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Interview with Dr. Guido Marcucci - ASCO 2014

Division of Hematology, Department of Internal Medicine, Ohio State University Wexner Medical Center, Columbus, Ohio, USA

Interview with Dr. Guido Marcucci, Division of Hematology, Department of Internal Medicine, Ohio State University Wexner Medical Center, Columbus, Ohio, USA. Dr. Marcucci's work at Ohio State University (USA) focuses on the pathogenesis, treatment and prognostic assessment of acute myeloid leukemia (AML).

 

There have been several trials, some of which were presented at ASCO 2014; flavopiridol, high-dose Ara-C, mitoxantrone vs 7+3 induction chemotherapy (cytarabine (Ara-C) for 7 days IV + anthracycline (daunorubicin) as 3 day IV push) or daunorubicin. These show the investigational arm has higher complete remission (CR) rates than the comparison arm, which usually is a conventional therapy (e.g. 7+3). However, we often do not see improved survival and the question is why?

Patients do achieve CR, but is that a true surrogate endpoint for treatment efficacy? We don’t know, but probably not, as we see in several studies that even when CR is reached it does not always lead to longer survival or even cure. Possibly we are not using CR in the right way. There may be different types of CR. We tend to define CR based on morphology of the marrow, after induction treatment and after the patient recover the counts. But, still, if we go deeper and use cytogenetic of glyco-analysis, we can see some patients that have a complete eradication, or at least disappearance of the disease, the patient would never achieve cytogenetic remission. You will always be able to find a few cells with the genetic aberration that was present before you started treatment. This is even more apparent when a minimal residual disease analysis is done, either by flow-cytometry or using certain molecular markers. E.g. in the presence of chromosomal translocation, the fusion gene could be a good marker for minimal residual disease. Thus, although these patients show CR, they still have evidence of chronic disease and have a lower chance on increased survival or even cure, and thus a higher risk for relapse. Therefore, Dr. Marcucci states that we will need to implement a new definition of CR in our clinical trials, which includes cytogenetic remission, molecular remission, and thus includes the disappearance of minimal residual disease.

Secondly, we also need to assess what is our understanding of the disease and what we are doing with the treatment. Research has done a great deal in understanding the inter-patient heterogeneity. We still need to do a lot of work on the intra-patient heterogeneity, i.e. what is the difference in subpopulations of cells that will eventually lead to leukemia phenotypes, present in a single patient. As not all myeloblasts (or myeloid blasts) or the malignant sensitive AML are created equal. Some have biological activities that may not be present in others, e.g. stemness. There are for instance blasts that can be very resistance to the therapy and eventually repopulate the marrow, in such acting as (malignant) stem cells.

Current AML treatment is targeting on the proliferating cell population, using chemotherapy, molecular targeting therapies, such as tyrosine-kinase inhibitors (TKIs), to really shut-off the proliferation and eventually send these cells into apoptosis. But, what are we doing to address the sub-population of cells that have stemness as a quality, and can actually retract in their niche, survive the therapy and flourish again after treatment and repopulate the bone marrow? We need to focus on this. We are already working on this, e.g. with bone marrow transplants this is what we are trying to combat, but allogeneic transplantation is a very complex approach. This should probably be simplified with molecular targeting therapies that on its own (or in combination with transplantation) is able to eradicate this subpopulation of cells.

Question: What stands in the way of conducting that kind of studies? We have to face the complexity of the disease, the complexity of the knowledge we are acquiring, and the practicality of conducting clinical trials. Clinical trial design is often aimed at a specific molecular endpoint, or a pharmacodynamic change, to allow for stratification, treatment selection, and treatment guidance (i.e. monitoring efficacy using early molecular markers). Large trials for drug approval are very expensive, hurdles are to be overcome to harmonize different labs, and to have the molecular results available in real time to enable implementation in treatment guidance. Therefore, it is often difficult for investigators and drug companies to accept the concept that AML is a complex disease that deserves a complex type of studies. But we go for low-hanging fruit with randomized trials, where we compare arm A with arm B and in the end we just look at P-values. That time is over, for true progress in AML (there has been no improvement over the last 30-40 years) we need to accept the complexity of the disease, its biology, and the need for a complex study design. Only if we implement the biological knowledge we are acquiring every day around the globe, into the clinical trials we may see a level of progression that can result in curing the majority of patients, if not all.


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