Towards Control Of Chronic Lymphocytic Leukemia With Targeted Agents

Chronic lymphocytic leukemia (CLL) represents one of the most active fields clinical research at present time.1, 2 This short review summarizes some basic, translational and that has led to substantial improvements management patients with CLL over past two decades. Biology: The use genetic genomic technologies an improved understanding biology CLL. Studies using fluorescent in-situ hybridization (FISH) chromosome banding have described recurrent frequent aberrations in CLL, which, such as del(17p) demonstrated profound prognostic impact.3 Moreover, mutational composition immunoglobulin heavy chain variable region (IGHV) genes separates apparently related, but biologically clinically different forms CLL.4, 5 These findings suggested a central role B-cell receptor (BCR) signaling this leukemia. In search for relevant disrupted by del(13q), found almost 50% cases, it was discovered deletion causes loss miRNAs (miR-15a 16-1), which initiate leukemogenesis.6, 7 It these induce up-regulation Bcl2 protein is usually highly overexpressed CLL.8 More recently, whole exome sequencing enabled description landscape CLL.9, 10 From studies we learned regulating inflammatory pathways, BCR differentiation, Notch signaling, Wnt DNA damage control, chromatin modification, RNA ribosomal processing are frequently altered CLL.10 Signaling through seems play important survival cells.11 activation cells induces several tyrosine kinases, Src family kinases (in particular LYN), Bruton kinase (BTK), Spleen (SYK), well phosphoinositide 3-kinases (PI3K).12 addition receive essential growth support various cell-membrane-bound soluble factors produced their cellular microenvironment.12 Leukemia associated macrophages particularly components microenvironment cells.13, 14 Even efficacy conventional therapeutics chemotherapy alkylators monoclonal antibodies seem mediate effects compartment restricted interactions macrophages.15 could show targeted disruption LYN or BTK reduces capacity leukemia-associated fibroblasts “feed” growth.16 Prognosis: staging systems Rai Binet stratify according disease-specific risk. With new therapies, value decreased, no longer differentiating intermediate from advanced stages.17 A large number biomarkers been identified provide additional information.18-20 parameters extracted trials long follow up IGHV status, serum ß2-microglobulin, presence and/or TP53 mutations. Usually, high-risk defined, least part, gene (i.e. mutations). plethora markers obtained next generation not yet provided predictive sufficiently validated, need be further tested trials. Using markers, scores stratification proposed based on multivariate analyses.17, 21, 22 models useful identify patient populations experimental protocols, also those very good prognosis even stages. international index (CLL-IPI) consists weighed score includes stage, age, ß 2-microglobulin, mutations.22 four subgroups, validated extensively. system predicting time first treatment (TTFT) early, asymptomatic disease recently (International Prognostic Score Early-stage [IPS-E]).23 Three covariates, unmutated gene, absolute lymphocyte count higher than 15 x 109/L, palpable lymph nodes were combined predict 5-year cumulative risk start 8.4%, 28.4%, 61.2% low-risk, intermediate-risk, patients, respectively. IPS-E will helpful counsel early stage Minimal residual disease: Like other malignancies, complete eradication obvious desired endpoint.24 At three methods, sensitive multicolor flow cytometry, PCR, next-generation able detect minimal (MRD) who otherwise achieve response. Efforts refine harmonize established typical cytometry-based assay comprises core panel six CD19, CD20, CD5, CD43, CD79b CD81).25 Patients defined having undetectable MRD (MRD-neg) remission if they blood marrow less cell per 10.000 leukocytes. Today, there exists ample evidence prospective, controlled long-term follow-up, therapies MRD-neg remissions consistently result significant improvement outcome, including overall survival.26-31 treated chemo(immuno)therapy assessment more response outcome.27 initial information, CLL-IPI dynamic (by assessment) may methods dynamically determine outcome probabilities individual utilizing predictors acquired time. Continuous Individualized Risk Index (CIRI) shows allows accurately following chemoimmunotherapy.32 Therapy: Chemoimmunotherapy: Progress therapy initiated combinations purine analogs cyclophosphamide, fludarabine cyclophosphamide (FC).33, 34 Thereafter, anti-CD20 antibody rituximab added FC backbone (FCR), yielding impressive rates.35 Based results, GCLLSG CLL8 protocol, comparing FCR FC. randomized protocol choice line therapy, FCR, improve patients.36 benefit shown comorbidities chlorambucil standard comparator arm (CLL11 protocol)37, 38 Interestingly, obinutuzumab, potent type II antibody, yielded when compared rituximab. specific subgroups mutated IGHV, trisomy 12 del(11q), achieving without detectable (commonly called MRD-negative remission).39-41 occurrence plus del(11q) rate above 90% years. Together, lessons were: 1) changes natural history disease. 2) We should give our best first. 3) Anti-CD20 therapy. 4) Long-term control (or cure) possible. Targeted agents: advent agents ibrutinib,42 idelalisib,43 venetoclax44, 45 armamentarium therapies. As became rapidly apparent single would long-lasting remissions, sought systematically combine mechanisms action rather testing monotherapy patients. CLL2-BAG trial received sequential debulking cycles bendamustine followed induction maintenance obinutuzumab venetoclax, high rates 95%.46 Therefore, CLL14 investigated fixed-duration venetoclax (VO) chlorambucil-obinutuzumab showed progression-free 24 months significantly VO group (88.2% vs. 64.1).47 observed all major subgroups. Very encouraging results reported regarding combination ibrutinib.48, 49 Future prospects: entered era where majority addition, ibrutinib delivers CLL.50 questions comparison concepts, fixed duration aimed maximal (undetectable MRD) versus agent inhibitors. CLL17 just opened recruitment address question (Figure 1). German Study Group intensify effort understand neutralize mechanism resistance Finally, importantly, make sure novel become available world-wide. I wish thank participating members teams University Cologne, centers many years fruitful cooperation. Hallek M, Shanafelt TD, Eichhorst B. leukaemia. Lancet. 2018;391(10129):1524-1537. Burger JA. Treatment Lymphocytic Leukemia. N Engl J Med. 2020;383(5):460-473. Döhner H, Stilgenbauer S, Benner A, et al. Genomic Aberrations Survival 2000;343(26):1910-1916. Damle RN, Wasil T, Fais F, Ig V mutation status CD38 expression indicators chronic [see comments]. Blood. 1999;94(6):1840-1847. Hamblin TJ, Davis Z, Gardiner Oscier DG, Stevenson FK. Unmutated V(H) aggressive form 1999;94(6):1848-1854. Calin GA, Dumitru CD, Shimizu Frequent deletions down-regulation micro- miR15 miR16 13q14 Proc Natl Acad Sci U S A. 2002;99(24):15524-15529. Klein U, Lia Crespo DLEU2/miR-15a/16-1 cluster controls B proliferation its leads Cancer Cell. 2010;17(1):28-40. Cimmino Fabbri miR-15 miR-16 apoptosis targeting BCL2. 2005;102(39):13944-13949. Puente XS, Bea Valdes-Mas R, Non-coding mutations Nature. 2015;526(7574):519-524. Landau DA, Tausch E, Taylor-Weiner AN, Mutations driving evolution progression relapse. 2015;526(7574):525-530. FK, Krysov Davies AJ, Steele Packham G. 2011;118(16):4313-4320. Wiestner Emerging kinase-targeted strategies Hematology Am Soc Hematol Educ Program. 2012;2012:88-96. Reinart N, Nguyen PH, Boucas J, Delayed development absence macrophage migration inhibitory factor. 2013;121(5):812-821. Galletti G, Caligaris-Cappio Bertilaccio MT. pursue common path toward 2016;30(12):2293-2301. Pallasch CP, Leskov I, Braun CJ, Sensitizing protective tumor microenvironments antibody-mediated 2014;156(3):590-602. Fedorchenko O, Rosen Kinase Tumor Microenvironment Is Essential Progression 2016;30(4):610-622. Pflug Bahlo Development comprehensive 2014;124(1):49-62. Cramer P, M. leukemia-what do know? Nat Rev Clin Oncol. 2011;8(1):38-47. Amaya-Chanaga CI, Rassenti LZ. Biomarkers leukemia: Clinical applications markers. Best Pract Res Haematol. 2016;29(1):79-89. Parikh SA, TD. Semin 2016;43(2):233-240. Wierda WG, O'Brien Wang X, nomogram previously untreated 2007;109(11):4679-4685. International IPI working group. An leukaemia (CLL-IPI): meta-analysis data. Lancet 2016;17(6):779-790. Condoluci Terzi di Bergamo L, Langerbeins early-stage 2020;135(21):1859-1869. Cheson BD, Catovsky D, iwCLL guidelines diagnosis, indications treatment, assessment, supportive 2018;131(25):2745-2760. Rawstron AC, Fazi C, Agathangelidis complementary multiparameter cytometry high-throughput detection European Research Initiative study. 2016;30(4):929-936. Bottcher Ritgen Fischer K, quantification independent predictor analysis trial. 2012;30(9):980-988. Kovacs Robrecht Fink AM, Residual Disease Assessment Improves Prediction Outcome Who Achieve Partial Response: Comprehensive Analysis Two Phase III Group. 2016;34(31):3758-3765. Dreger Dohner Allogeneic stem transplantation provides durable poor-risk CLL3X 2010;116(14):2438-2447. Moreton Kennedy B, Lucas Eradication B-Cell After Alemtuzumab Therapy Associated Prolonged Survival. 2005;23:2971-2979. Wendtner CM, Schweighofer Consolidation alemtuzumab remission--experience safety within multicenter phase (GCLLSG). 2004;18(6):1093-1101. Kwok Varghese 10-year 2016;128(24):2770-2773. Kurtz DM, Esfahani MS, Scherer Dynamic Profiling Serial Personalized Prediction. 2019;178(3):699-713 e619. BF, Busch Hopfinger Fludarabine alone younger 2006;107:885-891. Richards Matutes (the LRF CLL4 Trial): randomised 2007;370(9583):230-239. Keating MJ, Albitar Early chemoimmunotherapy regimen fludarabine, 2005;23(18):4079-4088. Fingerle-Rowson Addition leukaemia: randomised, open-label, 3 2010;376(9747):1164-1174. Goede V, Obinutuzumab coexisting conditions. 2014;370(12):1101-1110. Engelke frontline updated CLL11 2015;29(7):1602-1604. Thompson PA, Tam CS, SM, Fludarabine, achieves disease-free IGHV-mutated 2016;127(3):303-309. after CLL: 2016;127(2):208-215. Rossi Terzi-di-Bergamo De Paoli Molecular prediction first-line fludarabine-cyclophosphamide-rituximab 2015;126(16):1921-1924. Byrd JC, Furman RR, Coutre SE, Targeting relapsed 2013;369(1):32-42. Sharman JP, Idelalisib 2014;370(11):997-1007. Roberts AW, Davids Pagel JM, BCL2 Venetoclax Relapsed 2016;374(4):311-322. Schetelig refractory 17p deletion: multicentre, 2016;17(6):768-778. von Tresckow Bendamustine (CLL2-BAG): primary endpoint 2018;19(9):1215-1228. Al-Sawaf Coexisting Conditions. 2019;380(23):2225-2236. Jain Ibrutinib First-Line 2019;380(22):2095-2103. Hillmen Brock Plus Relapsed/Refractory Leukemia: CLARITY Study. 2019;37(30):2722-2729. Ahn IE, Tian Alterations. 2020;383(5):498-500. Keywords: Therapies, (CLL), Combination Therapies No conflicts interests pertinent abstract. GIANNI BONADONNA MEMORIAL LECTURE collaboration American Association Research, AACR) Ash Alizadeh, Stanford, CA, USA