Biologicals in the Treatment of Haematological Malignancies

Current status and advances in the treatment, research in biomarkers, molecular techniques and advances in immunotherapy

We met with Martin Dreyling of the University Clinic Munich, Campus Grosshadern, Munich, Germany to discuss about advances in the biological treatment of various haematological diseases, progress in the research of biomarkers, molecular techniques and advances in immunotherapy.

ESMO: What’s the current status of personalised medicine application in haematological malignancies?

Martin Dreyling: So far we have been lucky in fact as our standard treatments - one size fits all - were more efficient than in a couple of solid cancers. However this has changed now and I'll give you two examples - one in acute myeloid leukaemia, the other one in lymphoma.
Acute myeloid leukaemia - up until now we applied high-dose chemotherapy and achieved some cure. We've learnt during the last five years or so that with targeted therapy we might overcome the disease. By applying hypomethylated agents, we're switching the gene expression of the malignant cell and by that, surprisingly, even in a highly aggressive clinical course of acute myeloid leukaemia, we may see remissions and even long term success. So how can we predict which patient will respond to this approach? We have some data suggesting that we will be able to predict response just by specific gene expression and that would really open the door to finding what you might call personalised medicine even in acute leukaemia.
On the other hand, in lymphoma, currently it's fair to say there’s a revolution going on. So far we have been quite successful with standard chemotherapy complemented by targeted anti-CD-20 antibodies. However, we really learnt during the last couple of years that even highly aggressive lymphoma is still dependent on the B-cell receptor. And by targeting and inhibiting B-cell receptors, it's quite striking that even in the very advanced malignant diseases we might be able to achieve remissions and even complete remissions. We've further discovered, just recently by targeting these specific pathways, that the sensitivity of the cells is also dependent on both, the nature of the cells or of the specific mutations. So yes, so far personalised medicine was a minor theme in haematology, but things are just starting to change.

ESMO: Where do we stand in the area of haematological malignancies in terms of research in biomarkers?

Martin Dreyling: Biomarkers are a new theme in haematology and the reason is that in the past we applied an unspecific kind of treatment, chemotherapy. So yes, we do have some prognostic markers in the specific kind of diseases, some of them biological, namely cell proliferation, some of them even molecular and in fact in acute myeloid leukaemia we are really able to identify the specific molecular risk factors. However things have changed. Now as we're moving to targeted approaches, we in fact have to explore really predictive markers and we have to identify which patient is specifically prone to respond to one or another targeted approach.

ESMO: What about the application of particular molecular techniques and immunohistochemistry in the field of haematological malignancies?

Martin Dreyling: Surface markers play a very important role in not only the classification of haematological malignancies, but also in identifying risk profile. So in fact it has already been twenty years since we applied immunohistochemistry to differentiate different lymphoma subtypes. In addition to this classification tool, we now also apply these as a risk predictor. For example in aggressive lymphoma, we can identify cases with specific gene or marker rearrangements and that might be BCL-2 coupled with MYC and thereby, unbalancing two pathways - namely the proliferation and the cell apoptosis, we really can now identify higher risk cases upfront. In addition to these tools, in leukaemia, we have already known for quite some time that cytogenetics play a crucial role in planning the specific treatment strategies. In addition to that over the past ten years or so we are not only looking at whole chromosomes - or even chromosome bands - but we're looking at distinct genes which really identify the individualised disease risk.

ESMO: What about immunotherapy in the management of haematological diseases?

Martin Dreyling: The concept of immunotherapy has been taken into account for decades and one example is allogeneic transplantation in acute myeloid leukaemia. This approach only works by transfusing foreign immune system, which eventually attacks the tumour cells. However, this is unspecific immunotherapy.
In contrast, during the last twenty years or so, antibodies to specific surface markers have revolutionised the therapy of malignant lymphoma. Anti-CD-20 antibody - and I have to add CD-20 is expressed in the vast majority of malignant lymphoma - is very sufficient in proving even the long term outcome. So now essentially anti-CD-20 antibody rituximab is improving overall survival in ninety percent of all patients. Currently we are building on these achievements and trying to develop second and third generation antibodies which more specifically target the cell.
I really would like to refer to one specific approach, which is to amplify the efficacy of antibodies by conjugating either radioactive compounds (that had been the old principle) or by chemotherapy. This allows having a toxic agent which is brought to the cell, internalised; the toxin is relieved and destroys the cell from the inside, we now have specific tools to destroy the malignant cell without really bringing the normal cells into danger. Having said that, I'm afraid that - although I strongly believe in all we've learnt about basic science and molecular pathogenesis of this kind of disease - at the end of the day we still have to test these compounds in prospective trials to really define efficacy, toxicity and feasibility.

ESMO: What is important for patients to know about the advances in the treatment of haematological malignancies?

Martin Dreyling: I think it is very important that patients should refer to their national and European patient advocacy groups as sources of information. For example, in my case, coming from Germany, what we did is join our forces for all kinds of different lymphoma study groups and set up a web-based supported platform where patients can get additional information; the same is going on for ESMO and in other European bodies. I think it's very important to discuss with the caring physician, "are there any studies available?", and where the patient in fact does have a chance to be treated with these agents.
Having said that, I really would like to add a personal comment. Unfortunately due to European law, performing studies had become much more difficult during the last ten years. It's quoted as quality of care but it does not have anything to do with quality of care - it does have to do with, let’s say, the height of staples of papers that makes it more challenging. However, for our patients, this is really the chance to get their hands on the new possibilities of treating cancer without damaging the body and healthy cells.

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