Development and validation of liquid chromatography-tandem mass spectrometry method to quantify dasatinib in plasma and its application to a pharmacokinetic study

Abstract Dasatinib, a potent oral multi-targeted kinase inhibitor against Src and Bcr-Abl, can decrease inflammatory response in sepsis. A simple and cost-effective method for determination of an effective dose dasatinib was established. This method was validated in human plasma, with the aim of reducing the number of animals used, thus, avoiding ethical problems. Dasatinib and internal standard lopinavir were extracted from 180 uL of plasma using liquid-liquid extraction with methyl tert-butil ether, followed by liquid chromatography coupled to triple quadrupole mass spectrometry in multiple reaction monitoring mode. For the pharmacokinetic study, 1 mg/kg of dasatinib was administered to mice with and without sepsis. The method was linear over the concentration range of 1-98 ng/mL for DAS in mice and human plasma, with r2>0.99 and presented intra- and interday precision within the range of 2.3 - 6.2 and 4.3 - 7.0%, respectively. Further intra- and interday accuracy was within the range of 88.2 - 105.8 and 90.6 - 101.7%, respectively. The mice with sepsis showed AUC0-t = 2076.06 h*ng/mL and Cmax =102.73 ng/mL and mice without sepsis presented AUC0-t = 2128.46 h*ng/mL. Cmax = 164.5 ng/mL. The described analytical method was successfully employed in pharmacokinetic study of DAS in mice.

What happens to intolerant, relapsed or refractory chronic myeloid leukemia patients without access to clinical trials?

ABSTRACT Objective: To assess clinical outcomes of intolerant, relapsed or refractory patients who could not be treated with new tyrosine kinase inhibitors or experimental therapies. Methods: A retrospective cohort of 90 chronic myeloid leukemia patients in all phases of the disease treated with imatinib mesylate as their first TKI therapy, and with dasatinib or nilotinib as the next line of therapy. We evaluated clinical outcomes of these patients, with special focus on the group that needed more than two therapy lines. Results: Thirty-nine percent of patients were refractory or intolerant to imatinib. An 8-year overall survival rate of the patients who went through three or more lines of treatment was significantly lower, compared to those who were able to maintain imatinib as their first-line therapy (83% and 22%, respectively p < 0.01). Decreased overall survival was associated with advanced-phase disease (p < 0.01), failure to achieve major molecular response in first-line treatment (p < 0.01) and interruption of first-line treatment due to any reason (p = 0.023). Failure in achieving complete cytogenetic response and major molecular response and treatment interruption were associated with the progression to the third-line treatment. Conclusion: The critical outcome observed in relapsed, intolerant or refractory chronic phase CML patients reflects the unmet need for this group of patients without an alternative therapy, such as new drugs or experimental therapies in clinical trials. Broader access to newer treatment possibilities is a crucial asset to improve survival among CML patients, especially those refractory or intolerant to first-line therapies.

Management of chronic myeloid leukemia during pregnancy: a retrospective analysis at a single center

ABSTRACT We analyzed the management and outcomes of pregnancies of patients with chronic myeloid leukemia at a single center over fifteen years. Among the 203 CML female patients, there were ten pregnancies in seven women, all of them not planned. In three cases, the chronic myeloid leukemia diagnosis was made during pregnancy. Five patients received tyrosine kinase inhibitors in the first weeks of pregnancy and the drug was interrupted until delivery. One patient lost complete cytogenetic response, and two patients lost the hematological response. A patient with a stable major molecular response had two successful pregnancies without loss of response. There were four premature births. There were no maternal adverse events, fetal malformation or death. All patients received Interferon-alpha during gestation, and two received hydroxyurea for a short period. Leukapheresis was performed in two patients for hyperleukocytosis control. One patient with sickle cell disease died from disease progression six months after delivery. Conclusions: The tyrosine kinase inhibitors ministration should be interrupted during pregnancy. Patients should be advised to achieve a stable and deep molecular response if they plan to conceive, to avoid the risk of disease progression.

Hematoma intraparenquimatoso del sistema nervioso central asociado con dasatinib en el tratamiento de leucemia mieloide crónica en fase acelerada. Presentación de dos casos y revisión de la literatura / Intraparenchymal haematoma of the central nervous system associated with Dasatinib in the treatment of chronic myeloid leukaemia in accelerated phase. Presentation of two cases and review of literature

Resumen Se presentan dos casos clínicos de pacientes con leucemia mieloide crónica en fase acelerada, hospitalizados para inicio de terapia dirigida con inhibidores de tirosina cinasa (dasatinib). Posteriormente se determina la presencia de sangrado intraparenquimatoso a sistema nervioso central. Para finalizar, se revisa la literatura disponible a cerca de eventos adversos tipo sangrado asociados a dasatinib y los posibles condicionantes de este desenlace.

Abstract Two clinical cases are presented on patients with chronic myeloid leukaemia in accelerated phase, who were admitted to hospital for initiation of targeted therapy with tyrosine kinase inhibitors (Dasatinib). Intraparenchymal bleeding in the central nervous system was subsequently observed. A review was also made on the available literature on bleeding-related adverse events associated with Dasatinib and the possible determining factors of this outcome.

Guía de práctica clínica para la detección, tratamiento y seguimiento de leucemias linfoblástica y mieloide en población mayor de 18 años. Guía completa / Clinical practice guideline for the detection, treatment and monitoring of lymphoblastic and myeloid leukemias in a population over 18 years of age

La guía relaciona el diagnóstico y el tratamiento en población adulta de la leucemia linfoblástica aguda (LLA) y la leucemia mieloide aguda (LMA), como el diagnostico, el tratamiento y el seguimiento en población adulta de la leucemia mieloide crónica (LMC).

Eficacia y seguridad de nilotinib para el tratamiento de v pe leucemia mieloide crónica con resistencia o intolerancia a Imatinib y a Dasatinib, sin mutación T315I y ECOG 0-2 / Efficacy and safety of nilotinib for the treatment of chronic myeloid leukemia with resistance or intolerance to Imatinib and Dasatinib, without mutation T315I and ECOG 0-2

INTRODUCCIÓN: Antecedentes: El presente dictamen expone la evaluación de tecnología de la eficacia y seguridad de nilotinib para el manejo de pacientes con diagnóstico de leucemia mieloide crónica resistente o intolerante a imatinib y a dasatinib sin mutación T315I y ECOG 0-2. Aspectos Generales: La leucemia mieloide crónica (LMC) es una enfermedad mieloproliferativa, que se caracteriza por la proliferación de granulocitos en sangre y medula ósea. Más del 90% de los casos se debe a la traslocación recíproca de los cromosomas 9 y 22 [t (9; 22)] debido a la mutación del cromosoma Filadelfia (Ph+). Esta traslocación genera la fusión de una región del gen BCR del cromosoma 22 en la banda q11 y del gen ABL1 localizado en el cromosoma 9 en la banda q34. El producto de la fusión BDR-ABL1 es una proteína activa llamada tirosina quinasa. Esta proteína lleva a una proliferación celular incontrolada. Las personas con leucemia mieloide crónica, sin la mutación Filadelfia, tienen otros mecanismos de traslocación, pero resultan en la misma fusión de genes y la codificación de la proteína tirosina quinasa. Tecnologia Sanitaria de Interés: El nilotinib (Tasigna®, Novartis; C28H22F3N70), es un inhibidor de tirosina quinasa, derivado del imatinib. El nilotinib se une y estabiliza la conformación inactiva del dominio quinasa de la proteína Abl. METODOLOGIA: Estrategia de Búsqueda: Se realizó una búsqueda de la literatura con respecto a la eficacia y seguridad de nilotinib para el tratamiento de leucemia mieloide crónica en pacientes resistentes/intolerantes a imatinib y dasatinib. Esta búsqueda se realizó utilizando los meta-buscadores: Translating Research into Practice (TRIPDATABASE), National Library of Medicine (Pubmed-Medline) y Health Systems Evidence. Adicionalmente, se amplió la búsqueda revisando la evidencia generada por grupos internacionales que realizan revisiones sistemáticas (RS), evaluación de tecnologías sanitarias (ETS) y guías de práctica clínica (GPC), como la Cochrane Group, The National Institute for Health and Care Excellence (NICE), the Agency for Health care Research and Quality (AHRQ), The Canadian Agency for Drugs and Technologies in Health (CADTH) y The Scottish Medicines Consortium (SMC). RESULTADOS: Sinopsis de la Evidencia: Se realizó la búsqueda bibliográfica y de evidencia científica para el sustento del uso de nilotinib para el tratamiento de leucemia mieloide crónica en pacientes resistentes o intolerantes a imatinib/dasatinib. Se presenta la evidencia disponible según el tipo de publicación priorizada en los criterios de inclusión (i.e., GP, ETS, RS y ECA fase III). CONCLUSIONES: La presente evaluación de tecnología sanitaria tuvo por objetivo la evaluación de la eficacia y seguridad del uso de nilotinib como tercera línea de tratamiento de la LMC-FC, en pacientes resistentes y/o intolerantes a imatinib y dasatinib, sin mutación T315I y ECOG 0-2. Fueron incluidos un total de 6 publicaciones científicas (1 guía de práctica clínica, 1 revisión sistemática, 1 ensayo clínico y 3 ensayos observacionales). A pesar que la evidencia es de baja calidad dado que no existen estudios clínicos aleatorizados fase III del uso de nilotinib como tercera línea de tratamiento de LCM, los ECAs fase II y estudios observacionales encontrados muestran que nilotinib podría ser una alternativa eficaz como tercera línea. Además, existe plausibilidad biológica, pues los patrones de resistencia y de efectos adversos son diferentes para nilotinib, dasatinib e imatinib, excepto por la mutación T315I. Nilotinib puede ser considerado como una adecuada alternativa para el a' tratamiento de tercera línea, luego de haber recibido tratamiento con dos inhibidores de tirosina quinasa y haber mostrado resistencia o intolerancia a estos, aunque la respuesta podría no ser duradera. Ello teniendo en cuenta, además, que actualmente no se cuenta con más alternativas de tratamiento, pues los inhibidores de tirosina quinasa indicados para tratamiento de tercera línea no se encuentran en el mercado, y el trasplante no está indicado para todos los casos. El Instituto de Evaluación de Tecnologías en Salud e Investigación (IETSI) aprueba el uso de nilotinib como alternativa de tratamiento en pacientes con leucemia mieloide crónica con resistencia o intolerancia a imatinib y dasatinib sin mutación T315I y ECOG 0-2. El periodo de vigencia de este dictamen es de dos años y la continuación de dicha aprobación estará sujeta a los resultados obtenidos de los pacientes que se beneficien con dicho tratamiento y a nueva evidencia que pueda surgir en el tiempo.

Treatment with dasatinib or nilotinib in chronic myeloid leukemia patients who failed to respond to two previously administered tyrosine kinase inhibitors - a single center experience

OBJECTIVE: To evaluate hematological, cytogenetic and molecular responses as well as the overall, progression-free and event-free survivals of chronic myeloid leukemia patients treated with a third tyrosine kinase inhibitor after failing to respond to imatinib and nilotinib/dasatinib. METHODS: Bone marrow karyotyping and real-time quantitative polymerase chain reaction were performed at baseline and at 3, 6, 12 and 18 months after the initiation of treatment with a third tyrosine kinase inhibitor. Hematologic, cytogenetic and molecular responses were defined according to the European LeukemiaNet recommendations. BCR-ABL1 mutations were analyzed by Sanger sequencing. RESULTS: We evaluated 25 chronic myeloid leukemia patients who had been previously treated with imatinib and a second tyrosine kinase inhibitor. Nine patients were switched to dasatinib, and 16 patients were switched to nilotinib as a third-line therapy. Of the chronic phase patients (n=18), 89% achieved a complete hematologic response, 13% achieved a complete cytogenetic response and 24% achieved a major molecular response. The following BCR-ABL1 mutations were detected in 6/14 (43%) chronic phase patients: E255V, Y253H, M244V, F317L (2) and F359V. M351T mutation was found in one patient in the accelerated phase of the disease. The five-year overall, progression-free and event-free survivals were 86, 54 and 22% (p<0.0001), respectively, for chronic phase patients and 66%, 66% and 0% (p<0.0001), respectively, for accelerated phase patients. All blast crisis patients died within 6 months of treatment. Fifty-six percent of the chronic phase patients lost their hematologic response within a median of 23 months. CONCLUSIONS: Although the responses achieved by the third tyrosine kinase inhibitor were not sustainable, a third tyrosine kinase inhibitor may be an option for improving patient status until a donor becomes available for transplant. Because the long-term outcome ...