INTRODUCTION:Azacitidine-venetoclax (AZA-VEN) has become a standard treatment in older or chemotherapy-ineligible AML patients. While the registration trial showed a median overall survival (OS) of 14.7 months, most real-world studies have not reproduced this result. PATIENTS AND METHODS:We analyzed treatment patterns, adverse events, responses and outcomes in 199 patients treated with AZA-VEN in the DATAML registry. RESULTS:The median age was 75.6 years, 48.7% had secondary AML (11% post-MPN); 11.7% had another cancer, and 9% had received AZA for prior myelodysplastic syndrome. Cytogenetic risk was intermediate (55.8%) or adverse (43.7%). The most frequent gene mutations were ASXL1 (33%), TET2 (27%), TP53 (26%), RUNX1 (24%) and SRSF2 (24%). The first cycle was performed on an outpatient basis in 39.4% of patients. The median number of cycles was 4 and 37% received > 6 cycles. Beyond cycle 6, reductions in treatment dose or duration were attributed to VEN in 55% of patients and to AZA for 43%. The complete remission (CR) plus CR with incomplete hematologic recovery (CRi) rate was 58.5%, and day-30 death rate was 3%. Median OS was 8.9 months. mPRS and refined-ELN2024 classifications were significantly associated with response and OS. In CR/CRi patients, G-CSF use was significantly and independently associated with improved OS (median, 10.1 months without versus 20.3 with G-CSF; P = .001). In an external cohort, G-CSF was also associated with a trend towards improved OS. CONCLUSION:In real-world clinical practice, patients with more severe characteristics are typically selected for AZA-VEN, which could explain suboptimal outcomes. G-CSF should be prospectively explored in AZA-VEN treated patients.

The venetoclax-azacitidine (VEN-AZA) combination has become a standard treatment for AML in older patients (pts) or those ineligible for intensive chemotherapy (IC). While the VIALE-A registration study showed a median survival of 14.7 months (m), real-life studies did not to reproduce this result. In this study, we analyzed treatment patterns, adverse events, responses and outcomes of pts treated with VEN-AZA in the DATAML registry.MethodsMain inclusion criteria: age ≥ 18 y; newly diagnosed AML, de novo or secondary to cytotoxic therapy, MDS, CMML or MPN; IC ineligible; at least 1 cycle of VEN-AZA between 01/01/2020 and 12/31/2022. Exclusion criteria: previous exposure to VEN; participation in a clinical trial within 30 days prior to VEN.Pts were treated in 2 university and 21 regional hospitals. VEN-AZA was recommended according to the label, but bone marrow blast clearance at D21C1 allowed VEN to be stopped before D28. Tumor lysis syndrome, antimicrobial prophylaxis and G-CSF use were carried out according to local practices. Intervals between each cycle, duration of VEN treatment, AZA dose modification, use of antifungal and/or antibiotic prophylaxis, use of G-CSF, transfusion needs, site of treatment and hospitalizations were analyzed during the first 6 cycles.Results199 pts were included: median age, 75.6 y; male sex, 56%; PS 0-1, 72%; secondary AML, 49% (including 11% post-MPN); other cancer <5y, 12%; infection at diagnosis, 18%; WBC, 4.6 G/L, WBC≥25 G/L, 20%; adverse cytogenetics, 44%; mutations: TP53 (26%), NPM1 (17%), IDH1 (13%), NRAS (12%), IDH2 (11%), KRAS (7%), FLT3-ITD (6%);refined ELN2024 risk, favorable (29%), intermediate (18%), adverse (53%). 18 pts (9%) had received AZA for prior MDS.The first cycle was performed on an outpatient basis in 40% of pts. Antifungal or antibiotic prophylaxis was given in 79% and 32% of pts, respectively. G-CSF was given in 33% of pts at C1 then increasingly, up to 71% at C6. Pts received a median of 4 cycles (8 if CR/CRi, 2 if treatment failure), and 37% received > 6 cycles. The median number of venetoclax days per cycle was 24, 24, 21, 21, 14, 14 in C1 to 6. Median interval between 2 cycles was 33 days. Beyond C6, dose/duration reductions concerned 55% of pts for VEN and 43% for AZA.The rate of febrile neutropenia was 44%, 32%, 9%, 14%, 10% and 5% during C1 to 6. Death rate at D30 and D60 was 3% and 14%. Death rate from infection at D30 and D60 was1% and 6%.CR+CRi rate was 58% (CR, 32%, CRi, 26%). At D21C1, CR, CRi and MLFS were observed in 6%, 10% and 36% of pts. In pts with D21C1 BM blasts<5%, the CR/CRi rate was 86% after 2 cycles. Only 11% of pts received a second line after failure or relapse.With a median follow-up of 27 m, median OS was 8.9 m (IQR, 3.5-22.5), with significant variations according to mutations (NPM1, 28 m; IDH1/2, 20 m; TP53, 4.6 m; secondary-type mutations, 10 m) or refined ELN2024 risk (fav, 20.7 m; int, 11.9 m; adv, 5.1 m). In multivariate analyses (MV), secondary AML (HR 1.67), adverse cytogenetics (HR 1.51), IDH1mut (HR 0.54) and TP53mut (HR 2.34) were significantly associated with OS. For CR/CRi, only adverse cytogenetics (HR 0.36) was significant.Since a recent study showed a prolonged OS in CR/CRi pts who received G-CSF (DiNardo C, Am J Hematol 2024), we focused on this population. 17 CR/CRi pts did not and 90 did receive G-CSF during the first 6 cycles (n=45 at C1 and n=45 > C1). Median OS was 10.1 m (2.8-13.8) in pts without G-CSF vs 20.3m (8.4-39.5) in pts with G-CSF (p=0.001). G-CSF use was significantly associated with better OS in MV (HR, 0.41; 95% CI 0.23-0.73; p=0.003). Moreover, the number of G-CSF cycles was also significantly associated with better OS in MV (HR for each cycle from 0 to 6, 0.77; 95% CI 0.67-0.88; p<0.001). G-CSF use from C1 onwards was also associated with a higher rate of MRD negativity by flow cytometry in CR/CRi pts (63% vs 18%, p=0.017).ConclusionThis study confirms a markedly improved response rate compared to historical experience with AZA alone and confirms a major OS benefit in some subgroups (NPM1, IDH1/2). However, real-life experience has led to the selection of a more severe patient population negatively affecting OS compare to VIALE-A. Although the mechanisms by which G-CSF could improve treatment efficacy have not been established and a randomized study would be necessary, our study strongly suggests that G-CSF may improve response and survival in patients treated with VEN-AZA.

Introduction: Antibioprophylaxis in patients with cancer and neutropenia is controversial and is not a broadly recommended intervention in management of patients with hematological malignancies. Previous study showed that prophylactic treatment with levofloxacin (LEVO) is an effective and well-tolerated strategy to prevent febrile episodes and other relevant infection-related outcomes in patients with cancer and neutropenia, including acute leukemia ( Bucaneve et al., NEJM 2005). However, impact on microbial resistance discouraged the widespread use of this strategy., Venetoclax (VEN) and azacitidine (AZA) combination was recently approved in newly diagnosed patients with AML who are ineligible for intensive chemotherapy. VEN-AZA allowed higher rates of complete remission and longer overall survival but twice the incidence of febrile neutropenia compared to AZA alone making primary antibioprophylaxis a relevant question, especially in patients who are treated as outpatients or discharged after the seven days of AZA treatment. Methods: We retrospectively selected AML patients who received VEN-AZA treatment from the Toulouse-Bordeaux DATAML registry. The two centers have similar management protocols, but patients in Toulouse (but not in Bordeaux) receive antibacterial prophylaxis with LEVO 500 mg/day from day 11 during the neutropenia period following the 1 st course of VEN-AZA, until neutrophil recovery (>0.5 G/l). We included ≥ 18-year-old non-APL de novo or secondary AML receiving VEN-AZA treatment between June 2015 and May 2023, excluding patients that deceased before day 11 VEN-AZA or who were receiving antibiotherapy before start of VEN-AZA. The primary endpoint was the incidence of febrile neutropenia during the first course of VEN-AZA. Secondary endpoints included clinically documented infections, microbiologically documented infections, and safety data. Results: The population included 264 patients, 71 received LEVO as primary antibioprophylaxis during 1 st course of VEN-AZA and 193 received no prophylaxis [antibiotherapy in case of febrile neutropenia, i.e. standard of care (SOC)]. The median age was 69 (range 20-87) years, 55.3% of patients were male, 48.5% of patients received VEN-AZA as front-line treatment and others 51.5% ≥ 2 nd line of treatment. Febrile neutropenia occurred in 32.4% of patients who received LEVO prophylaxis leading to a hospitalization of 100% of patient with antibiotherapy for a median of 10 days (range 2-45), as compared with 38.9% of those in SOC group leading to hospitalization of 73.3% of patient with antibiotherapy for a median of 10 days (range 1-31), (23 of 71 vs. 75 of 193; relative risk, 0.90; IC95% 0.74-1.10; P=0.33). Delay from day 1 VEN-AZA to febrile neutropenia was 23 (range 10-38) and 18 (range 7-44) days in LEVO and SOC groups (p=0.008), respectively. The LEVO group had a significantly lower rate of clinically documented infections (26.1% vs 52.0%, relative risk, 0.65; IC95% 0.46-0.91; P=0.03) (Figure 1A), but similar microbiologically documented infections (30.4% vs 32.0%) (Figure 1B). It is noteworthy that among patients receiving LEVO prophylaxis, no urinary tract infections were reported. The rate of lung infections was considerably reduced (5% vs 25%) as well as gram-negative bacterial infections (50% vs 74%), consistent with LEVO's broad spectrum, including non-fermenting micro-organisms. Anaerobia infections could be due to the lack of activity of LEVO on this bacterial spectrum. There was no difference in frequency of intensive care unit (ICU) hospitalization (1.4% vs 5.2%, P=0.29). No selection of extended spectrum beta-lactamase bacteria nor burden of fluoroquinolone resistance has been detected. Clostridium difficile colitis has been detected in 2 patients, both in SOC group. No adverse musculoskeletal events have been observed. Conclusion: A short course of levofloxacin as primary prophylaxis in AML patients treated with VEN-AZA was well tolerated, seemed to have no impact on microbial resistance and was associated with a lower rate of clinically documented infection but not febrile neutropenia.

The peer review history for this article is available at https://publons.com/publon/10.1002/hon.2985. The data that support the findings of this study are available from the corresponding author upon reasonable request. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Multiple myeloma (MM) is rare in young patients, especially before age 40 years at diagnosis, representing <2% of all patients with MM. Little is known about the disease characteristics and prognosis of these patients. In this study, we examined 214 patients diagnosed with MM at age ≤40 years over 15 years, in the era of modern treatments. Among them, 189 patients had symptomatic MM. Disease characteristics were similar to older patients: 35% had anemia, 17% had renal impairment, and 13% had hypercalcemia. The staging was ISS-1 in 52.4%, ISS-2 in 27.5%, and ISS-3 in 20.1%. Overall, 18% of patients had high-risk cytogenetics [del 17p and/or t(4;14)]. Ninety percent of patients received intensive chemotherapy followed by autologous stem cell transplant, and 25% of patients had allogeneic stem cell transplant predominantly at time of relapse. The median follow-up was 76 months, the estimated median overall survival was 14.5 years, and the median progression free-survival was 41 months. In multivariate analysis, bone lesions (hazard ratio [HR], 3.95; P = .01), high ISS score (HR, 2.14; P = .03), and high-risk cytogenetics (HR, 4.54; P < .0001) were significant risk factors for poor outcomes. Among predefined time-dependent covariables, onset of progression (HR, 13.2; P < .0001) significantly shortened overall survival. At 5 years, relative survival compared with same age- and sex-matched individuals was 83.5%, and estimated standardized mortality ratio was 69.9 (95% confidence interval, 52.7-91.1), confirming that MM dramatically shortens the survival of young patients despite an extended survival after diagnosis.

European Journal of HaematologyVolume 103, Issue 4 p. 444-448 CASE REPORT Targeted therapy of BRAF V600E-mutant histiocytic sarcoma: A case report and review of the literature Benoît Branco, Corresponding Author Benoît Branco benoit.branco@gmail.com orcid.org/0000-0001-6518-3870 Department of Haematology, IUCT-Oncopole, Toulouse, France Correspondence Benoît Branco, Department of haematology, IUCT-Oncopole, Toulouse, France. Email: benoit.branco@gmail.comSearch for more papers by this authorThibault Comont, Thibault Comont Department of Internal Medicine, IUCT-Oncopole, Toulouse, FranceSearch for more papers by this authorLoïc Ysebaert, Loïc Ysebaert Department of Haematology, IUCT-Oncopole, Toulouse, FranceSearch for more papers by this authorMuriel Picard, Muriel Picard Department of Intensive Care, IUCT-Oncopole, Toulouse, FranceSearch for more papers by this authorCamille Laurent, Camille Laurent Department of Anatomopathology, IUCT-Oncopole, Toulouse, FranceSearch for more papers by this authorLucie Oberic, Lucie Oberic orcid.org/0000-0002-0039-1983 Department of Haematology, IUCT-Oncopole, Toulouse, FranceSearch for more papers by this author Benoît Branco, Corresponding Author Benoît Branco benoit.branco@gmail.com orcid.org/0000-0001-6518-3870 Department of Haematology, IUCT-Oncopole, Toulouse, France Correspondence Benoît Branco, Department of haematology, IUCT-Oncopole, Toulouse, France. Email: benoit.branco@gmail.comSearch for more papers by this authorThibault Comont, Thibault Comont Department of Internal Medicine, IUCT-Oncopole, Toulouse, FranceSearch for more papers by this authorLoïc Ysebaert, Loïc Ysebaert Department of Haematology, IUCT-Oncopole, Toulouse, FranceSearch for more papers by this authorMuriel Picard, Muriel Picard Department of Intensive Care, IUCT-Oncopole, Toulouse, FranceSearch for more papers by this authorCamille Laurent, Camille Laurent Department of Anatomopathology, IUCT-Oncopole, Toulouse, FranceSearch for more papers by this authorLucie Oberic, Lucie Oberic orcid.org/0000-0002-0039-1983 Department of Haematology, IUCT-Oncopole, Toulouse, FranceSearch for more papers by this author First published: 02 August 2019 https://doi.org/10.1111/ejh.13303Citations: 5Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Citing Literature Volume103, Issue4October 2019Pages 444-448 RelatedInformation