B (3:49)

Thank you very much Dr. Tasian. So maybe before discussing David Tietzcek, could you please also discuss rapidly what is included in your How I Treat paper and maybe also discuss your recent series paper.

A (4:05)

Thank you so much. It's always a pleasure to work with blood and write these articles. This one was one that I wrote with Stephen Hunger and Ryan Summers. As was mentioned before, T cell Acute Lymphoblastic leukemia represents about 15 to 20% of acute lymphoblastic leukemia DEP, depending on age and currently tall. The only way it's really classified in the clinic is based on immunophenotype and it's broken down into two main categories, one of which is early T cell precursor all, which is the main focus of the How I Treat article and then the other is more mature TALL which is the majority of cases of tall. The How I Treat article is really focused on comparing and contrasting patients of early T cell precursor ALL versus non early T cell precursor all and reducing some of the unknowns and myths that are out there. Patients with ETP all actually do, as well as patients of other forms of TALL in the newly diagnosed setting. The biggest difference is the type of events that they have. Other forms of TALL are more likely to have a relapse and ETP ALL is often more likely to have refractory disease. Other than that, the treatment is actually very similar in the front line. In contrast, in the relapse setting, when you start getting into newer therapies and small molecule inhibitors and immunotherapies, there are differences we see in response in patients of ETP ALL and other subtypes of tall. And that's where I really think it's important to know about ETP all. And then very briefly, the genomic classification was a paper by myself, Charles Mulligan and Petri Polonin and that was based on some recent work by our group and others who really looked to try to reclassify TLL at a Genomic level of using immunophenotype. There's pros and cons to both. Genomics are a lot more expensive and a lot more complicated. However, they're also more accurate at identifying some of the high risk subsets and really drilling down on what we care about. Early T cell precursor all is putting them into a single biologic group. So what we found was that patients of ETP immunophenotype fall into three broad genetic groups. TXL3 group A, BC11B group, and then this group that we proposed in new nomenclature, ETP like. And the patients who tend to do worse, that have refractory disease, who have the same kind of dysregulated signaling in JAK stat, who fail induction and respond better to medicines like Venetoclax, really fall in that ETP like basket. And the ones who fall in the other genetic baskets actually are no different than other forms of tall.

B (6:40)

Thank you David. First question for Dr. Tajian, maybe how to diagnose ph like, are you still using immunophenotype or moving to gene expression or even going directly to genomic alteration to diagnose this subset of patients?

C (6:56)

This is a very important point and I think has been certainly a bit of a moving target over the past 15 years. When we first identified PH like or BC label like Alo primarily in the pediatric and AYA population, both in North America as well as in Europe, our genomics really weren't what they are today. And you know, these were primarily expression based classifiers, as you know, and these were very difficult cases to identify. These were primarily higher risk patients, high rates of chemotherapy resistance and relapse, who were cytogenetically normal but had this kinase activated gene expression profile that for all intents and purposes mirrored exactly that of BCR ABL positive or PH positive, all but lacked that sentinel translocation. And what we have learned really again through the last 15 plus years is that the genomics are very important. We tend to classify patients with ph like all into one of two major bins genetically, even though there are now more than 80 discrete genomic fusions or sometimes mutations that drive these diseases. We know that one category of patients in the CRLF two rearranged or other CHK pathway alterations can be identified in part by diagnostic immunophenotyping. Those patients with CRLF2 rearrangements or cytokine receptor like Factor 2 rearrangements generally have increased cell surface expression of the phynex stromal lymphopoietin Receptor or TSLPR and so can be identified within 24 hours with diagnostic immunophenotyping, if that is an assay that is done in a clinical laboratory, which to date has not necessarily been the case for patients who have other types of PH like all we really are now relying on genomics and while in North America we have relied heavily on a low density microarray really to screen patients, particularly in pediatrics, to help identify that 15 or 20% of patients who need more detailed molecular testing. I think in modern times, with the advent of much more sophisticated and much more affordable and clinically rapid next generation sequencing, we are really primarily identifying these patients both in the CRLF2 and JAK pathway class as well as in the ABL class striped by genomics, whether these are targeted fusion panels or RNA sequencing that have a rapid turnaround time. So immune phenotyping is certainly important, I think to confirm the ba allow diagnosis and potentially to provide some clinical about increased TSLPR antigen expression. But at this point I think we have largely abandoned the older expression arrays that were very helpful for screening. Now that we can move directly to next generation technologies.

B (9:27)

Thank you very much, Dr. Tajan. So moving to therapy or PH like all the first advance was obviously to introduce TKIs in these patients. So it was easier in the ABL1 class because of the extended use of anti BCR able TKI. Now we do have some other tools to treat B cell precursor ll, namely blenatumumab. So what we are doing in Europe currently in PH like is to try to use all the weapons we have against this subset of all. I mean not only chemotherapy and blenatimumab, but also the TKI and even another antibody, the rituximab in those expressing CD20. So a lot of new drugs together. So what is your opinion on? I know that some trials with sticky eyes are still ongoing, especially with rixolitinib. But what is your opinion on the next future in treating this patient? In other words, do you think that BLINA and chemo will do all the job or we will still need TKIs?

C (10:36)

I think what's been challenging is there really have not been standards of care established to date for patients with PH like all. Certainly as you mentioned, I think the precedent really of the precision medicine paradigm and PH positive all with TKI addition to chemotherapy that has now been established for 25 years is a much easier leap of faith, if you will, for the able class PH like patient. And I think now that we can identify these patients more rapidly by efficient ngs. We are really encouraging patients, either as part of a clinical trial or certainly potentially outside of a clinical trial to have as early as possible TKI addition to induction therapy. Linutubamab, as you have mentioned, clearly has completely revolutionized our paradigm in how we are treating patients across the age spectrum from a pediatric perspective. We certainly have published very exciting recent results from our Children's Oncology Group ALL 1731 clinical trial that randomized children with standard risk BAL to receipt of standard of care chemotherapy versus chemotherapy with lonatumab intercalation. But I will note that patients with ph like all for the most part really weren't included in this trial because they're really not enriched in the standard risk age group. And so we've really focused a little bit more in the high risk paradigm and I think understanding now, particularly from our adult colleagues that have demonstrated remarkable success with lunatubumab addition to chemotherapy and frankly replacement of very toxic chemotherapy with lonatumumab and now in combination with TKIs in adult trials conducted in Europe as well as in North America, I think this is really very rapidly bec a new precedent for us and one that we would like to validate formally through clinical trials in a pediatric and adolescent and young adult patient population. And to that end we are now looking in a phase two pilot study through our SVAL and COG consortium, specifically in pediatric and AYA patients, the therapeutic potential of fusion specific TKIs with chemotherapy reduction bonatubumab intercalation. I think for the CRLF2 patient population and those with other JAK pathway alterations such as JAK2 fusions or lycopoietin rearrangement fusions. This has been a bit trickier. As you note, we have conducted based on very robust preclinical data, clinical trials exploring JAK inhibition in the sense of oxalitinib addition to chemotherapy, but have not specifically been able to ask a blunt tubamab focused question in that subset of pH. Like all, I will note that our patients with high risk B all from a pediatric in a way perspective have been allowed to participate in our high risk COG and European clinical trials, many of which are randomizing immunotherapy based questions. Through Our COG study all 1732 we were previously randomizing patients with high risk BAL to standard of care chemotherapy versus with intercalation of two blocks of inutuzumab. This study underwent several safety evaluations and some amendments and now with the success of bonatubamab has been revised completely as standard of care to get bonatubamab and still to be able to ask an imatuzumab randomization question. Hopefully the study will be opening soon. We have not tended to use as much rituximab and pediatric alo, but we are certainly aware of the data from our European and adult colleagues looking at that question more specifically.

B (13:49)

Thank you very much. My next question will be for both of you. Actually you mentioned both that your subset of interest PH like and ATP relatively resistant to induction chemotherapy, so usually presenting high level of minimal residual disease at the end of the first induction course even after consolidation. So in the old days this was a perfect situation to offer patient allogenic stem cell transplantation rapidly because the poor response to initial treatment Maybe a question specifically for David Teacher. Do you think that allogenic stem cell transplantation has to be recommended to all ATP all patients or only to those with resistance disease on the basis of high MRD level? And maybe the same question for you Dr. Tajan. If you can imagine a patient with PH like ELL and very good MRD response, it could happen. What about stem cell transplantation?

A (14:47)

I think one of the important things with NT ALL and ETP all in particular is the kinetics of response are slower. So patients with ETP all are more likely to be MRD positive or B Frank induction failures after the first month of therapy. But surprisingly after three months of therapy, if you look at the end of consolidation, their MRD negative rates are actually the same as other subsets of tall. So patients with TALL of any immunophenotype that still have detectable disease at the end of three months of therapy should definitely be considered for stem cell transplants. In the children's Oncology group we currently use a threshold of 0.1% based on some of our clinical trial data, but other groups use different different thresholds. I think it's more just a concept that if you still have persistent disease after a period of time, that's a bad sign. The other thing is we did a recent study in the Children's oncology Group, the ALL1231 clinical trial where we asked the question of maybe patients with persistent MRD don't need a transplant. So for that we took patients who still had persistent MRD after three blocks of therapy and then we gave them three intensification blocks based on blocks that are used in Europe. At the end of those three blocks, if they were MRD undetectable, we recommended they just get chemotherapy. If they still had detectable MRD at any level at the end of those three blocks we recommended they go to transplant. Now fortunately in kids not that many patients had N consolidation MRD positivity in the first place. But what we found was the patients who became MRD to undetectable with more chemo. Those patients did not do well and almost all of them did not survive. The patients who remained MRD positive despite the intensive chemo and went to transplant, almost all those patients are still alive showing a very strong graph versus leukemia effect. For patients of tall. I would caution the numbers in total were very small. It was less than 20 patients on each side. But the difference in overall survival was striking. It was 90% overall survival for the patients who went to transplant and it was less than 20% overall survival for the patients they try to treat with chemotherapy alone. Which I said I think definitively tells us there is a group of patients with T cell leukemia, both ETP and other types that need a transplant for Cure.

B (17:04)

And you Dr. Tajan?

C (17:06)

Sure. So I would say similarly we know the great prognostic impact of MRD positivity also in patients with PH like BA ll, patients with high risk, all who are end of induction MRD positive who then go on to have end consolidation MRD positivity we know have very poor outcome with standard of care chemotherapy and this for a long time for us in the children's oncology group as an indication for stem cell transplant in first remission. We also know specifically within the PhD patient population at least 2/3 of these patients are end of induction MRD positive and there are certain subpopulations that really are at enhanced risk for induction failure, particularly patients with the PDGFR beta effusions. We do think and hope that earlier introduction of TKI based therapies into induction regimens can help to mitigate some of that risk of end of induction and consolidation MRD positivity. But certainly historically for patients who were endoconsolidation or 10.2 MrD positive, this really was an indication for allogeneic stem cell transplant and first remission. And many sites in recent years using blonatubimab to overcome that chemotherapy resistance hopefully in a little bit more of an MRD level disease positivity to get there successfully. And I think that this has been an approach that potentially has differed for us a bit in pediatrics compared to our adult colleagues where stem cell transplantation remission was historically much more widely implemented even in states of MRD negativity because of the high risk of relapse of these patients. We certainly also know that CD19 car T cell immunotherapies and other immunotherapies are changing that landscape. But again, I think our emerging data from both pediatric and adult experience now that our diagnostics are better for these patients is that very early introduction of tyrosine kinase inhibitors, at least for the able class patients, similar to that of PH positive patients, sometimes within the first week of induction therapy, is really increasing the ability of patients to achieve end induction uncertainty and consolidation MRD negativity. And so our indication for stem cell transplant from an MRD perspective really is becoming quite small. We would estimate at this time, I think at less than 5%, which is really quite nice. And I think again learning lessons from our international colleagues and particularly from our medical hematology colleagues, I think the ability to use immunotherapy proactively in the front line will hopefully continue to decrease our indications for stem cell transplant and increase cure rates with less toxicity.

B (19:32)

Thank you Dr. Tajan. My last question both of you will be on relapsed refractory patients. Obviously I guess it's easier to treat relapsed patients with PH like all because of immunotherapy and CAR T cell possibilities, but maybe Sara, you could comment on the outcome of these patients relapsing and treated by immunotherapy like CAR T cells. And for you Dr. Tiche, possibilities or options to treat relapse patients with ETPLL are certainly less and more difficult to treat, but maybe you can comment on new agent or new things emerging for those relapse patients.

C (20:13)

We know historically when patients with PH like ALA were treated with chemotherapy, their five year event pre survival was somewhere between 30 to 50% with conventional therapies. How immunotherapies in the front line will change that metric? I think we don't quite yet understand fully and really need some of the clinical trial data in comprehensive landscapes to understand that fully. But I certainly can say that patients with PH like ALO have been highly enriched in our first and subsequent relapse trials, including some of the early bonatubumab and inatuzumab based studies, as well as heavily enriched in our CD19 and CD22 Pro T cell studies. We know that looking at high risk cytogenetics through some of the academic institutional CAR T cell studies have shown that patients with adverse genetics such as PHLI seem to have similar rates of remission induction after CD19 car T cell immunotherapy. They also have similar rates of post immunotherapy relapse again. So I don't think that we have necessarily thought about these patients now in modern times particularly differently than some of our other patients with relapse. B all but but I certainly think that buying immunotherapies in the relapse setting becomes critically important just given the long standing known risk of chemotherapy resistance. And timing of course matters for patients who relapse greater than three years from diagnosis. We certainly know that we often can put these patients back into remission, sometimes with a four drug induction, but I think to maximize chance of long term care and second remission, thinking about how to apply these immunotherapies at relapse and certainly in the front line, that becomes more important. Another question we haven't focused on in detail I think is which tki? We certainly know that there have been randomized trials recently demonstrating potential superiority of second and third generation TKIs compared to some of the first generation inhibitors such as imatinib, as well as the clear ability to combine some of these TKIs with clonativimab and other immunotherapies. And whether we need to be moving to next generation TKIs in a relapse setting such as dasatinib or ponatinib, asiminib or some of the other inhibitors, I think remains to be seen, but I think is an area of active early phase clinical trial research.

B (22:23)

Thank you so much. And David, for your relapse patient with atpl, it's tough.

A (22:29)

So while cure rates have improved remarkably over the past 20, 30 years for newly diagnosed patients of Tall and ETP all, we're still not moving the needle in patients with relapse disease. So the most important thing for patients of relapse disease was with early T cell precursor all is getting them to stem cell transplant because that is the only known definitive and curative therapy. As Dr. Tasia mentioned before in B All, we use a lot of factors sometimes to decide even in relapse who needs a transplant, including biology, time to relapse, side of relapse. In tll, it's much easier. If the disease comes back, you need a transplant and then the question is how you get a patient into remission to get to transplant. Because as we've intensified our frontline therapy and move new agents to the front line, it's just making it so our relapse population has seen a lot of different types of medicines and that they're more refractory now than they used to be in relapse. We still try traditional chemotherapy to try to get them in remission first, knowing that it works in some patients but not in others. And then we are relying more on targeted therapies and immunotherapies. Now in the relapse setting, early T cell precursor all tends to be more dependent on BCL2 and also more likely to have JAK STAT alterations. So agents that we think about in early T cell Precursor all include BCL2 inhibitors like venetoclax. But also there's a number of exciting second generation BCL2 inhibitors that are coming out. In contrast, more mature TLL is less likely to respond to a BCL2 directed agent and it needs something like targets BCL XL. There's also some trials ongoing in early T cell precursor all using JAK stat inhibitors like ruxolitinib and we anxiously await those data. There's been some nice recent data from China using Venetoclax and azacytidine actually in relapse tall and the group that tends to benefit from that the most, again small N data seems to be their early T cell precursor group. So they had some very nice data for Vena in the relapse setting. And then even more exciting I think right now is immunotherapies and tall. They have been behind in B all for a number of reasons. One, the toxicity of wiping out your good and your bad T cells. With CAR T cells there's the issue of fratricide. These patients are sicker. It's harder to manufacture a product from some of these patients. But some of the data are highly encouraging with off the shelf products, autologous products and donor derived products. Some of the studies on that have been published in in blood too. There's a couple exciting papers that came out of a lot of clinical trials using CAR T for TALL and early T cell precursor if anything seems to be more sensitive to immunotherapies or at least as sensitive as other subtypes of TLL. Again small N but CD7 cars are very exciting. There's data using the anti CD38 monoclonal antibody daratumumab that was recently studied in chemo in combination of chemotherapy in the Delphinist trial that was published in Blood just this year. So I think a lot of exciting promising things and we'll have to see how well they hold up as we continue to perform trials.

B (25:40)

Thank you so much with that. I would like to close the sessions. I thank you very much for participating in this Heat Blood series and to be with us today and sharing your experience with us. So I strongly recommend the listeners to go to the articles in the whole series in order to more learn about this difficult to treat subset of patients with all. Thank you so much and have a nice day.

A (26:10)

Thank you for listening to this review series on all. To read the articles, visit www.bloodjournal.org. this presentation is copyrighted by the American Society of Hemat.