iwAL 2019 | AML treatment: what does the data say?

Adriano Venditti, Christoph Röllig and Richard Larson

Here, key experts discuss the standard of care for acute myeloid leukemia (AML) and how it can be optimized, in a discussion chaired by Richard Larson, MD, of the University of Chicago Medicine, Chicago, IL. Joining Prof. Larson is Christoph Röllig, MD, of the Dresden University of Technology, Dresden, Germany, and Adriano Venditti, MD, of the University of Rome Tor Vergata, Rome, Italy. This video was recorded at the International Workshop on Acute Leukemias (iwAL) 2019, held in Barcelona, Spain. The discussants highlight the fact that age alone is not a determinant of treatment choice, but rather, the cytogenetic features of the leukemic cells within the patient should be considered as well.

Transcript (edited for clarity):

Dr. Larson:
Hello, I’m Dr. Richard Larson from the University of Chicago, and I’m here in Barcelona, at the International Workshop on Acute Leukemia, with two of my colleagues.

Dr. Röllig:
Yes. My name is Christoph Röllig. I’m working as a consultant hematologist at the university in Dresden, Germany.

Dr. Venditti:
I am Adriano Venditti and I am an associate professor at University Tor Vergata in Rome, Italy.

Dr. Larson:
And earlier this morning we’ve been discussing acute myeloid leukemia, some of the clinically important decisions that are made around risk assessment as well as the use of some novel agents both in older patients as well as in maintenance therapy. So I think I’ll ask Dr. Röllig first to tell us about what we know on the use of maintenance therapy in AML.

Dr. Röllig:
Yeah, so I try to kind of summarize the evidence that we have so far coming from a historical perspective that maintenance has been part of a regular treatment at the beginning of acute leukemia treatment from the 60s on. However that maintenance with the conventional cytotoxic agents that we know has not been very effective. It could maximum replace an intensive conditioning treatment but beyond that had no effect. I was kind of reviewing attempts to kind of use other drugs such as interleukins to obtain better results with maintenance treatments. Those agents like interleukin and the interference didn’t work very well either.

Dr. Röllig:
And then I focused on targeted agents that are upcoming and are now shaking up or moving the treatment area in AML and I tried to show the candidates from all the different classes of targeted agents that are active or that have been evaluated in our ongoing clinical trials and try to show for which agents we have randomized evidence and it’s only very few of them that have randomized evidence and I try to kind of sum it up and draw conclusions, all kind of post-questions on how to go ahead with maintenance treatment.

Dr. Larson:
So we know that acute myeloid leukemia can be polyclonal with a number of sub-clones. We had a lot of discussion this morning about how likely is it that a targeted therapy used in the maintenance setting is going to be able to cover the whole landscape of multiple sub-clones.

Dr. Röllig:
Well obviously based on what you just said it would be best to have an agent that is covering more than one target of possible. Maybe like when it comes to tyrosine kinase inhibitors for instance. Maybe less selective tyrosine kinase inhibitors could be effective than more targeted ones. However, we don’t know yet. Since we have some results post-allogeneic [transplant] with first generation TKIs midostaurin and sorafenib, but there are results that we still wait for from randomized trials for more with more specific TKIs such as gilteritinib.

Dr. Röllig:
And then on the other hand I think there is still hope that less specific targeted agents such as hypomethylating agents or maybe hedgehog inhibitors or other more broad working agents could improve results more than could have a good effect on outcome.

Dr. Larson:
So we’ve heard a little about immunotherapy. Do you think that the bispecific tumor engaging molecules like the development of the anti-CD123 and CD-3 molecules will have a role to play in maintenance therapy?

Dr. Röllig:
At least the data we’ve seen are still preliminary with small patient numbers and mainly focusing on feasibility and dose finding. However if we look at AML treatment landscape it seems that bispecific antibodies are monoclonal antibodies are best when it comes to eradicating MRD and that they work best when the tumor burden is low. So if that should be the case in AML too then the immunotherapies may have their best position in that area.

Dr. Larson:
Very good. Professor Venditti, can you tell us something about the GIMEMA trials, your recent results and your group’s evaluation of risk assessment in MRD?

Dr. Venditti:
Yes, well the GIMEMA, the idea behind the GIMEMA trial, the GIMEMA protocol is to refine risk certification of patients with AML, risk certification conventionally based on genetic and cytogenetic features. Well we find this approach by integrating, by incorporating MRD evaluation. And we believe that these MRD evaluations may help physicians optimize therapy especially the post-induction therapy. For instance making a more appropriate decision about the use of allogenic stem cell transplants or alternative approaches such as autologous [transplant] or intensive chemotherapy. And well that is what we did in our protocol and what we found was that especially for the intermediate category for whom the post-consolidation therapy was MRD driven, well we’ve found that this category had a duration of overall survival and disease-free survival that was superimposable to the one of low risk category.

Dr. Larson:
And what technique are you using to measure MRD? Is it leukemia associated immunophenotype, or PCR or some combination?

Dr. Venditti:
In the protocol we used the flow cytometry based approach. Actually we used the innate color assay but of course we know that there are some specific molecular markers that can be tracked by using PCR and probably this approach in this selected case will be more sensitive then the flow approach.

Dr. Larson:
So in my presentation I was asked to review the landscape of the treatment and outcomes for older patients with AML. And this is an area that’s rapidly changing as some of the new agents that have already been approved for relapsed refractory disease are making their way into front line use either as single agents or in combinations. So we’ve known for many years that AML is mostly a disease of older individuals. The median age is in the range 70 years old and yet these patients often have not been included in front line chemotherapy trials using intensive treatment. However there are some data that even for patients in their 80s if they can tolerate intensive chemotherapy they can get clinically useful benefit and prolong survival.

Dr. Larson:
So I tried to emphasize that age alone is not a determinant of whether a patient should be treated for AML but rather a surrogate for their medical fitness or alternatively their frailness in terms of being able to tolerate the treatment. But as we’ve already heard, cytogenetic features an molecular features within the leukemic cells also dictate the response to treatment, and I think that’s where some of the newer drugs may have their greatest impact. That is being able to cytoreduce patients, older patients achieve a complete remission with less toxicity than we’ve typically experienced with cytarabine and anthracycline regimens. Once patients are in remission of course additional treatment is required to cure AML and there the controversy, for those patients who are eligible for an allogeneic transplant is whether they should undergo an allogeneic transplant with a match donor or whether they should continue on conventional chemotherapy.

Dr. Larson:
And some recent data for patients between the ages of 60 and 77 suggests that at one year the survival is equivalent between those two groups between conventional chemotherapy and an allogeneic transplant. But beyond that point, patients who have survived and grafted well with an allogeneic transplant do seem to have a survival advantage. And this result is most clear I think in those patients with an adverse karyotype. So for patients over the age of 60 who are healthy enough to tolerate an allogeneic transplant in first remission, the recommendation is generally to proceed with an allogeneic transplant if they have an adverse karyotype but that conventional chemotherapy for consolidation treatment might be sufficient for those with a favorable or intermediate karyotype. So we’re looking forward to hearing more later this afternoon about some of the other novel developments in acute myeloid leukemia.

 

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