Expert Highlights Advances in Myeloproliferative Neoplasms

Srdan Verstovsek, MD, PhD

Both myelofibrosis and polycythemia vera (PV), are myeloproliferative neoplasms with very specific characteristics and treatment strategies, explains Srdan Verstovsek, MD, PhD.

One of those strategies was confirmed in June 2016, with the final 5-year efficacy and safety results of the phase III 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 ruxolitinib (Jakafi).

In the patients randomized to ruxolitinib, 59% had a ≥35% reduction in spleen volume at any point on study. The median duration of response was 168.3 weeks (95% CI, 107.7-NE). At a median follow-up of 268.4 weeks, the overall survival was not reached in the ruxolitinib arm and 200 weeks in the placebo arm (HR, 0.69; 95%, CI, 0.50-0.96; P = .025).

Verstovsek discussed treatment strategies for myeloproliferative neoplasms during the 2016 OncLive State of the Science Summit on Treatment of Hematologic Malignancies.

OncLive: Let’s first discuss myelofibrosis. How would you characterize this disease?

In an interview with OncLive, Verstovsek, a professor in the Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer, discussed the diagnosis and treatment options for PV and myelofibrosis.Verstovsek: Myelofibrosis is 1 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 5 to 7 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.

How are patients typically diagnosed?

The 3 mutations are JAK2 V617F, calreticulin, and MPL. These 3 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.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 1 test that will diagnose myelofibrosis.

What are the goals of therapy in intermediate-risk patients and what is the standard of care for them?

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.Within myelofibrosis, we have usually 4 types of patients based on the prognostications of their longevity. The low-risk patients have an average survival of 11 years, intermediate-risk patients 4 or 8 years, and then high-risk patients 2 years. Ruxolitinib is indicated in the United States for patients with intermediate- or high-risk of dying. Ruxolitinib 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.

If physicians start therapy with a JAK inhibitor, what is the optimal timing for it?

The question is whether early intervention with ruxolitinib—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 ruxolitinib, 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.The evidence that we have about ruxolitinib use in myelofibrosis comes from clinical studies. We had a long-term summary of the COMFORT-I study, where it was presented that patients who start earlier with ruxolitinib versus those who do not fair better. The same was seen a few months ago in another controlled prospective randomized study where ruxolitinib was compared with best available therapy.

What is your clinical experience with ruxolitinib?

In both studies, survival benefit is evident if you start ruxolitinib earlier. That means that we should not be waiting in everyday practice for patients to really be in bad shape. If the patient has intermediate or high-risk disease, one should be looking at the spleen or symptoms. If those are present, there is no reason to wait with the therapy. If a patient is suffering from symptomatic splenomegaly or has general symptoms, those are very good indications to start out with ruxolitinib.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 that 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 6 months.

What about PV? What is the morbidity and mortality associated with this disease?

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.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.

What efficacy data do we have for ruxolitinib in this indication?

Hydroxyurea is usually the first-line therapy, sometimes interferon is. Ruxolitinib has been developed now as a second-line therapy, which is a very effective therapy for all the 5 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 6000 to 7000 new cases in the United States. Average survival is about 20 years, so about 120,000 to 140,000 people live with PV.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% to 25% of patients don’t do well. They are refractory or intolerant. In that setting, ruxolitinib was approved. Ruxolitinib was approved based on a study that randomized those types of patients between ruxolitinib 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%—and to decrease the spleen that these patients had.

In this setting, ruxolitinib 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.

How often do you monitor blood count once patients are on therapy?

The interesting finding is that the safety analysis showed a significant decrease in cardiovascular events in patients on ruxolitinib compared to best available therapy.Once we decide to treat patients with PV with cytoreductive therapy, we would usually see patients every 2 to 4 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 ruxolitinib, 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.

Verstovsek S, Mesa R, Gotlib J, et al. Long-term outcomes of ruxolitinib therapy in patients with myelofibrosis: 5-year final efficacy and safety analysis from COMFORT-I. Presented at: 2016 European Hematology Association Congress; June 9-12, 2016; Copenhagen, Denmark.