RESUMO
BACKGROUND: Clostridium difficile infection (CDI) is a leading cause of infectious complications in allogeneic hematopoietic cell transplant recipients (alloHCT). We sought to evaluate whether prophylactic oral vancomycin reduces the incidence of CDI in alloHCT recipients. METHODS: We conducted a retrospective cohort study to examine the effectiveness of CDI prophylaxis with oral vancomycin, as compared to no prophylaxis, in 145 consecutive adult alloHCT recipients at the University of Pennsylvania between April 2015 and November 2016. Patients received oral vancomycin 125 mg twice daily, starting on admission and continuing until discharge. The primary outcome of interest was the association between oral vancomycin prophylaxis and CDI diagnosis. Secondary outcomes included graft-versus-host disease (GVHD) and relapse. RESULTS: There were no cases of CDI in patients that received prophylaxis (0/90, 0%), whereas 11/55 (20%) patients who did not receive prophylaxis developed CDI (P < .001). Oral vancomycin prophylaxis was not associated with a higher risk of acute, grades 2-4 GVHD (subhazard ratio [sHR] 1.59; 95% confidence interval [CI] 0.88-2.89; P = .12), acute, grades 3-4 GVHD (sHR 0.65; 95% CI 0.25-1.66; P = .36), or acute, grades 2-4 gastrointestinal GVHD (sHR 1.95; 95% CI 0.93-4.07; P = .08) at day 180 post-transplant. No associations between oral vancomycin and relapse or survival were observed. CONCLUSIONS: Prophylaxis with oral vancomycin is highly effective in preventing CDI in alloHCT recipients without increasing the risk of graft-versus-host disease or disease relapse. Further evaluation via a prospective study is warranted.
Assuntos
Antibioticoprofilaxia , Clostridioides difficile/efeitos dos fármacos , Infecções por Clostridium/etiologia , Infecções por Clostridium/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hipersensibilidade/complicações , Transplantados , Vancomicina/administração & dosagem , Administração Oral , Adulto , Idoso , Antibioticoprofilaxia/métodos , Clostridioides difficile/imunologia , Infecções por Clostridium/mortalidade , Feminino , Doença Enxerto-Hospedeiro/etiologia , Humanos , Hipersensibilidade/imunologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Tempo para o Tratamento , Transplante Homólogo/efeitos adversos , Adulto JovemRESUMO
Graft-versus-host disease (GVHD) remains the most common treatment-related complication after allogeneic hematopoietic cell transplantation (allo-HCT). Lymphocyte migration plays a critical role in the pathogenesis of GVHD. A previous phase I/II trial demonstrated that CCR5 blockade with maraviroc in the first 30days after allo-HCT resulted in a low incidence of early acute GVHD, primarily in visceral organs, but with no impact on late acute or chronic GVHD. We conducted a phase II trial to examine the efficacy of an extended course of maraviroc, administered through post-transplantation day +90 in addition to standard prophylaxis in 37 recipients of reduced-intensity-conditioned unrelated donor allo-HCT performed to treat hematologic malignancies. Extended maraviroc treatment was safe and feasible. The primary study endpoint, day +180 rate of grade II-IV acute GVHD, was 22 ± 7%, liver GVHD was not observed, and gut GVHD was uncommon. The day +180 rate of grade III-IV acute GVHD was 5 ± 4%. The 1-year rate of moderate to severe chronic GVHD was 8 ± 5% and that of disease relapse was 30 ± 8%. Overall survival at 1 year was 70 ± 8%. Compared with the previously studied short course of maraviroc, the extended course resulted in a significantly higher GVHD-free, relapse-free survival (adjusted hazard ratio [HR], .45; 95% confidence interval [CI], .25 to .82; Pâ¯=â¯.009) and overall survival (adjusted HR, .48; 95% CI, .24 to .96; Pâ¯=â¯.037). A combined analysis of both trials showed that high maraviroc trough concentrations on the day of hematopoietic cell infusion were associated with lower rates of acute GVHD. An extended course of maraviroc after reduced-intensity-conditioned unrelated donor allo-HCT is safe and effective in preventing acute and chronic GVHD and is associated with favorable survival.
Assuntos
Antagonistas dos Receptores CCR5/uso terapêutico , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/métodos , Maraviroc/uso terapêutico , Receptores CCR5/deficiência , Condicionamento Pré-Transplante/métodos , Adulto , Idoso , Feminino , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/mortalidade , Transplante de Células-Tronco Hematopoéticas/normas , Humanos , Masculino , Maraviroc/farmacologia , Pessoa de Meia-Idade , Análise de Sobrevida , Resultado do Tratamento , Doadores não RelacionadosRESUMO
Understanding the socioeconomic impact of chronic graft-versus-host disease (GVHD) on affected patients is essential to help improve their overall well-being. Using data from the Chronic GVHD Consortium, we describe the insurance, employment, and financial challenges faced by these patients and the factors associated with the ability to work/attend school and associated financial burdens. A 15-item cross-sectional questionnaire designed to measure financial concerns, income, employment, and insurance was completed by 190 patients (response rate, 68%; 10 centers) enrolled on a multicenter Chronic GVHD Consortium Response Measures Validation Study. Multivariable logistic regression models examined the factors associated with financial burden and ability to work/attend school. The median age of respondents was 56years, and 87% of the patients were white. A higher proportion of nonrespondents had lower income before hematopoietic cell transplantation and less than a college degree. All but 1 patient had insurance, 34% had faced delayed/denied insurance coverage for chronic GVHD treatments, and 66% reported a financial burden. Patients with a financial burden had greater depression/anxiety and difficulty sleeping. Nonwhite race, lower mental functioning, and lower activity score were associated with a greater likelihood of financial burden. Younger age, early risk disease, and higher mental functioning were associated with a greater likelihood of being able to work/attend school. In this multicenter cohort of patients with chronic GVHD, significant negative effects on finances were observed even with health insurance coverage. Future research should investigate potential interventions to provide optimal and affordable care to at-risk patients and prevent long-term adverse financial outcomes in this vulnerable group.
Assuntos
Emprego , Doença Enxerto-Hospedeiro/economia , Cobertura do Seguro , Classe Social , Doença Crônica , Estudos Transversais , Feminino , Doença Enxerto-Hospedeiro/psicologia , Humanos , Masculino , Pessoa de Meia-Idade , América do Norte , Pacientes , Inquéritos e QuestionáriosRESUMO
Blocking lymphocyte trafficking after allogeneic hematopoietic stem cell transplantation is a promising strategy to prevent graft-versus-host disease (GVHD) while preserving the graft-versus-tumor response. Maraviroc, a CCR5 antagonist, has shown promise in clinical trials, presumably by disrupting the migration of effector cells to GVHD target organs. We describe a phosphoflow assay to quantify CCR5 blockade during treatment with maraviroc and used it to evaluate 28 patients in a phase II study. We found that insufficient blockade of CCR5 was associated with significantly worse overall survival (HR, 10.6; 95% CI, 2.2 to 52.0; P = .004) and higher rates of nonrelapse mortality (HR, 146; 95% CI, 1.0 to 20,600; P = .04) and severe acute GVHD (HR, 12; 95% CI, 1.9 to 76.6; P = .009). In addition, we found that pretransplant high surface expression of CCR5 on recipient T cells predicted higher nonrelapse mortality and worse GVHD- and relapse-free survival. Our results demonstrate that pharmacodynamic monitoring of CCR5 blockade unravels interpatient variability in the response to therapy and may serve as a clinically informative biomarker.
Assuntos
Antagonistas dos Receptores CCR5 , Doença Enxerto-Hospedeiro , Maraviroc , Receptores CCR5 , Idoso , Antagonistas dos Receptores CCR5/administração & dosagem , Antagonistas dos Receptores CCR5/farmacocinética , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Masculino , Maraviroc/administração & dosagem , Maraviroc/farmacocinética , Pessoa de Meia-Idade , Taxa de SobrevidaRESUMO
Hematopoietic cell transplantation (HCT) is an expensive, medically complicated, and potentially life-threatening therapy for multiple hematologic and nonhematologic disorders with a prolonged trajectory of recovery. Similar to financial issues in other cancer treatments, adverse financial consequences of HCT are emerging as an important issue and may be associated with poor quality of life and increased distress in HCT survivors. Prescription medicine coverage for HCT for Medicare and some Medicaid beneficiaries, especially in the long-term, remains suboptimal because of inadequate payer formularies or prohibitive copays. With an increasing number of older patients undergoing HCT and improvement in the overall survival after HCT, the problem of financial burden faced by Medicare beneficiaries with fixed incomes is going to worsen. In this article, we describe the typical financial burden borne by HCT recipients based on estimated copayment amounts attached to the categories of key medications as elucidated through 2 case studies. We also suggest some possible solutions for consideration to help these patients and families get through the HCT by minimizing the financial burden from essential medications needed during the post-HCT period.
Assuntos
Acessibilidade aos Serviços de Saúde/economia , Doenças Hematológicas/economia , Transplante de Células-Tronco Hematopoéticas/economia , Medicare/economia , Medicamentos sob Prescrição/economia , Idoso , Aloenxertos , Custos e Análise de Custo , Feminino , Doenças Hematológicas/terapia , Humanos , Masculino , Estados UnidosRESUMO
OBJECTIVES: Emerging data suggest that the combination of tacrolimus and the CCR5 antagonist maraviroc, both cytochrome P450-3A4 substrates, may be effective in preventing graft-versus-host disease in patients undergoing allogeneic HSCT. This study evaluated whether a pharmacokinetic interaction exists between these agents. METHODS: The study included 36 allogeneic HSCT recipients who received maravirocâ+âtacrolimus and 43 recipients of tacrolimus alone. We used a difference-in-differences analysis to examine the change in the concentration/dose ratios of tacrolimus after the discontinuation of maraviroc. In addition, we analysed the concentrations and dose requirements of tacrolimus in the two groups. RESULTS: There was no significant difference in tacrolimus concentration/dose ratios in patients receiving maravirocâ+âtacrolimus compared with tacrolimus alone. Upon discontinuation of maraviroc, the change in concentration/dose ratio was small and not significant relative to the control group, and the effect estimate was further attenuated after adjustment for confounders [-0.35 (ng/mL)/(mg/day); Pâ=â0.46]. In addition, the change in mean tacrolimus dose after discontinuation of maraviroc was similar between the groups (0.12 mg/day; Pâ=â0.56), as was the change in mean tacrolimus concentration (0.02 ng/mL; Pâ=â0.97). CONCLUSIONS: Our findings do not support a significant inhibitory effect of maraviroc on the metabolism of tacrolimus. These data demonstrate that this drug combination is safe and imply that the protective effect of maraviroc against graft-versus-host disease was not mediated through an increase in tacrolimus concentrations. These findings are important for the design of clinical trials that evaluate maraviroc in combination with cytochrome P450-3A4 substrates.
Assuntos
Cicloexanos/farmacocinética , Interações Medicamentosas , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas , Fatores Imunológicos/farmacocinética , Tacrolimo/farmacocinética , Triazóis/farmacocinética , Adulto , Idoso , Cicloexanos/administração & dosagem , Feminino , Humanos , Fatores Imunológicos/administração & dosagem , Masculino , Maraviroc , Pessoa de Meia-Idade , Estudos Prospectivos , Tacrolimo/administração & dosagem , Transplante Homólogo , Triazóis/administração & dosagem , Adulto JovemAssuntos
Antineoplásicos/efeitos adversos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Doenças Pulmonares Intersticiais/induzido quimicamente , Pirazóis/efeitos adversos , Pirimidinas/efeitos adversos , Adenina/análogos & derivados , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , PiperidinasRESUMO
OBJECTIVE: To report the development of a spontaneous subcapsular splenic hematoma following filgrastim administration in a patient undergoing an allogeneic hematopoietic stem cell transplant. CASE SUMMARY: A 60-year-old female with myelodysplastic syndrome was admitted for a reduced-intensity allogeneic hematopoietic stem cell transplant from an unrelated donor. She received filgrastim 5 µg/kg starting on day 1 to accelerate neutrophil recovery. On day 5, she began reporting severe left chest-wall pain. Contrast-enhanced computed tomography of the abdomen/pelvis revealed a spontaneous subcapsular splenic hematoma. Upon discontinuation of filgrastim, the pain fully resolved. The patient was subsequently rechallenged with filgrastim, which led to recurrence of the left-sided chest-wall pain. Filgrastim was discontinued and the patient reported resolution of the pain. DISCUSSION: Filgrastim has been associated with splenic hematoma and splenic rupture, predominantly in healthy donors undergoing mobilization of peripheral blood stem cells. Although splenic rupture attributed to filgrastim in a patient undergoing allogeneic hematopoietic stem cell transplantation has been reported, to our knowledge, this is the first case report to establish causality. Using the Naranjo probability scale, an objective causality assessment revealed that the adverse drug event was highly probable. CONCLUSIONS: Although filgrastim-induced splenomegaly, splenic hematomas, and splenic rupture are rare, clinicians working in the bone marrow transplant setting should be cognizant of the potential of growth factors to cause these adverse events.
Assuntos
Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Hematoma/induzido quimicamente , Esplenopatias/induzido quimicamente , Feminino , Filgrastim , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/terapia , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêuticoRESUMO
OBJECTIVE: To review the available literature addressing the role of decitabine for the treatment of acute myeloid leukemia (AML). DATA SOURCES: Relevant literature was identified by a PubMed search (January 1970-March 2012) of English-language literature using the terms decitabine, acute myeloid leukemia, and DNA methyltransferase inhibitors. STUDY SELECTION AND DATA EXTRACTION: All published studies and abstracts, as well as relevant consensus guidelines, evaluating the current literature about the role of decitabine for the treatment of AML were included. DATA SYNTHESIS: Decitabine has been evaluated for the treatment of AML in several different settings. In patients with newly diagnosed AML who are not candidates for standard remission induction chemotherapy, a Phase 2 trial of decitabine administered for 5 days per cycle demonstrated a 24% complete remission rate (CR). A subsequent Phase 3 trial comparing decitabine and low-dose cytarabine or best supportive care in a similar patient population showed a greater CR rate (18% vs 8%; p = 0.001) but no overall survival benefit. A Phase 2 trial demonstrated a 47% CR rate with decitabine initially administered for 10 days per cycle, with subsequent doses customized to individual response and toxicity. This novel dosing schedule has yet to be evaluated in a Phase 3 trial. Decitabine is also being investigated for the treatment of relapsed/refractory AML and as bridge therapy to allogeneic hematopoietic stem cell transplantation. CONCLUSIONS: Decitabine offers a promising alternative therapeutic option for patients with AML who are not candidates for standard remission induction chemotherapy. Because of its acceptable safety profile, research is investigating the clinical benefit of decitabine in combination with other antileukemic therapies. The potential roles of decitabine in the treatment of AML continue to be explored in numerous clinical trials.
Assuntos
Antineoplásicos/uso terapêutico , Azacitidina/análogos & derivados , Metilases de Modificação do DNA/antagonistas & inibidores , Leucemia Mieloide Aguda/tratamento farmacológico , Antineoplásicos/farmacologia , Azacitidina/farmacologia , Azacitidina/uso terapêutico , Decitabina , HumanosRESUMO
OBJECTIVE: To review the available literature addressing the treatment of pancreatic neuroendocrine tumors (PNETs) and carcinoid tumors. DATA SOURCES: Relevant literature was identified by a PubMed search (January 1977-December 2011) of English-language literature using the terms gastroenteropancreatic neuroendocrine tumor, pancreatic neuroendocrine, carcinoid, and pancreatic islet cell tumor. STUDY SELECTION AND DATA EXTRACTION: All published studies and abstracts, as well as relevant consensus guidelines, evaluating the current literature about PNETs and carcinoid tumors were included. DATA SYNTHESIS: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a genetically diverse group of complex malignancies with varying biological and clinical courses. Historically believed to be rare, recent epidemiologic data suggest their incidence is rising. Two of the most commonly diagnosed GEP-NETs are PNETs and carcinoid tumors. Both subtypes are well-differentiated tumors and present as low or intermediate grade. The systemic manifestations of PNETs and carcinoid tumors are diverse and are related to the secretion of affected hormones and biogenic amines. Surgical resection of localized disease remains the only curative option. However, the utility of this approach is limited because most patients are diagnosed with advanced disease. Recent advances have led to an improvement in outcomes in patients with PNETs and carcinoid tumors. This review describes traditional therapies as well as emerging strategies being investigated to help manage these cancers. Treatment of poorly differentiated GEP-NETs is beyond the scope of this review. CONCLUSIONS: The advent of new therapies for PNETs and carcinoid tumors has introduced a paradigm shift in the management of this heterogeneous malignancy.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Gastrointestinais/tratamento farmacológico , Tumores Neuroendócrinos/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Citotoxinas/uso terapêutico , Neoplasias Gastrointestinais/cirurgia , Humanos , Interferon-alfa/uso terapêutico , Terapia de Alvo Molecular , Tumores Neuroendócrinos/cirurgia , Neoplasias Pancreáticas/cirurgia , Somatostatina/análogos & derivados , Somatostatina/uso terapêuticoRESUMO
Vitamin D promotes a shift from a proinflammatory to a more tolerogenic immune state in allogeneic hematopoietic cell transplant (HCT) recipients. The dominant mechanism responsible for this shift has not been elucidated. We took a multifaceted approach to evaluating the clinical and immunologic impact of low vitamin D levels in 53 HCT recipients. We used 28-plex flow cytometry for immunophenotyping, serum cytokine levels, T-cell cytokine production, and T-cell whole genome transcription. The median day-30 vitamin D level was 20 ng/mL, and deficiency was common in younger patients undergoing myeloablative transplantation. Low vitamin D levels were associated with a high CD8/Treg ratio, increased serum levels and T-cell production of proinflammatory cytokines, and a gene expression signature of unrestrained T-cell proliferation and epigenetic modulation through the PRC2/EZH2 complex. Immunophenotyping confirmed a strong association between high levels of vitamin D and an activated EZH2 signature, characterized by overexpression of ID3, which has a role in effector T-cell differentiation. Our findings demonstrate the critical role of vitamin D in modulating T-cell function in human GVHD and identify a previously undescribed interaction with EZH2 and ID3, which may impact effector differentiation and has implications to cell therapies and other forms of cancer immunotherapy. © 20XX American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Deficiência de Vitamina D , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Proteínas Inibidoras de Diferenciação , Proteínas de Neoplasias , Condicionamento Pré-Transplante , Transplante HomólogoRESUMO
Patients undergoing haploidentical or mismatched unrelated donor (haplo/MMUD) allogeneic hematopoietic cell transplantation (alloHCT) receiving post-transplant cyclophosphamide (PTCy) are at high risk of cytomegalovirus (CMV) infection. Experience with letermovir (LET) in this population is limited. This single center retrospective cohort study compared CMV and transplant outcomes between LET and a historical control with high-dose valacyclovir (HDV) prophylaxis in adults undergoing haplo/MMUD alloHCT. Thirty-eight CMV seropositive patients were included, 19 in each arm. LET reduced the incidence of CMV infection (5% vs. 53%, RR 0.01, 95% CI 0.014-0.71, p = .001) and need for CMV treatment by day +100 (5% vs. 37%, RR 0.14, 95% CI 0.18-0.99, p = .017) compared to HDV. Median CMV event-free-survival was improved with LET (not reached vs. 80 days, HR 0.114, 95% CI 0.07-0.61, p = .004). These data support the efficacy of LET in alternative donor transplants.
Assuntos
Infecções por Citomegalovirus , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Acetatos , Adulto , Ciclofosfamida/efeitos adversos , Citomegalovirus , Infecções por Citomegalovirus/etiologia , Infecções por Citomegalovirus/prevenção & controle , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Quinazolinas , Estudos Retrospectivos , Doadores não Relacionados , Valaciclovir/uso terapêuticoRESUMO
BACKGROUND: Elotuzumab plus lenalidomide and dexamethasone has shown improved progression-free and overall survival versus lenalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma. We aimed to assess these regimens in patients with newly diagnosed multiple myeloma who are ineligible for haematopoietic stem-cell transplantation (HSCT). METHODS: ELOQUENT-1 is an open-label, multicentre, randomised, phase 3 trial conducted at 185 hospitals, oncology practices, and research centres in 19 countries. Eligible patients were aged 18 years or older with newly diagnosed, untreated, symptomatic myeloma and not candidates for high-dose therapy plus HSCT, and an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or lower. Patients were randomly assigned (1:1) to receive elotuzumab plus lenalidomide and dexamethasone or lenalidomide and dexamethasone using an interactive voice response system, stratified by the International Staging System (ISS; stage I-II vs III), age (<75 years vs ≥75 years), and ECOG performance status (0 vs 1-2). Patients in the elotuzumab plus lenalidomide and dexamethasone group received elotuzumab administered intravenously at 10 mg/kg on days 1, 8, 15, and 22 during cycles 1 and 2, days 1 and 15 during cycles 3-18, and then at 20 mg/kg on day 1 for subsequent cycles. In both treatment groups, patients received 25 mg lenalidomide orally on days 1-21 of each cycle and 40 mg dexamethasone on days 1, 8, 15, and 22 of each cycle. The primary endpoint was progression-free survival, as per the primary definition from European Society for Blood and Marrow Transplantation criteria in all randomly assigned patients (intention-to-treat population). This study is registered with ClinicalTrials.gov, NCT01335399 (completed). FINDINGS: Between Aug 4, 2011, and June 19, 2014, 748 patients were randomly assigned (374 in each treatment group) and 742 patients received treatment (333 (90%) of 371 in the elotuzumab plus lenalidomide and dexamethasone group vs 339 (91%) of 371 in the lenalidomide and dexamethasone group discontinued treatment). The median age of patients was 73·0 years (IQR 69·0-78·0), 294 (39%) patients were 75 years or older. Most patients were White (711 [95%]) and male (412 [55%]). At a minimum follow-up of 65·3 months, the median progression-free survival was not significantly different between the groups: 31·4 months (95% CI 26·2-36·8) in the elotuzumab plus lenalidomide and dexamethasone group versus 29·5 months (23·5-34·3) in the lenalidomide and dexamethasone group (HR 0·93, 95·71% CI 0·77-1·12; stratified log-rank p=0·44). The median follow-up was 70·6 months (IQR 35·1-79·2). The most common grade 3-4 treatment-related adverse event was neutropenia (64 [17%] of 371 vs 79 [21%] of 371). Study drug toxicity was the reported cause of death in five (1%) versus four (1%) patients. INTERPRETATION: Elotuzumab plus lenalidomide and dexamethasone did not significantly improve progression-free survival versus lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma who are ineligible for HSCT. Although these data contribute to the treatment landscape, further research is needed to find ways to improve treatments in the front-line setting. FUNDING: Bristol Myers Squibb.
Assuntos
Mieloma Múltiplo , Idoso , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dexametasona , Humanos , Lenalidomida/efeitos adversos , Masculino , Mieloma Múltiplo/tratamento farmacológicoAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Terapia de Salvação/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Arabinonucleosídeos/administração & dosagem , Ciclofosfamida/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Humanos , Linfoma/complicações , Linfoma/tratamento farmacológico , Linfoma/patologia , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células T Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Recidiva , Terapia de Salvação/efeitos adversosRESUMO
Oropharyngeal mucositis (OPM) is common following conditioning for allogeneic hematopoietic cell transplantation (alloHCT) and results in pain, functional status decline, need for nutritional support, infections, and prolonged length of stay (LOS). Methotrexate (MTX) graft-versus-host disease (GVHD) prophylaxis exacerbates OPM and slows hematopoietic engraftment, which may prolong LOS. Previous studies have demonstrated reduced OPM and more rapid engraftment when leucovorin (LCV) is added following MTX GVHD prophylaxis, yet this practice is controversial. The primary objective of this study was to determine if the routine addition of LCV to MTX GVHD prophylaxis impacted the duration of grade 2 to 4 OPM. Secondary objectives included determination of the incidence of grade 2 to 4 and grade 3 to 4 OPM, time to engraftment, ability to receive all four planned MTX doses, use of total parenteral nutrition (TPN), use of patient-controlled analgesia (PCA), LOS, incidence of acute or chronic GVHD, relapse-free survival (RFS), and overall survival (OS). This single-center, retrospective cohort study compared alloHCT outcomes for 46 adult patients who received MTX 15 mg/m2 day +1; MTX 10 mg/m2 days +3, +6, and +11 (15-10-10-10); and LCV following days +3, +6, and +11 MTX compared to historical controls who did not. Patients who received myeloablative conditioning (MAC) and matched related donor (MRD) or matched unrelated donor (MUD) alloHCT were included. The addition of LCV resulted in significant reductions in the duration of grade 2 to 4 OPM (median, 6 days versus 10.5 days; P = .0004), duration of TPN (7 days versus 16 days; P = .001), PCA use (16% versus 39%; P = .0001), time to neutrophil engraftment (median, 18 versus 20 days; P = .008), and LOS (median, 27.5 versus 31 days; P = .017) compared to historical controls. Patients who received routine LCV had similar incidences of grade 2 to 4 acute GVHD (30% versus 28%; relative risk [RR], 1.08; 95% confidence interval [CI], .57 to 2.03; P = 1.0), grade 3 or 4 acute GVHD (2% versus 7%; RR, .33; 95% CI, .04 to 3.09; P = .62) and chronic GVHD (37% versus 30%; RR, 1.21; 95% CI, .67 to 2.16; P = .66) compared to historical controls. Graft failure occurred in 2% of patients in each group. In a multivariable logistic regression analysis, RFS was similar in the LCV group compared to historical controls (HR, .86; 95% CI, .24 to 1.2; P = .13); however, OS was improved in patients who received LCV (HR, .33; 95% CI, .13 to .83; P = .01). In patients undergoing MAC MRD/MUD alloHCT with four planned doses of MTX GVHD prophylaxis (15-10-10-10), LCV was associated with reduced duration of grade 2 to 4 OPM, faster neutrophil engraftment, reduced utilization of TPN and PCA, and shortened LOS compared to historical controls not receiving routine LCV. These benefits were apparent without an increased risk of acute or chronic GVHD or adverse effect on RFS. LCV improved OS; however, it is unclear if this was due to the intervention or an unmeasured confounder. A randomized, prospective trial of LCV prophylaxis in patients receiving MAC alloHCT and MTX 15-10-10-10 GVHD prophylaxis is warranted to confirm our findings.
Assuntos
Doença Enxerto-Hospedeiro , Mucosite , Adulto , Doença Enxerto-Hospedeiro/prevenção & controle , Hospitais , Humanos , Tempo de Internação , Leucovorina , Metotrexato , Mucosite/prevenção & controle , Recidiva Local de Neoplasia , Neutrófilos , Estudos Prospectivos , Estudos RetrospectivosRESUMO
Pegaspargase (PEG) increases venous thromboembolism (VTE) in acute lymphoblastic leukemia (ALL) potentially due to depletion of anticoagulation factors, including antithrombin (AT). The benefit and cost of AT supplementation in adults is unclear. We aimed to characterize VTE incidence and risk factors following AT and determine the characteristics and costs of supplementation. Fifty-three adults received PEG and AT. VTE occurred in 21% (grade ≥3 8%). T cell ALL and patients receiving prednisone during induction were at highest risk. Repeat AT levels post supplementation were subtherapeutic forty-four percent of the time. A median of 18 days elapsed between PEG and two sequential therapeutic AT levels despite supplementation. Patients received a median of 2 AT doses per PEG dose at a median cost of $11,145. VTE remains common in adults despite AT supplementation. More aggressive AT supplementation may reduce VTE but warrant prospective evaluation given the significant cost.
Assuntos
Tromboembolia Venosa , Adulto , Antitrombinas/efeitos adversos , Asparaginase/efeitos adversos , Suplementos Nutricionais , Humanos , Polietilenoglicóis , Estudos Prospectivos , Fatores de Risco , Tromboembolia Venosa/tratamento farmacológico , Tromboembolia Venosa/epidemiologia , Tromboembolia Venosa/etiologiaRESUMO
Prolonging overall survival (OS) remains an unmet need in relapsed or refractory multiple myeloma (RRMM). In ELOQUENT-2 (NCT01239797), elotuzumab plus lenalidomide/dexamethasone (ERd) significantly improved progression-free survival (PFS) versus lenalidomide/dexamethasone (Rd) in patients with RRMM and 1-3 prior lines of therapy (LoTs). We report results from the pre-planned final OS analysis after a minimum follow-up of 70.6 months, the longest reported for an antibody-based triplet in RRMM. Overall, 646 patients with RRMM and 1-3 prior LoTs were randomized 1:1 to ERd or Rd. PFS and overall response rate were co-primary endpoints. OS was a key secondary endpoint, with the final analysis planned after 427 deaths. ERd demonstrated a statistically significant 8.7-month improvement in OS versus Rd (median, 48.3 vs 39.6 months; hazard ratio, 0.82 [95.4% Cl, 0.68-1.00]; P = 0.0408 [less than allotted α of 0.046]), which was consistently observed across key predefined subgroups. No additional safety signals with ERd at extended follow-up were reported. ERd is the first antibody-based triplet regimen shown to significantly prolong OS in patients with RRMM and 1-3 prior LoTs. The magnitude of OS benefit was greatest among patients with adverse prognostic factors, including older age, ISS stage III, IMWG high-risk disease, and 2-3 prior LoTs.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Intervalo Livre de Doença , Feminino , Humanos , Lenalidomida/administração & dosagem , Lenalidomida/efeitos adversos , Masculino , Pessoa de Meia-Idade , Recidiva , Taxa de SobrevidaRESUMO
Steroid-refractory (SR) acute gastrointestinal (GI) graft-versus-host disease (GVHD) is associated with significant mortality in allogeneic hematopoietic cell transplantation recipients. We retrospectively evaluated the efficacy of tocilizumab for the treatment of SR biopsy-proven acute lower GI GVHD in 16 consecutive adult transplant recipients between October 2015 and July 2016. Tocilizumab 8 mg/kg was administered every 2 weeks until achievement of complete response, defined as resolution of all manifestations of GI GVHD, or until patients had progression or initiation of other therapy. Ten of 16 patients (62.5%; 95% CI, 0.39-82) achieved a complete response after a median time of 11 days (range, 2-28 days) from tocilizumab initiation. The median time to response onset (improvement in stage by at least 1) was 1 day (range, 1-4 days). Tocilizumab was administered at a median of 9 days (range, 3-75 days) from GVHD diagnosis and 10 days (range, 3-75 days) from initiation of high-dose steroids. At a median follow-up of 7.6 months (range, 0.8-27.7 months) from initiation of tocilizumab, 6/16 (37.5%) patients are alive and free of their underlying hematologic malignancy. Tocilizumab appears to be a highly active agent for the treatment of severe SR lower GI acute GVHD.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Gastroenteropatias/tratamento farmacológico , Doença Enxerto-Hospedeiro/tratamento farmacológico , Esteroides/farmacologia , Adulto , Idoso , Anticorpos Monoclonais Humanizados/farmacologia , Feminino , Gastroenteropatias/mortalidade , Gastroenteropatias/patologia , Doença Enxerto-Hospedeiro/mortalidade , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/patologia , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Trato Gastrointestinal Inferior , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Análise de Sobrevida , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
Inhibitors of the epidermal growth factor receptor (EGFR) are important treatment options for non-small cell lung cancer (NSCLC) patients with activating EGFR mutations. Erlotinib, gefitinib, afatinib, and osimertinib are approved for use in NSCLC patients, and several other agents are in clinical development. The objectives of this article are to review the pharmacokinetic and known drug interaction data for EGFR tyrosine kinase inhibitors (TKIs) available for use in NSCLC patients, as well as adverse events (AEs) commonly observed with EGFR-TKI treatment, and to discuss relevant management strategies. The importance of this information for patient care is explored from the perspective of advanced practitioners. Pharmacokinetic, drug-interaction, and safety data are included for EGFR inhibitors approved for NSCLC (erlotinib, gefitinib, afatinib, and osimertinib). Relevant dose modifications and AE management strategies are also reviewed. The interdisciplinary health-care team plays an essential role in patient education, care planning, and medication administration. As such, it is essential that advanced practitioners understand the safety profiles and the potential for drug interactions with EGFR TKIs to ensure patients achieve the maximum benefit from these agents.
RESUMO
Adoptive T cell therapy (ACT) is a promising new modality for malignancies. Here, we report that adoptive T cell efficacy in tumor-bearing mice is significantly affected by differences in the native composition of the gut microbiome or treatment with antibiotics, or by heterologous fecal transfer. Depletion of bacteria with vancomycin decreased the rate of tumor growth in mice from The Jackson Laboratory receiving ACT, whereas treatment with neomycin and metronidazole had no effect, indicating the role of specific bacteria in host response. Vancomycin treatment induced an increase in systemic CD8α+ DCs, which sustained systemic adoptively transferred antitumor T cells in an IL-12-dependent manner. In subjects undergoing allogeneic hematopoietic cell transplantation, we found that oral vancomycin also increased IL-12 levels. Collectively, our findings demonstrate an important role played by the gut microbiota in the antitumor effectiveness of ACT and suggest potentially new avenues to improve response to ACT by altering the gut microbiota.