Idiosyncratic drug-induced agranulocytosis is a rare but potentially fatal adverse drug reaction characterized by a sudden and profound drop in neutrophil count, predisposing patients to severe infections. Despite its low incidence, idiosyncratic drug-induced agranulocytosis remains a significant clinical challenge due to its unpredictable onset and the wide array of medications implicated in its occurrence. Traditional management relies on early recognition and immediate drug withdrawal, but preventive strategies have historically been limited. Recent advances in pharmacogenomics have improved our understanding of individual susceptibility, with certain HLA alleles and genetic polymorphisms emerging as key risk factors. The identification of risk clusters—including genetic, demographic, and clinical features—supports more tailored prevention. Big data analytics and artificial intelligence (AI) now offer promising tools for predictive modeling and real-time pharmacovigilance signal detection. Technological innovations such as telemedicine, wearable sensors, and home-based blood cell monitoring enable earlier detection and intervention, especially in high-risk patients. Therapeutic patient education (TPE) plays a crucial role in increasing awareness, promoting adherence to monitoring protocols, and empowering patients in self-management. This review highlights the convergence of scientific, clinical, and technological progress that supports a shift toward a more proactive, personalized, and preventive approach to idiosyncratic drug-induced agranulocytosis management in modern internal medicine.

Tafasitamab combined with lenalidomide was approved in Europe in 2021 for transplant-ineligible patients with relapsed/ refractory diffuse large B-cell lymphoma. Approval was based on the L-MIND study, which demonstrated a 57.5% overall response rate (ORR), 41.3% complete response (CR) rate, 12.1-month median progression-free survival (PFS), and 33.5-month median overall survival (OS) at 5 years. The multicenter retrospective EarlyMIND study analyzed real-world efficacy and treatment patterns of patients receiving tafasitamab plus lenalidomide for second-line (2L cohort) to fourth-line (3L + 4L cohort) treatment in the French Early Access Program. Outcomes were analyzed overall and according to number of previous lines of treatment. Post hoc analyses were conducted on subgroups based on prognostic factors, performance status, primary refractoriness, cell of origin, and treatment response. Overall, 186 patients were included (2L: N=105; 3L + 4L: N=81). The median age of the patients was 78 years; most patients had early relapsed disease (71.2%), including 60.2% with primary refractory disease. At a median follow-up of 8.2 months, best ORR was 46.8%, with a CR rate of 29%. The ORR was higher in the 2L cohort (50.5%) than in the 3L + 4L cohort (42%). The median PFS and OS were 4.7 and 10 months, respectively, in the overall population, 5.4 and 10.6 months in the 2L cohort, and 3.6 and 8.2 months in the 3L + 4L cohort. Long-lasting responses were observed in patients achieving CR, with median duration of response, PFS, and OS not reached. The median time to CR as best objective response was four cycles, regardless of treatment line. Despite involving a frail population with high-risk disease characteristics, results of this large real-world European retrospective study on tafasitamab plus lenalidomide are encouraging, with almost one third of patients experiencing long-lasting CR.

Background: Bosutinib (BOS) is approved in France for the treatment of newly diagnosed Philadelphia chromosome-positive (Ph+) chronic phase chronic myeloid leukemia (CML), and for patients (pts) with Ph+ CML previously treated with ≥1 tyrosine kinase inhibitor (TKI) and for whom imatinib, nilotinib and dasatinib are not considered appropriate treatment options. Aims: This study aimed to characterize the safety and effectiveness of BOS in pts with previously treated CML receiving treatment in a real-world clinical setting in France. Methods: BOSEVAL is a non-interventional, observational, prospective study conducted at 23 centers in Metropolitan France. Eligible pts, aged ≥18 yr, had a diagnosis of Ph+ and/or BCR::ABL1+ CML and were resistant/intolerant to prior treatment with ≥1 TKI. Primary outcomes measures were treatment-related adverse events (TRAEs) and permanent BOS discontinuation due to TRAEs, as determined by the investigator. Results: This study included 142 pts who commenced BOS treatment between Oct 22, 2015, and Dec 19, 2019, with a follow-up period of 3 yr from BOS initiation. Among the 139 pts evaluable for effectiveness, the median age at BOS initiation was 65.0 (range, 23.0−88.0) yr, 56.1% were male; 46.0%, 30.2% and 23.7% of pts received BOS as 2nd, 3rd, and ≥4th line treatment, respectively. Median time from CML diagnosis to the initiation of BOS treatment was 3.9 (range, 0.2−29.2) yr. In all, 64.7% of pts switched to BOS due to intolerance to their last TKI therapy; most common (≥20%) TKI therapies prior to BOS initiation were imatinib (46.8%) and dasatinib (33.1%). At study completion (median follow-up, 3.1 yr), 55.6% of pts were still receiving BOS; median duration of treatment was 2.8 (range, 0−3.4) yr. Median dose at treatment initiation was 200 (range, 100−500) mg/day, and the average dose during treatment was 300 (range, 57−500) mg/day. Dose escalations were reported in 76.1% of pts. Dose reductions and dose interruptions occurred in 50.0% and 43.7% of pts, respectively. Most common primary reasons for permanent BOS discontinuation were intolerance (27.5%) and loss of response/suboptimal response (11.3%). Adverse events (AEs) were reported in 99.3% of pts; 60.6% of patients experienced at least one serious AE and 88.0% of patients experienced TRAEs. Most common (≥10%) any grade TRAEs were diarrhea (53.5%), hepatocellular injury (14.8%), nausea (14.1%) and abdominal pain (10.6%). TRAEs led to permanent treatment discontinuation in 26.8% of pts; the most common (≥2%) were diarrhea, pleural effusion, hepatocellular injury, increased aspartate/alanine aminotransferase and vomiting in 7.7%, 4.9%, 4.9%, 2.8% and 2.1% of patients, respectively. BOS cross-intolerance was reported in 7 pts; cross-intolerance due to recurrence of pleural effusions was reported in 3 dasatinib-intolerant pts and 1 dasatinib and imatinib-intolerant pt, cross-intolerance due to cardiac failure, pain or diarrhea was reported in 3 imatinib-intolerant pts. Among the 139 pts, evaluable for effectiveness, 70.5% attained or maintained molecular responses at any time on treatment (MMR, 15.1%; MR4, 10.1%; MR4.5, 15.8%; MR5, 29.5%). Among responders, the Kaplan-Meier probability of maintaining a molecular response at 3 yr was 81% (95% CI, 72-88). On-treatment transformations to accelerated and blast phase occurred in 3 (2.2%) pts and 1 (0.7%) pt, respectively. The Kaplan-Meier estimated progression-free and overall survival rates at 3 yr were 93% (95% CI, 87−96) and 95% (95% CI, 89−97), respectively. During the study, 7 deaths occurred; 2 were considered related to CML and 1 was TRAE (pneumonia) per investigators. Conclusions: This real-world analysis characterized the safety and effectiveness of BOS in previously treated pts with CML in France.

Background: This study was a prospective, non-interventional, multicentre study to evaluate the safety and efficacy of Nivestim® (biosimilar of filgrastim) in chemotherapy-induced febrile neutropenia in real-life setting. Methods: Adult patients undergoing chemotherapy for solid tumor or hematological malignancy treated with prophylactic or curative Nivestim were included. Patients were followed for 1–6 chemotherapy cycles following study inclusion. The primary objective was the assessment of the safety of Nivestim. Results: 2102 patients (mean age, 63.5 years) were analyzed (1579 with solid tumor and 532 with hematological malignancy); 2065 (98.2%) received Nivestim as prophylaxis administered with a median time of two days after onset of chemotherapy. Chemotherapy regimens were associated with a high risk of febrile neutropenia for 19.4%, intermediate risk for 55.6% and low risk for 25.0%. Adverse events were reported for 20.4% (414/2034) of patients: the most common adverse event was muscle and/or bone pain (12.1%). In prophylactic patients, febrile neutropenia was reported in 98 patients (4.9%; 95% CI, 4.06–5.98), occurring at a median time of 14.0 days after the first chemotherapy cycle. Infection occurred in 61 patients (3.1%; 95% CI, 2.39–3.93) after a median time of 23.5 days following onset of chemotherapy. A total of 98 prophylactic patients (4.9%) who presented with febrile neutropenia and/or infection were hospitalized. Conclusions: The safety and efficacy of Nivestim in cancer patients in real-world clinical practice were consistent with the registration studies and in line with reference filgrastim in both the prophylactic and curative settings.

Ixazomib (IXA) is an oral proteasome inhibitor (PI) used in combination with lenalidomide and dexamethasone (IXA-Rd) for patients with relapsed and/or refractory multiple myeloma (RRMM). The REMIX study is one of the largest prospective, real-world analysis of the effectiveness of IXA-Rd in the setting of RRMM. Conducted in France between August 2017 and October 2019, the REMIX study, a non-interventional prospective study, included 376 patients receiving IXA-Rd in second line or later and followed for at least 24 months. Primary endpoint was the median progression-free survival (mPFS). Median age was 71 years (Q1-Q3 65.0 - 77.5) with 18.4% of participants older than 80 years. IXA-Rd was initiated in L2, L3 and L4 + for 60.4%, 18.1% and 21.5%, respectively. mPFS was 19.1 months (95% CI [15.9, 21.5]) and overall response rate (ORR) was 73.1%. mPFS was 21.5, 21.9 and 5.8 months in patients receiving IXA-Rd as L2, L3, L4 + respectively. Among patients receiving IXA-Rd in L2 and L3, mPFS was similar for patients previously exposed to lenalidomide (19.5 months) than for those lenalidomide naive (not exposed, 22.6 months, p = 0.29). mPFS was 19.1 months in patients younger than 80 years and 17.4 months in those 80 years or older (p = 0.06) with similar ORR (72.4% and 76.8%) in both subgroups. Adverse events (AEs) were reported in 78.2% of patients including 40.7% of treatment-related AE. IXA discontinuation was due to toxicity in 21% of patients. To conclude, the results of the REMIX study are consistent with the results of Tourmaline-MM1 and confirm the benefit of IXA-Rd combination in real life. It shows the interest of IXA-Rd in an older and frailer population, with an acceptable effectiveness and tolerance.

Background Evidence regarding the analgesic effect of distraction through immersion in virtual reality (VR) for care-induced pain has been documented in several phase 2 trials, but comparison with standard treatments in large, randomized studies is needed. Objective In this open-label, multicenter, randomized, phase 3 trial, we evaluated the safety and efficacy of a novel VR therapy solution for distraction in the context of bone marrow biopsy. Methods Bliss is a VR software with 4 imaginary interactive environments in 3 dimensions with binaural sound (head-mounted display). Efficacy regarding pain intensity was evaluated using a visual analog scale (VAS; score from 0 to 10) immediately after the biopsy. Secondary end points were anxiety and tolerance. Modified intention-to-treat analysis was performed. Results Overall, 126 patients with previously documented untreated or suspected malignant hemopathy between September 6, 2018, and May 18, 2020, were randomly assigned in a 1:1 ratio to receive pain prevention with a mixture of nitrous oxide/oxygen (MEOPA; n=63) or VR (n=63) before and during the bone marrow biopsy. We excluded 8 patients from the final analysis (3 in the MEOPA group and 5 in the VR group). All patients received local anesthesia (lidocaine) before biopsy. Follow-up was limited to 1 month after the biopsy. Participants’ median age was 65.5 (range 18-87) years, and 54.2% (64/118) of patients were male. The average pain intensity was 3.5 (SD 2.6, 95% CI –1.6 to 8.6) for the MEOPA group and 3.0 (SD 2.4, 95% CI –1.7 to 7.7) for the VR group, without any significant differences in age, sex, center, and hemopathy (P=.26). Concerning anxiety, 67.5% (79/117; fear of pain questionnaire) of the patients were afraid before the biopsy, and anxiety scores were moderate to very high in 26.3% (30/114; revised Spielberger State-Trait Anxiety Inventory questionnaire) of the patients before the biopsy and 9.0% (10/114) after the biopsy for all patients, without a significant difference between the 2 groups (P=.83). Immersion in VR was well tolerated by the majority (54/57, 95%) of patients in the VR group. Conclusions The intensity of pain did not significantly differ between both arms. VR was well tolerated, and the satisfaction of patients, nurses, and physicians was very high. VR could be an alternative treatment in case of contraindication or intolerance to MEOPA. Trial Registration ClinicalTrials.gov NCT03483194; https://clinicaltrials.gov/ct2/show/NCT03483194

Rituximab (R) or obinutuzumab (G) combined with CHOP chemotherapy are used in previously untreated follicular lymphoma (FL). The aim is to compare in real life setting the efficacy and safety of these therapeutic strategies and assess the economic impact of introducing G. This retrospective study, performed in 3 centers, included data from all patients who received R-CHOP or G-CHOP for previous untreated FL from June 1st, 2016 to December 31st, 2020. Progression-Free Survival (PFS) were estimated according to the Kaplan–Meier method. A budgetary impact model was performed from the French health care system’s perspective. N = 124 patients were included (58 G-CHOP; 66 R-CHOP). Fifty-one and 57 patients achieved a complete response at the end of induction in the G-CHOP and R-CHOP group, respectively. PFS was not significantly longer in the G-CHOP group (HR 0.28; 95

Background The management of newly diagnosed multiple myeloma (NDMM) patients under 70 years of age, in good health condition and without comorbidities, is based on an induction therapy followed by high-dose therapy with autologous stem cell transplantation (ASCT) and maintenance (1). Several studies have demonstrated this regimen to be effective up to 65 years of age (2). Beyond this age, patients are often excluded from clinical trials and few real-world evidence studies are available. The EMMY study, a large-scale real-world study designed to assess the epidemiology and real-life management of MM, describes the use of ASCT in patients aged of 65 and over and its efficacy compared to other treatments. Methods EMMY is a non-interventional, prospective study conducted in 72 IFM (Intergroupe Francophone du Myélome, sponsor) centers in France. Any patient initiating treatment for MM over a 3-month observation period, from October to December, is included, since 2017. It is a dynamic cohort with the inclusion of 800 to 1000 additional patients each year (3616 patients included at the end of 2020). Data are updated annually from hospital records up to 2021. NDMM patients aged 65 years and over, who received a front-line therapy with ASCT (ASCT+), were identified and described. Progression-free survival (PFS) (median and rates at 36 and 48 months (m)), time to next treatment (TTNT) (median and rates at 36m and 48m) and overall survival (OS) rates at 36m and 48m were described for ASCT+ patients ≥65 years and compared to ASCT+ patients <65 years identified in EMMY (Wilcoxon test). ASCT+ patients ≥65 years were also compared with non-autologous transplant patients (ASCT-) of the same age ([65-75[ years). Same analyses were conducted for the subgroup of ASCT+ / ASCT- patients aged of 66-70 years. Results Among the 1597 NDMM patients enrolled in EMMY, 156 NDMM patients ≥65 years of age received a first-line therapy with ASCT; 129 (82.7%) had less than 70 years and 27 beyond (17.3%). Patients were male (55.1%), without comorbidities (72.4%) with an ECOG of 0 or 1 (89.4%) and an ISS score of 1, 2, 3 for 30.3%, 39.4% and 30.3% of them. For those patients, mPFS was estimated at 47.7m (95 CI% [34.4 to not reached]) with 36m and 48m PFS rates estimated at 56.1% (95 CI% [46.2; 66.0]) and 48.6% (95 CI% [37.0; 60.3]). mTTNT was not reached while 36m and 48m TTNT rates were 67.6% (95 CI% [57.7; 77.4]) and 57.4% (95 CI% [45.3; 69.4]). Regarding OS, 36m and 48m rates were 96.2% (95 CI% [92.8; 99.5]) and 89.3% (95 CI% [81.0; 97.6]). Survival outcomes for ASCT+ patients aged ≥65 years did not differ from those for ASCT+ patients aged <65 years (n=397 in EMMY) for PFS (p=0.32), TTNT (p=0.54), and OS (p=0.54). ASCT+ patients aged ≥ 65 years had similar characteristics (M/F ratio, ECOG, ISS, comorbidities) than ASCT+ patients aged <65 years. Compared with ASCT- patients of same age (n=397), ASCT+ patients aged ≥65 years had higher survival outcomes with a significant improvement in PFS (mPFS of 47.7m vs. 19.4m and 36m rates of 56.1% vs. 32.8%, p<0.0001, Figure 1), in TTNT (mTTNT not achieved vs 23.4m in ASCT- patients and 36m rates of 67.6% vs. 34.7%, p<0.0001); and in OS (36m rates of 96.5% vs. 74.0%, p=0.0013). ASCT+ patients aged ≥ 65 years had a median age of 67.5 years (vs. 70.8 years), ECOG 0-1 for 89.4% (vs. 69.0%), comorbidities for 27.6% (vs. 44.3%) and ISS II or III for 69.7% (vs. 76.4%) compared to ACST- patients aged ≥65 years. Same comparisons performed with the 66-70 years subgroup of ASCT+ (n=105) and ASCT- (n=192) patients confirmed previous survival outcomes results in terms of PFS (mPFS of 47.5m vs 20.6m, p=0.0004), TTNT (p<0.0001) and OS (p=0.0002). Conclusion These results are among the first estimates of the higher efficacy of ASCT in selected patients aged 65 years and over. Almost half patients (46.2%) up to 70 years of age received ASCT as first-line therapy, less frequently (about 10%) beyond. Although the use of ASCT is usually reserved to healthy patients, its clinical benefit over 65 years is significant in terms of survival and equivalent to that observed in younger patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

6573 Background: The prevention of care-induced pain is a central concern for all healthcare teams in hematology units. Use of MEOPA (Oxygen + Nitrous Oxide) is today a standard of care for relaxation procedure. Distraction through immersion in virtual reality (VR) has already documented its analgesic effects in several phase II trials but comparison with standard treatments in a large randomized study is needed. Methods: We conducted an open-label multicenter randomized phase III trial (ClinicalTrials.gov identifier: NCT03483194). We assessed the safety and efficacy of a new therapeutic virtual reality solution for pain distraction, Bliss, in prevention of pain and anxiety before performing a bone marrow biopsy. Bliss is a VR software with four imaginary interactive environments in three dimensions with binaural sound (head-mounted display). Efficacy was evaluated by pain intensity with visual analog scale (score from 0 to 10) just after the biopsy and anxiety by 2 questionnaires (fear of pain before the biopsy and revised STAI questionnaire before and after the biopsy). The primary end point was patient-assessed pain intensity after the bone marrow procedure. Results: A total of 126 patients were enrolled with previously untreated malignant hemopathy between September 6, 2018 and May 18, 2020. They were randomly assigned in a 1:1 ratio to receive pain prevention with MEOPA (n=63) or Bliss (n=63) before and during their bone marrow biopsy. All patients received a local anesthesia with lidocaïne before the biopsy. Median age of the study population was 65.5 years old (range 18 to 87) and 54,2% were men. The average pain intensity was 3.5 (standard deviation 2.6) for the MEOPA group and 3.0 (SD 2.4) for the VR group (p=0,26) without any significant difference according to age, gender or hemopathy. Concerning anxiety, 67.5% of patients were afraid before the biopsy and anxiety scores were moderate to very high in 26.3% of patients before the biopsy (STAI questionnaire) and 9.0% after the biopsy for all patients (17.3% of reduction in anxiety for the MEOPA group and 17.2% for the VR group, p=0.83). Immersion in VR was well tolerated in 100% of patients included in the VR group. Physicans were very satisfied by the relaxation procedure in 64.9% of cases (52.5% in the MEOPA group and 77.6% in the VR group, p=0.01) and recommended re-use of the technique in 54.2% in the MEOPA group and 79,1% in the VR group (p=0.02). Conclusion: The intensity of pain did not significantly differ in both arms. Bliss-based relaxation method was well tolerated and the satisfaction of patients and physicians was very high in VR group. This study validates the use of immersion in VR with Bliss as a new digital therapeutics and support the integration of the software in the panel of supportive care. Key words: virtual reality, bone marrow biopsy, pain. Clinical trial information: 03483194.

The STI571 prospective randomised trial (SPIRIT) French trial is a four-arm study comparing imatinib (IM) 400 mg versus IM 600 mg, IM 400 mg + cytarabine (AraC), and IM 400 mg + pegylated interferon alpha2a (PegIFN-α2a) for the front-line treatment of chronic-phase chronic myeloid leukaemia (CML). Long-term analyses included overall and progression-free survival, molecular responses to treatment, and severe adverse events. Starting in 2003, the trial included 787 evaluable patients. The median overall follow-up of the patients was 13.5 years (range 3 months to 16.7 years). Based on intention-to-treat analyses, at 15 years, overall and progression-free survival were similar across arms: 85%, 83%, 80%, and 82% and 84%, 87%, 79%, and 79% for the IM 400 mg ( N = 223), IM 600 mg ( N = 171), IM 400 mg + AraC ( N = 172), and IM 400 mg + PegIFN-α2a ( N = 221) arms, respectively. The rate of major molecular response at 12 months and deep molecular response (MR4) over time were significantly higher with the combination IM 400 mg + PegIFN-α2a than with IM 400 mg: p = 0.0001 and p = 0.0035, respectively. Progression to advanced phases and secondary malignancies were the most frequent causes of death. Toxicity was the main reason for stopping AraC or PegIFN-α2a treatment.

Les anticorps anti-PD1 sont efficaces dans le traitement du carcinome épidermoïde cutané avancé ou métastatique. Ces anticorps peuvent être responsables d'effets secondaires dysimmunitaires mais également d'hyperprogressions tumorales paradoxales. Nous présentons ici un cas d'une hyperprogression associée à une évolution d'une maladie de Waldenström indolente chez un patient traité par anticorps anti-PD1 pour un carcinome épidermoïde métastatique. Un homme de 80 ans était suivi dans notre centre pour une maladie de Waldenström diagnostiquée en 1994 révélée par une protéinurie glomérulaire avec des lésions glomérulaires minimes à la biopsie rénale. Entre 1994 et 2014, il avait été traité de manière itérative par chimiothérapie (chlorambucil, fludarabine, rituximab-bendamustine) pour des poussées évolutives de son hémopathie. Depuis 2014, il était en rémission. En janvier 2021, le patient était adressé pour prise en charge d'un carcinome épidermoïde cutané métastatique ganglionnaire et pulmonaire. Après 4 administrations hebdomadaires de chimiothérapie (cetuximab, carboplatine et paclitaxel) interrompue pour toxicité, il était traité par nivolumab 240 mg toutes les 2 semaines. Le nivolumab était interrompu après 2 administrations du fait d'une hyperprogression clinique du carcinome. Parallèlement, on notait une insuffisance rénale aiguë avec une créatinine passant de 92 micromol/L à 160 micromol/L. La protéinurie des 24 h était mesurée à 3,81 g/24 h avec une chaine légère libre kappa à 50 mg/L. La biopsie rénale mettait en évidence des dépôts linéaires d'immunoglobulines monoclonales constituant un syndrome de Randall. Des phénomènes d'hyperprogression sous immunothérapie sont décrits avec une fréquence variable selon les types tumoraux. Le mécanisme physiopathologique consisterait en une régulation positive des lymphocytes T régulateurs par le blocage du récepteur PD1, entraînant une action immunosupressive sur les lymphocytes T CD8+ et un échappement aggravé des cellules tumorales au système immunitaire. Le phénomène de progression d'une hémopathie n'est pas décrit pour l'heure avec les inhibiteurs de checkpoint immunitaire. Dans le cas rapporté ici, le même phénomène de régulation positive des lymphocytes T régulateurs immunosupresseurs par les anticorps anti-PD1 a pu entraîner l'hypeprogression et l'aggravation de la maladie de Waldenström. Des investigations menées sur modèles murins vont dans le sens de cette hypothèse. Les inhibiteurs de checkpoint immunitaire peuvent entraîner une hyperprogression dans le cadre des tumeurs solides mais peut-être également d'une hémopathie sous-jacente. Le mécanisme physiopathologique commun pourrait reposer sur à une immunosuppression médiée par les lymphocytes T régulateurs stimulés par les anticorps anti-PD1.

A median serum B2M level was significantly higher in patients with > 3 FLs compared with 1 ‐ 3 FLs (p = 0.015). The initial ISS score was significantly associated with both PFS (p = 0.0045) and OS (p = 0.0081). EMD and HR cytogenetic did not significantly correlate with the PFS or the OS. In multivariable analysis, ISS score and > 3FLs were independent prognosticators for PFS (p = 0.010, p = 0.025 respectively). Blood flow cytometry, performed in 15 patients, detected 4 patients with abnormal plasma cells among 3 had FLs > 3 and one had a single bone lesion with EMD. Conclusion : Presence of > 3 FLs on PET/CT is a predictor of survival outcomes in patients with relapse/refractory MM treated with CD38 targeted therapy and correlates with tumour burden biomarker. considered critical organs. The scatter of the data is due to the large variability of the physiological parameters of the patients, in order to specify the obtained data the study is proceeded. EA – previously submitted to regional or national meetings (up to 1000 attendees). No conflicts of interests pertinent to the abstract.

Background: The most important series devoted to antithyroid drug-induced severe neutropenia and agranulocytosis are Japanese studies, almost specifically in relation to the intake of methimazole. The clinical data of 30 Caucasian patients followed up for antithyroid drug-induced neutropenia at a third-level hospital are reported. Methods: The data of 30 patients with idiosyncratic antithyroid drug-induced neutropenia and agranulocytosis from a cohort study on drug-induced neutropenia and agranulocytosis conducted at the University Hospital of Strasbourg (France) were retrospectively reviewed. Results: The mean patient age was 61.7 years old (range: 20–87), and the gender ratio (F/M) was 4. Several comorbidities were reported in 23 patients (76.7%), with the mean Charlson comorbidity index of 1. The causative drugs were carbimazole and benzylthiouracil, in 28 (93.3%) and 2 cases, respectively, prescribed primarily for multi-hetero-nodular goiter or thyroid nodule to 18 patients (60%). Sore throat and acute tonsillitis (40%), isolated fever (20%), septicemia (13.3%), documented pneumonia (6.7%), and septic shock (6.7%) were the main clinical features upon admission. The mean neutrophil count at nadir was 0.02 and 0 × 109/L (range: 0–0.3). Regarding the patients’ hospital course: 13 cases (43.3%) worsened during hospitalization, severe sepsis was found in 26.7%, systemic inflammatory response syndrome—in 13.3%, and septic shock—in 3.3% of the cases, respectively. Broad-spectrum antibiotics were indicated for all the patients, and 21 (73.3%) of them received hematopoietic growth factors. Hematological recovery (neutrophil count ≥ 1.5 × 109/L) was seen at 8.3 days (range: 2–24), but faster in those receiving hematopoietic growth factors (4.9 days, p = 0.046). Two patients died during hospitalization, and the rest had a favorable clinical outcome. Conclusions: Antithyroid drug-induced neutropenia represents a serious complication resulting from the rates of severe infections especially in those cases severe neutropenia. In this setting, an established procedure for the management of patients seems useful or even indispensable in view of potential mortality.

Les neutropénies sévères et les agranulocytoses induites par les antithyroïdiens de synthèse ont été principalement étudiées par les équipes japonaises, et notamment par la prise du méthimazole. Nous vous rapportons notre expérience au sein d’un centre de référence, au travers d’une série de 30 cas. Les données de 30 patients présentant une neutropénie sévère et une agranulocytose induite par un médicament antithyroïdien de synthèse ont été collectées de manière rétrospective durant la période 2010–2019. Tous les cas ont été extraits d’une étude de série menée dans le centre hospitalier universitaire de Strasbourg sur la neutropénie sévère et l’agranulocytose. L’âge moyen des 30 patients était de 61,7 ans (extrêmes : 20–87) et le sex-ratio (F/M) était de 4, le score moyen de comorbidité de Charlson de notre série s’établit à 1. Les médicaments responsables étaient le carbimazole et le benzylthiouracile, respectivement dans 28 cas (93,3 %) et 2 cas, prescrits principalement pour le goitre multi-hétéronodulaire ou le nodule thyroïdien pour 18 patients (60 %). Les principales présentations cliniques lors de l’hospitalisation comprenaient des maux de gorge ou une amygdalite aiguë (40 %), une fièvre isolée (20 %), un sepsis (13,3 %), une pneumonie documentée (6,7 %) et un choc septique (6,7 %). Le nombre moyen de neutrophiles au nadir était de 0,02 et 0 × 10 (9)/L (0–0,3). À l’hôpital, 13 patients (43,3 %) se sont aggravés cliniquement et présentaient des signes de sepsis (40 %), et de choc septique (3,3 %). Tous les patients ont été traités rapidement avec l’usage des antibiotiques à large spectre et 21 cas (73,3 %) ont reçu des facteurs de croissance hématopoïétiques. La durée moyenne de récupération hématologique (numération des neutrophiles ≥ 1,5 × 10(9)/L) était de 8,3 jours (2–24), qui a été réduite à 4,9 jours (2–24) (p = 0,046) avec des facteurs de croissance hématopoïétiques. Le résultat a été favorable chez 93,3 % des patients, tandis que deux patients sont décédés. Au cours des dernières années, des progrès significatifs ont été réalisés dans le domaine de la neutropénie et de l’agranulocytose d’origine iatrogène, conduisant à une amélioration de leur gestion et de leur pronostic. Les cliniciens doivent poursuivre leurs efforts pour améliorer leurs connaissances sur ces effets indésirables.

Ruxolitinib is a JAK-1/JAK-2 inhibitor indicated for the treatment of polycythemia vera and primary or secondary myelofibrosis. Only one patient (0.2%) was diagnosed with tuberculosis among the 485 patients receiving ruxolitinib in the four pivotal trials. Fourteen cases of tuberculosis have since been reported. We observed two (3%) mycobacterial infections (one due to Mycobacterium tuberculosis and one due to Mycobacterium avium complex) in our cohort of 65 patients receiving ruxolitinib. This observation suggests that the rate of mycobacterial infection might be higher than that observed in the pivotal trials and that atypical mycobacterial infections can also occur.

Erythropoiesis-stimulating agents are generally the first line of treatment of anemia in patients with lower-risk myelodysplastic syndrome. We prospectively investigated the predictive value of somatic mutations, and biomarkers of ineffective erythropoiesis including the flow cytometry RED score, serum growth-differentiation factor-15, and hepcidin levels. Inclusion criteria were no prior treatment with erythropoiesis-stimulating agents, low- or intermediate-1-risk myelodysplastic syndrome according to the International Prognostic Scoring System, and a hemoglobin level <10 g/dL. Patients could be red blood cell transfusion-dependent or not and were given epoetin zeta 40 000 IU/week. Serum erythropoietin level, iron parameters, hepcidin, flow cytometry Ogata and RED scores, and growth-differentiation factor-15 levels were determined at baseline, and molecular analysis by next-generation sequencing was also conducted. Erythroid response (defined according to the International Working Group 2006 criteria) was assessed at week 12. Seventy patients, with a median age of 78 years, were included in the study. There were 22 patients with refractory cytopenia with multilineage dysplasia, 19 with refractory cytopenia with unilineage dysplasia, 14 with refractory anemia with ring sideroblasts, four with refractory anemia with excess blasts-1, six with chronic myelomonocytic leukemia, two with del5q-and three with unclassifiable myelodysplastic syndrome. According to the revised International Prognostic Scoring System, 13 had very low risk, 47 had low risk, nine intermediate risk and one had high-risk disease. Twenty patients were transfusion dependent. Forty-eight percent had an erythroid response and the median duration of the response was 26 months. At baseline, non-responders had significantly higher RED scores and lower hepcidin:ferritin ratios. In multivariate analysis, only a RED score >4 (P=0.05) and a hepcidin:ferritin ratio <9 (P=0.02) were statistically significantly associated with worse erythroid response. The median response duration was shorter in patients with growth-differentiation factor-15 >2000 pg/mL and a hepcidin:ferritin ratio <9 (P=0.0008 and P=0.01, respectively). In multivariate analysis, both variables were associated with shorter response duration. Erythroid response to epoetin zeta was similar to that obtained with other erythropoiesis-stimulating agents and was correlated with higher baseline hepcidin:ferritin ratio and lower RED score. ClinicalTrials.gov registration: NCT 03598582.

In this paper, we report and discuss the diagnosis and management of severe neutropenia and agranulocytosis (neutrophil count of <0.5 x 109/L) related to non-chemotherapy drug intake, called “idiosyncratic”

This is a pivotal, multicenter, open-label study of moxetumomab pasudotox, a recombinant CD22-targeting immunotoxin, in hairy cell leukemia (HCL), a rare B cell malignancy with high CD22 expression. The study enrolled patients with relapsed/refractory HCL who had ≥2 prior systemic therapies, including ≥1 purine nucleoside analog. Patients received moxetumomab pasudotox 40 µg/kg intravenously on days 1, 3, and 5 every 28 days for ≤6 cycles. Blinded independent central review determined disease response and minimal residual disease (MRD) status. Among 80 patients (79% males; median age, 60.0 years), durable complete response (CR) rate was 30%, CR rate was 41%, and objective response rate (CR and partial response) was 75%; 64 patients (80%) achieved hematologic remission. Among complete responders, 27 (85%) achieved MRD negativity by immunohistochemistry. The most frequent adverse events (AEs) were peripheral edema (39%), nausea (35%), fatigue (34%), and headache (33%). Treatment-related serious AEs of hemolytic uremic syndrome (7.5%) and capillary leak syndrome (5%) were reversible and generally manageable with supportive care and treatment discontinuation (6 patients; 7.5%). Moxetumomab pasudotox treatment achieved a high rate of independently assessed durable response and MRD eradication in heavily pretreated patients with HCL, with acceptable tolerability.

Background: Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm for which treatment has been improved by the development of Imatinib, a Bcr-Abl Tyrosine-Kinase Inhibitor (TKI). Despite the excellent efficiency of this drug in the chronic phase of CML, cases of treatment failure or suboptimal response are not rare. Several mechanisms that lead to Imatinib resistance have been investigated, including pharmacogenetic resistance. In our study, we compared the distribution of several genotypes of a single nucleotide polymorphism (SNP) of ABCB1 (MDR1) and the outcome to Imatinib treatment. ABCB1 is an ATP-dependent drug efflux pump for xenobiotic compounds. It is responsible for a decrease in the accumulation of drugs (including Imatinib) and often mediates the development of resistance to anticancer drugs. Some of its SNP could increase this effect and thus lead to therapeutic resistance. Methods: A total of 78 chronic-phase CML adult patients who got a BCR-ABL major break-point were included in this study. All were treated by Imatinib in first line. Patients were classified in two groups according to the latest European Leukemia Net (ELN) recommendations. We identified thereby 42 optimal responders (OR) and 36 non-responders (NR) to Imatinib-therapy patients. DNA extraction from EDTA whole blood samples was carried out using QIAamp DNA Blood Mini Kit (QIAGEN). Non-synonymous ABCB1 SNP 2677G>T/A (rs2032582) was determined by pyrosequencing (Pyromark Q24, QIAGEN) using PCR and pyrosequencing primers designed using Pyromark Assay Design software (QIAGEN). Both Hardy-Weinberg equilibrium as well as the association between genotypes of SNP rs2032582 and Imatinib response were tested using a statistical χ2-test with one degree of freedom. This study was approved by the local ethics committee, and written informed consent in accordance to the Declaration of Helsinki was obtained from all patients. Results: Overall frequencies of ABCB1 2677 GG, GT, TT, TA and GA genotypes were respectively 38.5%, 34.6%, 21.8%, 2.6% and 2.5%. Homozygous individuals were not found for the allele 2677A. The distribution of each of these genotypes was in Hardy-Weinberg equilibrium. For this SNP, there was a significant difference in genotype frequencies distribution between NR and OR groups: 33.3% of NR vs 11.9% of OR were carrying the genotype TT (p = 0.02). The other genotypes distributions were not significantly different in the two groups. Conclusions: Our data shows that TT genotype of ABCB1 SNP 2677 G>TA is statistically linked to a poor response to Imatinib-treatment in CML patients according to the ELN recommendations. Determination of ABCB1 polymorphism (G2677T/A) might be a personalized laboratory test to predict the response to Imatinib treatment in patients with CML and thus designing individualized treatment programs. Legal entity responsible for the study: University Hospital of Strasbourg Funding: Institutional funding Disclosure: All authors have declared no conflicts of interest.