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Chemotherapy-induced differentiation of immature myeloid progenitors, such as acute myeloid leukemia (AML) cells or myeloid-derived suppressor cells (MDSCs), has remained a challenge for the clinicians. Testing our imidazo[1,2-b]pyrazole-7-carboxamide derivative on HL-60 cells, we obtained ERK phosphorylation as an early survival response to treatment followed by the increase of the percentage of the Bcl-xlbright and pAktbright cells. Following the induction of Vav1 and the AP-1 complex, a driver of cellular differentiation, FOS, JUN, JUNB, and JUND were elevated on a concentration and time-dependent manner. As a proof of granulocytic differentiation, the cells remained non-adherent, the expression of CD33 decreased; the granularity, CD11b expression, and MPO activity of HL-60 cells increased upon treatment. Finally, viability of HL-60 cells was hampered shown by the depolarization of mitochondria, activation of caspase-3, cleavage of Z-DEVD-aLUC, appearance of the sub-G1 population, and the leakage of the lactate-dehydrogenase into the supernatant. We confirmed the differentiating effect of our drug candidate on human patient-derived AML cells shown by the increase of CD11b and decrease of CD33+, CD7+, CD206+, and CD38bright cells followed apoptosis (IC50: 80 nM) after treatment ex vivo. Our compound reduced both CD11b+/Ly6C+ and CD11b+/Ly6G+ splenic MDSCs from the murine 4T1 breast cancer model ex vivo.
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Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Leucemia Mieloide Aguda/tratamiento farmacológico , Células Supresoras de Origen Mieloide/efectos de los fármacos , Pirazoles/farmacología , Animales , Antineoplásicos/química , Diferenciación Celular/efectos de los fármacos , Femenino , Células HL-60 , Humanos , Leucemia Mieloide Aguda/metabolismo , Masculino , Ratones Endogámicos BALB C , Persona de Mediana Edad , Células Supresoras de Origen Mieloide/citología , Células Supresoras de Origen Mieloide/metabolismo , Pirazoles/química , Células Tumorales Cultivadas , Adulto JovenRESUMEN
Since the introduction of tyrosine kinase inhibitors, the overall survival of patients with chronic myeloid leukemia has markedly improved. However long term use of these drugs results in various adverse events. Treatment with second generation dasatinib is often complicated by hemorrhagic events. Previous lumi-aggregometry studies have shown impaired platelet function in patients on dasatinib therapy. Dual agonist activated platelets (coated-platelets) are also sensitive indicators of platelet function. We hypothesized that dual activation with convulxin and thrombin of platelets in a flow cytometric assay could be a more sensitive method for detecting platelet dysfunction as compared to single agonist studies used in lumi-aggregometer. Platelets of healthy volunteers incubated with dasatinib as well as platelets from patients on dasatinib therapy were investigated. Low therapeutic plasma level dasatinib concentrations at which a considerable reduction in coated-platelet generation was observed in vitro, did not cause detectable change in platelet aggregation response. Coated-platelet assay and lumi-aggregometry were also investigated at 0, 1 and 4 hours after drug administration in dasatinib treated CML patients. Significant decrease was observed at 1 hour in maximal aggregation by collagen. Although the aggregation curves became normalized by 4 hours, coated-platelet generation was still inhibited in dasatinib treated patients. Nilotinib, another second generation tyrosine kinase inhibitor, had no effect on aggregation and on coated-platelet formation neither in vitro nor in ex vivo samples. At therapeutic plasma levels coated-platelet assay is more sensitive than lumi-aggregometry studies for the demonstration of the inhibitory effect of dasatinib on platelet function.
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Antineoplásicos/uso terapéutico , Dasatinib/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Antineoplásicos/farmacología , Dasatinib/farmacología , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , MasculinoRESUMEN
Tyrosine kinase inhibitors (TKI) such as the BCR-ABL inhibitor dasatinib and nilotinib are highly effective therapies for chronic myeloid leukemia (CML). However, several lines of evidence suggest that dasatinib can induce bleeding which may be due to impaired collagen-induced platelet adhesion, aggregation, and secretion. Sarcoma family kinases (SFK) play central role in the GPVI-induced signaling pathway. We aimed to investigate whether and how dasatinib can modulate SFK-mediated platelet procoagulant activity in a purified system and in dasatinib/nilotinib treated CML patients. In platelet rich plasmas of healthy volunteers, dasatinib dose-dependently reduced convulxin-induced phosphatidylserine exposure and attenuated thrombin formation. Similarly to these changes, integrin activation and clot retraction were also significantly inhibited by 100 nM dasatinib. Platelets isolated from dasatinib treated patients showed a significantly lower phosphatidylserine expression upon convulxin activation compared to premedication levels. In these samples, thrombin generation was significantly slower, and the quantity of formed thrombin was less compared to the trough sample. Western blot analyses showed decreased phosphorylation levels of the C-terminal tail and the activation loop of SFKs upon dasatinib administration. Taken together, these results suggest that dasatinib inhibits the formation of procoagulant platelets via the GPVI receptor by inhibiting phosphorylation of SFKs.
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Coagulación Sanguínea/efectos de los fármacos , Plaquetas/efectos de los fármacos , Retracción del Coagulo/efectos de los fármacos , Dasatinib/farmacología , Activación Plaquetaria/efectos de los fármacos , Plaquetas/metabolismo , Venenos de Crotálidos/farmacología , Humanos , Lectinas Tipo C , Leucemia Mielógena Crónica BCR-ABL Positiva/sangre , Fosfatidilserinas/metabolismo , Fosforilación/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Trombina/metabolismo , Familia-src Quinasas/metabolismoRESUMEN
Leukemia, the malignancy of the hematopoietic system accounts for 10% of cancer cases with poor overall survival rate in adults; therefore, there is a high unmet medical need for the development of novel therapeutics. Eight imidazo[1,2-b]pyrazole-7-carboxamides have been tested for cytotoxic activity against five leukemia cell lines: Acute promyelocytic leukemia (HL-60), acute monocytic leukemia (THP-1), acute T-lymphoblastic leukemia (MOLT-4), biphenotypic B myelomonocytic leukemia (MV-4-11), and erythroleukemia (K-562) cells in vitro. Imidazo[1,2-b]pyrazole-7-carboxamides hampered the viability of all five leukemia cell lines with different potential. Optimization through structure activity relationship resulted in the following IC50 values for the most effective lead compound DU385: 16.54 nM, 27.24 nM, and 32.25 nM on HL-60, MOLT-4, MV-4-11 cells, respectively. Human primary fibroblasts were much less sensitive in the applied concentration range. Both monolayer or spheroid cultures of murine 4T1 and human MCF7 breast cancer cells were less sensitive to treatment with 1.5â»10.8 µM IC50 values. Flow cytometry confirmed the absence of necrosis and revealed 60% late apoptotic population for MV-4-11, and 50% early apoptotic population for HL-60. MOLT-4 cells showed only about 30% of total apoptotic population. Toxicogenomic study of DU385 on the most sensitive MV-4-11 cells revealed altered expression of sixteen genes as early (6 h), midterm (12 h), and late response (24 h) genes upon treatment. Changes in ALOX5AP, TXN, and SOD1 expression suggested that DU385 causes oxidative stress, which was confirmed by depletion of cellular glutathione and mitochondrial membrane depolarization induction. Imidazo[1,2-b]pyrazole-7-carboxamides reported herein induced apoptosis in human leukemia cells at nanomolar concentrations.
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Antineoplásicos/química , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Pirazoles/química , Pirazoles/farmacología , Antineoplásicos/síntesis química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Evolución Molecular , Células HL-60 , Humanos , Estrés Oxidativo/efectos de los fármacos , Pirazoles/síntesis químicaRESUMEN
Acute myelogenous leukemia is a heterogeneous disease. Recent molecular mutational analysis techniques have shed more light on different, genetically well characterised types of the disease. Treatment approach is uniform except for acute promyelocytic leukemia. Application of the "3 + 7" induction treatment has been the gold standard in the past 40 years. While the dose of cytarabine has not been changed, escalating daunorubicine dose in younger (<60 years) patients with good performance status to 90 mg/m(2) had a positive impact on overall survival. High dose chemotherapy is tolerated poorly in patients older than 60 years of age and, as treatment is not curative in the elderly, improvement of overall survival and quality of life remains the main goal of management in these patients. Low intensity treatment is beneficial and can provide additional advantage over supportive care. Innovative and targeted therapy approaches might give promise to better management of patients with acute myelogenous leukemia.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioterapia de Inducción , Leucemia Mieloide Aguda/tratamiento farmacológico , Factores de Edad , Anciano , Citarabina/administración & dosificación , Daunorrubicina/administración & dosificación , Esquema de Medicación , Humanos , Quimioterapia de Inducción/métodos , Estado de Ejecución de Karnofsky , Persona de Mediana Edad , Terapia Molecular Dirigida , Calidad de Vida , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
INTRODUCTION: Mortality of acute myeloid leukemia is still 60-70% in young (<60 years) adults and 90% in elderly (≥60 years) patients. AIM: The aim of the authors was to analyse the outcome of treatment in their patients with acute myeloid leukemia. METHOD: From 2007 to 2013, 173 patients with acute myeloid leukemia were treated. Patients were classified according to the European LeukemiaNet prognostic guideline. Association between mortality and the type of acute myeloid leukemia (secondary or primary), dose of daunoblastin at induction of treatment, and the rate of minimal residual disease were investigated. RESULTS: The 5-year survival probability was 25% in young adults and 2% in the elderly. The survival was significantly influenced by these prognostic factors. The 5-year survival rate was 50% in the young, favorable prognostic group. The 90 mg/m2 daunoblastin dose was found to be beneficial. Addition of bortezomib to the standard induction protocol had an additional beneficial effect. CONCLUSIONS: The speed and depth of the response to induction therapy, and the initial white blood cell count had an apparent effect on survival.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioterapia de Inducción , Leucemia Mieloide Aguda/tratamiento farmacológico , Cuidados Paliativos/métodos , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Ácidos Borónicos/administración & dosificación , Bortezomib , Citarabina/administración & dosificación , Daunorrubicina/administración & dosificación , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Trasplante de Células Madre Hematopoyéticas , Humanos , Hungría/epidemiología , Idarrubicina/administración & dosificación , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/cirugía , Masculino , Persona de Mediana Edad , Mitoxantrona/administración & dosificación , Neoplasia Residual/tratamiento farmacológico , Pronóstico , Pirazinas/administración & dosificación , Estudios Retrospectivos , Análisis de Supervivencia , Tasa de Supervivencia , Trasplante Homólogo , Resultado del Tratamiento , Vidarabina/administración & dosificación , Vidarabina/análogos & derivadosRESUMEN
[This corrects the article DOI: 10.3389/pore.2024.1611497.].
RESUMEN
Purpose: This study aimed to provide real-world evidence on the characteristics, treatment patterns, and outcomes of patients with chronic myeloid leukemia (CML) receiving tyrosine kinase inhibitor (TKI) treatment in Hungary between 2011 and 2019. Patients and methods: This nationwide, retrospective study included patients who were newly diagnosed with CML in Hungarian clinical practice between January 2011 and December 2019. The analysis was based on the reimbursed prescription claims for imatinib, bosutinib, dasatinib, nilotinib, or ponatinib with the ICD-10 code C9210 in a public pharmacy between January 2009 and December 2019 using data from the National Health Insurance Fund (NHIF) of Hungary. CML incidence and prevalence, TKI treatment patterns, comorbidities, and overall survival (OS) were examined. Results: Between 2011 and 2019, altogether 1,407 patients were diagnosed with CML, with an annual average of 156 patients. The number of patients newly initiating first-line TKI therapy for CML significantly increased between 2011 and 2019 (2011: n = 136 vs. 2019: n = 191; p = 0.0043). Nilotinib was typically prescribed for younger patients (≤64 years), while older patients (≥65 years) mostly received imatinib. The most common comorbidity of CML patients was hypertension, and the proportion of patients with other malignancies was relatively high in all treatment groups. 5-year OS was 77.1% during the whole study period. Patients initiating first-line TKI treatment for CML in 2015 had significantly better 4-year OS compared to those starting treatment in 2011 (82.4% vs. 73.5%, respectively, (HR 0.53 (95%CI 0.32-0.87) p = 0.0118). Conclusion: This study is the first to provide insights into the characteristics, treatment patterns, and outcomes of CML patients treated with TKIs in Hungarian clinical practice between 2011 and 2019. We found slightly lower OS rates compared to other European countries, however, there was a statistically significant improvement in 4-year OS during the study period. The management of CML was in line with international guidelines and recommendations.
Asunto(s)
Leucemia Mielógena Crónica BCR-ABL Positiva , Humanos , Hungría/epidemiología , Estudios Retrospectivos , Mesilato de Imatinib , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/epidemiología , ComorbilidadRESUMEN
Essential thrombocythemia (ET) is an acquired myeloproliferative disorder with sustained increase of platelet count. This disease may be associated with thrombotic or bleeding complications due to the altered number and function of platelets. Coated-platelets produced by a simultaneous activation of collagen and thrombin represent a subpopulation of activated platelets with high prothombinase activity and the retention of several α-granule-derived coagulation factors on their surface. There is a growing body of evidence for a relationship between variable levels of coated-platelets and different hemostatic alterations. However, no data are available on coated-platelet formation in the pathogenesis of ET in the presence or absence of treatment. The levels of coated-platelets in 43 ET patients (15 non-treated and 28 hydroxyurea-treated) without known thrombotic or hemorrhagic complications were analyzed using flow cytometry. These results were compared with data of 31 healthy individuals. In addition, platelet function was analyzed with PFA-100 analysis, and P-selectin (CD62) positivity was also measured by flow cytometry. Increased P-selectin expression was detected with prolonged PFA-100 closure times in the ET group; however, significantly lower levels of coated-platelets were found in non-treated ET patients compared to controls (23.1 ± 8.8% vs. 37.6 ± 12.7%, p = 0.0008). This tendency was more evident in patients with JAK2-V617F mutation. Patients on hydroxyurea treatment had elevated coated-platelet levels (34.1 ± 12.3%) close to the normal value. In conclusion, lower than normal levels of coated-platelets were generated in ET, which were significantly (p = 0.0008) increased by hydroxyurea treatment. We suppose that abnormal coated-platelet level may also contribute to platelet dysfunction in ET.
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Plaquetas/fisiología , Hidroxiurea/uso terapéutico , Activación Plaquetaria , Trombocitemia Esencial/sangre , Trombocitemia Esencial/tratamiento farmacológico , Adulto , Anciano , Estudios de Casos y Controles , Femenino , Humanos , Janus Quinasa 2/genética , Janus Quinasa 2/metabolismo , Masculino , Persona de Mediana Edad , Mutación , Pruebas de Función PlaquetariaRESUMEN
Waldenström macroglobulinemia is a rare lymphoproliferative disease of B-cell origin.These tumorous B-cells produce monoclonal IgM type protein. Diagnosis is based on the detection of lymphoplasmacytic invasion of the bone marrow and serum electrophoresis. Clinical symptoms such as anemia, hyperviscosity and neuropathy are the commom consequences of bone marrow infiltration and serum monoclonal IgM protein. Former use of alkylating agents are replaced by purine analogues, rituximab and bortezomib. Additional clinical data have also accumulated regarding autologous and allogenous stem-cell transplantation. The authors present their own clinical experience and give a detailed review of current therapeutic approaches. Orv. Hetil., 154(50), 1970-1974.
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Linfocitos B , Macroglobulinemia de Waldenström , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Bortezomib , Humanos , Inmunoglobulina M/sangre , RituximabRESUMEN
Recent cytogenetical findings and novel molecular biology results of acute myeloid leukaemia have shed new lights of our understanding in the diagnosis and treatment of the disease. Acute myeloid leukaemia is not only represented by the wide variety of morphological and immunophenotypic diversity but also demonstrates cytogenetical and molecular biological heterogeneity of its own. It has an unfavorable prognosis, especially in the elderly. Overall survival of younger patients (<50-60 years) has increased in the past years due to high dose chemotherapy (daunorubicine, cytarabine). But in case of unfavorable prognostic factors (not only cytogenetical but also molecular biological characters of the disease), allogeneic stem cell transplantation is needed for successful overall outcome. Better understanding the biology of acute myeloid leukaemia could establish novel targeted therapies and help us eventually to cure the disease.
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Antineoplásicos/uso terapéutico , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/cirugía , Factores de Edad , Aminoglicósidos/administración & dosificación , Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trióxido de Arsénico , Arsenicales/administración & dosificación , Ácidos Borónicos/administración & dosificación , Bortezomib , Citarabina/administración & dosificación , Supervivencia sin Enfermedad , Resistencia a Antineoplásicos , Gemtuzumab , Humanos , Idarrubicina/administración & dosificación , Mitoxantrona/administración & dosificación , Terapia Molecular Dirigida/métodos , Óxidos/administración & dosificación , Pronóstico , Pirazinas/administración & dosificación , Recurrencia , Trasplante Homólogo , Resultado del Tratamiento , Tretinoina/administración & dosificación , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidoresRESUMEN
Understanding the pathogenesis and refine the treatment of chronic lymphocytic leukemia have been tremendously improved in the past decade. Treatment outcome and estimated prognosis have become more accurate due to the advanced molecular biological techniques and the classical prognostic markers. Incorporation of fludarabine and rituximab into the standard protocols fundamentally improved treatment outcome in chronic lymphocytic leukemia. Chemoimmunotherapy has improved not only the remission rates but had a significant impact on overall survival, as well. Eliminating residual leukemia and achieving complete hematological remissions at such high rates establish potential background for cure. Still, a great deal of dispute has been emerged regarding everyday clinical practice. Authors present their institutional experiences and review the literature.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Resistencia a Antineoplásicos , Humanos , Terapia Molecular Dirigida/métodos , Neoplasia Residual/tratamiento farmacológico , Pronóstico , Recurrencia , Inducción de Remisión , Rituximab , Resultado del Tratamiento , Vidarabina/administración & dosificación , Vidarabina/análogos & derivadosRESUMEN
Összefoglaló. A krónikus myeloid leukaemia ritka, klonális ossejt eredetu betegség. A myeloid sejtsor kóros muködését a 9-es és 22-es kromoszómák reciprok transzlokációja következtében kialakuló fúziós gén (BCR/ABL1) által kódolt patológiás (fokozott) aktivitású tirozin-kináz jelátviteli fehérje okozza. A tartós, gyakran élethosszig tartó BCR/ABL1 specifikus tirozin-kináz-gátló (TKI-) kezelés a betegek jelentos hányadában az egészséges populáció túlélését eléro teljes gyógyulást biztosít, melyhez folyamatos, a mindenkori szakmai ajánlásoknak megfelelo onkohematológiai ellenorzés szükséges. Az igen hatékony TKI-kezelés mellett azonban nemkívánatos mellékhatások jelentkezhetnek, melyek - számos szervrendszert érintve - a krónikus myeloid leukaemiás beteg kezelését multidiszciplináris együttmuködéssé szélesítik ki. Jelenleg Magyarországon ötféle TKI érheto el, melyek mellékhatásprofilja igen eltéro. A kezelés elindításakor, illetve terápiamódosítás esetén beteg- és kórképspecifikus szempontokat mérlegelve kell kiválasztani az adott TKI-kezelést. Tekintettel a tartós kezelés mellett elérheto kiváló túlélési eredményekre, egyre gyakoribb azoknak a krónikus myeloid leukaemiás betegeknek a száma, akiknél változó súlyosságú nemkívánatos mellékhatások jelentkeznek, melyek miatt a betegek sokszor nem a hematológus szakorvosnál jelentkeznek. A leggyakrabban észlelt szövodmények ismertetését saját beteganyagunk részletes elemzése kapcsán a mindennapi klinikai gyakorlatban is bemutatjuk. Igen fontos, hogy a társszakmák (háziorvos, belgyógyász, kardiológus, angiológus, diabetológus, tüdogyógyász, gasztroenterológus stb.) gyakorlói is tisztában legyenek az adott TKI-kezelés lehetséges mellékhatásaival, azok megelozésével, idoben történo felismerésével és hatékony kezelésével. Szakmai közremuködésük révén így segíthetik a klinikai hematológust a megfelelo terápia megtervezésében, valamint a betegek folyamatos kezelése kapcsán gyakran szükségessé váló szakmaspecifikus gondozásában is. Orv Hetil. 2021; 162(30): 1198-1207. Summary. Chronic myeloid leukemia is a rare clonal stem cell disorder. The pathological overproduction of the myeloid cell line is caused by abnormal function of a tyrosine kinase encoded by a fusion gene (BCR/ABL1) which is formed upon a reciprocal translocation of chromosomes 9 and 22. Long-term, often lifelong treatment with BCR/ABL1-specific tyrosine kinase inhibitors provides excellent disease control and overall survival rates close to the general survival of a healthy population in a significant proportion of patients. These patients require continuous oncohematological monitoring in accordance with the current diagnostic and treatment guidelines. However, undesirable side effects may occur that extend the treatment of the patients to a multidisciplinary approach involving a number of nonhematological specialities. Currently, five types of tyrosine kinase inhibitors are available in Hungary, with very different side effect profiles. At the start of treatment or in the event of a change in therapy, patient- and leukemia-specific assessments should be taken to select the most proper tyrosine kinase inhibitors treatment. Given the excellent survival outcomes achieved with long-term tyrosine kinase inhibitor treatment, there is an increasing number of patients who might experience adverse events of different kind or severity, which often results in patients ending up in different, nonhematological medical situations. The description of the most frequently observed complications in connection with a detailed cross-sectional analysis of our own patient cohort is also presented here resembling everyday clinical practice. It is very important that practitioners of other medical professions (general practitioner, internist, cardiologist, angiologist, diabetologist, pulmonologist, gastroenterologist, etc.) should be aware of the possible side effects of specific tyrosine kinase inhibitor therapies. They can help to assist the clinical hematologist in planning the appropriate tyrosine kinase inhibitor therapy as well as in professional caretaking of these patients. Orv Hetil. 2021; 162(30): 1198-1207.
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Leucemia Mielógena Crónica BCR-ABL Positiva , Leucemia Mieloide , Estudios Transversales , Humanos , Hungría , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Masculino , Inhibidores de Proteínas Quinasas/efectos adversosRESUMEN
BACKGROUND/AIM: BCR-ABL tyrosine kinase inhibitors (TKIs) are exceptionally effective drugs in the treatment of chronic myeloid leukemia, nevertheless, TKIs have also an effect on platelets. We aimed to investigate the effect of a third-generation TKI, ponatinib on platelet functions. MATERIALS AND METHODS: Collagen-induced platelet aggregation and coated-platelet formation were examined using in vitro and in ex vivo samples of patients on ponatinib therapy. RESULTS: In platelet rich plasma of healthy volunteers, ponatinib at a supra-therapeutic concentration (1,000 nM) significantly impaired collagen induced platelet aggregation (p≤0.01) and reduced the formation of coated-platelets at 150 nM ponatinib concentration (p≤0.05). In addition, upon glycoprotein VI (GPVI) receptor activation, a significantly lower percentage of PAC1 binding platelets (p≤0.05) was observed at 1,000 nM final concentration of ponatinib. Platelets, isolated from patients on ponatinib therapy showed impaired collagen elicited aggregation response, already in pre-dose samples compared to healthy donors. CONCLUSION: The therapeutic concentration of ponatinib impairs platelet activation processes elicited by GPVI receptor agonists.
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Antineoplásicos/uso terapéutico , Plaquetas/efectos de los fármacos , Colágeno/farmacología , Imidazoles/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Agregación Plaquetaria/efectos de los fármacos , Piridazinas/uso terapéutico , Adulto , Anciano , Estudios de Casos y Controles , Femenino , Estudios de Seguimiento , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Masculino , Persona de Mediana Edad , PronósticoRESUMEN
B-cell prolymphocytic leukemia (B-PLL) is a rare disorder characterized by marked lymphocytosis in the peripheral blood, matured lymphocytic infiltration in the bone marrow and splenomegaly. It has a distinct immunophenotype (CD19, CD20, CD22, FMC7, intensive surface immunoglobulin positivity) which helps to differentiate from other lymphoproliferative malignancies. It has a poor prognosis and its treatment is unsettled. The authors present a case of a patient with typical B-PLL treated with FCR-Lite (fludarabine, cyclophosphamide, rituximab) protocol achieving complete hematological (and immunophenotypic) remission. The treatment was well tolerated. Neither major infective complication nor tumor lysis syndrome was observed. According to the author's experience the FCR-Lite protocol can not only be used in patients with CLL but it also can be effective in patients with B-PLL. No clinical experience has been reported yet in the literature with this protocol.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Prolinfocítica Tipo Células B/tratamiento farmacológico , Anciano , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales de Origen Murino , Ciclofosfamida/administración & dosificación , Diagnóstico Diferencial , Humanos , Inmunofenotipificación , Leucemia Prolinfocítica Tipo Células B/diagnóstico , Masculino , Pronóstico , Rituximab , Resultado del Tratamiento , Vidarabina/administración & dosificación , Vidarabina/análogos & derivadosRESUMEN
Chronic lymphocytic leukaemia (CLL) may transform to either malignant lymphoid disorder or increase the occurrence of solid neoplasms. However myeloid malignancies seldom develop. We report a case of a patient who has remained untreated for CLL and developed myelodysplastic syndrome (refracter anemia with ringed sideroblasts) six years after the diagnosis of CLL. Development of myelodysplastic syndrome resulted in concurrent attenuation of CLL. Discussion of the pathogenesis of myeloid disorders occurring with CLL and review of the literature are also presented.
Asunto(s)
Médula Ósea/patología , Leucemia Linfocítica Crónica de Células B/patología , Síndromes Mielodisplásicos/patología , Transfusión Sanguínea , Citogenética , Femenino , Citometría de Flujo , Hemoglobinas/metabolismo , Humanos , Leucemia Linfocítica Crónica de Células B/sangre , Recuento de Leucocitos , Recuento de Linfocitos , Persona de Mediana Edad , Síndromes Mielodisplásicos/sangre , Síndromes Mielodisplásicos/terapia , Recuento de PlaquetasRESUMEN
UNLABELLED: Five years ago (in September, 2003), the activity of the 5th Haemopoietic Stem Cell Transplantation Centre of Hungary has begun. This centre has been registered as No 648. by the European Group for Blood and Marrow Transplantation-Centres. AIMS: To supply the needs of stem cell transplantation regions in north-east Hungary and to develop an active co-operation with the Hungarian and international centres. METHODS: Transplantations were made according to international criteria. RESULTS: 150 autologous stem cell transplantations has been performed so far, including 74 patients with myeloma multiplex, 43 patients with non-Hodgkin lymphoma, 27 patients with Hodgkin's disease, 4 patients with autoimmune disease, and one patient with leiomyosarcoma. The survival rates were similar to the previous Hungarian and international data. The centre played a role in other activities using stem cell therapy at the University of Debrecen (dendritic cell vaccine program, stem cell therapy in myocardial infarction, stem cell therapy in peripheral arterial- and autoimmune diseases). This centre performed the largest quantity of the conditioning protocol Zevalin, Bischloronitrosourea, Etoposide, cytosine-Arabinoside, Melphalan in non-Hodgkin lymphoma in Hungary; ten patients were treated with this protocol.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Células Madre Hematopoyéticas , Acondicionamiento Pretrasplante/métodos , Anticuerpos Monoclonales/administración & dosificación , Enfermedades Autoinmunes/cirugía , Citarabina/administración & dosificación , Etopósido/administración & dosificación , Enfermedad de Hodgkin/cirugía , Humanos , Hungría , Cooperación Internacional , Estimación de Kaplan-Meier , Leiomiosarcoma/cirugía , Linfoma no Hodgkin/cirugía , Melfalán/administración & dosificación , Mieloma Múltiple/cirugía , Compuestos de Nitrosourea/administración & dosificación , Factores de Tiempo , Trasplante Autólogo , Resultado del TratamientoRESUMEN
The most aggressive and rare manifestation of multiple myeloma is plasma cell leukaemia (PCL). While secondary form of PCL represents those heavily pretreated cases when leukaemic transformation develops terminally after intensive chemotherapy in patients with multiple myeloma, primary cases are characterized by leukaemic symptoms present at diagnosis. The secondary form has a rapid progression. The management of PCL is still unsolved. The authors present a case of a patient with non-secretory multiple myeloma who had developed plasma cell leukaemia after peripheral stem cell transplantation. PAD (bortezomib, doxorubicin, dexamethasone) treatment resulted in complete remission and 9-month survival of the patient. Previous case reports in the literature and our experience have revealed PAD protocol to be well tolerated and effective in PCL. Combination of PAD treatment with autologous and/or allogenic stem cell transplantation might further improve patients' outcome.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia de Células Plasmáticas/tratamiento farmacológico , Leucemia de Células Plasmáticas/etiología , Mieloma Múltiple/complicaciones , Trasplante de Células Madre de Sangre Periférica , Anciano , Antibióticos Antineoplásicos/administración & dosificación , Antineoplásicos Hormonales/administración & dosificación , Ácidos Borónicos/administración & dosificación , Bortezomib , Dexametasona/administración & dosificación , Doxorrubicina/administración & dosificación , Humanos , Masculino , Mieloma Múltiple/cirugía , Pirazinas/administración & dosificación , Inducción de Remisión , Trasplante Autólogo , Resultado del TratamientoRESUMEN
Although hairy cell leukaemia and hairy cell leukaemia variant are characterized by much alike clinical features, these two diseases are disparate in nature and treatment. While hairy cell leukaemia responds quite well to 2-chlorodeoxyadenosine (cladribine) treatment, hairy cell leukaemia variant has much worse response rate and has no effective treatment option yet. With other treatment modalities, including monoclonal antibody treatment, we have less experience. Alemtuzumab (Campath-1H, MabCampath) treatment has been reported in a case with hairy cell leukaemia in relaps while there is no data with alemtuzumab therapy in the treatment of hairy cell leukaemia variant. The authors present their case of a 58 year-old male who has been diagnosed with hairy cell leukaemia variant upon clinical findings and lymphocyte phenotyping. Alemtuzumab treatment was started (3 x 30 mg/week s.c. for 12 weeks). After 8 weeks of treatment haematologic remission was achieved; flow cytometry has revealed only 1.5% malignant cells. Alemtuzumab treatment can be favourable in those cases of hairy cell leukaemia and hairy cell leukaemia variant which is dominated mainly by bone marrow infiltration and present no lymphadenomegaly or splenomegaly. In our case the p53 mutation had no influence on the outcome of alemtuzumab treatment.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Antineoplásicos/uso terapéutico , Antineoplásicos/uso terapéutico , Leucemia de Células Pilosas/tratamiento farmacológico , Alemtuzumab , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados , Anticuerpos Antineoplásicos/administración & dosificación , Antígenos CD/sangre , Antineoplásicos/administración & dosificación , Biomarcadores de Tumor/sangre , Esquema de Medicación , Humanos , Leucemia de Células Pilosas/sangre , Leucemia de Células Pilosas/patología , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
Chronic neutrophilic leukemia is an uncommon hematological entity. According to the WHO classification it is recognized as part of the family of myeloproliferative disorders. In the last 20 years seven patients have been diagnosed with chronic neutrophilic leukemia at our department. All but one had splenomegaly, two patients developed severe anaemia and in one case thrombocytosis was present at the time of diagnosis. White blood cell count ranged between 39 x 10(9)/1-71 x 10(9)/l with 80% of neutrophils and striking myeloid hyperplasia were present in the bone marrow without evidence of any dysplasia resembling chronic myelocytic leukemia. Granulocyte alkaline phosphatase scores were increased except one case and both cytogenetics (Philadelphia chromosome) and molecular biologic analysis (bcr/abl) revealed no alteration of any. Four patients have been followed up. Three of them died due to progression of chronic neutrophilic leukemia. One patient, initially receiving hydroxyurea + interferon therapy and showing progression, developed complete hematological remission with an eight week imatinib mesylate (Glivec) treatment. Beside of their own experiences the authors review the current literature and discuss differential diagnostic and therapeutic challenges, as well.