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Interview with Dr. Srdan Verstovsek - ASCO 2014 | Part I
Medical oncologist and Professor in the Department of Leukemia, MD Anderson Cancer Center, Houston, Texas, USA
Interview by Dr. Guido Marcucci, Division of Hematology, Department of Internal Medicine, Ohio State University Wexner Medical Center, Columbus, Ohio, USA with Dr. Srdan Verstovsek, medical oncologist and Professor in the Department of Leukemia, MD Anderson Cancer Center, Houston, Texas, USA.
Dr. Marcucci starts by referring to the presentation of the first trials with ruxolitinib in polycythemia vera (a myeloproliferative blood cancer in which the bone marrow makes too many red blood cells) patients, refractory to hydroxyurea. The presentation showed that ruxolitinib is a better choice of treatment. Dr. Marcucci asks Dr. Verstovsek to place ruxolitinib in the context of what is going on in clinical research in polycythemia vera and myeloproliferative neoplasms.
Dr. Verstovsek responds that a common problem in myeloproliferative neoplasms is the hyperactivity of intracellular signaling – the JAK – STAT pathway is super-active. Ruxolitinib is a JAK inhibitor, controlling the growth of the cells and the inflammation that comes with the uncontrolled disease. It works in patients with myeloproliferative neoplasms regardless of the presence or absence of the JAK2 mutation, which is just one of the many. In polycythemia vera (PV) we know the main problem is too many red blood cells, white cells, platelets, splenal symptoms and we all focus on controlling hematocrit. We did a trial in 34 PV patients using ruxolitinib as a second-line treatment. Phlebotomy, aspirin, and when needed chemotherapy with hydroxyurea, which is well tolerated, are the first-line treatment options. Still, for a group of patients this is inadequate or they become intolerant. In this area of unmet need we tested ruxolitinib in a (now published) pilot study. 97% of the patients were able to control hematocrit within a month, and had normalized cell counts and symptoms.
Therefore, we now engage in the RESPONSE trial, a study with polycythemia vera subjects resistant to or intolerant of hydroxyurea, comparing ruxolitinib tablets vs the best available care, with as primary outcome the absence of phlebotomy eligibility and reduction in spleen volume. Results show much better control of the spleen and the need for phlebotomy is eliminated. Early indications are found that in fact the risks on various thrombotic events seems to be decreased.
Dr. Marcucci asks, if you want to move ruxolitinib into a first-line therapy position, you will need to compare it with hydroxyurea, so what is the rate of the symptoms and splenomegaly control of ruxolitinib compared to hydroxyurea, based on your experience? Dr. Verstovsek responds that, keeping in mind that the data from clinical trials do not fully correspond to clinical practice, significantly better responses were seen with ruxolitinib compared with what you would see with hydroxyurea in front-line treatment. But, a head-to-head comparison will be needed to confirm this. Also, would you use ruxolitinib for all patients, or in a selection of patients? One option could be to test patients that, in a front-line setting, have predicting (genetic) features of a bad outcome with current front-line treatment.
Dr. Marcucci points out that, besides the JAK-STAT pathway, several other components participate in disease pathogenesis, and then asks at what point in time should we start looking at combination therapies, instead of just testing one drug at a time? Dr. Verstovsek acknowledges that this is the direction the field is going, but first in myelofibrosis, as PV is relatively benign. In myelofibrosis ruxolitinib can control, but not eliminate the disease. There is a push to do combination studies, with a JAK inhibitor as a backbone, with Hedgehog inhibitor combinations, histone deacetylation, hypermethylation, PI3 kinase inhibitors, RAS mutation inhibitors, IDH2 inhibitors, etc. A wide range of combinations, with often investigational drugs, is being used in myelofibrosis trials, as we cannot cure it and people are still dying. Only when we find effective and save combinations to be used in the more aggressive myelofibrosis, the time will come to take these to PV patients, as was done with ruxolitinib.