Limited Sampling Strategy for Determination of Ibrutinib Plasma Exposure: Joint Analyses with Metabolite Data.

Therapeutic drug monitoring of ibrutinib is based on the area under the curve of concentration vs. time (AUCIBRU) instead of trough concentration (Cmin,ss) because of a limited accumulation in plasma. Our objective was to identify a limited sampling strategy (LSS) to estimate AUCIBRU associated with Bayesian estimation. The actual AUCIBRU of 85 patients was determined by the Bayesian analysis of the full pharmacokinetic profile of ibrutinib concentrations (pre-dose T0 and 0.5, 1, 2, 4 and 6 h post-dose) and experimental AUCIBRU were derived considering combinations of one to four sampling times. The T0-1-2-4 design was the most accurate LSS (root-mean-square error RMSE = 11.0%), and three-point strategies removing the 1 h or 2 h points (RMSE = 22.7% and 14.5%, respectively) also showed good accuracy. The correlation between the actual AUCIBRU and Cmin,ss was poor (r2 = 0.25). The joint analysis of dihydrodiol-ibrutinib metabolite concentrations did not improve the predictive performance of AUCIBRU. These results were confirmed in a prospective validation cohort (n = 27 patients). At least three samples, within the pre-dose and 4 h post-dose period, are necessary to estimate ibrutinib exposure accurately.

Brentuximab vedotin in real life, a seven year experience in patients with refractory/relapsed CD30+ T cell lymphoma.

INTRODUCTION: Brentuximab vedotin (Bv) has been approved for the treatment of Refractory/Relapsed (R/R) Anaplastic Large Cell Lymphomas (ALCL) and cutaneous T-Cell Lymphomas, but is also effective in other CD30+ malignancies. We report here the outcomes of patients with various R/R Peripheral T Cell Lymphoma (PTCL) treated with Bv in real life practice. METHOD: This was a retrospective, single-center study based on medical records of patients with R/R PTCL treated either with Bv alone or in combination with chemotherapy. RESULTS: Among 27 patients treated with Bv, neutropenia was the main serious adverse event observed in particular when Bv was used as combination treatment. The complete Response Rates (CRR) was 40.7%; it was significantly improved when Bv was used as combination treatment. The majority of eligible patients (7/10) underwent Stem Cell Transplantation. Median Progression Free Survival (PFS) and Overall Survival (OS) were 5.2 months and 12.5 months respectively. CONCLUSION: Our current study shows that Bv used in combination with chemotherapy provides a high CRR and thereby allows SCT in R/R PTCL. The use of Bv treatments in this setting warrants further investigation.

Safety of Pyrazinamide for the Treatment of Tuberculosis in Older Patients Over 75 Years of Age: A Retrospective Monocentric Cohort Study.

OBJECTIVES: Pyrazinamide (PZA) has a controversial safety profile in older patients. We aimed to assess the frequency and risk factors for adverse drug reactions (ADRs) in patients over 75 years of age treated for tuberculosis with or without PZA. METHODS: We conducted a retrospective monocentric study including patients aged over 75 years treated for active tuberculosis between 2008 and 2018. The frequency, type, seriousness, and causality assessment of ADRs to anti-tuberculosis treatment were compared between patients receiving PZA or not. Risk factors for ADRs were investigated using univariable and multivariable analyses by logistic regression. RESULTS: Among the 110 patients included, 54 (49.1%) received PZA (group 1) and 56 (50.9%) did not (group 2). ADRs to anti-tuberculosis drugs occurred in 31 patients (57.4%) in groups 1 and 15 (26.8%) in group 2 (p = 0.003). PZA-related ADRs occurred in 40.7% of exposed patients. Frequency of renal ADRs was higher in group 1 (9.3% vs 0%; p = 0.026). Rates of hepatic (18.5% vs 12.5%; p = 0.38), digestive (22.2% vs 8.9%; p = 0.054), and allergic (14.8% vs 5.4%; p = 0.12) ADRs were numerically higher in group 1 although the differences were not statistically significant. Serious ADRs occurred more frequently in group 1 (24.1% vs 8.9%; p = 0.03). The use of PZA was the only independent risk factor for ADRs to anti-tuberculosis drugs (odds ratio 3.75, 95% CI 1.5-9.6; p = 0.0056). No risk factors for PZA-related ADRs were identified. CONCLUSION: In older French patients, the use of PZA was associated with more frequent ADRs to anti-tuberculosis drugs.

A prognostic index predicting survival in transformed Waldenström macroglobulinemia.

Histological transformation into diffuse large B-cell lymphoma is a rare complication in patients with Waldenström macroglobulinemia (WM) usually associated with a poor prognosis. The objective of this study was to develop and validate a prognostic index for survival in transformed WM patients. Through this multicenter, international collaborative effort, we developed a scoring system based on data from 133 patients with transformed WM who were evaluated between 1995 and 2016 (training cohort). Univariate and multivariate analyses were used to propose a prognostic index with 2-year survival after transformation as an end-point. For external validation, a data set of 67 patients was used to evaluate the performance of the model (validation cohort). By multivariate analysis, three adverse covariates were identified as independent predictors of 2-year survival after transformation: elevated serum LDH (2 points), platelet count < 100 x 109/L (1 point) and any previous treatment for WM (1 point). Three risk groups were defined: low-risk (0-1 point, 24% of patients), intermediate-risk (2-3 points, 59%, hazard ratio (HR) = 3.4) and high-risk (4 points, 17%, HR = 7.5). Two-year survival rates were 81%, 47%, and 21%, respectively (P < 0.0001). This model appeared to be a better discriminant than the International Prognostic Index (IPI) and the revised IPI (R-IPI). We validated this model in an independent cohort. This easy-to-compute scoring index is a robust tool that may allow identification of groups of transformed WM patients with different outcomes and could be used for improving the development of risk-adapted treatment strategies.

Life-threatening complications after high-dose methotrexate and the benefits of glucarpidase as salvage therapy: a cohort study of 468 patients.

The aims of this study were to characterize the incidence and outcomes of severe toxicities following the administration of high-dose methotrexate (HD-MTX; ≥1 g/m2). Among the 468 patients included in the study, 69 (14.9%) developed at least one episode of acute kidney injury (AKI; 138/1264 HD-MTX administrations), including 34 (7.2%) who developed KDIGO stage 2-3 AKI. The three baseline factors independently associated with the risk of developing AKI were age, body mass index and a diagnosis of acute lymphoblastic leukemia. Higher plasma MTX concentration was associated with AKI and extra-renal toxicities. Notwithstanding potentially confounding factors, most patients with AKI who received glucarpidase (n = 41) developed extra-renal toxicity (leading to the death of two patients) despite early administration. Thus, severe toxicity and death can occur whether or not glucarpidase is administered, which confirms the need for further interventional studies to provide greater precision on its role in the management of HD-MTX toxicity.

Dermatological Toxicities of Bruton's Tyrosine Kinase Inhibitors.

The development of Bruton's tyrosine kinase (BTK) inhibitors represents a major breakthrough in the treatment of chronic lymphocytic leukemia and other B cell malignancies. The first-generation inhibitor ibrutinib works by covalent irreversible binding to BTK, a non-receptor tyrosine kinase of the TEC (transient erythroblastopenia of childhood) family that plays a critical role in the B-cell receptor signaling pathway. It also induces an 'off-target' inhibition of a range of other kinases including (but not limited to) epidermal growth factor receptor (EGFR), SRC, and other kinases of the TEC family (interleukin-2-inducible T-cell kinase [ITK], Tec, BMX). Dermatological toxicities are among the most common toxicities of ibrutinib, but remain of mild to moderate intensity in most cases and are readily manageable. Their incidence is highest during the first year of treatment and declines over time. In addition, it has been postulated that ibrutinib-related dermatologic adverse events are mediated by the direct binding to both BTK and other 'off-target' kinases. Bruising, ecchymoses, and petechiae represent the most characteristic dermatologic adverse events. Nail and hair changes are also common, as skin infections (opportunistic infections including herpes simplex and herpes zoster virus reactivations, and Staphylococcus aureus superinfection), folliculitis, and other types of rashes. Panniculitis, aphthous-like ulcerations with stomatitis, neutrophilic dermatosis, peripheral edema, and skin cracking can also occur. Next-generation BTK inhibitors, acalabrutinib and zanubrutinib, have been designed to optimize BTK inhibition and minimize off-target inhibition of alternative kinases (Tec, ITK, EGFR, SRC-family kinases). These drugs have been recently FDA-approved for relapsed or refractory mantle cell lymphoma. Although the overall incidence of their toxicities is expected to be more limited, acalubrutinib and zanubrutinib are associated with a range of dermatologic toxic effects that appear to be similar to those previously described with ibrutinib, including bruising and ecchymoses, panniculitis, human herpesvirus infections, cellulitis, and skin rash. In particular, both drugs induce skin bleeding events in more than 30% of patients treated. However, the available dermatological data are still rather limited and will have to be consolidated prospectively. This review article analyses the wide spectrum of dermatological toxicities that can be encountered with first- and second-generation BTK inhibitors. Finally, recommendations for appropriate treatment as well as a synthesis algorithm for management are also proposed.

Population Pharmacokinetics of Ibrutinib and Its Dihydrodiol Metabolite in Patients with Lymphoid Malignancies.

BACKGROUND AND OBJECTIVE: Ibrutinib is used for the treatment of chronic lymphocytic leukemia and other lymphoid malignancies. The aim of this work is to develop a population pharmacokinetic model for ibrutinib and its dihydrodiol metabolite to quantify pharmacokinetic inter- and intra-individual variability, to evaluate the impact of several covariates on ibrutinib pharmacokinetic parameters, and to examine the relationship between exposure and clinical outcome. METHODS: Patients treated with ibrutinib were included in the study and followed up for 2 years. Pharmacokinetic blood samples were taken from months 1 to 12 after inclusion. Ibrutinib and dihydrodiol-ibrutinib concentrations were assessed using ultra-performance liquid chromatography tandem mass spectrometry. A population pharmacokinetic model was developed using NONMEM version 7.4. RESULTS: A total of 89 patients and 1501 plasma concentrations were included in the pharmacokinetic analysis. The best model consisted in two compartments for each molecule. Absorption was described by a sequential zero first-order process and a lag time. Ibrutinib was either metabolised into dihydrodiol-ibrutinib or excreted through other elimination routes. A link between the dosing compartment and the dihydrodiol-ibrutinib central compartment was added to assess for high first-pass hepatic metabolism. Ibrutinib clearance had 67% and 47% inter- and intra-individual variability, respectively, while dihydrodiol-ibrutinib clearance had 51% and 26% inter- and intra-individual variability, respectively. Observed ibrutinib exposure is significantly higher in patients carrying one copy of the cytochrome P450 3A4*22 variant (1167 ng.h/mL vs 743 ng.h/mL, respectively, p = 0.024). However, no covariates with a clinically relevant effect on ibrutinib or dihydrodiol-ibrutinib exposure were identified in the PK model. An external evaluation of the model was performed. Clinical outcome was expressed as the continuation or discontinuation of ibrutinib therapy 1 year after treatment initiation. Patients who had treatment discontinuation because of toxicity had significantly higher ibrutinib area under the curve (p = 0.047). No association was found between cessation of therapy due to disease progression and ibrutinib area under the curve in patients with chronic lymphocytic leukemia. For the seven patients with mantle cell lymphoma studied, an association trend was observed between disease progression and low exposure to ibrutinib. CONCLUSIONS: We present the first population pharmacokinetic model describing ibrutinib and dihydrodiol-ibrutinib concentrations simultaneously. Large inter-individual variability and substantial intra-individual variability were estimated and could not be explained by any covariate. Higher plasma exposure to ibrutinib is associated with cessation of therapy due to the occurrence of adverse events within the first year of treatment. The association between disease progression and ibrutinib exposure in patients with mantle cell lymphoma should be further investigated. TRIAL REGISTRATION: ClinicalTrials.gov no. NCT02824159.

Venetoclax with high-dose methotrexate and rituximab seem effective and well-tolerated in the treatment of central nervous system involvement of chronic lymphocytic leukemia: A case report.

Venetoclax with high-dose methotrexate and rituximab seem effective and safe to treat central nervous system involvement of chronic lymphocytic leukemia.

Ribavirin for Chronic Hepatitis E Virus Infection in Ibrutinib-Exposed Patients.

Ibrutinib is an oral first-in-class Bruton's tyrosine kinase inhibitor approved for the therapy of various B-cell lymphoid malignancies. Among ibrutinib-related infections, viral hepatitis are poorly described. We report our single-center experience with 4 cases of chronic hepatitis E virus infection and their management with ribavirin.

Onsets of progression and second treatment determine survival of patients with symptomatic Waldenström macroglobulinemia.

Few reports assess prognosis during follow-up of patients with symptomatic Waldenström macroglobulinemia (WM). In 121 WM patients treated between 1993 and 2016, we analyzed the prognostic role during the clinical course of the initial International Prognostic Scoring System for WM (IPSSWM). Then, we assessed onset of response, progression, and second treatment initiation coded as time-dependent covariates. High-risk IPSSWM was an adverse prognostic factor for survival after first treatment initiation (SAFTI). Nevertheless, the corresponding Dxy concordance index obtained in multiple landmark analyses decreased from 0.24 to 0.08 during the first 6 years, in accordance with a departure from the proportional hazard assumption. By contrast with onset of response (whatever its level), onset of progression and initiation of second-line treatment retained prognostic value for SAFTI (P = .02 and P = .006, respectively). These findings were confirmed in cause-specific Cox models for deaths related to WM, but not for unrelated deaths. Time to progression after first-line treatment and time to initiation of second-line treatment had no prognostic value for survival after these 2 events. These results were confirmed in an independent series of 119 patients homogeneously treated with chemoimmunotherapy. Finally, after second-line and third-line treatment, onset of progression had significant prognostic value for subsequent risk of related death only. Thus, taking initial IPSSWM and delayed response to treatment into account, only onset of progression and second treatment initiation provided additional prognostic information for SAFTI. Therefore, progression-free survival or time to next treatment may be satisfactory surrogate end points of SAFTI in WM.

Early-onset invasive aspergillosis and other fungal infections in patients treated with ibrutinib.

Ibrutinib has revolutionized the management of chronic lymphocytic leukemia and is now being increasingly used. Although considered to be less immunosuppressive than conventional immunochemotherapy, the observation of a few cases of invasive fungal infections in patients treated with ibrutinib prompted us to conduct a retrospective survey. We identified 33 cases of invasive fungal infections in patients receiving ibrutinib alone or in combination. Invasive aspergillosis (IA) was overrepresented (27/33) and was associated with cerebral localizations in 40% of the cases. Remarkably, most cases of invasive fungal infections occurred with a median of 3 months after starting ibrutinib. In 18/33 cases, other conditions that could have contributed to decreased antifungal responses, such as corticosteroids, neutropenia, or combined immunochemotherapy, were present. These observations indicate that ibrutinib may be associated with early-onset invasive fungal infections, in particular IA with frequent cerebral involvement, and that patients on ibrutinib should be closely monitored in particular when other risk factors of fungal infections are present.

Bendamustine plus rituximab for indolent B-cell lymphoma of renal significance.

Treatment of indolent B-cell non-Hodgkin lymphomas (iNHL) of renal significance is challenging given the need for deep and prolonged hematological response to restore and control renal function overtime, yet to be balanced with the risk of adverse drug-related events. This prospective single-center study included 20 patients with iNHL of renal significance (tubulointerstitial presentation [n = 8], glomerulopathy with or without monoclonal Ig deposits [n = 12]) who received a steroid-sparing regimen of rituximab plus bendamustine (BR), with either no or <1 month of steroid intake (as a first line therapy in 80%). Seventeen patients (85%) achieved a complete (CHR, n = 12) or a partial (PHR, n = 5) hematological response. Nine out of the 12 patients (75%) with iNHL-related glomerulopathy had a complete (CRR) or a partial (PRR) renal response. Among the six patients with glomerulopathy and CHR, five had a CRR (83%) compared to 1/6 (17%) that did not reach CHR. eGFR increased from 38 to 58 mL/min/1.73 m2 , and returned to baseline in five patients. Among the eight patients with a tubulointerstitial presentation, six (75%) had a renal response (5 CRR), and eGFR increased from 29 to 48 mL/min/1.73 m2 . One patient with a PHR had a renal relapse. Mortality rate was 10% at 12 months. The BR regimen was well tolerated overall. Thus, despite severe renal disease at presentation, a relapsing iNHL in 20% of patients and several comorbidities, the BR regimen was efficient and safe in our series. It should be further assessed as a first line therapy for patients with iNHL of renal significance.

Neurologic, psychiatric, and other medical manifestations of nitrous oxide abuse: A systematic review of the case literature.

BACKGROUND/OBJECTIVES: Nitrous oxide (N2 O) is known to have abuse potential, although debate regarding the toxic effects of such abuse continues. Our objective was to review the case literature and present the neurologic, psychiatric and medical consequences of N2 O abuse. METHODS: A systematic literature review was completed for case reports using keywords "nitrous oxide" with "abuse/abusing" or "misuse/misusing" or "overuse/overusing" or "addiction." Non-English-language cases and cases not involving direct toxic effects of N2 O were excluded as were commentaries or personal essays. Clinical presentation, frequency of N2 O abuse, laboratory studies, imaging, ancillary tests, treatments and outcomes were collected from case reports. RESULTS: Our review returned 335 Pubmed, 204 Web of Science, 73 PsycINFO, 6 CINAHL, 55 EMBASE and 0 Grey Literature results, and after exclusion and removal of duplicates, 91 individual cases across 77 publications were included. There were also 11 publications reporting 29 cases of death related to N2 O abuse. The majority of cases (N = 72) reported neurologic sequelae including myeloneuropathy and subacute combined degeneration, commonly (N = 39) with neuroimaging changes. Psychiatric (N = 11) effects included psychosis while other medical effects (N = 8) included pneumomediastinum and frostbite. Across all cases N2 O abuse was correlated with low or low-normal Vitamin B12 (cyanocobalamin) levels (N = 52) and occasionally elevated homocysteine and methylmalonic acid. CONCLUSIONS/SCIENTIFIC SIGNIFICANCE: N2 O abuse represents a significant problem because of the difficulty involved with identification and the toxicity related to chronic abuse including possible death. Health professionals should be aware of the toxic effects of N2 O and be able to identify potential N2 O abuse. (Am J Addict 2016;25:358-369).

Emergent Management of Intracardiac Thrombosis during Liver Transplantation.

Intraoperative thromboembolism is a well-documented complication associated with orthotopic liver transplantation (OLT) but its identification and intraoperative treatment are still an emerging topic in anesthesia. Intracardiac thrombus during OLT is associated with a high mortality rate. There are only a few reports describing the successful management of thromboembolism during OLT. We describe a case where routine intraoperative transesophageal echocardiography during a live donor liver transplantation enabled early detection of an intracardiac thrombus with subsequent successful heparin treatment. Our case suggests that if an intracardiac thrombus is identified early (before hemodynamic instability occurs), the use of IV heparin may be a safe therapeutic option.