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Myelomas

Advances in the Therapy of Chronic Idiopathic Myelofibrosis

^a Departments of Internal Medicine and ^b Oncology, Hospital Nacional Edgardo Rebagliati Martins, Lima, Peru; ^c Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA

Key Words. Myelofibrosis • Myeloproliferative disorders • Therapy

Correspondence: Srdan Verstovsek, M.D., Ph.D., M.D. Anderson Cancer Center, Department of Leukemia, Unit 428, Houston, Texas 77230, USA. Telephone: 713-745-3429; Fax: 713-794-4297; e-mail: sverstov{at}mdanderson.org

Received April 28, 2006; accepted for publication July 19, 2006.

	LEARNING OBJECTIVES

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After completing this course, the reader will be able to:

1. Discuss the clinical manifestations of myelofibrosis with myeloid metaplasia and recent developments in the understanding of its pathogenesis.
   
2. Discuss the most recent clinical trials involving novel therapies for myelofibrosis with myeloid metaplasia.
   
3. Propose an algorithm-based approach to the treatment of patients with myelofibrosis with myeloid metaplasia.
   

	ABSTRACT

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The molecular basis of chronic idiopathic myelofibrosis (CIMF) has remained elusive, thus hampering the development of effective targeted therapies. However, significant progress regarding the molecular mechanisms involved in the pathogenes is of this disease has been made in recent years that will likely provide ample opportunity for the investigation of novel therapeutic approaches. At the fore front of these advances is the discovery that 35%–55% of patients with CIMF harbor mutations in the Janus kinase 2 tyrosine kinase gene. Until very recently, the management of patients with CIMF involved the use of supportive measures, including growth factors, transfusions, or interferon, and the administration of cyto-reductive agents, such as hydroxyurea and anagrelide. However, several trials have demonstrated the efficacy of antiangiogenic agents alone or in combination with corticosteroids. In addition, the use of reduced-intensity conditioning allogeneic stem cell transplantation has resulted in prolonged survival and lower transplant-related mortality.

	INTRODUCTION

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Chronic idiopathic myelofibrosis (CIMF) is a clonal hematopoietic stem cell disorder characterized by increased bone marrow collagen fibrosis and microvessel density, leukoerythroblastic anemia with teardrop-shaped red cells, splenomegaly, and extramedullary hematopoiesis [1, 2]. CIMF harbors the worst prognosis among the Philadelphia chromosome (Ph)-negative chronic myeloproliferative disorders (CMPDs) and varies considerably, as defined by a set of prognostic factors including hemoglobin level, constitutional symptoms, circulating blasts, leukocyte count, and cytogenetics [3]. Morbidity and mortality associated with CIMF [4] are most commonly a result of leukemic transformation, portal hypertension, infection, and thrombohemorrhagic events. CIMF may present as either idiopathic myelofibrosis with agnogenic metaplasia or as transformation from other CMPDs, such as polycythemia vera (PV) and essential thrombocythemia (ET) [1, 2].

Primary myelofibrosis accounts for approximately 90% of all cases [5, 6] and is usually diagnosed between the fifth and sixth decades of life. The incidence in the U.S. has been estimated at 1.46 cases per 100,000 annually, or approximately 1,600 new cases each year [2, 7]. Leukemic transformation occurs in nearly 20% of all patients with CIMF [8, 9]. Clinical manifestations of CIMF include fatigue, weight loss, low-grade fever, night sweats, and symptoms of extra-medullary hematopoiesis such as pleural effusion, cardiac tamponade, spinal cord compression, and pulmonary hypertension [1]. However, as many as one third of the patients with CIMF are asymptomatic at diagnosis [10]. Splenomegaly or abnormal blood findings are frequently discovered by accident upon routine examination. In advanced stages, general malaise, weight loss, and symptoms attributed to splenomegaly or splenic infarction may occur. These patients may present with leukocytosis, thrombocytosis, or variable degrees of cytopenias. Bone marrow fibrosis and myeloproliferation related to extra medullary hematopoiesis are manifested in the peripheral blood as myelopthisis and characterized by leukoerythroblastosis and dacryocytosis [1, 11–17]. Disruption of the immune response [2, 13] is also an important feature of CIMF.

The clonal character of CIMF has been demonstrated in different cell types [18]. Marrow fibrosis, however, is a polyclonal reactive process whose pathogenesis involves the interaction of several cytokines such as transforming growth factor beta 1 (TGF-ß1), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), osteocalcin, and osteoprotegerin [19].

The genetic basis underlying Ph-CMPDs has remained elusive, although thought to originate from somatic mutations in hematopoietic progenitors. Recently, several independent studies have described a novel activating somatic point mutation in the gene encoding the cytoplasmic Janus kinase 2 (JAK2), characterized by the substitution of valine to phenylalanine at codon 617 (JAK2^V617F) [20–24]. The incidence of JAK2^V617F was in the range of 37%–57% in five studies that included CIMF patients [20–24], although this was found to be as high as 91% in patients with postpolycythemic myelofibrosis in a mutational analysis performed in 157 patients with CIMF [25]. This exciting discovery has not only provided a common pathogenetic link for CMPDs that will aid in the diagnosis and taxonomy of these disorders but has also opened further avenues for the development of new targeted therapies.

CIMF carries the worst prognosis of all CMPDs, with a median survival time of 3.5–5.5 years [1], although interindividual survival may vary substantially [1–4, 10, 14, 26]. It has been shown that advanced age, anemia, hypercatabolic symptoms (fever, night sweats, and weight loss), leukocytosis, leukopenia, thrombocytopenia, karyotypic abnormalities, higher megakaryocytic count in bone marrow biopsy, and number of circulating blasts and CD34⁺ progenitors are independently correlated with short survival [3, 27–32]. The most serious complication in CIMF is transformation to acute leukemia [9]. Several prognostic systems have been developed to guide risk-adapted therapy in patients with CIMF by combining these variables. These models are most useful when considering aggressive therapeutic measures associated with significant side effects [3, 27–31]. Recent studies have shown that the presence of cytogenetic abnormalities different from 13q- or 20q- carry an independent prognostic effect for both survival and the risk for leukemic transformation [33, 34]. In addition, the presence of unfavorable cytogenetic aberrancies appeared to be the strongest predictor of poor survival in patients with post-PV or post-ET myelofibrosis, which suggests that cytogenetic findings might supersede current prognostic systems in patients with secondary myelofibrosis [34]. In one study, cytogenetic abnormalities were detected in 47 (45%) of 105 patients studied, and the JAK2^V617F mutation was detected in 52 (50%) [35]. Unfavorable cytogenetic findings clustered with homozygosity for JAK2^V617F, whereas the presence of favorable cytogenetic findings was associated with response to erythropoietin therapy [35].

Currently, allogeneic hematopoietic stemcell transplantation (allo-SCT) constitutes the only potentially curative option for CIMF. This treatment modality is largely limited to young patients with negligible comorbidities. Advances in conditioning regimens, including the use of nonmyeloablative approaches, have significantly improved the outcome of patients with CIMF undergoing allo-SCT [18, 19, 36, 37]. However, no therapy thus far has proven effective in prolonging overall survival in CIMF. Further study is justified for supportive research in the treatment of this disease.

The following review focuses on the medical management of CIMF with both standard and investigational therapies, including bone marrow transplant. Particular emphasis is given to recent reports discussing important mechanisms in CIMF pathogenesis that are amenable to novel targeted therapies, such as antiangiogenic and anti-cytokine agents.

	CONSERVATIVE THERAPY FOR MYELOFIBROSIS

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No therapeutic approach has been efficacious at reducing overall mortality, and therefore, medical therapy for CIMF is typically administered with supportive intent (Fig. 1). Treatment is aimed at improving quality of life through palliation of symptoms and control of peripheral blood counts (Table 1). However, in the subset of patients with CIMF who are asymptomatic at diagnosis, it is reasonable to withhold therapy until symptoms ensue or there is evidence of disease progression.

View larger version (26K): [in this window] [in a new window]   Figure 1. Algorithm of treatment for chronic idiopathic myelofibrosis

Corticosteroids have been administered to patients with CIMF for palliation of constitutional symptoms and anemia. Response rates are close to 30%, particularly in those patients in whom anemia might have a hemolytic etiology [46, 47]. Anecdotal data suggest that dexamethasone may render modest improvements in hemoglobin levels in selected patients with CIMF [48]. Currently, corticosteroids are considered to be more active when combined with other drugs, such as androgens and thalidomide [38, 43, 49].

Erythropoietin
Initial studies failed to show significant improvements in hemoglobin levels upon administration of recombinant erythropoietin (rEpo). However, more recent investigations have demonstrated significant responses and decreased transfusion dependence in anemic patients with CIMF [50–53]. The rEpo doses employed in those studies were in the range of 300–1,500 U/kg weekly. This finding underscores the current uncertainty about the optimal dose and schedule of rEpo in this disease. It is important to note that many patients with CIMF have normal serum erythropoietin levels, suggesting a potential lack of efficacy of rEpo in this setting [54]. Rodriguez et al. [51] showed that a serum erythropoietin level <123 mU/ml was highly predictive of response to rEpo. This was recently corroborated by Cervantes et al. [53] in a study in which rEpo was given at an initial dose of 10,000 U three times per week to 20 patients with CIMF. Nine patients (45%) responded, including four who achieved normal hemoglobin levels. A serum erythropoietin level <125 mU/ml was associated with a favorable response to rEpo in the multivariate analysis [53]. The combination of rEpo and thalidomide may represent a valid approach for patients with advanced CIMF [55].

Alternatively, epoetin beta has also shown efficacy in the management of anemia in hematological malignancies, with a more convenient once-weekly administration and fewer adverse effects [56]. However, its efficacy in patients with CIMF warrants further investigation.

Interferon Alpha
The immunomodulatory role of interferon (IFN)- in CMPDs suggested a potential role for this drug for the treatment of CIMF. IFN- inhibits megakaryocytes and fibroblast proliferation, and controls collagen production in experimental models of myelofibrosis [57]. In addition, IFN- inhibits, in vitro and in vivo, fibrogenic cytokines such as TGF-ß 1 and PDGF and, in vitro, has been shown to have an antiproliferative effect on hematopoietic progenitor stem cells [58, 59]. However, most prospective clinical studies have failed to demonstrate significant activity in patients with CIMF, except in those exhibiting hyperproliferative features (leukocytosis and thrombocytosis), for whom this agent acts in a nonspecific myelosuppressive manner [60–62]. This is in contrast to the remarkable results achieved by IFN- for other CMPDs [63–65]. In all of these studies, the most frequently used dose was 5 million U/day three to five times weekly, although lower doses may be adequate for the control of high blood counts in patients with CIMF. Preliminary results have been equally disappointing with IFN- [66] and pegylated interferon [67] because of the lack of tolerance and myelosuppression that have led to high dropout rates and precluded dose escalation.

Cytotoxic Agents
Hydroxyurea is a ribonucleotide reductase inhibitor that has been widely used for the control of leukocytosis, thrombocytosis, and splenomegaly in patients with CIMF [1]. Although there is no evidence that hydroxyurea alters the natural history of CIMF or prolongs survival, it is considered a first-line agent for many physicians at a dose of 15–20 mg/kg per day that is titrated to maintain normal peripheral blood counts [68, 69]. Hydroxyurea is generally well tolerated, although it can potentially worsen anemia and thus require concomitant administration of rEpo. It has been reported, although not validated in large clinical trials, that hydroxyurea may render marked reductions in bone marrow fibrosis [70]. The risk for leukemic transformation associated with hydroxyurea is a subject of ongoing debate because of the lack of randomized studies [71]. Several reports have failed to show an increase in DNA mutations in patients with CMPDs treated with hydroxyurea [68, 72]. Notably, in the recently published European Collaboration on Low-dose Aspirin in Polycythemia Vera (ECLAP) prospective project, which included 1,638 patients with PV, exposure to hydroxyurea as a single agent was not associated with progression to leukemia in a multivariate analysis [73].

Several cytotoxic agents have been used as alternatives to hydroxyurea, such as low-dose melphalan, busulphan, 6-thioguanine, and 2-chlorodeoxyadenosine (2-CDA). In a clinical trial of 104 patients with CIMF, normalization of clinical and hematological parameters was observed in 67% of the patients who received melphalan at a dose of 2.5 mg three times weekly for at least 6 months [74]. However, the drug was discontinued because of a 26% rate of leukemic transformation.

Busulphan is another efficacious agent in CIMF patients who have failed prior therapy with hydroxyurea [75, 76]. However, busulphan is also associated with a significant risk for leukemic transformation. Busulphan is also widely used in stem cell transplant preparative regimens.

2-CDA is a purine nucleoside analog with myelosuppressive properties that has been studied in a pilot trial to palliate thrombocytosis, leukocytosis, and progressive hepatomegaly in patients with CIMF after the rapeutics plenectomy [77]. A hematologic improvement was achieved in seven (78%) patients and a decrease in bone marrow fibrosis was seen in two (22%) patients who were treated surgically. Recently, a long-term follow-up analysis of 14 patients treated with 2-CDA showed improvement in hepatomegaly (56%), thrombocytosis (50%), and leukocytosis (55%) [78], with a median duration of response of 6 months. This evidence supports the palliative role of 2-CDA in this circumstance.

Anagrelide
Anagrelide hydrochloride is an oral imidazoquinazoline derivative approved by the U.S. Food and Drug Administration (FDA) as a first-line agent for the control of thrombocytosis associated with CMPDs because of its potent anti-platelet activity. Chronic exposure to anagrelide results in a left shift in megakaryocytic maturation and inhibition of endoduplication. This causes a decrease in ploidy and cell size and an increase in the number of promegakaryoblasts [79]. Its use in CIMF has been advocated on the basis of the important role that megakaryocytes play in the pathogenesis of CIMF by secreting cytokines that promote fibrosis and osteosclerosis [80]. Improvement in platelet counts was observed in 13 of 20 patients with advanced CIMF treated with anagrelide in a trial conducted by Yoon et al. [81]. How-ever, anagrelide had no impact on bone marrow fibrosis or on the production of the profibrotic cytokines TGF-ß and PDGF [81]. Importantly, a recent randomized trial comparing hydroxyurea with anagrelide in 809 high-risk patients with ET has challenged the status of anagrelide as first-line therapy in CMPDs. The excess rates of vascular events and transformation to myelofibrosis in the anagrelide group led to early termination of the study. This established hydroxyurea as the front-line therapy for patients with CMPDs and high platelet counts [82].

Splenectomy
Splenectomy has been extensively used for symptomatic palliation in CIMF. Recently, Mesa et al. [83] have reported on 314 patients with CIMF who underwent splenectomy between 1976 and 2004. The perioperative morbidity (infection, thrombosis, and bleeding) rate was 27.7% and the operative mortality rate was 6.7%. Symptomatic improvement was attained by most of the patients, and 50% of patients undergoing splenectomy for anemia experienced an improvement in their hemoglobin levels. The median overall survival time from the time of splenectomy was 19 months. Platelet count <100 x 10⁹/l prior to splenectomy was associated with a worse overall survival. Postsplenectomy accelerated hepatomegaly and thrombocytosis occurred in 10.2% and 28.6% of patients, respectively [83]. Leukemic transformation occurred in 14.3% of patients at a median time of 15.6 months after splenectomy but did not alter postoperative survival. Although historically it has been suggested that the risk for progression to leukemia is increased by splenectomy [84], there is no direct evidence to support this contention.

	RADIOTHERAPY

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The infiltrative nature of extramedullary hematopoiesis is not limited to the spleen but can also extend to the liver, peritoneum, and spinal cord, causing organ impingement and dysfunction. Because of the radiosensitive nature of myeloid progenitors in CIMF, the use of palliative external beam radiotherapy can be indicated when extramedullary hematopoiesis occurs in anatomical locations where surgical resection is risky or not feasible.

Splenic Irradiation
Radiation of the spleen has been widely used in CIMF [85–88]. In one study, the administration of a median of 277 cGy over a median of 7.5 fractions resulted in spleen shrinkage in 93.9% of courses accompanied by symptomatic improvement for a median time of 6 months [89]. However, 43.5% of patients experienced significant cytopenias, of which 13% were fatal as a result of sepsis or hemorrhage. Therefore, the use of external beam splenic radiotherapy is recommended for symptomatic patients with no significant cytopenias in whom splenectomy is contraindicated.

Pulmonary Irradiation
Pulmonary hypertension may complicate the course of CIMF as a consequence of myeloid infiltration of the lung and is associated with high morbidity and mortality. Therapy with whole-lung external beam radiotherapy in a single fraction of 100 cGy may induce marked improvement in performance status and pulmonary artery systolic pressure within 72 hours in patients with advanced CIMF [90].

Other Sites of Extramedullary Hematopoiesis
Expeditious administration of external beam radiotherapy is indicated when extramedullary hematopoiesis manifests as spinal cord compression or a paraspinal mass to avoid neurologic sequelae [12]. Concurrent administration of high-dose steroids further decreases the surrounding edema [91]. Palliative abdominal radiotherapy has also been administered to alleviate symptoms related to hepatomegaly and/or ascites resulting from peritoneal infiltration of myeloid progenitors using fractionated radiotherapy at doses of 50–1,000 cGy [92]. Symptomatic relief is achieved in the majority of patients, although responses are usually transient.

	INVESTIGATIONAL APPROACHES IN CIMF THERAPY

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Cumulative evidence regarding the importance of bone marrow stromal proliferation and neovascularization in CIMF [92] and the implication of a variety of profibrotic and proangiogenic cytokines in this process, such as bFGF, TGF-ß , and PDGF, have driven the development of agents targeted to the aforementioned factors and other signal transduction inhibitors. In addition, the recent introduction of reduced-intensity nonmyeloablative conditioning regimens has rekindled the interest in the use of allo-SCT. CIMF is a disease in which toxicity, rather than disease recurrence, has hindered the development of this therapeutic approach in the past.

Thalidomide and Immunomodulatory Drugs
Thalidomide has been used in CIMF based on its antiangiogenic and immunomodulatory properties [49, 93–99]. Thalidomide inhibits tumor necrosis factor (TNF)- and TNF-ß , bFGF, interleukin (IL)-1ß , IL-6, IL-12, and GM-CSF and stimulates T-lymphocyte proliferation [94–96]. A pooled analysis of 62 patients in five studies [94, 100–103], who were treated with thalidomide at doses of 100–600 mg daily, showed an improvement in anemia and platelet counts and decreased splenomegaly in 29%, 38%, and 41% of 49 patients treated for more than 4 weeks, respectively [98]. However, the overall dropout rate at 6 months was 66% because of poor tolerance. A phase II study, using thalidomide at a dose of 50 mg/d and prednisone at a dose of 0.5 mg/kg per day for the first 3 months, obtained improvements in anemia (62%) and platelet counts for 95% of the patients who were able to complete 3 months of therapy [49]. Of interest, no effect on bone marrow angiogenesis or fibrosis was seen in that study, which refuted the findings of Piccaluga et al. [102]. In two sequential phase II studies conducted at the Mayo Clinic (Rochester, MN), thalidomide was given to 36 patients with CIMF at either an initial dose of 200 mg/d with escalation to a maximum of 1,000 mg/d (n = 15) or at 50 mg/d in combination with prednisone (n = 21) [103]. Fifteen of 36 (42%) patients had an improvement in anemia, 10 of 13 (77%) had an improvement in their thrombocytopenia, and 5 of 30 (17%) experienced a decrease in spleen size. The combination of low-dose thalidomide and prednisone was better tolerated and more efficacious. After a median follow-up of 25 months, 10 of 36 (28%) patients showed an ongoing response [103]. Although thalidomide seems to be beneficial for the management of cytopenias in CIMF, some studies have reported negligible activity [104, 105]. For instance, in a double-blind study, 52 patients with CIMF were randomized to receive either thalidomide (400 mg daily) or placebo for 6 months. The main aim of the study was to evaluate the activity of thalidomide in increasing the hemoglobin level by 2 g/dl or reducing red blood cell transfusions by 20% in anemic patients with CIMF. No benefit was observed in survival or any other clinical or biological data [105].

Lenalidomide (CC-5013; Revlimid^®; Celgene Corporation, Warren, NJ) is a second-generation immunomodulatory drug with a superior toxicity profile relative to thalidomide, particularly regarding sedation, neuropathy, and constipation. Lenalidomide is also 2,000-fold more potent than thalidomide as a TNF- inhibitor [106] that shows increased antiangiogenic activity in vivo [107]. In a phase II study, 27 patients received lenalidomide (10 mg daily) for three consecutive 28-day cycles, with an additional three cycles given in case of response. After a median follow-up of 16 months, six patients experienced either a complete (three patients), partial (two patients became transfusion independent), or marginal (one patient) response [108]. Recently, results from two similarly designed phase II trials involving 68 patients with CIMF (both primary and secondary to other CMPDs) treated at the Mayo Clinic (n = 27) and M.D. Anderson Cancer Center (n = 41) have been jointly reported [109]. Therapy consisted of lenalidomide at a dose of 10 mg daily (5 mg daily if baseline platelet count was <100 x 10⁹/l) for 3–4 months. Overall response rates were 22% for anemia, 33% for splenomegaly, and 50% for thrombocytopenia. Eight patients with either baseline hemoglobin levels <10 g/dl or transfusion dependency experienced a normalization in their hemoglobin levels, and two patients had a decrease in bone marrow fibrosis and angiogenesis. Grade 3–4 adverse events included neutropenia (31%) and thrombocytopenia (19%). Based on its remarkable activity as a single agent, clinical trials combining lenalidomide with corticosteroids are planned for patients with CIMF.

Other Antiangiogenic Agents
Vatalanib (PTK787/ZK 222584), an oral inhibitor of the VEGF receptor (VEGFR)-1 and VEGFR-2 tyrosine kinases (Flt-1 and Flk-1/KDR) as well as the PDGFR and c-Kit [110], and SU5416, a synthetic inhibitor of VEGFR-2, c-Kit, and Flt-3, have been used in phase II trials in patients with CMPDs on the premise of their antiangiogenic activity [111, 112]. Overall, clinical activity was minimal. SU6668, in turn, inhibits the tyrosine kinase receptors of VEGF, c-Kit, bFGF, and PDGF and exhibits potent antiangiogenic activity. Analysis of its activity in CIMF is warranted [113].

Sorafenib (BAY 43-9006) is a potent inhibitor of Raf-1 (a member of the Raf/mitogen-activated protein kinase/extracellular-signal-regulated kinase (ERK) kinase (MEK)/ERK signaling pathway) and several receptor tyrosine kinases involved in neovascularization, including VEGFR-2, VEGFR-3, PDGFR-ß , Flt-3, and c-Kit [114]. However, continuous exposure for 14 days to this agent of peripheral blood mononuclear cells from patients with CIMF led to a median 50% inhibitory concentration of 12 µM. There was no detectable inhibition of colony formation in 8 of 12 CIMF samples [115]. These data do not support a clinical trial of sorafenib in CIMF.

Etanercept
Etanercept is a soluble, dimeric, recombinant form of the extracellular domain of human p75 TNF receptor fused to the Fc fragment of human IgG₁. It was originally used in rheumatoid arthritis because of its potent anti-TNF- activity [116]. Because TNF- is thought to be important in the pathogenesis of CIMF [28], etanercept was administered to 22 patients with CIMF at 25 mg twice weekly for up to 24 weeks [117]. Constitutional symptoms improved in 60% of patients, and 20% experienced regression of splenomegaly and/or improvement in cytopenias. Improvements in the latter two features were also observed in three of nine patients with CIMF treated with etanercept at a dose of 25 mg twice weekly for at least 8 weeks [118]. Mesa et al. [119] recently reported on 15 patients with CIMF treated with the combination of etanercept (25 mg s.c. twice weekly) with low-dose thalidomide (50 mg daily) and a 3-month prednisone taper starting at 0.5 mg/kg per day. Improvement in hemoglobin level and platelet count was observed in 6 of 11 anemic patients and all seven patients with thrombocytopenia, respectively. In addition, a >50% decrease in organomegaly was documented in 25% of patients and significant improvement in constitutional symptoms was observed in six patients with severe symptoms. Overall, therapy was well tolerated, but this regimen was not superior to the combination of thalidomide and prednisone.

Signal Transduction Inhibitors

Imatinib
Imatinib mesylate (Gleevec^®; Novartis Pharmaceuticals Corporation, East Hanover, NJ) is a specific inhibitor of the Abl, PDGFR, c-Kit, and Arg tyrosine kinases and has become the standard therapy in chronic myelogenous leukemia (CML) [120]. Imatinib was tested in patients with CIMF based on its inhibition of PDGF-mediated signaling and the amelioration of bone marrow fibrosis and microvessel density in patients with CML [121, 122]. In general, all phase II studies published to date [124–129] in patients with CIMF have shown modest results. Only one trial showed a significant improvement in splenomegaly, including four patients (29%) who had a normalization of spleen span [126]. Imatinib was administered at doses of 200–800 mg daily, but dropout rates were in excess of 50% across all trials. This was primarily because of a lack of tolerance secondary to edema, fatigue, and musculoskeletal pain [123–129]. Of note, Hasselbalch et al. [128] reported proliferative effects in 9 of 11 patients who received imatinib at a dose of 400 mg daily, requiring hydroxyurea to manage leukocytosis and thrombocytosis. Preliminary data on the efficacy of imatinib in CIMF reported in the European Myelofibrosis Network (EUMNET) trial documented an increase in the number of clonogenic megakaryocytic progenitors in bone marrow, suggesting that imatinib may restore megakaryocyte differentiation and thus be an effective treatment of thrombocytopenia in patients with CIMF [130].

Farnesyl Transferase Inhibitors
ras gene mutations are commonly encountered in a variety of hematologic disorders [131], including 6% of patients with CIMF [132]. Ras is initially synthesized in the cytoplasm as an inactive protein and later attaches to the membrane. This is a critical step in Ras function and is accomplished through a post-translational reaction termed prenylation, whereby a 15-carbon isoprenyl (farnesyl) group is attached to the Ras C-terminal cysteine by an enzyme called farnesyltransferase (Ftase) and to a lesser extent by geranylgeranyl-protein transferases [133]. Inhibition of these enzymes has been sought as a means of interfering with Ras processing and signaling, which led to the development of Ftase inhibitors (FTIs). However, suppression of tumor cells by FTIs also occurs in the absence of ras mutations, suggesting that other regulatory proteins equally dependent on prenylation may be more relevant for this effect. Examples of regulatory proteins include RhoBand the centromeric proteins CENP-E and CENP-F [134, 135]. Tipifarnib (R115777; Zarnestra^TM; Ortho Biotech Products, L.P., Bridgewater, NJ) is a nonpeptidomimetic FTI with significant in vitro antiproliferative activity in myeloid and megakaryocytic hematopoietic progenitor cells from patients with CIMF [136]. Cortes et al. [137] investigated the activity of tipifarnib at a dose of 600 mg orally twice daily for 4 weeks of every 6-week cycle in patients with hematologic malignancies. Two of eight patients with CIMF had a significant decrease in splenomegaly, one had normalization of white blood cell count and differential, and one became transfusion independent. Responders had markedly higher pretreatment plasma VEGF concentrations than nonresponders during therapy. Common toxicities included nausea (grade =2 in 55% of all patients) and fatigue (48%). In a recent phase II study of 34 patients with CIMF, tipifarnib was administered at a dose of 300 mg orally twice daily for the first 21 days of a 28-day cycle [138]. Eleven patients (33%) experienced significant decreases in organomegaly. However, the effect on anemia was negligible. Myelosuppression was the most frequent grade 3 toxicity, occurring in 13 patients, thus hampering improvements in cytopenias. Disappointingly, therapy was discontinued after a median of 5.5 months mainly because of disease progression and adverse reactions. Bone marrow fibrosis and neoangiogenesis did not change significantly in the few patients who responded to tipifarnib.

SCT-Based Approaches
Allo-SCT is the only available therapy for patients with CIMF with potential to eliminate bone marrow fibrosis and possibly cure patients [37, 139–144]. Nonetheless, the use of fully myeloablative conditioning regimens has been associated with high morbidity and mortality. In particular, the age of patients undergoing allo-SCT proved to be a critical prognostic factor in one study, in which 14% of patients older than 45 years at the time of transplantation survived beyond 5 years of follow-up [140].

Recently, a retrospective analysis of the outcomes of 320 patients with CIMF receiving allo-SCT between 1989 and 2002 was published [145]. Most patients received ablative conditioning with either total body irradiation (TBI) (n = 117) or busulphan (n = 150) and cyclophosphamide. Bone marrow was the graft source in 208 patients. HLA-identical sibling donors were used in 170 transplants, 117 were from a matched unrelated donor (MUD), and 33 were from an alternative related donor. The 100-day mortality rates were 22% after sibling transplants, 42% after MUD transplants, and 27% after alternative family donor transplants. Corresponding 5-year overall survival rates were 39%, 31%, and 31%, respectively. Multivariate analysis of 215 adult recipients of myeloablative transplants revealed that having an HLA-identical sibling donor, Karnofsky performance score =90%, younger age, more recent date of transplantation, and absence of blasts in peripheral blood prior to transplantation correlated with better survival. Eighteen patients with all of these factors had a 5-year probability of survival of 81%. Although the ideal conditioning regimen is yet to be defined, cyclophosphamide plus busulphan (with busulphan doses adjusted to achieve targeted plasma levels) resulted in better outcomes when compared with TBI-based regimens [37].

The introduction of reduced-intensity conditioning (RIC) nonmyeloablative regimens may be particularly applicable in CIMF (Table 2). The main complication of allo-SCT in patients older than 45 years is transplant-related mortality rather than relapse. The patients in this age group represent the bulk of patients with CIMF, and employing low-intensity conditioning may improve their probability of survival. Sustained engraftment and durable responses have been reported in several case reports involving patients with advanced-stage CIMF who receive fluda-rabine-based RIC regimens [36, 146–149]. Rondelli et al. [151] reported the results of 21 patients with poor Dupriez score CIMF who received nonmyeloablative allo-SCT at different institutions. Patients received allogeneic marrow (n = 3) or peripheral blood stem cells (n = 18) from HLA-matched related (n = 18), unrelated (n = 2), or one antigen–mismatched related (n = 1) donors. RIC regimens included fludarabine in combination with TBI (n = 6), melphalan (n = 7), and thiotepa (n = 1) or thiotepa plus cyclophosphamide (n = 7). All of the patients achieved full engraftment except one. Post-transplantation chimerism analysis showed >95% donor cells in 18 patients, while two patients achieved complete donor chimerism after donor leukocyte infusion. With a median follow-up of 31 months (range, 12–122 months), 18 patients were alive and 17 were in remission.

The high frequency with which CIMF is associated with very high levels of circulating CD34⁺ cells facilitates the collection of these progenitors for autologous SCT (auto-SCT). Although these CD34⁺ cells appear to have a clonal origin, they seem to retain the ability to differentiate [157]. The role of auto-SCT as a palliative procedure was assessed in 21 patients with CIMF who were not candidates for allo-SCT because of older age or a lack of suitable donors [158]. Myeloablative therapy consisted of oral busulphan (16 mg/kg). Tolerance was excellent, with a median time to neutrophil and platelet recovery after transplantation of 21 days. Transfusion independence and resolution of cytopenias occurred in approximately 50% of patients, and some experienced resolution of splenomegaly and improvement in bone marrow fibrosis. After a median follow-up of 390 days, six patients had died (three from disease progression) and the 2-year actuarial survival rate was 61%. Therefore, auto-SCT may have a palliative role in CIMF, and collection and storage of CD34⁺ cells in the early stages of the disease may be recommendable for selected patients.

Other Novel Investigational Agents for CIMF
Several other agents with potential activity in CIMF are currently being investigated. Aberrant CpG island hyper-methylation in regulatory areas of tumor suppressor genes leading to inactivation is a common phenomenon encountered in human cancer [159, 160]. Methylation of p15^INK4B, p16^INK4A, and the retinoic acid receptor ß has been reported in advanced-stage CIMF [161, 162]. Azacitidine and decitabine are DNA methyltransferase inhibitors that induce reactivation of methylated genes. These agents are currently under investigation in patients with CIMF in phase II studies.

There is evidence suggesting that spontaneous nuclear factor kappa B (NF- B) pathway activation associated with secretion of the fibrogenic cytokine TGF-ß 1 occurs in megakaryocytes, monocytes, and CD34⁺ cells from patients with CIMF. Preliminary data in a murine model of myelofibrosis suggest that the proteasome inhibitor bortezomib inhibits activation of the NF- B pathway and decreases plasma concentration of TGF-ß 1, thus inhibiting the development of myelofibrosis. Clinical trials of bortezomib in patients with CIMF are currently under way [163].

	CONCLUSION AND FUTURE DIRECTIONS

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CIMF is a rare and progressive CMPD for which no effective therapy is currently available. Allo-SCT is the only potentially curative therapy. However, high morbidity and mortality associated with this procedure limit this treatment modality to young patients with a good performance status and high-risk disease. Unfortunately, donor availability reduces this option to a small proportion of patients with CIMF. RIC regimens appear to improve the outcome of patients undergoing allo-SCT and warrant further study in larger clinical trials. Unfortunately, therapy for the majority of patients must be tailored toward symptom palliation. Participation in clinical trials involving investigational agents such as IMiDs, antiangiogenic agents, proteasome inhibitors, and novel signal transduction inhibitors, alone or in combination, should be highly encouraged. The recent discovery of an activating mutation in a highly conserved region of the JAK2^V617F kinase represents a major breakthrough toward a better understanding of the pathogenesis of CMPDs. It is significant that 30%–50% of patients with CIMF harbor this mutation, and this lends itself as an attractive target for small molecule inhibitors. Hence, the development of inhibitors of the JAK2^V617F mutation devoid of undesirable toxic effects represents the most immediate challenge in the treatment of CIMF.

	DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST

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The authors indicate no potential conflicts of interest.

	ACKNOWLEDGMENT

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Cecilia Arana-Yi and Alfonso Quintás-Cardama contributed equally to this manuscript.

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