Two types of myeloproliferative neoplasms – myelofibrosis and polycythemia vera (PV) – have very specific characteristics, and treatment strategies, says Srdan Verstovsek, M.D., Ph.D.
One of those strategies was confirmed in June 2016, with the final five-year efficacy and safety results of the phase 3 COMFORT-I study. The trial confirmed earlier findings of a significant benefit in intermediate-2 and high-risk patients with myelofibrosis who were treated with the JAK-2 inhibitor Jakafi (ruxolitinib).
In the patients randomized to Jakafi, 59 percent had a 35 percent or more reduction in spleen volume at any point on study. The median duration of response was 168.3 weeks. At a median follow-up of 268.4 weeks, the overall survival was not reached in the Jakafi arm and 200 weeks in the placebo arm.
Verstovsek, a professor in the Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer, discussed treatment strategies for myeloproliferative neoplasms in an interview with CURE.
Let's first discuss myelofibrosis. How would you characterize this disease?
Myelofibrosis is one of the myeloproliferative neoplasms—a chronic disease of the bone marrow. It is, unfortunately the aggressive type. It does affect the life expectancy of the patients. The average survival is about five to seven years. Unlike other myeloproliferative neoplasms — and the name implies that these myeloid cells, they’re the bone marrow cells — grow without control and overwhelm the bone marrow and blood.
It is a disease that we would perhaps even call chronic leukemia. Many patients come and ask, “Is it cancer?” Yes, it is a cancer. It does kill people. The underlying biological problem is hyperactivity of the JAK/STAT pathway as is in other myeloproliferative neoplasms, essential thrombocythemia and polycythemia vera. There are reasons for this intracellular signaling pathway to be active and leads to a disease that is mutation driven.
The three mutations are JAK2 V617F, calreticulin and MPL. These three mutations lead to hyperactivity of JAK/STAT pathway as uniform biological abnormality in every patient. Even if you don’t test patients for any of these driver mutations, which is advisable as part of the diagnostic process, know that there is a hyperactivity of JAK/STAT pathway in that patient.
How are patients typically diagnosed?
Myelofibrosis is a disease of the bone marrow where there is a reaction to the presence of malignant cells by developing fibers. Therefore, the bone marrow biopsy is a cornerstone of the diagnostic process for myelofibrosis. However, you cannot really diagnose myelofibrosis only based on a bone marrow biopsy. In fact, there is no one test that will diagnose myelofibrosis.
There are criteria that need to be fulfilled and this includes looking at the blood cell count, presence of anemia, leukoerythroblastic reaction, bone marrow cells in blood, systemic symptoms and an increase in lactate dehydrogenase. This is a task that clinicians need to undertake, putting things together and having a final diagnosis of myelofibrosis.
What are the goals of therapy in intermediate-risk patients, and what is the standard of care for them?
Within myelofibrosis, we have usually four types of patients based on the prognostications of their longevity. The low-risk patients have an average survival of 11 years, intermediate-risk patients four or eight years, and then high-risk patients two years. Jakafi is indicated in the United States for patients with intermediate- or high-risk of dying. Jakafi is certainly a very good choice and it will, in a great majority of the patients, control the signs and symptoms, and eventually make people live longer.
The question is whether early intervention with Jakafi — in patients without a spleen or symptoms — would make sense to prolong their life. This is a real question. It is being studied in a prospective randomized trial in Europe for patients who have a low-risk disease. They are being randomized in blinded way between Jakafi, a low-dose regimen, and a watch-and-wait approach, which is still standard practice here in the United States to see whether early intervention will make a difference.
What is the patient experience like with Jakafi?
Together, spleen reduction and improved quality of life is the aim of the therapy, and that is achievable in the great majority of the patients. This can be done in those that have anemia or are transfusion dependent. That can be done in patients who do develop anemia as a consequence of the therapy.
Dose adjustments are in order, transfusions can be given, but anemia is not a contraindication to therapy, nor does the anemia that develops on therapy require stopping the therapy. It can be expected with the dose adjustments, anemia will improve and there is also now a clear knowledge that there is a rebound in the production of red blood cells on therapy, even without dose adjustments, within the first six months.
In my own practice, I’m not too worried about anemia that develops at the very beginning in particular. My goal is to decrease the spleen as much as I can in a safe way, monitoring platelets but not much of the red blood cells.
What about PV? What is the morbidity and mortality associated with this disease?
Polycythemia vera is one of the myeloproliferative neoplasms which is manifested primarily by the increase in the red blood cells. Many patients have high white cell counts and platelets. The issue here is that uncontrolled blood cell growth increases the risk of thrombosis, and because of cardiovascular events, thrombosis, and, in some cases, also hemorrhage, these patients may have increased morbidity and even mortality.
Although overall expectations of life are close to normal, there is some statistical difference between the patients with PV and normal population. The main cause of death is complications related to thrombosis, bleeding, and cardiovascular events. Some patients can progress to myelofibrosis or even to acute myeloid leukemia. That’s very rare and that certainly affects their life expectancy.
Hydroxyurea is usually the first-line therapy, sometimes interferon is. Jakafi has been developed now as a second-line therapy, which is a very effective therapy for all the five aspects of a control of disease signs and symptoms. The disease is usually diagnosed in patients who are 60 or older. The incidence is somewhere about 2.2 per 100,000 people, about 6,000 to 7,000 new cases in the United States. Average survival is about 20 years, so about 120,000 to 140,000 people live with PV.
What efficacy data do we have for Jakafi in this indication?
Polycythemia vera is a disease that is relatively benign. We are not talking about eliminating disease to cure people to prolong their life. Their life expectancy is close to normal. We would like to eliminate disease nevertheless, but, at this point in time, we don’t have medication to do that. We are, therefore, talking about the risk of thrombosis that comes with the disease presence. Uncontrolled blood cell growth will increase the risk of thrombosis, and many patients are at the high risk of having such a blood clot if they have PV. We identify those patients by presence of age over 60 or history of blood clot, perhaps even by increased white cell count at this time which hasn’t been defined completely yet. We are learning as we go.
In patients in whom we implement cytoreductive therapy, this is usually hydroxyurea, and about 20 percent to 25 percent of patients don’t do well. They are refractory or intolerant. In that setting, Jakafi was approved. Jakafi was approved based on a study that randomized those types of patients between Jakafi and best available therapy. The goal of therapy was two-fold as a primary goal to control hematocrit very tightly for a period of time — below 45 percent — and to decrease the spleen that these patients had.
In this setting, Jakafi was markedly better than best available therapy. In secondary endpoints, it also verified what we knew from the past experience from a phase II study that it can also, in many patients, control white cells, platelets and symptoms.
The interesting finding is that the safety analysis showed a significant decrease in cardiovascular events in patients on Jakafi compared to best available therapy.
How often should patients on therapy have their blood count monitored?
Once we decide to treat patients with PV with cytoreductive therapy, we would usually see patients every two to four weeks. This is very important for the first few months because this is where the dose adjustments are necessary. This is also the case with Jakafi, which is a new medication for therapy of PV as it is compared with hydroxyurea, which has been around for decades. The same applies perhaps to other therapies like interferon, which I would probably see patients every month at the beginning to adjust the dose, if necessary.
In general, with any institution of therapy in PV, the first few months are critical. This is where most of the toxicity occurs and where most of the dose adjustments are necessary. However, to improve the benefit for patients, you [may] also need to adjust more.