Next Article in Journal
Zoledronic Acid Ameliorates the Bone Turnover Activity and Periprosthetic Bone Preservation in Cementless Total Hip Arthroplasty
Next Article in Special Issue
Targeting the Hematopoietic Stem Cell Niche in β-Thalassemia and Sickle Cell Disease
Previous Article in Journal
Application of Fucoidan in Caco-2 Model Establishment
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Pharmaceuticals
Volume 15
Issue 4
10.3390/ph15040419
pharmaceuticals-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Case Report

Efficacy and Immunomodulating Properties of Eltrombopag in Aplastic Anemia following Autologous Stem Cell Transplant: Case Report and Review of the Literature

by
Marta Bortolotti
1,2,
Loredana Pettine
1,
Anna Zaninoni
1,
Giorgio Alberto Croci
1,2,
Wilma Barcellini
1 and
Bruno Fattizzo
1,2,*
1
Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
2
Department of Oncology and Hemato-Oncology, University of Milan, 20122 Milan, Italy
*
Author to whom correspondence should be addressed.
Pharmaceuticals 2022, 15(4), 419; https://doi.org/10.3390/ph15040419
Submission received: 7 March 2022 / Revised: 23 March 2022 / Accepted: 28 March 2022 / Published: 30 March 2022
(This article belongs to the Special Issue Drug Design and Development for Rare Hematologic Diseases)
Browse Figures
Review Reports Versions Notes

Abstract

:
Thrombopoietin receptor agonists (TPO-RA) are currently indicated for the treatment of chronic immune thrombocytopenia and relapsed refractory aplastic anemia. However, the off-label use of these drugs is more and more frequent, including in the setting of aplasia secondary to chemotherapy and hemopoietic stem cell transplant (SCT). Growing evidence suggests that mechanisms of action of TPO-RA go beyond the TPO-receptor stimulation and point at the immunomodulating properties of these drugs. Here, we present a case of prolonged bone marrow aplasia secondary to autologous SCT treated with eltrombopag. We describe the clinical efficacy and the immunomodulating effect of this drug on inflammatory cytokine profile and bone marrow histology. Furthermore, we provide a review of the most recent literature highlighting the efficacy and safety of TPO-RA after SCT and chemotherapy for hematologic conditions.

Graphical Abstract

1. Introduction

Thrombopoietin receptor agonists (TPO-RA), eltrombopag and romiplostim, are two polyhedric drugs initially licensed for the treatment of immune thrombocytopenia (ITP). Both act by triggering the TPO receptor on megakaryocytes (MK) and hematopoietic stem cells, inducing activation of the JAK2/STAT5 pathway with subsequent MK proliferation and an increase in platelet generation [1,2]. However, the two drugs present some differences both in biological properties and mechanisms of action [3]. In particular, eltrombopag appears to target the earlier precursor of MK, stimulating not only the proliferation pathway but also differentiation [1,4]. Furthermore, growing evidence is pointing at a broader spectrum of action of this small molecule, including immunomodulating properties and iron mobilization [5]. Eltrombopag is administered orally and is currently indicated for the treatment of chronic ITP after failure of first line therapy, relapsed refractory aplastic anemia (AA) and thrombocytopenia secondary to hepatitis C during treatment with interferon (IFN). Romiplostim has a subcutaneous route of administration and is licensed for chronic ITP only. However, the off-label use of these two drugs is more and more frequent, particularly in the setting of aplasia secondary to chemotherapy and hemopoietic stem cell transplant (HSCT), and thrombocytopenia associated with lymphoproliferative disorders and myelodysplastic syndromes (MDS) [6]. In this case report, we describe the clinical efficacy and the immunomodulating effect of eltrombopag on inflammatory cytokine profile in a patient experiencing prolonged aplasia following autologous stem cells transplant (ASCT) for amyloidosis AL. Furthermore, we provide a review of the most recent literature highlighting the efficacy of TPO-RA after HSCT and chemotherapy for hematologic conditions.

2. Methods

The patient gave informed consent, and the study was conducted according to the Helsinki declaration. All information regarding patient clinical history, hematologic parameters and bone marrow (BM) evaluation were prospectively collected from September 2019 until the time of writing. Cytokine studies and molecular studies by next generation sequencing (NGS) were sequentially performed during eltrombopag therapy. The following cytokines were evaluated in serum using commercial ELISA kits (High Sensitivity Elisa kits, Invitrogen by Thermo Fisher Scientific, Boston, MA, USA, human TGF-beta elisa kit, Immunological Sciences, Rome, Italy): interleukin (IL)6, IL10, IL17, tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, and transforming growth factor (TGF)-beta. Cytokine levels were compared with 40 age- and sex-matched healthy controls. The NGS study was performed by next generation sequence technology (Ion Torrents5), Ion Reporters software 5.2, which evaluates mutational status of 69 potentially oncogenic genes present in the Oncomine Myeloid Research Assay diagnostic panel, specifically, hotspot genes (ABL1, BRAF, CBL, CSFR3, DNMT3A, FLT3, GATA2, HRAS, IDH1, IDH2, JAK2, KIT, KRAS, MOL, MYD88, NPM1, NRAS, PTPN11, SETPB1, SF3B1, SRSF2, U2AF1, WT1), full genes (ASXL1, BCOR, CALR, CEBPA, ETV6, EZH2, IKZF1, NF1, PHF6, PRPF8, RB1, RUNX1, SH2B3, STAG2, TET2, TP53, ZRSR2), and fusion transcripts (ABL1, ALK, BCL2, BRAF, CCDN1, CREBBP, EGFR, ETV6, FGFR1, FGFR2, FUS, HMGA2, JAK2, KMT2A, MECOM, MET, MLLT10, MLLT3, MYBL1, MYH11, NTRK3, NUP214, PDGFRA, PDGFRB, RARA, RBM15, RUNX1, TCF3, TFE3). Only variants with an allelic frequency (VAF) > 5% were reported.
A review of literature on TPO-RA use in the setting of aplastic anemia post-HSCT or thrombocytopenia following chemotherapy for hematologic conditions was performed by searching for indexed articles and published abstracts up to January 2022 in MEDLINE via PubMed and the National Library of Medicine.

3. Results

3.1. Case Description

A 60-year-old woman was referred to our center to receive autologous stem cell transplant (ASCT) due to amyloidosis AL with renal and cardiac disorder. The latter had been diagnosed one year before, and treated with 4 cycles of bortezomib, cyclophosphamide and dexamethasone without significant improvement. Following stem cell mobilization with granulocyte colony-stimulating factor (G-CSF), 6 × 106 CD34+ cells/kg were collected. After admission, she was conditioned with Melphalan 200 mg/square meter and two days later, she was reinfused with 4 × 106 CD34+ cells/kg. The post-transplant period was complicated by extremely severe acute kidney injury, hemorrhagic shock secondary to hematemesis due to severe mucositis, Pneumococcus pneumonia, sepsis by Bacillus cereus and graft failure requiring 3 further peripheral blood stem cell infusions and prolonged stimulation with G-CSF. After 35 days from ASCT, the patient was transfusion-dependent on red blood cells (RBC) and platelets (PLT), and BM evaluation showed severe aplasia. Eltrombopag was started at 50 mg per day (Figure 1), and subsequently increased to 100 mg per day, but then ceased on day 52 due to apparently scarce efficacy on platelet count. Neutrophils’ recovery started from day 45 after ASCT and she was discharged on day 63 with persistent need of RBC and PLT transfusions. On day 91, BM revaluation showed a cellularity of 10% without pathological infiltrate or amyloid deposition. On day 129, due to the persistence of severe thrombocytopenia, a new attempt with eltrombopag at 150 mg per day was performed. The patient progressively became transfusion independent from day 200 for RBC and 249 for PLT and these latter increased above 30 × 109/L from day 262. By day 390, given stable PLT counts > 50 × 109/L, eltrombopag was de-escalated to 100 mg per day and subsequently to 50 mg per day, until discontinuation on day 536. At the last follow up, 30 months after ASCT, amyloidosis is still in remission and the patient displays normal blood counts (Hb 12 g/dL, neutrophils 2070 × 106/L, PLT 151 × 109/L) off therapy. Regarding safety, the patient did not show treatment-emergent adverse events during eltrombopag therapy, including thrombosis and increase in bone marrow reticulin fibrosis (WHO grade MF-0 at all evaluations).

3.2. Monitoring of Clonal Evolution during Eltrombopag Therapy

To investigate efficacy and clonal evolution under eltrombopag therapy, BM was performed at 3, 6, and 12 months of eltrombopag treatment. It showed a progressive improvement of cellularity along with an increasing polyclonal lymphoid infiltrate of double-negative T-CD3+ cells (Figure 2). No signs of dysplasia or blasts increase were reported. Cytogenetics was persistently normal. Flow-citometry for paroxysmal nocturnal hemoglobinuria clones was performed at 3 months from eltrombopag start and was negative. By NGS analysis on peripheral blood after 6 months of eltrombopag, a mutation of the RB1 gene, with a variant allele frequency of 52.8%, was detected. A re-evaluation at 12 months did not confirm this finding and showed an absence of mutations.

3.3. Cytokine Analysis

Figure 3 shows the cytokine levels during eltrombopag treatment. The T helper1 (Th1) cytokines IFN-γ and TNF-α were at lower limit of normality of controls and remained stable along eltrombopag treatment. The T helper 2 (Th2) cytokines IL-6 and IL-10 levels and the immunoregulatory cytokine IL-17 were higher than in controls, and persisted elevated during therapy, with a peak of IL-6 levels at 12 months. Finally, the inhibitory cytokine TGF-β was progressively increased along eltrombopag treatment, although within the normal range.

3.4. Literature Review

Several studies have been published about the use of TPO-RA for aplasia secondary to HSCT and chemotherapy both in adult and pediatric settings (Table 1 and Table 2). A total of 1218 patients received TPO-RA post-HSCT, of whom, 581 (48%) eltrombopag, 122 (10%) romiplostim, and 515 (42%) both agents. The great majority were retrospective studies, including small series of around 30 patients, a larger study of 86 cases, a meta-analysis of 378 patients, and 6 prospective trials (Table 1).
Overall, they highlight a highly variable efficacy in post HSCT aplasia, and a recent meta-analysis on 378 patients documented a pooled response rate of 73% (95% CI: 68–78%) for both eltrombopag and romiplostim [34]. However, the majority of the studies analyzed the efficacy of these drugs in an allogenic HSCT setting and only few data are available for post ASCT aplasia. To the best of our knowledge, only 8 articles, for a total of 28 cases, reported the use of TPO-RA after ASCT, and pooled efficacy may be calculated from 3 retrospective studies only, including 8 patients with 100% response rate [8,9,10,13,19,27,32,39]. Notably, responding patients within the various reports could discontinue TPO-RA after persistent recovery of cytopenia and bone marrow function. However, such small series carry the bias of reporting only successful cases and a prospective evaluation would be necessary.
Far fewer studies are available about the use of TPO-RA after chemotherapy in hematologic malignancies (2 retrospective, 2 prospective trials, and 1 case report), for a total of 233 patients, the great majority receiving eltrombopag. Different efficacy endpoints were considered, often expressed as median time to PLT count recovery [43,44,45,46,47]. The latter was reported to be about 22.5 (16–43) days in acute myeloid leukemia patients and 7.4 (4.9–9.9) days in lymphoma patients [45,46]. Interestingly, even in these cases, TPO-RA discontinuation was possible after cytopenia recovery. Finally, novel anti-cancer drugs such as immune checkpoint inhibitors (nivolumab, ipilimumab, pembrolizumab, etc.) re-activate the immune system to recognize tumor specific antigens but may in turn cause autoimmune hyperinflammatory reactions, including autoimmune cytopenias. In this context, TPO-RA have been used in 6 cases with a good efficacy and safety profile [48,49,50,51,52,53]. Similarly, CAR-T cell therapy has been related to late-onset cytopenias, resembling primary autoimmune ones, often responding to immunosuppressive drugs [54]. A case report about the use of romiplostim for thrombocytopenia following CAR-T cells in a patient affected by relapsed/refractory diffuse large B-cell lymphoma was recently published [55] (Table 3).
Some ITP patients have been reported to benefit from switching from one TPO-RA to another. However, no data are available in the setting of aplastic anemia post-chemotherapy or after HSCT, except for a case switched from eltrombopag to romiplostim after umbilical stem cell transplant [56].
Regarding safety data, TPO-RA appear to have a good profile also in these off-label settings. From the meta-analysis of Yao et al., the pooled rate of adverse events (AE) was 3% (95%CI: 1–7%), with no severe AEs reported [34]. Similarly, the phase II study conducted by Ahmed S et al. highlighted no differences in grade 2 or higher AE rates between the eltrombopag and placebo arm, particularly regarding bone marrow fibrosis, cataract, vision changes, or thrombosis [39]. Finally, we identified only one case of pulmonary embolism secondary to eltrombopag therapy, while the most frequent reported AE was a transient elevation of liver function tests.
Research on ClinicalTrials.gov (accessed on 22 January 2022) returned 29 registered trials regarding the use of TPO-RA in aplasia post-chemotherapy for hematologic disease and post-HSCT (Table 4). The results will be important to better define efficacy, dosage, timing, and side effects of these drugs in these off-label settings.

3.5. Immunomodulatory Effects of Eltrombopag

Several mechanisms of action have been proposed to explain the immunomodulating properties of eltrombopag. The most agreed hypothesis is the restoration of an antigen-specific tolerance through induction of T cell anergy by increased exposure to PLT antigens [57]. More interesting, eltrombopag appeared to be able to recover immune tolerance by improving T-regulatory cells (T-regs) function and TGF-α levels [58]. The latter are key immunomodulatory factors inducing the suppression of self-reactive clones, but also contributing to bone marrow microenvironment homeostasis. In fact, the TGF-beta superfamily is implied in the regulation of late-stage erythropoiesis that is affected in patients with aplastic anemia and bone marrow failure. These observations are also supported by a recent study by Lozano et al., suggesting a possible role of platelet-derived ectosomes (a type of microparticles) in inducing T-regs differentiation in TPO-RA treated patients, and the involvement of additional cellular pathways (i.e., FOXP3, PTPN1, and PPARγ) that may modulate immune response and induce immune tolerance [57]. Moreover, eltrombopag was shown to restore Fcγ receptor (FcγR) balance through the inhibition of FcγRIIb on monocytes, mitigating phagocytic capacity, often hyperactivated in ITP patients [59]. In this context, the drug may also promote the switch of macrophage phenotype from the M1 proinflammatory type to the M2 anti-inflammatory type, dampening autoinflammation and disease chronicization [60]. Finally, eltrombopag may exert immunomodulating properties by promoting B regulatory cells’ function [61]. An additional mechanism related to autoinflammation and bone marrow failure is the interference of eltrombopag with iron metabolism [62,63,64,65,66]. In fact, the drug exhibits iron-chelating properties that may alleviate bone marrow stress and improve hematopoiesis by avoiding iron-induced damage mechanisms, i.e., reactive oxygen species (ROS) generation. Concurrently, iron chelation could contribute to restoring immune functions, often impaired by disturbance of iron homeostasis [5,67].
The new insights on immunomodulatory effects of eltrombopag are extremely interesting even though most of the current evidence is limited to ITP. Thus, further studies would be important to evaluate these mechanisms in other settings such as primary bone marrow failures (AA and MDS) and aplasia secondary to chemotherapy and HSCT, where the degree of immune activation and the composition of bone marrow microenvironment are different.

4. Discussion and Conclusions

We presented a case of prolonged bone marrow aplasia secondary to ASCT treated with eltrombopag at the same dosage used for AA. During treatment, our patient did not show neither hepatologic toxicity nor thrombotic events and bone marrow evaluations did not display an increase in fibrosis. Our observations are consistent with the several evidence about the efficacy and safety of TPO-RA in post-HSCT and aplasia post chemotherapy, where the reported pooled response is about 70%, similarly to primary ITP.
One of the major concerns about the use of TPO-RA, particularly in the oncologic setting, is clonal evolution. In our case, sequential BM evaluation did not show an increase in blasts percentage, nor the emergence of cytogenetic aberrations; furthermore, the detection of RB1 gene mutation by NGS was not confirmed in the subsequent analysis and PNH clone testing was negative. In the literature, the risk of clonal escape is controversially reported for AA and MDS, which, however, carry an intrinsic risk of leukemic evolution [68,69,70]. In this context, a recent trial analyzing the efficacy and safety of eltrombopag added to immunosuppressive therapy in severe AA, also collected sequential mutational data by NGS, and did not detect clonal evolution after a median follow-up of 24 months [71].
Another concern with eltrombopag is the increase in reticulin bone marrow fibrosis. Although specific data in the setting of aplastic anemia following chemotherapy, HSCT, or novel anti-cancer drugs are not available, several studies in ITP and primary aplastic anemia demonstrated that it is mainly low-grade fibrosis, remitting after TPO-RA discontinuation [3,72,73]. Notably, our patient and many of those described in the literature were able to discontinue TPO-RA after robust recovery of cytopenias and bone marrow cellularity. This is also reported for ITP patients in about 1/3 of cases and is likely linked to an immunomodulatory effect of the drug.
Accordingly, in our study, we demonstrated an immunomodulatory effect of eltrombopag on different cytokines. Particularly, we observed that the patient’s IL-6 and IL-10 levels were increased compared to controls, in agreement with the several reports of increased levels in plasma cell dyscrasias [74,75]; additionally, IL-10 is a negative regulator of Th1 cytokines and might have accounted for the reduced levels of TNF-α and IFN-γ observed during eltrombopag therapy. Consistently, the reduction of the latter two cytokines may have resulted in decreased inhibition of Th 2 response with an amplification of the autoimmune process. Regarding immunoregulatory cytokines, IL-17 was higher than controls, further amplifying the proinflammatory and autoimmune response. Interestingly, the inhibitory cytokine TGF-β, which was initially at the lower limit of normal, increased over time, in an attempt to downregulate the pro-inflammatory/autoimmune response. This might be related with a restoration of T-regs/T-helper 17 cells ratio already described in patients treated with eltrombopag [58].
Another interesting finding is the histologic demonstration of a polyclonal double negative T-cells infiltrate in patient bone marrow, increasing over time in parallel with bone marrow cellularity. These cells belong to a neglected class of T cells called CD3+CD4-CD8- and have been described to play a homeostatic role in suppressing exuberant immune responses [76]. Along with the immune reconstitution after ASCT, this observation may further suggest an immunomodulatory effect of eltrombopag in this setting.
Finally, the new insights on the immunomodulatory effects of TPO-RA are intriguingly expanding the spectrum of use of these drugs. In the near future, treatment of “peripheral” (ITP) and “central” (AA, MDS) autoimmune diseases will take advantage of TPO-RA to either stimulate the stem cells compartment and exert a slower, but likely less toxic, immunomodulatory effect.
In conclusion, the case presented and the literature review highlight the efficacy and safety of eltrombopag in aplastic anemia following ASCT, HSCT, and chemotherapy for hematologic malignancies. Furthermore, cytokine studies and bone marrow findings support the emerging immunomodulatory effect of the drug. Altogether, growing evidence suggests eltrombopag use in these off-label settings, particularly in the case of prolonged cytopenias following poor graft function or chemotherapy.

Author Contributions

M.B. and L.P. collected data. M.B. and B.F. wrote the manuscript. A.Z. performed cytokine analyses. G.A.C. revised histologic preparate. W.B. and B.F. revised the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by research funding from Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico (RC 2021).

Institutional Review Board Statement

The study was conducted in accordance with the Declaration of Helsinki, and approved by the Ethics Committee of Comitato Etico Milano Area 2 (protocol code 2093 and date of approval 9 March 2021).

Informed Consent Statement

Informed consent was obtained from all subjects involved in the study.

Data Availability Statement

Data is contained within the article.

Conflicts of Interest

The authors declare no conflict of interest. B.F. received consultancy from Apellis, Momenta, and Novartis and lecture fee/congress support from Alexion and Apellis. W.B. received consultancy from Agios, Alexion, Apellis, Biocryst, Bioverativ, Incyte, Momenta, and Novartis and lecture fee/congress support from Alexion, Incyte, Novartis, and Sanofi.

References

  1. Erickson-Miller, C.L.; Delorme, E.; Tian, S.-S.; Hopson, C.B.; Landis, A.J.; Valoret, E.I.; Sellers, T.S.; Rosen, J.; Miller, S.G.; Luengo, J.I.; et al. Preclinical Activity of Eltrombopag (SB-497115), an Oral, Nonpeptide Thrombopoietin Receptor Agonist. Stem Cells 2009, 27, 424–430. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. Broudy, V.C.; Lin, N.L. AMG531 stimulates megakaryopoiesis in vitro by binding to Mpl. Cytokine 2004, 25, 52–60. [Google Scholar] [CrossRef] [PubMed]
  3. Ghanima, W.; Cooper, N.; Rodeghiero, F.; Godeau, B.; Bussel, J.B. Thrombopoietin receptor agonists: Ten years later. Haematologica 2018, 104, 1112–1123. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. Will, B.; Kawahara, M.; Luciano, J.P.; Bruns, I.; Parekh, S.; Erickson-Miller, C.L.; Aivado, M.A.; Verma, A.; Steidl, U. Effect of the nonpeptide thrombopoietin receptor agonist Eltrombopag on bone marrow cells from patients with acute myeloid leukemia and myelodysplastic syndrome. Blood 2009, 114, 3899–3908. [Google Scholar] [CrossRef]
  5. Fattizzo, B.; Levati, G.; Cassin, R.; Barcellini, W. Eltrombopag in immune thrombocytopenia, aplastic anemia and myelodysplastic syndrome: From Megakaryopoiesis to immunomodulation. Drugs 2019, 79, 1305–1319. [Google Scholar] [CrossRef]
  6. Capecchi, M.; Serpenti, F.; Giannotta, J.; Pettine, L.; Reda, G.; Martinelli, I.; Artoni, A.; Barcellini, W.; Fattizzo, B. Off-label use of thrombopoietin receptor agonist: Case series and review of the literature. Front. Oncol. 2021, 11, 680411. [Google Scholar] [CrossRef]
  7. Calmettes, C.; Vigouroux, S.; Tabrizi, R.; Milpied, N. Romiplostim (AMG531, Nplate) for secondary failure of platelet recovery after allo-SCT. Bone Marrow Transplant. 2011, 46, 1587–1589. [Google Scholar] [CrossRef]
  8. Gangatharan, S.A.; Cooney, J.P. Persistent thrombocytopenia post auto-SCT for AML treated with romiplostim in a patient with HIV. Bone Marrow Transplant. 2011, 46, 1280–1281. [Google Scholar] [CrossRef]
  9. Reid, R.; Bennett, J.M.; Becker, M.; Chen, Y.; Milner, L.; Ii, G.L.P.; Liesveld, J. Use of eltrombopag, a thrombopoietin receptor agonist, in post-transplantation thrombocytopenia. Am. J. Hematol. 2012, 87, 743–745. [Google Scholar] [CrossRef] [Green Version]
  10. Liesveld, J.L.; Phillips, G.L., II; Becker, M.; Constine, L.S.; Friedberg, J.; Andolina, J.R.; Chen, Y. A phase 1 trial of eltrombopag in patients undergoing stem cell transplantation after total body irradiation. Biol. Blood Marrow Transplant. 2013, 19, 1745–1752. [Google Scholar] [CrossRef] [Green Version]
  11. Fujimi, A.; Kamihara, Y.; Hashimoto, A.; Kanisawa, Y.; Nakajima, C.; Hayasaka, N.; Yamada, S.; Okuda, T.; Minami, S.; Ono, K.; et al. Identification of anti-thrombopoietin receptor antibody in prolonged thrombocytopenia after allogeneic hematopoietic stem cell transplantation treated successfully with eltrombopag. Int. J. Hematol. 2015, 102, 471–476. [Google Scholar] [CrossRef] [PubMed]
  12. Battipaglia, G.; Ruggeri, A.; Brissot, E.; Mamez, A.-C.; Malard, F.; Belhocine, R.; Vekhoff, A.; Giannotti, F.; Ledraa, T.; Labopin, M.; et al. Safety and feasibility of romiplostim treatment for patients with persistent thrombocytopenia after allogeneic stem cell transplantation. Bone Marrow Transplant. 2015, 50, 1574–1577. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Raut, S.S.; Shah, S.A.; Sharanangat, V.V.; Shah, K.M.; Patel, K.A.; Anand, A.S.; Talati, S.S.; Panchal, H.P.; Patel, A.A.; Parikh, S.K.; et al. Safety and Efficacy of Eltrombopag in Post-hematopoietic Stem Cell Transplantation (HSCT) Thrombocytopenia. Indian J. Hematol. Blood Transfus. 2015, 31, 413–415. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  14. Tanaka, T.; Inamoto, Y.; Yamashita, T.; Fuji, S.; Okinaka, K.; Kurosawa, S.; Kim, S.-W.; Tanosaki, R.; Fukuda, T. Eltrombopag for Treatment of Thrombocytopenia after Allogeneic Hematopoietic Cell Transplantation. Biol. Blood Marrow Transplant. 2016, 22, 919–924. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  15. Dyba, J.; Tinmouth, A.; Bredeson, C.; Matthews, J.; Allan, D.S. Eltrombopag after allogeneic haematopoietic cell transplantation in a case of poor graft function and systematic review of the literature. Transfus. Med. 2016, 26, 202–207. [Google Scholar] [CrossRef] [PubMed]
  16. Hartranft, M.; Clemmons, A.; DeRemer, D.L.; Kota, V. Evaluation of romiplostim for the treatment of secondary failure of platelet recovery among allogeneic hematopoietic stem cell transplant patients. J. Oncol. Pharm. Pract. 2017, 23, 10–17. [Google Scholar] [CrossRef]
  17. Tang, C.; Chen, F.; Kong, D.; Ma, Q.; Dai, H.; Yin, J.; Li, Z.; Chen, J.; Zhu, X.; Mao, X.; et al. Successful treatment of secondary poor graft function post allogeneic hematopoietic stem cell transplantation with eltrombopag. J. Hematol. Oncol. 2018, 11, 103. [Google Scholar] [CrossRef]
  18. Bosch-Vilaseca, A.; García-Cadenas, I.; Roldán, E.; Novelli, S.; Barba, P.; Esquirol, A.; Valcárcel, D.; Martino, R.; Sierra, J. Usefulness of thrombopoietin receptor agonists for persistent clinically relevant thrombocytopenia after allogeneic stem cell transplantation. Eur. J. Haematol. 2018, 101, 407–414. [Google Scholar] [CrossRef]
  19. Mori, S.; Patel, R.D.; Boyd, A.; Simon, S.; Nelson, J.; Goldstein, S.C. Eltrombopag Treatment for Primary and Secondary Thrombocytopenia Post Allogeneic and Autologous Stem Cell Transplantation is Effective and Safe. Biol. Blood Marrow Transplant. 2018, 24, S343–S344. [Google Scholar] [CrossRef]
  20. Li, S.; Wu, R.; Wang, B.; Fu, L.; Zhu, G.; Zhou, X.; Ma, J.; Zhang, L.; Qin, M. Eltrombopag for Delayed Platelet Recovery and Secondary Thrombocytopenia Following Allogeneic Stem Cell Transplantation in Children. J. Pediatr. Hematol. Oncol. 2019, 41, 38–41. [Google Scholar] [CrossRef]
  21. Rivera, D.; Bastida, J.M.; Corral, L.L.; Sanchez-Guijo, F.; Cabrero, M.; Martin, A.; Perez, E.; Lopez-Parra, M.; Avendaño, A.; Veiga, A.; et al. Usefulness of eltrombopag for treating thrombocytopenia after allogeneic stem cell transplantation. Bone Marrow Transplant. 2019, 54, 757–761. [Google Scholar] [CrossRef] [PubMed]
  22. Rudakova, T.A.; Kulagin, A.; Moiseev, I.S.; Bykova, T.A.; Bondarenko, S.N.; Barabanshikova, M.V.; Beinarovich, A.V.; Osipova, A.A.; Ovechkina, V.N.; Alyanskiy, A.L.; et al. Thrombopoietin receptor agonists for treatment of poor graft function after allogeneic hematopoietic stem cell transplantation in adults. Cell. Ther. Transplant. 2019, 8, 38–44. [Google Scholar] [CrossRef]
  23. Fu, H.; Zhang, X.; Han, T.; Mo, X.; Wang, Y.; Chen, H.; Han, W.; Wang, J.; Wang, F.; Yan, C.; et al. Eltrombopag is an effective and safe therapy for refractory thrombocytopenia after haploidentical hematopoietic stem cell transplantation. Bone Marrow Transplant. 2019, 54, 1310–1318. [Google Scholar] [CrossRef] [PubMed]
  24. Marotta, S.; Marano, L.; Ricci, P.; Cacace, F.; Frieri, C.; Simeone, L.; Trastulli, F.; Vitiello, S.; Cardano, F.; Pane, F.; et al. Eltrombopag for post-transplant cytopenias due to poor graft function. Bone Marrow Transplant. 2019, 54, 1346–1353. [Google Scholar] [CrossRef]
  25. Yuan, C.; Boyd, A.M.; Nelson, J.; Patel, R.D.; Varela, J.C.; Goldstein, S.C.; Ahmad, S.; Zhu, X.; Mori, S. Eltrombopag for Treating Thrombocytopenia after Allogeneic Stem Cell Transplantation. Biol. Blood Marrow Transplant. 2019, 25, 1320–1324. [Google Scholar] [CrossRef]
  26. Bento, L.; Bastida, J.M.; García-Cadenas, I.; García-Torres, E.; Rivera, D.; Bosch-Vilaseca, A.; De Miguel, C.; Martínez-Muñoz, M.E.; Fernández-Avilés, F.; Roldán, E.; et al. Thrombopoietin Receptor Agonists for Severe Thrombocytopenia after Allogeneic Stem Cell Transplantation: Experience of the Spanish Group of Hematopoietic Stem Cell Transplant. Biol. Blood Marrow Transplant. 2019, 25, 1825–1831. [Google Scholar] [CrossRef]
  27. Samarkandi, H.; Al Nahedh, M.; Alfattani, A.; Alsharif, F.; Bakshi, N.; Rasheed, W.; Aljurf, M. Evaluation of eltrombopag in thrombocytopenia post Hematopoietic cell transplantation: Retrospective observational trial. Hematol. Oncol. Stem Cell Ther. 2020, in press. [Google Scholar] [CrossRef]
  28. Peffault de Latour, R.; Chevret, S.; Ruggeri, A.L.; Suarez, F.; Souchet, L.; Michonneau, D.; Sicre de Fontbrune, F.; Coman, T.; Dhedin, N.; Rubio, M.T.; et al. Romiplostim in patients undergoing hematopoietic stem cell transplantation: Results of a phase 1/2 multicenter trial. Blood 2020, 135, 227–229. [Google Scholar] [CrossRef]
  29. Masetti, R.; Vendemini, F.; Quarello, P.; Girardi, K.; Prete, A.; Fagioli, F.; Pession, A.; Locatelli, F. Eltrombopag for thrombocytopenia following allogeneic hematopoietic stem cell transplantation in children. Pediatr. Blood Cancer 2020, 67, e28208. [Google Scholar] [CrossRef]
  30. Aydin, S.; Dellacasa, C.; Manetta, S.; Giaccone, L.; Godio, L.; Iovino, G.; Bruno, B.; Busca, A. Rescue treatment with eltrombopag in refractory cytopenias after allogeneic stem cell transplantation. Ther. Adv. Hematol. 2020, 11, 2040620720961910. [Google Scholar] [CrossRef]
  31. Gao, F.; Zhou, X.; Shi, J.; Luo, Y.; Tan, Y.; Fu, H.; Lai, X.; Yu, J.; Huang, H.; Zhao, Y. Eltrombopag treatment promotes platelet recovery and reduces platelet transfusion for patients with post-transplantation thrombocytopenia. Ann. Hematol. 2020, 99, 2679–2687. [Google Scholar] [CrossRef] [PubMed]
  32. Mahat, U.; Rotz, S.J.; Hanna, R. Use of Thrombopoietin Receptor Agonists in Prolonged Thrombocytopenia after Hematopoietic Stem Cell Transplantation. Biol. Blood Marrow Transplant. 2020, 26, e65–e73. [Google Scholar] [CrossRef] [PubMed]
  33. Nampoothiri, R.V.; Ho, L.; McEwan, C.; Pasic, I.; Lam, W.; Law, A.D.; Michelis, F.V.; Thyagu, S.; Kim, D.H.; Gerbitz, A.; et al. Efficacy and cost analysis of eltrombopag in thrombocytopenia and poor graft function post allogeneic hematopoietic cell transplantation. Bone Marrow Transplant. 2021, 56, 2471–2476. [Google Scholar] [CrossRef] [PubMed]
  34. Yao, Y.; Tang, Y.; Qi, J.; Li, X.; Zhang, R.; Xu, X.; Pan, T.; Han, Y. Efficacy and safety of thrombopoietin receptor agonists in the treatment of thrombocytopenia after hematopoietic stem cell transplantation: A meta-analysis and systematic review. Expert Rev. Hematol. 2021, 14, 1041–1048. [Google Scholar] [CrossRef]
  35. Yaman, Y.; Elli, M.; Şahin, Ş.; Özdilli, K.; Bilgen, H.; Bayram, N.; Nepesov, S.; Anak, S. Eltrombopag for treatment of thrombocytopenia after allogeneic hematopoietic cell transplantation in children: Single-centre experience. Pediatr. Transplant. 2021, 25, e13962. [Google Scholar] [CrossRef]
  36. Uria-Oficialdegui, M.L.; Alonso, L.; Benitez-Carabante, M.I.; Renedo, B.; Oliveras, M.; Diaz-De-Heredia, C. Use of eltrombopag for the treatment of poor graft function after hematopoietic stem cell transplantation in children. Pediatr. Transplant. 2021, 25, e14010. [Google Scholar] [CrossRef]
  37. Christakopoulos, G.E.; DeFor, T.E.; Hage, S.; Wagner, J.E.; Linden, M.A.; Brunstein, C.; Bejanyan, N.; Verneris, M.R.; Smith, A.R. Phase I Dose-Finding, Safety, and Tolerability Trial of Romiplostim to Improve Platelet Recovery After UCB Transplantation. Transplant. Cell Ther. 2021, 27, 497.e1–497.e6. [Google Scholar] [CrossRef]
  38. Pasvolsky, O.; Shargian, L.; Rozovski, U.; Wolach, O.; Ram, R.; Shapira, M.Y.; Avni, B.; Stepensky, P.; Israeli, M.; Vidal-Fisher, L.; et al. Eltrombopag for enhancement of platelet engraftment in patients undergoing allogeneic cord blood transplantation. Leuk. Lymphoma 2021, 62, 2747–2754. [Google Scholar] [CrossRef]
  39. Ahmed, S.; Bashir, Q.; Bassett, R.; Poon, M.-Y.C.; Valdez, B.; Konoplev, S.; Alousi, A.M.; Andersson, B.S.; Ciurea, S.; Hosing, C.; et al. Eltrombopag for Post-Transplantation Thrombocytopenia: Results of Phase II Randomized, Double-Blind, Placebo-Controlled Trial. Transplant. Cell Ther. 2021, 27, 430.e1–430.e7. [Google Scholar] [CrossRef]
  40. Giammarco, S.; Sica, S.; Chiusolo, P.; Laurenti, L.; Sorá, F.; Martino, M.; Metafuni, E.; Busca, A.; Risitano, A.; Vallejo, C.; et al. Eltrombopag for the treatment of poor graft function following allogeneic stem cell transplant: A retrospective multicenter study. Int. J. Hematol. 2021, 114, 228–234. [Google Scholar] [CrossRef]
  41. Qiu, K.; Liao, X.; Huang, K.; Wu, R.; Xu, H.; Xu, L.; Li, Y.; Weng, W.; Zhou, D.; Fang, J. Eltrombopag as first-line treatment for thrombocytopenia among paediatric patients after allogeneic haematopoietic stem cell transplantation. Br. J. Clin. Pharmacol. 2021, 87, 2023–2031. [Google Scholar] [CrossRef] [PubMed]
  42. Liu, S.; Que, L.P.; Huang, K.; Fang, J.P.; Wang, K.M.; Zhan, L.P.; Liu, D.D.; Xu, H.G. Eltrombopag for thrombocytopenia in 24 children after hematopoietic stem cell transplantation. Zhonghua Er Ke Za Zhi 2021, 59, 311–315. [Google Scholar] [PubMed]
  43. Demeter, J.; Istenes, I.; Fodor, A.; Paksi, M.; Dombi, P.; Valasinyószki, E.; Csomor, J.; Matolcsy, A.; Nagy, Z.G. Efficacy of romiplostim in the treatment of chemotherapy induced thrombocytopenia (CIT) in a patient with mantle cell lymphoma. Pathol. Oncol. Res. 2011, 17, 141–143. [Google Scholar] [CrossRef] [PubMed]
  44. Frey, N.; Jang, J.H.; Szer, J.; Illés, Á.; Kim, H.-J.; Ram, R.; Chong, B.H.; Rowe, J.M.; Borisenkova, E.; Liesveld, J.; et al. Eltrombopag treatment during induction chemotherapy for acute myeloid leukaemia: A randomised, double-blind, phase 2 study. Lancet Haematol. 2019, 6, e122–e131. [Google Scholar] [CrossRef]
  45. Strickland, S.A.; Wang, X.V.; Cerny, J.; Rowe, J.M.; Rybka, W.; Tallman, M.S.; Litzow, M.; Lazarus, H.M. A novel PrECOG (PrE0901) dose-escalation trial using eltrombopag: Enhanced platelet recovery during consolidation therapy in acute myeloid leukemia. Leuk. Lymphoma 2020, 61, 2191–2199. [Google Scholar] [CrossRef] [PubMed]
  46. Zhu, Q.; Yang, S.; Zeng, W.; Li, M.; Guan, Z.; Zhou, L.; Wang, H.; Liu, Y.; Gao, Y.; Qiu, S.; et al. A Real-World Observation of Eltrombopag and Recombinant Human Thrombopoietin (rhTPO) in Lymphoma Patients with Chemotherapy Induced Thrombocytopenia. Front. Oncol. 2021, 11, 701539. [Google Scholar] [CrossRef] [PubMed]
  47. Al-Samkari, H.; Parnes, A.D.; Goodarzi, K.; Weitzman, J.I.; Connors, J.M.; Kuter, D.J. A multicenter study of romiplostim for chemotherapy-induced thrombocytopenia in solid tumors and hematologic malignancies. Haematologica 2021, 106, 1148–1157. [Google Scholar] [CrossRef]
  48. Kanameishi, S.; Otsuka, A.; Nonomura, Y.; Fujisawa, A.; Endo, Y.; Kabashima, K. Idiopathic thrombocytopenic purpura induced by nivolumab in a metastatic melanoma patient with elevated PD-1 expression on B cells. Ann. Oncol. 2016, 27, 546–547. [Google Scholar] [CrossRef]
  49. Song, P.; Zhang, L. Eltrombopag treatment for severe refractory thrombocytopenia caused by pembrolizumab. Eur. J. Cancer 2019, 121, 4–6. [Google Scholar] [CrossRef]
  50. Ito, M.; Kanda, S.; Yoshida, T.; Okuma, Y.; Jo, H.; Fukuhara, S.; Maeshima, A.M.; Ohe, Y. Eltrombopag olamine for refractory immune-related thrombocytopenia induced by pembrolizumab in a non-small cell lung cancer patient. Lung Cancer 2020, 146, 363–365. [Google Scholar] [CrossRef]
  51. Suyama, T.; Hagihara, M.; Kubota, N.; Osamura, Y.; Shinka, Y.; Miyao, N. Acquired amegakaryocytic thrombocytopenia after durvalumab administration. J. Clin. Exp. Hematop. 2021, 61, 53–57. [Google Scholar] [CrossRef] [PubMed]
  52. Fu, S.; Wang, T.; Xu, F. Delayed immune thrombocytopenia after discontinuation of nivolumab therapy: A case report and literature review. J. Oncol. Pharm. Pract. 2021, 27, 1548–1552. [Google Scholar] [CrossRef] [PubMed]
  53. Younan, R.G.; Raad, R.A.; Sawan, B.Y.; Said, R. Aplastic anemia secondary to dual cancer immunotherapies a physician nightmare:case report and literature review. Allergy Asthma Clin. Immunol. 2021, 17, 112. [Google Scholar] [CrossRef] [PubMed]
  54. Schubert, M.-L.; Schmitt, M.; Wang, L.; Ramos, C.; Jordan, K.; Müller-Tidow, C.; Dreger, P. Side-effect management of chimeric antigen receptor (CAR) T-cell therapy. Ann. Oncol. 2021, 32, 34–48. [Google Scholar] [CrossRef] [PubMed]
  55. Baur, R.; Jitschin, R.; Kharboutli, S.; Stoll, A.; Völkl, S.; Büttner-Herold, M.; Schmidt, D.; Rösler, W.; Mackensen, A.; Mougiakakos, D. Thrombopoietin receptor agonists for acquired thrombocytopenia following anti-CD19 CAR-T-cell therapy: A case report. J. Immunother. Cancer 2021, 9, e002721. [Google Scholar] [CrossRef] [PubMed]
  56. Matsumoto, R.; Ito, K.; Hosono, N.; Matsuda, Y.; Tai, K.; Sakamaki, I.; Aoki, G.; Yamazaki, H.; Nakao, S.; Yamauchi, T. Acute myeloid leukemia developing secondary immune thrombocytopenia after umbilical cord blood transplantation. Rinsho Ketsueki 2017, 58, 433–437. [Google Scholar]
  57. Lozano, M.; Segú-Vergés, C.; Coma, M.; Álvarez-Roman, M.; González-Porras, J.; Gutiérrez, L.; Valcárcel, D.; Butta, N. Elucidating the Mechanism of Action of the Attributed Immunomodulatory Role of Eltrombopag in Primary Immune Thrombocytopenia: An In Silico Approach. Int. J. Mol. Sci. 2021, 22, 6907. [Google Scholar] [CrossRef]
  58. Bao, W.; Bussel, J.B.; Heck, S.; He, W.; Karpoff, M.; Boulad, N.; Yazdanbakhsh, K. Improved regulatory T-cell activity in patients with chronic immune thrombocytopenia treated with thrombopoietic agents. Blood 2010, 116, 4639–4645. [Google Scholar] [CrossRef] [Green Version]
  59. Liu, X.G.; Liu, S.; Feng, Q.; Liu, X.N.; Li, G.S.; Sheng, Z.; Chen, P.; Liu, Y.; Wei, Y.; Dong, X.Y.; et al. Thrombopoietin receptor agonists shift the balance of Fcã receptors toward inhibitory receptor IIb on monocytes in ITP. Blood 2016, 128, 852–861. [Google Scholar] [CrossRef]
  60. Di Paola, A.; Palumbo, G.; Merli, P.; Argenziano, M.; Tortora, C.; Strocchio, L.; Roberti, D.; Santoro, C.; Perrotta, S.; Rossi, F. Effects of Eltrombopag on In Vitro Macrophage Polarization in Pediatric Immune Thrombocytopenia. Int. J. Mol. Sci. 2021, 22, 97. [Google Scholar] [CrossRef]
  61. Li, X.; Zhong, H.; Bao, W.; Boulad, N.; Evangelista, J.; Haider, M.A.; Bussel, J.; Yazdanbakhsh, K. Defective regulatory B-cell compartment in patients with immune thrombocytopenia. Blood 2012, 120, 3318–3325. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  62. Roth, M.; Will, B.; Simkin, G.; Narayanagari, S.; Barreyro, L.; Bartholdy, B.; Tamari, R.; Mitsiades, C.S.; Verma, A.; Steidl, U. Eltrombopag inhibits the proliferation of leukemia cells via reduction of intracellular iron and induction of differentiation. Blood 2012, 120, 386–394. [Google Scholar] [CrossRef] [PubMed]
  63. Lambert, M.P.; Witmer, C.M.; Kwiatkowski, J.L. Therapy induced iron deficiency in children treated with eltrombopag for immune thrombocytopenia. Am. J. Hematol. 2017, 92, E88–E91. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  64. Vlachodimitropoulou, E.; Chen, Y.-L.; Garbowski, M.; Koonyosying, P.; Psaila, B.; Sola-Visner, M.; Cooper, N.; Hider, R.; Porter, J. Eltrombopag: A powerful chelator of cellular or extracellular iron (III) alone or combined with a second chelator. Blood 2017, 130, 1923–1933. [Google Scholar] [CrossRef] [PubMed]
  65. Punzo, F.; Tortora, C.; Argenziano, M.; Casale, M.; Perrotta, S.; Rossi, F. Iron chelating properties of Eltrombopag: Investigating its role in thalassemia-induced osteoporosis. PLoS ONE 2018, 13, e0208102. [Google Scholar] [CrossRef]
  66. Fattizzo, B.; Cavallaro, F.; Milesi, G.; Barcellini, W. Iron mobilization in a real life cohort of aplastic anemia patients treated with eltrombopag. Am. J. Hematol. 2019, 94, E237–E239. [Google Scholar] [CrossRef] [Green Version]
  67. Di Paola, A.; Palumbo, G.; Tortora, C.; Argenziano, M.; Catanoso, M.; Di Leva, C.; Ceglie, G.; Perrotta, S.; Locatelli, F.; Rossi, F. Eltrombopag in paediatric immune thrombocytopenia: Iron metabolism modulation in mesenchymal stromal cells. Br. J. Haematol. 2022, 197, 110–119. [Google Scholar] [CrossRef]
  68. Desmond, R.; Townsley, D.M.; Dumitriu, B.; Olnes, M.J.; Scheinberg, P.; Bevans, M.; Parikh, A.R.; Broder, K.; Calvo, K.; Wu, C.O.; et al. Eltrombopag restores trilineage hematopoiesis in refractory severe aplastic anemia that can be sustained on discontinuation of drug. Blood 2014, 123, 1818–1825. [Google Scholar] [CrossRef]
  69. Dickinson, M.; Cherif, H.; Fenaux, P.; Mittelman, M.; Verma, A.; Portella, M.S.O.; Burgess, P.; Ramos, P.M.; Choi, J.; Platzbecker, U. Azacitidine with or without eltrombopag for first-line treatment of intermediate- or high-risk MDS with thrombocytopenia. Blood 2018, 132, 2629–2638. [Google Scholar] [CrossRef]
  70. Patel, B.A.; Groarke, E.M.; Lotter, J.; Shalhoub, R.N.; Gutierrez-Rodrigues, F.; Rios, O.J.; Raffo, D.Q.; Wu, C.O.; Young, N.S. Long-term outcomes in patients with severe aplastic anemia treated with immunosuppression and eltrombopag: A phase 2 study. Blood 2022, 139, 34–43. [Google Scholar] [CrossRef]
  71. Peffault de Latour, R.; Kulasekararaj, A.; Iacobelli, S.; Terwel, S.R.; Cook, R.; Griffin, M.; Halkes, C.J.; Recher, C.; Barraco, F.; Forcade, E.; et al. Eltrombopag Added to Immunosuppression in Severe Aplastic Anemia. N. Engl. J. Med. 2022, 386, 11–23. [Google Scholar] [CrossRef] [PubMed]
  72. Wong, R.; Saleh, M.N.; Khelif, A.; Salama, A.; Portella, M.S.O.; Burgess, P.; Bussel, J.B. Safety and efficacy of long-term treatment of chronic/persistent ITP with eltrombopag: Final results of the EXTEND study. Blood 2017, 130, 2527–2536. [Google Scholar] [CrossRef] [PubMed]
  73. Olnes, M.J.; Scheinberg, P.; Calvo, K.; Desmond, R.; Tang, Y.; Dumitriu, B.; Parikh, A.R.; Soto, S.; Biancotto, A.; Feng, X.; et al. Eltrombopag and improved hematopoiesis in refractory aplastic anemia. N. Engl. J. Med. 2012, 367, 11–19. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  74. Barcellini, W.; Fattizzo, B. The changing landscape of autoimmune hemolytic anemia. Front. Immunol. 2020, 11, 946. [Google Scholar] [CrossRef]
  75. Lauta, V.M. A review of the cytokine network in multiple myeloma: Diagnostic, prognostic, and therapeutic implications. Cancer 2003, 97, 2440–2452. [Google Scholar] [CrossRef]
  76. D’Acquisto, F.; Crompton, T. CD3+CD4-CD8- (double negative) T cells: Saviours or villains of the immune response? Biochem. Pharmacol. 2011, 82, 333–340. [Google Scholar] [CrossRef] [Green Version]
Pharmaceuticals 15 00419 g001 550
Figure 1. Hemoglobin (red line), neutrophils (blue line) and platelets (green line) trends from ASCT to eltrombopag discontinuation. ASCT, autologous stem cells transplant; G-CSF, granulocyte colony-stimulating factor.
Figure 1. Hemoglobin (red line), neutrophils (blue line) and platelets (green line) trends from ASCT to eltrombopag discontinuation. ASCT, autologous stem cells transplant; G-CSF, granulocyte colony-stimulating factor.
Pharmaceuticals 15 00419 g001
Pharmaceuticals 15 00419 g002 550
Figure 2. Bone marrow histology at 3, 6 and 12 months (mo) of eltrombopag treatment. The 3-months-biopsy (a) Giemsa, 200×, depicts a hypocellular bone marrow, with hematopoiesis mostly represented by erythroid islands, in the absence of remarkable features of morphologic dysplasia, nor increased blast count. An adjoining lymphoid population is very scant and mostly represented by small CD3+ T-cells; (b) CD3, 200×, interstitial in their distribution, with very rare CD4+ cells; (c) 200× and a minor component of CD8+ cells; (d) 200×, thus, consistent with the presence of a CD4-/CD8- subpopulation. The 6-months biopsy documents an increasing cellularity, with relative over-representation of erythroid series; (e) Giemsa, 200×, coupled with a heavier T-cell infiltrate 10–15% of overall cellularity; (f) CD3, 200×, patterned in a micronodular and interstitial configuration, with no intrasinusoidal features, still partially lacking CD4; (g) 200× and CD8; (h) 200× expression. The 12-months biopsy displays a hematopoiesis within ranges; (i) Giemsa, 200×, notably featuring scattered giant, hyperlobated megakaryocytes (morphologic appearance consistent with therapy related modifications) and a T-cell infiltrate; (j) CD3, 200×; (k) CD4, 200×; (l) CD8, 200× overlapping the previous picture. Grade of marrow fibrosis at 3, 6, and 12 months: MF-0. Not shown in the present panel, no significant amount of lymphoid cells are seen expressing CD56, CD57, TCR-delta, FoxP3, CD25, and TdT. Furthermore, focal, perivascular amyloid deposits are observed, without evidence of residual plasma cell neoplasm component.
Figure 2. Bone marrow histology at 3, 6 and 12 months (mo) of eltrombopag treatment. The 3-months-biopsy (a) Giemsa, 200×, depicts a hypocellular bone marrow, with hematopoiesis mostly represented by erythroid islands, in the absence of remarkable features of morphologic dysplasia, nor increased blast count. An adjoining lymphoid population is very scant and mostly represented by small CD3+ T-cells; (b) CD3, 200×, interstitial in their distribution, with very rare CD4+ cells; (c) 200× and a minor component of CD8+ cells; (d) 200×, thus, consistent with the presence of a CD4-/CD8- subpopulation. The 6-months biopsy documents an increasing cellularity, with relative over-representation of erythroid series; (e) Giemsa, 200×, coupled with a heavier T-cell infiltrate 10–15% of overall cellularity; (f) CD3, 200×, patterned in a micronodular and interstitial configuration, with no intrasinusoidal features, still partially lacking CD4; (g) 200× and CD8; (h) 200× expression. The 12-months biopsy displays a hematopoiesis within ranges; (i) Giemsa, 200×, notably featuring scattered giant, hyperlobated megakaryocytes (morphologic appearance consistent with therapy related modifications) and a T-cell infiltrate; (j) CD3, 200×; (k) CD4, 200×; (l) CD8, 200× overlapping the previous picture. Grade of marrow fibrosis at 3, 6, and 12 months: MF-0. Not shown in the present panel, no significant amount of lymphoid cells are seen expressing CD56, CD57, TCR-delta, FoxP3, CD25, and TdT. Furthermore, focal, perivascular amyloid deposits are observed, without evidence of residual plasma cell neoplasm component.
Pharmaceuticals 15 00419 g002
Pharmaceuticals 15 00419 g003 550
Figure 3. Cytokine levels during eltrombopag treatment. Red dots represent patient’s values; boxplots represent the median, quartiles, and ranges for cytokine levels in 40 age- and sex-matched healthy controls. IFN-γ, interferon gamma; IL, interleukin 6, 10, 17; TGF-β, transforming growth factor beta; TNFα, tumor necrosis factor alpha; 6, 12 and 24 months (mo) of eltrombopag treatment.
Figure 3. Cytokine levels during eltrombopag treatment. Red dots represent patient’s values; boxplots represent the median, quartiles, and ranges for cytokine levels in 40 age- and sex-matched healthy controls. IFN-γ, interferon gamma; IL, interleukin 6, 10, 17; TGF-β, transforming growth factor beta; TNFα, tumor necrosis factor alpha; 6, 12 and 24 months (mo) of eltrombopag treatment.
Pharmaceuticals 15 00419 g003
Table
Table 1. Studies on TPO-RA post-HSCT.
Table 1. Studies on TPO-RA post-HSCT.
TypeNo. ptsE/RResultsReferences
retrospective7RORR 100%Calmettes C et al., Bone Marrow Transpl, 2011 [7]
case report1RORR 100%Gangatharan SA et al., Bone Marrow Transplant, 2011 [8]
case report2EORR 100%Reid R et al., Am J Hematol, 2012 [9]
phase 1 study19EORR naLiesveld JL et al., Biol Blood Marrow Transplant, 2013 [10]
case report1EORR 100%Fujimi A et al., Int J Hematol, 2015 [11]
retrospective8RORR 62.5%Battipaglia G et al., Bone Marrow Transplant, 2015 [12]
retrospective12EORR naRaut S et al., Indian J Hematol Blood Transf, 2015 [13]
retrospective12EORR 60%Tanaka T et al., Biol Blood Marrow Transpl, 2016 [14]
case report1EORR 100%Dyba J et al., Transfus Med, 2016 [15]
retrospective13RORR 53%Hartranft ME et al., J Oncol Pharm Pract, 2017 [16]
retrospective12EORR 83%Tang C et al., J Hematol Oncol, 2018 [17]
retrospective20E/RORR 60%Bosch-Vilaseca A et al., Eur J Hematol, 2018 [18]
retrospective19EORR 74%Mori S et al., Biol Blood Marrow Transplant, 2018 [19]
case report3 (ped)EORR 66.6%Li S et al., J Pediatr Hematol Oncol, 2019 [20]
retrospective14EORR 57%Rivera D et al., Bone Marrow Transpl, 2019 [21]
retrospective31E/RORR 52%Rudakova TA et al., Cellular Ther Transplant, 2019 [22]
retrospective38EORR 63%Fu H et al., Bone Marrow Transpl, 2019 [23]
retrospective13EORR 53%Marotta S et al., Bone Marrow Transpl, 2019 [24]
phase 2 study13EORR 62%Yuan C et al., Biol Blood Marrow Transpl, 2019 [25]
retrospective86E/RORR 72%Bento L et al., Biol Blood Marrow Transpl, 2019 [26]
retrospective21EORR 75%Samarkandi H et al., Hematol Oncol Stem Cell Ther, 2020 [27]
phase 1/2 study24RORR 66%Peffault De Latour R et al., Blood, 2020 [28]
retrospective9 (ped)EORR 88%Masetti R et al., Pediatr Blood Cancer, 2020 [29]
retrospective12EORR 83%Aydin S et al., Ther Adv Hematol, 2020 [30]
retrospective32EORR 65.6%Gao F et al., Ann Hematol, 2020 [31]
review121/49 E/RE/RORR 67/82% E/RMahat U et al., Biol Blood Marrow Transpl, 2020 [32]
retrospective17EORR 76.5%Nampoothiri RV et al., Bone Marrow Transplant, 2021 [33]
meta-analysis378E/RORR 73%Yao Y et al., Expert Rev Hematol, 2021 [34]
retrospective18 (ped)EORR 77.7%Yaman Y et al., Pediatr Transplant, 2021 [35]
retrospective study5 (ped)EORR 80%Uria-Oficialdegui ML et al., Pediatr Transplant, 2021 [36]
phase 1 study20RORR 100%Christakopoulos GE et al., Transplant Cell Ther, 2021 [37]
phase 2a study12 (2 ped)EORR naPasvolsky O et al., Leuk Lymphoma, 2021 [38]
phase 2 (E vs. PbO)60 (2/1)EORR 36 vs. 28%Ahmed S et al., Transplant Cell Ther, 2021 [39]
retrospective48EORR 75%Giammarco S et al., Int J Hematol, 2021 [40]
retrospective43 (ped)EORR 81%Qiu KY et al., Br J Clin Pharmacol. 2021 [41]
retrospective24 (ped)EORR 92%Liu S et al., Zhonghua Er Ke Za Zhi, 2021 [42]
E, Eltrombopag; HSCT, hemopoietic stem cell transplant; ORR, overall response rate; PbO, placebo; ped, pediatric patients; pts, patients; R, Romiplostim. Bolded studies report the use of TPO-RA for aplasia post-autologous stem cell transplant.
Table
Table 2. Studies on TPO-RA after chemotherapy.
Table 2. Studies on TPO-RA after chemotherapy.
TypeNo. ptsHematologic
Disease		E/RResultsReferences
case report1MCLRORR 100%Demeter J et al., Pathol Oncol Res, 2011 [43]
phase 2 study (E vs. PbO)148 (1/1)AMLEnaFrey N et al., Lancet Haematol, 2019 [44]
phase 1 study14AMLETPR 22.5 (16–43) * dStrickland SA et al., Leuk Lymphoma, 2020 [45]
retrospective50LymphomaETPR 7.43 + 2.54 ° dZhu Q et al., Front Oncol, 2021 [46]
retrospective20Lymphoma/MMRORR 10%Al-Samkari H et al., Haematologica, 2021 [47]
AML, acute myeloid leukemia; d, days; E, Eltrombopag; MCL, mantle cell lymphoma; MM, multiple myeloma; na, not available; ORR, overall response rate; PbO, placebo; pts, patients; R, Romiplostim; TPR, time for platelets count recovery. * median days for platelet recovery (minimum-maximum). ° mean days for platelet recovery (mean + SD).
Table
Table 3. Studies on TPO-RA after immune checkpoint inhibitors therapy and CAR-T therapy.
Table 3. Studies on TPO-RA after immune checkpoint inhibitors therapy and CAR-T therapy.
TypeSettingNo. ptsDiseaseE/RResultsReferences
retrospectiveCPI (N)1melanomaRORR 100%Kanameishi S et al., Ann Oncol, 2016 [48]
retrospectiveCPI (P)1NSCLCEnaSong P et al., Eur J Cancer, 2019 [49]
retrospectiveCPI (P)1NSCLCEORR 100%Ito M et al., Lung Cancer, 2020 [50]
retrospectiveCPI (D)1SCLCEORR 100%Suyama T et al., J Clin Exp Hematop, 2021 [51]
retrospectiveCPI (N)1NSCLCEORR 100%Fu S et al. J Oncol Pharm Pract, 2021 [52]
retrospectiveCPI (N)1RCCEORR 0%Younan RG et al., Allergy Asthma Clin Immunol, 2021 [53]
retrospectiveanti-CD19 CAR-T (Axi-cel)1NHLRORR 100%Baur R et al., J Immunother Cancer, 2021 [55]
CPI, checkpoint inhibitors; D, durvalumab; E, Eltrombopag; N, Nivolumab; NHL, Non-Hodgkin Lymphoma; NSCLC, non–small cell lung cancer; ORR, overall response rate; P, Pembrolizumab; pts, patients; R, Romiplostim; RCC, renal cell carcinoma; SCLC, small cell lung cancer.
Table
Table 4. Registered trials on ClinicalTrials.gov (accessed on 22 January 2022).
Table 4. Registered trials on ClinicalTrials.gov (accessed on 22 January 2022).
Trial No.TypeDrugSetting
NCT04673266Phase 2RPost-CT in Lymphoma
NCT04600960Phase 2EPost-CT
NCT04478123Phase 2RPost-CT and post-ASCT in MM, NHL, HL
NCT03948529Phase 2EPost-allogenic HSCT
NCT03902041ObservationalEPost-allogenic HSCT
NCT03718533Phase 2EPoor graft function
NCT03701217Phase 2/3EPost-CT in AML
NCT03603795Phase 2EPost-CT in AML of elderly pts
NCT03515096Phase 3E vs. rhTPOPost-HSCT
NCT03437603Phase 2EPost-allogenic HSCT
NCT03343847Phase 3RPost-CT in Lymphoma
NCT02071901Phase 2EPost-CT in AML of elderly pts
NCT02052882Phase 2RPost-CT
NCT02046291Phase 1RPost-UCBT
NCT01980030Phase 1/2RPost-allogenic HSCT
NCT01940562Phase 2EPost-UCBT in pediatric pts
NCT01927731Phase 2EPost-HSCT
NCT01791101Phase 2EPost-HSCT
NCT01757145Phase 2EPost-UCBT
NCT01676961Phase 2RPost-CT in MM
NCT01656252Phase 1/2EDuring CT in AML
NCT01516619Phase 2RPost-CT in NHL
NCT01428635Phase 2/3EDuring TKI in CML and PMF
NCT01286675Early phase 1E & G-CSFMobilization CD34+ cell in MM
NCT01000051Phase 2EPost-HSCT
NCT00903929Phase 1EPost-TBI
NCT00299182Phase 1/2RPost-CT in Lymphoma
NCT00283439Phase 1/2RPost-CT in Lymphoma
NCT00102726Phase 2EPost-CT
AML, acute myeloid leukemia; CML, chronic myeloid leukemia; CT, chemotherapy; E, Eltrombopag; HL, Hodgkin lymphoma; HSCT, hematopoietic stem cell transplant; MM, multiple myeloma; NHL, non-Hodgkin lymphoma; PMF, primary myelofibrosis; R, Romiplostim; TBI, total body irradiation; TKI, tyrosine kinase inhibitor; UCBT, umbilical cord blood transplant.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Bortolotti, M.; Pettine, L.; Zaninoni, A.; Croci, G.A.; Barcellini, W.; Fattizzo, B. Efficacy and Immunomodulating Properties of Eltrombopag in Aplastic Anemia following Autologous Stem Cell Transplant: Case Report and Review of the Literature. Pharmaceuticals 2022, 15, 419. https://doi.org/10.3390/ph15040419

AMA Style

Bortolotti M, Pettine L, Zaninoni A, Croci GA, Barcellini W, Fattizzo B. Efficacy and Immunomodulating Properties of Eltrombopag in Aplastic Anemia following Autologous Stem Cell Transplant: Case Report and Review of the Literature. Pharmaceuticals. 2022; 15(4):419. https://doi.org/10.3390/ph15040419

Chicago/Turabian Style

Bortolotti, Marta, Loredana Pettine, Anna Zaninoni, Giorgio Alberto Croci, Wilma Barcellini, and Bruno Fattizzo. 2022. "Efficacy and Immunomodulating Properties of Eltrombopag in Aplastic Anemia following Autologous Stem Cell Transplant: Case Report and Review of the Literature" Pharmaceuticals 15, no. 4: 419. https://doi.org/10.3390/ph15040419

APA Style

Bortolotti, M., Pettine, L., Zaninoni, A., Croci, G. A., Barcellini, W., & Fattizzo, B. (2022). Efficacy and Immunomodulating Properties of Eltrombopag in Aplastic Anemia following Autologous Stem Cell Transplant: Case Report and Review of the Literature. Pharmaceuticals, 15(4), 419. https://doi.org/10.3390/ph15040419

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop