Is polycythemia vera or essential thrombocytosis a cancer or it is a non-malignant condition?
MPNs were previously classified as ‘myeloproliferative disorders’ but in 2008 the World Health Organization (WHO) re-classified them as blood cancers called ‘myeloproliferative neoplasms’. However, MPNs are often slowly progressing diseases and can remain stable for many years. People with MPNs can live with these diseases for years following diagnosis. This means they are different to some other blood cancers which are more quickly progressing such as acute myeloid leukemia (AML).
What causes polycythemia vera (PV)?
Polycythemia vera is a rare blood disease in which a person’s body produces too many red blood cells, white blood cells, and platelets. The cause of PV is not fully understood. Almost everyone with PV has an acquired mutation of the Janus kinase 2 (JAK2) gene; however other unrecognized mutations may exist. The mutation occurs in a bone marrow stem cell, causing uncontrolled production of blood cells, especially red cells.
What causes myelofibrosis (MF)?
The cause of PMF is unknown (idiopathic). Approximately 50% of patients with primary myelofibrosis (PMF) harbor a mutation in JAK2, 25% a mutation in the calreticulin (CALR) gene, and 5-10% mutation in the MPL gene. However, the exact mechanism how mutations in JAK2 or MPL genes cause PMF is unknown.
What causes essential thrombocythemia (ET)?
The exact cause of ET is not known (idiopathic). Similar to primary myelofibrosis, mutations in the JAK2 gene are identified in 50% of patients, calreticulin mutations in 25% of cases and mutation of MPL in 1% of patients with ET.
Does a diagnosis of MPN mean a shorter lifespan?
With proper treatment and precautions, people with polycythemia vera (PV) or essential thrombocythemia (ET) are likely to have a normal lifespan. With myelofibrosis (MF), life expectancy differs with each case and largely depends on the overall health of the patient, how aggressively the disease behaves and how early treatment begins. The survival time ranges widely from 12 months in high-risk disease to more than 15 years in low-risk disease.
I was recently diagnosed with CALR mutation. What does it mean for me?
Mutation in calreticulin (CALR) is the second most common genetic defect (JAK2 is the first) in essential thrombocythemia and myelofibrosis. It is not commonly found in polycythemia vera. CALR mutation is found more frequently in younger patients and is associated with higher platelet count and hemoglobin level. CALR patients with ET have blood clots less frequently; patients with myelofibrosis tend to live longer compared with those with JAK2-positive diseases.
If I have an MPN, are my children and siblings more likely to get it?
Most MPN cases are random – the changes in DNA that drive the development of MPNs are acquired during a person’s lifetime. This means they are not inherited from parents and cannot be passed on to children. However, researchers have found that there is a predisposition towards developing MPN in some families, known as ‘familial MPN’. Individuals in these families have a greater chance of developing MPN than normal.(1)
What can I do to manage MPN in my daily life?
Maintaining a healthy lifestyle is an important first step.
- Get moderate regular exercise, such as walking or swimming, which will decrease your risk of blood clots and improve blood circulation.
- Avoid tobacco and alcohol.
- Keep your skin healthy and use lotion to keep it moist.
- Avoid hottubs, heated whirlpools, hot showers and baths.
- Avoid scratching or damaging your skin, as this can increase the risk of infection.
- Avoid extreme temperatures. In hot weather, protect yourself from direct sunlight and remain well hydrated. In cold weather, wear warm clothing, particularly on your hands and feet.
- Inspect your legs regularly and watch for leg sores. Patients with MPN, and in particular PV, have impaired blood circulation.
What physical activity is advised if I have an enlarged spleen?
Moderate exercise can safely raise your heart rate and improve blood flow to your body. But if you experience pain in the left part of your stomach because of an enlarged spleen, start your exercises at a lower intensity level. Avoid situations where you may be at risk of injury, such as contact sports. If you are injured, particularly in the abdominal area, seek treatment right away and tell the person treating you that you have MPN.
Should I make any changes to my diet?
In general, people with MPN should adopt the same healthy eating habits recommended for everyone. Adopt a lower fat diet with less red meat and less salt, in regular portions with a balance of fruits and vegetables. Use healthy oils like olive, sunflower and canola oil, and reduce animal fats. Stay well hydrated, in particular in warm weather. Avoid refined food, caffeine, alcohol and tobacco.
Should I take vitamin and mineral supplements or other food supplements?
There are no studies suggesting that any herb or nutritional supplement offers therapeutic benefits to people with MPN. Patients with polycythemia vera who undergo phlebotomies should avoid iron supplementation and high amounts of vitamin C. Because of increased risk of blood clots, most hematologists recommend against estrogen-based hormonal contraception or hormone replacement.
Should I see a physiotherapist or naturopathic doctor?
There are no special recommendations about physiotherapy or naturopathic therapy. If you decide to consult physiotherapist, look for a person with experience in caring for people with chronic illness.
Is it safe for me to fly?
Long-distance travel is considered a risk factor for blood clots forming in veins. However, while people with MPN are prone to blood clotting, it is not recommended that patients avoid travel. Avoid alcohol and sleeping pills, and do leg exercises during the flight. You may need graduated compression stockings, preflight aspirin or blood thinners. Discuss these options with your hematologist.
Is it safe for me to get vaccinations, like flu and zoster?
If you have had your spleen removed, you must get vaccinations to prevent future infections. You should avoid live vaccines, but should get the annual flu vaccine. Ask you hematologist for advice.
Where do I find information about novel treatment options for MPN?
Usually, novel drugs are tested in the setting of a clinical trial. Currently, there are several clinical trials open at centres across Canada.. For more information about current clinical trials and where trials are open, please see the clinical trials page http://www.mpncanada.com/treatment-options/clinical-trials/ or contact Canadian MPN Group at firstname.lastname@example.org
Can hydroxyurea cause another cancer?
There is a very low risk of developing skin cancer, or even more rarely leukemia (another blood cancer) due to treatment of polycythemia vera (PV) or essential thrombycothemia (ET) with hydroxyurea.
When cancer does occur in a person who has been treated with hydroxyurea, it is usually many years after starting treatment with the drug. It is important to avoid direct sunlight on the skin at the time of the day when the sun is strongest (between 10 and 2pm). On sunny days we advise “common sense” protection: staying in the shade, wearing sunscreen, sunglasses, hat and long sleeves/pants.
How does phlebotomy work?
Phlebotomy, also known as bloodletting or venesection, is the mainstay of PV treatment. It is used to remove excess iron and maintain low body iron stores. Iron is used by bone marrow stem cells to produce new red blood cells. By reducing the amount of available iron, called iron deficiency, phlebotomy controls excessive red blood cell production.
How can I get in touch with a patient support group?
Does diagnosis of PV require bone marrow aspiration and biopsy?
Bone marrow biopsy may not be required in cases with sustained absolute erythrocytosis: hemoglobin levels >185 g/L in men (hematocrit, 55.5%) or >165 g/L in women (hematocrit, 49.5%) in the presence of the JAK2V617F or JAK2 exon 12 mutation. However, initial myelofibrosis (present in up to 20% of patients) can only be detected by performing a bone marrow biopsy; this finding may predict a more rapid progression to overt myelofibrosis (post-PV MF).(2) (3)
2 Arber DA et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood, 2016; 127(20): 2391-2405
3 Sirhan S et al. Evolving Therapeutic Options for Polycythemia Vera: Perspectives of the Canadian Myeloproliferative Neoplasms Group. Clin Lymphoma Myeloma Leuk. 2015; 15(12):715-27.
Would you advise iron supplementation therapy for a patient with post-PV myelofibrosis who has started on ruxoltinib?
Anemia is a known and predicted side effect of ruxoltinib. For asymptomatic patients with Hb >100 g/L we do not recommend iron replacing therapy. Routine assessment with ferritin level and reticulocyte count pre-therapy is useful. However, if anemia is symptomatic or limits proper application of ruxoltinib, oral iron replacement therapy (iron fumarate, iron gluconate, etc) is advisable.
Would you recommend starting cytoreductive therapy in young, asymptomatic, low-risk PV/ET patients?
Current guidelines recommend starting cytoreduction in low-risk patients who cannot be managed by other modalities. This includes:
- Intolerance to phlebotomy (fatigue, hypotension, symptoms of iron deficiency, poor venous access, etc.);
- Progressively increasing spleen;
- Severe symptoms related to PV/ET (fatigue, early satiety, abdominal discomfort, inactivity, night sweats, itching, bony pain, fever, weight loss, decreased concentration, etc.);
- Severe thrombocytosis (Plt >1500 x 109/L) or progressively increasing WBC.(4)
In young, asymptomatic ET patients we recommend active surveillance with low-dose ASA and vigorous control of cardiovascular risk factors. Note: Current guidelines are consensus-based and mainly target risk of vascular events. Risks of vascular events are not always interchangeable with disease burden.
How should patients on hydroxyurea be managed pre-operatively?
In case of elective surgery, these patients should be referred to a hematologist in advance. In general, hydroxyurea should be continued until the day of surgery, or stopped 24 hours before and then re-started within a week of surgery. Surgical safety/wound healing should be taken into consideration and discussed with the surgery team.
Aspirin should be stopped at least 1 week before elective surgery that involves a high risk of bleeding or in which even minor bleeding could result in life-threatening complications, such as neurosurgery or surgery requiring heparin prophylaxis. The drug can be restarted 24 hours after stopping heparin.
Low-molecular-weight heparin (LMWH) at a prophylactic dose starting 12 hours before surgery is probably indicated in all patients with MPN because of the high thrombotic risk, although there are no prospective studies in this setting.
Finally, these patients must be followed carefully for the paradoxical predisposition to both bleeding and thrombotic perioperative complications.(5)
What is meant by an intolerance or resistance to hydroxyurea in PV?
Resistance to hydroxyurea is defined as:
1. Continuous need for phlebotomy to maintain HCT <45%, in spite of being on HU;
2. Platelet and WBC are not on target (PLT >400 x 109/L and WBC >10 x 109/L)
3. Failure to reduce spleen by >50% or no relief from symptoms of splenomegaly. Note: Assessment should be done after treating patients for more than three months when the patient is at maximum tolerated dose or 2 g/day.(6)
Intolerance to hydroxyurea is defined as:
Development of hematological or non-hematological toxicity when the patient is at the lowest dose of HU to achieve either partial or complete response from PV/ET.
Hematological toxicity is any of the following cytopenias: ANC <1.0 x 109/L; Hemoglobin <100 g/L, platelets <100 x 109/L. Non-hematological side effects include: chronic leg ulcers, GI toxicity (poorly controlled nausea, vomiting, dyspepsia, diarrhea), fever, mucositis, development of skin cancers, and allopecia.(7)
What is the safety difference between regular and long-acting interferons?
Regular IFN is administered subcutaneously daily (starting dose 3 million units). Pegylated IFN is administered weekly (starting dose 45-90 mcg). Peg-IFN appears to be better tolerated (20-25% discontinuation rate compared with 20-40% with regular IFN).
The serious side effects associated with IFN-α use include an increased risk of depression, exacerbation of autoimmune diseases, neuropathy, hypothyroidism, retinitis, and reversible left heart failure. Long-term toxicity data on patients being treated with pegylated IFN-α beyond two years are not available.(8)
8 Kiladjian JJ, et al. Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera. Blood 2008;112:3065-3072; Gugliotta L, et al. PEG Intron Treatment in 90 Patients with Essential Thrombocythemia (ET) Final Report of a Phase II Study. ASH Annual Meeting Abstracts. 2005;106:2600; Gowin K, et al. Experience with pegylated interferon alpha-2a in advanced myeloproliferative neoplasms in an international cohort of 118 patients. Haematologica 2012;97:1570-1573.
What are the updated criteria for polycythemia vera (PV)?
In the 2016 revision to the World Health Organization (WHO) classification of myeloid neoplasms major criterion #1 was updated. New hemoglobin and hematocrit parameters were lowered as following: Hb >165 g/L in men and >160 in women, or hematocrit >49% in men and >48% in women. The utility of bone marrow morphology as a reproducible criterion for the diagnosis of PV is recognized and upgraded from a minor to a major criterion #2: BM biopsy showing hypercellularity for age with trilineage growth (panmyelosis) including prominent erythroid, granulocytic, and megakaryocytic proliferation with pleomorphic, mature megakaryocytes (differences in size). Presence of the JAK2V617F mutation or JAK2 exon 12 mutation is unchanged and is criterion #3.
The WHO 2016 revision for PV has only one minor criterion: Subnormal serum erythropoietin (EPO) level. Previous minor criterion: endogenous erythroid colony formation in vitro is removed.
Diagnosis of PV requires meeting either all 3 major criteria, or the first 2 major criteria and the minor criterion.
Does the use of cytoreductive therapy with hydroxyurea cause secondary cancers?
Hydroxyurea inhibits the synthesis of DNA, but has little or no effect on RNA or protein synthesis. Hydroxyurea may directly damage DNA, however the association of hydroxyurea and secondary malignancies is not proven, except in non-melanoma skin cancer. (9)
Over the past 25 years, substantial experience has accumulated regarding hydroxyurea safety for patients with sickle cell anemia (SCA). Based on tens of thousands of exposure years, hydroxyurea used at therapeutic doses in young patients with SCA does not appear to confer an increased risk of malignancy. There are no confirmed teratogenic effects of hydroxyurea (10) . In 2009, Ballas et al. reported on pregnancy outcomes in patients with sickle-cell disease receiving hydroxyurea during a controlled trial, which failed to show evidence of increased teratogenic risk. (11) A recent pediatric hydroxyurea phase III, multicenter double-blinded placebo-controlled randomized clinical trial (BABY HUG) found that hydroxyurea treatment was not associated with any significant increases in genotoxicity compared to placebo treatment. (12)
9 Best PJ, Petitt RM. Multiple skin cancers associated with hydroxyurea therapy. Mayo Clin Proc. 1998; 73(10):961-963).
10 Agrawal RK, Patel RK. Hydroxyurea in Sickle Cell Disease: Drug Review. Indian J Hematol Blood Transfus. 2014; 30(2):91–96
11 Ballas SK et al. Multicenter study of hydroxyurea in sickle cell anemia. Exposure to hydroxyurea and pregnancy outcomes in patients with sickle cell anemia. J Natl Med Assoc. 2009; 101:1046–1051
12 McGann PT et al. Genotoxicity associated with hydroxyurea exposure in infants with sickle cell anemia: results from the BABY-HUG Phase III Clinical Trial1 (BABY HUG Investigators). Pediatr Blood Cancer. 2012; 59(2):254-257.