Questions List

Open question: In this regard, since IKZF1 deletions increase adhesive properties of leukemic cells, are there emergent approaches to target adhesive and niche molecules in Ph+ ALL with IKZF1 alterations?Posted onMay 9, 2021 3:26 pm

To Sarah Tasian: Given the talk by Afonso Almeida, and although IL7R mutant cases are just a fraction of B-ALL in general and Ph-like ALL in particular, the frequency of IL7R-positive cases is certainly higher. Dr. Tasian mentioned the use of CAR T cells against TSLPR for CRLF2-rearranged cases in Ph-like ALL, which makes a lot of sense, but do you know of any efforts to target IL7R expressing leukemias via immunotherapy?Posted onMay 9, 2021 3:05 pm

Question to Afonso Almeida: Do you think human Ph-like ALL can be eligible for different targeted therapies, based on their Ph-L1 or Ph-L2 profile? Is Ruxolitinib (or other JAK inhibitors) equally effective to both subtypes? Posted onMay 9, 2021 3:04 pm

Diego from Mexico. Question for Dr. Tasian: Reproducibility of Ph-like gene expression signatures has been a common issue. What can you recommend for middle income countries, as a cheaper but comprehensive approach to find Ph-like cases? Is larger scale transcriptome analysis always necessary, or are the 8- and 15-genes signature approaches suitable and reproducible in other populations? Thank you!Posted onMay 9, 2021 3:01 pm

What have been your observation on the correlation of CRLF2 expression on Flow cytometry and FISH analysisPosted onMay 9, 2021 3:00 pm

************* Session 9 **************Posted onMay 9, 2021 1:55 pm

a question for Maria. Maybe I did not see all your results (my connection is quiet bad at home) but are all T-ALL you tested expressing pre-TCR or only a fraction of them? and are all of them sensitive to a anti-pre-TCR therapeutic strategy? if yes, do you think this would need to be combined with chemotherapy to enhance efficiency?Posted onMay 9, 2021 1:39 pm

Question to Dr. Advani: Are there differences in CD38 expression across the whole T-ALL lineage? Is this clinically relevant (at least anecdotically) for daratumumab efficacy, for T-ALL or mixed-lineages leukemias?Posted onMay 9, 2021 1:38 pm

For Dra Toribio: Could preTCR be a suitable target for CAR-T cell therapy in T-ALL? Tnak you. Posted onMay 9, 2021 1:36 pm

Question to Maria Toribio: How do you reconcile your data with earlier studies from Harald von Boehmer and other researchers that pre-TCR and Rag recombinase are not essential for T-ALL development in mice?Posted onMay 9, 2021 1:35 pm

To Maria Toribio: Very nice talk. You showed that pre-TCR is required for Notch-induced T-ALL in mice. However, T-ALLs arising in mice with ICN1 expression occur at the CD4 CD8 DP stage, whereas pre-TCR is required for T-cell development from double-negative to DP stage. So, it may be that, in your C80G TCR epsilon model, T-ALL is prevented merely because T cell precursors do not get in sufficient numbers to the DP stage rather than pre-TCR being effectively needed for the leukemogenic process. Did you check this possibility?Posted onMay 9, 2021 1:33 pm

JR Regueiro to ML Toribio: how to TCR+pTa- and TCR-pTa+ cells compare Nck-wise??Posted onMay 9, 2021 1:32 pm

Is Isatuximab still developed in T-ALL/LL ? Posted onMay 9, 2021 1:32 pm

A question for the entire panel: Do you have any experience with Bortezomib in the relapse setting, potentially in combination with Venetoclax? Thank you.Posted onMay 9, 2021 1:31 pm

is the anti-pre-TCR antibody an antagonistic antibody? Or does it activate the pre-TCR signaling? What does it do to leukemic cells?Posted onMay 9, 2021 1:29 pm

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Is it feasible to combine venetoclax with Daratumumab for refractory T-ALL? As we can't access Navitoclax in my country.. ThanksPosted onMay 9, 2021 1:18 pm

am curious as to the differences between the UK ALL and the French treatment protocols that may account for the shown difference by Dr. MacIntyre Mark Minden-CanadaPosted onMay 9, 2021 12:54 pm

I have a question to first lecture: Is it possible that if we will design a special diet for ALL pateint (without asparagin) cancer cell which is not able to syntesize asparagine will die without any treatment? Posted onMay 9, 2021 12:46 pm

In GMALL study with R/R T-ALL and Nelarabine - would You use aloSCT after Nelarabine for both MRD negative and positive patients?Posted onMay 9, 2021 12:25 pm

Dear panelists, We heard yesterday compelling work by Adele Fielding and others about the contribution of tumor microenvironment to leukemia/lymphoma progression. Given its specific clinical manifestations, could you comment on a differential impact for T-ALL and T-LBL? The clinical response to L-asparaginase as an example is known to be framed by the stroma hijacked by the leukemic blasts to fuel them. Are they any consideration of targeting the TME in addition to the tumor itself? Thanks for this great session. Guillaume P. Andrieu Institut Necker-Enfants Malades ParisPosted onMay 9, 2021 12:22 pm

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************ Session 8 ************* Posted onMay 8, 2021 6:18 pm

Leonard paper - dasatinib inhibition of blina (not with imatinib), Weber paper - dasatinib inhibition of CAR T cells. Thank you! (Sarah Tasian)Posted onMay 8, 2021 5:50 pm

what is the pace of Rituximab in treatments including BLIN or InO ?Posted onMay 8, 2021 5:49 pm

Thank you Vana Posted onMay 8, 2021 5:48 pm

Question for Anjali, Hagop, and Sabina - do you think that dasatinib or ponatinib with anti-SRC activity could be at all T cell-inhibitory to blinatumomab given its need for T cell engagement (as opposed to imatinib with fewer SRC effects)? Are your trials intercalating such correlative biology studies to help answer this question? We struggle with this question a lot in developing new Ph-like pediatric trials. (Sarah Tasian, Philadelphia)Posted onMay 8, 2021 5:44 pm

Yes not eligible as elderly In the UK unfortunately not all options are available Vana Katsomitrou Posted onMay 8, 2021 5:38 pm

Do you foresee a place for Asciminib in Ph+ALL in the setting of chemo-free regimens ? Posted onMay 8, 2021 5:37 pm

Diego from Mexico. Question to Dr. Chiaretti, are there any FAK inhibitors or retinoid-based therapy being proved in formal trials for IKZF1del BCR-ABL1+ ALL? Are there any other preclinical options for this poor prognosis subtype?Posted onMay 8, 2021 5:37 pm

Yes elderly patientPosted onMay 8, 2021 5:36 pm

In relapsed PH positive ALL, in patient not eligible for transplant, which novel agent would you prefer inotuzimab or blinatuzimab? Thank you Vana Katsomitrou UKPosted onMay 8, 2021 5:33 pm

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************** 7 **************Posted onMay 8, 2021 4:24 pm

I would like to understand why not use inhibitors of immune checkpoints or other molecules controlling the immune system? Or this could be a possibility? Posted onMay 8, 2021 4:11 pm

What is the criteria for "controlled CNS disease" to make patient eligible for CART infusion? Posted onMay 8, 2021 4:00 pm

Question for Claire: what work might the UCL team be doing for donor-derived CAR T cells for your post-HSCT relapsed patients? If these donors are presumably younger/fitter, might this help to overcome aging/elderly T cell biology issues in part to aid in remission reinduction and perhaps persistence? (Sarah Tasian, Philadelphia)Posted onMay 8, 2021 3:59 pm

Have you any idea why CART results are better and and are remaining longer in children as compared to adults? Would the use of allo CART of the shelf may be change a bit this? Yves Chalandon Geneva CHPosted onMay 8, 2021 3:56 pm

How would you treat a patient with persistent molecular MRD beyond 3 months from CAR T cell infusion with ongoing B cell aplasia and detectable CAR t cells, who is not a candidate for 2nd transplant?Posted onMay 8, 2021 3:51 pm

Question to Prof David Marks: If you have tolerability issues with dasatinib and imatinib after transplant, and because of that you have to stop TKI, and some months later you find positive MRD, what would you do? Try another TKI? DLI? Thank you! Ana, from PortugalPosted onMay 8, 2021 3:50 pm

Question to D. Marks – in case of Ph+ ALL relapse post aloSCT without tyrosine kinase mutations (no T315I) with MRD positivity in bone marrow and CNS can DLI be combined with TKI and/or IT therapy? If MRD negativity achieved can TKI ever be stopped? In case of no kinase domain mutations if only exposed to Imatinib should Imatinib be renewed or changed to other TKI?Posted onMay 8, 2021 3:48 pm

************* Session 6 *******Posted onMay 8, 2021 3:44 pm

Question to C. Roddie - thank You for the interesting data regarding CNS and CART. What is the data with Blinatumumab and CNS disease? Can CART/Blinatumumab be combined with intrathecal therapy concomitantly?Posted onMay 8, 2021 3:34 pm

Diego from Mexico. Question to Dr. Fielding: There are not many papers about the IL-8 /CXCR4 axis in ALL. We found CXCL8 overexpression as a very interesting poor prognosis marker in primary samples, at diagnosis. We were thinking about in maybe an intrinsic resistance mecanism, would you have any thoughts about this? Thanks! Posted onMay 8, 2021 2:42 pm

Could you please comment about mediastinal irradiation in T-ALL? Best Regards, Armine Farmazyan (Armenia)Posted onMay 8, 2021 2:32 pm

Jule Vasquez from Peru, my question is for Dr. Stephen Hunger. How do you treat patients with Ph+ ALL with T315I mutation at diagnosis, and if ponatinib is not available in your country do you recommend treatment with only intensive chemotherapy for the induction?Posted onMay 8, 2021 2:30 pm

To Adele Fileding : Does thin filtration or ultra centrifugation of conditioned medium impare MSC activation?Posted onMay 8, 2021 2:28 pm

Question for Quentin Van Thillo: are there Beta-catenin inhibitors that could be used to treat this subset of TCF7-SPI1fusion positive cases?Posted onMay 8, 2021 2:27 pm

Nuno Santos (Portugal), to Thilo: 1) Is the cell of origin for NRas mice a thymocyte, and for NRAS+fusion mice a BM precursor, given the distinct organ involvement? 2) Is the Beta-cat domain mutant non-leukemogenic, considering that leukemia was similar to NRas-only?Posted onMay 8, 2021 2:27 pm

Question to C. Hurtz - thank You for interesting presentation, could DYRK1 A and menin inhibitors have a role in KMT2C or only KMT2A?Posted onMay 8, 2021 2:14 pm

Are all T-ALL cells (and PDX) responding in a similar way to dopamine receptor antagonists? Or is this response dependent on their basal lipid metabolism?Posted onMay 8, 2021 2:08 pm

In GIMEMA LAL 2116 study was Dasatinib and Blinatumumab used concomitantly or subsequently? Which one is the better approach?Posted onMay 8, 2021 1:56 pm

Do patients with kinase mutations (eg Ras or JAK-STAT) without ABL-class fusions also benefit from TKIs?Posted onMay 8, 2021 1:38 pm

Is there a role of tki maintenance after transplant or cart? In pH-like which tki would you use? Thank you Vana Katsomitrou UK Posted onMay 8, 2021 1:33 pm

Which TKI do you preferentially use in Ph-like ALL?Posted onMay 8, 2021 1:25 pm

Nuno dos Santos (Portugal), to Adele Fielding: After treatment in vitro of MSCs with chemo drugs, are genes expression changes reversible? Do stromal cells get back to normal after chemo cessation?Posted onMay 8, 2021 1:24 pm

question to Adele: do you think that the poor prognosis of specific subtypes of ALL is due to the effects of the leukemia cells on the stromal cells?Posted onMay 8, 2021 1:21 pm

*********** Session 5 **********Posted onMay 8, 2021 1:01 pm

Is there difference in you knowledge between MRD flow and PCR in patients with t(1;19)? (Italy)Posted onMay 8, 2021 12:48 pm

Open question: Regarding the association of genetic alterations & risk, are there any identified alterations associated with lower risk/better response in elderly patients?Posted onMay 8, 2021 12:48 pm

Would it be possible to stymulate on T cells CD19 expression in human body? There are data that PAMPS could stimulate Toll like receptor to induction of TNF receptor on cell sufrace. I lern thi during the curs on Harvard and I think that this is a common way to induce antigens on cell surfice. Do you think that this is real to do, it will be a natural way of cancer treatment witho any therapy add as drugs you use now. How is your opinion?Posted onMay 8, 2021 12:46 pm

To R. Hough. What is the % of TYA patients who are expected to be treated in the LowRisk group of ALLTogether and thus to receive treatment desescalation ?Posted onMay 8, 2021 12:45 pm

When patients relapse afetr Blin or InO, would you use this agent again ? Posted onMay 8, 2021 12:37 pm

Question to Dr.Jabour, when is the best time to assess for MRD with HyperCVAD protocolPosted onMay 8, 2021 12:35 pm

Posted onMay 8, 2021 12:34 pm

Could it be possible to incubate cancer cells with anticancer drugs before treatment? I did it for CLL, but it could be possible also for any cancers, including ALL. From my point of view it is possible, but we need a person who will be able to monitor under microscope what has happend to cells. Each leukemic type should look characteristically when drug will be active and enter for example apoptosis. This is not complicated to do and for choicing purposes and when was active, but gets resistance to therapy. It is always better to prevent resistance. I hope that together we can change roles of drugs choosing to avoid randomisation, and to give pateint active drug. Posted onMay 8, 2021 12:16 pm

Question for Dr Selina Luger What is your opinion on EWALL protocol for elderly aptients Ph negative?Posted onMay 8, 2021 11:59 am

To Rachel Hough: You showed very nicely the how treatment can be adjusted based on MRD risk stratification in TYA ALL. Do you think this can be further refined using risk stratification based on the newly described genetic subtypes? /Henrik Lilljebjörn, Sweden.Posted onMay 8, 2021 11:58 am

Is is wright that genetic alterations increase when pateint is older. It could be a reason of homeostasis disturbansesPosted onMay 8, 2021 11:52 am

Thanks very much!Posted onMay 8, 2021 10:44 am

***Posted onMay 8, 2021 10:34 am

In mice with big thymic lymphoma, was there peripheral disease as well, or not at all?Posted onMay 8, 2021 10:33 am

What was the T-cell immunophenotype of TAL1+Akt+ leukemic cells in the thymus?Posted onMay 8, 2021 10:30 am

Do you see CD44 - OPN overexpression also in the other cases with HOXA expression - have you analyzed this? Posted onMay 8, 2021 10:06 am

which copy number alterations should be used as diagnostic markers (in addition to the commonly used IKZF1 CNVs)?Posted onMay 8, 2021 9:53 am

What is the phenotype of normal myeloid cells in the blood of the leukemic mice?Posted onMay 8, 2021 9:46 am

does loss of CDKN2A affect cell cycle ? was that investigated?Posted onMay 8, 2021 9:37 am

***** Day 2 *************Posted onMay 8, 2021 8:24 am

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I'm Diego, from Mexico. Question for Mercedes: would you perform an analysis to look for structural rearrangements in your RNAseq data and see if these correlate with the gene expression profiles? Congratulations for your workPosted onMay 7, 2021 5:55 pm

For Bruno Lopes: Stanulla et al suggested that proper analysis of exon 1 is difficult with any assay because of the GC rich sequences (so high likelihood of secondary structures). Does this work better with M-PCR?Posted onMay 7, 2021 5:30 pm

can someone warn the presenter that we cannot hear her?Posted onMay 7, 2021 5:22 pm

Posted onMay 7, 2021 5:11 pm

agree with life long TKI Posted onMay 7, 2021 4:51 pm

For Elyse: Does HMGN1 Crispr KO reduce expression of CFLR2 mutant? Is that the mechanism explaining reduced SET-2 leukemogenesis caused by HMGN1 ko?Posted onMay 7, 2021 4:49 pm

I'm Diego, from Mexico. Open question: do the same challenges to accurately detect MRD in Ph+ subtypes apply to other subtypes with ambigous lineages like PAXmut, ZNF384? Can you tell us about your experience in these subtypes? Thanks!Posted onMay 7, 2021 4:37 pm

could it be that if p190 occurs in an HSC there is a short time to the development of a "lymphoid blast crisis" and that gives the CML like picture Posted onMay 7, 2021 4:35 pm

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Prof Zuna, do you think there is an argument for in dual monitoring (fusion vs Ig/TCR) in ALL with ABL class fusions generally? Could there be a subgroup that go on to behave like the CML like group in BCR-ABL1 positive disease?Posted onMay 7, 2021 4:34 pm

How are we going to know who has BCR-ABL in myeloid lineages? Without knowing this, we cannot know which method (transcript vs IG/TCR) is more informative.Posted onMay 7, 2021 4:33 pm

Monika and Beat, are your laboratories checking for KMT2A rearrangements for MRD in T-ALL? We detect one or two cases annually and work then up for MRD, however this subgroup seems to be under recognised in current trial protocols. Kerry Wall Posted onMay 7, 2021 4:30 pm

Question for Elyse - Great talk. Is HMGN1 expressed in all CRLF2r patients, or only patients with Down syndrome? Posted onMay 7, 2021 4:30 pm

Would you agree that at present we still do not have enough data to reduce the intensity if treatment (for instance avoiding Allo SCT) based on MRD for Ph positive patients? Luciana Tucunduva, BrazilPosted onMay 7, 2021 4:30 pm

Question for Elyse - Great talk. Is HMGN1 expression increased in all CRLF2r patients, or only patients with Down syndrome? Posted onMay 7, 2021 4:28 pm

Congratulations Jan. Would you treat CML-like cases with TKI as well as regular CML, in order to induce negativity of BCR-ABL1? Luca Lo Nigro (Italy)Posted onMay 7, 2021 4:27 pm

From Josep Ribera to all speakers. Is the 0.01% level too high for MRD response definition?Posted onMay 7, 2021 4:25 pm

Prof Bruggemann, what would you recommend as an optimal MRD monitoring strategy for a KMT2A rearranged B-ALL patient where the KMT2A rearrangement does not achieve an acceptable QR for MRD (excess background amplification). The only clonal Ig/TCR rearrangement which achieves an acceptable QR is an IGH D-J representing a low proportion of total reads on NGS (approx. 3%). I am concerned that there is a risk that the D-J rearrangement is not representing the full leukaemic clone and Ig/TCR MRD could be misleading. This represents an occasional but recurrent problem in some KMT2A rearranged B-ALLs.Posted onMay 7, 2021 4:24 pm

Dr. Zuna- In clinic, how can we distinguish CML-like vs typical ALL to decide the MRD method to use (BCR-ABL DNA vs transcript)? Is there a CLIA-certified method (sorting is not)?Posted onMay 7, 2021 4:24 pm

M. Bouzani / Greece How Could discriminate between CML-like ALL and blastic phase of CML? Thank you very much!Posted onMay 7, 2021 4:15 pm

What TKI is being used in the Ph+ ALL study being presented and if start with imatinib is there a change if inadequate decreased in levels?Posted onMay 7, 2021 4:14 pm

what is x axis of time-is it months?Posted onMay 7, 2021 4:12 pm

any difference in p190 vs p210 in the discordant cases Posted onMay 7, 2021 4:06 pm

Are there quality assessments of bone marrow samples that are included in the assessment of residual disease? Following on from this, are there marrow samples that should be considered as inadequate for assessment and if so how is that determined?Posted onMay 7, 2021 4:00 pm

Question to Beat Schäfer: Do you also looking into other quantitative methods to measure MRD? tex droplet digital PCR or digital PCRPosted onMay 7, 2021 3:41 pm

Posted onMay 7, 2021 3:29 pm

or a transcriptomic-based signature? Posted onMay 7, 2021 3:04 pm

To adolfo: have you seen differences in MYC and NOTCH post-translational regulation at diagnosis versus relapse? Posted onMay 7, 2021 3:00 pm

general question on T-ALL: knowing all these mutations are there some solid genetic signatures of relapse using diagnosis samples?. JF Peyron Inserm Nice, FrancePosted onMay 7, 2021 2:58 pm

Maria Toribio from Madrid/Spain What is the effect of anti-CD3 treatment on normal T cells? Posted onMay 7, 2021 2:54 pm

To Telmo (and Jacques): Does TCR stimulation strength alone explain differences in T-ALL development versus apoptosis? Any evidence on whether intermitence of stimulation may also be of relevance?Posted onMay 7, 2021 2:53 pm

Do you believe the cell death from TCR signaling is BCL-2 dependent? Posted onMay 7, 2021 2:53 pm

Any hypothesis around differential evolution among gender?Posted onMay 7, 2021 2:49 pm

Nuno dos Santos (Porto, PT) to Adolfo: Great talk! I believe mismatch repair gene mutations are not very frequent in T-ALL. Do they increase in frequency in relapse T-ALL? And are they underlying microsatellite instability? ThanksPosted onMay 7, 2021 2:48 pm

What proportion of T-ALL have productive TcR rearrangements and surface CD3 and is there an age difference Mark MindenPosted onMay 7, 2021 2:42 pm

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Hallo, I think that you should find an answer to question: when and how it is possible that lymphoblasts could move from bone marrow into blood? this could be a way to find out whe lymphoblasts occur in the blood. From my point of view this is a problem. Lymphoblasts usualy stay in the bone marrow and somewhaw transferlocating into blood. That could be mutations when all patients have mutations, but if not we can look for the other reason. could be also comlexed and more factors also be important if you can see some differences between patients Posted onMay 7, 2021 1:46 pm

Are the panel aware of any particular issues with respect to Ig/TCR MRD monitoring in ZNF384 rearranged MPAL? Is there any risk that one of the cell populations at diagnosis may not carry Ig/TCR rearrangements?Posted onMay 7, 2021 1:38 pm

Question for Charles: what is the bioavailability of the tested PROTACs, and have you tested multiple E3 ligasesPosted onMay 7, 2021 1:25 pm

Another question to Ester: Do you think that the switching phenomenon is a trasient one? Or does it represent a definitive switching of the blast phenotipic characteristics?Posted onMay 7, 2021 1:25 pm

To Scott Armstrong. Congratulations Scott. What about the normal hematopoietic stem cell compartment under the inhibition treatment? Luca Lo Nigro (Italy) Posted onMay 7, 2021 1:25 pm

To Charles Mullighan. Congratulation Charles. Would you address the PROTACS schema as soon as possible to children with Down syndrome and ALL? Luca Lo Nigro Posted onMay 7, 2021 1:22 pm

Nuno dos Santos (Porto) to Ester Meijstrikova. : Regarding the malingant phenotype, do monocytoid cells grow in PDX mice?Posted onMay 7, 2021 1:22 pm

Question to Dr. Mullighan. Diego Barcenas from Mexico. Is rux resistance common among JAK-r cases? Preliminary, we've identified recurrent JAK2-rearrangements in a small cohort, and ruxolitinib could be a great opportunity of targeted therapy for these cases. Thank you!Posted onMay 7, 2021 1:21 pm

Question to Ester Mejstrikova: When you face a switching phenomenon, how do you classify that ALL form then on? Do you have any different treatment approach? Do you think this is a bad prognosis feature? Thank you very much. Ana Mata from PortugalPosted onMay 7, 2021 1:21 pm

P2RY8-CLRF2 fusions looks to be frequently present within subclones, which impact on PROTACs strategies ? ?Posted onMay 7, 2021 1:08 pm

Ester Mejstrikova: Kowing that immunophenotype evaluation is performed to evaluate relapse since dedades ago, Why have not seen swALL since then?Posted onMay 7, 2021 12:51 pm

Question to Ester - is there any reason why MLLr has an increased susceptibility to lineage switch after blinatumomab? Posted onMay 7, 2021 12:43 pm

To Henrik Lilljebjorn: would you consider the complete UKALL CNA profiles to be of diagnostic use (as usually only IKZF1 is mentioned as diagnostic)? Is the status of all genes in these profiles routinely checked in the diagnostic work-up? - Anne Benard, The NetherlandsPosted onMay 7, 2021 12:37 pm

Els Van Valckenborgh - Belgium. Is the RNA sequencing for ALL reimbursed in Sweden? If so, how much reimbursement is received?Posted onMay 7, 2021 12:35 pm

Question to Henrik Lilljebjorn - what ar the therapeutic implications (if any at this point) if TCR3-PBX1 is present in adult B-ALL?Posted onMay 7, 2021 12:33 pm

Congratulations Scott. What about the normal Hematopoietic stem cell compartment? Did you detect a detriments? Luca Lo NigroPosted onMay 7, 2021 12:23 pm

***** Day 1 *********Posted onMay 7, 2021 10:50 am

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