1. Basic concept of PMF
PMF is a clonal disease originating from bone marrow hematopoietic stem cells, which is reflected in the excessive proliferation of bone marrow fibrous tissue. The main features are anemia, bone marrow often dry draw, biopsy confirmed bone marrow fibrous tissue hyperplasia. Teardrop-like red blood cells are seen in peripheral blood and hepatosplenomegaly is present.
2. PMF etiology and pathogenesis
The etiology is unknown. Radiation, certain contrast agents and industrial solvents (e.g. benzene, toluene) may increase the risk of disease.
The disease can develop in all age groups. It is slightly more common in men than in women, and the median age of onset is 65 years. An age of onset greater than 65 years is an indicator of poor prognosis. Pediatric patients usually occur within 3 years of age.
The median survival time is 3.5-5.5 years. 10-year survival rate is less than 20%.
Twenty percent of patients will convert to acute leukemia (AL) within 10 years.
3. Signs and symptoms of PMF
Major symptoms
25% of patients have no obvious symptoms, only splenomegaly or blood cell abnormalities found on physical examination
Common symptoms: easy fatigue, weakness, dyspnea and palpitations (due to anemia); early satiety, left upper abdominal discomfort (due to splenomegaly); weight loss, night sweats, hypothermia (due to hypermetabolic state)
The presence of systemic symptoms such as weight loss, night sweats, and low fever is one of the indicators of poor prognosis.
Splenomegaly or even giant spleen is the most distinctive feature of PMF
Physical examination.
Giant spleen: firm, smooth, no tenderness
Splenic infarction: significant pressure pain and friction sounds
Other signs.
Hepatomegaly: seen in 60% of patients
Pallor: seen in 60% of patients
Petechiae: seen in 20% of patients
Lymph node enlargement: seen in 20% of patients
Portal hypertension: seen in 10% of patients
4. Routine blood and bone marrow characteristics of PMF
Routine blood and peripheral blood smear
Anemia. Hemoglobin below 10g/dl is one of the indicators of poor prognosis
Teardrop-like red blood cells can be seen on blood smear, which is unique to the disease and has an auxiliary diagnostic value
Leukocytosis in the early stages and leukopenia in the late stages. A leukocyte count above 25 x10/L is one of the indicators of a poor prognosis. Among them, leukocytosis (>30×10/L) has a high risk of conversion to acute leukemia.
Intermediate and late juvenile granulocytes may be seen, and even a few progenitors and early juvenile granulocytes are present. Peripheral blood progenitor cells ≥1% is one of the indicators of poor prognosis.
Early thrombocytosis and late thrombocytopenia are seen.
Bone marrow routine and bone marrow biopsy
Routine bone marrow aspiration is often dry and is characteristic of the disease
Bone marrow biopsy is necessary to confirm the diagnosis. Biopsy specimens show active bone marrow proliferation, megakaryocytosis, increased reticulocytes, and uneven distribution of reticulin.
Chromosomal abnormalities may be present in 50-60% of patients. Chromosomal karyotype abnormalities suggest poor prognosis.
5.Diagnosis and risk score of PMF
What tests are required for the suspected diagnosis of PMF?
(1) Detailed medical history and physical examination
(2) Routine blood and peripheral blood smear
(3) Bone marrow routine and bone marrow biopsy, bone marrow chromosome examination
(4) Bone marrow genetic testing
BCR/ ABL gene test: used to exclude CML.
JAK2V617F mutation test: positive in about 50-60% of patients, used as an aid to diagnosis
(5) Exclusion of secondary MF is particularly important
Other tumors, including myeloma, lymphoma, and CML, can be associated with myelofibrosis due to the tumor itself. In these cases, myelofibrosis can be reversed after treatment of the underlying disease. Similarly, myeloid granulomatous diseases such as histoplasmosis and tuberculosis may also lead to myelofibrosis.
6. PMF treatment
PMF treatment currently lacks specific measures.
The main purpose of treatment is to improve bone marrow hematopoietic function, correct anemia, bleeding, and relieve the compression symptoms caused by splenomegaly.
After the diagnosis of MPN, you should have a detailed and in-depth communication with your primary care physician to understand your disease status, underlying diseases and economic situation to choose the suitable treatment plan for you.
(1) JAK2 inhibitor
are the latest generation of oral medications for PMF. Among these drugs, INCB018424 (Ruxolitinib), CEP-701, XL019, TG101348 and ITF2357 have been approved by the US FDA in November 2011 for the treatment of patients with intermediate to high risk PMF. Several dozen patients are currently enrolled in clinical trials in China, and the drug is being tested free of charge. It is expected to be available in China next year. The results of the international clinical trial showed that Ruxolitinib could shrink the spleen by more than 35% in 41% of patients at 24 weeks of administration, and further results showed that the drug could improve the overall survival time of PMF patients. The most common adverse effects of this drug were thrombocytopenia, anemia, diarrhea and edema.
(2) Interferon
Interferon alpha (IFN-α) inhibits the proliferation of megakaryocyte lines and suppresses the production and release of megakaryocyte/platelet-derived fibrillogenic growth factors such as PDGF and TGF-β, suggesting that IFN-α may be used in the treatment of PMF. Recently, IFN-α has been shown to be an effective cytokine-lowering agent in the early hyperproliferative phase, but has extremely limited efficacy in patients with severe myelofibrosis who have severe anemia or allogeneic cytopenia. The commonly used dose is 3.5×106 units/dose three times a week for a minimum of 12 months.
(3) Hormones
Androgens may improve anemia in 1/3 to 1/2 patients, and glucocorticoids may improve severe anemia or thrombocytopenia in 1/3 patients. Therefore, patients with anemia and/or thrombocytopenia may be treated initially with a combination of androgens (stanozolol, 6 mg/d or danazol, 200 mg, orally, q6h or q8h) and glucocorticoids (prednisone, 40 mg/d) for at least 3 months.
(4) Immunomodulators
Thalidomide (thalidomide) has anti-angiogenic, immunomodulatory and down-regulatory effects on TNF-α levels and improves anemia, thrombocytopenia and splenomegaly in PMF patients. The total effective rate of thalidomide is about 60% at 100 mg~400 mg/d alone. The main adverse effects include drowsiness, weakness, constipation, dizziness, depression and tremor. Better in combination with prednisone
As a second generation immunomodulatory drug (IMiD), lenalidomide is more chemically stable than thalidomide and has stronger antitumor and immunomodulatory effects, while overcoming the common adverse effects of thalidomide. Lenalidomide can be used as a single agent or in combination with prednisone.
(5) Hematopoietic stem cell transplantation
Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) is the only promising cure for PMF to date. The main factors affecting the efficacy of transplantation are Hb<100g/L before transplantation, myelosclerosis and severe acute and chronic GVHD after transplantation. splenectomy before transplantation may reduce delayed implantation, therefore splenectomy is recommended before transplantation in patients with significantly enlarged spleens. Younger patients with a poorer prognosis may be treated with Allo-HSCT if a suitable relevant donor is available. For patients >45 years of age who have failed conventional treatment, autologous hematopoietic stem cell transplantation (Auto-HSCT) is another treatment option.
(6) Chemotherapy
Oral chemotherapy drugs: Maryland and other alkylating agents, 6-TG, hydroxyurea make some patients’ spleen and hepatomegaly shrink, night sweating, weight loss and other symptoms improve, can make hemoglobin increase, platelet count, bone marrow fiber content decrease, the efficiency is 40%.
Intravenous chemotherapeutic agents: Cladribine, Decitidine (DAC), Azacytidine (5AC), Farnesyl inhibitor (Tipifarnib) can be tried with an efficiency of 20%.
(7) Splenectomy
Indication for surgery: painful splenomegaly;
Large blood transfusion or combination of refractory hemolytic anemia;
Severe thrombocytopenia;
Portal hypertension.
Contraindications to surgery:
Active hepatitis;
Severe pulmonary and cardiovascular disease;
High platelet count.
(8) Splenic radiation therapy
Indications for clinical application are.
①Severe pain in the splenic area (splenic infarction);
(ii) Significant splenomegaly with contraindication to splenectomy;
③ ascites caused by peritoneal myeloid metaplasia;
(iv) Severe localized skeletal pain;
⑤ extramedullary fibrous hematopoietic neoplasm.
Limitations: short maintenance time
7.Efficacy assessment of PMF
International Working Group (IWG) consensus criteria for response to treatment of myelofibrosis with myeloid metaplasia
1. Complete remission (CR)
(1) Complete disappearance of disease-related signs and symptoms, including palpable hepatosplenomegaly.
(2) Peripheral blood count remission was defined as Hb ≥ 110 g/L, PLT ≥ 100×109/L, and ANC ≥ 1×109/. Moreover, all 3 lineage cell counts should not be higher than the upper limit of normal.
(3) Normal peripheral blood smear leukocyte sorting counts including nucleated red blood cells, primitive cells and naive granulocytesa in the absence of splenectomy.
(4) Bone marrow histologic remission was defined by an age-calibrated nucleated cell count grade, primitive granulocytes <5%, and myelofibrosis grading ≤ grade 1b.
2. Partial remission (PR) Meets all criteria in CR except for myeloid histological remission. A bone marrow biopsy is required for the evaluation of PR to detect changes that may or may not be favorable although they do not meet CR criteria.
3, Clinical improvement (CI) neither meets CR/PR nor PD criteria (see below), can meet one of the following conditions and lasts ≥ 8 weeks.
(1) Increased Hb level of at least 20 g/L or off transfusion (only for patients with basal Hb level <100 g/L)c.
(2) Palpable splenomegaly of at least 50% retraction for basal values of at least 10 cm or palpable splenomegaly becoming nonpalpable for basal values >5 cmd.
(3) PLT count is at least 100% elevated and the absolute count is ≥50×109/L (only for patients with a platelet count basal value <50×109/L).
(4) ANC increased by at least 100% and ANC ≥ 0.5×109/ (only for patients with ANC basal value <1×109/L).
4, Disease progression (PD) is required for one of the following conditionse.
(1) Progressive splenomegaly: defined as the appearance of palpable splenomegaly >5 cm below the left costal margin in those without prior splenomegaly or splenomegaly with a basal value of 5-10 cm that is at least 100% larger or splenomegaly with a basal value >10 cm that is at least 50% larger.
(2) Leukemic transformation was determined when the bone marrow primitive cells were ≥20%.
(3) The percentage of peripheral blood primitive cells increased to at least 20% and lasted at least 8 weeks.
5.Stable disease (SD) does not meet any of the above.
6. relapse Loss of CR, PR or CI. in other words, a patient with CR or PR should be considered to have relapsed when he or she no longer even meets the criteria for CI. However, the change from CR to PR or from CR/PR to CI should be formally documented and reported.