Investigational treatments for myeloproliferative neoplasms promise more than symptom palliation.
When it comes to controlling myeloproliferative neoplasms (MPNs), keeping symptoms at bay has long been the go-to treatment strategy. But drugs that can attack the disease itself are hovering on the horizon for the treatment of MPNs, rare blood cancers that are caused by mutations in the stem cells and characterized by the excess production of white blood cells in the bone marrow. The three main types are polycythemia vera, myelofibrosis and essential thrombocythemia; chronic myeloid leukemia is also considered an MPN, although biologically distinct and treated differently. MPNs that are chronic can, in some cases, turn into acute leukemia.
While patients with asymptomatic or lower-risk disease can opt for observation, treatment is called for in those with higher-risk cases.
In myelofibrosis, one common symptom, anemia, is treated with blood transfusion, hormone therapy or immunomodulatory drugs such as Revlimid (lenalidomide). Another symptom, an enlarged spleen, can be treated with surgery, chemotherapy or radiation. While allogeneic stem cell transplant may promise a cure, most patients are not eligible due to age, disease stage or overall health.
Similarly, polycythemia vera is treated through relief of its major symptom: too many blood cells. This is accomplished via phlebotomy; medication that limits the bone marrow’s production of blood cells, such as Droxia or Hydrea (hydroxyurea); medication such as antihistamines to reduce itching; or with aspirin, which helps prevent blood clots. Essential thrombocythemia, too, can be treated with Droxia, while other options include the platelet reducer Agrylin (anagrelide), immunological agent interferon alfa or platelet pheresis, which is only used in emergencies when very high counts can cause clotting and organ damage.
But there are new techniques on the horizon. One relatively new targeted drug uses a different strategy to palliate symptoms, others are on the horizon, and yet another investigational agent is designed to fight the disease itself.Many MPNs share a genetic glitch known as the JAK2 (Janus Kinase 2) V617F mutation. Nearly all patients with polycythemia vera have it, and so do 50 to 60 percent of those with myelofibrosis or essential thrombocythemia, according to Gabriela S. Hobbs and Raajit K. Rampal, hematologists who wrote about the phenomenon for Contemporary Oncology, a sister publication to CURE. Even patients with MPNs who don’t have the mutation will likely still have a disruption in the messages sent along a cell-signaling pathway known as JAK-STAT, the doctors point out.
Addressing these issues in patients with intermediate- or high-risk myelofibrosis is the drug Jakafi (ruxolitinib), a JAK1/2 inhibitor approved by the U.S. Food and Drug Administration in 2011. In two studies, the drug reduced spleen volume and increased overall survival, and in one of the studies, nearly half the patients who took the drug experienced a significant improvement in symptoms overall.
Now, Hobbs and Rampal say, several studies are testing the drug in patients with polycythemia vera and essential thrombocythemia. Meanwhile, investigational JAK inhibitors are being tested in the clinic, including pacritinib (SB1518), momelotinib (CYT387) and NS-018.
Also in these populations, JAK inhibitors are being tested in combination with other drugs, including Pomalyst (pomalidomide), which is used in the treatment of multiple myeloma, and the chemotherapy decitabine. Finally, a couple of other drugs are looking promising in preclinical trials: heat shock protein 90, which blocks JAK-STAT signaling, and LDE225, an inhibitor of the hedgehog cell-signaling pathway.In two clinical trials whose results were published recently in the New England Journal of Medicine, a drug called imetelstat successfully treated myelofibrosis and essential thrombocythemia not by palliating symptoms, but by whittling away at the genetic anomaly that causes the blood-cell overload at the heart of the cancers.
Imetelstat is a telomerase inhibitor, and it prevents a patient’s body from preserving the genetic code of MPN cells as they divide to spread the disease.
In the first study, treatment with imetelstat induced a hematologic response in 100 percent of patients with essential thrombocythemia, with 89 percent experiencing a complete hematologic response. In the second study, the objective response rate with imetelstat was 21 percent for patients with myelofibrosis. In both trials, responses to imetelstat were durable and side effects were largely reversible.
“The data…provide compelling evidence that use of a telomerase inhibitor, such as imetelstat, may result in ground-breaking changes in how we approach the future treatment of hematologic myeloid malignancies,” John A. Scarlett, a medical doctor and president and chief executive officer at Geron, the company developing the drug, said in a statement.
The lead author of the study of imetelstat in myelofibrosis patients explained more about why the drug’s mechanism is unusual.
“Typically, myelofibrosis is characterized by marrow scarring, and, although patients may derive symptomatic relief from other treatments, such as ruxolitinib, they usually do not revert back to normal bone marrow,” Ayalew Tefferi, a hematologist at Mayo Clinic, said in a statement. “Some patients treated with imetelstat have reverted back to normal bone marrow.”
In essential thrombocythemia patients, side effects included fatigue, diarrhea, nausea, dizziness and signs of liver damage via blood tests. Serious or severe side effects were reported by 83 percent of patients, the most common of which was neutropenia (low white blood cell counts), and which also included anemia, headache and loss of consciousness due to low blood pressure.
In myelofibrosis patients, side effects of any grade were seen in 45 percent of patients, serious side effects in 27 percent and severe side effects in 18 percent. Severe side effects included lowered blood platelets, low white blood cell counts, anemia and signs of liver damage via blood tests.