Clinical Lymphoma, Myeloma & Leukemia, Vol.21, Suppl.1 - September 2021

S136 E XABS-19 2 -C LL Ma n age m e n t of I n fectio n s i n Patie n ts with C LL Carste n Utoft Nie m a nn 1, * 1 Department of Hematology, Rigshospitalet and Copenhagen University, Copenhagen, Denmark *Correspo n di n g author: carsten.utoft.niemann@regionh.dk Keywords CLL, chronic lymphocytic leukemia, immune dysfunction, antibiotics, immunoglobulins, preemptive treatment Abstract Although chronic lymphocytic leukemia (CLL) is a malignancy characterized by accumulation of tumor cells in the blood, bone marrow, lymph nodes, and secondary lymphoid tissue, 1 the hallmark of the disease and the major cause of death for patients with CLL is actually immune dysfunction and infections. 2 Despite improvement in treatment based on combination chemoimmunotherapy and targeted treatment with BTK inhibitors and BCL-2 inhibitors, leading to longer overall survival for patients with CLL, the mortality due to infections has not improved over the last four decades. 2 Thus, infections are now the main cause of death for patients with CLL, posing threats to the patient whether during the premalignant state of monoclonal B lymphocytosis (MBL), 3 during watch-and-wait for treatment-naïve patients, 4 or upon treatment with chemoimmunotherapy or targeted treatment. 5,6 To test whether the natural history of immune dysfunction and infections in CLL can be changed, we have developed the machine learning-based algorithm CLL-TIM.org to identify these patients. 7 The CLL-TIM algorithm is currently being used for the selection of patients for the clinical trial PreVent- ACaLL (NCT03868 7 22), testing whether short-term treatment with the BTK inhibitor acalabrutinib and the BCL-2 inhibitor venetoclax can improve immune function and decrease the risk of infections for this high-risk patient population. Background As increased prescription of specific types of antimicrobials can be demonstrated decades prior to diagnosis of CLL, 3 as an indication of increased frequency of infections. It is not (yet) clear whether the premalignant clone of MBL or immune dysfunction is the first event in the development of CLL. The CLL cell interactions with microenvironmental cells probably represent the link between CLL and immune dysfunction, thus allowing for the targeting of this interaction when aiming to improve immune function and outcome by targeted therapy. 8 The incidence and type of infections vary during development of CLL; 9,10 thus, the microbial landscape at different stages of CLL should guide empirical supportive care for patients, whether in terms of antibiotics, vaccinations, or immunoglobulin substitution, as summarized in current guidelines. 11 Immune dysfunction for patients with CLL has also been demonstrated in terms of higher mortality upon COVID-19 infection for both treatment-naïve and treated patients. 12,13 This immune dysfunction also results in an impaired serological response upon vaccination against COVID-19 for CLL patients; 14 thus, a need exists for considering intensified or prolonged therapy for COVID-19, as well as adapted therapy for CLL during the COVID-19 pandemic. 15–1 7 Management of Infections Early empirical antibiotic treatment, covering gram-negative and gram-positive infections, should be initiated upon signs of clinical infection for patients with CLL due to the high risk of mortality. 9,11 Full microbiological workup should be prioritized prior to initiation of antibiotics to allow for subsequent targeted antimicrobial therapy. The risk of invasive fungal infections should be considered in patients with CLL, with a particular caveat for patients receiving BTK inhibitors and corticosteroids. However, routine antifungal prophylaxis is not recommended due to the low incidence of systemic fungal infections and the risk of pharmacokinetic interaction between antifungals and targeted agents for CLL. Vaccination and Prophylaxis Based on increased risk of invasive pneumococcal infection in CLL, 10 pneumococcal vaccination with a conjugated vaccine is recommended, 18 along with seasonal flu vaccination. 11 Serological vaccine response may be abrogated in CLL, in general, and particularly impaired in patients recently treated with CD20- targeting monoclonal antibodies or immunosuppressive agents, such as corticosteroids or BTK inhibitors. 11,14,18–20 Thus, vaccination in patients with CLL cannot preclude subsequent infection with a microbial agent that the patient has been previously vaccinated for. Immunoglobulin substitution is only recommended for patients with repeated severe infections and severe hypogammaglobulinemia, as replacement therapy has not been demonstrated to impact overall survival, and only very limited data support immunoglobulin replacement therapy. 11,21