RESUMEN

The therapeutic landscape of chronic myeloid leukemia (CML) has profoundly changed over the past 7 years. Most patients with chronic phase (CP) now have a normal life expectancy. Another goal is achieving a stable deep molecular response (DMR) and discontinuing medication for treatment-free remission (TFR). The European LeukemiaNet convened an expert panel to critically evaluate and update the evidence to achieve these goals since its previous recommendations. First-line treatment is a tyrosine kinase inhibitor (TKI; imatinib brand or generic, dasatinib, nilotinib, and bosutinib are available first-line). Generic imatinib is the cost-effective initial treatment in CP. Various contraindications and side-effects of all TKIs should be considered. Patient risk status at diagnosis should be assessed with the new EUTOS long-term survival (ELTS)-score. Monitoring of response should be done by quantitative polymerase chain reaction whenever possible. A change of treatment is recommended when intolerance cannot be ameliorated or when molecular milestones are not reached. Greater than 10% BCR-ABL1 at 3 months indicates treatment failure when confirmed. Allogeneic transplantation continues to be a therapeutic option particularly for advanced phase CML. TKI treatment should be withheld during pregnancy. Treatment discontinuation may be considered in patients with durable DMR with the goal of achieving TFR.

Asunto(s)

Antineoplásicos/uso terapéutico , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Mesilato de Imatinib/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Compuestos de Anilina/uso terapéutico , Toma de Decisiones Clínicas , Conferencias de Consenso como Asunto , Dasatinib/uso terapéutico , Manejo de la Enfermedad , Proteínas de Fusión bcr-abl/genética , Proteínas de Fusión bcr-abl/metabolismo , Expresión Génica , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/mortalidad , Esperanza de Vida/tendencias , Monitoreo Fisiológico , Nitrilos/uso terapéutico , Pirimidinas/uso terapéutico , Calidad de Vida , Quinolinas/uso terapéutico , Análisis de Supervivencia

RESUMEN

Mastocytosis is a myeloproliferative neoplasm characterized by expansion of abnormal mast cells (MCs) in various tissues, including skin, bone marrow, gastrointestinal tract, liver, spleen, or lymph nodes. Subtypes include indolent systemic mastocytosis, smoldering systemic mastocytosis and advanced systemic mastocytosis (AdvSM), a term collectively used for the three most aggressive forms of the disease: aggressive systemic mastocytosis, mast cell leukemia, and systemic mastocytosis with an associated clonal hematological non-mast cell disease (SM-AHNMD). MC activation and proliferation is physiologically controlled in part through stem cell factor (SCF) binding to its cognate receptor, KIT. Gain-of-function KIT mutations that lead to ligand-independent kinase activation are found in most SM subtypes, and the overwhelming majority of AdvSM patients harbor the KITD816V mutation. Several approved tyrosine kinase inhibitors (TKIs), such as imatinib and nilotinib, have activity against wild-type KIT but lack activity against KITD816V. Midostaurin, a broad spectrum TKI with activity against KITD816V, has a 60% clinical response rate, and is currently the only drug specifically approved for AdvSM. While this agent improves the prognosis of AdvSM patients and provides proof of principle for targeting KITD816V as a driver mutation, most responses are partial and/or not sustained, indicating that more potent and/or specific inhibitors are required. Avapritinib, a KIT and PDGFRα inhibitor, was specifically designed to inhibit KITD816V. Early results from a Phase 1 trial suggest that avapritinib has potent antineoplastic activity in AdvSM, extending to patients who failed midostaurin. Patients exhibited a rapid reduction in both symptoms as well as reductions of bone marrow MCs, serum tryptase, and KITD816V mutant allele burden. Adverse effects include expected toxicities such as myelosuppression and periorbital edema, but also cognitive impairment in some patients. Although considerable excitement about avapritinib exists, more data are needed to assess long-term responses and adverse effects of this novel TKI.

RESUMEN

Philadelphia chromosome-positive (Ph+) B-cell precursor acute lymphoblastic leukemia (ALL) expressing BCR-ABL1 oncoprotein is a major subclass of ALL with poor prognosis. BCR-ABL1-expressing leukemic cells are highly dependent on double-strand break (DSB) repair signals for their survival. Here we report that a first-in-class HDAC1,2 selective inhibitor and doxorubicin (a hyper-CVAD chemotherapy regimen component) impair DSB repair networks in Ph+ B-cell precursor ALL cells using common as well as distinct mechanisms. The HDAC1,2 inhibitor but not doxorubicin alters nucleosomal occupancy to impact chromatin structure, as revealed by MNase-Seq. Quantitative mass spectrometry of the chromatin proteome along with functional assays showed that the HDAC1,2 inhibitor and doxorubicin either alone or in combination impair the central hub of DNA repair, the Mre11-Rad51-DNA ligase 1 axis, involved in BCR-ABL1-specific DSB repair signaling in Ph+ B-cell precursor ALL cells. HDAC1,2 inhibitor and doxorubicin interfere with DISC (DNA damage-induced transcriptional silencing in cis)) or transcriptional silencing program in cis around DSB sites via chromatin remodeler-dependent and -independent mechanisms, respectively, to further impair DSB repair. HDAC1,2 inhibitor either alone or when combined with doxorubicin decreases leukemia burden in vivo in refractory Ph+ B-cell precursor ALL patient-derived xenograft mouse models. Overall, our novel mechanistic and preclinical studies together demonstrate that HDAC1,2 selective inhibition can overcome DSB repair 'addiction' and provide an effective therapeutic option for Ph+ B-cell precursor ALL.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Reparación del ADN/efectos de los fármacos , Proteínas de Fusión bcr-abl/metabolismo , Histona Desacetilasa 1/antagonistas & inhibidores , Histona Desacetilasa 2/antagonistas & inhibidores , Cromosoma Filadelfia/efectos de los fármacos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamiento farmacológico , Animales , Línea Celular Tumoral , Roturas del ADN de Doble Cadena/efectos de los fármacos , Doxorrubicina/administración & dosificación , Humanos , Ratones , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo

Asunto(s)

Resistencia a Antineoplásicos/efectos de los fármacos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Niacinamida/análogos & derivados , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Resistencia a Antineoplásicos/genética , Proteínas de Fusión bcr-abl/genética , Humanos , Células K562 , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Niacinamida/farmacología

RESUMEN

Here, we present a case of a tracheal fistula due to an anastomotic insufficiency following abdominothoracic esophageal resection. Despite immediate discontinuity resection, the tracheal fistula could not be surgically closed, resulting in incomplete control of the source of infection and an alternative treatment concept in the form of interventional fistula closure using a Y-tracheal stent. However, owing to existing severe acute respiratory distress syndrome (ARDS), which is associated with a considerable risk of peri-interventional hypoxia, a temporary bridging concept using venovenous extracorporeal membrane oxygenation (ECMO) was implemented successfully.

Asunto(s)

Oxigenación por Membrana Extracorpórea/métodos , Fístula/cirugía , Control de Infecciones/métodos , Síndrome de Dificultad Respiratoria/terapia , Sepsis/prevención & control , Enfermedades de la Tráquea/cirugía , Anastomosis Quirúrgica/métodos , Broncoscopía , Humanos , Masculino , Persona de Mediana Edad , Síndrome de Dificultad Respiratoria/diagnóstico por imagen , Síndrome de Dificultad Respiratoria/etiología , Sepsis/diagnóstico por imagen , Stents , Tomografía Computarizada por Rayos X

Asunto(s)

Antineoplásicos/uso terapéutico , Mesilato de Imatinib/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielomonocítica Crónica/tratamiento farmacológico , Anciano , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Leucemia Mielomonocítica Crónica/genética , Leucemia Mielomonocítica Crónica/patología , Masculino , Mutación

RESUMEN

Chronic myeloid leukemia (CML) patients who relapse on imatinib due to acquired ABL1 kinase domain mutations are successfully treated with second-generation ABL1-tyrosine kinase inhibitors (ABL-TKIs) such as dasatinib, nilotinib or ponatinib. However, ~40% of relapsed patients have uncharacterized BCR-ABL1 kinase-independent mechanisms of resistance. To identify these mechanisms of resistance and potential treatment options, we generated ABL-TKI-resistant K562 cells through prolonged sequential exposure to imatinib and dasatinib. Dual-resistant K562 cells lacked BCR-ABL1 kinase domain mutations, but acquired other genomic aberrations that were characterized by next-generation sequencing and copy number analyses. Proteomics showed that dual-resistant cells had elevated levels of FOXO1, phospho-ERK and BCL-2, and that dasatinib no longer inhibited substrates of the PI3K/AKT pathway. In contrast to parental cells, resistant cells were sensitive to growth inhibition and apoptosis induced by the class I PI3K inhibitor, GDC-0941 (pictilisib), which also induced FOXO1 nuclear translocation. FOXO1 was elevated in a subset of primary specimens from relapsed CML patients lacking BCR-ABL1 kinase domain mutations, and these samples were responsive to GDC-0941 treatment ex vivo. We conclude that elevated FOXO1 contributes to BCR-ABL1 kinase-independent resistance experienced by these CML patients and that PI3K inhibition coupled with BCR-ABL1 inhibition may represent a novel therapeutic approach.

Asunto(s)

Resistencia a Antineoplásicos , Proteína Forkhead Box O1/fisiología , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Dasatinib/farmacología , Tolerancia a Medicamentos , Proteína Forkhead Box O1/análisis , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Humanos , Mesilato de Imatinib/farmacología , Indazoles/farmacología , Células K562 , Inhibidores de las Quinasa Fosfoinosítidos-3 , Sulfonamidas/farmacología , Células Tumorales Cultivadas

Asunto(s)

Proteínas de Fusión bcr-abl/genética , Imidazoles/uso terapéutico , Indazoles/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Mutación/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , Axitinib , Humanos

RESUMEN

Chronic myelomonocytic leukemia (CMML) is a hematologic malignancy nearly confined to the elderly. Previous studies to determine incidence and prognostic significance of somatic mutations in CMML have relied on candidate gene sequencing, although an unbiased mutational search has not been conducted. As many of the genes commonly mutated in CMML were recently associated with age-related clonal hematopoiesis (ARCH) and aged hematopoiesis is characterized by a myelomonocytic differentiation bias, we hypothesized that CMML and aged hematopoiesis may be closely related. We initially established the somatic mutation landscape of CMML by whole exome sequencing followed by gene-targeted validation. Genes mutated in ⩾10% of patients were SRSF2, TET2, ASXL1, RUNX1, SETBP1, KRAS, EZH2, CBL and NRAS, as well as the novel CMML genes FAT4, ARIH1, DNAH2 and CSMD1. Most CMML patients (71%) had mutations in ⩾2 ARCH genes and 52% had ⩾7 mutations overall. Higher mutation burden was associated with shorter survival. Age-adjusted population incidence and reported ARCH mutation rates are consistent with a model in which clinical CMML ensues when a sufficient number of stochastically acquired age-related mutations has accumulated, suggesting that CMML represents the leukemic conversion of the myelomonocytic-lineage-biased aged hematopoietic system.

Asunto(s)

Biomarcadores de Tumor/genética , Hematopoyesis/genética , Leucemia Mielomonocítica Crónica/genética , Mutación/genética , Proteínas/genética , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Exoma , Femenino , Estudios de Seguimiento , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Leucemia Mielomonocítica Crónica/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Proteínas de Unión al ARN , Tasa de Supervivencia , Adulto Joven

RESUMEN

Activation of nuclear ß-catenin and expression of its transcriptional targets promotes chronic myeloid leukemia (CML) progression, tyrosine kinase inhibitor (TKI) resistance, and leukemic stem cell self-renewal. We report that nuclear ß-catenin has a role in leukemia cell-intrinsic but not -extrinsic BCR-ABL1 kinase-independent TKI resistance. Upon imatinib inhibition of BCR-ABL1 kinase activity, ß-catenin expression was maintained in intrinsically resistant cells grown in suspension culture and sensitive cells cultured in direct contact (DC) with bone marrow (BM) stromal cells. Thus, TKI resistance uncouples ß-catenin expression from BCR-ABL1 kinase activity. In ß-catenin reporter assays, intrinsically resistant cells showed increased transcriptional activity versus parental TKI-sensitive controls, and this was associated with restored expression of ß-catenin target genes. In contrast, DC with BM stromal cells promoted TKI resistance, but had little effects on Lef/Tcf reporter activity and no consistent effects on cytoplasmic ß-catenin levels, arguing against a role for ß-catenin in extrinsic TKI resistance. N-cadherin or H-cadherin blocking antibodies abrogated DC-based resistance despite increasing Lef/Tcf reporter activity, suggesting that factors other than ß-catenin contribute to extrinsic, BM-derived TKI resistance. Our data indicate that, while nuclear ß-catenin enhances survival of intrinsically TKI-resistant CML progenitors, it is not required for extrinsic resistance mediated by the BM microenvironment.

Asunto(s)

Proteínas de Fusión bcr-abl/fisiología , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Tirosina Quinasas/antagonistas & inhibidores , beta Catenina/fisiología , Cadherinas/fisiología , Línea Celular Tumoral , Resistencia a Antineoplásicos , Humanos , Mesilato de Imatinib/uso terapéutico , Proteínas Proto-Oncogénicas/fisiología , Proteínas Wnt/fisiología , Proteína Wnt-5a

Asunto(s)

Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Proteínas de Fusión bcr-abl/genética , Mutación , Dominios y Motivos de Interacción de Proteínas/genética , Inhibidores de Proteínas Quinasas/farmacología , Proteínas de Fusión bcr-abl/química , Humanos , Inhibidores de Proteínas Quinasas/química

RESUMEN

Targeted therapy of chronic myeloid leukemia (CML) is currently based on small-molecule inhibitors that directly bind the tyrosine kinase domain of BCR-ABL1. This strategy has generally been successful, but is subject to drug resistance because of point mutations in the kinase domain. Kinase activity requires transactivation of BCR-ABL1 following an oligomerization event, which is mediated by the coiled-coil (CC) domain at the N terminus of the protein. Here, we describe a rationally engineered mutant version of the CC domain, called CC(mut3), which interferes with BCR-ABL1 oligomerization and promotes apoptosis in BCR-ABL1-expressing cells, regardless of kinase domain mutation status. CC(mut3) exhibits strong proapoptotic and antiproliferative activity in cell lines expressing native BCR-ABL1, single kinase domain mutant BCR-ABL1 (E255V and T315I) or compound-mutant BCR-ABL1 (E255V/T315I). Moreover, CC(mut3) inhibits colony formation by primary CML CD34(+) cells ex vivo, including a sample expressing the T315I mutant. These data suggest that targeting BCR-ABL1 with CC mutants may provide a novel alternative strategy for treating patients with resistance to current targeted therapies.

Asunto(s)

Resistencia a Antineoplásicos/genética , Proteínas de Fusión bcr-abl/química , Proteínas de Fusión bcr-abl/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Mutación Puntual/genética , Multimerización de Proteína/genética , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Apoptosis , Proliferación Celular , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Fosforilación , Inhibidores de Proteínas Quinasas/farmacología , Estructura Terciaria de Proteína , Células Tumorales Cultivadas , Ensayo de Tumor de Célula Madre

RESUMEN

Extreme, abrupt Northern Hemisphere climate oscillations during the last glacial cycle (140,000 years ago to present) were modulated by changes in ocean circulation and atmospheric forcing. However, the variability of the Atlantic meridional overturning circulation (AMOC), which has a role in controlling heat transport from low to high latitudes and in ocean CO2 storage, is still poorly constrained beyond the Last Glacial Maximum. Here we show that a deep and vigorous overturning circulation mode has persisted for most of the last glacial cycle, dominating ocean circulation in the Atlantic, whereas a shallower glacial mode with southern-sourced waters filling the deep western North Atlantic prevailed during glacial maxima. Our results are based on a reconstruction of both the strength and the direction of the AMOC during the last glacial cycle from a highly resolved marine sedimentary record in the deep western North Atlantic. Parallel measurements of two independent chemical water tracers (the isotope ratios of (231)Pa/(230)Th and (143)Nd/(144)Nd), which are not directly affected by changes in the global cycle, reveal consistent responses of the AMOC during the last two glacial terminations. Any significant deviations from this configuration, resulting in slowdowns of the AMOC, were restricted to centennial-scale excursions during catastrophic iceberg discharges of the Heinrich stadials. Severe and multicentennial weakening of North Atlantic Deep Water formation occurred only during Heinrich stadials close to glacial maxima with increased ice coverage, probably as a result of increased fresh-water input. In contrast, the AMOC was relatively insensitive to submillennial meltwater pulses during warmer climate states, and an active AMOC prevailed during Dansgaard-Oeschger interstadials (Greenland warm periods).

Asunto(s)

Cubierta de Hielo , Movimientos del Agua , Océano Atlántico , Foraminíferos , Sedimentos Geológicos/química , Groenlandia , Historia Antigua , Incertidumbre

RESUMEN

Creating magnetized jets in the laboratory is relevant to studying young stellar objects, but generating these types of plasmas within the laboratory setting has proven to be challenging. Here, we present the construction of a solenoid designed to produce an axial magnetic field with strengths in the gap of up to 5 T. This novel design was a compact 75 mm × 63 mm × 88 mm, allowing it to be placed in the Titan target chamber. It was robust, surviving over 50 discharges producing fields ≲ 5 T, reaching a peak magnetic field of 12.5 T.

Asunto(s)

Campos Magnéticos , Gases em Plasma

RESUMEN

BACKGROUND: Ponatinib is a potent oral tyrosine kinase inhibitor of unmutated and mutated BCR-ABL, including BCR-ABL with the tyrosine kinase inhibitor-refractory threonine-to-isoleucine mutation at position 315 (T315I). We conducted a phase 2 trial of ponatinib in patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL). METHODS: We enrolled 449 heavily pretreated patients who had CML or Ph-positive ALL with resistance to or unacceptable side effects from dasatinib or nilotinib or who had the BCR-ABL T315I mutation. Ponatinib was administered at an initial dose of 45 mg once daily. The median follow-up was 15 months. RESULTS: Among 267 patients with chronic-phase CML, 56% had a major cytogenetic response (51% of patients with resistance to or unacceptable side effects from dasatinib or nilotinib and 70% of patients with the T315I mutation), 46% had a complete cytogenetic response (40% and 66% in the two subgroups, respectively), and 34% had a major molecular response (27% and 56% in the two subgroups, respectively). Responses were observed regardless of the baseline BCR-ABL kinase domain mutation status and were durable; the estimated rate of a sustained major cytogenetic response of at least 12 months was 91%. No single BCR-ABL mutation conferring resistance to ponatinib was detected. Among 83 patients with accelerated-phase CML, 55% had a major hematologic response and 39% had a major cytogenetic response. Among 62 patients with blast-phase CML, 31% had a major hematologic response and 23% had a major cytogenetic response. Among 32 patients with Ph-positive ALL, 41% had a major hematologic response and 47% had a major cytogenetic response. Common adverse events were thrombocytopenia (in 37% of patients), rash (in 34%), dry skin (in 32%), and abdominal pain (in 22%). Serious arterial thrombotic events were observed in 9% of patients; these events were considered to be treatment-related in 3%. A total of 12% of patients discontinued treatment because of an adverse event. CONCLUSIONS: Ponatinib had significant antileukemic activity across categories of disease stage and mutation status. (Funded by Ariad Pharmaceuticals and others; PACE ClinicalTrials.gov number, NCT01207440 .).

Asunto(s)

Imidazoles/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridazinas/uso terapéutico , Trombosis/inducido químicamente , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Imidazoles/efectos adversos , Masculino , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/efectos adversos , Piridazinas/efectos adversos , Trombocitopenia/inducido químicamente , Adulto Joven

RESUMEN

PURPOSE: To evaluate the effectiveness and safety of percutaneous vesselplasty in pathological vertebral fractures of the thoracolumbar spine in selected tumor patients. MATERIALS AND METHODS: Eleven pathological vertebral fractures in nine patients were treated with vesselplasty (Vessel-X®, MAXXSPINE). Nine of eleven vertebras (81.8 %) had major posterior wall deficiency (> 30 %). Clinical and radiological (CT) measures were obtained before and 3 months after the procedure. RESULTS: The mean VAS improved significantly from preoperative to postoperative (6.9 ± 2.2 to 3.7 ± 2.3; p < 0.05), as did the ODI (59.7 %± 19.2 % to 40.3 %± 24.0 %; p < 0.05). The physical component summary of the SF-36 was significantly improved by the operation (19.2 ± 8.0 to 31.0 ± 16.5; p < 0.05). Symptomatic cement leakage or other operation-associated complications were not observed. Three patients were primarily treated with concomitant minimally invasive stabilization via fixateur interne. One patient had to undergo minimally invasive stabilization via fixateur interne 4 months after vesselplasty due to further collapse of the treated vertebral body. CONCLUSION: From these preliminary results, vesselplasty appears to be a treatment option worth considering in pathological vertebral fractures, even in the case of posterior wall deficiency. Selected tumor patients might benefit from vesselplasty as a minimally invasive procedure for stabilization of the fractured vertebra, pain control, and improvement in body function and quality of life. Long-term prospective studies with a larger sample size are required to validate these results.

Asunto(s)

Fracturas Espontáneas/diagnóstico por imagen , Fracturas Espontáneas/cirugía , Cifoplastia/instrumentación , Cifoplastia/métodos , Vértebras Lumbares/diagnóstico por imagen , Vértebras Lumbares/cirugía , Procedimientos Quirúrgicos Mínimamente Invasivos/instrumentación , Procedimientos Quirúrgicos Mínimamente Invasivos/métodos , Mieloma Múltiple/diagnóstico por imagen , Mieloma Múltiple/cirugía , Prótesis e Implantes , Fracturas de la Columna Vertebral/diagnóstico por imagen , Fracturas de la Columna Vertebral/cirugía , Neoplasias de la Columna Vertebral/diagnóstico por imagen , Neoplasias de la Columna Vertebral/secundario , Neoplasias de la Columna Vertebral/cirugía , Vértebras Torácicas/diagnóstico por imagen , Vértebras Torácicas/cirugía , Anciano , Anciano de 80 o más Años , Cementos para Huesos/uso terapéutico , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/diagnóstico por imagen , Radiografía

RESUMEN

Tyrosine kinase inhibitors (TKIs) of BCR-ABL have turned chronic myeloid leukemia (CML) from a deadly disease into a chronic ailment. Unfortunately, evidence is accumulating that TKIs are not curative, since CML stem cells are not addicted to BCR-ABL, and persist despite TKI therapy. On closer view this is not surprising, as it reflects fundamental principles of CML pathogenesis. Strategies to eradicate CML stem cells will most likely be based on synthetic lethality though parallel inhibition of BCR-ABL and other critical pathways.

RESUMEN

In patients with chronic myeloid leukemia (CML), disease in the initial chronic phase (CP) and subsequent progression are driven by the oncogenic activity of the BCR-ABL fusion kinase. Imatinib, a tyrosine kinase inhibitor of BCR-ABL, has been the mainstay of first-line therapy for CML for 10 years. Although patients with CML-CP respond well to imatinib, those who have delayed reductions in leukemic burden during imatinib therapy, such as not achieving a complete cytogenetic response (CCyR) by 12 months, have an increased risk of disease progression. It has been recognized, with 8 years of observation, that patients who achieve an early major molecular response (MMR) on imatinib have a very low probability of disease progression. Recent randomized phase 3 trials have shown that first-line treatment with dasatinib or nilotinib-more potent BCR-ABL inhibitors-results in significantly higher rates and more rapid achievement of CCyR and MMR in comparison with standard-dose imatinib. These trials suggest that CML treatment can be improved with more potent BCR-ABL inhibition during initial therapy, but further follow-up is needed to confirm that the improved response rates with dasatinib and nilotinib are maintained long term.

Asunto(s)

Antineoplásicos/uso terapéutico , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Antineoplásicos/farmacología , Humanos