Impact Analysis of Aspirin over the Cardiac Activity

Cardiovascular disease (CVD) is the leading cause of death in most developed countries, including the United States, with a significant economic impact. Lifestyle changes and the administration of antiplatelet medication, like aspirin, may significantly contribute to the secondary prevention of CVD in adults. For years, aspirin has been utilized for both secondary and primary cardiovascular disease prevention. Aspirin has been extensively used because of the belief that it may have a positive impact on primary prevention, despite the debate surrounding its usage. This study briefly examines usage patterns and discusses the potential variables and factors that can decrease the ability of aspirin to prevent cardiovascular disease. The present study also explore the key studies of aspirin use in the context of recent recommendations. The risk of bleeding has been observed to significantly rise, although large randomized clinical studies have demonstrated a reduction or absence of CVD events. Prevention strategies for cardiovascular disease with low-dose aspirin are no longer advised for persons at intermediate risk. To determine whether taking aspirin is worth the potential dangers, the benefits must be evaluated.Copyright © 2022 Novyi Russkii Universitet. All rights reserved.

PACE-A: An international phase 3 randomised controlled trial (RCT) comparing stereotactic body radiotherapy (SBRT) to surgery for localised prostate cancer (LPCa)-Primary endpoint analysis

Background: People presenting with early-stage LPCa have several treatment options. There is therapeutic equipoise with lack of randomised evidence for superiority of radiotherapy or surgery. PACE-A aimed to determine if there is improved quality of life (QoL) following SBRT compared to surgery. Method(s): PACE (NCT01584258) is a phase 3 open-label multiple-cohort RCT. In PACE-A, people with LPCa, T1-T2, Gleason<=3+4, PSA<=20ng/mL & suitable for surgery were randomised (1:1) to SBRT or surgery. SBRT dose was 36.25Gy/5 fractions in 1-2 weeks;surgery was laparoscopic or robotically assisted prostatectomy. Androgen deprivation was not permitted. Co-primary endpoints were patient reported outcomes (PROs) of Expanded Prostate Index Composite (EPIC-26) questionnaire number of absorbent pads per day & EPIC bowel subdomain score at 2 years. Target sample size was 234 participants (pts) to detect 9% difference in urinary incontinence (80% power, 5% 2-sided alpha) & 5-point difference in mean bowel subdomain score (90% power, 5% 2-sided alpha) with higher EPIC score (range 0-100) indicating better QoL. Secondary endpoints included clinician reported toxicity and additional PROs (1% significance level). Analysis is by treatment received. Result(s): From Aug 2012 to Feb 2022, 123 men from 10 UK centres were randomised. The IDMC advised stopping recruitment after a 2-year gap in during COVID. Pts had median age 66years (IQR: 61, 69), median PSA 8ng/ml (6, 11) with 52% tumours >=T2b and 79% Gleason 3+4;93% pts were of white race. 58/63 pts received SBRT as allocated (2 received surgery, 2 unknown, 1 withdrawn);48/60 received surgery as allocated (1 received SBRT, 3 received CRT, 2 unknown, 6 withdrawn). 8 laparoscopic and 42 robotic assisted operations were performed. Median follow-up is 50 months (IQR 41, 74). At 2 years, fewer SBRT pts reported use of urinary pads: 2/43 (4.5%) vs 15/32 (46.9%), p<0.001. SBRT pts had significantly worse bowel subdomain score (mean (SD) 88.4 (12.7) vs 97.3 (5.5), p<0.001). 7/45 (15.6%) SBRT and 0/31 (0%) surgery pts reported moderate/big problem with bowel symptoms (p=0.04). SBRT pts reported less EPIC sexual subdomain score (58.0 (31.9) vs 29.3 (20.5), p<0.001);there was no evidence of a difference in urinary subdomain score (85.5 (19.8) vs 80.5 (20.8), p=0.29). At 2 years, CTCAE genitourinary grade 2 or higher(G2+) toxicity was seen in 5/54 (9.3%) SBRT vs 4/42 (9.5%) surgery pts (p=0.97);there was no G2+ gastrointestinal (GI) events seen in either group. Conclusion(s): PACE-A contributes the first randomised data to the comparison of SBRT with surgery in LPCa providing PRO data relevant to informed decision making. Compared to surgery, pts receiving SBRT had better urinary continence & sexual bother score;clinician reported GI toxicity was low but SBRT pts reported more bowel bother at 2 years.

Toxicity patterns associated with chronic ketamine exposure

Introduction: Synthesized in 1962, ketamine is used as a sedative, antidepressant and for the management of complex chronic pain. More recently, besides its therapeutic use, ketamine has been increasingly used as a recreational drug among young adults. As a result, an increasing number of reports have described side effects associated with its chronic exposure. This review aims to present the current evidence on the toxicity associated with chronic ketamine exposure. Method(s): Considering the limited literature on the topic, Pubmed and Embase were searched and all types of articles were considered, including systematic reviews, retrospective studies, case series and animal studies. Evidence: Chronic ketamine exposure is associated with urological toxicity manifesting mainly by lower urinary tract symptoms with features of ulcerative cystitis. More severe forms with upper urinary tract involvement can require multiple line treatments, including surgery. There are reports of gastrointestinal toxicity with abdominal pain, liver function test derangement and cholangiopathy. More recently, reports have described the association between prolonged ketamine sedation during covid-19 outbreak and cholangiopathies. Development of tolerance, brain and psychiatric changes have been described. These can manifest in cognitive impairment and psychiatric disorders, with schizophrenia-like symptoms. Possible cardiovascular alterations have been described in few reports. Whereas supportive treatment can offer transient relief, ketamine cessation remains the cornerstone of the treatment. Conclusion(s): There is evidence of toxicity associated with chronic ketamine exposure on the different systems studied in this review. Nevertheless, due to the limitation of the studies more prospective studies would be required to clarify those findings.Copyright © 2023 Societe Francaise de Toxicologie Analytique

A Phase II Study of Metformin with Pemetrexed/Carboplatin in Patients with Metastatic Non-Squamous Non-Small Cell Lung Cancer

Introduction: There is a subset of NSCLC patients ineligible for benefit from TKIs/Immunotherapy (e.g. STK11 mutation conferring resistance to Immunotherapy). Besides, many patients cannot afford these therapies. Metformin has anticancer properties acting both on glycolytic metabolism and tumor microenvironment. In vitro studies suggest synergism between metformin and pemetrexed. STK11 deficient cell lines are more sensitive to metformin. Clinical studies combining metformin with chemotherapy are limited by small sample size. We conducted an exploratory phase-2 clinical trial of metformin with pemetrexed/carboplatin in advanced non-squamous NSCLC. Methods: This was a single center, open label, single arm phase 2 clinical trial with a Simon’s two stage design. The null hypothesis was that the combination would not improve the 6-month PFS rate by 15%, from 50%. Treatment-naive, non-diabetic patients aged 18-75 years with NSCLC (adenocarcinoma/not-otherwise-specified) with stage IV disease having ECOG PS 0-2 with unmutated EGFR/ALK and without brain metastasis or with asymptomatic brain metastases were treated with pemetrexed-carboplatin chemotherapy and metformin for six months. The primary outcome was 6-month progression free survival (PFS) rate. Secondary outcomes were safety, overall survival (OS), overall response rate (ORR), proportion of STK 11 mutation and effect of STK 11 mutation on 6-month PFS rate. PFS and OS were estimated using the Kaplan-Meier method. Targeted sequencing was attempted for available tissue specimens. Results: The first interim analysis was performed after enrollment of 26 patients for the first stage (before the target accrual of first stage was reached) due to slow accrual, in view of COVID pandemic. The study was terminated after first stage for futility. The median age of patients in the study was 52 years (range, 30 to 68) and 18 patients (69.0%) were males. Half of the patients had ECOG-PS 2. Brain metastases were present in eight (31%) patients and among these four (50%) were symptomatic at presentation. The median follow-up time was 25 months. The median PFS was four months. 6-month PFS rate was 28% (95% CI - 0.12 to 0.46). Of the 25 evaluable patients, five (20%) had a partial response, and eight (32%) had stable disease;13 (52%) of the patients had disease control. The median OS was 16 months. During combined therapy, 14 (54%) and 3 (11%) patients had any grade and grade 3 anemia respectively. One patient had grade 3 neutropenia. Among non-hematological toxicities, gastrointestinal toxicities (nausea, vomiting and diarrhea) were the most common. No grade 4 toxicities were reported. There were no treatment discontinuations, however treatment delay due to grade three toxicities was present in two patients. Dose modification for Metformin was required in four patients. Targeted Sequencing was possible in nine cases. Two of these patients had STK11 mutation and an associated bad outcome (PFS < 2 months). Conclusions: We could not demonstrate the benefit of combination of Metformin with pemetrexed-carboplatin in terms of improvement in 6-month PFS rate. The addition of metformin to pemetrexed-carboplatin has an acceptable safety profile. Future trials should test metformin in specific subsets (STK11 mutated) and in combination with immunotherapy and TKIs. Keywords: Metformin, NSCLC, STK11

Moderate hypofractionated radiotherapy after prostatectomy in the context of the COVID19

Purpose or Objective We designed a hypofractionated radiotherapy protocol for adjuvant or salvage treatment after radical prostatectomy. In this first report we present the implementation of this protocol in the context of a COVID-19 pandemic. Materials and Methods Patients meeting the inclusion criteria (high-risk features on histopathology or biochemical recurrence) received radiotherapy to the prostate bed 51 Gy in 17 fractions, elective treatment of the pelvis at a dose of 36 Gy in 12 fractions was permited. Acute gastrointestinal (GI) and genitourinary (GU) toxicity was evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events versión 4.03. The disease-related quality of life, urinary, gastrointestinal, sexual and hormonal function were evaluated with the Expanded Prostate Cancer Index Composite (EPIC), QLQc30 and PR25 questionnaires at baseline before the start of radiotherapy and at one month after radiotherapy, then every six monts for two years. In addition, the incidence of COVID-19 cases was reported in the patients recruited in the trial and in those who underwent standard fractionation treatment (1.8-2.0 Gy per fraction), and in health personnel involved in the treatment of patients in study period. Results From August 2020 to March 2021, 22 patients have been registered. Fourteen patients have completed treatment and are included in this report. The median age was 64 years and most had a Gleason 3 + 4 (50%), with a pT3a (35.7%) and negative surgical margins (71.4%). Three patients (21.4%) were staged as pN1. Most patients were treated for salvage (57.1%), with an median PSA prior to the start of RT of 0,29 ng/ml. Most patients report minimal or low acute radiation effects in terms of GI and GU toxicity, with an acute toxicity grade 2 GI and GU of 50% and 14.3%, respectively. Without Grade 3 or higher GI / GU toxicity. Of the 14 patients who received the trial protocol, none had a clinical of COVID-19 infection, while one patient who received treatment with conventional fractionation development a COVID-19 infection. Conclusion We present the implementation of an protocol of hypofractionated schedule of postoperative prostate radiotherapy in an academic center in a developing country in the context of a COVID-19 pandemic. Preliminary results show the absence of COVID infection in the included patients, and low GU and GI toxicity.

RT with hyperthermia in recurrent and radiation-induced sarcomas: preliminary results of NCT04398095

Purpose or Objective The role of perioperative treatment in radiation-induced and in-field recurrent sarcomas (RIS/IFRS) is unknown. Reirradiation may be associated with a risk of significant toxicity;thus, it is rarely used. We hypothesized that the combination of preoperative or definitive 12x 3 Gy radiotherapy (RT) with or without integrated 3.5 Gy to 42 Gy boost combined with regional hyperthermia twice a week will enable satisfactory local control without significant late toxicity in patients with RIS/IFRS. Materials and Methods A prospective phase II, single-arm clinical trial was conducted. We included patients with locally advanced RIS/IFRS without distant metastases. Treatment combined three weeks of radiotherapy, four fractions per week, 3 or 3.5 Gy per fraction, with regional hyperthermia, followed by surgery or observation. The choice of the boost or no-boost regimen was based on resectability (Figure 1). The intervention would be deemed tolerable if significant RT-related (grade 3+ CTCAE 5.0) late adverse events occur in less than 20% of patients. We planned to enroll 20 patients based on Wilson’s method for calculation of confidence intervals. (Figure Presented) Results We recruited 20 patients. All patients completed the treatment without interruptions. Eight of them had RIS whereas twenty were diagnosed with IFRS. Patients’ characteristics were provided in Table 1. Twelve patients from planned 15 underwent surgery. Two patients with potentially resectable tumors did not undergo surgery due to COVID-related reasons. One patient preferred not to undergo surgery after the preoperative no-boost regimen. The remaining five patients were deemed unresectable at the enrollment and received the simultaneous boost. In five patients who underwent resection, we observed extensive pathological response according to the European Organization for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group recommendations for pathological examination and reporting, namely grade A in two cases and grade C in three cases. In four patients we observed complete radiological response. The median follow-up was 13 months. In 14 patients we noted mild or moderate radiation dermatitis. One patient experienced grade 2 gastrointestinal toxicities. From the late toxicities, we observed restricted limb mobility (grade 1) in one patient and chronic skin ulceration (grade 2) in one patient. None of the patients who developed grade 3 or higher late toxicity. Two patients who received the no-boost regimen and did not undergo resection developed local progression. One patient experienced borderline local relapse after surgery. None of the patients who received the boost regimen developed local progression. Three patients developed distant metastases. One patient was lost to follow-up. (Figure Presented) Conclusion Preliminary data suggest that the tolerance of the regimen is acceptable;however, data regarding late toxicity may change during the follow-up period. Boost may play a significant role in achieving local control in non-resected tumors.

TOXICITY OF REMDESIVIR AS TREATMENT OF NONCRITICALLY ILL COVID-19 PATIENTS

Background and importance Remdesivir is currently included in clinical guidelines for COVID-19 treatment. Although safety data were published in ACTT-1, the toxicity of this drug in regular clinical practice is still unknown. Aim and objectives In this study we aimedd to describe remdesivir's toxicity in patients only requiring supplemental lowflow oxygen (no high-flow oxygen requirements or other noninvasive ventilation at start of treatment). Material and methods Retrospective cohort including patients treated with remdesivir following Spanish Medicines and Health Products Agency criteria (non-critical patients requiring low-flow oxygen) between August and October 2020 in a tertiary- level hospital. Exclusion criteria were being under 18 years of age and participation in clinical trials with remdesivir. The percentage of adverse reactions occurring in the 14 days following on from the beginning of treatment was the primary outcome. Secondly, the number of treatment discontinuations were assessed. Categorical variables were expressed as proportions while continuous values were formulated as median and interquartile range (IQR). Results 264 patients were included (59.2% men, mean age 66 years;IQR 54-82). In the 14 days following on from the beginning of treatment, an adverse reaction (AR) was reported in 146 (55.3%) patients. In 91 (34.5%) of them it was grade ≥2 AR, in 31 (11.7%) grade ≥3 and in 8 (3.0%) of them grade ≥4. Median of days until toxicity began was 3.5 days (IQR 1.2-9.0). The most common AR was an increase in transaminases, which happened in 114 (43.2%) patients, 29.1% of them being grade ≥3 and 3.9% grade ≥4. Regarding renal toxicity, an increase in serum creatinine occurred in 51 (19.8%) patients, 27.5% of them being grade ≥3 and 9.8% grade ≥4. One patient suffered a grade 3 anaphylactic reaction during infusion and another one developed hepatitis during the follow-up period. Two more patients suffered gastrointestinal toxicity (grade 1-2 nausea and diarrhoea). During the study period, 31 (12.1%) patients discontinued remdesivir treatment,12.5% of them due to AR or toxicity related to the drug. Conclusion and relevance Increased transaminases was the most common AR in this population, matching remdesivir's European Public Assessment Report (EPAR) specifications, followed by an increase in the serum creatinine levels (frequency not detailed on the EPAR). However, only 12.5% of treatment discontinuations were due to adverse reactions or toxicity linked to remdesivir. Further investigation is needed to unravel the degree of involvement of the drug in this toxicity.

Preliminary analysis of the MM21 trial: Response adaptive salvage treatment with daratumumab-lenalidomide-dexamethasone (DRD) for newly diagnosed transplant eligible multiple myeloma patients failing front-line bortezomib-based induction therapy

BACKGROUND Bortezomib-based induction (V-IND) approaches are used in >90% of Australian newly diagnosed transplant eligible multiple myeloma (NDTE MM) patients (pts) with a maximum of 4 cycles of V-IND therapy available via the pharmaceutical benefits scheme (PBS) prior to a planned autologous stem cell transplantation (ASCT). However, NDTE MM patients failing V-IND (defined as best response < partial response [PR]) demonstrate shortened survival and continue to represent a sub-group of MM where a clear unmet medical need persists. The ALLG MM21 was designed to evaluate the efficacy of an early response adapted approach with a switch to an intensive Daratumumab-lenalidomide-dexamethasone (DRd)-based salvage-ASCT- consolidation strategy in patients failing V-IND. METHOD We present the results of a planned interim analysis of the multi-centre single arm study MM21 (ACTRN12618001490268). Eligible pts were NDTE MM who had received V-IND pre-ASCT and demonstrated either a sub-optimal response (SOR - defined as <minimal response [MR] after 2 cycles or <PR after 4 cycles of V-IND) or primary refractoriness (1REF - defined as disease progression while on or within 60 days of completing V-IND). Pre-ASCT DRd was DARA 16mg/kg IV days 1, 8, 15 and 22 for cycles 1 (C1) and 2, and on days 1 and 15 of C3 and C4;Lenalidomide 25mg OD D1-21;and, dexamethasone 40mg PO on D 1, 8, 15 and 22 of each 28-day cycle for C1 to C4. Anti-thrombotic and anti-viral prophylaxis was as per individual institutional practice. Between C3 and C4, patients underwent a G-CSF mobilised PBSC collection with a melphalan 200mg/m2 conditioned ACST after C4. Patients underwent D100 post-ASCT disease response assessment including EuroFlow minimal residual disease (MRD) testing. In the absence of disease progression, patients then received 12, 28-day cycles of consolidation comprising DARA IV 16mg/kg on D1, 15 of C1 and C2 and on D1 of C3 to C12, lenalidomide 25mg PO on D1-21 of C1 and C2 and 10mg OD on days 1-28 of C3 to C12;dexamethasone 40mg was weekly from C1 to C12. RESULTS Fifty patients were recruited from 7 Australian sites between March 2019 and July 2020. Median age was 61 years with 66% males. Disease status at study entry was SOR in 72% (<MR n = 9, <PR n = 27) and 1REF in 28%. Data cut-off date was June 30 2021. 45 patients (90%) received 4 complete cycles of salvage DRd. 11/50 (22%) patients did not undergo ASCT and 4 patients failed stem cell collection. Two pts were withdrawn due to treatment related gastrointestinal toxicity - persistent oesophagitis (n =1) and recurrent colitis (n=1). There were two deaths, due to COVID-19 pneumonia (n =1) and septic shock (n =1). Pre-ASCT response was evaluable in 43 patients, overall response rate (ORR) was 70% - complete response (CR) 6%, very good partial response (VGPR) 18%, partial response (PR) 46%, clinical benefit rate (CBR) 83% - MR 11% and stable disease (SD) 2% on Intention to Treat (ITT n = 50) analysis. 33 patients were assessed for MRD - MRD negative 6% on ITT (3/33 9%). Pre-consolidation disease assessment was evaluable in 37 pts, both ORR and CBR were 72% - stringent complete response (sCR) 4%, CR 14%, VGPR 24%, PR 30% ITT analysis. 31 pts were evaluated for MRD - MRD negative 28% ITT (14/31 45%). In 6 patients, MRD was omitted or could not be performed due to pre-analytical issues. Post-C2 consolidation assessment was evaluable in 37 pts, ORR 72% - sCR 2%, CR 24%, VGPR 26%, PR 20%, CBR 74% - SD 2% ITT analysis. To date, 22 patients have been evaluated for MRD with 4 patients awaiting results, MRD negative rate of 38% ITT (10/22 45%). MRD sample collection at this time-point was omitted in 7 patients, potentially skewing MRD negativity on ITT analysis. CONCLUSION Preliminary analysis of the MM21 trial demonstrates early response-adaptive escalation to DRd facilitated ASCT in the majority patients with robust ORR post-autologous stem cell transplant and substantial improvement in disease control, as reflected in improved rates of MRD and disease response to treatment. At both post-ASCT time-p ints there was significant drop off in MRD testing due to testing omission, potential skewing results of MRD analysis. MRD and duration of response analysis following C12 consolidation is planned and will be of interest. Current data suggests this drug combination shows potential for substantial benefit in the study population. (Figure Presented).

Preliminary results of the FILO phase 2 trial for untreated fit patients with intermediate risk chronic lymphocytic leukemia comparing ibrutinib plus venetoclax (IV) vs. FCR

With the emergence of targeted therapies, defining the best strategy for the treatment of previously untreated CLL patients remains challenging. The aim of this phase 2 study was to compare the efficacy of an association with ibrutinib and venetoclax (IV) to the standard FCR regimen in fit patients with intermediate-risk CLL defined by either unmutated IGHV status, 11q deletion, or complex karyotype in the absence of TP53 abnormality. Patients were randomized 1:1 between two treatment arms, i.e. FCR 6 cycles or IV. After a lead-in phase of ibrutinib as a single agent from the month (M)1 to M3, the total duration of treatment with IV was based on the response achieved at M9;if bone marrow (BM) MRD was <0.01% using flow cytometry, the treatment was continued for 6 additional months until M15 and then stopped;if BM MRD at M9 was ≥0.01%, the treatment with IV was continued for 18 additional months until M27. The primary endpoint was the percentage of patients with BM MRD <0.01% at M27 in both arms. We present here the preliminary results on the first evaluation done at M9 including CT-scan, BM biopsy, and MRD assessment in PB and BM after the inclusion of all the 120 patients as initially planned. One hundred and twenty patients were enrolled from September 2019 to February 2021. The median age was 59 [34-72] and 61 [34-74] years in the FCR and IV arms, respectively. The characteristics of the patients were well-balanced between the 2 arms in terms of gender (male 72% FCR, 74% IV), PS ECOG 0-1 (59% FCR, 68% IV), and Binet stage (A, B, and C 15, 64, 21% for FCR;8.5, 59, and 32% for IV). No major difference in terms of cytogenetic features was noted, all patients but one had unmutated IGHV. At the time of data cut-off for this interim analysis, the median follow-up for all cohort was 12.7 [4.5.9-21.4] months. The frequency of patients presenting all grades adverse events (AE) so far was 90% (grade ≥3: 45%) in the FCR arm and 80% (grade ≥3: 45%) in the IV arm. The rate of infusion-related reactions (IRR) in the FCR arm was 35% on cycle 1-day 1 (14% grade 3-4);for the IV arm, 5% of patients experienced tumor lysis syndrome (TLS) (grade 3 for 1 patient). Ibrutinib doses were reduced for seven patients (four permanently stopped and three resumed at a lower dose because of toxicities (digestive, hepatic, or hematological). Venetoclax was permanently discontinued before M9 in four patients (digestive toxicities and grade 4 neutropenia). Fifty-two serious adverse events were reported of which 22 were in the IV arm (among them one sudden death, one ischemic stroke, one acute coronary syndrome, two atrial fibrillations, two TLS, two acute renal failures, one hepatitis, one neutropenia, two COVID pneumonitis, and one osteoporotic fracture) and 30 in the FCR arm (among them five febrile neutropenia, one hemolytic anemia, one thrombocytopenia, three IRR, three TLS, three COVID pneumonitis, one acute myeloid leukemia, one myelodysplasic syndrome). All patients with COVID pneumonitis had a favorable evolution with the need for intensive care and convalescent plasma for three of them. The first 85 patients included in the study have reached M9 and among them, nine prematurely discontinued the study, (one active hemolysis, one ischemic stroke, one TLS, one hepatitis, and one sudden death in the IV arm;three hematologic toxicities and one early progression in the FCR arm). In the evaluated patients (n=74), 69% of patients in the FCR arm and 43% of patients in the IV arm achieved bone BM MRD <0.01%. The complete (CR, CRi) and partial response rates were 56 and 44% in the FCR arm and 74 and 26% in the IV arm, respectively. In conclusion, preliminary results show a lower BM MRD rate in the IV arm compared to the FCR arm at M9, with toxicity that remains significant and relatively similar between the two arms. However, BM MRD rate may improve after longer exposure to the IV combination and the analysis of the primary endpoint at M27 will be decisive in determining the best therapeutic strategy.

Preliminary Results of the Filo Phase 2 Trial for Untreated Fit Patients with Intermediate Risk Chronic Lymphocytic Leukemia Comparing Ibrutinib Plus Venetoclax (IV) Versus FCR

With the emergence of targeted therapies, defining the best strategy for the treatment of previously untreated CLL patients remains challenging. The aim of this phase 2 study was to compare the efficacy of an association with ibrutinib and venetoclax (IV) to the standard FCR regimen in fit patients with intermediate risk CLL defined by either unmutated IGHV status, 11q deletion or complex karyotype in the absence of TP53 abnormality. Patients were randomized 1:1 between two treatment arms, ie FCR 6 cycles or IV. After a lead-in phase of ibrutinib as a single agent from month (M)1 to M3, the total duration of treatment with IV was based on the response achieved at M9;if bone marrow (BM) MRD was < 0.01% using flow cytometry, the treatment was continued for 6 additional months until M15 and then stopped;if BM MRD at M9 was ≥ 0.01%, the treatment with IV was continued for 18 additional months until M27. The primary endpoint was the percentage of patients with BM MRD < 0.01% at M27 in both arms. We present here the preliminary results on the first evaluation done at M9 including CT-scan, BM biopsy and MRD assessment in PB and BM after the inclusion of all the 120 patients as initially planned. One hundred and twenty patients were enrolled from September 2019 to February 2021. The median age was 59 [34-72] and 61 [34-74] years in the FCR and IV arms, respectively. The characteristics of the patients were well balanced between the 2 arms in terms of gender (male 72% FCR, 74% IV), PS ECOG 0-1 (59% FCR, 68% IV) and Binet stage (A, B and C 15%, 64%, 21% for FCR;8.5%, 59% and 32% for IV). No major difference in terms of cytogenetic features was noted, all patients but one had unmutated IGHV. At the time of data cut-off for this interim analysis, the median follow-up for the all cohort was 11 [2.9 - 19.8] months. The frequency of all grades adverse events (AE) observed so far was 53% (grade 3-4, 24%) in the FCR arm and 47% (grade 3-4, 17%) in the IV arm. The rate of infusion-related reactions (IRR) in the FCR arm was 35% on cycle 1-day 1 (14% grade 3-4);for the IV arm, 6% of patients experienced tumor lysis syndrome (TLS) (grade 4 for 4 patients). ibrutinib doses were reduced for 7 patients (4 permanently stopped and 3 resumed at a lower dose because of toxicities (digestive, hepatic or haematological)). Venetoclax was permanently discontinued before M9 in 4 patients (digestive toxicities and grade 4 neutropenia). Forty serious adverse events were reported of which 15 in the IV arm (1 sudden death, 1 ischemic stroke, 2 atrial fibrillations, 2 clinical TLS, 1 hepatitis, 1 neutropenia, 4 COVID pneumonitis and one osteoporotic fracture) and 25 in the FCR arm (2 neutropenias, 1 anemia, 1 thrombocytopenia, 1 autoimmune haemolytic anemia, 3 IRR, 4 TLS, 2 COVID pneumonitis, 4 fever episodes of undetermined origin, 1 community-acquired pneumonia, 1 gastrointestinal toxicity, 1 confusion, 2 chest pains, 1 acute myeloid leukemia, 1 myelodysplasic syndrome). The patients with COVID pneumonitis had a favorable evolution with the need for intensive care and convalescent plasma for 3 of them. The first 60 patients included in the study have reached M9 and among them, 6 prematurely discontinued the study, 3 in each arm (active hemolysis, ischemic stroke and sudden death in the IV arm;2 grade 4 hematologic toxicities and 1 early progression in the FCR arm). In the evaluated patients (n=54), 71% of patients in the FCR arm and 48% of patients in the IV arm achieved bone BM MRD < 0.01%. The complete (CR, CRi) and partial response rates were 54% and 46% in the FCR arm and 76% and 24% in the IV arm respectively. In conclusion, the preliminary results show a lower BM MRD rate in the IV arm compared to the FCR arm at M9, with a toxicity that remains significant and relatively similar between the two arms. However, BM MRD rate should improve after longer exposure to the IV combination and the analysis of the primary endpoint at M27 will be decisive in determining the best therapeutic strategy. Disclosures: Quinquenel: Abbvie: Honoraria;Jansse : Honoraria;AstraZeneca: Honoraria. Laribi: Le Mans Hospital: Research Funding;Novartis: Other: Personal Fees, Research Funding;Takeda: Other: Personal Fees, Research Funding;BeiGene: Other: Personal Fees;IQONE: Other: Personal Fees;AbbVie: Other: Personal Fees, Research Funding;Astellas Phama, Inc.: Other: Personal Fees;AstraZeneca: Other: Personal Fees;Jansen: Research Funding. Cymbalista: Lilly-LOXO: Honoraria, Membership on an entity's Board of Directors or advisory committees;Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees;ASTRA ZENECA: Honoraria, Membership on an entity's Board of Directors or advisory committees;Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees;Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Leblond: AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Lilly: Consultancy;AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support;Roche: Honoraria;Amgen: Honoraria;Beigene: Honoraria, Membership on an entity's Board of Directors or advisory committees;Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Dartigeas: Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress;Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress;Janssen: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress. Ferrant: Janssen: Other: Travel, Accommodations, Expenses;AbbVie: Honoraria, Other: Travel, Accommodations, Expenses;AstraZeneca: Honoraria. de Guibert: Janssen: Consultancy, Honoraria;AbbVie: Consultancy, Honoraria;Gilead: Consultancy, Honoraria. Feugier: Astrazeneca: Consultancy, Honoraria;Gilead: Consultancy, Honoraria;Abbvie: Consultancy, Honoraria;Amgen: Honoraria;Janssen: Consultancy, Honoraria. Cartron: Roche, Celgene-BMS: Consultancy;Danofi, Gilead, Novartis, Jansen, Roche, Celgene-BMS, Abbvie, Takeda: Honoraria. Ysebaert: Abbvie, AstraZeneca, Janssen, Roche: Other: Advisory Board, Research Funding.