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1.
Br J Haematol ; 204(4): 1139-1140, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38375783

RESUMO

Clinical research has not been able to establish whether the differences between first- and second-generation BCR-ABL 1 kinase inhibitors are clinically relevant with regard to outcome. In the study by Alcazer et al., a relevant difference seems to emerge-paradoxically in the absence of the drugs-as demonstrated by differences in the relapse kinetics after cessation of therapy. Commentary on: Alcazer et al. Kinetics of molecular recurrence after tyrosine kinase inhibitor cessation in chronic phase chronic myelogenous leukaemia patients. Br J Haematol 2024;204:1536-1539.


Assuntos
Proteínas de Fusão bcr-abl , Leucemia Mielogênica Crônica BCR-ABL Positiva , Humanos , Proteínas de Fusão bcr-abl/genética , Recidiva Local de Neoplasia/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico
3.
Acta Oncol ; 62(10): 1286-1294, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37656802

RESUMO

BACKGROUND: Patients with myeloproliferative neoplasms (MPNs) suffer from substantial symptoms and risk of debilitating complications, yet observational data on their labor market affiliation are scarce. MATERIAL AND METHODS: We conducted a descriptive cohort study using data from Danish nationwide registries, including patients diagnosed with MPN in 2010-2016. Each patient was matched with up to ten comparators without MPN on age, sex, level of education, and region of residence. We assessed pre- and post-diagnosis labor market affiliation, defined as working, unemployed, or receiving sickness benefit, disability pension, retirement pension, or other health-related benefits. Labor market affiliation was assessed weekly from two years pre-diagnosis until death, emigration, or 31 December 2018. For patients and comparators, we reported percentage point (pp) changes in labor market affiliation cross-sectionally from week -104 pre-diagnosis to week 104 post-diagnosis. RESULTS: The study included 3,342 patients with MPN and 32,737 comparators. From two years pre-diagnosis until two years post-diagnosis, a larger reduction in the proportion working was observed among patients than comparators (essential thrombocythemia: 10.2 [95% CI: 6.3-14.1] vs. 6.8 [95% CI: 5.5-8.0] pp; polycythemia vera: 9.6 [95% CI: 5.9-13.2] vs. 7.4 [95% CI: 6.2-8.7] pp; myelofibrosis: 8.1 [95% CI: 3.0-13.2] vs. 5.8 [95% CI: 4.2-7.5] pp; and unclassifiable MPN: 8.0 [95% CI: 3.0-13.0] vs. 7.4 [95% CI: 5.7-9.1] pp). Correspondingly, an increase in the proportion of patients receiving sickness benefits including other health-related benefits was evident around the time of diagnosis. CONCLUSION: Overall, we found that Danish patients with essential thrombocythemia, polycythemia vera, myelofibrosis, and unclassifiable MPN had slightly impaired labor market affiliation compared with a population of the same age and sex. From two years pre-diagnosis to two years post-diagnosis, we observed a larger reduction in the proportion of patients with MPN working and a greater proportion receiving sickness benefits compared with matched individuals.


Assuntos
Transtornos Mieloproliferativos , Policitemia Vera , Mielofibrose Primária , Trombocitemia Essencial , Humanos , Policitemia Vera/epidemiologia , Mielofibrose Primária/epidemiologia , Estudos de Coortes
4.
Eur J Haematol ; 109(5): 526-541, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35900040

RESUMO

Few studies have assessed healthcare resource utilization (HRU) in patients with Philadelphia-negative myeloproliferative neoplasms (MPN) using a matched cohort design. Further, no detailed assessment of HRU in the years preceding an MPN diagnosis exists. We conducted a registry-based nationwide Danish cohort study, including patients with essential thrombocythemia, polycythemia vera, myelofibrosis, and unclassifiable MPN diagnosed between January 2010 and December 2016. HRU data were summarized annually from 2 years before MPN diagnosis until emigration, death, or end of study (December 2017). We included 3342 MPN patients and 32 737 comparisons without an MPN diagnosis, matched on sex, age, region of residence, and level of education. During the study period, the difference in HRU (rate ratio) between patients and matched comparisons ranged from 1.0 to 1.5 for general practitioner contacts, 0.9 to 2.2 for hospitalizations, 0.9 to 3.8 for inpatient days, 1.0 to 4.0 for outpatient visits, 1.3 to 2.1 for emergency department visits, and 1.0 to 4.1 for treatments/examinations. In conclusion, MPN patients had overall higher HRU than the matched comparisons throughout the follow-up period (maximum 8 years). Further, MPN patients had substantially increased HRU in both the primary and secondary healthcare sector in the 2 years preceding the diagnosis.


Assuntos
Transtornos Mieloproliferativos , Policitemia Vera , Estudos de Coortes , Atenção à Saúde , Dinamarca/epidemiologia , Humanos , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/epidemiologia , Transtornos Mieloproliferativos/terapia , Policitemia Vera/complicações
5.
Eur J Haematol ; 107(6): 617-623, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34418168

RESUMO

OBJECTIVES: Treatment-free remission (TFR) has emerged as a treatment goal in chronic myeloid leukemia in the chronic phase (CML-CP). Attempts to increase proportion of patients achieving TFR include combination of tyrosine kinase inhibitors (TKI) and other drugs. Interferon-α in addition to TKI has shown promising efficacy but with dose-dependent toxicity and discontinuations. NordCML007 was initiated to study the efficacy and safety of low dose pegylated IFN-α (PegIFN-α) in combination with dasatinib (DAS) in CML-CP. METHODS: Forty patients with newly diagnosed CML-CP were given DAS upfront. After month 3 (M3) 15 µg/wk of PegIFN-α was added and increased to 25 µg/wk from M7 until M15. DAS treatment was continued and adverse events and BCR-ABL1 qRT-PCR values were reported yearly after M24. Results from M1 to M18 have previously been published, and here we present long-term data. RESULTS: After 5 years of follow-up, there were no suspected unexpected serious adverse reactions, no increase in serosal effusions, no disease progressions and no CML-related deaths. Rates of MR3.0 (MMR), MR4.0 and MR4.5 were 84.6%, 64.1% and 51.3% respectively at M60, and 95% of patients reached MMR at some point during the study. CONCLUSION: Initial addition of PegIFN-α to DAS shows good long-term efficacy without increased toxicity.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Dasatinibe/uso terapêutico , Interferon-alfa/uso terapêutico , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Polietilenoglicóis/uso terapêutico , Adulto , Idoso , Dasatinibe/administração & dosagem , Feminino , Seguimentos , Humanos , Interferon-alfa/administração & dosagem , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/administração & dosagem , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/uso terapêutico , Resultado do Tratamento , Adulto Jovem
6.
Haematologica ; 105(10): 2432-2439, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33054083

RESUMO

Myeloid and lymphoid malignancies are postulated to have distinct pathogenetic mechanisms. The recent observation that patients with a myeloproliferative neoplasm have an increased risk of developing lymphoproliferative malignancy has challenged this assumption. We collected a nationwide cohort of patients with both malignancies. Patients diagnosed in 1990-2015 were identified through the national Danish Pathology Registry. We identified 599 patients with myeloproliferative neoplasm and a concomitant or subsequent diagnosis of lymphoma. Histopathological review of the diagnostic samples from each patient led to a final cohort of 97 individuals with confirmed dual diagnoses of myeloproliferative neoplasm and lymphoma. The age range at diagnosis was 19-94 years (median: 71 years). To avoid the inclusion of cases of therapy-induced myeloproliferative neoplasm occurring in patients previously treated for lymphoma, only patients with myeloproliferative neoplasm diagnosed unequivocally before the development of lymphoma were included. The average time interval between the diagnoses of the two malignancies was 1.5 years. In the majority of patients (90%) both diagnoses were established within 5 years from each other. Among the lymphoma entities, the frequency of peripheral T-cell lymphomas was markedly increased. Interestingly, all but one of the T-cell lymphomas were of angioimmunoblastic type. These findings suggest that myeloproliferative neoplasm and lymphoproliferative malignancy developing in the same patient may have common pathogenetic events, possibly already at progenitor level. We believe that the molecular characterization of the newly developed biorepository will help to highlight the mechanisms driving the genesis and clonal evolution of these hematopoietic malignancies.


Assuntos
Doenças Hematológicas , Neoplasias Hematológicas , Linfoma de Células T Periférico , Transtornos Mieloproliferativos , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/epidemiologia , Neoplasias Hematológicas/etiologia , Humanos , Pessoa de Meia-Idade , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/epidemiologia , Adulto Jovem
7.
Blood ; 129(17): 2384-2394, 2017 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-28122740

RESUMO

Understanding leukemia heterogeneity is critical for the development of curative treatments as the failure to eliminate therapy-persistent leukemic stem cells (LSCs) may result in disease relapse. Here we have combined high-throughput immunophenotypic screens with large-scale single-cell gene expression analysis to define the heterogeneity within the LSC population in chronic phase chronic myeloid leukemia (CML) patients at diagnosis and following conventional tyrosine kinase inhibitor (TKI) treatment. Our results reveal substantial heterogeneity within the putative LSC population in CML at diagnosis and demonstrate differences in response to subsequent TKI treatment between distinct subpopulations. Importantly, LSC subpopulations with myeloid and proliferative molecular signatures are proportionally reduced at a higher extent in response to TKI therapy compared with subfractions displaying primitive and quiescent signatures. Additionally, cell surface expression of the CML stem cell markers CD25, CD26, and IL1RAP is high in all subpopulations at diagnosis but downregulated and unevenly distributed across subpopulations in response to TKI treatment. The most TKI-insensitive cells of the LSC compartment can be captured within the CD45RA- fraction and further defined as positive for CD26 in combination with an aberrant lack of cKIT expression. Together, our results expose a considerable heterogeneity of the CML stem cell population and propose a Lin-CD34+CD38-/lowCD45RA-cKIT-CD26+ population as a potential therapeutic target for improved therapy response.


Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Células-Tronco Neoplásicas/efeitos dos fármacos , Inibidores de Proteínas Quinases/uso terapêutico , Análise de Célula Única/métodos , ADP-Ribosil Ciclase 1/deficiência , ADP-Ribosil Ciclase 1/genética , ADP-Ribosil Ciclase 1/imunologia , Antígenos CD34/genética , Antígenos CD34/imunologia , Biomarcadores Tumorais/imunologia , Estudos de Casos e Controles , Linhagem da Célula/imunologia , Dipeptidil Peptidase 4/genética , Dipeptidil Peptidase 4/imunologia , Expressão Gênica , Heterogeneidade Genética , Humanos , Imunofenotipagem , Proteína Acessória do Receptor de Interleucina-1/genética , Proteína Acessória do Receptor de Interleucina-1/imunologia , Subunidade alfa de Receptor de Interleucina-2/genética , Subunidade alfa de Receptor de Interleucina-2/imunologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/imunologia , Antígenos Comuns de Leucócito/deficiência , Antígenos Comuns de Leucócito/genética , Antígenos Comuns de Leucócito/imunologia , Células-Tronco Neoplásicas/imunologia , Células-Tronco Neoplásicas/patologia , Proteínas Proto-Oncogênicas c-kit/deficiência , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/imunologia , Resultado do Tratamento
8.
Platelets ; 29(3): 270-276, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-28409645

RESUMO

Whole blood aggregometry is a functional assay for determination of platelet function. Until now, whole blood aggregometry has not been considered feasible at low platelet counts. Hence, the objectives of the present study were to explore platelet function in thrombocytopenia using a novel index of impedance aggregometry adjusted for platelet count and evaluate the association to platelet function assessed by flow cytometry. Hirudin anticoagulated blood was collected from 20 healthy volunteers, 20 patients with primary immune thrombocytopenia (ITP), and 17 hematological cancer patients. Platelet function was analyzed by impedance aggregometry and by flow cytometry. Collagen, adenosine diphosphate, thrombin receptor agonist peptide-6, and ristocetin were used as agonists for both analyses. Thrombocytopenia in healthy whole blood was induced in vitro employing a recently published method. Platelet aggregation of thrombocytopenic patients was evaluated relative to the aggregation of healthy volunteers at the same platelet count. In flow cytometry, platelet function was described as expression of the platelet surface glycoproteins: bound fibrinogen, CD63, and P-selectin. Similar platelet counts were obtained in the patient groups (p = 0.69) (range: 13-129 × 109/l). Aggregation adjusted for platelet count was significantly increased in ITP patients compared to healthy platelets across all agonists. The platelet aggregation was high in the 95% prediction interval, with 18 ITP patients above the prediction interval in at least two agonists. In contrast, the platelet aggregation was low in the prediction interval in cancer patients, and three cancer patients with platelet aggregation below the prediction interval in at least one agonist. ITP patients displayed increased expression of bound fibrinogen and CD63 following activation, compared with particularly cancer patients, but also compared with healthy platelets. This study demonstrated the feasibility of a novel approach to perform platelet function analyses in thrombocytopenia using impedance aggregometry adjusted for platelet count.


Assuntos
Plaquetas/metabolismo , Testes de Função Plaquetária , Trombocitopenia/sangue , Biomarcadores , Plaquetas/efeitos dos fármacos , Estudos de Casos e Controles , Citometria de Fluxo , Humanos , Imunofenotipagem , Agregação Plaquetária/efeitos dos fármacos , Contagem de Plaquetas , Trombocitopenia/diagnóstico , Trombocitopenia/etiologia
9.
Haematologica ; 102(8): 1361-1367, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28522574

RESUMO

Monitoring of single cell signal transduction in leukemic cellular subsets has been proposed to provide deeper understanding of disease biology and prognosis, but has so far not been tested in a clinical trial of targeted therapy. We developed a complete mass cytometry analysis pipeline for characterization of intracellular signal transduction patterns in the major leukocyte subsets of chronic phase chronic myeloid leukemia. Changes in phosphorylated Bcr-Abl1 and the signaling pathways involved were readily identifiable in peripheral blood single cells already within three hours of the patient receiving oral nilotinib. The signal transduction profiles of healthy donors were clearly distinct from those of the patients at diagnosis. Furthermore, using principal component analysis, we could show that phosphorylated transcription factors STAT3 (Y705) and CREB (S133) within seven days reflected BCR-ABL1IS at three and six months. Analyses of peripheral blood cells longitudinally collected from patients in the ENEST1st clinical trial showed that single cell mass cytometry appears to be highly suitable for future investigations addressing tyrosine kinase inhibitor dosing and effect. (clinicaltrials.gov identifier: 01061177).


Assuntos
Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Pirimidinas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Análise de Célula Única/métodos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteínas de Fusão bcr-abl/metabolismo , Humanos , Leucemia Mieloide de Fase Crônica/patologia , Leucócitos/metabolismo , Fosforilação , Proteínas Tirosina Quinases/uso terapêutico , Pirimidinas/farmacologia , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/imunologia
11.
Leukemia ; 38(4): 781-787, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38278960

RESUMO

Tyrosine kinase inhibitor (TKI) discontinuation in chronic myeloid leukemia (CML) has become part of routine care for patients with a sustained deep molecular response (DMR). Approximately 50% experience a molecular relapse upon TKI cessation. Most of them quickly regain DMR upon TKI resumption. Whether these patients can achieve a second treatment-free remission (TFR) remains unclear. DAstop2 (ClinicalTrials.gov ID: NCT03573596) is a prospective study including patients with a failed first TFR attempt re-treated with any TKI for ≥ one year. Upon entering the study, patients received the TKI dasatinib for additional two years. Patients with sustained DMR for ≥1 year qualified for a second TKI stop. Ninety-four patients were included between Oct 2017-Dec 2021. At the time of data analysis, 62 patients had attempted a 2nd stop. After a median follow-up of 27 months from 2nd stop, TFR rates were 61, 56 and 46% at 6, 12 and 24 months respectively. No progression to advanced stage disease was seen and 87% had re-achieved MR4 within a median of 3 months from TKI re-initiation. In summary, we show that a 2nd TFR attempt after dasatinib treatment is safe, feasible and TFR rates seem in the range of those reported in trials of a first TKI stop.


Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Inibidores de Proteínas Quinases , Humanos , Dasatinibe/efeitos adversos , Estudos Prospectivos , Inibidores de Proteínas Quinases/efeitos adversos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Indução de Remissão , Resultado do Tratamento
12.
Br J Haematol ; 160(2): 228-36, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23151086

RESUMO

Haemostatic treatment modalities alternative to platelet transfusion are desirable to control serious acute bleeds in primary immune thrombocytopenia (ITP). This study challenged the hypothesis that recombinant activated factor VII (rFVIIa) combined with fibrinogen concentrate may correct whole blood (WB) clot formation in ITP. Blood from ITP patients (n = 12) was drawn into tubes containing 3·2% citrate and corn trypsin inhibitor 18·3 µg/ml. WB [mean platelet count 22 × 10(9) /l (range 0-42)] was spiked in vitro with buffer, donor platelets (+40 × 10(9) /l), rFVIIa (1 or 4 µg/ml), fibrinogen (1 or 3 mg/ml), or combinations of rFVIIa and fibrinogen. Coagulation profiles were recorded by tissue factor (0·03 pmol/l) activated thromboelastometry. Coagulation in ITP was characterized by a prolonged clotting time (CT, 1490 s (mean)) and a low maximum velocity (MaxVel, 3·4 mm × 100/s) and maximum clot firmness (MCF, 38·2 mm). Fibrinogen showed no haemostatic effect, whereas rFVIIa reduced the CT and increased the MaxVel. The combination of fibrinogen and rFVIIa revealed a significant synergistic effect, improving all parameters (CT 794 s, MaxVel 7·9 mm × 100/s, MCF 50·7 mm) even at very low platelet counts. These data suggest that rFVIIa combined with fibrinogen corrects the coagulopathy of ITP even at very low platelet counts, and may represent an alternative to platelet transfusion.


Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Fator VIIa/farmacologia , Fibrinogênio/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Contagem de Plaquetas , Púrpura Trombocitopênica Idiopática/sangue , Adulto , Idoso , Avaliação Pré-Clínica de Medicamentos , Sinergismo Farmacológico , Fator VIIa/administração & dosagem , Feminino , Fibrinogênio/administração & dosagem , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Técnicas In Vitro , Masculino , Pessoa de Meia-Idade , Plasma Rico em Plaquetas , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Púrpura Trombocitopênica Idiopática/terapia , Receptores Fc/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacologia , Tromboelastografia , Trombina/biossíntese , Tromboplastina/farmacologia , Trombopoetina/uso terapêutico
13.
Blood ; 118(12): 3228-35, 2011 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-21685374

RESUMO

Biologic and clinical observations suggest that combining imatinib with IFN-α may improve treatment outcome in chronic myeloid leukemia (CML). We randomized newly diagnosed chronic-phase CML patients with a low or intermediate Sokal risk score and in imatinib-induced complete hematologic remission either to receive a combination of pegylated IFN-α2b (Peg-IFN-α2b) 50 µg weekly and imatinib 400 mg daily (n = 56) or to receive imatinib 400 mg daily monotherapy (n = 56). The primary endpoint was the major molecular response (MMR) rate at 12 months after randomization. In both arms, 4 patients (7%) discontinued imatinib treatment (1 because of blastic transformation in imatinib arm). In addition, in the combination arm, 34 patients (61%) discontinued Peg-IFN-α2b, most because of toxicity. The MMR rate at 12 months was significantly higher in the imatinib plus Peg-IFN-α2b arm (82%) compared with the imatinib monotherapy arm (54%; intention-to-treat, P = .002). The MMR rate increased with the duration of Peg-IFN-α2b treatment (< 12-week MMR rate 67%, > 12-week MMR rate 91%). Thus, the addition of even relatively short periods of Peg-IFN-α2b to imatinib markedly increased the MMR rate at 12 months of therapy. Lower doses of Peg-IFN-α2b may enhance tolerability while retaining efficacy and could be considered in future protocols with curative intent.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Interferon-alfa/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva , Piperazinas/uso terapêutico , Polietilenoglicóis/uso terapêutico , Pirimidinas/uso terapêutico , Indução de Remissão/métodos , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzamidas , Biomarcadores/análise , Cálculos da Dosagem de Medicamento , Feminino , Proteínas de Fusão bcr-abl/análise , Proteínas de Fusão bcr-abl/biossíntese , Humanos , Mesilato de Imatinib , Interferon-alfa/administração & dosagem , Interferon-alfa/efeitos adversos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Pessoa de Meia-Idade , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/efeitos adversos , Reação em Cadeia da Polimerase , Proteínas Tirosina Quinases/análise , Proteínas Tirosina Quinases/biossíntese , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Fatores de Risco , Resultado do Tratamento
14.
J Clin Invest ; 132(17)2022 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-36047494

RESUMO

In chronic myeloid leukemia (CML), combination therapies with tyrosine kinase inhibitors (TKIs) aim to improve the achievement of deep molecular remission that would allow therapy discontinuation. IFN-α is one promising candidate, as it has long-lasting effects on both malignant and immune cells. In connection with a multicenter clinical trial combining dasatinib with IFN-α in 40 patients with chronic-phase CML (NordCML007, NCT01725204), we performed immune monitoring with single-cell RNA and T cell receptor (TCR) sequencing (n = 4, 12 samples), bulk TCRß sequencing (n = 13, 26 samples), flow cytometry (n = 40, 106 samples), cytokine analyses (n = 17, 80 samples), and ex vivo functional studies (n = 39, 80 samples). Dasatinib drove the immune repertoire toward terminally differentiated NK and CD8+ T cells with dampened functional capabilities. Patients with dasatinib-associated pleural effusions had increased numbers of CD8+ recently activated effector memory T (Temra) cells. In vitro, dasatinib prevented CD3-induced cell death by blocking TCR signaling. The addition of IFN-α reversed the terminally differentiated phenotypes and increased the number of costimulatory intercellular interactions and the number of unique putative epitope-specific TCR clusters. In vitro IFN-α had costimulatory effects on TCR signaling. Our work supports the combination of IFN-α with TKI therapy, as IFN-α broadens the immune repertoire and restores immunological function.


Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Linfócitos T CD8-Positivos , Citocinas/metabolismo , Dasatinibe/farmacologia , Dasatinibe/uso terapêutico , Humanos , Interferon-alfa , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico
15.
Blood Adv ; 6(7): 2107-2119, 2022 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-34507355

RESUMO

Although somatic mutations influence the pathogenesis, phenotype, and outcome of myeloproliferative neoplasms (MPNs), little is known about their impact on molecular response to cytoreductive treatment. We performed targeted next-generation sequencing (NGS) on 202 pretreatment samples obtained from patients with MPN enrolled in the DALIAH trial (A Study of Low Dose Interferon Alpha Versus Hydroxyurea in Treatment of Chronic Myeloid Neoplasms; #NCT01387763), a randomized controlled phase 3 clinical trial, and 135 samples obtained after 24 months of therapy with recombinant interferon-alpha (IFNα) or hydroxyurea. The primary aim was to evaluate the association between complete clinicohematologic response (CHR) at 24 months and molecular response through sequential assessment of 120 genes using NGS. Among JAK2-mutated patients treated with IFNα, those with CHR had a greater reduction in the JAK2 variant allele frequency (median, 0.29 to 0.07; P < .0001) compared with those not achieving CHR (median, 0.27 to 0.14; P < .0001). In contrast, the CALR variant allele frequency did not significantly decline in those achieving CHR or in those not achieving CHR. Treatment-emergent mutations in DNMT3A were observed more commonly in patients treated with IFNα compared with hydroxyurea (P = .04). Furthermore, treatment-emergent DNMT3A mutations were significantly enriched in IFNα-treated patients not attaining CHR (P = .02). A mutation in TET2, DNMT3A, or ASXL1 was significantly associated with prior stroke (age-adjusted odds ratio, 5.29; 95% confidence interval, 1.59-17.54; P = .007), as was a mutation in TET2 alone (age-adjusted odds ratio, 3.03; 95% confidence interval, 1.03-9.01; P = .044). At 24 months, we found mutation-specific response patterns to IFNα: (1) JAK2- and CALR-mutated MPN exhibited distinct molecular responses; and (2) DNMT3A-mutated clones/subclones emerged on treatment.


Assuntos
Hidroxiureia , Transtornos Mieloproliferativos , Genômica , Humanos , Hidroxiureia/uso terapêutico , Interferon-alfa/uso terapêutico , Mutação , Transtornos Mieloproliferativos/tratamento farmacológico , Transtornos Mieloproliferativos/genética
17.
Ugeskr Laeger ; 183(42)2021 10 18.
Artigo em Dinamarquês | MEDLINE | ID: mdl-34709157

RESUMO

Recent studies have shown the Philadelphia-negative myeloproliferative neoplasms (MPN) to be massively underdiagnosed and often preceded by a long pre-diagnostic phase of several years, in which many patients suffer serious vascular events. In this review, we focus on the urgent need for earlier diagnosis and treatment of MPN. Such efforts are foreseen to decrease morbidity and mortality for the individual patients and potentially reduce costs for health and social care systems.


Assuntos
Transtornos Mieloproliferativos , Neoplasias , Doenças Vasculares , Contagem de Células Sanguíneas , Humanos , Transtornos Mieloproliferativos/diagnóstico
18.
Leukemia ; 35(5): 1344-1355, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33707652

RESUMO

The ENESTfreedom trial assessed the feasibility of treatment-free remission (TFR) in patients with chronic myeloid leukemia in chronic phase (CML-CP) following frontline nilotinib treatment. Results for long-term outcomes after a 5-year follow-up are presented herein. Patients who had received ≥2 years of frontline nilotinib therapy and achieved MR4.5 underwent a 1-year nilotinib treatment consolidation phase before attempting TFR. At the 5-year data cut-off, 81/190 patients entering the TFR phase (42.6%) were still in TFR, with 76 (40.0%) in MR4.5. Patients who lost major molecular response (MMR) entered a treatment re-initiation phase; 90/91 patients entering this phase (98.9%) regained MMR and 84/91 patients (92.3%) regained MR4.5. The Kaplan-Meier estimated treatment-free survival rate at 5 years was 48.2%. No disease progression or CML-related deaths were reported. Whereas the incidence of adverse events (AEs) declined from 96 weeks following the start of TFR, an increase in AE frequency was observed for patients in the treatment re-initiation phase. Low Sokal risk score, BCR-ABL1IS levels at 48 weeks of TFR and stable MR4.5 response for the first year of TFR were associated with higher TFR rates. Overall, these results support the efficacy and safety of attempting TFR following upfront nilotinib therapy of >3 years in patients with CML-CP.


Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Adolescente , Feminino , Humanos , Estimativa de Kaplan-Meier , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Leucemia Mieloide de Fase Crônica/mortalidade , Masculino , Taxa de Sobrevida , Resultado do Tratamento
19.
Oncoimmunology ; 8(9): e1638210, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31428530

RESUMO

Changes in the immune system induced by tyrosine kinase inhibitors (TKI) have been shown to positively correlate with therapy responses in chronic myeloid leukemia (CML). However, only a few longitudinal studies exist and no randomized comparisons between two TKIs have been reported. Therefore, we prospectively analyzed the immune system of newly diagnosed CML patients treated with imatinib (n = 20) or bosutinib (n = 13), that participated in the randomized BFORE trial (NCT02130557). Comprehensive immunophenotyping, plasma protein profiling, and functional assays to determine activation levels of T and NK cells were performed at diagnosis, 3, and 12 months after therapy start. All results were correlated with clinical parameters such as Sokal risk and BCR-ABL load measured according to IS%. At diagnosis, low Sokal risk CML patients had a higher frequency of cytotoxic cells (CD8 + T and NK cells), increased cytotoxic potential of NK cells and lower frequency of naïve and central memory CD4 + T cells. Further, soluble plasma protein profile divided patients into two distinct clusters with different disease burden at diagnosis. During treatment, BCR-ABL IS% correlated with immunological parameters such as plasma proteins, together with different memory subsets of CD4+ and CD8 + T cells. Interestingly, the proportion and cytotoxic potential of NK cells together with several soluble proteins increased during imatinib treatment. In contrast, no major immunological changes were observed during bosutinib treatment. In conclusion, imatinib and bosutinib were shown to have differential effects on the immune system in this randomized clinical trial. Increased number and function of NK cells were especially observed during imatinib therapy.

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