Naval Daver:
Hello. I’m Naval Daver from the Department of Leukemia at MD Anderson Cancer Center and I’m very happy that you’re joining this program. We’re going to be talking today about venetoclax in acute myeloid leukemia. And I’m really delighted to have three of the leading world experts in venetoclax with me. We have Dr. Courtney DiNardo also at MD Anderson, Dr. Andrew Wei from Australia and Dr. Marina Konopleva at MD Anderson. We’re going to discuss some of the clinical data as well as emerging mechanisms of resistance and future directions for venetoclax, which I think is really the biggest blockbuster drug we’ve had in AML in the last two decades. And we’ve been very happy and excited with the data so far. Maybe starting with that, I think the biggest piece for venetoclax this year was the VIALE-A data. Courtney, you led that study. Do you want to give some of the highlights of the findings and how you think it will be applied in the US and ex-US?

Courtney DiNardo:
Definitely. Thank you for the opportunity. Just to kind of recap that the VIALE-A study, which again, was the confirmatory phase three study, trying to show hopefully that the combination of azacitidine and venetoclax led to an improvement in overall survival then azacitidine alone. And that’s thankfully exactly what we’re seeing. In a large multi-center international study of over 430 patients, not only did we see an improvement and complete remission rate and composite remission rates of about 66% composite remission rates with azacitidine and venetoclax compared to 28% with azacitidine alone, we saw an improved rate of composite remission kind of regardless of genomics and high-risk cytogenetics, but most importantly there was an improvement in overall survival with azacitidine alone, that azacitidine placebo arm with a median survival of about nine to 10 months. Exactly what we would expect to see with AZA alone, with an improvement to about 15 months with the combination.

Courtney DiNardo:
The main take home, I think is that this really can be seen, as you had mentioned as a new standard of care for our older unfit AML patients. And we may get into some of the nuances a little bit later, of some of the kind of genomic groups that are still high risk, but I think overall, this is definitely a great step forward for our patients.

Naval Daver:
One of the important things I think is also safety and we’ve all been concerned that the myelosuppression could be something that we’re worried would pan out to toxicities outside of the major centers, but it was good to see that the early mortality, I think it was equal at four weeks and eight weeks. It was feasible even in 150 centers to give the combination, which I think is good for all the community doctors who will use it, of course, with caution and monitoring.

Courtney DiNardo:
Absolutely. Yeah, there were, I think three cases of mild laboratory TLS at the very beginning of the dose escalation phase. That’s important to bring up also that, it’s important to monitor your patients, especially people who are proliferative or have an elevated LDH or have maybe FLT3 mutations or even particularly sensitive patients like NPM1, IDH mutant patients, follow them at the beginning, but with appropriate monitoring and uric acid reducing agents, we saw no significant tumor lysis syndrome. And then the myelosuppression is absolutely something that is seen, but is manageable with the importance of an end of cycle one bone marrow to make sure if your patient’s in a remission, there’s no persistent leukemia, but there’s still cytopenias then holding the next cycle, waiting for counts to recover. Once patients are in a remission, giving GCSF, all of these are really important management tools, but that can effectively kind of keep patients doing well with minimal toxicity.

Naval Daver:
And Andrew you’ve used a lot of the low dose ara-c combination. Led the phase one, as well as the phase three and what’s your take on the data of the low dose ara-c venetoclax? We know that the primary endpoint wasn’t met, but with prolonged followup there is survival advantage. Responses were good. And do you think that’ll continue to be used? How do you think this will happen in ex-US sites?

Andrew Wei:
The VIALE-C trial was run in parallel with VIALE-A and I think the strongest elements of those two trials was the internal consistency in terms of quite a dramatic improvement in response rates compared to the low dose backbone with each trial. With respect to VIALE-C, because it was a smaller trial, only 211 patients with a two to one randomization, the initial analysis didn’t hit its primary overall survival endpoint. But as you mentioned, with six months of additional follow up, there was an improvement in survival from 4.1 to 8.4 months. Outside of the US where azacitidine is not available everywhere in terms of a backbone therapy for older patients, low dose ara-c plus venetoclax certainly affords those patients quite a reasonably useful improvement in response rate, because I think we all know getting patients into remission is really critical for their quality of life, transfusion independence and also the possibility of survival extension.

Andrew Wei:
With the low dose ara-c venetoclax response rate was 48%. The major difference, between the two studies was the inclusion of about 20% of patients with prior HMA exposure. And if we remove that subgroup out of the equation, the overall response rate was about 55%. Getting closer, but obviously I still think if we had both options available, I think the current preference would be to use the HMA backbone with venetoclax.

Andrew Wei:
What we now see is that these two regimens, particularly azacitidine plus venetoclax really creates this really complex gray zone of patients where we know there are patients who are clearly unfit and a low intensity therapy is clearly the appropriate option. And there are the super fit patients where I think allogeneic transplant and intensive chemotherapy is clearly the option. But I think increasingly now there’s this battle zone of gray zone patients where they could be fit for either. And we have many new therapies which could augment the benefits of either intensive chemotherapy with addition to GO and CPX-351 and now with CC-486 in terms of prolonging remission duration after intensive chemotherapy. And now we have this fantastic backbone of azacitidine venetoclax and I think as Courtney mentioned, understanding individual patient aspects, biology, fitness, as well as the potential for even allogeneic transplant in older patients, I think will be the new step forward in trying to work out what is the right thing for this individual patient?

Naval Daver:
Yeah, I think this is something we discuss every week or every other day in our leukemia group is when you have the 60 to 70 or even 60 to 65, I think is even tougher patient, who’s kind of reasonably fit. The question is if you’re a fit for induction, should you get induction if you believe maybe something else could do similarly? And that’s the problem. We don’t have long term data, but some of these triplets are very attractive. We’ll talk about the IDH, the FLT3 triplets, maybe TP53, where at least the early signals and the doublet data from those individual combos seems to suggest that this could be as good. And I think that’s where at least in our group, we’re kind of pushing more, I would say towards the triplets, even in the little bit 60 to 70 could be fit for intensive chemo, but I don’t know. I don’t know if that will end up at five years being equal or not as much. But yeah, that’s a debate that we have now.

Naval Daver:
Let me ask a Marina, she’s worked a lot on the biology and the preclinical aspects even for many decades now and is very familiar with the agent. Marina, biologically what do you think are the next steps to improve on venetoclax targeted therapy, other approaches, what are you excited about?

Marina Konopleva:
Thank you Naval. I think as everybody already pointed out this is a great backbone, but if we look at long term outcomes, so on average we can cure only about maybe 30% of our patients, but it’s important what substance you’re looking at. Patients will have NPM1 mutation and IDH2 mutation, they seem to enjoy a long-term survival benefit. On the other hand, they will have a cohort of patients who are not doing well with this combination. I think in particular patients who have p53 mutations and complex karyotypes, unfortunately the outcomes don’t seem to be better than with HMA alone.

Marina Konopleva:
And there’s not a lot of preclinical work done indicating what are the mechanisms of resistance in p53 null or p53 mutated patients. And I think this is clearly an unmet medical need as of right now. And we don’t have great agents for P53 mutated AML, but at least there are two clinical trials that are ongoing right now, building up on HMA event combination, one with anti-CD47, 5F9 antibody. And the second one is with APR-246, which is affecting the mutant p53, perhaps. These triplets are going forward and we just have to see how they will perform in the future.

Marina Konopleva:
The second cohort of patients that we identified in our introspective analysis, the paper is in Blood from last year with Andrew, Courtney and myself and our colleagues is a cohort of patients will have what we call signaling mutation, such as mutations in FLT3 or MAP kinase pathway, PTPN11 or Ras pathway. Those patients tend to respond, but then they relapse earlier than others. And some of them are maybe primary factual, those smaller cohorts. Of course, there there’s a lot of opportunities to use a FLT3 inhibitors and we in the lab have demonstrated that the FLT3 inhibitors affect them. One protein which is a norm against resistance for venetoclax and therefore the combination is highly synergistic. And this is now taking forward into clinical trials. We are part of the clinical trials of gilteritinib with venetoclax in relapsed/refractory AML. That seems to have a quite high response rate with about 50% CR rate as reported at last ASH and good safety profile.

Marina Konopleva:
And we also have at MD Anderson, the trial of quizartinib plus venetoclax and we went into triplets, so AZA-H, venetoclax and a FLT3 inhibitor combo for all the patients with FLT3 mutations. I think those things are exciting as far as the RAS-MAP kinase pathway, again, that we’ll have limited choices there so far, we have tried to use the MEK inhibitor cobimetinib trial, which was unfortunately stopped because of the, I would say, narrow therapeutic window and the lack of efficacy. We are now have internally the trial was trametinib, which is another MEK inhibitor, but some of the maybe newer agents at some point, maybe RAS degraders or PLK inhibitors, may play into this cohort of patients.

Marina Konopleva:
And finally, maybe I will bring up the immunotherapy combinations. We’re all very excited about that. One thing that we exploited pre-clinically and this now went into clinical trials is a combination with monoclonal antibodies, specifically the anti-CD123 drug conjugate from a Humanigen, that again went into triplet, the aza-ven and IMGN263 trial that is currently ongoing. And really in the lab we have shown quite remarkable synergy between these agents and cure of some of the animals that injected with leukemia when we use this triple combination.

Marina Konopleva:
And the second approach, which is perhaps earlier in development is combination with checkpoint inhibitors. You have done a lot of work with aza, PD1 nivolumab combination in the relapse/refractory AML. We know that there is some efficacy, about 30% of patients enjoying long-term survival, but I think we need to improve of that. And there are some data published from AbbVie this year that indicate that venetoclax actually select for the T-cell, memory T-cell that can enhance the efficacy of the checkpoint inhibitors. So again, we have a clinical trial ongoing in that space and it’s very early to say how that will play out. I think I’ll stop here and see what others have to say.

Naval Daver:
It’s a lot of exciting triplets that our group is very excited about and some of those are multicenter and then some of those are open here. And Courtney, you’re doing the triplet with the IDH inhibitors, some very early data. I know initially two, three years ago, when we all talked, there was a concern for antagonism. Definitely doesn’t seem like that. May be some synergy. What is your feeling on this? And I think it’s a little bit more challenging than FLT3 and TP53, because the doublet does well. How would you differentiate the triplet from the doublet? What parameters do you think you can use?

Courtney DiNardo:
All great points and you’re exactly right. Patients with IDH1 and IDH2 mutants in general seem to respond really well to combinations of venetoclax with hypomethylating agents. It’s a little bit different than some of the other higher-risk genomic patterns that you guys were just describing. It’s not enough to look at an improved response rate because you’re going to see an excellent 80% or so composite remission rate with aza and venetoclax alone so the question is when you incorporate an IDH inhibitor, are you going to not necessarily improve remission rates, although of course that would be great to get to a 100%, but to have more durable responses, to become MRD negative, stay MRD negative to really have that curative intent.

Courtney DiNardo:
And I think the longer we’ve treated patients on azacitidine venetoclax combinations, which we started the original clinical trials back in 2014. We have a handful of patients with IDH mutations that have had really nice durable remissions, but we still see those IDH mutations persist when you do kind of deep sequencing. And I’ve had several unfortunately relapse 18 months, two years later. And so that’s exactly what we’re trying to see with the triplet is not so much the early time points of remission, but durability. And it’s, you’re exactly right, it’s small. We presented some of our interim data at EHA and ASCO this past year. And we’re seeing remission rates above 80%. In the relapse setting, we’re seeing remission rates close to 70%, which is really quite encouraging in the relapse setting where we don’t have a lot of data, but historical comparisons at various different institutions, suggest a 40 to 50% response rate of IDH mutant patients in the relapse setting with ven based or IDH based therapy.

Courtney DiNardo:
And so I think we’re seeing nice responses, but the tincture of time is really what we’re going to need to prove that these triplets are in IDH mutant patients, the way to go. But I personally think that given what I’ve seen with aza-ven patients with IDH mutations kind of slowly relapsing with time, I hope that this will be a particularly effective strategy to maintain the remissions.

Naval Daver:
Yeah. I think so, too. The cure rate is still probably not close to 70, 80% and the triplet is very safe. I think compared to some other triplets, the IDH myelosuppression is not as additive. And so the safety has been good. Yeah, I guess with long term, there should be a good chance for the triplet. In the relapsed, I agree the response rates were almost double of the single agent that you showed. Yeah, that should be exciting. Yeah. And then Andrew, you published recently the induction plus venetoclax CAVEAT data. Where is that moving forward? How do you see that going forward in Australia, Europe, other areas?

Andrew Wei:
Yeah, certainly with the success of venetoclax in older patients, unfit for intensive chemotherapy the obvious question is whether we can extend those benefits to fitter and younger patients. I think at this stage, the feasibility of these combinations still requires some degree of optimization. I think what we do know is we can combine venetoclax with intensive chemotherapy, particularly in younger and fitter patients with possibly 7 + 3. In older patients, we’ve attenuated the doses of chemotherapy to a 5 + 2 equivalent and we find that we can get response rates in the 70% range and then de novo AML, above 90%. What we don’t know is what’s the optimal post-remission therapy. I think we find that across the board patients can recover from the first cycle of chemotherapy quite well. However, whether we can deliver repeated cycles of chemotherapy, I think will depend very closely on what type of schedule that is used.

Andrew Wei:
For instance, in our experience when we continue to use anthracyclines in the consolidation phase, we do find that we are getting prolonged bone marrow suppression and cytopenia. Whereas I think with Courtney utilizing a non-anthracycline consolidation, perhaps that problem is less evident. However, I think more studies need to be done. From a more basic biological perspective, I do feel however that the patient’s biology still will become a major determinant in whether there are good outcomes long-term regardless of the intensity of chemotherapy used with venetoclax. For instance, a favorable risk patients, such as an NPM1 mutant patient I think will do just as well on a low intensity regimen as a high intensity regimen. And there are patients with porous disease, like HMA failure, P53 mutation and possibly to some extent, some poor-risk adverse karyotype patients where I don’t think even intensive chemotherapy will be sufficient to overcome the biological hurdle and barrier which is placed before us.

Andrew Wei:
And so I think new agents are still required as well as an increased understanding of the biological aspects of those poor risk patients. The role of allogeneic stem cell transplant as I mentioned before, even in older patients should still be a consideration, particularly for patients that we know won’t be cured with even venetoclax, regardless of the combination like p53, until we have some of these newer agents into standard practice. And so other possibilities include trying to circumvent some of the apoptosis barriers imparted by p53, by using other BH3 mimetics in combination. And there are preliminary studies using venetoclax and other BCL-2 inhibitors in combination with MCL-1 inhibitors and obviously with other pro-survival inhibitors in other hematologic diseases. Whether these are ultimately feasible and sufficient to give us the benefit we need over what we have are still I think remains an open question.

Naval Daver:
Thanks a lot. I think, yeah, those are the directions as to whether it’s going to be improving chemo or developing triplets with novel agents, which one will kind of take a bigger piece of the population. And I think that’s what we’ll find out in the next four or five years. That’ll be interesting. And Marina, you’ve also done a lot of work in ALL with venetoclax. Now there’s some exciting early data with the BCL-xL plus venetoclax, navitoclax, venetoclax, and chemo, and also in T-cell ALL that you and others have shown. Where do you think there’s going to be a role for ven in ALL? And what population do you think we should go for?

Marina Konopleva:
Yeah, I think the ALL is somewhat lagging behind AML field. In part, because we have so many options in ALL, especially in B-ALL with monoclonal antibodies and bispecific antibodies. We have done a small clinical trial between us and Dana-Farber where we treated the elderly patients with ALL, B-ALL and T-ALL with what we call mini CBD, minimal chemotherapy combination and venetoclax. And we have shown quite impressive response rates above 80% and a fraction of those patients, even though they were elderly, they went for the allogenic stem cell transplant, because they had p53 mutation or some other inferior outcome prognostic features. And so far they have done very well so in fact with about a year follow up, we are not aware of relapses, but of course this is almost too good to be true.

Marina Konopleva:
You mentioned the navitoclax, Tony Letai has published that T-ALL, other than ETP, they perhaps depend more on the BCL-xL. We have similar data from our lab. While ETP ALL which is poorest cohort in T-ALL, they do depend more on a BCL-2. And there was a clinical trial combining again, minimal chemotherapy with vincristine steroid suppression based regimen, navitoclax and venetoclax, which was led by AbbVie. Was a multi-center trial in relapse refractory pediatric and adult ALL. Gave quite an impressive response rates of close to 60% and high in some subsets. It wasn’t really clear that whether T-cell ALL were doing better than B-ALL and a lot of younger patients were able to go towards stem cell transplantation.

Marina Konopleva:
I think at this point, it’s not very clear how this will be developed, that we have had a lot of discussions internally with AbbVie, what is the clinical path for the potential use of venetoclax in ALL, which subsets and maybe navitoclax can also come into play, but there are certain clinical trials that are being designed and planned to address that, that is on the level of the guideline indication. I think there’s clearly a role for venetoclax in the some subsets of ALL.

Naval Daver:
Yeah. it’s really interesting, but in ALL, of course, in MDS, there are frontline studies now ongoing, randomized studies and even in myelofibrosis now, navitoclax added to the JAK inhibitor, there’s a phase III study that’s starting. It sounds like this is kind of be like a pan-heme potentially agent, which is very cool. Yeah, I think there’s a lot of interesting directions that ASH abstracts are not yet out. And I think there’s going to be a lot of exciting things. FLT3 combinations, there’s two or three of those that have been submitted. There’s some data I think, with some of the antibodies that will be there. And then I think a lot of the triplets are too early to be presented, but hopefully by next year we’ll have more data on those, including the immune checkpoints and CD47, APR, others.

Naval Daver:
Yeah, it should be very exciting. And I think this is, as I think Andrew mentioned, it’s kind of the beginning of the research. We still need a lot of novel drugs. 30%, 35% is better than 10% at three years, but we’re still far away from 80, 90% where we’d like to be. And so I think now we each have something that we can build on and hopefully we’ll have a better update and more progress when we speak again in a year or so. With that, I would like to thank you all so much. It’s very early in the morning for Andrew, late in the evening for us and I hope to talk to you all soon again. Thank you very much for listening. Bye.