Immunochemotherapy has demonstrated high cure rates in primary mediastinal large B-cell lymphoma (PMBCL). Recent findings from the IELSG 37 study show that certain specific dose-dense treatment regimens are more likely to eliminate the need for consolidative radiation therapy, thereby reducing long-term toxicity. Here, we report our experience with DA-R-EPOCH in a cohort of 70 patients treated at our cancer center. This retrospective, observational, single-center study includes patients treated between 2013 and 2021. Treatment response was evaluated using positron emission tomography-computed tomography (PET-CT) scans and assessed according to the Deauville Score. With a median follow-up of 36.4 months, 29% of patients achieved a complete metabolic response (CMR) on interim PET-CT, while 71% achieved CMR at the end of treatment. Despite these results, 3-year overall survival (OS) and progression-free survival (PFS) rates were 99% and 93%, respectively. Our findings highlight the importance of tailoring treatment regimens, allowing for reduced reliance on consolidative therapies in line with recent advancements. Notably, none of the patients who achieved CMR on interim PET-CT experienced relapse, and no disease progression was observed beyond 1 year after completing DA-R-EPOCH. Additionally, our results indicate that dose intensification beyond level 2 does not appear to improve survival, emphasizing the important implications for minimizing treatment-related toxicity. We also analyzed the management and outcomes of refractory and relapsed cases, underscoring the challenges in treating non-responding patients identified by interim PET-CT, the limited efficacy of salvage immunochemotherapy, and the interesting role of radiation therapy in these cases.

Listeria monocytogenes is an opportunistic food-borne pathogen that can cross the blood–brain barrier and infect the central nervous system, causing potentially life-threatening neurolisteriosis, including brain abscess. Ibrutinib is a potent and irreversible small-molecule inhibitor of Bruton's tyrosine kinase. It has demonstrated efficacy in the treatment of various lymphoid cancers, and its use has increased exponentially in recent years. We describe here a case of neurolisteriosis in a patient treated with ibrutinib for chronic lymphoid leukemia and discuss the potential pathogenesis.

Objectives: Bispecific antibodies (BsAbs) are an effective treatment used in relapsed or refractory multiple myeloma. Despite a well-tolerated safety profile, infectious events appear to be frequent in clinical trials. Real-world data on epidemiology, characteristics, risk factors, and outcomes of infections in patients treated with BsAb are still needed. Methods: A retrospective, multicentre study in BsAb-treated patients with multiple myeloma was performed in 14 French centres from December 2020 to February 2023. The primary objective was to describe the incidence of infections that required hospitalization, specific treatment, or adaptation in BsAb administration. Results: Among 229 patients with multiple myeloma treated with BsAb, 153 (67%) received teclistamab, 47 (20%) received elranatamab, and 29 (13%) talquetamab. We reported a total of 234 infections, including 123 (53%) of grade of >= 3. Predominant infections affected the respiratory tract (n = 116, 50%) followed by bacteraemias (n = 36, 15%). The hospitalization rate was 56% ( n = 131), and 20 (9%) infections resulted in death. Global cumulative incidence of the first infection was 70% in all patients, 73% in patients treated with B-cell maturation antigen-targeting, and 51% with GPRC5D-targeting BsAb. In univariate analyses, corticosteroids for cytokine release syndrome (CRS)/immune effector cell-associated neurotoxicity syndrome (ICANS) were associated with a higher risk of first infection (HR = 2.13; 95% CI, 1.38-3.28), whereas GPRC5D-targeting BsAb and anti-bacterial prophylaxis were associated with a lower risk (HR = 0.53; 95% CI, 0.3-0.94 and HR = 0.65; 95% CI, 0.46-0.9). Fine and Gray multivariate model found that only corticosteroids for CRS/ICANS were correlated with a higher risk of first infection (HR = 2.01; 95% CI, 1.27-3.19). Discussions: The implementation of preventive measures that aim to mitigate the risk of infection under BsAb is pivotal, notably in patients who received corticosteroids for CRS/ICANS. (c) 2024 The Authors. Published by Elsevier Ltd on behalf of European Society of Clinical Microbiology and Infectious Diseases. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Background. Bispecific antibodies (BsAb) are a new effective treatment for relapsed/refractory multiple myeloma (RRMM). Although these immunotherapies are well tolerated, infectious complications emerged as a predominant issue, mainly with anti-BCMA BsAb. Recent guidelines were presented to prevent and manage these complications based on clinical trials safety signals. In this study, we aimed to report incidence and characteristics of infectious complications in patients treated with anti-BCMA and anti-GPRC5D BsAb. Methods. A retrospective study was conducted in 13 tertiary centers including patients with RRMM treated by BsAb between December 2020 and February 2023. We reported infectious complications events requiring specific treatment, delay in BsAb administration or hospitalisation and occurring up to three months after interruption of treatment. Results. Among the 229 patients included, 200 (87%) received an anti-BCMA BsAb with teclistamab (n=153, 67%) or elranatamab (n=47, 20%) and 29 patients (13%) received an anti-GPRC5D BsAb with talquetamab. 40% (n=90) of patients were treated in monotherapy, 42% (n=94) had dexamethasone in addition to the BsAb after step up doses and 18% (n=41) received a combination with an anti CD38, immunomodulatory treatment, proteasome inhibitor or other. The median age was 67 years (range 38-85), median of prior line of therapy was 4 (range 0-15). 62 (32%) patients had a high cytogenetic risk and 187 (82%) had a triple refractory disease. With a median follow up of 7 months (IQR 4-12 months) 234 infectious events were documented in 142 patients (62%) including 53% grade ≥ 3 and 8.4% (n=19) deaths due to infection. All infections grade ≥ 4 (n= 48; 20.6%) occurred in patients treated with anti-BCMA BsAb. Predominant localisation was pulmonary tract (n= 97, 41%) and disseminated infection (n=52, 22%) . Among the documented infections, 91 (55%) were bacterial, 64 (39%) were viral and 8 (5%) were fungal (Figure 1A). Two (1.2%) infectious events were from a parasite. Most frequent pathogens were Enterobacteriaceae (n=28, 12%), SARS-CoV-2 (n=19, 8%), anaerobic bacteria (n=10, 4%) Pseudomonas aeroginosa (n=6, 2.5%). Invasive pulmonary aspergillosis was found in 6 (2.5%) patients, and 2 (1.2%) event was PML (progressive multifocal leukoencephalopathy) and 1 (0.6%) was disseminated toxoplasmosis. Hospitalization rate was 57% (n=131), including 13% (n=30) requiring intensive care with a median hospitalization time of 10 (range 1-111) days. Overall, n=113 (47%) of the infectious events had an impact on the course of treatment. Illustrated by interruption in n=31 (14%) events, delayed administration in n=70 (32%) events or change in frequency of administration in 2 (0.9%) events. Considering immunosuppression, 125 (68%) of these infections occurred in patients associated with hypogammaglobulinemia (<3 g/L) and 22% (n=50) in patients supplemented with intravenous immunoglobulin. Regarding infectious prophylaxis, n=104 (47%) infectious events occurred despite a bacterial prophylaxis (n=104), 91% (n=125) occurred under viral prophylaxis, 73% (n=166) with trimethoprim-sulfamethoxazole or atovaquone and 11% (n=25) with pentamidine use. Global cumulative incidence of first infection was 70% in all patients, 73% in patients treated with anti-BCMA and 51% with anti-GPR5CD. Treatment with anti-GPRC5D BsAb was independently associated with a lower risk of first infection in a multivariate model adjusted for infectious prophylaxis, and hypogammaglobulinemia, HR 0.43 (IC95% 0.23; 0.77); p=0.005 (Figure 1B). Conclusion. This study highlights the rate of infectious event with BsAb treatment in RRMM setting. We describe higher frequency of infections in patients receiving anti-BCMA agents compare to anti-GPRC5D group. Impact on treatment administration is huge and dosing intervals strategy and prophylaxis appear necessary and effective to improve the morbidity and mortality rate of this hightly effective agents.

Abstract After T-cell replete haploidentical stem cell transplantation, GVHD prophylaxis with post-transplant cyclophosphamide (PT-Cy) is now evaluated in unrelated donor (UD) transplants, where antithymocyte globulin (ATG) remains standard. We report the outcome of patients transplanted from HLA-10/10 matched unrelated donor (MUD) treated with PT-Cy (n=30), in comparison with a historical cohort treated with ATG (n=64). In the PT-Cy group, we observed lower 2-4 acute GVHD (23% vs. 45%, p=0.014), lower chronic GVHD (all grades: 13% vs 33%, p=0.029; moderate to severe: 10% vs. 27%, p=0.039) but no difference in the relapse (20% vs. 11%, p=0.628), non-relapse mortality (3% vs 11%, p=0.169), progression free survival (77% vs 78%, p=0.638) and overall survival (87% vs 83%, p=0.602). Neutrophil (19 vs 17 days, p=0.049) and platelet (26 vs 10 days, p<0.001) recovery was significantly delayed in the PT-Cy group. Then, we followed the GVHD and the immunosuppressive treatments (IST) prevalence in disease free patients as marker of quality of life. At 6 months, 5% and 36% in the PT-Cy group were living with GVHD and IST, versus 26% (p=0.030) and 64% (p=0.049). We conclude that PT-Cy is an effective GVHD prophylaxis in 10/10-HLA MUD allo-SCT, representing a valuable alternative to ATG.

Introduction: Patients with relapsed or refractory (R/R) diffuse large B cell lymphoma (DLBCL) after frontline chemotherapy have a dismal prognosis. Salvage chemotherapy followed by high dose consolidation chemotherapy supported with autologous stem cell transplantation (ASCT) can achieve cure in about 50%, and remains the standard of care for fit patients under 70 yo. Nevertheless, this approach is less effective for patients with primo-refractory disease (refractory to 1st line CT or experiencing relapse during the 12 months after completion of 1st line treatment). With the advent of autologous CAR T cells targeting CD19 in second line of treatment, the place of ASCT must be redefined based on robust clinical data to offer candidate patients their best available treatment. As part of this "choose wisely" approach, we report the outcomes of patients receiving ASCT as consolidation therapy at our center. Methods: we report the retrospective experience of a monocentric transplantation program. Inclusion criteria were: 1) R/R DLBCL 2) In response to salvage therapy according to Deauville score criteria. Complete response (CR) was defined as Deauville scores 1-2-3, partial response (PR) as Deauville 4 or 5. 3) ASCT between 2010 and 2020 at IPC, Marseille 4) Conditioning regimen with BEAM or Bendamustine-Eam. The patients were stratified according to the NCCN-IPI in 2 groups: low risk (NCCN-IPI≤3) and high risk (NCCN-IPI>3). Univariate analyses included age, aaIPI, NCCN IPI and disease status pre ASCT. Multivariate analyse included disease status pre ASCT and NCCN-IPI Results: Ninety eight patients with a median age of 57 yo (26-71) were included. Most of them were primary refractory (52 patients, 53%). Patients received a median number of 2 lines of chemotherapy (2-4) before ASCT. At time of reinjection, all were in response (78% were in CR and 22% in PR). With a median follow up of 42 months (33-60), 3 year progression free survival (PFS) and overall survival (OS) were 68% and 82% respectively, and 3 year cumulative incidence of relapse (CIR) was 27%. In the whole group, 12 month NRM was 2%.Age was not associated with an increased risk of NRM (SHR 2.3 CI95 [0.44-12.24], p:0.3) . Three year PFS and OS were significantly higher in patients who underwent ASCT in CR: 3 years PFS 74% CR vs. 43% PR (HR 3.04 95CI [1.5-6.17], p: 0.001.), 3 year OS 88% CR vs 61% PR (HR 4.53 95CI [1.74-11.81 ], p< 0.001.). This was confirmed by multivariate analyse (HR 3.08 95CI [1.50,6.29] , p=0.0021 for PFS and HR 5.4 95CI [1.99-14.65 ], p=0.0009 for OS). Disease status at the time of ASCT and NCCN IPI >3 were strongly associated with PFS and OS (3 year PFS 71% CR and NCCN IPI ≤3 vs. 17% PR and NCCNIPI >3 (HR 5.62 95CI [2.03-15.54], p<.001 ) . Three year OS for CR and NCCN IPI ≤3 vs. PR and NCCNIPI >3 were: 86% vs. 17% (HR 16.15 95CI [4.87-53.57], p<.001). In the primary refractory group, 3 year PFS, OS and CIR were 70%, 75% and 22% respectively. No differences were observed with non primary refractory group (3 years PFS 66% vs. 70%, p=0.56 , 3 years OS 90% vs 75%, p= 0.077) Conclusion : We confirm that ASCT provides good disease control with few toxicity and remains a valid option in 2nd line DLBCL until 70 years of age. However, our results appear to be superior to previously published reports, even more in the group of primary refractory diseases, possibly due to a strict selection of patients achieving complete response after salvage therapy. Disease status before ASCT remains the most relevant parameter to predict survival, and should be incorporated in treatment decision algorithms to elect the optimal treatment sequence. Questions remain about the best strategy for patients in PR before ASCT, and we await long term results of randomized phase 3 CART cells studies (ZUMA7, TRANSFORM). According to our results, given the unfavorable prognosis of the group of patients in PR and NCCN IPI ≥ 3 could be the subgroup of patients that would most certainly benefit from CART cells. In conclusion, the best 2nd line strategy between ASCT and CAR T cells should be decided according to response quality, the access to CAR T cells program and economic impact. Moreover, the combination of pre treatment prognostic factors ( NCCN IPI) and pre-ASCT response to treatment could be even more halpful to choose the best consolidation treatment. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Introduction: Large B-cell lymphomas (LBCL) are aggressive but curable subtypes of non-Hodgkin lymphoma (NHL). Patients with multiple relapses or refractory (R/R) LBCL have a very poor prognosis with a median overall survival of about 6 months. Until recently, allogenic stem cell transplantation (allo-SCT) was the only curative option for chemotherapy-refractory patients or relapses after an autologous stem cell transplantation (auto-SCT). However, its efficacy was limited by significant toxicity and high non-relapse mortality (NRM), mainly due to graft-versus-host disease (GVH) and infections. Lately, approval of autologous CD19-directed chimeric antigen receptor T-cell therapy (CAR-T) significantly improved therapeutic management for R/R LBCL after 2 or more lines of systemic therapy, providing long-term remissions in 35 to 40% of patients with manageable toxicity. Most recently, ZUMA-7 and TRANSFORM trials demonstrated the superiority of second-line CAR-T over standard of care chemotherapy with or without auto-SCT for R/R LBCL. To investigate the positioning of allo-SCT in the current therapeutic landscape of R/R LBCL, we performed a retrospective analysis of patients treated with allo-SCT or CAR-T for this indication in our institute. Materiel & Method: All patients who underwent allo-SCT or CAR-T from February 2010 to January 2022 at Institute Paoli-Calmettes (Marseille, France) were included in this retrospective study. LBCL included diffuse large B-cell lymphoma DLBCL, high-grade B-cell lymphoma with translocations involving MYC and BCL2 or BCL6, or Burkitt like-lymphoma (HGBL), Primary Mediastinal B-cell lymphoma (PMBCL), Grey-Zone lymphoma (GZL), and transformed follicular or marginal zone lymphoma (t-FL and t-MZL). Results: We analyzed 95 successive patients with R/R LBLC treated with allo-SCT (from Feb 2010 to Dec 2020; N = 39; median age: 56 (range 20-71); Donor type: matched related donor: 13; mismatched related donor: 15; matched unrelated doner: 9; mismatched unrelated donor: 1 cord blood = 1) or CAR T cell therapy (from Jan 2019 to Jan 2022; N = 56; median age : 58 (range 19-75); Axi-Cel n = 40, Tisa-Cel n = 16). Median number of prior lines received before cellular therapy were 3 and 2 for allo-SCT and CAR-T groups respectively, bridging therapy excluded. The CAR-T group had a significantly greater proportion of patients with primary refractory disease (71,4% vs 38,4%). The two-year OS and PFS rates for the allo-SCT group were 69% [95% confidence interval (CI): (56-85)] and 66% [95% CI: (53-83)] respectively. The cumulative incidence of NRM at 2-year post allo-SCT was 13% [95% CI: (6-30)]. The two-year OS and PFS rates for the CAR-T group were 67% [95% confidence CI: (53-84)] and 43% [95% CI: (31-61)] respectively. At a median follow-up of 23,2 months, 28 patients experienced relapse/progression after CAR-T. 5 patients underwent allo-SCT after CAR-T failure, 1 of whom was in partial response at the time of conditioning and the 4 others with complete responses. With a median follow up of 14 months: 4 patients are still in response after allo-SCT and only 1 patient had an early relapse (<3 months). Conclusion: Our results confirm efficacy and safety of CAR-T in R/R LBCL with durable complete responses in about 40% of patients in the 3rd line setting. However, early failures after infusion require prompt diagnosis and management because they portend a very dismal prognosis. In this context, our data show that allo-SCT remains a curative option for selected LBCL patients relapsing after CAR T-cell therapy with manageable toxicity. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Hepatic dysfunction (HD) is common in patients with haematological malignancies. Hepatic haemophagocytosis (HH) was detected in >50% of liver biopsies taken when HD remained unresolved after standard examination. We aimed to explore the contribution of liver biopsy in patients with both haematological malignancies and HD, describe the population of patients with HH, assess the prognostic impact of HH, and investigate haemophagocytic syndrome diagnostic score (HScore) utility in patients with HH. Between 2016 and 2019, 116 consecutive liver biopsies (76 transjugular, 40 percutaneous) were taken in 110 patients with haematological malignancy and HD (hyperbilirubinaemia, elevated transaminases, and/or cholestasis) and without a clear diagnosis. Liver biopsies were safe and diagnostically efficient. Predominant diagnoses included: HH (56%), graft-versus-host disease (55%), associated infections (24%), sinusoidal obstruction syndrome (15%), and tumoral infiltration (8%). Of patients, 35% were critically ill and 74% were allogeneic haematopoietic stem cell transplantation recipients, while 1-year overall survival (OS) was 35% with HH versus 58% without HH (p = 0.026). The 1-year OS was 24% with a HScore of ≥169 versus 50% with a HScore of <169 (p = 0.019). Liver biopsies are feasible in and contribute significantly to haematology patients with HD. HH occurred frequently and was associated with a poor prognosis. Combined with liver biopsy, the HScore may be helpful in refining haemophagocytic syndrome diagnosis.

Autoimmune cytopenias (AIC) are well-known complications of chronic lymphocytic leukemia (CLL).1 There is no consensus regarding their optimal management. No prospective trial has ever been conducted in this particular setting, and patients with uncontrolled AIC are systematically excluded from clinical trials. The first-line therapy is usually based on corticosteroids, but in most cases, this treatment does not result in a long-term response of AIC. It is hypothesized that an optimal control of CLL should lead to a longer control of AIC. Novel drugs targeting B-cell receptor (BCR) signaling, such as ibrutinib and idelalisib have dramatically changed the outcome of patients with progressive CLL.2, 3 They affect the malignant clone by disrupting the signaling pathway downstream of the BCR, but they also impact the ability of CLL cells to interact with the tumor microenvironment, which plays an important role in the onset of CLL-associated AIC. Thus, kinase inhibitors (KI) may represent a valuable option for the management of CLL-associated AIC. The aim of this study was to retrospectively analyze the outcome of CLL patients suffering from AIC and being treated with KI because of these autoimmune events. Forty-four patients from 15 centers belonging to the FILO (French Innovative Leukemia Organization) were included in this study. First KI was ibrutinib for 25 patients and idelalisib for 19 patients. Among the ibrutinib treated patients, diagnosis of AIC was autoimmune hemolytic anemia (AIHA) for 16 patients (64%), immune thrombocytopenia (ITP) for 5 (20%), Evans syndrome for 3 (12%), and pure red cell aplasia for 1 (4%). In the idelalisib group, 12 patients were treated for AIHA (63%), 6 for ITP (32%), and 1 for an Evans syndrome (5%). At the time of KI initiation, 70% of patients presented with active CLL disease requiring treatment by itself, regardless of AIC. When available, study of common prognostic factors revealed that most patients presented with adverse prognostic factors, as expected in CLL-associated AIHA. Details of the demographic, clinical, and biological characteristics of the patients by KI group and for each type of AIC (AIHA, ITP, and Evans syndrome) are available in Tables S1 to S4. Most patients (93%) were previously treated for either CLL progression without AIC, AIC alone, or both (45%, 77%, and 34%, respectively). The median number of prior therapies was 3 (0-6). Previous lines of treatment are summarized in Table S5. In most cases, KI were introduced at standard doses, 150 mg twice daily in combination with rituximab according to the French marketing authorization label in 18/19 patients for idelalisib (95%), and 420 mg daily for ibrutinib. Ibrutinib was associated with rituximab in five patients (20%). The majority of patients (66%) received concomitant short-term AIC therapy (corticosteroids or thrombopoietin receptor agonists, Table S6). In nearly all cases, both ibrutinib and idelalisib resulted in satisfactory control of AIC. Response criteria are detailed in the supporting information. In terms of AIC, overall response rates (ORRs) to ibrutinib and idelalisib were 92% and 95%, respectively and were not correlated to the AIC type. Considering CLL, ORR, and CR were 100% and 24%, respectively for ibrutinib treated patients, and 95% and 37%, respectively, for idelalisib treated patients. Response rates of both AIC and underlying CLL for each type of associated AIC are detailed in Figure 1A. KI therapy allowed corticosteroids discontinuation in 86% of ibrutinib patients and in 67% of idelalisib patients. In this specific population, it is of interest to consider the safety profile of ibrutinib and idelalisib as the frequent concomitant exposure to corticosteroids might increase the rate of infections.4 Twenty-one of our 44 patients (48%) experienced at least one grade from 3 to 5 adverse events while on KI therapy, 10 in the ibrutinib group (40%), and 11 in the idelalisib group (58%). The increased bleeding risk induced by ibrutinib should be considered especially for ITP patients. Four patients (16%), all 4 treated for AIHA, presented grade 3/4 hemorrhagic syndrome. No severe hemorrhagic event was reported in ibrutinib patients with ITP. Two patients (8%) developed atrial fibrillation. Four patients (16%) experienced severe infections. In the idelalisib group, four patients (21%) developed colitis, and hepatic toxicity was reported in four patients. Severe infections occurred in five patients (26%), mainly pneumonia (cytomegalovirus n = 1, Pneumocystis jirovecii n = 2, pneumococcus n = 1). At the last follow-up, in the ibrutinib group, most patients were still receiving ibrutinib. Conversely, more than 60% of the patients had stopped idelalisib, mainly because of severe adverse events in accordance with the toxicity profile of the drug. Reasons for KI discontinuation are detailed in Table S7. In our cohort, KI compared favorably with previously published data on immunochemotherapy in CLL-associated AIC.5, 6 After a median follow-up of 27.8 months (range, 2.8-47.7), the estimated 2-year overall survival (2y-OS) of the whole cohort was 88%. The two-year progression-free survival (2y-PFS) was 75.3% for CLL and 65.1% for AIC. The AIC type did not significantly impact 2y-PFS (Figure S1). In the ibrutinib cohort, 2y-OS was 95% and 2y-PFS were 81% for AIC and 94.4% for CLL (Figure 1B,C). In the idelalisib arm, 2y-OS was 80% and median PFS was 19 months for AIC and 25.7 months for CLL (Figure 1D,E). At the last follow-up, 66% of the whole cohort was still responding to treatment. Fifteen patients experienced progression of CLL, AIC, or both (CLL along with AIC progression n = 5, CLL without AIC progression n = 6, AIC without CLL progression n = 4). The nine AIC relapses all occurred in patients with AIHA, and not surprisingly after KI discontinuation in most cases, owing the suspensory effect of these agents. Finally, it is important to note that this retrospective study was not designed to make a direct comparison between ibrutinib and idelalisib, and that shorter PFS in the idelalisib group may be linked to the shorter exposure to the drug. Our results indicate that BCR inhibitors, such as ibrutinib and idelalisib, are able to induce sustained responses on AIC and may offer new therapeutics options for AIC. A.Q. and T.A. designed the study; A.Q., T.A., S.G., L.Y., C.D., J.D., A.C., L.G., S.L., M.S.D., M.V., S.D.G., N.D., E.D., D.G., D.R., E.T., F.M. included patients in the study, A.Q. and M.C.B. created the database, H.O. and V.L. performed statistics, A.Q., S.G., A.D. and T.A. wrote the manuscript. 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.

Background Autoimmune cytopenia (AIC) are well-known complications of chronic lymphocytic leukemia, occurring in approximately 4 to 10% of patients. The management of CLL-associated AIC is not consensual and patient with uncontrolled AIC are systematically excluded from clinical trials. Few data evaluating the efficacy of BCR inhibitors on CLL-related AIC are available. If some preliminary data focusing on patients included in clinical trials with controlled AIC suggested that ibrutinib was able to control AIC, the duration of responses were unknown. Moreover, no data regarding the ability of idelalisib to control AIC have been currently reported. The aim of this study was to retrospectively analyze the outcome of CLL patients suffering from autoimmune hemolytic anemia (AIHA), immune thrombocytopenia (ITP), Evans syndrome or pure red cell anemia (PRCA) and treated with ibrutinib or idelalisib. Results Forty-four patients from 15 FILO centers were included in this study. First kinase inhibitor (KI) was ibrutinib for 25 patients and idelalisib for 19 patients. Among the ibrutinib treated patients, diagnosis of AIC was AIHA for 16 patients (64%), ITP for 5 patients (20%), Evans syndrome for 3 patients (12%) and PRCA for one patient (4%). In the idelalisib group, 12 patients were treated for AIHA (63%), 6 patients for ITP (32%) and one patient for an Evans syndrome (5%). Most patients presented with adverse prognostic factors such as 11q or 17p deletion by FISH and unmutated IgHV. Most patients had previously been treated either for CLL progression, autoimmune cytopenia or both and median number of prior therapies was 1 (0 to 6). Before starting ibrutinib or idelalisib, 34 patients (77%) had a history of AIC and had previously received corticosteroid monotherapy (N=15), rituximab monotherapy (N=15), a combination of rituximab, cyclophosphamide and dexamethasone (N=23) or rituximab and bendamustine (N=15). At the time of KI initiation, 66% of patients were receiving concomitant AIC therapy, consisting in corticosteroids in 26 patients (59%) or TPO (thrombopoietin) receptor agonists in 3 patients (7%). Overall response rates (ORRs) to ibrutinib and idelalisib on AIC were 92% and 95% respectively, and were not correlated to the AIC type. On ibrutinib therapy, 87.5% of patients with AIHA and 100% of patients with ITP or Evans syndrome achieved at least partial response (PR). In the idelalisib group, the ORR was 92% for AIHA patients and 100% for patients with ITP or PRCA. Considering CLL, Ibrutinib ORR and bone marrow unconfirmed complete response (CR) were 100% and 24% respectively. ORR and BM unconfirmed CR on CLL were 95% and 37% respectively the idelalisib group. KI therapy allowed discontinuing corticosteroids in 86% of ibrutinib patients and in 67% of idelalisib patients. Fifteen patients (34%) of the whole cohort experienced progression of CLL, CAI or both during the follow-up. Among them, nine (20%) experienced relapses of the CAI, and all of them were AIHA. In the ibrutinib arm, 1 patient withdrew ibrutinib shortly after initiation because of uncontrolled AIHA and 2 patients experienced relapse of AIHA while on therapy. In the idelalisib group, treatment failed to control AIHA in one case, but for responding patients, no AIHA relapse was described during idelalisib treatment. Five patients experienced relapse of AIHA after idelalisib discontinuation. With a median follow-up of the entire cohort of 26.8 months, the estimated two years overall survival (2y-OS) of the whole cohort was 88%, while the estimated two years progression free survival (2y-PFS) were 75.3% for CLL and 65.1% for AIC. In the ibrutinib cohort, 2y-OS was 95% and 2y-PFS were 81% for AIC and 94.4% for CLL. In the idelalisib arm, 2y-OS was 80%. Median PFS was 19 months for AIC and 25.7 months for CLL. Conclusion Our results demonstrate that kinase inhibitors are able to induce long-term control of both AIC and CLL and represent new therapeutics options for patients with AIC associated with CLL. Quinquenel: Jansen Cilag: Honoraria, Research Funding; Abbvie: Honoraria. Ysebaert:Roche: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Janssen: Consultancy, Research Funding.

Abstract Introduction : Significant improvements of leukemia free survival have been obtained over the last 30 years in AML. This progress has resulted from optimization of the same chemotherapy-based "one-size-fits-all" approach. However, even though the majority of patients eligible for intensive chemotherapy achieve complete remission (60% to 80%), the majority still relapse and ultimately die (5-year overall survival being around 20%). Recent genomic studies have revealed the heterogeneity of AML at the molecular level, stressing the need for personalized therapeutic approaches. The fundamental idea in genomic medicine is that somatic genetic alterations can be identified and matched with drugs targeting those abnormalities for a patient's benefit. However, there are not that many potent, tolerated targeted agents in the clinic that can induce significant clinical responses. Interestingly, the majority of the most effective drugs do not function by exploiting genetic mutations in individual tumors. Thus, additional functional approaches are needed to identify new drugs and assign existing drugs to larger numbers of patients with AML.From this perspective, the"chemogenomic" approach realizes an integratedanalysis of the molecular clonal abnormalities for the leukemic patients, and compares it to a functional drug sensitivity testing (DST) which can test simultaneously dozens of drugsex vivo. This approach aims to identify correlations between genomic changes and sensibilities increased in certain categories of drugs. The CEGAL project is a prospectivemonocentric study aiming to evaluate the feasibility of this personalized approach for relapse or refractory AML patientsby determining the proportion of patients whosechemogenomic results are available in less than 21 days. Methods : Patients with relapsed and/or refractory AML were eligible if no alternative therapy was available. Written consent was obtained from all patients (Study CeGAL-IPC 2014-012, EUDRACT 2014-A01209-38). Ex vivo sensitivity profiling was performed on freshly isolated AML blasts derived from patient bone marrow aspirates and peripheral blood with a panel of 78 drugs representative of the main therapeutic classeskwown to be active in AML. After 48h of incubation, cellular viability was measured with the CellTiter-Glo© Luminescent cell viability assay (Promega) kit to obtain one EC50. Next generation sequencing (NGS) was performed on a 200 genes panel with Mi-Seq (Illumina) and genomic profils by cGH-array (Agilent4x180K) were established. Personalized treatment plans were then reviewed by an institutional personalized committee, which issued final treatment recommendations. Results: A total of 48 AML patients were included (refractory=8,relapse=40) with a median age of 64 years old (range 24-81) and a median number of prior therapies of 2. More than half of the patients presented an adverse prognostic according to the 2017 ELN risk stratification (n=29). The most frequent genomic alterations were TET2 in 32.5% of the patients, ASXL1 (27.5%), DNMT3A (25%), TP53 (22.5%), SRSF2 (20%) and RUNX1 (17.5%). The median number of mutations per patient was 5,6. The main objective was completed with chemogenomic results in less than 21 days for 62.5% of the patients (n=25) with a median time of 22.4 days. Twenty four patients (67,5%, n=27) had targetable mutations and for 36 patients (90%), there was at least one drug predicted efficient. In light of the chemogenomic analysis, we found a correlation between genomic alteration and drug sensitivy for 28 patients. Thirteen patients (32.5%) received a treatment guided by the analysis whatsoever chemotherapies or targeted therapies. The 27 others didn't receive a personalized treatment either because the molecule wasn't commercially available or because the physician decided so. Conclusion : In our experience, the chemogenomic is an innovative and promising approach, allowing to assign patient-specific treatment options according to their mutational profile and to in vitro drugs' response in a median time of 3 weeks. Disclosures No relevant conflicts of interest to declare.

Purpose of Review We aimed to produce a comprehensive update on clinical and biological data regarding two rare lymphoid neoplasms, B and T prolymphocytic leukemias, and assess therapeutic management in the light of new molecular insights and the advent of targeted therapies. Recent Findings B cell prolymphocytic leukemia (B-PLL) diagnosis remains challenging in the absence of clear immunophenotypic or cytogenetic signature and overlap with mantle cell lymphoma. New molecular defects have been identified in T cell prolymphocytic leukemia (T-PLL), especially in the JAK STAT pathway. Like in chronic lymphocytic leukemia (CLL), B-PLL treatment depends on the presence of TP53 dysfunction. In T-PLL, alemtuzumab still remains the standard of care. Allogeneic transplantation is the only curable option. Thanks to reduced intensity conditioning regimens, it has become accessible to a larger number of patients. Summary PLL prognosis remains poor with conventional therapies. However, great advances in the understanding of both T- and B-PLL pathogenesis lead to promising new therapeutic agents.

Although the amount of CD34+ cells in peripheral blood stem cell (PBSC) graft could affect engraftment and outcome after allogeneic hematopoietic stem cell transplantation (Allo-HSCT), the optimal CD34+ cell dose remains unknown.1 In the early 2000s, we reported that high dose CD34+ cells (>8 × 106/kg) was associated with an increased incidence of graft-versus-host disease (GVHD) after Allo-HSCT prepared by myeloablative conditioning (MAC) regimens.2 However, transplantation procedures strongly changed during the past 15 years, especially with the development of reduced intensity conditioning (RIC) regimen to treat patients with advanced age and/or comorbidities.3 In this setting, it was shown that the use of antithymocyte globulins (ATG) as part of RIC regimen is highly effective as GVHD prophylaxis.4 Thus, we wondered if the negative impact of high CD34+ cell doses observed in the setting of MAC (initially reported without ATG) remains true after RIC regimens. Registry-database studies have evaluated the impact of CD34+ cell dose on outcome after RIC regimen. The experience of the CIBMTR showed that outcome was better when higher doses of CD34+ cells (>4 × 106/kg) were infused.5 In contrast, the EBMT series found that a high amount of CD34+ cells (>8.25 × 106/kg) was associated with increased risk of GVHD and poor outcome.6 These discordant results may be due to the heterogeneity of included patients in terms of conditioning regimens, in vivo T-cell depletion, disease risk, and/or GVHD prophylaxis. We therefore investigated the role of CD34+ PBSC graft composition on outcome after Allo-HSCT in a cohort of patients homogeneously prepared with an ATG-based RIC regimen. We retrospectively analyzed consecutive patients who underwent Allo-HSCT from 2005 to 2013, at the Paoli Calmettes Institute. Patients with following criteria were eligible for analysis: (1) hematological malignancies; (2) RIC regimen based on fludarabine (150 mg/m2), busulfan (260 mg/m2 total dose) and rabbit ATG (5 mg/kg total dose); (3) PBSC from matched related (MRD) or 10/10 matched unrelated donor (MUD) as graft source; (4) Cyclosporine A (CSA) alone as GVHD prophylaxis. Details about conditioning regimen, donor stem cell mobilization, cell enumeration methods and statistical analyses are available in the Supporting Information File 1. We analyzed 246 patients, with a median age of 59 years (19-71). Median dose of CD34+ cells was 6.5 × 106/kg (range: 1-14) (Details in Supporting Information File 2). Briefly, 142 patients (58%) had a matched-related donor, 44 patients (18%) had low disease risk index, and 110 patients (46%) had a hematopoietic cell transplantation comorbidity index ≥ 3. All patients engrafted and median follow-up after Allo-HSCT was 36 months (5-99). Based on our previous report in the setting of MAC, we decided to first analyze the CD34+ cell dose as a categorical variable using 8 × 106/kg as cut off.2 We found no difference in the cumulative incidences of both grade III-IV acute GVHD (≤ vs. >8 × 106/kg: 9% vs. 10%, P = .705) and extensive chronic GVHD (≤ vs. > 8 × 106/kg: 24% vs. 22%, P = 0.715; Table 1, Supporting Information File 3—Fig. A,B) according to CD34+ cell dose. Adjusted Cox model confirmed that of CD34+ cells in PBSC graft > 8 × 106/kg was not associated with increased incidence of acute or chronic GVHD, (acute III-IV: Hazard ratio (HR) = 0.96, 95% confidence interval (95 CI) = [0.42-2.23], P = .929; extensive chronic: HR = 0.84 [0.44-1.60], P = .603, Table 1). Thus, in a population of patients who were homogeneously prepared by ATG-based RIC regimen, we found no impact of CD34+ cell dose on the incidence of GVHD, contrasting with the previous results obtained in the setting of MAC.2 This could be explained in part by the use of ATG, which probably plays a major role as GVHD prophylaxis and may counterbalance the negative impact of the high CD34+ cell doses. It is also important to notice that optimal cutoff defining high dose of CD34+ is not well defined and varied across different studies. To explore the possibility that the optimal cut off may be different than 8 × 106/kg when patients receive a ATG-based RIC regimen, we also analyzed the CD34+ cell dose as a continuous variable (Table 1) and as a categorical variable dichotomized using the median of CD34+ cell dose (6.5 × 106/kg) or quartiles. As shown using the cutoff of 8 × 106/kg, none of these methods found an association between high dose of CD34+ cells and the occurrence of GVHD (Supporting Information File 4). Moreover, we found no impact of CD34+ cell dose on non-relapse mortality, relapse, progression-free survival, and overall survival (Table 1 and Supporting Information File 4). In addition, we used the random survival forest method to evaluate trends of association between CD34+ cell dose and GVHD. We showed that both day-100 acute and 3-year chronic GVHD were not strongly influenced by CD34+ cell dose, after either MRD or MUD Allo-HSCT (Supporting Information File—Fig. C,D). The trends of these curves (horizontal and flat) support that there is no ideal cutoff for analyzing the impact of CD34+ cell dose. In our series, we were not able to explore the impact of very low CD34+ cell doses, and acknowledge that a minimal amount of CD34+ is needed for good engraftment.1 Indeed, only three patients had a less than 2 × 106/kg of CD34+ cells and no patients experienced graft failure. In conclusion, we found no significant impact of CD34+ PBSC graft composition on GVHD and outcome after ATG-based RIC Allo-HSCT. In this situation, the optimal CD34+ cell dose remains unknown, contradicting what was observed using MAC regimens. Thus, we suppose that there is no evidence for limiting the maximal amount of PBSC dose in Allo-HSCT prepared by ATG-based RIC regimen. The authors declare that they have no competing interests. AC, SF, SH, AG, BC, CF, CL, PJW, CC, DB and RD edited and approved the manuscript; AC, SF, SH, AG, CF, DB and RD enrolled patients and collected the data; BC, CL and CC were in charge of donor mobilization and collection, and performed cell numeration; AC and RD performed statistical analyses; DB and RD design the study; AC and RD wrote the manuscript. Authors thank the nursing staff under supervision of Laurence Caymaris for providing excellent care for our patients. Additional Supporting Information may be found in the online version of this article. 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.