Emerging treatments in the area of hematology

Following the 18th European Hematology Association Congress, pharmaphorum's Hannah Blake spoke with hematology expert, Dr Moshe Talpaz, to find out more about the research and development landscape of blood diseases and cancers.

It's been said that research into the area of hematology, otherwise known as the study of blood, can be traced back 5,000 years ago to the Ancient Egyptians.

What followed was an exciting history of discoveries and developments. In 1628, the concept of circulation in the human body was introduced and in 1642, Dutch scientist Anthony van Leeuwenhoek constructed a microscope and distinguished blood cells. The first successful transfusion of human blood to a patient happened in 1818, but it wasn't until 1914 when sodium citrate was found to prevent blood from clotting, allowing blood to be stored between collection and transfusion. The list goes on and today, unsurprisingly, the possibilities are endless.

In June 1992, the European Hematology Association (EHA) was established in Brussels, with the aim to "promote excellence in clinical practice, research and education in European hematology". Since 1998, EHA has organised an annual congress, which over the years, has become the leading meeting place for all European hematologists from various fields of this speciality.

Following this year's 18th EHA congress, we caught up with Dr Moshe Talpaz, Professor of Internal Medicine, Associate Director of Translational Research and Associate Chief of Hematology / Oncology at the University of Michigan Comprehensive Cancer Center.

In our interview, Dr Talpaz provides us with an overview of the hematology treatment landscape of today and his thoughts on where the future of R&D in this extensive area will take us.

Interview summary

HB: Hello Dr Talpaz, it's really great to speak with you today. Can you start by telling us a bit about your background and your current role please?

MT: I am an academic physician, so while I am not working in or for the pharmaceutical industry, I collaborate with them. I am currently the associate director for translational research at the University of Michigan Comprehensive Cancer Centre, and also the co-director of hematological malignancies bone marrow transplant programme of that centre. And in that capacity I interact with pharma quite extensively, and I can tell you that I work with numerous companies, and under various capacities, mostly doing clinical studies, either under industrial contract or based on our investigator generated R&D. I am also consulting to several companies, but again, my primary role is as an academic physician.

HB: What emerging treatments in hematology do you think are showing the most promise?

MT: I think that perhaps the most exciting area right now goes on in lymphoid malignancies, and perhaps the most exciting drug is the one that is being co-developed by Janssen and Pharmacyclics, known as ibrutinib. It's a drug with remarkable responses, and is one of a series of drugs that now is starting to be a group of targeted therapies in lymphoma. Lymphoma seems to be an area which is changing rapidly, and going through a transition, hopefully, from chemotherapy to more specific targeted therapy.

Other diseases in which we see changes include multiple myeloma. Second generation proteasome inhibitors have extensive potential and are more effective than second generation drugs, such as the drug from Onyx, carfilzomib, which is a very effective drug. And, a third generation Immunomodulatory Drug (IMID) from Celgene is also raising a great deal of interest – this drug is known as pomalidomide. Pomalidomide is less toxic, better tolerated, and perhaps a little bit more active. These are the new drugs in myeloma.

In the lymphoid malignancies arena we see the development of several new drugs. In the myeloid, the CML is a fairly saturated area - the latest drug to be developed was ponatinib or Iclusig, which is a highly powerful BCR-ABL inhibitor, and we now also have five tyrosine kinase inhibitors, which are BCR-ABL inhibitors for CML. So we have a whole spectrum of drugs for this disease.

As far as the myeloproliferative neoplasia, which are not BCR-ABL positive, we have one group of drugs known as the JAK2 inhibitors. There are several companies who are in various stages of developing JAK2 inhibitors.

That gives you a general guide to what's going on in our field.

HB: What does the treatment landscape currently look like for patients with myelofibrosis?

MT: For many years, myelofibrosis has been justifiably called a "disease without treatment" or an "orphan disease" or "something that was not well understood". This was until the discovery of a JAK2 mutation in this group of diseases, particularly polycythaemia vera, and to a lesser extent essential thrombocythemia. With myelofibrosis, about 50% of the patients have JAK2 mutations. I assume that the mutation was the incentive to develop a JAK2 inhibitor, but it's important to emphasise that the JAK2 inhibitors are equally functioning in both mutated and non-mutated situations. So it was perhaps an anecdote that the mutation was discovered and then the drug directed supposedly against the mutation was developed, but it seems that the JAK2 pathway is generally activated in myelofibrosis and therefore the JAK2 inhibitors are effective in this disease.

The first drug to be approved for the treatment of myelofibrosis is ruxolitinib. I think it was approved about two years ago. The major benefit of this drug, as it represents a number of similar drugs, is it has good symptom-alleviating effects and improvement in quality of life. The most remarkable effect seen in a fraction of the patients is the significant shrinkage of the spleen, because splenomegaly is one of the dominant features in this disease. So these drugs are characterised by making the patients feel better, losing symptoms that relate to the disease, having improvement in the spleen size. Preliminary data from the study of ruxolitinib, called Comfort-I, also showed early evidence for survival improvement. However, I would like to see a few more years of follow up to see what is the extent and magnitude of survival benefit and whether that's a real phenomenon.

The good news is that there are newer treatment advancements being studied for myelofibrosis including Sanofi's JAK2 inhibitor (SAR302503), in which I presented data at EHA. Prior to the congress, phase 3 data from the JAKARTA trial showed that SAR302503 met the primary end point of a reduction in spleen volume of at least 35% in two dose groups (400 mg and 500 mg), which is consistent with data reported in previous trials. At EHA I presented updated results from the phase 2 open-label randomized dose-ranging study in patients with intermediate-2 or high-risk myelofibrosis. Patients were given SAR302503 for up to 24 weeks (6 cycles at 300 mg, 400 mg, or 500 mg), and effectiveness was evaluated at 12 and 24 weeks.

It should be emphasised that these treatments are not curative by any means. Patients exhibit the improved symptoms and spleen volume reduction, but do not get a complete remission, and by measuring the JAK2 mutation as a marker of the extent of the clonal disease these drugs do not eliminate the clonal disease. Apparently, this is not the definitive treatment of the disease, yet it's a good start in a disease where there was really no treatment.

HB: How do you see this landscape changing over the next 10 years?

MT: We don't understand a lot about the disease. We don't know enough. If you look at modern oncology or modern oncologic haematology it is heavily driven by characterising a molecular defect and going after that specific target. Regretfully in the case of myelofibrosis we have the event of JAK2, but JAK2 may be a necessary but not sufficient event that drives the disease. Additional set of genes such as ASXL, IDH2, TET2 and others may be participating in the disease, and it's possible that we have not yet defined the ultimate driver of the disease, if there is one. So it's very difficult to talk about how a development of treatment is going to take place.

We can think about two avenues, however. The first is the evolutionary avenue, which means gradual addition of treatment that is empirical to improve on the current results of the JAK2 by inhibiting other proliferative pathways in the disease, like MTOR inhibitors, and other JAK inhibitors and so forth. But this will be non-specific, and it will just direct treatment against the augmented proliferation of the disease. The second avenue is a different approach, and one that hopefully will work in the future. This is the discovery of a new mutation or a new abnormality which drives this particular malignancy and which its inhibition totally revolutionises the treatment of this disease. In other words, we just don't know yet which path it will take. The easy assumption is okay we don't know what really drives the disease; we will gradually build on the JAK2 and come with other agents that will improve the suppression of the disease. That's the obvious pathway. I hope that the other one, where we will identify more molecular drivers of the disease, will be the one that happens in the near future.

HB: Finally, what area of hematological malignancies is most in need of research?

MT: I would say acute leukaemia is the area in most urgent need of treatment development. It is a fairly common problem, with between 10,000 to 15,000 cases a year of acute leukaemia in the US. However, there are objective problems there. Scientists characterise many of the abnormalities in this disease, and the first thing that they have characterised is the fact that it's not one disease, its many different diseases driven by different molecular events. This means that you cannot develop one treatment, you have to develop many treatments directed for each subset. The second issue is the ability to develop treatments for this. The target is very difficult, because most of them are not enzymes like in CML, they are not straightforward targets, they appear to be much more complex than that, and there may be transcription factors in the nucleus protein-protein interactions, epigenetic regulators, and it's more difficult to develop treatment for those. So we have two problems, 1) it's not one disease it's many diseases and 2) the target may be in the nucleus or the target may be difficult to go after. But I hope that a treatment option will be found in the future.

HB: Thank you for your time today Dr Talpaz, that was really interesting.

MT: You are welcome, thank you.

About the interviewee:

Dr. Moshe Talpaz is Associate Director of Translational Research at the University of Michigan Comprehensive Cancer Center and Associate Chief of the Division of Hematology / Oncology.

Dr Talpaz also serves as Professor in the Department of Internal Medicine. He attended Hadassah Medical School of Hebrew University in Jerusalem, Israel. Dr Talpaz went on to a residency at Kaplan Hospital followed by fellowships in developmental therapeutics and immunology at the University of Texas MD Anderson Cancer Center. He is board certified in internal medicine and medical oncology.

Where do you see research and development in hematology heading in the future?