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, | ICD9 = | Image = | Caption = | ICDO = 9932, 9961 | OMIM = | DiseasesDB = 8616 | MedlinePlus = | eMedicineSubj = | eMedicineTopic = | MeshID = D009191 |Myelofibrosis with myeloid metaplasia, also known as agnogenic myeloid metaplasia, chronic idiopathic myelofibrosis, and primary myelofibrosis,Older terms include "myelofibrosis with myeloid metaplasia" and "agnogenic myeloid metaplasia". The World Health Organization utilizes the name "chronic idiopathic myelofibrosis", while the International Working Group on Myelofibrosis Research and Treatment calls the disease "primary myelofibrosis". was first described in 1879 and is currently classified as a myeloproliferative disease caused by the growth and proliferation of an abnormal bone marrow stem cell, resulting in the replacement of the bone marrow with fibrous connective tissue. An eponym for the disease is Heuck-Assmann disease, or Assmann's Disease.
Presentation The bone marrow is replaced by collagen fibrosis, impairing the patient's ability to generate new blood cells resulting in a progressive anemia. It is usually reactive following other myeloproliferative disorders, such as polycythemia rubra vera or essential thrombocytosis. Extramedullary haematopoeisis occurs as the haemopoetic cells migrate away from the bone marrow, to the liver and spleen. Patients often have hepatosplenomegaly and poikilocytosis. The mean survival is 5 years and causes of death include infection, bleeding, organ failure, portal hypertension, and leukemic transformation.
Diagnosis Diagnosis is based upon:
# Normochromic normocytic anaemia
# Red cell poikilocytosis on blood film (tear drop RBCs)
# JAK 2 mutation on Val 617 Phe locus in 50%
# Raised lactate dehydrogenase
# Raised neutrophil alkaline phosphatase score
# Bone marrow biopsy may show increased cellularity and fibrosis
Treatment Treatment of chronic idiopathic myelofibrosis (primary myelofibrosis, agnogenic myeloid metaplasia)
Ayalew Tefferi, MDINTRODUCTION — Agnogenic myeloid metaplasia (AMM, called chronic idiopathic myelofibrosis (CIMF) in the WHO classification and primary myelofibrosis by the International Working Group on
Myelofibrosis Research and Treatment), is one of the chronic myeloproliferative diseases . In addition to AMM, the group includes essential thrombocythemia (ET), and polycythemia vera (PV), both of which may undergo delayed disease transformation into a fibrotic state called postthrombocythemic myeloid metaplasia (PTM) and postpolycythemic myeloid metaplasia (PPM), respectively. The conversion rates after 10 to 20 years of disease are less than 5 percent for ET and approximately 10 to 20 percent for PV. AMM, PPM, and PTM are all referred to as myelofibrosis with myeloid metaplasia (MMM). The primary disease process in AMM is a clonal hematopoietic stem cell disorder which results in chronic myeloproliferation and atypical megakaryocytic hyperplasia. The secondary process of bone marrow fibrosis (BMF) is the result of nonclonal fibroblastic proliferation and hyperactivity induced by growth factors abnormally shed from clonally expanded megakaryocytes. BMF is the hallmark of AMM and contributes to the impaired hematopoiesis that leads to severe anemia. In addition to BMF and anemia, patients with AMM have marked degrees of splenomegaly, extramedullary hematopoiesis, and severe constitutional symptoms. Similar to the situation with other stem cell diseases, the only treatment modality with curative potential in AMM involves allogeneic hematopoietic cell transplantation 1,2. All other current treatment strategies are palliative 3,4. This topic will review the treatment of AMM 5. An overview of the myeloproliferative disorders, as well as discussions of pathogenetic mechanisms, clinical manifestations, and diagnosis of AMM are discussed separately. (See "Overview of myeloproliferative disorders" and see "Clinical manifestations and diagnosis of chronic idiopathic myelofibrosis (primary myelofibrosis, agnogenic myeloid metaplasia)" and see "Pathogenetic mechanisms in chronic idiopathic myelofibrosis (primary myelofibrosis, agnogenic myeloid metaplasia)"). PROGNOSIS — Most patients with AMM present with anemia, marked splenomegaly, early satiety, and hypercatabolic symptoms including severe fatigue, low grade fever, night sweats, and weight loss 3. During their clinical course, most patients experience massive hepatosplenomagaly along with progressive anemia requiring frequent red blood cell transfusions. Portal hypertension may occur due to either marked splenomegaly or intrahepatic obstruction. In some patients, extramedullary hematopoiesis (EMH) develops around the spinal column, causing cord compression, or in the pleural and peritoneal cavity, causing pleural effusion or ascites, respectively. In an epidemiologic study of patients within Olmsted county, the three-year survival rate was 52 percent 6. Similar results have been noted by others. In one series, risk factors for decreased survival included advanced age (>60 years), hepatomegaly, weight loss, anemia (hemoglobin <10 gm/dL), leukocytosis (white blood cell count WBC >30,000/microL), leukopenia (WBC <4000/microL), circulating blasts (>2 percent), thrombocytopenia (platelet count <150,000/microL) and abnormal karyotype 7. In contrast, splenomegaly and the degree of bone marrow fibrosis did not affect survival. A simplified prognostic scoring system was devised, based upon the following two findings 7: Hemoglobin <10 g/dL White blood cell count <4000/microL or >30,000/microL Median survivals were 93, 26, and 13 months for those with none (low risk), one (intermediate risk), or both (high risk) of these adverse prognostic risk factors, respectively. In a Mayo Clinic cohort of 160 patients with AMM <60 years of age, we devised a prognostic scoring system based on the following three adverse prognostic findings 8: Hemoglobin <10 g/dL White blood cell count <4000/microL or >30,000/microL Platelet count <100,000/microL Median survivals were 155, 69, and 24 months for those with zero, one, or 2 of these adverse features. Several other studies have reported similar prognostic parameters in AMM 9-12. Some reports have identified other predictors for worse survival including constitutional symptoms 13, clonal cytogenetic abnormalities 14-16, decreased erythropoiesis or red cell aplasia 12, increased plasma levels of soluble interleukin (IL)-2 receptor 17, and advanced bone marrow fibrosis 18. In one series of 47 patients, for example, 32 percent had clonal abnormalities; these patients had a much shorter median survival than those with normal chromosomes (30 months versus not reached at six years) 14. Response criteria — In addition to serving as prognostic parameters, changes in these disease-related features (eg, anemia, splenomegaly, constitutional symptoms, WBC and platelet counts) may be used to evaluate response to treatment 19,20. Patients of transplant age — The prognostic variables in the above studies were determined in all patients, most of whom were over the age of 55 and not candidates for allogeneic hematopoietic cell transplantation (allo-HCT). This issue was addressed in a report of 123 patients with AMM under the age of 55, who might be candidates for allo-HCT 21. This subgroup, representing approximately 25 percent of all patients with AMM, had a median survival of 11 years, three years longer than the low-risk group noted above 7. Three factors predicted poor survival in these younger patients: Hemoglobin <10 g/dL Constitutional symptoms (fever, sweats, weight loss) Circulating blasts >1 percent Median survival was 15 and 3 years for those with no or one adverse factor versus two or more adverse factors, respectively. TREATMENT — At present, allogeneic hematopoietic cell transplantation (allo-HCT) constitutes the only treatment modality with a curative potential in AMM. Other modalities that have been successfully employed include androgens, chemotherapy, hydroxyurea, anagrelide, splenectomy, radiation therapy to the spleen, and thalidomide 22,23. Allogeneic HCT — Allo-HCT has traditionally been limited to patients below the age of 60 years and to those who have an HLA-identical sibling donor, although there has been increasing use of both matched unrelated and mismatched related donors. (See "Donor selection for hematopoietic cell transplantation"). In addition to limited availability of donors, other problems associated with allo-HCT include a high transplant-related mortality due to complications such as acute and chronic graft-versus-host disease (GVHD). On the other hand, responses to donor lymphocyte infusions in patients relapsing after allo-HCT suggest the presence of a graft-versus- myelofibrosis effect in this disorder 23,24. (See "Clinical manifestations and diagnosis of acute graft-versus-host disease" and see "Clinical manifestations and diagnosis of chronic graft-versus-host disease"). Most reports of allo-HCT in AMM have included small numbers of patients 1,2,25-28. Furthermore, the median age was usually about 40; this represents a small subset of patients, since only 17 percent of those with AMM present before the age of 50 9. A study from the French Society of Bone Marrow Transplantation described 12 patients with AMM (mean age 40 years), 10 of whom had been splenectomized 1. All but one of the donors was an HLA-identical sibling. Engraftment occurred in 11, grade II-IV acute GVHD in 10, and extensive chronic GVHD in four. At a median follow-up of 25 months, estimated 4-year overall and event-free survivals were 71 and 59 percent, respectively. A report from Seattle described allo-HCT in 56 patients (mean age 43, range: 10 to 66 years) with AMM or the spent phase of polycythemia vera or essential thrombocythemia 2. Estimated three-year overall survival was 58 percent for the entire group and 76 percent for those conditioned with targeted dose busulfan plus cyclophosphamide. The 100-day treatment related mortality was 14 percent. A third study included 55 patients with AMM (median age 42 years) who underwent allo-HCT, 90 percent of whom engrafted 29. Overall survival at five years was 47 percent; 22 patients (40 percent) achieved a complete histohematologic remission (ie, complete hematologic remission plus disappearance of marrow fibrosis) . Five- year survivals of 83, 43, and 31 percent were seen in the low, intermediate, and high risk groups, as defined above (see "Prognosis" above) 7. Predictors of survival at five years were hemoglobin >10 g/dL and the absence of osteomyelosclerosis; predictors of failure were abnormal pretransplant karyotype, absence of grade II to IV acute GVHD, and age >45 at transplant 30. It has been concluded that young patients with two or more adverse features (ie, hemoglobin <10 g/dL, constitutional symptoms, isolated cytogenetic abnormality, or blasts >1 percent) 21,29 should be considered for HCT shortly after diagnosis. For low-risk patients, who might live 10 to 15 years with supportive treatment 21, but might have a transplant-related mortality of at least 8 percent, the answer is not yet clear. Until further information is available, a suggested strategy is to offer transplantation to the latter group when an adverse risk factor appears 23,31. Although the above study noted an estimated five-year overall survival post-transplant of 14 percent for patients 45 years of age 29,30, a preliminary report from Seattle indicated three- and five-year disease-free survival rates of 63 and 50 percent, respectively, for patients in that age range 32. Initial studies raised a concern that engraftment would be delayed in the severely fibrotic marrow. However, the above observations suggest that engraftment is not a problem in most patients with MMM. This is in keeping with a study that compared the outcome after HCT in 33 patients with severe myelofibrosis to 33 matched controls without myelofibrosis; there was no significant difference between the two groups in engraftment parameters 33. Similarly, preliminary information from Seattle indicated no significant advantage or disadvantage of splenectomy on posttransplantation outcome 34. Nonmyeloablative allogeneic HCT — A number of studies have reported on the successful use of allogeneic HCT following reduced-intensity conditioning in patients with AMM 23,24,35-38. In one series of 21 patients, treatment-related mortality was zero and 16 percent at 100 days and one year, respectively 37. Complete histopathological remission was achieved in 75 percent, with estimated 3-year overall and disease-free survivals of 84 percent. Autologous HCT — Autologous HCT using peripheral blood stem cell rescue following myeloablative single agent chemotherapy with busulfan has been attempted in 21 patients with advanced MMM (ie, anemia, thrombocytopenia, neutropenia, symptomatic splenomegaly, and/or inadequately controlled disease-related symptoms) 39. There were 6 deaths, 3 of non-relapse causes. At a median follow-up of 390 days, estimated two-year actuarial survival was 61 percent. Responses were noted in 10 of 17 anemic patients and 4 of 8 patients with thrombocytopenia, while symptomatic splenomegaly improved in 7 of 10 patients. Further investigation of this approach appears warranted. Androgens — Patients who are not candidates for allo-HCT are treated palliatively. The combination of an androgen preparation (fluoxymesterone, Halotestin, 10 mg PO twice per day) and a corticosteroid (prednisone 30 mg/day PO) improves anemia in some patients. After one month of therapy, treatment with fluoxymesterone is continued in responders and the corticosteroid is tapered. All patients treated with androgens should have periodic monitoring of liver function tests and men should be screened for prostate cancer (digital rectal examination and measurement of serum prostate specific antigen) before initiating therapy. The virilizing side effects of this treatment program should be emphasized in advance to female patients. In our experience, approximately one-third of the patients respond to androgens, although rates varying from 29 to 57 percent have been reported 40,41. In one series of 23 patients, the response rate was 92 percent in those with normal chromosomes compared to 22 percent in those with chromosomal abnormalities 41. Nonresponders were more likely to have severely compromised hematopoiesis, as evidenced by the presence of thrombocytopenia, erythroid suppression on ferrokinetic studies, and lack of activity on bone marrow scans. In a controlled study of 24 patients with chronic myeloproliferative disease (more than one-half of whom had myelofibrosis), a good response to fluoxymesterone, 30 mg/day, was seen in 4 of 14 (29 percent) compared to no good responses in the control arm 40. As in the above-noted study, non-responders were more likely than responders to have reduced effective erythropoiesis. Patients who fail to respond to one androgenic preparation may respond to another, such as oxymetholone or one of the injectable testosterone preparations. (See "Testosterone treatment of male hypogonadism", section on Testosterone preparations). Responses may not occur until after at least three months of treatment. Supportive therapy for anemia — Anemic patients not responding to androgen therapy are usually supported by periodic red cell transfusions. Secondary hemosiderosis from chronic blood transfusion may be palliated by the use of chelation therapy. (See "Iron overload syndromes other than hereditary hemochromatosis", section on Chelation therapy). Other modalities have been tried with variable success: Erythropoietin or darbepoietin have generally not been successful in alleviating the anemia associated with AMM 42-44, although others have reported responses, most often in patients not requiring transfusional support and/or those with inappropriately low serum erythropoietin levels 45-47. Some patients respond to danazol (200 to 800 mg/day), both in our experience and that of others 48,49. Approximately 25 to 50 percent of anemic patients experience a reduction in transfusion requirement after splenectomy (see "Splenectomy" belowsee "Splenectomy" below) 50-52. Coombs-positive autoimmune hemolytic anemia has been described in AMM; it usually responds to prednisone at a dose of 40 mg/m2 per day PO. Immune mechanisms also may impair erythropoiesis. Cyclosporine has been employed in occasional patients with AMM, severe anemia, and immune defects who do not respond to prednisone. One series evaluated ten patients with MMM and steroid-resistant anemia; eight showed evidence of immune defects 53. Three responded to a six month course of cyclosporine (5 mg/kg PO twice per day). Chemotherapy — Chemotherapy in AMM is used to diminish the degree of hepatosplenomegaly with attendant improvement in ascites, pain and/or cytopenias, to relieve constitutional symptoms such as fever and weight loss, or reduce symptomatic thrombocytosis. In the Mayo Clinic series of patients with AMM receiving chemotherapy, a significant reduction in splenic size with relief of pressure symptoms occurred in 70 percent of patients 54. Responses lasted a median of 4.5 months and only 16 percent of patients obtained sustained symptomatic relief. Toxicity was common and often necessitated cessation of treatment. Busulfan (Busulfex, Myleran; starting dose 2 to 4 mg/day PO) and other alkylating agents have been used in the past 54. However, patients with AMM are unusually sensitive to these agents, which may result in prolonged and severe cytopenias even after therapy has been discontinued. An Italian study employed the alkylating agent melphalan (Alkeran) in reduced doses (initial dose 2.5 mg PO three times/week increasing to a maximum dose of 2.5 mg/day) in 104 patients with AMM and splenomegaly, transfusion-dependent anemia, leucocytosis, and/or thrombocytosis 55. All eligible patients were pretreated with danazol (200 mg/day) or prednisone (0.25 mg/kg per day) for at least two months. Responses were noted in 66 of 99 evaluable patients at a median time of 6.7 months. Splenic size, leukocytosis, and thrombocytosis were normalized in 23, 86, and 93 percent, respectively. Anemia improved in 12 of 20 severely anemic patients not requiring transfusion; of the 16 patients requiring transfusion, six became transfusion independent. Hematologic toxicity was common, but was reversible in all patients by discontinuing or reducing the treatment. However, the potential leukemogenicity of this agent has tempered our enthusiasm for its use in this disorder. Hydroxyurea — Because of its demonstrated utility in the other chronic myeloproliferative disorders (eg, chronic myelogenous leukemia, PV, and ET), hydroxyurea has become the agent of choice for such treatment 56. Hydroxyurea may result in a reduction in spleen size and/or control of thrombocytosis and leukocytosis in some patients with AMM 56-59. In one series of 59 patients with a chronic myeloproliferative disease (10 with AMM) and thrombocytosis, chronic therapy with hydroxyurea reduced the platelet count to less than 500,000/microL in six of the ten with AMM (and over 80 percent of those with PV or ET) 56. In another report by the same authors, hydroxyurea also reduced the degree of bone marrow fibrosis in these patients 57. Although the suggested starting dose for hydroxyurea in PV and ET is 15 mg/kg per day PO (average adult daily dose of 500 mg twice per day PO), the initial dose in advanced AMM should be much lower, given the presence of cytopenias in many patients. A starting oral dose of 500 to 1000 mg every other day, with dose modifications depending upon results of frequent blood counts and the patient's clinical status, would seem to be the most prudent approach under these circumstances. Splenectomy — Splenomegaly, often massive and occupying a large portion of the abdomen, is present in virtually all patients with AMM. Surgical removal of such spleens is considered for patients who have symptomatic splenomegaly as manifested by mechanical discomfort, recurrent episodes of splenic infarction, transfusion-dependent anemia, refractory thrombocytopenia, hypercatabolic symptoms, or portal hypertension 50-52,60. (See "Clinical manifestations and diagnosis of chronic idiopathic myelofibrosis (primary myelofibrosis, agnogenic myeloid metaplasia)", section on Splenomegaly). Preoperative laboratory evidence of low-grade disseminated intravascular coagulation (positive soluble fibrin monomer and plasma D-dimer >500 microg/L) may increase the risk of perioperative bleeding, and it is recommended that the operation be postponed until these abnormalities are corrected. At experienced centers, the mortality rate from the procedure should be less than 10 percent, provided that the operation is conducted by an experienced senior surgeon, who pays meticulous attention to achieving hemostasis. Given the complications that may be associated with removing a massively enlarged spleen (see below), an initial report described success with subtotal splenectomy in three patients 61. More experience is required before this approach can be recommended. Two large reported series analyzed the indications for and efficacy of splenectomy in AMM in 321 published cases and 314 patients at a single institution, respectively 50,51. The following findings were noted: The main indications for the procedure were transfusion-dependent anemia (25 percent) and symptomatic splenomegaly (49 percent) 51 The frequency of improvement in one series was 97 percent for painful splenomegaly, 83 percent for portal hypertension, 70 percent for anemia, and 56 percent for thrombocytopenia 50. However, long-term improvements were less common in the second series, with respective values of 49, 40, 50, and 30 percent, respectively 51. The operative mortality after splenectomy was 7.5 to 9 percent, rising to 26 percent after three months; operative morbidity was 31 to 46 percent 50. Patients at greatest risk for perioperative death were those with spleen weight exceeding 2000 g or a platelet count less than 70,000/microL 50. In the second series, operative mortality was in the range of 5.5 to 7.6 percent, with a perioperative morbidity of 25 percent 51. Postsplenectomy thrombocytosis of >450,000 and >1,000,000/microL occurred in 29 and 5 percent of patients, respectively, and was significantly associated with postoperative thrombosis and decreased survival 51. There was no evidence for an effect of splenectomy on survival, the median values for which were 13 and 19 months after surgery in the two series 50,51. The main causes of death not related to surgery were infection, cardiac or thrombotic events, bleeding, and leukemic transformation (which occurred in 11 to 16 percent of patients). Complications — Splenectomy is not a trivial procedure in AMM and is associated with both immediate postoperative and longer term complications. Postsurgical complications include intraabdominal bleeding, subphrenic abscess, sepsis, extreme thrombocytosis that may be associated with thrombosis (eg, stroke, pulmonary embolus, portal vein thrombosis), and accelerated hepatomegaly in 16 to 24 percent due to worsening hepatic myeloid metaplasia and/or loss of splenic sequestration of immature myeloid precursors 51,52. The thrombocytosis and hepatomegaly may be transiently controlled with plateletpheresis, hydroxyurea (starting dose 500 mg PO three times per day) or cladribine (a two-hour intravenous administration of 0.14 mg/kg per day for five days) 62. As noted above, splenectomy is often performed in an attempt to reduce extremely high transfusion requirements associated with splenic sequestration. The question has been raised concerning the potential effect of splenectomy in removing an important site of (extramedullary) erythropoiesis, thereby worsening transfusion requirements. The following information may be helpful in making this decision: Massively enlarged spleens, even with significant degrees of erythropoiesis, also exhibit significant degrees of splenic sequestration and ineffective erythropoiesis. The transfusion requirement for an adult with no effective erythropoiesis (as in severe aplastic anemia or pure red cell aplasia) is usually two to three units of packed red cells every two weeks. Thus, a chronic transfusion requirement in a nonbleeding patient with AMM greater than three units of red cells every two weeks indicates that the spleen is not an "effective" source of red cell production. Another concern that has been raised is the potential facilitation of leukemic transformation following splenectomy 63. The concern of these investigators was based on a retrospective series of splenectomized patients compared to a "control" group of patients who had not undergone splenectomy. In our experience, it is impossible to case-match patients who are in need of splenectomy. However, splenic histopathology may help in determining the course of the disease post-splenectomy 64. Thus, the presence of microscopic splenic infarcts, a pattern of immature granulocyte predominance, or the detection of an abnormal splenic karyotype were found to be significantly associated with decreased survival post-splenectomy. Radiation therapy Splenic irradiation — Splenic irradiation (SI) usually provides a transient (three to six months) benefit and can be appropriate for patients who are poor surgical candidates. In our series of 23 patients with MMM, eight of whom received multiple courses of SI, 94 percent of courses resulted in an objective reduction in splenic size and symptomatic relief; the median duration of response was six months 65. The median dose of SI per course was 2.8 Gy, administered in a median of 7.5 fractions. Significant cytopenia occurred in 32 percent of courses, and life-threatening pancytopenia after a single course of SI occurred in six patients (26 percent), resulting in fatal sepsis or hemorrhage in three. Nine patients underwent subsequent splenectomy with a perioperative mortality of 11 percent; three of these required reexploration for postoperative bleeding. Other centers have used total SI doses as low as 0.15 Gy and as high as 65 Gy, with generally excellent results, especially if SI is started in small fractions of 0.25 to 0.50 Gy given two to three times per week, with modifications as dictated by the clinical situation and frequently obtained blood counts. The range of regimens can be illustrated by the following two reports: In a retrospective study of 14 patients with MMM treated with SI for symptoms due to splenomegaly, doses ranged from 7 to 24 Gy 66. Relief of symptoms was achieved in all patients, with 30 to 70 percent reduction in splenic size. Side effects were mild and did not require interruption of treatment, although four patients developed severe anemia. In another series, 17 patients with CML or MMM were treated with SI to a total dose of 0.15 to 16 Gy, with fractions given only two to three times per week 59. Fourteen of 19 courses given for splenic pain produced a significant subjective relief, while 17 of 26 courses given for splenomegaly obtained at least 50 percent reduction in splenic size. Other sites of disease — Radiation therapy is extremely successful in the management of symptomatic foci of extramedullary hematopoiesis (EMH), including the spinal cord, peritoneal and pleural cavities, focal areas of bone pain due to granulocytic sarcoma (chloroma) or periostitis, and whole-lung treatment for pulmonary hypertension. (See "Clinical features, diagnosis, and prognosis of acute myeloid leukemia", section on Extramedullary presentations/Granulocytic sarcoma). Specific treatment programs that have been successfully employed include 67-70: In four patients with paraspinal or intraspinal EMH, the median dose of radiation was 1 Gy (range: 1 to 10 Gy), delivered in one to five fractions. Two patients with pulmonary and/or pleural EMH requiring treatment received 1.0 to 1.5 Gy delivered in one to 10 fractions. Administration of fractional doses of radiation (0.25 Gy/day, with rotation into all four abdominal quadrants, to a total dose of 5 to 10 Gy) is extremely effective in the treatment of ascites due to peritoneal implants of EMH 69. Low-dose radiation to the liver (median dose per course: 1.50 Gy; range: 0.50 to 10 Gy) has been given for symptomatic hepatomegaly in 14 patients with advanced MMM 70. Such treatment has been found to be myelosuppressive, providing only temporary (median three months), and mainly subjective, relief. Anagrelide — Anagrelide is an oral agent that has a specific platelet-lowering effect in humans, and is capable of controlling thrombocytosis associated with PV and ET 71. In one study, 17 patients with MMM (including patients with post-polycythemia and post-thrombocythemia myelofibrosis) were treated with anagrelide (starting and median maintenance doses of 1 mg/day PO) for a median period of 2 years 72. Platelet counts were decreased in 13, unchanged in one, and increased in three patients. No clinical benefit was obtained in any patient in terms of anemia, transfusion requirement, or reduction in hepatosplenomegaly. Bone marrow megakaryocyte numbers were increased after six months of treatment; no patient had a significant change in either bone marrow fibrosis or osteosclerosis. Interferon alfa — Interferon alfa (IFNa) induces both hematologic and cytogenetic remissions in chronic-phase CML, and has shown utility in ET and PV. IFNa has multiple effects on reducing proliferation of fibroblasts and bone marrow progenitor cells in vitro, suggesting that it might be useful in patients with MMM. The efficacy of IFNa has been best evaluated in a series 54 patients with myeloproliferative disease (PV, ET, and MMM) who were treated with initial subcutaneous doses of IFNa of five million IU/day; the following benefits were noted 73: Control of thrombocythemia was seen in 24 of 24 patients with this problem Control of hyperleukocytosis was seen in 14 of 14 patients At least a 10 percent reduction in splenic size was seen in 26 of 39 patients with splenomegaly. The median follow-up was 7.3 years and at the time of publication, one-half were still participating at a median follow-up of 3.8 years. Treatment was generally well-tolerated; toxicity caused treatment withdrawal in 7 patients (13 percent). Thirty-nine of the 54 patients maintained the response for a median of 39 weeks after withdrawal of IFNa; repeat courses of therapy in previously responding patients produced similar results. However, our own, as well as the ECOG, experience with IFNa has not been favorable 74. In a phase II trial involving 11 patients with previously untreated "hyperproliferative" MMM, weekly doses of up to 15 million units of IFNa were given for as long as one year 75. Unacceptable drug toxicity was present in seven of the 11 patients, necessitating discontinuation. No beneficial changes in splenic size, reticulin fibrosis, osteosclerosis, or microvessel density were seen in any patient. Thalidomide — Thalidomide has been evaluated mainly in previously-treated patients with MMM. Beneficial responses, which have been seen in 20 to 40 percent of patients, have included disappearance of constitutional symptoms, reduction in splenic size, improvements in hemoglobin concentration, white blood cell, and platelet counts, as well as transfusion independence 76-80. In these studies, few patients were able to tolerate doses higher than 400 mg/day because of side effects, which included drowsiness, constipation, fatigue, paresthesias, and neutropenia 81. In one study of 63 patients, the median maximally-tolerated dose was 100 mg/day and the cumulative drop-out rate due to adverse drug side effects was 51 percent after six months of therapy 79. In our study, the median duration of treatment was only 16 weeks; preliminary results suggested that low starting doses (ie, 50 mg/day) with more gradual dose escalation may be as effective and more tolerable 78,82. Adverse hematologic effects were seen in four of 15 patients (eg, extreme thrombocytosis and leukocytosis and pericardial extramedullary hematopoiesis with clinical tamponade). Thalidomide and prednisone — In order to improve tolerability of thalidomide, we prospectively treated symptomatic MMM patients with low-dose thalidomide (50 mg/day PO) plus a three-month oral prednisone taper (starting prednisone dose 0.5 mg/kg PO per day) 82,83. Twenty of the 21 patients were able to complete the 3-month course, with an objective clinical response in 13. Responses included improvement of anemia in 13 patients, red cell transfusion independence in four, platelet count increases in six, and >50 percent decreases in splenic size in four. This dose of thalidomide was better tolerated than those used in previous studies (see "Thalidomide" above). Leukocytosis and thrombocytosis were observed in 38 and 19 percent of patients, respectively; one episode of deep vein thrombosis was noted, a complication which has been seen with this agent when used in other malignant disorders. Adverse events associated with prednisone were mild and transient. (See "Thrombotic complications following treatment with thalidomide and its analogues"). At a median follow-up of 25 months for the 36 patients treated with thalidomide in our two series, the overall long-term response rate was 28 percent (10 patients) 78,82,83. Durable treatment responses were seen for anemia and thrombocytopenia, but not for splenomegaly. Lenalidomide — A number of cooperative phase II studies are evaluating the utility of the thalidomide analog lenalidomide with or without prednisone in patients with AMM. In one report, overall response rates were 22, 33, and 50 percent for anemia, splenomegaly, and thrombocytopenia, respectively 84. Grades 3 or 4 adverse events included neutropenia and thrombocytopenia in 31 and 19 percent of patients, respectively. Etanercept — Use of etanercept (Enbrel, 25 mg SQ twice weekly), a soluble tumor necrosis factor receptor, resulted in improvement of constitutional symptoms (eg, weight loss, night sweats, fatigue, fever) in 12 of 20 evaluable patients with MMM 85. Objective responses (eg, anemia, thrombocytopenia, spleen size) were noted in four patients. Reversible pancytopenia was noted in one patient, necessitating cessation of this agent. Toxicity was otherwise mild and well tolerated. In an small phase II trial, the combination of thalidomide, prednisone, and eternacept alleviated symptoms and was well tolerated, but did not appear to be superior to thalidomide/prednisone in terms of therapeutic value for anemia, thrombocytopenia, or splenomegaly 86. Imatinib mesylate — We have conducted a phase II trial with the tyrosine kinase inhibitor imatinib mesylate in 23 patients with MMM 87. Toxicity was appreciable, with no discernible clinical benefit. In a second study, 13 of 18 patients treated with this agent showed only minor degrees of clinical or hematologic improvement 88. RECOMMENDATIONS Prognosis and treatment overview — The prognosis and need for treatment of agnogenic myeloid metaplasia (AMM) or the fibrotic states following polycythemia vera or essential thrombocythemia (postpolycythemic myeloid metaplasia and postthrombocythemic myeloid metaplasia, respectively) are strongly dependent upon the presence or absence of signs and symptoms of the disease (eg, anemia, painfully enlarged spleen, systemic symptoms, refractory cytopenias, thrombocytosis, portal hypertension, cord compression secondary to foci of extramedullary hematopoiesis). (See "Clinical manifestations and diagnosis of chronic idiopathic myelofibrosis (primary myelofibrosis, agnogenic myeloid metaplasia)"). In the absence of adverse prognostic factors such as anemia and constitutional symptoms, there may be very little need for treatment, with an expected survival in excess of 10 years (see "Prognosis" above). Survival and quality of life can be severely limited in this disorder, with an expected survival as short as one year for the most symptomatic patients (see "Prognosis" above). While allogeneic hematopoietic cell transplantation (HCT) is the only curative treatment for this disorder, it is associated with a high treatment-related mortality, and may not be available for older patients with severe comorbidities and those without a suitable donor. Other than HCT, all of the other available treatment modalities are palliative, with variable degrees of efficacy and treatment-related complications. There are few randomized trials comparing these modalities, preventing our ability to give strong recommendations for selecting one treatment over another. Hematopoietic cell transplantation For younger patients with two or more adverse features (ie, hemoglobin <10 g/dL, constitutional symptoms, isolated cytogenetic abnormality, or blasts >1 percent) we suggest that the patient be considered for hematopoietic cell transplantation HCT shortly after diagnosis (Grade 2B). (See "Allogeneic HCT" above). For low-risk patients, who might live 10 to 15 years with supportive treatment alone, but might have a transplant-related mortality of at least 8 percent, the answer is not yet clear. Until further information is available, we suggest HCT for the latter group when an adverse risk factor appears (Grade 2C). Supportive modalities In the absence of allogeneic HCT as a therapeutic option, we suggest the use of one or more of the following palliative modalities for the symptomatic patient (Grade 2C). For each of the agents listed below, the symptom(s) for which is agent is most effective is noted in parentheses. Androgens, danazol (anemia) Blood transfusions with or without erythropoietin (anemia) Hydroxyurea (splenomegaly, thrombocytosis, leukocytosis) Alkylating agents (splenomegaly, thrombocytosis, leukocytosis) Thalidomide and prednisone (systemic symptoms, anemia, splenomegaly, refractory cytopenias) Etanercept (systemic symptoms) Splenic irradiation (painful splenomegaly) Radiation therapy (symptomatic areas of extramedullary hematopoiesis, cord compression) Splenectomy — Splenectomy can be considered in selected patients with a painfully enlarged spleen, anemia and other refractory cytopenias, and/or severe degrees of portal hypertension. This procedure carries a very high operative mortality and morbidity, and should not be undertaken lightly
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