Key Updates from ASCO 2020 and EHA 2020: Experts Discuss Data and Implications Important to Clinical Practice

Published on October 7, 2020 in Treatment

Naval Daver, MD
Associate Professor
Department of Leukemia
The University of Texas MD Anderson Cancer Center
Houston, Texas
Alexander Perl, MD
Associate Professor of Medicine
Abramson Cancer Center
University of Pennsylvania
Philadelphia, Pennsylvania

Introduction

The annual congresses of the American Society of Clinical Oncology (ASCO) and the European Hematology Association (EHA) feature a multitude of clinical data, and it is often difficult for practicing physicians to determine which studies are most relevant for their practice and interpret the significance of these findings. In this article, Naval Daver, MD, and Alexander E. Perl, MD discuss their choices of the most important data in acute myeloid leukemia (AML) and their implications to clinical practice.

These discussions were part of an accredited activity titled, “New Advances in AML Live Interactive Webcast Series.” To read about details of the trials discussed in this article, click here.


VIALE-A: Venetoclax plus Azacitidine Confirmed as the Standard of Care for Unfit or Elderly Patients with Newly Diagnosed AML1

“It's important to recognize that this was not a study designed for people under the age of 75 who refused induction chemotherapy. They had to have proven comorbidity to get on the study, so in relation, it is not possible based on this study that this is better than induction chemotherapy in someone who is fit for induction therapy. But for those who, for reasons of age or reasons of comorbidity, would be potentially harmed by induction chemotherapy, this is the best option that we have for them and it's now a data-driven recommendation.”

Alexander E. Perl, MD

What is the clinical relevance of these findings?

Naval Daver, MD: We found that the median overall survival (OS) was significantly improved at 15 months vs 9 months and even at the 2-year follow up, and we are seeing continued separation of the curves and a plateau on azacitidine/venetoclax at about 35% to 40%. Conceptually, this is extremely important because in older AML not fit for intensive induction, which was the target population of this trial, historically, we have never been able to get median survival above 10 months, and we have never really had more than 10% to 15% survival at 2 years. To see a plateau at 35% to 40% which could potentially continue is very exciting.

Alexander E. Perl, MD: We now have a new standard of care that is data from a prospective, randomized, placebo-controlled comparison. The study showed statistically significant improvement in OS from the use of venetoclax in combination with azacitidine over azacitidine alone, and this gives us an evidence-based approach to our patients who are not fit for induction chemotherapy.

How can the community practitioner integrate these data into practice?

Naval Daver, MD: I think that this study really confirms what many of us have already embarked on, which is using azacitidine plus venetoclax as the standard for older AML, especially those aged older than 70 years. In general, I would consider it for pretty much all those patients, with rare exceptions, who may be able to tolerate intensive chemotherapy and even for patients 65 and above, if they have significant comorbidities or there is a high risk for early mortality based on organ dysfunction or patient characteristics, so we have been moving more and more towards azacitidine and venetoclax.

I also think that this study really shows that azacitidine alone has a very limited, if any, role now in the treatment of older AML unsuitable for chemotherapy. There may always be rare examples, such as 90-year-old and 94-year-old patients, where we are worried that the venetoclax addition may increase myelosuppression, but this may make up 2% or 3% of patients in our older AML practice. I think for 95% or more of patients, we would be giving azacitidine/venetoclax in older AML populations not suitable for induction approaches. So, it really has changed our current practice, and established a new standard. It's already FDA approved, and I think this is the approach we would be taking.

Alexander E. Perl, MD: This phase 3 randomized study has now confirmed what many of us were already doing in our practice, which was using frontline azacitidine in combination with venetoclax in older AML, definitely those aged above 75 years, but even those aged between 60 and 75 years who were considered to be unsuitable for induction either because of significant comorbidities, organ dysfunction, or concern for high early mortality due to other reasons.

One of the important things that was noted in this study was also that the combination of azacitidine and venetoclax definitely seems to cause more significant and prolonged myelosuppression. So even though it is more effective in achieving complete response/complete response with incomplete neutrophil recovery (CR/CRi) as well as a longer median OS, more monitoring is required, including blood work probably once or twice a week during the initial one or two cycles, as well as early bone marrow assessment end of cycle one. If patients are achieving a marrow remission but have low counts, one really should consider interruption of the venetoclax and azacitidine for up to a couple of weeks to allow for count recovery before starting subsequent cycles.

Please see the section below for more information on monitoring patients on venetoclax-based therapy

VIALE-C: Venetoclax plus Low-dose Cytarabine in Older Patients with Newly Diagnosed AML—6-month Update2

How do we interpret these findings?

Naval Daver, MD: Although the primary endpoint of OS at the time of the cutoff was not met in this study, with an additional 3 months of follow up we do see that the survival benefit is now significant. I think the study was over ambitious in the number of patients selected and the hazard ratio that was selected, but if you look at the overall data, it does seem to be clinically positive with numerically near doubling of the median OS with LDAC plus venetoclax. In the end though, the azacitidine/venetoclax study from VIALE-A does show the most encouraging response and survival, and that is our go-to for frontline newly diagnosed/old AML not suitable for intensive induction.

So, I think both VIALE-C and VIALE-A, when taken in aggregate, clearly show that venetoclax added to a backbone, ideally a hypomethylating agent (HMA) in the United States but potentially LDAC in other areas of the world, dramatically improve response rates, CR rates, duration of response, and overall survival, and is now a very exciting backbone for older AML and, of course, this is the beginning of the research for older AML in our opinion. We hope to improve on that backbone by adding targeted agents, FLT3 inhibitors, and IDH inhibitors in people who harbor those mutations, or other agents, immune drugs like CD47, ADCs, and TP53-directed agents like APR, etc. So, hopefully, we will start seeing very effective triplets/quadruplets giving us potentially even more durable survival in older AML patients in the near future.

Alexander E. Perl, MD: There were few notable differences between that VIALE-C and VIALE-A. First, that VIALE-C allowed a prior hypomethylating agent, and a substantial number of patients did have that therapy. But VIALE-A did not allow prior azacitidine. And so, if you look at VIALE-C, it's a high-risk population in and of itself. Secondly, I don't know that we would necessarily say that LDAC is a very standard approach in the United States. So looking at this result, can we say this should change our practice? I think the big question is, how much benefit is there for the combination over just low-intensity therapy alone? We know that in this population, meaning those who are not induction candidates, that there's a benefit for treating leukemia, even with low-dose cytarabine over supportive care alone with hydroxyurea and transfusions and antibiotics. But how much better can you do? That has never been proven with any combination except perhaps glasdegib plus low-dose cytarabine, which quite honestly is seldom used in this country.

What I would say about this is that there were updates from VIALE-C shown at ASCO and at EHA that are 6 months further follow up from the primary endpoint, and these longer follow ups showed that that study actually did show a statistically significant improvement in OS for the combination. So, what do we do with this? Is this now taking a study that's negative and turning it into a positive? Was the study just underpowered? I think you have to look at what a P-value really reflects. A P-value just means that if we did the same study 20 times, we're willing to accept that we will get the wrong answer one time out of 20 and we will accept that the status quo is no better than the new therapy, even if in reality the new therapy is better. That may be what we saw here. With longer follow up, we're actually seeing better survival on that study. And to my eyes, I think this is a real finding and I do think this study was likely underpowered to answer the question, and I would say that overall I do think that the VIALE-C study is a positive study and that there is a benefit for this, even though if you look at the published data which, for right or for wrong, was appropriately powered in the planner's mind to answer the question, they didn't come up with that answer. So, I think from the community standpoint, the data are in combinations of venetoclax plus low-intensity chemotherapy are better than the low-intensity chemotherapy alone, and that's how we should be using these drugs.

Recommendations for Monitoring Patients on Venetoclax-based Therapy

Alexander E. Perl, MD: How do we use these drugs in the safest manner? One thing that's notable about giving venetoclax in combination with either low-dose cytarabine or in combination with a hypomethylating agent is that we often have to do treatment interruptions for low blood counts. That is a very common finding in this therapy, and we need to consider how often we want to do bone marrow biopsies, as it's an uncomfortable procedure. Even when they're responding, we can see ongoing cytopenias. How often do we assess these patients to rule out lack of response, relapse, or drug toxicity?

I can tell you what I do, and there are some guidelines regarding this from published authors on these phase 1 through 3 studies of venetoclax and either low-dose cytarabine or hypomethylating agents, such as Courtney DiNardo and Andrew Wei in Blood.3 or Brian Jonas and Daniel Pollyea in Leukemia.4



What I do is in parallel with those recommendations, which is after a first cycle of therapy, no more than 28 days of venetoclax, I check a bone marrow biopsy and see if the patient has cleared marrow blasts at that time. Often when patients are responding, their bone marrow looks aplastic or very hypoplastic. Again, these are often old patients with relatively low cellularity, even when we look at them in full remission, they might have 10% or 20% cellularity. So, still under the effects of the venetoclax, you see very little cellularity in patients responding to this regimen. But if you see less than 5% blasts, we typically will hold therapy. If the marrow is aplastic, we can even give them growth factor like G-CSF and not uncommonly a few days after getting growth factor, the neutrophil count goes up and that can allow patients to stay more or less on therapy without too long of a treatment break.

I'm not too worried about a treatment break if I think the patient is responding to therapy. What I often will do on the second cycle is to drop back the number of days that patients are receiving venetoclax, whether they do it on their second cycle or in subsequent cycles. Thus, instead of receiving 28 days on the second cycle, I might choose 14 or 21 days, and for patients who really had significant difficulty getting through the regimen but who are responding, I might go even lower than that. It's not uncommon that I will drop the number of azacitidine days from 7 to 5, again, to minimize the risk of cytopenias. However, we don't have a lot of data on which of these changes impacts long-term outcomes other than these kinds of changes allowed on the studies that showed superior outcome compared to standard therapy that did not include venetoclax, and I think there should be some acceptance that these modifications are probably necessary from a safety standpoint to decrease the major risk of these patients which has to do with infectious toxicity from prolonged myelosuppression from venetoclax in the setting of a marrow remission. The treatment-related mortality of both of the arms on VIALE-A were less than 10%, so we're not talking about a very dangerous therapy either with or without venetoclax, and would not be substantially higher in the venetoclax arm. I think we can reasonably say that as long as we're careful about patients, make these dose modifications, and avoid this kind of overtreating patients with continuous dosing of venetoclax until count recovery, which really puts patients at risk of infections, we are doing our patients' right in that approach.

I should also point out that on these studies, azole antifungals were allowed but required dose modification. There's a significant drug-drug interaction between venetoclax and all of the azole antifungals. The amount of dose reduction depends on whether the drug is a moderate or strong CYP3A4 inhibitor. The dosing reductions for moderate CYP3A4 inhibitors are a 50% reduction in venetoclax dose. So, from 400 mg to 200 mg of venetoclax. For voriconazole, which is a strong inhibitor, the dosing recommendations on the label are 100 mg of venetoclax with a drug like fluconazole or isavuconazole, and for posaconazole, 70 mg of venetoclax. I do recommend using those dose modifications when treating patients with these drugs concurrently.

Emerging TP53-directed therapy: Magrolimab and APR-246

“We're getting more data on novel therapies and how well they work, in particular for patients with really high-risk AML, which includes patients with TP53 mutation. We're starting to get a little better and looking for options other than standard chemotherapy for this group because I think data really say that standard chemotherapy is an inadequate treatment for patients with TP53 mutation, particularly those with complex karyotype or antecedent hematologic disorder such as myelodysplastic syndromes. We have many therapies that have activity here, but no therapies that have longer acceptable survival. Really, the best therapy for this group is allogeneic transplant—even with allogeneic transplant, survival is inferior to patients who lack this mutation. I think we need to look at this as a group that really has no effective therapy and no optimal therapy, and any time we can offer a clinical trial we should offer a clinical trial.”

Alexander E. Perl, MD

Phase 1b Results with Magrolimab in AML Patients Unfit for Intensive Chemotherapy5,6

What is the clinical relevance of these findings?

Alexander E. Perl, MD: What's interesting about magrolimab is that the drug had some activity as a single agent but rather substantial activity when combined with a hypomethylating agent. It also has induced complete remissions in patients, almost without regard to cytogenetic findings, including TP53 mutation and complex karyotype, albeit with small numbers from trials and limited follow up. But substantial numbers of patients have entered complete remission and those remissions, thus far, have been durable, though with a limited amount of follow up. So, again, we're not looking at 1, 2, or 3 years of follow up here, but we're getting out past the 6-month range, so if you're wondering, you can take a response to an agent like this and go to transplant and hopefully do well post-transplant. We're starting to get an approach that hopefully will keep the patient fit, keep the patient well, and give you enough time to plan for transplant that we might be able to offer curative therapy to patients once we know that this is the right approach. And again, there will be randomized studies of this drug forthcoming.

Phase 2 Findings of APR-246 in TP53-mutated MDS and AML7

How might APR-246 impact clinical practice?

Alexander E. Perl, MD:APR-246 is a drug that is hypothesized to have activity through reactivation of p53 through the unfolding of the protein that has been altered by mutation of its gene. So, it’s not for patients who have a mutation in TP53 causing deletion, or a chromosomal loss of TP53 locus, but actually for those who have a point mutation in TP53 that encodes an intact protein but affects its function. This drug is said to alter the folding of p53 and reactivate its function. In doing so, it reactivates the ability of TP53 to guard against DNA damage and cell replication in that setting. It actually promotes apoptosis of the cells in the presence of chemotherapy. This drug has been developed with hypomethylating agents and a study with azacitidine has been enrolled, and basically the indication they're looking for is frontline patients with primarily myelodysplastic syndromes (MDS) that have TP53 mutation. But patients with AML and low blast percentage have been enrolled on that study as well. We look forward to getting updates from a randomized study comparing azacitidine to the combination of APR-246 and azacitidine, which are forthcoming.

Naval Daver, MD: Although APR-246 and magrolimab are not yet in the community, I think given the really poor outcomes in TP53-mutated frontline AML, these are probably patients who should be referred out for clinical trials whenever possible.

For more information about the magrolimab trial, please click here.8

For more information about the APR-246 trial, please click here.9

References

  1. DiNardo C, Jonas B, Puullarkat V, et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med. 2020;383(7):617-629.
  2. Wei AH, Montesinos P, Ivanov V, et al. Venetoclax plus LDAC for newly diagnosed AML ineligible for intensive chemotherapy: A phase 3 randomized placebo-controlled trial. Blood. 2020;135(24):2137-2145.
  3. DiNardo CD, Wei AH. How I treat acute myeloid leukemia in the era of new drugs. Blood. 2020;135(2):85-96.
  4. Jonas BA, Pollyea DA. How we use venetoclax with hypomethylating agents for the treatment of newly diagnosed patients with acute myeloid leukemia. Leukemia. 2019;33(12):2795-2804.
  5. Sallman DA, Al Malki M, Asch AS, et al. Tolerability and efficacy of the first-in-class anti-CD47 antibody magrolimab combined with azacitidine in MDS and AML patients: Phase 1b results. J Clin Oncol. 2020;38 (suppl):Abstract 7507.
  6. Daver NG, Al Malki M, Asch A, et al. The first-in-class anti-CD47 antibody magrolimab combined with azacitidine is well-tolerated and effective in AML patients: Phase 1b results. EHA 2020. Abstract S144.
  7. National Institutes of Health, US National Library of Medicine. Magrolimab monotherapy or magrolimab in combination with azacitidine in patients with hematological malignancies. Available at: https://clinicaltrials.gov/ct2/show/NCT03248479. Accessed September 8, 2020.
  8. Sallman DA, DeZern AE, Garcia-Manero G, et al. Phase 2 results of apr-246 and azacitidine (aza) in patients with tp53 mutant myelodysplastic syndromes (mds) and oligoblastic acute myeloid leukemia (aml). Blood. 2019;134( suppl 1): Abstract 676.
  9. National Institutes of Health, US National Library of Medicine. APR-246 in combination with azacitidine for TP53 mutated AML (acute myeloid leukemia) or MDS (myelodysplastic syndromes) following allogeneic stem cell transplant. Available at: Available at: https://clinicaltrials.gov/ct2/show/NCT03931291?term=APR-246&cond=MDS+AML&draw=2&rank=1. Accessed September 8, 2020.

Last modified: October 13, 2020