A proportion of asymptomatic patients remains stable for years and they do not require specific treatment. Constitutional symptoms, anemia, thrombocytopenia, and splenomegaly are the principal initial reasons for therapy. A hemoglobin less than 10 g/dL,12,14,20 a white count less than 4000/μL (4.0 × 109/L) or greater than 30,000/μL (30.0 × 109/L),13 a platelet count under 100,000/μL (100 × 109/L), and blood blasts above 1 percent of total leukocytes12,20,406 predict more rapid progression of disease. In addition, patients may have a loss of sense of well-being, fatigue, night sweats, loss of weight, low-grade fever, and loss of functionality as a result of the accompanying elaboration of inflammatory cytokines. Staging protocols may be useful in comparing concurrent and sequential clinical trial results (see “Course and Prognosis” below). In an individual patient under the care of a clinician experienced in the disease, following the disease for evidence of progression is a very important additional factor in determining the timing of treatment, even in patients deemed at higher risk by formulaic techniques, especially before introducing allogeneic stem cell transplantation with its morbidity and potential mortality in this age group.
Patients with severe anemia or with moderate but symptomatic anemia may require periodic red cell transfusions (Chap. 138). Alternative mechanisms for raising the blood hemoglobin concentration include use of recombinant erythropoietin and androgen therapy.
RECOMBINANT HUMAN ERYTHROPOIETIN FOR ANEMIA
Serum erythropoietin levels usually are appropriate to the severity of anemia in patients with myelofibrosis.407 Thus, use of erythropoietin for anemia is, usually, disappointing. In some studies, patients selected by their inappropriately low serum erythropoietin levels (<125 U/L) for the degree of anemia, beneficial effects can result.408,409
ANDROGENS AND GLUCOCORTICOIDS FOR ANEMIA
Severe anemia may improve with androgen therapy in some patients.410 Testosterone, oxymetholone, and fluoxymesterone have been used but have virilizing effects. In addition, they have the potential for hepatic injury and other side effects. Danazol, 600 to 800 mg/day orally for up to 6 months, can be used. The drug is tapered to the minimum effective dose or discontinued if no significant response occurs. Improvement may be limited to a decreased frequency of red cell transfusion. Androgens often are used after splenectomy if anemia returns and requires transfusion of red cells. They are more effective in splenectomized patients or those with less splenic enlargement. Patients undergoing androgen therapy should have periodic assessment of liver size by physical examination, measurement of liver function tests, and, if appropriate, ultrasonographic imaging to detect liver injury (e.g., peliosis) or tumors.411 Evaluation of male patients for prostatic enlargement or cancer is prudent before starting androgen therapy. Patients with significant hemolytic anemia may benefit from glucocorticoid therapy. Prednisone 25 mg/m2 per day orally can be tried. If tolerated, the dose can be continued for 1 to 2 months and then tapered gradually. In children, high-dose glucocorticoid therapy can ameliorate marrow fibrosis and improves hematopoiesis.412,413
DRUG THERAPY FOR MYELOPROLIFERATION, SPLENOMEGALY, OR CYTOPENIAS
A variety of drugs have been used for treatment of massive splenomegaly, thrombocytosis, or constitutional symptoms.
JAK2V617F Kinase Inhibitors
Because JAK2 mutations and the resulting effects on JAK-STAT signaling are thought to be a key factor in the clonal expansion leading to primary myelofibrosis in at least 50 percent of patients, an effort to synthesize and test inhibitors of the mutant JAK2 protein product were conducted.414 Early studies of the JAK2 kinase inhibitor TG101209, an oral, bioavailable small molecule, and a potent inhibitor of JAK2 kinase, showed its ability to inhibit JAK2V617F-dependent phosphorylation of STAT3 and STAT5, inhibit colony growth of cells harboring JAK2 and MPL mutations, and to have therapeutic effects in a nude mouse model of JAK2V617F-induced myeloproliferative disease.415 The effects of several JAK2 inhibitors have been described.416,417,418 Although their effects are somewhat different, the most striking and consistent effect with each agent is a decrease in spleen size and reversal of constitutional symptoms. They often suppress blood cell counts, and thrombocytopenia can be dose-limiting. At least initially, the anemia worsens although this laboratory deterioration may be transient, lasting only for few months. Typically, in spite of progression of anemia, most treated patients report decreased fatigue. The reduction in large spleen size and the improvement in the quality of life of many patients have been dramatic and were similar in those with and without a JAK2 mutation. This effect may be explained by the drug’s ability to inhibit JAK1 and JAK2 isoforms, the former having a role in cytokine elaboration. These agents may decrease morbidity and mortality, prolonging survival (see “Course and Prognosis” below).419,420,421,422,423
In 2011, ruxolitinib, an oral JAK2 inhibitor, was approved by the FDA for use in patients with intermediate or high-risk myelofibrosis. It decreases spleen size, fatigue, night sweats, pruritus, and red cell transfusion requirements, and can result in weight gain in a significant proportion of patients. The principal dose-limiting side effect is a decreased platelet count. Although some patients may have worsened anemia or neutropenia, the net effect often was beneficial, with improvement in fatigue and other symptoms. Headache, dizziness, and diarrhea also may occur but are usually manageable without discontinuing the drug. After 6 months of treatment approximately 40 percent of treated patients have a significant decrease in spleen size and constitutional symptoms. The initial drug trials were limited to patients with a platelet count at the initiation of ruxolitinib therapy of 100 × 109/L; however, newer studies using lower starting doses of ruxolitinib and gradually incrementing those doses have indicated that patients with platelet counts of between 50 and 100 × 109/L may receive similar benefits from carefully incremented drug doses. Table 86–4 shows a suggested approach to initial dosage. Of all available therapeutic modalities for primary myelofibrosis, ruxolitinib is the only therapy that has shown benefit in clinical trials that included a comparison group given a placebo.
Table 86–4.Guideline for Initial Oral Ruxolitinib Dose in Primary Myelofibrosis ||Download (.pdf) Table 86–4. Guideline for Initial Oral Ruxolitinib Dose in Primary Myelofibrosis
|Platelet Count ||Dose |
|>200 × 109/L ||20 mg twice daily |
|100–200 × 109/L ||15 mg twice daily |
|50–100 × 109/L ||5 mg twice daily (increasing each month by 5 mg daily until maximal splenic size reduction, only if platelet count stays above 40 × 109/L)* |
Hydroxyurea is a commonly used agent for exaggerated accumulation of platelets, occasional very high leukocyte counts, troublesome areas of extramedullary hematopoiesis, and symptomatic splenomegaly.424,425,426 Hydroxyurea can, inconsistently, decrease the size of the spleen and liver, decrease or eliminate constitutional symptoms of night sweats or weight loss, and occasionally lead to an increase in hemoglobin concentration, a decrease of platelet counts, and a decrease in the degree of marrow fibrosis. Patients with myelofibrosis often do not have the marrow tolerance to chemotherapy of patients with other chronic myeloproliferative diseases. Hydroxyurea can be administered in doses of 0.5 to 1.0 g/day or 1 to 2 g orally two to three times per week, depending on the level of pretreatment blood cell counts. Patients should be evaluated for dose adjustment at least every week for 1 month and, if appropriate, eventually extended to evaluation every 3 months. Although alkylating agents, especially busulfan and other cytotoxic agents, have been used successfully, they have largely been replaced by hydroxyurea. Use of alkylating agents has resurfaced with the suggestion that melphalan or busulfan may be useful as therapy.427,428
Thalidomide is poorly tolerated at optimal doses of approximately 800 mg/day. Most patients receive about half that amount and are tapered to the lowest effective dose. One study of 14 patients found the drug was not beneficial and had high toxicity rates.429 Other studies found some decrease in spleen size and improvement in blood hemoglobin and platelet counts in a minority of patients receiving up to 600 mg/day.430,431 In subsequent studies, lower doses of thalidomide (50 mg/day) coupled with prednisone were more tolerable and resulted in improvement of anemia and thrombocytopenia in about half of patients, with sustained improvement in some patients after treatment was stopped.432 The thalidomide congener lenalidomide may supersede thalidomide use. Lenalidomide has provided responses in a significant minority of patients.433,434,435,436 The drug can result in marked improvement in hemoglobin concentration or avoidance of a requirement for transfusion (22 percent of patients treated), improvement in platelet count (50 percent of patients treated), and decrease in spleen size (33 percent of patients treated). Neutropenia and thrombocytopenia were the most troubling side effects.433 The drug has also been useful in patients with primary myelofibrosis who have a 5q– cytogenetic abnormality.435,436 Another thalidomide congener, pomalidomide, has completed a phase 3 trial and has not been shown to decrease transfusion requirements.437
Cyclosporine has been used to achieve a serum level of 100 to 200 ng/mL in severely anemic patients with evidence of immune abnormalities (positive Coombs test, antinuclear antibodies).438 Three of six patients responded with an increased hemoglobin concentration. Cyclosporine has been used with apparent success in a single patient with myelofibrosis and red cell aplasia.439
TNF-α has been proposed as a target to inhibit its possible effects in the pathogenesis of primary myelofibrosis.440 Of 20 patients treated with soluble TNF-α receptor (etanercept), 12 had improvement in constitutional symptoms (fever, night sweats, fatigue, weight loss), and four had improved blood counts and decreased spleen size.441,442
Imatinib mesylate for treatment of myelofibrosis has been examined on empirical grounds and has been largely ineffective in influencing the disease course.442,443 Modest doses have not been well tolerated, and responses have been infrequent and insubstantial.
The farnesyl transferase inhibitor tipifarnib is not well tolerated.444 Although it may decrease spleen size, it has shown no advantages over hydroxyurea.
Interferon-α and interferon-γ act synergistically to inhibit myeloproliferation.445 Interferon-α has been used extensively for treatment of CML prior to the availability of mutant tyrosine kinase (BCR-ABL) inhibitors (Chap. 89). Interferon-α has not been used extensively in primary myelofibrosis, but has been useful for treatment of splenic enlargement, bone pain, and thrombocytosis in select patients.446 Trials comparing interferon therapy with hydroxyurea or other therapy have not been reported.447 Hydroxyurea is easier to use (oral versus parenteral) and has less-frequent and less-severe side effects than interferon, especially in older patients. A polyethylene glycol conjugated interferon-α preparation may prove more practical and tolerable for use in patients with myelofibrosis. Although largely ineffective in later stages of myelofibrosis, it has shown efficacy in the early myeloproliferative stage of primary myelofibrosis with mild to moderate marrow fibrosis.448,449,450,451
Cytarabine Ascites resulting from peritoneal hematopoietic implants has been treated with intraperitoneal cytarabine.452 Intrasplenic cytarabine administered via a splenic artery catheter has resulted in significant improvement in a patient (see also “Radiotherapy” below).453
Although autoimmune or systemic lupus erythematosus-related myelofibrosis has responded to glucocorticoids or intravenous immune globulin251,254 and a variety of other fibrotic disorders occasionally respond,454 primary myelofibrosis does not have a sustained response to such therapy because the fundamental lesion is the hematopoietic multipotential cell neoplasm, neoplastic megakaryocytosis, severe megakaryocytic dysmorphia, and cytokine release with resultant fibrogenesis and, sometimes, osteogenesis.
BISPHOSPHONATES FOR BONE DISEASE
Debilitating bone pain can be a vexing problem in some patients with osteosclerosis and periostitis. Dramatic improvement in bone pain and hematopoiesis after etidronate 6 mg/kg per day on alternate months455 or clodronate 30 mg/kg per day for several months, during which marked improvement was still present 33 months later,456 highlight the potential usefulness of this family of drugs for bone symptoms.457
Radiotherapy can be useful for patients with primary myelofibrosis in several situations. For example, in the presence of severe splenic pain (splenic infarctions) or massive splenic enlargement with contraindication to splenectomy (e.g., thrombocytosis), repeated doses of 0.5 to 2.0 Gy to the spleen can ameliorate the pain.458 Splenic radiation can result in further cytopenias or worsening cytopenias, especially thrombocytopenia, referred to as an abscopal effect on marrow production, perhaps because of the circulation of large numbers of CD34+ cells exposed in the spleen. Other situations in which radiation may be useful are ascites resulting from myeloid metaplasia of the peritoneum,459 focal areas of severe bone pain (periostitis or the osteolysis of a myeloid sarcoma),272,458,460 and extramedullary fibrohematopoietic tumors,157,458 especially of the epidural space.191 Low-dose radiation to the liver for symptomatic hepatomegaly and ascites provides only short-term relief.458,461 Low-dose radiotherapy to the lung has been used successfully to palliate the effects of pulmonary hypertension thought to result from extensive extramedullary hematopoiesis in the organ. Low-dose radiotherapy has relieved signs of respiratory insufficiency, especially hypoxemia,226 but in several unreported instances known to the authors, this approach has led to deterioration of pulmonary function.
Splenectomy has been important in the management of primary myelofibrosis.462 The major indications for splenectomy include (1) painful enlarged spleen (~50 percent of patients), (2) excessive transfusion requirements or refractory hemolytic anemia (~25 percent of patients), (3) portal hypertension (~15 percent of patients), and (4) severe thrombocytopenia (~10 percent of patients).
Patients who have a prolonged bleeding time or coagulation times are at serious risk for hemorrhage with surgery and should not undergo the procedure unless the abnormalities can be corrected by platelet transfusion and factor replacement therapy. Evidence of low-grade intravascular coagulation, such as elevated D-dimer levels, may require prophylactic heparin therapy and platelet transfusion should excessive bleeding occur.
Removal of the spleen in patients with primary myelofibrosis may be difficult. Usually the spleen is adherent to neighboring serosal surfaces and structures (e.g., inferior surface of left hemidiaphragm) and has numerous collateral vessels and very dilated splenoportal arteries and veins. Immediate postoperative mortality is a function of surgical experience and skill and of the rapidity of recognition of postoperative complications. In experienced hands, perioperative mortality is approximately 10 percent. Postoperative morbidity from hemorrhage, subphrenic hematoma, subphrenic abscess, injury to the tail of the pancreas, pancreatic fistulas, or portal vein stump or mesenteric vessel thrombosis occurs in approximately 30 percent of patients. Infection, especially, pneumonia occurs in approximately 10 percent of patients. Later postoperative changes include liver enlargement (sometimes massive), extramedullary hematopoietic tumors, thrombocytosis, and a decrease in teardrop-shaped red cells. Leukemic blast transformation occurs in approximately 15 percent of patients after splenectomy. Hydroxyurea or aspirin and anagrelide may be useful for exaggerated thrombocytosis (Chap. 85). The morbidity and mortality from splenectomy and the modest extension of life have led to increasing conservatism regarding its use. However, splenectomy can improve the condition for which it was performed in approximately 50 percent of patients. Median survival after splenectomy has been approximately 18 months.
PORTAL-SYSTEMIC VASCULAR SHUNT SURGERY
Circulatory dynamic studies are performed at the time of surgery in patients undergoing operation for portal hypertension and bleeding varices or refractory ascites. In patients in whom the hepatic wedge pressure elevations result from markedly increased blood flow from the spleen to the liver, the preferred treatment procedure for portal hypertension is splenectomy. In patients who have portal hypertension resulting from intrahepatic block or hepatic vein thrombosis and who have a hepatic venous pressure gradient well above the upper limits of normal (6 torr), a splenorenal shunt can be performed463 or, to avoid abdominal surgery, a transjugular intrahepatic portosystemic shunt can be used.464,465 Variceal sclerotherapy or variceal ligation has been used to treat bleeding varices resulting from portal hypertension.
HEMATOPOIETIC STEM CELL TRANSPLANTATION
Marrow transplantation is the only curative approach to primary myelofibrosis. Marrow transplantation therapy has been used increasingly in younger patients with a poor prognosis (e.g., severe anemia and leukopenia or exaggerated leukocytosis) who have a histocompatible sibling.466,467,468,469,470,471,472,473 The median age in most studies is approximately 50 years, whereas the median age of all patients is approximately 70 years.322 Patients engraft at a rate similar to the rate of patients with hematologic diseases without marrow fibrosis (Chap. 23). The decision to use full-conditioning allogeneic transplantation is a function of the patient’s age (<50 years), the severity of the blood cell and marrow abnormalities, and the likelihood of a protracted indolent course without transplantation. Younger patients, especially those younger than age 50 years, with a DNA-based matched sibling donor, progressive disease, and poor prognostic findings, such as hemoglobin less than 10 g/dL, blast cells greater than 1 percent of blood cells, unfavorable cytogenetics (e.g., abnormalities involving chromosome 5, 7, or 17, or cells with three or more abnormalities) are usually considered for transplantation. Although a large spleen may slightly delay the expression of donor granulopoiesis, on average the results in patients with a spleen is the same as those who had prior splenectomy.471,474 In addition, the latter procedure incurs significant risk of morbidity or mortality.
Patients younger than age 50 years who are transplanted with stem cells from a matched sibling donor have a lower posttransplantation mortality and have better outcomes than those older than age 50 years.460 Transplant-related mortality using full-conditioning regimens is approximately 35 to 40 percent and 5-year survival is approximately 50 percent in patients younger than 50 years of age.
Donor lymphocyte infusion in patients who have lost donor dominance of hematopoiesis and a return of myelofibrosis can result in regression of fibrosis and return to normal hematopoiesis for at least 6 and 20 months at the time of reporting.475,476
In JAK2V617F-positive patients, real-time polymerase chain reaction analysis can permit a sensitive determination of residual JAK2V617F-positive cells after transplantation. In a study of patients receiving low-intensity conditioning, 17 of 21 patients became JAK2V617F-negative, and in one case donor lymphocyte infusion eliminated JAK2V617F-positive cells.477
The option of nonmyeloablative transplantation in older patients is gaining favor.470,471,478,479,480,481,482 Several reports of lower posttransplantation mortality and salutary outcomes have led some to consider this approach as the preferred approach in patients older than 50 years of age, and perhaps in younger patients as well. One study showed that the outcome of nonmyeloablative transplantation was dramatically better than myeloablative transplant.470 The study compared 17 patients receiving a myeloablative conditioning regimen and 10 receiving nonmyeloablative conditioning. The median age was 50 years (age range: 5 to 63 years) at transplantation. After a median followup of 55 months, 20 patients were alive. The transplantation-related mortality was 10 percent in the nonmyeloablative group and 30 percent in the myeloablative group. There was no difference in survival for high- or low-risk patients or between sibling and unrelated donor transplantations. This study confirmed prior smaller comparisons of myeloablative and nonmyeloablative stem cell transplantation.483
A large cooperative study of reduced conditioning transplantation found the most favorable results in transplants using matched-related donors and in intermediate stage disease.482
Autologous blood stem cells mobilized with granulocyte colony-stimulating factor (G-CSF) and administered after busulfan conditioning produced clinical benefit, including improved erythropoiesis, improved platelet counts, and decreased splenic size, in a plurality of 21 patients with primary myelofibrosis whose age range was 45 to 75 years. The 2-year actuarial survival rate was 61 percent.484
The European LeukemiaNet and European Blood and Marrow Transplantation Group provided a consensus recommendation that patients with intermediate-2-or- high-risk disease and age <70 years should be considered as candidates for allogeneic stem cell transplant. Patients with intermediate-1-risk disease and age <65 years should be considered as candidates if they present with either transfusion-dependent anemia or greater than 2% blasts in the blood, or adverse cytogenetic findings. In all other cases the disease outcome is better without transplantation.512