RESUMEN
Therapy-resistant microenvironments represent a major barrier toward effective elimination of disseminated malignancies. Here, we show that select microenvironments can underlie resistance to antibody-based therapy. Using a humanized model of treatment refractory B cell leukemia, we find that infiltration of leukemia cells into the bone marrow rewires the tumor microenvironment to inhibit engulfment of antibody-targeted tumor cells. Resistance to macrophage-mediated killing can be overcome by combination regimens involving therapeutic antibodies and chemotherapy. Specifically, the nitrogen mustard cyclophosphamide induces an acute secretory activating phenotype (ASAP), releasing CCL4, IL8, VEGF, and TNFα from treated tumor cells. These factors induce macrophage infiltration and phagocytic activity in the bone marrow. Thus, the acute induction of stress-related cytokines can effectively target cancer cells for removal by the innate immune system. This synergistic chemoimmunotherapeutic regimen represents a potent strategy for using conventional anticancer agents to alter the tumor microenvironment and promote the efficacy of targeted therapeutics.
Asunto(s)
Modelos Animales de Enfermedad , Leucemia Linfocítica Crónica de Células B/inmunología , Leucemia Linfocítica Crónica de Células B/terapia , Microambiente Tumoral , Animales , Ciclofosfamida/uso terapéutico , Citocinas/inmunología , Resistencia a Antineoplásicos , Xenoinjertos , Humanos , Inmunidad Innata , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Macrófagos/inmunología , Ratones , Trasplante de NeoplasiasRESUMEN
Bruton tyrosine kinase (BTK) inhibitors are highly active drugs for the treatment of chronic lymphocytic leukemia (CLL). To understand the response to BTK inhibitors on a molecular level, we performed (phospho)proteomic analyses under ibrutinib treatment. We identified 3466 proteins and 9184 phosphopeptides (representing 2854 proteins) in CLL cells exhibiting a physiological ratio of phosphorylated serines (pS), threonines (pT), and tyrosines (pY) (pS:pT:pY). Expression of 83 proteins differed between unmutated immunoglobulin heavy-chain variable region (IGHV) CLL (UM-CLL) and mutated IGHV CLL (M-CLL). Strikingly, UM-CLL cells showed higher basal phosphorylation levels than M-CLL samples. Effects of ibrutinib on protein phosphorylation levels were stronger in UM-CLL, especially on phosphorylated tyrosines. The differentially regulated phosphopeptides and proteins clustered in pathways regulating cell migration, motility, cytoskeleton composition, and survival. One protein, myristoylated alanine-rich C-kinase substrate (MARCKS), showed striking differences in expression and phosphorylation level in UM-CLL vs M-CLL. MARCKS sequesters phosphatidylinositol-4,5-bisphosphate, thereby affecting central signaling pathways and clustering of the B-cell receptor (BCR). Genetically induced loss of MARCKS significantly increased AKT signaling and migratory capacity. CD40L stimulation increased expression of MARCKS. BCR stimulation induced phosphorylation of MARCKS, which was reduced by BTK inhibitors. In line with our in vitro findings, low MARCKS expression is associated with significantly higher treatment-induced leukocytosis and more pronounced decrease of nodal disease in patients with CLL treated with acalabrutinib.
Asunto(s)
Adenina/análogos & derivados , Agammaglobulinemia Tirosina Quinasa , Movimiento Celular/efectos de los fármacos , Leucemia Linfocítica Crónica de Células B , Sustrato de la Proteína Quinasa C Rico en Alanina Miristoilada/metabolismo , Proteínas de Neoplasias , Piperidinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Adenina/farmacología , Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Agammaglobulinemia Tirosina Quinasa/metabolismo , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/enzimología , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/metabolismo , Fosforilación/efectos de los fármacosRESUMEN
Clinical management of chronic lymphocytic leukaemia (CLL) in patients aged ≥80 years is based on limited evidence due to the lack of published information. Therefore, we analysed CLL patients aged ≥80 years using data from seven phase III clinical trials of the German CLL Study Group. Among 3552 participants, 152 were ≥80 years old at initiation of first-line study treatment. Median age was 82 years (range 80-90). Concomitant diseases were present in 99% of the patients, with a median cumulative illness rating scale score of 8 (0-18). Chemoimmunotherapy with chlorambucil-obinutuzumab (CLB-OB) or chlorambucil-rituximab (CLB-R) was administered to 61 (40%) and 56 (37%) patients. The remaining patients received CLB (n = 19) or fludarabine (F, n = 10), F/cyclophosphamide (FC, n = 1), FC/rituximab (FCR, n = 2) or bendamustine/rituximab (BR, n = 3). Rates of grade 3 or 4 neutropenia and infections were 35% and 13%. Overall response rate was 77% with 13% complete remissions. Median progression-free survival and treatment-free survival were 17·2 and 32·3 months, respectively. Median overall survival was 48·3 months; adverse events (22%) and progressive CLL (16·4%) were the most frequent causes of death. These findings suggest that anti-leukaemic treatment including chemoimmunotherapy is feasible and efficacious in ≥80-year-old CLL patients. However, this group of patients lives for a shorter time than age-matched controls of the general population.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Anciano de 80 o más Años , Causas de Muerte , Ensayos Clínicos Fase III como Asunto , Terapia Combinada , Supervivencia sin Enfermedad , Alemania/epidemiología , Enfermedades Hematológicas/inducido químicamente , Humanos , Inmunoterapia/métodos , Infecciones/inducido químicamente , Leucemia Linfocítica Crónica de Células B/mortalidad , Neoplasias Primarias Secundarias/mortalidad , Resultado del TratamientoRESUMEN
BACKGROUND: The monoclonal anti-CD20 antibody rituximab, combined with chemotherapeutic agents, has been shown to prolong overall survival in physically fit patients with previously untreated chronic lymphocytic leukemia (CLL) but not in those with coexisting conditions. We investigated the benefit of the type 2, glycoengineered antibody obinutuzumab (also known as GA101) as compared with that of rituximab, each combined with chlorambucil, in patients with previously untreated CLL and coexisting conditions. METHODS: We randomly assigned 781 patients with previously untreated CLL and a score higher than 6 on the Cumulative Illness Rating Scale (CIRS) (range, 0 to 56, with higher scores indicating worse health status) or an estimated creatinine clearance of 30 to 69 ml per minute to receive chlorambucil, obinutuzumab plus chlorambucil, or rituximab plus chlorambucil. The primary end point was investigator-assessed progression-free survival. RESULTS: The patients had a median age of 73 years, creatinine clearance of 62 ml per minute, and CIRS score of 8 at baseline. Treatment with obinutuzumab-chlorambucil or rituximab-chlorambucil, as compared with chlorambucil monotherapy, increased response rates and prolonged progression-free survival (median progression-free survival, 26.7 months with obinutuzumab-chlorambucil vs. 11.1 months with chlorambucil alone; hazard ratio for progression or death, 0.18; 95% confidence interval [CI], 0.13 to 0.24; P<0.001; and 16.3 months with rituximab-chlorambucil vs. 11.1 months with chlorambucil alone; hazard ratio, 0.44; 95% CI, 0.34 to 0.57; P<0.001). Treatment with obinutuzumab-chlorambucil, as compared with chlorambucil alone, prolonged overall survival (hazard ratio for death, 0.41; 95% CI, 0.23 to 0.74; P=0.002). Treatment with obinutuzumab-chlorambucil, as compared with rituximab-chlorambucil, resulted in prolongation of progression-free survival (hazard ratio, 0.39; 95% CI, 0.31 to 0.49; P<0.001) and higher rates of complete response (20.7% vs. 7.0%) and molecular response. Infusion-related reactions and neutropenia were more common with obinutuzumab-chlorambucil than with rituximab-chlorambucil, but the risk of infection was not increased. CONCLUSIONS: Combining an anti-CD20 antibody with chemotherapy improved outcomes in patients with CLL and coexisting conditions. In this patient population, obinutuzumab was superior to rituximab when each was combined with chlorambucil. (Funded by F. Hoffmann-La Roche; ClinicalTrials.gov number, NCT01010061.).
Asunto(s)
Anticuerpos Monoclonales Humanizados/administración & dosificación , Antígenos CD20/inmunología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Clorambucilo/administración & dosificación , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Clorambucilo/efectos adversos , Comorbilidad , Supervivencia sin Enfermedad , Humanos , Persona de Mediana Edad , Inducción de Remisión , RituximabRESUMEN
Mutations in TP53, NOTCH1, and SF3B1 were analyzed in the CLL8 study evaluating first-line therapy with fludarabine and cyclophosphamide (FC) or FC with rituximab (FCR) among patients with untreated chronic lymphocytic leukemia (CLL). TP53, NOTCH1, and SF3B1 were mutated in 11.5%, 10.0%, and 18.4% of patients, respectively. NOTCH1(mut) and SF3B1(mut) virtually showed mutual exclusivity (0.6% concurrence), but TP53(mut) was frequently found in NOTCH1(mut) (16.1%) and in SF3B1(mut) (14.0%) patients. There were few significant associations with clinical and laboratory characteristics, but genetic markers had a strong influence on response and survival. In multivariable analyses, an independent prognostic impact was found for FCR, thymidine kinase (TK) ≥10 U/L, unmutated IGHV, 11q deletion, 17p deletion, TP53(mut), and SF3B1(mut) on progression-free survival; and for FCR, age ≥65 years, Eastern Cooperative Oncology Group performance status ≥1, ß2-microglobulin ≥3.5 mg/L, TK ≥10 U/L, unmutated IGHV, 17p deletion, and TP53(mut) on overall survival. Notably, predictive marker analysis identified an interaction of NOTCH1 mutational status and treatment in that rituximab failed to improve response and survival in patients with NOTCH1(mut). In conclusion, TP53 and SF3B1 mutations appear among the strongest prognostic markers in CLL patients receiving current-standard first-line therapy. NOTCH1(mut) was identified as a predictive marker for decreased benefit from the addition of rituximab to FC. This study is registered at www.clinicaltrials.gov as #NCT00281918.
Asunto(s)
Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Mutación , Fosfoproteínas/genética , Receptor Notch1/genética , Ribonucleoproteína Nuclear Pequeña U2/genética , Proteína p53 Supresora de Tumor/genética , Anciano , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Antimetabolitos/uso terapéutico , Antineoplásicos Alquilantes/uso terapéutico , Ciclofosfamida/uso terapéutico , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/genética , Masculino , Persona de Mediana Edad , Pronóstico , Factores de Empalme de ARN , Rituximab , Análisis de Supervivencia , Resultado del Tratamiento , Vidarabina/uso terapéuticoRESUMEN
BACKGROUND: Autologous peripheral blood stem cells (PBSCs) are usually cryopreserved before high-dose chemotherapy (HDCT) and autologous peripheral blood stem cell transplantation (PBSCT). The freezing process requires the addition of cryoprotectants such as dimethyl sulfoxide (DMSO), which is vital for cell viability in frozen aliquots. DMSO has a number of well-described side effects. However, severe neurologic side effects assigned to DMSO are exceedingly rare. CASE REPORT: A 64-year-old female underwent HDCT followed by PBSCT as consolidation therapy in relapsed high-grade (Grade 3B) Stage IIIA follicular lymphoma. PBSCs were mobilized using granulocyte-colony stimulating factor and plerixafor after the second cycle of R-DHAP (rituximab, dexamethasone, high-dose Ara-C, cisplatin) salvage chemotherapy. A total of 7.18 × 106 /kg body weight CD34+ cells were cryopreserved using 10% DMSO. HDCT was administered some weeks later followed by reinfusion of two bags of PBSCs, each containing 98 mL with 1.6 × 106 /kg body weight CD34+ cells. Within a few minutes the patient developed a motor aphasia and became very agitated. Brain imaging did not reveal any pathologic finding. After being transferred to the intensive care unit the patient's condition steadily improved and the motor aphasia resolved completely within 6 hours after its onset. CONCLUSION: This is, to our knowledge, the first report to describe an episode of severe motor aphasia during PBSCT. Given the close timely correlation with PBSCT, this episode appears to be caused by dimethyl sulfoxide (DMSO) and might possibly have been prevented by use of lower concentrations of DMSO.
Asunto(s)
Afasia de Broca/inducido químicamente , Criopreservación/métodos , Dimetilsulfóxido/efectos adversos , Trasplante de Células Madre de Sangre Periférica/métodos , Femenino , Humanos , Linfoma Folicular/terapia , Persona de Mediana Edad , Agonistas Mieloablativos/uso terapéutico , Acondicionamiento Pretrasplante/métodos , Trasplante AutólogoRESUMEN
Pharmacological inhibition of phosphatiylinositide-3-kinase (PI3K)-mediated signaling holds great promise for treating chronic lymphocytic leukemia (CLL). Therefore we assessed three structurally related PI3K inhibitors targeting the PI3K-δ isoform for their ability to inhibit the survival of freshly isolated CLL cells. The purely PI3K-δ-selective inhibitor idelalisib was compared to copanlisib (BAY 80-6946) and duvelisib (IPI-145), with isoform target profiles that additionally include PI3K-α or PI3K-γ, respectively. The concentrations leading to half-maximal reduction of the survival of CLL cells were more than ten-fold lower for copanlisib than for idelalisib and duvelisib. At concentrations reflecting the biological availability of the different inhibitors, high levels of apoptotic response among CLL samples were attained more consistently with copanlisib than with idelalisib. Copanlisib selectively reduced the survival of CLL cells compared to T cells and to B cells from healthy donors. In addition copanlisib and duvelisib impaired the migration of CLL cells towards CXCL12 to a greater extent than equimolar idelalisib. Similarly copanlisib and duvelisib reduced the survival of CLL cells in co-cultures with the bone marrow stroma cell line HS-5 more strongly than idelalisib. Survival inhibition by copanlisib and idelalisib was enhanced by the monoclonal CD20 antibodies rituximab and obinutuzumab (GA101), while antibody-dependent cellular cytotoxicity mediated by alemtuzumab and peripheral blood mononuclear cells was not substantially impaired by both PI3K inhibitors for the CLL-derived JVM-3 cell line as target cells. Taken together, targeting the α- and δ- p110 isoforms with copanlisib may be a useful strategy for the treatment of CLL and warrants further clinical investigation.
Asunto(s)
Anticuerpos Monoclonales de Origen Murino/farmacología , Isoquinolinas/farmacología , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Purinas/farmacología , Pirimidinas/farmacología , Quinazolinas/farmacología , Quinazolinonas/farmacología , Antineoplásicos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Quimiocina CXCL12/fisiología , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Concentración 50 Inhibidora , Isoenzimas/antagonistas & inhibidores , Isoenzimas/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Rituximab , Transducción de SeñalRESUMEN
The recovery of the host immune system after allogeneic hematopoietic stem cell transplantation is pivotal to prevent infections, relapse, and secondary malignancies. In particular, numerical CD4+ T cells reconstitution is delayed and CD4 helper cell function is considered impaired as a consequence of the transplant procedure and concomitant immunosuppressive medication. From HIV/AIDS patients, it is known that numerical and functional CD4 defects increase the risk of opportunistic infections. However, and in contrast to patients with HIV, anti-infective prophylaxis after allogeneic transplantation is usually given for 6 months depending on immunosuppressive medication and existing graft-versus-host disease but independently of absolute CD4+ T cells counts. We hypothesized that a qualitative T cell defect is existing after allogeneic transplantation, especially in patients with delayed immune-reconstitution. Applying transcriptional as well as functional approaches, we show that CD4+ T cells with delayed recovery have a distinct transcriptional profile and cluster differently from T cells originated from patients with completed immune recovery. Moreover, inhibitory signatures are substantially enriched within the transcriptional profile of these T cells translating to functional defects and impaired interleukin 2 production. In addition to time after transplant, CD4+ T cells numbers should be considered for the decision to stop or maintain antimicrobial prophylaxis in patients after allogeneic stem cell transplantation.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Huésped Inmunocomprometido/inmunología , Trasplante de Células Madre/tendencias , Adulto , Anciano , Recuento de Células/métodos , Células Cultivadas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Trasplante de Células Madre/efectos adversos , Linfocitos T Colaboradores-Inductores/inmunología , Trasplante Homólogo/efectos adversos , Trasplante Homólogo/tendencias , Adulto JovenRESUMEN
In this issue of Blood, Sampath and colleagues provide an important missing link in how microRNAs (miRs) can be silenced in chronic lymphocytic leukemia (CLL):histone deacetylases (HDACs) that are overexpressed in CLL block critical miRs in the malignant B cell resulting in pro-survival signals. Thus,HDAC inhibition is an attractive new therapeutic strategy in CLL.
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Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Sulfonamidas/administración & dosificación , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Compuestos Bicíclicos Heterocíclicos con Puentes/efectos adversos , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/patología , Masculino , Persona de Mediana Edad , Sulfonamidas/efectos adversosRESUMEN
This study investigated the impact of comorbidity in 555 patients with chronic lymphocytic leukemia enrolled in two trials of the German Chronic Lymphocytic Leukemia Study Group on first-line treatment with fludarabine plus cyclophosphamide, fludarabine, or chlorambucil. Patients with two or more comorbidities and patients with less than two comorbidities differed in overall survival (71.7 versus 90.2 months; P<0.001) and progression-free survival (21.0 versus 31.5 months; P<0.01). After adjustment for other prognostic factors and treatment, comorbidity maintained its independent prognostic value in a multivariate Cox regression analysis. Chronic lymphocytic leukemia was the major cause of death in patients with two or more comorbidities. Disease control in patients with two or more comorbidities was better with fludarabine plus cyclophosphamide than with fludarabine treatment, but not with fludarabine compared to chlorambucil treatment. These results give insight into interactions between comorbidity and therapy of chronic lymphocytic leukemia and suggest that durable control of the hematologic disease is most critical to improve overall outcome of patients with increased comorbidity. The registration numbers of the trials reported are NCT00276848 and NCT00262795.
Asunto(s)
Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/epidemiología , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Comorbilidad , Femenino , Alemania/epidemiología , Humanos , Leucemia Linfocítica Crónica de Células B/diagnóstico , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Factores de Riesgo , Resultado del TratamientoRESUMEN
The clinical value of imaging is well established for the follow-up of many lymphoid malignancies but not for chronic lymphocytic leukemia (CLL). A meta-analysis was performed with the dataset of 3 German CLL Study Group phase 3 trials (CLL4, CLL5, and CLL8) that included 1372 patients receiving first-line therapy for CLL. Response as well as progression during follow-up was reassessed according to the National Cancer Institute Working Group1996 criteria. A total of 481 events were counted as progressive disease during treatment or follow-up. Of these, 372 progressions (77%) were detected by clinical symptoms or blood counts. Computed tomography (CT) scans or ultrasound were relevant in 44 and 29 cases (9% and 6%), respectively. The decision for relapse treatment was determined by CT scan or ultrasound results in only 2 of 176 patients (1%). CT scan results had an impact on the prognosis of patients in complete remission only after the administration of conventional chemotherapy but not after chemoimmunotherapy. In conclusion, physical examination and blood count remain the methods of choice for staging and clinical follow-up of patients with CLL as recommended by the International Workshop on Chronic Lymphocytic Leukemia 2008 guidelines. These trials are registered at http://www.isrctn.org as ISRCTN 75653261 and ISRCTN 36294212 and at http://www.clinicaltrials.gov as NCT00281918.
Asunto(s)
Leucemia Linfocítica Crónica de Células B/diagnóstico por imagen , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Recuento de Células Sanguíneas , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Leucemia Linfocítica Crónica de Células B/sangre , Masculino , Persona de Mediana Edad , Pronóstico , Recurrencia , Inducción de Remisión , Tomografía Computarizada por Rayos XRESUMEN
Merkel cell polyomavirus (MCPyV) is detected in approximately 80% of Merkel cell carcinomas (MCC). Yet, clonal integration and truncating mutations of the large T antigen (LTAg) of MCPyV are restricted to MCC. We tested the presence and mutations of MCPyV in highly purified leukemic cells of 70 chronic lymphocytic leukemia (CLL) patients. MCPyV was detected in 27.1% (n = 19) of these CLL cases. In contrast, MCPyV was detected only in 13.4% of normal controls (P < .036) in which no LTAg mutations were found. Mutational analyses revealed a novel 246bp LTAg deletion in the helicase gene in 6 of 19 MCPyV-positive CLL cases. 2 CLL cases showed concomitant mutated and wild-type MCPyV. Immunohistochemistry revealed protein expression of the LTAg in MCPyV-positive CLL cases. The detection of MCPyV, including LTAg deletions and LTAg expression in CLL cells argues for a potential role of MCPyV in a significant subset of CLL cases.
Asunto(s)
Antígenos Transformadores de Poliomavirus/análisis , Antígenos Transformadores de Poliomavirus/genética , Leucemia Linfocítica Crónica de Células B/virología , Poliomavirus/patogenicidad , Eliminación de Secuencia , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células de Merkel/virología , Análisis Mutacional de ADN , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/patología , Masculino , Células de Merkel , Persona de Mediana Edad , Poliomavirus/genética , Poliomavirus/inmunología , Infecciones Tumorales por VirusRESUMEN
Although chronic lymphocytic leukemia (CLL) is a disease of elderly patients, subjects older than 65 years are heavily underrepresented in clinical trials. The German CLL study group (GCLLSG) initiated a multicenter phase III trial for CLL patients older than 65 years comparing first-line therapy with fludarabine with chlorambucil. A total of 193 patients with a median age of 70 years were randomized to receive fludarabine (25 mg/m(2) for 5 days intravenously, every 28 days, for 6 courses) or chlorambucil (0.4 mg/kg body weight [BW] with an increase to 0.8 mg/kg, every 15 days, for 12 months). Fludarabine resulted in a significantly higher overall and complete remission rate (72% vs 51%, P = .003; 7% vs 0%, P = .011). Time to treatment failure was significantly shorter in the chlorambucil arm (11 vs 18 months; P = .004), but no difference in progression-free survival time was observed (19 months with fludarabine, 18 months with chlorambucil; P = .7). Moreover, fludarabine did not increase the overall survival time (46 months in the fludarabine vs 64 months in the chlorambucil arm; P = .15). Taken together, the results suggest that in elderly CLL patients the first-line therapy with fludarabine alone does not result in a major clinical benefit compared with chlorambucil. This trial is registered with www.isrctn.org under identifier ISRCTN 36294212.
Asunto(s)
Antineoplásicos Alquilantes/administración & dosificación , Clorambucilo/administración & dosificación , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/mortalidad , Vidarabina/análogos & derivados , Anciano , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Inducción de Remisión , Tasa de Supervivencia , Vidarabina/administración & dosificaciónRESUMEN
BACKGROUND: Sentinel lymph node biopsy (SLNB) is a widely accepted procedure to accurately stage patients with cutaneous melanoma. Disadvantages of the SLNB procedure are the overall costs and potential side effects of the operation [J Dtsch Dermatol Ges 2009;7:318-327; J Am Dermatol 2010;62:737-748]. OBJECTIVE: The purpose of our study was to evaluate whether high-resolution ultrasound combined with power Doppler sonography (PDS) is an appropriate tool for preoperative identification and characterization of sentinel lymph nodes (SLNs) in patients with cutaneous melanoma. METHODS: In a prospective study eighty-one consecutive patients with cutaneous melanoma (33 females and 48 males) in whom dissection of SLNs was indicated underwent ultrasound examinations before and after the preoperative lymphoscintigraphy. RESULTS: A total of 170 SLNs (mean 2.1 per patient) were removed and examined by histopathology. High resolution ultrasound combined with PDS correctly identified 2 of 9 positive SLNs. The sensitivity, specificity, positive predictive value, and negative predictive values of ultrasound were 22.2% (95% confidence interval (CI) = 2.8-60.0), 100% (95% CI = 97.7-100.0), 100.0% (95% CI = 15.8-100.0), and 95.8% (95% CI = 91.6-98.3), respectively. CONCLUSIONS: Although high-resolution ultrasound combined with PDS cannot substitute SLNB, this technique offers earlier diagnosis of lymph node involvement in a small subgroup of patients (with subcapsular location of metastases), and introduces the possibility to exclude those patients from SLN procedure and directly prepare them for complete lymph node dissection (CLND).
Asunto(s)
Melanoma/diagnóstico por imagen , Biopsia del Ganglio Linfático Centinela , Neoplasias Cutáneas/diagnóstico por imagen , Ultrasonografía Doppler , Adulto , Anciano , Femenino , Humanos , Masculino , Melanoma/patología , Persona de Mediana Edad , Estadificación de Neoplasias , Estudios Prospectivos , Sensibilidad y Especificidad , Neoplasias Cutáneas/patologíaRESUMEN
BACKGROUND: Infection with SARS-CoV-2 leads to COVID-19, the course of which is highly variable and depends on numerous patient-specific risk factors. Patients with tumor diseases are considered to be more susceptible to severe COVID-19; however, they also represent a heterogeneous group of individuals with variable risk. Identifying specific risk factors for a severe course of COVID-19 in patients with cancer is of great importance. METHODS: Patients diagnosed with solid tumors or hematological malignancies and PCR-confirmed SARS-CoV-2 infection were included into the multicentric ADHOK (Arbeitsgemeinschaft der Hämatologen und Onkologen im Krankenhaus e.V.) coronavirus tumor registry. Detailed information about the patients' cancer disease, treatment, and laboratory parameters prior to infection, was collected retrospectively. The outcome of the SARS-CoV-2 infection was graded according to the WHO. RESULTS: A total of 195 patients (68% with solid neoplasms and 32% with hematological malignancies) were included in the registry. Overall, the course of the SARS-CoV-2 infection varied greatly, as 69% of all patients were either asymptomatic or encountered a mild to moderate course, while 23% of the cohort died from COVID-19. In multivariable analysis, preinfection laboratory parameters (determined at least 10 days and a median of 21 days before the first documentation of SARS-CoV-2 infection) significantly correlated with severe course of the disease. Out of these, the absolute neutrophil count prior to infection showed the strongest association with COVID-19-related death. CONCLUSION: The course of COVID-19 in patients with tumor diseases is highly variable. Preinfection laboratory parameters may aid to identify patients at risk for severe COVID-19 at an early stage prior to infection with the virus. German Clinical Trials Register identification: DRKS00023012.
Asunto(s)
Biomarcadores/sangre , COVID-19/mortalidad , Neoplasias/virología , Neutrófilos/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , COVID-19/inmunología , Niño , Preescolar , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/inmunología , Neoplasias/mortalidad , Estudios Retrospectivos , SARS-CoV-2 , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
Actinic keratoses frequently occur in sun-exposed areas of the skin and, today, a variety of therapeutic options are available, including topical application of 5-fluorouracil (5-FU). Usually, 5-FU ointment needs to be applied twice daily for 2-4 weeks to achieve a therapeutic skin reaction. Here, we report on an immediate inflammatory reaction after single application of topical 5-FU in a patient receiving systemic treatment with the multitargeted tyrosine kinase inhibitor nilotinib for chronic myeloid leukemia. This side effect of nilotinib is new and might be of clinical relevance. We, therefore, discuss possible modes of action including other reports about different tyrosine kinase inhibitors which led to regression of aggravation of actinic keratoses.