Diagnosis
The diagnosis of primary myelofibrosis should be made with particular caution in patients with other neoplastic diseases. This is because other tumors including myeloma and lymphoma can be accompanied by 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.
BCR/ ABL gene rearrangement test: for excluding chronic granulocytic leukemia.
JAK2V617F mutation test: positive in about 50C60 % of patients.
Differential diagnosis
Chronic granulocytic leukemia
Hairy cell leukemia
Histoplasmosis
Myelodysplastic syndromes
True Erythrocytosis
Primary thrombocythemia
Tuberculosis
Principles of treatment
The treatment of primary myelofibrosis is mainly supportive therapy. This includes blood transfusions. Hydroxyurea can be given for thrombocytosis. Low-risk, asymptomatic patients can be observed without treatment.
Drug therapy
JAK1 and JAK2 inhibitor, ruxolitinib (Jakafi): Based on the results of the COMFORT-1 and COMFORT-2 trials, this drug was approved by the U.S. Food and Drug Administration (FDA) in November 2011 for the treatment of myelofibrosis.
In the previous COMFORT-1 trial, patients with intermediate-risk-2 or high-risk myelofibrosis were randomized to two groups: ruxolitinib (15 mg or 20 mg orally, twice daily) and placebo. The primary endpoint was the proportion of patients with ≥35% reduction in spleen volume at 24 weeks of treatment as assessed by CT or MRI. The proportion of patients who ultimately reached this efficacy endpoint was 41.9%, compared with 0.7% in the placebo group. [17].
The COMFORT-II trial was a randomized phase III study comparing the efficacy of ruxolitinib with the most current effective treatment for patients with primary and secondary myelofibrosis. The primary endpoint was the proportion of patients with a 35% reduction in spleen volume as evaluated by MRI at 48 weeks of treatment. The results suggested an efficacy rate of 28% to achieve the primary endpoint, compared to 0% in the other treatment groups. [18].
Further follow-up showed that ruxolitinib improved the overall survival time of patients with myelofibrosis.
Other drugs such as hydroxyurea, interferon, cladribine, and leucovorin master are also commonly used to control leukocytosis, thrombocytosis, or organomegaly. Toxicity should be noted when applied.
Interferon can be used as an alternative to hydroxyurea therapy. Especially in young patients <45 years old. The overall response rate is 50%. Good efficacy in patients with hematocytosis.
Intense chemotherapy can be used to induce disease remission. However, hematologic remission is not obtained and does not alter the disease process.
Androgens and glucocorticoids can be used to treat severe anemia and to improve symptoms. The effectiveness of treatment is about 30%.
Thalidomide in combination with prednisone: Low-dose thalidomide (50 mg) in combination with prednisone has fewer side effects than high-dose thalidomide. However, some patients have a significant increase in white blood cell or platelet counts during treatment, usually occurring at 4-8 weeks, when additional cytoreductive therapy may be required.
The clinical effectiveness of low-dose thalidomide in combination with prednisone in 21 patients with symptomatic myelofibrosis was 62% (13 patients). 10 patients were red cell transfusion dependent, 7 (70%) improved and 4 (40%) were no longer transfusion dependent. 8 patients with thrombocytopenia (platelet count <100×109/L) and 6 (75%) had elevated platelet counts ≥50 Four of the 21 patients (19%) had a reduction in spleen size of more than 50%.
Lenalidomide can be used for the treatment of multiple myeloma and 5q-syndrome in myelodysplastic syndromes. The study showed that the overall response rate for lenalidomide treatment of 68 patients with symptomatic myelofibrosis was 22% for anemia; 33% for splenomegaly; and 50% for thrombocytopenia.
New drugs for the treatment of myelofibrosis are under investigation. These include farnesyl transferase inhibitors, tyrosine kinase inhibitors, vascular endothelial growth factor inhibitors, and Janus kinase 2 (JAK2) inhibitors.
Although thalidomide and lenalidomide may relieve anemia in patients with myelofibrosis, the side effects of peripheral neuropathy and bone marrow suppression limit their use. Pomalidomide, a new generation of immunomodulators, can reduce toxicity and enhance antitumor and immunomodulatory effects
Pomalidomide is effective in the treatment of myelofibrosis-related anemia. phase II multicenter, randomized, double-blind study was designed with four study arms, including pomalidomide 2mg/d plus placebo, pomalidomide 2mg/d fortified with pine, pomalidomide 0.5mg/d fortified with pine, and prednisone plus placebo. pomalidomide was administered continuously for 28 days as a course of 12 treatments. Eighty-four patients with myelofibrosis-associated anemia were randomized and 20 patients achieved efficacy, 15 of whom were no longer transfusion dependent. Efficacy rates were 23%, 16%, 36% and 19% in the four groups, respectively. The efficacy response was durable (range, 3.2-16.9 months). Grade 3+ toxicity was rare and included: neutropenia (9%, 16%, 5% and 5%), thrombocytopenia (14%, 16%, 9% and 5%) and thrombosis (9%, 5%, 0% and 0%).
Patients with myelofibrosis also have activation of the Akt/mTOR pathway. phase 1/2 clinical study used the mTOR inhibitor everolimus in the treatment of 39 patients at high or intermediate risk of primary or secondary myelofibrosis. phase 2 study evaluated the efficacy in 30 patients. No dose-limiting toxicity was observed below a maximum dose of 10 mg/d. The most common toxic reaction was grade 1-2 oral mucositis. Spleen shrinkage was rapid and sustained, with 22% of patients having spleen shrinkage of more than 50%; 44% of patients had spleen shrinkage of more than 30%.
Complete remission of systemic symptoms and skin pruritus was achieved in 69% and 80% of patients. The clinical response was independent of the amount of JAK2 V617F mutation and did not correlate with CD34+ cell or cytokine levels. Instead, the known targets of mTOR action: CCDN1 mRNA and phosphorylated p70s6k levels, and WT1 gene levels may correlate with efficacy.
Allogeneic hematopoietic stem cell transplantation
Allogeneic hematopoietic stem cell transplantation is a radical treatment for primary myelofibrosis. Myelofibrosis can regress after allogeneic transplantation, and durable remission after transplantation has been reported. However, hemoglobin <10 g/dl, karyotype abnormalities, osteosclerosis and old age are poor prognostic factors for transplantation. Transplantation with HLA-matched siblings as donors has a 1-year mortality rate of 30%. Recent studies have shown that non-cleared marrow transplantation may reduce early mortality thereby improving overall outcome.
Splenectomy
Splenectomy can be used to treat symptomatic splenomegaly in cases of portal hypertension, transfusion-dependent progressive anemia, or when hydroxyurea therapy has failed. Splenectomy is also used for severe thrombocytopenia. However, the efficacy is not sustained. Patients with myelofibrosis have a significantly higher incidence of post-splenectomy complications, including: infection, bleeding and thrombosis. The mortality rate varies from 9 to 38%. Significant hepatomegaly and thrombocytosis may also occur after splenectomy.
An increased conversion rate of AML has been reported after splenectomy, up to 55%, compared to 27% in patients who did not undergo splenectomy. Splenectomy is an independent risk factor for the conversion of myelofibrosis to AML.
Radiotherapy
Radiotherapy can be used to treat symptomatic extramedullary hematopoiesis. It is also used to treat pain caused by tumors or osteochondritis. Irradiation of the splenic region has a therapeutic response to splenomegaly or splenic infarction, but the efficacy is short-lived (median duration of efficacy is 6 months) [35]. After splenic irradiation, 25% of patients may experience persistent allogeneic cytopenia. In addition, splenectomy after radiotherapy to the splenic region is associated with a very high risk of intra-abdominal hemorrhage. Therefore, splenic region radiotherapy is only performed in patients without indications for surgery.