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1.
Br J Haematol ; 187(5): 615-626, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31394591

RESUMO

This observational, prospective study assessed, in a daily clinical practice, the molecular response, safety, quality of life (QoL) and treatment adherence in 183 patients with chronic myeloid leukaemia in chronic phase (CML-CP), receiving nilotinib as first-line treatment. Premature study termination before 24 months of follow-up occurred in 61 patients (33·3%), and was essentially due to nilotinib treatment discontinuation (n = 53; 29%), motivated by treatment intolerance (n = 29; 15·8%) and inefficacy (n = 19; 10·4%). After 24 months of treatment, 112/122 patients (91·8%) had a molecular assessment, 95·5% of whom achieved a major molecular response (MMR), 32·1% achieved uMR4 , defined as an undetectable molecular disease with 4-log molecular response sensitivity (≥10 000 ABL1 transcripts). The Morisky Green Levine Medication Adherence Scale was completed by 94/122 patients (77·0%), and 89·4% of these patients obtained a satisfactory level of treatment adherence, defined as a score ≥3. Patients' QoL was good at baseline and stable during the follow-up period. The two most common nilotinib-related adverse events (AEs) were pruritus (14·8%) and asthenia (13·7%). Seven patients (3·8%) experienced at least one cardiovascular ischaemic AE. This French nationwide cohort study provides relevant information in daily clinical practice indicating that nilotinib is a valuable first-line treatment option for CML-CP patients.


Assuntos
Antineoplásicos/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Pirimidinas/uso terapêutico , Qualidade de Vida , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Astenia/induzido quimicamente , Biomarcadores Tumorais/genética , Toxidermias/etiologia , Feminino , Seguimentos , Proteínas de Fusão bcr-abl/genética , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Masculino , Adesão à Medicação/estatística & dados numéricos , Pessoa de Meia-Idade , Estudos Prospectivos , Proteínas Tirosina Quinases/antagonistas & inibidores , Prurido/induzido quimicamente , Psicometria , Pirimidinas/efeitos adversos , Resultado do Tratamento , Adulto Jovem
3.
Hemoglobin ; 39(6): 438-41, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26291966

RESUMO

Methemoglobinemia can be acquired (oxidizing drugs or chemicals products) or inherited either by mutations affecting globin chains [M hemoglobins (M Hbs)] or by defects in the enzymatic system involved in the reduction of spontaneous Hb oxidation: nicotinamide adenine dinucleotide (NADH)-cytochrome b5 reductase. It is encoded by the CYB5R3 gene: there are two phenotypes of autosomal recessive congenital methemoglobinemia, in type II CYB5R deficiency is generalized and affects all cells, leading to an early onset, whereas in type I, the enzyme deficiency is restricted to erythrocytes, usually discovered in infancy but not exclusively. We report a new case of methemoglobinemia discovered in a patient from Bahrain who exhibited an unknown dyspnea at the age of 37 years without trigger events or oxidizing products. We discovered a new mutation in the CYB5R3 gene: exon 9, codon 266 (delGAG) (GLU) (CYB5R3: c.726_729delGAG) in the homozygous state. Appearance of methemoglobinemia in an adult usually suggests an acquired cause but our case illustrated that it could also reveal a type I mutation of cytochrome b5 reductase.


Assuntos
Citocromo-B(5) Redutase/genética , Genes Recessivos , Metemoglobinemia/diagnóstico , Metemoglobinemia/genética , Mutação , Adulto , Códon , Consanguinidade , Análise Mutacional de DNA , Índices de Eritrócitos , Éxons , Homozigoto , Humanos , Masculino , Metemoglobinemia/tratamento farmacológico , Linhagem , Fenótipo
5.
Blood Adv ; 7(14): 3582-3591, 2023 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-37042865

RESUMO

Momelotinib is the first inhibitor of Janus kinase 1 (JAK1) and JAK2 shown to also inhibit activin A receptor type 1 (ACVR1), a key regulator of iron homeostasis, and has demonstrated improvements in splenomegaly, constitutional symptoms, and anemia in myelofibrosis (MF). This long-term analysis pooled data from 3 randomized phase 3 studies of momelotinib (MOMENTUM, SIMPLIFY-1, and SIMPLIFY-2), representing MF disease from early (JAK inhibitor-naive) to late (JAK inhibitor-experienced) stages. Patients in the control arms (danazol in MOMENTUM, ruxolitinib in SIMPLIFY-1, and best available therapy in SIMPLIFY-2) could cross over to receive momelotinib at the end of the 24-week randomized period, and all patients could continue momelotinib treatment after the completion of these studies via an extended access protocol (XAP). Across these studies, 725 patients with MF received momelotinib; 12% remained on therapy for ≥5 years, with a median treatment exposure of 11.3 months (range, 0.1-90.4 months). The most common nonhematologic treatment-emergent adverse event (AE) occurring in ≥20% of patients was diarrhea (any grade, 27% and grade ≥3, 3%). Any-grade thrombocytopenia, anemia, and neutropenia occurred in 25%, 23%, and 7% of patients, respectively. The most common reason for momelotinib discontinuation was thrombocytopenia (4% discontinuation rate). The incidence of AEs of clinical importance (eg, infections, malignant transformation, peripheral neuropathy, and hemorrhage) did not increase over time. This analysis of one of the largest randomized trial databases for a JAK inhibitor to date in MF demonstrated a consistent safety profile of momelotinib without long-term or cumulative toxicity. These trials were registered at www.clinicaltrials.gov as: MOMENTUM (#NCT04173494), SIMPLIFY-1 (#NCT01969838), SIMPLIFY-2 (#NCT02101268), and XAP (#NCT03441113).


Assuntos
Anemia , Inibidores de Janus Quinases , Mielofibrose Primária , Trombocitopenia , Humanos , Mielofibrose Primária/diagnóstico , Inibidores de Janus Quinases/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Anemia/induzido quimicamente , Trombocitopenia/induzido quimicamente
6.
Kidney Int Rep ; 8(12): 2733-2741, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38106568

RESUMO

Introduction: Chronic myelomonocytic leukemia (CMML) is a hematologic disorder that is an overlap syndrome between myelodysplastic syndromes and myeloproliferative neoplasms, and can be associated with autoimmune and inflammatory diseases. This study aimed to describe kidney involvement in patients with CMML, their treatments, and outcomes. Methods: We conducted a French and American multicenter retrospective study in 15 centers, identifying patients with CMML with acute kidney injury (AKI), chronic kidney disease (CKD), and urine abnormalities. Results: Sixteen patients (males, n = 14; median age 76.5 years [71.9-83]) developed a kidney disease 6 months [1.6-25.6] after the diagnosis of CMML. At the time of kidney disease diagnosis, median urinary protein-to-creatinine ratio was 2 g/g [1.25-3.4], and median serum creatinine was 2.26 mg/dl [1.46-2.68]. Fourteen patients (87.5%) underwent a kidney biopsy, and the 2 main pathological findings were lysozyme nephropathy (56%) and renal infiltration by the CMML (37.5%). Ten patients received a new treatment following the CMML-associated kidney injury. Among patients with monitored kidney function, and after a median follow-up of 15 months [9.9-34.9], 4 patients had CKD stage 3, 4 had CKD stage 4, 1 had an end-stage kidney disease. In our patient series, 2 patients evolved to an acute myeloid leukemia (AML), and 5 died. Compared with 116 CMML controls, patients who had a kidney involvement had a higher monocyte count (P < 0.001), had more CMML-1 (P = 0.005), were more susceptible to develop an AML (P = 0.02), and were more eligible to receive a specific hematologic treatment, with hydroxyurea, or hypomethylating agents (P < 0.001), but no survival difference was seen between the 2 groups (P = 0.6978). Conclusion: In this cohort of patients with CMML with a kidney injury, the 2 most frequent renal complications were lysozyme-induced nephropathy and renal infiltration by the CMML. Kidney involvement should be closely monitored in patients with CMML.

8.
Cancers (Basel) ; 13(9)2021 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-33947035

RESUMO

Minimal residual disease (MRD) is now a powerful surrogate marker to assess the response to chemotherapy in acute myeloid leukemia (AML). DNMT3A mutation has been associated with adverse outcomes. In this study, we aimed to investigate the impact of DNMT3A status on NPM1 MRD predictive value for survival in a retrospective cohort of AML patients aged over 60 years old treated intensively. A total of 138 patients treated for NPM1-mutated AML in two French institutions were analyzed retrospectively. DNMT3A status did not influence the probability of having a ≥ 4log MRD1 reduction after induction. Only 20.4% of FLT3-ITD patients reached ≥ 4log MRD1 reduction compared to 47.5% in FLT3wt cases. A 4log reduction of NPM1 MRD was associated with a better outcome, even in FLT3-ITD mutated patients, independent of the allelic ratio. DNMT3A negative patients who reached a 4log reduction had a superior outcome to those who did not (HR = 0.23; p < 0.001). However, postinduction NPM1 MRD1 reduction was not predictive of OS and LFS in DNMT3Amut patients. These results confirm that post-induction NPM1 MRD1 is a reliable tool to assess disease outcome in elderly AML patients. However, the presence of DNMT3A also identifies a subgroup of patients at high risk of relapse.

9.
Leukemia ; 35(8): 2332-2345, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33483613

RESUMO

The STI571 prospective randomised trial (SPIRIT) French trial is a four-arm study comparing imatinib (IM) 400 mg versus IM 600 mg, IM 400 mg + cytarabine (AraC), and IM 400 mg + pegylated interferon alpha2a (PegIFN-α2a) for the front-line treatment of chronic-phase chronic myeloid leukaemia (CML). Long-term analyses included overall and progression-free survival, molecular responses to treatment, and severe adverse events. Starting in 2003, the trial included 787 evaluable patients. The median overall follow-up of the patients was 13.5 years (range 3 months to 16.7 years). Based on intention-to-treat analyses, at 15 years, overall and progression-free survival were similar across arms: 85%, 83%, 80%, and 82% and 84%, 87%, 79%, and 79% for the IM 400 mg (N = 223), IM 600 mg (N = 171), IM 400 mg + AraC (N = 172), and IM 400 mg + PegIFN-α2a (N = 221) arms, respectively. The rate of major molecular response at 12 months and deep molecular response (MR4) over time were significantly higher with the combination IM 400 mg + PegIFN-α2a than with IM 400 mg: p = 0.0001 and p = 0.0035, respectively. Progression to advanced phases and secondary malignancies were the most frequent causes of death. Toxicity was the main reason for stopping AraC or PegIFN-α2a treatment.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Citarabina/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Humanos , Mesilato de Imatinib/administração & dosagem , Interferon-alfa/administração & dosagem , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/administração & dosagem , Prognóstico , Estudos Prospectivos , Proteínas Recombinantes/administração & dosagem , Taxa de Sobrevida , Adulto Jovem
10.
Blood ; 112(8): 3065-72, 2008 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-18650451

RESUMO

Interferon-alpha (IFN-alpha) is a nonleukemogenic treatment of polycythemia vera (PV) able to induce cytogenetic remissions. Its use is limited by toxicity, leading to treatment discontinuation in approximately 20% of patients. We completed a phase 2 multicenter study of pegylated IFN-alpha-2a in 40 PV patients. Objectives included evaluation of efficacy, safety, and monitoring of residual disease using JAK2V617F quantification (%V617F). Median follow-up was 31.4 months. At 12 months, all 37 evaluable patients had hematologic response, including 94.6% complete responses (CRs). Only 3 patients (8%) had stopped treatment. After the first year, 35 patients remained in hematologic CR, including 5 who had stopped pegylated IFN-alpha-2a. Sequential samples for %V617F monitoring, available in 29 patients, showed %V617F decrease in 26 (89.6%). Median %V617F decreased from 45% before pegylated IFN-alpha-2a to 22.5%, 17.5%, 5%, and 3% after 12, 18, 24, and 36 months, respectively. Molecular CR (JAK2V617F undetectable) was achieved in 7 patients, lasting from 6(+) to 18(+) months, and persisted after pegylated IFN-alpha-2a discontinuation in 5. No vascular event was recorded. These results show that pegylated IFN-alpha-2a yields high rates of hematologic and molecular response in PV with limited toxicity, and could even eliminate the JAK2 mutated clone in selected cases. Available at www.clinicaltrials.gov as #NCT00241241.


Assuntos
Interferon-alfa/uso terapêutico , Policitemia Vera/sangue , Policitemia Vera/terapia , Polietilenoglicóis/uso terapêutico , Adulto , Portadores de Fármacos/uso terapêutico , Feminino , Humanos , Interferon alfa-2 , Janus Quinase 2/genética , Perda de Heterozigosidade , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas Recombinantes , Indução de Remissão , Fatores de Tempo , Resultado do Tratamento
13.
Curr Med Res Opin ; 26(2): 307-17, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19961284

RESUMO

OBJECTIVE: To assess real-life treatment practices with imatinib for chronic-phase chronic myeloid leukaemia (CP-CML) in France. RESEARCH DESIGN AND METHODS: In the observational 'Unmet Needs in CML' (UNIC) study of CML management in Europe, case report forms were completed retrospectively for eligible patients (> or =18 years of age, currently treated for CML) during enrolment (September 2006-March 2007). Results from the subset of patients from France are presented. MAIN OUTCOME MEASURES: Primary objectives were to estimate from the collected data the proportions of patients ever treated with imatinib and those experiencing imatinib resistance and/or intolerance as determined by physicians' diagnoses of resistance/intolerance leading to a change in imatinib use. Collected data were analysed descriptively. Secondary descriptive measures included imatinib dose modifications and methods for treatment response monitoring. RESULTS: Of the 654 French CP-CML patients, 95.9% had received imatinib. Of these, 15% were judged by physicians as imatinib-resistant and 31% as imatinib-intolerant (not mutually exclusive) during treatment, 44% required dose modification and 23% discontinued imatinib. In the 12 months preceding the last observation, 65% had a cytogenetic features analysis and 93% had a polymerase chain reaction (PCR) assessment of molecular response. Importantly, and contrasting with European recommendations, 46% of imatinib-resistant patients had never been assessed for BCR-ABL mutations. LIMITATIONS: The observational study design limits data collection and interpretation. The findings are specific to the French healthcare system and may not apply to other countries. CONCLUSION: This observational study of CP-CML management in France confirmed that most patients are treated with imatinib, a treatment widely recognised as efficacious. The study highlights opportunities for optimising CML management, as a proportion of patients may require alternative treatment strategies due to imatinib resistance/intolerance. Response monitoring rates differ from recommendations, representing another opportunity for improving care for CP-CML patients through early identification of patients failing current therapy.


Assuntos
Necessidades e Demandas de Serviços de Saúde , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Prática Profissional , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Feminino , França , Necessidades e Demandas de Serviços de Saúde/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Prática Profissional/estatística & dados numéricos , Estudos Retrospectivos , Adulto Jovem
14.
Eur J Haematol ; 77(2): 145-9, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16608501

RESUMO

BACKGROUND: Liver iron content (LIC) assessment by magnetic resonance imaging (MRI) is validated but not standardized. In a single center, we tried to assess the accuracy of a specific, simple MRI procedure adapted to high LIC from a well-established simple and routine procedure known to quantify LIC. METHODS: In 27 cases of monthly transfused patients, we compared biochemical values of LIC assessed on liver biopsy specimens and results obtained by two signal intensity ratio of gradient echo imaging (R2*) MRI protocols. The first was Gandon's routine procedure previously validated in liver disease and the second, our own method, was an addition of a gradient echo sequence specifically adapted to high LIC encountered in hematology practice. RESULTS: Twenty-seven liver biopsies were performed in 18 adult patients (myelodysplastic syndrome = 5, beta-thalassemia = 13). LIC by biopsy ranged from 1.4 to 54 mg/g liver dry weight (mg/g dw) (median 9.4 mg/g dw). Correlation between LIC by biopsy and by MRI with Gandon's procedure was good (R = 0.80) in patients with LIC falling within the range reported by Gandon. By contrast, a weak correlation was demonstrated (R = 0.52) in patients with high LIC (above 11.2 mg/g dw). With our sequences, the correlation was good both in the entire group of patients (R = 0.83) and in patients with LIC above 11.2 mg/g dw (R = 0.85). CONCLUSION: Our results suggest that the addition of a specific shorter-gradient echo sequence to a very simple, fast technique produces an accurate estimation of LIC in post-transfusional iron overload.


Assuntos
Sobrecarga de Ferro/diagnóstico , Ferro/análise , Fígado/química , Imageamento por Ressonância Magnética/métodos , Reação Transfusional , Adolescente , Adulto , Idoso , Biópsia , Feminino , Humanos , Sobrecarga de Ferro/metabolismo , Sobrecarga de Ferro/patologia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/patologia , Síndromes Mielodisplásicas/terapia , Talassemia beta/patologia , Talassemia beta/terapia
16.
Blood ; 108(6): 2037-40, 2006 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-16709929

RESUMO

V617F JAK2 mutation is a reliable molecular marker of polycythemia vera (PV), potentially useful to monitor the effect of treatments in this disease. In a phase 2 study of pegylated (peg) IFN-alpha-2a in PV, we performed prospective sequential quantitative evaluation of the percentage of mutated JAK2 allele (%V617F) by real-time polymerase chain reaction (PCR). The %V617F decreased in 24 (89%) of 27 treated patients, from a mean of 49% to a mean of 27% (mean decrease of 44%; P < .001), and no evidence for a plateau was observed. In one patient, mutant JAK2 was no longer detectable after 12 months. In 3 patients homozygous for the mutation, reappearance of 50% of wild-type allele was observed during treatment. The results seem to confirm the hypothesis that IFN-alpha preferentially targets the malignant clone in PV and show that %V617F assessment using a quantitative method may provide the first tool to monitor minimal residual disease in PV. This trial was registered at www.clinicaltrials.gov as #NCT00241241.


Assuntos
Interferon-alfa/uso terapêutico , Policitemia Vera/tratamento farmacológico , Policitemia Vera/genética , Polietilenoglicóis/uso terapêutico , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Adulto , Idoso , Feminino , Marcadores Genéticos , Humanos , Interferon alfa-2 , Janus Quinase 2 , Masculino , Pessoa de Meia-Idade , Mutação Puntual , Proteínas Recombinantes , Fatores de Tempo
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