Showing papers by "Gabriel Etienne published in 2022"

Therapy related myeloid neoplasms following PARP inhibitors: real-life experience.

Abstract: PURPOSE To provide insights into the diagnosis and management of therapy-related myeloid neoplasms (t-MN) following PARP inhibitors (PARPi). EXPERIMENTAL DESIGN In a French cancer center, we identified and described the profiles of 13 t-MN diagnosed among 37 ovarian cancer (OC) patients referred to hematology consultation for cytopenia under PARPi. Next, we described these 13 t-MN post PARPi among 37 t-MN post OC according to PARPi exposure. Finally, we described 69 t-MN post PARPi in a national cohort. RESULTS From 2016 to 2021, cumulative incidence of t-MN was 3.5% (13/373) among OC patients treated with PARPi. At time of hematological consultation, patients with t-MN had a longer PARPi exposure (9 months vs. 3, p= 0.01), lower platelet count (74 vs. 173 G/L, p=0.0005), and more cytopenias (2 vs. 1, p=0.0005). Compared to t-MN not exposed to PARPi, t-MN-PARPi patients had more BRCA1/2 germline mutation (61.5% vs. 0% p=0.03) but similar OS. In the national cohort, most t-MN post PARPi had a complex karyotype (61%) associated with a high rate of TP53 mutation (71%). Median OS was 9.6 months (IQR, 4-14.6). In multivariate analysis, a longer time between end of PARPi and t-MN (HR 1.046, p=0.02), olaparib compared to others PARPi (HR 5.82, p=0.003) and AML (HR 2.485, p=0.01) were associated with shorter OS. CONCLUSIONS In a large series, we described a high incidence of t-MN post PARPi associated with unfavorable cytogenetic and molecular abnormalities leading to poor OS. Early detection is crucial, particularly in cases of delayed cytopenia.

Kinetics of early and late molecular recurrences after first-line imatinib cessation in chronic myeloid leukemia: updated results from the STIM2 trial

Abstract: Discontinuation of tyrosine kinase inhibitors in chronic phase chronic myeloid leukemia is feasible in clinical practice based on recently published international recommendations. Nevertheless, factors predictive of molecular recurrence have not been fully elucidated and long-term follow-up of patients enrolled in clinical studies are required in order to update knowledge on discontinuation attempts particularly in terms of the safety and durability of treatment-free remission (TFR). In the current study, we updated results from the STIM2 study in the light of the consensual criterion of molecular recurrence reported in different international recommendations. Among the 199 patients included in the perprotocol study, 108 patients lost a major molecular response. With a median follow-up of 40.8 months (5.5-111 months), the probability of treatment-free remission was 43.4% [36.3-50.4] at 5 years, 40.9% [32.8-47.3] at 7 years and 34.5% [25.6-43.3] at 9 years. Molecular recurrence occurred between 0 to 6 months, 6 to 24 months and after 24 months in 75 patients (69%), 15 patients (14%) and 18 patients (17%), respectively. Notably, the kinetics of molecular recurrence differed significantly between these three subgroups with a median time from loss of MR4 (BCR::ABL1 IS≤0.01%) to loss of major molecular response of 1, 7 and 22 months, respectively. Predictive factors of molecular recurrence differed according to the time of occurrence of the molecular recurrence. Durations of imatinib treatment and deep molecular response as well as BCR::ABL1/ABL1 levels at cessation of tyrosine kinase inhibitor treatment, as quantified by reverse transcriptase droplet digital polymerase chain reaction, are involved in molecular recurrence occurring up to 24 months but not beyond. (ClinicalTrial.gov Identifier NCT#0134373).

Dasatinib plus Peg‐Interferon alpha 2b combination in newly diagnosed chronic phase chronic myeloid leukaemia: Results of a multicenter phase 2 study (DASA‐PegIFN study)

Abstract: Superior rates of deep molecular response (DMR) have been reported with the combination of tyrosine kinase inhibitors and pegylated‐interferon‐alpha (Peg‐IFN) in patients with newly diagnosed chronic phase‐chronic myeloid leukaemia (CP‐CML). In this setting, this study investigated the efficacy and safety of dasatinib combined to Peg‐IFN‐α2b (Dasa‐PegIFN, NCT01872442). A total of 79 patients (age ≤65 years) started dasatinib; 61 were eligible for Peg‐IFNα‐2b add‐on therapy at month 3 for a maximum 21‐months duration. Dasatinib was continued thereafter. The primary endpoint was the cumulative rate of molecular response 4.5 log (MR4.5) by 12 months. The results are reported for the 5‐year duration of the study. Grade 3 neutropenia was frequent with the combination but did not induce severe infection (one of grade 3). Other adverse events were generally low grade (4% of grade 3–4) and expected. Seventy‐nine per cent and 61% of patients continued the Peg‐IFN until months 12 and 24, respectively. Overall, at these time points, MR4.5 rates were 25% and 38%, respectively. Thereafter, 32% and 46% of patients achieved a sustained (≥2 years) MR4.5 or MR4, respectively. This work established the feasibility and high rates of achievement of early and sustained DMR (a prerequisite for treatment‐free‐remission) with dasatinib and Peg‐IFNα‐2b combination as initial therapy.

[Practical management of PARP inhibitors: A French DELPHI consensus].

Abstract: Malgré un nombre croissant d’indications thérapeutiques, il n’existe pas de recommandation spécifique de gestion des inhibiteurs de PARP au-delà des résumés des caractéristiques produits de chaque molécule disponible. Une démarche de consensus national de type Delphi a été réalisée afin d’établir des conseils pratiques répondant aux besoins identifiés par les professionnels de santé et les patients. Suivant la méthodologie Delphi, des assertions permettant d’optimiser la gestion des inhibiteurs de PARP ont été formulées par un Comité de Pilotage pluridisciplinaire composé de 17 experts. Ces assertions ont été soumises au vote indépendant et anonyme de cliniciens impliqués dans la prise en charge de patients sous inhibiteur de PARP. Ce travail présente 52 assertions sur les thématiques suivantes : initiation et conduite du traitement ; gestion des effets indésirables (hématologiques, digestifs, rénaux, pulmonaires, cutanés, hypertension artérielle, insomnie, fatigue, vertiges) ; populations et situations particulières ; communication avec le patient ; observance. Au total, 49 assertions ont obtenu le consensus des votants après trois tours de vote. Deux spécialistes en hématologie et en néphrologie ont enrichi ce travail en formulant un avis d’expert sur le risque de survenue de leucémie secondaire et le risque de toxicité néphrologique. Ce travail représente le premier consensus Delphi sur la gestion pratique des inhibiteurs de PARP. Les préconisations pragmatiques résultant de ce travail devraient permettre de mieux gérer les effets indésirables des inhibiteurs de PARP et ainsi prévenir les arrêts prématurés de traitement et améliorer l’observance des patients à travers une qualité de vie préservée. Despite an increasing number of therapeutic indications, there are no specific recommendations regarding the management of PARP inhibitors other than what is specified in the SmPC of each substance. A Delphi French consensus was conducted to establish practical guidelines to meet the needs identified by healthcare professionals and patients. Following the Delphi method, statements to optimize PARP inhibitor management were drafted by a multidisciplinary Steering Committee made up of 17 experts. These statements were submitted to the independent and anonymous vote of clinicians involved in treating patients on PARP inhibitors. This article presents 52 statements on the following topics: initiation and treatment; management of adverse events (hematological effects, gastrointestinal effects, renal effects, pulmonary effects, cutaneous effects, hypertension, insomnia, fatigue, dizziness); special populations and situations; communication with the patient; adherence. Forty-nine statements obtained voter consensus after 3 voting rounds. A hematologist and a nephrologist supplemented this task by drafting an expert opinion on the risk of occurrence of secondary leukemia and nephrological toxicity. This paper is the first Delphi consensus on the practical management of PARP inhibitors. The pragmatic recommendations resulting from this paper should make it possible to manage the side effects of PARP inhibitors better and thus prevent early treatment discontinuation and improve patient adherence by preserving quality of life.

Gestion pratique des inhibiteurs de PARP : Un consensus national DELPHI

Abstract: Malgré un nombre croissant d’indications thérapeutiques, il n’existe pas de recommandation spécifique de gestion des inhibiteurs de PARP au-delà des résumés des caractéristiques produits de chaque molécule disponible. Une démarche de consensus national de type Delphi a été réalisée afin d’établir des conseils pratiques répondant aux besoins identifiés par les professionnels de santé et les patients. Suivant la méthodologie Delphi, des assertions permettant d’optimiser la gestion des inhibiteurs de PARP ont été formulées par un Comité de Pilotage pluridisciplinaire composé de 17 experts. Ces assertions ont été soumises au vote indépendant et anonyme de cliniciens impliqués dans la prise en charge de patients sous inhibiteur de PARP. Ce travail présente 52 assertions sur les thématiques suivantes : initiation et conduite du traitement ; gestion des effets indésirables (hématologiques, digestifs, rénaux, pulmonaires, cutanés, hypertension artérielle, insomnie, fatigue, vertiges) ; populations et situations particulières ; communication avec le patient ; observance. Au total, 49 assertions ont obtenu le consensus des votants après trois tours de vote. Deux spécialistes en hématologie et en néphrologie ont enrichi ce travail en formulant un avis d’expert sur le risque de survenue de leucémie secondaire et le risque de toxicité néphrologique. Ce travail représente le premier consensus Delphi sur la gestion pratique des inhibiteurs de PARP. Les préconisations pragmatiques résultant de ce travail devraient permettre de mieux gérer les effets indésirables des inhibiteurs de PARP et ainsi prévenir les arrêts prématurés de traitement et améliorer l’observance des patients à travers une qualité de vie préservée. Despite an increasing number of therapeutic indications, there are no specific recommendations regarding the management of PARP inhibitors other than what is specified in the SmPC of each substance. A Delphi French consensus was conducted to establish practical guidelines to meet the needs identified by healthcare professionals and patients. Following the Delphi method, statements to optimize PARP inhibitor management were drafted by a multidisciplinary Steering Committee made up of 17 experts. These statements were submitted to the independent and anonymous vote of clinicians involved in treating patients on PARP inhibitors. This article presents 52 statements on the following topics: initiation and treatment; management of adverse events (hematological effects, gastrointestinal effects, renal effects, pulmonary effects, cutaneous effects, hypertension, insomnia, fatigue, dizziness); special populations and situations; communication with the patient; adherence. Forty-nine statements obtained voter consensus after 3 voting rounds. A hematologist and a nephrologist supplemented this task by drafting an expert opinion on the risk of occurrence of secondary leukemia and nephrological toxicity. This paper is the first Delphi consensus on the practical management of PARP inhibitors. The pragmatic recommendations resulting from this paper should make it possible to manage the side effects of PARP inhibitors better and thus prevent early treatment discontinuation and improve patient adherence by preserving quality of life.

P705: multi-center chart review study examining treatment patterns and clinical outcomes among patients with chronic phase (cp) chronic myeloid leukemia (cml) treated in third-line (3l) or later in france

Abstract: Background: The standard of care for CML has substantially evolved over a relatively short period of time; pharmacologic inhibition of ABL1 with adenosine triphosphate (ATP)-competitive tyrosine kinase inhibitors (TKIs) remains the cornerstone of modern treatment. Clinical guidelines for CP-CML recommend that patients who have failed ≥2 prior TKIs switch to an alternative 2nd or 3rd generation TKI. However, up to 65% of these patients have prior exposure to ATP-competitive TKIs and history of either TKI intolerance or resistance. Aims: This retrospective, multi-center, chart review study aimed to characterize the disease burden, treatment patterns, and clinical outcomes of CP-CML patients who have failed ≥2 TKIs. Methods: De-identified demographic and clinical data for adult patients diagnosed with CP-CML treated in 3L or later at three reference centers in France were abstracted from medical charts using electronic case report forms. Descriptive statistics were summarized for patient characteristics, clinical outcomes during 3L treatment, and adverse events. Molecular data were standardized and expressed in the international scale (IS). The cumulative incidence of patients achieving molecular response (major molecular response [MMR, 0.01% IS ≤0.1%] or deep molecular response [MR4.0, 0.0032% < BCR–ABL1IS ≤0.01% or MR4.5, BCR–ABL1IS ≤0.0032%]) were summarized at specific time points. Progression-free survival (PFS) and overall survival (OS) from 3L initiation were examined using the Kaplan–Meier (KM) method. Results: Medical data for 157 CP-CML patients were assessed; the mean follow-up was 66.9 months, the median age at 3L initiation was 62.1 years, 56% were male, and 90% had major BCR-ABL1 rearrangement (among the 89 patients with mutation status assessed, 7 [8%] had BCR-ABL1 T315I mutation, 3 [3%] had M244V, and 3 [3%] had F359I). According to EUTOS long-term survival score, 40% of patients had low risk, 25% had intermediate risk, and 11% had high risk of death due to CML. Cardiovascular diseases were present in 55% of patients at 3L; mean systolic and diastolic blood pressure were 140.9 and 78.9 mmHg, respectively. Mean ± SD low-density lipoprotein cholesterol was 141.0 ± 54.0 mg/dl. Median duration of 3L therapy was 17.0 months. TKIs received in 3L were dasatinib (32%), nilotinib (19%), imatinib (18%), ponatinib (17%), and bosutinib (14%). Treatment-free remission was initiated by 16 (10%) patients. In patients with documented responses, 42% patients achieved MMR, 27% achieved MR4.0, and 14% achieved MR4.5 at 12 months. Although median PFS and OS were not reached as of data collection, 19 (12%) patients died due to disease progression (n=7), toxicity (n=1), or other reasons (n=10) and 1 patient had an unknown cause of death. Approximately 50% of patients discontinued treatment; 37% had ≥4 lines of treatment and 16% had ≥5 lines. The primary reasons for discontinuation (not mutually exclusive) were intolerance (54/78 [69%]), resistance (18/78 [23%]), and signs of ineffectiveness (14/78 [18%]). AEs were documented for 139/157 patients (89%). The mean number of AEs per patient was 2.7; infections (18%) and asthenia (13%) were the more commonly documented AEs. Summary/Conclusion: CP-CML patients continue to experience a substantial disease burden and poor prognosis after 3L treatment with available TKIs, underscoring the need for novel therapies that are well tolerated and can achieve durable responses.