https://jitc.bmj.com/content/jitc/10/4/e002838.full.pdf , JAK inhibitors and COVID-19: Consider Linkage to PMF

Primary myelofibrosis (PMF) is a rare bone marrow blood cancer.^[1] It is classified by the World Health Organization (WHO) as a type of myeloproliferative neoplasm, a group of cancers in which there is activation and growth of mutated cells in the bone marrow. This is most often associated with a somatic mutation in the JAK2, CALR, or MPL genes. In PMF, the bony aspects of bone marrow are remodeled in a process called osteosclerosis; in addition, fibroblasts secrete collagen and reticulin proteins that are collectively referred to as fibrosis. These two pathological processes compromise the normal function of bone marrow resulting in decreased production of blood cells such as erythrocytes (red cells), granulocytes and megakaryocytes, the latter cells responsible for the production of platelets.

Signs and symptoms include fever, night sweats, bone pain, fatigue, and abdominal pain. Increased infections, bleeding and an enlarged spleen (splenomegaly) are also hallmarks of the disease. Patients with myelofibrosis have an increased risk of acute meyloid leukemia and frank bone marrow failure.

In 2016, prefibrotic primary myelofibrosis was formally classified as a distinct condition that progresses to overt PMF in many patients, the primary diagnostic difference being the grade of fibrosis.^[2]

Signs and symptoms

The primary feature of primary myelofibrosis is bone marrow fibrosis,^[3] but it is often accompanied by:

• Abdominal fullness related to an enlarged spleen (splenomegaly).
• Enlargement of both the liver and spleen
  • Splenomegaly due to extramedullary hematopoiesis (hematopoiesis occurring outside of the bone marrow)
• Bone pain
• Bruising and easy bleeding due to inadequate numbers of platelets
• Increased risk of thrombosis
• Cachexia (loss of appetite, weight loss, and fatigue)
• Fatigue
• Fevers
• Chills
• Weight loss
• Gout and high uric acid levels
• Increased susceptibility to infection, such as pneumonia
• Pallor and shortness of breath due to anemia
• Leukoerythroblastic smear (tear-drop RBCs, nucleated RBCs, and immature granulocytes)
• In rarer cases, a raised red blood cell volume
• Cutaneous myelofibrosis is a rare skin condition characterized by dermal and subcutaneous nodules.^[4]: 746

Causes

The underlying cause of PMF is almost always related to an acquired mutation in JAK2, CALR or MPL in a hematopoietic stem/progenitor cell in the bone marrow.^[5] There is an association between mutations to the JAK2, CALR, or MPL genes and myelofibrosis.^[6] Approximately 90% of those with myelofibrosis have one of these mutations; 10% do not have mutations in these three genes. These mutations are not specific to myelofibrosis, but are observed in other myeloproliferative neoplasms, specifically polycythemia vera and essential thrombocythemia.^[3]

The JAK2 protein is mutated giving risk to a variant protein with an amino acid substitution commonly referred to as V617F; the mutation causing this variant is found in approximately half of individuals with primary myelofibrosis.^[7] The V617F substitution is an amino acid change of valine to phenylalanine at the 617 position in the JAK2 protein. Janus kinases (JAKs) are non-receptor tyrosine kinase part of the signaling pathway activated by receptors that recognize cytokines and growth factors. These include receptors for erythropoietin, thrombopoietin, most interleukins and interferon.^[7] JAK2 mutations play a significant role in the pathogenesis of all the myeloproliferative neoplasms because the recognized mutations all cause constitutive activation of the pathway controlling the production of blood cells arising from hematopoietic stem cells. The V617F subsustition also renders hematopoietic cells more sensitive to growth factors that use JAK2 for signal transduction, which include erythropoietin and thrombopoietin.^[8]

The MPL gene codes for a protein that acts as a receptor for thrombopoietin, a growth factor that enhances production of platelets. A mutation in that gene, resulting in the substitution W515L, results in thrombopoietin receptor that is constitutively active even in the absence of thrompoietin. Abnormal megakaryocytes redominate in the bone marrow and platelet production is enhanced. The mutant megakaryocytes also release growth factors that stimulate other cells in the bone marrow including fibroblasts, the cells that are stimulated to secrete excess collagen,^[9] by secreting PDGF and TGF-β1.^[10]

Mechanism

Myelofibrosis is a clonal neoplastic disorder of hematopoiesis, the formation of blood cellular components. It is one of the myeloproliferative disorders, diseases of the bone marrow in which excess cells are produced at some stage. Production of cytokines such as fibroblast growth factor by the abnormal hematopoietic cell clone (particularly by megakaryocytes)^[11] leads to replacement of the hematopoietic tissue of the bone marrow by connective tissue via collagen fibrosis. The decrease in hematopoietic tissue impairs the patient’s ability to generate new blood cells, resulting in progressive pancytopenia, a shortage of all blood cell types. However, the proliferation of fibroblasts and deposition of collagen is a secondary phenomenon, and the fibroblasts themselves are not part of the abnormal cell clone.^{[citation needed]}

In primary myelofibrosis, progressive scarring, or fibrosis, of the bone marrow occurs, for the reasons outlined above. The result is extramedullary hematopoiesis, i.e. blood cell formation occurring in sites other than the bone marrow, as the hemopoietic cells are forced to migrate to other areas, particularly the liver and spleen. This causes an enlargement of these organs. In the liver, the abnormal size is called hepatomegaly. Enlargement of the spleen is called splenomegaly, which also contributes to causing pancytopenia, particularly thrombocytopenia and anemia. Another complication of extramedullary hematopoiesis is poikilocytosis, or the presence of abnormally shaped red blood cells.^{[citation needed]}

Myelofibrosis can be a late complication of other myeloproliferative disorders, such as polycythemia vera, and less commonly, essential thrombocythemia. In these cases, myelofibrosis occurs as a result of somatic evolution of the abnormal hematopoietic stem cell clone that caused the original disorder. In some cases, the development of myelofibrosis following these disorders may be accelerated by the oral chemotherapy drug hydroxyurea.^[12]

Sites of hematopoiesis

The principal site of extramedullary hematopoiesis in myelofibrosis is the spleen, which is usually markedly enlarged, sometimes weighing as much as 4000 g. As a result of massive enlargement of the spleen, multiple subcapsular infarcts often occur in the spleen, meaning that due to interrupted oxygen supply to the spleen partial or complete tissue death happens. On the cellular level, the spleen contains red blood cell precursors, granulocyte precursors and megakaryocytes, with the megakaryocytes prominent in their number and in their bizarre shapes. Megakaryocytes are believed to be involved in causing the secondary fibrosis seen in this condition, as discussed under “Mechanism” above. Sometimes unusual activity of the red blood cells, white blood cells, or platelets is seen. The liver is often moderately enlarged, with foci of extramedullary hematopoiesis. Microscopically, lymph nodes also contain foci of hematopoiesis, but these are insufficient to cause enlargement.^{[citation needed]}

There are also reports of hematopoiesis taking place in the lungs. These cases are associated with hypertension in the pulmonary arteries.^[13]

The bone marrow in a typical case is hypercellular and diffusely fibrotic. Both early and late in disease, megakaryocytes are often prominent and are usually dysplastic.^{[citation needed]}

Diagnosis

Epidemiologically, the disorder usually develops slowly and is mainly observed in people over the age of 50.^[14]

Diagnosis is made on the basis of bone marrow biopsy. Fibrosis grade 2 or 3 defines overt PMF whereas grade 0 or 1 defines prefibrotic primary myelofibrosis.^{[citation needed]}

A physical exam of the abdomen may reveal enlargement of the spleen, the liver, or both.^[3] Bone marrow biopsy shows fibrosis of the bone marrow. In early stages, this fibrosis is characterised by scattered linear reticulin fibers.

Treatment

The one known curative treatment is allogeneic stem cell transplantation, but this approach involves significant risks.^[15] Other treatment options are largely supportive, and do not alter the course of the disorder (with the possible exception of ruxolitinib, as discussed below).^[16] These options may include regular folic acid,^[17] allopurinol^[18] or blood transfusions.^[19] Dexamethasone, alpha-interferon and hydroxyurea (also known as hydroxycarbamide) may play a role.^[20][21][22]

Lenalidomide and thalidomide may be used in its treatment, though peripheral neuropathy is a common troublesome side-effect.^[22]

Splenectomy is sometimes considered as a treatment option for patients with myelofibrosis in whom massive splenomegaly is contributing to anaemia because of hypersplenism, particularly if they have a heavy requirement for blood transfusions. However, splenectomy in the presence of massive splenomegaly is a high-risk procedure, with a mortality risk as high as 3% in some studies.^[23]

In November 2011, the US Food and Drug Administration (FDA) approved ruxolitinib (Jakafi) as a treatment for intermediate or high-risk myelofibrosis.^[24][25] Ruxolitinib serves as an inhibitor of JAK 1 and 2. Data from two phase III studies of ruxolitinib showed that the treatment significantly reduced spleen volume, improved symptoms of myelofibrosis, and was associated with much improved overall survival rates compared to placebo.^[26][27] However, the beneficial effect of ruxolitinib on survival has been recently questioned.^[28]

In August 2019, the FDA approved fedratinib (Inrebic) as a treatment for adults with intermediate-2 or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis (MF).^[29]

In March 2022, the FDA approved pacritinib (Vonjo) with an indication to treat adults who have intermediate or high-risk primary or secondary myelofibrosis and who have platelet (blood clotting cells) levels below 50,000/μL.^[30]

Momelotinib (Ojjaara) was approved for medical use in the United States in September 2023.^[31] It is indicated for the treatment of intermediate or high-risk myelofibrosis, including primary myelofibrosis or secondary myelofibrosis [post-polycythemia vera and post-essential thrombocythemia], in adults with anemia.^[31][32]

History

Myelofibrosis was first described in 1879 by Gustav Heuck.^[33][34] Eponyms for the disease are Heuck-Assmann disease or Assmann’s Disease, for Herbert Assmann,^[35] who published a description under the term “osteosclerosis” in 1907.^[36]

It was characterised as a myeloproliferative condition in 1951 by William Dameshek.^[37][38]

The disease was also known as myelofibrosis with myeloid metaplasia and agnogenic myeloid metaplasia^[39] The World Health Organization utilized the name chronic idiopathic myelofibrosis until 2008, when it adopted the name of primary myelofibrosis.

In 2016, the WHO revised their classification of myeloproliferative neoplasms to define Prefibrotic primary myelofibrosis as a distinct clinical entity from overt PMF.^[2]

Prognosis and Life Expectancy of Myelofibrosis

• Pain management
• Treatment side effects
• Life expectancy
• Coping
• FAQs
• Takeaway

Life expectancy for myelofibrosis varies based on age, blood cell counts, and symptoms. Some experience rapid progression, while others may live longer without symptoms. Treatment can help extend your life span.

Myelofibrosis (MF) is a type of bone marrow cancer. This condition affects how your body produces blood cells. MF is a progressive disease that affects each person differently.

Read on to learn more about MF, including the factors that may affect the outlook for this disease.

Managing the pain that accompanies MF

Some people may go years without experiencing symptoms of MF, while others may experience symptoms earlier.

One of the most common symptoms of MF is pain. Causes vary and can include:

• gout, which can lead to bone and joint pain
• anemia, which also results in fatigue
• a side effect of treatment

If you’re in a lot of pain, talk with a doctor about medications or other ways to manage it.

You may be able to reduce pain at home with:

• light exercise
• stretching
• getting enough rest

Side effects of treatment for MF

Treatment side effects depend on many different factors. Not everyone will have the same side effects. Reactions depend on variables such as your age, treatment, and medication dosage. Your side effects may also relate to other health conditions you have or have had.

Some of the most common treatment side effects include:

• nausea
• dizziness
• pain or tingling in the hands and feet
• fatigue
• shortness of breath
• fever
• temporary hair loss

Side effects usually go away after your treatment is completed. If you’re concerned about your side effects or have trouble managing them, talk with your doctor or another member of your care team about other options.

If a hematologist-oncologist, a doctor specializing in diagnosing and treating blood cancers determines that you are low risk and if you do not have symptoms, you may not require treatment until symptoms develop.

Outlook for MF

Predicting the outlook for MF is difficult and depends on many factors.

Although a staging system is used to measure the severity of many other types of cancer, there’s no staging system for MF.

However, doctors and researchers have identified some factors that can help predict a person’s outlook with MF. These factors are used in the International Prognosis Scoring System (IPSS) to help doctors predict average years of survival.

“Myelofibrosis management has come a long way in the last 10 years. The list of effective myelofibrosis drugs is growing. These medications help patients live longer with fewer symptoms and better quality of life.”

— Ivy Altomare, MD

It’s important to note that these survival estimates are based on survival averages and currently available treatments. As newer treatments are developed, survival rates may also change.

Meeting one of the factors below means the average survival rate is about six years. Meeting three or more can lower the expected survival rate to around one and almost three years. These factors include:

• being over age 65
• experiencing symptoms that affect your entire body, such as fever, fatigue, and weight loss
• having anemia, or a low red blood cell count
• having an abnormally high white blood cell count
• having circulating blood blasts (immature white blood cells) greater than 1 percent
• needing a transfusion
• having a specific chromosomal abnormality

A doctor may also consider genetic abnormalities of the blood cells to help determine your outlook.

People who don’t meet the above criteria, excluding age, are considered in the low risk category and have a median survival of over 15 years.

A 2022 study that examined the effect of treatment on MF also found that treating with Janus Kinase (JAK) inhibitors led to a median overall survival of 84 monthsTrusted Source, which is an improvement from about 64 months a decade ago.

Coping strategies

MF is a chronic, life-altering disease. Coping with the diagnosis and treatment can be difficult, but your doctor and healthcare team can help. Communicating with them openly can help you feel comfortable with the care you’re receiving and recommend additional support, such as therapy or support groups. If you have questions or concerns, consider writing them down as you think of them so you can discuss them with your doctors and nurses.

Being diagnosed with a progressive disease like MF can also create additional stress on your mind and body. Make sure to take care of yourself. Eating right and getting mild exercise like walking, swimming, or yoga will help give you energy. It can also help take your mind off the stress involved in having MF.

Remember that it’s OK to seek support during your journey. Talking with your family and friends can help you feel less isolated and more supported. It will also help your friends and family learn how to support you. If you need their help with daily tasks like housework, cooking, or transportation — or to even listen to you — it’s all right to ask.

Sometimes you may not want to share everything with your friends or family, and that’s fine too. Many local and online support groups can help connect you with others living with MF or similar conditions. These people can relate to what you’re going through and offer advice and encouragement.

If you begin to feel overwhelmed by your diagnosis, consider talking with a trained mental health professional like a counselor or psychologist. They can help you understand and cope with your MF diagnosis on a deeper level.

Frequently asked questions

The following includes common questions about myelofibrosis.

What is the end stage of myelofibrosis?

Myelofibrosis, unlike other types of cancer, does not use a staging system. Instead, it uses risk categories to estimate average survival rates.

About 10-20% of MF cases develop into acute myeloid leukemia (AML), which is challenging to treat and associated with a poor outcome.

What is the life expectancy of a person of someone with myelofibrosis?

The life expectancy for a person with myelofibrosis depends on individual risk factors, including age, disease progression, and response to treatment. According to a 2022 study, treatment can add as much as 7 yearsTrusted Source to a person’s lifespan.

Is myelofibrosis a critical illness?

MF can progress quickly or slowly depending on genetic factors, age, and disease progression. Symptoms may include fever, fatigue, and changes in blood cell counts. As the disease advances, it causes bone marrow scarring and can lead to serious complications such as blood clots, anemia, and excessive bleeding. In about 20%Trusted Source of cases, MF can progress to AML.

What is the best treatment for myelofibrosis?

The only treatment that can cure MF is a stem cell transplant. However, this procedure comes with many risks, especially for older adults and people with additional health conditions. Otherwise, medications are available to manage the symptoms.

Takeaway

A person’s outlook with myelofibrosis can vary from around 1 year to more than 15 years, depending on individual risk factors and disease progression.

Some people may go years without developing symptoms, while others may have a more rapid progression.

Treatment may help reduce symptoms, slow disease progression, and improve your quality of life.