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  SESSION I – The genomic and epigenomic landscape of CLL and clinical consequences
Chairs: Jennifer Brown (Boston), Christopher Oakes (Columbus)
  Genetic predisposition
Jennifer Brown (Boston)
  Genetic landscape
Cathy Wu (Boston)
  Ibrutinib resistance
Jennifer Woyach (Colombus)
  Epigenetic landscape
Christopher Oakes (Columbus)
  Risk stratification in CLL
Antonio Cuneo (Ferrara)
  General Discussion
  SESSION II – The role of BCR activation and signalling for CLL
Chairs: Paolo Ghia (Milan), Kostas Stamatopoulos (Thessaloniki)
  BCR isotypes/autonomous signalling
Hassan Jumaa (Ulm)
  The latest news on stereotypes
Kostas Stamatopoulos (Thessaloniki)
  Novel BCR targets
Andrew Steele (Southampton)
  Next generation BTK inhibitors (covalent/non-covalent?)
Anthony Mato (New York)
  Mutational landscape of CLL mice models overexpressing aid identify proliferative-associated tumor genes involved in leukemic progression
Pablo Oppezzo (Montevideo)
  General Discussion
  Clinical Poster Walk
Leaders: Matthew Davids (Boston), Alessandra Tedeschi (Milan)
  SESSION III – Therapeutic options for CLL
Chairs: Alain Delmer (Reims)*, Michael Hallek (Cologne)
  Ibrutinib for everybody
Jennifer Woyach (Columbus)
  Ibrutinib for a small subgroup only
Florence Cymbalista (Bobigny)
John Seymour (Melbourne)
  CLL14 update
Kirsten Fischer (Cologne)
  Neddylation pathway regulates treg differentiation and T-cell function in Chronic Lymphocytic Leukemia ex vivo and murine in vivo studies
Scott Best (Portland)
  General Discussion
  SESSION IV – Long term follow up of clinical trials versus real world data (Outside Clinical Trials data-OCT)
Chairs: Jennifer Woyach (Columbus)
  Ibrutinib trials
Alessandra Tedeschi (Milan)
  Ibrutinib real world
Loïc Ysebaert (Toulouse)
  Venetoclax trials
Matthew Davids (Boston)
  Venetoclax / PI3K real world
Lindsey Roeker (New York)
  Sequential treatment with bendamustine, obinutuzumab(GA101) and ibrutinib in Chronic Lymphocytic Leukemia: final results of the CLL2-BIG trial of the German CLL study group (GCLLSG)
Julia von Tresckow (Essen)
  General discussion
  SATELLITE SYMPOSIUM: Utilization of MRD assessment in the clinical management of CLL patients
Chair: Barbara Eichhorst (Cologne)
Speakers: Barbara Eichhorst (Cologne), Lanny Kirsch (Seattle), Anna Schuh (Oxford)
This symposium is organised and funded by Adaptive Biotechnologies
  Biology Poster Walk
Leaders: Alexey Danilov (Duarte), Davide Rossi (Bellinzona)
  SESSION V – The increasing role of the leukaemic microenvironment
Chairs: Silvia Deaglio (Turin), Adrian Wiestner (Bethesda)
  Role of stromal cells
Andrea Brendolan (Milan)
  Hypoxia, metabolic reprogramming and immunosuppression occurring in CLL niche
Silvia Deaglio (Turin)
  Role of T cells
Arnon Kater (Amsterdam)
  Immunomodulatory effects of kinase inhibitors
Adrian Wiestner (Bethesda)
  Expansion of antitumor cytotoxic CD8+ T cells in CLL patients treated with ibrutinib
Maria Joao Baptista (Badalona)
  General discussion

Question: in concern to the TCL-1 in vitro studies, which factors did you add to the culture to keep the TCL1 cells alive?

Answer: When we culture these cells, we do not add anything beside conventional medium. We perform experiments using cells straight from the peritoneal cavity of leukemic mice. At that point viability is high and slowly decreases over the course of 3 days to about 60-70%.


Question: Thanks for the interesting data – do you think the phenotype is associated to the aging phenotype of the CLL patients? Best regards Tanja Hartmann

Answer: Yes, there os for sure a role of ageing but still, dye to presence of leukemia the phenotype is even further skewed. Nevertheless, we think using OT-I cells partly overcomes this variations.


Question: Do you plan to study immune response of CLL patients to COVID-19 vaccination, and would you hypothesize that CLL patients on BTKi therapy might have an impaired response to such vaccines?

Answer: Yes, based on our Heplisav vaccine data, we are concerned that patients on BTKi may have impaired responses, even more so than CLL patients in general. We would like to make Covid vaccines available to CLL patients – at the same time I think we need to learn more how to best achieve robust immune responses in these patients. We don’t know about the response on venetoclax – but what is well known is that for up to 6 months post anti-CD20 you would also expect absent or impaired vaccine responses. We are working to designing our vaccine studies accordingly. A practical consequence for now is that if CLL patients are vaccinated (for Covid), I would hope that there is a response but emphasize that the patient should continue to heed all precautions as if they had not been vaccinated.


Question: Hello. Congratulation on the presentations. I have a question about hypoxia. If I understood correctly hypoxia promotes the M2 phenotype of macrophages and downregulation of immune response. Have you examined the expression profile of genes that promote angiogenesis? Because one hallmark of the tumors is the creation of vascular tissues.

Answer: Very interesting question. We have never worked with endothelial cells, so the answer is I have no data in our models.There is however a rich literature on pro-angiogenetic effects of hypoxia


Question: This is very intersting and confirm why in some patients changes also in microenvironment are a reason of changes in drugs sensitivity

Answer: This is an important question and indeed it is possible that a different configuration of the structural microenvironment (fibroblasts and ECM) may associate with reduced sensitivity to drug treatment, though at this stage we did not have the chance to analyse the microenvironment in the context
of drug resistance. Thank you.


Question: We have published a case report showing a case of young women with standard and in developed active form of disease (after less than 2 years) and cells incubeted from this women dispay diversity i reactivity to drugs (like hear leukemia B and leukemia A results). I am very happy that you can see also diversities.

Answer: I anticipate that according to the configuration of the microenvironment drug sensitivity may change. Unfortunately it is difficult to test this by analysing human CLL biopsies but 3D spheroid models or other emerging 3D models including pre-clinical models may help to clarify this important question. Thank you.

  SESSION VI – Therapeutic options 2: The use of cellular and non-cellular immunotherapies in CLL
Chairs: Matthew Davids (Boston), Peter Dreger (Heidelberg)
  Next generation PI3K inhibitors
Peter Hillmen (Leeds)
  Novel inhibitors at preclinical level (MCL1 & CDK inhibitors)
Alexey Danilov (Duarte)
  Mechanistic effects of BH3 Mimetics in CLL
Eric Eldering (Amsterdam)
  CAR-T cells
Stephen Schuster (Philadelphia)
Peter Dreger (Heidelberg)
  General discussion

Question: You showed increase in MCL1, BCLxL, and BCL2 in circulating CLL cells during venetoclax ramp up. Does that reflect that cells with lower expression of pro-survival molecules are more easily killed by venetoclax? On ibrutinib – do you feel confident that the CD5/CXCR4 phenotype still works to separate cell emigrant/immigrant populations? For example the CD5 expression contracts to homogeneously low expression – reflecting inhibition of cell activation. Adrian

Answer by Dr. Schuster: yes I do think that a stochastically determined variation in pro-survival proteins may determine ‘which cells go first’ during VEN ramp-up. We have not been able to uncover a regulated response pathway, which does not mean there is none, of course.Second, on IBR we are pretty confident the CD5/CXCR4 staining still works even as the CLL cells change phenotype during the first cycles. Indeed there are differences among patients, and not all show a ‘perfect’ pattern, but overall it holds up.


Question: Some time ago I red that venotoclax it is an inhibitor of mRNA of Bcl-2 expression. Did it changed? The same we have observe not a realy high expression of Mcl-1 in CLL cells but this protein should be cleaved to induce apoptosis. Anyway at this time we can studie the pelyotropic function of drug to different pathways inside cells

Answer: We’ve looked in <10 patients for changes in Bcl-2 mRNA under VEN treatment and could not find a consistent pattern, even though the protein levels appear to go up.

Question: Would MCL-1 inhibition be expected to be beneficial only in patients who have higher expression or amplification of MCL-1 (whether prior to treatment or as a mechanism of resistance to treatment) or could there be a role for MCL-1 inhibition even in those without over-expression or amplification?

Answer: Not necessarily. Cells may be dependent on Mcl-1 even if it is not highly expressed or amplified. In some pre-clinical studies lower expression was associated with Mcl-1 effect. I believe this has more to do with overall balance in the anti- and pro-apoptotic proteins rather than one particular one

Question: Do you know why venetoclax work on Bcl-2 and not act for Mcl-1 or BclXL? Maybe have some specific sequence that could bnd and inhibit expression? Do you think about it?

Answer: Venetoclax is a direct selective inhibitor of Bcl-2. Hence lack of effect on Mcl-1 or Bcl-xL. Navitoclax also targets Bcl-xL and Bfl-1, hence the side effect of thrombocytopenia.

Question: Do you kow that not only Bcl-2 could be a reason of resistance against venotoclax? Previous lecture sugest it?

Answer: Indeed, there are additional mechanisms of resistance to ventoclax, not just Bcl-2 mutations. Those could include upregulation of Pi3K signaling, mutations in chromatin modifiers (SWI/SNF) etc

  SESSION VII – Efficacy through safety
Chairs: Barbara Eichhorst (Cologne), John Seymour (Melbourne)
Javid Moslehi (Nashville)
Nicole LeBoeuf (Boston)
  Infectious diseases
Michele Bartoletti (Bologna)
Stefano Fagiuoli (Bergamo)
  General discussion
  SESSION VIII – Clonal heterogeneity, clonal evolution and mechanisms of drug resistance
Chairs: Davide Rossi (Bellinzona), John Seymour (Melbourne)
  Clonal evolution
Davide Rossi (Bellinzona)
Jennifer Brown (Boston)
John Seymour (Melbourne)
  Aid-mediated mechanisms of resistance to BCR inhibitors in Chronic Lymphocytic Leukemia (CLL)
Chiara Pighi (Turin)
  NOTCH2 contributes to venetoclax resistance in Chronic Lymphocytic Leukemia
Stefania Fiorcari (Modena)
  General discussion

Question: Question for Chiara Pighi: Could you tell us about what is the AID signature (canonical or non-canonical) origin for the 8/23 off-target genes mentioned for Idealisib and for the 3/23 off-target genes mentioned for Ibrutinib? From Pablo Oppezzo

Answer: So far we focused on the canonical AID signatures for all off-target genes


Question: Question for Dr. Pighi. I would like to ask how many cells did she use as a starting material for the sequencing. Thank you.

Answer: We used 20 ng of DNA for library preparation (Ampliseq, Illumina) which correspond to 3000-4000 cells.


Question: S.Casola to Dr Pighi: Do mutation rates and number of mutated genes displaying a putative AID signature in Idelalisib and Ibrutinib-treated patients correlate with expression levels of AID? Do the treatments increase mutation frequency at clonal IG VH/VL rearrangements?

Answer: Unfortunately, we do not have data of AID expression levels in patient samples to correlate with their mutational signature. We have already demonstrated that both treatments increase AID-dependent SHM at IgH locus in mouse germinal center B cells (Compagno et al., Nature 2017). In human B cells we have only data on increased IgH translocation frequency in human B cell lines. We are planning to study SHM in our cohort of patients treated with idelalisib or ibrutinib.​

  SESSION IX – Contrasting therapeutic concepts
Chairs: Jennifer Brown (Boston), Michael Hallek (Cologne)

  MRD as a dynamic endpoint
Peter Hillmen (Leeds)
  Dynamic risk profiling using serial tumor biomarkers for personalized outcome prediction in lymphoid malignancies including CLL
David M. Kurtz (Stanford)
  Sequential vs combination treatments
William Wierda (Houston)
  Time limited vs continuous treatments
Barbara Eichhorst (Cologne)
  General discussion
   Closing Remarks