RESUMO
Chemotherapy-induced thrombocytopenia (CIT) is a common challenge of cancer therapy and can lead to chemotherapy dose reduction, delay, and/or discontinuation, affecting relative dose intensity, and possibly adversely impacting cancer care. Besides changing anticancer regimens, standard management of CIT has been limited to platelet transfusions and supportive care. Use of the thrombopoietin receptor agonist romiplostim, already approved for use in immune thrombocytopenia, has shown promising signs of efficacy in CIT. In a phase 2 prospective randomized study of solid tumor patients with platelet counts <100 × 109/L for ≥4 weeks due to CIT, weekly romiplostim corrected the platelet count to >100 × 109/L in 93% (14/15) of patients within 3 weeks versus 12.5% (1/8) of untreated patients (p < 0.001). Including patients treated with romiplostim in an additional single-arm cohort, 85% (44/52) of all romiplostim-treated patients responded with platelet count correction within 3 weeks. Several retrospective studies of CIT have also shown responses to weekly romiplostim, with the largest study finding that poor response to romiplostim was predicted by tumor invasion of the bone marrow (odds ratio, 0.029; 95% CI: 0.0046-0.18; p < 0.001), prior pelvic irradiation (odds ratio, 0.078; 95% CI: 0.0062-0.98; p = 0.048), and prior temozolomide treatment (odds ratio 0.24; 95% CI: 0.061-0.96; p = 0.043). Elsewhere, lower baseline TPO levels were predictive of romiplostim response (p = 0.036). No new safety signals have emerged from romiplostim CIT studies. Recent treatment guidelines, including those from the National Comprehensive Cancer Network, now support consideration of romiplostim use in CIT. Data are expected from two ongoing phase 3 romiplostim CIT trials.
Assuntos
Antineoplásicos , Receptores Fc , Proteínas Recombinantes de Fusão , Trombocitopenia , Trombopoetina , Humanos , Receptores Fc/uso terapêutico , Trombopoetina/uso terapêutico , Trombopoetina/efeitos adversos , Proteínas Recombinantes de Fusão/uso terapêutico , Proteínas Recombinantes de Fusão/efeitos adversos , Proteínas Recombinantes de Fusão/administração & dosagem , Trombocitopenia/tratamento farmacológico , Trombocitopenia/induzido quimicamente , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Contagem de Plaquetas , Receptores de Trombopoetina/agonistas , Resultado do TratamentoRESUMO
Chronic myeloid leukemia is defined by the presence of the Philadelphia translocation t (9; 22) resulting in the BCR::ABL1 fusion. The other myeloproliferative neoplasms (MPN) subtypes also carry typical chromosomal abnormalities, which however are not pathognomonic for a specific entity of MPN. According to the WHO classification the distinction between these entities is still based on the integration of cytological, histopathological and molecular findings. Progression of CML into accelerated and blastic phase is usually driven by additional chromosome abnormalities and ABL1 kinase mutations. In the other MPN subtypes the additional mutations besides driver gene mutations in JAK2, MPL and CALR have a decisive impact on the propensity for progression. In addition, the sequence in which the driver mutations and risk conveying additional mutations have been acquired appears to play an important role. Here, we review cytogenetic and molecular changes in CML and MPN that should be evaluated during diagnosis and disease monitoring.
Assuntos
Janus Quinase 2 , Leucemia Mielogênica Crônica BCR-ABL Positiva , Mutação , Transtornos Mieloproliferativos , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/patologia , Janus Quinase 2/genética , Aberrações Cromossômicas , Genômica/métodos , Proteínas de Fusão bcr-abl/genética , Receptores de Trombopoetina/genética , Calreticulina/genética , Translocação GenéticaRESUMO
Introduction: Eltrombopag (EPAG), a thrombopoietin receptor agonist, was approved for the treatment of severe aplastic anemia (SAA) combined with immunosuppressive therapy (IST). However, EPAG contains a typical biphenyl structure, which causes liver function damage. Methods: Twenty patients with SAA who were intolerant or refractory to EPAG were enrolled in a multicenter prospective registry of the Chinese Eastern Collaboration Group of Anemia (ChiCTR2100045895) from October 2020 to June 2023. Results: Eight patients who were ineffective to EPAG, six with kidney impairment, and nine with abnormal liver function (two with concomitant liver and kidney impairment) were converted to avatrombopag (AVA) therapy with the median duration of AVA treatment was 6 (3-24) months. 17 cases (85%) achieved trilineage hematological response (HR): complete remission (CR) in 3 cases (15%), good partial remission (GPR) in 4 cases (20%), partial remission (PR) in 10 cases (50%), and no response (NR) in 3 cases (15%). The median time to response was 1.7 (0.5-6.9) months, with 16 cases (94%) achieving response within six months and 17 cases (100%) within 12 months. 9 cases (50%) achieved transfusion independence. AVA converted treatment was associated with higher neutrophil counts (0.8×109/L vs 2.2×109/L, p=0.0003), platelet counts (11×109/L vs 39×109/L, p=0.0008), hemoglobin count (59g/L vs 98g/L, p=0.0002), red cell count (1.06×1012/L vs 2.97×1012/L, p=0.001), and absolute reticulocyte count (31.99 ×109/L vs 67.05×109/L p=0.0004) were all significantly elevated compared with the pre-treatment level. After the conversion to AVA therapy, liver and kidney function indexes were maintained within the normal range, no AVA related grade 2 or higher adverse events occurred, and no thrombotic events occurred. Conclusion: The conversion to AVA was an optimal choice for patients with SAA who were EPAG intolerant or refractory. Clinical trial registration: http://www.chictr.org.cn/showproj.html?proj=125480, identifier ChiCTR2100045895.
Assuntos
Anemia Aplástica , Benzoatos , Pirazóis , Humanos , Masculino , Feminino , Anemia Aplástica/tratamento farmacológico , Anemia Aplástica/terapia , Adulto , Benzoatos/uso terapêutico , Benzoatos/efeitos adversos , Pessoa de Meia-Idade , Pirazóis/uso terapêutico , Pirazóis/efeitos adversos , Adulto Jovem , Adolescente , Pirazolonas/uso terapêutico , Hidrazonas/uso terapêutico , Receptores de Trombopoetina/agonistas , Resultado do Tratamento , Estudos Prospectivos , Imunossupressores/uso terapêutico , Imunossupressores/efeitos adversos , Idoso , Hidrazinas/uso terapêutico , Hidrazinas/efeitos adversos , Tiazóis , TiofenosRESUMO
We previously reported the Marimo cell line, which was established from the bone marrow cells of a patient with essential thrombocythemia (ET) at the last stage after transformation to acute myeloid leukemia (AML). This cell line is widely used for the biological analysis of ET because it harbors CALR mutation. However, genetic processes during disease progression in the original patient were not analyzed. We sequentially analyzed the genetic status in the original patient samples during disease progression. The ET clone had already acquired CALR and MPL mutations, and TP53 and NRAS mutations affected the disease progression from ET to AML in this patient. Particularly, the variant allele frequency of the NRAS mutation increased along with the disease progression after transformation, and the NRAS-mutated clone selectively proliferated in vitro, resulting in the establishment of the Marimo cell line. Although CALR and MPL mutations co-existed, MPL was not expressed in Marimo cells or any clinical samples. Furthermore, mitogen-activated protein kinase (MAPK) but not the JAK2-STAT pathway was activated. These results collectively indicate that MAPK activation is mainly associated with the proliferation ability of Marimo cells.
Assuntos
Calreticulina , Evolução Clonal , Leucemia Mieloide Aguda , Mutação , Receptores de Trombopoetina , Trombocitemia Essencial , Humanos , Trombocitemia Essencial/genética , Trombocitemia Essencial/patologia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Calreticulina/genética , Calreticulina/metabolismo , Receptores de Trombopoetina/genética , Evolução Clonal/genética , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , GTP Fosfo-Hidrolases/genética , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Masculino , Progressão da Doença , Feminino , Linhagem Celular Tumoral , Idoso , Pessoa de Meia-IdadeRESUMO
Myeloproliferative neoplasms (MPN) are hematological diseases associated with genetic driver mutations in the JAK2, CALR, and MPL genes and exacerbated oncoinflammatory status. Analyzing public microarray data from polycythemia vera (n = 41), essential thrombocythemia (n = 21), and primary myelofibrosis (n = 9) patients' peripheral blood by in silico approaches, we found that pro-inflammatory and monocyte-related genes were differentially expressed in MPN patients' transcriptome. Genes related to cell activation, secretion of pro-inflammatory and pro-angiogenic mediators, activation of neutrophils and platelets, coagulation, and interferon pathway were upregulated in monocytes compared to controls. Together, our results suggest that molecular alterations in monocytes may contribute to oncoinflammation in MPN.
Assuntos
Monócitos , Transtornos Mieloproliferativos , Transcriptoma , Humanos , Monócitos/metabolismo , Monócitos/imunologia , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/sangue , Inflamação/genética , Inflamação/sangue , Perfilação da Expressão Gênica/métodos , Policitemia Vera/genética , Policitemia Vera/sangue , Janus Quinase 2/genética , Mielofibrose Primária/genética , Mielofibrose Primária/sangue , Trombocitemia Essencial/genética , Trombocitemia Essencial/sangue , Receptores de Trombopoetina/genética , Regulação Neoplásica da Expressão GênicaRESUMO
Introduction. The international consensus and the American Society of Hematology guidelines from 2019 established thrombopoietin analogues as the second-line therapy for primary immune thrombocytopenia cases. Objectives. To describe romiplostim usefulness in patients with immune thrombocytopenia in a third-level hospital in Cuenca, Ecuador. Materials and methods. We conducted a descriptive and retrospective study in patients with immune thrombocytopenia treated with romiplostim. We evaluated the following variables: age, gender, previous therapies to romiplostim, dose, frequency, complications, change of thrombopoietin analogue, and treatment discontinuation. Results. We included 21 patients with immune thrombocytopenia treated with romiplostim, with a median age of 49 years. All patients received corticosteroids as first-line treatment. Three patients required longer administration intervals (over a week), with weekly doses lower than those recommended (< 1 µg/kg). Due to lack of efficacy, six patients replaced elthrombopag with romiplostim. Of the total, three suffered thrombotic complications: two had portal venous thrombosis, and one had pulmonary thromboembolism; five of the patients discontinued romiplostim scheme without resuming it. Conclusions. Romiplostim constitutes a convenient second-line therapy in immune thrombocytopenia. Despite the small sample size, romiplostim early use can minimize toxicities and infectious risks.
Introducción: El consenso internacional y la guía del 2019 de la American Society of Hematology, establecieron a los análogos de la trombopoyetina como medicamentos de segunda línea para tratar la trombocitopenia inmunitaria primaria. En Ecuador, se comercializan dos trombomiméticos: romiplostim y eltrombopag OBJETIVOS: Describir el uso de romiplostim en pacientes con trombocitopenia inmunitaria, en un hospital de tercer nivel en Cuenca (Ecuador). Materiales y métodos. Se adelantó un estudio descriptivo y retrospectivo en pacientes con trombocitopenia inmunitaria y tratamiento con romiplostim. Se evaluaron las siguientes variables: edad, sexo, tratamientos previos a romiplostim, dosis, frecuencia, complicaciones, cambio de análogo de trombopoyetina y discontinuación de la terapia. RESULTADOS: Veintiún pacientes con trombocitopenia inmunitaria fueron tratados con romiplostim, con una mediana de 49 años. Todos recibieron corticoides como tratamiento de primera línea. Tres precisaron de intervalos más prolongados que el semanal, con dosis semanales menores de las recomendadas (< 1 µg/kg). Por falta de eficacia, en seis pacientes se reemplazó la terapia con eltrombopag por romiplostim. Tres pacientes padecieron complicaciones trombóticas: dos, trombosis venosa portal, y uno, tromboembolia pulmonar. En cinco, se discontinuó el tratamiento con romiplostim, sin necesidad de reanudarlo. CONCLUSIONES: Romiplostim constituye un tratamiento de segunda línea para la trombocitopenia inmunitaria primaria. A pesar del reducido tamaño de la muestra, se observó que la administración temprana del medicamento puede minimizar toxicidades y riesgos infecciosos.
Assuntos
Benzoatos , Púrpura Trombocitopênica Idiopática , Pirazóis , Receptores Fc , Proteínas Recombinantes de Fusão , Trombopoetina , Humanos , Proteínas Recombinantes de Fusão/uso terapêutico , Proteínas Recombinantes de Fusão/administração & dosagem , Trombopoetina/uso terapêutico , Trombopoetina/administração & dosagem , Pessoa de Meia-Idade , Estudos Retrospectivos , Feminino , Masculino , Receptores Fc/uso terapêutico , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Adulto , Idoso , Pirazóis/uso terapêutico , Benzoatos/uso terapêutico , Benzoatos/administração & dosagem , Hidrazinas/uso terapêutico , Adulto Jovem , Receptores de Trombopoetina/agonistas , Corticosteroides/uso terapêuticoRESUMO
This study aimed to assess hematological diseases next-generation sequencing (NGS) panel enhances the diagnosis and classification of myeloid neoplasms (MN) using the 5th edition of the WHO Classification of Hematolymphoid Tumors (WHO-HAEM5) and the International Consensus Classification (ICC) of Myeloid Tumors. A cohort of 112 patients diagnosed with MN according to the revised fourth edition of the WHO classification (WHO-HAEM4R) underwent testing with a 141-gene NGS panel for hematological diseases. Ancillary studies were also conducted, including bone marrow cytomorphology and routine cytogenetics. The cases were then reclassified according to WHO-HAEM5 and ICC to assess the practical impact of these 2 classifications. The mutation detection rates were 93% for acute myeloid leukemia (AML), 89% for myelodysplastic syndrome (MDS), 94% for myeloproliferative neoplasm (MPN), and 100% for myelodysplasia/myeloproliferative neoplasm (MDS/MPN) (WHO-HAEM4R). NGS provided subclassified information for 26 and 29 patients with WHO-HAEM5 and ICC, respectively. In MPN, NGS confirmed diagnoses in 16 cases by detecting JAK2, MPL, or CALR mutations, whereas 13 "triple-negative" MPN cases revealed at least 1 mutation. NGS panel testing for hematological diseases improves the diagnosis and classification of MN. When diagnosed with ICC, NGS produces more classification subtype information than WHO-HAEM5.
Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Mutação , Síndromes Mielodisplásicas , Transtornos Mieloproliferativos , Humanos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/classificação , Adulto , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/classificação , Idoso de 80 Anos ou mais , Janus Quinase 2/genética , Organização Mundial da Saúde , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/classificação , Leucemia Mieloide Aguda/diagnóstico , Receptores de Trombopoetina/genética , Calreticulina/genética , Adulto JovemRESUMO
TPO receptor agonists (TPO-RAs) are a class of clinical second-line regimens for the treatment of primary immune thrombocytopenia (ITP). It can promote megakaryocyte maturation and increase platelet production, but its effect on immunosuppressive cells in patients with ITP has not been explored. Sixty-two ITP patients and 34 healthy controls (HCs) were included in this study. The proportion and functions of myeloid-derived immunosuppressive cells (MDSCs) in ITP patients and HCs were investigated. We found that the proportion and function of MDSCs in ITP patients treated with TPO-RAs were significantly higher than those treated with glucocorticoids (GCs), which was correlated with the clinical efficacy. The proportion and function of cytotoxic Th1 cells and CD8+T cells decreased, while the proportion and immunosuppressive function of Treg cells increased in ITP patients treated with TPO-RAs. We further proved, through MDSC depletion tests, that the inhibitory effect of MDSCs on Th1 cells and the promotion of Treg cells in the original immune micro-environment of GCs-treated ITP patients were impaired; however, these MDSCs' functions were improved in TPO-RAs-treated patients. Finally, we found that the KLF9 gene in MDSCs cells of ITP patients treated with TPO-RAs was down-regulated, which contribute to the higher mRNA expression of GADD34 gene and improved function of MDSCs. These results demonstrate a novel mechanism of TPO-RAs for the treatment of ITP through the assessment of MDSCs and their subsequent impact on T cells, which provides a new basis for TPO-RAs as first-line treatment approach to the treatment of ITP.
Assuntos
Células Supressoras Mieloides , Púrpura Trombocitopênica Idiopática , Receptores de Trombopoetina , Humanos , Células Supressoras Mieloides/efeitos dos fármacos , Células Supressoras Mieloides/imunologia , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Púrpura Trombocitopênica Idiopática/imunologia , Feminino , Masculino , Receptores de Trombopoetina/agonistas , Adulto , Pessoa de Meia-Idade , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Idoso , Adulto Jovem , Células Th1/imunologia , Células Th1/efeitos dos fármacos , Imunomodulação/efeitos dos fármacos , Trombopoetina/uso terapêutico , Trombopoetina/farmacologiaRESUMO
While studies have explored the feasibility of switching between various thrombopoietin receptor agonists in treating immune thrombocytopenia (ITP), data on the switching from eltrombopag to hetrombopag remains scarce. This post-hoc analysis of a phase III hetrombopag trial aimed to assess the outcomes of ITP patients who switched from eltrombopag to hetrombopag. In the original phase III trial, patients initially randomized to the placebo group were switched to eltrombopag. Those who completed this 14-week eltrombopag were eligible to switch to a 24-week hetrombopag. Treatment response, defined as a platelet count of ≥ 50 × 109/L, and safety were evaluated before and after the switch. Sixty-three patients who completed the 14-week eltrombopag and switched to hetrombopag were included in this post-hoc analysis. Response rates before and after the switch were 66.7% and 88.9%, respectively. Among those with pre-switching platelet counts below 30 × 109/L, eight out of 12 patients (66.7%) responded, while eight out of nine patients (88.9%) with pre-switching platelet counts between 30 × 109/L and 50 × 109/L responded post-switching. Treatment-related adverse events were observed in 50.8% of patients during eltrombopag treatment and 38.1% during hetrombopag treatment. No severe adverse events were noted during hetrombopag treatment. Switching from eltrombopag to hetrombopag in ITP management appears to be effective and well-tolerated. Notably, hetrombopag yielded high response rates, even among patients who had previously shown limited response to eltrombopag. However, these observations need to be confirmed in future trials.
Assuntos
Benzoatos , Hidrazinas , Púrpura Trombocitopênica Idiopática , Pirazóis , Pirazolonas , Receptores de Trombopoetina , Humanos , Pirazóis/uso terapêutico , Pirazóis/efeitos adversos , Pirazóis/administração & dosagem , Masculino , Feminino , Benzoatos/uso terapêutico , Benzoatos/efeitos adversos , Benzoatos/administração & dosagem , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Púrpura Trombocitopênica Idiopática/sangue , Pessoa de Meia-Idade , Adulto , Idoso , Hidrazinas/uso terapêutico , Hidrazinas/efeitos adversos , Hidrazinas/administração & dosagem , Receptores de Trombopoetina/agonistas , Pirazolonas/uso terapêutico , Substituição de Medicamentos , Contagem de Plaquetas , Resultado do Tratamento , HidrazonasRESUMO
The purpose of this study is to investigate the molecular interactions and potential therapeutic uses of Eltrombopag (EPAG), a small molecule that activates the cMPL receptor. EPAG has been found to be effective in increasing platelet levels and alleviating thrombocytopenia. We utilized computational techniques to predict and confirm the complex formed by the ligand (EPAG) and the Thrombopoietin receptor (TPO-R) cMPL, elucidating the role of RAS, JAK-2, STAT-3, and other essential elements for downstream signaling. Molecular dynamics (MD) simulations were employed to evaluate the stability of the ligand across specific proteins, showing favorable characteristics. For the first time, we examined the presence of TPO-R in human umbilical cord mesenchymal stem cells (hUCMSC) and human gingival mesenchymal stem cells (hGMSC) proliferation. Furthermore, treatment with EPAG demonstrated angiogenesis and vasculature formation of endothelial lineage derived from both MSCs. It also indicated the activation of critical factors such as RUNX-1, GFI-1b, VEGF-A, MYB, GOF-1, and FLI-1. Additional experiments confirmed that EPAG could be an ideal molecule for protecting against UVB radiation damage, as gene expression (JAK-2, ERK-2, MCL-1, NFkB, and STAT-3) and protein CD90/cMPL analysis showed TPO-R activation in both hUCMSC and hGMSC. Overall, EPAG exhibits significant potential in treating radiation damage and mitigating the side effects of radiotherapy, warranting further clinical exploration.
What is the context?â Chemotherapy, radiation treatment, or immunological disorders can cause a decrease in platelet count (thrombocytopenia) or decrease all blood cell types (pancytopenia) in the bone marrow. This can make it challenging to choose the appropriate cancer treatment plan.â Eltrombopag (EPAG) is an oral non-peptide thrombopoietin (TPO) mimetic that activates the cMPL receptor in the body. This activation leads to cell differentiation and proliferation, stimulating platelet production and reducing thrombocytopenia. The cMPL receptor is present in liver cells, megakaryocytes, and hematopoietic cells. However, its effects on stem cell proliferation and differentiation are not entirely understood.What is the new?â This study delves into the molecular interactions and therapeutic applications of EPAG, a small molecule that activates cMPL (TPO-R).â The study offers a comprehensive analysis of the ligand-receptor complex formation, including an examination of downstream signaling elements. Furthermore, molecular dynamics simulations demonstrate the stability of the ligand when interacting with targeted proteins.â The research investigates the presence of TPO-R on stem cell-derived endothelial cells, shedding insight into the ability of EPAG TPO-mimetic to promote angiogenesis and vasculature formation.â The study revealed that EPAG has the potential to protect against UVB-induced radiation damage and stimulate stem cell growth.What is the implications?The study emphasizes the potential of EPAG as a promising option for addressing radiation injury and minimizing the adverse effects of radiotherapy. It could revolutionize treatments not only for thrombocytopenia but also for enhancing the growth of stem cells. Furthermore, the research deepens our understanding of EPAG's molecular mechanisms, providing valuable insights for developing future drugs and therapeutic approaches for cell therapy to treat radiation damage.
Assuntos
Benzoatos , Pirazóis , Receptores de Trombopoetina , Humanos , Pirazóis/farmacologia , Benzoatos/farmacologia , Receptores de Trombopoetina/metabolismo , Hidrazonas/farmacologia , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/efeitos dos fármacos , Hidrazinas/farmacologia , Hidrazinas/uso terapêutico , Simulação de Dinâmica Molecular , AngiogêneseRESUMO
Thrombopoietin receptor agonists (TPO-RAs) induce trilineage hematopoiesis under conditions with acquired hematopoietic failure. We evaluated safety, tolerability, and preliminary efficacy of a TPO-RA, romiplostim (Nplate), with or without standard-of-care immunosuppressive therapy (±IST) for children (ages < 21 y) with newly diagnosed and relapsed/refractory severe aplastic anemia (SAA) and myelodysplastic syndrome (MDS). Data were collected from an observational study and a single arm interventional pilot study. The safety outcome was treatment-related adverse events (AEs). Efficacy was evaluated by complete hematopoietic response (CHR) at week 24. Romiplostim was commenced at 5 µg/kg/week, with dose escalation of 2.5 µg/kg/week (maximum, 20 µg/kg/dose) based on platelet response. Romiplostim was continued until CHR was observed. Ten subjects (SAA, 9 [IST, 4; without IST, 5]; MDS, 1) completed the study (median age: 9.2 y). Median romiplostim dose was 10 µg/kg/week (range: 5 to 17.5 µg/kg/week). The cumulative incidence of CHR was 70.4% (95% CI, 20.2%-92.6%). Among 21 AEs (Grade 1 to 3), 3 were attributed to romiplostim. At a median posttherapy follow-up of 10.9 months (range: 0.7 to 77.5), no clonal evolution, bone marrow fibrosis or mortality was reported. This proof-of-concept study provides data about short-term safety, tolerability, and preliminary efficacy of romiplostim (±IST) for treatment of pediatric SAA/MDS.
Assuntos
Anemia Aplástica , Síndromes Mielodisplásicas , Receptores Fc , Proteínas Recombinantes de Fusão , Trombopoetina , Humanos , Proteínas Recombinantes de Fusão/uso terapêutico , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/efeitos adversos , Receptores Fc/uso terapêutico , Receptores Fc/administração & dosagem , Anemia Aplástica/tratamento farmacológico , Trombopoetina/uso terapêutico , Trombopoetina/efeitos adversos , Trombopoetina/administração & dosagem , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/patologia , Criança , Feminino , Adolescente , Masculino , Adulto Jovem , Pré-Escolar , Projetos Piloto , Adulto , Receptores de Trombopoetina/agonistasRESUMO
Essential thrombocythaemia (ET) is a myeloproliferative neoplasm characterized by an increased risk of vascular complications and a tendency to progress to myelofibrosis and acute leukaemia. ET patients have traditionally been stratified into two thrombosis risk categories based on age older than 60 years and a history of thrombosis. More recently, the revised IPSET-thrombosis scoring system, which accounts for the increased risk linked to the JAK2 mutation, has been incorporated into most expert recommendations. However, there is increasing evidence that the term ET encompasses different genomic entities, each with a distinct clinical course and prognosis. Moreover, the effectiveness and toxicity of cytoreductive and anti-platelet treatments differ depending on the molecular genotype. While anti-platelets and conventional cytoreductive agents, mainly hydroxycarbamide (hydroxyurea), anagrelide and pegylated interferon, remain the cornerstone of treatment, recent research has shed light on the effectiveness of novel therapies that may help improve outcomes. This comprehensive review focuses on the evolving landscape of treatment strategies in ET, with an emphasis on the role of molecular profiling in guiding therapeutic decisions. Besides evidence-based management according to revised IPSET-thrombosis stratification, we also provide specific observations for those patients with CALR-, MPL-mutated and triple-negative ET, as well as cases with high-risk mutations.
Assuntos
Trombocitemia Essencial , Humanos , Trombocitemia Essencial/tratamento farmacológico , Trombocitemia Essencial/genética , Janus Quinase 2/genética , Janus Quinase 2/antagonistas & inibidores , Inibidores da Agregação Plaquetária/uso terapêutico , Inibidores da Agregação Plaquetária/efeitos adversos , Mutação , Receptores de Trombopoetina/agonistas , Receptores de Trombopoetina/genética , CalreticulinaRESUMO
OBJECTIVE: To evaluate the incidence, clinical laboratory characteristics, and gene mutation spectrum of Ph-negative MPN patients with atypical variants of JAK2, MPL, or CALR. METHODS: We collected a total of 359 Ph-negative MPN patients with classical mutations in driver genes JAK2, MPL, or CALR, and divided them into two groups based on whether they had additional atypical variants of driver genes JAK2, MPL, or CALR: 304 patients without atypical variants of driver genes and 55 patients with atypical variants of driver genes. We analyzed the relevant characteristics of these patients. RESULTS: This study included 359 patients with Ph-negative MPNs with JAK2, MPL, or CALR classical mutations and found that 55 (15%) patients had atypical variants of JAK2, MPL, or CALR. Among them, 28 cases (51%) were male, and 27 (49%) were female, with a median age of 64 years (range, 21-83). The age of ET patients with atypical variants was higher than that of ET patients without atypical variants [70 (28-80) vs. 61 (19-82), p = 0.03]. The incidence of classical MPL mutations in ET patients with atypical variants was higher than in ET patients without atypical variants [13.3% (2/15) vs. 0% (0/95), p = 0.02]. The number of gene mutations in patients with atypical variants of driver genes PV, ET, and Overt-PMF is more than in patients without atypical variants of PV, ET, and Overt-PMF [PV: 3 (2-6) vs. 2 (1-7), p < 0.001; ET: 4 (2-8) vs. 2 (1-7), p < 0.05; Overt-PMF: 5 (2-9) vs. 3 (1-8), p < 0.001]. The incidence of SH2B3 and ASXL1 mutations were higher in MPN patients with atypical variants than in those without atypical variants (SH2B3: 16% vs. 6%, p < 0.01; ASXL1: 24% vs. 13%, p < 0.05). CONCLUSION: These data indicate that classical mutations of JAK2, MPL, and CALR may not be completely mutually exclusive with atypical variants of JAK2, MPL, and CALR. In this study, 30 different atypical variants of JAK2, MPL, and CALR were identified, JAK2 G127D being the most common (42%, 23/55). Interestingly, JAK2 G127D only co-occurred with JAK2V617F mutation. The incidence of atypical variants of JAK2 in Ph-negative MPNs was much higher than that of the atypical variants of MPL and CALR. The significance of these atypical variants will be further studied in the future.
Assuntos
Laboratórios Clínicos , Fatores de Transcrição , Humanos , Feminino , Masculino , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Mutação , Receptores de Trombopoetina/genética , Janus Quinase 2/genéticaRESUMO
BACKGROUND: Porcine antilymphocyte globulin (p-ALG) combined with cyclosporine (CsA) has been commonly used for severe aplastic anemia (SAA) patients, but few studies on the combination of p-ALG and thrombopoietin receptor agonist (TPO-RA). RESEARCH DESIGN AND METHODS: We retrospectively analyzed the data of 85 people with diagnosed SAA who underwent p-ALG plus CsA, with or without TPO-RA from 2014 to 2023. RESULTS: The overall response rates were 55.3% and 65.9% at 3 and 6 months, and the TPO-RA group were 66.7% and 72.3% at 3 and 6 months, without TPO-RA group were 27.8% and 55.6%. In multivariate analysis, baseline platelet count of > 10 × 109/L was a simple predictor of favorable response at 6 months (p = 0.015). The median follow-up time for all patients was 39 months (range 0.4 ~ 104), the 5-year overall survival (OS) rate was 90.6% [95% CI = 82.1-95.2%], and the failure-free survival (FFS) rate was 68.9% [95% CI = 56.6-78.4%]. Having hematologic responses in 6 months was an independent positive predictor for FFS (p = 0.000). Twelve patients (14.1%) suffered from serum sickness, and 9.5% of patients had mild hepatic impairment. CONCLUSIONS: p-ALG along with CsA is an effective choice for patients with SAA. p-ALG combined with TPO-RA may contribute to the early restoration of hematopoiesis.
Assuntos
Anemia Aplástica , Soro Antilinfocitário , Ciclosporina , Receptores de Trombopoetina , Humanos , Anemia Aplástica/tratamento farmacológico , Anemia Aplástica/mortalidade , Ciclosporina/uso terapêutico , Masculino , Feminino , Estudos Retrospectivos , Pessoa de Meia-Idade , Soro Antilinfocitário/uso terapêutico , Adulto , Receptores de Trombopoetina/agonistas , Resultado do Tratamento , Animais , Adolescente , Idoso , Suínos , Adulto Jovem , Quimioterapia Combinada , Criança , Índice de Gravidade de Doença , Imunossupressores/uso terapêuticoRESUMO
ABSTRACT: Somatic mutants of calreticulin (CRT) drive myeloproliferative neoplasms (MPNs) via binding to the thrombopoietin receptor (MPL) and aberrant activation of the JAK/STAT pathway. Compared with healthy donors, platelets from mutant CRT-expressing patients with MPN display low cell surface MPL. Additionally, coexpression of MPL with an MPN-linked CRT mutant (CRTDel52) reduces cell surface MPL, suggesting that CRTDel52 may induce MPL degradation. We show that lysosomal degradation is relevant to the turnover of CRTDel52 and MPL. Furthermore, CRTDel52 increases the lysosomal localization and degradation of MPL. Mammalian target of rapamycin (mTOR) inhibitors reduce cellular CRTDel52 and MPL, secreted CRTDel52 levels, and impair CRTDel52-mediated cell proliferation. mTOR inhibition also reduces colony formation and differentiation of CD34+ cells from patients with MPN but not from healthy donors. Together, these findings indicate that low-surface MPL is a biomarker of mutant CRT-mediated MPN and that induced degradation of CRTDel52 and MPL is an avenue for therapeutic intervention.
Assuntos
Calreticulina , Lisossomos , Mutação , Transtornos Mieloproliferativos , Receptores de Trombopoetina , Humanos , Calreticulina/metabolismo , Calreticulina/genética , Receptores de Trombopoetina/metabolismo , Receptores de Trombopoetina/genética , Transtornos Mieloproliferativos/metabolismo , Transtornos Mieloproliferativos/genética , Lisossomos/metabolismo , Proteólise , Serina-Treonina Quinases TOR/metabolismo , Proliferação de CélulasRESUMO
Thrombopoietin, the primary regulator of blood platelet production, was postulated to exist in 1958, but was only proven to exist when the cDNA for the hormone was cloned in 1994. Since its initial cloning and characterization, the hormone has revealed many surprises. For example, instead of acting as the postulated differentiation factor for platelet precursors, megakaryocytes, it is the most potent stimulator of megakaryocyte progenitor expansion known. Moreover, it also stimulates the survival, and in combination with stem cell factor leads to the expansion of hematopoietic stem cells. All of these growth-promoting activities have resulted in its clinical use in patients with thrombocytopenia and aplastic anemia, although the clinical development of the native molecule illustrated that "it's not wise to mess with mother nature", as a highly engineered version of the native hormone led to autoantibody formation and severe thrombocytopenia. Finally, another unexpected finding was the role of the thrombopoietin receptor in stem cell biology, including the development of myeloproliferative neoplasms, an important disorder of hematopoietic stem cells. Overall, the past 30 years of clinical and basic research has yielded many important insights, which are reviewed in this paper.