Myelofibrosis & JAK2 Gene Mutations

Myelofibrosis is a long-term blood cancer. Abnormal blood-forming cells build up in the bone marrow and trigger the growth of scar tissue. The marrow slowly loses its ability to make normal blood cells. The spleen and liver take over some of that work, which is why the spleen gets bigger.

It can start on its own, which is called primary myelofibrosis. Or it can develop out of two related conditions, polycythemia vera and essential thrombocythemia. It belongs to a family of diseases called myeloproliferative neoplasms.

Some people have no symptoms for years, and a routine blood count picks it up. Others feel it clearly. Tiredness that sleep does not fix. Drenching night sweats. Mild fevers. Itching. Bone or joint pain. Weight loss they did not plan. Easy bruising. Pain or fullness under the left ribs from the swollen spleen. Feeling full after a few bites of food is a classic symptom, and people often do not mention it.

Three genes account for most cases.

• JAK2, usually the V617F change, is the most common.
• CALR mutations tend to carry a better outlook.
• MPL mutations are the least common of the three.

About one in ten people have none of these. They are described as triple negative, which usually carries a less favorable outlook.

All three changes are picked up during life, in a blood stem cell. You did not inherit them, and you cannot pass them on. Beyond the driver mutation, many centers test a wider panel of genes. Changes in genes such as ASXL1, SRSF2, EZH2, IDH1 and IDH2 add information about outlook, and can shape transplant decisions.

Diagnosis usually involves a complete blood count and a look at the blood cells under the microscope. It also involves a bone marrow biopsy that shows the scarring, chromosome analysis, and molecular testing for the driver and other mutations. The bone marrow biopsy is uncomfortable but brief. It is the test that confirms the diagnosis.

Myelofibrosis varies enormously. Some people live well for many years with little treatment. Others face a disease that moves fast. Risk scoring is how your team sorts this out.

The DIPSS, or Dynamic International Prognostic Scoring System, uses five factors: age over 65, general symptoms such as fever, night sweats and weight loss, hemoglobin below 10 g/dL, a white cell count above 25 x 10^9/L, and immature cells called blasts making up 1 percent or more of blood cells. It sorts people into low, intermediate-1, intermediate-2 and high risk. It can be worked out again over time as things change. DIPSS-Plus adds platelet count, transfusion need and chromosome findings.

Your category is worth asking about. It drives whether treatment aims at controlling symptoms or at moving toward transplant.

Watchful waiting suits people with low-risk disease and no symptoms. Regular monitoring is the treatment here. It is not neglect.

JAK inhibitors are the main drug class. Ruxolitinib was the first. It reliably shrinks the spleen and eases symptoms. Fedratinib is an option after ruxolitinib, or instead of it. Pacritinib is used when platelet counts are low. Momelotinib was approved for myelofibrosis with anemia. None of these cures the disease. Stopping one suddenly can bring symptoms back fast, so make any change with your hematologist.

Treating anemia may involve transfusions, danazol, erythropoiesis-stimulating agents, or picking a JAK inhibitor with anemia in mind. Interferon, hydroxyurea, thalidomide-family drugs and, rarely, removal of the spleen or radiation to the spleen are used in specific situations.

Allogeneic stem cell transplant is the only treatment that can cure myelofibrosis. It replaces your blood-forming system with a donor's. It also carries real risks, including graft-versus-host disease and infection. So it is usually kept for people with intermediate-2 or high-risk disease who are fit enough. Asking for a transplant consultation early is reasonable, even if you expect to say no. It puts real numbers in front of you.

Everyone involved tends to underestimate how heavy the symptoms of myelofibrosis are. Patients do too. Tools like the MPN symptom assessment form give your team a number to track over time. Report itching, sweats, fullness and fatigue plainly. They are part of the disease, and they can be treated.

• Call your treatment team at once if your temperature reaches 100.4°F (38°C) or higher while you are on treatment. NCI warns that infection during cancer treatment can be life threatening and needs urgent medical attention, so this is not something to sit on until the clinic opens. Ring them at any hour, and if you cannot get through, go to an emergency department and say you are on cancer treatment.
• Call 911 or go to an emergency department if speech, balance or thinking change suddenly, or if you stop a JAK inhibitor and then struggle for breath, run a fever, or feel faint and clammy — the label warns symptoms can flare hard after these drugs are withdrawn.
• Call your care team the same day if a painful band of blisters appears on one side of your body. Shingles is a known problem on ruxolitinib.
• Call your care team within a day or two if bruises appear without cause, gums bleed, or the ache under your left ribs sharpens or spreads to your left shoulder. Also mention if a few mouthfuls of food now leave you full.

• DailyMed: JAKAFI (ruxolitinib) prescribing information
• NCI: Infection and Neutropenia during Cancer Treatment
• NCI drug information: ruxolitinib phosphate
• NCI drug information: fedratinib hydrochloride
• FDA Drug Trials Snapshot: OJJAARA (momelotinib)
• DIPSS-Plus prognostic scoring in primary myelofibrosis (JCO)
• NCI: Stem Cell Transplants in Cancer Treatment