ALBERT

Description: 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. Disclosures Quinquenel: Jansen Cilag: Honoraria, Research Funding; Abbvie: Honoraria. Ysebaert:Roche: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Janssen: Consultancy, Research Funding.

Description: 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.