Systematic literature review and meta-analysis on use of Thrombopoietic agents for chemotherapy-induced thrombocytopenia.

BACKGROUND: Currently, there are no approved options to prevent or treat chemotherapy-induced thrombocytopenia (CIT). We performed a systematic literature review and meta-analysis on use of thrombopoietic agents for CIT. PATIENTS AND METHODS: We searched Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, PubMed, EMBASE, ClinicalTrials.gov, and health technology assessments from January 1995 to March 2021 for studies evaluating thrombopoietic agents for CIT, including recombinant human thrombopoietin (rhTPO), megakaryocyte growth and development factor (MGDF), romiplostim, and eltrombopag. Random effects meta-analyses were conducted for efficacy and safety endpoints. RESULTS: We screened 1503 titles/abstracts, assessed 138 articles, and abstracted data from 39 publications (14 recombinant human thrombopoietin, 7 megakaryocyte growth and development factor, 9 romiplostim, 8 eltrombopag, and 1 romiplostim/eltrombopag). Random effects meta-analyses of data from multiple studies comparing thrombopoietic agents versus control (comparator, placebo, or no treatment) showed that thrombopoietic agents did not significantly improve chemotherapy dose delays and/or reductions (21.1% vs 40.4%, P = 0.364), grade 3/4 thrombocytopenia (39.3% vs 34.8%; P = 0.789), platelet transfusions (16.7% vs 31.7%, P = 0.111), grade ≥ 2 bleeding (6.7% vs 16.5%; P = 0.250), or thrombosis (7.6% vs 12.5%; P = 0.131). However, among individual studies comparing thrombopoietic agents with placebo or no treatment, thrombopoietic agents positively improved outcomes in some studies, including significantly increasing mean peak platelet counts (186 x 109/L with rhTPO vs 122 x 109/L with no treatment; P < 0.05) in one study and significantly increasing platelet count at nadir (56 x 109/L with rhTPO vs 28 x 109/L with not treatment; P < 0.05) in another study. Safety findings included thrombosis (n = 23 studies) and bleeding (n = 11), with no evidence of increased thrombosis risk with thrombopoietic agents. CONCLUSION: Our analyses generate the hypothesis that thrombopoietic agents may benefit patients with CIT. Further studies with well-characterized bleeding and platelet thresholds are warranted to explore the possible benefits of thrombopoietic agents for CIT.

Ex Vivo Manufacture of Megakaryocytes and Platelets from Stem Cells: Recent Advances Toward Transfusion in Humans.

The generation of ex vivo functional megakaryocytes (MK) and platelets is an important issue in transfusion medicine as donor dependence implies in limitations, such as shortage of eligible volunteers. Indeed, platelet transfusion is still a procedure that saves the lives of patients with defective platelet production. Recent technological development has enabled the isolation and expansion of stem cells that can be used as a source for the production of functional platelets for transfusion. In this review, we discuss recent approaches of in vitro or ex vivo production of MK and platelets, suggesting that, in the near future, donor-independent sources may become a possibility. The feasibility of using these cells in the clinic may be safer, and in vitro manipulation could generate universally compatible products, solving problems related to platelet refractoriness. However, functionality and survival testing of these products in human beings are scarce; therefore, additional studies are needed to consolidate this purpose.

In vitro generation of platelets: Where do we stand?

Millions of platelets, specialized cells that participate in haemostatic and inflammatory functions, are transfused each year worldwide, but their supply is limited. Platelets are produced by megakaryocytes by extending proplatelets, directly into the bloodstream. Bone marrow structure and extracellular matrix composition together with soluble factors (e.g. Thrombopoietin) are key regulators of megakaryopoiesis by supporting cell differentiation and platelet release. Despite this knowledge, the scarcity of clinical cures for life threatening platelet diseases is in a large part due to limited insight into the mechanisms that control the developmental process of megakaryocytes and the mechanisms that govern the production of platelets within the bone marrow. To overcome these limitations, functional human tissue models have been developed and studied to extrapolate ex vivo outcomes for new insight on bone marrow functions in vivo. There are many challenges that these models must overcome, from faithfully mimicking the physiological composition and functions of bone marrow, to the collection of the platelets generated and validation of their viability and function for human use. The overall goal is to identify innovative instruments to study mechanisms of platelet release, diseases related to platelet production and new therapeutic targets starting from human progenitor cells.

Integrated Biophysical and Biochemical Signals Augment Megakaryopoiesis and Thrombopoiesis in a Three-Dimensional Rotary Culture System.

Platelet transfusion has been widely used in patients undergoing chemotherapy or radiotherapy; however, the shortage of the platelet supply limits the care of patients. Although derivation of clinical-scale platelets in vitro could provide a new source for transfusion, the devices and procedures for deriving scalable platelets for clinical applications have not been established. In the present study, we found that a rotary cell culture system (RCCS) can potentiate megakaryopoiesis and significantly improve the efficiency of platelet generation. When used with chemical compounds and growth factors identified via small-scale screening, the RCCS improved platelet generation efficiency by as much as ∼3.7-fold compared with static conditions. Shear force, simulated microgravity, and better diffusion of nutrients and oxygen from the RCCS, altogether, might account for the improved efficient platelet generation. The cost-effective and highly controllable strategy and methodology represent an important step toward large-scale platelet production for future biomedical and clinical applications. Significance: Platelet transfusion has been widely used in patients undergoing chemotherapy or radiotherapy; however, the shortage of platelet supply limits the care of patients. Thus, derivation of clinical-scale platelets in vitro would provide a new source for transfusion. The present study evaluated a rotary suspension cell culture system that was able to potentiate megakaryopoiesis and significantly improved the efficiency of platelet generation. When used with chemical compounds and growth factors identified via small-scale screening, the three-dimensional system improved platelet generation efficiency compared with the static condition. The three-dimensional device and the strategy developed in the present study should markedly improve the generation of large-scale platelets for use in future biomedical and clinical settings.

Las trombopoyetinas en el tratamiento de la púrpura trombocitopénica inmunitaria y otras trombocitopenias / Thrombopoietines in the treatment of the thrombocytopenic purpura and other thrombocytopenics

La purpura trombocitopénica inmunitaria y las trombocitopenias secundarias representan condiciones patológicas graves cuyo tratamiento plantea diversos grados de dificultad. La aproximación terapéutica convencional ha sido la administración de esteroides, la esplenectomía y el uso de inmunoglobulina intravenosa u otros tipos de anticuerpos (e.g., anti-D). La mejor comprensión de la fisiología y fisiopatología de la trombopoyesis aunado a los avances en biología molecular ha permitido el desarrollo de una nueva aproximación terapéutica, la aplicación de las trombopoyetinas sintéticas o no inmunogénicas. Dentro de este grupo resaltan dos compuestos: el romiplostin (una proteína de fusión) y el eltrombopag (un compuesto sintético de bajo peso molecular). Ambas se encuentran disponibles comercialmente. Los estudios clínicos indican que estos medicamentos tienen un efecto satisfactorio en el tratamiento de las trombocitopenias, particularmente en los casos refractarios a los tratamientos convencionales.

Immune thrombocytopenic purpura and the secondary thrombocytopenias are conditions potentially severe with diverse degrees of treatment difficulties. Steroids administration, splenectomy and the use of intravenous immunoglobulin and other antibodies (e.g., anti-D) had been the conventional therapy. The better understanding of the thrombopoiesis physiology and physiopathology togetter with the biology advances have permitted the development of a new terapheutic approach: the use of synthetic or nonimmunogenic thrombopoietines. Among this group highlights composites: romiplostim (a fusion protein) and eltrombopag (a synthetic composite with low molecular wheigt). Both are already available and produce a satisfactory effect particularly in nonrespondent cases to the conventional treatment.

[Treatment of chronic immune thrombocytopenic purpura. Looking for something better. Review]. / Tratamiento de la púrpura trombocitopénica inmune crónica. Buscando algo mejor. Revisión.

Chronic Immune Thrombocytopenic Purpura (cITP) has become a field of multiple therapeutic assays. More than 20 types of treatment have been developed to obtain a favorable and prolonged platelet response. The treatment of cITP is oriented to inhibit the antiplatelet antibodies production by interference with the macrophage of the reticulum endothelial system and a blockade of the antigenic response with a decrease in the amplification of the immunological response. Steroids of the glucocorticoids type and splenectomy constitute the first line of treatment. Failure of these treatments leads to the use of second line drugs such as non steroid immuno-supressors and the immunoglobulins type IgG and anti-D. Therapeutic assays with others immunomodulators have been reported. The introduction of new drugs destined to increase the megakaryocytic bone marrow platelet production, has opened a new way to treat the cITP. However, the splenectomy remains as the simplest, safest and most effective treatment in cITP. The principal criteria does not have to be focused on obtaining a normal platelet count, but to reach safe hemostatic levels in absence of hemorrhage, for a prolonged time. On the other hand, despite the persistence of thrombocytopenia, the hematologist can choose to maintain the patient with no treatment and with only a strict clinical observation. It is obvious that the cost-benefit from the different treatments is inclined towards those of lower cost and minimal secondary effects.

Romiplostim: a novel thrombopoiesis-stimulating agent.

PURPOSE: The pharmacology, pharmacokinetics, dosage and administration, efficacy, safety, effects on quality of life, and place in therapy of romiplostim are reviewed. SUMMARY: Romiplostim is a second- generation thrombopoietic agent that stimulates the thrombopoietin receptor and platelet production without inducing production of autoantibodies. Romiplostim, a peptibody, bears no structural resemblance to endogenous thrombopoietin, thus minimizing the risk for development of thrombopoietin autoantibodies. Clinical trials have shown that romiplostim increases platelet counts compared with placebo in both splenectomized and non-splenectomized adult patients with chronic idiopathic thrombocytopenic purpura (ITP). Clinical trials with romiplostim are ongoing for patients with myelodysplastic syndrome and those receiving chemotherapy for treatment of malignancies. Romiplostim may confer an increased risk of bone marrow reticulin formation or fibrosis, malignancy, thrombosis, and thrombocytopenia that is more severe than the level present before initiation of romiplostim. While all patients receiving romiplostim in clinical trials experienced at least one adverse event, most were mild to moderate in severity. The most frequent adverse effects were ecchymosis, headache, and petechiae. Romiplostim is initiated at a dosage of 1 microg/kg subcutaneously once weekly and titrated to achieve platelet counts between 50 and 200 x 10(9) platelets/L, with a maximum dose of 10 microg/kg. Romiplostim is only available through the manufacturer's risk-management program. The current wholesale price of romiplostim is $1,062.50 for a single-use vial of 250 microg or $2,125 for a single-use vial of 500 microg. The extrapolated drug cost for weekly dosing for one year is approximately $55,250. CONCLUSION: Romiplostim is a novel thrombopoietic-stimulating agent for use in patients with chronic ITP who have not responded to other therapies.

Assessment of megakaryopoiesis in children with acute lymphoblastic leukemia.

The effect of the underlying disease and chemotherapy on megakaryopoiesis has not been extensively studied in children with acute lymphoblastic leukemia (ALL) during and at the end of therapy. Using a serum-free assay, we assessed the megakaryocyte (Mk) colony formation in vitro from bone marrow mononuclear cells of 25 children with ALL during chemotherapy and shortly after the cessation of it. Twelve children with solid tumors without bone marrow involvement and cord blood from 10 full-term normal vaginal deliveries were used as controls. A significant reduction in the number of Mk colonies was observed at diagnosis of ALL, and Mk colony formation remained lower than controls throughout the different phases of leukemia treatment. Our study suggests that defects in megakaryopoiesis of children with ALL in long-term remission may persist during chemotherapy and at least shortly after the end of it.