RESUMO
BACKGROUND: In the GLOW study, fixed-duration ibrutinib-venetoclax showed superior progression-free survival versus chlorambucil-obinutuzumab in patients with previously untreated chronic lymphocytic leukaemia who were older or had comorbidities, or both, at a median follow up of 27·7 months. In this Article, we report updated outcomes from GLOW after a 46-month median follow-up. METHODS: GLOW was a randomised, multicentre, phase 3 study done at 67 hospital centres across 14 countries. Patients aged 65 years and older or 18-64 years with previously untreated chronic lymphocytic leukaemia and a cumulative illness rating scale score of more than 6 or creatinine clearance less than 70 mL/min, or both, and an Eastern Cooperative Oncology Group performance status of 2 or less were randomly assigned (1:1) via an interactive web system with permuted blocks (block size of four) and stratified by IGHV mutational status and the presence of del11q aberration to the ibrutinib-venetoclax group (three cycles of ibrutinib lead-in [420 mg/day, orally], followed by 12 cycles of ibrutinib plus venetoclax [400 mg/day, orally, including a 5-week dose ramp-up]) or the chlorambucil-obinutuzumab group (six cycles of chlorambucil [0·5 mg/kg, orally, on days 1 and 15 of each cycle], and obinutuzumab [1000 mg, intravenously, on days 1 (or 100 mg on day 1 and 900 mg on day 2), 8, and 15 of cycle 1 and day 1 of cycles 2-6]). The primary endpoint was progression-free survival in the intention-to-treat population, assessed by an independent review committee. The safety population included all randomised patients who received at least one dose of the study treatment. This study is registered with ClinicalTrials.gov (NCT03462719) and the EU Clinical Trials Register (EudraCT 2017-004699-77). FINDINGS: Between May 4, 2018, and April 5, 2019, 211 patients (122 [58%] were male and 89 [42%] were female) were randomly assigned to receive ibrutinib-venetoclax (n=106) or chlorambucil-obinutuzumab (n=105). At a median of 46 months (IQR 43-47) of follow-up, progression-free survival remained superior for the ibrutinib-venetoclax group (hazard ratio 0·214 [95% CI 0·138-0·334]; p<0·0001); 42-month progression-free survival rates were 74·6% (95% CI 65·0-82·0) for ibrutinib-venetoclax and 24·8% (16·5-34·1) for chlorambucil-obinutuzumab. Following the primary analysis, one patient in the chlorambucil-obinutuzumab group had a serious adverse event of myelodysplastic syndrome. Treatment-related deaths were reported in one patient receiving ibrutinib-venetoclax (cardiac failure, pneumonia, and sinus node dysfunction) and in one patient receiving chlorambucil-obinutuzumab (pneumonia). There were 15 deaths in the ibrutinib-venetoclax group (of which three were due to post-treatment infections) and 30 deaths in the chlorambucil-obinutuzumab group (of which 10 were due to post-treatment infections). INTERPRETATION: After 4 years of follow-up, ibrutinib-venetoclax continues to significantly prolong progression-free survival (vs chemoimmunotherapy) in patients with previously untreated chronic lymphocytic leukaemia, supporting its use as a first-line option. FUNDING: Janssen Research & Development and Pharmacyclics.
Assuntos
Leucemia Linfocítica Crônica de Células B , Pneumonia , Feminino , Humanos , Masculino , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Clorambucila/efeitos adversos , Clorambucila/uso terapêutico , Seguimentos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Pneumonia/induzido quimicamenteRESUMO
OBJECTIVE: Previous studies examining the role of single foods or nutrients in the aetiology of non-Hodgkin lymphoma (NHL) have produced inconsistent findings. Few studies have examined associations for dietary patterns, which may more accurately reflect patterns of consumption and the complexity of dietary intake. The objective of the present study was to examine whether dietary patterns identified by factor analysis were associated with NHL risk. DESIGN: Case-control. SETTING: Population-based sample residing in Nebraska from 1999 to 2002. SUBJECTS: A total of 336 cases and 460 controls. RESULTS: Factor analysis identified two major dietary patterns: (i) a 'Meat, Fat and Sweets' dietary pattern characterized by high intakes of French fries, red meat, processed meat, pizza, salty snacks, sweets and desserts, and sweetened beverages; and (ii) a 'Fruit, Vegetables and Starch' dietary pattern characterized by high intakes of vegetables, fruit, fish, and cereals and starches. In multivariable logistic regression models, the 'Meat, Fat and Sweets' dietary pattern was associated with an increased risk of overall NHL (ORQ4 v. Q1 = 3·6, 95 % CI 1·9, 6·8; P trend = 0·0004), follicular lymphoma (ORQ4 v. Q1 = 3·1, 95 % CI 1·2, 8·0; P trend = 0·01), diffuse large B-cell lymphoma (ORQ4 v. Q1 = 3·2, 95 % CI 1·1, 9·0; P trend = 0·09) and marginal zone lymphoma (ORQ4 v. Q1 = 8·2, 95 % CI 1·3, 51·2; P trend = 0·05). No association with overall or subtype-specific risk was detected for the 'Fruit, Vegetables and Starch' dietary pattern. No evidence of heterogeneity was detected across strata of age, sex, BMI, smoking status or alcohol consumption. CONCLUSIONS: Our results suggest that a dietary pattern high in meats, fats and sweets may be associated with an increased risk of NHL.
Assuntos
Dieta Ocidental/efeitos adversos , Comportamento Alimentar , Linfoma não Hodgkin/etiologia , Idoso , Estudos de Casos e Controles , Inquéritos sobre Dietas , Análise Fatorial , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
Greater consumption of red meat, processed meat and dairy products has been associated with an increased risk of non-Hodgkin lymphoma (NHL) in several previous reports. Phytanic acid, a saturated fatty acid obtained primarily through the consumption of ruminant meat and dairy products, may offer a potential underlying mechanism for these associations. In a population-based case-control study of 336 cases and 460 controls conducted in Nebraska during 1999-2002, we examined whether phytanic acid-containing foods or total phytanic acid intake, estimated from a food frequency questionnaire and the published phytanic acid values of 151 food items, were associated with increased NHL risk. Unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals for overall NHL and the common NHL histologic subtypes. In multivariable models, higher intakes of density-adjusted beef [OR(T3 vs. T1) = 1.5 (1.1-2.2); P(trend) = 0.02], total dairy products [OR = 1.5 (1.1-2.2); P(trend) = 0.02) and milk [OR = 1.6 (1.1-2.3); P(trend) = 0.01] were associated with an increased risk of NHL. Intake of total phytanic acid was positively associated with NHL risk [OR = 1.5 (1.0-2.1); P(trend) = 0.04]. In analyses stratified by NHL subtype, greater consumption of beef was associated with an increased risk of diffuse large B-cell lymphoma, and greater consumption of milk was associated with an increased risk of follicular lymphoma (FL). Total phytanic acid intake was associated with an increased risk of FL and small lymphocytic lymphoma/chronic lymphocytic leukemia. Our results provide support that total phytanic acid and phytanic acid-containing foods may increase NHL risk.
Assuntos
Linfoma não Hodgkin/induzido quimicamente , Ácido Fitânico/toxicidade , Adulto , Idoso , Estudos de Casos e Controles , Registros de Dieta , Humanos , Produtos da Carne/análise , Pessoa de Meia-Idade , Nebraska , Ácido Fitânico/administração & dosagem , Ácido Fitânico/análise , Fatores de Risco , Inquéritos e QuestionáriosRESUMO
We examined whether smoking prior to non-Hodgkin lymphoma (NHL) diagnosis was associated with overall survival (OS) and conducted a meta-analysis to assess the evidence relating pre-diagnosis cigarette smoking with OS. Among 523 NHL patients, worse OS was suggested for greater pre-diagnostic smoking habits when compared to never smokers. In the meta-analysis (n = 5 patient populations), inferior OS was observed for greater number of cigarettes smoked per day, years of cigarette smoking, and pack-years of cigarette smoking. The inferior survival was more pronounced for follicular than for diffuse large B cell lymphoma. Pre-diagnosis cigarette smoking may adversely impact the survival of NHL patients.
Assuntos
Linfoma não Hodgkin/mortalidade , Fumar/epidemiologia , Adulto , Idoso , Causas de Morte , Estudos de Coortes , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Fumar/efeitos adversos , Análise de SobrevidaRESUMO
The phase 3 SELENE study evaluated ibrutinib + chemoimmunotherapy (CIT; bendamustine and rituximab [BR]; or rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP]) for patients with relapsed/refractory (R/R) follicular lymphoma (FL) or marginal zone lymphoma (MZL). Adult patients who had received ≥1 prior line of CIT were randomized 1:1 to oral ibrutinib (560 mg) or placebo daily, plus 6 cycles of BR/R-CHOP. The primary end point was investigator-assessed progression-free survival (PFS). Overall, 403 patients were randomized to ibrutinib + CIT (n = 202) or placebo + CIT (n = 201). Most patients received BR (90.3%) and had FL (86.1%). With a median follow-up of 84 months, median PFS was 40.5 months in the ibrutinib + CIT arm and 23.8 months in the placebo + CIT arm (hazard ratio [HR], 0.806; 95% confidence interval [CI], 0.626-1.037; P = .0922). Median overall survival was not reached in either arm (HR, 0.980; 95% CI, 0.686-1.400). Grade ≥3 treatment-emergent adverse events (TEAEs) were reported in 85.6% and 75.4% of patients in the ibrutinib + CIT and placebo + CIT arms, respectively. In each arm, 13 patients had TEAEs leading to death. The addition of ibrutinib to CIT did not significantly improve PFS compared with placebo + CIT. The safety profile was consistent with known profiles of ibrutinib and CIT. This trial was registered at www.clinicaltrials.gov as #NCT01974440.
Assuntos
Linfoma de Zona Marginal Tipo Células B , Linfoma Folicular , Adulto , Humanos , Rituximab/efeitos adversos , Cloridrato de Bendamustina/uso terapêutico , Piperidinas/uso terapêutico , Vincristina/efeitos adversos , Ciclofosfamida/efeitos adversos , Prednisona/efeitos adversos , Doxorrubicina/efeitos adversos , Linfoma de Zona Marginal Tipo Células B/tratamento farmacológico , Linfoma Folicular/tratamento farmacológicoRESUMO
PURPOSE: In GLOW, fixed-duration ibrutinib + venetoclax showed superior progression-free survival (PFS) versus chlorambucil + obinutuzumab in older/comorbid patients with previously untreated chronic lymphocytic leukemia (CLL). The current analysis describes minimal residual disease (MRD) kinetics and any potential predictive value for PFS, as it has not yet been evaluated for ibrutinib + venetoclax treatment. METHODS: Undetectable MRD (uMRD) was assessed by next-generation sequencing at <1 CLL cell per 10,000 (<10-4) and <1 CLL cell per 100,000 (<10-5) leukocytes. PFS was analyzed by MRD status at 3 months after treatment (EOT+3). RESULTS: Ibrutinib + venetoclax achieved deeper uMRD (<10-5) rates in bone marrow (BM) and peripheral blood (PB), respectively, in 40.6% and 43.4% of patients at EOT+3 versus 7.6% and 18.1% of patients receiving chlorambucil + obinutuzumab. Of these patients, uMRD (<10-5) in PB was sustained during the first year post-treatment (EOT+12) in 80.4% of patients receiving ibrutinib + venetoclax and 26.3% receiving chlorambucil + obinutuzumab. Patients with detectable MRD (dMRD; ≥10-4) in PB at EOT+3 were more likely to sustain MRD levels through EOT+12 with ibrutinib + venetoclax versus chlorambucil + obinutuzumab. PFS rates at EOT+12 were high among patients treated with ibrutinib + venetoclax regardless of MRD status at EOT+3: 96.3% and 93.3% in patients with uMRD (<10-4) and dMRD (≥10-4) in BM, respectively, versus 83.3% and 58.7% for patients receiving chlorambucil + obinutuzumab. PFS rates at EOT+12 also remained high in patients with unmutated immunoglobulin heavy-chain variable region (IGHV) receiving ibrutinib + venetoclax, independent of MRD status in BM. CONCLUSION: Molecular and clinical relapses were less frequent during the first year post-treatment with ibrutinib + venetoclax versus chlorambucil + obinutuzumab regardless of MRD status at EOT+3 and IGHV status. Even for patients not achieving uMRD (<10-4), PFS rates remained high with ibrutinib + venetoclax; this is a novel finding and requires additional follow-up to confirm its persistence over time.
Assuntos
Leucemia Linfocítica Crônica de Células B , Humanos , Idoso , Intervalo Livre de Progressão , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Neoplasia Residual/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Clorambucila/efeitos adversosRESUMO
BACKGROUND: GLOW is a phase 3 trial evaluating the efficacy and safety of ibrutinib-venetoclax in older patients and/or those with comorbidities with previously untreated chronic lymphocytic leukemia (CLL). METHODS: We randomly assigned (1:1) patients 65 years of age or older or those 18 to 64 years of age who also had a Cumulative Illness Rating Scale (CIRS) score greater than 6 (CIRS scores range from 0 to 56, with higher scores indicating more impaired function of organ systems) or creatinine clearance of less than 70 ml/min, to ibrutinib-venetoclax (3 cycles ibrutinib lead-in, then 12 cycles ibrutinib-venetoclax) or chlorambucil-obinutuzumab (6 cycles). The primary end point was progression-free survival (PFS) assessed by an independent review committee. Secondary end points included undetectable minimal residual disease (uMRD), response rates, and safety. RESULTS: This study enrolled 211 patients, with 106 randomly assigned to ibrutinib-venetoclax and 105 to chlorambucil-obinutuzumab. With a median follow-up of 27.7 months, there were 22 PFS events for ibrutinib-venetoclax and 67 events for chlorambucil-obinutuzumab. PFS was significantly longer for ibrutinib-venetoclax than for chlorambucil-obinutuzumab (hazard ratio, 0.216; 95% confidence interval [CI], 0.131 to 0.357; P<0.001). The improvement in PFS with ibrutinib-venetoclax was consistent across predefined subgroups, including patients 65 years of age or older or with a CIRS score greater than 6. The best uMRD rate in bone marrow by next-generation sequencing was significantly higher for ibrutinib-venetoclax (55.7%) than for chlorambucil-obinutuzumab (21.0%; P<0.001). The proportion of patients with sustained uMRD in peripheral blood from 3 to 12 months after end of treatment was 84.5% for ibrutinib-venetoclax and 29.3% for chlorambucil-obinutuzumab. Four patients treated with ibrutinib-venetoclax required subsequent therapy compared with 27 patients receiving chlorambucil-obinutuzumab (hazard ratio, 0.143; 95% CI, 0.050 to 0.410). Adverse events grade 3 or greater occurred for 80 (75.5%) and 73 (69.5%) patients receiving ibrutinib-venetoclax and chlorambucil-obinutuzumab, respectively, with neutropenia being most common in both arms (37 [34.9%] and 52 [49.5%]). There were 11 (10.4%) and 12 (11.4%) all-cause deaths in the ibrutinib-venetoclax and chlorambucil-obinutuzumab arms, respectively. CONCLUSIONS: Ibrutinib-venetoclax, an all-oral, once-daily, fixed-duration combination, demonstrated superior PFS and deeper and better sustained responses versus chlorambucil-obinutuzumab as first-line CLL treatment in older patients and/or those with comorbidities. (Funded by Janssen Research & Development, LLC, and Pharmacyclics; ClinicalTrials.gov number, NCT03462719.)
Assuntos
Adenina , Leucemia Linfocítica Crônica de Células B , Piperidinas , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/mortalidade , Idoso , Masculino , Feminino , Pessoa de Meia-Idade , Adenina/análogos & derivados , Piperidinas/uso terapêutico , Piperidinas/efeitos adversos , Adulto , Comorbidade , Idoso de 80 Anos ou mais , Pirimidinas/uso terapêutico , Pirimidinas/efeitos adversos , Pirimidinas/administração & dosagem , Pirazóis/uso terapêutico , Pirazóis/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Adulto Jovem , Antineoplásicos/uso terapêutico , Antineoplásicos/efeitos adversosRESUMO
Abstract We conducted a systematic review of grade 3/4 adverse events (AEs) reported in prospective trials enrolling patients with follicular lymphoma (FL) and mantle cell lymphoma (MCL) receiving maintenance rituximab (MR). Random-effects models were used to calculate summary estimates and 95% confidence intervals for the proportion of AEs occurring during MR. Differences by induction program, histology, setting and MR schedule were examined by stratified analyses and univariate random-effects meta-regression. Eleven trials met the search criteria, with nine sufficiently reporting AEs during the MR phase. Of 1009 patients receiving MR, the proportion experiencing cumulative grade 3/4 toxicity was 24% (95% confidence interval [CI]: 14-36%). Patients receiving MR every 6 months as four weekly infusions for 2 years had significantly less toxicity compared with those receiving MR every 2 months (10% vs. 28%; p = 0.035). Patients treated with rituximab alone during induction had fewer toxicities compared to those treated with rituximab plus chemotherapy induction (12% vs. 35%; p = 0.031). Myelosuppression and infections were the most common toxicities. Our literature analysis suggests that MR given every 6 months and rituximab alone as induction may be associated with fewer grade 3/4 AEs for patients with FL and MCL; however, assessing the true independent impact of induction regimens and schedule on toxicity will require prospective trials.
Assuntos
Anticorpos Monoclonais Murinos/efeitos adversos , Anticorpos Monoclonais Murinos/uso terapêutico , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Linfoma Folicular/tratamento farmacológico , Linfoma de Célula do Manto/tratamento farmacológico , Anticorpos Monoclonais Murinos/administração & dosagem , Antineoplásicos/administração & dosagem , Ensaios Clínicos como Assunto , Esquema de Medicação , Humanos , Quimioterapia de Manutenção , Rituximab , Resultado do TratamentoRESUMO
Hematopoietic stem cell differentiation involves the silencing of self-renewal genes and induction of a specific transcriptional program. Identification of multiple covalent cytosine modifications raises the question of how these derivatized bases influence stem cell commitment. Using a replicative primary human hematopoietic stem/progenitor cell differentiation system, we demonstrate dynamic changes of 5-hydroxymethylcytosine (5-hmC) during stem cell commitment and differentiation to the erythroid lineage. Genomic loci that maintain or gain 5-hmC density throughout erythroid differentiation contain binding sites for erythroid transcription factors and several factors not previously recognized as erythroid-specific factors. The functional importance of 5-hmC was demonstrated by impaired erythroid differentiation, with augmentation of myeloid potential, and disrupted 5-hmC patterning in leukemia patient-derived CD34+ stem/early progenitor cells with TET methylcytosine dioxygenase 2 (TET2) mutations. Thus, chemical conjugation and affinity purification of 5-hmC-enriched sequences followed by sequencing serve as resources for deciphering functional implications for gene expression during stem cell commitment and differentiation along a particular lineage.
Assuntos
Metilação de DNA , Células Eritroides/metabolismo , Eritropoese/genética , Sequências Reguladoras de Ácido Nucleico , 5-Metilcitosina/análogos & derivados , Antígenos CD34/genética , Antígenos CD34/metabolismo , Células Cultivadas , Citosina/análogos & derivados , Citosina/análise , Dioxigenases/genética , Dioxigenases/metabolismo , Células Eritroides/citologia , Células Eritroides/efeitos dos fármacos , Histonas/metabolismo , Humanos , Mutação , Fatores de Transcrição/metabolismoRESUMO
Although an increased incidence of mantle cell lymphoma (MCL) has been reported, age-specific incidence patterns have not been described. Further analyses could inform investigation into the etiology of this disease. We conducted an epidemiologic study using the 13 Surveillance, Epidemiology, and End Results (SEER) registries to evaluate MCL incidence from 1992 through 2009. We calculated the proportional changes in the incidence of MCL for subpopulations defined by age, race/ethnicity and gender over time and the racial/ethnic and gender disparities. We observed a 130.9% increase in MCL incidence from 1992-1994 to 2005-2009. The increase was strongest for males (199.0%) and for whites (153.0%). The incidence increased 161%, 200%, 398% and 429% from 1992-1994 to 2005-2009 in white men ages 50-59, 60-69, 70-79 and 80+, respectively, whereas the increase in white females was 86%, 82%, 50% and 193% in the corresponding age groups. We observed a male-to-female incidence rate ratio (IRR) of 2.65 and a white-to-black IRR of 2.21. Our analysis confirmed significant increases in MCL, and illustrated that the incidence is increasing more rapidly in elderly persons, particularly in white males. We also identified novel age-specific temporal trends by race/ethnicity and sex. In addition, we found that the gender and white-to-black disparities have grown over time. Our findings may impact MCL etiologic investigation and treatment research.
Assuntos
Linfoma de Célula do Manto/epidemiologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Programa de SEER , Estados Unidos/epidemiologia , Adulto JovemRESUMO
In a cohort of 301 patients with non-Hodgkin lymphoma (NHL), we examined whether the pre-diagnostic consumption of fruits and vegetables, or of nutrients concentrated in fruits and vegetables, was associated with overall survival (OS). Proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause mortality. A total of 91 deaths occurred in the patient cohort over a median follow-up period of 8.2 years. No association with OS was detected for a dietary pattern characterized by high intakes of fruits, vegetables and starch; fruit intake; vegetable intake; or nutrient intake in patients diagnosed with overall NHL, follicular lymphoma or diffuse large B-cell lymphoma. Higher intakes of carotene-rich vegetables (HR = 0.4 [0.2-1.0]; p trend = 0.05) and α-carotene (HRT3 vs. T1 = 0.4 [0.2-0.9]; p trend = 0.03) were associated with better OS among ever smokers. Overall, our data suggest that the intake of fruits and vegetables prior to diagnosis is not associated with OS in patients with NHL.
Assuntos
Comportamento Alimentar , Frutas , Linfoma não Hodgkin/etiologia , Linfoma não Hodgkin/mortalidade , Verduras , Adulto , Idoso , Dieta , Feminino , Seguimentos , Humanos , Linfoma não Hodgkin/diagnóstico , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Modelos de Riscos Proporcionais , Fatores de RiscoRESUMO
Aquaporin-2 (AQP2), when expressed in fully differentiated 3T3-L1 adipocytes, displays cAMP-dependent plasma membrane translocation in a manner similar to its behavior in renal epithelial cells. The translocation of AQP2 required phosphorylation at serine 256, as the expression of AQP2/S256D was constitutively plasma membrane localized, whereas AQP2/S256A was refractory to forskolin stimulation. Unlike GLUT4, this property is not inhibited by depolymerization of cortical actin. In addition, coexpression with the dominant negative form of TC10 (TC10/T31N) or inhibition of phosphatidylinositol 3-kinase did not abrogate the cAMP-mediated response. Under basal conditions, AQP2 is localized in both the perinuclear region and in punctate vesicles scattered within the periphery of the cell. Two- and three-dimensional confocal immunofluorescence microscopy demonstrated that the adipocyte AQP2 cAMP-responsive compartment was distinct from the GLUT4 insulin-responsive compartment. Consistent with this conclusion, insulin was an effective stimulator of GLUT4 translocation but had no effect on AQP2. Conversely, forskolin induced AQP2 translocation but not GLUT4. Colocalization studies with the early endosomal marker EEA1 and transferrin receptor suggested that the AQP2 compartment is mostly distinct from endosomal vesicles. Interestingly, however, the peripheral AQP2 vesicles significantly overlapped vesicle-associated membrane protein-2, underscoring the role of the latter in hormone-regulated exocytosis. To acquire insulin responsiveness following biosynthesis, GLUT4 undergoes a slow sorting step that requires 6-9 h. In contrast, AQP2 rapidly acquires forskolin responsiveness (3 h following biosynthesis) and directly enters the cAMP-regulated compartment without transiting the plasma membrane. Together, these data demonstrate that adipocytes display two different intracellular sorting mechanisms that direct distinct hormone-sensitive partitioning of GLUT4 and AQP2.