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New Statistical Designs for Clinical Trials of Immunomodulating Agents
Published in Thomas F. Kresina, Immune Modulating Agents, 2020
Suppose that one is developing a hematopoietic growth factor to reduce the period of thrombocytopenia after cis-platinum-based cancer chemotherapy and the compound has never been used previously in humans. The first clinical trial would attempt to identify a maximum tolerated dose for the compound. Although the target population is patients undergoing chemotherapy for cancer, the toxic effects of the compound will be most clearly seen in subjects not debilitated from cancer and not experiencing the side effects of chemotherapy. Hence, a phase I trial in normal volunteers would be desirable as a first clinical trial. Such a trial should be conducted sequentially with dose increased for subsequent cohorts of subjects. The size of the cohorts depends on the incidence of toxicity that one wishes to detect. For example, if one wants the incidence of “significant” toxicity at the MTD to be less than 20%, then a cohort size of 10 subjects is appropriate. The probability of observing at least one case of “significant” toxicity among 10 patients is about 0.90 when the true probability of toxicity is 0.20. If one can be confident that the compound is rapidly cleared and that toxicity does not depend on cumulative dose, then one can increase the efficiency of the phase I trial by using intrasubject dose escalations. A dose level would be considered below the MTD if 10 patients could be escalated to receive it without dose-limiting toxicity. If intrasubject dose escalations are not used, smaller cohort sizes may be used until a lower grade of toxicity is observed.
Pharmacologic alternatives to blood
Published in Jennifer Duguid, Lawrence Tim Goodnough, Michael J. Desmond, Transfusion Medicine in Practice, 2020
Thrombopoietin is the hematopoietic growth factor responsible for megakaryocytic growth, development, and platelet production. While its existence had been postulated for almost half a century, it was not until the early 1990s that real progress was made in identifying this elusive factor. Vigon et al67 cloned the human homologue of the v-mpl oncogene transduced in the myeloproliferative leukemia retrovirus and described its striking similarities to members of the hematopoietic growth receptor superfamily. c-mpl knockout mice have approximately a 90% reduction in platelet count as a result of a reduction in megakaryocyte progenitors and a decrease in megakaryocyte ploidy.67,68 In 1994, cloning of the gene for the c-Mpl ligand led to the identification of thrombopoietin.69,70 Thrombopoietin promotes the full spectrum of megakaryocyte growth and development.71 Two forms of recombinant thrombopoietin were developed for human studies: pegylated recombinant human megakaryocyte growth and development factor (PEG–rHuMGDF) and recombinant human thrombopoietin (rhTPO).
Congenital Amegakaryocytic Thrombocytopenia
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Homozygous or compound heterozygous mutations in the myeloproliferative leukemia virus oncogene (MPL) on chromosome 1p34.2 encoding a thrombopoietin receptor (MPL) underlie the molecular pathogenesis of CAMP. An altered MPL loses its ability to interact with its ligand thrombopoietin (THPO, a hematopoietic growth factor), affecting the production of multipotent hematopoietic progenitor cells and platelets, and leading to thrombocytopenia and megakaryocytopenia without physical anomalies. While nonsense MPL mutations cause a complete loss of function in MPL (type I CAMT, with early onset of severe pancytopenia, decreased bone marrow activity, and very low platelet counts), missense MPL mutations affect the extracellular domain of MPL and partially impair its function (type II CAMT, with transient increases of platelet during the first year of life and an onset of bone marrow failure from 3 years of age) [1].
IPW-5371 mitigates the delayed effects of acute radiation exposure in WAG/RijCmcr rats when started 15 days after PBI with bone marrow sparing
Published in International Journal of Radiation Biology, 2023
Brian L. Fish, Barry Hart, Tracy Gasperetti, Jayashree Narayanan, Feng Gao, Dana Veley, Lauren Pierce, Heather A. Himburg, Thomas MacVittie, Meetha Medhora
The attacks on the World Trade Center and Pentagon on 11 September 2001, have accelerated research to develop reagents to prevent, mitigate, and/or treat injuries from a radiological or nuclear attack or accident. The NIH funded consortiums and independent laboratories to study ARS and the later developing DEARE. The FDA mandated the development of medical countermeasures (MCM) for ARS and DEARE under the FDA animal rule, as it is unethical to expose humans to radiation (Food and Drug Administration and HHS 2002; Aebersold 2012; Food and Administration 2015). Guideline 3 from the animal rule states, ‘The animal study endpoint is clearly related to the desired benefit in humans, which is generally the enhancement of survival or prevention of major morbidity’. Via the animal rule, the FDA has approved drugs for bone-marrow toxicity during ARS. These countermeasures include the hematopoietic growth factor filgrastim (Neupogen®), pegfilgrastim (Neulasta®), sargramostim (Leukine®), and/or romiplostim (Nplate®). However, no FDA-approved drugs for the mitigation of DEARE either for lung, heart, or kidney injuries are available.
The delayed effects of acute radiation exposure (DEARE): characteristics, mechanisms, animal models, and promising medical countermeasures
Published in International Journal of Radiation Biology, 2023
The standard management of H-ARS includes supportive care such as blood and platelet transfusions and hematopoietic growth factor therapy including FDA-approved Neupogen (filgrastim, G-CSF), Neulasta (pegfilgrastim, pegylated G-CSF), Leukine (sargramostim, GM-CSF) and Nplate (romiplostim) (Singh and Seed 2020; MacVittie and Farese 2021; Satyamitra et al. 2021). Although essential in the clinical setting, HSC transplantation for H-ARS has been met with limited success and its utility in H-ARS is debatable (Qian and Cen 2020). Although these FDA-approved hematopoietic growth factor MCMs increase survival and life-saving recovery of disease-fighting blood cells and clotting elements, survivors of H-ARS are plagued with multi-organ insufficiency for life, and none of these FDA-approved show efficacy in DEARE (MacVittie and Farese 2021). To date, there are no MCM approved for the DEARE (MacVittie and Farese 2021). This review will cover MCMs with a significant database supporting their potential usefulness in DEARE. Due to limited space, it is not feasible to provide an exhaustive list of all MCM under evaluation for DEARE. Routinely used therapeutic drugs, glucocorticoids, antibiotics, nutritional support, surgical treatments, and therapies for inhaled/ingested radionuclides are not included in this review.
Emerging data on thrombopoietin receptor agonists for management of chemotherapy-induced thrombocytopenia
Published in Expert Review of Hematology, 2023
Andrew B. Song, Hanny Al-Samkari
Thrombopoietin (TPO) was discovered in 1994 as the key hematopoietic growth factor regulating platelet production. TPO is constitutively produced by the liver and released into peripheral circulation where most TPO is bound and cleared by TPO receptors on platelets (acting as a ‘sink’), subsequently undergoing internalization and degradation. The residual TPO binds to bone marrow megakaryocytes, increases endomitosis and ploidy to expand the megakaryocyte pool, and stimulates maturation of megakaryocytes to increase platelet production; it also prevents apoptosis of early and late megakaryocytes [12]. This physiologic balance is demonstrated by the observation that the level of circulating TPO is inversely related to the rate of platelet production [13]. In patients receiving chemotherapy, platelet production is reduced due to cytotoxic and myelosuppressive effects of treatment (although there may be more diverse mechanisms of CIT as discussed later). The reduced clearance of TPO by platelets subsequently leads to an increase in circulating TPO and has been shown to demonstrate a log-linear relationship between the onset of thrombocytopenia and increase in TPO levels [14].