La notification de clusters de cas d’encéphalopathies, survenues apre s le changement de marche de l’ifosfamide vers la spécialité Ifosfamide EG®, auprès des Centres Régionaux de PharmacoVigilance (CRPV) de Clermont-Ferrand et Montpellier, puis de Nantes et Rennes, a conduit a l’ouverture d’une enque te officielle de pharmacovigilance le 17 mars 2015.
On notait un taux d’EII très important dès la mise sur le marche d’Ifosfamide EG®, qui dépassait d’emblée celle d’Holoxan®.
186 cas notifiés du 01/06/2012 au 01/09/2015 ont été analysés montrant une prédominance de cas graves et de cas « pédiatriques » déclarés durant cette période avec Ifosfamide EG®. Suite à cela une analyse comparative dans cette population a éte re alise e avec un inte re t limite cependant compte tenu du faible effectif total (n 71) et en particulier pour Holoxan® (n=9).
Il n’a pas été retrouve de diffe rence significative pour le de lai de survenue et le grade de l’encéphalopathie entre les deux spécialités mais un délai de survenue plus rapide avec les deux spécialités par rapport aux mentions du Re sume des Caractéristiques du Produit (entre 25 et 50 heures après le début de la perfusion).
Une analyse de la BNPV a été réalisée sur la période du 1er juillet 2016 au 30 juin 2017 pour évaluer l’impact d’une raccourcissement de la durée de conservation de l’Ifosfamide EG® à 7 mois. Dans la population pédiatrique, 13 cas sont survenus : 6 avec Ifosfamide EG® de durée de péremption inférieure a 7 mois, 6 cas avec Holoxan® et 1 cas sans précision de la spécialité ce qui n’a pas permis de conclure sur une possible différence entre les deux spécialités.
Plusieurs CHU ont change leur marche pour revenir a la spe cialite Holoxan®, notamment pour la population pédiatrique. Devant le faible nombre de cas d’encéphalopathies notifiés dans la Base Nationale de Pharmacovigilance (BNPV), il n’a pas e te possible de de terminer pre cise ment une e volution d’incidence des ence phalopathies en pe diatrie et une e tude a 2 ans (juillet 2016 juin 2018) est pre vue a cet effet, dans la mesure ou les ventes d’Ifosfamide EG® ne poursuivent pas leur diminution dans cette population. La déclaration des cas d’EII auprès de la BNPV étant faite de manière spontanée, nous avons décidé de réaliser une étude en analysant les dossiers médicaux de manière rétrospective.
L’objectif de notre étude est de comparer l’incidence de l’EEI dans un groupe d’enfants traités par Holoxan® et un groupe d’enfants traités par Ifosfamide EG® au sein du service d’oncohématologie du CHU de Nancy, décrire les facteurs prédisposants associés ainsi que les caractéristiques des EII.
ARTICLE
OCCURRENCE OF IFOSFAMIDE-INDUCED ENCEPHALOPATHY: A COMPARISON BETWEEN TWO IFOSFAMIDE FORMULATIONS
Mathilde Arabska1, Phi Linh Nguyen-Thi, MD, PhD2, Ludovic Mansuy, MD1, Marie-Amelyne Le Rouzic, MD1, Julie Valduga, MD1,Pauline Barbier-Lider, PharmD3, Pascal Chastagner, MD, PhD1
1 Department of Pediatric Oncology and Hematology, Nancy University Hospital
2 Plateforme d’Aide à la Recherche Clinique (PARC), Nancy University Hospital
3 Department of Pharmacy, Nancy University Hospital
Abstract
Background: Ifosfamide-induced encephalopathy (IIE) is a specific neurotoxic adverse
effect. The purpose of this study was to compare the incidence of encephalopathy in patients treated with two formulations of ifosfamide, assess for predisposing factors influencing the incidence and compare the characteristics of episodes between the two groups.
Methodology: A retrospective study was conducted in the Department of Pediatric Oncology
of Nancy University Hospital. The formulation of ifosfamide changed from powder form (Holoxan®, Product 1) to hydrated form (Ifosfamide EG®, Product 2) in January 2013. The Department stopped using Product 2 in April 2016. A pharmacy dispensing report enabled to enroll patients chronologically backwards. IIE events were identified through chart review.
Results: Out of the 66 patients enrolled, 7 patients from 36 patients treated with Product 1
and 14 from 30 treated with Product 2 experienced encephalopathy (p=0.03). The following
predisposing factors were analysed including clinical (cerebral, renal or pelvic tumoral location), biological (increased urea or creatininemia, hypoalbuminemia, hypoprotidemia, hyponatremia, elevated liver enzymes) and pharmacological factors (anterior cisplatin use, concomitant use of etoposide, opoids, benzodiazepines, aprepitant, alizapride, antiemetic antidopaminergic, corticoids). There were no lethal events. The median storage time of lots of Product 2 causing IIE was 14.25 months.
Conclusions: This study confirms our hypothesis with a 2.4 times higher incidence of IIE in
patients treated with Product 2. No predictive factors could be identified. With Product 2, all episodes happened more than 7 months after lots production, further studies should be conducted to evaluate the impact of the recent limitation of the storage time.
INTRODUCTION
Ifosfamide is an alkylating agent structurally similar to cyclophosphamide and widely used in the treatment of malignant diseases. In pediatric oncology, it is mostly used as a component of multiagent chemotherapy in the treatment of soft tissue sarcoma, osteosarcoma, Ewing sarcoma, rhabdomyosarcoma as well as germ-cell tumors and lymphomas. (1,2)
Ifosfamide is a prodrug that requires activation by the hepatic micosomal enzymes to obtain the active form, the ifosfamide mustard. By alkylating DNA, it forms cross-links that lead to inhibition of DNA synthesis and cell apoptosis.
It presents well known specific toxicities such as hemorrhagic cystitis, a common adverse effect mostly related to one of its metabolites, acrolein, which is now mostly prevented by administrating mesna (sodium 2 mercaptoethane sulphonate).
Ifosfamide-induced encephalopathy (IIE) is the dose limiting side effect. Initially described by Van Dyck et al. in 1972, the incidence varies in the studies from 10%-15% up to 40%. IIE has no precise definition but usually includes every neuropsychiatric event that takes place during or following an ifosfamide intravenous infusion.
Episodes associated with IIE are characterized by a wide clinical spectrum ranging from somnolence, confusion, blurred vision to, in more severe cases, seizures, coma rarely even leading to death. (3–6)
The exact etiology of the condition is still unknown, inactive metabolites are suspected to be involved.
Previously described risk factors include some factors resulting from alteration of renal function (pelvic disease, increase in creatininemia, previous cisplatin exposure), short infusion duration and some factors influencing metabolism (hypoalbuminemia, concomitant use of cytochrome P450 inhibitors, especially aprepitant) as well as history of brain tumour or metastasis.
In France, there are two formulations of ifosfamide: Product 1, a powder form in 1000 mg or 2000 mg vials, authorized since may 1994 and Product 2, 40 mg/mL a hydrated form in 25 mL or 50 mL vials, since May 2005.
An increased number of IIE in several oncology departments, since the change of formulation from Product 1 to Product 2, has attracted attention. A pharmacovigilance investigation was opened on 17th March of 2015.
pediatrics, have stopped using Product 2, making the comparison even more difficult. The investigation was inconclusive on a one-year timeframe and it is still ongoing.
The primary aim of this study was to compare the incidence of IIE in the Department of Pediatric Oncology of Nancy University Hospital for patients treated with Product 1 and those treated with Product 2. The secondary goals were to identify significant differences between patients who did and did not develop IIE and describe the characteristics of IIE episodes in both groups.
METHODS
A retrospective monocentric study was conducted in the Department of Pediatric Oncology and Hematology of Nancy University Hospital. The formulation of ifosfamide changed in the hospital pharmacy in January 2013 from a powder form (Holoxan® -Baxter, Product 1) to a hydrated form (Ifosfamide EG® Product 2). The Department chose to stop using product 2 in April 2016. A pharmacy dispensing report was used to identify all patients who received Product 2 and completed at least one cycle of treatment between January 2013 and 5th April 2016 (when the formulation was again replaced by Product 1). Thirty-eight patients were identified as treated with Product 2. Then, going chronologically backward from January 2013 the same number of patients treated with Product 1 was identified.
Patients were included into the study if they were less than 18 years old at the beginning of the first cycle of treatment. Patients were excluded if they received chemotherapy cycles outside of the Nancy’s Pediatric Oncology Department or if they received both formulations during the same protocol of treatment.
Data Collection
Data was collected through medical chart review. It was consistent with previous studies. For each patient, we recorded: age, sex, diagnosis, protocol of treatment, brain location, concomitant cytotoxic agents, ifosfamide dose per cycle, maximum daily dose per square meter, cumulative ifosfamide dose per square meter, duration of infusion, concomitant drugs (opioids, aprepitant, alizapride, antidopaminergic agents, corticoids), hemoglobin level, urea and creatinine serum levels, alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT), serum albumin and protein level, natremia (determined at the initiation of each ifosfamide cycle and at encephalopathy onset.
assessment of IIE in the chart in the absence of a differential diagnosis explaining the symptoms.
Data Analysis
All variables were described for the whole sample and separately by product group.
Descriptive analyses for quantitative variables were expressed as a mean (+ standard deviation) or median (range) and for qualitative variables as percentages.
The dose variables used in mean daily dose per square meter, mean cumulative dose per square meter and mean duration of infusion.
For the biological factors, we used liver transaminase levels > 105 UI/L, definition of anemia, hyper uremia and elevated creatinine were adapted to age as well as creatinine clearance retrospectively estimated with Schwartz equation. Characteristics between groups were compared using the Pearson Chi Square or Fisher’s exact test for categorical variables and the Student’s test or Wilcoxon-Mann-Whitney test for continuous variables.
Factors associated with IEE were treated as dependent variables in logistic regression. The level of significance for variables, retained in the multivariate models, was set at 0.05. Statistical analysis was performed using SAS 9.4 statistical software.
Univariated logistic regression was used to assess potential predisposing factors. RESULTS
The first group of patients treated with Product 1 consisted of 36 patients, after one patient was excluded because he had undergone treatment with both formulas.
In the second group, 38 patients were identified as treated with Product 2. Two patients were excluded because they had also been treated in another Oncology Department and had two medical charts for the same period, two others were more than 18 years old when first treated and four received both formulations during their chemotherapy protocol.
The characteristics of both groups are summarized in Table 1.
In the group of 36 patients treated with Product 1, 7 patients developed an IIE episode (19.4%).
Whereas, in the group of 30 patients treated with Product 2, 14 cases of IIE were identified (46,7%) resulting in statistically higher incidence (p=0,03).
Univariated logistic regression was applied to patients’ age, it appeared to be the only significant variable among the clinical and biological factors we chose to analyse, which accounted for development or non-development of IIE.
TABLE 1: Patients characteristics
Product 1 Product 2 N=36 N=30 n %/mean SD* n %/mean SD* p** Age (months) 119.6 65.7 125.5 57.3 0.7 Sex 0.93 Male 22 61.1 18 60 Female 14 38.9 12 40 Cerebral location 3 8,3 5 16.7 0.3 Renal location 3 8.3 0 0 0.11 Pelvic location 14 41.2 9 31 0.4 Associated nephrotoxic chemotherapy 15 41.7 15 50 0.5 Number of cures 5.8 2.3 5.1 3,5 0.35 Total cumulated dose (mg) 49 715 29030 45 880 35 084 0.63 Dose cum/m2 (mg/m2) 42 242 19 865.4 34 729 22 810.5 0.17 Infusion time (h) 4.4 4.5 4.1 3 0.78
Daily mean dose
(mg/m2) 2848 466 2696 540 0.23
* standard deviation
** Chi-2 test for qualitative variables , test from the Student test for quantitative variables
The following predisposing factors were analysed : previous cisplatin exposure, concomitant exposure to nephrotoxic chemotherapy, hypoprotidemia, elevated serum creatinin, elevated liver transaminase levels, concomitant use of opioids, benzodiazepines, alizapride, emend, anti-dopaminergic anti emetic agents, corticoids and cerebral, renal or pelvic location.
TABLE 2: IIE predisposing factors analysis
Without IIE IIE
N=45 N=21 N n (%) N n (%) p** Age (months) 45 109.4+-63 21 150+-48.5 0.0176 Sex 0.7889 Male 28 62.2 12 57.1 Female 17 37.8 9 42.9 Cerebral location 45 7 (15.6) 21 1 (4.8) 0.4193 Renal location 45 2 (4.4) 21 1 (5) 1 Pelvic location 45 15 534.9) 21 8 (40) 0.7813 Nephrotoxic chemotherapy 45 19 (42.2) 21 11 (52.4) 0.5963 Number of courses 45 5.5+- 2.8 21 5.3+-3.2 0.6777
Total cumulated dose 42 43 946+-26367 19 59 678+-37660 0.1442
Cumulated dose/m2 44 37 531+-20 052 19 42 474+-24 264 0.6441 Associated treatment: Etoposide 43 26 (60.5) 20 13 (65) 0.7868 Cisplatin 43 7 (16.3) 21 3 (14.3) 1 Opioids 42 4 (9.5) 21 2 (9.5) 1 Benzodiazepines 39 0 20 1 Aprepitant 33 15 (45.5) 19 10 (52.6) 0.7743 Alizapride 35 9 (25.7) 19 9 (47.4) 0.1365 Antidopaminergic antiemetics 34 29 (89.3) 19 15 (78.9) 0.7059 Corticoids 28 25 (89.3) 17 17 (100) 0.2788 Anemia 14 13 (92.9) 15 14 (93.3) 1 Elevated uremia 30 1 (3.3) 18 1 (5.6) 1 Elevated creatinine 31 6 (19.4) 18 3 (16.7) 1 Hyprotidemia 26 4 (15.4) 17 3 (17.6) 1 Hypoalbuminemia 11 8 (72.7) 7 100 0.2451 Elevated alanine transaminase 31 3 (9.7) 18 3 (16.7) 0.6557 Elevated aspartate transaminase 31 1 (3.2) 18 3 (16.7) 0.6557 Hyponatremia 15 1 (5) 14 2 (14.3) 0.5977
* standard deviation N: Number of patients with available data
** Chi-2 test for qualitative variables, Wilcoxon test for quantitative variables
The same predisposing factors were not found to be different while comparing patients who received Product 1 or Product 2 except for the concomitant use of emend that was significantly lower in the second group (64% vs 32%, p<0,05).
Regarding the patients with IIE episodes, none of the studied characteristics of IIE events were statistically different between the 2 groups. In both groups the median course of treatment when first symptoms of IIE appeared was the first cure. The exact time between the first dose of Ifosfamide of the course and the first symptoms could not be evaluated.
TABLE 3: Ifosfamide-induced encephalopathy characteristics
Product 1 Product 2 N=7 N=14 n Mean (%) n Mean( %) Cure number 7 2±1.7 14 3.2±3.4 Grade 1 3 42.9 5 35.7 2 1 14.3 3 21.4 3 2 28.6 5 35.7 4 1 14.3 1 7,1 EEG 1 14,3 4 28.6 Brain imaging 2 28.6 2 14.3
Associated toxicity None 6 85.7 11 84.6
Encephalopathy MTX 0 0 2 15.4 Methylene blue 7 100 9 64.3 Re-administration 7 100 13 92.9 Conditions of readministration None 0 0 1 7.1 Perfusion duration > 6h 0 0 2 14.3 Alkalinisation 0 0 1 7.1 Perfusion duration > 6h + alkalinisation 5 83.3 6 42.9 Perfusion duration > 6h + alkalinisation + MB 1 16.7 4 28.6
Recurrence of IIE None 3 42.9 9 64.3
1 4 57.1 4 28.6 > 1 0 0 1 7.1 Grade of 2nd episode 1 0 0 1 20 2 1 33.3 0 0 3 2 66.7 2 40 4 0 0 2 40 Endoxan replacement 1 33 5 56 * standard deviation
** Chi-2 test for qualitative variables, Wilcoxon test for quantitative variables
DISCUSSION
Our study shows, that in the first group of patients treated with Product 1, the IIE rate is 19,4%, which complies with the range of IIE from 10 to 30% found in scientific literature. (4,8,9)
In the second group, 47% of patients experienced signs of neurotoxicity which gives 2.4 times higher rate of IIE among children treated with Product 2 (p<0.05). It confirms results obtained by recent studies. (10, 11)
Filhon et al. highlighted this difference in toxicity between the two formulations of Ifosfamide with lower incidence of IIE (4.3% with Product 1 vs. 21.1% with Product 2) but with a 5 times higher rate.
According to a French national study, conducted by the ANSM (French National Agency for Medicines and Health Products Safety) in 2015, 6.9 times more children presented IIE when treated with Product 2 versus Product 1.
Some studies describe higher rates of IIE among children in comparison to adults, this could be explained by smaller volume of distribution, a more permeable blood-brain barrier and a higher sensitivity to inhibition of the mitochondrial respiratory chain. (12)
The exact physiopathology of IIE remains unknown, with numerous possible pathways described in literature. Hydroxylation is known to be much slower in the metabolism of ifosfamide than cyclophosphamide, allowing other metabolic pathways to be taken.
The most widely accepted hypothesis is that IIE is produced by ifosfamide metabolites, particularly chloroacetaldehyde (CAA). (13,14)
Küpfer et al. (15) described a direct neurotoxic effect of CAA. which is structurally similar to acetaldehyde and trichloroacetaldehyde, respectively neurotoxic metabolites of ethanol and of chloral hydrate. (16)
The depletion of CNS (Central Nervous System) glutathione can also be responsible for IIE as CAA undergoes glutathione conjugation in the brain and the liver. Lauterburg et al. found decreased plasma levels of glutathione, cysteine and homocysteine by 80% in patients treated by ifosfamide reflecting the depletion. (17) Glutathione depletion is held responsible by affecting cellular detoxification. (18) As suggested by Nicolao et al. a lower amount of glutathione found in CNS cells than in hepatic cells explains a greater rate of neurotoxicity.
The third mechanism implied is the inhibition of mitochondrial oxidative phosphorylation resulting in an impaired fatty acid metabolism. (18,20)
Although CAA is thought to be the most implicated in IIE physiopathology, another metabolite of ifosfamide has been studied more recently; chloroethylamine (CAE). (21) Multiple mechanisms are suggested: a direct toxicity or the formation of a metabolite similar to ketamine, which can have a direct or indirect action on the CNS.
CAE was also found to be oxidized in the mitochondrial cristae by the monoamine oxidase to form CAA. (9) The implication of each metabolite in IIE mechanisms is thus very difficult to establish.
Even though studying the direct implication of ifosfamide metabolites was beyond the scope of this paper, our findings support the hypothesis that IIE results from degradation of the products. It has been suggested that the more recent formulation is less chemically stable and causes a higher incidence of IIE. (11)
The major difference between the two ifosfamide formulations is the galenic form. Product 1 is in a powder form and needs to be reconstituted and then to be used within four days whereas Product 2 is a hydrated form, ready for use.
Even if still controversial, pharmacological data report a degradation of ifosfamide with time when in hydrated form.
There are specifications describing maximal levels of impurities allowed while producing ifosfamide. According to European Pharmacopeia regulations, the level of CAE should be less than 0.25% measured with thin layer chromatography.
Following the national study conducted by the ANSM, it seems that levels of impurities in Product 2 where variable throughout time (11) which resulted in progressive reduction of storage time from 24 to 18 months in July 2014 and then, to 7 months in June 2016.
A technical committee of pharmacovigilance of the ANSM highlighted that IIE symptoms where more frequent in patients treated with Product 2 when it was used after 7 months of conservation of the production lots.
The exact production dates of the batches could not be obtained by us but we estimated them from the expiry dates. It appears that all IIE episodes happened after 7 months of storage of the Product 2. It should be noted that each lot is responsible for the same number of IIE cases.
albumin, elevated serum creatinine, the presence of tumour in the lower abdomen and pelvis, the presence of a cerebral tumour, pre-treatment with cisplatin or concomitant treatment with etoposide. (4,8,22–26) Concomitant treatment by aprepitant, alizapride or opioids has also been discussed. (27,28) There is little evidence to substantiate these links and there is no consensus regarding the importance of each of these factors in the development of IIE.
In our study, none of the above-mentioned risk factors could be identified among patients who presented IIE, probably due to the retrospective nature of the study and missing data in medical charts.
Rieger et al. did not find any risk factors either and suggested an individual predisposition in each patient. (29)
While analysing the same predisposing factors in patients treated with Product 1 or Product 2, the only difference was the concomitant use of aprepitant found significantly lower in the second group. This can be explained by the fact that this treatment was suggested to be a predictive factor of IIE in literature, which lead physicians to be more cautious to prescribe it. Prediction of encephalopathy is complex. Meanwell et al. (8) designed a nomogram to predict the probability of developing grade III or IV encephalopathy based on serum albumin, serum creatinine and the presence or absence of disease below the renal pedicles. However, it has not entered routine clinical practice, as other studies could not successfully validate this nomogram. (30–32)
Regarding the characteristics of IIE, there is no significant difference in between the two groups studied.
Most episodes appeared during the two first courses of treatment (5/7 with Product 1 and 9/14 with Product 2) but neurotoxicity can still appear after multiple courses of treatment without complications.
In our study the majority of encephalopathies were of grades I and III. All grade IV encephalopathies were characterized by generalized seizures and there were no deaths in our study.
In a retrospective study of 17 adult patients with ifosfamide encephalopathy, 4 grade I, 2 grade II, 7 grade III and 4 grade IV occurred. (29) In a French pediatric series of 15 cases of IIE, 3 presented grade II, 6 encephalopathies grade III and 6 grade IV. (26)
According to previous studies, EEG only shows diffuse abnormalities suggesting a toxic encephalopathy. There is no correlation between an EEG made before treatment and the risk of developing an IIE but there is a correlation between EEG and clinical grading. (4,8,33).