = 18)
|
ROMI 1–7 μg/kg (n = 18)
EP 50–150 mg (n = 2)
|
CR: ≥ 30 × 109/L for 7 consecutive days without PLT transfusion
|
60%
ROMI: 66.6%
EP: 0%
|
28 d to response
|
Age < 40 y, previous response to other hematopoietic growth factors, and presence
of MK in BM were associated with higher responses
|
|
Fu et al[74]
|
n = 38
|
SFPR (n = 15), PGF (n = 15), DPE (n = 8)
|
EP 50–100 mg daily
|
CR: PLT recovery to ≥ 50 × 109/L for 7 consecutive days without PLT transfusion
R: PLT recovery to independence from PLT transfusion but with a PLT count < 50 × 109/L during or within 7 days after EP treatment
OR: CR and R
|
OR: 63.2%
CR: 52.6%
R: 10.5%
|
17 (2–89) d to PLT response
32 (7–127) d to CR
|
Presence of MK before initiation
|
|
Yuan et al[75]
|
n = 13
|
PFPR (n = 6) and SFPR (n = 7)
|
EP 25–50 mg
|
PLT ≥ 50 × 109/L for 7 consecutive days without PLT transfusion
|
62%
|
33 (11–68) d to response
|
Both patients with adequate and decreased MK in BM responded
|
|
Marotta et al[76]
|
n = 13
|
PFPR (n = 1)
PGF (n = 12)
|
EP 50–150 mg
|
CR: PLT > 80 × 109/L, Hb > 11 g/dL, and ANC > 1.5 × 109/L
|
46%
|
28–120 d to response
|
NR
|
|
Bento et al[77]
|
n = 86
|
PIT (n = 16) and SFPR (n = 71)
|
EP 25–150 mg (n = 51)
ROMI 1–7 μg/kg (n = 35)
|
PLT ≥ 50 × 109/L for 7 consecutive days without PLT transfusion
|
72%
|
66 (2–247) d to response
|
Decreased numbers of MK in BM were associated with a slower response
|
|
Aydin et al[78]
|
n = 12
|
PEF (n = 1), PGF (n = 11)
|
EP 50–150 mg daily
|
CR: PLT > 50 × 109/L, ANC > 1.500 × 106/L, Hb > 10 g/dL without transfusions or G-CSF support
|
CR: 83.3%
|
66 (44–425) d for PLT counts 141 (6–291) d for Hb levels
200 (21–379) d for ANC
|
NR
|
|
Gao et al[79]
|
n = 32
|
PGF (n = 15), SFPR (n = 17)
|
EP 50–100 mg daily
|
CR: PLT ≥ 100 × 109/L for 7 consecutive days without transfusion
PR: PLT ≥ 50 × 109/L but < 100 × 109/L for 7 consecutive days without PLT transfusion
OR: CR and PR
|
CR: 43.8%
PR: 22.8%
OR: 65.6%
|
41 d to PR, 62 d to CR
|
PGF-independent risk factor of OR, decreased MK amounts, and splenomegaly independent
risk factors of CR
|
|
Halahleh et al[80]
|
n = 14
|
PGF
|
EP 50–150 mg
|
PLT > 50 × 109/L, Hb > 10 g/dL, and ANC > 1.0 × 109/L
|
57%
|
30 (6–43) d to response
|
All patients with adequate MK in BM responded
|
|
Giammarco et al[81]
|
n = 48
|
PGF
|
EP 25–100 mg
|
CR: PLT > 50 × 109/L, Hb > 10 g/dL, ANC > 1.5 × 109/L
PR: transfusion independence, Hb > 8 g/dL, PLT > 20 × 109/L, ANC > 0.5 × 109/L
|
CR: 50%
PR: 25%
OR: 75%
|
60 (14–300) d to response
|
HLA-matched donor, CD34+ dose at transplant > 4 × 106/kg, EP initiation at least 90 d after transplantations were positive predictors of
response
|
|
Yan et al[82]
|
n = 34
|
PIT (n = 7) and SFPR (n = 27)
|
EP 25–100 mg
|
CR: PLT > 50 × 109/L for 7 consecutive days without PLT transfusion
PR: PLT > 20 × 109/L for 7 consecutive days without PLT transfusion
|
CR: 60.7%
PR: 72.1%
|
8 (1–51) d to PR,
23 (2–117) d to CR
|
Hypoplasia of BM and decreased MK numbers were found to be risk factors for CR and
OR
|
|
Zhou et al[83]
|
n = 61
|
DPE (n = 35), SFPR (n = 26)
|
Avatrombopag 20–60 mg
|
CR: PLT > 50 × 109/L for 7 consecutive days without PLT transfusion
OR: PLT > 20 × 109/L for at least 7 consecutive days with independence of PLT transfusion
|
CR: 39.3%
OR: 68.9%
|
21 (6–33) d to response,
25 (9–40) d to CR
|
Adequate number of MK-independent protective factor for OR and CR
|
Abbreviations: ANC, absolute neutrophil count; ATG, antithymocyte globulin; BM, bone
marrow; CR, complete response; DPE, delayed platelet engraftment; EP, eltrombopag;
G-CSF, granulocyte-colony-stimulating factor; Hb, hemoglobin; HLA, human-leucocyte
antigen; MK, megakaryocytes; NR, not reported; OR, overall response; PEF, primary
engraftment failure; PFPR, primary failure of platelet recovery; PGF, poor graft function;
PIT, persistent isolated thrombocytopenia; PLT, platelets; PR, partial response; R,
response; ROMI, romiplostim; SFPR, secondary failure of platelet recovery.
Thrombopoietin Receptor Agonists in Inherited Thrombocytopenias
Thrombopoietin Receptor Agonists in Inherited Thrombocytopenias
Inherited thrombocytopenias (ITs) embrace a heterogenous group of rare disorders,
which are defined by reduction of platelet numbers with a bleeding tendency at various
extents, depending on the severity of thrombocytopenia.[87] ITs may derive either from ineffective platelet production, mostly due to defects
in commitment-differentiation of HSC to megakaryocytes, transcription factors necessary
for megakaryocyte maturation or proplatelet formation, or from increased platelet
clearance.[87] Although breakthrough advances on the recognition of IT genetics have been made,
with multiple genes being incriminated, management of these conditions remains troublesome.[87] Besides suggesting patients for taking precautions, antifibrinolytics and platelet
transfusions are the only available treatment options for most cases, in the event
of a major bleeding or an invasive procedure, whereas allo-HSCT remains as the only
curative solution.[87]
Use of TPO-RAs in the management of ITs is a highly promising approach. The rationale
for their use in ITs lies upon the fact that TPO-RAs could stimulate for megakaryopoiesis
in ITs, provided that megakaryocyte maturation in response to TPO is not disrupted,
as is, for instance, in the case of myosin heavy chain 9 (MYH9) related disorders
(MYH9-RDs).[87] So far, experience in this setting is restricted. As seen in [Table 3], reports from the available studies showed that TPO-RAs were well-tolerated and
achieved an increase in platelet numbers in the vast majority, thus indicating a potential
benefit.[88]
[89]
[90]
[91] Importantly, a retrospective study evaluated the use of ROMI in pediatric patients
with Wiskott-Aldrich syndrome (WAS) as bridging treatment until HSCT displayed good
responses, thus making it a probable safe transit until HSCT.[91] Moreover, increasing case series and reports, mostly in IT patients with an imminent
invasive procedure or an elective surgery, demonstrate a successful transient raise
in platelet counts with the use of TPO-RAs, thus potentially replacing pre- or perioperative
platelet transfusions.[87]
Table 3
Results from studies of the use of thrombopoietin receptor agonists in inherited thrombocytopenias
|
Disease
|
Type of study
|
Sample
|
TPO-RA
|
PLT counts
|
Response rate
|
Treatment duration
|
|
Pecci et al[88]
|
MYH9-RD
|
Prospective, Phase II
|
n = 12
|
EP
50–75 mg/d
|
31.2 × 109/L
|
R: 92%
CR: 67%
BR: 80%
|
3–6 wk
|
|
Gerrits et al[89]
|
WAS
|
Prospective, Phase II
|
n = 8
|
EP
9–75 mg/d
|
19 × 109/L
|
R: 62.5%
CR: 50%
BR: 75%
|
20–187 wk
|
|
Zaninetti et al[90]
|
MYH9-RD
ANKRD26-RT
WAS
mBSS
ITGB3-RT
|
Prospective, Phase II
|
n = 24
|
EP
25–75 mg/d
|
40 × 109/L
|
R: 91.3%
CR: 47%
BR: 83%
|
3–6 wk
|
|
Khoreva et al[91]
|
WAS
|
Retrospective
|
n = 67
|
ROMI
9 μg/kg/wk
|
2,109/L
|
R: 60%
CR: 33%
BR: 100%
|
1–12 mo
|
Abbreviations: ANKRD26-RT, ankyrin repeat domain containing 26 related thrombocytopenia;
BR, reduction or absence of bleeding events independent of platelet count raise; CR,
complete response; EP, eltrombopag; ITGB3-RT, integrin subunit β3-related thrombocytopenia;
mBSS, monoallelic Bernard-Soulier syndrome; MYH9-RD, myosin heavy chain 9 related
disorders; PLT, platelet; R, response, whichever response observed; ROMI, romiplostim;
WAS, Wiskott-Aldrich syndrome.
In the wake of these results, TPO-RAs could potentially be considered in the management
of ITs, either as a short-term treatment for preparation for an invasive procedure
or as an intermediate step before HSCT, as prolonged treatment in patients with serious
bleeding events, so as to achieve a durable reduction of bleeding severity and frequency.
Additional research is needed to establish the efficacy and safety of TPO-RAs in thrombocytopenia
of genetic origin as well as to define the proper dose and timing of administration.
Thrombopoietin Receptor Agonists in Infections
Thrombopoietin Receptor Agonists in Infections
EP has been efficiently utilized in the management of thrombocytopenic patients due
to HCV infection and laid the foundation for subsequent investigation of EP's use
in the case of infections. During the past years, EP has been examined not only as
a means for raising platelet counts in some infections but also as an antimicrobial,
antiviral, and antifungal agent, in the context of drug repurposing.
Eltrombopag in Dengue Virus–Related Thrombocytopenia
Dengue virus (DENV), a mosquito-transmitted flaviviridae RNA virus, strikes as an
increasing problem in tropical and subtropical regions, where it is endemic and is
accountable for high morbidity and mortality rates.[92] It usually presents with a mild or moderate febrile syndrome; yet in 1 to –5%, it
presents with severe bleeding manifestations, that is, dengue hemorrhagic fever (DHF).[92] Thrombocytopenia is a common finding, even in the mildest cases and is associated
with the clinical outcome. It usually occurs between the third and the seventh day
of fever, with platelet counts reaching below 30,000/μL.[92] Thrombocytopenia is multifactorial and is attributed to reduced platelet production,
mostly due to DENV-associated myelosuppression, as well as increased peripheral platelet
destruction.[92] Therapeutic choices are restricted with variable efficacies and include platelet
transfusions, anti-D immune globulin, and papaya Carica leaves.[92]
A randomized controlled phase II clinical trial evaluated the efficacy and safety
of EP to improve thrombocytopenia in moderate to severe dengue patients at doses of
25 and 50 mg, given for 3 consecutive days when platelets first fell below 100,000/μL.[93] It was shown that EP led to significant increase in platelet counts, above 150,000/μL,
on day 7 of enrollment, in 91% of patients, contrary to 55% of control-group patients.[93] Moreover, both doses were equally effective, whereas 25-mg dose was safer than the
higher one.[93] Similarly, a cross-sectional observational study also investigated efficacy and
safety of short-course EP, given at the aforementioned doses in DHF, and showed high
platelet recovery rates in up to 94%.[94] Finally, a case report demonstrated efficacy of ROMI in a patient with multiple
myeloma and DENV-associated thrombocytopenia.[95]
Considerably, these findings indicate a potential use of TPO-RAs in the management
of DHF; yet, more studies need to be conducted to further determine their efficacy
and optimize dose and timing of administration.
Thrombopoietin Receptor Agonists in Staphylococcal Infections
Staphylococcus epidermidis (S. epidermidis) is a common Gram (+) bacterium that is present both in the environment and human
skin.[96] Due to its capacity to form biofilms, an assemblage of bacterial biomass, which
is firmly adhered to a surface, represents a serious concern, as it can enter circulation
and trigger systemic infection, particularly in immunocompromised patients.[96] Moreover, persister cells inside biofilms contribute to significant resistance to
conventional antibiotics.[96]
Staphylococcus aureus (S. aureus) is the most frequent cause of bacterial infections worldwide, with surfacing multiresistant
pathogens, such as methicillin-resistant S. aureus (MRSA), hindering management of these infections.[97] Hence, the need for development of novel treatments has arisen.
In the context of drug repurposing, an in vitro study evaluated the antistaphylococcal
effects of EP against 2 strains and 12 clinical isolates of S. epidermidis and showed that EP exerts bacteriostatic effects against them, with a minimal inhibition
concentration (MIC) of 8 μg/mL.[96] Additionally, it has bactericidal potential, with minimal bactericidal concentrations
being slightly higher than MICs and dose-dependent.[96] Importantly, EP was competent to impede in a strain-dependent way biofilm formation
and eradicate preexisting ones.[96] Furthermore, persister cells, which are resistant to vancomycin even in high doses,
were efficiently eliminated by EP, but in a dose- and strain-dependent way.[96] Of note, concurrent administration of low-dose EP with vancomycin demonstrated a
synergistic efficacy, while higher EP doses were not toxic for mammalian cells.[96]
Similar findings were reported regarding efficacy against S. aureus.[97]
[98] EP had bacteriostatic against 55 S. aureus clinical isolates, including resistant ones, with MIC comparable to that of common
antibiotics, and also inhibited S. aureus intestinal colonies growth in a cell line model, with minimum toxicity.[97] Furthermore, it exhibited antimicrobial activity in an in vivo mouse infection model.[97] Correspondingly, a recent study reported EP's potency against S. aureus, MRSA included, both alone and in combination with vancomycin.[98] It also showed that it can hamper dose dependently S. aureus biofilm formation, while in vivo activity against MRSA was also confirmed, using
a wound and a thigh infection model, and a peritonitis model as well, without toxicity
being observed.[98] Although exact mechanism of EP's antistaphylococcal activity is unknown, previous
studies suggested that endopeptidase lytE and endonuclease yokF may be involved, while
it was also shown that EP disrupts and weakens proton motive force, which is vital
for bacteria.[97]
[98]
Conclusively, EP displays antistaphylococcal activity and is an appealing agent that
could possibly be employed in the treatment of these infections, especially MRSA.
Thrombopoietin Receptor Agonists in Viral Infections
CMV poses a great threat to HSCT recipients and is a significant cause of morbidity
and transplantation failure.[86] Although various treatment options such as ganciclovir exist, they are usually correlated
to critical adverse events, as is thrombocytopenia.[86] A single case report demonstrated an efficient response of platelet counts when
EP was administrated in a patient with CMV-associated thrombocytopenia, previously
unresponsive to conjugated immunosuppressive and antiviral treatment.[99]
Engrossingly, a subsequent study revealed that EP bears antiviral activity through
its iron chelation properties.[86] Specifically, it was shown that EP hampers viral replication during the late stages
of replication cycle of various CMV strains, resistant ones included, with concentrations
being within therapeutic plasma concentration range.[86] Moreover, its combination with either ganciclovir or foscarnet exerted synergistic
effects against CMV.[86] Trying to unveil its inhibitory mechanism of action, it was demonstrated that EP
impedes viral replication, in a TPO-R-independent way, since same effects were observed
in human and murine fibroblasts, which lack TPO-R.[86] Also, it was reported that these effects were attributed to iron depletion provoked
by EP, given that addition of Fe3+ obstructed EP's action and coadministration with deferasirox displaying antagonistic
effects.[86] Importantly, although iron chelators were previously shown to inhibit CMV replication,
some of them also affected other dividing cells, and EP did not affect cell proliferation.[86]
Although results for CMV derive from a single study, similar findings regarding EP's
antiviral potency were previously described. In particular, EP exhibited antiviral
activity against severe fever with thrombocytopenia syndrome virus.[86] Conversely, EP was found to be a lead activator of HIV-1 proviral transcription,
which could be useful for activating and then eliminating latently infected cells.[100] In conclusion, EP's utility in viral infections is of great interest and initial
results are quite encouraging, thereby sowing the seeds for further research.
Thrombopoietin Receptor Agonists in Fungal Infections
Fungal infections are an increasing threat that are responsible for notable morbidity,
mainly in immunocompromised patients, with Cryptococcosis, an invasive fungal infection
provoked by Cryptococcus neoformans (C. neoformans)/Cryptococcus gattii (C. gattii) species complex, being among the most prevalent.[100] Cryptococcosis treatment is rather troublesome, since amphotericin B is nephrotoxic,
5-flucytosine is usually locally available, and fluconazole-resistant isolates keep
emerging.[101]
An in vitro study investigated EP's antifungal activity against Cryptococcus isolates
and other fungi as well.[101] It was demonstrated that EP was fungistatic but not fungicidal, particularly in
higher temperatures, against C. neoformans/C. gattii species complex, Candida glabrata, and Trichophyton rubrum, whereas no activity was observed against other Candida species, Aspergillus fumigatus, or Fusarium solani.[101] Moreover, EP disrupted cryptococcal virulence factors, inducing a reduction of biofilm
and capsule development and impairment of melanin production, thus confining cryptococcal
spread.[101] It was also suggested that EP's mechanism of action may be mediated by calcineurin
pathway and is different from that of azoles.[101]
In conclusion, although available data derive from a single in vitro study, EP exhibited
excellent anticryptococcal activity and this should provide the basis for further
research of EP's potency as an antifungal agent.
Thrombopoietin Receptor Agonists in Acute Radiation Syndrome
Thrombopoietin Receptor Agonists in Acute Radiation Syndrome
Acute radiation syndrome (ARS) is a rare but usually lethal event and involves whole
body irradiation exposure for a short time.[102] High penetrating radiation doses are demanded for the manifestation of ARS.[102] Depending on radiation doses and tissues' radiosensitivity, ARS can be presented
with various clinical syndromes of variable severity, which frequently involves the
gastrointestinal, the hematopoietic, and central nervous system (CNS) and may lead
either to multiorgan failure and a prompt death or a delayed passing, within weeks
or months, usually because of recurrent infections or bleedings induced by underlying
BM failure.[102]
Management of ARS is an emergency, particularly in the case of nuclear accidents,
and it should not be detained. Medical countermeasures encompass standard supportive
care such as fluids and antibiotics, transfusions, G-CSF, EPO, and interleukin-3 administration,
until restoration of hematopoiesis is accomplished, whereas HSCT, which would be favorable,
is not widely available and is accompanied by higher complication rates, exceptionally
when it is urgently conducted.[102] Efforts have been made to optimize a treatment protocol for ARS and recently incorporation
of ROMI to ARS therapy has been examined.
Hirouchi et al evaluated survival of mice exposed to lethal γ-radiation doses after
adding ROMI to standard G-CSF, EPO, and nandrolone administration and demonstrated
superior survival in the combination arm that reached 100% on day 30 versus 50% in
the arm where ROMI was not administered.[103] Another study investigated ROMI's use as monotherapy in the same setting and reported
that ROMI was competent to suppress lethal γ-irradiation effects, with survival rates
reaching 85% on 200th day.[104] Remarkably, ROMI not only improved all hematologic parameters but also augmented
reconstitution and recovery of intestinal mucosa.[104] In agreement with these findings, enhanced repair of liver damage was also described.[105] Similar findings regarding the mitigative effects of ROMI were also reported by
its coadministration with pegfilgrastim in non-human primates.[106]
Interestingly, ROMI's mechanism of action in ARS was also explored. Previous data
support that BM stem cell deficiency can result in promoted hematopoiesis in the lungs,
where hematopoietic progenitors are present, and can further migrate and repopulate
BM.[105] Correspondingly, a study indicated that ROMI enhanced megakaryopoiesis in the lungs
and spleen of irradiated mice, where increased megakaryocyte progenitors were observed.[105] Rapid hematopoiesis in the spleen along with an increase in mesenchymal cells was
also reported.[105] It has been previously shown that TPO-RAs contribute to non-homologous end joining
(NHEJ) DNA repair in HSCs.[3] The aforementioned studies reported that ROMI repressed DNA double-strand breakage
in BM cells of irradiated mice and led to increased DNA repair and also inhibited
cellular apoptosis.[104]
[105] Moreover, a study demonstrated ROMI-induced reduction in expression of three miRNAs,
miR-296–5p, miR-328–3p, and miR-486–5P, which were elevated in irradiated mice and
correlated with radiation-induced leukemogenesis.[105] MiRNAs are enclosed in exosomes, which derive from various cells such as MSCs and
maintain parental properties as is tissue damage repair. Given the observed expansion
of MSCs in the spleen of irradiated mice, ROMI could possibly regulate miRNAs expression
and exert its actions via exosomes targeting HSCs.[105] Of note, some studies reported decreased levels of plasminogen activator inhibitor
1 (PAI-1) among irradiated mice on ROMI administration.[105] PAI-1 is a significant regulator of cellular senescence and its downregulation enacts
antioxidative enzymes and suspends ROS production. Collectively, these findings support
that ROMI, apart from improving hematopoiesis in various organs, produces significant
multitarget effects that contribute to increased survival rates and recovery of damaged
tissues.
In light of these results, ROMI got FDA approval, under the animal rule, as a medical
countermeasure for ARS.[107] Further studies should be conducted to determine appropriate dose and duration of
treatment and to elucidate the exact mechanisms of action.
Conclusions
Evidently, use of TPO-RAs is progressively being incorporated in the management of
non–immune-mediated thrombocytopenia, both in benign and malignant diseases. TPO-RAs
are easy to administer and have low potential for drug-to-drug interactions. Besides
TPO agonism, increasing evidence highlights a broad spectrum of multitarget effects
that TPO-RAs, and EP in particular, may possess and could render TPO-RAs as a highly
promising approach, in terms of efficacy in heterogenous contexts, in the near future.
TPO-RAs could possibly be employed as a supportive measure in the management of HSCT
patients or those with HMs or SOTs, to whom disease- or treatment-related thrombocytopenia
poses a major problem. Similar to patients with CLD, TPO-RAs could be of use in patients
with ITs as a short-term treatment, whenever an invasive procedure is planned. Although
data are restricted and mostly derive from small studies, thorough research and future
trials will possibly pave the way for TPO-RAs' application not only in thrombocytopenic
patients but also in infections as an antiviral, antibacterial, or antifungal agent.
It is important to note that while these potential uses of TPO-RAs are intriguing,
further research is needed to establish their safety and efficacy in these contexts.
Although TEE rates and transient blast proliferation seem not to be correlated with
a particular TPO-RA, and are probably a class effect or are attributed to the underlying
disease, further study is needed to draw strong conclusions. Finally, increasing use
of TPO-RAs in various settings may be accompanied by previously infrequent risks,
such as increased incidence of neutralizing antibodies against ROMI, EP-induced MPN-like
features, and reticulin fibrosis or EP-mediated iron-deficiency anemia; so, patients
should receive these agents in the context of a clinical trial and be carefully monitored,
whenever possible. In conclusion, the future of novel TPO-RA applications holds exciting
possibilities and ongoing research will potentially expand TPO-RA's use beyond their
current approved indications.
What is known about this topic?
-
Thrombopoietin receptor agonists (TPO-RAs) are potent stimulators of megakaryopoiesis
and can elicit tri-linage responses well.
-
TPO-RAs are widely used in the management of immune thrombocytopenia, aplastic anemia,
HCV-related thrombocytopenia, and recently in patients with chronic liver disease
undergoing invasive procedures.
What does this paper add?
-
A comprehensive review of potential novel TPO-RAs' uses, based on findings from recent
studies in various thrombocytopenic settings, including hematologic malignancies,
chemotherapy-induced thrombocytopenia, inherited thrombocytopenias, and thrombocytopenia
post-hematopoietic stem cell transplantation, as well as acute radiation syndrome.
-
An insight into employment of TPO-RAs in infections, as an antistaphylococcal, antiviral,
and antifungal agent, in terms of drug repurposing.
-
Shedding light on possible multitarget effects of TPO-RAs.
