RESUMEN
Asciminib is a myristoyl site BCR::ABL1 inhibitor approved for chronic phase chronic myeloid leukaemia (CP-CML) patients failing ≥2 prior lines of therapy. The Australasian Leukaemia & Lymphoma Group (ALLG) conducted the ASCEND study to assess efficacy of asciminib for newly-diagnosed CP-CML. Patients commenced asciminib 40 mg twice daily (BID) and thereafter were managed according to molecular milestones. Patients with treatment failure, defined as BCR::ABL1 >10% (IS) at 3 or 6 months, or >1% at 12 or 18 months, received either imatinib, nilotinib or dasatinib in addition to asciminib. In patients with suboptimal response, defined as levels of 1-10% at 6 months, >0.1-1% at 12 months, or >0.01%-1% at 18 months, the asciminib dose was increased to 80 mg BID. With a median follow-up of 21 months (range 0-36), 82/101 patients continue asciminib. The most frequent reasons for treatment discontinuation were adverse events (6%), loss of response (4%) and withdrawn consent (5%). There were no deaths; one patient developed lymphoid blast crisis at 6 months. The co-primary endpoints were early molecular response (BCR::ABL1 ≤10% at 3 months), achieved in 93% (96% CI 86-97%), and major molecular response by 12 months achieved in 79%; (95% CI 69.7-86.8%), respectively. The cumulative incidence of MR4.5 was 53% by 24 months. One patient had 2 cerebrovascular events; no other arterial occlusive events were reported. Asciminib as frontline therapy in CP-CML produces high rates of molecular response with excellent tolerance and a low rate of discontinuation for toxicity. (ANZ Clinical Trials Registry ACTRN12620000851965).
RESUMEN
ABSTRACT: Patients with chronic myeloid leukemia who are eligible for treatment-free remission (TFR) may still relapse after tyrosine kinase inhibitor (TKI) cessation. There is a need for accurate predictors of outcome to enable patients with a favorable profile to proceed while avoiding futile attempts. Sensitive detection of residual disease in total leukocytes at treatment cessation is associated with relapse but is not highly discriminatory, likely because it is a composite measure of residual leukemia derived from different cell lineages, whereas only some lineages are relevant for relapse. We prospectively measured BCR::ABL1 DNA as a predictive yes/no binary test in 5 cellular fractions from 48 patients meeting conventional criteria for TKI discontinuation. The median BCR::ABL1 DNA level was higher in granulocytes and T cells, but not in other lineages, in patients who relapsed. Among the 40 patients undergoing their first TFR attempt, we defined 3 groups with differing relapse risk: granulocyte-positive group (100%), granulocyte-negative/T-cell-positive group (67%), and granulocyte-negative /T-cell-negative group (25%). These data show the critical importance of lineage-specific assessment of residual disease in the selection of patients who can attempt to achieve TFR with a high expectation of success and, concurrently, defer patients who have a high probability of relapse.
Asunto(s)
Proteínas de Fusión bcr-abl , Leucemia Mielógena Crónica BCR-ABL Positiva , Humanos , Proteínas de Fusión bcr-abl/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Inhibidores de Proteínas Quinasas , Recurrencia , Inducción de Remisión , ADNRESUMEN
Asciminib, a first-in-class allosteric inhibitor of BCR::ABL1 kinase activity, is now approved for the treatment of patients with chronic-phase chronic myeloid leukemia who failed 2 lines of therapy or in patients with the T315I mutation. Promising attributes include high specificity and potency against BCR::ABL1, activity against most kinase domain mutations, and potential for combination therapy with ATP-competitive tyrosine kinase inhibitors. Clinicians now have expanded third-line options, which in most cases will involve a choice between asciminib and ponatinib.
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Antineoplásicos , Leucemia Mielógena Crónica BCR-ABL Positiva , Leucemia Mieloide de Fase Crónica , Antineoplásicos/farmacología , Resistencia a Antineoplásicos , Proteínas de Fusión bcr-abl/genética , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Mutación , Niacinamida/análogos & derivados , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazoles , Insuficiencia del TratamientoRESUMEN
Chronic myeloid leukemia (CML) is a model of genomically based diagnosis and management where BCR::ABL1 is successfully targeted by tyrosine kinase inhibitor (TKI) therapy in most patients. The dynamics of BCR::ABL1 transcript decline during therapy is a dependable biomarker of response, relapse, and drug resistance. Missense mutations acquired within the BCR::ABL1 kinase domain that disrupt TKI binding can evolve during therapy and are frequently detected in patients for whom TKI treatment fails. Importantly, specific BCR::ABL1 missense mutations are targetable alterations and direct therapeutic decisions based on the individual mutant TKI sensitivity profile. Nevertheless, BCR::ABL1 mutations are only implicated in approximately half of the cases of acquired resistance. Furthermore, not all patients with a single BCR::ABL1 mutation that is predicted to be sensitive to a specific TKI will experience a response when switched to that TKI. Progression to blast phase heralds independence from BCR::ABL1, and this phase of the disease is notoriously difficult to treat. The independent drivers of resistance and disease progression have long been investigated to both predict progression and to find targets for therapeutic intervention. Recent data reaffirm that drug resistance and disease progression is a mutation-driven process in CML, and somatic variants in genes that are known to drive acute myeloid and lymphoid leukemia have been detected in patients in the advanced phases of CML. Genomic testing over the last few decades for patients with blood cancer has revealed of variety of genomic aberrations that drive disease. Consequently, incorporation of genomic factors into patient management for a range of blood cancers has led to the implementation of high-throughput gene testing to detect clinically actionable variants. Is it time to integrate broader genomic screening into clinical management strategies for patients with CML?
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Proteínas de Fusión bcr-abl , Leucemia Mielógena Crónica BCR-ABL Positiva , Humanos , Proteínas de Fusión bcr-abl/genética , Resistencia a Antineoplásicos/genética , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Genómica , Progresión de la EnfermedadRESUMEN
Asciminib is a novel allosteric STAMP (specifically targets the ABL myristoyl pocket) inhibitor of the BCR::ABL1 oncogene. Real-world clinical outcomes of patients with tyrosine kinase inhibitor (TKI)-resistant/intolerant chronic myeloid leukaemia (CML) in Australia on the Managed Access Programme for asciminib showed higher molecular responses for those with intolerance versus resistance ± intolerance to their last TKI. There remains a clinical need to improve outcomes in patients with CML who have resistance to multiple TKIs, especially in the ponatinib-pretreated cohort.
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Leucemia Mielógena Crónica BCR-ABL Positiva , Inhibidores de Proteínas Quinasas , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Australia , Masculino , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/uso terapéutico , Femenino , Resultado del Tratamiento , Anciano , Adulto , Resistencia a Antineoplásicos , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Antineoplásicos/uso terapéutico , Piridazinas/uso terapéutico , Anciano de 80 o más Años , Niacinamida/análogos & derivados , PirazolesRESUMEN
With treatment-free remission (TFR) rapidly becoming the ultimate goal of therapy in chronic myeloid leukemia (CML), there is a need to develop strategies to maximize sustained TFR by improving our understanding of its key determinants. Chronic-phase CML patients attempting TFR were evaluated to identify the impact of multiple variables on the probability of sustained TFR. Early molecular response dynamics were included as a predictive variable, assessed by calculating the patient-specific halving time of BCR-ABL1 after commencing tyrosine kinase inhibitor (TKI) therapy. Overall, 115 patients attempted TFR and had ≥12 months of follow-up. The probability of sustained TFR, defined as remaining in major molecular response off TKI therapy for 12 months, was 55%. The time taken for the BCR-ABL1 value to halve was the strongest independent predictor of sustained TFR: 80% in patients with a halving time of <9.35 days (first quartile) compared with only 4% if the halving time was >21.85 days (last quartile) (P < .001). The e14a2 BCR-ABL1 transcript type and duration of TKI exposure before attempting TFR were also independent predictors of sustained TFR. However, the BCR-ABL1 value measured at 3 months of TKI was not an independent predictor of sustained TFR. A more rapid initial BCR-ABL1 decline after commencing TKI also correlated with an increased likelihood of achieving TFR eligibility. The association between sustained TFR and the time taken for BCR-ABL1 to halve after commencing TKI was validated using an independent dataset. These data support the critical importance of the initial kinetics of BCR-ABL1 decline for long-term outcomes.
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Proteínas de Fusión bcr-abl/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
The BCR::ABL1 gene fusion initiates chronic myeloid leukemia (CML); however, evidence has accumulated from studies of highly selected cohorts that variants in other cancer-related genes are associated with treatment failure. Nevertheless, the true incidence and impact of additional genetic abnormalities (AGA) at diagnosis of chronic phase (CP)-CML is unknown. We sought to determine whether AGA at diagnosis in a consecutive imatinib-treated cohort of 210 patients enrolled in the TIDEL-II trial influenced outcome despite a highly proactive treatment intervention strategy. Survival outcomes including overall survival, progression-free survival, failure-free survival, and BCR::ABL1 kinase domain mutation acquisition were evaluated. Molecular outcomes were measured at a central laboratory and included major molecular response (MMR, BCR::ABL1 ≤0.1%IS), MR4 (BCR::ABL1 ≤0.01%IS), and MR4.5 (BCR::ABL1 ≤0.0032%IS). AGA included variants in known cancer genes and novel rearrangements involving the formation of the Philadelphia chromosome. Clinical outcomes and molecular response were assessed based on the patient's genetic profile and other baseline factors. AGA were identified in 31% of patients. Potentially pathogenic variants in cancer-related genes were detected in 16% of patients at diagnosis (including gene fusions and deletions) and structural rearrangements involving the Philadelphia chromosome (Ph-associated rearrangements) were detected in 18%. Multivariable analysis demonstrated that the combined genetic abnormalities plus the EUTOS long-term survival clinical risk score were independent predictors of lower molecular response rates and higher treatment failure. Despite a highly proactive treatment intervention strategy, first-line imatinib-treated patients with AGA had poorer response rates. These data provide evidence for the incorporation of genomically-based risk assessment for CML.
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Antineoplásicos , Leucemia Mielógena Crónica BCR-ABL Positiva , Leucemia Mieloide de Fase Crónica , Humanos , Mesilato de Imatinib/uso terapéutico , Antineoplásicos/uso terapéutico , Cromosoma Filadelfia , Proteínas de Fusión bcr-abl/genética , Proteínas de Fusión bcr-abl/metabolismo , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
With the focus of leukaemia management shifting to the implications of low-level disease burden, increasing attention is being paid on the development of highly sensitive methodologies required for detection. There are various techniques capable of identification of measurable residual disease (MRD) either evidencing as relevant mutation detection [e.g. nucleophosmin 1 (NPM1) mutation] or trace levels of leukaemic clonal populations. The vast majority of these methods only permit detection of a single clone or mutation. However, mass spectrometry and next-generation sequencing enable the interrogation of multiple genes simultaneously, facilitating a more complete genomic profile. In the present review, we explore the methodologies of both techniques in conjunction with the important advantages and limitations associated with each assay. We also highlight the evidence and the various instances where either technique has been used and propose future strategies for MRD detection.
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Biomarcadores de Tumor , Análisis Mutacional de ADN/métodos , Leucemia/diagnóstico , Leucemia/etiología , Mutación , Neoplasia Residual/diagnóstico , Análisis Costo-Beneficio , Análisis Mutacional de ADN/economía , Análisis Mutacional de ADN/normas , Secuenciación de Nucleótidos de Alto Rendimiento/economía , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Secuenciación de Nucleótidos de Alto Rendimiento/normas , Humanos , Espectrometría de Masas/métodos , Espectrometría de Masas/normas , Tasa de Mutación , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
Recent approval of asciminib, a novel "specifically targeting the ABL myristoyl pocket" (STAMP) BCR-ABL1 inhibitor, for the treatment of chronic myeloid leukaemia (CML) patients who have either failed ≥2 lines of therapy or have the T315I mutation, has provided clinicians with a wider selection of potentially effective treatment options. Asciminib has the attractive twin attributes of high potency directed against BCR-ABL1 and good tolerability based on its limited off-target effects. However, it is unclear exactly where asciminib will be positioned amongst the other available tyrosine kinase inhibitors (TKIs), especially ponatinib which is also available for the same indications. There are many questions yet to be answered with regard to the optimal use of asciminib which include its role in the first- and second-line settings, combination therapy with other TKIs, and effectiveness in advanced phase CML. In this review, we discuss the available data on asciminib while exploring a number of clinical trials in progress. Finally, we provide our opinion based on the current data about where asciminib is most likely to be the optimal choice, which will hopefully assist clinicians with therapy selection.
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Antineoplásicos , Leucemia Mielógena Crónica BCR-ABL Positiva , Humanos , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Resistencia a Antineoplásicos/genética , Mutación , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Proteínas de Fusión bcr-abl/genética , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacologíaRESUMEN
There is currently no biomarker that reliably predicts treatment-free remission (TFR) in chronic myeloid leukaemia (CML). We characterised effector and suppressor immune responses at the time of tyrosine kinase inhibitor (TKI) cessation in patients from the CML8 and CML10 clinical studies. Natural killer (NK) cells with increased expression of activating NK receptors were higher in patients who achieved TFR. There was no difference in the proportion of CD4+ or CD8+ T cells. Furthermore, we found that FoxP3+ regulatory T cells (T reg) and monocytic myeloid-derived suppressor cells (Mo-MDSCs) were concomitantly decreased in TFR patients, suggesting that the effector and suppressor arms of the immune system work in concert to mediate TFR. A discovery cohort (CML10) was used to generate a predictive model, using logistic regression. Patients classified into the high-risk group were more likely to relapse when compared with the low-risk group (HR 7·4, 95% CI 2·9-19·1). The model was successfully validated on the independent CML8 cohort (HR 8·3, 95% CI 2·2-31·3). Effective prediction of TFR success may be obtained with an effector-suppressor score, calculated using absolute NK cell, T reg, and Mo-MDSC counts, at TKI cessation, reflecting the contribution of both immune suppressors and effectors in the immunobiology underlying successful TFR.
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Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Leucemia Mielógena Crónica BCR-ABL Positiva/inmunología , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Células Supresoras de Origen Mieloide/inmunología , Células Supresoras de Origen Mieloide/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/efectos adversos , Antineoplásicos Inmunológicos/uso terapéutico , Biomarcadores , Femenino , Humanos , Inmunomodulación/efectos de los fármacos , Células Asesinas Naturales/efectos de los fármacos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/mortalidad , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Células Supresoras de Origen Mieloide/efectos de los fármacos , Pronóstico , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/uso terapéutico , Receptores de Células Asesinas Naturales/genética , Receptores de Células Asesinas Naturales/metabolismo , Recurrencia , Inducción de Remisión , Resultado del TratamientoRESUMEN
With the advent of tyrosine kinase inhibitors (TKIs), the goals of therapy in chronic myeloid leukemia (CML) are steadily shifting. Long-term disease control on TKI therapy has been the goal and expectation for most patients. More recently, treatment-free remission (TFR) has entered mainstream practice and is increasingly being adopted as the main goal of therapy. This therapeutic shift not only influences TKI selection but also, has necessitated the refinement and dissemination of highly sensitive and accurate molecular monitoring techniques. Measurement of BCR-ABL1 messenger RNA expression through reverse transcription quantitative polymerase chain reaction, reported according to the International Scale, has become the primary tool for response assessment in CML. Achieving specific time-dependent molecular milestones, as defined by global therapeutic guidelines, has been established as critical in maximizing optimal outcomes while identifying patients at risk of therapy failure. Depth and duration of a deep molecular response have become the new therapeutic targets in patients considered for TFR. Consequently, molecular monitoring in CML has become even more critical to ongoing response assessment, identifying patients with TKI resistance and poor drug adherence, and enabling TFR to be attempted safely and effectively.
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Antineoplásicos/uso terapéutico , Proteínas de Fusión bcr-abl/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , ARN Mensajero/genética , Adulto , Antineoplásicos/farmacología , Monitoreo de Drogas/métodos , Femenino , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida/métodos , Inhibidores de Proteínas Quinasas/farmacologíaRESUMEN
Genomic events associated with poor outcome in chronic myeloid leukemia (CML) are poorly understood. We performed whole-exome sequencing, copy-number variation, and/or RNA sequencing for 65 patients to discover mutations at diagnosis and blast crisis (BC). Forty-six patients with chronic-phase disease with the extremes of outcome were studied at diagnosis. Cancer gene variants were detected in 15 (56%) of 27 patients with subsequent BC or poor outcome and in 3 (16%) of 19 optimal responders (P = .007). Frequently mutated genes at diagnosis were ASXL1, IKZF1, and RUNX1 The methyltransferase SETD1B was a novel recurrently mutated gene. A novel class of variant associated with the Philadelphia (Ph) translocation was detected at diagnosis in 11 (24%) of 46 patients comprising fusions and/or rearrangement of genes on the translocated chromosomes, with evidence of fragmentation, inversion, and imperfect sequence reassembly. These were more frequent at diagnosis in patients with poor outcome: 9 (33%) of 27 vs 2 (11%) of 19 optimal responders (P = .07). Thirty-nine patients were tested at BC, and all had cancer gene variants, including ABL1 kinase domain mutations in 58%. However, ABL1 mutations cooccurred with other mutated cancer genes in 89% of cases, and these predated ABL1 mutations in 62% of evaluable patients. Gene fusions not associated with the Ph translocation occurred in 42% of patients at BC and commonly involved fusion partners that were known cancer genes (78%). Genomic analysis revealed numerous relevant variants at diagnosis in patients with poor outcome and all patients at BC. Future refined biomarker testing of specific variants will likely provide prognostic information to facilitate a risk-adapted therapeutic approach.
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Biomarcadores de Tumor/genética , Genómica , Leucemia Mielógena Crónica BCR-ABL Positiva , Proteínas de Neoplasias/genética , Cromosoma Filadelfia , Translocación Genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/mortalidad , Masculino , Persona de Mediana Edad , Factores de Riesgo , Tasa de SupervivenciaAsunto(s)
Leucemia Mielógena Crónica BCR-ABL Positiva , Proteínas de Fusión bcr-abl/genética , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Reacción en Cadena de la Polimerasa , Probabilidad , Inhibidores de Proteínas Quinasas , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
OBJECTIVES: This study describes the safety, clinical effectiveness and trough plasma concentration (Cmin) of intravenous (iv) posaconazole, provided as part of Merck Sharp and Dohme Australia's Named Patient Programme (NPP) in non-clinical trial settings. METHODS: A multicentre, retrospective study on the NPP use of iv posaconazole between July 2014 and March 2015 across seven Australian hospitals. RESULTS: Seventy courses of iv posaconazole were prescribed and evaluated in 61 patients receiving treatment for haematological malignancy. Sixty-one courses were prescribed for prophylaxis against invasive fungal disease (IFD), the majority of which (59) were initiated in patients with gastrointestinal disturbances and/or intolerance to previous antifungals. The median (IQR) duration for prophylaxis was 10 (6-15) days. No breakthrough IFD was observed during or at cessation of iv posaconazole. Nine courses of iv posaconazole were prescribed for treatment of IFD with a median (IQR) duration of 19 (7-30) days. Improvement in signs and symptoms of IFD was observed in five cases at cessation of, and six cases at 30 days post-iv posaconazole. Cmin was measured in 39 courses of iv posaconazole, with the initial level taken [median (IQR)] 4 (3-7) days after commencing iv posaconazole. The median (IQR) of initial Cmin was 1.16 (0.69-2.06) mg/L. No severe adverse events specifically attributed to iv posaconazole were documented, although six courses were curtailed due to potential toxicity. CONCLUSIONS: This non-clinical trial experience suggests that iv posaconazole appeared to be safe and clinically effective for prophylaxis or treatment of IFD in patients receiving treatment for haematological malignancies.
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Antifúngicos/efectos adversos , Antifúngicos/farmacocinética , Quimioprevención/métodos , Micosis/tratamiento farmacológico , Micosis/prevención & control , Triazoles/efectos adversos , Triazoles/farmacocinética , Administración Intravenosa , Adulto , Antifúngicos/administración & dosificación , Australia , Quimioprevención/efectos adversos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Femenino , Neoplasias Hematológicas/complicaciones , Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas , Humanos , Masculino , Persona de Mediana Edad , Plasma/química , Estudios Retrospectivos , Trasplante Homólogo , Resultado del Tratamiento , Triazoles/administración & dosificaciónAsunto(s)
Algoritmos , Proteínas de Fusión bcr-abl/análisis , Pruebas Genéticas/normas , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Recurrencia Local de Neoplasia/diagnóstico , Antineoplásicos/uso terapéutico , Proteínas de Fusión bcr-abl/genética , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , Inducción de RemisiónRESUMEN
Despite the dramatic improvements in outcomes for the majority of chronic myeloid leukemia (CML) patients over the past 2 decades, a similar improvement has not been observed in the more advanced stages of the disease. Blast phase CML (BP-CML), although infrequent, remains poorly understood and inadequately treated. Consequently, the key initial goal of therapy in a newly diagnosed patient with chronic phase CML continues to be prevention of disease progression. Advances in genomic investigation in CML, specifically related to BP-CML, clearly demonstrate we have only scratched the surface in our understanding of the disease biology, a prerequisite to devising more targeted and effective therapeutic approaches to prevention and treatment. Importantly, the introduction of the concept of "CML-like" acute lymphoblastic leukemia (ALL) has the potential to simplify the differentiation between BCR::ABL1-positive ALL from de novo lymphoid BP-CML, optimizing monitoring and therapeutics. The development of novel treatment strategies such as the MATCHPOINT approach for BP-CML, utilizing combination chemotherapy with fludarabine, cytarabine, and idarubicin in addition to dose-modified ponatinib, may also be an important step in improving treatment outcomes. However, identifying patients who are high risk of transformation remains a challenge, and the recent 2022 updates to the international guidelines may add further confusion to this area. Further work is required to clarify the identification and treatment strategy for the patients who require a more aggressive approach than standard chronic phase CML management.
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Leucemia Mielógena Crónica BCR-ABL Positiva , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Crisis Blástica/terapia , Crisis Blástica/diagnóstico , Resultado del Tratamiento , Progresión de la Enfermedad , Leucemia-Linfoma Linfoblástico de Células Precursoras/genéticaRESUMEN
Variability in the molecular response to frontline tyrosine kinase inhibitor (TKI) therapy in chronic myeloid leukemia may be partially driven by differences in the level of kinase inhibition induced. We measured in vivo BCR::ABL1 kinase inhibition (IVKI) in circulating mononuclear cells after 7 days of therapy. In 173 patients on imatinib 600 mg/day, 23% had low IVKI (<11% reduction in kinase activity from baseline); this was associated with higher rates of early molecular response (EMR) failure; lower rates of major molecular response (MMR), and MR4.5 by 36 months, compared to high IVKI patients. Low IVKI was more common (39%) in patients with large spleens (≥10 cm by palpation). Notably 55% of patients with large spleens and low IVKI experienced EMR failure whereas the EMR failure rate in patients with large spleens and high IVKI was only 12% (p = 0.014). Furthermore, patients with large spleen and low IVKI had a higher incidence of blast crisis, inferior MMR, MR4.5, and event-free survival compared to patients with large spleen and high IVKI and remaining patients. In nilotinib-treated patients (n = 73), only 4% had low IVKI. The combination of low IVKI and large spleen is associated with markedly inferior outcomes and interventions in this setting warrant further studies.
Asunto(s)
Leucemia Mielógena Crónica BCR-ABL Positiva , Leucemia Mieloide , Humanos , Esplenomegalia/tratamiento farmacológico , Esplenomegalia/etiología , Mesilato de Imatinib/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Crisis BlásticaRESUMEN
Dysregulation of immune-checkpoint receptors has been reported at diagnosis of chronic myeloid leukemia (CML), however, their role in the maintenance of remission after tyrosine kinase inhibitor (TKI) cessation is unclear. We assessed programmed cell death-1 (PD-1), T-cell immunoglobulin, and mucin-domain containing protein-3 (TIM-3), cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), lymphocyte-activation gene-3 (LAG-3), and T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domains (TIGIT) expression on T-cell subsets, regulatory T cells (T-regs), and natural killer (NK) cells at the time of TKI cessation in 44 patients (22 patients sustained treatment-free remission [TFR] and 22 experienced molecular relapse [MolR]). We confirmed our previous finding that absolute numbers of T-regs are increased in patients who experienced MolR compared with those who sustained TFR. The immune-checkpoint receptors PD-1, CTLA-4, LAG-3, and TIGIT on T or NK cells were not differentially expressed between the MolR and TFR groups. However, TIM-3 was consistently upregulated on bulk T cells (CD3+) and T-cell subsets including, CD4+ T cells, CD8+ T cells, and T-regs, in patients who relapsed in comparison with those who maintained TFR after discontinuation. Furthermore, gene expression analysis from publicly available data sets showed increased TIM-3 expression on CML stem cells compared with normal hematopoietic stem cells. These findings suggest that among the targetable immune-checkpoint molecules, TIM-3 blockade may potentially improve effector immune response in patients with CML stopping TKI, while concomitantly targeting leukemic stem cells and could be a promising therapeutic strategy for preventing relapse after cessation of TKI in patients with CML.