March 13, 2023
Contributed by Dr. Muneeb Niazi, Medical Fellow at SurvivorNet.
Myelofibrosis (MF) belongs to a group of blood cancers called myeloproliferative neoplasms (MPNs). These cancers originate in the myeloid tissue, commonly known as the bone marrow, which lines the inside of large bones, such as the vertebral column or the hip bones.
“The [abnormal] cell of origin [for these cancers] is in the bone marrow… There are three classical MPNs, essential thrombocytosis, which is too many platelets, polycythemia vera, which is too many red cells, and MF, which is a condition in which there is a proliferation of cells in the bone marrow. But there’s also a significant amount of scarring or fibrosis in the bone marrow,” explains Dr. James Mangan, Hematologist/Medical Oncologist at the University of California San Diego.
A common side effect of a type of MF treatment called Janus kinase (JAK) inhibitors is anemia, or a decrease in a patient’s red blood cell count (which can cause issues like fatigue, weakness, dizziness, etc.) There are some promising new treatment options for myelofibrosis-related anemia, but before we get into those, it’s important to understand how the disease works.
It Starts Within the Bone Marrow
Bone marrow is a red, spongy tissue that contains the mother cells, known as the stem cells, which generate all the life-sustaining products of the blood, including red blood cells (RBCs), white blood cells (WBCs), and platelets. The bone marrow produces these cells day in, day out. Yet if the marrow starts to produce one or more of these cells at an abnormal rate, cancers can develop.
Dr. Mangan explains, “the cell of origin [for these cancers] is in the bone marrow… There are three classical MPNs, essential thrombocytosis, which is too many platelets, polycythemia vera, which is too many red cells, and MF, which is a condition in which there is a proliferation of cells in the bone marrow. But there’s also a significant amount of scarring or fibrosis in the bone marrow.”
Primary MF: A Scarring Bone Marrow
Primary MF is the replacement of healthy bone marrow cells with its namesake fibrous tissue, commonly known as scar tissue. This tissue is produced by fibroblasts. Over a period, these cells take over the bone marrow. Since they are incapable of producing normal blood products, the population of healthy blood cells starts to decline.
The specific cause of MF is unknown. However, many patients carry JAK2 mutations. JAK2 genes (JAK1 and JAK2) code for a protein enzyme that promotes the growth and proliferation of normal bone marrow cells. Mutations in this gene can rev up cell production within the marrow, which can ultimately result in cancers such as MF. This mutation is not required, and almost half of the patients may lack such mutations. Overall, there is an increase in chemicals that stimulate fibroblasts, cells that form connective tissues from collagen but not blood products. These cells slowly take over and replace the normal marrow cells, resulting in a decreased production of RBCs, WBCs, and platelets. This process is termed fibrosis.
Symptoms of MF result from a lack of RBCs and platelets. Of note, as RBC production decreases within the bone marrow, the body compensates for it by increasing production in other areas of the body, such as the spleen and the liver, causing them to enlarge. Symptoms may include:
- Profound Fatigue (tiredness)
- Shortness of breath
- Night sweats
- Unintentional weight loss
- Splenomegaly (enlarged spleen)
- Hepatomegaly (enlarged liver)
- Abdominal fullness due to splenomegaly and/or hepatomegaly
- Abnormal blood work
Around 20% of people with this disorder may have no symptoms and are only incidentally diagnosed based on lab work obtained for some other reason. “MF can [be diagnosed] sometimes through labs or sometimes through symptoms. I’ve seen patients present both ways,” recalls Dr. Mangan.
How is MF Treated?
There are several different treatments for MF, such as watchful waiting, targeted therapies, chemotherapy, immunotherapy, and allogenic stem-cell transplantation (ASCT). ASCT is the only curative treatment, but it comes at the cost of significant, sometimes life-threatening complications.
“We’re only curing maybe 50 to 55% of patients with a transplant. [And] the decision to get a transplant is a big decision that carries risk … I’m actually very optimistic about some of the [other] treatment tools we have for treating MF. I tend to manage [my patients] with medical therapies or symptom-directed therapies [first],” Dr. Mangan says. “Patients may live for five, six, or seven years with a good quality of life before they must subject themselves to the risks of a transplant. [Therefore], we defer transplants in MF.”
Targeted therapies exploit unique features of cancer cells and use drugs that target these features. Janus-associated kinase-1 and 2 (JAK1 and JAK2) are two enzymes that are involved in the aberrant production of cells in MF. Targeting these enzymes using JAK inhibitors, such as ruxolitinib, can help control MF. While they can be extremely effective, they carry their own side effects and can especially increase the risk of symptomatic anemia and low platelet counts in patients.
“Unfortunately, the JAK inhibitors [can make] the anemia a little bit worse and [become] a drag on platelet counts,” notes Dr. Mangan. “Thus, we must turn to alternative therapies to improve the anemia in [such] patients.”
Luspatercept: A Promising Potential Treatment For Anemia in Myelofibrosis
Luspatercept (tradename Reblozyl) is a first-in-its-class medication, which serves to enhance the production of RBCs within the blood. Technically, it binds to proteins from the transforming growth factor-beta (TGFβ) and diminishes the TGFβ-assisted cascade of events that regulates RBC production. In doing so, it enhances RBC numbers and alleviates anemia. It has been approved by the Food and Drug Administration (FDA) for treatment in patients with β-thalassemia who require regular blood transfusions and certain myelodysplastic syndromes (a group of diseases resulting in abnormal blood cell production).
It has not been approved for MF-related anemia just yet. But that does not mean it is not effective. In fact, preliminary clinical trials in MF patients have shown significant promise. Their findings have greenlit an ongoing phase 3 clinical trial, called INDEPENDENCE, the results of which could mean FDA approval for luspatercept for MF-associated anemia.
Currently, the promising study results have led to luspatercept being used as an off-label treatment for these patients.
“I’ll disclose that this is an off-label use… there’s a drug called luspatercept, which has been effective in anemia in certain subtypes of myelodysplastic syndrome. [It] seems to work well in MF. And so, at our institution we have been putting a lot of [MF patients with anemia who are candidates for] JAK inhibition on a combination of ruxolitinib and Luspatercept,” notes Dr. Mangan.
Other Promising Treatment: Imetelstat, Pacritinib, and Momelotinib
Another first-in-its-class medication, Imetelstat works differently than Luspatercept. It inhibits telomerase, which is a naturally occurring enzyme that is active in proliferating cells but silent in mature, adult cells. It has been shown to aid in the development of many cancers, including MF. By inhibiting this enzyme, Imetelstat kills off malignant parent cells within the bone marrow which reduces the production of cancer cells.
“Imetelstat seems to be very promising, but it is currently [being tested] in clinical trials,” says Dr. Mangan. This means that it is also not yet FDA-approved for MF-related anemia.
Pacritinib is an inhibitor of JAK2 and some other proteins. It has previously been FDA-approved for the treatment of MF patients with low platelet counts based on the results of a large-scale clinical trial. However, further analyses of this same study demonstrate the benefits of this medication for anemia alleviation, as measured by a decrease in the frequency of blood transfusions required by MF patients. Like the previous two medications, it has not yet been explicitly greenlit by the FDA for MF-associated anemia, however, it is being used as an off-label drug for MF patients with anemia in clinical practice.
Momelotinib is an investigational drug for myelofibrosis that is a strong inhibitor of three proteins, including JAK1, JAK2, and Activin A receptor, type I (ACVR1). Its combative actions against anemia are mainly achieved through ACVR1 inhibition. ACVR1 inhibition reduces the levels of activin-like kinase-2 (ALK2), which is a protein present on the outside surface of liver cells. This prevents the generation of a hormone called hepcidin. Hepcidin decreases how much iron is available for use by the body. Its levels are often elevated in MF patients. By lowering these levels, Momelotinib increases the circulating iron within the body, making it readily available for bone marrow cells. This leads to increased production of hemoglobin, an iron-containing protein, and RBCs alleviating the anemia. Momelotinib was studied in a large-scale clinical trial with positive results. It is currently under review by the FDA for use in clinical settings.
The Future Holds Even More Promise
Dr. Mangan expresses optimism that these experimental but promising treatments will soon become part of the standard of care for the treatment of anemia in MF patients.
“[Currently] these therapies are a little bit more on the clinical trial spectrum than standard-of-care spectrum. Although I think soon that’s [going to change], especially with luspatercept and migalastat,” Dr. Mangan concludes.