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What to do at Diagnosis
- CBC with differential, complete metabolic panel, including liver function tests
- Peripheral smear, serum LDH, erythropoietin level and iron studies
- JAK2 V617F mutation analysis:
- in those who end up being JAK2V617F negative and have underlying erythrocytosis , consider JAK2 exon12 mutation
- consider an MPL mutation analysis in MPN suspicious patients who lack the JAK2V617F mutation
- Sedimentation rate, C-Reactive protein
Imaging and Pathology
- KUB/ultrasound/ or CT scan to establish any baseline splenomegaly in those individuals with non-palpable splenomegaly
- Bone marrow aspirate & biopsy
- Cytogenetics (20 metaphases)
- Bcr-Abl analysis to exclude chronic myeloid leukemia
- Why is a bone marrow necessary?
- Need baseline to assess morphology for evidence of myeloproliferative histopathology with megakaryocytic and other histologic changes
- Establish baseline degree of reticulin fibrosis
- To exclude other potential causes of reactive myeloproliferation
- Helpful to review entire karyotype as both a baseline and to monitor along with the disease
- Baseline assessment of myeloblasts to be certain there is no movement toward acute leukemia
How to Follow Your Patient
Polycythemia Vera and ET
The goal of therapy with P Vera and ET is primarily to try to decrease the risks of thrombosis and bleeding, and as such, the therapy is aspirin, phlebotomy (in all patients who have erythrocytosis) and normalization of platelets in those individuals with high risk disease (age over 60, prior vascular event, strong cardiovascular risk factors and potentially JAK2V617F mutated ET).
- CBC and differential with complete metabolic panel. CBCs weekly when initiating new myelosuppressive therapy, hydroxyurea, anagrelide, pegylated interferon or JAK2 inhibitor on clinical trial, with decreasing frequency as the counts stabilize. Monitor particularly for liver function tests as these agents can increase liver function tests.
- Bone marrow aspirate and biopsy with cytogenetics (20 metaphases). Typically, repeated every few years in patients with stable disease; in particular for individuals on an agent for which a bone marrow transplant would be considered if they were to progress.
- Consider repeating the bone marrow aspirate/biopsy at time of evidence of disease progression toward myelofibrosis with increasing splenomegaly, worsening symptoms, worsening cytopenias, or increasing peripheral blood blasts.
The goals of Myelofibrosis are more complex than those with PV and ET and basically fall into one of three categories: pure observation, medical therapy to improve the quality of life and perhaps survival of individuals with myelofibrosis and, finally, curative therapy with stem cell transplantation.
- CBC with differential and complete metabolic panel. Again, when initiating a therapy, either to improve anemia, to decrease painful splenomegaly symptoms, or to help palliate the disease, labs likely will begin on a weekly basis and then decrease in frequency depending upon response.
- Spleen measurements. Typically, the spleen can be followed by physical examination, with repeat imaging mainly for those individuals on clinical trials.
- Bone marrow aspirate and biopsy with cytogenetics. The importance of following bone marrow aspirate with cytogenetics at this point is most relevant for those individuals in which progression of the disease would lead to the decision to initiate stem cell transplantation. In those individuals who are not going to be stem cell transplant candidates, bone biopsies would be performed at the time of evidence of clear disease progression toward acute leukemia or to monitor experimental therapies. Current medical therapies have had very limited impact on the fibrotic histology of myelofibrosis.
Therapeutic Management Pearls
ET and PV
Patients can be quite symptomatic from increased blood counts well short of them having had a vascular event or a TIA. Take a thorough history with your patient to look for issues of uncontrolled pruritus, difficulties of concentration, migraines with aura or complex migraines and other peripheral extremity symptoms. These are important for you to be certain that the degree of myelosuppression that has been chosen is appropriate.
- Asymptomatic patients who are low risk and who have platelet counts less than one million may well be able to be managed with an aspirin alone if they are asymptomatic.
- Pegylated interferon is an increasingly utilized therapy for these patients with further validation ongoing in clinical trials. It is important to start this medication at a very low dose and be very patient with its efficacy, typically starting patients at 45 micrograms weekly with a goal dose of 90 micrograms weekly. There are individuals who will not be able to have their myeloproliferation fully controlled by pegylated interferon alpha alone and the addition of chemotherapy with hydroxyurea is reasonable.
- If myelosuppressive therapy is chosen it is important to try to keep the platelet count well under 400,000 if tolerated.
- Anagrelide could be a helpful medicine as an adjunct or as a solitary agent for controlling the platelet count in appropriate settings, but being very mindful of palpitations as well as GI symptoms and headache.
- Hydroxyurea’s main toxicity, in addition to excess myelosuppression, can be skin-related issues and close observation for non-healing leg ulcers, cutaneous malignancies, and other difficulties need to be followed.
The single most important discussion that you have with your patient who has myelofibrosis is to determine the goals of their therapy. If they are on a curative therapy path and wish to pursue an aggressive route with stem cell transplant or if they are on a medical therapy path without plans for SCT, be sure to establish the goal of that therapy so that you are both in accordance. Is it to improve their anemia; is it to improve splenomegaly; is it to improve symptoms; or is it trying to improve all three areas or some other goal?
- Ruxolitinib is helpful for the constitutional symptoms of myelofibrosis, probably across the board, from low risk to high risk patients.
- The benefits symptomatically for MF patients are relevant whether the patient has a large spleen or not or whether the patient has already been splenectomized, and whether the patient has the JAK2 mutation or not.
- Lower doses of ruxolitinib have been successfully used in individuals with a platelet count of less than 100,000, but need to be done with caution, close observation of the platelet count, and likely starting at a low dose and increasing the dose as the patient tolerates.
- Hydroxyurea as a therapy for myelofibrosis is very modest in terms of efficacy. It is helpful for controlling thrombocytosis, but its efficacy for controlling symptoms, splenomegaly, or improving cytopenias is marginal at best.
- Therapy of anemia in myelofibrosis clearly requires a somewhat different approach, utilizing IMiDs, androgens or, in people with low EPO levels, erythropoietin. Almost all anemia responses with medications will tend to occur within three months.
- A not insignificant number of patients with myelofibrosis can have myelodysplastic-like features with increasing blasts, dysplasia, pancytopenias, and even a lack of significant splenomegaly. With these individuals it is important to still consider agents useful in patients with MDS as these patients might have some degree of overlap. Agents such as azacytidine, decitabine, and lenalidomide are all reasonable considerations.
Stem Cell Transplant
The timing of transplant continues to be a challenge. We clearly can do it too early in individuals who have a long life expectancy, but we can clearly wait too long and have potential SCT candidates deteriorate and then do poorly with transplant. Involving a transplant early on in the discussion with the patient and their support team is important. My rule of thumb is that individuals who are reasonable transplant candidates and who have a life expectancy of less than five years certainly should receive a very thorough discussion regarding consideration of a stem cell transplant.
At this point in time it is not clear that monitoring the level of the allele burden in a patient with a JAK2V617F mutation is clinically meaningful. That may change in the future. There are multiple other mutations which have been identified and these fall in the same category of being interesting, but it remains unclear what the best molecular monitoring approach is for these patients.