Primary myelofibrosisD47.4

Diagnostic criteria according to WHO

Diagnostic criteria of prefibrotic PMF

Main criteria

• Megakaryocytic proliferation and atypia without reticulin fibrosis >grade 1, concomitant age-dependent increased cellularity, granulocytic proliferation, and frequently reduced erythropoiesis.
• WHO criteria for BCR-ABL1+ CML, PV, ET, PMF, MDS or other MPN not met.
• JAK2, MPL or CALR mutation or other clonal marker present or no evidence of low-grade reactive bone marrow fibrosis.

Ancillary criteria

• Anemia
• Palpable splenomegaly
• Leukocytes >11 x 109/l
• Elevated LDH

Diagnostic criteria of PMF

The diagnostic criteria of conventional fibrotic (according to WHO: 'overt fibrotic') PMF have been modified in the WHO classification 2016 compared to the previous version and in particular adapted to the current state of molecular diagnostics.

Main criteria

• Megakaryocytic proliferation and atypia accompanied by reticulin and/or collagen fibrosis grade 2 or 3
• WHO criteria for BCR-ABL1+ CML, PV, ET, PMF, MDS or other MPN not met.
• JAK2, MPL or CALR mutation or other clonal marker present or no evidence of low-grade reactive bone marrow fibrosis.
• JAK2, MPL515 or CALR mutation or other clonal marker present
• or other clonal marker present
• or no evidence of reactive myelofibrosis

Ancillary criteria

• Anemia
• Palpable splenomegaly
• Leukocytes > 11 x 109/l
• Elevated LDH

Diagnostic criteria of post-PV-MF and post-ET-MF (WHO 2017).

The diagnosis of post-polycythaemia vera myelofibrosis (post-PV-MF) or post-essential thrombocythemia myelofibrosis (post-ET-MF) is made according to the 2008 International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) criteria. The diagnosis of post- PV-MF or post-ET-MF usually cannot be distinguished histologically from primary myelofibrosis unless progression bone marrow histologies are available.

Diagnostic criteria for post-PV MF

Required criteria

• Documentation of previous diagnosis of PV according to WHO criteria
• Bone marrow fibrosis grade 2 to 3 (on a scale of 0 to 3)
• Grade 3 to 4 (on a scale of 0 to 4)

Additional criteria (two required)

• Anemia or
• no longer required phlebotomy therapy (without cytoreductive therapy) or
• Leukoerythroblastic blood count
• Increasing splenomegaly (defined as either an increase in an enlarged spleen >5 cm below the left costal arch or newly diagnosed palpable splenomegaly)
• Development of 2 or all 3 of the following constitutional symptoms:
• >10% weight loss in 6 months, night sweats, aetiologically unexplained fever (>37.5 degrees Celsius).

PMF is a rare disease with an annual incidence of 0.5 to 1.5/ 100,000 population/year (Tefferi A (2000)

PMF is a biologically and clinically heterogeneous disease of the hematopoietic stem cell. Pathogenetically significant are various somatic gene mutations (so-called "driver mutations"). These allow the differentiation of several molecular subtypes. The consequence of pathological gene products are constitutively activated signal transduction pathways (e.g. of JAK2), which lead to increased cell proliferation.

The mean age at diagnosis is 65 years. Men are slightly more frequently (65%) affected by the disease. However, familial clustering does occur. Patients with pre-PMF are younger than those with overt PMF, with a median age of 57 years (Guglielmelli P et al. 2017).

In the initial stage, PMF is usually asymptomatic. Not infrequently, splenomegaly (possibly pressure in the left upper abdomen) is the first noticeable symptom. Thromboembolic complications may be present as an initial manifestation before diagnosis or at the time of diagnosis. In the further course, signs of insufficient hematopoiesis (anemia, thrombocytopenia, leukocytopenia, usually associated with LDH elevation) and general symptoms (reduced performance, fever, night sweats, loss of appetite and weight loss) develop due to the increasing fibrosis in the bone marrow and displacement of normal hematopoiesis, as well as impairments due to extramedullary hematopoiesis (splenomegaly, hepatomegaly, bone pain).

As the disease progresses, signs of ineffective hematopoiesis (anemia, thrombocytopenia, leukocytopenia, usually associated with LDH elevation) and general symptoms (decreased performance, fever, night sweats, loss of appetite, and weight loss), as well as impairments due to extramedullary hematopoiesis (splenomegaly, hepatomegaly, bone pain) develop as a result of increasing fibrosis in the bone marrow and displacement of normal hematopoiesis. The most frequent causes of death represented transformation to acute myeloid leukemia (20.1%), cardiovascular disease (12.3%), and infection (10.4%).

In rare cases, cutaneous extramedullary hematopoiesis may also occur with very distinct clinical symptoms.

Physical examination usually reveals splenomegaly, hepatomegaly and anemia in patients. In the early stage, especially in the so-called prefibrotic phase, thrombocythaemia is often present. In the blood smear, especially in advanced stages, an increase of normoblasts and a leftward shift of granulopoiesis to myeloblasts can be seen (so-called leukoerythroblastic blood picture). Poikilocytosis, anisocytosis and dacryocytosis ("teardrop shape") of the erythrocytes can be seen in the blood smear. The absolute and relative reticulocyte count is not or only inadequately increased. In the clinical chemistry findings, elevated uric acid and LDH levels are often present. In some PMF patients, hemolysis underlies the anemia, so that routine determination of hemolysis parameters is useful in these cases.

The bone marrow findings are diagnostically decisive. Bone marrow cytology is usually unproductive (punctio sicca). In bone marrow histology, increased cell density with proliferation of dysplastic and atypically distributed megakaryocytes without significant reticulin fiber proliferation (≤ grade 1), as well as precursors of granulopoiesis and erythropoiesis with left shift and dysplasia are found in the prefibrotic early stage. In cases of conventional ('overt fibrotic') PMF, marked medullary fibrosis (≥ grade 2) is already present at diagnosis. In the course of PMF or in the late stages, a clear fibrosis and osteosclerosis of the bone marrow is always detectable.

The differential diagnosis of PMF includes

• tumor infiltration of the bone marrow with secondary fibrous proliferation
• Bone marrow fibrosis e.g. in autoimmune diseases (collagenoses), tuberculosis of the bone marrow
• "Idiopathic" as a consequence of interstitial myelitis and locally after radiation treatment
• Other myeloproliferative neoplasms
• Systemic mastocytosis
• Hairy cell leukemia
• Myelodysplastic syndromes with fibrosis
• Acute myelofibrosis in acute megakaryocytic leukemia (FAB type M7)

The distinction between PMF, acute myelofibrosis, and myelodysplasia with myelofibrosis can be difficult. However, the distinction is clinically relevant because acute myelofibrosis and myelodysplasia with myelofibrosis are associated with a significantly worse prognosis. Patients with acute myelofibrosis generally have severe constitutional symptoms and pancytopenia without organomegaly. In this case, the clinic is one of the most important factors.

The most frequent causes of death were transformation into acute myeloid leukemia (20.1%), cardiovascular diseases (12.3%) and infections (10.4%) (Hultcrantz M et al.2015). In part, serious clinical problems can be caused by thromboembolic complications, which, as in other myeloproliferative disorders, can manifest in atypically localized ways (e.g. portal and splenic vein thrombosis, Budd Chiari syndrome). The rate of venous thromboembolism is 1.7% per patient/year.

Curative therapy: The only potentially curative therapy is allogeneic stem cell transplantation (alloSCC). However, this is burdened with a not insignificant morbidity and a transplantation-associated mortality of 20 to 30%, and the rate of relapse and treatment failure after 5 years is 29% (Kröger NM et al. (2015. A matching donor is a prerequisite. Curative alloSZT should be given especially to patients in the prognostically unfavorable intermediate risk 2 and high risk stages according to the IPSS or DIPSS score, if they are in a transplantable state and have a biological age up to ~ 70 years.

AlloSZT is performed with either a family donor or an unrelated donor. Typically, what is known as dose-reduced conditioning is now used, which can achieve the best results. However, the results of transplantation in an acceleration or blast phase are poor, so that in these patients alloSZT should be performed before reaching these phases, if possible. In a paper published in the EBMT, the following results were obtained in 103 PMF patients (median age 55 years, (32-68 years)) with dose-reduced conditioning with fludarabine and busulfan (Kröger N et al. (2009): acute GvHD grade II-IV occurred in 27% of patients, chronic GvHD was observed in 43% of patients. In new studies of alloSZT, JAK inhibitors, such as ruxolitinib, are used before transplantation to reduce the size of the spleen and improve MF-related symptoms and thus general condition before transplantation.

Palliative / symptomatic therapy

Ruxolitinib: Since 2012, the oral JAK1/2 inhibitor ruxolitinib is the first approved, effective and well-tolerated drug therapy with a tyrosine kinase inhibitor for the treatment of primary myelofibrosis (PMF) or post-PV/post-ET myelofibrosis. Ruxolitinib positively affects splenomegaly and disease-associated symptoms in particular. A significant life-prolonging effect has been demonstrated for ruxolitinib (Harrison C et al. 2012). The use of ruxolitinib is indicated for disease-related symptomatic splenomegaly or symptomatology in adults with primary myelofibrosis (PMF), post-PV-MF and post-ET-MF. Therapeutic regimen for ruxolitinib (dosing is primarily based on platelet count):

• (a) >200 x 109/l platelets: 2 x 20mg/day.
• b) 100-200 x 109/l platelets 2 x 15mg/day
• c) 50-100 x 109/l platelets 2 x 5mg/day and possibly increase slowly in 5 mg steps to 2 x 10mg/day
• d) Discontinue ruxolitinib below 50 x 109/l platelets or give only under close monitoring.

In the course, the dose is adjusted to the effect and the side effects. In the case of clear anaemia, possibly already requiring transfusion, it has become established in clinical practice that a lower dose is started, which is adjusted in the course of therapy. The duration of therapy with ruxolitinib is not limited. Patients usually respond within the first 12 weeks of treatment.

Watch and Wait Strategy

Patients with a low-risk or intermediate-risk 1 without clinical problems (no splenomegaly-related symptoms, no constitutional MF-related symptoms) should be assigned to a watch and wait strategy or enrolled in an appropriate trial design because of the relatively good prognosis (Barbui T et al 2018).

Problem-oriented strategies

Hyperproliferation (thrombocytosis, leukocytosis): To control hyperproliferation (thrombocytosis, leukocytosis) with or without splenomegaly, hydroxyurea is primarily used. Hydroxyurea was considered the standard drug therapy for myelofibrosis until the approval of ruxolitinib for the treatment of myelofibrosis, which remains the only approved drug therapy for myelofibrosis (Barbui T et al. (2018). Many observations point to a slowing of progression and, in some cases, a beneficial effect on pre-existing anemia and a temporary improvement in quality of life (Martínez-Trillos A et al. 2011). Hydroxyurea and ruxolitinib have been successfully combined in single trial protocols (Caocci G et al. 2018). Pegylated interferon alpha is also a suitable drug to treat leukocytosis and thrombocytosis in these patients. Randomized trials of this observation are lacking and interferon is not currently approved for the treatment of myeloproliferative neoplasms.

Anemia and/or thrombocytopenia: Corticosteroids are often used successfully to treat anemia requiring therapy, especially in the presence of additional autoimmune hemolysis (low haptoglobin and possibly positive Coombs test) (Martínez-Trillos A et al. 2011) (initial: 0.5 mg prednisolone per kg body weight for 3 weeks, later reduction of dose reduced ; if successful, continuous therapy with small doses below the Cushing threshold .

Erythropoietin treatment: dosage: 3 x 10,000 I.U. per week. A response can be expected in about half of the patients. Complete remissions (no more transfusion dependence and normal Hb value) occur in about 20-25% of cases. A serum erythropoietin level <125 U/l is a prerequisite for a favorable response to erythropoietin.

Androgens (nandrolone) and danazol have been used in single case reports for anemia requiring transfusion (dosage of danazol (gonadotropin inhibitor): 2-3 times 200 mg/day). Efficacy can only be assessed after 2-3 months (Cervantes F etal. (2000).

Splenomegaly: Spleen irradiation or splenectomy should be discussed only if problems arise due to lack of response or side effects of the above-mentioned therapy.

• Splenic irradiation: Splenic irradiation is only a temporary but effective measure for the treatment of splenomegaly (Mesa RA (2009). There is a positive influence on the disease even in the presence of pronounced general symptoms. The average response time after irradiation is a maximum of 6 months. Repeated irradiations are possible during the course, especially if only smaller doses have been used previously. Indications for splenectomy should be considered before starting radiotherapy, as complication rates for splenectomy increase significantly after radiotherapy.
• Splenectomy: This is associated with very high morbidity and mortality as therapy for splenomegaly. The perioperative mortality rate is 7% (perioperative bleeding, infection and thrombosis). There is a significant correlation between the occurrence of perioperative thrombosis and postoperative thrombocytosis. Nevertheless, a palliative benefit of splenectomy, i.e. improvement of general condition and lack of discomfort due to the large spleen, could be proven for 76% of patients after one year (Mesa RA et al. 2006).

Other drugs effective in versch. Studies effective drugs

Pegylated interferon alpha: Improvement in constitutional symptoms or a decrease in splenomegaly was achieved in 82% and 46.5% of patients, respectively. Peg-IFNα-2a works best when the spleen is not too large (< 6cm below costal margin), thrombocytopenia and need for transfusion with red cell concentrates is not too pronounced and an early form of fibrosis is present, thus overall an early form of myelofibrosis (Ianotto JC et al 2018).

Imide: In several phase II trials, thalidomide has been shown to be effective in patients with hematopoietic insufficiency, particularly with respect to anemia or thrombocytopenia (Marchetti M et al 2004). However, the high therapy discontinuation rates are problematic, which are about 50% with a thalidomide dose between 50 and 400/d mg. The main side effect leading to treatment discontinuation with thalidomide is peripheral neuropathy.

mTOR inhibitors: In myelofibrosis, activation of the AKT/mTOR pathway plays a significant pathogenetic role. In a phase I/II study in 39 high-risk or intermediate-risk patients, the mTOR inhibitor everolimus was used (Guglielmelli P et al (2011). Response was evaluated in a total of 30 patients. The most common toxicity at the 10 mg/day dose was grade 1/2 stomatitis. A spleen size reduction of >50% and >30% was found in 20% and 44% of patients, respectively. Complete regression of constitutional symptoms was seen in 69% of patients.

Telomerase inhibitor: The telomerase inhibitor imetelstat achieved complete or partial remission in 7 (21%) in a pilot study of 33 intermediate-2 or high-risk patients with myelofibrosis (Tefferi A et al 2015).

JAK inhibitors and therapeutic combinations: Apart from ruxolitinib, other JAK inhibitors have been evaluated (Griesshammer M et al.2017) . This concerns pacritinib, fedratinib and momelotinib.

New approaches use combination therapy of ruxolitinib with pomalidomide or thalidomide or ruxolitinib with azacytidine.

Experimental is the approach with Sotatercept, an Activin receptor type 2A IgG-Fc fusion protein.

The clinical course of patients with PMF varies. Statements regarding a median survival time are only possible to a limited extent. In non-selected patient collectives, the median life expectancy is 3.5 to 5.5 years. In a study of younger patients (age <55 years), the median survival of 128 months (10.7 years) was reported to be almost twice as high.

In cases of familial clustering of MPN, human genetic counseling is recommended.

Clinical examination (attention to changes in spleen size), blood count including differential blood count and clinical chemistry: intervals depend on the form of therapy and the phase of therapy as well as the individual course of the disease. In the initial phase of therapy short-term, after reaching a stable phase usually control intervals up to a quarter of a year or longer possible.

Follow-up examinations of the bone marrow to detect the rare transitions to acute leukemia, acceleration of PMF or increase in myelofibrosis are performed depending on the individual course. If there is evidence of progression of PMF (increasing anemia or thrombocytopenia, blasts in the peripheral blood, etc.), a follow-up examination of the bone marrow should be considered.

Quantitative progression monitoring of mutated JAK2 allele is currently not routinely recommended, but may be helpful in individual cases when making treatment decisions.

Upper abdominal sonography once a year is recommended.

PMF used to be called "myelofibrosis with myeloid metaplasia" or "agnogenic myeloid metaplasia" in the Anglo-Saxon world. Since the universally accepted WHO classification of 2008, myelofibrosis is now uniformly referred to as primary myelofibrosis (PMF). With the 2016 WHO classification, new prefibrotic myelofibrosis (prePMF) was added as a new subentity.

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