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1.
Lancet Oncol ; 25(8): e340-e351, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-39089312

RESUMEN

Historically, dose selection of anticancer drugs has mainly been based on establishing the maximum tolerated dose in phase 1 clinical trials with a traditional 3 plus 3 design. In the era of targeted therapies and immune-modulating agents, this approach does not necessarily lead to selection of the most favourable dose. This strategy can introduce potentially avoidable toxicity or inconvenience for patients. Multiple changes in drug development could lead to more rational dose selection, such as use of better predictive preclinical models, adaptive and randomised trial design, evaluation of multiple dose levels in late-phase development, assessment of target activity and saturation, and early biomarker use for efficacy and safety evaluation. In this Review, we evaluate the rationale and validation of dose selection in each phase of drug development for anticancer drugs approved by the European Medicines Agency and US Food and Drug Administration from Jan 1, 2020, to June 30, 2023, and give recommendations for dose optimisation to improve safety and patient convenience. In our evaluation, we classified 20 (65%) of the 31 recently registered anticancer agents as potential candidates for dose optimisation, which could be achieved either by reducing the dose (n=10 [32%]) or adjusting the dosage regimen (n=10 [32%]). Dose selection seemed to be adequately justified for nine (29%) of the drugs, whereas the reviewed data were inconclusive for formulating a recommendation on dose optimisation for two (6%) of the drugs.


Asunto(s)
Antineoplásicos , Dosis Máxima Tolerada , Neoplasias , Humanos , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Neoplasias/tratamiento farmacológico , Desarrollo de Medicamentos , Relación Dosis-Respuesta a Droga
2.
Ann Hematol ; 2024 Aug 12.
Artículo en Inglés | MEDLINE | ID: mdl-39129028

RESUMEN

Bariatric surgery is increasingly performed to treat severe obesity. As a result of anatomical and physiological changes in the gastrointestinal tract, the pharmacokinetics (PK) of oral drugs can be altered, affecting their efficacy and safety. This includes the class of tyrosine kinase inhibitors (TKIs) which are used to treat chronic myeloid leukemia (CML). This case series describes the clinical course of four CML cases with a history of bariatric surgery. The patients used various TKIs (nilotinib, dasatinib, bosutinib, ponatinib, and imatinib) for which 15 drug levels were measured. The measured TKI concentrations were in part subtherapeutic, and highly variable when compared to mean levels measured in the general population. Multiple drug levels were measured in these patients, as the clinicians were aware of the possible impact of bariatric surgery. The drug levels were used as additional input for clinical decision-making. All four patients required TKI switches and/or dose modifications to achieve an effective and tolerable treatment. Eventually, adequate clinical and molecular remissions were achieved in all cases. In summary, TKI concentrations of patients undergoing bariatric surgery may be subtherapeutic. Moreover, there is substantial interindividual and intraindividual variation, which may be explained by the complex interference of bariatric surgery and associated weight loss. For clinical practice, therapeutic drug monitoring is advised in patients with a history of bariatric surgery in case of suboptimal response or loss of response.

3.
Eur J Haematol ; 2024 Jul 12.
Artículo en Inglés | MEDLINE | ID: mdl-38994654

RESUMEN

Precise and reliable predictive parameters to accurately identify chronic myeloid leukemia (CML) patients who can successfully discontinue their tyrosine kinase inhibitor (TKI) treatment are lacking. One promising parameter is depth of molecular response measured by BCR::ABL1 digital PCR (dPCR). The aim of this study was to validate a previously described prediction cutoff of 0.0023%IS and to assess the value of dPCR for treatment-free remission (TFR) prediction in relation to other clinical parameters. A droplet-based dPCR assay assessed BCR::ABL1 %IS prior to TKI discontinuation. The primary endpoint was molecular recurrence (MolR) by 36 months. A total of 186 patients from Canada, Germany, and the Netherlands were included. In patients with a first TKI discontinuation attempt (n = 163), a BCR::ABL1 dPCR < and ≥0.0023%IS had a MolR probability of 33% and 70%, respectively. Patients treated less than 6 years with a BCR::ABL1 dPCR <0.0023%IS had a MolR probability of 31%. After correction for treatment duration, both high dPCR value and the use of imatinib (vs. second-generation TKI) were significantly associated with a higher risk of MolR (HR of 3.66, 95%CI 2.06-6.51, p < .001; and 2.85, 95%CI 1.25-6.46, p = .013, respectively). BCR::ABL1 dPCR was not associated with TFR outcome after second TKI discontinuation, however, with the limitation of a small number of patients analyzed (n = 23). In conclusion, BCR::ABL1 digital PCR based on the cutoff of 0.0023%IS is a valuable predictive tool to identify CML patients with a high probability of TFR success after first TKI discontinuation, including patients treated for less than 6 years.

4.
Am J Hematol ; 99(2): E32-E36, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37994196

RESUMEN

The safety and efficacy of sabatolimab, a novel immunotherapy targeting T-cell immunoglobulin domain and mucin domain-3 (TIM-3), was assessed in combination with hypomethylating agents (HMAs) in patients with HMA-naive revised International Prognostic System Score (IPSS-R) high- or very high-risk myelodysplastic syndromes (HR/vHR-MDS) or chronic myelomonocytic leukemia (CMML). Sabatolimab + HMA had a safety profile similar to that reported for HMA alone and demonstrated durable clinical responses in patients with HR/vHR-MDS. These results support the ongoing evaluation of sabatolimab-based combination therapy in MDS, CMML, and acute myeloid leukemia.


Asunto(s)
Anticuerpos Monoclonales , Leucemia Mieloide Aguda , Leucemia Mielomonocítica Crónica , Síndromes Mielodisplásicos , Humanos , Azacitidina/uso terapéutico , Decitabina/uso terapéutico , Antimetabolitos Antineoplásicos/uso terapéutico , Síndromes Mielodisplásicos/tratamiento farmacológico , Receptor 2 Celular del Virus de la Hepatitis A/uso terapéutico , Leucemia Mielomonocítica Crónica/tratamiento farmacológico , Leucemia Mieloide Aguda/tratamiento farmacológico , Anticuerpos/uso terapéutico , Resultado del Tratamiento
5.
Support Care Cancer ; 32(9): 579, 2024 Aug 08.
Artículo en Inglés | MEDLINE | ID: mdl-39115709

RESUMEN

PURPOSE: Haematology patients with high-risk neutropenia are prone to mucosal-barrier injury-associated laboratory-confirmed bloodstream infections (MBI-LCBI). We assessed risk factors for MBI-LCBI including candidaemia in neutropenic haematology patients with fever. METHODS: This prospective observational study was performed in six dedicated haematology units in the Netherlands. Eligible haematology patients had neutropenia < 500/mL for ≥ 7 days and had fever. MBI-LCBIs were classified according to Centers for Disease Control (CDC) definitions and were followed until the end of neutropenia > 500/mL or discharge. RESULTS: We included 416 patients from December 2014 until August 2019. We observed 63 MBI-LCBIs. Neither clinical mucositis scores nor the blood level of citrulline at fever onset was associated with MBI-LCBI. In the multivariable analysis, MASCC-score (odds ratio [OR] 1.16, 95% confidence interval [CI] 1.05 to 1.29 per point decrease), intensive chemotherapy (OR 3·81, 95% CI 2.10 to 6.90) and Pichia kudriavzevii (formerly Candida krusei) colonisation (OR 5.40, 95% CI 1.75 to 16.7) were retained as risk factors for MBI-LCBI, while quinolone use seemed protective (OR 0.42, 95% CI 0.20 to 0.92). Citrulline level (OR 1.57, 95% CI 1.07 to 2.31 per µmol/L decrease), active chronic obstructive pulmonary disease (OR 15.4, 95% CI 1.61 to 14.7) and colonisation with fluconazole-resistant Candida (OR 8.54, 95% CI 1.51 to 48.4) were associated with candidaemia. CONCLUSION: In haematology patients with fever during neutropenia, hypocitrullinaemia at fever onset was associated with candidaemia, but not with bacterial MBI-LCBI. Patients with intensive chemotherapy with a low MASCC-score and colonisation with Pichia kudriavzevii had the highest risk of MBI-LCBI. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02149329) at 19-NOV-2014.


Asunto(s)
Fiebre , Mucositis , Neutropenia , Humanos , Masculino , Femenino , Estudios Prospectivos , Persona de Mediana Edad , Factores de Riesgo , Mucositis/etiología , Neutropenia/etiología , Neutropenia/complicaciones , Anciano , Fiebre/etiología , Adulto , Países Bajos , Índice de Severidad de la Enfermedad , Candidemia/etiología , Candidemia/epidemiología , Neoplasias Hematológicas/complicaciones
6.
Clin Infect Dis ; 77(1): 38-45, 2023 07 05.
Artículo en Inglés | MEDLINE | ID: mdl-36905147

RESUMEN

BACKGROUND: Invasive aspergillosis (IA) by a triazole-resistant Aspergillus fumigatus is associated with high mortality. Real-time resistance detection will result in earlier initiation of appropriate therapy. METHODS: In a prospective study, we evaluated the clinical value of the AsperGenius polymerase chain reaction (PCR) assay in hematology patients from 12 centers. This PCR assay detects the most frequent cyp51A mutations in A. fumigatus conferring azole resistance. Patients were included when a computed tomography scan showed a pulmonary infiltrate and bronchoalveolar fluid (BALf) sampling was performed. The primary end point was antifungal treatment failure in patients with azole-resistant IA. RESULTS: Of 323 patients enrolled, complete mycological and radiological information was available for 276 (94%), and probable IA was diagnosed in 99/276 (36%). Sufficient BALf for PCR testing was available for 293/323 (91%). Aspergillus DNA was detected in 116/293 (40%) and A. fumigatus DNA in 89/293 (30%). The resistance PCR was conclusive in 58/89 (65%) and resistance detected in 8/58 (14%). Two had a mixed azole-susceptible/azole-resistant infection. In the 6 remaining patients, treatment failure was observed in 1. Galactomannan positivity was associated with mortality (P = .004) while an isolated positive Aspergillus PCR was not (P = .83). CONCLUSIONS: Real-time PCR-based resistance testing may help to limit the clinical impact of triazole resistance. In contrast, the clinical impact of an isolated positive Aspergillus PCR on BALf seems limited. The interpretation of the EORTC/MSGERC PCR criterion for BALf may need further specification (eg, minimum cycle threshold value and/or PCR positive on >1 BALf sample).


Asunto(s)
Aspergilosis , Infecciones Fúngicas Invasoras , Aspergilosis Pulmonar Invasiva , Humanos , Estudios Prospectivos , Aspergilosis Pulmonar Invasiva/diagnóstico , Aspergilosis Pulmonar Invasiva/tratamiento farmacológico , Aspergilosis Pulmonar Invasiva/microbiología , Azoles/farmacología , Azoles/uso terapéutico , Aspergilosis/diagnóstico , Aspergilosis/tratamiento farmacológico , Aspergilosis/microbiología , Aspergillus , Aspergillus fumigatus , Infecciones Fúngicas Invasoras/diagnóstico , Infecciones Fúngicas Invasoras/tratamiento farmacológico , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Triazoles/farmacología , Triazoles/uso terapéutico , Antifúngicos/farmacología , Antifúngicos/uso terapéutico , Farmacorresistencia Fúngica
7.
Ann Hematol ; 102(6): 1395-1408, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-37119314

RESUMEN

In order to improve molecular response for a discontinuation attempt in chronic myeloid leukemia (CML) patients in chronic phase, who had not achieved at least a molecular response <0.01% BCR-ABL1IS (MR4.0) after at least 2 years of imatinib therapy, we prospectively evaluated whether they could attain MR4.0 after a switch to a combination of nilotinib and 9 months of pegylated interferon-α2b (PegIFN). The primary endpoint of confirmed MR4.0 at month 12 (a BCR-ABL1IS level ≤ 0.01% both at 12 and 15 months) was reached by 44% (7/16 patients, 95% confidence interval (CI): 23- 67%) of patients, with 81% (13/16 patients, 95% CI: 57-93%) of patients achieving an unconfirmed MR4.0. The scheduled combination was completed by 56% of the patients, with premature discontinuations, mainly due to mood disturbances after the introduction of PegIFN, questioning the feasibility of the combination of nilotinib and PegIFN for this patient population and treatment goal. A comprehensive clinical substudy program was implemented to characterize the impact of the treatment changes on the immunological profile. This trial was registered at www.clinicaltrials.gov as #NCT01866553.


Asunto(s)
Leucemia Mieloide de Fase Crónica , Inhibidores de Proteínas Quinasas , Humanos , Proteínas de Fusión bcr-abl/genética , Mesilato de Imatinib/uso terapéutico , Interferón-alfa/uso terapéutico , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Polietilenglicoles/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Resultado del Tratamiento
8.
Eur J Haematol ; 111(6): 938-945, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37731314

RESUMEN

OBJECTIVES: Acquired missense mutations in the BCR::ABL1 kinase domain (KD) may cause tyrosine kinase inhibitor (TKI) treatment failure. Based on mutation-specific in vitro derived IC50-values, alternative TKI may be selected. We assessed clinical practice of BCR::ABL1 KD mutation testing, clinical response in relation to IC50-values, and clinical outcome of tested patients. METHODS: Patients from six Dutch CML reference centers and a national registry were included once a mutational analysis was performed. Reasons for testing were categorized as suboptimal TKI response, and primary or secondary TKI resistance. RESULTS: Four hundred twenty analyses were performed in 275 patients. Sixty-nine patients harbored at least one mutation. Most analyses were performed because of suboptimal TKI response but with low mutation incidence (4%), while most mutations were found in primary and secondary resistant patients (21% and 51%, respectively). Harboring a BCR::ABL1 mutation was associated with inferior overall survival (HR 3.2 [95% CI, 1.7-6.1; p < .001]). Clinically observed responses to TKI usually corresponded with the predicted TKI sensitivity based on the IC50-values, but a high IC50-value did not preclude a good clinical response per se. CONCLUSIONS: We recommend BCR::ABL1 KD mutation testing in particular in the context of primary or secondary resistance. IC50-values can direct the TKI choice for CML patients, but clinical efficacy can be seen despite adverse in vitro resistance.


Asunto(s)
Proteínas de Fusión bcr-abl , Leucemia Mielógena Crónica BCR-ABL Positiva , Humanos , Proteínas de Fusión bcr-abl/genética , Resistencia a Antineoplásicos/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Mutación , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología
9.
Br J Haematol ; 196(2): 329-335, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34632583

RESUMEN

Most patients with myelodysplastic syndromes (MDS) require therapeutic intervention. However, there are few approved treatments for MDS. To explore reasons, we searched clinicaltrials.gov and clinicaltrialsregister.eu for MDS trials from 2000 to 2020. We assessed which agents were under investigation and analysed clinical trial characteristics and continuation rates from phase I to II to III to approval. As such, we identified 384 unique agents in 426 phase I, 430 phase II and 48 phase III trials. Success rates for phase III trials and agents were low, and MDS trials took markedly longer to complete than the average clinical trial. Although success rates were higher when MDS-specific phase I trials were conducted, 52% of the agents had not been evaluated in a phase I trial for MDS. MDS trials often failed to include quality of life, an especially important outcome for older MDS patients. Our work identifies factors potentially contributing to the paucity of available agents for MDS. We suggest a framework to improve clinical research in MDS that might ultimately augment the number of available agents.


Asunto(s)
Síndromes Mielodisplásicos/terapia , Toma de Decisiones Clínicas , Ensayos Clínicos como Asunto , Terapia Combinada , Manejo de la Enfermedad , Progresión de la Enfermedad , Humanos , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/etiología , Pronóstico , Resultado del Tratamiento
10.
Br J Haematol ; 196(5): 1219-1224, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-34865221

RESUMEN

Studies on the conditional life expectancy of patients with chronic myeloid leukaemia (CML) are lacking. Using data from the Netherlands Cancer Registry, we examined the life expectancy of patients with CML in the Netherlands diagnosed during 1989-2018. As of the early 2010s, the life expectancy of patients with CML who survived several years after diagnosis came narrowly close to the general population's life expectancy, regardless of age. This finding can essentially be ascribed to the introduction and broader application of tyrosine kinase inhibitors (TKIs) and provide optimism to patients with CML who can look forward to a near-normal life expectancy in a modern TKI era.


Asunto(s)
Leucemia Mielógena Crónica BCR-ABL Positiva/epidemiología , Adulto , Femenino , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Esperanza de Vida , Masculino , Persona de Mediana Edad , Países Bajos/epidemiología , Inhibidores de Proteínas Quinasas/uso terapéutico , Análisis de Supervivencia
11.
N Engl J Med ; 381(24): 2315-2326, 2019 12 12.
Artículo en Inglés | MEDLINE | ID: mdl-31826340

RESUMEN

BACKGROUND: Asciminib is an allosteric inhibitor that binds a myristoyl site of the BCR-ABL1 protein, locking BCR-ABL1 into an inactive conformation through a mechanism distinct from those for all other ABL kinase inhibitors. Asciminib targets both native and mutated BCR-ABL1, including the gatekeeper T315I mutant. The safety and antileukemic activity of asciminib in patients with Philadelphia chromosome-positive leukemia are unknown. METHODS: In this phase 1, dose-escalation study, we enrolled 141 patients with chronic-phase and 9 with accelerated-phase chronic myeloid leukemia (CML) who had resistance to or unacceptable side effects from at least two previous ATP-competitive tyrosine kinase inhibitors (TKIs). The primary objective was to determine the maximum tolerated dose or the recommended dose (or both) of asciminib. Asciminib was administered once or twice daily (at doses of 10 to 200 mg). The median follow-up was 14 months. RESULTS: Patients were heavily pretreated; 70% (105 of 150 patients) had received at least three TKIs. The maximum tolerated dose of asciminib was not reached. Among patients with chronic-phase CML, 34 (92%) with a hematologic relapse had a complete hematologic response; 31 (54%) without a complete cytogenetic response at baseline had a complete cytogenetic response. A major molecular response was achieved or maintained by 12 months in 48% of patients who could be evaluated, including 8 of 14 (57%) deemed to have resistance to or unacceptable side effects from ponatinib. A major molecular response was achieved or maintained by 12 months in 5 patients (28%) with a T315I mutation at baseline. Clinical responses were durable; a major molecular response was maintained in 40 of 44 patients. Dose-limiting toxic effects included asymptomatic elevations in the lipase level and clinical pancreatitis. Common adverse events included fatigue, headache, arthralgia, hypertension, and thrombocytopenia. CONCLUSIONS: Asciminib was active in heavily pretreated patients with CML who had resistance to or unacceptable side effects from TKIs, including patients in whom ponatinib had failed and those with a T315I mutation. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT02081378.).


Asunto(s)
Antineoplásicos/administración & dosificación , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Niacinamida/análogos & derivados , Pirazoles/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Relación Dosis-Respuesta a Droga , Resistencia a Antineoplásicos , Femenino , Estudios de Seguimiento , Proteínas de Fusión bcr-abl/genética , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Modelos Logísticos , Masculino , Persona de Mediana Edad , Mutación , Niacinamida/administración & dosificación , Niacinamida/efectos adversos , Niacinamida/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazoles/efectos adversos , Pirazoles/farmacocinética
12.
Eur J Haematol ; 109(1): 90-99, 2022 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-35403752

RESUMEN

OBJECTIVES: To describe the real-world effectiveness and safety of bosutinib in patients with chronic myeloid leukemia (CML). METHODS: This was a multi-center, retrospective, non-interventional chart review study conducted in 10 hospitals in the United Kingdom and the Netherlands. RESULTS: Eighty-seven patients were included. Bosutinib was the third-line tyrosine kinase inhibitor (TKI) in 33 (38%) and fourth-line in 44 (51%) patients. Median treatment duration was 15.6 months. Among 84 patients in chronic phase (CP) at baseline, 26 (31%) switched to bosutinib due to resistance and 57 (68%) due to intolerance to prior TKIs. Cumulative complete cytogenetic and major molecular response rates in CP patients were 67% and 55%, respectively. After a median follow-up of 21.5 months, nine (11%) patients in CP died; estimated overall survival rates at 1 and 2 years postbosutinib initiation were 95% and 91%, respectively. Overall, 33/87 (38%) patients discontinued bosutinib due to either lack of efficacy/disease progression (17%), adverse events (14%), death (2%), or other reasons (5%). Eighty-two (94%) patients experienced ≥1 adverse event possibly related to bosutinib, most commonly diarrhea (52%). CONCLUSIONS: Bosutinib used in routine clinical practice in heavily pretreated patients with CML is an effective treatment for patients in CP and is generally tolerable.


Asunto(s)
Antineoplásicos , Leucemia Mielógena Crónica BCR-ABL Positiva , Quinolinas , Compuestos de Anilina , Antineoplásicos/efectos adversos , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/epidemiología , Países Bajos/epidemiología , Nitrilos , Inhibidores de Proteínas Quinasas/efectos adversos , Quinolinas/efectos adversos , Estudios Retrospectivos
13.
Curr Oncol Rep ; 24(11): 1387-1400, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-35653050

RESUMEN

PURPOSE OF REVIEW: Treatment of elderly patients with acute myeloid leukemia is a known challenge for hematologists due to patient diversity, heterogeneous disease biology, and a rapidly evolving treatment landscape. Here, we highlight the importance of determining fitness, review the latest therapeutic developments, and discuss clinical scenarios to provide guidance on individualized treatment for older AML patients. RECENT FINDINGS: Several factors, like age, performance status, and comorbidities, play a role in fitness and are associated with outcome. Comorbidity scoring systems and geriatric assessments are tools to help physicians select the most appropriate treatment for each patient. The addition of venetoclax, targeted therapy with IDH1/2 and FLT3 inhibitors, and enhanced formulas of existing drugs like CPX-351 and oral azacitidine have improved responses and outcomes. New drugs and combination therapies have increased the therapeutic options for elderly AML patients but determination of fitness and disease biology is essential to select patient-tailored treatments.


Asunto(s)
Leucemia Mieloide Aguda , Humanos , Anciano , Leucemia Mieloide Aguda/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Azacitidina/uso terapéutico
14.
Mol Cell Proteomics ; 19(5): 884-899, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-32102969

RESUMEN

Acute myeloid leukemia (AML) is a clonal disorder arising from hematopoietic myeloid progenitors. Aberrantly activated tyrosine kinases (TK) are involved in leukemogenesis and are associated with poor treatment outcome. Kinase inhibitor (KI) treatment has shown promise in improving patient outcome in AML. However, inhibitor selection for patients is suboptimal.In a preclinical effort to address KI selection, we analyzed a panel of 16 AML cell lines using phosphotyrosine (pY) enrichment-based, label-free phosphoproteomics. The Integrative Inferred Kinase Activity (INKA) algorithm was used to identify hyperphosphorylated, active kinases as candidates for KI treatment, and efficacy of selected KIs was tested.Heterogeneous signaling was observed with between 241 and 2764 phosphopeptides detected per cell line. Of 4853 identified phosphopeptides with 4229 phosphosites, 4459 phosphopeptides (4430 pY) were linked to 3605 class I sites (3525 pY). INKA analysis in single cell lines successfully pinpointed driver kinases (PDGFRA, JAK2, KIT and FLT3) corresponding with activating mutations present in these cell lines. Furthermore, potential receptor tyrosine kinase (RTK) drivers, undetected by standard molecular analyses, were identified in four cell lines (FGFR1 in KG-1 and KG-1a, PDGFRA in Kasumi-3, and FLT3 in MM6). These cell lines proved highly sensitive to specific KIs. Six AML cell lines without a clear RTK driver showed evidence of MAPK1/3 activation, indicative of the presence of activating upstream RAS mutations. Importantly, FLT3 phosphorylation was demonstrated in two clinical AML samples with a FLT3 internal tandem duplication (ITD) mutation.Our data show the potential of pY-phosphoproteomics and INKA analysis to provide insight in AML TK signaling and identify hyperactive kinases as potential targets for treatment in AML cell lines. These results warrant future investigation of clinical samples to further our understanding of TK phosphorylation in relation to clinical response in the individual patient.


Asunto(s)
Antineoplásicos/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/metabolismo , Fosfotirosina/metabolismo , Proteómica , Antineoplásicos/farmacología , Línea Celular Tumoral , Análisis por Conglomerados , Simulación por Computador , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Sistema de Señalización de MAP Quinasas , Terapia Molecular Dirigida , Mutación/genética , Fosforilación/efectos de los fármacos , Proteínas Quinasas/metabolismo , Proteoma/metabolismo , Reproducibilidad de los Resultados , Tirosina Quinasa 3 Similar a fms/metabolismo
15.
Haematologica ; 106(7): 1876-1882, 2021 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-32616528

RESUMEN

Fatigue is a common side effect of tyrosine kinase inhibitor (TKI) therapy in chronic myeloid leukemia (CML) patients. However, the prevalence of TKI-induced fatigue remains uncertain and little is known about predictors of fatigue and its relationship with physical activity. In this study, 220 CML patients receiving TKI therapy and 110 gender- and age-matched controls completed an online questionnaire to assess fatigue severity and fatigue predictors (Part 1). In addition, physical activity levels were objectively assessed for 7 consecutive days in 138 severely fatigued and non-fatigued CML patients using an activity monitor (Part 2). We demonstrated that the prevalence of severe fatigue was 55.5% in CML patients and 10.9% in controls (P<0.001). We identified five predictors of fatigue in our CML population: age (OR 0.96, 95% CI 0.93-0.99), female gender (OR 1.76, 95% CI 0.92-3.34), Charlson Comorbidity Index (OR 1.91, 95% CI 1.16-3.13), the use of comedication known to cause fatigue (OR 3.43, 95% CI 1.58-7.44), and physical inactivity (OR of moderately active, vigorously active and very vigorously active compared to inactivity 0.43 (95% CI 0.12-1.52), 0.22 (95% CI 0.06-0.74), and 0.08 (95% CI 0.02-0.26), respectively). Objective monitoring of activity patterns confirmed that fatigued CML patients performed less physical activity on both light (P=0.017) and moderate to vigorous intensity (P=0.009). In fact, compared to the non-fatigued patients, fatigued CML patients performed 1 hour less of physical activity per day and took 2000 fewer steps per day. Our findings facilitate the identification of patients at risk of severe fatigue and highlight the importance to set the reduction of fatigue as a treatment goal in CML care. This study was registered at The Netherlands Trial Registry, NTR7308 (Part 1) and NTR7309 (Part 2).


Asunto(s)
Leucemia Mielógena Crónica BCR-ABL Positiva , Inhibidores de Proteínas Quinasas , Ejercicio Físico , Fatiga/epidemiología , Fatiga/etiología , Femenino , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/epidemiología , Países Bajos , Inhibidores de Proteínas Quinasas/efectos adversos
16.
Eur J Haematol ; 107(3): 364-369, 2021 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-34114691

RESUMEN

OBJECTIVE: To investigate the incidence and severity of adverse drug reactions of cyclosporine using AUC-targeted therapeutic drug monitoring (TDM) compared to trough level (Ctrough )-targeted TDM in adult allogeneic stem cell recipients. METHODS: Blind, monocenter, intervention study. Subjects were 1:1 randomized into either an AUC group or a Ctrough group. Adverse drug reactions were accessed two and four weeks after start of treatment. RESULTS: Forty patients were included, resulting in 15 evaluable subjects (AUC group) and 13 evaluable subjects (Ctrough group). Grade two/three toxicity was observed in 46% (Ctrough group) versus 60% of subjects (AUC group) (P = .463). There was no significant difference between two and four weeks after start of cyclosporine for nausea (P = .142 resp. P = .122), renal dysfunction (P = .464 resp. P = 1.000), and hypomagnesemia (P = 1.000 resp. P = .411). Subjects in the AUC group reached the therapeutic goal earlier (72,7% versus 43,0% at third sampling point, P = .332) and were within the target range more consistently. CONCLUSION: This study showed no reduction in incidence and severity of cyclosporine-induced toxicity with AUC- versus trough level-targeted TDM. Although modeled dosing based on AUC led to faster optimal target attainment, this did not result in less toxicity in the early days after transplantation.


Asunto(s)
Ciclosporina/efectos adversos , Inmunosupresores/efectos adversos , Leucemia Mieloide Aguda/terapia , Linfoma/terapia , Mieloma Múltiple/terapia , Náusea/inducido químicamente , Defectos Congénitos del Transporte Tubular Renal/inducido químicamente , Adulto , Área Bajo la Curva , Ciclosporina/farmacocinética , Monitoreo de Drogas/métodos , Femenino , Rechazo de Injerto/etiología , Rechazo de Injerto/inmunología , Rechazo de Injerto/patología , Supervivencia de Injerto/fisiología , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Inmunosupresores/farmacocinética , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/patología , Linfoma/inmunología , Linfoma/patología , Masculino , Persona de Mediana Edad , Mieloma Múltiple/inmunología , Mieloma Múltiple/patología , Náusea/inmunología , Náusea/patología , Curva ROC , Distribución Aleatoria , Defectos Congénitos del Transporte Tubular Renal/inmunología , Defectos Congénitos del Transporte Tubular Renal/patología , Trasplante Homólogo
17.
Eur J Haematol ; 107(3): 343-353, 2021 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-34053123

RESUMEN

OBJECTIVES: This study aims to retrospectively assess C-lectin-like molecule 1 (CLL-1) bimodal expression on CD34+ blasts in acute myeloid leukemia (AML) patients (total N = 306) and explore potential CLL-1 bimodal associations with leukemia and patient-specific characteristics. METHODS: Flow cytometry assays were performed to assess the deeper immunophenotyping of CLL-1 bimodality. Cytogenetic analysis was performed to characterize the gene mutation on CLL-1-negative subpopulation of CLL-1 bimodal AML samples. RESULTS: The frequency of a bimodal pattern of CLL-1 expression of CD34+ blasts ranged from 8% to 65% in the different cohorts. Bimodal CLL-1 expression was most prevalent in patients with MDS-related AML (P = .011), ELN adverse risk (P = .002), NPM1 wild type (WT, P = .049), FLT3 WT (P = .035), and relatively low percentages of leukemia-associated immunophenotypes (P = .006). Additional immunophenotyping analysis revealed the CLL-1- subpopulation may consist of pre-B cells, immature myeloblasts, and hematopoietic stem cells. Furthermore, (pre)-leukemic mutations were detected in both CLL-1+ and CLL-1- subfractions of bimodal samples (N = 3). CONCLUSIONS: C-lectin-like molecule 1 bimodality occurs in about 25% of AML patients and the CLL-1- cell population still contains malignant cells, hence it may potentially limit the effectiveness of CLL-1-targeted therapies and warrant further investigation.


Asunto(s)
Biomarcadores de Tumor/genética , Células de la Médula Ósea/metabolismo , Lectinas Tipo C/genética , Leucemia Mieloide Aguda/genética , Mutación , Células Mieloides/metabolismo , Receptores Mitogénicos/genética , Antígenos CD34/genética , Antígenos CD34/inmunología , Biomarcadores de Tumor/inmunología , Células de la Médula Ósea/inmunología , Células de la Médula Ósea/patología , Análisis Citogenético , Femenino , Citometría de Flujo , Perfilación de la Expresión Génica , Regulación Leucémica de la Expresión Génica , Células Madre Hematopoyéticas/inmunología , Células Madre Hematopoyéticas/metabolismo , Células Madre Hematopoyéticas/patología , Humanos , Inmunofenotipificación , Lectinas Tipo C/inmunología , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , Células Mieloides/inmunología , Células Mieloides/patología , Células Precursoras de Linfocitos B/inmunología , Células Precursoras de Linfocitos B/metabolismo , Células Precursoras de Linfocitos B/patología , Cultivo Primario de Células , Receptores Mitogénicos/inmunología
18.
Blood ; 131(22): 2485-2489, 2018 05 31.
Artículo en Inglés | MEDLINE | ID: mdl-29669779

RESUMEN

Controversy exists whether internal tandem duplication of FMS-like tyrosine kinase 3 (FLT3-internal tandem duplication [ITD]) allelic ratio (AR) and/or length of the ITD should be taken into account for risk stratification of pediatric acute myeloid leukemia (AML) and whether it should be measured on RNA or DNA. Moreover, the ITD status may be of relevance for selecting patients eligible for FLT3 inhibitors. Here, we included 172 pediatric AML patients, of whom 36 (21%) harbored FLT3-ITD as determined on both RNA and DNA. Although there was a good correlation between both parameters ARspearman = 0.62 (95% confidence interval, 0.22-0.87) and ITDlengthspearman = 0.98 (95% confidence interval, 0.90-1.00), only AR ≥ 0.5 and length ≥48 base pairs (bps) based on RNA measurements were significantly associated with overall survival (AR: Plogrank = .008; ITDlength: Plogrank = .011). In large ITDs (>156 bp on DNA) a remarkable 90-bp difference exists between DNA and RNA, including intron 14, which is spliced out in RNA. Ex vivo exposure (n = 30) to FLT3 inhibitors, in particular to the FLT3-specific inhibitor gilteritinib, showed that colony-forming capacity was significantly more reduced in FLT3-ITD-AR ≥ 0.5 compared with ITD-AR-low and ITD- patient samples (P < .001). RNA-based FLT3-ITD measurements are recommended for risk stratification, and the relevance of AR regarding eligibility for FLT3-targeted therapy warrants further study.


Asunto(s)
Compuestos de Anilina/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazinas/uso terapéutico , ARN/genética , Estaurosporina/análogos & derivados , Tirosina Quinasa 3 Similar a fms/genética , Alelos , Antineoplásicos/uso terapéutico , Niño , Duplicación Cromosómica , ADN/genética , Femenino , Humanos , Masculino , Mutación , Estaurosporina/uso terapéutico , Secuencias Repetidas en Tándem , Resultado del Tratamiento , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores
20.
Eur J Haematol ; 105(2): 148-155, 2020 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-32243653

RESUMEN

OBJECTIVES: Taking advantage of its food-dependent bioavailability, the present study investigated the effect of a reduced dose taken with real-life meals on the pharmacokinetics (PK) of nilotinib in chronic myeloid leukaemia (CML) patients. METHODS: Nilotinib was taken fasted (300 mg BID, days 1-4) or with real-life meals (200 mg BID, days 5-11). Rich sampling (days 1, 3, 8, 11) allowed for non-compartmental PK analysis. Nilotinib exposure (AUC0-12 h  -Cmin -Cmax ) and its intra- and interpatient variability were compared between the two regimens. Adverse events were recorded by means of a patient diary and ECG monitoring. RESULTS: Fifteen patients aged 40-74 years participated. Nilotinib PK following 200 mg BID taken with a meal strongly resembled that of 300 mg BID taken fasted (Cmin percentile (P)10-P90: 665-1404 ng/mL and 557-1743 ng/mL, respectively). Meals delayed nilotinib absorption. Intra- and interpatient variability were not increased by intake with meals. Nilotinib with food was well tolerated. CONCLUSION: With support of therapeutic drug monitoring, the use of a reduced 200 mg nilotinib dose with real-life meals seems feasible and safe. Future (confirmatory) studies should further explore the usefulness of nilotinib dosing together with food, including the relationship with treatment efficacy as well as long-term effects on quality of life. CLINICAL TRIAL REGISTRATION: NTR5000 (Netherlands Trial Register, www.trialregister.nl).


Asunto(s)
Leucemia Mielógena Crónica BCR-ABL Positiva/terapia , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Adulto , Anciano , Área Bajo la Curva , Esquema de Medicación , Ayuno , Femenino , Humanos , Masculino , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacocinética , Pirimidinas/administración & dosificación , Pirimidinas/efectos adversos , Pirimidinas/farmacocinética , Calidad de Vida , Resultado del Tratamiento
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