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2.
Haematologica ; 2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33626866

RESUMO

Myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) are associated with systemic inflammatory or autoimmune diseases in 10-20 % of cases. Among them, immune thrombocytopenia (ITP) has been reported but large studies assessing this association are missing. Whether such patients have a particular phenotype and require particular management is unclear. This study analyzes the clinical spectrum, outcome and therapeutic management of patients with ITP associated with MDS or CMML, in comparison (i) to patients with primary ITP without MDS/CMML and (ii) to patients with MDS/CMML without ITP. Forty-one MDS/CMML-associated ITP patients were included, with chronic ITP in 26 (63%) patients, low-risk myelodysplasia in 30 (73%) patients and CMML in 24 (59%) patients. An associated autoimmune disease was noted in 10 (24%) patients. In comparison to primary ITP patients, MDS/CMML-associated ITP patients had a higher occurrence of severe bleeding despite similar platelet counts at diagnosis. First-line treatment consisted of glucocorticoids (98%) and intravenous immunoglobulin (IVIg) (56%). Response achievement with IVIg was more frequent in primary ITP than in MDS/CMML-associated ITP patients. Response rates to second-line therapies were not statistically different between primary ITP and MDS/CMMLassociated ITP patients. Ten percent (n=4) of patients with MDS/CMML-associated ITP had multirefractory ITP versus none in primary ITP controls. After a median follow-up of 60 months, there was no difference in overall survival between MDS/CMML-associated ITP and primary ITP patients. Leukemia-free-survival was significantly better in MDS/CMMLassociated ITP patients than in MDS/CMML without ITP MDS/CMML-associated ITP have a particular outcome with more severe bleeding and multirefractory profile than primary ITP, similar response profile to primary ITP therapy except for IVIg, and less progression toward acute myeloid leukemia than MDS/CMML without ITP.

3.
Artigo em Inglês | MEDLINE | ID: mdl-33164099

RESUMO

OBJECTIVES: Systemic inflammatory and autoimmune diseases can be associated with myelodysplastic syndromes. Current treatments (steroids, immunosuppressive agents, biologics) are unsatisfactory because of their low response rate, dependence or adverse events. We aimed at evaluating the effects of low doses of IL-2 (ld-IL2) as a regulatory T-cell inducer in this context. METHODS: We treated three patients with ld-IL2 with myelodysplastic syndromes and an associated dysimmune disorder (polymyalgia rheumatic, relapsing polychondritis associated with Sweet's syndrome and vasculitis with cutaneous and joint involvement, respectively). All three patients were dependent on steroids and refractory to biologics or azacitidine. They received doses of 1-1.5 million units of proleukin/day during 5 days and then every fortnight. RESULTS: The treatment led to a clinical improvement and steroid sparing in 2/3 patients with no serious adverse events, and no progression of the disease. CONCLUSION: Our results support the investigation of ld-IL2 in MDS associated with immune disorders in controlled clinical studies.

10.
Cancer Med ; 8(8): 3846-3854, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31173485

RESUMO

A recent phase 3 trial showed that outcome of older patients with secondary acute myeloid leukemia (AML) may be improved by a liposomal encapsulation of cytarabine and daunorubicin (CPX-351). This phase 3 study represents a unique example of prospective data in this rare subgroup providing basis for comparison with real life data. Here, we retrospectively assessed characteristics and outcome of patients aged 60-75 years with secondary or therapy-related AML in real life. Out of 218 patients that fulfilled CPX-351 study criteria, 181 patients (83.0%) received antileukemic treatment either intensive chemotherapy (n = 121) or hypomethylating agents (HMA, n = 60). As compared with patients treated by chemotherapy, HMA-treated patients were older, had lower WBC, more often AML with antecedent myelodysplastic syndrome and adverse cytogenetic risk. In chemotherapy-treated patients, the complete response rate was 69%, median overall survival (OS) was 11 months whereas 3-year and 5-year OS was 21% and 17%, respectively. In HMA-treated patients, the complete response rate was 15%, median OS was 11 months whereas 3-year and 5-year OS was 15% and 2%, respectively. In conclusion, although outcome of older patients with high-risk AML is very poor, a significant proportion of patients treated by standard intensive chemotherapy but not HMA are long-term survivors.


Assuntos
Leucemia Mieloide Aguda/epidemiologia , Segunda Neoplasia Primária/epidemiologia , Fatores Etários , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Comorbidade , Feminino , Humanos , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/etiologia , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Segunda Neoplasia Primária/diagnóstico , Segunda Neoplasia Primária/etiologia , Segunda Neoplasia Primária/terapia , Avaliação de Resultados da Assistência ao Paciente , Prognóstico , Resultado do Tratamento
11.
Lancet Haematol ; 6(1): e48-e57, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30528137

RESUMO

BACKGROUND: Anti-programmed cell death 1 (PD-1) and anti-programmed cell death ligand 1 (PD-L1) antibodies are novel immunotherapies for cancer that can induce immune-related adverse events (irAEs). These adverse events can involve all organs, including the haemopoietic system. Thus far, haematological irAEs (haem-irAEs) have not been extensively characterised. This study aims to provide a comprehensive report of the haem-irAEs induced by anti-PD-1 or anti-PD-L1. METHODS: In this descriptive observational study, we included consecutive patients aged at least 18 years with grade 2 or worse haem-irAEs induced by anti-PD-1 or anti-PD-L1 immunotherapy registered in three French pharmacovigilance databases: the Registre des Effets Indésirables Sévères des Anticorps Monoclonaux Immunomodulateurs en Cancérologie (REISAMIC; a prospective registry of patients treated with anti-PD-1 or anti-PD-L1 at a single centre), the ImmunoTOX committee of Gustave Roussy (a national referral database of suspected irAEs in patients treated with immunotherapy), and the registry of the Centre de Référence des Cytopénies Auto-Immunes de l'Adulte (CeReCAI; a national database of autoimmune cytopenias). Cases were reviewed by a central committee; adverse events had to be classed as certainly or probably related to anti-PD-1 or anti-PD-L1 therapy, and their severity was assessed according to the Common Terminology Criteria for Adverse Events (version 4.03). The primary endpoint was clinical description of haem-irAEs, as reported in all databases, and their frequency, as reported in the prospective REISAMIC registry. FINDINGS: We screened 948 patients registered in the three databases from June 27, 2014, to June 29, 2018 (745 from REISAMIC, 190 from the ImmunoTOX committee, and 13 from CeReCAI). 35 patients (21 men and 14 women) with haem-irAEs related to anti-PD-1 or anti-PD-L1 were included in the study. Of 745 patients in the REISAMIC registry treated with anti-PD-1 or anti-PD-L1, four had haem-irAEs, giving a frequency of 0·5%. Median age in the 35 patients was 65 years (IQR 51-75), and the most common tumour types were melanoma (15 [43%] patients), non-small-cell lung cancer (12 [34%] patients), and lymphoma (four [11%] patients). 20 (57%) patients received nivolumab, 14 (40%) received pembrolizumab, and one (3%) received atezolizumab. Among the 35 patients, neutropenia, autoimmune haemolytic anaemia, and immune thrombocytopenia were the most common types of haem-irAE (each in nine patients [26%]), followed by pancytopenia or aplastic anaemia (five patients [14%]), bicytopenia (one patients with thrombocytopenia plus anaemia and one patient with neutropenia plus anaemia [6%]), and pure red cell aplasia (one patient [3%]). The maximum grade of severity was grade 2 in three (9%) patients, grade 3 in five (14%) patients, and grade 4 in 25 (71%) patients; two (6%) patients died from febrile neutropenia during haem-irAE related to anti-PD-1. Haem-irAEs resolved in 21 (60%) of the 35 patients. INTERPRETATION: Haem-irAEs induced by PD-1 or PD-L1 inhibitors are rare but potentially life-threatening events. The most common clinical presentations are neutropenia, autoimmune haemolytic anaemia, immune thrombocytopenia, and aplastic anaemia. Investigations into earlier detection and better management are warranted. FUNDING: Gustave Roussy and Gustave Roussy Immunotherapy Program.


Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Imunoterapia/efeitos adversos , Receptor de Morte Celular Programada 1/efeitos dos fármacos , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
12.
J Immunother Cancer ; 6(1): 120, 2018 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-30446009

RESUMO

Commentary on « Ipilimumab induced vasculitis ¼ by Padda A. et al., J Immunother Cancer. 2018;6:12. The authors diagnosed a small vessel vasculitis following treatment with anti-CTLA-4 (ipilimumab) for a resected stage III B/C melanoma. We report a similar case of acral vasculitis occurring with a combination of anti-CTLA-4 (tremelimumab) and anti-PD-L1 (durvalumab) prescribed for the management of a metastatic urothelial bladder cancer. In contrast to Padda A. et al., we observed a significant improvement with oral corticosteroids.


Assuntos
Antineoplásicos , Melanoma , Neoplasias Cutâneas , Vasculite , Humanos , Ipilimumab
13.
Bull Cancer ; 105(11): 1042-1051, 2018 Nov.
Artigo em Francês | MEDLINE | ID: mdl-30243477

RESUMO

Minimal residual disease (MRD) is widely used in oncohematology. In chronic lymphocytic leukemia (CLL), it can be measured by flow cytometry or polymerase chain reaction and is getting a greater place, owing to the dramatic therapeutic advances in the management this disease. As MRD decrease after chemoimmunotherapy is associated with improved progression free and overall survivals, its measure is now recommended as a surrogate marker for cytotoxic drugs licensures. This association is independent from treatment received and raises a few questions, such as sequential MRD measures to stop treatment in case of an early deep response and on the opposite, treatment continuation until reaching undetectable MRD (with the possible use of maintenance therapy). Furthermore, following MRD after a cytotoxic treatment could lead clinical trials investigators to propose pre-emptive treatments in case of MRD re-growth, to avoid overt relaspe. MRD re-growth kinetics and CD4 count after treatment completion can improve MRD-based survival predictions. On the other hand, BCR inhibitors do not lead to undetectable MRD, but their association with chemoimmunotherapy increases the proportion of patients reaching that goal. Moreover, BCL2 inhibitors do lead to deep response including in the relapse/refractory setting, giving to MRD a central place in currently investigated treatments evaluation.


Assuntos
Leucemia Linfocítica Crônica de Células B/patologia , Neoplasia Residual , Antineoplásicos/uso terapêutico , Citometria de Fluxo , Humanos , Imunoterapia , Leucemia Linfocítica Crônica de Células B/mortalidade , Leucemia Linfocítica Crônica de Células B/terapia
15.
Eur J Haematol ; 100(5): 412-418, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29360249

RESUMO

OBJECTIVE: To assess the benefits and harms to initiate corticosteroids with intravenous methylprednisolone at a conventional dose (1 mg/kg/d) to treat adults with immune thrombocytopenia (ITP). METHODS: Population stemmed from the prospective multicenter CARMEN registry and included newly diagnosed hospitalized ITP adults with platelet counts<30 × 109 /L. We compared the patients treated with conventional-dose methylprednisolone (CDMP) before continuing with oral prednisone to patients treated with just conventional-dose oral prednisone (CDOP). The primary outcome was the time until response. Secondary outcomes were time until complete response, response rate, complete response rate, duration of hospital stay, and occurrence of adverse drug reactions. Analyzes were adjusted for propensity score and for exposure to intravenous immunoglobulin. RESULTS: Among the included 87 patients, the median time to response was 3 days in the CDMP group vs 4 in the CDOP group (adjusted hazard ratio [aHR]: 1.35; 95%CI: 0.76-2.41). The CDMP group had an earlier complete response (aHR: 2.29; 95%CI: 1.20-4.36). There was no difference between the groups regarding other secondary outcomes. CONCLUSIONS: Initiating methylprednisolone at a conventional dose provided no significant benefit compared to giving oral prednisone only to adults with ITP.


Assuntos
Imunossupressores/administração & dosagem , Metilprednisolona/administração & dosagem , Pré-Medicação , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Administração Intravenosa , Adulto , Idoso , Idoso de 80 Anos ou mais , Coagulação Sanguínea/efeitos dos fármacos , Feminino , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Imunossupressores/efeitos adversos , Estimativa de Kaplan-Meier , Masculino , Metilprednisolona/efeitos adversos , Pessoa de Meia-Idade , Contagem de Plaquetas , Prednisona/administração & dosagem , Estudos Prospectivos , Púrpura Trombocitopênica Idiopática/diagnóstico , Resultado do Tratamento
17.
Leuk Res ; 61: 62-67, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28910610

RESUMO

Platelet transfusion refractoriness (PTR) is a major adverse event in the management of acute myeloid leukemia (AML). In a series of 897 adult patients with AML receiving intensive chemotherapy, we identified 41 patients (4.8%) with PTR. PTR was more frequently observed in parous women, patients with extra-medullary disease, a low white blood cell count, an infection, or hemophagocytic syndrome. Among the 31 patients with anti-human leucocyte antigen (HLA) antibodies, an HLA-matched donor was identified for 18 patients (58.1%). Median time between diagnosis of PTR and the first HLA-matched transfusion was 12.5days. HLA-matched transfusions induced a significant increment in platelet counts in 37% of cases. Thrombopoietin receptor agonists were given to 10 patients but did not shorten the duration of thrombocytopenia, reduce severe bleeding, or early death. Grade 3-4 bleeding events during induction, early death caused by bleeding, and death caused by bleeding at any time were significantly greater in patients that had platelet transfusion refractoriness (22% vs. 4.1%, P<0.0001; 12.2% vs. 1.4%, P=0.0006; and 24.4% vs. 5.3%, P<0.0001; respectively). PTR during chemotherapy for AML significantly increased the risk of early and late deaths caused by a severe bleeding event. Improved understanding of platelet destruction is needed to design mechanism-based therapeutic strategies.


Assuntos
Leucemia Mieloide Aguda/tratamento farmacológico , Transfusão de Plaquetas , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Trombocitopenia/induzido quimicamente , Trombocitopenia/terapia
19.
Orphanet J Rare Dis ; 12(1): 95, 2017 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-28532436

RESUMO

BACKGROUND: Vinblastine is the standard treatment for children with Langerhans cell histiocytosis (LCH). Whether this treatment could be extended to adults with LCH is questionable. This retrospective multicenter study included 35 adult patients (median age 33 years; 23 men; 80% with multisystem LCH) who were treated with vinblastine + steroids as a first-line chemotherapy and followed for a median time of 83 months. The objectives were to determine the overall response rate (based on the Histiocyte Society criteria), disease reactivation rate, toxicity, permanent consequences, and survival rate corresponding to this treatment. The lung involvement outcome was based on serial lung function tests. The distribution of right-censored end points was estimated by the Kaplan-Meier method. Univariate Cox model with time-fixed and time-varying covariates was used for the predictive analysis of reactivation in the responders. Univariate analyses of risk factors for neurotoxicity were based on nonparametric Wilcoxon rank sum tests and exact Fisher tests. RESULTS: The median duration of the first course of vinblastine was 7.6 months, with a median cumulative dose of 160 mg [IQR 120-212]. Seventy percent of the patients were responders at the end of this treatment. Subsequently, LCH reactivation occurred with a 5-year cumulative incidence of 40%. During the study, 27 reactivations were observed in 17 patients, and half of these episodes were retreated with vinblastine. At the end of the last vinblastine treatment, 70% of the patients were responders. None of the patients with impaired lung function improved. No grade 3-4 peripheral neuropathy was observed. At the final vinblastine treatment, permanent LCH consequences, primarily pituitary stalk involvement, were present in 15 (43%) patients, and all were present at the time of vinblastine initiation. The 10-year survival rate was 86.2% (95CI, 71.8-100%), and the 2 patients who died from LCH had risk organ localizations. CONCLUSIONS: Vinblastine is an effective and well-tolerated first-line treatment for adult LCH except in patients with lung involvement and impaired lung function. However, a significant portion of patients experienced LCH reactivation during long-term follow up. As in childhood LCH, the presence of risk organ involvement has a negative impact on patient prognosis.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Histiocitose de Células de Langerhans/tratamento farmacológico , Vimblastina/uso terapêutico , Adulto , Feminino , Seguimentos , Histiocitose de Células de Langerhans/diagnóstico , Histiocitose de Células de Langerhans/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida/tendências
20.
Am J Hematol ; 92(6): 493-500, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28240787

RESUMO

The clinical epidemiology of immune thrombocytopenia (ITP) is not well known in adults. This study was aimed at assessing the clinical epidemiology of incident ITP adults, the factors associated with chronicity and exposure to treatments. This study was conducted in the CARMEN registry, a multicentric prospective cohort aimed at including all newly diagnosed ITP adults in the French Midi-Pyrénées region, South of France (3 million inhabitants) from June 2013. Descriptive analyses and multivariate logistic regression models were conducted. Out of 121 newly diagnosed ITP until December 2014, 113 patients were followed in the region and gave informed consent. Median age was 65 years. Half of the patients were female, 20.3% had a secondary ITP, 50.4% had a Charlson's score ≥1, median platelet count was 17 × 109 /L; 50.9% had bleeding symptoms, including 2 severe gastrointestinal tract and 1 intracranial bleedings; 21.4% had another autoimmune disease and 20.3% experienced an infection within the six weeks before ITP onset. Persistency and chronicity rates were 68.2% and 58.7%, respectively. Antinuclear antibodies were associated with chronicity (OR: 2.89, 95% CI: 1.08-7.74). Sixty-eight (60.2%) patients were treated during the week following the diagnosis. Factors associated with the use of intravenous corticosteroids were secondary ITP and high bleeding score. Those associated with the use of intravenous immunoglobulin (IVIg) were a high bleeding score and low platelet count. In conclusion, severe bleeding is rare at ITP onset. Associated autoimmune diseases and recent infections were frequent. Antinuclear antibodies seem predictors of chronicity. Intravenous corticosteroids and IVIg were frequently used.


Assuntos
Púrpura Trombocitopênica Idiopática/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Doença Crônica , Feminino , França/epidemiologia , Humanos , Fatores Imunológicos/uso terapêutico , Incidência , Masculino , Pessoa de Meia-Idade , Razão de Chances , Vigilância da População , Estudos Prospectivos , Púrpura Trombocitopênica Idiopática/diagnóstico , Púrpura Trombocitopênica Idiopática/terapia , Sistema de Registros , Fatores de Risco , Adulto Jovem
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