RESUMO
We report herein a multicentre retrospective analysis of 192 consecutive patients with symptomatic refractory/relapsed multiple myeloma (RRMM) treated with daratumumab in combination with bortezomib or lenalidomide as salvage therapy at 9 haematological centres in Puglia. Choice of both regimens was based on previous treatment and/or physicians' preference. Considering the under-representation of older patients (very old patient ≥ 80 years) in clinical trials and the prognostic and predictive importance and value of frailty status, here, we further characterised the patient cohort by age. The overall response rate (ORR) was generally lower than what was previously reported in the CASTOR (ORR 72.6% vs 85%) and POLLUX (ORR 86.5% vs 93%) trials. The lower ORR in our analysis compared to the CASTOR and POLLUX trials could be related to a less selected population. Similarly, amongst very old patients, the ORR was encouraging: ORR to treatment with DVd (daratumumab + bortezomib + dexamethasone) was 66.7%, and ORR to treatment with DRd (daratumumab + lenalidomide + dexamethasone) was 92.3%. Median TTP (time to progression) was 10.8 months (1-year TTP: 44.7%; 2-year TTP: 25.3%) in the DVd group; median TTP was not reached in the DRd group (1-year TTP: 82.7%; 2-year TTP: 71.4%). Median OS (overall survival) was not reached either in the DRd group (1-year OS: 85.9%; 2-year OS: 73.7%) or the DVd group (1-year OS: 70.2%; 2-year OS: 58.9%).
Assuntos
Mieloma Múltiplo , Neoplasias de Plasmócitos , Anticorpos Monoclonais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bortezomib , Dexametasona , Seguimentos , Humanos , Lenalidomida , Mieloma Múltiplo/tratamento farmacológico , Estudos Retrospectivos , Terapia de SalvaçãoRESUMO
BACKGROUND: The incidence of chronic myeloid leukemia (CML) increases with age, but it is unclear how the characteristics of the disease vary with age. In children, where CML is very rare, it presents with more aggressive features, including huge splenomegaly, higher cell count and higher blast cell percentage. PATIENTS AND METHODS: To investigate if after childhood the disease maintains or loses these characteristics of aggressiveness, we analyzed 2784 adult patients, at least 18 years old, registered by GIMEMA CML WP over a 40-year period. RESULTS: Young adults (YAs: 18-29 years old) significantly differed from adults (30-59 years old) and elderly patients (at least 60 years old) particularly for the frequency of splenomegaly (71%, 63% and 55%, P < 0.001), and the greater spleen size (median value: 4.5, 3.0 and 1.0 cm, P < 0.001). According to the EUTOS score, that is age-independent, high-risk patients were more frequent among YAs, than among adult and elderly patients (18%, 9% and 6%, P < 0.001). In tyrosine kinase inhibitors-treated patients, the rates of complete cytogenetic and major molecular response were lower in YAs, and the probability of transformation was higher (16%, 5% and 7%, P = 0.011). CONCLUSIONS: The characteristics of CML or the host response to leukemia differ with age. The knowledge of these differences and of their causes may help to refine the treatment and to improve the outcome. CLINICAL TRIAL NUMBERS: NCT00510926, NCT00514488, NCT00769327, NCT00481052.
Assuntos
Antineoplásicos/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Esplenomegalia/epidemiologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Proteínas Tirosina Quinases/antagonistas & inibidores , Baço/patologia , Adulto JovemRESUMO
PURPOSE: We compared the risk factors, the diagnostic tools and the outcome of filamentous fungal infections (FFIs) in hematological patients (HAEs) and non-hematological patients (non-HAEs). METHODS: Prospective surveillance (2009-2011) of proven and probable FFIs was implemented in 23 Italian hospitals. RESULTS: Out of 232 FFIs, 113 occurred in HAEs and 119 in non-HAEs. The most frequent infection was invasive aspergillosis (76.1 % for HAEs, 56.3 % for non-HAEs), and the localization was principally pulmonary (83.2 % for HAEs, 74.8 % for non-HAEs). Neutropenia was a risk factor for 89.4 % HAEs; the main underlying condition was corticosteroid treatment (52.9 %) for non-HAEs. The distribution of proven and probable FFIs was different in the two groups: proven FFIs occurred more frequently in non-HAEs, whereas probable FFIs were correlated with the HAEs. The sensitivity of the galactomannan assay was higher for HAEs than for non-HAEs (95.3 vs. 48.1 %). The overall mortality rate was 44.2 % among the HAEs and 35.3 % among the non-HAEs. The etiology influenced the patient outcomes: mucormycosis was associated with a high mortality rate (57.1 % for HAEs, 77.8 % for non-HAEs). CONCLUSIONS: The epidemiological and clinical data for FFIs were not identical in the HAEs and non-HAEs. The differences should be considered to improve the management of FFIs according to the patients' setting.
Assuntos
Fungos/classificação , Fungos/isolamento & purificação , Micoses/epidemiologia , Micoses/microbiologia , Sistema de Registros , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Testes Diagnósticos de Rotina , Feminino , Neoplasias Hematológicas/complicações , Hospitais , Humanos , Itália/epidemiologia , Masculino , Técnicas Microbiológicas/métodos , Pessoa de Meia-Idade , Micoses/diagnóstico , Micoses/mortalidade , Estudos Prospectivos , Análise de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVES: To describe the diagnostic tests used and their comparative performance in dogs diagnosed with sinonasal aspergillosis in the United Kingdom. A secondary objective was to describe the signalment, clinical findings and common clinicopathologic abnormalities in sinonasal aspergillosis. MATERIALS AND METHODS: A multi-centre retrospective survey was performed involving 23 referral centres in the United Kingdom to identify dogs diagnosed with sinonasal aspergillosis from January 2011 to December 2021. Dogs were included if fungal plaques were seen during rhinoscopy or if ancillary testing (via histopathology, culture, cytology, serology or PCR) was positive and other differential diagnoses were excluded. RESULTS: A total of 662 cases were entered into the database across the 23 referral centres. Four hundred and seventy-five cases met the study inclusion criteria. Of these, 419 dogs had fungal plaques and compatible clinical signs. Fungal plaques were not seen in 56 dogs with turbinate destruction that had compatible clinical signs and a positive ancillary test result. Ancillary diagnostics were performed in 312 of 419 (74%) dogs with observed fungal plaques permitting calculation of sensitivity of cytology as 67%, fungal culture 59%, histopathology 47% and PCR 71%. CLINICAL SIGNIFICANCE: The sensitivities of ancillary diagnostics in this study were lower than previously reported challenging the clinical utility of such tests in sinonasal aspergillosis. Treatment and management decisions should be based on a combination of diagnostics including imaging findings, visual inspection, and ancillary testing, rather than ancillary tests alone.
RESUMO
BACKGROUND: The best therapeutic approach for primary plasma cell leukemia (PPCL) remains unknown so far. In very limited studies, the poor clinical outcome of this aggressive variant of multiple myeloma seemed to be ameliorated by the use of the proteasome inhibitor bortezomib. Aiming to provide more consolidated data, this multicenter retrospective survey focused on unselected and previously untreated PPCL patients who had received bortezomib as frontline therapy. PATIENTS AND METHODS: Twenty-nine patients with PPCL were collected. Bortezomib was given at standard doses and schedules, in various combinations with dexamethasone, thalidomide, doxorubicin, melphalan, prednisone, vincristine, and cyclophosphamide. RESULTS: An overall response rate of 79% was observed, with 38% of at least very good partial remission. Grade 3-4 hematological, neurological, infectious, and renal toxic effects occurred in 20%, 21%, 16%, and 4% of patients, respectively. After a median follow-up of 24 months, 16 patients were alive (55%), 12 of whom were in remission phase and 4 relapsed. The best long-term results were achieved in patients who received stem-cell transplantation after bortezomib induction. CONCLUSION: Bortezomib, used as initial therapy, is able to increase the percentage and the quality of responses in PPCL patients, producing a significant improvement of survival.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Plasmocitária/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Ácidos Borônicos/administração & dosagem , Bortezomib , Ciclofosfamida/administração & dosagem , Dexametasona/administração & dosagem , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Feminino , Humanos , Estimativa de Kaplan-Meier , Leucemia Plasmocitária/mortalidade , Masculino , Melfalan/administração & dosagem , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Pirazinas/administração & dosagem , Estudos Retrospectivos , Talidomida/administração & dosagem , Resultado do Tratamento , Vincristina/administração & dosagemRESUMO
BACKGROUND: Epidemiological and clinical information on primary plasma cell leukemia (pPCL) are rarely reported. The aims are to evaluate the clinical features, prognostic factors, and efficacy of treatments in pPCL. PATIENTS AND METHODS: A multicenter retrospective cohort study was carried out from January 2000 to December 2008 in 26 Italian hematology divisions. A total of 128 cases of plasma cell leukemia were collected, and 73 of them (57%) were classified as primary (male/female 43/30). RESULTS: Sixty-four patients had at least 1 sign of end-organ damage and 10 had extramedullary localization. One patient died early; of the remaining patients, 36 (50%) received anthracycline-based regimens as first-line therapy, 17 (24%) single alkylating agents, and 30 (42%) bortezomib or thalidomide as additional (n = 11) or unique treatments (n = 19). Twenty-three patients (31%) underwent autologous and/or allogeneic hematopoietic stem cell transplantation (HSCT). The median overall survival (OS) was 12.6 months; complete or partial response was achieved in 22 (30%) and 18 patients (25%), respectively; the median duration of response (DOR) was 16.4 months. HSCT patients had a longer OS and DOR (median 38.1 and 25.8 months, respectively) compared with nontransplanted patients (9.1 and 7.3 months, respectively, P < 0.001). OS was influenced by nonresponse to treatment, hypoalbuminemia, and HSCT. DOR was favorably influenced only by HSCT. CONCLUSIONS: pPCL is an aggressive disease with a poor prognosis and a low response rate to conventional therapy. HSCT is effective, increasing OS and DOR by 69% and 88%, respectively. The use of bortezomib and thalidomide may improve outcomes.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Plasmocitária/terapia , Recidiva Local de Neoplasia/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antraciclinas/administração & dosagem , Ácidos Borônicos/administração & dosagem , Bortezomib , Estudos de Coortes , Terapia Combinada , Feminino , Seguimentos , Transplante de Células-Tronco Hematopoéticas , Humanos , Masculino , Pessoa de Meia-Idade , Pirazinas/administração & dosagem , Estudos Retrospectivos , Taxa de Sobrevida , Talidomida/administração & dosagem , Transplante Autólogo , Resultado do Tratamento , Adulto JovemRESUMO
PURPOSE: The aim of was study was to evaluate the accuracy of computed tomography (CT)-guided core needle biopsy (CNB) performed by modified coaxial technique as an alternative tool to surgical biopsy in patients with suspected malignant lymphoma. MATERIALS AND METHODS: Between May 2005 and December 2008, 67 CT-guided CNB of deep lesions were performed on 64 patients with suspected malignant lymphoma. In 19 out of 64 patients (29.7%), recurrent lymphoma was suspected. A modified coaxial technique was used in all cases, and multiple samples were obtained for histological and immunohistochemical studies. RESULTS: A diagnosis of malignant lymphomas with specification of subtype according to the World Health Organization (WHO) classification was established in 41/67 cases. Other malignant neoplasms were found in 13/67, lymphoma without subtype specification was diagnosed in 7/67, whereas no conclusive diagnosis could be established in 6/67 cases. Overall diagnostic accuracy was 80.1%. In patients with a final diagnosis of malignant lymphoma, accuracy was 75.9%. No complications occurred. CONCLUSIONS: Percutaneous CT-guided CNB is a safe, effective and reliable tool in the management of lymphomas in patients without superficial lymphadenopathy and can be considered an alternative approach to surgical sampling. The modified coaxial technique represents an effective tool that has a good diagnostic accuracy value with a low complication rate.
Assuntos
Biópsia por Agulha/métodos , Linfoma/patologia , Radiografia Intervencionista/métodos , Tomografia Computadorizada por Raios X , Adulto , Idoso , Idoso de 80 Anos ou mais , Diagnóstico Diferencial , Feminino , Humanos , Imuno-Histoquímica , Linfoma/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Estadiamento de NeoplasiasRESUMO
This study aimed to identify which graft product subset of CD34+ cells might be the most predictive of early hematopoietic recovery following allogeneic peripheral SCT (allo-PBSCT). The relationship between the number of 'mature' subsets of CD34+ cells (CD34+/CD33+, CD34+/CD38+, CD34+/DR+ and CD34+/CD133-) and 'immature' subsets of CD34+ cells (CD34+/CD33-, CD34+/CD38-, CD34+/DR- and CD34+/CD133+) and early neutrophil and platelet engraftment were studied in a homogeneous series (for disease, pre transplant chemotherapy, conditioning regimen and GVHD prophylaxis) of 30 AML patients after allo-PBSCT from HLA-identical siblings. In our experience, the total CD34+/CD133+ cell number was inversely correlated with the days required for the recovery of 0.5 x 10(9)/l neutrophils (r=or-0.82, P=0.02) and platelets of 20 x 10(9)/l (r=or-0.60, P=0.06); this correlation was better than the total CD34+ cell dose and neutrophil (r=or-0.70, P=0.04) and platelet engraftment (r=or-0.56, P=0.07). We suggest that a high number of CD34+/CD133+ PBSC may be associated with faster neutrophil and platelet recovery; these findings may help to predict the repopulating capacity of PBSC in patients after allo-PBSCT, especially when a relatively low number of CD34+ cells is infused.
Assuntos
Antígenos CD34 , Sobrevivência de Enxerto/imunologia , Leucemia Mieloide Aguda/terapia , Transplante de Células-Tronco de Sangue Periférico/métodos , Antígeno AC133 , Adolescente , Adulto , Antígenos CD , Diferenciação Celular , Estudos de Coortes , Feminino , Glicoproteínas , Doença Enxerto-Hospedeiro/prevenção & controle , Teste de Histocompatibilidade , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeos , Relações entre Irmãos , Células-Tronco/classificação , Células-Tronco/citologia , Transplante HomólogoRESUMO
We investigated genetically affected leukemic cells in FIP1L1-PDGFRA+ chronic eosinophilic leukemia (CEL) and in BCR-ABL1+ chronic myeloid leukemia (CML), two myeloproliferative disorders responsive to imatinib. Fluorescence in situ hybridization specific for BCR-ABL1 and for FIP1L1-PDGFRA was combined with cytomorphology or with lineage-restricted monoclonal antibodies and applied in CML and CEL, respectively. In CEL the amount of FIP1L1-PDGFRA+ cells among CD34+ and CD133+ cells, B and T lymphocytes, and megakaryocytes were within normal ranges. Positivity was found in eosinophils, granulo-monocytes and varying percentages of erythrocytes. In vitro assays with imatinib showed reduced survival of peripheral blood mononuclear cells but no reduction in colony-forming unit growth medium (CFU-GM) growth. In CML the BCR-ABL1 fusion gene was detected in CD34+/CD133+ cells, granulo-monocytes, eosinophils, erythrocytes, megakaryocytes and B-lymphocytes. Growth of both peripheral blood mononuclear cells and CFU-GM was inhibited by imatinib. This study provided evidence for marked differences in the leukemic masses which are targeted by imatinib in CEL or CML, as harboring FIP1L1-PDGFRA or BCR-ABL1.
Assuntos
Proteínas de Fusão bcr-abl/análise , Síndrome Hipereosinofílica/patologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Células-Tronco Neoplásicas/enzimologia , Proteínas de Fusão Oncogênica/análise , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/análise , Fatores de Poliadenilação e Clivagem de mRNA/análise , Antígeno AC133 , Antígenos CD/análise , Antígenos CD34/análise , Antineoplásicos/uso terapêutico , Benzamidas , Linhagem da Célula , Doença Crônica , Células Clonais/enzimologia , Resistência a Medicamentos , Eosinófilos/enzimologia , Eritrócitos/enzimologia , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Glicoforinas/análise , Glicoproteínas/análise , Granulócitos/enzimologia , Células-Tronco Hematopoéticas/enzimologia , Humanos , Síndrome Hipereosinofílica/tratamento farmacológico , Síndrome Hipereosinofílica/enzimologia , Síndrome Hipereosinofílica/genética , Mesilato de Imatinib , Imunofenotipagem , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/enzimologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Subpopulações de Linfócitos/enzimologia , Megacariócitos/enzimologia , Monócitos/enzimologia , Células Mieloides/enzimologia , Proteínas de Fusão Oncogênica/antagonistas & inibidores , Peptídeos/análise , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Ensaio Tumoral de Célula-Tronco , Inativação do Cromossomo X , Fatores de Poliadenilação e Clivagem de mRNA/antagonistas & inibidoresRESUMO
The molecular basis of advanced systemic mastocytosis (SM) is not fully understood and despite novel therapies the prognosis remains dismal. Exome sequencing of an index-patient with mast cell leukemia (MCL) uncovered biallelic loss-of-function mutations in the SETD2 histone methyltransferase gene. Copy-neutral loss-of-heterozygosity at 3p21.3 (where SETD2 maps) was subsequently found in SM patients and prompted us to undertake an in-depth analysis of SETD2 copy number, mutation status, transcript expression and methylation levels, as well as functional studies in the HMC-1 cell line and in a validation cohort of 57 additional cases with SM, including MCL, aggressive SM and indolent SM. Reduced or no SETD2 protein expression-and consequently, H3K36 trimethylation-was found in all cases and inversely correlated with disease aggressiveness. Proteasome inhibition rescued SETD2 expression and H3K36 trimethylation and resulted in marked accumulation of ubiquitinated SETD2 in SETD2-deficient patients but not in patients with near-normal SETD2 expression. Bortezomib and, to a lesser extent, AZD1775 alone or in combination with midostaurin induced apoptosis and reduced clonogenic growth of HMC-1 cells and of neoplastic mast cells from advanced SM patients. Our findings may have implications for prognostication of SM patients and for the development of improved treatment approaches in advanced SM.
Assuntos
Histona-Lisina N-Metiltransferase/genética , Histonas/genética , Lisina/genética , Mastocitose Sistêmica/genética , Adulto , Idoso , Apoptose/efeitos dos fármacos , Apoptose/genética , Linhagem Celular Tumoral , Feminino , Humanos , Células K562 , Masculino , Mastócitos/efeitos dos fármacos , Mastocitose/genética , Mastocitose Sistêmica/tratamento farmacológico , Metilação/efeitos dos fármacos , Pessoa de Meia-Idade , Mutação/efeitos dos fármacos , Mutação/genética , Prognóstico , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/genética , Estaurosporina/análogos & derivados , Estaurosporina/farmacologiaRESUMO
Mutations in exon 12 of the nucleophosmin (NPM1) gene occur in about 60% of adult AML with normal karyotype. By exploiting a specific feature of NPM1 mutants, that is insertion at residue 956 or deletion/insertion at residue 960, we developed highly sensitive, real-time quantitative (RQ) polymerase chain reaction (PCR) assays, either in DNA or RNA, that are specific for various NPM1 mutations. In all 13 AML patients carrying NPM1 mutations at diagnosis, cDNA RQ-PCR showed >30 000 copies of NPM1-mutated transcript. A small or no decrease in copies was observed in three patients showing partial or no response to induction therapy. The number of NPM1-mutated copies was markedly reduced in 10 patients achieving complete hematological remission (five cases: <100 copies; five cases: 580-5046 copies). In four patients studied at different time intervals, the number of NPM1 copies closely correlated with clinical status and predicted impending hematological relapse in two. Thus, reliable, sensitive RQ-PCR assays for NPM1 mutations can now monitor and quantify MRD in AML patients with normal karyotype and NPM1 gene mutations.
Assuntos
Dosagem de Genes , Leucemia Mieloide/diagnóstico , Leucemia Mieloide/genética , Neoplasia Residual/diagnóstico , Neoplasia Residual/genética , Proteínas Nucleares/genética , Doença Aguda , Análise Mutacional de DNA/métodos , Perfilação da Expressão Gênica , Humanos , Mutação , Nucleofosmina , Valor Preditivo dos Testes , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodosRESUMO
Acute myeloid leukemia (AML) blasts are immature committed myeloid cells unable to spontaneously undergo terminal maturation, and characterized by heterogeneous sensitivity to natural differentiation inducers. Here, we show a molecular signature predicting the resistance or sensitivity of six myeloid cell lines to differentiation induced in vitro with retinoic acid or vitamin D. The identified signature was further validated by TaqMan assay for the prediction of response to an in vitro differentiation assay performed on 28 freshly isolated AML blast populations. The TaqMan assay successfully predicts the in vitro resistance or responsiveness of AML blasts to differentiation inducers. Furthermore, performing a meta-analysis of publicly available microarray data sets, we also show the accuracy of our prediction on known phenotypes and suggest that our signature could become useful for the identification of patients eligible for new therapeutic strategies.
Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Leucemia Mieloide/tratamento farmacológico , Leucemia Mieloide/genética , Tretinoína/farmacologia , Doença Aguda , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Análise por Conglomerados , Bases de Dados Factuais , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Humanos , Leucemia Mieloide/patologia , Metanálise como Assunto , Análise de Sequência com Séries de Oligonucleotídeos , Valor Preditivo dos Testes , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Vitamina D/farmacologia , Vitaminas/farmacologiaRESUMO
Six patients with de novo acute myeloid leukemia (AML) and a t(2;3)(p15-21;q26-27) were identified among approximately 1000 cases enrolled in the GIMEMA trial. The t(2;3) was the sole anomaly in three patients, whereas in three cases monosomy 7, trisomy 15 and 22, and trisomy 14 represented additional aberrations. No cryptic chromosome deletions at 5q, 7q, 12p, and 20q were observed. One patient carried a FLT3 D835 mutation; FLT3 internal tandem duplication (ITD) was not detected in three patients tested. Characterization of the translocation breakpoints using a 3q26 BAC contig specific for the PRDM3 locus showed that the breakpoints were located 5' to EVIl as follows: within myelodysplatic syndrome (MDS) intron 1 (# 3), between MDS1 exons 2 and 3 in three patients (# 1, 2, 4) with a 170bp cryptic deletion distal to the breakpoint in one (# 2), and in a more centromeric position spanning from intron 2 to the 5' region of EVI1 (# 6, 5). A set of 2p16-21 BAC probes showed that the breakpoints on chromosome 2p were located within BCL11A in two separate regions (# 1, 4 and # 2-5), within the thyroid adenoma-associated (THADA) gene (# 6) or distal to the ZFP36L2 locus (# 3). Regulatory elements were present in proximity of these breakpoints. RACE PCR studies revealed a chimeric transcript in 1/6 patient analyzed, but no fusion protein. Quantitative PCR showed a 21-58-fold over-expression of the EVIl gene in all cases analyzed. The patients showed dysplasia of at least two myeloid cell lineages in all cases; they had a low-to-normal platelet count and displayed an immature CD34+ CD117+ immunophenotype. Despite intensive chemotherapy and a median age of 43 years (range 36-59), only two patients attained a short-lived response; one patient is alive with active disease at 12 months, five died at 4-14 months. We arrived at the following conclusions: (a) the t(2;3) is a recurrent translocation having an approximate 0.5% incidence in adult AML; (b) breakpoints involve the 5' region of EVIl at 3q26, and the BCL11A, the THADA gene or other regions at 2p16.1-21; (c) cryptic deletions distal to the 3q26 breakpoint may occur in some cases; (d) the juxtaposition of the 5' region of EVIl with regulatory elements normally located on chromosome 2 brings about EVI1 overexpression; (e) clinical outcome in these cases is severe.
Assuntos
Cromossomos Humanos Par 2/genética , Cromossomos Humanos Par 3/genética , Leucemia Mieloide/genética , Translocação Genética/genética , Doença Aguda , Adulto , Análise Citogenética/métodos , Feminino , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Leucemia Mieloide/diagnóstico , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Valor Preditivo dos Testes , Prognóstico , TrissomiaRESUMO
We investigated, lymphocyte count (LC) and lymphocyte subpopulations (LS) in a real life setting of Fingolimod (FTY) treated Relapsing MS (RMS) patients. Peripheral blood counts with LS, relapses and MRI scans were recorded in a cohort of 119 FTY patients, during one year of treatment. Simple and multivariate logistic regression models, were performed. ROC analysis identified cut-off values of LS predicting a higher risk of relapses and of Gd+ lesions. We demonstrated a FTY-induced re-modulation of the immune system, suggesting that LS in RMS FTY treated patients can predict the clinical response to the drug.
Assuntos
Cloridrato de Fingolimode/uso terapêutico , Imunossupressores/uso terapêutico , Subpopulações de Linfócitos/imunologia , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/imunologia , Adulto , Biomarcadores/sangue , Estudos de Coortes , Feminino , Cloridrato de Fingolimode/farmacologia , Seguimentos , Humanos , Imunossupressores/farmacologia , Subpopulações de Linfócitos/efeitos dos fármacos , Subpopulações de Linfócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/sangue , Resultado do TratamentoRESUMO
Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) has a dismal prognosis. We prospectively evaluated minimal residual disease (MRD) by measuring BCR/ ABL levels with a quantitative real-time PCR procedure after induction and after consolidation in 45 adults with Ph+ ALL who obtained complete hematological remission after a high-dose daunorubicin induction schedule. At diagnosis, the mean BCR-ABL/GUS ratio was 1.55 +/- 1.78. A total of 42 patients evaluable for outcome analysis were operationally divided into two MRD groups: good molecular responders (GMRs; n = 28) with > 2 log reduction of residual disease after induction and > 3 log reduction after consolidation therapy, and poor molecular responders (PMRs; n = 14) who, despite complete hematological remission, had a higher MRD at both time points. In GMR, the actuarial probability of relapse-free, disease-free and overall survival at two years was 38, 27 and 48%, respectively, as compared to 0, 0 and 0% in PMR (P = 0.0035, 0.0076 and 0.0026, respectively). Salvage therapy induced a second sustained complete hematological remission in three GMR patients, but in no PMR patient. Our data indicate that, as already shown in children, adult Ph+ ALL patients have a heterogeneous sensitivity to treatment, and that early quantification of residual disease is a prognostic parameter in this disease.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteínas de Fusão bcr-abl/genética , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , Adulto , Antibióticos Antineoplásicos/uso terapêutico , Antimetabólitos Antineoplásicos/uso terapêutico , Antineoplásicos Fitogênicos/uso terapêutico , Asparaginase/uso terapêutico , Citarabina/uso terapêutico , Daunorrubicina/uso terapêutico , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasia Residual/tratamento farmacológico , Neoplasia Residual/genética , Neoplasia Residual/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Valor Preditivo dos Testes , Prognóstico , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Vincristina/uso terapêuticoRESUMO
We retrospectively studied 181 patients with polycythaemia vera (n=67), essential thrombocythaemia (n=67) or primary myelofibrosis (n=47), who presented a first episode of splanchnic vein thrombosis (SVT). Budd-Chiari syndrome (BCS) and portal vein thrombosis were diagnosed in 31 (17.1%) and 109 (60.3%) patients, respectively; isolated thrombosis of the mesenteric or splenic veins was detected in 18 and 23 cases, respectively. After this index event, the patients were followed for 735 patient years (pt-years) and experienced 31 recurrences corresponding to an incidence rate of 4.2 per 100 pt-years. Factors associated with a significantly higher risk of recurrence were BCS (hazard ratio (HR): 3.03), history of previous thrombosis (HR: 3.62), splenomegaly (HR: 2.66) and leukocytosis (HR: 2.8). Vitamin K-antagonists (VKA) were prescribed in 85% of patients and the recurrence rate was 3.9 per 100 pt-years, whereas in the small fraction (15%) not receiving VKA more recurrences (7.2 per 100 pt-years) were reported. Intracranial and extracranial major bleeding was recorded mainly in patients on VKA and the corresponding rate was 2.0 per 100 pt-years. In conclusion, despite anticoagulation treatment, the recurrence rate after SVT in myeloproliferative neoplasms is high and suggests the exploration of new avenues of secondary prophylaxis with new antithrombotic drugs and JAK-2 inhibitors.
Assuntos
Síndrome de Budd-Chiari/fisiopatologia , Policitemia Vera/fisiopatologia , Mielofibrose Primária/fisiopatologia , Trombocitemia Essencial/fisiopatologia , Trombose Venosa/fisiopatologia , Adulto , Idoso , Síndrome de Budd-Chiari/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Policitemia Vera/complicações , Veia Porta/fisiopatologia , Mielofibrose Primária/complicações , Modelos de Riscos Proporcionais , Recidiva , Estudos Retrospectivos , Fatores de Risco , Trombocitemia Essencial/complicações , Trombose Venosa/etiologiaRESUMO
The optimal duration of treatment with vitamin K antagonists (VKA) after venous thromboembolism (VTE) in patients with Philadelphia-negative myeloproliferative neoplasms (MPNs) is uncertain. To tackle this issue, we retrospectively studied 206 patients with MPN-related VTE (deep venous thrombosis of the legs and/or pulmonary embolism). After this index event, we recorded over 695 pt-years 45 recurrences, venous in 36 cases, with an incidence rate (IR) of 6.5 per 100 pt-years (95% confidence interval (CI): 4.9-8.6). One hundred fifty-five patients received VKA; the IR of recurrent thrombosis per 100 pt-years was 4.7 (95% CI: 2.8-7.3) on VKA and 8.9 (95% CI: 5.7-13.2) off VKA (P=0.03). In patients receiving VKA, the IR of recurrent thrombosis per 100 pt-years was 5.3 (95% CI: 3.2-8.4) among 108 patients on long-term VKA and 12.8 (95% CI: 7.3-20.7) after discontinuation among the 47 who ceased treatment (P=0.008), with a doubled risk of recurrence after stopping VKA (hazard ratio: 2.21, 95% CI: 1.19-5.30). The IR of major bleeding per 100 pt-years was 2.4 (95%: CI: 1.1-4.5) on VKA and 0.7 (95% CI: 0.08-2.5) off VKA (P=0.08). In conclusion, in MPN patients with VTE recurrent thrombosis is significantly reduced by VKA and caution should be adopted in discontinuation; however, the incidence of recurrence on treatment remains high, calling for clinical trials aimed to improve prophylaxis in this setting.
Assuntos
Neoplasias da Medula Óssea/complicações , Fibrinolíticos/uso terapêutico , Pré-Medicação/métodos , Tromboembolia Venosa/tratamento farmacológico , Vitamina K/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Fibrinolíticos/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Mieloproliferativos/complicações , Embolia Pulmonar/tratamento farmacológico , Embolia Pulmonar/etiologia , Recidiva , Estudos Retrospectivos , Tromboembolia Venosa/etiologiaRESUMO
PURPOSE: Recent reports of extramedullary disease (EMD) at recurrence in acute promyelocytic leukemia (APL) have raised increasing concern about a possible role of retinoic acid (RA) therapy. PATIENTS AND METHODS: We analyzed the risk of developing EMD localization at relapse in APL patients enrolled onto two consecutive studies of the Gruppo Italiano Malattie Ematologiche dell'Adulto. The studies investigated chemotherapy alone (LAP0389) versus RA plus chemotherapy (AIDA). RESULTS: When all relapse types were taken into account, 94 (51%) of 184 patients and 131 (18%) of 740 patients who attained hematologic remission underwent relapse in the LAP0389 and AIDA studies, respectively (P < .0001). EMD localization was documented in five (5%) of 94 and 16 (12%) of 131 patients (P = .08). Hematologic and/or molecular relapse was diagnosed concomitantly in all but two patients with EMD in the AIDA study. For patients in the LAP0389 and AIDA series, the probability of EMD localization of any type at relapse was 3% and 4.5%, respectively (P = .79), while the probability of CNS involvement was 0.6% and 2% (P = .28). No significant differences were found with regard to mean WBC count and promyelocytic leukemia/retinoic acid receptor-alpha junction type in comparisons of patients with EMD and hematologic relapse. CONCLUSION: APL patients receiving all-trans retinoic acid in addition to chemotherapy have no increased risk of developing EMD at relapse as compared with those treated with chemotherapy alone.
Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Promielocítica Aguda/tratamento farmacológico , Tretinoína/uso terapêutico , Adulto , Feminino , Hematopoese Extramedular , Humanos , Leucemia Promielocítica Aguda/líquido cefalorraquidiano , Leucemia Promielocítica Aguda/patologia , Masculino , Pessoa de Meia-Idade , RNA/análise , Receptores do Ácido Retinoico/análise , Receptores do Ácido Retinoico/genética , Recidiva , Receptor alfa de Ácido Retinoico , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Risco , Tretinoína/administração & dosagem , Tretinoína/efeitos adversosRESUMO
PURPOSE: Preliminary reports suggest that leukemic cell expression of CD56, a neural cell adhesion molecule, is associated with adverse clinical outcome in either acute myeloid leukemia with t(8;21) or acute promyelocytic leukemia (APL). We investigated the prognostic relevance of CD56 in a series of patients with APL who were treated homogeneously with all-trans-retinoic acid (ATRA) and chemotherapy. PATIENTS AND METHODS: Clinicobiologic presenting features and therapeutic results were analyzed in a series of 100 patients with genetically proven APL who were treated, according to the example of the Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto multicenter trial, with ATRA plus idarubicin (AIDA) and for whom data on CD56 expression were available at diagnosis. RESULTS: Fifteen patients (15%) showed expression of CD56 in greater than or equal to 20% blasts at diagnosis and were considered as CD56(+). No differences were found regarding age, sex, WBC and platelet counts, incidence of coagulopathy, hemoglobin and fibrinogen levels, promyelocytic leukemia/retinoic acid receptor (PML/RAR) alpha fusion type, or complete remission (CR) rate in the comparison of the CD56(+) and CD56(-) populations. Conversely, compared with patients who were CD56(-), patients with CD56(+) APL had shorter CR duration (P =.04) and overall survival (P =.002). In the multivariate analysis, CD56 positivity and initial WBC count greater than 10 x 10(9) cells/L retained statistical significance in overall survival (P =.04 and P =.02, respectively). CONCLUSION: The expression of CD56 is significantly associated with inferior CR duration and survival in patients with APL who were treated with modern frontline treatment that included ATRA and simultaneous chemotherapy. Combined with other well-established prognostic factors such as WBC count, CD56 expression at diagnosis might be used to build prognostic scores for risk-adapted therapy in APL.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno CD56/metabolismo , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/metabolismo , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Idarubicina/administração & dosagem , Leucemia Promielocítica Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Análise de Sobrevida , Tretinoína/administração & dosagemRESUMO
One hundred eight consecutive patients with proved coronary artery disease and reproducible exercise-induced myocardial ischemia were studied. During repeated exercise testing, 52 patients (Group I) had myocardial ischemia in the absence of pain (silent ischemia) whereas 56 patients (Group II) experienced anginal symptoms in the presence of electrocardiographic signs of ischemia. A pulpal test was carried out in all patients using an electrical dental stimulator commonly used in dentistry. Electrical current was delivered in increasing intensity from 10 to 500 mA, and the dental pain threshold and the reaction of the patients to maximal stimulation were determined. During the pulpal test, 71.2% of the patients in Group I did not experience pain, even at maximal stimulation (threshold 0), 11.5% were sensitive at threshold I (10 to 200 mA) and 17.3% felt pain at threshold II (210 to 500 mA). In Group II, 69.7% of the patients complained of dental pain at the low intensity test current (threshold I), 10.7% at threshold II and 19.6% at threshold 0. In Group I, 71.2% of patients did not have discomfort (reaction -), even at maximal stimulation, 21.1% had a mild reaction (reaction +) and 7.7% had an intense painful reaction (reaction ++). In Group II, 80.4% of patients were sensitive to the pulpar test (67.9% reported intense painful sensation at maximal stimulation, 12.5% had a mild reaction); 19.6% of patients had no reaction. The two groups of patients were similar with respect to age, sex and angiographic features.(ABSTRACT TRUNCATED AT 250 WORDS)