Efficacy of Front-Line Ibrutinib and Rituximab Combination and the Impact of Treatment Discontinuation in Unfit Patients with Chronic Lymphocytic Leukemia: Results of the Gimema LLC1114 Study

The GIMEMA group investigated the efficacy, safety, and rates of discontinuations of the ibrutinib and rituximab regimen in previously untreated and unfit patients with chronic lymphocytic leukemia (CLL). Treatment consisted of ibrutinib, 420 mg daily, and until disease progression, and rituximab (375 mg/sqm, given weekly on week 1–4 of month 1 and day 1 of months 2–6). This study included 146 patients with a median age of 73 years, with IGHV unmutated in 56.9% and TP53 disrupted in 22.2%. The OR, CR, and 48-month PFS rates were 87%, 22.6%, and 77%, respectively. Responses with undetectable MRD were observed in 6.2% of all patients and 27% of CR patients. TP53 disruption (HR 2.47; p = 0.03) and B-symptoms (HR 2.91; p = 0.02) showed a significant and independent impact on PFS. The 48-month cumulative rates of treatment discontinuations due to disease progression (DP) or adverse events (AEs) were 5.6% and 29.1%, respectively. AEs leading more frequently to treatment discontinuation were atrial fibrillation in 8% of patients, infections in 8%, and non-skin cancers in 6%. Discontinuation rates due to AEs were higher in male patients (HR: 0.46; p = 0.05), patients aged ≥70 years (HR 5.43, p = 0.0017), and were managed at centers that enrolled <5 patients (HR 5.1, p = 0.04). Patients who discontinued ibrutinib due to an AE showed a 24-month next treatment-free survival rate of 63%. In conclusion, ibrutinib and rituximab combination was an effective front-line treatment with sustained disease control in more than half of unfit patients with CLL. Careful monitoring is recommended to prevent and manage AEs in this patient population.

P-EGS01 Cholecystectomy after gall stone pancreatitis

Background According to the UK guidelines for the management of acute pancreatitis commissioned by the British Society of Gastroenterology, All patients presenting with gallstone pancreatitis should be considered for cholecystectomy when they are well enough to undergo surgery. In cases of mild biliary pancreatitis, cholecystectomy should ideally be performed during the index admission or within 2 weeks of discharge as interval cholecystectomy is associated with a significant risk of readmission for recurrent biliary events. In cases of severe gallstone pancreatitis, cholecystectomy may need to be delayed until collections have improved, unless the patient is well enough for surgery and the gallbladder is some distance from the collection Methods Methods Inclusion Criteria Exclusion Criteria Results 80 patients were collected during the study period, 96 % of them were classified as mild pancreatitis Cholecystectomy rate Total percentage of cholecystectomies performed for mild gall stone pancreatitis during index admission or within 2 weeks from discharge : 37% Percentage of early cholecystectomies for eligible patients (i.e.after ruling out unfit patients, patients declining treatment, previous cholecystectomy..etc) : 54% Re-admission rate Re-admission rate for early cholecystectomy patients : 7.4% Re-admission rate for delayed cholecystectomy patients : 20.7% Conclusions

Pyogenic and Non-Pyogenic Spinal Infections: Diagnosis and Treatment

: Spinal infection (SI) is an infection of vertebral bodies, intervening disc, and/or adjoining para-spinal tissue. It represents less than 10 % of all skeletal infections. There are numerous factors that predispose to developing a SI. Due to the low specificity of signs, delayed diagnosis is common. Hence, SI may be associated with poor outcomes. Diagnosis of SI must be supported by clinicopathological and radiological findings. MRI is a reliable modality of choice. Treatment options vary according to the site of the infection, disease progression, neurology, presence of instability, and general condition of the subject. Conservative treatment (orthosis/ bed-rest + antibiotics) is recommended during the early course with no/ lesser degree of neurological involvement and to medically unfit patients. Nevertheless, when conservative measures alone fail, surgical interventions must be considered. The use of concomitant antimicrobial drugs intravenously during initial duration followed by oral administration is a necessity. Controversies exist regarding the optimal duration of antimicrobial therapy, yet never given less than six weeks. Heterogeneity in clinical picture and associated co-morbidities with a range of treatment modalities are available; however, a common applicable guideline for SI does not exist. Managing SI must be tailored on a case-to-case basis.

Better Therapeutic Approach after Comprehensive Geriatric Evaluation in Older Patients with ACUTE Myeloid Leukemia and Myelodysplasic Syndromes

INTRODUCTION Most patients with Acute Myeloid Leukemia (AML) and Myelodysplastic Syndromes (MDS) are of advanced age and it is often difficult to identify those who may benefit from specific treatment strategies. The comprehensive geriatric assessment (CGA) is considered the gold standard tool to classify older patients according to their frailty profile. A multidisciplinary approach that includes a geriatrician is essential. CGA can be helpful in personalizing the treatment plan and detecting conditions that may be reversible through geriatric interventions. Our objective is to evaluate the impact of CGA on therapeutic decisions in patients with AML and MDS. METHODS From January 2018 to April 2021, 97 elderly patients with AML and MDS, who were candidates to receive any treatment, were systematically evaluated through the CGA, which includes validated instruments to assess comorbidity, polypharmacy, functional status, geriatric syndromes, mood, cognition and social state. According to the CGA, the patients were classified into 3 frailty categories: fit, medium fit and unfit. RESULTS The mean age was 78 years (range 67-90); 55% were men, 50 patients (51,5%) with AML and 47 (37.1%) with MDS (Table 1). Diagnoses were classified according to the 2017 WHO's AML criteria: 7 (7.2%) patients had AML and related neoplasm (unclassifiable), 11 (11.3%) AML with recurrent genetic abnormalities, 14 (14.4%) AML NOS, 18 (18.5%) AML with dysplasia-related changes and 6 (6.2%) Therapy Related Myeloid Neoplasm. According to 2017 WHO's MDS criteria: 13 (13.4%) had MDS-EB, 11 (11.4%) CMML, 2 (2.1%) MDS-RS, 1 (1%) MDS with isolated del (5q), 8 (8.2%) MDS-MLD, 5 (5.1%) MDS-RS-MLD and 1 (1%) MDS unclassifiable. R-IPSS assessment for MDS was: 2 patients (6.1%) very low, 7 (21.2%) low, 10 (30.3%) intermediate, 9 (27.27%) high, and 5 (15.15%) very high risk. As for CMML prognostic, CPSS was: 4 (44.4%) high, 3 int-1(33.3%) and 2 (22.2%) low. For AML, 2017 European Leukemia Network (ELN) categories were 23 (37.7%) favorable, 24 (39.3%) intermediate and 14 (22.9%) adverse. According to the CGA, in AML, 23 (46%) patients were classified as fit, 23 (46%) as medium fit and 4 (8%) as unfit. In the MDS, 25 (54.2%), 14 (29.8%) and 8 (17%) were fit, medium fit and unfit, respectively. Regarding treatment, a total of 85.4% of fit, 78.9% of medium fit and 45.5% of unfit patients received hemato-specific treatment (p 0.03). According to the CGA category, 35.4% of fit, 50% of medium fit and 100% of unfit patients required intervention (p 0.001). Furthermore, for the CGA domains taken into consideration, depression and cognitive deficit were detected in 31 (32%) and 9 (9.3%) of patients, respectively. Also, 5 (5,2%) and 17 (17.5%) of patients had basic activities of daily livings (bADL) and instrumental activities of daily livings (iADL) deficiencies, respectively. This indicates dependence on assistance for tasks such as managing finances, use the phone, prepare meals or manage medicines. Regarding Charlson Comorbidity Index (CCI), 55 (56,7%) of patients scored ≥2 and 6 (6.2%) of patients had falls (Table 1). In addition, 48.5% of patients (54% AML) required intervention in different measures by physiotherapy, nutrition, pharmacy, psychology, social work or palliative treatment. Geriatric assessed frailty categories were a powerful OS predictor and could discriminate three different groups regarding OS. Patients classified as fit had better median overall survival (OS;1.8 years 95% CI 1.4-2.1) compared to medium fit (1.1 y 95% CI 0.8-1.4) and unfit patients (0.8 y 95% CI 0.3-1.3) (p 0.016; Figure 1). Multivariate analysis performed included gender, age CGA categories and hemato-specific treatment showed that medium fit and unfit categories were associated with poor survival, independent of hemato-specific treatment, age and gender (HR 2.1; 95% CI, 1.1-4.2; p 0.022 and HR 2.4; 95% CI, 0.98-5.99; p 0.05) CONCLUSIONS Incorporating CGA within a multidisciplinary approach provides the opportunity to better classify patients according to frailty profiles to guide interventions and treatment decisions. CGA showed efficacy in predicting survival and demonstrates potential implications for shaping the decision-making process for hematologic therapies Figure 1 Figure 1. Disclosures Sureda: Roche: Other: Support for attending meetings and/or travel; GSK: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Mundipharma: Consultancy; Bluebird: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding, Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Speakers Bureau. Arnan: BMS/Celgene: Consultancy, Other: Participation in clinical trials; Takeda: Other: Participation in clinical trials; Novartis: Consultancy, Other: Participation in clinical trials; Astellas: Other: Participation in clinical trials; Jazz: Other: Participation in clinical trials.

Risk Stratification of Elderly Patients with Newly Diagnosed Acute Myeloid Leukemia Unfit for Intensive Chemotherapy

Background. Acute myeloid leukemia (AML) incidence increases with age, but elderly patients are often too frail to receive intensive chemotherapy (IC). Instead, treatment with hypomethylating agents (HMAs) is usually proposed, even if they have not demonstrated any real improvement over best supportive care. However, clinical practice has shown a significant difference in overall survival (OS) between responding and non-responding patients to HMAs. Thus, we aimed to assess predictive criteria of HMA response in elderly and frail AML patients. We reviewed the literature for any existing scores: none was found for elderly unfit patients. On the other hand, 3 models/scores existed for fit elderly patients undergoing IC : in the ALFA 9803 trail published by Malfuson and al, the HOCSG model in the MRC AML11 and LRF AML trails by Wheatley and al and finally the MDACC model by Kantarijan and al. Methods. We reviewed all patients aged ≥ 60 years old (y.o) diagnosed with AML, unfit for IC and treated with Azacytidine (AZA) alone in first line from July 2015 to December 2019 in Poitiers' University Hospital. The ineligibility to IC was defined by an age &gt; 75 y.o and/or the appreciation by the physician based on performance status (ECOG) and the evaluation of comorbidities with Charlson Comorbidity Index (CCI). The type of AML (de novo versus secondary) and the 2017 ELN prognosis score were also assessed. Results. Among 63 patients recruited, 86% were older than 70 y.o and 29% older than 80. Frailty criteria were found with a ECOG ≥ 2 in 11 (17%) and a CCI ≥ 3 in 29 (45%) patients. Secondary AML was found in 41 (63%) of patients. Adverse karyotype was detected in 21 (32%) patients and 2017 ELN score was quoted as adverse in 25 (38%) patients. After a median follow up of 10.75 months (IQR 3.98 - 17.94) for the whole cohort, median OS was 10.75 months (95%CI 6.37476 - 14.984). Among 54 (86%) evaluable patients, 50 reached some response: at least hematological improvement according to 2003 International Working Group criteria in 20 of them (37%), and stable disease in 30 (55.6%) patients. Patients reaching at least hematological improvement were able to complete a median of 11.5 cycles (IQR 7.5 - 17) vs 6.5 cycles (IQR 3 - 12). Sadly 23 (35%) patients died before achieving 6 cycles. In our cohort the 2017 ELN score failed to predict risk assessment in elderly frail patients. The ALFA model and HOCSG score were also not able to identify treatable patients neither to predict mortality in our cohort. Interestingly the MDACC high-risk category was able to identify the patients who would not benefit from AZA treatment with worst survival rates (HR 3.01; 95%CI 1.04 - 8.79). Conclusion. To date, stratification scores were developed for young fit patients, undergoing IC. Those scores predict poorly response to HMA and OS in unfit patients. In the era of new treatments and combinations with AZA, there is an urgent and growing need for dedicated prognosis model for unfit elderly AML patients. Disclosures Leleu: Bristol-Myers Squibb: Honoraria; Carsgen Therapeutics Ltd: Honoraria; Gilead Sciences: Honoraria; Celgene: Honoraria; Janssen-Cilag: Honoraria; Karyopharm Therapeutics: Honoraria; Merck: Honoraria; Mundipharma: Honoraria; Novartis: Honoraria; Amgen: Honoraria; AbbVie: Honoraria; Oncopeptides: Honoraria; Pierre Fabre: Honoraria; Roche: Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Other: Non-financial support.

Treatment Options for Elderly/Unfit Patients with Chronic Lymphocytic Leukemia in the Era of Targeted Drugs: A Comprehensive Review

Chronic lymphocytic leukemia (CLL) incidence increases with age reaching 37.9/100,000 in patients over 85 years. Although there is no standardized geriatric tool specifically validated for CLL, a correct framing of the fitness status is of critical importance to individualize treatment strategies. Based on the evidence available to date, frontline chemoimmunotherapy has an increasingly narrowing application, being eligible for candidacy only in elderly fit patients without or with minimal geriatric syndromes. On the other hand, treatment with BCR inhibitors, monotherapy, or in combination with anti-CD20 antibodies (e.g., obinutuzumab), must be preferred both for frontline and relapsed CLL not only in unfit patients, but also in fit patients with unmutated IGHV or harboring del(17p) and/or TP53 mutations/deletions. Second-generation inhibitors (e.g., acalabrutinib, zanubrutinib, pirtobrutinib) are novel compounds that, due to their better safety profile and different specificity, will help physicians overcome some of the safety issues and treatment resistances. In the era of targeted therapies, treatment decisions in elderly and/or unfit patients with CLL must be a balance between efficacy and safety, carefully evaluating comorbidities and geriatric syndromes to ensure the best approach to improve both quality of life and life expectancy.