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Frequently Asked Questions

Find answers to your frequently asked questions about the treatment and diagnosis of MPNs. 

How are MPNs diagnosed?

What are the stages of myelofibrosis?

Myelofibrosis doesn’t have a formal staging system. Instead, myelofibrosis is graded by the degree of fibrosis (or scarring) evident in the bone marrow. Various medical parameters including the degree of marrow fibrosis, blood cell count abnormalities, symptoms and molecular/genetic features of the malignant cells are used to help physicians identify those patients at greatest risk for problems.  

I have had some borderline elevated hemoglobin and hematocrit values, and was found to have the JAK2 V617F mutation. However, the allele burden of the mutant gene was reported to be less than 2%. Does this mean anything?

DNA analysis in blood samples from thousands of normal, healthy people has been found to occasionally contain somatic mutations in genes that have been associated with MPNs (or other hematologic malignancies). Such somatic mutations are rarely found in individuals who are less than 40 years old. In fact, their detection rises strikingly with increasing age. Such disease-associated mutations can be incidentally found in as many as 10-20% of those who are in their eighth decade. When known mutations are found in the absence of clinical symptoms or other signs of MPN, they are now referred to as “clonal hematopoiesis of indeterminate potential” (or “CHIP”). The allele burden in these cases is extremely low, typically less than 2%. Such patients should be followed for development of clinically overt MPN since they may represent “pre-malignant” states. However, screening for CHIP among healthy adults is not advised because the risk of progression to clinically overt MPN is low (about 0.5 to 1 percent per year), and there is currently no therapy known to prevent progression to an overt MPN.

How are MPNs diagnosed?

MPNs are disorders of blood formation, so the diagnosis involves detailed analysis of the blood and the factory for blood cells, the bone marrow. This evaluation includes looking at the blood cell counts and proportion of cells in the blood. The evaluation also includes a detailed pathologic examination of the types of blood forming cells in the bone marrow. Examination of the bone marrow requires a bedside biopsy to be performed with local anesthetic. At Weill Cornell Medicine, the bone marrow samples are then evaluated by highly-specialized pathologists, called hematopathologists, who are trained to examine these blood cells. Weill Cornell Medicine has a world-renowned team of hematopathologists. 

Are MPNs cancer?

Are MPNs forms of cancer or blood disorders?

Myeloproliferative neoplasms (MPNs) are characterized by abnormal growth of blood forming cells including the over production of red blood cells, white blood cells or platelets, leading some to wonder if they are a cancer or a blood disorder. The original term for this group of diseases was myeloproliferative disorders, but more recently, the preferred term has become myeloproliferative neoplasms since this term more accurately describes the blood forming abnormalities that characterize these diseases. Neoplasm is the medical term for an abnormal cellular growth, including cancers. The term cancer, frightening as it may sound, is not always associated with a life-threatening condition. Many people with myeloproliferative neoplasms who receive optimal therapy have a normal or near normal life expectancy.

Is polycythemia vera a cancer?

Polycythemia vera is type of cancer affecting the blood forming system in the bone marrow. However it is important to recognize that not all malignancies (types of cancer) are equally aggressive. Life expectancy for most people with polycythemia vera is about normal when the disease is appropriately controlled.

Can MPNs change?

What is primary myelofibrosis vs. secondary myelofibrosis?

Primary myelofibrosis is myelofibrosis that is diagnosed without any preceding myeloproliferative neoplasm. Secondary myelofibrosis refers to the bone marrow fibrosis that sometimes forms in people who were first diagnosed with polycythemia vera or essential thrombocythemia. Secondary myelofibrosis is sometimes referred to as a fibrotic phase of essential thrombocythemia or polycythemia vera. Alternatively, secondary myelofibrosis is called post-PV myelofibrosis or post-ET myelofibrosis to indicate the disease that had transformed to the fibrotic phase. Primary and secondary myelofibrosis have many of the same complications and treatments. 

Should I be concerned about the risk of leukemia with hydroxyurea therapy?

The leukemic risk of hydroxyurea, if any, has been a matter of controversy for decades. At this point, the consensus is that hydroxyurea is associated with very little if any risk of causing leukemia, even over long periods of treatment. However, no clinical study has directly addressed this question in patients with MPNs over the long periods of time that would be required to identify excess risk of leukemia due to hydroxyurea.  Potential risks of hydroxyurea should be discussed with your medical team. 

Will my MPN transform to an acute leukemia?

To a greater or lesser extent, all of the classic MPNs are associated with an increased risk for transformation to acute leukemia, irrespective of treatment. When acute leukemia develops in a patient with MPN, it is hard to treat. For this reason, identifying risk factors for transformation is an active area of laboratory and clinical research. This research promises new treatment approaches that could fundamentally change the risks of leukemic transformation. For instance, although it is true that the great majority of patients who die from CML do so because of transformation to acute leukemia (the so-called “blast crisis”), the risk of this happening has been remarkably reduced by the advent of targeted tyrosine kinase inhibitors (prototypically imatinib).

For the other MPNs, the risk of transformation to acute leukemia depends upon the specifics of the disease diagnosis, clinical parameters such as blood cell counts and the particular mutations present in the MPN cells. Myelofibrosis is associated with the greatest risk of transformation whereas essential thrombocythemia generally has the lowest risk. Some older treatments unquestionably increased to risk of transformation to acute leukemia in the MPNs. These included radiophosphorus (P32), chlorambucil, and some other alkylating agents such as pipobroman.  These agents are still sometimes used in older patients because they are well tolerated and the time to leukemic transformation can be quite long. 

How do MPNs change from one MPN to another?

How one MPN transforms to another is a vast area of ongoing research to discover ways to predict who is likely to convert to a more aggressive MPN. There are certain mutations found in the malignant MPN cells, and monitoring and evaluating these may be helpful in predicting who may transform. However, no perfect marker yet exists, so doctors routinely monitor the disease for signs of changes that may indicate that an MPN may convert to a fibrotic (or worsened fibrotic) or leukemic state.

Which MPNs transform?

Myeloproliferative neoplasms (MPNs) can transform into myelofibrosis (MF) or an acute leukemia. The likelihood with which they transform is variable and dependent on the disease itself. Essential thrombocythemia (ET) is the least likely to transform to a fibrotic or leukemic phase. The risk is slightly higher in polycythemia vera (PV), but still, the vast majority of patients do not transform. Myelofibrosis (MF) tends to be progressive over time with worsening fibrosis. However, the pace with which MF advances is variable from patient to patient and depends somewhat on the particular characteristics of the malignant cells. MF is also the most likely to transform to an acute leukemia, but even in this instance it is relatively rare.

How will having an MPN affect my life?

Am I going to die from my MPN?

Any cancer diagnosis can feel very scary. Myeloproliferative neoplasms are often associated with near-normal life expectancies when optimally treated and managed. No two people are the same and it is important that treatment is individualized based on the diagnosis, other health conditions and personal history, and one’s overall risk for complications.

What kinds of blood clots (thrombosis) are patients with MPN predisposed to? What causes this predisposition?

MPN patients have an increased risk for both venous thrombosis (such as DVT and pulmonary embolism or abdominal vein thrombosis) and arterial thrombosis (such as stroke or heart attack). This increased risk may be due to mechanical effects of excess blood counts on blood vessels, but more commonly, is thought to be due to abnormal interactions between the MPN cells and the endothelial cells that line the blood vessels.

We know that in patients with PV, the elevated red blood cell numbers are at least partly responsible for the thrombosis risk. Increased hematocrit (the proportion of the blood volume occupied by red blood cells) in PV causes actual thickening of the blood (referred to as increased “viscosity”). A high hematocrit also changes the distribution of blood cells within small blood vessels and this too can promote clots. This is why the general guidelines for the treatment of PV include maintenance of hematocrit below 45% in men and 42% in women.

But excess blood viscosity only accounts for a small part of the risk of clots seen in MPNs. For instance, high platelet counts (“thrombocytosis”) and high white blood cell counts (“leukocytosis”) do not affect blood viscosity significantly. There are undoubtedly other reasons for the thrombosis risk in the MPNs because these complications can occur even when the blood counts are well controlled and completely normal. Abnormal function of platelets (increased stickiness), and abnormalities of white cells or the blood vessel wall itself may contribute to the risk of abnormal blood clots in patients with MPNs, but these risk factors have not been precisely identified. Nonetheless, it is known that taking aspirin can help reduce the risk of abnormal clots in patients with MPNs. Aspirin works by making platelets less sticky and it is also recommended that all patients with MPNs take low-dose aspirin to help prevent clots unless there is a medical reason to avoid aspirin.  Find out more about blood clots and thrombosis.

What lifestyle or dietary adjustments should I make if I have ET?

There is no known influence of diet and/or exercise on the ET or other MPNs. For people with essential thrombocythemia, and other MPNs, there is every reason to believe that following a healthy diet and engaging in physical activity is beneficial for overall wellness.

It is advisable for patients to maintain a healthy lifestyle to lower the risk of developing other conditions that can contribute to blood clotting, such as diabetes, high blood pressure and high cholesterol. Patients should try to develop healthy eating habits, exercise regularly and avoid smoking.

Can ET be cured?

Currently, the only curative therapy for ET is a hematopoietic stem cell (bone marrow) transplant (HSCT or BMT). However for most people, ET it is a chronic condition, that when optimally managed doesn’t alter life expectancy and does not require aggressive therapy such as a HSCT. There is a vast amount of ongoing research to help identify new and potentially curative therapies for ET and other myeloproliferative neoplasms that don’t require transplant.

What are the symptoms of ET?

Often people who have ET do not experience any symptoms and the diagnosis is made after abnormal results appear during routine blood testing. However, some patients do have symptoms and many are at risk for complications if not optimally managed. Patients with ET are at increased risk of abnormal blood clots in veins (deep vein thromboses/DVT) or arteries (for example heart attack or stroke). Paradoxically, some patients with ET, particularly those with very high platelet counts, can have abnormal bleeding. Sometimes, the diagnosis of ET is made after one of these complications occurs. Fatigue and sometimes itchiness are also occasionally seen in patients with ET. Once ET has been treated and is optimally managed, these complications are far less common and life expectancy is about normal.

Common symptoms of ET can include headache, vision disturbance, dizziness or lightheadedness, coldness in fingers or toes, and burning, redness, and pain in the hands and feet. Sometimes, if there is bleeding caused by ET, patients can experience easy bruising, nosebleeds, heavy periods, gastrointestinal bleeding, or blood in urine. Some patients may experience no symptoms at all. 

What causes MPNs?

What causes myelofibrosis?

Myelofibrosis is caused by acquired mutations in blood forming stem cells. Myelofibrosis is almost always caused by one of three mutations:
1. A mutation in JAK2
2. A mutation in MPL
3. A mutation in CALR

These mutations all lead to inappropriate signals to blood forming cells and excessive blood cell formation. In myelofibrosis, this excessive blood cell formation is associated with scarring of the bone marrow that can eventually lead to inadequate blood cell formation and low blood cell counts. 

Is Essential Thrombocythemia hereditary?

Essential thrombocythemia is not considered a hereditary or inherited disease. The same is true for chronic myelogenous leukemia (CML), polycythemia vera (PV) and myelofibrosis (MF).  In virtually all cases of myeloproliferative neoplasms, they are acquired by chance. They are not inherited from parents and cannot be passed down to children. There are extremely rare exceptions to this, and if multiple members of your family have had a myeloproliferative neoplasm, you should visit an experienced center that can evaluate whether there are transmissible genetic risks.

What causes CML?

CML is caused by a particular mutation in blood-forming stem cells. CML is always associated with the Philadelphia chromosome, which is the result of the rearrangement and abnormal connections (a so-called translocation) between chromosomes 9 and 22. This translocation sticks together, or fuses, two genes (BCR and ABL) that don’t normally connect. This new BCR-ABL gene causes your bone marrow to produce too many blood cells because the mutant BCR-ABL fusion causes the ABL signaling protein to get stuck in the “ON” state leading it to continuously stimulate blood cell production. Thankfully, there are very effective medications that block the abnormal ABL signals thereby normalizing blood cell production. These drugs are so effective that after treatment, the CML in most patients can only be detected using the most sensitive molecular techniques and some patients may even be cured. 

Is my MPN genetic?

The causes of MPNs are always associated with mutations of certain genes in the malignant cells. However, these mutations are acquired during life rather than inherited. The most common acquired mutations in most patients’ MPN cells occur in one of four genes, JAK2, MPL, CALR, or BCR-ABL. These mutations typically coexist with other acquired mutations that are less common.

But these are not the kinds of mutations that can be passed on from one generation to the next.  “Mutations” can be either so-called “germline mutations” or “somatic mutations.” Germline mutations are present within germ cells (sperm or egg) and they are therefore present at conception and can affect every cell in the body of the offspring of an affected parent. Some examples of such diseases are cystic fibrosis, hemophilia, sickle cell disease, etc. In contrast, somatic cell mutations arise at some time after conception in an individual’s life, and they can occur in any cell type where they may cause problems such as cancers. However, because they are not present in the germ cells, they are not transmitted to offspring and they are not inherited from parents. In the case of the MPNs, the mutations happen to arise in blood cell-forming stem cells and cause a blood disease.

There are extremely rare instances in which an MPN seems to run through a family. When documented, these are known as “familial myeloproliferative neoplasms.” So how can this occur? There are now known to be more than 50 different hereditary cancer syndromes, including hereditary predisposition to acute leukemia or myelodysplastic syndromes. The same occurs in MPNs. In these cases, affected individuals harbor one or more germline mutations, which cause a predisposition (increased risk) for also developing somatic mutations (like JAK2, CALR, BCR-ABL) that drive or cause an MPN to develop. Even in the absence of a known family history of MPN, one clue that this might be the case is the occurrence of MPN at an uncharacteristically young age. In our patients who are suspected to have an inherited form of MPN, detailed molecular genetic studies can be performed to assess whether MPN risks may have been inherited.

What is a JAK2 gene mutation?

JAK2 is part of the network that allows cells to communicate with their environment. Certain hormones in the body called cytokines control blood formation by signaling through JAK2. The JAK2 gene mutation is found in nearly all people who have polycythemia vera (PV) and 30-50% of people who have essential thrombocythemia (ET) or myelofibrosis (MF). The JAK2 mutations in MPNs lead to excess blood cell formation. This occurs because the mutated JAK2 sends signals even when it isn’t supposed to do so and this leads to excess blood cell production.  There are now drugs that help block signaling through JAK2 (JAK2-inhibitors). 

What causes polycythemia vera?

Polycythemia vera is caused by acquired mutations in blood forming stem cells. Virtually all polycythemia vera is linked to a particular mutation in a gene called JAK2. JAK2 is like a switch used to turn on production of certain blood cell types and this mutation makes them get stuck in the “ON” position. 

Richard T. Silver MD Myeloproliferative Neoplasms Center 525 East 70th St., Starr Pavillion, 3rd Floor New York, NY 10021