Myelofibrosis is a disease in which fibrous tissue replaces hematopoietic cells in bone marrow, which leads to erythrocytes appearance of an abnormal shape in peripheral blood, anemia development and liver and spleen enlargement, and different complications from these organs. As the disease progresses, more and more bone marrow is involved in pathological process. It leads to thrombocytopenia (platelets decrease in number) and hemorrhagic complications, leukopenia (leukocytes decrease in number) and infectious complications. In some patients, the number of leukocytes, on the contrary, increases, and the disease can transform into acute leukemia.
The cause of myelofibrosis is unknown, this pathology occurs infrequently. It can be primary (develops as an independent disease) and secondary (accompanying other diseases, for example, chronic myelogenous leukemia, true polycythemia, thrombocythemia, multiple myeloma and lymphoma). In addition, secondary myelofibrosis can occur in patients with tuberculosis, pulmonary hypertension, systemic lupus erythematosus, systemic sclerosis, and HIV infection, and in case when a malignant tumor of a certain localization spreads to the bones.
Mostly, primary myelofibrosis progresses slowly, so a patient with this diagnosis can live for 10 years or more even without medical intervention (it depends on how well the bone marrow functions). Sometimes the severity of the disease increases sharply, or it transforms into acute leukemia. Treatment is aimed at slowing myelofibrosis progression and preventing complications. Nevertheless, only a hematopoietic stem cells transplantation can cure the disease.
The Maimonides Medical Center works under the patronage “Keren Or for our Child” the Charitable Foundation. Therefore, all our patients who need expensive treatment, but cannot pay for it on their own, can count on help – full or partial payment of diagnostic and treatment process, depending on the situation.
If a patient is diagnosed with primary myelofibrosis, it is very important for him to attend a qualified specialist, because the doctor must assess all the risks, assign the patient to a certain category and determine the tactics – intensive treatment or observation. The forecast completely depends on this.
Such highly qualified specialists work in Maimonides Multidisciplinary Medical Center. Our clinic works in close cooperation with the best Israeli oncology and hematology centers. We chose Israeli medicine as one of the most effective in the world as a model of providing medical services. Each individual case of primary myelofibrosis is managed jointly by the attending hematologist in Ukraine, the head of the department and the responsible oncology hematologist directly from Israel. Thanks to this coordinated work of such a professional team, decisions regarding the management tactics of a patient with myelofibrosis are always made correctly, and the results of treatment are mostly positive.
In their medical activities, our doctors are guided only by modern clinical recommendations and global treatment protocols , so every patient can be sure in quality of medical services provision. But an outstanding feature of Israeli medicine, including our clinic, is an individual approach to each patient, because there are no two identical people and no two identical diseases. Making up an examination and treatment plan, the specialist takes into account not only standard treatment regimens, but also his own experience of using certain treatment methods, the age and gender of the patient, the type of disease, its spread and stage, the presence of serious concomitant pathologies, patient’s wishes regarding treatment, etc. Thanks to this approach, we manage to achieve success even in the most difficult situations.
An important primary myelofibrosis treatment advantage at MC Maimonides is an application of multidisciplinary approach. Help for a patient with a myeloproliferative disease is provided not only by hematologists, but by a whole team of specialized specialists – oncologists, chemotherapists, radiation therapists, surgeons, transplant specialists, hepatologists, rehabilitation specialists, infectious disease specialists, etc.
In our medical institution, only modern and safe medical and diagnostic equipment of expert class is used. If a certain narrow specialist or rare medical and diagnostic equipment is not available, the patient is referred to subsidiary institutions of Maimonides Medical Center or our Israeli partner clinics, where he is guaranteed to receive the full range of necessary medical services.
Primary myelofibrosis causes
Primary myelofibrosis is the result of malignant transformation of bone marrow pluripotent stem cells. These primary myelofibrosis cells stimulate excessive amounts of collagen production by bone marrow fibroblasts (which are not involved in the process of malignant transformation). Most often, primary myelofibrosis occurs between the ages of 50 and 70 and mainly in men. The immediate cause of such changes has not yet been established.
Janus kinase 2 (JAK2) gene mutations are present in most cases of primary myelofibrosis. Thrombopoietin receptor gene (MPL) mutations or calreticulin gene (CALR) can also cause primary myelofibrosis. However, there are rare cases of primary myelofibrosis in which none of these three mutations are present (triple-negative primary myelofibrosis). Some of these patients have other rare MPL gene mutations that can only be detected by next-generation genome sequencing techniques.
In primary myelofibrosis, nucleated erythrocytes (normoblasts) and myelocytes enter the peripheral blood (leucoerythroblastosis) as a result of extramedullary hematopoiesis (that is, due to fibrosis in bone marrow, the function of hematopoiesis is taken over by other organs – most often the spleen and liver). Eventually, bone marrow failure develops, with further development of anemia and thrombocytopenia. Rapidly progressive acute leukemia, which is not amenable to chemotherapy, develops in approximately 30% of patients with primary myelofibrosis.
Malignant myelofibrosis (sometimes called acute myelofibrosis) is a rare form of myelofibrosis characterized by pancytopenia, myeloblastosis, and bone marrow fibrosis that is rapidly progressive and usually complicated by acute megakaryoblastic leukemia.
Primary myelofibrosis symptoms
Primary myelofibrosis is asymptomatic in many patients . Some have signs related to hematopoiesis suppressionin bone marrow and the appearance of extramedullary foci of hematopoiesis in internal organs (most often the liver and spleen).
Common symptoms of myelofibrosis may include:
- Fatigue.
- Night sweats.
- Subfebrile prolonged fever.
- Unmotivated weight loss.
- Feeling of fullness or discomfort in stomach.
- Dysuric phenomena.
- Hematuria – blood in the urine.
- Gastrointestinal bleeding.
- Joint pain and bone pain.
Anemia can occur as a result of ineffective erythropoiesis, erythroid germ cell hypoplasia, and hypersplenism (increased spleen function). Symptoms of anemia are non-specific. Anemia is diagnosed by a general blood test.
Splenomegaly (spleen enlargement) can lead to early satiety during meals and discomfort in the left hypochondrium. Infarcts of spleen , perisplenitis or subcapsular hematoma accompanied by severe abdominal pain may occur. Sometimes patients may have diarrhea associated with increased pressure on the large intestine because of spleen large size.
Diagnosis methods of primary myelofibrosis
As you know, the earlier the disease is diagnosed, the better the prognosis and treatment result. Therefore, high-quality and quick diagnosis is an extremely important stage . Maimonides Clinic uses only modern equipment of an expert class, all our doctors perfectly master all examination methods of a patient primary myelofibrosis suspected, are able to correctly interpret the received data, which helps them to create a modern, individual and effective treatment plan.
The diagnosis of primary myelofibrosis is established on the basis of the following examinations:
- Complete blood count (CBCand peripheral blood smear.
- Bone marrow aspiration and biopsyconfirm ATRT diagnosis with myelogram study and pathohistological examination of tissue samples.
- Research on JAK2, CALR, and MPL gene mutations.
- Peripheral blood fluorescence in situ hybridization (FISH) or reverse transcription-polymerase chain reaction (RT-PCR) for BCR-ABL1.
- Erythropoietin (EPO) level.
- Cytogenetic analysis of bone marrow aspirate for the Philadelphia chromosome.
If this disease is suspected, it is necessary to perform a general blood test and examine formed elements in a peripheral blood smear, and conduct a bone marrow biopsy. Myelofibrosis cfn be present in bone marrow aspirate and biopsy (which can be detected by reticulin staining or by trichrome staining – increased collagen content and osteosclerosis). Also, the specialist should eliminate other diseases accompanied by myelofibrosis.
Primary myelofibrosis diagnosis is confirmed by detection of a JAK2, CALR or MPL mutation. In some cases, none of these mutations are expressed (triple negative myelofibrosis). A modern panel of next-generation sequencing of a wider spectrum allows the detection of gene mutations associated with an increased risk of leukemic transformation and, therefore, can be informative for prognosis.
Molecular genetic tests are used to identify certain types of lymphomas, and in personalized immunotherapy selection (biological, targeted). An example of such modern diagnostics is systems for molecular genetic testing. For example, Foundation One and Caris Molecular Testing.
We send all materials after the biopsy to the world's best pathogistological laboratories (Israel, Germany, USA).Thanks to such double checks, we are absolutely sure of diagnosis correctness and effectiveness of the selected treatment tactics.
Instrumental studies are also used in patients with suspected myelofibrosis. Skeleton radiographs show increased bone density and pronounced bone trabeculae in individuals with primary myelofibrosis. The increased bone density may be focal, resulting in spotting on radiographs.
Magnetic resonance imaging (MRI) can help the clinician assess the severity and progression of primary myelofibrosis. On Ultrasound and computed tomography (CT), liver and spleen increase is observed.
All necessary diagnostic procedures can be performed directly in the clinic, without leaving Ukraine.
Primary Myelofibrosis modern treatment
One of blood diseases treatment important advantages at Maimonides Medical Center is the application of a comprehensive approach to each individual clinical case. Struggling against the disease, our doctor uses the entire available arsenal of methods. Therapy is always a combination of two, three, or even more methods. As a rule, the treatment scheme includes symptomatic therapy, pathogenetic treatment and influence on the cause of anemia. In some cases, certain innovative methods of treatment are added to the treatment program (targeted drugs, immunobiological drugs, hematopoietic stem cell transplantation, etc.).
Treatment is mainly aimed at relieving symptoms and preventing complications. For some patients, observation without treatment is enough.
In early primary myelofibrosis , pegylated interferon has been shown to reduce bone marrow fibrosis and spleen size and can be used in patients at low risk of myelofibrosis transforming into acute leukemia.
Currently, the nonspecific inhibitor of JAK pathway, ruxolitinibis the therapy of choice for progressive primary myelofibrosis treatment. It has a therapeutic effect regardless of JAK2 mutation or splenomegaly presenceThe main side effects of ruxolitinib treatment are anemia and thrombocytopenia. Caution should be exercised stopping ruxolitinib, because withdrawal syndrome may lead to significant worsening of symptoms, partly due to spleen enlargement and inflammatory cytokines restoration in body. A short course of low-dose corticosteroids can be used to control symptoms. With significant splenomegaly, ruxolitinib can cause tumor lysis syndrome.
Fedratinib, also a Janus kinase (JAK-2) inhibitor, can be used for ruxolitinib resistanceor intolerance.
A third JAK-2 inhibitor, pacritinib, is available for patients whose platelet counts are too low to start ruxolitinib therapy.
For patients with advanced disease and at high risk, allogeneic hematopoietic stem cell transplantationmay be effective. Long-term and complete remission can be achieved after bone marrow transplantation. After successful allogeneic transplantation, regression of bone marrow fibrosis occurs.
Before bone marrow transplantation, patient must undergo high-dose chemotherapy chemotherapy is often used to destroy all malignant cells. A feature of this treatment is large doses of drugs, which kill not only all malignant cells, but also healthy bone marrow cells. Therefore, during this period (between chemotherapy, the direct grafting procedure and the time of new bone marrow engraftment), the body becomes completely defenseless against any infection. That is why it is so important to follow all the rules of infection control to minimize the risk of infection, the patient is placed in a sterile box during this period. In our clinic, the patient will be provided with all the necessary conditions for a quick recovery after the procedure.
After treatment, patient undergoes a recovery course in clinic's rehabilitation center under the supervision of high-level rehabilitation specialists. This significantly improves prognosis and reduces long-term side effects from therapy.
A patient with primary myelofibrosis is also prescribed symptomatic and supportive therapy. In the case of refractory splenomegaly (treatment-resistant spleen enlargement), splenectomy (spleen removal) may be indicated. Radiation therapy may be used to treat symptomatic extramedullary hematopoiesis.
One of the drugs currently being explored for myelofibrosis treatment is luspatercept, an activin receptor ligand. For some patients, participating in a clinical trial may be the best treatment option. Clinical trials use new drugs or treatment metods to study their effectiveness. Trials are closely monitored and you can exit them at any time. But they are not suitable for everyone. If you are interested in participating in a clinical trial, talk to your doctor about your options. All our patients have the opportunity to participate in clinical trials of certain treatment types, if they meet the stated criteria.
In each primary myelofibrosis clinical case, decision on the combination of certain treatment methods is made jointly by a team of specialists . Each person and their disease is different, so our doctors, based on their experience in treatment of this pathology, often go beyond the standard protocols, changing treatment regimens and doses of the necessary drugs in order to get the best possible results for their patients.