Myelofibrosis

Signs and Symptoms

MF has the most heterogeneous clinical presentation of the three MPNs; patients can present with no or few symptoms in the early stages of the disease or with severe signs and symptoms, such as fatigue, transfusion-dependent anemia, and symptomatic splenomegaly as the disease progresses. Although leukopenia and thrombocytopenia are most common as the disease progresses, some patients may present with leukocytosis or thrombocytosis. These patients are at greater risk of developing thrombohemorrhagic complications. Nearly half of patients present with anemia.

Extramedullary hematopoiesis can lead to marked hepatosplenomegaly. Up to 85% of patients present with palpable splenomegaly and 50% have hepatomegaly. Splenomegaly can cause abdominal discomfort, early satiety, and pain under the left ribs. Complications associated with splenohepatomegaly include portal hypertension, variceal bleeding, and splenic infarcts. Extramedullary hematopoiesis can also lead to pulmonary hypertension, ascites, pericardial tamponade, cord compression, and paralysis.

Debilitating constitutional symptoms are common and can lead to very poor quality of life. Fatigue is the most common of these: 84% of patients reported having fatigue in an internet-based survey. Other common symptoms include night sweats (56% of patients), pruritus (50% of patients), bone pain (47%), unintentional weight loss (20% of patients), and fevers (18% of patients).

Pathology and Laboratory Features

Peripheral blood

The peripheral blood smear typically shows leukoerythroblastosis (nucleated red blood cells and left-shifted granulopoiesis), with teardrop-shaped red blood cells, large platelets, and rare myeloblasts. Circulating CD34+ cells are also elevated.

Bone marrow

Bone marrow biopsy shows clustering of variably sized megakaryocytes with hyperchromatic and hyperlobulated nuclei. In the prefibrotic stage, bone marrow may be hypercellular. In the fibrotic stage, there is marked expansion of bone marrow sinusoids and increased interstitial reticulin fibrosis, as well as collagen fibrosis.

Other laboratory findings

Serum lactate dehydrogenase is often elevated; vitamin B12 levels can be elevated; and some patients experience hyperuricemia.

Cytogenetic and Molecular Findings

Chromosomal abnormalities

The incidence of chromosomal abnormalities in MF has been reported to range from 32% to 48%. The most common abnormalities are del(13q), del(20q), trisomy 8 or 9, and abnormalities of chromosome 1 [partial trisomy and der(6)t(1;6)]. Sole deletions of 13q or 20q, or trisomy 9 alone or with one other abnormality, are considered “favorable” abnormalities, as they associated with survival times that are similar to those of patients with the diploid karyotype. Abnormalities of chromosomes 5 or 7, or the presence of more than three chromosomal abnormalities (complex karyotype) define an “unfavorable” karyotype and are associated with shorter overall survival time. Abnormalities in chromosome 17 are associated with the poorest survival.

Somatic mutations

Mutations in genes that activate JAK-STAT (Janus kinase/signal transducer and activator of transcription) signaling are thought to drive the disease process in most patients with primary MF. Approximately 50% to 60% of patients carry the JAK2^V617F mutation, and an additional 5% carry a mutation in MPL (MPL^W151L/K). Mutations in CALR, another gene involved in dysregulated JAK-STAT signaling, have been found in 25% to 35% of PMF cases, and appear to be mutually exclusive with JAK2 and MPL mutations. Other described mutations found in approximately 3% to 20% of patients include those in ASXL1, SRSF2, EZH2, TET2, DNMT3, CBL, and IDH1/IDH2. These mutations often co-occur with the three driver mutations and are not exclusive of each other. While the prognostic relevance of these mutations has not been definitively shown, studies evaluating their prognostic relevance in patients with primary MF suggest that mutations of CALR (favorable) and ASXL1, EZH2, and SRSF2 (unfavorable) have prognostic significance that is independent of the Dynamic International Prognostic Scoring System (D-IPSS).

Diagnosis

Primary MF is diagnosed according to 2008 WHO criteria on the basis of clinical, histological, and molecular characteristics (Table 1). Secondary MF (post-PV or post-ET MF) is diagnosed according to criteria developed in 2007 by the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) (Table 4).

TABLE 3: International Working Group for Myelofibrosis Research and Treatment recommended criteria for diagnosis of post–polycythemia vera and post–essential thrombocythemia myelofibrosis

TABLE 4: International prognostic score for essential thrombocythemia (IPSET) and IPSET-thrombosis

Primary MF is diagnosed based on assessment of clinical and laboratory findings as well as careful pathological examination of the bone marrow. The differential diagnosis should include bone marrow fibrosis associated with other neoplastic and non-neoplastic conditions. Post-PV and post-ET MF should be diagnosed based on criteria defined by the IWG-MRT, which include the following: previous diagnosis of PV or ET by WHO criteria; bone marrow fibrosis grade 2–3 (on a 0–3 scale) or grade 3–4 (on a 0–4 scale); and presence of two additional criteria (anemia, leukoerythroblastic peripheral blood picture, increasing splenomegaly, increased lactate dehydrogenase level [for ET], or development of one or more constitutional symptoms (> 10% weight loss in 6 months, night sweats, unexplained fever).

Prognosis

The most common fatal complications of MF are thrombohemorrhagic complications, infections, and transformation to acute leukemia. The International Prognostic Scoring System (IPSS) constructed by the IWG-MRT in 2009, which is designed to be used at diagnosis to guide treatment decisions, is the most widely used prognostic scoring system (Table 5). The risk factors included in the model are age > 65 years, presence of constitutional symptoms, hemoglobin < 10 g/dL, leukocyte counts > 25 × 10⁹/L, and circulating blasts > 1%. The prognostic model stratifies patients into four risk categories with estimated median survival times ranging from 2.3 years (high risk) to 11.3 years (low risk).

TABLE 5: Prognostic scoring systems for primary myelofibrosis

An updated version of the IPSS, the D-IPPS, which treats the risk factors as time-dependent covariates in the multivariate model, can be used to define prognosis at any point in the course of a patient’s treatment. The only difference in scoring between the IPSS and D-IPSS is that in the D-IPSS, anemia is given 2 points instead of 1 (see Table 5). Patients stratified by the D-IPSS have survival times ranging from 1.5 years (high risk) to “not reached” for those categorized as low-risk. A third prognostic model, DIPSS-plus, which includes red blood cell–transfusion dependence, platelet count < 100 × 10⁹/L, and unfavorable karyotype as additional risk factors, has also been developed. This model also stratifies patients into four risk categories, with survival ranging from 1.3 years (high risk) to 15.4 years (low risk).

A summary of the three prognostic scoring systems is shown in Table 5. All of these prognostic risk-stratification systems can be useful for identifying high-risk patients who may benefit most from intensive treatment strategies, such as allogeneic stem cell transplantation (ASCT). Recent studies have suggested an association between mutations and prognosis. CALR has been associated with longer survival, while survival duration is predicted to be shorter for patients who do not have any of the known driver mutations (JAK2, CALR, MPL), so-called “triple-negative” disease. In addition, mutations in epigenetic modulator genes have been associated with worse survival (ASXL1, SRSF2, EZH2) and risk of transformation to acute leukemia (ASXL1, SRSF2, EZH2, IDH1/IDH2). How best to implement this molecular information in clinical practice has not yet been determined.

Treatment

Risk stratification should be performed at diagnosis to guide treatment decisions. While younger patients in the intermediate-2 and high-risk groups should be considered for allogeneic stem cell transplantation (ASCT), treatment planning for patients not eligible for ASCT and for those in the lower-risk categories is usually based on the presence of disease-related symptoms and signs. A recommended treatment algorithm is shown in Table 6.

Treatments for anemia

TABLE 6: Treatment approach for patients with myelofibrosis

Progressive anemia with transfusion dependency remains a significant problem in managing patients with MF. Options for managing MF-related anemia include the use of erythroid-stimulating agents, steroids, androgens, or immunomodulatory drugs (thalidomide [Thalomid] or lenalidomide [Revlimid]). Subcutaneous erythropoietin (EPO) injections (40,000 U/wk) can be given to patients with low serum EPO (< 125 U/L). Corticosteroids, such as prednisone (0.5–1 mg/kg/d), or androgens, such as testosterone enanthate injections (400–600 mg/wk) and oral fluoxymesterone (10 mg tid) have also been shown to be useful. Immunomodulatory drugs such as thalidomide and lenalidomide have also been shown to improve MF-related anemia. Thalidomide can be given at low doses (50 mg/day) in combination with tapering doses of prednisone (for first 3 months only). A phase II study combining lenalidomide and prednisone for the first 3 months reported a 30% hemoglobin response, but only in patients without baseline thrombocytopenia or neutropenia.

Treatments for splenomegaly and constitutional symptoms

The majority of patients with symptomatic MF report significant splenomegaly and constitutional symptoms that severely reduce quality of life. Options for managing these symptoms include HU, alkylating agents (melphalan, busulfan, or cladribine), IFN-a, immunomodulatory agents, JAK2 inhibitors, splenectomy, and splenic radiation. The pros and cons of each are discussed below.

Conventional drug therapy. Before the approval of ruxolitinib, HU was considered the first-line treatment for splenomegaly. However, the response rate is less than 50% and HU rarely induces complete spleen regression. In addition, high dosbides are often necessary to elicit a significant response and can result in intolerable cytopenias. Oral alkylating agents have also been used, but their use often results in severe and prolonged cytopenias. Immunomodulatory agents, such as low-dose thalidomide or lenalidomide, have been shown to be useful in reducing splenomegaly, in addition to improving anemia. Lenalidomide, given in combination with prednisone for the first 3 months, has been shown to reduce splenomegaly in up to 40% of patients and anemia in up to 30%. In addition, evidence suggests that the combination may occasionally reduce JAK2 allele burden and improve bone marrow fibrosis.

Interferon-a. IFN-a has been evaluated as a therapy for MF, but response rates have been low and the significant toxicity of this agent prevents its use in many patients. However, it has been suggested that IFN-a may alter the natural history of disease and reverse bone marrow fibrosis if used in early-stage MF and in patients with proliferative features (high blood count) but without splenomegaly. Thus, pegylated IFN-a, which has been reported to have fewer side effects, may be worth studying in this setting. We at MD Anderson recommend using IFN-a for women of childbearing age contemplating pregnancy.

JAK inhibitors. Before the discovery of the essential role of dysregulated JAK-STAT signaling in MF, treatments for MF were mainly palliative, had limited efficacy in reducing clinical manifestations, and were often poorly tolerated. The development of JAK2 inhibitors and the approval of ruxolitinib in the US, Europe, and Canada represent a significant milestone in the development of therapies for MF. In addition to ruxolitinib, several other JAK inhibitors are being evaluated in clinical trials.

Regulatory approval of ruxolitinib for use in patients with MF was based on the results of two pivotal phase III trials, one comparing ruxolitinib against placebo (COMFORT-I) and the other comparing it against best available therapy (COMFORT-II). Both studies showed that significantly more patients in the ruxolitinib arms had a ≥ 35% reduction in spleen volume from baseline (as measured by MRI or CT; approximately 50% reduction by palpation) at week 24 (COMFORT-I) or week 48 (COMFORT-II). Ruxolitinib also improved MF-related symptoms and quality of life significantly more than either placebo or best available therapy. More importantly, long-term follow-up analyses have shown that these effects are durable and that ruxolitinib may even improve survival and possibly delay or reverse bone-marrow fibrosis in the long term.

The most common toxicities associated with ruxolitinib are thrombocytopenia and anemia. However, most patients with symptomatic splenomegaly or systemic MF-related symptoms, even those with transfusion-dependent anemia, can be successfully treated with ruxolitinib. Current recommendations are to use a starting dose of 20 mg twice per day (bid) in patients with platelet levels above 200 × 10⁹/L, 15 mg bid in patients with platelet levels between 100 and 200 × 10⁹/L, and 5 mg bid for patients with platelet counts between 50 × 10⁹/L and 100 × 10⁹/L. The dose can then be modified as tolerated to a maximum dose of 25 mg bid.

Splenectomy and radiation. Splenectomy is only indicated in patients with symptomatic portal hypertension, severe splenomegaly associated with pain or severe cachexia that is refractory to drug therapy, or frequent red blood cell transfusions and cytopenia. The procedure is associated with significant morbidity and mortality: up to 50% of patients have complications after splenectomy, and perioperative mortality is 5% to 10%.

For cases of painful hepatosplenomegaly, radiation can provide transient symptomatic relief (median duration of response, 3–6 months); however, it is associated with a > 10% mortality rate due to complications. Therefore, splenic radiation is only recommended as a last resort for palliation in patients who have not responded to other therapy.

Allogeneic stem cell transplantation

ASCT is the only curative treatment for MF; however, less than 10% of patients undergo the procedure owing to advanced age, severe comorbidities, or not having a donor. Patients with intermediate-2 or high-risk disease should be considered for ASCT if they have good performance status and no comorbidities. Reduced-intensity conditioning may be used in older patients and those with comorbidities. The role of splenectomy before ASCT is controversial and this procedure is not routinely recommended. More recently, it has been suggested that therapy with ruxolitinib may be used as a bridge to ASCT. Prospective studies are underway to evaluate whether pretreatment with ruxolitinib may be an effective strategy to improve outcomes after ASCT and potentially increase the number of patients who are eligible for this procedure.