RESUMEN
Hematopoietic stem cell (HSC) release is positively regulated by the sympathetic nervous system through the ß3 adrenergic receptor. Preclinical studies have demonstrated that the combination of desipramine and G-CSF resulted in improved HSC mobilization. Here, we present the results of an open-label single-arm pilot study in patients with multiple myeloma undergoing autologous stem cell transplantation (ASCT) to assess the safety and efficacy of desipramine combined with G-SCF to induce HSC mobilization. The primary endpoint was safety of the combination including engraftment kinetics. The secondary endpoint was the proportion of patients who collected ≥5 × 106 CD34+ cells/kg. Outcomes were compared with historical matched controls during the same time period with multiple myeloma mobilized with G-CSF. All study patients received desipramine 100 mg daily for 7 days, starting 4 days prior to G-CSF administration (D-3) and continued taking it along with G-CSF for a total of 7 days. Six of ten patients enrolled completed the protocol with minimal side effects. All of them achieved the target collection of 5 × 106 CD34 cells/kg in a median of 1.5 apheresis session with two patients needing additional plerixafor (16%), while 11 out of 13 patients (85%) achieved the target of 5 × 106 CD34 cells/kg in the historical control group in a median of 2 apheresis procedures and seven patients needed plerixafor (54%). The combination of desipramine and G-CSF is safe and signals improved mobilization over G-CSF alone, providing a possible alternative means of mobilization that needs further investigation.
Asunto(s)
Inhibidores de Captación Adrenérgica/uso terapéutico , Antígenos CD34/inmunología , Desipramina/uso terapéutico , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Movilización de Célula Madre Hematopoyética/métodos , Trasplante de Células Madre Hematopoyéticas , Mieloma Múltiple/terapia , Adolescente , Inhibidores de Captación Adrenérgica/administración & dosificación , Adulto , Anciano , Bencilaminas , Ciclamas , Desipramina/administración & dosificación , Quimioterapia Combinada , Femenino , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Factor Estimulante de Colonias de Granulocitos/efectos adversos , Células Madre Hematopoyéticas/efectos de los fármacos , Células Madre Hematopoyéticas/inmunología , Células Madre Hematopoyéticas/metabolismo , Compuestos Heterocíclicos/administración & dosificación , Compuestos Heterocíclicos/efectos adversos , Compuestos Heterocíclicos/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/sangre , Proyectos Piloto , Receptores Adrenérgicos beta 3/metabolismo , Adulto JovenAsunto(s)
Biopsia con Aguja/efectos adversos , Examen de la Médula Ósea/efectos adversos , Médula Ósea/patología , Ilion/diagnóstico por imagen , Articulación Sacroiliaca/lesiones , Sacro/lesiones , Tomografía Computarizada por Rayos X , Anciano , Vasos Sanguíneos/lesiones , Examen de la Médula Ósea/instrumentación , Examen de la Médula Ósea/métodos , Femenino , Hemorragia/etiología , Humanos , Masculino , Persona de Mediana Edad , Dolor/etiología , Traumatismos de los Nervios Periféricos/etiología , Traumatismos de los Nervios Periféricos/prevención & control , Articulación Sacroiliaca/diagnóstico por imagen , Sacro/diagnóstico por imagenRESUMEN
Pathologists and haematologists generally agree that the length of the biopsy core is a good surrogate for the diagnostic quality of the bone marrow. Previous studies suggested that the angulation of the biopsy needle from the posterior superior iliac spine (PSIS) could influence the length of the biopsy cores, targeting the anterior superior iliac spine (ASIS) from the PSIS would yield longer specimens than the traditional angulation technique (TAT), where the biopsy needle is directed straight in, perpendicular to the plane of the back. Twenty five adult haematology patients were prospectively recruited by haematologists-in-training (HITs), who were trained to target the ASIS using a lateral angulationtechnique (LAT). The mean length of biopsy cores was 16 mm and that was significantly longer (p=0.003) than a comparable group of bone marrow biopsies previously obtained by HITs using the TAT approach. These results support the LAT as a new standard of haematology practice. TRIAL REGISTRATION NUMBER: NCT 02524613.
Asunto(s)
Médula Ósea/patología , Ilion/patología , Adulto , Biopsia con Aguja Gruesa , Examen de la Médula Ósea , Femenino , Humanos , Modelos Lineales , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
SEER data and a Bronx validation cohort demonstrate that Hispanics present with AML at younger age but have shorter survival than whites.Increased frequency of high-risk mutations in Hispanics provides a potential biologic explanation for poorer outcomes in Hispanics.
RESUMEN
Myelofibrosis (MF) is a bone marrow disorder characterized by clonal myeloproliferation, aberrant cytokine production, extramedullary hematopoiesis, and bone marrow fibrosis. Although somatic mutations in JAK2, MPL, and CALR have been identified in the pathogenesis of these diseases, inhibitors of the Jak2 pathway have not demonstrated efficacy in ameliorating MF in patients. TGF-ß family members are profibrotic cytokines and we observed significant TGF-ß1 isoform overexpression in a large cohort of primary MF patient samples. Significant overexpression of TGF-ß1 was also observed in murine clonal MPLW515L megakaryocytic cells. TGF-ß1 stimulated the deposition of excessive collagen by mesenchymal stromal cells (MSCs) by activating the TGF-ß receptor I kinase (ALK5)/Smad3 pathway. MSCs derived from MPLW515L mice demonstrated sustained overproduction of both collagen I and collagen III, effects that were abrogated by ALK5 inhibition in vitro and in vivo. Importantly, use of galunisertib, a clinically active ALK5 inhibitor, significantly improved MF in both MPLW515L and JAK2V617F mouse models. These data demonstrate the role of malignant hematopoietic stem cell (HSC)/TGF-ß/MSC axis in the pathogenesis of MF, and provide a preclinical rationale for ALK5 blockade as a therapeutic strategy in MF.