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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...

Hodgkin’s lymphoma (HL) is a hematological neoplasm generally related to a favorable prognosis, since approximately 80% of patients will be cured with actual regimen treatment. However, 10 to 30% o...

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

International audience; 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.

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.

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. 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. 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. 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. ClinicalTrials.gov no. NCT02824159.

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.

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

Introduction: Therapeutic drug monitoring (TDM) entails the measurement of drug concentrations and the individualization of drug dosages or schedules to maximize therapeutic effects and minimize toxicity. Ibrutinib (IBR), the first-in-class inhibitor of BTK (Bruton tyrosine kinase) is approved for the therapy of relapsed/refractory chronic lymphocytic leukemia (R/R CLL), mantle cell lymphoma (MCL) and Waldenström's disease (WM), at the dose of 420-560mg/d. Drug-drug interactions (DDI), older age, liver diseases have been reported to impact PK parameters of ibrutinib, but dosing is not yet part of clinical practice, despite TDM of imatinib and other kinase inhibitors is routinely used in chronic myeloid leukemia. In this study, we sought to determine whether TDM of ibrutinib should be proposed for patients, in a preliminary cohort of 73 patients included in the PK-e3i trial (NCT02824159). Methods: Serial plasma PK samples were collected at steady-state after one month of therapy in 73 patients: before intake (residual concentration), and then at time 0.5-1-2-4-6h. Key PK parameters for ibrutinib and its metabolite DHD-ibrutinib were calculated: Cmax, Cmin, tmax,AUC24h. Analysis of DDI was made by an oncology pharmacist in 49/73 patients. Treatment-related adverse events were monitored by phonecalls given by an oncology nurse (AMA procedure) and during consultations with hematologist (at least twice a month the first 6 months, then monthly until 12 months, then every 3 months), and severity graded according CTCAE version 4 scale. Efficacy of therapy in CLL patients was assessed with an "effect marker" to demonstrate biological efficacy, the redistribution hyperlymphocytosis seen in 70% of patients the first month of therapy. Results: we reported very similar PK results for ibrutinib as compared to pivotal phase 1 trials in CLL and other B-cell lymphoid malignancies (Advani RH, J Clin Oncol 2013, Byrd JC, New Engl J Med 2013). Mean peak plasma concentrations were observed 1-2h after dosing, Cmax and AUC results showing an important inter-patient heterogeneity. Median Cmax was 150ng/ml (8.2-596ng/ml), and median AUC24h was 412.4 ng h/mL ((32.2-2906 ng h/mL). According to published phase I trials, complete or near complete BTK occupancy was observed in patients with AUCs exceeding 160 ng h/mL, suggesting ibrutinib dose might have been supramaximal in 67 of our patients. Adverse events the first 3 months were seen in 96% (grade 1), 63% (grade 2), 25% (grade 3) and 6.5% (grade 4), respectively. We plotted AUC results for the total cohort of 73 patients (Figure 1), and for 49 patients with adverse events monitoring available at 3 months (9/49 needed drug dose reduction due to toxicity) (Figure 2), both emphasizing the absence of correlations between AUC levels and toxicities. We next splited up toxicities into 10 sub-groups (bleeding, cardiac, liver, muscle, joint, skin, infection, gastro-intestinal, hematologic, neurologic disorders). Again, we could not identify a specific organ toxicity associated with a significant increase of Cmax or AUC24h, nor we could identify a specific DDI signature explaining side effects in our patents (data not shown: 13/49 had CYP3A4 inhibitors, 25/49 had pgp inhibitors). In 45 CLL patients with PK parameters and lymphocyte counts available after one month of therapy, we made the intriguing observation that lower Cmax correlated with the lack of observable, transient hyperlymphocytosis (a class-effect of ibrutinib, correlating with PFS in the Resonate trial) (Figure 3). Altogether, our data did not find any positive correlation between high ibrutinib exposure and efficacy or safety profile. Conclusions: our preliminary results suggested that higher Cmax and AUC24h did not correlate neither to efficacy nor to classical toxicities reported with ibrutinib intake. On one hand, we think that dosing intra-cellular concentrations could be more reliable than in plasma. On the other hand, we could consider TDM of ibrutinib in the context of a clinical trial reducing the doses of drug over time, to limit clinical and financial toxicity of this highly efficient drug. Disclosures No relevant conflicts of interest to declare.

Patients with acute leukemia receiving intensive chemotherapy encounter deep and prolonged neutropenia, exposing them to life-threatening invasive fungal infections (IFIs). IFIs are frequently caus...