RESUMEN
Although multiple myeloma is an incurable disease, the past decade has witnessed significant improvement in patient outcomes. This was brought about by the development of T-cell redirection therapies such as chimeric antigen receptor (CAR) T-cells, which can leverage the natural ability of the immune system to fight myeloma cells. The approval of the B-cell maturation antigen (BCMA)-directed CAR T, idecabtagene vicleucel (ide-cel), and ciltacabtagene autoleucel (cilta-cel) has resulted in a paradigm shift in the treatment of relapsed/refractory multiple myeloma. Overall response rates ranging from 73 to 97% are currently achievable. However, the limitations of KarMMa-1 and CARTITUDE-1 studies spurred the generation of real-world data to provide some insights into the effectiveness of ide-cel and cilta-cel among patients who were excluded from clinical trials, particularly those who received prior BCMA-targeted or other T-cell redirection therapies. Despite their unprecedented clinical efficacy in heavily pretreated patients, responses to CAR T remain non-durable. Although the underlying mechanisms of resistance to these agents haven't been fully elucidated, studies have suggested that resistance patterns could be multifaceted, implicating T-cell exhaustion and tumor intrinsic mechanisms such as BCMA target loss, upregulation of gamma-secretase, and others. Herein, we provide a succinct overview of the development of CAR T-cells, manufacturing process, and associated toxicities/complications. In this review, we also recapitulate the existing literature pertaining MM CAR-T as well as emerging data from some of the ongoing clinical trials designed to mitigate the shortcomings of these agents, and improve the clinical efficacy of CAR T, especially in the relapsed/refractory setting.
RESUMEN
ABSTRACT: Teclistamab (Tec) is a first-in-class BCMA × CD3 bispecific T-cell engager antibody approved for treating multiple myeloma progressing after at least 4 lines of therapy. The objective of this study was to evaluate the rate of cytokine release syndrome (CRS) in patients who were treated with commercial Tec and had prior exposure to other T-cell redirection therapies. A retrospective chart review was performed to identify patients who completed the Tec step-up dosing phase between November 2022 and November 2023. Patients were divided into 2 cohorts based on prior exposure to T-cell redirection therapy (cohort 1: T-cell redirection therapy experienced; cohort 2: T-cell redirection therapy naïve). The primary objective was to compare the differences in the rates of CRS between the 2 cohorts. Univariate and multivariate logistic regression analyses were performed to assess the association between CRS rates with Tec and prior treatment with T-cell redirection therapy. A total of 72 patients were included in the analysis (27 in cohort 1 and 45 in cohort 2). The CRS rates were significantly lower in cohort 1 (37%, n = 10) compared with cohort 2 (80%, n = 36; P = .0004). Based on multivariate logistic regression analysis, patients without prior exposure to T-cell redirection therapy (cohort 2) had about a fourfold increase in the incidence of CRS (95% confidence interval, 1.40-14.90; P = .0002) with Tec. In our study, prior exposure to T-cell redirection therapy reduced the risk of CRS with Tec during the step-up dosing phase. This observation will allow for the optimization of CRS prophylactic strategies for Tec.
Asunto(s)
Síndrome de Liberación de Citoquinas , Mieloma Múltiple , Linfocitos T , Humanos , Mieloma Múltiple/terapia , Mieloma Múltiple/tratamiento farmacológico , Masculino , Femenino , Persona de Mediana Edad , Síndrome de Liberación de Citoquinas/etiología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Estudios Retrospectivos , Anciano , Anticuerpos Biespecíficos/uso terapéutico , Antígeno de Maduración de Linfocitos B/antagonistas & inhibidoresRESUMEN
Polycythemia vera (PV) is a myeloproliferative neoplasm characterized by unregulated red blood cell production resulting in elevated hemoglobin and/or hematocrit levels. Patients often have symptoms such as fatigue, pruritus, and painful splenomegaly, but are also at risk of thrombosis, both venous and arterial. Ruxolitinib, a selective Janus kinase inhibitor, is approved by the US Food and Drug Administration as second-line cytoreductive treatment after intolerance or inadequate response to hydroxyurea. Although ruxolitinib has been widely used in this setting, limited data exist in the literature on ruxolitinib treatment patterns and outcomes among patients with PV in routine clinical practice. We report a retrospective, observational, cohort study of patients treated for PV with ruxolitinib across three US centers (academic and regional practice) from December 2014-December 2019. The study included 69 patients, with a median follow-up duration of 3.7 years (95% CI, 2.9-4.4). Our data demonstrate very high rates of hematocrit control (88% of patients by three months and 89% by six months); few patients required dose adjustments or suspension. No arterial thromboses were observed; however, the follow-up duration does not allow for the generation of meaningful conclusions from this. Three patients had thrombotic events; one was in the setting of a second malignancy, one post-operative, and a third related to prolonged immobility. We also found that 28% of patients initiated ruxolitinib as a result of poorly controlled platelet counts, second only to hydroxyurea intolerance (46%) as a reason to start therapy. In clinical practice, ruxolitinib continues to be effective in controlling hematocrit levels after three and six months of treatment in patients and is associated with low thrombotic risk.
Asunto(s)
Nitrilos , Policitemia Vera , Pirazoles , Pirimidinas , Trombosis , Humanos , Pirazoles/uso terapéutico , Pirazoles/efectos adversos , Policitemia Vera/tratamiento farmacológico , Policitemia Vera/complicaciones , Policitemia Vera/sangre , Pirimidinas/uso terapéutico , Femenino , Masculino , Hematócrito , Estudios Retrospectivos , Anciano , Persona de Mediana Edad , Trombosis/etiología , Trombosis/prevención & control , Anciano de 80 o más Años , Adulto , Estudios de SeguimientoRESUMEN
ABSTRACT: Outcomes for patients with relapsed/refractory multiple myeloma (R/RMM) have dramatically improved after the development and now growing utilization of B-cell maturation antigen-targeted chimeric antigen receptor (CAR) T-cell therapy and bispecific antibody (BsAb) therapy. However, health care utilization as a quality-of-life metric in these growing populations has not been thoroughly evaluated. We performed a retrospective cohort study evaluating the frequency and cause of unscheduled health care interactions (UHIs) among patients with R/RMM responding to B-cell maturation antigen-targeted BsAb and CAR T-cell therapies (N = 46). This included the analysis of remote UHIs including calls to physicians' offices and messages sent through an online patient portal. Our results showed that nearly all patients with R/RMM (89%) receiving these therapies required a UHI during the first 125 days of treatment, with a mean of 3.7 UHIs per patient. Patients with R/RMM responding to BsAbs were significantly more likely to remotely contact their physicians' offices (1.8-fold increase; P = .038) or visit an urgent care center (more than threefold increase; P = .012) than patients with R/RMM responding to CAR T-cell therapies. This was largely due to increased reports of mild upper respiratory tract infections in BsAb patients. Our results underscore the need to develop preemptive management strategies for commonly reported symptoms that patients with R/RMM experience while receiving CAR T-cell or BsAb therapies. This preemptive management may significantly reduce unnecessary health care utilization in this vulnerable patient population.
Asunto(s)
Inmunoterapia Adoptiva , Mieloma Múltiple , Humanos , Mieloma Múltiple/terapia , Masculino , Inmunoterapia Adoptiva/métodos , Persona de Mediana Edad , Femenino , Estudios Retrospectivos , Anciano , Anticuerpos Biespecíficos/uso terapéutico , Adulto , Receptores Quiméricos de Antígenos/uso terapéutico , Calidad de VidaRESUMEN
ABSTRACT: Teclistamab, a B-cell maturation antigen (BCMA)- and CD3-targeting bispecific antibody, is an effective novel treatment for relapsed/refractory multiple myeloma (R/RMM), but efficacy in patients exposed to BCMA-directed therapies and mechanisms of resistance have yet to be fully delineated. We conducted a real-world retrospective study of commercial teclistamab, capturing both clinical outcomes and immune correlates of treatment response in a cohort of patients (n = 52) with advanced R/RMM. Teclistamab was highly effective with an overall response rate (ORR) of 64%, including an ORR of 50% for patients with prior anti-BCMA therapy. Pretreatment plasma cell BCMA expression levels had no bearing on response. However, comprehensive pretreatment immune profiling identified that effector CD8+ T-cell populations were associated with response to therapy and a regulatory T-cell population associated with nonresponse, indicating a contribution of immune status in outcomes with potential utility as a biomarker signature to guide patient management.
Asunto(s)
Antineoplásicos , Mieloma Múltiple , Humanos , Mieloma Múltiple/tratamiento farmacológico , Antígeno de Maduración de Linfocitos B/uso terapéutico , Estudios Retrospectivos , Antineoplásicos/uso terapéutico , Linfocitos T CD8-positivos/metabolismoRESUMEN
PURPOSE: Patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib are at risk of developing cardiovascular side effects (CVSE). The molecular determinants of CVSEs have not been fully elucidated. We interrogated genetic polymorphisms in the Bruton tyrosine kinase (BTK) signaling pathway for their association with ibrutinib-related CVSEs. EXPERIMENTAL DESIGN: We conducted a retrospective/prospective observational pharmacogenetic study of 50 patients with newly diagnosed or relapsed CLL who received ibrutinib at a starting daily dose of 420 mg for at least 6 months. CVSEs, primarily atrial fibrillation and hypertension, occurred in 10 patients (20%), of whom 4 discontinued therapy. DNA was isolated from buccal swabs of all 50 patients and genotyped for 40 SNPs in GATA4, SGK1, KCNQ1, KCNA4, NPPA, and SCN5A using a customized next-generation sequencing panel. Univariate and multivariate logistic regression analysis were performed to determine genetic and clinical factors associated with the incidence of ibrutinib-related CVSEs. RESULTS: GATA4 rs804280 AA (P = 0.043), KCNQ1 rs163182 GG (P = 0.036), and KCNQ1 rs2237895 AA (P = 0.023) genotypes were univariately associated with ibrutinib-related CVSEs. On the basis of multivariate analysis, a high genetic risk score, defined as the presence of at least two of these genotypes, was associated with 11.5-fold increased odds of CVSEs (P = 0.019; 95% confidence interval, 1.79-119.73). CONCLUSIONS: Our findings suggest possible genetic determinants of ibrutinib-related CVSEs in CLL. If replicated in a larger study, pretreatment pharmacogenetic testing for GATA4 and KCNQ1 polymorphisms may be a useful clinical tool for personalizing treatment selection for CLL and/or instituting early risk mitigation strategies.
Asunto(s)
Leucemia Linfocítica Crónica de Células B , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/genética , Estudios Retrospectivos , Canal de Potasio KCNQ1 , Piperidinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
Medication-related osteonecrosis of the jaw (MRONJ) is a rare but serious drug-related adverse event. To identify pharmacogenomic markers of MRONJ associated with bisphosphonate therapy, we conducted a genomewide association study (GWAS) meta-analysis followed by functional analysis of 5,008 individuals of European ancestry treated with bisphosphonates, which includes the largest number of MRONJ cases to date (444 cases and 4,564 controls). Discovery GWAS was performed in randomly selected 70% of the patients with cancer and replication GWAS was performed in the remaining 30% of the patients with cancer treated with intravenous bisphosphonates followed by meta-analysis of all 3,639 patients with cancer. GWAS was also performed in 1,369 patients with osteoporosis treated with oral bisphosphonates. The lead single-nucleotide polymorphism (SNP), rs2736308 on chromosome 8, was associated with an increased risk of MRONJ with an odds ratio (OR) of 2.71 and 95% confidence interval (CI) of 1.90-3.86 (P = 3.57*10-8 ) in the meta-analysis of patients with cancer. This SNP was validated in the MRONJ GWAS in patients with osteoporosis (OR: 2.82, 95% CI: 1.55-4.09, P = 6.84*10-4 ). The meta-analysis combining patients with cancer and patients with osteoporosis yielded the same lead SNP rs2736308 on chromosome 8 as the top SNP (OR: 2.74, 95% CI: 2.09-3.39, P = 9.65*10-11 ). This locus is associated with regulation of the BLK, CTSB, and FDFT1 genes, which had been associated with bone mineral density. FDFT1 encodes a membrane-associated enzyme, which is implicated in the bisphosphonate pathway. This study provides insights into the potential mechanism of MRONJ.
Asunto(s)
Osteonecrosis de los Maxilares Asociada a Difosfonatos/genética , Cromosomas Humanos Par 8/genética , Sitios Genéticos/genética , Estudio de Asociación del Genoma Completo/métodos , Osteonecrosis de los Maxilares Asociada a Difosfonatos/diagnóstico , Estudios de Casos y Controles , Difosfonatos/efectos adversos , Difosfonatos/uso terapéutico , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Osteoporosis/tratamiento farmacológico , Osteoporosis/genética , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
PURPOSE: We estimated the prevalence of potentially actionable pharmacogenetic (PGx) variants related to symptom control medications (SCMs) based on institutional prescribing patterns and correlated presenting symptoms with SCM prescribing. METHODS: This was a retrospective study of adult ambulatory cancer patients undergoing electronic distress screening (EDS) within 90 days of intake to the cancer hospital. We estimated the proportion prescribed SCM(s) with PGx evidence within 90 days of intake. Those with potentially actionable variants were estimated using population frequency data from 1000 genomes. The expected number at risk of altered drug response was estimated. The associations between symptom scores and SCM(s) were estimated with logistic regression and threshold analyses performed with receiver operating characteristic (ROC) curves. RESULTS: Of 6985 patients, 3222 (46%) received ≥ one SCM. Of these, 2760 (86%) received SCM(s) with PGx evidence for CYP2B6, CYP2C19, CYP2D6, or SLC6A4; 2719 (84%) received a drug metabolized by CYP2D6, most commonly hydrocodone (40.4%), ondansetron (35.6%), oxycodone (24.2%), and/or tramadol (7.1%). Based on this, about one quarter were expected to have altered metabolism and/or drug response. One third were prescribed two or more SCMs with PGx evidence. About half reported at least one severe symptom, which significantly correlated with SCM prescribing (p < 0.001). Threshold scores were identified that highly correlated with SCM prescribing for anxiety, depression, nausea, neuropathy, pain, and sleep. CONCLUSION: About half presented with significant symptom burden, which highly correlated with SCM prescribing. Most received SCMs with PGx evidence. Preemptive PGx testing for these variants should be evaluated in prospective trials to evaluate the impact on symptom control.
Asunto(s)
Pruebas de Farmacogenómica , Variantes Farmacogenómicas , Adulto , Citocromo P-450 CYP2D6 , Humanos , Farmacogenética , Estudios Prospectivos , Estudios Retrospectivos , Proteínas de Transporte de Serotonina en la Membrana PlasmáticaRESUMEN
INTRODUCTION: Daratumumab is an anti-CD38 monoclonal antibody widely used for treating patients with newly diagnosed or relapsed/refractory multiple myeloma. The subcutaneous formulation of daratumumab was developed with the purpose of minimizing the treatment burden (to patients and health care system) associated with intravenous daratumumab. Given its recent approval, there is a knowledge gap regarding the best practices that should be instituted for safe administration of subcutaneous daratumumab. METHODS: A retrospective chart review was performed from August 2020 until November 2020 to identify patients either switched to or treated upfront (daratumumab naive) with any subcutaneous daratumumab-based treatment regimen. All patients received appropriate premedications per institutional standards of care. The study end points were to report real-world data regarding administration-related reaction rates (at or following discharge from infusion center), as well as compare their incidence rates to those noted in the COLUMBA study (historical cohort). RESULTS: The study included 58 patients, of whom 38% (n = 22) were daratumumab naive. The majority (84%, n = 49) received subcutaneous daratumumab in combination with various antimyeloma regimens. There were no cases of administration-related reactions at infusion center or after discharge irrespective of previous exposure to intravenous daratumumab. None of the patients included herein required rescue home medications or visited the emergency department within 24 to 48 hours after subcutaneous daratumumab administration. These translated into a significant difference in incidence of administration-related reactions compared with historical cohort (0% vs. 13%, P = .003). CONCLUSION: Subcutaneous daratumumab was extremely well tolerated and could be safely administered without need for monitoring or rescue home medications.
Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Reacción en el Punto de Inyección/epidemiología , Mieloma Múltiple/tratamiento farmacológico , Guías de Práctica Clínica como Asunto , Pautas de la Práctica en Medicina/normas , Adulto , Anticuerpos Monoclonales/efectos adversos , Femenino , Humanos , Incidencia , Infusiones Intravenosas/efectos adversos , Infusiones Intravenosas/normas , Infusiones Intravenosas/estadística & datos numéricos , Infusiones Intravenosas/tendencias , Reacción en el Punto de Inyección/etiología , Inyecciones Subcutáneas/efectos adversos , Inyecciones Subcutáneas/normas , Inyecciones Subcutáneas/estadística & datos numéricos , Inyecciones Subcutáneas/tendencias , Masculino , Oncología Médica/normas , Oncología Médica/tendencias , Persona de Mediana Edad , Pautas de la Práctica en Medicina/tendencias , Estudios RetrospectivosRESUMEN
The North Carolina Precision Health Collaborative is an interdisciplinary, public-private consortium of precision health experts who strategically align statewide resources and strengths to elevate precision health in the state and beyond. Pharmacogenomics (PGx) is a key area of focus for the North Carolina Precision Health Collaborative. Experts from Atrium Health's Levine Cancer Institute, Duke University/Duke Health System, Mission Health and the University of North Carolina (UNC) at Chapel Hill/UNC Health System have collaborated since 2017 to implement strategic PGx initiatives, including basic sciences research, translational research and clinical implementation of germline testing into practice and policy. This institutional profile highlights major PGx programs and initiatives across these organizations and how the collaborative is working together to advance PGx science and implementation.
Asunto(s)
Farmacogenética , Medicina de Precisión , Diversidad de Anticuerpos , Hospitales Universitarios , Humanos , North Carolina , Asociación entre el Sector Público-Privado , Investigación , Investigación Biomédica TraslacionalRESUMEN
Intolerance is the most common reason for kinase inhibitor (KI) discontinuation in chronic lymphocytic leukemia (CLL). Umbralisib, a novel highly selective phosphatidylinositol 3-kinase δ (PI3Kδ)/CK1ε inhibitor, is active and well tolerated in CLL patients. In this phase 2 trial (NCT02742090), umbralisib was initiated at 800 mg/d in CLL patients requiring therapy, who were intolerant to prior BTK inhibitor (BTKi) or PI3K inhibitor (PI3Ki) therapy, until progression or toxicity. Primary end point was progression-free survival (PFS). Secondary end points included time to treatment failure and safety. DNA was genotyped for CYP3A4, CYP3A5, and CYP2D6 polymorphisms. Fifty-one patients were enrolled (44 BTKi intolerant and 7 PI3Kδi intolerant); median age was 70 years (range, 48-96), with a median of 2 prior lines of therapy (range, 1-7), 24% had del17p and/or TP53 mutation, and 65% had unmutated IGHV. Most common adverse events (AEs) leading to prior KI discontinuation were rash (27%), arthralgia (18%), and atrial fibrillation (16%). Median PFS was 23.5 months (95% CI, 13.1-not estimable), with 58% of patients on umbralisib for a longer duration than prior KI. Most common (≥5%) grade ≥3 AEs on umbralisib (all causality) were neutropenia (18%), leukocytosis (14%), thrombocytopenia (12%), pneumonia (12%), and diarrhea (8%). Six patients (12%) discontinued umbralisib because of an AE. Eight patients (16%) had dose reductions and were successfully rechallenged. These are the first prospective data to confirm that switching from a BTKi or alternate PI3Ki to umbralisib in this BTKi- and PI3Ki-intolerant CLL population can result in durable well-tolerated responses.
Asunto(s)
Antineoplásicos/uso terapéutico , Fosfatidilinositol 3-Quinasa Clase I/antagonistas & inhibidores , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Proteínas de Neoplasias/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/uso terapéutico , Adenina/efectos adversos , Adenina/análogos & derivados , Adenina/uso terapéutico , Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Enfermedades Cardiovasculares/inducido químicamente , Erupciones por Medicamentos/etiología , Resistencia a Antineoplásicos , Femenino , Enfermedades Gastrointestinales/inducido químicamente , Compuestos Heterocíclicos de 4 o más Anillos/efectos adversos , Humanos , Estimación de Kaplan-Meier , Leucemia Linfocítica Crónica de Células B/enzimología , Leucemia Linfocítica Crónica de Células B/mortalidad , Masculino , Persona de Mediana Edad , Piperidinas/efectos adversos , Piperidinas/uso terapéutico , Supervivencia sin Progresión , Inhibidores de Proteínas Quinasas/efectos adversosRESUMEN
The approval of letermovir provided a new option for cytomegalovirus (CMV) prophylaxis in CMV seropositive allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Data are limited on the use of letermovir for the treatment of CMV infection. We performed a single-center retrospective review of allo-HSCT recipients who received letermovir off-label for treatment of CMV infection (CMV DNAemia and CMV disease) from November 2017 until November 2019. Fifteen patients were included, 14 of which received letermovir for treatment of CMV DNAemia. The median duration from transplant to CMV DNAemia was 41 days and median duration of letermovir therapy was 53 days (IQR, 43-59). Median time to first undetectable CMV viral load from the start of letermovir was 16 days (IQR, 13-21). No significant correlation was noted between the time to CMV DNA clearance and either CMV DNA at the time of starting letermovir (r = -.12, 95% CI: -0.63-0.46; P = .69) or CMV DNA peak (r = .04, 95% CI: -0.51-0.58, P = .87). Three patients had late reactivation of CMV after completion of letermovir (20%) after 87 days (IQR, 68-103) of therapy cessation. Clinical failure or treatment intolerance occurred in two patients (14%). One patient failed to achieve an undetectable viral load. In another patient, letermovir was discontinued due to documented therapy-related thrombocytopenia. Our analysis suggests that letermovir might have a potential role for the treatment of CMV infection in select patients with contraindication or intolerance to more validated therapies.
Asunto(s)
Acetatos/uso terapéutico , Infecciones por Citomegalovirus , Trasplante de Células Madre Hematopoyéticas , Quinazolinas/uso terapéutico , Antivirales/uso terapéutico , Infecciones por Citomegalovirus/tratamiento farmacológico , Humanos , Estudios Retrospectivos , Receptores de TrasplantesRESUMEN
VKORC1 and CYP2C9 genotypes explain less variability in warfarin dose requirements in African Americans compared with Europeans. Variants in BCKDK and GATA-4 gene regions, purported to regulate VKORC1 and CYP2C9 expression, have been shown to play an important role in warfarin dose requirements in Europeans and Asians, respectively. We sought to determine whether rs56314408 near BCKDK or GATA-4 rs2645400 influence warfarin dose requirements in 200 African Americans. Unlike the strong linkage disequilibrium (LD) between rs56314408 and VKORC1 rs9923231 in Europeans, they were not in LD in African Americans. No associations were found on univariate analysis. On multivariable analysis, rs56314408 was associated (P = 0.027) with dose in a regression model excluding VKORC1 rs9923231, and GATA-4 rs2645400 was associated (P = 0.032) with dose in a model excluding CYP2C (CYP2C9*2, *3, *5, *6, *8, and *11, CYP2C rs12777823) variants. Neither variant contributed to dose in the model that included both VKORC1 rs9923231 and CYP2C variants. Our results do not support contributions of the studied variants to warfarin dose requirements in African Americans. However, they illustrate the value of studies in African descent populations, who have low LD in their genome, in teasing out genetic variation underlying drug response associations. They also emphasize the importance of confirming associations in persons of African ancestry.
Asunto(s)
Anticoagulantes/administración & dosificación , Negro o Afroamericano/genética , Factor de Transcripción GATA4/genética , Proteínas Quinasas/genética , Warfarina/administración & dosificación , Adulto , Anciano , Anticoagulantes/farmacocinética , Citocromo P-450 CYP2C9/metabolismo , Relación Dosis-Respuesta a Droga , Femenino , Factor de Transcripción GATA4/metabolismo , Humanos , Desequilibrio de Ligamiento , Masculino , Persona de Mediana Edad , Variantes Farmacogenómicas , Polimorfismo de Nucleótido Simple , Proteínas Quinasas/metabolismo , Vitamina K Epóxido Reductasas/metabolismo , Warfarina/farmacocinéticaRESUMEN
Recent CYP2D6 phenotype standardization efforts by CYP2D6 activity score (AS) are based on limited pharmacokinetic (PK) and pharmacodynamic (PD) data. Using data from two independent clinical trials of metoprolol, we compared metoprolol PK and PD across CYP2D6 AS with the goal of determining whether the PK and PD data support the new phenotype classification. S-metoprolol apparent oral clearance (CLo), adjusted for clinical factors, was correlated with CYP2D6 AS (P < 0.001). The natural log of CLo was lower with an AS of 1 (7.6 ± 0.4 mL/minute) vs. 2-2.25 (8.3 ± 0.6 mL/minute; P = 0.012), similar between an AS of 1 and 1.25-1.5 (7.8 ± 0.5 mL/minute; P = 0.702), and lower with an AS of 1.25-1.5 vs. 2-2.25 (P = 0.03). There was also a greater reduction in heart rate with metoprolol among study participants with AS of 1 (-10.8 ± 5.5) vs. 2-2.25 (-7.1 ± 5.6; P < 0.001) and no significant difference between those with an AS of 1 and 1.25-1.5 (-9.2 ± 4.7; P = 0.095). These data highlight linear trends among CYP2D6 AS and metoprolol PK and PD, but inconsistencies with the phenotypes assigned by AS based on the current standards. Overall, this case study with metoprolol suggests that utilizing CYP2D6 AS, instead of collapsing AS into phenotype categories, may be the most precise approach for utilizing CYP2D6 pharmacogenomics in clinical practice.
Asunto(s)
Antagonistas de Receptores Adrenérgicos beta 1/farmacocinética , Citocromo P-450 CYP2D6/genética , Genotipo , Metoprolol/farmacocinética , Administración Oral , Antagonistas de Receptores Adrenérgicos beta 1/administración & dosificación , Adulto , Anciano , Presión Sanguínea/efectos de los fármacos , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Masculino , Metoprolol/administración & dosificación , Persona de Mediana Edad , Farmacogenética , Fenotipo , Polimorfismo de Nucleótido Simple , Estudios ProspectivosRESUMEN
INTRODUCTION: Intravenous daratumumab has shown unprecedented anti-myeloma activity when used as a single agent or in combination with other myeloma therapies. Recently, a subcutaneous formulation of daratumumab was approved for use in both the United States and European Union based on data which showed shorter infusion times and decreased rate of infusion reactions while maintaining non-inferior efficacy. AREAS COVERED: We cover the physiology behind subcutaneous daratumumab and summarize the relevant clinical data with a particular focus on the pharmacokinetics, pharmacodynamics, safety, and clinical efficacy. Articles used to generate this review were obtained by searching pubmed (https://pubmed.ncbi.nlm.nih.gov/) with the search terms 'subcutaneous daratumumab' and 'daratumumab hyaluronidase'. EXPERT OPINION: Subcutaneous daratumumab is associated with lower risk of infusion reactions and decreased administration time while maintaining non-inferior efficacy. We support the use of subcutaneous daratumumab for all approved indications and for investigational use moving forward.
Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Mieloma Múltiple/tratamiento farmacológico , Administración Cutánea , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Composición de Medicamentos , Europa (Continente)/epidemiología , Humanos , Inyecciones Subcutáneas , Mieloma Múltiple/epidemiología , Mieloma Múltiple/patología , Resultado del Tratamiento , Estados Unidos/epidemiologíaRESUMEN
INTRODUCTION: A subcutaneous formulation of daratumumab, a human immunoglobulin G1 kappa monoclonal antibody targeting CD38, recently achieved FDA approval for both newly diagnosed and relapsed refractory multiple myeloma amid promises to decrease infusion times and rates of infusion reactions in myeloma patients. AREAS COVERED: In this article the biology behind subcutaneous administration of oncologic antibody therapies is reviewed and the subcutaneous formulation of daratumumab is covered in depth. The most recent results from the PAVO, COLUMBA, and PLEIADES clinical trials evaluating subcutaneous daratumumab as a single agent, and in combination, in both newly diagnosed, and relapsed and refractory myeloma patients are summarized. The efficacy, safety, and PK data from these trials are reviewed, and the potential of the subcutaneous formulation to improve quality of life in myeloma patients and decrease healthcare resource use is discussed. EXPERT OPINION: Subcutaneous daratumumab is non-inferior to conventional intravenous daratumumab with lower risk of infusion-related reactions and decreased administration time. Based on these data, and the recent FDA and European Commission approvalsthe widespread use of the subcutaneous formulation for both conventional and investigational practice is supported.
Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Antineoplásicos Inmunológicos/administración & dosificación , Mieloma Múltiple/tratamiento farmacológico , ADP-Ribosil Ciclasa 1/antagonistas & inhibidores , Administración Intravenosa , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor , Ensayos Clínicos como Asunto , Humanos , Inyecciones Subcutáneas , Glicoproteínas de Membrana/antagonistas & inhibidores , Terapia Molecular Dirigida , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/etiología , Mieloma Múltiple/mortalidad , Pronóstico , Resultado del TratamientoRESUMEN
Tacrolimus is the gold standard immunosuppressant administered in solid organ and stem cell transplantation to avoid graft rejection post-transplant. Despite its widespread use, there is a large variation in response to therapy, likely due to high inter-individual pharmacokinetic variability. Therapeutic drug monitoring is employed to improve clinical response and reduce toxicity. There is substantial evidence that pharmacogenetics influences drug exposure and response. CYP3A5 genotype significantly impacts oral tacrolimus concentrations and response after solid organ transplantation. There are fewer studies in stem cell transplantation and with intravenous tacrolimus dosing. This report highlights recent evidence suggesting genes such as CYP3A4 and ABCB1 play a larger role after intravenous dosing compared with CYP3A5, and the role for novel genes on tacrolimus outcomes.
Asunto(s)
Inmunosupresores/administración & dosificación , Farmacogenética/métodos , Trasplante de Células Madre/métodos , Tacrolimus/administración & dosificación , Vías de Administración de Medicamentos , Humanos , Farmacogenética/tendencias , Trasplante de Células Madre/efectos adversos , Trasplante de Células Madre/tendenciasRESUMEN
INTRODUCTION: Daratumumab is approved for the treatment of multiple myeloma in both frontline and relapsed/refractory settings. Its major limitation is the long infusion time, especially with the first dose. Recent data demonstrated the feasibility of infusing daratumumab at an accelerated rate of 90 minutes starting from cycle 1 on day 15. Herein, we report the safety profile and cost associated with rapid daratumumab infusion protocol. PATIENTS AND METHODS: A chart review was performed to identify patients who completed at least 1 cycle of daratumumab (single agent or in combination) from April 2016 to October 2018. Patients were divided into 2 cohorts: cohort 1 received rapid daratumumab infusion after its implementation in March 2018, whereas cohort 2 included patients treated with daratumumab administered at the standard rate. The primary endpoint was to compare differences in rates of infusion-related reactions (IRRs). An Excel (Microsoft)-based model was developed to estimate cost and productivity. RESULTS: A total of 100 patients with relapsed/refractory disease were included in this study (53 in cohort 1 and 47 in cohort 2). Of the 53 patients in cohort 1, 18 (34%) received rapid daratumumab infusion starting with cycle 1. Overall, there was no statistically significant difference in rates of IRRs between cohort 1 and 2 (1.9% vs. 4.3%, P = .59); 1 patient in cohort 1 developed an IRR. The total costs estimated for a 52-week regimen of daratumumab infused at standard and rapid rates were $137,200 and $122,200 (P < .001), respectively. CONCLUSION: Our findings indicate that rapid daratumumab infusion is safe and tolerable and provides cost savings for patients with relapsed/refractory disease.
Asunto(s)
Anticuerpos Monoclonales/economía , Anticuerpos Monoclonales/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/farmacología , Análisis Costo-Beneficio , Femenino , Humanos , Bombas de Infusión , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
PURPOSE: Approximately 30% of patients with cancer who have pain have symptomatic improvement within 1 month using conventional pain management strategies. Engaging clinical pharmacists in palliative medicine (PM) and use of pharmacogenomic testing may improve cancer pain management. METHODS: Adult patients with cancer with uncontrolled pain had baseline assessments performed by PM providers using the Edmonton Symptom Assessment Scale. Pharmacotherapy was initiated or modified accordingly. A subset of patients consented to pharmacogenomic testing. The first pharmacy assessment occurred within 1 week of baseline and a second assessment was done within another week if intervention was required. Each patient's final visit was at 1 month. Pain improvement rate (a reduction of two or more points on a 0-to-10 pain scale) from baseline to final visit was compared applying the Fisher exact test to published historical control data, and between patients with and without pharmacogenomic testing. Multivariate logistic regression identified pain improvement covariates. RESULTS: Of 142 patients undergoing pharmacy assessments, 53% had pain improvement compared with 30% in historical control subjects (P < .001). Pain improvement was not different between those who received (n = 43) and did not receive (n = 99) pharmacogenomics testing (56% v 52%; P = .716). However, of 15 patients with an actionable genotype, 73% had pain improvement. Higher baseline pain (odds ratio [OR], 1.79; 95% CI, 1.43 to 2.24; P < .001), black or other race (OR, 0.42; 95% CI, 0.18 to 0.95; P = .04), and performance status 3 or 4 (OR, 0.18; 95% CI, 0.04 to 0.83; P = .03) were associated with odds of pain improvement, but pharmacogenomic testing was not (P = .64). CONCLUSION: Including pharmacists in PM improves pain management effectiveness. Although pharmacogenomics did not statistically improve pain, a subset of patients with actionable genotypes may have benefited, warranting larger and randomized studies.