Progressive erythrocytosis under lenvatinib treatment in patients with advanced hepatocellular carcinoma.

PURPOSE: This manuscript reports on the occurrence of early and frequent erythrocytosis in advanced hepatocellular carcinoma (HCC) patients treated with lenvatinib. METHODS: A cohort of 23 patients with advanced HCC, treated with this antiangiogenic drug for at least one month, was retrospectively analyzed. RESULTS: These patients (82.7% men, median age 58.3, cirrhosis in 60.8%) were treated between October 2019 and September 2020 with lenvatinib, as first-line systemic therapy for 82.6% of them. For 20 patients (87%), an early and significant increase in hemoglobin (Hb) level, up to 1.41 g/dL (p < 0.001) was reported and remained elevated. Ten patients (43.5%), all men, reached erythrocytosis (Hb > 16.5 g/dL), 7 were treated with low-dose aspirin for primary thromboprophylaxis and 2 needed phlebotomy. None underwent thromboembolic complications. A significant Hb decrease was observed after treatment discontinuation (p < 0.05). Erythropoietin (EPO) serum levels also increased, which was attributed to HCC after immunostaining for EPO in liver biopsies. The Naranjo adverse drug reaction probability scale documented the relationship between erythrocytosis and lenvatinib and regression at treatment discontinuation. Erythrocytosis was hypothesized to be a class effect of anti-VEGF therapies, the magnitude of which might depend on the IC50 value of each molecule. CONCLUSION: This report documents the frequent occurrence of erythrocytosis during lenvatinib treatment for advanced HCC, likely secondary to EPO secretion by tumor cells through the antiangiogenic activity levatinib. An early and close monitoring of hematologic parameters is, thus, recommended, together with thromboprophylaxis by low-dose aspirin and phlebotomy in case of symptomatic erythrocytosis.

Agreement between a regional pharmacovigilance centre and an adjudication committee regarding adverse drug reactions on a cohort of hospitalised children.

BACKGROUND AND PURPOSE: The EREMI project was set up to collect data on adverse drug reactions (ADRs) occurring due to off-label and/or unlicensed drugs prescribed to hospitalised children in France. These events were evaluated by a regional pharmacovigilance centre (RPC) and an adjudication committee (AC). The aim of this study was to assess the agreement between these two different entities on their evaluation of ADRs. EXPERIMENTAL APPROACH: The RPC first validated the ADRs and assessed their causality using the Naranjo scale. The AC assessed then ADRs using all available information, including the RPC evaluation. The agreement on severity and nature of ADRs, role of treatment (suspect or concomitant) and drug causality was calculated using Cohen's nonparametric kappa coefficient (k). KEY RESULTS: Three hundred and eighty-six events were reported in 219 children. The RPC excluded 65 events and validated 321 ADRs. Agreement was very good on nature of ADRs (k=0.85) and role of treatment (k=0.81), moderate on severity of ADRs (k=0.60) and very poor on drug causality (k=0.05). CONCLUSION AND IMPLICATIONS: Agreement between the RPC and the AC was not constant throughout this evaluation. They troubled to agree on severe ADRs and on drug causality.

Characteristics of insulinopenic and non insulinopenic diabetes related to immune checkpoint inhibitors: A French pharmacovigilance study.

INTRODUCTION: Immune checkpoint inhibitor-induced diabetes mellitus (ICI-DM) is an immune-related adverse drug reaction (irADR). Hyperglycemia can be linked to endogenous insulin deficiency with ketoacidosis or associated with preserved beta-cell function. OBJECTIVES: We aimed to identify the characteristics of both types of ICI-DM (type 1 and type 2 DM), to improve our understanding of this irADR and its management. METHODS: Data for ICI-DM recorded in the French Pharmacovigilance Database from 2015 to October 2019 were analyzed according to the French causality assessment. RESULTS: In total, 60 subjects were included. Anti-PD1/PDL1 pathway blockade therapy (nivolumab: 61.7%+3.3% in association with ipilimumab pembrolizumab: 28.3%) was most frequently implicated in ICI-DM, but some reports involved anti-CTLA4 drug (ipilimumab: 6.7%+3.3% in association with nivolumab). One third of reports occurred within one month of the initiation of immunotherapy. Decreased insulin secretion (defined by the presence of ketone bodies) were confirmed in 80% of reports. Among them, 54% of patients met the diagnostic criteria for fulminant diabetes. Overall, 17.7% of the reports had pre-existing type 2 diabetes T2D. Four deaths due to hyperglycemia were declared, with altered insulin secretion in only two of these reports. BMI was lower in the insulinopenic group (23.4±0.7 vs. 27.9±1.6, P=0.004) and other irADRs were more frequently observed in patients with persistent insulin secretion (66.7 vs. 18.8%, P=0.02). We found no difference in age, indication or cumulative ICI dose between the two groups (with and without insulinopenia). The presence of GAD antibodies was associated with a shorter time to diabetes onset (42.6±6.1 vs. 208.1±41.6 days, P=0.029). CONCLUSIONS: ICI-DM is a rare but serious irADR triggered by all classes of immunotherapy. The observation period for ICI-DM can be shortened for patients positive for anti-GAD antibodies. Endogenous insulin deficiency did not appear to be the only mechanism involved in ICI-DM, as beta-cell function was preserved in 20% of reports. Improvements in our understanding of this complication will be required for its prevention.

Severe immune-related hepatitis induced by immune checkpoint inhibitors: Clinical features and management proposal.

BACKGROUND: Immune-related hepatitis (IRH) occurs in 1 to 18% of immune checkpoint inhibitor (ICI)-treated patients. Steroids are usually recommended for grade≥3 IRH, but their impact on IRH resolution and patient survival remains unclear. METHODS: We retrospectively analyzed a prospective cohort of 339 patients treated at Saint-Louis Hospital (Paris, France) with ICIs for advanced melanoma. Cases of grade≥3 IRH were collected and analyzed. Two groups were compared for their biological features and time for IRH resolution and survival: patients who received steroids (steroids group: SG) and patients who did not (nonsteroids group: NSG). FINDINGS: Grade≥3 IRH was observed in 21 patients. Thirteen were treated with steroids (SG), and 8 were not (NSG). The median time for toxicity resolution was 49 days in SG and 24 days in NSG (P=0.62). All but one patient showed a favorable outcome. Two-year survival was 56% in SG and 54% in NSG (P=0.83). Higher transaminase (P=0.002) and bilirubin (P=0.008) and lower prothrombin (P=0.035) levels were observed in SG than in NSG. For 8 (4 SG/4 NSG) patients, ICI was resumed without any hepatitis relapse. INTERPRETATION: Favorable outcomes may be achieved spontaneously and with no steroids in patients with severe IRH. Steroid initiation should be discussed in cases of high bilirubin levels and decreased prothrombin levels. ICI could be resumed without hepatitis relapse. We propose a management algorithm for grade≥3 IRH that should be validated in larger and prospective cohorts.

Severe gastrointestinal toxicity of MEK inhibitors.

Gastrointestinal toxicities of MEK inhibitors in melanoma patients are frequent. In clinical trials, the most common digestive adverse events were nausea, vomiting, and diarrhoea. However, severe toxicities such as colitis and gastrointestinal perforation, some with fatal outcomes, have been reported. These rare but severe adverse events are not well described. We performed a retrospective analysis of all patients with stage IV and unresectable stage III melanoma treated with a MEK inhibitors at Saint-Louis Hospital, Paris, between 1 August 2013 and 15 October 2018. Among 119 patients exposed to MEK inhibitors, 78 were treated with trametinib, 19 with cobimetinib, four with binimetinib, and 18 patients with two different MEK inhibitors at separate times. All grade digestive adverse events were observed in 39 (32.7%) patients. Grade 3 and 4 adverse events occurred in 6 (5%) patients: 2 (1.7%) developed perforations, 3 (2.5%) had colitis and 1 (0.8%) had grade 4 diarrhoea. These adverse events were all reversible following a permanent discontinuation of the MEK inhibitors, or a temporary interruption followed by resumption at a dose lower than conventional posology. There were no fatal outcomes; however one patient had a permanent ileostomy. The mechanism underlying these toxicities is not well known. Clinicians should be aware of such toxicities.

Osteopenia and fractures associated with long-term therapy with MEK inhibitors.

Targeted therapies have markedly improved the survival of patients with melanoma. We report the case of two patients with advanced melanoma controlled by long-term MEK inhibitor or combination of BRAF and MEK inhibitors, who developed fractures related to severe osteopenia. A 48-year-old woman was treated by pimasertib after the failure of two lines of chemotherapy, and a 42-year-old man was treated by an association of BRAFi (dabrafenib) and MEKi (trametinib) after the failure of one line of chemotherapy. During follow-up, both complained of buttock pain, revealing primary fractures of the pelvis and lumbar vertebra. In both patients, none had osteoporosis risk factors; DEXA scan revealed osteopenia, and analysis ruled out metastatic bone lesion or secondary osteoporosis. Zoledronic acid, cholecalciferol (vitamin D3), oral calcium, and pain killers were introduced, leading to no further bone event. Numerous pathways are involved in the homeostasis of bone turnover, and the effect of tyrosine kinase inhibitors on those pathways is not well known yet. The absence of usual causes of osteoporosis or metastatic bone lesion and kinetics of symptoms lead us to suggest that MEK inhibitors were responsible for the development of osteoporosis. To the best of our knowledge, this is the first report of fractures associated with osteopenia in patients treated with MEKi. Long-term survival owing to new targeted treatment could be associated with yet underestimated adverse effects such as osteopenia/osteoporosis that could impair patient's quality of life and should be investigated.

Occurrence of type 1 and type 2 diabetes in patients treated with immunotherapy (anti-PD-1 and/or anti-CTLA-4) for metastatic melanoma: a retrospective study.

Anti-PD-1 and anti-CTLA-4 antibodies cause immune-related side effects such as autoimmune type 1 diabetes (T1D). It has also been suggested that by increasing TNF-α, IL-2 and IFN-γ production, anti-PD-1 and/or anti-CTLA-4 treatment could affect pancreatic beta cell function and insulin sensitivity. This study was based on a retrospective observational analysis from 2 July 2014 to 27 June 2016, which evaluated the occurrence of T1D and changes in glycemia and C-reactive protein (CRP) plasma concentrations in patients undergoing anti-PD-1 and/or anti-CTLA-4 treatment for melanoma at the Saint Louis Hospital. All cases of T1D that developed during immunotherapy registered in the French Pharmacovigilance Database (FPVD) were also considered. Among the 132 patients included, 3 cases of T1D occurred. For the remaining subjects, blood glucose was not significantly affected by anti-PD-1 treatment, but CRP levels (mg/l) significantly increased during anti-PD-1 treatment (p = 0.017). However, 1 case of type 2 diabetes (T2D) occurred (associated with a longer therapy duration). Moreover, glycemia of patients pretreated (n = 44) or concomitantly treated (n = 8) with anti-CTLA-4 tended to increase during anti-PD-1 therapy (p = 0.068). From the FPVD, we obtained 14 cases of T1D that occurred during immunotherapy and were primarily characterized by the rapidity and severity of onset. In conclusion, in addition to inducing this rare immune-related diabetes condition, anti-PD-1 treatment appears to increase CRP levels, a potential inflammatory trigger of insulin resistance, but without any short-term impact on blood glucose level.

Baraitser-Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases.

Baraitser-Winter, Fryns-Aftimos and cerebrofrontofacial syndrome types 1 and 3 have recently been associated with heterozygous gain-of-function mutations in one of the two ubiquitous cytoplasmic actin-encoding genes ACTB and ACTG1 that encode ß- and γ-actins. We present detailed phenotypic descriptions and neuroimaging on 36 patients analyzed by our group and six cases from the literature with a molecularly proven actinopathy (9 ACTG1 and 33 ACTB). The major clinical anomalies are striking dysmorphic facial features with hypertelorism, broad nose with large tip and prominent root, congenital non-myopathic ptosis, ridged metopic suture and arched eyebrows. Iris or retinal coloboma is present in many cases, as is sensorineural deafness. Cleft lip and palate, hallux duplex, congenital heart defects and renal tract anomalies are seen in some cases. Microcephaly may develop with time. Nearly all patients with ACTG1 mutations, and around 60% of those with ACTB mutations have some degree of pachygyria with anteroposterior severity gradient, rarely lissencephaly or neuronal heterotopia. Reduction of shoulder girdle muscle bulk and progressive joint stiffness is common. Early muscular involvement, occasionally with congenital arthrogryposis, may be present. Progressive, severe dystonia was seen in one family. Intellectual disability and epilepsy are variable in severity and largely correlate with CNS anomalies. One patient developed acute lymphocytic leukemia, and another a cutaneous lymphoma, indicating that actinopathies may be cancer-predisposing disorders. Considering the multifaceted role of actins in cell physiology, we hypothesize that some clinical manifestations may be partially mutation specific. Baraitser-Winter cerebrofrontofacial syndrome is our suggested designation for this clinical entity.

The use of dabigatran in elderly patients.

Recent approval by the US Food and Drug Administration (FDA) of dabigatran etexilate, an oral direct thrombin inhibitor, for the prevention of stroke in patients with atrial fibrillation will likely extend its administration in elderly patients. The risk of major overdosage of dabigatran etexilate in this population is, however, much increased owing to frequent renal function impairment, low body weight, drug interactions that cannot be detected with a routine coagulation test, and no antagonist available. We report herein 2 clinical cases, including 1 fatal case, illustrating our concern regarding the risk of bleeding events in elderly patients.

Interest in an original methodology to define the optimal dosage of interferon-alpha-2a in metastatic melanoma patients.

Interferon-α-2a (IFNa) has proven antitumor activity in a variety of neoplastic diseases, but no clear modality of administration has been validated. The aim of our study was to estimate the optimal dose of continuous subcutaneous administration of IFNa in stage IV metastatic melanoma patients. An innovative dose-finding approach, combining phase I and phase II trials, was planned to evaluate the toxicity and efficacy of four dose levels of IFNa (3, 6, 9, and 12 MIU/day). Sixteen patients were enrolled in this study. Three patients were treated according to the dose-allocation rule with IFNa at 3 MIU/day, nine patients at 6 MIU/day, and four patients at 9 MIU/day. Dose-limiting toxicities were grade 3 in five patients (three at a dose level of 6 MIU/day and two at a dose level of 9 MIU/day). Four clinically relevant responses were obtained, one at dose level 3 MIU/day, one at a dose level of 6 MIU/day, and two at a dose level of 9 MIU/day. The three final responses, at dose levels of 6 and 9 MIU/day, were associated with a dose-limiting toxicity. A dose level of 6 MIU/day was well tolerated but did not reach the desired efficacy target of 20%, and a dose level of 9 MIU/day was estimated to be too toxic. This original dose-finding methodology made it possible to estimate the rate of toxicity and efficacy in a small sample of patients without toxicity associated with each dose level.

[Treatment of erectile dysfunction by phosphodiesterase-5 inhibitors and nonarteritic anterior ischemic optic neuropathy (NOIAN)]. / Traitement de la dysfonction erectile par les inhibiteurs de la phosphodiestérase-5 et troubles oculaires par neuropathie optique ischémique antérieure non artéritique (NOIAN).

INTRODUCTION: Following the notification of forty cases of varying degrees of vision loss in patients using phosphodiesterase-5 (PDE-5) inhibitors, the FDA (Food and Drug Administration) examined the possible link between these treatments of erectile dysfunction and NOIAN (nonarteritic anterior ischemic optic neuropathy). Following this investigation, the FDA requested modification of the summary of product characteristics (SPC) for this therapeutic category. The authors review this problem, especially in France. METHOD: The authors performed a search of the Pubmed database and the French Pharmacovigilance database. RESULTS: Since September 2006, 11 publications concerning 19 cases (14 with sildenafil and 2 with tadalafil) have been published. The mean age of these patients was 59.5 years (range: 42 to 69). Doses varied from 50 to 100 mg for sildenafil and 20 mg for tadalafil. Adverse effects (loss of visual acuity and decreased visual field) occurred between 30 min and 36 h after oral dosing. In 5 cases, treatment had been taken for more than one year. Ocular fundus examination showed papilloedema associated with several haemorrhages. Three patients presented a positive challenge. Several patients had a known risk factor for the development of NOIAN. One case was also reported to French Pharmacovigilance. DISCUSSION: The population with erectile dysfunction also often presents generalized endothelial disease, which also constitutes a risk factor for NOIAN. Although no cases of NOIAN were reported during the initial clinical trials, the rapid onset of NOIAN after the dose of PDE-5 inhibitor and several cases of positive challenge suggest a possible causal relationship with these drugs. The ocular action of PDE-5 inhibitors could be explained by a modification of retinal blood flow related to their pharmacological effects. CONCLUSION: The link between PDE-5 inhibitors and NOIAN has not been formally established. Before new studies are conducted to clarify this situation, practitioners must be aware of the potential ocular adverse effects related to the dose of PDE-5 inhibitors so that they can inform patients and notify any new cases. The SPCs of PDE-5 inhibitors were modified at the request of the FDA on 8 July 2005.

Child overdose: the value of the French pharmacovigilance causality assessment method.

BACKGROUND: In France, the regional pharmacovigilance centres manage drug overdose as adverse drug reactions (ADRs) using the French ADR causality assessment method, and some poison control centres (e.g. in Paris) do likewise for the most serious cases. AIM: The aim of the study was to analyse and compare the chronological and semiological scores calculated with this method, in cases of drug overdose and ADRs in children recorded in the French pharmacovigilance ADR database. RESULTS: In total, 7963 cases were analysed. The distribution of semiological criteria in drug overdose and ADR cases differed significantly (G-test), with a similar result for chronological criteria (but to a lesser degree). CONCLUSION: The distinction of two types of criteria in the French ADR causality assessment method appears useful for analysing cases of drug overdose in children. This finding triggers a renewed interest in the use of this method of causality assessment of drug overdose in children, and possibly in adults.