Myelofibrosis
I. What every physician needs to know.
Myelofibrosis is a disorder of the bone marrow, in which the marrow is replaced by scar (fibrous) tissue. Other names for the disorder include myeloid metaplasia, chronic idiopathic myelofibrosis, osteomyelofibrosis, and primary myelofibrosis (PMF).
In general, myelofibrosis is a myeloproliferative disease in which the proliferation of an abnormal type of bone marrow stem cell results in fibrosis or the replacement of the bone marrow with collagenous tissue. As a result, the extensive scarring of the bone marrow leads to impairment of the bone marrow to produce blood cells, leading to severe anemia, weakness, fatigue, and usually hepatosplenomegaly. Myelofibrosis is a type of chronic leukemia. It can occur on its own (primary myelofibrosis), or it can occur as a result of another bone marrow (secondary myelofibrosis).
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In addition to PMF, the term myelofibrosis also includes essential thrombocythemia and polycythemia vera. Both of these may transform into a fibrotic state called post essential thrombocythemia myelofibrosis (PETM) or post polycythemia vera myelofibrosis (PPVM). The conversion rates after 10-20 years of the disease are less than 5% for essential thrombocythemia and 10-20% for polycythemia vera. PMF, PETM, PPVM are all referred to as myelofibrosis.
This chapter will focus primarily on primary myelofibrosis.
II. Diagnostic Confirmation: Are you sure your patient has Myelofibrosis?
Complete blood count (CBC), a peripheral blood smear and a bone marrow biopsy as well as cytogenetic testing are essential to make the diagnosis. Anemia is typically apparent on the CBC and worsens over time.
Blood cell morphology is variable. Red blood cells (RBCs) are poikilocytic. Reticulocytosis and polychromatophilia may be present. Morphological features are noted in the form of teardrop shaped RBCs which are also called dacrocytes. Nucleated RBCs and neutrophil precursors are typically present in the peripheral blood.
White blood cell (WBC) are usually elevated but they can be low; a low WBC usually indicates a poor prognosis.
Neutrophils are immature and myeloblasts may be present even in the absence of acute leukemia. Platelets may be high, normal or decreased. Thrombocytopenia is also present and the platelet count drops as the disease progresses.
Bone marrow aspiration is usually dry. Because demonstration of bone marrow fibrosis is required and fibrosis may not be uniform throughout the bone marrow, biopsy should be repeated at two different sites if the first is nondiagnostic. Bone marrow biopsy will typically demonstrate extensive fibrosis.
Cluster of Differentia 34+ (CD34+) cell count on peripheral blood can be done to help confirm the diagnosis as levels are much higher in those with PMF. Additionally, increased CD34+ counts correlate with increased disease severity.
The World Health Organization (WHO) criteria for diagnosis of PMF was revised in 2016 to include novel molecular findings and clarification of minor criteria for diagnosis of PMF.
A. History Part I: Pattern Recognition:
In most patients myelofibrosis is asymptomatic.
Some patients may have symptoms of anemia and/or hepatosplenomegaly such as fatigue. In the late presentation they may have general malaise, weight loss, fever (B symptoms as seen in lymphomas) and splenic infarction. If hepatomegaly occurs, patients might also have variceal bleeding related to portal hypertension or ascites.
B. History Part 2: Prevalence:
The peak incidence of primary myelofibrosis (PMF) is between 50-70 years of age.
PMF is more common than secondary myelofibrosis and it results from neoplastic transformation of a multipotent bone marrow stem cell. These PMF progeny can stimulate bone marrow fibroblasts to secrete excessive collagen.
Secondary myelofibrosis (SMF) can occur as a result of many hematologic, malignant and nonmalignant conditions.
Malignant myelofibrosis or acute myelofibrosis is an unusual variant and it has a more rapidly progressive course; this variant may be a true megakaryocytic leukemia.
C. History Part 3: Competing diagnoses that can mimic Myelofibrosis.
PMF requires exclusion of other conditions that can cause myelofibrosis as a secondary cause.
Conditions associated with secondary myelofibrosis:
Cancer
Cancer with bone marrow involvement/metastases
Leukemia (particularly Chronic Myelocytic and Hairy Cell Leukemia)
Multiple Myeloma
Non-Hodgkin Lymphoma
Polycythemia vera
Infections
Osteomyelitis
Tuberculosis
Primary Pulmonary Hypertension
Toxins
Benzene
Thorium dioxide
Nuclear radiation exposure
Autoimmune Disorders
System lupus erythematosus (SLE)
Systemic Sclerosis
D. Physical Examination Findings.
Splenomegaly and/or hepatomegaly and signs of portal hypertension are the most common physical exam findings as are stigmata of anemia such as pallor, pale conjunctiva, and poor capillary refill.
E. What diagnostic tests should be performed?
There are no specific physical exam findings that confirm the diagnosis.
1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
As described in diagnostic confirmation.
2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
There are no specific imaging studies that confirm the diagnosis. However, a computed tomography (CT) scan of the abdomen and pelvis with and without contrast would help to confirm the presence of an enlarged liver or spleen.
F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.
NA
III. Default Management.
Treatment is directed at management and supportive care. There is no cure for PMF.
Androgens, splenectomy, chemotherapy and splenic embolization and radiation therapy have been used merely for palliation.
A. Immediate management.
For patients with low erythropoietin levels relative to the degree of anemia, erythropoietin may increase hemoglobin sufficiently – otherwise red blood cell transfusion is necessary.
B. Physical Examination Tips to Guide Management.
Patients will have signs of anemia such as pallor, pale conjunctive, poor capillary refill and hair loss. They may also have low grade fever, night sweats and weight loss. During their clinical course as patients progress, they may have marked splenomegaly.
C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.
The International Working Group for Myelofibrosis Research and Treatment has devised a treatment response criteria based on splenic size, hemoglobin level, white blood cell count, platelet count, peripheral blood smear and bone marrow histology.
D. Long-term management.
Treatment is aimed at supportive care.
For younger patients with advanced disease, allogeneic hematopoietic stem cell transplantation should be considered. Nonmyeloablative allogeneic stem cell transplantation has been successfully used even in some older patients although it is usually limited to those younger than 65 years of age.
While there is no current curative drug therapy, there are multiple modalities used for disease control and symptom management. Inhibitors of the JAK pathway appear to have a significant effect on splenomegaly and abnormal peripheral hematologic abnormalities. Two studies have shown that a low burden of the JAK2V617F allele in PMF might indicate the presence of an overriding V617F-negative clone that confers a more aggressive disease phenotype with shortened overall survival, although the biological mechanisms are not clearly understood.
Palliative modalities include androgenic drugs for anemia, hydroxyurea for splenomegaly, radiation therapy for foci of extramedullary hematopoiesis, thalidomide with prednisone for anemia and lenalidomide for those with the presence of del (5q).
Splenectomy has been used as a last resort and palliative means for the pain and presence of an enlarged spleen and/or thrombocytopenia.
E. Common Pitfalls and Side-Effects of Management.
Some patients may become refractory to supportive RBC and platelet transfusion leading to bleeding complications.
IV. Management with Co-Morbidities.
There are no specific changes in the management of PMF with respect to co-morbidities.
A. Renal Insufficiency.
No change in standard management.
B. Liver Insufficiency.
No change in standard management.
C. Systolic and Diastolic Heart Failure.
No change in standard management.
D. Coronary Artery Disease or Peripheral Vascular Disease.
No change in standard management.
E. Diabetes or other Endocrine issues.
No change in standard management.
F. Malignancy.
If a type of cancer is the underlying cause leading to secondary myelofibrosis then the underlying primary cancer diagnosis is treated first and foremost.
G. Immunosuppression (HIV, chronic steroids, etc).
No change in standard management.
H. Primary Lung Disease (COPD, Asthma, ILD).
No change in standard management.
I. Gastrointestinal or Nutrition Issues.
No change in standard management.
J. Hematologic or Coagulation Issues.
No change in standard management.
K. Dementia or Psychiatric Illness/Treatment.
No change in standard management.
V. Transitions of Care.
A. Sign-out considerations While Hospitalized.
If a patient has signs of portal hypertension, gastrointestinal bleeding is always a concern especially from varices.
B. Anticipated Length of Stay.
There is no specific anticipated length of stay. Once the diagnosis of myelofibrosis is made, most supportive therapy can be managed as an outpatient.
C. When is the Patient Ready for Discharge.
There is no specific criteria for discharge other than making sure the patient has a hemoglobin greater than 8 grams/deciliter (g/dl) and platelet count >10,000 cells/microliter minimizing risk of bleeding.
D. Arranging for Clinic Follow-up.
1. When should clinic follow up be arranged and with whom.
Hematology-Oncology within 1-2 weeks of discharge after initial diagnosis should be arranged.
2. What tests should be conducted prior to discharge to enable best clinic first visit.
None
3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.
A CBC might be useful prior to the patient’s first clinic appointment in order to see if transfusion of blood or platelets might be required.
E. Placement Considerations.
There are no specific placement considerations except as the disease progresses, when hospice services or even inpatient hospice might be considered.
F. Prognosis and Patient Counseling.
The median survival is 5 years from onset of diagnosis. Some studies have reported that 3 year survival rates may be as low as 52%. Some patients have a very rapidly progressive disease course with short survival and some may have a delay in diagnosis. As the disease progresses palliative measures should be discussed with the patient and hospice considered.
A number of prognostic models have been proposed for assessing prognosis in PMF. The most widely accepted is that proposed by the International Working Group Scoring System which looks at initial presenting signs and symptoms (called the IPSS) and then is modified by taking into account the adverse effect of acquisition of risk factors as the patients disease course progresses (called the Dynamic IPSS).There is also the IPSS-independent prognostic factor scoring system which takes into account unfavorable karyotype. There are two new prognostic models MIPSS (mutation-enhanced international prognostic scoring system) and GPSS (genetics-based prognostic system) which take into account specific mutations and genetic predisposition.
VI. Patient Safety and Quality Measures.
A. Core Indicator Standards and Documentation.
There are no Joint Commission Core indicators that are referable to this disease.
B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.
Readmission to the hospital can be prevented in those patients with thrombocytopenia if bleeding complications are minimized by keeping platelets above 10,000 cells/microliter.
Symptoms related to shortness of breath secondary to anemia which often leading to admission and emergency room visits can be minimized by frequent blood draws and transfusions to keep the hemoglobin greater than 10g/dl, particularly in older patients.
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