Review

Authors: James B Bussel, Gerald Soff, Adriana Balduzzi...

Thrombocytopenia results from a variety of conditions, including radiation, chemotherapy, autoimmune disease, bone marrow disorders, pathologic conditions associated with surgical procedures, hematopoietic stem cell transplant (HSCT), and hematologic disorders associated with severe aplastic anemia. Immune thrombocytopenia (ITP) is caused by immune reactions that accelerate destruction and reduce production of platelets. Thrombopoietin (TPO) is a critical component of platelet production pathways, and TPO receptor agonists (TPO-RAs) are important for the management of ITP by increasing platelet production and reducing the need for other treatments. Romiplostim is a TPO-RA approved for use in patients with ITP in the United States, European Union, Australia, and several countries in Africa and Asia, as well as for use in patients with refractory aplastic anemia in Japan and Korea. Romiplostim binds to and activates the TPO receptor on megakaryocyte precursors, thus promoting cell proliferation and viability, resulting in increased platelet production. Through this mechanism, romiplostim reduces the need for other treatments and decreases bleeding events in patients with thrombocytopenia. In addition to its efficacy in ITP, studies have shown that romiplostim is effective in improving platelet counts in various settings, thereby highlighting the versatility of romiplostim. The efficacy of romiplostim in such disorders is currently under investigation. Here, we review the structure, mechanism, pharmacokinetics, and pharmacodynamics of romiplostim. We also summarize the clinical evidence supporting its use in ITP and other disorders that involve thrombocytopenia, including chemotherapy-induced thrombocytopenia, aplastic anemia, acute radiation syndrome, perisurgical thrombocytopenia, post-HSCT thrombocytopenia, and liver disease.

Topics: Clinical Trials as Topic; Humans; Purpura, Thrombocytopenic, Idiopathic; Receptors, Fc; Recombinant Fusion Proteins; Thrombopoietin

PubMed: 34079225
DOI: 10.2147/DDDT.S299591

Review

Authors: Waleed Ghanima, Nichola Cooper, Francesco Rodeghiero...

The two thrombopoietin receptor agonists (TPO-RA), eltrombopag and romiplostim, were licensed in the US for treatment of immune thrombocytopenia (ITP) in 2008 and, since then, their use has progressively increased around the world; they are currently used in more than 100 countries. The six largest randomized controlled trials conducted in ITP have used one of these two agents. All studies have demonstrated a platelet response rate between 50-90%, depending on the criteria used, with good safety and tolerability. TPO-RA were shown to be effective in reducing bleeding and the need for concomitant or rescue medication. Many other investigations of their mechanism of effect, prospective and retrospective trials, and studies focusing on toxicity have been performed widening our knowledge of these two agents. Initial concerns on issues such as myelofibrosis have not been confirmed. Only a small number of patients develop moderate-severe reticulin fibrosis and/or collagen fibrosis; however, these are usually reversed after discontinuation of TPO-RA. Studies indicate, however, that TPO-RA may increase the risk of venous thromboembolism. Both TPO-RA are currently approved in patients with chronic ITP aged >1-year who are refractory to at least one other treatment. Eltrombopag has acquired two additional indications: severe aplastic anemia refractory to first-line treatment and hepatitis C patients undergoing treatment with interferon-ribavirin. Despite these wide-ranging studies, important questions still need to be answered. This summary review on TPO-RA will summarize what is known regarding efficacy in ITP, evaluate safety concerns in more depth, and focus on the questions that remain.

Topics: Animals; Benzoates; Biomarkers; Blood Coagulation; Clinical Trials as Topic; Disease Susceptibility; Humans; Hydrazines; Purpura, Thrombocytopenic, Idiopathic; Pyrazoles; Receptors, Fc; Receptors, Thrombopoietin; Recombinant Fusion Proteins; Signal Transduction; Thrombopoietin; Treatment Outcome

PubMed: 31073079
DOI: 10.3324/haematol.2018.212845

Randomized Controlled Trial

Authors: Gerald A Soff, Yimei Miao, Gemma Bendheim...

PURPOSE

Chemotherapy-induced thrombocytopenia (CIT) leads to delay or reduction in cancer treatment. There is no approved treatment.

METHODS

We conducted a phase II randomized trial of romiplostim versus untreated observation in patients with solid tumors with CIT. Before enrollment, patients had platelets less than 100,000/μL for at least 4 weeks, despite delay or dose reduction of chemotherapy. Patients received weekly titrated romiplostim with a target platelet count of 100,000/μL or more, or were monitored with usual care. The primary end point was correction of platelet count within 3 weeks. Twenty-three patients were treated in a randomization phase, and an additional 37 patients were treated in a single-arm, romiplostim phase. Resumption of chemotherapy without recurrent CIT was a secondary end point.

RESULTS

The mean platelet count at enrollment was 62,000/μL. In the randomization phase, 14 of 15 romiplostim-treated patients (93%) experienced correction of their platelet count within 3 weeks, compared with one of eight control patients (12.5%; < .001). Including all romiplostim-treated patients (N = 52), the mean platelet count at 2 weeks of treatment was 141,000/μL. The mean platelet count in the eight observation patients at 3 weeks was 57,000/μL. Forty-four patients who achieved platelet correction with romiplostim resumed chemotherapy with weekly romiplostim. Only three patients (6.8%) experienced recurrent reduction or delay of chemotherapy because of isolated CIT.

CONCLUSION

This prospective trial evaluated treatment of CIT with romiplostim. Romiplostim is effective in correcting CIT, and maintenance allows for resumption of chemotherapy without recurrence of CIT in most patients.

Topics: Adult; Aged; Antineoplastic Agents; Blood Platelets; Female; Humans; Male; Middle Aged; New York City; Platelet Count; Prospective Studies; Receptors, Fc; Recombinant Fusion Proteins; Thrombocytopenia; Thrombopoietin; Time Factors; Treatment Outcome

PubMed: 31545663
DOI: 10.1200/JCO.18.01931

Review

Authors: David J Kuter

Thrombopoietin regulates platelet production through activation of the thrombopoietin receptor (TPO-R). TPO-R agonists (TPO-RAs) are available to treat thrombocytopenia in chronic immune thrombocytopenia (ITP), chronic liver disease (CLD) patients who are undergoing a procedure, severe aplastic anemia (SAA), and hepatitis C virus (HCV) infection. There are four TPO-RAs approved in the US and Europe: romiplostim (ITP), eltrombopag (ITP, SAA, HCV), avatrombopag (ITP, CLD), and lusutrombopag (CLD). It is important to understand pharmacological characteristics of these agents when evaluating treatment options. Avatrombopag interacts with the transmembrane domain of the TPO-RA and does not compete with endogenous thrombopoietin for TPO-R binding. Structural differences between avatrombopag and other TPO-RAs may impart differential downstream effects on cell signaling pathways, potentially resulting in clinically relevant differences in outcome. Avatrombopag has a favorable pharmacological profile with similar exposure in Japanese, Chinese, or Caucasian patients and no drug-drug interactions, food interactions, or potential for chelation.

Topics: Anemia, Aplastic; Hepatitis C; Humans; Liver Diseases; Receptors, Thrombopoietin; Thiazoles; Thiophenes; Thrombopoietin

PubMed: 34815110
DOI: 10.1016/j.blre.2021.100909

Review

Authors: John W Semple, Alexandra Schifferli, Nichola Cooper...

Immune thrombocytopenia (ITP) is an autoimmune bleeding disease caused by immune-mediated platelet destruction and decreased platelet production. ITP is characterized by an isolated thrombocytopenia (<100 × 10/L) and increased risk of bleeding. The disease has a complex pathophysiology wherein immune tolerance breakdown leads to platelet and megakaryocyte destruction. Therapeutics such as corticosteroids, intravenous immunoglobulins (IVIg), rituximab, and thrombopoietin receptor agonists (TPO-RAs) aim to increase platelet counts to prevent hemorrhage and increase quality of life. TPO-RAs act via stimulation of TPO receptors on megakaryocytes to directly stimulate platelet production. Romiplostim is a TPO-RA that has become a mainstay in the treatment of ITP. Treatment significantly increases megakaryocyte maturation and growth leading to improved platelet production and it has recently been shown to have additional immunomodulatory effects in treated patients. This review will highlight the complex pathophysiology of ITP and discuss the usage of Romiplostim in ITP and its ability to potentially immunomodulate autoimmunity.

Topics: Humans; Receptors, Fc; Thrombopoietin; Recombinant Fusion Proteins; Purpura, Thrombocytopenic, Idiopathic; Receptors, Thrombopoietin

PubMed: 38942688
DOI: 10.1016/j.blre.2024.101222

Review

Authors: Hanny Al-Samkari

Chemotherapy-induced thrombocytopenia (CIT) is a common complication of antineoplastic therapy, resulting in antineoplastic therapy dose reductions, treatment delays, treatment discontinuation, and morbid bleeding events. Despite several decades of research into thrombopoietic growth factors in CIT, there are presently no available U.S. FDA- or EMA-approved agents to treat CIT. However, a respectable body of evidence has been published evaluating the thrombopoietin receptor agonists (TPO-RAs) for the management and prevention of CIT in patients with solid tumors, and critical studies are ongoing with the TPO-RAs romiplostim and avatrombopag. When employed in the appropriate patient population and used properly, TPO-RAs can successfully and safely manage CIT for extended periods of time with minimal apparent risks. This comprehensive review discusses the evidence for TPO-RAs in CIT in patients with solid tumors, provides detailed guidance for their use in the clinic, and discusses ongoing essential clinical trials in management of CIT.

Topics: Humans; Thrombocytopenia; Receptors, Thrombopoietin; Antineoplastic Agents; Neoplasms; Risk

PubMed: 37914568
DOI: 10.1016/j.blre.2023.101139

Review

Authors: Jeffrey Gilreath, Mimi Lo, Joseph Bubalo...

The thrombopoietin receptor agonists (TPO-RAs) romiplostim, eltrombopag, avatrombopag, and lusutrombopag carry unique US Food and Drug Administration (US FDA)- and European Medicines Agency (EMA)-approved indications and may be used to increase platelet counts in a variety of conditions. Current indications for available TPO-RAs include treatment of chronic immune thrombocytopenia (ITP) in cases of insufficient response to prior treatment (avatrombopag, eltrombopag, romiplostim), management of thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo a procedure (avatrombopag, lusutrombopag), management of severe aplastic anemia (eltrombopag), and management of thrombocytopenia associated with interferon-based therapy for hepatitis C (eltrombopag). Across current indications, pharmacists can assist in stabilizing platelet counts and help to reduce large undulations commonly seen when starting, stopping, or transitioning between these agents. If therapy modifications may benefit the patient, pharmacists should discuss possible changes with the patient's treatment team or treating physician. When used for ITP, romiplostim, eltrombopag, and avatrombopag stimulate TPO receptors on hematopoietic stem cells (also known as c-Mpl, or CD110) to promote platelet production; however, romiplostim is the only TPO-RA that binds at the same site as endogenous TPO. These subtle mechanistic differences may explain why switching TPO-RA may be clinically advantageous in some situations. As pharmacists are called to counsel patients on TPO-RA use, a deep understanding of potential adverse events and management strategies, as well as appropriate monitoring, will increase the likelihood that patients meet their goals of therapy in the shortest timeframe. Other uses of TPO-RAs are also discussed in this review, including use following hematopoietic stem cell transplant, use in myelodysplastic syndrome, and use in chemotherapy-induced thrombocytopenia.

Topics: Benzoates; Cinnamates; Dose-Response Relationship, Drug; Drug Monitoring; Health Knowledge, Attitudes, Practice; Humans; Hydrazines; Pharmacists; Platelet Count; Pyrazoles; Receptors, Fc; Receptors, Thrombopoietin; Recombinant Fusion Proteins; Thiazoles; Thiophenes; Thrombocytopenia; Thrombopoietin

PubMed: 34160821
DOI: 10.1007/s40265-021-01553-7

Authors: David J Kuter

Chemotherapy-induced thrombocytopenia (CIT) is a common complication of the treatment of non-hematologic malignancies. Many patient-related variables (e.g., age, tumor type, number of prior chemotherapy cycles, amount of bone marrow tumor involvement) determine the extent of CIT. CIT is related to the type and dose of chemotherapy, with regimens containing gemcitabine, platinum, or temozolomide producing it most commonly. Bleeding and the need for platelet transfusions in CIT are rather uncommon except in patients with platelet counts below 25x109/L in whom bleeding rates increase significantly and platelet transfusions are the only treatment. Nonetheless, platelet counts below 70x109/L present a challenge. In patients with such counts, it is important to exclude other causes of thrombocytopenia (medications, infection, thrombotic microangiopathy, post-transfusion purpura, coagulopathy and immune thrombocytopenia). If these are not present, the common approach is to reduce chemotherapy dose intensity or switch to other agents. Unfortunately decreasing relative dose intensity is associated with reduced tumor response and remission rates. Thrombopoietic growth factors (recombinant human thrombopoietin, pegylated human megakaryocyte growth and development factor, romiplostim, eltrombopag, avatrombopag and hetrombopag) improve pretreatment and nadir platelet counts, reduce the need for platelet transfusions, and enable chemotherapy dose intensity to be maintained. National Comprehensive Cancer Network guidelines permit their use but their widespread adoption awaits adequate phase III randomized, placebo-controlled studies demonstrating maintenance of relative dose intensity, reduction of platelet transfusions and bleeding, and possibly improved survival. Their potential appropriate use also depends on consensus by the oncology community as to what constitutes an appropriate pretreatment platelet count as well as identification of patient-related and treatment variables that might predict bleeding.

Topics: Antineoplastic Agents; Humans; Neoplasms; Platelet Count; Platelet Transfusion; Thrombocytopenia

PubMed: 35642485
DOI: 10.3324/haematol.2021.279512

Authors: Hanny Al-Samkari, Aric D Parnes, Katayoon Goodarzi...

Chemotherapy-induced thrombocytopenia (CIT) frequently complicates cancer treatment causing chemotherapy delays, dose reductions, and discontinuation. There is no FDA-approved agent available to manage CIT. This study retrospectively evaluated patients with CIT treated on institutional romiplostim treatment pathways at 4 U.S. centers. The primary outcome was achievement of a romiplostim response [median on-romiplostim platelet count (Plt) ≥75x109/L and ≥30x109/L above baseline]. Secondary outcomes included time to Plt≥100x109/L and rates of the following: Plt<100x109/L, Plt<75x109/L, Plt<50x109/L, thrombocytosis, chemotherapy dose reduction/treatment delay, platelet transfusion, bleeding, and thromboembolism. Multivariable regression was used to identify predictors of romiplostim non-response and compare weekly dosing with intracycle/intermittent dosing. 173 patients (153 solid tumor, 20 lymphoma or myeloma) were treated, with 170 (98%) receiving a median of 4 (range, 1-36) additional chemotherapy cycles on romiplostim. Romiplostim was effective in solid tumor patients: 71% of patients achieved a romiplostim response, 79% avoided chemotherapy dose reductions/treatment delays and 89% avoided platelet transfusions. Median per-patient Plt on romiplostim was significantly higher than baseline (116x109/L vs. 60x109/L, P<0.001). Bone marrow tumor invasion, prior pelvic irradiation, and prior temozolomide predicted romiplostim non-response. Bleeding rates were lower than historical CIT cohorts and thrombosis rates were not elevated. Weekly dosing was superior to intracycle dosing with higher response rates and less chemotherapy dose reductions/treatment delays (IRR 3.00, 95% CI 1.30-6.91, P=0.010) or bleeding (IRR 4.84, 95% CI 1.18-19.89, P=0.029). Blunted response (10% response rate) was seen in non-myeloid hematologic malignancy patients with bone marrow involvement. In conclusion, romiplostim was safe and effective for CIT in most solid tumor patients.

Topics: Antineoplastic Agents; Hematologic Neoplasms; Humans; Neoplasms; Receptors, Fc; Recombinant Fusion Proteins; Retrospective Studies; Thrombocytopenia; Thrombopoietin

PubMed: 32499239
DOI: 10.3324/haematol.2020.251900

Review

Authors: Andrew B Song, Hanny Al-Samkari

INTRODUCTION

Chemotherapy-induced thrombocytopenia (CIT) is a common complication of cancer treatment, frequently leading to reduced relative dose intensity, and is associated with reduced survival. Given the lack of FDA-approved therapies for CIT, thrombopoietin receptor agonists (TPO-RAs) have received significant attention for treatment and prevention of CIT.

AREAS COVERED

This review will summarize the development of prior agents for treatment of CIT, discuss the existing literature investigating the use of TPO-RAs in CIT primarily in patients with solid tumor malignancies, and offer insights on the future direction of TPO-RAs and other therapeutics for CIT.

EXPERT OPINION

In alignment with NCCN guidelines, we recommend that patients with CIT participate in a clinical trial for consideration of TPO-RA treatment or consider off-label use of romiplostim when participation in clinical trials is not possible. The literature to date supports the use of TPO-RAs for treatment of persistent CIT. Further data is needed to describe the long-term efficacy, safety, and prescribing practices of TPO-RAs in a diverse patient population with a variety of tumor types and chemotherapy regimens in addition to exploring the underlying biology of CIT.

Topics: Humans; Antineoplastic Agents; Benzoates; Neoplasms; Purpura, Thrombocytopenic, Idiopathic; Receptors, Fc; Receptors, Thrombopoietin; Recombinant Fusion Proteins; Thrombocytopenia

PubMed: 37039010
DOI: 10.1080/17474086.2023.2201428