Introduction
Prevention of major bleeding in pediatric and adolescent patients with severe inherited
or acquired thrombocytopenia is still very challenging.[1] The frequency and severity of bleeding is not strictly associated with the number
of platelets,[2] but may be accompanied by platelet dysfunction, particularly in inherited thrombocytopenias.[3] Inherited thrombocytopenias are rare, but result from a wide variety of genetic
defects and must often be understood as symptom of a multisystemic disorder.[4] Since prophylactic transfusion of (adult) donor platelets associates with potential
harm through selective inflammatory or immune processes,[5]
[6] pharmacologic treatment options gain a more predominant position in strategies for
preventing bleeding complications. Over the last decade, the spectrum of options to
manage inherited thrombocytopenias or bleeding disorders has been significantly expanded.
Nowadays, the administration of thrombopoietin receptor agonists (TPO-RAs) in children
and adolescents is also included, as it is most intensively studied for second-line
treatment in persistent and chronic primary immune thrombocytopenia (ITP).
TPO-RAs are a class of drugs that mimic the action of thrombopoietin (TPO), the primary
humoral regulator of megakaryopoiesis.[7] Through binding to the TPO receptor (TPO-R), they activate downstream JAK2/STAT5
signaling pathways, thereby enhancing the proliferation and differentiation of megakaryocytes
(MK) in the bone marrow.[8]
[9] TPO-RAs effectively increase circulating platelet counts. They replaced first-generation
megakaryopoietic growth factors, such as recombinant human TPO (rhTPO), pegylated
megakaryocyte growth and development factor (PEG-rHuMGDF), and TPO–cytokine fusion
proteins (e.g., promegapoietin), following reports that rhTPOs were associated with
the risk of developing anti-TPO antibodies.[10] The group of TPO-RAs consists mainly of TPO peptide mimetics (e.g., romiplostim)
and TPO non-peptide mimetics (e.g., eltrombopag).[11] These substances are used mainly to selectively treat pediatric and adult patients
with persistent or chronic primary ITP, severe aplastic anemia (SAA), and adult patients
with thrombocytopenia associated with chronic liver disease (CLD).[11]
[12]
[13] The use of TPO-RAs has significantly reduced the long-term immunologic or infectious
complications associated with repetitive platelet transfusions, potent immunosuppressants,
and splenectomy.[14]
This review summarizes current data on the use of TPO-RAs for treating severe thrombocytopenia
in infants, children, and adolescents. It focuses on substances approved by the U.S.
Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for use
in these age groups. Specific emphasis is given to the rationale and the limited data
on the use of TPO-RAs in rare inherited thrombocytopenias. Despite often moderately
(or eventually highly) elevated endogenous TPO plasma concentrations in these thrombocytopenias,
the individual use of TPO-RA follows the concept of inducing TPO-R downstream signaling
through alternate TPO-R binding or increasing platelet mass to enhance platelet activation,
immune response, or immune modulation. Future developments in the use of various TPO-RAs
in pediatric patients are outlined based on ongoing registered randomized controlled
trials (RCTs).
Methods
For this narrative review, a literature search strategy was performed by consulting
the PubMed platform of the National Center for Biotechnology Information (NCBI). The
literature search included peer-reviewed papers, published in English and German language,
updated from January 2018 to May 2023. We used the MeSH term “platelet disorders”
or “thrombocytopenia” and “child” or “pediatrics” or “adolescent” and the search terms “romiplostim” or “eltrombopag” or “avatrombopag” or “lusutrombopag” or “hetrombopag,” respectively. We also searched in the resource provided by the U.S.
National Library of Medicine for clinical trials (https://clinicaltrials.gov/) on the use of TPO-RA in pediatric and adolescent patients. Additionally, results
from personal communication within the THROMKIDplus working group of the Gesellschaft für Thrombose und Hämostaseforschung (GTH) during the pediatric GTH (pedGTH) meeting held in September 2022 in Igls (Austria)
were considered.
Thrombopoietin Receptor Agonists: Similar, but Different
Two different TPO-RAs, romiplostim (TPO peptide mimetic) and eltrombopag (TPO non-peptide
mimetic/small molecule), were both licensed in 2008, and subsequently approved for
use in pediatric and adolescent patients. They are currently widely used for the treatment
of persistent (disease duration of 4–12 months) or chronic (>12 months of disease)
ITP in children older than 1 year and adults who are refractory to standard treatment.[15] Eltrombopag has been also approved for children aged over 2 years with SAA in combination
with standard immunosuppressive treatment.[11]
[12] The use of both drugs was initially very carefully monitored, especially concerning
their putative risk of causing bone marrow fibrosis that usually reverses after discontinuation
of treatment[16]
[17]
[18] and proapoptotic effects of TPO in experimental models of brain injury.[19]
[20]
[21]
Notably, there are marked differences between romiplostim and eltrombopag ([Table 1]), which may explain different responsiveness and compliance of patients, in particular
children. More recently, two additional nonpeptide TPO-RAs, avatrombopag and lusutrombopag,
are available and already used in adults for the treatment of ITP (avatrombopag) and
thrombocytopenia associated with CLD (both substances).[11]
[12] In addition, hetrombopag has been developed in China as fourth non-peptide TPO-RA
and successfully applied in adults with persistent or chronic ITP and SAA.[22]
[23]
[24] Due to the variety of these substances ([Table 1]), it is important to understand pharmacological characteristics when evaluating
treatment options for children and adolescents with ITP or severe inherited thrombocytopenias
at risk for hemorrhage and bleeding disorders.
Table 1
Clinically relevant characteristics of thrombopoietin-receptor agonists (TPO-RA)
|
Romiplostim
|
Eltrombopag
|
Avatrombopag
|
Lusutrombopag
|
Hetrombopag
|
|
Structure
|
Peptide TPO-RA
|
Small molecule/non-peptide TPO-RA
|
Small molecule/non-peptide TPO-RA
|
Small molecule/non-peptide TPO-RA
|
Small molecule/non-peptide TPO-RA
|
|
Binding site
|
Binds competitively to the extracytoplasmic domain of the TPO-R in same ways as TPO
|
Binds to the transmembrane and juxtamembrane domains of the TPO-R
|
Binds to the transmembrane domain of the TPO-R
|
Binds to the transmembrane domain of the TPO-R
|
Binds to the transmembrane domain of the TPO-R
|
|
Effect on endogenous thrombopoietin
|
Can displace TPO from its receptor
|
No displacement of TPO, may be additive
|
No displacement of TPO, may be additive
|
No displacement of TPO, may be additive
|
No displacement of TPO, may be additive
|
|
Confirmed signaling pathways
|
JAK2/STAT5
P13K/Akt
ERK
STAT3
|
JAK2/STAT5
P13K/Akt
ERK
|
JAK2/STAT5
STAT3
ERK
|
JAK2/STAT5
STAT3
|
JAK2/STAT5
P13K/Akt
ERK
STAT3
|
|
Route of administration
|
Subcutaneous
|
Oral
|
Oral
|
Oral
|
Oral
|
|
Dosing frequency
|
Weekly
|
Daily
|
Daily
|
Daily
|
Daily
|
|
Approved indications by FDA and EMA
|
• Immune thrombocytopenia (adults and children)
|
• Immune thrombocytopenia (adults and children)
• Hepatitis C–associated thrombocytopenia (adults)
• Severe aplastic anemia (adults and children)
|
• Periprocedural thrombocytopenia in chronic liver disease patients (adults)
• Immune thrombocytopenia (adults)
|
• Periprocedural thrombocytopenia in chronic liver disease patients (adults)
|
• None so far
|
Romiplostim is a 14-amino acid peptide with no sequence homology to TPO. This chimeric molecule
(60 kDa) is composed of human IgG1 antibody Fc fragments, which binds directly and
competitively to the extracellular domain of the TPO-R and mostly stimulates mature
megakaryocyte precursors.[8] Romiplostim is subcutaneously (sc) applied and, in pediatric RCTs, mostly given
in titrated doses (starting with 1 µg/kg per week up to 10 µg/kg per week) upon the
individual response in platelet counts. In children and adolescents (≥1 year to <18
years) with primary ITP (≥6 months of disease), a multicenter phase 3 RCT (n = 62 patients; 2:1 allocation; 1 µg/kg/week single dose sc; increasing doses with
1 µg/kg/week, up to 10 µg/kg/weeks; NCT01444417) showed in 52% of patients the efficacy
of romiplostim over a treatment period of 24 weeks (primary endpoint: platelet counts
≥50 to ≤200/nL).[25] Systematic reviews indicated a beneficial effect as second-line treatment in children
older than 1 year with persistent/chronic ITP.[26]
[27]
[28] These reviews, however, did not include most recent data of the subsequent international
phase 3b RCT on the long-term use of romiplostim in children with ITP, following the
same protocol over a 36-month period (NCT02279173). This RCT showed a median remission
rate of 50.0% (interquartile range (IQR) 16.7–83.3%) during the first 6 months, increasing
to 78.2% (IQR 26.7–90.4%) during the overall 36-month treatment period.[29] Eleven patients (5.4%) achieved sustained responses (consecutive platelet counts
≥50/nL without other ITP medications for ≥24 weeks). Treatment-related adverse events
(AEs) occurred in 56 out of 203 patients (27.6%, including epistaxis, headache, and
vomiting), with 8 (3.9%) experiencing serious treatment-related AEs. Together with
43 cases (21.2%) with lack of efficacy, this finding contributed to the discontinuation
of treatment in 95 out of 203 patients (46.8%). There were eight cases (3.9%) of neutralizing
antibodies (romiplostim, n = 7 [transient: n = 4]; endogenous TPO, n = 1 [transient]). Bleeding occurred in 141 patients (69.5%), decreasing over time;
grade ≥3 bleeding events occurred in 20 (9.9%). At year 2 of treatment, 8 of 63 evaluable
patients (12.7%) showed grade 2 reticulin staining in bone marrow specimens. Although
the authors concluded that long-term romiplostim resulted in sustained on-treatment
platelet responses with an overall safety profile consistent with previous studies,[29] an updated meta-analysis is pending.
Concerning rare inherited disorders, the use of romiplostim has been reported in one
patient with macrothrombocytopenia in Fechtner syndrome (OMIM #155100),[30] and in one patient with another missense mutation (c.5507A >G) in the MYH9 gene locus, encoding the non-muscle myosin heavy chain II-A (OMIM #160775).[31] Pecci et al described a family with congenital amegakaryocytic thrombocytopenia
(CAMT) caused by a homozygous mutation (p.R119C) of the THPO gene (CAMT2; OMIM #620481) and low circulating TPO concentrations, who was successfully
treated with romiplostim.[32] A retrospective analysis on the safety and efficacy of romiplostim treatment (9
µg/kg weekly for at least 4 weeks) showed benefits in reducing thrombocytopenia and
bleeding tendency in 67 children (median age: 1–3 years) with genetically confirmed
Wiskott-Aldrich syndrome (WAS, an inherited X-linked disorder caused by mutations
in the WAS gene, encoding WAS protein that exhibits three distinct functional domains important
for actin cytoskeleton control; NCT04350164), in which thrombocytopenia is characterized
by small platelet size and increased splenic destruction involving both immune and
non-immune mechanisms. The individual follow-up was performed for 8 months (range:
1–12 months).[33] Complete or partial responses (platelet counts >100/nL or >50/nL after 1 week) were
observed in 22 (33%) and 18 (27%) patients, respectively. In the non-responder group,
the risk of hemorrhagic events decreased significantly to 21% after the first month
of treatment.[33] An ongoing monocentric randomized open-label, two-arm phase 2 trial recruiting 30
children with WAS (age < 18 years) compares the effect of romiplostim (1 × 9 µg/kg/week
sc for 4 weeks) versus eltrombopag (2–3 mg/kg/d orally [po] in the age of 0–5 years;
75 mg/d po in the age of ≥ 6 years for 4 weeks) with a primary endpoint of platelet
counts > 100/nL and with a switch in the study arm of non-responders (NCT04371939,
Shcherbina A et al, Moscow, Russia).
Another monocentric open-label phase 1 / phase 2 trial currently analyses the short-term
safety and efficacy of romiplostim in patients at the age of 0 to 21 years with inherited
and acquired hematopoietic failure. This study recruits 25 patients into two study
arms. Arm A: romiplostim treatment (1 × 5 µg/kg/weeks sc, increasing with additional 2.5 µg/kg/week
to a maximum of 20 µg/kg/week for 24–52 weeks) in (1) aplastic anemia, (2) refractory
cytopenia of childhood without an evidence of cytogenetic abnormality with predisposition
to leukemia, (3) myelo-suppression contributing to severe pancytopenia, and (4) inherited
bone marrow failure without chromosomal fragility disorder. Arm B: romiplostim treatment (1 × 2 µg/kg/weeks sc, increasing with additional 1 µg/kg/week
to a maximum of 10 µg/kg/week for 24–52 weeks) in (1) myelo-suppression with thrombocytopenia
in children with solid tumors secondary to chemotherapy or radiation therapy, and
(2) patients undergoing stem cell transplantation and experiencing persistent thrombocytopenia.
Primary outcome is a platelet number >100/nL (NCT04478227; Sharathkumar A et al, Iowa,
United States). Concerning the use of romiplostim in CIT, a retrospective multicenter
study in children and young adults (3–33 years age) with Ewing sarcoma (of different
stages, including bone metastases) showed safety of romiplostim and its efficacy associated
with higher doses (starting dose: 3 µg/kg [range: 1–5 µg/kg], with dose escalation
weekly or every other week by 1 to 2 µg/kg [maximum dose: 4–10 µg/kg]).[34] This information is important, since (1) CIT is the primary issue in maintaining
high treatment intensity in Ewing sarcoma, and (2) the implication of TPO/TPO-R in
regulating bone hemostasis.[35]
[36]
Eltrombopag is an allosteric small molecule which binds to the transmembrane and juxtamembrane
domains of the TPO-R on the surface of platelet-producing cells, stimulating MK precursor
cells and MK differentiation by activation of the STAT3, P13K/Akt, and ERK signaling
pathways down of the TPO-R domain.[37]
[38] However, eltrombopag also has off-target effects. As such, it chelates both extra-
and intracellular calcium and iron, and can shuttle iron out of cells.[39] The iron-chelating action has an antiproliferative effect on leukemic cell lines,[40] and a TPO-independent function on stimulating stem cells and MK precursors in vivo.[41]
[42]
Eltrombopag is an oral medication that is taken once daily. It is approved for the
treatment of children older than 1 year and adolescents with persistent/chronic ITP
or SAA, and in adults with hepatitis C-associated thrombocytopenia. Established doses
are 0.7 mg/kg/d (maximum: 2 mg/kg/d) in children at the age between 1 and 5 years,
and 25 mg/d (maximum: 75 mg/d) at the age between 6 and 17 years. It is recommended
to monitor liver function, and dose adjustments can be necessary in certain populations
(e.g., Asian patients and patients with impaired liver function).
Most experience in using eltrombopag in children and adolescents results from the
PETIT (Eltrombopag in PEdiatric patients with Thrombocytopenia from ITp) trials.[43]
[44] The efficacy of 7 or 13 weeks' therapy with eltrombopag (up to 2 mg/kg/d in children
at an age between 1 and 5 years; up to 75 mg/d at higher age) as second-line treatment
was compared with that of placebo in patients aged 1 to 17 years with previously treated
ITP (≥6 months) in these multicenter phase 2 and 3 RCTs (PETIT, NCT00908037, and PETIT-2,
NCT01520909). The platelet response rate (primary endpoint of PETIT) and the sustained
platelet response rate (primary endpoint of PETIT-2) were significantly higher with
eltrombopag than with placebo. In PETIT-2, 63 patients were assigned to receive eltrombopag,
and 29 patients assigned to receive placebo. In 3 out of 63 patients, eltrombopag
treatment was discontinued because of increased liver aminotransferases, while one
withdrew occurred in the placebo group because of abdominal hemorrhage. Twenty-five
(40%) patients who received eltrombopag, compared with one (3%) patient who received
placebo, achieved the primary outcome of platelet counts of at least 50/nL for 6 of
the last 8 weeks of the double-blind period (odds ratio: 18; p < 0.001). Responses were independent of the children's age. Proportionately, fewer
patients who received eltrombopag (23 of 63 patients, 37%) had WHO grades 1 to 4 bleeding
at the end of the double-blind study period than those who received placebo (16 of
29 patients, 55%); grades 2 to 4 bleeding events were similar (three [5%] patients
who received eltrombopag vs. two [7%] patients who received placebo).[44] A recent meta-analysis of both PETIT trials, however, indicated that in children
there was no overall difference between eltrombopag (total n = 108) and placebo (total n = 51) for a platelet response ≥50/nL (RR: 3.93; 95% CI: 0.56–27.79) and the number
of AEs (RR: 0.59; 95% CI: 0.25–1.41) as secondary outcome measures. However, a lower
incidence of bleeding was observed (RR: 0.47; 95% CI: 0.27–0.83). Notably, the certainty
of evidence concerning these measures was low to moderate.[45] The results of the meta-analysis contrast to reports of nonrandomized (mostly retrospective
observational) cohorts successfully treated with eltrombopag as second-line treatment
of persistent/chronic ITP in childhood and adolescence.[46]
[47]
[48]
[49]
[50]
[51] This raises the question, how previous first-line treatment with other medication
or their combination with eltrombopag affects treatment response. In adults, a meta-analysis
on multiple drugs for the treatment of ITP showed that the efficacy of eltrombopag
plus rituximab was significantly superior than placebo or dexamethasone alone.[52] A systematic review of prospective studies in pediatric ITP showed that rituximab
and TPO-RAs had similar rates of overall platelet response (≥50/nL), but rituximab
was associated with higher rates of rescue therapy.[53] This indicates that (1) comparative studies with eltrombopag and other drugs for
second-line treatment of pediatric ITP and (2) RCTs on the use of eltrombopag for
first-line treatment (either alone and combined with standard treatment) are warranted.
Indeed, the results of a multicenter, open-label, phase 3 RCT (NCT03939637) that compares
eltrombopag to standard first-line management (steroids vs. immunoglobulins vs. Rho(D)
immunoglobulin) in children (n = 162) with newly diagnosed ITP (≤3 months from diagnosis) are expected in 2024.[54]
The fact that eltrombopag binds to the transmembrane and juxtamembrane but not to
the classical extracellular binding domains of the TPO-R makes this substance appealing
for use in rare inherited thrombocytopenia, especially in CAMT. This group of congenital
thrombocytopenias is characterized by ineffective megakaryopoiesis without typical
features of syndromic conditions. In most cases, CAMT is caused by deleterious (homozygous
or compound heterozygous) mutations in the MPL gene CAMT-MPL/CAMT1 (OMIM 604498).[55] Seventy percent of all mutations are located in the five coding exons of the extracellular
cytokine receptor homology domain, providing the rationale to use a TPO-RA such as
eltrombopag, which finds alternate receptor binding and activates downstream signaling.[56] Yet, Pecci et al reported on 12 patients with MYH9-associated thrombocytopenia (<50/nL) treated with eltrombopag for 3 weeks (NCT01133860).[57] A total of eight patients achieved platelet counts of ≥100/nL or a threefold increase
in baseline platelet count. In three patients, a doubling of the baseline value was
still achieved, and in only one patient there was no platelet increase. Only mild
headache was reported as adverse effect. Zaninetti et al reported in a multicenter,
open-label, dose-escalation phase 2 trial 20 patients with MYH9-associated thrombocytopenia (NCT02422394) who experienced a decrease in bleeding
tendency during eltrombopag treatment.[58]
[59] Case reports of successful treatment with eltrombopag are available in five other
patients with MHY9-associated thrombocytopenia.[60]
[61]
[62]
[63]
Besides one case report,[64] Gerrits et al described eight patients with WAS (grades 2–4) who were treated with
eltrombopag for a time period ranging from 22 to 209 weeks (NCT00909363).[65] In five patients an increase in platelet count to >50/nL or a doubling of the baseline
value was achieved during treatment with eltrombopag. Six patients showed reduced
bleeding symptoms. Two patients were classified as non-responders responders. One
of these patients was subsequently successfully treated with romiplostim. No serious
side effects were observed in any of these patients. Moreover, one patient has been
reported who was successfully treated with eltrombopag for the hereditary ANKRD26-related thrombocytopenia (OMIM 188000),[66] with normal platelet size, modestly increased TPO plasma concentrations, high number
and size of megakaryocyte precursors, but delayed differentiation.[67] In addition, nine patients with WAS were treated with eltrombopag in the aforementioned
study by Zaninetti et al.[58] In five patients, mild bleeding symptoms disappeared, while one patient was considered
as non-responder.[58] Currently, a prospective, open-label, two-arm RCT is conducted to evaluate the safety
and efficacy of eltrombopag in comparison to romiplostim for the treatment of thrombocytopenia
in pediatric patients with WAS, and the results are expected to be published in 2024
(NCT04371939, Shcherbina A et al, Moscow, Russia).
Of note, the use of eltrombopag may be extended to other systemic diseases or conditions
associated with thrombocytopenia in children and adolescents. As in adults, eltrombopag
has been tested in patients aged 1 to 18 years with SAA in combination with cyclosporine
A (CsA) versus CsA alone. Recruitment of this phase 1/phase 2 open label trial (ELTROPLASTIC,
NCT03243656) has been completed, but publication of the results is pending (Ahmed
MA et al, Asyut, Egypt). There are two other trials in SAA ongoing: A multicenter
phase 2 RCT testing eltrombopag combined with cyclosporine and human anti-thymocyte
globulin (hATG) versus hATG and CsA as first-line treatment (NCT03413306; Novichkova
G and Maschan A, Moscow, Russia), and a multicenter, open label, intrapatient dose
escalation phase 2 study to characterize the pharmacokinetics of eltrombopag in combination
with immunosuppressive therapy in pediatric patients with previously untreated or
relapsed/refractory SAA or recurrent aplastic anemia (NCT03025698, United States).
In pediatric oncology, an open label, single-arm prospective pilot trial (phase 1)
currently aims to test eltrombopag in patients aged 1 to 18 years undergoing intensive
chemotherapy for malignant solid tumors (NCT04485416, Pawar A et al, Sacramento, California,
United States). REGALIA, a prospective phase 2 RCT, currently recruits pediatric patients
to demonstrate whether eltrombopag improves poor graft function after allogenic hematopoietic
cell transplantation (NCT03948529, Yakoub-Agha I et al, Lille, France).
These ongoing studies suggest that the use of eltrombopag may be extended in pediatric
thrombocytopenia of different origin.
Avatrombopag, a more recently developed TPO-RA, is also an oral non-peptide small molecule that
apparently binds to the TPO-R similar to eltrombopag, but does not have any dietary
limitations.[68]
[69] Therefore, avatrombopag may potentially be more suitable in pediatrics. Avatrombopag
has been approved by FDA in adult patients for the treatment of thrombocytopenia-associated
CLD,[70] and subsequently for second-line treatment of ITP.[71]
[72] A recent systematic review comparing various TPO-RAs in adults with persistent or
chronic ITP showed that avatrombopag may yield the highest efficacy, because it has
the most favorable balance of benefits and acceptability.[73] Thus, recent studies focus on the therapeutic values of switching TPO-RA treatment
from romiplostim or eltrombopag to avatrombopag. An observational multicenter trial
in adults (n = 44) with chronic ITP showed a significant benefit of avatrombopag in 14 non-responders
to previous treatment with romiplostim or eltrombopag. On avatrombopag, 41/44 patients
(93%) achieved a platelet response (≥50/nL) and 38/44 patients (86%) achieved a complete
response (≥100/nL). The median platelet count was 28/nL on romiplostim/eltrombopag
versus 88/nL on avatrombopag (p = 0.025). Fifty-seven percent of patients receiving concomitant ITP medications before
switching discontinued them after switching, including 63% of patients permanently
receiving corticosteroids.[74] This indicates that in heavily pretreated chronic ITP patients, avatrombopag can
be a very attractive choice of TPO-RAs. The efficacy and safety of avatrombopag as
first choice TPO-RA is also currently tested in an international multicenter phase
3 RCT with open-label extension phase in pediatric and adolescent patients (age of
1–17 years) with persistent/chronic ITP (n = 72; 3:1 allocation). Herein, avatrombopag (20 mg/d po) is tested as second-line
treatment in study arm A for 12 weeks and in study arm B for up to 2 years (NCT04516967,
Sobi Inc., United States). Concerning rare inherited thrombocytopenias, one adult
patient with a MYH9-related disorder was recently successfully treated with avatrombopag, following failed
treatment with eltrombopag.[75]
Lusutrombopag, another more recently developed TPO-RA, is also an oral non-peptide small molecule,
which can activate the TPO-R signal transduction pathway as endogenous TPO.[76] It was first approved in Japan by Pharmaceuticals and Medical Devices Agency (PMDA)
for the treatment of thrombocytopenia associated with CLD in adult patients.[77] In 2018, the substance was also approved for this indication by FDA and EMA. In
single patients, portal vein thrombosis has been reported as serious AE associated
with lusutrombopag. Apparently, no indication for ITP or IT is yet being pursued.
Data on the use of lusutrombopag in children and adolescents are not accessible yet.
Hetrombopag is another similar oral TPO-RA that has been recently developed in China and tested
for various conditions of thrombocytopenia in adults, including chronic ITP.[22]
[78]
[79]
[80] It is not yet approved for clinical use by the FDA and EMA. There are currently
no data on the use of hetrombopag in pediatrics accessible. However, the results of
a monocentric two-part, double-blind, randomized, placebo-controlled, and open-label
phase 3 study to investigate the efficacy and safety of hetrombopag in pediatric patients
(n = 117, age 6–17 years) with previously treated ITP (≥6 months) are expected to be
completed soon (NCT04737850, Wang et al,[48] Beijing, China).
Switching between TPO-RAs
TPO-RAs differ in their molecular structure, binding sites, pharmacokinetic profile,
and the manner in which they stimulate the TPO-R. In pediatric ITP, the efficacy and
safety of two TPO-RA, romiplostim and eltrombopag, have been compared not only to
placebo but also directly in a total of 261 patients aged 1 to 17 years,[81] included in the aforementioned RCTs.[25]
[43]
[44] These studies confirmed that TPO-RAs were superior to placebo, but found no significant
difference in the efficacy and safety between romiplostim and eltrombopag.[81] Similarly, a previous retrospective multicenter trial (ICON2), which compared TPO-RA
treatment in 79 children (28 eltrombopag, 43 romiplostim, 8 trialed on both) at different
stages of ITP (18% with new diagnosed, 22% with persistent, and 61% with chronic ITP),
showed similar response rates (platelets >50/nL) with romiplostim (86%) and eltrombopag
(81%). However, only 40% of patients demonstrated a stable response with consistent
dosing over time.[82] This raises the question of whether switching between TPO-RAs can provide beneficial
longer-term effects. Unlike romiplostim, eltrombopag and avatrombopag do not compete
with endogenous TPO for the classical TPO-R binding site ([Table 1]). Binding to the classic TPO-R domain may induce greater Akt pathway activation
compared with JAK2/STAT5 effects following transmembrane TPO-R activation.[83] These subtle mechanistic differences seem to have clinically relevant effects, as
patients experiencing toxicities or lack of efficacy with one TPO-RA may benefit from
switching to an alternative TPO-RA. Consequently, the most common reasons for switching
include loss or lack of efficacy of the initial TPO-RA followed by patient preferences
(oral, less frequent drug taking without food restrictions) or side effects.[84]
[85] The potential impact of switching from eltrombopag to avatrombopag was retrospectively
studied in 11 children with chronic ITP, who changed medication due to ineffectiveness
(n = 7), adverse effects, or inconvenience. Overall response was achieved in 9 out of
11 patients (including 2 who had responded to eltrombopag). The median platelet count
increased from 7/nL (range: 2–33/nL) up to 74/nL (15–387/nL; p < 0.05), with 6 out of 11 achieving complete remission (>100/nL). Notably, treatment
was terminated in 7 out of 11 patients within 3 to 6 months after switching to avatrombopag.[86]
Importantly, recent studies generally indicate that pharmacologic differences among
TPO-RA therapies may have real-life effects on the efficacy of agents in the individual
patient.[12]
[74]
[83]
[84] In addition, the pharmacokinetics of different TPO-RAs vary considerably, particularly
in terms of maximum concentration (C
max), area under the curve (AUCo-inf), and time to maximum concentration (T
max). This variation is particularly notable for eltrombopag, where food composition
can interfere with absorption or causes chelation of polyvalent cations, in contrast
to avatrombopag and lusutrombopag.[11] In comparison to orally administered TPO-RA, administration of romiplostim in adult
ITP patients has been reported to result in exaggerated pharmacologic effects, leading
to wide variations in platelet counts.[11] An unexpected but important outcome of TPO-RA treatment in adult ITP patients is
that up to 30% achieve sustained remission off-treatment (SROT). While romiplostim
and eltrombopag demonstrate similar SROT rates, recent data suggest that first and
early use of romiplostim, especially within the first year of diagnosis, may be associated
with higher SROT rates.[87] This directs current research toward exploring the immunomodulatory effects of TPO-RA,
both as standalone treatment and in combination with other first- or second-line drugs
used in pediatric and adult ITP.
