JAK2 Inhibitors and Stem Cell Transplants for Myelofibrosis
Several treatments are available for myelofibrosis. However, there are also side effects of some of these treatments. One of these treatments involves the use of JAK2 inhibitors. Another type of treatment involves the use of stem cell transplants.
Primary myelofibrosis
Among the three types of myeloproliferative neoplasms, primary myelofibrosis is one of the least common. It is caused by the proliferation of fibroblasts, resulting in a build-up of scar tissue in the bone marrow. The scar tissue prevents the bone marrow from producing normal blood cells. This results in anemia and thrombocytopenia, which are symptoms of primary myelofibrosis. The symptoms develop gradually over time, and most people with this condition are asymptomatic. However, some people will need treatment to ease the symptoms of the condition.
Primary myelofibrosis is classified as a chronic myeloproliferative disorder and can be treated by biotherapy, chemotherapy, and an allogeneic stem cell transplant. Treatment is usually initiated when there is a high risk of the progression of the disease. In addition, patients may have to undergo regular check-ups and undergo periodic blood transfusions. The only cure for this condition is an allogeneic stem cell transplant, which requires the donor to be a matching match for the patient. This procedure involves radiotherapy and high doses of chemotherapy. Although this is an effective treatment, it also comes with significant risks.
Typical symptoms of primary myelofibrosis include anemia, splenomegaly, thrombocytopenia, reticulin/collagen fibrosis, and aberrant inflammatory cytokine expression. The condition is often characterized by an abnormally large spleen, and can also be accompanied by weight loss, loss of appetite, and joint pain.
Typically, white blood cells are higher than normal in the early stages of the disease. The condition also may involve the presence of myeloblasts, which are large red blood cells that are nucleated and may appear in the peripheral blood. The bone marrow is usually normal, but it is often affected by the disease. This leads to the production of scar tissue, which prevents the bone marrow from producing new blood cells. When extramedullary hematopoiesis occurs, the nucleated red blood cells are released into circulation. These cells are poikilocytosis, teardrop-shaped, and contain a nucleus.
A JAK2 gene mutation may occur in more than 50% of primary myelofibrosis patients, and a JAK2 V617F mutation is associated with an increased risk of leukemic transformation. A JAK2 inhibitor may be a useful treatment but may worsen anemia. Other options include chemotherapy and pegylated interferon, which can reduce splenomegaly. A mutation in the MPL gene can also be a cause of primary myelofibrosis. A next-generation sequencing panel can detect certain genetic mutations associated with an increased risk of leukemic transformation.
Primary myelofibrosis may be diagnosed by physical examination, blood tests, and a bone marrow biopsy. During a bone marrow biopsy, abnormal fibrosis is usually observed in the marrow cavity. In some cases, bone marrow aspiration may be difficult because of fibrosis. However, it is recommended that a bone marrow biopsy be performed for patients who experience symptoms of primary myelofibrosis.
Symptoms of primary myelofibrosis may also be accompanied by other symptoms, including hepatosplenomegaly, abdominal discomfort, and bleeding problems. Patients with the disease may also have generalized itching and unintended weight loss. Other nonspecific symptoms include fever, indigestion, fatigue, and palpitations. These symptoms may also be caused by another condition, and a doctor may need to order other tests to rule them out.
Stem cell transplants
Various medical treatment options are available for patients with myelofibrosis, including chemotherapy and organ transplantation. Patients can take part in clinical trials and receive targeted therapies. The National Bone Marrow Registry is a database that can be accessed by patients. A stem cell transplant is a treatment that involves transplanting new stem cells into the bone marrow. These stem cells can then mature into healthy red and white blood cells. These cells are important to fight infection. They carry oxygen to the body’s tissues. They also help to clot blood.
Myelofibrosis is a rare type of blood cancer. This disease usually affects people who are younger than 70 years old. Patients may not need immediate treatment, or they may be able to live with the disease for many years. The goal of treatment is to reduce the risk of relapse. After transplantation, patients may need transfusions for a period of time. They may also need to visit a doctor frequently. In addition, a stem cell transplant may not be the right treatment for everyone, depending on their comorbidities.
Myelofibrosis can occur as a result of a mutation in the JAK2 gene. Other common mutations include MPL and CALR. If a patient has one of these mutations, then they may be diagnosed with essential thrombocythemia. The disease can also develop from a previous polycythemia vera. Patients who are diagnosed with myelofibrosis may be eligible for a stem cell transplant, as long as they are not pregnant or nursing.
There are two types of stem cell transplants: allogeneic and nonmyeloablative. Allogeneic transplants are made from stem cells from a healthy donor. Nonmyeloablative transplants use a lower dose of chemotherapy. This reduces the risk of infection after the transplant. The risk of graft-versus-host disease is also reduced.
To determine whether a patient is eligible for a stem cell transplant, doctors will perform blood tests. These tests will help them to determine the effectiveness of the transplant. If the blood tests show that the transplant is successful, then the patient can expect to have a complete recovery. However, this may take several months. Patients may need to stay in the hospital for several weeks. They may also have to receive IV antibiotics to prevent infections. If the blood cells begin to engraft, they may be able to go home. They will need to attend frequent follow-up visits to monitor their blood cell levels.
If a patient does not have a family member who is willing to donate bone marrow, they can register in the national donor registry. This will make it easier for them to find a donor. However, it may take several weeks or months before a patient can receive a transplant.
The Myeloproliferative Disease Research Consortium (MDRC) conducted a study that evaluated outcomes of HLA-mismatched or HLA-matched unrelated donor transplants. Both groups had similar overall survival rates. However, the unrelated donor transplants had a lower disease-free survival rate.
Side effects of JAK2 inhibitors
Various clinical trials have evaluated the side effects of JAK2 inhibitors for myelofibrosis. Although clinical trials have shown significant symptom palliation with JAK inhibitors, patients with myelofibrosis may experience disease persistence. The purpose of this review is to examine the mechanism of disease persistence with ruxolitinib, an investigational JAK2 inhibitor, and to discuss strategies for improving treatment.
In primary myelofibrosis, JAK2 is over-activated by mutations. The mutations can lead to abnormal platelet levels, extramedullary hematopoiesis, and bone marrow fibrosis. Approximately 50%-60% of patients with primary myelofibrosis carry activating mutations in the JAK2 gene. These mutations result in a nonspecific, highly inflexible substitution that activates the JAK2-STAT pathway. This signaling is a major driver of pathology in myelofibrosis. Interestingly, these mutations may also be responsible for the low red blood cell count that many patients with myelofibrosis have.
The presence of a JAK2 gene mutation increases the production of blood cells, which damages the bone marrow. As a result, patients with myelofibrosis often have low red blood cell counts and a need for frequent blood transfusions. However, thrombocytopenia appears to be reversible.
The current era of kinase inhibitor research has been fueled by the recent discovery of JAK2 gene mutations. This has led to a renewed interest in targeting the JAK-STAT pathway for the treatment of myelofibrosis and other cancers. However, these drugs carry with them significant hematologic and constitutional adverse events, such as thrombocytopenia, diarrhea, and dizziness.
There are several JAK2 inhibitors currently in clinical trials. The most advanced is ruxolitinib. In this study, 309 patients with intermediate-risk or high-risk primary or secondary myelofibrosis were assigned to either a 15- or 20-mg dose of ruxolitinib or to a placebo. The primary endpoint was a reduction in spleen volume by 35% by week 24. Approximately 14% of patients experienced clinical improvement, and 44% of patients experienced a 50% reduction in splenomegaly. In addition, weight gain was observed in the treatment group, and exercise capacity was improved.
Some of the side effects of JAK2 inhibitors include low red blood cell levels, thrombocytopenia, and peripheral neuropathy. These adverse events are relatively mild and can be controlled by drug taper. Other side effects include nausea and diarrhea. Thrombocytopenia may also be associated with withdrawal syndrome, which is a serious, but reversible, adverse event. Currently, JAK inhibitors are used in patients with myelofibrosis, polycythemia vera, and essential thrombocythemia. Depending on the disease, JAK inhibitors are used in combination with erythropoietic drugs. Some patients with myelofibrosis are candidates for transplant, although this is a rare and unreliable option.
Other clinical trials have evaluated second-line JAK inhibitors in patients with myelofibrosis. Those trials included ruxolitinib and pacritinib, which are ATP-competitive inhibitors that inhibit fms-like tyrosine kinase 3. These inhibitors are effective and have demonstrated clinical benefits in patients with myelofibrosis. In addition, ruxolitinib may improve patient quality of life.
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