A new class of drugs has redefined treatment for patients with myeloproliferative neoplasms by easing their symptom burden while extending their lives.
Clinicians who treat patients with these difficult-to-cure diseases — including myelofibrosis, polycythemia vera and essential thrombocythemia — have shifted their focus toward easing symptoms, reducing disease-associated biological abnormalities, improving quality of life and prolonging survival.
“This significant symptom reduction is more than palliation — it is life altering,” said Srdan Verstovsek, M.D., Ph.D., a professor of Leukemia at MD Anderson Cancer Center, who has led and is leading numerous trials of new treatments for myeloproliferative neoplasms.
Of the myeloproliferative neoplasms, myelofibrosis — marked by an uncontrolled growth of bone marrow cells, reactive bone marrow fibrosis and a subsequent lack of red blood cells — is the most aggressive. Myelofibrosis can cause enlargement of the spleen or liver, systemic symptoms related to inflammation and anemia. These issues together can lead to cachexia, difficulty walking and poor performance status; patients with myelofibrosis typically die within 5-7 years of their diagnosis.
Until recently, no treatments were approved for myelofibrosis, and the disease was treated with the off-label use of drugs such as hydroxyurea, thalidomide, lenalidomide and steroids. But in late 2011, the JAK2 inhibitor ruxolitinib was approved by the Food and Drug Administration (FDA) for the treatment of myelofibrosis. And phase III trials of newer JAK2 inhibitors, pacritinib and momelotinib, for the treatment of myelofibrosis are underway at MD Anderson.
JAK2 inhibitors can effectively treat organomegaly and systemic symptoms caused by myelofibrosis. Nearly all patients with myeloproliferative neoplasms have mutations that activate the intracellular JAK/STAT pathway; indeed, JAK2 inhibition has led to responses in patients with or without a JAK2 gene mutation.
“The antiproliferative and anti-inflammatory effects of JAK2 inhibitors are evident, and people treated with these drugs get better. They don’t have any more bone aches, itching and sweating; they gain weight; and they walk more. And now we know that with good control of these symptoms, we actually can make people live a few years longer,” Verstovsek said.
Ruxolitinib was approved for the treatment of myelofibrosis not because it can cure the disease but because it can make the disease much more bearable.
“Drugs are usually approved on the basis of how many patients have their disease eliminated and how long that lasts. But with myelofibrosis, the FDA has recognized the need to address the suffering that this disease brings to patients and the benefits of improving the symptoms — helping people enjoy life again, travel, do what they want, and live longer — without eliminating the disease,” Verstovsek said. “We are realizing that this type of strategy makes a difference in patients with myeloproliferative neoplasms.”
Researchers intend to continue improving this type of treatment and combining JAK2 inhibitors with other new drugs to increase the inhibitors’ efficacy and decrease their side effects.
Path to definitive treatment
JAK2 inhibitors and other drugs currently used to treat myelofibrosis and other myeloproliferative neoplasms do not cure the disease. Chemotherapy followed by stem cell transplantation is the only treatment with the potential to cure myelofibrosis. But most patients with myelofibrosis are too sick to withstand the process, and the few who do undergo transplantation are at a significant risk of dying from complications of the transplant, such as graft-versus-host disease.
However, treatment with JAK2 inhibitors has been shown to help some patients with myelofibrosis become healthy enough to undergo transplantation successfully. The targeted therapy thus not only treats symptoms and improves functional status in these patients but also improves the chances of a cure for some. Verstovsek said, “With further progress in symptom-controlling treatment, we hope that the number of patients eligible for the transplant will increase and that we will eventually be able to cure more people. So that’s another path forward.”
Although JAK2 inhibitors can benefit many patients with myelofibrosis, myelofibrosis with anemia as the chief symptom is less likely to respond to JAK2 inhibitors. For patients with anemia and other symptoms, JAK2 inhibitors may improve other symptoms, but the anemia will likely persist. Several drugs for treating myelofibrosis-related anemia are being tested in clinical trials at MD Anderson, including the activin receptor antagonist sotatercept.
Another new direction in myelofibrosis research is the direct treatment of the fibrosis. Verstovsek said, “We are testing antifibrotic medications that target the underlying biological problem in the bone marrow with the hope that the fibrosis itself will resolve and thus improve the red blood cell count, decrease symptoms, and shrink the spleen.” Two phase II trials at multiple institutions, including MD Anderson, are testing the antifibrotic drugs PRM-151 and GS-6624, alone or in combination with the JAK2 inhibitor ruxolitinib. The PRM-151 trial recently completed enrollment for its first phase and will soon begin enrolling patients for its second phase, but the GS-6624 trial has completed enrollment.
Polycythemia vera and essential thrombocythemia treatment
Patients with polycythemia vera, an uncontrolled growth of bone marrow cells that increases the total blood volume, and those with essential thrombocythemia, an overproduction of platelets, have a near-normal life expectancy but also have an increased risk of thrombosis. In these patients, treatment usually focuses on decreasing the risk of thrombosis. Patients with polycythemia vera usually are treated with regular phlebotomies.
Patients with polycythemia vera often also receive aspirin to reduce the risk of thrombosis, as do patients with essential thrombocythemia. Patients with either disease who have an extremely high risk of thrombosis often are given the chemotherapy agent hydroxyurea to try to permanently normalize blood counts.
However, in about 20% of patients with polycythemia vera, hydroxyurea does not lead to a durable response or causes intolerable side effects. Until recently, these patients had few other options, as other cytotoxic chemotherapy agents carry a significant risk of transforming the disease into acute myelogenous leukemia.
In a recently completed phase III trial led by Verstovsek at MD Anderson, patients whose polycythemia vera could not be managed with hydroxyurea received either the JAK2 inhibitor ruxolitinib or the best available treatment option as judged by the treating physician. A significantly greater percentage of patients who received ruxolitinib had decreased red blood cell counts, decreased spleen volume, improved symptoms, and normalized white blood cell and platelet counts compared with the patients who received alternative treatments; and the patients who received ruxolitinib appeared to have a lower rate of clotting. Ninety-four percent of patients whose disease responded to ruxolitinib continued to show a response for at least 1 year, and most adverse events from the drug were low grade.
Ruxolitinib and other JAK2 inhibitors are being tested both in patients with polycythemia vera and in patients with essential thrombocythemia; two such trials for momelotinib are under way at MD Anderson.
Sequencing myeloproliferative neoplasms
Researchers at MD Anderson and elsewhere have been sequencing blood and bone marrow samples from patients with myeloproliferative neoplasms to analyze the incidences of specific mutations in myelofibrosis, polycythemia vera, and essential thrombocythemia. Several mutations have been associated with particular diagnoses: for example, the JAK2 V617F mutation occurs in almost all patients with polycythemia vera and in about half of patients with myelofibrosis or essential thrombocythemia. In contrast, CALR gene mutations are seen in a small proportion of patients with myelofibrosis and essential thrombocythemia but never in patients with polycythemia vera.
Characterizing the genetic profiles of myelofibrosis at different stages also may reveal genetic changes that coincide with the transformation of this disease into acute myelogenous leukemia, which typically kills the patient in about 5 months. At MD Anderson, the world’s largest tissue bank and clinical database specific to myeloproliferative neoplasms are being used to look for the genetic events that lead to this transformation.
“Many people have concluded that the accumulation of multiple mutations makes myelofibrosis more aggressive and more likely to transform to acute leukemia,” Verstovsek said. “So we are analyzing the relationships between multiple genetic abnormalities. We have created a 28-gene panel to better understand the influence of these mutations on overall outcomes, and every patient undergoes this testing. But we aren’t using this type of analysis in clinical practice yet.”
This article originally appeared in the October 2014 issue of OncoLog.