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TKIs long-term treatment in CML may lead to persistent adverse events (AEs) that can promote relevant morbidity and mortality. Consequently, TKIs dose reduction is often used to prevent AEs. However, data on its impact on successful treatment-free remission (TFR) are quite scarce. We conducted a retrospective study on the outcome of CML subjects who discontinued low-dose TKIs from 54 Italian hematology centers participating in the Campus CML network. Overall, 1.785 of 5.108 (35.0%) regularly followed CML patients were treated with low-dose TKIs, more frequently due to relevant comorbidities or AEs (1.288, 72.2%). TFR was attempted in 248 (13.9%) subjects, all but three while in deep molecular response (DMR). After a median follow-up of 24.9 months, 172 (69.4%) patients were still in TFR. TFR outcome was not influenced by gender, Sokal/ELTS risk scores, prior interferon, number and last type of TKI used prior to treatment cessation, DMR degree, reason for dose reduction or median TKIs duration. Conversely, TFR probability was significantly better in the absence of resistance to any prior TKI. In addition, patients with a longer DMR duration before TKI discontinuation (i.e., >6.8 years) and those with an e14a2 BCR::ABL1 transcript type showed a trend towards prolonged TFR. It should also be emphasized that only 30.6% of our cases suffered from molecular relapse, less than reported during full-dose TKI treatment. The use of low-dose TKIs does not appear to affect the likelihood of achieving a DMR and thus trying a treatment withdrawal, but might even promote the TFR rate.
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BACKGROUND: The COVID-19 pandemic has created enormous challenges for the clinical management of patients with hematological malignancies (HMs), raising questions about the optimal care of this patient group. METHODS: This consensus manuscript aims at discussing clinical evidence and providing expert advice on statements related to the management of HMs in the COVID-19 pandemic. For this purpose, an international consortium was established including a steering committee, which prepared six working packages addressing significant clinical questions from the COVID-19 diagnosis, treatment, and mitigation strategies to specific HMs management in the pandemic. During a virtual consensus meeting, including global experts and lead by the European Society for Medical Oncology and the European Hematology Association, statements were discussed and voted upon. When a consensus could not be reached, the panel revised statements to develop consensual clinical guidance. RESULTS AND CONCLUSION: The expert panel agreed on 33 statements, reflecting a consensus, which will guide clinical decision making for patients with hematological neoplasms during the COVID-19 pandemic.
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COVID-19 , Neoplasias Hematológicas , Humanos , Consenso , Prueba de COVID-19 , Neoplasias Hematológicas/epidemiología , Neoplasias Hematológicas/terapia , PandemiasRESUMEN
Skin is usually the first and most affected organ involved in graft-versus-host disease (GvHD), and treatment is still a clinical challenge. Although the need for skin-directed treatments such as physical treatments and topical medications are generally agreed on, what the gold standard treatment strategy should be remains open to debate. The aim of this scoping review was to synthesize the current knowledge on the topical and physical treatments of cutaneous GvHD in haematopoietic stem cell transplantation patients and to highlight the best evidence available so as to reduce the gap between 'what is known' and 'what is done' in the clinical practice. Twenty-eight studies were included in this qualitative synthesis. Photo-biomodulation with psoralen was not included in this review. Phototherapy (ultraviolet A or B or narrowband B) was the physical treatment most described in the literature in both acute GvHD and chronic GvHD. Topical calcineurin inhibitors such as tacrolimus ointment and pimecrolimus cream as well as corticosteroid creams such as clobetasol and triamcinolone are mainly used in case of chronic GvHD. In all of the studies included in the review, topical treatments were always associated with systemic therapy. None of the topical interventions identified in our review provided strong evidence supporting its use, and the topical approaches seemed to have an adjuvant role in the treatment of cutaneous GvHD.
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Enfermedades de la Piel , Inhibidores de la Calcineurina/uso terapéutico , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Fototerapia , Piel , Enfermedades de la Piel/tratamiento farmacológicoRESUMEN
The occurrence of acute myeloid leukemia (AML) within six months from a diagnosis of breast cancer (BC) is rarely reported in the literature, and it is associated with a poor prognosis. We report herein the case of a 40-year-old woman referred to our centre affected by BC and simultaneous AML. The patient proved refractory to first line therapy and achieved complete remission (CR) with a clofarabine-based regimen followed by allogeneic stem cell transplantation (ASCT). Both during salvage chemotherapy and after ASCT, the patient presented severe infectious complications ( acute cholecistytis and Nocardia pneumonia, respectively) treated with surgery, and currently she is alive in CR for both diseases after 29 months of follow-up. The case highlights the importance of a diagnostic assessment of any unexplained cytopenia in association with solid neoplasia under treatment, underlining the feasibility and priority of a timely treatment of the haematological neoplasm in order to achieve long-term survival.
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Preliminary data suggest that allogeneic stem cell transplantation (allo-SCT) may be effective in T-prolymphocytic leukemia (T-PLL). The purpose of the present observational study was to assess the outcome of allo-SCT in patients aged 65 years or younger with a centrally confirmed diagnosis of T-PLL. Patients were consecutively registered with the EBMT at the time of transplantation and followed by routine EBMT monitoring but with an extended dataset. Between 2007 and 2012, 37 evaluable patients (median age 56 years) were accrued. Pre-treatment contained alemtuzumab in 95% of patients. Sixty-two percent were in complete remission (CR) at the time of allo-SCT. Conditioning contained total body irradiation with 6 Gy or more (TBI6) in 30% of patients. With a median follow-up of 50 months, the 4-year non-relapse mortality, relapse incidence, progression-free (PFS) and overall survival were 32, 38, 30 and 42%, respectively. By univariate analysis, TBI6 in the conditioning was the only significant predictor for a low relapse risk, and an interval between diagnosis and allo-SCT of more than 12 months was associated with a lower NRM. This study confirms for the first time prospectively that allo-SCT can provide long-term disease control in a sizable albeit limited proportion of patients with T-PLL.
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Trasplante de Células Madre Hematopoyéticas , Leucemia Prolinfocítica de Células T , Sistema de Registros , Acondicionamiento Pretrasplante , Irradiación Corporal Total , Adolescente , Adulto , Anciano , Aloinjertos , Supervivencia sin Enfermedad , Femenino , Humanos , Leucemia Prolinfocítica de Células T/mortalidad , Leucemia Prolinfocítica de Células T/terapia , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Tasa de SupervivenciaRESUMEN
Background: Chronic lymphocytic leukemia (CLL) has a heterogeneous clinical course. Beside patients requiring immediate treatment, others show an initial indolent phase followed by progression and others do not progress for decades. The latter two subgroups usually display mutated IGHV genes and a favorable FISH profile. Patients and methods: Patients with absence of disease progression for over 10 years (10-34) from diagnosis were defined as ultra-stable CLL (US-CLL). Forty US-CLL underwent extensive characterization including whole exome sequencing (WES), ultra-deep sequencing and copy number aberration (CNA) analysis to define their unexplored genetic landscape. Microarray analysis, comparing US-CLL with non-US-CLL with similar immunogenetic features (mutated IGHV/favorable FISH), was also carried out to recognize US-CLL at diagnosis. Results: WES was carried out in 20 US-CLL and 84 non-silent somatic mutations in 78 genes were found. When re-tested in a validation cohort of 20 further US-CLL, no recurrent lesion was identified. No clonal mutations of NOTCH1, BIRC3, SF3B1 and TP53 were found, including ATM and other potential progression driving mutations. CNA analysis identified 31 lesions, none with known poor prognostic impact. No novel recurrent lesion was identified: most cases showed no lesions (38%) or an isolated del(13q) (31%). The expression of 6 genes, selected from a gene expression profile analysis by microarray and quantified by droplet digital PCR on a cohort of 79 CLL (58 US-CLL and 21 non-US-CLL), allowed to build a decision-tree capable of recognizing at diagnosis US-CLL patients. Conclusions: The genetic landscape of US-CLL is characterized by the absence of known unfavorable driver mutations/CNA and of novel recurrent genetic lesions. Among CLL patients with favorable immunogenetics, a decision-tree based on the expression of 6 genes may identify at diagnosis patients who are likely to maintain an indolent disease for decades.
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Cadenas Pesadas de Inmunoglobulina/genética , Región Variable de Inmunoglobulina/genética , Leucemia Linfocítica Crónica de Células B/genética , Estudios de Cohortes , Variaciones en el Número de Copia de ADN , Progresión de la Enfermedad , Genes p53 , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Hibridación Fluorescente in Situ , Mutación , Análisis de Secuencia por Matrices de Oligonucleótidos , Secuenciación del ExomaRESUMEN
Interactions between killer-immunoglobulin-like receptors (KIRs) and their HLA class I ligands are instrumental in natural killer (NK) cell regulation and protect normal tissue from NK cell attack. Human KIR haplotypes comprise genes encoding mainly inhibitory receptors (KIR A) or activating and inhibitory receptors (KIR B). A substantial fraction of humans lack ligands for inhibitory KIRs (iKIRs), that is, a 'missing ligand' genotype. KIR B/x and missing ligand genotypes may thus give rise to potentially autoreactive, unlicensed NK cells. Little is known regarding the impact of such genotypes in untransplanted acute myeloid leukemia (AML). For this study, NK cell phenotypes and KIR/HLA genotypes were determined in 81 AML patients who received immunotherapy with histamine dihydrochloride and low-dose IL-2 for relapse prevention (NCT01347996). We observed that presence of unlicensed NK cells impacted favorably on clinical outcome, in particular among patients harboring functional NK cells reflected by high expression of the natural cytotoxicity receptor (NCR) NKp46. Genotype analyses suggested that the clinical benefit of high NCR expression was restricted to patients with a missing ligand genotype and/or a KIR B/x genotype. These data imply that functional NK cells are significant anti-leukemic effector cells in patients with KIR/HLA genotypes that favor NK cell autoreactivity.
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Genotipo , Antígenos HLA/genética , Leucemia Mieloide Aguda/genética , Receptores KIR/genética , Ensayos Clínicos Fase IV como Asunto , Antígenos HLA/inmunología , Humanos , Inmunoterapia , Interleucina-2/farmacología , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/terapia , Ligandos , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/inmunología , Estudios Multicéntricos como Asunto , Pronóstico , Receptores KIR/metabolismo , Análisis de Supervivencia , Resultado del TratamientoAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bortezomib/uso terapéutico , Dexametasona/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Oligorribonucleótidos/antagonistas & inhibidores , Oligorribonucleótidos/uso terapéutico , Anciano , Quimiocina CXCL12 , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismoAsunto(s)
Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Factores de Edad , Anciano , Anticuerpos Monoclonales/uso terapéutico , Ensayos Clínicos Fase III como Asunto , Humanos , Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/genética , Persona de Mediana Edad , Ensayos Clínicos Controlados Aleatorios como AsuntoAsunto(s)
Análisis Mutacional de ADN/métodos , Resistencia a Antineoplásicos/genética , Proteínas de Fusión bcr-abl/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adulto , Anciano , Antineoplásicos/uso terapéutico , Femenino , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Humanos , Masculino , Persona de Mediana Edad , Mutación , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/genética , Neoplasia Residual/diagnóstico , Neoplasia Residual/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
In order to evaluate the predictive value of positron emission tomography-computed tomography (PET/CT) in discriminating the presence of a Richter's syndrome (RS) or a second malignancy (SM), as well as to evaluate its prognostic value in patients with chronic lymphocytic leukemia (CLL), we retrospectively analyzed the data of 90 patients who, in the suspicion of a RS or a SM, underwent PET/CT followed by the biopsy of the involved tissue. The median maximum Standardized Uptake Value (SUV max) in the presence of a CLL/small lymphocytic lymphoma, a diffuse large B-cell lymphoma (DLBCL), a Hodgkin lymphoma (HL), a SM were 3.5, 14.6, 7.0 and 6.3, respectively (P ⩽ 0.0001). A SUV max cutoff value ⩾ 5 showed a sensitivity, specificity, positive and negative predictive values of 88.2, 71.2, 51.3 and 94%, respectively, for the presence of a more aggressive disease (DLBCL, HL and SM). A SUV max ⩾ 5 identified also a subset of treatment naive patients with an inferior progression-free survival (P = 0.011) and overall survival (P = 0.067). These findings suggest that PET/CT may helpfully integrate the biologically-based prognostic stratification of CLL. Prospective clinical trials including larger cohorts of patients are needed to conclusively define the role and prognostic impact of PET/CT in the routine management of CLL patients.
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Enfermedad de Hodgkin/diagnóstico , Leucemia Linfocítica Crónica de Células B/diagnóstico , Linfoma de Células B Grandes Difuso/diagnóstico , Neoplasias Primarias Secundarias/diagnóstico , Tomografía de Emisión de Positrones/métodos , Tomografía Computarizada por Rayos X/métodos , Adulto , Anciano , Anciano de 80 o más Años , Terapia Combinada , Femenino , Estudios de Seguimiento , Enfermedad de Hodgkin/mortalidad , Enfermedad de Hodgkin/terapia , Humanos , Leucemia Linfocítica Crónica de Células B/mortalidad , Leucemia Linfocítica Crónica de Células B/terapia , Linfoma de Células B Grandes Difuso/mortalidad , Linfoma de Células B Grandes Difuso/terapia , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Primarias Secundarias/mortalidad , Neoplasias Primarias Secundarias/terapia , Pronóstico , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
Bleeding phenotype in factor XI (FXI)-deficient patients is variable, and not related to baseline FXI:Act. Aims of our study were to describe the characteristics and the management of surgery and deliveries in FXI-deficient patients, and to investigate the relationship between the haemorrhagic phenotype and the baseline FXI:Act. Ninety-five patients were diagnosed and followed in our centre for a median follow-up of 0.9 years (0.1-36.2); median FXI:Act of all patients: 38% (0.5-69%). Fifty-six patients (59%) experienced bleeding episodes not surgery-related. Prior to diagnosis, 64 patients underwent 132 surgeries, and after diagnosis, 23 patients underwent 36 surgeries. Globally 26 of 168 surgeries were prophylactically treated, whereas 142 of 168 were not. As regard as surgeries performed without prophylaxis, 30 bleeding events (21%) occurred in 21 patients. At diagnosis, the median FXI:Act of bleeding and non-bleeding patients was 28% and 37%, respectively, without statistically significant difference between the two groups (P = 0.26). As regard as surgeries performed under prophylactic treatment just 1 bleeding event occurred. Prior to diagnosis, 31 spontaneous deliveries (SD) and eight caesarian sections (CS) were performed without prophylaxis: 4 postpartum haemorrhages (10.5%) occurred (patients FXI:Act: 2%, 6%, 27%, 52.3% respectively). After diagnosis, four SD and five CS were performed with prophylaxis: no postpartum haemorrhages occurred. We confirm the wide bleeding phenotype variability in FXI-deficient patients, not related to the baseline FXI:Act levels. We highlight the importance of performing a correct diagnosis and follow-up, because a good management of prophylactic treatment, dramatically reduces the bleeding rate in case of surgery or deliveries.
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Deficiencia del Factor XI/tratamiento farmacológico , Factor XI/uso terapéutico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Pérdida de Sangre Quirúrgica/prevención & control , Cesárea , Niño , Preescolar , Femenino , Hemostasis Quirúrgica , Humanos , Lactante , Masculino , Persona de Mediana Edad , Fenotipo , Hemorragia Posparto/prevención & control , Embarazo , Estudios Retrospectivos , Adulto JovenAsunto(s)
Factores de Transcripción de Tipo Kruppel/genética , Linfoma de Células B de la Zona Marginal/genética , Mutación , Neoplasias del Bazo/genética , Alelos , Transformación Celular Neoplásica , Análisis Mutacional de ADN , Eliminación de Gen , Dosificación de Gen , Células HEK293 , Humanos , Hibridación Fluorescente in Situ , Células Jurkat , Polimorfismo de Nucleótido SimpleRESUMEN
Strongyloides stercoralis infections may be documented in low-endemicity areas, particularly in immigrants from endemic areas. The case of a patient from Bangladesh, an immigrant to Italy who developed a S. stercoralis infection after allogeneic stem cell transplant, is described, and 7 further cases are reviewed. Because of the atypical clinical presentation, the low predictive role of the eosinophil count, and the low sensitivity of the microbiological tests, diagnosis of strongyloidiasis is a challenging problem. When a case of S. stercoralis infection is suspected, previous exposure may be the only clue to guide the diagnostic approach.
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Trasplante de Células Madre/efectos adversos , Strongyloides stercoralis/aislamiento & purificación , Estrongiloidiasis/etiología , Adulto , Animales , Humanos , Masculino , Estrongiloidiasis/parasitología , Trasplante HomólogoRESUMEN
Application of G-CSF in AML is controversial as leukemic blasts may express receptors interacting with the cytokine, which may stimulate leukemia growth. We retrospectively analyzed the impact of G-CSF use to accelerate neutrophil recovery after auto-SCT on outcome. Adults with AML in first CR autografted between 1994 and 2010 were included. Nine hundred and seventy two patients were treated with G-CSF after auto-SCT whereas 1121 were not. BM and PB were used as a source of stem cells in 454 (22%) and 1639 (78%) cases, respectively. The incidence of relapse at 5 years in the BM-auto-SCT group was 38% for patients receiving post-transplant G-CSF and 43% for those not treated with G-CSF, P=0.46. In the PB-auto-SCT cohort, respective probabilities were 48% and 49%, P=0.49. No impact of the use of G-CSF could be demonstrated with respect to the probability of leukemia-free survival: in the BM-auto-SCT group, 51% for G-CSF(+) and 48% for G-CSF(-), P=0.73; in PB-auto-SCT group, 42% for G-CSF(+) and 43% for G-CSF(-), P=0.83. Although G-CSF administration significantly shortened the neutropenic phase, no beneficial effect was observed with regard to non-relapse mortality. In patients with AML, the use of G-CSF after auto-SCT is not associated with increased risk of relapse irrespective of the source of stem cells used.
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Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia Mieloide Aguda/terapia , Neutrófilos/efectos de los fármacos , Acondicionamiento Pretrasplante/métodos , Adolescente , Adulto , Anciano , Femenino , Humanos , Incidencia , Leucemia Mieloide Aguda/sangre , Leucemia Mieloide Aguda/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Neutrófilos/citología , Recurrencia , Estudios Retrospectivos , Adulto JovenRESUMEN
We conducted a phase II, noncomparative, open-label, multicenter GIMEMA (Gruppo Italiano Malattie EMatologiche dell'Adulto) study (CLL0809) to assess the efficacy and safety of bendamustine in combination with ofatumumab (BendOfa) in relapsed/refractory chronic lymphocytic leukemia (CLL). Forty-seven patients from 14 centers were evaluated. Therapy consisted of bendamustine (70 mg/m(2)) for 2 consecutive days every 28 days, and ofatumumab 300 mg on day 1 and 1000 mg on day 8 during the first cycle, and 1000 mg on day 1 subsequently. Treatment was administered up to six cycles. The overall response rate (ORR), as per intention-to-treat analysis, was 72.3% (95% confidence of interval (CI), 57-84%), with 17% complete responses. After a median follow-up of 24.2 months, the overall survival was 83.6% (95% CI, 73.0-95.7%) and the progression-free survival (PFS) was 49.6% (95% CI, 35.9-68.6%). The median PFS was 23.6 months. Univariate and multivariate analyses were used to identify clinical and biological characteristics associated with ORR and PFS. Myelosuppression was the most common toxicity; grade ≥3 neutropenia was observed in 61.7% of patients; however, grade ≥3 infections occurred in 6% of patients. BendOfa is feasible and effective in relapsed/refractory CLL patients, including patients with high-risk clinical and biological features.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Anciano , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados , Clorhidrato de Bendamustina , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/patología , Masculino , Compuestos de Mostaza Nitrogenada/administración & dosificación , RecurrenciaRESUMEN
Mucormycosis is the third cause of invasive mycosis after candidiasis and aspergillosis in AML patients, representing a poor prognostic factor associated with a high rate of fatal outcome. We report a case of a patient with AML and a concomitant pulmonary mucormycosis at diagnosis, who obtained a complete remission both of her AML and of the fungal infection. The incidence of the infection at the onset of leukemia is extremely unusual, and, to our knowledge, the sporadic cases reported in the literature are included in heterogeneous series retrospectively examined. In our case, Liposomal Amphotericin B as single agent appeared incapable of controlling the infection, so anti-infective therapy was intensified with posaconazole and simultaneously antileukemic treatment with 5-azacitidine was started, with the understanding that the only antifungal treatment would not have been able to keep the infection under control for a long time if not associated with a reversal of neutropenia related to the disease. We observed a progressive improvement of the general conditions, a healing of pneumonia and a complete remission of the leukemic disease, suggesting that a careful utilization of the new compounds available today, in terms of both antifungal and antileukemic treatment, may offer a curative chance a patient who would have otherwise been considered unfit for a potentially curative therapeutic strategy.