RESUMO
Chimeric antigen receptor T cell (CAR T) therapy has been integrated into treatment algorithms for acute leukemia, lymphoma, and, most recently, multiple myeloma. The number of clinical trials in both hematologic and solid tumor malignancies for new products and potential indications continues to grow. The clinical toxicities of CAR T therapy include cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, which often warrant inpatient admission for close monitoring and treatment. Consequently, many centers have built processes around the administration of these cells in the inpatient setting. As new products gain Food and Drug Administration approval with more manageable toxicity profiles, and as institutions gain experience with the management of these toxicities, outpatient administration and monitoring should be expected. In addition, payor reimbursements for inpatient treatment have put the sustainability of inpatient CAR T therapy in jeopardy, especially for centers with a payor mix that includes a high proportion of Medicare patients. This has the serious potential to limit access to care. As the use of CAR T therapy continues to expand, changes in payment models, care settings, or both are needed to ensure the sustainability of safe, efficient, and cost-effective treatment. This review outlines the efficacy and toxicity of currently approved products, as well as best practices to optimize the management of CAR T cell therapy in the outpatient setting.
Assuntos
Imunoterapia Adotiva , Receptores de Antígenos Quiméricos , Idoso , Terapia Baseada em Transplante de Células e Tecidos , Humanos , Medicare , Pacientes Ambulatoriais , Resultado do Tratamento , Estados UnidosRESUMO
Hematopoietic cell transplantation (HCT) is an essential component of potentially curative therapy for patients with hematologic malignancies. High-dose chemotherapy with autologous (auto) stem cell rescue is used to overcome chemoresistance in multiple myeloma, non-Hodgkin lymphoma, and Hodgkin lymphoma. Alternatively, poor-risk acute leukemias rely on the graft versus leukemia effect of allogeneic (allo) products. Long-term remissions are feasible with both auto- and allo-HCT; however, disease relapse is the leading cause of death after HCT for many patients. In recognition of this, novel therapies are being investigated in the upfront, relapsed/refractory, and post-HCT maintenance settings to deepen response and maintain disease control. To date, the most robust data to support this approach are in multiple myeloma, where post-transplant maintenance therapy has improved clinical outcomes. In Hodgkin lymphoma, patients with high-risk features may benefit from post-auto-HCT vedotin (BV) regardless of pre-HCT BV exposure. Apart from mantle cell lymphoma, where rituximab maintenance is generally accepted, post-auto-HCT maintenance in other forms of NHL is less established. In patients who undergo allo-HCT, the utilization of maintenance therapy is an important component of improving post-HCT outcomes, however, an individualized approach that considers patient factors such as residual toxicity from HCT, an immature graft with poor graft function, infection, and graft-versus-host disease create a complex environment for aggressive interventions. Initiation of directed agents in patients with identified mutations prior to allo-HCT, including FLT3 in acute myeloid leukemia and Philadelphia chromosome in acute lymphoid leukemia have generally improved post-HCT outcomes. Ongoing studies are exploring the safety and efficacy of additional maintenance strategies post-allo-HCT in an effort to further improve post-HCT outcomes.
Assuntos
Antineoplásicos/administração & dosagem , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Antineoplásicos/farmacologia , Terapia Combinada , Resistencia a Medicamentos Antineoplásicos , Neoplasias Hematológicas/patologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Transplante AutólogoAssuntos
Antineoplásicos Alquilantes/efeitos adversos , Ciclofosfamida/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante Haploidêntico/efeitos adversos , Ativação Viral , Viroses/etiologia , Antineoplásicos Alquilantes/uso terapêutico , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Ciclofosfamida/uso terapêutico , Doença Enxerto-Hospedeiro/etiologia , Humanos , Hospedeiro Imunocomprometido , Fatores de Risco , Ativação Viral/imunologia , Viroses/diagnósticoRESUMO
Haploidentical hematopoietic cell transplant (haplo-HCT) with post-transplant cyclophosphamide (PTCY) is utilized for patients with hematological disorders but without conventional donors. The effects of new-onset post-transplant diabetes mellitus (PTDM) following haplo-HCT are unknown. We examined PTDM incidence and outcomes after haplo-HCT with PTCY. Patients without diabetes receiving haplo-HCT (n=64) were analyzed for PTDM diagnosis (defined as blood glucose≥ 200 mg/dL). By day 100, 14 (22%) patients developed PTDM (median, 18 days). Hyperglycemia (blood glucose ≥ 200 mg/dL) preceded corticosteroids in 11 (79%) individuals. PTDM patients had increased death/relapse (p=0.029). PTDM occurs frequently, precedes corticosteroids, and leads to inferior outcomes following haplo-HCT. PTDM prophylaxis/treatment may improve HCT survival.
RESUMO
Curative therapy for individuals with severe sickle cell disease (SCD) who lack an HLA-identical sibling donor has been frustratingly elusive. In with the goal of improving engraftment while minimizing transplantation-related morbidity, a multi-institutional learning collaborative was developed in the context of a Phase II clinical trial of nonmyeloablative, related HLA-haploidentical (haplo) bone marrow transplantation (BMT) with post-transplantation cyclophosphamide. All eligible participants had hemoglobin SS, and 89% (16 of 18) had an identifiable donor. The median patient age was 20.9 years (IQR, 12.1 to 26.0 years), and the most common indication for transplantation was overt stroke (in 69%; 11 of 16). In the first 3 patients, the conditioning regimen consisted of antithymocyte globulin, fludarabine, cyclophosphamide, and low-dose total body irradiation. Graft-versus-host disease (GVHD) prophylaxis included post-transplantation cyclophosphamide, mycophenolate mofetil, and sirolimus. Primary graft rejection occurred in 2 of the 3 patients (67%), which triggered the study-stopping rule. To reduce graft rejection risk, thiotepa was added to the conditioning regimen, and then 15 patients (including 2 with previous graft rejection) underwent haplo-BMT with this thiotepa-augmented conditioning regimen. At a median follow-up of 13.3 months (interquartile range [IQR], 3.8 to 23.1 months), 93% (14 of 15) had >95% stable donor engraftment at 6 months, with 100% overall survival. The median time to neutrophil engraftment (>500) was 22 days (IQR, 19 to 27 days), and that for platelet engraftment (>50 x 109/L) was 28 days (IQR, 27 days to not reached). Two patients had grade III-IV acute GVHD, 1 patient had mild chronic GVHD, and 86% of patients (6 of 7) were off immunosuppression therapy by 1-year post-transplantation. Our data suggest that haplo-BMT with post-transplantation cyclophosphamide and thiotepa improves donor engraftment without significantly increasing morbidity or mortality and could dramatically expand curative options for individuals with SCD.
Assuntos
Anemia Falciforme/tratamento farmacológico , Antineoplásicos Alquilantes/uso terapêutico , Transplante de Medula Óssea/métodos , Ciclofosfamida/uso terapêutico , Imunossupressores/uso terapêutico , Tiotepa/uso terapêutico , Adolescente , Adulto , Antineoplásicos Alquilantes/farmacologia , Criança , Ciclofosfamida/farmacologia , Feminino , Humanos , Imunossupressores/farmacologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Tiotepa/farmacologia , Doadores de Tecidos , Adulto JovemRESUMO
Administration of immune effector cell (IEC) therapy is a complex endeavor requiring extensive coordination and communication of various healthcare and administrative teams. Chimeric antigen receptor (CAR) T cells are the most established IEC therapy available. As of July 2018 two commercial gene therapy products, tisagenlecleucel and axicabtagene ciloleucel, have been approved by the US Food and Drug Administration. To gain insight into the infrastructure and practices across the country, the American Society for Blood and Marrow Transplantation Pharmacy Special Interest Group conducted an electronic survey on the current administrative, logistic, and toxicity management practices of CAR T cell therapy across the United States. This survey consists of 52 responses from institutions of varying sizes, most of which (â¼80%) had previous investigational experience with CAR T cell therapy. Absorbing the energy of this exciting new treatment has challenged hematopoietic cell transplant programs across the country to strengthen department infrastructure, develop new committees and policies, and implement significant education to ensure safe administration. With the variety of experience with CAR T cell therapy, we hope this survey can contribute to the existing published literature and provide support and consensus to established and developing IEC programs and practice guidelines.
Assuntos
Antígenos CD19/uso terapêutico , Terapia Genética , Receptores de Antígenos de Linfócitos T/administração & dosagem , Receptores de Antígenos Quiméricos/administração & dosagem , Antígenos CD19/administração & dosagem , Produtos Biológicos , Humanos , Imunoterapia Adotiva , Guias de Prática Clínica como Assunto , Estados UnidosRESUMO
There is no standard therapy for refractory acute myeloid leukemia (AML), but several salvage therapies are available (National Comprehensive Cancer Network [NCCN], 2018). Recently, there have been major developments in the treatment of AML focusing on the development of targeted and novel therapies. Ivosidenib is the first approved oral, targeted, small-molecule inhibitor of the isocitrate dehydrogenase 1 (IDH1) mutation seen in AML. IDH1 mutations have been associated with significantly worse outcomes in disease-free survival, relapse-free survival, and overall survival (NCCN, 2018). This article reviews the clinical trials and dose escalation studies that led to the U.S. Food & Drug Administration approval for ivosidenib in patients with relapsed or refractory AML with a susceptible IDH1 mutation. Patient counseling and monitoring, including dosing and administration, are important steps that advanced practitioners should be aware of. The mechanism of action and pharmacokinetic information for ivosidenib is discussed, as well as recommendations for drug-drug interaction management. Adverse events and monitoring parameters are addressed in detail, as well as how to interrupt and resume treatment due to adverse events.
RESUMO
Allogeneic hematopoietic cell transplantation (HCT) patients are at an increased risk of developing central line-associated bloodstream infections (CLABSIs) due to prolonged periods of myelosuppression, immunosuppression, and indwelling catheter days. CLABSIs are among the most serious complications in HCT recipients and can lead to prolonged hospitalizations, intensive care unit admissions, lengthy antimicrobial therapies, and increased mortality. There is a lack of data regarding the incidence and risk factors associated with the development of CLABSIs in the HCT population undergoing outpatient transplantation. This was a single-center, retrospective analysis of adult patients who underwent allogeneic HCT between July 2012 and July 2016 in an outpatient transplant unit at a tertiary academic medical center. The primary outcome was the cumulative incidence of CLABSIs from the date of central line placement through the first 100 days post-transplantation. Secondary outcomes included risk factors for CLABSI, number of hospitalizations due to CLABSI, mortality rate at 6 months post-transplantation, and the cumulative incidence, speciation, and presence of multidrug resistance in identified microorganisms. Three hundred fifty-nine patients underwent allogeneic HCT at Vanderbilt University Medical Center and 352 were included for analysis. The cumulative incidence of CLABSIs was 9%, with the majority occurring within the first 30 days post HCT (67%). The use of a matched unrelated donor (MUD) and/or haploidentical donor (odds ratio, 3.993; 95% confidence interval [CI], 1.329 to 12.001; P = .0136) and use of an ablative conditioning regimen (odds ratio, 2.394; 95% CI, 1.052 to 5.446; P = .0374) were independently associated with development of a CLABSI on multivariate analysis. The most common organism implicated in CLABSI was Staphylococcus epidermidis (34%). Patients who developed a CLABSI had an almost 5 times higher risk of mortality at 6 months post-transplantation compared with patients who did not develop a CLABSI (hazard ratio, 4.932; 95% CI, 2.463 to 9.878; P < .001). There is a low incidence of CLABSIs in patients undergoing HCT in the outpatient setting. Patients who underwent HCT using a MUD or haploidentical donor and received ablative conditioning were at higher risk for developing CLABSIs. Overall mortality at 6 months post-transplantation was higher in patients who developed a CLABSI. Additional prospective studies are needed to confirm these observations.
Assuntos
Cateterismo Venoso Central/efeitos adversos , Transplante de Células-Tronco Hematopoéticas , Unidades de Terapia Intensiva , Pacientes Ambulatoriais , Condicionamento Pré-Transplante , Adulto , Idoso , Infecções Relacionadas a Cateter/etiologia , Intervalo Livre de Doença , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
Hematopoietic stem cell transplantation (HSCT) is a potentially life-saving therapy for patients with malignant and nonmalignant disease states. Transplant has been associated with high treatment-related morbidity and mortality, therefore limiting its usefulness in patients with baseline liver dysfunction. In the event that a patient with hepatic insufficiency is selected for HSCT, dosage adjustments may be considered; however, no reliable endogenous biomarkers can serve as a guide for adjustments. There is no clear standard or guideline for how to approach these patients, and most adjustments are made empirically on the basis of expert opinion. This article offers practical advice and outlines our personal approaches to provide dosing recommendations for commonly-used preparative agents in the setting of hepatic impairment with the aim to optimize dosing for this patient population.
Assuntos
Doenças Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas , Hepatopatias/terapia , Agonistas Mieloablativos/uso terapêutico , Condicionamento Pré-Transplante/métodos , Esquema de Medicação , Cálculos da Dosagem de Medicamento , Monitoramento de Medicamentos , Guias como Assunto , Doenças Hematológicas/complicações , Doenças Hematológicas/patologia , Humanos , Hepatopatias/complicações , Hepatopatias/patologiaRESUMO
OBJECTIVE: To discuss the clinical efficacy and safety of ipilimumab, vemurafenib, and investigational agents for the treatment of unresectable stage III and stage IV melanoma and define current strategies of first-line treatment selection. DATA SOURCES: Literature was accessed through MEDLINE and International Pharmaceutical Abstracts (1970-November 2012) using the terms melanoma, metastatic melanoma, ipilimumab, vemurafenib, dabrafenib, and trametinib. In addition, reference citations from publications identified were reviewed. STUDY SELECTION AND DATA EXTRACTION: All articles published in English identified from the data sources were evaluated. Studies and abstracts including more than 10 adult patients were included in the review. DATA SYNTHESIS: Treatment options for unresectable stage III and IV melanoma are poor and have remained largely unchanged for the past 40 years. Two randomized Phase 3 clinical trials have demonstrated a significant survival benefit with the use of ipilimumab compared to a melanoma vaccine (10.1 vs 6.4 months; p = 0.003) and compared to dacarbazine (11.2 months, 95% CI 9.4-13.6 vs 9.1 months, 95% CI 7.8-10.5). Additionally, long-term follow-up has revealed cases of durable responses of greater than 3 years. Response rates of 50% and greater have been described in vemurafenib-treated patients (1 Phase 1, 1 Phase 2, and 1 Phase 3 randomized trial), although duration of response has not been fully determined. Both new agents possess unique toxicity profiles including immune-related adverse events with ipilimumab and secondary cutaneous cancers reported with vemurafenib use. CONCLUSIONS: Treatment strategies have changed for patients with advanced melanoma with the use of ipilimumab and vemurafenib as first-line agents. Increased clinical experience and further published data with these and investigational agents will guide the development of treatment algorithms outlining optimal drug selection and sequencing as well as improve management of their novel adverse events.