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1.
Med Oncol ; 39(8): 110, 2022 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-35666320

RESUMO

Granulocyte-colony stimulating factor (G-CSF) stimulates bone marrow progenitor cell proliferation and enhances neutrophil production. Exogenous G-CSF administration is indicated for chemotherapy-induced neutropenia management. However, there is a paucity of basic research examining the effects of the concomitant use of G-CSF and chemotherapy on myeloid cells in vivo. Whether concomitant G-CSF and chemotherapy adversely affect myeloid cell proliferation have not been determined. Herein, we examined the effects of the concomitant use of pegfilgrastim and 5-fluorouracil on myeloid cells and peripheral blood cells in mouse models. Balb/c mice were treated intraperitoneally with 5-fluorouracil (20 µg/g b.w.) or a vehicle as a control for 5 days, and pegfilgrastim was administered subcutaneously at 1 µg/g b.w. on day 3. As a result, we demonstrated that the concomitant use of pegfilgrastim suppressed the 5-fluorouracil-induced decrease of granulocytic cells in both bone marrow and peripheral blood in mice. To assess the clinical efficacy of early administration of pegfilgrastim during docetaxel, cisplatin, and 5-fluorouracil therapy in patients with esophageal cancer, we retrospectively identified 42 consecutive patients treated with this regimen. The incidence of both febrile neutropenia and grade 4 neutropenia was significantly lower in patients who received pegfilgrastim than in those who did not receive it (P = 0.002 and P = 0.002, respectively). These results suggest that the concomitant use of pegfilgrastim and chemotherapy, consisting of continuous infusions of 5-fluorouracil, improved chemotherapy-induced neutropenia without detrimental effects on proliferating myeloid granulocytic cells.


Assuntos
Medula Óssea , Neutropenia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Filgrastim/farmacologia , Fluoruracila , Fator Estimulador de Colônias de Granulócitos/farmacologia , Granulócitos , Humanos , Camundongos , Neutropenia/induzido quimicamente , Neutropenia/tratamento farmacológico , Polietilenoglicóis , Proteínas Recombinantes/efeitos adversos , Estudos Retrospectivos
2.
Leukemia ; 36(6): 1654-1665, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35459873

RESUMO

Peripheral T-cell lymphoma (PTCL) is a rare, heterogenous malignancy with dismal outcomes at relapse. Hypomethylating agents (HMA) have an emerging role in PTCL, supported by shared mutations with myelodysplasia (MDS). Response rates to azacitidine in PTCL of follicular helper cell origin are promising. Guadecitabine is a decitabine analogue with efficacy in MDS. In this phase II, single-arm trial, PTCL patients received guadecitabine on days 1-5 of 28-day cycles. Primary end points were overall response rate (ORR) and safety. Translational sub-studies included cell free plasma DNA sequencing and functional genomic screening using an epigenetically-targeted CRISPR/Cas9 library to identify response predictors. Among 20 predominantly relapsed/refractory patients, the ORR was 40% (10% complete responses). Most frequent grade 3-4 adverse events were neutropenia and thrombocytopenia. At 10 months median follow-up, median progression free survival (PFS) and overall survival (OS) were 2.9 and 10.4 months respectively. RHOAG17V mutations associated with improved PFS (median 5.47 vs. 1.35 months; Wilcoxon p = 0.02, Log-Rank p = 0.06). 4/7 patients with TP53 variants responded. Deletion of the histone methyltransferase SETD2 sensitised to HMA but TET2 deletion did not. Guadecitabine conveyed an acceptable ORR and toxicity profile; decitabine analogues may provide a backbone for future combinatorial regimens co-targeting histone methyltransferases.


Assuntos
Azacitidina , Linfoma de Células T Periférico , Azacitidina/efeitos adversos , Azacitidina/análogos & derivados , Decitabina/uso terapêutico , Genômica , Humanos , Linfoma de Células T Periférico/tratamento farmacológico , Linfoma de Células T Periférico/genética , Síndromes Mielodisplásicas/patologia , Recidiva Local de Neoplasia/induzido quimicamente , Neutropenia/induzido quimicamente , Resultado do Tratamento
3.
Addict Biol ; 27(3): e13166, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35470549

RESUMO

Levamisole is a veterinary anthelmintic drug and a common adulterant of misused drugs. This study analyses the lethal, antinociceptive and haematological effects produced by acute or repeated levamisole administration by itself or combined with morphine. Independent groups of male Swiss Webster mice were i.p. injected with 100 mg/kg morphine, 31.6 mg/kg levamisole (lethal doses at 10%, LD10 ) or the same doses combined. Naloxone pretreatment (10 mg/kg, i.p.) prevented morphine-induced death, as did 2.5 mg/kg, i.p. mecamylamine with levamisole. Co-administration of levamisole and morphine (Lvm + Mor) increased lethality from 10% to 80%. This augmented effect was prevented by 30 mg/kg, i.p. naloxone and reduced with 10 mg/kg naloxone plus 2.5 mg/kg, i.p. mecamylamine. In independent groups of mice, 17.7 mg/kg, i.p. levamisole antagonized the acute morphine's antinociceptive effect evaluated in the tail-flick test. Repeated 17.7 mg/kg levamisole administration (2×/day/3 weeks) did not affect tolerance development to morphine (10 mg/kg, 3×/day/1 week). Blood samples obtained from mice repeatedly treated with levamisole showed leukopenia and neutropenia. Morphine also produced neutropenia, increased erythrocyte count and other related parameters (e.g. haemoglobin). Lvm + Mor had similar effects on leukocyte and neutrophil counts to those seen with levamisole only, but no erythrocyte-related alterations were evident. Blood chemistry analysis did not indicate liver damage but suggested some degree of electrolyte balance impairment. In conclusion, Lvm + Mor increased death risk, altered morphine-induced antinociceptive effects and produced haematologic abnormalities. The importance of studying combinations of drugs of abuse lies in the fact that drug users frequently combine drugs, which are commonly adulterated.


Assuntos
Morfina , Neutropenia , Analgésicos , Animais , Levamisol/farmacologia , Masculino , Mecamilamina , Camundongos , Morfina/farmacologia , Naloxona/farmacologia , Neutropenia/induzido quimicamente
4.
Eur J Cancer ; 167: 23-31, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35366570

RESUMO

BACKGROUND: We performed a pooled analysis of TRIBE and TRIBE2 studies to assess the efficacy and safety of the intensification of upfront chemotherapy backbone - from doublets to the triplet FOLFOXIRI - in combination with bevacizumab (bev) in patients with early-onset metastatic colorectal cancer (EO-mCRC; aged <50 years) and to explore whether EO-mCRCs have a peculiar tumour genomic profiling. MATERIALS AND METHODS: Subgroup analyses according to age (<50 versus ≥50 years) and treatment (FOLFOXIRI/bev versus doublets/bev) were carried out for rates of any grade and grade ≥3 (≥G3) overall and singular adverse events, progression-free survival (PFS), overall survival (OS) and objective response rate (ORR). Tumour genomic profiling was obtained using a DNA-based next-generation sequencing platform. RESULTS: Of 1187 patients included, 194 (16%) patients were aged <50 years. Females were more frequently diagnosed with EO-mCRC (P = 0.04). Patients aged <50 years showed a lower risk of ≥G3 neutropenia (P = 0.07), diarrhoea (P = 0.04), asthenia (P = 0.008) and a higher risk of any grade nausea (P < 0.01) and vomiting (P < 0.01). Patients receiving FOLFOXIRI/bev more frequently experienced ≥G3 chemotherapy-related adverse events respect to doublets/bev, regardless of age (Pinteraction = 0.60). FOLFOXIRI/bev was associated to a lower incidence of neutropenia (P = 0.04) and asthenia (P = 0.01) in patients <50 years old, than those aged ≥50 years. PFS, OS and ORR did not differ according to age (PFS P = 0.81, OS P = 0.44, ORR P = 0.50) and no interaction between age and the benefit from the intensification of upfront chemotherapy was observed (PFS Pinteraction = 0.72, OS Pinteraction = 0.54, ORR Pinteraction = 0.65). Genomic profiling was assessed in 296 patients, showing an enrichment of FBXW7 and POLE mutations in EO-mCRC. CONCLUSIONS: Upfront FOLFOXIRI/bev shows a favourable efficacy/safety balance in EO-mCRC. TRIAL REGISTRATION: Clinicaltrials.gov Identifiers NCT00719797, NCT0233-9116.


Assuntos
Neoplasias Colorretais , Neutropenia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Astenia/induzido quimicamente , Bevacizumab/efeitos adversos , Camptotecina/análogos & derivados , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Feminino , Fluoruracila/efeitos adversos , Humanos , Leucovorina/efeitos adversos , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Compostos Organoplatínicos
5.
Biol Pharm Bull ; 45(4): 452-459, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35370269

RESUMO

The aim of this study was to investigate whether low-dose valganciclovir (VGCV) prophylaxis for cytomegalovirus (CMV) infection increased the risk of developing neutropenia in heart transplant recipients (HTRs). Forty-three HTRs receiving VGCV were divided into two groups: those who received VGCV prophylaxis (n = 22) and those who did not (n = 21). Neutropenia was defined as an absolute neutrophil count ˂1500/µL and was monitored for approximately one year post-transplantation. In the prophylaxis group, 77.3% (17/22) of HTRs experienced neutropenia, which was significantly higher than that in the no prophylaxis group (42.9% [9/21], p = 0.031). No significant differences in the duration of VGCV administration and cumulative dose up to the first neutropenia episode were observed between the groups. Meanwhile, the cumulative dose of mycophenolate mofetil was significantly higher in the prophylaxis group than in the no prophylaxis group (p = 0.018); the daily maintenance dose and regularly measured area under the concentration-time curve (AUC) of mycophenolic acid did not significantly differ between groups. In conclusion, the risk of developing neutropenia was higher in HTRs receiving low-dose VGCV prophylaxis than it was in those not receiving prophylaxis, probably not attributed to dosing period and cumulative dose of VGCV until the onset of neutropenia.


Assuntos
Transplante de Coração , Neutropenia , Antivirais/uso terapêutico , Ganciclovir/efeitos adversos , Humanos , Neutropenia/induzido quimicamente , Neutropenia/tratamento farmacológico , Neutropenia/prevenção & controle , Medição de Risco , Valganciclovir
6.
Cancer Treat Res Commun ; 31: 100555, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35421820

RESUMO

PURPOSE: To depict the treatment journey for patients with small cell lung cancer (SCLC) and evaluate health care resource utilization (HCRU) associated with myelosuppression, a complication induced by chemotherapy or chemotherapy plus radiation therapy. PATIENTS AND METHODS: This was a descriptive, retrospective study of patients with SCLC aged ≥65 years, identified from linked Surveillance, Epidemiology, and End Results (SEER)-Medicare data curated between January 2012 and December 2015. Treatment types (chemotherapy, radiation therapy, surgery) were classified as first, second, or third line, depending on the temporal sequence in which regimens were prescribed. For each year, the proportions of patients completing 4- or 6-cycle chemotherapy regimens, with hospital admissions associated with myelosuppression, or who used granulocyte colony-stimulating factors (G-CSFs), blood/platelet transfusions, or erythropoiesis-stimulating agents (ESAs), were calculated. RESULTS: Chemotherapy was administered as initial treatment in 7,807/11,907 (65.6%) patients whose treatment journey was recorded. Approximately one-third (n = 3,985) subsequently received radiation therapy. In total, 5,791 (57.8%) patients completed the guideline-recommended 4-6 cycles of chemotherapy. Among all chemotherapy-treated patients, 10,370 (74.3%) experienced ≥1 inpatient admission associated with myelosuppression (anemia, 7,366 [52.8%]; neutropenia, 4,642 [33.3%]; thrombocytopenia, 2,375 [17.0%]; pancytopenia, 1,983 [14.2%]). Supportive care interventions included G-CSF (6,756 [48.4%] patients), ESAs (1,534 [11.0%]), and transfusions (3,674 [26.3%]). CONCLUSION: Chemotherapy remains a cornerstone of care for patients with SCLC. Slightly over half of patients completed the recommended number of cycles, underscoring the frailty of patients and aggressiveness of SCLC. HCRU associated with myelosuppression was prominent, suggesting a substantial burden on older patients with SCLC.


Assuntos
Neoplasias Pulmonares , Neutropenia , Carcinoma de Pequenas Células do Pulmão , Idoso , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Medicare , Neutropenia/induzido quimicamente , Neutropenia/tratamento farmacológico , Estudos Retrospectivos , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Estados Unidos/epidemiologia
7.
BMC Cancer ; 22(1): 216, 2022 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-35227236

RESUMO

OBJECTIVE: Neuroblastoma is a common extracranial solid tumor of childhood. Recently, multiple treatments have been practiced including Iodine-131-metaiodobenzylguanidine radiation (131I-MIBG) therapy. However, the outcomes of efficacy and safety vary greatly among different studies. The aim of this meta-analysis is to evaluate the efficacy and safety of 131I-MIBG in the treatment of neuroblastoma and to provide evidence and hints for clinical decision-making. METHODS: Medline, EMBASE database and the Cochrane Library were searched for relevant studies. Eligible studies utilizing 131I-MIBG in the treatment of neuroblastoma were included. The pooled outcomes (response rates, adverse events rates, survival rates) were calculated using either a random-effects model or a fixed-effects model considering of the heterogeneity. RESULTS: A total of 26 clinical trials including 883 patients were analyzed. The pooled rates of objective response, stable disease, progressive disease, and minor response of 131I-MIBG monotherapy were 39%, 31%, 22% and 15%, respectively. The pooled objective response rate of 131I-MIBG in combination with other therapies was 28%. The pooled 1-year survival and 5-year survival rates were 64% and 32%. The pooled occurrence rates of thrombocytopenia and neutropenia in MIBG monotherapy studies were 53% and 58%. In the studies of 131I-MIBG combined with other therapies, the pooled occurrence rates of thrombocytopenia and neutropenia were 79% and 78%. CONCLUSION: 131I-MIBG treatment alone or in combination of other therapies is effective on clinical outcomes in the treatment of neuroblastoma, individualized 131I-MIBG is recommended on a clinical basis.


Assuntos
3-Iodobenzilguanidina/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Radioisótopos do Iodo/uso terapêutico , Neuroblastoma/tratamento farmacológico , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Tumores Neuroendócrinos/tratamento farmacológico , Neutropenia/induzido quimicamente , Taxa de Sobrevida , Resultado do Tratamento
8.
N Engl J Med ; 386(10): 942-950, 2022 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-35263519

RESUMO

BACKGROUND: In a previous analysis of this phase 3 trial, first-line ribociclib plus letrozole resulted in significantly longer progression-free survival than letrozole alone among postmenopausal patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. Whether overall survival would also be longer with ribociclib was not known. METHODS: Here we report the results of the protocol-specified final analysis of overall survival, a key secondary end point. Patients were randomly assigned in a 1:1 ratio to receive either ribociclib or placebo in combination with letrozole. Overall survival was assessed with the use of a stratified log-rank test and summarized with the use of Kaplan-Meier methods after 400 deaths had occurred. A hierarchical testing strategy was used for the analysis of progression-free survival and overall survival to ensure the validity of the findings. RESULTS: After a median follow-up of 6.6 years, 181 deaths had occurred among 334 patients (54.2%) in the ribociclib group and 219 among 334 (65.6%) in the placebo group. Ribociclib plus letrozole showed a significant overall survival benefit as compared with placebo plus letrozole. Median overall survival was 63.9 months (95% confidence interval [CI], 52.4 to 71.0) with ribociclib plus letrozole and 51.4 months (95% CI, 47.2 to 59.7) with placebo plus letrozole (hazard ratio for death, 0.76; 95% CI, 0.63 to 0.93; two-sided P = 0.008). No new safety signals were observed. CONCLUSIONS: First-line therapy with ribociclib plus letrozole showed a significant overall survival benefit as compared with placebo plus letrozole in patients with HR-positive, HER2-negative advanced breast cancer. Median overall survival was more than 12 months longer with ribociclib than with placebo. (Funded by Novartis; MONALEESA-2 ClinicalTrials.gov number, NCT01958021.).


Assuntos
Aminopiridinas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Letrozol/administração & dosagem , Purinas/administração & dosagem , Idoso , Aminopiridinas/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Feminino , Humanos , Análise de Intenção de Tratamento , Letrozol/efeitos adversos , Pessoa de Meia-Idade , Gradação de Tumores , Neutropenia/induzido quimicamente , Purinas/efeitos adversos , Receptor ErbB-2 , Receptores de Estrogênio , Análise de Sobrevida
9.
Expert Rev Anticancer Ther ; 22(4): 335-341, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35249433

RESUMO

INTRODUCTION: Despite rapid advances in the treatment landscape of urothelial cancer, there is a substantial unmet need for safe and effective therapies for patients with locally advanced and metastatic urothelial cancer. Sacituzumab govitecan (SG) is an antibody-drug conjugate, consisting of a Trop-2 directed monoclonal antibody linked to SN-38, the active metabolite of irinotecan. Trop-2 is a glycoprotein overexpressed in various carcinomas, including urothelial carcinomas. AREAS COVERED: We review the available data on SG, including mechanism of action, pharmacology, efficacy, safety, and clinical studies regarding locally advanced or metastatic urothelial cancer. EXPERT OPINION: SG performed well in the TROPHY-U-01 phase II trial with an objective response rate of 27%. The most common adverse effects were diarrhea, nausea, fatigue, alopecia, and neutropenia, with the most common grade ≥ 3 treatment-related AEs being neutropenia, leukopenia, anemia, diarrhea, and febrile neutropenia. However, these effects were managed effectively with supportive care. SG currently has an accelerated approval for patients with locally advanced or metastatic urothelial cancer who have received platinum-based chemotherapy and either programmed cell death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor. Several studies are evaluating SG in urothelial cancers as single-agent or in combination with other agents.


Assuntos
Anticorpos Monoclonais Humanizados , Camptotecina , Carcinoma de Células de Transição , Imunoconjugados , Neoplasias da Bexiga Urinária , Anticorpos Monoclonais Humanizados/efeitos adversos , Camptotecina/efeitos adversos , Camptotecina/análogos & derivados , Carcinoma de Células de Transição/tratamento farmacológico , Ensaios Clínicos Fase II como Assunto , Diarreia/induzido quimicamente , Humanos , Imunoconjugados/efeitos adversos , Irinotecano , Neutropenia/induzido quimicamente , Neoplasias da Bexiga Urinária/tratamento farmacológico
10.
Blood ; 139(21): 3148-3158, 2022 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-35303070

RESUMO

Bruton tyrosine kinase (BTK) inhibitor is an established treatment for relapsed/refractory (R/R) mantle cell lymphoma (MCL). Zanubrutinib, a highly selective BTK inhibitor, is approved for patients with MCL who have received ≥1 prior therapy. We report the long-term safety and efficacy results from the multicenter, open-label, phase 2 registration trial of zanubrutinib. Patients (n = 86) received oral zanubrutinib 160 mg twice daily. The primary endpoint was the overall response rate (ORR), assessed per Lugano 2014. After a median follow-up of 35.3 months, the ORR was 83.7%, with 77.9% achieving complete response (CR); the median duration of response was not reached. Median progression-free survival (PFS) was 33.0 months (95% confidence interval [CI], 19.4-NE). The 36-month PFS and overall survival (OS) rates were 47.6% (95% CI, 36.2-58.1) and 74.8% (95% CI, 63.7-83.0), respectively. The safety profile was largely unchanged with extended follow-up. Most common (≥20%) all-grade adverse events (AEs) were neutrophil count decreased (46.5%), upper respiratory tract infection (38.4%), rash (36.0%), white blood cell count decreased (33.7%), and platelet count decreased (32.6%); most were grade 1/2 events. Most common (≥10%) grade ≥3 AEs were neutrophil count decreased (18.6%) and pneumonia (12.8%). Rates of infection, neutropenia, and bleeding were highest in the first 6 months of therapy and decreased thereafter. No cases of atrial fibrillation/flutter, grade ≥3 cardiac AEs, second primary malignancies, or tumor lysis syndrome were reported. After extended follow-up, zanubrutinib demonstrated durable responses and a favorable safety profile in R/R MCL. The trial is registered at ClinicalTrials.gov as NCT03206970.


Assuntos
Linfoma Folicular , Linfoma de Célula do Manto , Neutropenia , Adulto , Humanos , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/patologia , Neutropenia/induzido quimicamente , Piperidinas , Inibidores de Proteínas Quinases/efeitos adversos , Pirazóis/efeitos adversos , Pirimidinas/efeitos adversos , Resultado do Tratamento
11.
J Am Soc Nephrol ; 33(6): 1193-1207, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35354600

RESUMO

BACKGROUND: Long-term outcomes after multiple courses of rituximab among children with frequently relapsing, steroid-dependent nephrotic syndrome (FRSDNS) are unknown. METHODS: A retrospective cohort study at 16 pediatric nephrology centers from ten countries in Asia, Europe, and North America included children with FRSDNS who received two or more courses of rituximab. Primary outcomes were relapse-free survival and adverse events. RESULTS: A total of 346 children (age, 9.8 years; IQR, 6.6-13.5 years; 73% boys) received 1149 courses of rituximab. A total of 145, 83, 50, 28, 22, and 18 children received two, three, four, five, six, and seven or more courses, respectively. Median (IQR) follow-up was 5.9 (4.3-7.7) years. Relapse-free survival differed by treatment courses (clustered log-rank test P<0.001). Compared with the first course (10.0 months; 95% CI, 9.0 to 10.7 months), relapse-free period and relapse risk progressively improved after subsequent courses (12.0-16.0 months; HRadj, 0.03-0.13; 95% CI, 0.01 to 0.18; P<0.001). The duration of B-cell depletion remained similar with repeated treatments (6.1 months; 95% CI, 6.0 to 6.3 months). Adverse events were mostly mild; the most common adverse events were hypogammaglobulinemia (50.9%), infection (4.5%), and neutropenia (3.7%). Side effects did not increase with more treatment courses nor a higher cumulative dose. Only 78 of the 353 episodes of hypogammaglobulinemia were clinically significant. Younger age at presentation (2.8 versus 3.3 years; P=0.05), age at first rituximab treatment (8.0 versus 10.0 years; P=0.01), and history of steroid resistance (28% versus 18%; P=0.01) were associated with significant hypogammaglobulinemia. All 53 infective episodes resolved, except for one patient with hepatitis B infection and another with EBV infection. There were 42 episodes of neutropenia, associated with history of steroid resistance (30% versus 20%; P=0.04). Upon last follow-up, 332 children (96%) had normal kidney function. CONCLUSIONS: Children receiving repeated courses of rituximab for FRSDNS experience an improving clinical response. Side effects appear acceptable, but significant complications can occur. These findings support repeated rituximab use in FRSDNS.


Assuntos
Agamaglobulinemia , Nefrose Lipoide , Síndrome Nefrótica , Neutropenia , Agamaglobulinemia/induzido quimicamente , Agamaglobulinemia/tratamento farmacológico , Criança , Feminino , Humanos , Imunossupressores/uso terapêutico , Masculino , Nefrose Lipoide/tratamento farmacológico , Síndrome Nefrótica/tratamento farmacológico , Neutropenia/induzido quimicamente , Neutropenia/tratamento farmacológico , Recidiva , Estudos Retrospectivos , Rituximab/efeitos adversos , Esteroides/uso terapêutico , Resultado do Tratamento
12.
Cancer Med ; 11(9): 1956-1964, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35233973

RESUMO

BACKGROUND: Patients with primary refractory and relapsed neuroblastoma have a poor prognosis since safe and effective chemotherapies for these patients are currently limited. The development of new chemotherapy regimens for these patients is imperative to improve survival outcomes. METHODS: We retrospectively analyzed 40 patients with refractory (n = 36) or relapsed (n = 4) neuroblastoma who received irinotecan, etoposide, and carboplatin (IREC) as a second-line treatment. We evaluated their therapeutic response and the toxicity of IREC. We also assessed the impact of UGT1A1 gene polymorphisms, which are involved in irinotecan metabolism, on outcomes and toxicity. RESULTS: A total of 112 cycles of IREC were administered to 40 patients with a median of 2 cycles per patient (range, 1-9). Six (15%) patients (UGT1A1 wild-type [n = 2] and heterozygous [n = 4]) showed objective responses, including partial response (n = 1), tumor shrinkage (n = 4), and improved findings on their MIBG scan (n = 1). Grade 4 neutropenia, grade 4 leukopenia, and grades 3-4 gastrointestinal toxicity were observed in 110 (98%), 88 (79%), and 3 (3%) cycles, respectively. There was no IREC-related mortality. Patients with UGT1A1 polymorphisms showed a higher frequency of grade 4 leukopenia, but these patients did not have increased treatment-related mortality or non-hematologic toxicity. CONCLUSIONS: IREC showed an objective response rate of 15% including 1 case with partial response. IREC was well tolerated regardless of UGT1A1 genotype. This study suggests that IREC is a promising second-line chemotherapy for refractory or relapsed neuroblastoma.


Assuntos
Neuroblastoma , Neutropenia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Camptotecina , Carboplatina , Etoposídeo , Humanos , Irinotecano , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Neuroblastoma/tratamento farmacológico , Neuroblastoma/genética , Neutropenia/induzido quimicamente , Estudos Retrospectivos
13.
Am J Hematol ; 97(7): 942-950, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35358350

RESUMO

Bruton tyrosine kinase inhibitors (BTKi) are important treatment options in Waldenström's macroglobulinemia (WM). Whether second-generation BTKi are associated with improved outcomes and/or better safety profile remains unclear. We did a systematic review and meta-analysis of clinical trials that reported data on the outcomes of patients with WM who received either first- or second-generation BTKi in the period between January 2010 and August 2021. Studies with twenty or fewer patients were excluded. The primary outcomes were efficacy measured by response and survival data. Eleven studies met the eligibility criteria and were included in the final analysis (n = 730 patients). A total of 298 patients received 1st-generation BTKi and 432 received a 2nd-generation BTKi. Pooled overall response rate (ORR) and major response rate (MRR) for both generations were similar (94.2% and 78.5% in 1st vs. 88.9% and 75.1% in 2nd, respectively). MRR for both generations was higher in MYD88 Mut/CXCR4 WT patients compared to MYD88 Mut/CXCR4 Mut patients (odds ratio [OR]: 3.9, 95% CI: 2.2 to 5.5). Pooled 18-mo progression-free survival (PFS) was similar for both generations (88.5% vs. 87.3%). Grade 3/4 atrial fibrillation was higher in 1st-generation BTKi (3.1% vs. 0.4%); however, grade-3/-4 infections and neutropenia were more frequent in 2nd-generarion BTKi (20.9% vs. 13.2%, 17.7% vs. 12%, respectively). The efficacy of 1st- and 2nd-generation BTKis is comparable. The 1st-generation BTKi were associated with a higher risk of atrial fibrillation, whereas infections and neutropenia occurred more frequently in 2nd-generation BTKi.


Assuntos
Fibrilação Atrial , Linfoma de Células B , Neutropenia , Macroglobulinemia de Waldenstrom , Fibrilação Atrial/induzido quimicamente , Humanos , Linfoma de Células B/tratamento farmacológico , Mutação , Fator 88 de Diferenciação Mieloide/genética , Neutropenia/induzido quimicamente , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas/efeitos adversos , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Macroglobulinemia de Waldenstrom/genética
14.
JCO Glob Oncol ; 8: e2100276, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35324270

RESUMO

PURPOSE: This study evaluated the efficacy, safety, and immunogenicity of biosimilar pegfilgrastim (PegFilBS) and originator pegfilgrastim (PegFilOR) in patients with stage 2-4 breast cancer. METHODS: This phase III randomized, multicenter, evaluator-blinded, noninferiority study recruited women with stage 2-4 breast cancer in Argentina who were scheduled to receive chemotherapy. Stratification was based on the breast cancer stage. The primary end point was the duration of severe neutropenia (DSN, noninferiority margin: 1 day) in the first chemotherapy cycle. Secondary end points assessed were incidence of severe neutropenia, grade 3 neutropenia, febrile neutropenia, infections, postchemotherapy hospitalization and duration, and the incidence of adverse drug reactions (ADRs). RESULTS: A total of 120 patients were randomly assigned to receive PegFilBS (58 patients) or PegFilOR (62 patients). Severe neutropenia occurred in 52 of 283 cycles (18.4%) for 27 patients who received PegFilBS and in 48 of 297 cycles (16.2%) for 20 patients who received PegFilOR (P = .48). During the first cycle, severe neutropenia occurred in 16 patients who received PegFilBS (DSN: 0.78 ± 1.53 days) and in 11 patients who received PegFilOR (DSN: 0.53 ± 1.25 days; 95% CI, -0.26 to 0.76 days). In the intention-to-treat analysis, the mean DSN values were 0.90 ± 1.79 days for the PegFilBS group and 0.50 ± 1.21 for the PegFilOR group (95% CI, -0.15 to 0.95 days). No significant differences were observed for the secondary efficacy end points. Three patients experienced seven ADRs in the PegFilBS group while 10 patients experienced 31 ADRs in the PegFilOR group. The most common ADR was myalgia. CONCLUSION: Relative to PegFilOR, PegFilBS provided noninferior efficacy outcomes in Argentinian women with stage 2-4 breast cancer who were treated using myelosuppressive chemotherapy.


Assuntos
Antineoplásicos , Medicamentos Biossimilares , Neoplasias da Mama , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Neutropenia , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Medicamentos Biossimilares/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Feminino , Filgrastim , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Humanos , Neutropenia/induzido quimicamente , Neutropenia/tratamento farmacológico , Neutropenia/prevenção & controle , Polietilenoglicóis
15.
Curr Oncol Rep ; 24(6): 671-686, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35230594

RESUMO

PURPOSE OF REVIEW: Pediatric oncology patients frequently experience episodes of prolonged neutropenia which puts them at high risk for infection with significant morbidity and mortality. Here, we review the data on infection prophylaxis with a focus on both pharmacologic and ancillary interventions. This review does not include patients receiving hematopoietic stem cell transplantation. RECENT FINDINGS: Patients with hematologic malignancies are at highest risk for infection. Bacterial and fungal prophylaxis decrease the risk of infection in certain high-risk groups. Ancillary measures such as ethanol locks, chlorhexidine gluconate baths, GCSF, IVIG, and mandatory hospitalization do not have enough data to support routine use. There is limited data on risk of infection and role of prophylaxis in patients receiving immunotherapy and patients with solid tumors. Patients with Down syndrome and adolescent and young adult patients may benefit from additional supportive care measures and protocol modifications. Consider utilizing bacterial and fungal prophylaxis in patients with acute myeloid leukemia or relapsed acute lymphoblastic leukemia. More research is needed to evaluate other supportive care measures and the role of prophylaxis in patients receiving immunotherapy.


Assuntos
Neoplasias Hematológicas , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Neutropenia , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adolescente , Antibioticoprofilaxia/métodos , Antifúngicos/uso terapêutico , Criança , Neoplasias Hematológicas/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Neutropenia/induzido quimicamente , Neutropenia/tratamento farmacológico , Neutropenia/prevenção & controle , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adulto Jovem
16.
BMC Cardiovasc Disord ; 22(1): 40, 2022 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-35148681

RESUMO

BACKGROUND: Clopidogrel is a widely-used antiplatelet and acts as an adenosine diphosphate receptor inhibitor. Neutropenia is a rare but serious adverse effect of clopidogrel. It is unknown whether this adverse effect has any association with impaired kidney function. CASE PRESENTATION: An 80-year-old male with chronic kidney disease was diagnosed with non-ST elevation myocardial infarction and underwent percutaneous coronary intervention. During hospitalization, the patient was diagnosed with contrast-induced nephropathy, treated symptomatically, and discharged with a back-to-baseline creatinine level. Two weeks later, the patient presented to the emergency department with fever and chills. Complete blood count showed leukopenia (0.84 × 103/mm3) and severe neutropenia (0.13 × 103/mm3). Blood cultures were positive for Pseudomonas aeruginosa. Clopidogrel was stopped immediately and switched into ticagrelor. Imipenem and granulocyte colony-stimulating factor were administered to the patient. The patient's white blood cell and absolute neutrophil count were within the normal range after four days of treatment. The patient was discharged after a 10-day hospitalization, and his complete blood counts were normal during further follow-ups. CONCLUSIONS: Clopidogrel was the most likely primary cause of neutropenia in our case. The incidence of clopidogrel-induced neutropenia is low and the exact mechanism is not fully explained. We provide suggestions on the management of clopidogrel-associated neutropenia, and summarize all five cases of clopidogrel-induced neutropenia in patients with impaired kidney function.


Assuntos
Clopidogrel/efeitos adversos , Doença da Artéria Coronariana/terapia , Neutropenia/induzido quimicamente , Intervenção Coronária Percutânea , Inibidores da Agregação Plaquetária/efeitos adversos , Insuficiência Renal Crônica/complicações , Idoso de 80 Anos ou mais , Clopidogrel/administração & dosagem , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/diagnóstico , Substituição de Medicamentos , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Imipenem/uso terapêutico , Masculino , Neutropenia/sangue , Neutropenia/diagnóstico , Neutropenia/tratamento farmacológico , Inibidores da Agregação Plaquetária/administração & dosagem , Insuficiência Renal Crônica/diagnóstico , Fatores de Risco , Ticagrelor/administração & dosagem , Resultado do Tratamento
17.
Acta Psychiatr Scand ; 145(5): 423-441, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35178700

RESUMO

OBJECTIVE: Clozapine is substantially underutilized in most countries and clinician factors including lack of knowledge and concerns about adverse drug effects (ADEs) contribute strongly to treatment reluctance. The aim of this systematic review was to provide clinicians with a comprehensive information source regarding clozapine ADEs. METHODS: PubMed and Embase databases were searched for English language reviews concerned with clozapine ADEs; publications identified by the automated search were manually searched for additional relevant citations. Following exclusion of redundant and irrelevant reports, pertinent information was summarized in evidence tables corresponding to each of six major ADE domains; two authors reviewed all citations for each ADE domain and summarized their content by consensus in the corresponding evidence table. This study was conducted in accordance with PRISMA principles. RESULTS: Primary and secondary searches identified a total of 305 unique reports, of which 152 were included in the qualitative synthesis. Most clozapine ADEs emerge within 3 months, and almost all appear within 6 months, after initiation. Notable exceptions are weight gain, diabetic ketoacidosis (DKA), severe clozapine-induced gastrointestinal hypomotility (CIGH), clozapine-induced cardiomyopathy (CICM), seizures, and clozapine-induced neutropenia (CIN). Most clozapine ADEs subside gradually or respond to dose reduction; those that prompt discontinuation generally do not preclude rechallenge. Rechallenge is generally inadvisable for clozapine-induced myocarditis (CIM), CICM, and clozapine-induced agranulocytosis (CIA). Clozapine plasma levels >600-1000 µg/L appear more likely to cause certain ADEs (e.g., seizures) and, although there is no clear toxicity threshold, risk/benefit ratios are generally unfavorable above 1000 µg/L. CONCLUSION: Clozapine ADEs rarely require discontinuation.


Assuntos
Antipsicóticos , Cardiomiopatias , Clozapina , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Miocardite , Neutropenia , Antipsicóticos/efeitos adversos , Clozapina/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Humanos , Miocardite/induzido quimicamente , Neutropenia/induzido quimicamente , Convulsões
18.
N Engl J Med ; 386(12): 1132-1142, 2022 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-35179323

RESUMO

BACKGROUND: Darolutamide is a potent androgen-receptor inhibitor that has been associated with increased overall survival among patients with nonmetastatic, castration-resistant prostate cancer. Whether a combination of darolutamide, androgen-deprivation therapy, and docetaxel would increase survival among patients with metastatic, hormone-sensitive prostate cancer is unknown. METHODS: In this international, phase 3 trial, we randomly assigned patients with metastatic, hormone-sensitive prostate cancer in a 1:1 ratio to receive darolutamide (at a dose of 600 mg [two 300-mg tablets] twice daily) or matching placebo, both in combination with androgen-deprivation therapy and docetaxel. The primary end point was overall survival. RESULTS: The primary analysis involved 1306 patients (651 in the darolutamide group and 655 in the placebo group); 86.1% of the patients had disease that was metastatic at the time of the initial diagnosis. At the data cutoff date for the primary analysis (October 25, 2021), the risk of death was significantly lower, by 32.5%, in the darolutamide group than in the placebo group (hazard ratio 0.68; 95% confidence interval, 0.57 to 0.80; P<0.001). Darolutamide was also associated with consistent benefits with respect to the secondary end points and prespecified subgroups. Adverse events were similar in the two groups, and the incidences of the most common adverse events (occurring in ≥10% of the patients) were highest during the overlapping docetaxel treatment period in both groups. The frequency of grade 3 or 4 adverse events was 66.1% in the darolutamide group and 63.5% in the placebo group; neutropenia was the most common grade 3 or 4 adverse event (in 33.7% and 34.2%, respectively). CONCLUSIONS: In this trial involving patients with metastatic, hormone-sensitive prostate cancer, overall survival was significantly longer with the combination of darolutamide, androgen-deprivation therapy, and docetaxel than with placebo plus androgen-deprivation therapy and docetaxel, and the addition of darolutamide led to improvement in key secondary end points. The frequency of adverse events was similar in the two groups. (Funded by Bayer and Orion Pharma; ARASENS ClinicalTrials.gov number, NCT02799602.).


Assuntos
Antagonistas de Receptores de Andrógenos/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Pirazóis/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Antagonistas de Androgênios/uso terapêutico , Antagonistas de Receptores de Andrógenos/efeitos adversos , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Docetaxel/efeitos adversos , Docetaxel/uso terapêutico , Quimioterapia Combinada , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica/tratamento farmacológico , Neutropenia/induzido quimicamente , Modelos de Riscos Proporcionais , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/patologia , Neoplasias de Próstata Resistentes à Castração , Pirazóis/efeitos adversos
19.
Am J Hematol ; 97(5): 623-629, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35170082

RESUMO

Angioimmunoblastic T-cell lymphoma (AITL) is a common type of peripheral T-cell lymphoma (PTCL) with a poor prognosis, and an effective first-line therapy is lacking. Chidamide is a selective histone deacetylase inhibitor and has been approved by the China Food and Drug Administration for relapsed or refractory PTCL. We conducted a multicenter phase II clinical trial combining chidamide with prednisone, etoposide, and thalidomide (CPET regimen) for a total of eight cycles in untreated AITL patients in China. The primary objectives were the overall response rate (ORR) and complete remission (CR) rate after eight cycles of the CPET regimen. The secondary endpoints were progression-free survival (PFS) and safety. Of the 71 enrolled patients, 51 completed the eight cycles of the CPET regimen. The ORR and CR of the 51 patients were 90.2 and 54.9%, respectively. After a median follow-up of 11.4 months (95% confidence interval [CI], 9.9-17.0), the median PFS of the 51 patients was 42.6 months (95% CI, 27.7-not reached) and the median overall survival (OS) was not reached. The 2-year PFS rate and OS rate were 66.5 and 82.2%, respectively. Sixty-eight patients received at least one cycle of CPET regimen and were included as the safety assessment population. The most common grade 3/4 adverse event was neutropenia (n = 22, 32.3%). Twelve patients showed treatment-related infections and recovered from antibiotic therapy; the other adverse events were mostly mild and reversible. The oral CPET regimen is an effective, tolerable, and economical choice for untreated AITL in a Chinese population. This trial was registered in www.clinicaltrials.gov as NCT03273452.


Assuntos
Linfoma de Células T Periférico , Neutropenia , Aminopiridinas , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzamidas , Etoposídeo/efeitos adversos , Humanos , Neutropenia/induzido quimicamente , Prednisona , Talidomida/uso terapêutico , Resultado do Tratamento
20.
Cancer ; 128(9): 1801-1811, 2022 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-35195913

RESUMO

BACKGROUND: RESILIENT (NCT03088813) is a phase 2/3 study assessing the safety, tolerability, and efficacy of liposomal irinotecan monotherapy in patients with small cell lung cancer and disease progression on/after first-line platinum-based therapy. Here, we present results from RESILIENT part 1. METHODS: This open-label, single-arm, safety run-in evaluation with dose-exploration and dose-expansion phases included patients ≥18 years old with Eastern Cooperative Oncology Group performance status of 0/1; those with asymptomatic central nervous system metastases were eligible. The primary objectives were to evaluate safety and tolerability and recommend a dose for further development. Efficacy end points were objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). RESULTS: During dose exploration, 5 patients received intravenous liposomal irinotecan at 85 mg/m2 (deemed not tolerable; dose-limiting toxicity) and 12 patients received 70 mg/m2 (deemed tolerable). During dose expansion, 13 additional patients received intravenous liposomal irinotecan at 70 mg/m2 . Of these 25 patients (median age [range], 59.0 [48.0-73.0] years, 92.0% with metastatic disease), 10 experienced grade ≥3 treatment-related treatment-emergent adverse events (TEAEs), most commonly diarrhea (20.0%) and neutropenia (16.0%), and 3 had serious treatment-related TEAEs, of whom 2 died. ORR was 44.0% (95% confidence interval [CI]: 24.40-65.07; 1 complete response, 10 partial responses) and median (95% CI) PFS and OS were 3.98 (1.45-4.24) months and 8.08 (5.16-9.82) months, respectively. CONCLUSION: Overall, no new safety signals were identified with liposomal irinotecan, and antitumor activity was promising. RESILIENT part 2, a randomized, controlled, phase 3 study of liposomal irinotecan versus topotecan, is ongoing. LAY SUMMARY: Small cell lung cancer (SCLC) is an aggressive disease with few treatment options after platinum-based therapy. Administering 1 option, irinotecan, as a "liposomal" formulation, may extend drug exposure and improve outcomes. The RESILIENT part 1 trial assessed the safety and efficacy of liposomal irinotecan in 25 adults with SCLC after disease progression despite platinum-based therapy. No new safety concerns were reported. The most common moderate-to-severe side effects were diarrhea (20% of patients) and neutropenia (16%). Tumors responded to treatment in 44% of patients. Average survival was 8.08 months, and time to disease progression was 3.98 months. Liposomal irinotecan trials are ongoing.


Assuntos
Irinotecano , Lipossomos , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Idoso , Diarreia/etiologia , Progressão da Doença , Humanos , Irinotecano/efeitos adversos , Lipossomos/efeitos adversos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/patologia
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