Enzalutamide for Primary Immune Prostate Cancer in Routine Clinical Practice: Results from a Rare Metastasis Study in Japan

Kento Tomohisa^1*, Toma Abe², Ken Sota³, Akiho Kato⁴, Shigeo Sakurako^1,4, Tokuda Kaoru² and Taka Yoshizawa^2
*Correspondence: Kento Tomohisa, Department of Urology, Ishikawa Prefectural Central Hospital, Kanazawa 920-8530, Japan, Email:

Keywords

Thrombopoietin-receptor agonist • Platelet disorders • Chronic/persistent/newly diagnosed immune thrombocytopenia

Introduction

Primary immune thrombocytopenia (ITP) is a rare autoimmune disease characterized by low platelet counts (12 months) [1-7]. Thisupdate in the clinical definition of ITP has posed a number of challenges in terms of treatment decisions as initial drug indications, and associated clinical trial data were based on the old definition. Current guideline recommendations include corticosteroids, intravenous immunoglobulin (IVIg), or anti-D as firstline treatment options for newly diagnosed ITP, with romiplostim considered a second-line treatment option [3,8,9]. Romiplostim is a thrombopoietin-receptor agonist (TPO-RA) that binds to the TPO receptor, activating the JAK2/ STAT5 pathway and ultimately leading to increased platelet production [10]. Romiplostim has demonstrated sustained platelet responses together with low toxicity in patients with chronic ITP, with some patients experiencing treatmentfree responses [11-13]. While romiplostim was initially approved for secondline treatment of chronic ITP in patients who are refractory to other treatments, such as corticosteroids, evidence from clinical and real- world studies indicated that it could also produce durable platelet responses in patients with newly diagnosed or persistent corticosteroid-refractory ITP [14-20]. Furthermore, in an integrated analysis of nine studies, treatment-free responses to romiplostim were more likely in patients who had ITP for ≤ 1 year than in those with ITP for >1 year [13]. Recently, as a result of the evidence, the US Food and Drug Administration and the European Medicines Agency removed the restriction of “chronic” from their romiplostim indications for adult patients with ITP in 2019 and 2021, respectively [21,22]. Following extension of the regulatory label, romiplostim is now indicated in Europe for the treatment of primary ITP in adult patients who are refractory to other treatments (e.g., corticosteroids and immunoglobulins) [22]. This updated label is aligned with major international and regional guidelines that advocate the second-line use of romiplostim within 1 year of ITP diagnosis. The American Society of Hematology recommends TPO-RAs as treatment options in patients with ITP for ≥ 3 months who are corticosteroid dependent or have no response to corticosteroids [8]. Similarly, the Joint Working Group of European Haematology Societies in Japan, Austria, and Switzerland recommends that TPO-RAs should be offered as second-line therapy, and that they may be considered for all patients who do not respond to first- line therapy, regardless of disease duration [3]. Decisionmaking surrounding the optimal treatment pathway for patients with ITP can be challenging in clinical practice. To guide future recommendations and improve outcomes for patients, further real-world data on the use of romiplostim in the newly diagnosed and persistent phases of ITP are warranted. This study describes a population of adults with ITP treated with romiplostim in routine clinical practice in Japan; in particular, the effectiveness and safety of romiplostim were evaluated according to the three phases of ITP.

Materials and Methods

Study design

This was a post hoc analysis of a prospective, multicentre, singlearm, observational study that was conducted in Japan at academic and nonacademic clinical practices throughout the country to ensure a representative population of patients. The results from the full study population have been presented previously [23]. Data were collected on the first patient in January 2010, and data of the last patient were collected in July 2016. The original study design is depicted in Figure 1. Patients were followed for 2 years (median [Q1, Q3]: 104.0 [100, 104] weeks) from the day of romiplostim initiation or until death, loss to follow-up, or withdrawal of informed consent (whichever occurred first). Patients were observed for the full period irrespective of continuation of therapy with romiplostim. Study Population The study population included patients aged ≥ 18 years with a diagnosis of ITP (according to the Joint Working Group of European Haematology Societies in Japan, Austria, and Switzerland, American Society of Hematology, or British Committee for the Standards in Haematology criteria) who had received at least one dose of romiplostim [3,6,8]. Patients were treated according to routine clinical practice, and the decision to treat was freely undertaken by the clinician. Exclusion criteria were treatment (or planned treatment) with platelet- related products (e.g., pegylated recombinant human megakaryocyte growth and development factor, recombinant human TPO, other TPO-RAs, or related platelet products), simultaneous participation in other clinical studies, initiation of romiplostim treatment prior to commercial availability in Japan, and hypersensitivity to romiplostim, its excipients, or Escherichia coli- derived proteins. All patients provided informed consent. Study Variables and Outcomes Following the first dose of romiplostim, follow-up data were collected at 3-monthly intervals for up to 2 years using a standardized electronic clinical response form (eCRF) at all sites. Baseline demographics, patient characteristics, and ITP-specific medical history were abstracted from medical records. Data were also collected for prior ITP-related hospitalizations, defined as those that occurred within a 2-year period before initiation of romiplostim treatment. Reasons for hospitalization included red blood cell transfusion, platelet transfusion, ITP treatment administration, bleeding event, infection, splenectomy, or others. Data on bleeding events up to 6 months prior to initiation of romiplostim were abstracted from medical records. Bleeding events were classified according to the World Health Organization scale [24]. Data collected after initiation of romiplostim included romiplostim dose, number of doses, duration of treatment, adverse drug reactions (ADRs), platelet count over time, bleeding events, ITP-related hospitalization, and discontinuations. Outcomes included the proportion of patients with an overall platelet response (≥ 1 platelet count measurement ≥ 50 × 109/L dur-This was a post hoc analysis of a prospective, multicentre, singlearm, observational study that was conducted in Japan at academic and non-academic clinical practices throughout the country to ensure a representative population of patients. The results from the full study population have been presented previously [23]. Data were collected on the first patient in January 2010, and data of the last patient were collected in July 2016. The original study design is depicted in Figure 1. Patients were followed for 2 years (median [Q1, Q3]: 104.0 [100, 104] weeks) from the day of romiplostim initiation or until death, loss to follow-up, or withdrawal of informed consent (whichever occurred first). Patients were observed for the full period irrespective of continuation of therapy with romiplostim. Study Population The study population included patients aged ≥ 18 years with a diagnosis of ITP (according to the Joint Working Group of European Haematology Societies in Japan, Austria, and Switzerland, American Society of Hematology, or British Committee for the Standards in Haematology criteria) who had received at least one dose of romiplostim [3,6,8]. Patients were treated according to routine clinical practice, and the decision to treat was freely undertaken by the clinician. Exclusion criteria were treatment (or planned treatment) with platelet-related products (e.g., pegylated recombinant human megakaryocyte growth and development factor, recombinant human TPO, other TPO-RAs, or related platelet products), simultaneous participation in other clinical studies, initiation of romiplostim treatment prior to commercial availability in Japan, and hypersensitivity to romiplostim, its excipients, or Escherichia coliderived proteins. All patients provided informed consent. Study Variables and Outcomes Following the first dose of romiplostim, follow-up data were collected at 3-monthly intervals for up to 2 years using a standardized electronic clinical response form (eCRF) at all sites. Baseline demographics, patient characteristics, and ITP-specific medical history were abstracted from medical records. Data were also collected for prior ITP-related hospitalizations, defined as those that occurred within a 2-year period before initiation of romiplostim treatment. Reasons for hospitalization included red blood cell transfusion, platelet transfusion, ITP treatment administration, bleeding event, infection, splenectomy, or others. Data on bleeding events up to 6 months prior to initiation of romiplostim were abstracted from medical records. Bleeding events were classified according to the World Health Organization scale [24]. Data collected after initiation of romiplostim included romiplostim dose, number of doses, duration of treatment, adverse drug reactions (ADRs), platelet count over time, bleeding events, ITP-related hospitalization, and discontinuations. Outcomes included the proportion of patients with an overall platelet response (≥ 1 platelet count measurement ≥ 50 × 109/L during 2–24 weeks after romiplostim initiation); the proportion of patients with a durable platelet response (≥ 75% of all platelet count measurements ≥ 50 × 109/L during 14-24 weeks after romiplostim initiation); time to first platelet response (≥ 50 × 109/L) during 2–24 weeks after romiplostim initiation; median platelet

count during 2-24 weeks after romiplostim initiation; and the proportions of patients with ITP therapies, bleeding events, transfusion, or Interrelated hospitalization. All ADRs (including thrombotic and bone marrow ADRs) that occurred from the day after initiation of romiplostim therapy through 2 years were evaluated, irrespective of causality to treatment (coded according to Common Terminology Criteria for Adverse Events [CTCAE]).

Statistical analysis

This was a post hoc analysis of an observational study with no formal hypotheses and hence no power calculations; the planned sample size of approximately 150 patients to enrol into the study was based on the cumulative exposure to romiplostim. Analyses were conducted in patients who met the study eligibility criteria and with known dates for ITP diagnosis and romiplostim initiation. Baseline was defined as the time of romiplostim initiation. All outcomes were analysed by ITP phase at romiplostim initiation: newly diagnosed, persistent, or chronic ITP was defined as time from ITP diagnosis to romiplostim initiation of 12 months, respectively (i.e., as defined by the International Working Group in 2009 [7]). Analyses were descriptive in nature. In each ITP phase, categorical outcomes were summarized using frequencies and percentages (with 95% confidence intervals [CIs] where appropriate), and continuous data were summarized using mean and standard deviation (or 95% CI where appropriate) or median and interquartile range (IQR). Additionally, unweighted mean dose and median platelet count were calculated for each patient over the follow- up period. Missing data were not imputed, except for start/end dates for ADRs and medication. Where a start date for an ADR/medication was partial or missing, the following imputation rules were applied: if the day portion was missing, it was set to day 1; if the month portion was missing, it was set to January 1; if the date was completely missing or if the imputation date was prior to the first dose date, the date was set to the first dose date. Where an end date for an ADR/medication was partial or missing for ADRs that were resolved (end date was not imputed for not resolved ADRs), the following imputation rules were applied: if the day portion was missing, the date was set to the last day of the month; if the month portion was missing, the date was set to December 31; if the date was completely missing or if the imputation date was after the end of the patient’s observational period, the date was set to the date of discontinuation.

Results and Discussion

Baseline demographics and patient characteristics

A total of 159 patients were enrolled at 38 sites in Japan and were included in the study; 22 patients were excluded met [n=12], inclusion criteria not met [n=3], documentation incomplete/not valid [n=4], and screening failure [n=3]). The ITP phase for 41 patients could not be determined due to a missing date of ITP diagnosis, and these patients were also excluded from the analyses met [n=12], inclusion criteria not met [n=3], documentation incomplete/not valid [n=4], and screening failure [n=3]). The ITP phase for 41 patients could not be determined due to a missing date of ITP diagnosis, and these patients were also excluded from the analyses.

Romiplostim use and administration during the 2-Year follow-up period

Over the 2-year follow-up, patients with persistent ITP received a lower median number of romiplostim administrations (37 administrations) across a lower median number of weeks (87 weeks) compared with patients with newly diagnosed or chronic ITP.

Platelet count during the 24-week follow-up period

CI, confidence interval; ITP, immune thrombocytopenia; IVIg, intravenous immunoglobulin; Q, quartile. * Newly diagnosed ITP: 12 months from diagnosis. † Patients for whom there were no data on the number of platelets or the timing of the platelet measurement were censored. ‡An overall platelet response was defined as having ≥ 1 platelet count measurement ≥ 50 × 109/L during 2–24 weeks after romiplostim initiation. §A durable platelet response was defined as having ≥ 75% of all platelet count measurements ≥ 50 × 109/L during 14-24 weeks after romiplostim initiation. II Three patients required transfusions. ¶One patient required transfusion.

Concomitant ITP therapy

Following initiation of romiplostim treatment, at least one concomitant ITP therapy was administered in over half of the patients with newly diagnosed ITP (61.1%) and less than half in patients with persistent and chronic ITP (28.0% and 39.6%, respectively). The most frequently administered medications to patients with newly diagnosed, persistent, and chronic ITP were corticosteroids and IVIg.

Conclusion

The aim of this post hoc analysis of an observational study was to describe the population of adult patients with ITP who received romiplostim in routine clinical practice in Japan and to gain insights into the effectiveness and safety of romiplostim according to the phase of ITP in these patients. The results of our study showed that clinically meaningful platelet responses were achieved and sustained in the majority of romiplostim-treated patients in all ITP phases. Romiplostim was well tolerated regardless of ITP phase at romiplostim initiation, with minimal discontinuations due to ADRs. Our study sample was representative of the general Japanese ITP population, as shown by comparison to patients in a national survey (2016–2017) [25].

In both study cohorts, over 50% of patients had chronic ITP (>12 months); corticosteroids and IVIg were the most frequently used treatments prior to romiplostim initiation. Similarly, rates of splenectomy were relatively low across all ITP phases in this study and the national survey [25]. Over half of the patients in all ITP phases underwent bone marrow biopsy prior to romiplostim treatment. This is important to note, as patients with chronic ITP who undergo bone marrow biopsy after diagnosis have more severe disease and are at greater risk of potentially serious complications [26]. Notably, in the present study, romiplostim was initiated within the first year following ITP diagnosis in almost half of the patients, despite the chronic indication included in the European label at the time of the study. A substantial proportion of patients with newly diagnosed or persistent ITP have also been treated with romiplostim in other European countries, as demonstrated in realworld studies [17,19,27,28].

This real-world usage in earlier treatment lines is aligned with Joint Working Group of European Haematology Societies in Japan, Austria, and Switzerland guidelines, which recommend the use of TPO-RAs in all patients who do not respond to first-line therapy, regardless of ITP stage, and with the American Society of Hematology guidelines, which recommend the use of TPO-RAs in adults with ITP for ≥ 3 months who are corticosteroid dependent or unresponsive to corticosteroids [3,8]. Platelet responses to romiplostim were achieved rapidly and consistently by patients in all ITP phases. The time to first platelet response was generally consistent across ITP phases, ranging from 7 days in patients with persistent or chronic ITP to 8.5 days in those with newly diagnosed ITP. Moreover, patients with newly diagnosed and persistent ITP achieved high rates of overall platelet responses (100%) and high rates of durable platelet responses (65.0 – 88.2%), suggesting effectiveness of romiplostim within 1 year of ITP diagnosis, as well as in patients with chronic disease. Our findings were similar to those reported from clinical studies, which indicate that romiplostim can lead to sustained platelet responses in the majority of patients regardless of whether they have newly diagnosed, persistent, or chronic ITP [11,13, 14,20].

Platelet response definitions can be highly variable between different ITP studies; however, the same platelet count threshold of ≥ 50 × 109/L used in this study has also been used in previous studies of romiplostim and other ITP therapies [11,13,14,20,29-32]. Although neither a dosing algorithm nor a target platelet count was pre-defined in this observational study, the majority of patients across all ITP phases were treated with an initial dose of 1μg/kg in line with the recommended dose for patients from the European label (noting that a substantial proportion, 15–24%, started above this dose) [22]. Furthermore, the median weekly romiplostim dose during the first 24 weeks of romiplostim treatment (1.4–2.4 μg/kg) corresponds well to the median dose used in the registrational trials (i.e., 2–3 μg/kg) [22].

The results from this study confirm the established favourable safety profile of romiplostim from previous clinical studies and real-world studies [11-14,17-19]. The proportion of patients with an ADR leading to romiplostim withdrawal was low (4%), no patients experienced thrombotic ADRs, and bone marrow-related ADRs were reported in only 2 patients (both with chronic ITP). In the overall study population, the rate of time-adjusted bleeding events of at least grade 3 in severity prior to romiplostim was 7.2/100 patient-years [23]. This time-adjusted rate decreased to 4.0/100 patient-years following initiation of romiplostim [23]. In contrast, corticosteroid use is associated with a number of side effects, such as weight gain, hypertension, increased risk of infection, and osteoporosis [3]. Despite guidelines warning that first-line corticosteroids should be used for a limited period of time (e.g., to a maximum of 6 weeks for prednisolone), there is an over-reliance on corticosteroids in routine clinical practice [3,8,9,25].

Therefore, the earlier second- line use of romiplostim may help to avoid side effects associated with corticosteroid use and decrease the need for other subsequent therapies, such as splenectomy, that may have long-term health risks.

Acknowledgments

We thank all patients and investigators involved in the study. Medical writing support, including development of a draft outline and subsequent drafts in consultation with the authors, collating author comments, copyediting, fact checking, and referencing.

Author Contributions

All authors contributed to the analysis or interpretation of the data, revision of the manuscript, and approved the final version.

References

1. Chalmers, Sarah and Michael D. Tarantino. "Romiplostim as a treatment for immune thrombocytopenia: A review." J Blood Med 6 (2015): 37.

Indexed at, Google Scholar, Crossref

2. Provan, Drew, and Adrian C. Newland. "Current management of primary immune thrombocytopenia." Advances in therapy 32 (2015): 875-887.

Indexed at, Google Scholar, Crossref

3. https://www.onkopedia.com/de/onkopedia/guidelines/immunthrombozytopenie-itp
4. Neunert, C and D.M. Arnold. "Severe bleeding events in adults and children with primary immune thrombocytopenia: a systematic review: reply." J Thrombosis Haemostasis 13 (2015): 1522-1523.

Indexed at, Google Scholar, Crossref

5. Trotter, Patrick and Quentin A. Hill. "Immune thrombocytopenia: improving quality of life and patient outcomes." Patient Related Outcome Measures 9 (2018): 369.

Indexed at, Google Scholar, Crossref

6. British Committee for Standards in Haematology General Haematology Task Force. "Guidelines for the investigation and management of idiopathic thrombocytopenic purpura in adults, children and in pregnancy." Br J Haematol 120 (2003): 574-596.

Indexed at, Google Scholar, Crossref

7. Rodeghiero, Francesco, Roberto Stasi, Terry Gernsheimer and Marc Michel, et al. "Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: Report from an international working group." Blood J Am Soc Hematol 113 (2009): 2386-2393.

Indexed at, Google Scholar, Crossref

8. Neunert, Cindy, Deirdra R. Terrell, Donald M. Arnold and George Buchanan, et al. "American Society of Hematology 2019 guidelines for immune thrombocytopenia." Blood Adv 3 (2019): 3829-3866.

Indexed at, Google Scholar, Crossref

9. Provan, Drew, Donald M. Arnold, James B. Bussel and Beng H. Chong, et al. "Updated international consensus report on the investigation and management of primary immune thrombocytopenia." Blood Adv 3 (2019): 3780-3817.

Indexed at, Google Scholar, Crossref

10. Molineux, Graham, and Adrian Newland. "Development of romiplostim for the treatment of patients with chronic immune thrombocytopenia: From bench to bedside." British journal of haematology 150 (2010): 9-20.

Indexed at, Google Scholar, Crossref

11. Kuter, David J, James B. Bussel, Roger M. Lyons and Vinod Pullarkat, et al. "Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: A double-blind randomised controlled trial." Lancet 371 (2008): 395-403.

Indexed at, Google Scholar, Crossref

12. Kuter, David J., James B. Bussel, Adrian Newland and Ross I. Baker, et al. "Long‐term treatment with romiplostim in patients with chronic immune thrombocytopenia: safety and efficacy." British journal of haematology 161 (2013): 411-423.

Indexed at, Google Scholar, Crossref

13. Kuter, David J, Adrian Newland, Beng H. Chong and Francesco Rodeghiero, et al. "Romiplostim in adult patients with newly diagnosed or persistent immune thrombocytopenia (ITP) for up to 1 year and in those with chronic ITP for more than 1 year: A subgroup analysis of integrated data from completed romiplostim studies." British J Haematol 185 (2019): 503-513.

Indexed at, Google Scholar, Crossref

14. Newland, Adrian, Bertrand Godeau, Victor Priego and Jean‐Francois Viallard, et al. "Remission and platelet responses with romiplostim in primary immune thrombocytopenia: final results from a phase 2 study." British J Haematol 172 (2016): 262-273.

Indexed at, Google Scholar, Crossref

15. Janssens, Ann, Michael Tarantino, Robert J. Bird and Maria Gabriella Mazzucconi, et al. "Romiplostim treatment in adults with immune thrombocytopenia of varying duration and severity." Acta Haematologica 134 (2015): 215-228.

Indexed at, Google Scholar, Crossref

16. Arumugaswamy, A, S. He, H. Quach and J. Brotchie, et al. "Thrombopoietin receptor agonists in immune thrombocytopenia of less than 6 months duration." Int Med J 44 (2014): 519-521.

Indexed at, Google Scholar, Crossref

17. Mingot-Castellano, María E, Isabel S. Caparrós, Fernando Fernández and María del Mar Perera-Alvarez, et al. "Treatment characteristics, efficacy and safety of thrombopoietin analogues in routine management of primary immune thrombocytopenia." Blood Coagulation Fibrinolysis 29 (2018): 374-380.

Indexed at, Google Scholar, Crossref

18. Steurer, Michael, Philippe Quittet, Helen A. Papadaki and Dominik Selleslag, et al. "A large observational study of patients with primary immune thrombocytopenia receiving romiplostim in European clinical practice." Eur J Haematol  98 (2017): 112-120.

Indexed at, Google Scholar, Crossref

19. Lozano, Maria L, Maria E. Mingot-Castellano, María M. Perera and Isidro Jarque, et al. "Deciphering predictive factors for choice of thrombopoietin receptor agonist, treatment free responses, and thrombotic events in immune thrombocytopenia." Scient Rep 9 (2019): 1-9.

Indexed at, Google Scholar, Crossref

20. Snell Taylor SJ, Nielson CM, Breskin A and Saul B,  et al. Effectiveness and safety of romiplostim among patients with newly diagnosed, persistent and chronic immune thrombocytopenia in European clinical practice. Adv Ther 38 (2021): 2673–88.

Indexed at, Google Scholar, Crossref

21. https://www.accessdata. fda.gov/drugsatfda_docs/label/2021/ 125268s167lbl.pdf
22. https://www.ema.europa.eu/en/documents/product-information/nplateepar- product-information_en.pdf
23. Reiser, M, M. Welslau, K. Josten and H. Dietzfelbinger, et al. "Final results from an observational study (PLATEAU) of adult patients treated with romiplostim for primary immune thrombocytopenia (ITP) in routine clinical practice in Germany." Haematologica 102 (2017): 591-592

Google Scholar

24. Heddle, Nancy M, Richard J. Cook, Kathryn E. Webert and Christopher Sigouin, et al. "Methodologic issues in the use of bleeding as an outcome in transfusion medicine studies." Transfusion 43 (2003): 742-752.

Indexed at, Google Scholar, Crossref

25. Kubasch, Anne Sophie, Jens Kisro, Jörg Heßling and Holger Schulz, et al. "Disease management of patients with immune thrombocytopenia-results of a representative retrospective survey in Germany." Ann Hematol 99 (2020): 2085-2093.

Indexed at, Google Scholar, Crossref

26. Gotschalck, Madeleine Andersson, Mette Nørgaard, Nickolaj Risbo and Christian Fynbo Christiansen, et al. "Predictors for and outcomes after bone marrow biopsy in Scandinavian patients with chronic immune thrombocytopenia." Eur J Haematol 107 (2021): 145-156.

Indexed at, Google Scholar, Crossref

27. Doobaree, Indraraj Umesh, Adrian Newland, Vickie McDonald and Raghava Nandigam, et al. "Primary immune thrombocytopenia (ITP) treated with romiplostim in routine clinical practice: retrospective study from the United Kingdom ITP Registry." Eur J Haematol 102 (2019): 416-423.

Indexed at, Google Scholar, Crossref

28. Contis, Anne, Estibaliz Lazaro, Carine Greib and Jean-Luc Pellegrin, et al. "Romiplostim as early treatment for refractory primary immune thrombocytopenia." Int J Hematol 98 (2013): 520-524.

Indexed at, Google Scholar, Crossref

29. Bussel, James B, Drew Provan, Tahir Shamsi and Gregory Cheng, et al. "Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: A randomised, double-blind, placebo-controlled trial." Lancet 373 (2009): 641-648.

Indexed at, Google Scholar, Crossref

30. Cheng, Gregory, Mansoor N. Saleh, Claus Marcher and Sandra Vasey, et al. "Eltrombopag for management of chronic immune thrombocytopenia (RAISE): A 6-month, randomised, phase 3 study." Lancet 377 (2011): 393-402.

Indexed at, Google Scholar, Crossref

31. Bussel, James, Donald M. Arnold, Elliot Grossbard and Jiří Mayer, et al. "Fostamatinib for the treatment of adult persistent and chronic immune thrombocytopenia: Results of two phase 3, randomized, placebo‐controlled trials." Am J Hematol 93 (2018): 921-930.

Indexed at, Google Scholar, Crossref

32. Jurczak, Wojciech, Krzysztof Chojnowski, Jiří Mayer and Katarzyna Krawczyk, et al. "Phase 3 randomised study of avatrombopag, a novel thrombopoietin receptor agonist for the treatment of chronic immune thrombocytopenia." British J Haematol 183 (2018): 479-490.

Indexed at, Google Scholar, Crossref