Questions List
Posted onOctober 17, 2021 4:04 pm
Thank you so much for this opportunity! Remarkable meeting!
Antonio Macedo, BrazilPosted onOctober 17, 2021 4:03 pm
Thank you!Posted onOctober 17, 2021 3:53 pm
To all panelists > any evidence or rationale for split dosing (with lower doses at each infusion) of CAR T cell therapy across time, say, at 0, 3, 6, 9, and 12 mos (for instance, for indolent lymphoma or multiple myeloma) to enhance persistence and reduce relapse?
Antonio Macedo, BrazilPosted onOctober 17, 2021 3:51 pm
What types of biomarkers can be used to predict response earlier? Would that enable an earlier switch in therapy and better overall survival?Posted onOctober 17, 2021 3:48 pm
Anand Jeyasekharan (National University of Singapore)- to all panelists- do we foresee that bispecifics (and possibly generic versions of these) will ultimately be the “global lymphoma care” choice for regions of the world where the infrastructure for CAR-T is going to be challenging to set up? Should we focus on combinatorial trials that aim to enhance bispecific efficacy?Posted onOctober 17, 2021 3:33 pm
Maybe the panel wants to debate - as their personal view - whether the emergence of bispecific antibodies will reduce the need for CART cell therapies? Michael Hallek, ColognePosted onOctober 17, 2021 3:20 pm
Question to Jacobson:
Were the CD58 mutations in the ctDNA analysis detected at diagnosis or relapse? In the latter case, do you think CD58 wt cases should qualify for earlier CART treatment?
Thank you
Posted onOctober 17, 2021 2:58 pm
Question to Ranjana Advani: Do you know any data or do you have experience with combinations of BTK or PI3K inhibitors and anti-CD47 antibodies? Michael Hallek, Cologne
Posted onOctober 17, 2021 2:48 pm
*********************Posted onOctober 17, 2021 1:03 pm
Great discussion. Thank you!Posted onOctober 17, 2021 1:01 pm
thanks , we knew prior therapy could impact T cell function for CAR T cell therapy , Can prior therapy impact B cell function and quality of B cell anti-bodies ,BITS responses? Ezzat Elhassadi Posted onOctober 17, 2021 12:58 pm
Thank you very much for the presentations
Thank you very much for the presentations
I would like to ask you the algorthym for the future diagnosis and progression evaluation of the DLBCL regarding the type of sampling : do you thing core biopsy is suitable for initial diagnosis and molecular sub classification
Regarding the which methods are recommended ? NGS for every patient ?
Isinsu Kuzu / Turkey
Posted onOctober 17, 2021 12:48 pm
Could you maybe compared results of CART therapy with previous patient immunological strength? Could be immunological strength a factor that might be important in choosing therapy? Do you think that in general, we should improve immunological strength to avoid any diseases, including cancersPosted onOctober 17, 2021 12:46 pm
Thanks, hypothetical question, Is T cell pheresis in the early disease course with better T cell quality, a better approach in high-risk DLBCL rather than early CAR-T cell therapy? Posted onOctober 17, 2021 12:44 pm
Before the CAR-T cell therapy and other T-cell engager therapies, a DLBCL patients take multiple chemotherapies (fist line, second line and ASCT) This process exhaust T cells of these patients. Wİll there be any guides to minimize the T cell exhaustion? For example T cell apheresis after fist line treatment or Tcell election from collected stem cells for planned ASCT. Escpecially for high risk patients. Posted onOctober 17, 2021 12:42 pm
Véronique Baud, Paris, France: Great satelitte session! How dysregulated oncogenic pathways in R/R DLBCL may impact on CAR T-cell efficacy? As an example, NF-kB activation is recognized to be involved in CAR T cell persistence. Posted onOctober 17, 2021 12:29 pm
Do you know the differenced between personalized medicine and targeted therapy? First is a choosing type of treatment based on mutations and markers. Second is to choosing curing after in vitro cells incubations with anticancer drugs. The differences is that when you give a directed tharapy still could give to some pateints resistance. While when patients cells are resistant to drug in vitro, this drugs should be excluded. I did my habilitation on this subject for CLL and this works (Malgorzata Rogalinska; I have poster on this topic)Posted onOctober 17, 2021 12:27 pm
For double or triple hit lymphomas can we indentify which mutation is the driver mutation? May be the driver mutation is bcl-2 and secondary mutations are bcl-6 or myc. can we see mix type genotypes and fenotypes in one biopsy samples? May be DLBCL arised from bcl-2 mutated low grade lymphomas. Vedat Aslan/TURKEYPosted onOctober 17, 2021 12:19 pm
Could you see some diversities in studies generated in mice. There should be some differences like between humans?Posted onOctober 17, 2021 12:18 pm
Can you see some diversities related with resistance to treatment? Is is possible to comapare resistance with immunological pateint strenght?Posted onOctober 17, 2021 12:16 pm
************* Day 4 *************Posted onOctober 16, 2021 8:38 pm
After new agents, we achieved loner overall survival in all lymphoma types. Are the treatment of all lymphoma types turning to non-chemoterapy regimens at first line and chemotherapy at last. Chemotherapy also harms the immune microinvoirement of lymphomas. Posted onOctober 16, 2021 7:37 pm
************ Session 7 ************Posted onOctober 16, 2021 6:28 pm
King Lam, Netherlands @ Steven Treon: would you agree that enrichment by selecting the malignant cells rather than using PCR or NGS is more important to increase the sensitivity of detecting MYD88 L265P mutation?Posted onOctober 16, 2021 4:25 pm
Do you know that targeted therapy based on genetic markers could also fail, while personalized therapy chosen in vitro during cell culturing with anticancer drugs will show resistance, and this experiments perform before drug administration to patient gives the opportunity to exclude resistance to treatment before drug administration to patients. There is a paper which explains this diversity.Posted onOctober 16, 2021 4:16 pm
Thank you for the interesting discussion! When we learn more on disease biology, we can identify more and more subgroups. How to justify the (unmet) need in these often marginal in size patient groups to regulators and payers? (TJ, Finland) Posted onOctober 16, 2021 4:16 pm
Peoples differs. Do we have enough apparatus to monitor what has happen to molecules in the human body to choose effective treatment? From my point of view human being should forward money from space discovery for some time into international studies to invent apparatus that will be able to monitor how drug molecules are dispers and translocate in the human body. Whitout this apparatus we try to cure pateints, but because we choose some markers as a standard for drug selections, smoetimes, because of some other alterations pateints are resistance to therapyPosted onOctober 16, 2021 4:05 pm
********************* Janssen Posted onOctober 16, 2021 3:31 pm
Great session!Posted onOctober 16, 2021 3:30 pm
For Dr. James Phelan, many thanks for your talk. In regards to autophagy did you observe a compensation mechanism i.e other autophagy related genes activate when you added BTK inhibition? Thanks, Harpreet Mandhair, Switzerland.Posted onOctober 16, 2021 3:27 pm
Veronique Baud, Paris, France: We just published that RelB, the alternative NF-kB subunit, is frequently activated in both ABC and GCB DLBCL and define a subset of DLBCL patients with worse prognosis. Not so surprisingly, there is a correlation between TRAF3 mutations and RelB activation. Do you have clues on the impact of TRAF3 mutations in response to different types of inhibitors?Posted onOctober 16, 2021 3:24 pm
Veronique Baud, Paris, France to Marek Mraz: Since CD40 induces both classical and alternative NF-kB pathway, have you checked if TRAF4 is also involved in the regulation of the NF-kB alternative pathway downstream of CD40 in CLL cells.Posted onOctober 16, 2021 3:12 pm
Adrian, with your ibrutinib-resistant CLL samples, Art Shaffer in my lab showed that there was an increased association of RAC2 with PLCG2, which is a work around way to activate PLCG2 when BTK kinase is inhibited
Posted onOctober 16, 2021 3:10 pm
Véronique Baud (Paris, France) to James Phelan: Great talk James! Lou Staudt presented data showing that young R/R MCD DLBCL patients are more sensitive to Ibrutinib. Do you have clues on difference in activity in chronic selective autophagy in young vs older DLBCL patients , or at least A20 expression levels?Posted onOctober 16, 2021 2:53 pm
For Jim Phelan from Dan Hodson, UK. Really great work! Were the ATG13 deletions you showed found in BTKi-relapsing patients? Can you see evidence that patients who relapse on BTKi have down-modulated this autophagy pathway - perhaps by non-genetic means? Also, are MYD88WT and MYD88_L265P both equally susceptible to this form of autophagy?Posted onOctober 16, 2021 2:35 pm
Posted onOctober 16, 2021 1:36 pm
**** Session 6 ******Posted onOctober 16, 2021 1:36 pm
Posted onOctober 16, 2021 1:31 pm
Fantastic lectures, thank youPosted onOctober 16, 2021 1:31 pm
thanks , in WM can MRD used to consider limited duration for BTi+anti CD antibody? Posted onOctober 16, 2021 1:13 pm
WHEN DO YOU RECOMEND IBRU+RITUXI INSTEAD OF ONLY IBRU
THANKSPosted onOctober 16, 2021 1:13 pm
Is zanubritib efficace in the treatment of refractory relapsed Waldenstorm with haemolytic anemia And unmutated MYD88?
Thanks a lot Posted onOctober 16, 2021 1:10 pm
What is known about the frequency and severity of Post-Acute Covid Syndrome (LongCOVID) in Waldenström (or lymphoma) patients with persisting SARS-VoV2 antibodies? Michael Hallek, University of ColognePosted onOctober 16, 2021 1:08 pm
Can low dose ibrutinib be effective in WM. It wil be helpful for toxiicity managementPosted onOctober 16, 2021 12:52 pm
Thank You Posted onOctober 16, 2021 12:23 pm
********* BeiGene sympo *******Posted onOctober 16, 2021 12:19 pm
HAVE YOU EVER ATTEMPTED TO MEASURE MATRIX STIFFNESS IN EXTRANODAL LYMPHOMAS? DO YOU SUSPECT DIFFERENT FUNCTIONAL ROLES OF THE MATRIX IN NODAL VS EXTRANODAL LYMPHOMAS? CHRIS PARK (USA)Posted onOctober 16, 2021 12:11 pm
Are you thinking of including d-dimer or other biological variables to the THROLY score. There is an inflammatory environment upon diagnosis with HL- reflected by ESRPosted onOctober 16, 2021 11:43 am
Posted onOctober 16, 2021 11:42 am
Posted onOctober 16, 2021 11:33 am
Posted onOctober 16, 2021 11:33 am
Posted onOctober 16, 2021 11:33 am
Posted onOctober 16, 2021 11:32 am
TestPosted onOctober 16, 2021 11:31 am
Do you think tumor plasticity is linked with mechanisms of therapy resistance?
Jim Phelan, NCIPosted onOctober 15, 2021 5:56 pm
Do class switch process (Shifting IgM secretion to IgA, IgG, IgE) block the memory cells to enter the germinal cells?Posted onOctober 15, 2021 5:55 pm
Posted onOctober 15, 2021 5:55 pm
To Bertrand and Dan:
We now see that FL had transcriptome more as gradient b/w GC amd Memory like, while CLL transcriptome is little more clear classification b/w U-vs M-CLL. As more/less both entities has some GC involved what could be reason for this difference. Does FL heterogeneity classification benefits from identifying some extracellular marker like CD5 and BCR-SHM status for CLL??Posted onOctober 15, 2021 5:39 pm
For David. From Dan Hodson. Very impressive technology. How many phased variants are you tracking in a typical DLBCL patient and what sort of deduplicated depth are you sequencing the plasma DNA to?Posted onOctober 15, 2021 5:38 pm
Othman Al-Sawaf, Cologne: @David and @Dan - Do you think there might be a way for MRD measurements without germline or tumour information?Posted onOctober 15, 2021 5:36 pm
For Anand, from Dan Hodson, UK. Fascinating study. Can you expand a bit on exactly how the drug sensitivity assay was performed?Posted onOctober 15, 2021 5:27 pm
Have you extract ctDNA from serum?Posted onOctober 15, 2021 5:26 pm
Question to Kurtz:
What is the minimum number of variants and the lowest VAF you could detect with Phased-seq in PET-neg/CAPPseq-neg time points?
How do you distinguish, in such time points, between possible CHIP mutions (maybe therapy-induced) and persistent or emerging tumour clones at VAF below 1% ? Posted onOctober 15, 2021 5:00 pm
Singh, Netherlands
Hi Dan,
Excellent talk. It is quite interesting to see that mutant clone can support survival of WT CLL clone via IL4/Notch pathway. However, it is not clear to me why Ibrutinib cannot inhibit IL4 mediated survival in WT cells, as it is shown to be the case in many invitro/exvivo studies. My expectation was to see some novel relapse pathways.Posted onOctober 15, 2021 4:43 pm
Are these ctDNA are secreted exosome related DNA particles or from the vesicles occuring during apopitosis? normally free DNA with Histons causes thrombosis as seen in NETozis. Posted onOctober 15, 2021 4:42 pm
To Bertrand Nadel. From Dan Hodson, UK. There are several studies that try to map bulk RNA seq signatures of lymphoma subtypes (mainly DLBCL) onto individual stages of normal GC lifecycle derived from SC-RNA-Seq, to try to narrow down the cell of origin. Given the broad continuum of differentiation state that you just showed within a single tumour do you think this is a meaningful approach?Posted onOctober 15, 2021 4:14 pm
Cédric Ménard (France) to Bertrand: if FL cells (at least some clones) are still able to proliferate, do you still think Bcl2 can inhibit entry in cell cycle ?Posted onOctober 15, 2021 4:13 pm
*********** Session 5 ************Posted onOctober 15, 2021 4:05 pm
[comment/not a panel question]@Thomas Oellerich on your question on deconvolution: Do you expect simultaneous biological processes cause overlapping proteomic expression signatures that you want to deconvolute? If so, you might want to look into our method signal dissection by correlation maximization for your current analysis (https://www.nature.com/articles/s41467-019-12713-5), instead of hierarchical clustering or NMF etc. This might yield signatures of higher specificity and stronger outcome association, as we showed for DLBCL gene expression. You could also dissect your proteome matrix simultaneously with the RNA-seq matrix to discover combined signatures. (Michael Grau, AG Lenz, Germany; would also be glad to help if Georg agrees).Posted onOctober 15, 2021 3:51 pm
Posted onOctober 15, 2021 3:50 pm
Are zinc finger proteins the main target of steroids that is used for lymphoma treatment. Posted onOctober 15, 2021 3:22 pm
Suzanne Turner, Cambridge UK
Hi Kojo, nice to see the updates. Do you see TCR expression on the tumours that develop in the mice? Is there any evidence in these mice as to whether an active TCR (tonic or active signalling) is required for lymphomagenesis?Posted onOctober 15, 2021 3:22 pm
Proteasomes are important for NFKb function because IkB degradation is needed for NFKb for enterance no nucleus. So theoretically proteosome inhibitor can be effective for ABC type DLBCL. Do you think that the NFKb targeted therapies will be the main therapy options? Posted onOctober 15, 2021 2:56 pm
Posted onOctober 15, 2021 2:48 pm
Can you culture cells obtained in biopsy with anticancer drugs to choose an effective drug?Posted onOctober 15, 2021 2:48 pm
Q for Thomas O: Do your proteomic clusters show a survival difference? Dan hodson UKPosted onOctober 15, 2021 2:37 pm
Thomas- very nice work. Are there any proteins which you find from the proteomics survey to be very highly expressed in lymphoma samples compared to reactive lymphoid tissue, which do not show similar discrimination at the mRNA level?- thanks. Anand Jeyasekharan (NUS Singapore)Posted onOctober 15, 2021 2:36 pm
Great talk Thomas. Since you have the gene expression and the proteomics can you estimate how much extra information the proteomics provides - ie how much regulation happens at the post-transcriptional level?Posted onOctober 15, 2021 2:35 pm
Can you diverse prognosis of patients to anticancer drugs using genetic profile alterations? Is it successful for all patients? What is with personal patient diversities, also in response to treatment?Posted onOctober 15, 2021 2:34 pm
Posted onOctober 15, 2021 2:31 pm
Does BCR signals in My-T-BCR complexes? If not, What is the role of BCR in the My-T-BCR complexes?Posted onOctober 15, 2021 2:29 pm
*********** Session 4 *********Posted onOctober 15, 2021 2:15 pm
A potentially naive question to all speakers of this - by the way excellent! - session: can you imagine for the future some more specific, targeted inhibitors of targets rather than the general HDAC inhibitors that we are mostly using now?
Or in a broader sense, can we modulate epigenetic regulation more specifically for therapeutic purposes in lymphoma?
Michael Hallek, Cologne
Posted onOctober 15, 2021 2:03 pm
thanks , is there crosstalk between DNA methylation status and BCL2 expression or activity ?Posted onOctober 15, 2021 2:03 pm
Mutated histone H1 proteins are still in the cell. Your KO-model has no loss-of-function proteins in the cells. Do you expect differences between these situations? (Stefan Nagel, DSMZ, Germany)Posted onOctober 15, 2021 1:53 pm
To Dr Melnick from elias campo: Acquiring stemness properties may be an advantage to terminally differentiated cells or cells that may not re-acquire proliferation but lymphoid cells, contrary to terminally differentiated epitelial cells, may physiologically re-acquire the properties of proliferation upon different stimulations. What is the selective advantage to B-cell to acquire this stem cell properties? Posted onOctober 15, 2021 1:48 pm
Dr Hodson, Any insight into how DDX3X mutant lymphomas activate DDX3Y expression? How might you target DDX3Y therapeutically?
Jim Phelan, NCIPosted onOctober 15, 2021 1:43 pm
Stefano Casola for Dr Hodson: Nice talk. Is DDx3Y possibly expressed in germinal center B cells?Posted onOctober 15, 2021 1:42 pm
A question for Daniel Hodson from Tarik Moroy, Montreal, Canada: could you elaborate how the dominant negative effect of the DDX3X mutations is executed in male or female BL and through which mechanism DDX3Y upregulation takes place in case of LOF of DDX3X in males.Posted onOctober 15, 2021 1:42 pm
Andrei Thomas-Tikhonenko (Philadelphia, USA) - question for DH: Very nice story! Have you looked at lengths of and microRNA site abundance in 3'UTRs of DDX3X-dependent transcripts to see if miR-based mechanisms cooperate with or antagonize DDX3X effects? This would be interesting, because MYC negatively affects microRNA biogenesis, which could lead to proteotoxic stress.Posted onOctober 15, 2021 1:41 pm
Maria Toribio to Teresa palomero.
Great talk Teresa, thank you.
How much TCR-dependent are PTCL? Could TCR be envisaged as a potential therapeutic target?Posted onOctober 15, 2021 1:40 pm
In view of the essential roles of DDX3X and DDX3Y (such as general translational regulation) how do you think your findings can be leveraged for BL or DLBCL therapy? Ester, CHPosted onOctober 15, 2021 1:37 pm
Thank you very much for the excellent talks for all of the speakers
My question is to Dr. Palomero
You demonstrated the certain fusions which are related to the subclasifying and differentiation of PTCL entities. On practical diagnostic approach do you thing there could be an algorthym drown strating with immunhistochemistry ( TFH markers, GATA3, TBET, ) and followed by methods targetting to seach these certain chromosomal alterations (by FISH ?), searching Rhoa, TET mutations by sequencing. These cases are difficult and carry challenges in differential diagnosis. The diagnostic algorthym may also help for giving information for targetting epigenetic factors?
Question is from Isinsu Kuzu Ankara /Turkey
Posted onOctober 15, 2021 1:32 pm
my question is to Palomero
Regaarding to the differential diagnosis of the PTCL Nos, AITCL, PTCL follicular Posted onOctober 15, 2021 1:19 pm
Does RHOA mutations can be find together with FY-TRAF3ip2? and if yes, the tumor that develops has the phenotype of PTCL, NOS?
In your experience how often are TET2 mutations found in T-cell lymphomas? (Leticia Quintanilla-Fend, Germany)Posted onOctober 15, 2021 1:09 pm
From Suzanne Turner, Cambridge, UK
For Teresa Palomero: Does stimulation though the TCR contribute to lymphomagenesis due to RhoA mutant or Vav mutant (either tonic or active)? Have you tried engaging the TCR in these mouse models - if so, does it affect the phenotype and/or latency of tumour development? Alternatively do you see a tonic or active TCR signalling expression programme in the resulting tumours? Or do these oncogenic events maybe inhibit transduction from the TCR?Posted onOctober 15, 2021 1:06 pm
To the panel many thanks for your talk. My question is for Prof. Ari Melnick. Your data has demonstrated that H1 is indeed a tumour suppressor under non pathological conditions. The loss of this drives lymphomagenesis. Is there any data or correlation that it may coordinate DLBCL migration/ dissemination? (from Harpreet Mandhair, Switzerland).Posted onOctober 15, 2021 12:58 pm
Stefano Casola (Italy) to Dr Martin-Subero: great talk! Did you find somatic mutations differing classical from nnMCL within the TAD including the SOX11 gene and its supernehancer, which may explain the different frequency of contacts between the Sox11 gene and its super-enhancer in the two groups of tumors?Posted onOctober 15, 2021 12:52 pm
Great talk! Is there any clue why the loop between SOX11 and the enhancer occurs? Leticia Quintanilla-Fend, GermanyPosted onOctober 15, 2021 12:48 pm
Do mantle cells express high amount bcr (Immunglobulin heavy chain) and Cyclin D1 at the same time? Do high expression causes the risk of translocation mutation? t(11;14)Posted onOctober 15, 2021 12:47 pm
Q to Ari from Bertrand Nadel (France). Fascinating talk Ari thank you. 2 Q. Q1regarding de-differentiation. Might the H1 alterations in FL help explain the higher propensity of mem-like Follicular Lymphoma cells to return to rounds of GC reaction (which is rare in normal B cells)? Q2 (more philosophical) regarding self-renewal: Once transformed (and once the telomere shortening pb is resolved), is there necessarily a need for cancer cells to self-renew? Or are you specifically refering to CPC?Posted onOctober 15, 2021 12:31 pm
Posted onOctober 15, 2021 12:12 pm
********* Session 3 ************Posted onOctober 15, 2021 11:41 am
Posted onOctober 14, 2021 6:03 pm
Posted onOctober 14, 2021 6:01 pm
Remark King Lam, Netherlands: we have left het Working Formulation a long time ago!Posted onOctober 14, 2021 6:01 pm
I may have missed it when listening to you, Andrew and Lou, but what is the biology underlying the ineffective response to ibrutinib in OLDER non-GCB (or MCD) lymphoma patients? Michael Hallek, ColognePosted onOctober 14, 2021 5:58 pm
Can you please comment on how MRD in lymphoma will evolve (cell based vs plasma based) - especially in terms of regulatory perspective etc.,Posted onOctober 14, 2021 5:53 pm
Posted onOctober 14, 2021 5:52 pm
Stefano Casola (Italy): to Dr Staudt: I like your hypothesis that MCD-subset of DLBCL is "hiding" in immunopriviledged site. I suspect it is the result of the specific signaling pathways active in these tumors. Immunopriviledged sites include the dark zone of the GC. Why are DZ-derived DLBCL tumors (i.e.DHL) not selecting an MCD-like mutational landscape....?Posted onOctober 14, 2021 5:51 pm
Thanks excellent talks
in AML setting , AZA over come MCL1 resistance to venetoclax when us in combination , 1. can this applied in B cell lymphoma to enhance BCL2i
2. is there relation between methylation status and BCL2 expression or activity? Posted onOctober 14, 2021 5:49 pm
Jim Phelan, NCI - The various molecular classification systems are remarkable in their overlapping findings, yet they seem to treat genetic homogeneity differently. Can the panel comment on the DLBCL samples that do not fit into a LymphGen category but are clustered with clustering models? Are these borderline 'LymphGen' cases clinically similar to the core subtype cases or are they clinically and molecularly distinct? Would you treat them similarly to a core case clinically?Posted onOctober 14, 2021 5:42 pm
If T cell rich lymphomas are hiding from T cell immune attack? Why are they T cell rich lymphomas? Are T cell migrate to lymphoid tissues by homing mechanism with cytokines? Posted onOctober 14, 2021 5:42 pm
There are rare families with both cHL and PMBL - do we know if these cases have different genetic features from the norm? Martin Dyer UKPosted onOctober 14, 2021 5:41 pm
Dr Staudt, Was the unpublished data on the diff subtypes and outcomes in phoenix you shared restricted to younger pts OR did data include ALL pts on study? Thanks (Ranjana Advani, USA)
Posted onOctober 14, 2021 5:36 pm
Anand Jeyasekharan (Singapore)- great talks everyone. Do plasmablastic lymphomas occupy a niche within DLBCL genetic subtypes?Posted onOctober 14, 2021 5:36 pm
Andrei Thomas-Tikhonenko (Philadelphia, USA): Great talks this afternoon, thank you to all! A big-picture question for the entire group really: if the ultimate goal of any classification is to identify responders to existing drugs (say, ibrutinib), could there be an advantage to first performing supervised clustering based on responses to the drug across multiple trials and then using machine learning to identify genetic determinants of response? Same data, the opposite direction of analysis...Posted onOctober 14, 2021 5:29 pm
Question to Dr Staudt
Thank you very much for your great talk. Regarding to the trial you have presented the preliminary results. We know that there are some additional mutations such as CXCR4, related with the resistance to ibrutinib therapy in Lymphoplasmacytic lymphomas. In your cohort which expresses Ibrutinib efficiency in younger patients. Did you look for the mutations which are related with Ibrutinib resistance especially in the group of older patients ? Dr.Isinsu Kuzu Ankara /Turkey Posted onOctober 14, 2021 5:12 pm
Question for dr Shipp. Thank you the very nice presentations. DLBCL is clearly very heterogeneous. Can you speculate on driver of the malignancy? Does a B-cell need so many mutations and genetic alterations to transform to a malignant cell? In other words, can you speculate on an essential oncogenic driver for the malignant transformation? Posted onOctober 14, 2021 5:02 pm
Dear Lou, reg. Phoenix: do you think there could also be a negative interaction of Ibrutinib and Rituiximab (ie BTKi inhibiting activity of of R )? Thorsten ZenzPosted onOctober 14, 2021 4:52 pm
Is there any relation between ABCL type Diffuse use large B cell lymphoma and Richter transformation of Small cell lymphocytic leukemia or other low grade lymphomas? Are they CD5 positive? Posted onOctober 14, 2021 4:48 pm
Q to Margaret (B Nadel France): single-cell studies show that a given genetic subset can adopt various transcriptional states, with likely impact on response to therapy. Could you elaborate on the relatively low concordance between genetic subclasses and single-cell classes revealed by the recent Steen paper (Alizadeh group), and comment on the role of TME on switching/adopting transcriptional statesPosted onOctober 14, 2021 4:36 pm
Q to Margaret (B Nadel France): single-cell studies show that a given genetic subset can adopt various transcriptional states, with likely impact on response to therapy. Could you elaborate on the relatively low concordance between genetic subclasses and single-cell classes revealed by the recent Steen paper (Alizadeh group), and comment on the role of TME on switching/adopting transcriptional statesPosted onOctober 14, 2021 4:35 pm
What dose the genetic aberration similarity between PMBCL and HL imply to the potential treatment approach these 2 distinct lymphomas. Is there likelihood of overlap or similarity in the treatment?Posted onOctober 14, 2021 4:34 pm
Posted onOctober 14, 2021 4:30 pm
Do you think CNS and testicular lymphomas are molecularly different from other extra nodal C5/MCD DLBCL, ex: leg type or intravascular lymphomasPosted onOctober 14, 2021 4:30 pm
.Posted onOctober 14, 2021 4:15 pm
************ Session 2 ***************Posted onOctober 14, 2021 3:45 pm
Posted onOctober 14, 2021 3:44 pm
Absolutely great discussion. Great session!Posted onOctober 14, 2021 3:43 pm
Posted onOctober 14, 2021 3:34 pm
Question to David Scott (from Francesco Forconi/Southampton): very nice talk! have you found any signatures associated with BCR post-translational modifications (mannosylated BCR) in the DZ GCB-DLBCL? Thanks.
Posted onOctober 14, 2021 3:32 pm
Are CAR T cell therapy and checkpoint inhibitors suited/ tested to treat lymphomas?Posted onOctober 14, 2021 3:26 pm
To David Scott - Can you elaborate why a DHit-signature cluster defining a subset of poor-outcome GC DLBCL was not picked up when the original GCB/UNC/ABC cell-of-origin signatures were being described? In other words, what does DHit have that the GCB signature is missing. Thank you! Michał Hoppe from Singapore.Posted onOctober 14, 2021 3:26 pm
Posted onOctober 14, 2021 3:21 pm
Questions for David Scott: Is there an overlap between transformed follicular lymphoma and "double hit" dark zone GCB lymphomas? In terms of the sequence of transformation events, is it broadly thought that the BCL2 translocation occurs first then CREBBP/epigenetic modifier mutations occur followed by MYC translocation/over-expression? Finally, what level of heterogeneity exists within the DHIT signature, are there further molecular subtypes that could be identified? (Laabiah Wasim, Francis Crick Institute, UK)
Posted onOctober 14, 2021 3:19 pm
To David Scott from Elias Campo in Barcelona: Being Burkitt Lymphoma and High grade B cell lymphoma originating in the dark zone and having similar gene expression signature and MYC tranalocation, what makes them so different in the response to therapy and outcome?
Posted onOctober 14, 2021 3:18 pm
James Nolan - Ireland
Really found your talk illuminating David. Is there any observation that more "indolent" follicular lymphomas have more of a light zone signature than higher grade (grade 3A/B) or more clinically aggressive follicular lymphomas which might have a dark zone signature?
Posted onOctober 14, 2021 3:18 pm
Posted onOctober 14, 2021 3:17 pm
Thank you for a very interesting session. I have a question about DLBCL, non germinal center, with only BCL 6 translocation, which treatment would you recommend?
thank you
Posted onOctober 14, 2021 3:17 pm
To Klaus Rajewsky: Did you study the distinct/different roles of PI3K versus BTK, SYK or Src Kinases in their capacity to (partially) replace BCR signaling? And does their role differ in different types of B cell lymphoma? Michael Hallek, ColognePosted onOctober 14, 2021 3:14 pm
Peijia, Netherlands: To Prof. Kuppers, two HL cell lines are T cell derived if I remember correctly. Is there any difference in CD30 or other gene expression profiling between these two cell lines and other B cell derived HL cell linesPosted onOctober 14, 2021 3:12 pm
My question is to Laura Pasquallucci
Are the CREPPB and KMT2D genes targets of the hypermutational machinery in GCs for mutation?
Akif Yavuz
Istanbul, TurkeyPosted onOctober 14, 2021 3:11 pm
To David Scott from Sergio Roa (Spain): How would double-expressor MYC+BCL2+ lymphomas without underlying genetic alterations (and more frequently associated to ABC-DLBCL) fit in your conclusions for DHIT "cell-of-origin"?Posted onOctober 14, 2021 3:10 pm
Q to David (B Nadel France): isn't the "DZ signature" in fact a "MYC signature", compatible with BL and DH/TH, and back to Klaus talk, shouldn't MYC be attempted to be targeted ? Also, there are many ways to increase MYC function and stability, including GSK3b post-transcriptional modifications. These might increase the cohort of GCB with bad prognosisPosted onOctober 14, 2021 3:10 pm
Given the critical role of GSK3B in linking BCR signal to MYC, is it surprising that we don't see inactivating mutation of GSK3B in lymphoma?Posted onOctober 14, 2021 3:07 pm
Any role for antibiotic treatment of Moraxella in LP-hodgkin to remove the antigenic signal to tumour?Posted onOctober 14, 2021 3:05 pm
Andrei Thomas-Tikhonenko (Philadelphia, USA): A question for DS: Are there distinct mutational or expression signatures corresponding to BCL2- vs BCL6-translocated DHL?Posted onOctober 14, 2021 2:59 pm
Enrico Tiacci (Perugia - Italy). Hi Ralf, do you know if the LPHL cases with Moraxella IgG serum antibodies were all (or largely) IgD+?
Posted onOctober 14, 2021 2:45 pm
Based on your findings on CD30 function, do you know whether or do you think CD30 might be involved in the pathogenesis of Gray zone lymphomas? (Esther, Switzerland)Posted onOctober 14, 2021 2:43 pm
Stefano Casola (Italy): Very nice talk, Ralf. How is CD30 controlling MYC function? Is it controlling expression of the MYC gene? Stabilization of MYC protein or does it influence MYC-controlled gene expression?Posted onOctober 14, 2021 2:39 pm
Andrei Thomas-Tikhonenko (Philadelphia, USA): A question for RK: Given that the MYC signature is rather broad, I wonder whether or not CD30+ HRS cells bear any similarity at the transcriptome level to (8;14)-translocated lymphomas. If they do, what are the overlapping MYC targets?Posted onOctober 14, 2021 2:34 pm
Prof. Ralf Kuppers: is it known how CD30 expression is regulated?
Dinis Calado; Crick Institute, LondonPosted onOctober 14, 2021 2:31 pm
Question to Prof. Laura Pasqualucci: is the loss of KMT2D and CREBBP synergistic in lymphoma development in the mouse compared to the single mutants? Is the addition of BCL2 over-expression required?
Dinis Calado; Crick Institute, LondonPosted onOctober 14, 2021 2:29 pm
Q to Laura (B NADEL France): Crebbp, KMT2D and others are powerful oncogenes when combined with BCL2, but not alone or when combined together. Is BCL2 merely providing survival, or also the required genomic instability to acquire additional hits? Did you test mutation landscapes in the various combinations? Do Crebbp and KMT2D have the power to initiate tumorigenesis without prior BCL2 (or equivalent) deregulation?Posted onOctober 14, 2021 2:29 pm
Did you know that results you show could be different if circumstances will change. This is a main human mistake, when experiments condition changes, like for example human diet could also metersPosted onOctober 14, 2021 2:26 pm
Stefano Casola (Italy): very nice talk Laura! Are haploinsufficient CBP/KMT2D (GC) B cells switching from H3K4me1 to H3K3me3 at target enhancer regions? I say this because you don't seem to see effects on H3K4me3 levels upon CBP inactivationPosted onOctober 14, 2021 2:23 pm
What is the action in experimental feature when some cells from patiens have mutations (50) and in other 50 is lack is mutation?Posted onOctober 14, 2021 2:16 pm
sorry forgot to state my name: Bertrand Nadel FRANCEPosted onOctober 14, 2021 1:59 pm
Question to Klaus: Wonderful talk thank you!! Considering the central AKT/GSK3b/MYC axis dependency you demonstrate in BCR+ lymphomas, are we underappreciating the role of MYC beside translocated MYC cases (DH/TH)? Myc has proved to be a very tough oncogene to modulate, eg with little success with BET inhibitors. What would you recommand to focus on regarding therapeutic target in this axis?Posted onOctober 14, 2021 1:58 pm
Stefano Casola (Italy): Great talk ,Klaus! have you had the chance to see which additional mutations are eventually required to get MM triggered by combination of MMSET/CCND1 and IKK2ca?
Posted onOctober 14, 2021 1:58 pm
Is is possible to modulate gene expression by targeting BCR receptorPosted onOctober 14, 2021 1:48 pm
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ChinaPosted onOctober 14, 2021 1:18 pm
***** Day 1 *****Posted onOctober 14, 2021 1:01 pm
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Test 123Posted onOctober 13, 2021 9:19 pm
Posted onOctober 17, 2021 4:04 pm
Thank you so much for this opportunity! Remarkable meeting! Antonio Macedo, BrazilPosted onOctober 17, 2021 4:03 pm
Thank you!Posted onOctober 17, 2021 3:53 pm
To all panelists > any evidence or rationale for split dosing (with lower doses at each infusion) of CAR T cell therapy across time, say, at 0, 3, 6, 9, and 12 mos (for instance, for indolent lymphoma or multiple myeloma) to enhance persistence and reduce relapse? Antonio Macedo, BrazilPosted onOctober 17, 2021 3:51 pm
What types of biomarkers can be used to predict response earlier? Would that enable an earlier switch in therapy and better overall survival?Posted onOctober 17, 2021 3:48 pm
Anand Jeyasekharan (National University of Singapore)- to all panelists- do we foresee that bispecifics (and possibly generic versions of these) will ultimately be the “global lymphoma care” choice for regions of the world where the infrastructure for CAR-T is going to be challenging to set up? Should we focus on combinatorial trials that aim to enhance bispecific efficacy?Posted onOctober 17, 2021 3:33 pm
Maybe the panel wants to debate - as their personal view - whether the emergence of bispecific antibodies will reduce the need for CART cell therapies? Michael Hallek, ColognePosted onOctober 17, 2021 3:20 pm
Question to Jacobson: Were the CD58 mutations in the ctDNA analysis detected at diagnosis or relapse? In the latter case, do you think CD58 wt cases should qualify for earlier CART treatment? Thank you Posted onOctober 17, 2021 2:58 pm
Question to Ranjana Advani: Do you know any data or do you have experience with combinations of BTK or PI3K inhibitors and anti-CD47 antibodies? Michael Hallek, Cologne Posted onOctober 17, 2021 2:48 pm
*********************Posted onOctober 17, 2021 1:03 pm
Great discussion. Thank you!Posted onOctober 17, 2021 1:01 pm
thanks , we knew prior therapy could impact T cell function for CAR T cell therapy , Can prior therapy impact B cell function and quality of B cell anti-bodies ,BITS responses? Ezzat Elhassadi Posted onOctober 17, 2021 12:58 pm
Thank you very much for the presentations Thank you very much for the presentations I would like to ask you the algorthym for the future diagnosis and progression evaluation of the DLBCL regarding the type of sampling : do you thing core biopsy is suitable for initial diagnosis and molecular sub classification Regarding the which methods are recommended ? NGS for every patient ? Isinsu Kuzu / Turkey Posted onOctober 17, 2021 12:48 pm
Could you maybe compared results of CART therapy with previous patient immunological strength? Could be immunological strength a factor that might be important in choosing therapy? Do you think that in general, we should improve immunological strength to avoid any diseases, including cancersPosted onOctober 17, 2021 12:46 pm
Thanks, hypothetical question, Is T cell pheresis in the early disease course with better T cell quality, a better approach in high-risk DLBCL rather than early CAR-T cell therapy? Posted onOctober 17, 2021 12:44 pm
Before the CAR-T cell therapy and other T-cell engager therapies, a DLBCL patients take multiple chemotherapies (fist line, second line and ASCT) This process exhaust T cells of these patients. Wİll there be any guides to minimize the T cell exhaustion? For example T cell apheresis after fist line treatment or Tcell election from collected stem cells for planned ASCT. Escpecially for high risk patients. Posted onOctober 17, 2021 12:42 pm
Véronique Baud, Paris, France: Great satelitte session! How dysregulated oncogenic pathways in R/R DLBCL may impact on CAR T-cell efficacy? As an example, NF-kB activation is recognized to be involved in CAR T cell persistence. Posted onOctober 17, 2021 12:29 pm
Do you know the differenced between personalized medicine and targeted therapy? First is a choosing type of treatment based on mutations and markers. Second is to choosing curing after in vitro cells incubations with anticancer drugs. The differences is that when you give a directed tharapy still could give to some pateints resistance. While when patients cells are resistant to drug in vitro, this drugs should be excluded. I did my habilitation on this subject for CLL and this works (Malgorzata Rogalinska; I have poster on this topic)Posted onOctober 17, 2021 12:27 pm
For double or triple hit lymphomas can we indentify which mutation is the driver mutation? May be the driver mutation is bcl-2 and secondary mutations are bcl-6 or myc. can we see mix type genotypes and fenotypes in one biopsy samples? May be DLBCL arised from bcl-2 mutated low grade lymphomas. Vedat Aslan/TURKEYPosted onOctober 17, 2021 12:19 pm
Could you see some diversities in studies generated in mice. There should be some differences like between humans?Posted onOctober 17, 2021 12:18 pm
Can you see some diversities related with resistance to treatment? Is is possible to comapare resistance with immunological pateint strenght?Posted onOctober 17, 2021 12:16 pm
************* Day 4 *************Posted onOctober 16, 2021 8:38 pm
After new agents, we achieved loner overall survival in all lymphoma types. Are the treatment of all lymphoma types turning to non-chemoterapy regimens at first line and chemotherapy at last. Chemotherapy also harms the immune microinvoirement of lymphomas. Posted onOctober 16, 2021 7:37 pm
************ Session 7 ************Posted onOctober 16, 2021 6:28 pm
King Lam, Netherlands @ Steven Treon: would you agree that enrichment by selecting the malignant cells rather than using PCR or NGS is more important to increase the sensitivity of detecting MYD88 L265P mutation?Posted onOctober 16, 2021 4:25 pm
Do you know that targeted therapy based on genetic markers could also fail, while personalized therapy chosen in vitro during cell culturing with anticancer drugs will show resistance, and this experiments perform before drug administration to patient gives the opportunity to exclude resistance to treatment before drug administration to patients. There is a paper which explains this diversity.Posted onOctober 16, 2021 4:16 pm
Thank you for the interesting discussion! When we learn more on disease biology, we can identify more and more subgroups. How to justify the (unmet) need in these often marginal in size patient groups to regulators and payers? (TJ, Finland) Posted onOctober 16, 2021 4:16 pm
Peoples differs. Do we have enough apparatus to monitor what has happen to molecules in the human body to choose effective treatment? From my point of view human being should forward money from space discovery for some time into international studies to invent apparatus that will be able to monitor how drug molecules are dispers and translocate in the human body. Whitout this apparatus we try to cure pateints, but because we choose some markers as a standard for drug selections, smoetimes, because of some other alterations pateints are resistance to therapyPosted onOctober 16, 2021 4:05 pm
********************* Janssen Posted onOctober 16, 2021 3:31 pm
Great session!Posted onOctober 16, 2021 3:30 pm
For Dr. James Phelan, many thanks for your talk. In regards to autophagy did you observe a compensation mechanism i.e other autophagy related genes activate when you added BTK inhibition? Thanks, Harpreet Mandhair, Switzerland.Posted onOctober 16, 2021 3:27 pm
Veronique Baud, Paris, France: We just published that RelB, the alternative NF-kB subunit, is frequently activated in both ABC and GCB DLBCL and define a subset of DLBCL patients with worse prognosis. Not so surprisingly, there is a correlation between TRAF3 mutations and RelB activation. Do you have clues on the impact of TRAF3 mutations in response to different types of inhibitors?Posted onOctober 16, 2021 3:24 pm
Veronique Baud, Paris, France to Marek Mraz: Since CD40 induces both classical and alternative NF-kB pathway, have you checked if TRAF4 is also involved in the regulation of the NF-kB alternative pathway downstream of CD40 in CLL cells.Posted onOctober 16, 2021 3:12 pm
Adrian, with your ibrutinib-resistant CLL samples, Art Shaffer in my lab showed that there was an increased association of RAC2 with PLCG2, which is a work around way to activate PLCG2 when BTK kinase is inhibited Posted onOctober 16, 2021 3:10 pm
Véronique Baud (Paris, France) to James Phelan: Great talk James! Lou Staudt presented data showing that young R/R MCD DLBCL patients are more sensitive to Ibrutinib. Do you have clues on difference in activity in chronic selective autophagy in young vs older DLBCL patients , or at least A20 expression levels?Posted onOctober 16, 2021 2:53 pm
For Jim Phelan from Dan Hodson, UK. Really great work! Were the ATG13 deletions you showed found in BTKi-relapsing patients? Can you see evidence that patients who relapse on BTKi have down-modulated this autophagy pathway - perhaps by non-genetic means? Also, are MYD88WT and MYD88_L265P both equally susceptible to this form of autophagy?Posted onOctober 16, 2021 2:35 pm
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**** Session 6 ******Posted onOctober 16, 2021 1:36 pm
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Fantastic lectures, thank youPosted onOctober 16, 2021 1:31 pm
thanks , in WM can MRD used to consider limited duration for BTi+anti CD antibody? Posted onOctober 16, 2021 1:13 pm
WHEN DO YOU RECOMEND IBRU+RITUXI INSTEAD OF ONLY IBRU THANKSPosted onOctober 16, 2021 1:13 pm
Is zanubritib efficace in the treatment of refractory relapsed Waldenstorm with haemolytic anemia And unmutated MYD88? Thanks a lot Posted onOctober 16, 2021 1:10 pm
What is known about the frequency and severity of Post-Acute Covid Syndrome (LongCOVID) in Waldenström (or lymphoma) patients with persisting SARS-VoV2 antibodies? Michael Hallek, University of ColognePosted onOctober 16, 2021 1:08 pm
Can low dose ibrutinib be effective in WM. It wil be helpful for toxiicity managementPosted onOctober 16, 2021 12:52 pm
Thank You Posted onOctober 16, 2021 12:23 pm
********* BeiGene sympo *******Posted onOctober 16, 2021 12:19 pm
HAVE YOU EVER ATTEMPTED TO MEASURE MATRIX STIFFNESS IN EXTRANODAL LYMPHOMAS? DO YOU SUSPECT DIFFERENT FUNCTIONAL ROLES OF THE MATRIX IN NODAL VS EXTRANODAL LYMPHOMAS? CHRIS PARK (USA)Posted onOctober 16, 2021 12:11 pm
Are you thinking of including d-dimer or other biological variables to the THROLY score. There is an inflammatory environment upon diagnosis with HL- reflected by ESRPosted onOctober 16, 2021 11:43 am
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TestPosted onOctober 16, 2021 11:31 am
Do you think tumor plasticity is linked with mechanisms of therapy resistance? Jim Phelan, NCIPosted onOctober 15, 2021 5:56 pm
Do class switch process (Shifting IgM secretion to IgA, IgG, IgE) block the memory cells to enter the germinal cells?Posted onOctober 15, 2021 5:55 pm
Posted onOctober 15, 2021 5:55 pm
To Bertrand and Dan: We now see that FL had transcriptome more as gradient b/w GC amd Memory like, while CLL transcriptome is little more clear classification b/w U-vs M-CLL. As more/less both entities has some GC involved what could be reason for this difference. Does FL heterogeneity classification benefits from identifying some extracellular marker like CD5 and BCR-SHM status for CLL??Posted onOctober 15, 2021 5:39 pm
For David. From Dan Hodson. Very impressive technology. How many phased variants are you tracking in a typical DLBCL patient and what sort of deduplicated depth are you sequencing the plasma DNA to?Posted onOctober 15, 2021 5:38 pm
Othman Al-Sawaf, Cologne: @David and @Dan - Do you think there might be a way for MRD measurements without germline or tumour information?Posted onOctober 15, 2021 5:36 pm
For Anand, from Dan Hodson, UK. Fascinating study. Can you expand a bit on exactly how the drug sensitivity assay was performed?Posted onOctober 15, 2021 5:27 pm
Have you extract ctDNA from serum?Posted onOctober 15, 2021 5:26 pm
Question to Kurtz: What is the minimum number of variants and the lowest VAF you could detect with Phased-seq in PET-neg/CAPPseq-neg time points? How do you distinguish, in such time points, between possible CHIP mutions (maybe therapy-induced) and persistent or emerging tumour clones at VAF below 1% ? Posted onOctober 15, 2021 5:00 pm
Singh, Netherlands Hi Dan, Excellent talk. It is quite interesting to see that mutant clone can support survival of WT CLL clone via IL4/Notch pathway. However, it is not clear to me why Ibrutinib cannot inhibit IL4 mediated survival in WT cells, as it is shown to be the case in many invitro/exvivo studies. My expectation was to see some novel relapse pathways.Posted onOctober 15, 2021 4:43 pm
Are these ctDNA are secreted exosome related DNA particles or from the vesicles occuring during apopitosis? normally free DNA with Histons causes thrombosis as seen in NETozis. Posted onOctober 15, 2021 4:42 pm
To Bertrand Nadel. From Dan Hodson, UK. There are several studies that try to map bulk RNA seq signatures of lymphoma subtypes (mainly DLBCL) onto individual stages of normal GC lifecycle derived from SC-RNA-Seq, to try to narrow down the cell of origin. Given the broad continuum of differentiation state that you just showed within a single tumour do you think this is a meaningful approach?Posted onOctober 15, 2021 4:14 pm
Cédric Ménard (France) to Bertrand: if FL cells (at least some clones) are still able to proliferate, do you still think Bcl2 can inhibit entry in cell cycle ?Posted onOctober 15, 2021 4:13 pm
*********** Session 5 ************Posted onOctober 15, 2021 4:05 pm
[comment/not a panel question]@Thomas Oellerich on your question on deconvolution: Do you expect simultaneous biological processes cause overlapping proteomic expression signatures that you want to deconvolute? If so, you might want to look into our method signal dissection by correlation maximization for your current analysis (https://www.nature.com/articles/s41467-019-12713-5), instead of hierarchical clustering or NMF etc. This might yield signatures of higher specificity and stronger outcome association, as we showed for DLBCL gene expression. You could also dissect your proteome matrix simultaneously with the RNA-seq matrix to discover combined signatures. (Michael Grau, AG Lenz, Germany; would also be glad to help if Georg agrees).Posted onOctober 15, 2021 3:51 pm
Posted onOctober 15, 2021 3:50 pm
Are zinc finger proteins the main target of steroids that is used for lymphoma treatment. Posted onOctober 15, 2021 3:22 pm
Suzanne Turner, Cambridge UK Hi Kojo, nice to see the updates. Do you see TCR expression on the tumours that develop in the mice? Is there any evidence in these mice as to whether an active TCR (tonic or active signalling) is required for lymphomagenesis?Posted onOctober 15, 2021 3:22 pm
Proteasomes are important for NFKb function because IkB degradation is needed for NFKb for enterance no nucleus. So theoretically proteosome inhibitor can be effective for ABC type DLBCL. Do you think that the NFKb targeted therapies will be the main therapy options? Posted onOctober 15, 2021 2:56 pm
Posted onOctober 15, 2021 2:48 pm
Can you culture cells obtained in biopsy with anticancer drugs to choose an effective drug?Posted onOctober 15, 2021 2:48 pm
Q for Thomas O: Do your proteomic clusters show a survival difference? Dan hodson UKPosted onOctober 15, 2021 2:37 pm
Thomas- very nice work. Are there any proteins which you find from the proteomics survey to be very highly expressed in lymphoma samples compared to reactive lymphoid tissue, which do not show similar discrimination at the mRNA level?- thanks. Anand Jeyasekharan (NUS Singapore)Posted onOctober 15, 2021 2:36 pm
Great talk Thomas. Since you have the gene expression and the proteomics can you estimate how much extra information the proteomics provides - ie how much regulation happens at the post-transcriptional level?Posted onOctober 15, 2021 2:35 pm
Can you diverse prognosis of patients to anticancer drugs using genetic profile alterations? Is it successful for all patients? What is with personal patient diversities, also in response to treatment?Posted onOctober 15, 2021 2:34 pm
Posted onOctober 15, 2021 2:31 pm
Does BCR signals in My-T-BCR complexes? If not, What is the role of BCR in the My-T-BCR complexes?Posted onOctober 15, 2021 2:29 pm
*********** Session 4 *********Posted onOctober 15, 2021 2:15 pm
A potentially naive question to all speakers of this - by the way excellent! - session: can you imagine for the future some more specific, targeted inhibitors of targets rather than the general HDAC inhibitors that we are mostly using now? Or in a broader sense, can we modulate epigenetic regulation more specifically for therapeutic purposes in lymphoma? Michael Hallek, Cologne Posted onOctober 15, 2021 2:03 pm
thanks , is there crosstalk between DNA methylation status and BCL2 expression or activity ?Posted onOctober 15, 2021 2:03 pm
Mutated histone H1 proteins are still in the cell. Your KO-model has no loss-of-function proteins in the cells. Do you expect differences between these situations? (Stefan Nagel, DSMZ, Germany)Posted onOctober 15, 2021 1:53 pm
To Dr Melnick from elias campo: Acquiring stemness properties may be an advantage to terminally differentiated cells or cells that may not re-acquire proliferation but lymphoid cells, contrary to terminally differentiated epitelial cells, may physiologically re-acquire the properties of proliferation upon different stimulations. What is the selective advantage to B-cell to acquire this stem cell properties? Posted onOctober 15, 2021 1:48 pm
Dr Hodson, Any insight into how DDX3X mutant lymphomas activate DDX3Y expression? How might you target DDX3Y therapeutically? Jim Phelan, NCIPosted onOctober 15, 2021 1:43 pm
Stefano Casola for Dr Hodson: Nice talk. Is DDx3Y possibly expressed in germinal center B cells?Posted onOctober 15, 2021 1:42 pm
A question for Daniel Hodson from Tarik Moroy, Montreal, Canada: could you elaborate how the dominant negative effect of the DDX3X mutations is executed in male or female BL and through which mechanism DDX3Y upregulation takes place in case of LOF of DDX3X in males.Posted onOctober 15, 2021 1:42 pm
Andrei Thomas-Tikhonenko (Philadelphia, USA) - question for DH: Very nice story! Have you looked at lengths of and microRNA site abundance in 3'UTRs of DDX3X-dependent transcripts to see if miR-based mechanisms cooperate with or antagonize DDX3X effects? This would be interesting, because MYC negatively affects microRNA biogenesis, which could lead to proteotoxic stress.Posted onOctober 15, 2021 1:41 pm
Maria Toribio to Teresa palomero. Great talk Teresa, thank you. How much TCR-dependent are PTCL? Could TCR be envisaged as a potential therapeutic target?Posted onOctober 15, 2021 1:40 pm
In view of the essential roles of DDX3X and DDX3Y (such as general translational regulation) how do you think your findings can be leveraged for BL or DLBCL therapy? Ester, CHPosted onOctober 15, 2021 1:37 pm
Thank you very much for the excellent talks for all of the speakers My question is to Dr. Palomero You demonstrated the certain fusions which are related to the subclasifying and differentiation of PTCL entities. On practical diagnostic approach do you thing there could be an algorthym drown strating with immunhistochemistry ( TFH markers, GATA3, TBET, ) and followed by methods targetting to seach these certain chromosomal alterations (by FISH ?), searching Rhoa, TET mutations by sequencing. These cases are difficult and carry challenges in differential diagnosis. The diagnostic algorthym may also help for giving information for targetting epigenetic factors? Question is from Isinsu Kuzu Ankara /Turkey Posted onOctober 15, 2021 1:32 pm
my question is to Palomero Regaarding to the differential diagnosis of the PTCL Nos, AITCL, PTCL follicular Posted onOctober 15, 2021 1:19 pm
Does RHOA mutations can be find together with FY-TRAF3ip2? and if yes, the tumor that develops has the phenotype of PTCL, NOS? In your experience how often are TET2 mutations found in T-cell lymphomas? (Leticia Quintanilla-Fend, Germany)Posted onOctober 15, 2021 1:09 pm
From Suzanne Turner, Cambridge, UK For Teresa Palomero: Does stimulation though the TCR contribute to lymphomagenesis due to RhoA mutant or Vav mutant (either tonic or active)? Have you tried engaging the TCR in these mouse models - if so, does it affect the phenotype and/or latency of tumour development? Alternatively do you see a tonic or active TCR signalling expression programme in the resulting tumours? Or do these oncogenic events maybe inhibit transduction from the TCR?Posted onOctober 15, 2021 1:06 pm
To the panel many thanks for your talk. My question is for Prof. Ari Melnick. Your data has demonstrated that H1 is indeed a tumour suppressor under non pathological conditions. The loss of this drives lymphomagenesis. Is there any data or correlation that it may coordinate DLBCL migration/ dissemination? (from Harpreet Mandhair, Switzerland).Posted onOctober 15, 2021 12:58 pm
Stefano Casola (Italy) to Dr Martin-Subero: great talk! Did you find somatic mutations differing classical from nnMCL within the TAD including the SOX11 gene and its supernehancer, which may explain the different frequency of contacts between the Sox11 gene and its super-enhancer in the two groups of tumors?Posted onOctober 15, 2021 12:52 pm
Great talk! Is there any clue why the loop between SOX11 and the enhancer occurs? Leticia Quintanilla-Fend, GermanyPosted onOctober 15, 2021 12:48 pm
Do mantle cells express high amount bcr (Immunglobulin heavy chain) and Cyclin D1 at the same time? Do high expression causes the risk of translocation mutation? t(11;14)Posted onOctober 15, 2021 12:47 pm
Q to Ari from Bertrand Nadel (France). Fascinating talk Ari thank you. 2 Q. Q1regarding de-differentiation. Might the H1 alterations in FL help explain the higher propensity of mem-like Follicular Lymphoma cells to return to rounds of GC reaction (which is rare in normal B cells)? Q2 (more philosophical) regarding self-renewal: Once transformed (and once the telomere shortening pb is resolved), is there necessarily a need for cancer cells to self-renew? Or are you specifically refering to CPC?Posted onOctober 15, 2021 12:31 pm
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********* Session 3 ************Posted onOctober 15, 2021 11:41 am
Posted onOctober 14, 2021 6:03 pm
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Remark King Lam, Netherlands: we have left het Working Formulation a long time ago!Posted onOctober 14, 2021 6:01 pm
I may have missed it when listening to you, Andrew and Lou, but what is the biology underlying the ineffective response to ibrutinib in OLDER non-GCB (or MCD) lymphoma patients? Michael Hallek, ColognePosted onOctober 14, 2021 5:58 pm
Can you please comment on how MRD in lymphoma will evolve (cell based vs plasma based) - especially in terms of regulatory perspective etc.,Posted onOctober 14, 2021 5:53 pm
Posted onOctober 14, 2021 5:52 pm
Stefano Casola (Italy): to Dr Staudt: I like your hypothesis that MCD-subset of DLBCL is "hiding" in immunopriviledged site. I suspect it is the result of the specific signaling pathways active in these tumors. Immunopriviledged sites include the dark zone of the GC. Why are DZ-derived DLBCL tumors (i.e.DHL) not selecting an MCD-like mutational landscape....?Posted onOctober 14, 2021 5:51 pm
Thanks excellent talks in AML setting , AZA over come MCL1 resistance to venetoclax when us in combination , 1. can this applied in B cell lymphoma to enhance BCL2i 2. is there relation between methylation status and BCL2 expression or activity? Posted onOctober 14, 2021 5:49 pm
Jim Phelan, NCI - The various molecular classification systems are remarkable in their overlapping findings, yet they seem to treat genetic homogeneity differently. Can the panel comment on the DLBCL samples that do not fit into a LymphGen category but are clustered with clustering models? Are these borderline 'LymphGen' cases clinically similar to the core subtype cases or are they clinically and molecularly distinct? Would you treat them similarly to a core case clinically?Posted onOctober 14, 2021 5:42 pm
If T cell rich lymphomas are hiding from T cell immune attack? Why are they T cell rich lymphomas? Are T cell migrate to lymphoid tissues by homing mechanism with cytokines? Posted onOctober 14, 2021 5:42 pm
There are rare families with both cHL and PMBL - do we know if these cases have different genetic features from the norm? Martin Dyer UKPosted onOctober 14, 2021 5:41 pm
Dr Staudt, Was the unpublished data on the diff subtypes and outcomes in phoenix you shared restricted to younger pts OR did data include ALL pts on study? Thanks (Ranjana Advani, USA) Posted onOctober 14, 2021 5:36 pm
Anand Jeyasekharan (Singapore)- great talks everyone. Do plasmablastic lymphomas occupy a niche within DLBCL genetic subtypes?Posted onOctober 14, 2021 5:36 pm
Andrei Thomas-Tikhonenko (Philadelphia, USA): Great talks this afternoon, thank you to all! A big-picture question for the entire group really: if the ultimate goal of any classification is to identify responders to existing drugs (say, ibrutinib), could there be an advantage to first performing supervised clustering based on responses to the drug across multiple trials and then using machine learning to identify genetic determinants of response? Same data, the opposite direction of analysis...Posted onOctober 14, 2021 5:29 pm
Question to Dr Staudt Thank you very much for your great talk. Regarding to the trial you have presented the preliminary results. We know that there are some additional mutations such as CXCR4, related with the resistance to ibrutinib therapy in Lymphoplasmacytic lymphomas. In your cohort which expresses Ibrutinib efficiency in younger patients. Did you look for the mutations which are related with Ibrutinib resistance especially in the group of older patients ? Dr.Isinsu Kuzu Ankara /Turkey Posted onOctober 14, 2021 5:12 pm
Question for dr Shipp. Thank you the very nice presentations. DLBCL is clearly very heterogeneous. Can you speculate on driver of the malignancy? Does a B-cell need so many mutations and genetic alterations to transform to a malignant cell? In other words, can you speculate on an essential oncogenic driver for the malignant transformation? Posted onOctober 14, 2021 5:02 pm
Dear Lou, reg. Phoenix: do you think there could also be a negative interaction of Ibrutinib and Rituiximab (ie BTKi inhibiting activity of of R )? Thorsten ZenzPosted onOctober 14, 2021 4:52 pm
Is there any relation between ABCL type Diffuse use large B cell lymphoma and Richter transformation of Small cell lymphocytic leukemia or other low grade lymphomas? Are they CD5 positive? Posted onOctober 14, 2021 4:48 pm
Q to Margaret (B Nadel France): single-cell studies show that a given genetic subset can adopt various transcriptional states, with likely impact on response to therapy. Could you elaborate on the relatively low concordance between genetic subclasses and single-cell classes revealed by the recent Steen paper (Alizadeh group), and comment on the role of TME on switching/adopting transcriptional statesPosted onOctober 14, 2021 4:36 pm
Q to Margaret (B Nadel France): single-cell studies show that a given genetic subset can adopt various transcriptional states, with likely impact on response to therapy. Could you elaborate on the relatively low concordance between genetic subclasses and single-cell classes revealed by the recent Steen paper (Alizadeh group), and comment on the role of TME on switching/adopting transcriptional statesPosted onOctober 14, 2021 4:35 pm
What dose the genetic aberration similarity between PMBCL and HL imply to the potential treatment approach these 2 distinct lymphomas. Is there likelihood of overlap or similarity in the treatment?Posted onOctober 14, 2021 4:34 pm
Posted onOctober 14, 2021 4:30 pm
Do you think CNS and testicular lymphomas are molecularly different from other extra nodal C5/MCD DLBCL, ex: leg type or intravascular lymphomasPosted onOctober 14, 2021 4:30 pm
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************ Session 2 ***************Posted onOctober 14, 2021 3:45 pm
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Absolutely great discussion. Great session!Posted onOctober 14, 2021 3:43 pm
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Question to David Scott (from Francesco Forconi/Southampton): very nice talk! have you found any signatures associated with BCR post-translational modifications (mannosylated BCR) in the DZ GCB-DLBCL? Thanks. Posted onOctober 14, 2021 3:32 pm
Are CAR T cell therapy and checkpoint inhibitors suited/ tested to treat lymphomas?Posted onOctober 14, 2021 3:26 pm
To David Scott - Can you elaborate why a DHit-signature cluster defining a subset of poor-outcome GC DLBCL was not picked up when the original GCB/UNC/ABC cell-of-origin signatures were being described? In other words, what does DHit have that the GCB signature is missing. Thank you! Michał Hoppe from Singapore.Posted onOctober 14, 2021 3:26 pm
Posted onOctober 14, 2021 3:21 pm
Questions for David Scott: Is there an overlap between transformed follicular lymphoma and "double hit" dark zone GCB lymphomas? In terms of the sequence of transformation events, is it broadly thought that the BCL2 translocation occurs first then CREBBP/epigenetic modifier mutations occur followed by MYC translocation/over-expression? Finally, what level of heterogeneity exists within the DHIT signature, are there further molecular subtypes that could be identified? (Laabiah Wasim, Francis Crick Institute, UK) Posted onOctober 14, 2021 3:19 pm
To David Scott from Elias Campo in Barcelona: Being Burkitt Lymphoma and High grade B cell lymphoma originating in the dark zone and having similar gene expression signature and MYC tranalocation, what makes them so different in the response to therapy and outcome? Posted onOctober 14, 2021 3:18 pm
James Nolan - Ireland Really found your talk illuminating David. Is there any observation that more "indolent" follicular lymphomas have more of a light zone signature than higher grade (grade 3A/B) or more clinically aggressive follicular lymphomas which might have a dark zone signature? Posted onOctober 14, 2021 3:18 pm
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Thank you for a very interesting session. I have a question about DLBCL, non germinal center, with only BCL 6 translocation, which treatment would you recommend? thank you Posted onOctober 14, 2021 3:17 pm
To Klaus Rajewsky: Did you study the distinct/different roles of PI3K versus BTK, SYK or Src Kinases in their capacity to (partially) replace BCR signaling? And does their role differ in different types of B cell lymphoma? Michael Hallek, ColognePosted onOctober 14, 2021 3:14 pm
Peijia, Netherlands: To Prof. Kuppers, two HL cell lines are T cell derived if I remember correctly. Is there any difference in CD30 or other gene expression profiling between these two cell lines and other B cell derived HL cell linesPosted onOctober 14, 2021 3:12 pm
My question is to Laura Pasquallucci Are the CREPPB and KMT2D genes targets of the hypermutational machinery in GCs for mutation? Akif Yavuz Istanbul, TurkeyPosted onOctober 14, 2021 3:11 pm
To David Scott from Sergio Roa (Spain): How would double-expressor MYC+BCL2+ lymphomas without underlying genetic alterations (and more frequently associated to ABC-DLBCL) fit in your conclusions for DHIT "cell-of-origin"?Posted onOctober 14, 2021 3:10 pm
Q to David (B Nadel France): isn't the "DZ signature" in fact a "MYC signature", compatible with BL and DH/TH, and back to Klaus talk, shouldn't MYC be attempted to be targeted ? Also, there are many ways to increase MYC function and stability, including GSK3b post-transcriptional modifications. These might increase the cohort of GCB with bad prognosisPosted onOctober 14, 2021 3:10 pm
Given the critical role of GSK3B in linking BCR signal to MYC, is it surprising that we don't see inactivating mutation of GSK3B in lymphoma?Posted onOctober 14, 2021 3:07 pm
Any role for antibiotic treatment of Moraxella in LP-hodgkin to remove the antigenic signal to tumour?Posted onOctober 14, 2021 3:05 pm
Andrei Thomas-Tikhonenko (Philadelphia, USA): A question for DS: Are there distinct mutational or expression signatures corresponding to BCL2- vs BCL6-translocated DHL?Posted onOctober 14, 2021 2:59 pm
Enrico Tiacci (Perugia - Italy). Hi Ralf, do you know if the LPHL cases with Moraxella IgG serum antibodies were all (or largely) IgD+? Posted onOctober 14, 2021 2:45 pm
Based on your findings on CD30 function, do you know whether or do you think CD30 might be involved in the pathogenesis of Gray zone lymphomas? (Esther, Switzerland)Posted onOctober 14, 2021 2:43 pm
Stefano Casola (Italy): Very nice talk, Ralf. How is CD30 controlling MYC function? Is it controlling expression of the MYC gene? Stabilization of MYC protein or does it influence MYC-controlled gene expression?Posted onOctober 14, 2021 2:39 pm
Andrei Thomas-Tikhonenko (Philadelphia, USA): A question for RK: Given that the MYC signature is rather broad, I wonder whether or not CD30+ HRS cells bear any similarity at the transcriptome level to (8;14)-translocated lymphomas. If they do, what are the overlapping MYC targets?Posted onOctober 14, 2021 2:34 pm
Prof. Ralf Kuppers: is it known how CD30 expression is regulated? Dinis Calado; Crick Institute, LondonPosted onOctober 14, 2021 2:31 pm
Question to Prof. Laura Pasqualucci: is the loss of KMT2D and CREBBP synergistic in lymphoma development in the mouse compared to the single mutants? Is the addition of BCL2 over-expression required? Dinis Calado; Crick Institute, LondonPosted onOctober 14, 2021 2:29 pm
Q to Laura (B NADEL France): Crebbp, KMT2D and others are powerful oncogenes when combined with BCL2, but not alone or when combined together. Is BCL2 merely providing survival, or also the required genomic instability to acquire additional hits? Did you test mutation landscapes in the various combinations? Do Crebbp and KMT2D have the power to initiate tumorigenesis without prior BCL2 (or equivalent) deregulation?Posted onOctober 14, 2021 2:29 pm
Did you know that results you show could be different if circumstances will change. This is a main human mistake, when experiments condition changes, like for example human diet could also metersPosted onOctober 14, 2021 2:26 pm
Stefano Casola (Italy): very nice talk Laura! Are haploinsufficient CBP/KMT2D (GC) B cells switching from H3K4me1 to H3K3me3 at target enhancer regions? I say this because you don't seem to see effects on H3K4me3 levels upon CBP inactivationPosted onOctober 14, 2021 2:23 pm
What is the action in experimental feature when some cells from patiens have mutations (50) and in other 50 is lack is mutation?Posted onOctober 14, 2021 2:16 pm
sorry forgot to state my name: Bertrand Nadel FRANCEPosted onOctober 14, 2021 1:59 pm
Question to Klaus: Wonderful talk thank you!! Considering the central AKT/GSK3b/MYC axis dependency you demonstrate in BCR+ lymphomas, are we underappreciating the role of MYC beside translocated MYC cases (DH/TH)? Myc has proved to be a very tough oncogene to modulate, eg with little success with BET inhibitors. What would you recommand to focus on regarding therapeutic target in this axis?Posted onOctober 14, 2021 1:58 pm
Stefano Casola (Italy): Great talk ,Klaus! have you had the chance to see which additional mutations are eventually required to get MM triggered by combination of MMSET/CCND1 and IKK2ca? Posted onOctober 14, 2021 1:58 pm
Is is possible to modulate gene expression by targeting BCR receptorPosted onOctober 14, 2021 1:48 pm
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ChinaPosted onOctober 14, 2021 1:18 pm
***** Day 1 *****Posted onOctober 14, 2021 1:01 pm
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Test 123Posted onOctober 13, 2021 9:19 pm