Abstract: Background: Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is an uncommon peripheral T-cell lymphoma most frequently arising around a textured surface breast implant. It has been shown that capsule infiltration (T2, T3 and T4 of the TNM staging system) was an adverse prognostic factor. In this context, chemotherapy (with or without brentuximab vedotin [BV]) may be proposed, considering other factors such as metastatic disease or incomplete resection. Furthermore, the need for adjuvant chemotherapy in patients with stage IIA (T4N0M0) and complete en-bloc excision without residual disease is debated. Aim: To assess the management of BIA-ALCL with capsule infiltration, in particular: 1) To assess the impact of BV in those patients; 2) To evaluate the need for adjuvant chemotherapy in patients with stage IIA and complete en-bloc excision without residual disease. Methods: Since 2016, a national multidisciplinary meeting has been implemented by the French National Cancer Institute (NCI) to optimize management of patients with BIA-ALCL, particularly those with advanced disease. Meanwhile, a national registry has been set up by the LYSA, in collaboration with health authorities. Central pathological review has been carried out within the French NCI-labeled Lymphopath network. Results: From 2009 to 2023, 125 patients with BIA-ALCL were recorded, of which 111 (94 from France and 17 from Belgium) had complete data and were included in the present analysis. Overall, median age at diagnosis of BIA-ALCL was 58 years (24-82 years). Reasons for initial implantation were breast cancer reconstruction (n=54; 49%), cosmetic (n=45; 41%) or other (n=12; 10%). The median interval from first implantation to diagnosis of BIA-ALCL was 12.3 years (4-40 years). The median number of implants in the breast involved by BIA-ALCL was 2 (1-8), including at least one silicone implant in 95 (86%) patients, and at least one textured implant in all informative cases (n=102; Most often Allergan Biocell implants). At diagnosis of BIA-ALCL, 78/110 (71%) patients presented with periprosthetic effusion only, 20 (18%) had effusion and a breast mass, 6 (5.5%) had a breast mass only, and 6 (5.5%) had neither. At pathological examination of the capsule, T-stage was T1 (confined to effusion or a layer on luminal side of capsule) in 73/111 (66%) cases, T2-T3 (capsule infiltration) in 5 (4.5%) cases, T4 (lymphoma infiltrates beyond the capsule) in 32 (29%) cases, and unclassifiable in 1 case. Moreover, 18/111 (16%) patients had at least one non-breast extranodal involvement. Among the 36 patients with capsule infiltration (5 T2-T3 and 31 T4), 13 (including 11 T4) were treated with BV-CH(E)P regimen, 12 (all T4) with a CHOP/CHOP-like regimen, and 11 (including 8 T4) did not receive any chemotherapy. The main reasons for receiving chemotherapy were metastatic disease, incomplete resection, or no surgery. Patients who did not receive chemotherapy had a localized disease (3 stage IB/IC and 8 stage IIA) with complete en-bloc excision and no residual disease. Patients treated with BV-CH(E)P regimen and CHOP/CHOP-like regimen had similar characteristics without significant differences regarding age, clinical presentation, stage and surgery. After a median follow-up of 47 months from BIA-ALCL diagnosis, for BV-CH(E)P and CHOP/CHOP-like groups, the respective 4-year PFS rates were 100% and 57% (p=0.01), and the respective 4-year OS rates were 100% and 73% (p=0.07). Regarding the 11 patients who did not receive chemotherapy, 4-year PFS and OS were both 75%, which corresponds to a single event being a death without progression occurring more than 3 years after the diagnosis of lymphoma (4-year lymphoma-specific survival was 100%). Conclusions: 1) In patients with capsule infiltration requiring chemotherapy, BV-CH(E)P regimen was associated with improved PFS and OS compared with CHOP/CHOP-like regimen; 2) Patients with stage IIA and complete en-bloc excision without residual disease had favorable outcome without the need for adjuvant chemotherapy. These results should be confirmed prospectively.

Abstract: The use of novel small molecule inhibitors alone or in combination with anti-CD20 monoclonal antibodies for chronic lymphocytic leukemia (CLL) has raised a number of questions on efficacy, tolerability, long-term treatment adherence in patients with heterogeneous clinical features. To fill this gap, we designed a study focusing on treatment sequencing in patients with CLL in order to (i) compare the outcome of patients treated with chemoimmunotherapy (CIT) combinations in first-line versus those receiving Bruton's tyrosine kinase inhibitors (BTKi); (ii) characterize the efficacy and tolerability of venetoclax-based regimens; (ii) understand the impact of treatment sequencing when it comes to chemo-free options including venetoclax after BTKi and vice versa. Data from consecutive sets of patients diagnosed with CLL between 2000-2020 attended at 77 institutions affiliated with ERIC were collected and analyzed. Collected variables included: demographics, clinical stage at diagnosis, IGHV gene somatic hypermutation status; cytogenetic status for chromosomes 11q, 13q 17p and 12 determined by fluorescence in situ hybridization; TP53 gene mutation status; treatment; treatment response; discontinuation; reason for discontinuation; death. We included 9173 patients with a diagnosis of CLL who received at least one line of treatment. The median age at diagnosis was 67 years with a male:female ratio of 1.9. The median follow-up was 78 months (IQR, 48-120 months). Regarding novel targeted agents, 1860/9173 (20.2%) patients had received at least one line of treatment with BTKi (ibrutinib, n=1788; acalabrutinib, n=72) over the disease course; 631/9173 (6.9%) with venetoclax; and, 447/9173 (4.9%) with the PI3K inhibitor idelalisib. Seventy-nine patients were treated with both BTKi and venetoclax (59 BTKi followed by BCL2i, 20 vice versa). At last follow-up, 5870/9173 patients (64.0%) were alive, 3229/9173 (35.2%) died and 74/9173 (0.8%) were lost to follow-up. Patients treated with BTKi in first-line were enriched for TP53 aberrations [del(17p) 27.6%, TP53 mutation 26.3%] and unmutated IGHV genes (69%) and obtained an ORR of 87.7%. Of these, 136 (26.3%) discontinued treatment after a median of 1.2 years (0.07-5.98); main reasons of discontinuation were toxicity (40.5%) and failure (26.2%). Among 631 patients treated with venetoclax at any line, 100 (15.8%) received BCL2 +/- anti-CD20 as first-line; 170 (26.9%) as second line (125 previously treated with CIT, 27 with BTKi); and, 361 as third or subsequent line. ORR ranged between 71.5% (≥3 lines) with 30.5% CR/CRi to 90.3% (first-line) with 68.1% CR/CRi. Treatment discontinuation was due to toxicity in 28.6% of patients treated in the first-line, and 17.6% and 21.8% of patients treated in second and third-or-higher-line, respectively. Disease progression led to treatment discontinuation in 14.3%, 20.6% and 33.6% in first, second and third-or-higher line, respectively. CIT was used as front-line treatment in 5465 patients (59.6%). Of these, 2070 (37.9%) and 1018 (18.6%) patients received a second and third line of treatment, respectively. The great majority (865/1086 cases, 79.7%) of patients who received a second line before 2014 were retreated with CIT, most commonly Bendamustine-Rituximab (284/1086, 26.1%) and Fludarabine-Cyclophosphamide-Rituximab (252/1086, 23.2%); alemtuzumab monotherapy was used in 55/1086 (5%) of patients. After 2014, 415/984 patients (42.1%) were retreated with BTKi; 93 (9.5%) with venetoclax; 70 (7.2%) with idelalisib; 50 (5%) with Alemtuzumab monotherapy, and 315 (32%) with CIT. Similarly, in the third-or-higher line of treatment, most patients (86.3%) were retreated with CIT before 2014, while BTKi, BCL2i, and PI3Ki were mainly used after 2014 (in 43.1%, 15.7% and 14.7% of cases, respectively). Finally, our cohort included 1075 patients with TP53 aberrations. The ORR of patients receiving BTKis (n=171) as first-line of treatment was 86.5% (22.2 CR+64.3 PR), while the ORR with venetoclax +/- anti-CD20 (n=15) was 91% (45.5% CR+45.5 PR). Patients treated with CIT (n=694) had an ORR of 68.7% (28.3% CR+40.4% PR). In conclusion, in a large international study we provide real world data regarding the selection and sequencing of treatment in CLL, charting a major shift in treatment patterns before and after the introduction of novel trargeted agents and confirming their efficacy even in high-risk CLL. Disclosures Scarfo: Janssen: Honoraria, Other: Travel grants; Astra Zeneca: Honoraria; Abbvie: Honoraria. Iacoboni: BMS/Celgene, Gilead, Novartis, Janssen, Roche: Honoraria. Collado: Abbvie,: Other: pharmaceutical Company, Research Funding; Janssen: Other: Pharmaceutical Company, Research Funding. Galimberti: AbbVie, Janssen: Honoraria, Other: Travel grants; Incyte: Speakers Bureau. García-Serra: AbbVie: Other: Educational grands; Janssen: Other: Educational grants; Novartis: Other: Educational grants. Gozzetti: Janssen: Honoraria; AbbVie: Honoraria. Hatzimichael: Amgen, Roche, Genesis, Novartis, Bristol Mayer Squibb, Celgene, Pfizer: Consultancy; Abbvie, Amgen, Bristol Mayer Squibb, MSD, Gilead, Janssen Cilag, Genesis Pharma, Roche, Takeda: Honoraria. Herishanu: AbbVie: Honoraria, Research Funding; Janssen: Honoraria; Roche: Honoraria; Medison: Honoraria. Jaksic: Roche, Oktal-Pharma/Celtrion, Sandoz: Consultancy, Honoraria. Kater: Janssen, AstraZeneca: Other: Ad Board, steering committee, Research Funding; Abbvie: Honoraria, Other: Ad Board, Research Funding; BMS, Roche/Genentech: Other: Ad Board, , Research Funding; Genmab, LAVA: Other: Ad Board, Steering Committee. Kotsianidis: Astellas: Other: NONE, Research Funding, Speakers Bureau; Genesis: Consultancy, Other: NONE; Janssen Hellas: Consultancy, Other: NONE, Speakers Bureau; Bristol Hellas: Consultancy, Other: NONE, Research Funding, Speakers Bureau; Novartis Hellas: Consultancy, Other: NONE, Research Funding, Speakers Bureau; Abbvie: Consultancy, Other: NONE, Research Funding, Speakers Bureau. Kreitman: NIH: Patents & Royalties: Moxetumomab Pasudotox; Genentech: Research Funding; Teva: Research Funding; AstraZeneca/MedImmune: Research Funding; Innate: Research Funding; GSK/Novartis: Research Funding; Array BioPharma/Pfizer: Research Funding. Laribi: BeiGene: Other: Personal Fees; Jansen: Research Funding; Novartis: Other: Personal Fees, Research Funding; Astellas Phama, Inc.: Other: Personal Fees; AstraZeneca: Other: Personal Fees; Le Mans Hospital: Research Funding; Takeda: Other: Personal Fees, Research Funding; AbbVie: Other: Personal Fees, Research Funding; IQONE: Other: Personal Fees. Lopez-Garcia: Roche: Other: Speaker Honoraria, Travel and accommodation grants; Novonordisk: Other: Speaker Honoraria; Fresenius: Other: Speaker Honoraria; Celgene: Other: Speaker Honoraria; Abbvie: Other: Speaker Honoraria, Advisor, Travel and accommodation grants; Janssen: Other: Speaker Honoraria, Advisor, Travel and accommodation grants, Research Funding. Milosevic: Roche: Honoraria; Abbvie,: Honoraria; Janssen: Honoraria; Sandoz: Honoraria. Reda: Beigene: Consultancy; Astra Zeneca: Consultancy; Abbvie: Consultancy; Janssen: Consultancy. Ruchlemer: AbbVie: Consultancy, Honoraria, Research Funding. Šimkovič: Janssen, Gilead, Roche, AstraZeneca, and AbbVie: Other: consultancy fees, advisory board participation fees, travel grants, and honoraria; University Hospital Hradec Kralove: Current Employment; AbbVie: Consultancy, Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Merck: Current equity holder in publicly-traded company; Eli Lilly: Current equity holder in publicly-traded company; J & J: Current equity holder in publicly-traded company; Gilead: Other: Travel, Accommodations, Expenses. Špaček: AbbVie, AstraZeneca, Gilead, Janssen, and Roche: Honoraria. Tadmor: Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Visentin: Italfarmaco and Gilead: Speakers Bureau. Vassilakopoulos: AstraZeneca: Honoraria; Amgen: Honoraria, Research Funding; Pfizer: Research Funding; Dr. Reddy's: Research Funding; Novartis: Consultancy, Honoraria; GlaxoSmithKline: Honoraria, Other: Travel; Merck: Honoraria, Research Funding; Integris: Honoraria; Roche: Consultancy, Honoraria, Other: Travel; Genesis Pharma: Consultancy, Honoraria, Other: Travel; Takeda: Consultancy, Honoraria, Other: Travel, Research Funding; AbbVie: Consultancy, Honoraria; Karyopharm: Research Funding. Vitale: Janssen: Honoraria. Yáñez: Gilead-Kite, Janssen, AbbVie, AstraZeneca, Beigene, Roche, Pfizer, Jazz, BMS, and Merck: Other: Advisory board participation fees ; Janssen, AbbVie, AstraZeneca, Gilead-Kite, Roche, Pfizer, and Merck: Speakers Bureau. Antic: AbbVie, Janssen, and Roche: Honoraria. Coscia: Janssen: Honoraria, Other, Research Funding; Gilead: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria, Other. Cuneo: AstraZeneca: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau. Gaidano: Beigene: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astrazeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Guièze: Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Astrazeneca: Consultancy, Honoraria. Laurenti: AstraZeneca: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Roche: Honoraria, Research Funding; Gilead: Honoraria; Janssen: Consultancy, Honoraria; BeiGene: Honoraria. Murru: Abbvie: Consultancy, Honoraria, Other: travel and accommodation; Janssen: Consultancy, Honoraria. Sportoletti: AstraZeneca: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Tam: Beigene: Research Funding; Janssen: Research Funding; Abbvie: Research Funding; Loxo: Honoraria; Beigene: Honoraria; Janssen: Honoraria; Abbvie: Honoraria. Trněný: Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Gilead Sciences: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Celgene: Consultancy; 1st Faculty of Medicine, Charles University, General Hospital in Prague: Current Employment; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Portola: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses. Bosch Albareda: Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria; Abbvie: Consultancy; AstraZeneca: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Kite: Honoraria; Sanofi: Honoraria; Lilly: Honoraria. Doubek: Janssen-Cilag, AbbVie, AstraZeneca, Amgen, Gilead, Novartis: Honoraria, Research Funding. Chatzidimitriou: Abbvie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Ghia: AbbVie: Consultancy, Honoraria, Research Funding; Acerta/AstraZeneca: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; ArQule/MSD: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Celgene/Juno/BMS: Consultancy, Honoraria; Gilead: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Sunesis: Research Funding. Stamatopoulos: AstraZeneca: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Janssen: Honoraria, Research Funding.

Abstract: Abstract 2623 Introduction. Relapsed or refractory acute myeloid leukemia (AML) patients (pts) have a dismal outcome and conventional chemotherapy offers almost no chance of cure. Consequently, allogeneic transplantation (alloSCT) has been widely used for these patients, but outcome is limited by a high relapse rate. There is no generally established standard for reinduction of remission. Clofarabine is a second-generation purine nucleoside analogue mainly evaluated in older adults with untreated AML, but there are limited data in relapsed/refractory AML. The aim of the present study was to establish the role of clofarabine in a large series of adults with relapsed/refractory AML. Methods. Eighteen French centers participated in this retrospective study. Eligibility criteria were as follows: confirmed diagnosis of AML, pts 〉 18 years (yrs) old at clofarabine treatment, and clofarabine used outside of a clinical trial. Relapses after alloSCT were included, but use of clofarabine as part of the conditioning regimen of alloSCT was not included. Data were collected regarding patient demographics, leukemia characteristics, previous treatments and the use of clofarabine including the regimen used and the outcome following treatment. Results. Between January 2007 and June 2011, 100 pts were treated with clofarabine for relapsed/refractory AML. At first diagnosis of AML, median age was 58 yrs, male:female ratio was 60:40, 86% of pts had performance status 0–1, 57% had white blood cells 〈 10000/mm3, 37% had secondary AML (prior myelodysplastic syndrome 54%), 39% had unfavorable cytogenetics, 58% had intermediate cytogenetics and 3% had favorable cytogenetics, 14/55 had NPM1 mutation, 19/69 had FLT3 internal tandem duplication. At clofarabine treatment, median age was 59 yrs (range 18–77), 42 pts were in first relapse, 35 in relapse 〉 1, and 23 had primary refractory AML. Anthracycline was previously used in 92 pts. Twenty three relapses occurred after alloSCT. Clofarabine was used as single agent (n=22) or in combination with low-dose cytarabine (LDAC, 20–40 mg/m2/d for 4–14 days, n=18) or intermediate-dose cytarabine (IDAC, 1000–2000 mg/m2/d for 3–5 days, n=56) or other drugs (n=4). The dose of clofarabine at cycle 1 was 20 mg/m2/d (n=26), 30 mg/m2/d (n=32), 40 mg/m2/d (n=40) or other (n=2) for a median number of 5 days (mean 4.9, range 3–5). Among all pts, 30 achieved complete remission (CR), and 9 achieved CR with incomplete recovery (CRi), for an overall response rate of 39%. Six pts died during cycle 1, all of infection. Responding pts received a median number of 2 cycles (mean 2.1, range 1–6). Thirteen pts underwent subsequent alloSCT and four pts proceeded to donor lymphocyte infusion. No predictive factor of response was found in univariate analysis among age (cut-off at 60 yrs), sex, de novo vs secondary AML, cytogenetics (unfavorable vs intermediate), molecular genetics, line of treatment (first relapse vs relapse 〉 1 vs refractory AML), relapse after alloSCT vs other relapse (for patients 〈 65 yrs with equally distributed cytogenetics), regimen (monotherapy vs LDAC vs IDAC) or dose of clofarabine (20 vs 30 vs 40 mg/m2/d). The median disease-free survival (DFS) was 17 months (mo). No factor significantly influenced DFS in univariate analysis, even though DFS tended to be better in relapse after alloSCT than in other relapse (for patients 〈 65 yrs with equally distributed cytogenetics) with 1-yr DFS being 100% vs 60% (p=0.1). Median overall survival (OS) was 19 mo for responding pts (CR+CRi) vs 3 mo in treatment failure (p 〈 0.0001). In univariate analysis, median OS was better in male than in female (6.8 mo vs 4.1 mo, p=0.03), and in intermediate vs unfavorable cytogenetics (5.4 mo vs 4.1 mo, p=0.04); median OS tended to be better in relapse after alloSCT than in other relapse (for patients 〈 65 yrs with equally distributed cytogenetics) with median OS being 21 mo vs 4 mo (p=0.09). In multivariate analysis, cytogenetics was the only prognostic factor for OS (p=0.02). Conclusion. This study suggests that clofarabine-based salvage regimen is safe and can be effective in the treatment of relapsed/refractory AML. Durable remissions were achieved, especially in AML relapsed after alloSCT, allowing pts the option of (second) transplantation with the potential of long term cure. Disclosures: Off Label Use: clofarabine is approved for relapsed ALL in children.

Abstract: Crebbp inactivation perturbs B-cell development, but cooperates with Bcl2 overexpression to promote lymphoma. Transcriptional and epigenetic signatures of Crebbp loss implicate Myc in disease etiology.

Abstract: BACKGROUND: The prognosis of patients with acute myeloid leukemia (AML) varies depending on the presence of mutations in the FLT3 tyrosine kinase. Internal tandem duplications (ITD) and mutations in the tyrosine kinase domain (TKD) result in continuous activation of FLT3, leading to uncontrolled blast proliferation. Since the publication of the clinical trial CALGB 10603 (RATIFY), it has been established that adding midostaurine to intensive chemotherapy improves the overall survival (OS) of patients with mutated FLT3. However, it is worth noting that this study only included patients 18-59 years old. Subsequently, a phase II clinical trial (AMLSG 16-10 trial) conducted a subgroup analysis suggesting that midostaurine may also benefit to patients between 60 and 70 years of age. Nevertheless, these findings have not been studied in real-world clinical practice. METHODS : This is multicentric non-interventional retrospective real-world study including patients ≥60 years of age with newly diagnosed FLT3-mutated AML treated with intensive chemotherapy and midostaurine (50 mg orally twice daily, d8-22) between 1st 2017 and July, 30 th 2021 from the French Innovate Leukemia Organization (FILO) and the Programa Español de Tratamientos en Hematología (PETHEMA). The primary objective was to evaluate the efficacy of midostaurine in combination with intensive chemotherapy in patients over 60 years old. We assessed the rate of complete remission (CR) or complete remission with incomplete hematologic recovery (CRi) after induction therapy, OS and event-free Survival (EFS). RESULTS: A total of 191 patients (FILO Group 122 (63.9%); PETHEMA Group 69 (36.1%)), aged between 60 and 77 years, were enrolled in the study. The patients had a median age of 67.8 years (range 60.1; 77.6). Among them, 134 (70.2%) were aged less than 70 years, while 57 (29.8%) were aged 70 years or older. 159 (83.3%) had a performance status (ECOG) of 1 or lower, while 24 (12.6%) had an ECOG of 2 or higher. 151 (79.1%) had de novo acute myeloid leukemia (AML), and 40 (20.9%) had secondary AML at diagnosis. The median white blood cell count at diagnosis was 26.5 x 10^9/L [5.99; 107]. The median percentage of blasts in the bone marrow at diagnosis was 76% [55; 88.5] . The frequency of FLT3-ITD mutation was 154 (80.6%), FLT3-TKD mutation was 44 (23%), and double mutations were observed in 7 (3.7%) patients. The median FLT3 ITD/wt ratio was 57% [22.5 - 78]. 119 (62.3%) were NPM1 muted. Regarding the intensive chemotherapy schedule in induction, 162 (84.8%) patients were treated with idarubicin-based regimens, 18 (9.4%) with daunorubicin-based regimens, and 8 (4.2%) with CPX-351. After induction, 150 (78.5%) of the patients achieved complete remission/complete remission with incomplete hematologic recovery (CR/CRi). Of those patients, 96 (64%) proceeded to intensive chemotherapy schedule in consolidation, with 83 (86.5%) of them receiving midostaurine. In contrast, 32 (21.3%) received non-intensive chemotherapy consolidation, with 27 (84.4%) receiving midostaurine. Additionally, 37 (24.7%) of the patients who achieved CR/CRi after induction underwent a hematopoietic-cell transplantation (HCT), with 33 (89.2%) undergoing allogeneic HCT and 4 (12.1%) undergoing autologous HCT. The median follow-up of the patients was 32 months. OS for the entire population was 23 months with a 2-years OS of 49.1% (95%CI: 41.5-56.7). Median EFS for the entire population was 11.1 months with a 2-years EFS of 37.1%. (95%CI: 29.6-44.5). For patients undergoing allogeneic HCT after achieving CR/CRi following induction, the median OS was not reached, with a 2-year OS of 69% (95% CI: 54.6-88.3). In contrast, for patients who achieved CR/CRi after induction but did not undergo allogeneic HCT, the OS was 32.6 months with a 2-year OS of 50.2% (95% CI: 48.4-68.2). CONCLUSIONS: This real-life study suggests that the addition of midostaurine to intensive chemotherapy regimens in elderly patients could result in acceptable CRc, OS and EFS. In order to establish the benefit of midostaurin, we will compare these results with a historical control cohort.

Abstract: Introduction. Chronic lymphocytic leukemia (CLL) has typically an indolent course but can undergo transformation into a more aggressive lymphoma (mainly of diffuse large B-cell lymphoma histology) that is called Richter's syndrome. While the advent of novel therapies targeting the BCR signaling or the BCL-2 protein is transforming the management of patients with CLL, these drugs failed to prevent the risk of RS that is estimated to be 0.5-1% per year. RS is associated with a very poor outcome and is thus becoming the main obstacle to long term CLL cure. Allogeneic stem-cells transplantation (allo-SCT) has been recommended as the treatment of choice in eligible patients with clonally related RS (Rossi Blood 2018) but previous experience is still limited to less than 50 cases. We here aimed to investigate the safety and efficacy of allo-SCT for patients with RS. Methods. We report on a retrospective study of consecutive patients with RS who underwent allo-HSCT between 2005 and 2016 in 15 French and Belgian centers from the Société Francophone de Greffe de Moelle et de Transplantation Cellulaire (SFGM-TC). Inclusion criteria were: age 〉 18, confirmed RS diagnosis, allo-HCST from either sibling or unrelated donor. Data quality was ensured using computerized discrepancy errors and on-site data verification. Results. A total of 24 patients (median age=59 years [19-69], M/F= 18/6) were included in the present study. Median time from CLL to RS diagnosis was 59 months [0-198] . The histology was DLBCL (86%) or HL (14%). The patients received a median of 1 [0-4] therapeutic line for CLL and 1 [0-3] for RS. Nine (38%) patients underwent auto-SCT prior to allo-HCT. At allo-HCT, 17 (71%) of patients were in complete and 7 (29%) in partial response. Most patients received reduced intensity conditioning (RIC) regimen (n= 18, 75%) and peripheral blood (76%) as source of stem-cells. Two (8%) patients received bone marrow stem cells and 4 (16%) cord blood stem cells. Donors were related (n=8) or unrelated (mismatched, n=8; matched, n=5; missing, n=3). A total of 15 patients (63%) received total body irradiation (TBI) within the conditioning. With a median follow-up of 27 months, 2-year OS was 44% (figure 1). The 100-day non-relapse mortality was 25%. Cause of death was relapse (n=3), treatment toxicity (n=10; GVHd, n=3; infectious complications, n=6; pulmonary toxicity, n=1), infection complications (n=1) and cerebral stroke (n=1). 2-year OS was significantly shorter for older patients (20% if 〉 59 years old vs 64% if ≤59,P = 0.031). The 2-year OS was influenced by presence of cGVHD (73% vs 25%,P = 0.006). Neither donor type, prior auto-SCT, disease status prior to allo-HCT, use of antilymphocyte serum infusions nor the regimen conditioning significantly impact OS. Conclusion. Our study suggests that allo-HCT is a strategy achieving prolonged survival but should be performed in young patients to limit the risk of NRM. The favorable impact of GVHd suggests an anti-RS allogenic effect. Disclosures Guieze: abbvie: Honoraria; janssen: Honoraria; gilead: Honoraria.

Abstract: Dysregulated immune response is the key factor leading to unfavorable coronavirus disease 2019 (COVID-19) outcome. Depending on the pathogen-associated molecular pattern, the NLRP3 inflammasome can play a crucial role during innate immunity activation. To date, studies describing the NLRP3 response during severe acute respiratory syndrome coronavirus 2 infection in patients are lacking. We prospectively monitored caspase-1 activation levels in peripheral myeloid cells from healthy donors and patients with mild to critical COVID-19. The caspase-1 activation potential in response to NLRP3 inflammasome stimulation was opposed between nonclassical monocytes and CD66b+CD16dim granulocytes in severe and critical COVID-19 patients. Unexpectedly, the CD66b+CD16dim granulocytes had decreased nigericin-triggered caspase-1 activation potential associated with an increased percentage of NLRP3 inflammasome impaired immature neutrophils and a loss of eosinophils in the blood. In patients who recovered from COVID-19, nigericin-triggered caspase-1 activation potential in CD66b+CD16dim cells was restored and the proportion of immature neutrophils was similar to control. Here, we reveal that NLRP3 inflammasome activation potential differs among myeloid cells and could be used as a biomarker of a COVID-19 patient’s evolution. This assay could be a useful tool to predict patient outcome. This trial was registered at www.clinicaltrials.gov as #NCT04385017.

Abstract: Introduction : KSHV/HHV-8 associated multicentric Castleman disease (HHV-8 MCD) is a rare lymphoproliferative disorder associating lymphadenopathy, splenomegaly, fever and inflammatory symptoms with high serum CRP, hypergammaglobulinemia and high plasma HHV-8 DNA viral load. HHV-8 MCD mainly affects HIV infected patients but can also be observed in HIV negative patients born in countries with high HHV-8 prevalence or in men who have sex with men. In a large cohort of HIV negative patients, we sought to describe patient and disease characteristics and to compare them with those observed in a large cohort of HIV-infected patients with HHV8 MCD. Methods : We analysed a cohort of 80 HIV negative patients with HHV8+ MCD and compared them to 228 HIV-infected patients with HHV8+ MCD. These patients have been prospectively enrolled in the national registry for Castleman disease held by the Reference Center for Castleman Disease in Paris, over a 30-year period. Results : Most of these patients (67,5 %) originated from Sub saharan or Northern Africa. The baseline characteristics were similar in HIV- and HIV+ patients although HIV negative patients were older at MCD diagnosis (median, 67 vs 43 years) with 20% of the patients above 75 years, and the male predominance was slightly lower in the HIV negative population (74% vs 82%). They also presented less frequently with previous Kaposi sarcoma lesions (34% vs 52%). Biological markers including cytopenia, serum CRP and gamma globulins levels as well as blood HHV8 DNA viral load were very similar in both groups, although MCD attacks in HIV negative patients were rather less agressive than in HIV-infected patients. Of notice, the median CD4 + T cell count was normal in the HIV negative group (600 x10 6/L) The incidence of lymphoma during follow-up remains high but very similar in both groups : 3,12 /100 pt.y. in HIV negative patients and 3,10 /100 pt.y. in HIV-infected patients The median overall survival (OS) was 8,8 years (95%CI, 5,5-15) in HIV- patients and 20,6 years (95%CI, 6,3-24,1) in HIV-infected patients (p=0.19). Although the follow-up was shorter in HIV negative patients (24 vs 56 months), the 5-year probability of survival (79,2%; 95%CI 61,7-89,4) was very similar to that observed in HIV-infected patients (81,2% ; CI95% 74,6-86,2). Death was related to HHV8 complications or treatment in 6 /15 (40%) HIV negative patients and in 31 /57 (54%) HIV-infected patients. The slightly higher proportion of deaths not related to HHV8 in the HIV negative population might be explained by the older age of these patients. Conclusions : Using a large cohort of HIV negative patients, we could show that HHV8 MCD in this population is very similar to that observed in HIV-infected patients. Despite the fact that these patients were older at diagnosis, the overall survival was similar to that observed in HIV-infected patients, at least at 5-year from diagnosis.