Under the guidance of Dr. Srdan Verstovsek, Chief of the Section of Myeloproliferative Neoplasms, MD Anderson has become the largest center in the world for MPN research and treatment. Our work has been recognized both nationally and internationally, and Dr. Verstovsek is frequently an invited speaker at most significant hematology meetings worldwide, including annual meetings for the American Society for Hematology, American Society for Clinical Oncology, and European Hematology Association. It is fair to say that MD Anderson has become a leader of all major new initiatives in the MPN field, and Dr. Verstovsek is Principal Investigator of a great majority of clinical studies underway for these diseases. In addition, Dr. Verstovsek has been first or corresponding author on many important publications in the MPN field.
It is crucial that we identify treatment strategies to effectively treat MPN to prolong patients’ lives and ultimately cure the disease. In addition to improving quality of life and life expectancy for patients with MPN, the study of these relatively rare malignancies may provide insights for the treatment of more common medical problems. For example, knowledge about intracellular signaling and transduction pathways which result in an over-abundance of immature red blood cells in polycythemia vera, may help to devise medications to treat patients with potentially fatal anemia. Similarly, identifying new therapies that decrease platelet numbers in ET could lead to treatments for thrombocytopenia (more common problem of low platelet number in the blood) and end-stage leukemia that increase platelet numbers. Therapies that would eliminate fibrosis in PMF may help patients with many other fibrotic diseases (e.g. lung fibrosis).
The development of novel therapies for patients with MPN has been historically hampered by limited understanding of the abnormal processes and molecular causes of these diseases. However, great strides have been made in this regard over the last several years. The most important recent finding in the MPN field was a discovery of a mutation in the gene called Janus kinase 2 (JAK2), present in 50% of ET and PMF patients, and 97% of PV patients. The mutated JAK2 gene makes abnormal JAK2 protein, an enzyme that is active all the time (constitutively activated). Notably, even in patients who don’t carry the JAK2 mutation, the JAK-STAT pathway had been shown to be chronically upregulated. Thus, it is believed that constitutively activated JAK2 protein is a major reason for the existence and progression of the myeloproliferative diseases.
JAKs are intracellular tyrosine kinases that relay extracellular signals via type I cytokine receptors (e.g., erythropoietin and thrombopoietin receptors in hematopoietic cells) to stimulate cell proliferation, differentiation and survival as well as the production of pro-inflammatory cytokines. Cytokine binding induces receptor dimerization and activation of JAKs, associated with the receptor inside the cell. Activated JAK phosphorylates the cytokine receptor, allowing the binding and phosphorylation of STAT (signal transducer and activator of transcription) proteins. Phosphorylation of STAT proteins induces their dimerization and translocation to the nucleus where they regulate transcription of various genes involved in cell growth and survival.
Given the importance of the dysregulated JAK-STAT pathway in the pathogenesis of myelofibrosis, several JAK inhibitors have been developed to treat patients with MPN, particularly those with myelofibrosis. More a dozen different JAK2 inhibitors have been developed for evaluation in patients with MPN, and in particular those with PMF. A majority of them are being tested in clinical trials at MD Anderson, with Dr. Verstovsek as Principal Investigator.
Ruxolitinib, a JAK inhibitor, is the first and only treatment for myelofibrosis to be approved by the US Food and Drug Administration. Ruxolitinib has been shown to dramatically improve the signs and symptoms of the disease, allowing patients to live a fuller more active life, with fewer disease-related symptoms. Phase III clinical study results have recently been published in the New England Journal of Medicine, with Dr. Verstovsek as the first author.
Several other JAK inhibitors are also in clinical development, including pacritinib, CYT387, fedratinib (SAR302503), LY2784544, lestaurtinib (CEP701), and others.
Separately, Dr. Verstovsek has conducted a clinical study with a medication called Pegasys, in ET and PV. Roche Laboratories developed a semi-synthetic form of long lasting interferon-alpha (IFN-α), called Pegasys, by attaching a polyethylene glycol molecule to regular IFN-α. This significantly prolongs its presence in blood and provides extended activity over one week. The drug is conveniently given at home once a week by self-injection of a pre-filled syringe. Toxicities are less pronounced and happen less often than with regular IFN-α. Patient compliance is enhanced due to convenience and better tolerance of side effects. Pegasys was evaluated in a phase II study at MD Anderson for ET and PV patients. Eighty patients participated and 80% achieved complete response, making Pegasys the best medication on the market that can be used off-label as therapy for ET and PV.
Thalidomide and Lenalidomide
Thalidomide, an agent with putative antiangiogenic (prevents new blood vessel formation) and immunomodulatory (modifies immune system) effects, has activity in myelofibrosis. Improvements in blood cell counts and reduction in splenomegaly have been reported in selected patients but at the expense of significant side effects, including sedation, neurotoxicity, and constipation. When given with prednisone (corticosteroid), these side effects are diminished and patients can tolerate a prolonged course of therapy; this translates into the improvement of blood cell counts in a significant number of patients. There is a need for more potent and less toxic analogs of thalidomide.
Lenalidomide (Revlimid) is an oral thalidomide analog that has recently been approved by the FDA as therapy for patients with 2 other bone marrow diseases – myelodysplastic syndrome and multiple myeloma. A clinical trial studying the efficacy and safety of Revlimid and prednisone in myelofibrosis was recently conducted at MD Anderson by Dr. Verstovsek. The regimen proved to be effective in 35% of patients, making this combination the best therapy (at the moment) that can be prescribed to patients with myelofibrosis with medications that are approved for different bone marrow diseases (off label use).