Questions List

Posted onDecember 2, 2020 4:12 pm

Do you anticipate the bar being raised to consider FCR (e.g., not only IGHV mutated and no TP53, but also lack of NOTCH1 and BIRC3) in clinical practice given the novel options (both time limited and continuous)? Thank you - excellent conference!Posted onNovember 19, 2020 3:25 pm

Great meeting, giving the possibility to participate for lot of people. This should be continued also after Corona:)Posted onNovember 19, 2020 3:24 pm

Thank you very much for interesting Conference. I am open for cooperation with somebody who wants to change for better anticancer treatment for CLL patients. Thank youPosted onNovember 19, 2020 3:16 pm

@Bill Wierda: The PFS plateau in patients with mutated IGHV status is so far only observed with FCR. However, the KM plots show that ca. 50% of these patients relapse, before the plateau occurs. For the patients this means a 50:50 chance for potential "cure". Do you know what drives these progressions in mutatedIGHV patients?Posted onNovember 19, 2020 3:11 pm

To Dr Kurtz Your model is depend on avaiable information, which have been collected in different trial. To me it seems that in can be applied retrospectively, but is is useful to really predict outcome or can be used in prospective manner?Posted onNovember 19, 2020 3:01 pm

Question to Dr Eichhorst: In Murano trial, 28% pts discontinued Ven+Rit due to adverse events. These patients had a mPFS of 24.3 months. Theoretically, these patients should have benefited from a time-limited treatment, but soon afterwards stopping the medication (time to stop 11 months), they progressed one year after.Posted onNovember 19, 2020 3:01 pm

Venetoclax Rituximab has been approved as a 2 years fixed duration. In most of the centers MRD is not performed in everyday clinica practice. So based on what we should decide to retreat patients with venetoclcax. Lenght of Resposne duration? 1-2-3 years? Thanks Alessandra TedeschiPosted onNovember 19, 2020 2:59 pm

Question for Prof Wierda: In the current clinical practice, which sequential treatment would you advise? Ibrutinib first that Venetoclax-based or the opposite one? Posted onNovember 19, 2020 2:58 pm

@David Kurtz: Do we know what drives cfDNA shedding from lymphoma, incl. CLL? Is it possible that cfDNA levels could be "falsely" higher under treatment, due to cell death by cytotoxic agents? Thanks; Othman Al-Sawaf, ColognePosted onNovember 19, 2020 2:56 pm

Question for Dr. Eichhorst: in 1L CLL IgHV unmutated pts would you start with a time-fixed or a continuous approach, on the basis of the longer follow-up data for ibrutinib than for Ven+Obi?Posted onNovember 19, 2020 2:56 pm

For Bill and Barbara from Matt Davids: how does the potential future approval of CAR-T for CLL impact your thinking on the continuous vs time-limited treatment approaches, particularly for younger patients with high-risk disease?Posted onNovember 19, 2020 2:55 pm

How do you know which target is the best for this particulary pateint? Posted onNovember 19, 2020 2:28 pm

For Kurtz: in analogy with sports (red card, injury) how does an (non-treatment related) AE affect CIRI? (Eric Eldering)Posted onNovember 19, 2020 2:20 pm

Do you think that the CIRI model may help determine the duration of a time limited therapy?Posted onNovember 19, 2020 2:18 pm

To Prof Hillmen Do you see relapses in MRD negativ patients that are not detecable due to being in immune priviliged niches?Posted onNovember 19, 2020 2:04 pm

For dr Hillmen; what (survival?) mechanism can account for a patient requiring 2 yr of IBR+VEN to reach uMRD status? Posted onNovember 19, 2020 2:03 pm

Could you give a suggestion where to find out a good effective method to study MRD?Posted onNovember 19, 2020 2:03 pm

The published IC50 of VEN is around 50% (at 4nM) in purified CLL cells in vitro. That would also explain the good in vivo outcome of CLL with Tri12Posted onNovember 19, 2020 1:36 pm

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In this line: Do these mutations in MAPK pathway) accumulate in the UM-CLL more commonly?Posted onNovember 19, 2020 1:24 pm

Is there data regarding the importance of steady BTK occupancy and the emergence of particular and perhaps more aggressive clones / development of more aggressive disease? Because BTKis have different profiles of BTKi occupancy but is terms of efficacy (PFS) they show quite similar results. Posted onNovember 19, 2020 1:21 pm

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 OppezzoPosted onNovember 19, 2020 1:20 pm

For dr Fiorcari: Can you measure in vitro decreased sensitivity for VEN in Notch mutated CLL? Posted onNovember 19, 2020 1:20 pm

@Davide Rossi: In other malignancies, particularly solid cancers like NSCLC, genomic instability often goes along with "whole genome doubling", which is very detrimental. Have you seen something like in your data or are aware of any in the CLL context? Best wishes, Othman Al-Sawaf, Cologne Posted onNovember 19, 2020 1:20 pm

Question for Dr. Pighi. I would like to ask how many cells did she use as a starting material for the sequencing. Thank you.Posted onNovember 19, 2020 1:17 pm

Agreed, but what about del11q, compl KTPosted onNovember 19, 2020 1:17 pm

If TRIS12 is associated with increased MCL1 levels, would you not expect that TRIS12 patients have a shorter response duration? I think this has not clearly been seen in the trials. Thank you, ArnonPosted onNovember 19, 2020 1:16 pm

If TRIS12 is associated with increased MCL1 levels, would you not expect that TRIS12 patients have a shorter response duration? I think this has not clearly been seen in the trials. Thank you, ArnonPosted onNovember 19, 2020 1:16 pm

to Stefania Fiorcari: Notch signaling is considered to promote CLL progression and a poor prognosis. Trisomy 12 on the other hand, is associated with a rather good prognosis. How do you reconcile these views and data? Any difference between Notch1 and Notch2 in this regard? Michael Hallek Posted onNovember 19, 2020 1:14 pm

Dear Dr Fiorcari thank you for your beautiful presentation. Are your observed differences in terms of VEN respose only visible for very low VEN level? How do these reults look like for 4-10 nM of VEN in vitro? BRPosted onNovember 19, 2020 1:10 pm

what about NOTCH1 and venetoclax? Posted onNovember 19, 2020 1:09 pm

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?Posted onNovember 19, 2020 1:03 pm

I underenstand that you study what has happand to Bcl-2 in venotoclax resistance. did you try to combine your results with some other fators what could matter in resistance?Posted onNovember 19, 2020 12:52 pm

For John Seymour: is there any indication or hypothesis that subclonal BCL2 mutations can confer PARACRINE help to the non-mutated CLL in the microenvironment? (Eric Eldering)Posted onNovember 19, 2020 12:50 pm

Dear Prof Seymour thank you for your great presentation. Could you estimate especially the role of BCL2 mutations for resistance in time-limited regimens? Best regardsPosted onNovember 19, 2020 12:50 pm

From Stefano Casola to Dr Brown: Great talk. We have previously shown (Varano et al. Nature 2017) in a mouse MYC-driven B cell tumor model that ablation of the BCR and thereby inhibition of the downstream PI3K pathway can be rescued by activation of the RAS/MAPK pathway. BCR-less tumors gaining RAS gain-of-function mutations are resistant to PI3Kd inhibitors and restore full tumor cell fitness through normalization of GSK3b phosphorylation. Was did observed in your PI3Kd inhibitor resistant CLL cells?Posted onNovember 19, 2020 12:37 pm

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Did you have for each samples that Idelalisib not reduce pERK in non-responders? If so it could be a great marker, but when I usually ask if something occurs in every pateints, the answer is not. Posted onNovember 19, 2020 12:33 pm

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Are you able to monitor pateints disease development and what has happend to patients after several drug courses? From my point of view comparison between patients treated with drug and placebo have not a big sens, because we have some personal differences that could affect responce to any drug, including anticancer drugs. In my studied control cells were cells obtained from the same patient. but not incubated with drugs. Could you maybe see that the differences in cell signaling could affect responce to treatmentPosted onNovember 19, 2020 12:26 pm

Are there genetic lesions detectable in circulating tumor DNA which may herald the onset of Richter's syndrome?Posted onNovember 19, 2020 12:17 pm

From my knowledge mutation in P53 gene is not very often. I remember that occurs in about 8% of CLL cases. Of course this is a bad prognostc factor, but from biological point of view there must be others often changed factors, related for expression with cells proliferation or similar to preparing as in metastatic cells in solid tumors. Posted onNovember 19, 2020 12:16 pm

Can CIT determine specific mutations in treated CLL cells, as we can observe in ALL?Posted onNovember 19, 2020 12:12 pm

******** Day 4 *********Posted onNovember 19, 2020 10:40 am

Good reply! thank you. Michael HallekPosted onNovember 18, 2020 6:41 pm

To all speakers: do you have, in your center, interdisciplinary structures to take care of patients with side effects of kinase inhibitors? Do you think they would be needed? Michael HallekPosted onNovember 18, 2020 6:36 pm

Dr. Moslehi, do you think ibrutinib-related ectopy is dose-dependent?Posted onNovember 18, 2020 6:35 pm

Could we see some relevance between strenghts of patients immunology and obtaining coexistent infections during anticancer treatment?Posted onNovember 18, 2020 6:26 pm

For Michele Bartoletti from Matt Davids: can you please provide your perspective on the likely efficacy of COVID-19 vaccination in CLL patients? Do you anticipate differential efficacy in untreated patients compared with patients on active treatment? Any differences anticipated between patients on BTKi vs venetoclax +/- CD20 mAb therapy?Posted onNovember 18, 2020 6:04 pm

I think that uour lecture is very important. Many medical doctors talk about drug function and anticancer activity but not about side effects. I have a question. What do you think: who could have a better chance to have such side effects: stronger person or heavily pretreated? This is similar for persons having a strong covid infection related symptoms, for example in the group of patients taking for long distance drugsPosted onNovember 18, 2020 6:03 pm

For Javid Moslehi from Matt Davids: the CSKi knockout data in the mouse are interesting. Is there a CSKi specific inhibitor, and if so have you recapitulated the knockout data with more specific pharmacologic inhibition?Posted onNovember 18, 2020 5:30 pm

This is a very iportant lecure showing what we have to think for drugs activity and also on side effects or other syptoms coincided with CLL develpment. Posted onNovember 18, 2020 5:16 pm

I just have found that CD19 is present on all B cells, so from one side CAR T therapy could be similar as a working target to rituximab, because it should reduce the level of B cells from the blood. We have to remember that CD19 on remodeling T cells could bind to different targets and it could give a side effects. From other point rituximab is a antibody and coudl have some implication in immunology. From my point of view choosing of any anticancer administration should be check before treatment administration of have a chance to work, and it could avoid resistance to treatmentPosted onNovember 18, 2020 5:09 pm

Thank you Eric! Lukas Posted onNovember 18, 2020 4:52 pm

Question to Matthew (based on Eric's data): Do you already have any experience in treating venetoclax-resistant patients with Mcl-1 inhibitors?Posted onNovember 18, 2020 4:43 pm

To Stephen Schuster: Is concurrent ibrutinib beneficial for CAR-T therapy? Presentations at ASH 2018 by Gauthier and Gill suggested so but as you showed the published data by Gauthier showed no superior PFS for the ibrutinib group. I don’t think the Gill data has been published. Adrian Posted onNovember 18, 2020 4:39 pm

To Eric Eldering: 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 Posted onNovember 18, 2020 4:39 pm

Dear Professor, I underestand that these new treatment types for example CAR T cells you administer to pateints before allogenic transplantation. I am not an expert in transplantation but I remember that usually in CLL pateints because of age there was an auto transplantation possible, because it could increase the chance to bone marrow better function after transplantation? Is it important these days?Posted onNovember 18, 2020 4:36 pm

Can you elaborate on the integration site and functional ability of CAR-T cells?Posted onNovember 18, 2020 4:24 pm

To Stephen Schuster: Do you think ITK inhibition is required / desired for the combination of BTKi with CAR-T cells (cellular immunotherapy)? If so, is ibrutinib preferred over acalabrutinib for such combinations? Adrian Wiestner Posted onNovember 18, 2020 4:23 pm

I have other simple question. Do you know maybe if we have in the blood or vena some receptors the same or similar to CD 19? Posted onNovember 18, 2020 4:16 pm

Could you seee some side effects of T CAR therapy? T cells could react and have a plenty of CD and other targets able to connect? Do you maybe know about such studies?Posted onNovember 18, 2020 4:11 pm

Do you kow that not only Bcl-2 could be a reason of resistance against venotoclax? Previous lecture sugest it? Posted onNovember 18, 2020 4:05 pm

Dear Eric, great presentation, thank you. Were you able to check for BIM and NOXA via flow in CLL during IBR/VEN? Best regards LukasPosted onNovember 18, 2020 3:59 pm

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?Posted onNovember 18, 2020 3:52 pm

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? Posted onNovember 18, 2020 3:47 pm

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 cellsPosted onNovember 18, 2020 3:44 pm

Didi you lower doses when pateint react very hard for therapy? I my studies related with personalized therapy for CLL I could observe 3 groups of patients rective, senstitive to drugs and to in vitro condition, and resistant to tharapy. Results on presonalized therapy for CLL are publishedPosted onNovember 18, 2020 3:30 pm

********** Session 6 ************Posted onNovember 18, 2020 3:18 pm

From my point of view xypoxia will change expression for several genes that are related to preparing to metastasis. This is very important for solid tumors, but could also be important for some changes in CLL behaviour. This in sure are not natural environment and could cause some diversities. The most problem in cancer treatment that is it is not easy to prevent response when you have so many factors that could depend on patient reaction to treatment. We might need a better technique related to kind of microskopy in real time to observe what has happend to cells incubated with drugsPosted onNovember 18, 2020 3:10 pm

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.Posted onNovember 18, 2020 3:07 pm

To Adrian: Concerning re-synthesis of Btk; to what extent does it affect experiments in vitro - should we add IBR? (to counter objections from Francesco Forconi to our data.. best Eric E)Posted onNovember 18, 2020 3:05 pm

Is the adenosine signaling involved in shaping endothelial cell functions?Posted onNovember 18, 2020 3:05 pm

I have an invitation to special number of Cancer to write a manuscript on kinase inhibitors. The dead line is approaching 30 of November. Bacause I can see that you can see some more than only for B cells function for drugs I am open for cooperation in studies and in preparing of this manuscript. Please let me know for e-mail: if you are interested in cooearation on this topic? Thank you very muchPosted onNovember 18, 2020 2:52 pm

What about ibrutinib effect on myeloid cells (monocytes, macrophages) ans its consequence on COVID-19 response of ibru-treated patients?Posted onNovember 18, 2020 2:47 pm

For sylvia: in concern to the TCL-1 in vitro studies, which factors did you add to the culture to keep the TCL1 cells alive?Posted onNovember 18, 2020 2:39 pm

Could venetoclax induce some changes also i T cells? or possible also in other cells except B cells?Posted onNovember 18, 2020 2:38 pm

To Adrian Wiestner: If the (humoral) immune response to vaccines is impaired when treating with ibrutinib, would you recommend to continue ibrutinib therapy for CLL patients at risk for COVID-19 or with an overt SARS-CoV2 infection? Or when vaccinations will be given against SARS-CoV2 in the hopefully near future? Michael HallekPosted onNovember 18, 2020 2:35 pm

Question for Dr. Wiestner from Matt Davids: 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?Posted onNovember 18, 2020 2:33 pm

Dr. Deaglio: Thank you for the talk. Could you comment more about the mechanism of synergism between A2A agonist and venetoclax? Is ADO directly involved in apoptosis, or do you think the effect is indirect from the removal of cell protection?Posted onNovember 18, 2020 2:32 pm

Do you have data about COVID-19 and BTKi?Posted onNovember 18, 2020 2:26 pm

To Arnon Kater: THanks for the interesting data - do you think the phenotype is associated to the aging phenotype of the CLL patients? Best regards Tanja HartmannPosted onNovember 18, 2020 2:10 pm

Can we compare human T cells with mause immunology? I ask because we can see some diversities between patients? This question is important in contex of diverse responce and imunological strenght in covid virus infections?Posted onNovember 18, 2020 2:10 pm

Have you got some data confriming that hypoxia force cancer cells to metastasis? Posted onNovember 18, 2020 1:52 pm

@Andrea Brendolan Thank you very much for this great talk. May I ask two questions: - Leukemia A and B is derived from the same TCL1 transplantation setup? What is your hypothesis, why they have a different impact on stroma cells? - Did you also look at the bone marrow compartment of stroma cells? Posted onNovember 18, 2020 1:48 pm

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. Posted onNovember 18, 2020 1:44 pm

This is very intersting and confirm why in some patients changes also in microenvironment are a reason of changes in drugs sensitivityPosted onNovember 18, 2020 1:38 pm

****** Day 3 - session 5 ***********Posted onNovember 18, 2020 1:23 pm

Bye guys, well done! Eric EPosted onNovember 17, 2020 4:54 pm

Is it a possible to find out what is a reason for resistance? Posted onNovember 17, 2020 4:42 pm

WHat happens to Bcl-2 when you add VEN in your system, is degraded? Posted onNovember 17, 2020 4:40 pm

Because of sometimes changes in drug sensitivity between humans from my point of view this studies are a life science hobby but has nothinh to do with human difference in drug sensitivityPosted onNovember 17, 2020 4:33 pm

Arnon Kater: ROR1 is also expressed on adipose tissue and pancreas tissue. what kind of side-effects might be expected? Posted onNovember 17, 2020 4:23 pm

Which fluorescent dye do you use for the cellular barcoding and which dilutions do you make? Posted onNovember 17, 2020 4:13 pm

What is the fibrablast cell line was used in experimentsPosted onNovember 17, 2020 4:10 pm

Ibrutinib is not known to kill CLL, so is this a result of your culture system? Posted onNovember 17, 2020 4:09 pm

At cellular barcoding, are using total cell lysates from aberrant B cells?Posted onNovember 17, 2020 4:09 pm

Thank ypu for interestng talk. Can you see from your studies the higher volume of doses needed to incubate with CLL cells because of microenvironmental drugs accumulation?Posted onNovember 17, 2020 4:07 pm

Very nice talk! I also find it interesting that there is a "flare" of BTK mutation during the initial period of venetoclax therapy. Was it during the ramp-up (lower doses of venetoclax)?Posted onNovember 17, 2020 4:00 pm

How much of mutation we can check and are we shure that we can detect every mutation in CLL cells? Posted onNovember 17, 2020 3:59 pm

How long did it typically take to eliminate BTK mutation during treatment with venetoclax?Posted onNovember 17, 2020 3:59 pm

What is the method for MRD monitoring with the higher applicability in clinical practice in middle-term? ASO-PCR, FC or NGS?Posted onNovember 17, 2020 3:42 pm

Should MRD be tested as a routine in patients outside of clinical Trials? Should we use it as a guidance for the Duration of the Treatment?Posted onNovember 17, 2020 3:41 pm

For all speakers: is there a place for ctDNA determination in MRD for CLL; is it technically feasible at sufficient depth to detect 'hidden' sites? (Eric Eldering, Amsterdam)Posted onNovember 17, 2020 3:27 pm

Could we find some general marker presend for example on cell surface to veryfy MRD cells?Posted onNovember 17, 2020 3:18 pm

For dr Kirsch: Is the technique also suitable for ctDNA?Posted onNovember 17, 2020 3:08 pm

Is there interest in a US registry trial to look at sequencing of novel agents?Posted onNovember 17, 2020 2:41 pm

in pandemic times, would you then sometimes suggest to start venetoclax mono rather than combined with rituximab?Posted onNovember 17, 2020 2:34 pm

To Matthew Davids and Lindsay Roekers: Does Rituximab add Benefit to Venetoclax or not? If no, does this also apply for time-limited therapy with venetocax?Posted onNovember 17, 2020 2:29 pm

Should we not be much more critical with the use of "real world" data, as they often represent insights from uncontrolled use of drugs with less stringent criteria for data monitoring, evaluation of side effects and molecular diagnostics, and clearly defined endpoints? - Should not be used to define the standard of care. Would you agree? Posted onNovember 17, 2020 2:21 pm

Any RWE on outcomes sequencing BCL-2i in 1L CLL followed by BTKi in R/R CLL vs the opposite order?Posted onNovember 17, 2020 2:20 pm

What is the role of laboratory in patients treated with ibrutinib? is these a role for BTK mutations monitoring by ASO PCR or NGS to identify resistant clone precociously? If yes, what is the right timing for monitoring?Posted onNovember 17, 2020 2:19 pm

To Matthew Davids and Lindsay Roekers: Does Rituximab add Benefit to Venetoclax or not? If no, does this also apply to time-limited therapy with venetocax?Posted onNovember 17, 2020 2:17 pm

Dr. Treschkow, very interesting study. Could you comment about retreatment in 5 patients who relapsed after treatment discontinuation?Posted onNovember 17, 2020 2:16 pm

When you combine venetoclax with rituximab did you see that patients are weaker after this therapy? Rituximab reduced to almost 0 the number of lymphocytes B which are important for antibody production?Posted onNovember 17, 2020 2:03 pm

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How long patients could get venetoclax? Could you observe during venetoclax administration some others side effects?Posted onNovember 17, 2020 1:42 pm

To Loic The impact of the AMA program is fascinating. Would you consider that the intensity of interactions between patient and health care professional may be the main difference of RCT vs “real world” experiences? For example the premature discontinuation in your AMA program seems to match what is seen in clinical trials. Thanks. Adrian Wiestner Posted onNovember 17, 2020 1:40 pm

I am biochemist and I am sure that if you treat pateints with cell signalling inhibitors and when sometimes doeas not work, this might be a reason of using of some alternative pathways. We differ and it could cause also diversities in response to treatment. This is very important because sometimes cancer treatment could cause secondary cancersPosted onNovember 17, 2020 1:38 pm

Question to first speaker: Can you observe that sometimes some patients react unspecifically to treatment? Do you check why such patients react unspecifically? From my opinion there is a group of patients reactive on treatmen and these patients have a great chance to respond to most of treatments. But there is a group of pateints for whom drug should be choosen, to prevent resistance. Posted onNovember 17, 2020 1:33 pm

****** Session 4 ************Posted onNovember 17, 2020 1:08 pm

Day 2 ***************Posted onNovember 17, 2020 11:28 am

QUestion to Scott Best Have you seen the same effect with BCL2 inhibitor?Posted onNovember 16, 2020 9:12 pm

In the subgroup of untreated CLL patients with progressive disease, p53 dysruption and active AIHA controlled with steroids, which would be your upfront therapy afterwards? Ibrutinib or Venetoclax+Obinutuzumab?Posted onNovember 16, 2020 9:06 pm

@Jennifer Woyach: Where do you place CD20 antibodies in the context of continous BTK-inhibitors? For rituximab it seems to be clear, for obinutuzumab it seems more tricky given the data from the Elevate study.Posted onNovember 16, 2020 9:00 pm

Question to Prof Seymour. At first relapse, which patients do you advise to treat with a time-limited approach and which patients with a continuous approach?Posted onNovember 16, 2020 9:00 pm

Question to Prof Cymbalista Which cardiovascular disorders in the clinical history of CLL patients would prevent you from starting a BTKi inhibitor? In case that you choose to start with venetoclax, if the patient progress under venetoclax, what to do afterwards (which BTKi)?Posted onNovember 16, 2020 8:57 pm

@John Seymour: Do you think that in certain high-risk patients, obinutuzumab rather than rituximab might be more useful in the rrCLL cohort, given the higher uMRD rates that can be expected with obinutuzumab.Posted onNovember 16, 2020 8:52 pm

To Jennifer Woyach: What is your experience with ibrutinib dose reduction in patients with side effects commonly associated with treatment discontinuation such as arthralgia in the real life setting? Might it even be equally effective based on early clinical trials?Posted onNovember 16, 2020 8:46 pm

Questions for Prof. Seymour 1) In the slide of genomic aberrations &MRD, has IgHV mutational status, been analyzed? 2) Considering that 61% out of 83 pts uMRD EOT has progressed within three years from EOT, would you advise a continuous or a time-limited approach in these patients? What about to the other (100) patients who did not reach uMRD at the end of 2 years of treatment?Posted onNovember 16, 2020 8:45 pm

Do you think that even without results comparing venetoclax+Gazyva with FCR or BR we could use it in fit patients? Posted onNovember 16, 2020 8:42 pm

To Dr. Fischer: Treatment inherence is an issue with continous treatment, but how many patients discontinued treatment with venetoclax-obinutuzumab and did you see progression during treatment with venetoclax-obinutuzumab?Posted onNovember 16, 2020 8:40 pm

From Matt Davids, for Scott Best: would you anticipate that pevonedistat might enhance CAR-T cell activity in CLL patients? Any pre-clinical data yet to investigate this?Posted onNovember 16, 2020 8:40 pm

Regarding the possible second malignancy concern with VenO, is there equivalent scrutiny and case identification that of the ChlbO arm, even after subsequent treatments?Posted onNovember 16, 2020 8:29 pm

Dr Fischer, what are your thoughts on the reason for the emerging difference in PFS within the VenO arm by IGVH mutational status? Is 12 Mo Ven sufficient treatment duration for IGVH unmutated cases?Posted onNovember 16, 2020 8:22 pm

Florence, do you feel cardiovascular risk factors are a contraindication to all BTKi, or just Ibrutinib?Posted onNovember 16, 2020 7:55 pm

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Jennifer, given your clear demonstration of the better tolerance of acalabrutinib than ibrutinib, and the comparable superior efficacy of acalabrutinib over O-Chlb, why do you recommend Ibrutinib as your preferred BTKi rather than acalabrutinib? Posted onNovember 16, 2020 7:45 pm

Session 3 **************Posted onNovember 16, 2020 7:25 pm

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what role played the CLL-IPI in light of novel, targeted therapies? Any insight?Posted onNovember 16, 2020 5:32 pm

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Any ALL cases in other studies by the GLL group?Posted onNovember 16, 2020 4:59 pm

Any data on immunoglobulin levelsPosted onNovember 16, 2020 4:57 pm

***Posted onNovember 16, 2020 4:46 pm

Did the absolute number of PD-1 expressing T cells, in addition to %, decrease with therapy? Sorry if I missed it in your slides.Posted onNovember 16, 2020 4:45 pm

Could you comment if the observed immune effects were driven by the direct impact of therapy on T cells or reduction of CLL burden (indirect)?Posted onNovember 16, 2020 4:44 pm

Since Syk is involved in Fc gamma receptor (FcγR) signaling, do you think that may interfere with anti-CD20 efficacy?Posted onNovember 16, 2020 4:43 pm

Poster walk *****************Posted onNovember 16, 2020 4:38 pm

Should subset #2/subset #169 OR IGLV3-21-R110 be studied in the clinical practice?Posted onNovember 16, 2020 4:14 pm

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To Anthony Mato, You emphasized that there is no comparative data available for outcome of del17p treated in front-line with ibrutinib. We recently reported outcome of 34 patients with TP53 alterations treated in first-line with ibrutinib. Median follow up was 6.5 years, PFS at 2 years was 85% (for comparison to zanubrutinib) and was 61% at 6 years (Ahn, NEJM 2020). Adrian Wiestner Posted onNovember 16, 2020 4:05 pm

From Matt Davids, for Dr. Steele: in the PDX mouse model, what toxicities were observed with the AQX + ibrutinib combination, and do you expect any issues in this regard if this combination were explored in CLL patients?Posted onNovember 16, 2020 3:43 pm

For Hassan and Kostas: when a CLL clone does NOT belong to any known stereotype, does it still signal in the Ca-assay? (Eric Eldering)Posted onNovember 16, 2020 3:29 pm

From Matt Davids, for Prof Stamatopoulos: For young fit patients with M-IGHV who we are considering treating with FCR, should we be routinely sequencing to identify patients in subset 2 (and satellites) and directing those patients instead toward novel agent based approaches? If so, how can we make this stereotypy assessment in clinical practice?Posted onNovember 16, 2020 3:28 pm

To Hassan Juma: You referred to IGVL 3-21 R110 mutations as counter-selected in normal B cells. Why/how “counter-selected”? If counter selected in normal B cells, what is the detrimental impact of R110 and how are prospective CLL cells able to tolerate that detrimental impact? Is the prospective CLL cell formed before it acquires R110? You report that virtually all CLL show autonomous signaling. Do you find CLL BCR structures (stereotypes) in normal B cells? Is autonomous signaling a property of subsets of normal B cells – and does this feature basically identify the cell of origin? Adrian Wiestner Posted onNovember 16, 2020 3:20 pm

@Cathy Wu: In solid tumors, particularly in NSCLC, whole-genome doubling events are very detrimental (and quite frequent). Do you have any data on this in the context of CLL?Posted onNovember 16, 2020 2:50 pm

excellent session and discussion. michael hallekPosted onNovember 16, 2020 2:47 pm

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To Dr. Oakes: 1-Do you think DNA methylation associated with complex karyotype? 2-Really interesting work on ITGA4. Wer other subunits of integrin alpha looked at for their methylation status?Posted onNovember 16, 2020 2:33 pm

Ruth Clifford University Hospital Limerick, Ireland 1. To Anthony Cuneo - is there a subgroup within the IGVH mutated group of patients where we can be certain of these excellent prolonged responses, given the excellent activity of novel agents and the risk of MDs for patients given chemo? 2. To Cathy Wu - can we set up an international collaboration for ALL of these Richter's patients, as numbers are so low in individual centres, and outcomes so poor, and apply these cutting edge technologies in the setting of novel combinations of treatments? Thank you so much RuthPosted onNovember 16, 2020 2:30 pm

Αmutation analysis on lymph nodes or bone marrow samples can give further prognostic informations compared to peripheral blood? Posted onNovember 16, 2020 2:29 pm

Question to Christpher Oakes: Hypomethylation is a rather negative prognostic event. Yet it occurs in trisomy 12, which is a rather good prognostic subgroup. I may have missed a point, but please expand on this a little bit. Michael Hallek Posted onNovember 16, 2020 2:27 pm

@Antonio Cuneo: Thank you for the great overview! Where do you place the Continuous Individualized Risk Index for CLL (CIRI-CLL, Kurtz et al Cell 2019) and what do you make of the methodology?Posted onNovember 16, 2020 2:26 pm

For Prof Cuneo: in the new ibrutinib risk model, how much of the survival outcomes are being drive by R/R vs. frontline status? It would be interesting to see how the other factors look in terms of their predictive power in separate cohorts of R/R and frontline patients.Posted onNovember 16, 2020 2:25 pm

could please comment whether there is a solid link between uIGHV and tp53-susceptibility? thank youPosted onNovember 16, 2020 2:25 pm

For Prof Cuneo: was the shorter PFS with ven + obin in CLL14 in patients with CKT driven mainly by TP53 disruption, or did patients with CKT without TP53 disruption also have shorter PFS?Posted onNovember 16, 2020 2:21 pm

For Jennifer W: What mechanism(s) can drive the paracrine IBR resistance do you think? (Eric Eldering)Posted onNovember 16, 2020 1:48 pm

@ Cathy Wu: Do you think that assessment of CLL subclone composition will guide the choice of therapy in the near or further future and -despite technical availability-what are the main challenges we are facing today in doing so? Thank you. Posted onNovember 16, 2020 1:44 pm

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tzPosted onNovember 16, 2020 1:05 pm

Good luck!! looking forward to this fantastic meeting!Posted onNovember 16, 2020 12:52 pm

Have you started the event?Posted onNovember 16, 2020 12:13 pm

******** Day 1 ***********Posted onNovember 16, 2020 8:08 am

Test1Posted onNovember 13, 2020 10:37 am