ASH 2013 - New Orleans, LA, US
Chemo-free treatment for acute promyelocytic leukaemia
Dr Luca Mazzarella - European Institute of Oncology, Milan, Italy
APL is acute promyelocytic leukaemia, it’s a subtype of AML. It’s a relatively rare disease but it’s one of the most successful stories in the history of oncology probably because it was one of the first diseases where a targeted biologically based approach was attempted, now more than twenty years ago, with the advent of retinoic acid. This has now become one of the first diseases that we can treat with a completely chemotherapy free regimen with a combination of retinoic acid and arsenic trioxide. This was a very recent achievement from the group of Francesco Lo-Coco in Rome published earlier this year in the New England Journal of Medicine.
It has also been a particularly instructive disease for understanding a number of biological mechanisms in oncology: the action of oncogenes and onco-suppressors and their interaction with epigenetic modifications and several other features. So even if research on APL has a relatively small impact on the outcome of patients, because nowadays APL patients tend to be very efficiently cured, it’s a very instructive disease to understand the biology of cancer.
Are the patients cured or do they have to take the treatment continuously?
It depends, nowadays the treatment has to be administered… the chemotherapy-free regimen is still experimental. Actually it’s paradoxical that even if an Italian group carried out the whole experimentation, the whole trial, the arsenic trioxide is not approved in Italy so it’s not possible to give it through the national health service. So it depends a little bit on the regimen; most patients tend to have a defined treatment with standard protocols with retinoic acid and an anthracycline and then they undergo salvage therapy or bone marrow transplantation in the rare cases of relapse after the initial therapy.
What is the relationship between the disease and metabolism/obesity?
What our group, in collaboration with Lo-Coco’s group, found out a couple of years ago was that this disease is particularly susceptible to the effect of systemic metabolism. Actually, even earlier data from Esteva’s group at MD Anderson found that APL patients tend to be, on average, much more obese or overweight than the normal population and also more obese than other types of AML. What we found out last year was that not only obesity increases the incidence of APL but it also worsens the outcome of these patients. So this is, as I said, a very curable disease but obese patients tend to have a relapse rate that is about threefold higher than non-obese patients. This same relationship is not as strong in other types of AML so there seems to be something specific to the biology of APL that makes it so dependent on systemic metabolism. So what we have been trying to do in the lab is to try to understand why this is happening, so how is it possible that a fat host environment shapes the biology of this disease in a different way than a non-fat environment. We’ve been looking at a number of things and we’ve been trying to model this phenomenon in the mouse. In the mouse this has given us very striking results because APL has a very well defined and very universally used model; it’s a mouse that continuously develops the disease but with intermediate penetrants, so only 60% of these mice get the disease in their lifetime. If you subject these mice to a high fat diet the mice, of course, get fat and 100% of these mice develop the leukaemia and the latency with which they develop the disease is shortened significantly by about fifty days, it’s about a fifth of their leukaemia free survival. Now we’re trying to understand why this is happening and we think we have preliminary results showing that this may have to do with the DNA stability in the haematopoietic stem cell compartments.
We also have been carrying out studies on other types of cancer, namely breast cancer, where we also know and we’ve also furthered this evidence that obesity does influence both the incidence and the outcome of this disease. One important thing to stress here is that it’s very likely that obesity is not going to have the same impact on all types of cancer, probably different types of cancer, depending on their biology, will respond differently both to obesity and, very importantly, to dietary interventions of different sorts. So one thing that I didn’t mention is that in our APL model we’ve seen that caloric restriction, so the opposite of obesity, has a dramatic impact on the outcome of the disease because if you inject APL cells into a mouse that has been subjected to caloric restriction the outcome, the mortality of these mice, is dramatically ameliorated by caloric restriction. This is something that, of course, can be immediately translated into the clinic because it is now possible to propose dietary intervention programmes, as we are trying to do at the EIO as well, to help as a sort of adjuvant to anti-cancer therapy. There now is a mechanistic rationale for doing this.
