Ankur R. Parikh and Matthew J. Olnes
The chronic myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell diseases characterized by overproduction of one or more blood cell lines that were first recognized by William Dameshek in 1951.1 Unlike myelodysplasia, the MPNs are associated with normal maturation and effective hematopoiesis (Fig. 8.1). Organomegaly is common and often symptomatic. Varying degrees of extramedullary hematopoiesis and leukemic transformation are also seen.
A diagnostic marker important to Philadelphia chromosome-negative MPNs was identified in 2005 in Janus Kinase 2 (JAK2) V617F, a tyrosine kinase in the JAK-STAT pathway responsible for erythropoietin (EPO) receptor signaling. Somatic mutation JAK2V617F is a valine to phenylalanine substitution at codon 617 on chromosome 9. This mutation is present in the majority of polycythemia vera (PV) and to varying degrees in essential thrombocytosis (ET) and primary myelofibrosis (PMF) as well as other myeloid malignancies (Table 8.1).2,3 Other mutations including MPL, LNK, CBL, TET2, ASXL1, IDH, IKZF1, EZH2, and DNMT3A have also been identified in subsets of MPN patients, but their pathogenic role is unclear at present.
Although algorithms have been devised for PV, ET, and PMF, diagnosis may remain problematic in some instances because of significant overlap of hematological manifestations. This chapter focuses on PV, ET, and PMF. Chronic myelogenous leukemia (CML) and systemic mastocytosis are also included in the category of MPNs but are discussed in other chapters. Chronic myelomonocytic leukemia (CMML) is included as well, although it is placed in a separate disease category (myeloproliferative/myelodysplastic neoplasms) by the World Health Organization (WHO).4
POLYCYTHEMIA VERA
PV was first described by Vaquez in 1892. In the early 1900s, Osler recommended phlebotomy as treatment for PV, and Dameshek classified PV as a myeloproliferative disorder in 1951.1 In 1967, Wasserman organized the Polycythemia Vera Study Group (PSVG) designed to define the natural history of PV and to determine optimal therapeutic management.
FIGURE 8.1 Bone marrow hematopoiesis. Baso, basophil; CBL, chronic basophilic leukemia; CEL, chronic eosinophilic leukemia; CML, chronic myelogenous leukemia; CMML, chronic myelomonocytic leukemia; CNL, chronic neutrophil leukemia; Eos, eosinophil; ET, essential thrombocytosis; Mono, monocytes; PMN, polymorphonuclear leukocytes; P. vera, polycythemia vera; RBC, red blood cells.
Epidemiology
The incidence of PV is 2 per 100,000. Rare familial cases have been described.5 The median age at presentation is 60 years, and there is a slight male predominance of the disease. The median survival of untreated symptomatic PV is 6 to 18 months from diagnosis, 3.5 years for PV treated with phlebotomy, and 7 to 12 years for PV treated with myelosuppression. The incidence of leukemic transformation is 5% to 10% in the first 15 years after diagnosis.
Pathophysiology
PV is a clonal stem cell disorder with trilineage myeloid involvement. Some studies suggest that PV involves the B lymphocytes as well. PV is characterized by growth factor-independent erythroid proliferation producing an elevated red cell mass; in vitro, endogenous erythroid colony growth means that progenitors form colony forming units-erythrocyte-derived (CFU-E-derived) and burst forming units-erythrocyte derived (BFU-E-derived) colonies in the absence of EPO. PV may evolve from a proliferative phase of increased marrow activity and splenomegaly to a spent phase characterized by a leukoerythroblastic blood smear and extramedullary hematopoiesis producing massive hepatosplenomegaly, known as fibrotic transformation.
The JAK2V617F mutation was identified in 96% of patients with PV. In ET and PMF the JAK2V617F mutation is heterozygous, while in PV this mutation is homozygous.5 A higher JAK2V617F mutant allele burden is associated with fibrotic transformation and pruritus in patients with PV.6 In a minority of patients with PV that lack JAK2V617F, there are frameshift or point mutations in exon12 of JAK2. These patients have erythrocytosis without thrombocytosis or leukocytosis, a low serum EPO level, and marrow erythroid hyperplasia without megakaryocyte or granulocyte abnormalities.7,8 While a few cases of congenital polycythemia caused by abnormal expression of a truncated form of the EPO receptor have been described,9 there is no evidence that EPO receptor mutations are involved in the pathogenesis of PV. Splicing defects in the EPO receptor RNA in some patients with PV are of unclear significance.10
At diagnosis, 10% to 20% of patients with PV have abnormal cytogenetics, including trisomy 8, trisomy 9, and deletion 20q. Loss of heterozygosity at chromosome 9p24, undetectable on routine cytogenetics, is found in 33% of patients. The frequency of chromosomal abnormalities increases with disease progression.4
Clinical Features
The elevated red cell mass in PV may result in a myriad of clinical signs and symptoms including:
Hypertension
Thrombosis, venous or arterial
Pruritis
Erythromelalgia (a sudden, severe burning pain in the hands or feet, usually accompanied by a reddish or bluish coloration of the skin)
Ulceration of fingers and toes
Joint pain
Epigastric pain
Weight loss
Headache
Weakness
Paresthesias
Visual disturbances
Vertigo
Tinnitus
Ruddy cyanosis
Conjunctival plethora
Pruritis aggravated by bathing is a distinctive feature of PV and is present in almost 50% of patients. PV is the most common cause of erythromelalgia, which often responds to aspirin therapy. Increased cellular turnover in PV may result in gout or kidney stones. Palpable splenomegaly is found in 70% of patients.
Both bleeding and thrombosis can occur in PV. Less than 10% of patients experience major bleeding episodes, and hemorrhage is the cause of death in only 2% to 10% of PV. A variety of platelet defects are detectable and acquired von Willebrand disease exists in 33% of patients.
Thrombotic events (coronary events, cerebral vascular accidents, deep venous thrombosis (DVT), pulmonary embolism (PE), mesenteric thrombosis, and many others) are a major complication of PV. They likely arise from abnormalities in blood viscosity, platelets, and leukocytes.11 Multiple series have documented the incidence of major thrombosis to be 34% to 39% at diagnosis; 66% of these are arterial events and one third are venous.11-13 Increased risk of thrombosis is associated with age >65 years, hematocrit >45%,14 leukocytosis of ≥15 × 109/L,15 and a history of thrombosis. Patients at high risk of thrombosis and thrombocytosis (i.e., older individuals, patients with a history of thrombosis or atherosclerotic disease), should be treated with hydroxyurea to lower platelet counts to <400,000 cells/µL.16
While erythrocytosis distinguishes PV from the other MPN, only 20% of PV patients present with erythrocytosis alone, while 40% have trilineage hyperplasia at the onset of disease. PV can also present with isolated leukocytosis or thrombocytosis. Laboratory abnormalities include elevated leukocyte alkaline phosphatase, lactate dehydrogenase (LDH), uric acid, and elevated serum B12 (in 40% of patients). Secondary causes of an elevated red cell mass should also be excluded. Typical bone marrow findings in PV include hypercellularity, atypical megakaryocyte hyperplasia and clustering, and decreased stainable iron.
The risk of transformation to acute leukemia is 1.5% in patients treated with phlebotomy alone. Patients with PV have a 10% to 25% risk of fibrotic transformation at 10 and 25 years of follow-up, respectively. Fibrotic transformation is characterized by normalization of the red cell mass associated with cytopenias, increasing splenomegaly due to extramedullary hematopoiesis, progressive reticulin deposition, and collagen fibrosis of the bone marrow.
Diagnostic Criteria
The WHO criteria for the diagnosis of PV are based on clinical and laboratory characteristics (Table 8.2).4 A bone marrow biopsy is not mandatory to make a diagnosis of PV in a patient who otherwise fulfills the WHO criteria. In the 2008 WHO guidelines, an elevated red cell mass is not an absolute requirement for diagnosis, while a JAK2V617F or a similar mutation can be used to diagnose PV. While erythrocytosis distinguishes PV from the other MPNs, not all patients with PV have elevated hematocrits and not all patients with elevated hematocrits have PV. Although dehydration can cause spurious elevation of the hematocrit, resulting in apparent erythrocytosis, a hematocrit greater than 60% in men or 55% in women is usually caused by an elevated red cell mass. Direct determination of blood volume and red cell mass is usually needed. Conversely, erythrocytosis may be masked by expanded plasma volume secondary to splenomegaly or by occult blood loss. Iron deficiency can also cause a decrease in the hematocrit in patients with PV. Secondary erythrocytosis caused by elevation of serum EPO must also be excluded.
Conditions associated with physiologically appropriate production of EPO caused by hypoxemia as well as diseases associated with inappropriate EPO production that result in erythrocytosis are listed in Table 8.3.
Laboratory studies that may be useful in evaluation of erythrocytosis are:
Arterial blood gas measurement
Iron studies
Serum EPO level
Liver and kidney function studies
Abdominal ultrasound or computed tomography (CT) scan
Bone marrow aspirate and biopsy
Red cell mass
Table 8.4 shows clinical findings and assay results other than JAK2 mutational status that can be useful for distinguishing secondary polycythemia from PV. Gene expression profiling and mutational analysis are being investigated to help discriminate PV from secondary polycythemia.3,16,17 For example, a polymerase chain reaction (PCR)-based assay for overexpression of PRV1 (CD177) mRNA in peripheral granulocytes is positive in most patients with PV but not in secondary erythrocytosis.18 Reduced thrombopoietin (TPO) receptor (c-MPL) levels have been described in PV megakaryocytes and platelets and in some patients with ET and PMF. Production of endogenous erythroid colonies in vitro is seen in PV but not in secondary erythrocytosis.19 When it is impossible to make a definitive diagnosis, laboratory evaluation should be repeated in 3 months.
Staging and Prognostic Features
In untreated PV, median survival is only 6 to 18 months; death most frequently results from thrombosis.12 Age greater than 65 years and a previous history of thrombosis are the major risk factors for thrombosis.16 Other causes of mortality include transformation to acute leukemia or fibrotic transformation.
Table 8.3 Conditions Related to Erythropoietin Production
EPO Overproduction Secondary to Hypoxia
Lung disease
High altitude
Smoking (carboxyhemoglobin)
Cyanotic heart disease
Methemoglobinemia
High oxygen affinity hemoglobin
Cobalt
EPO Overproduction
Tumors—renal, brain, hepatoma, uterine fibroids, pheochromocytoma
Renal artery stenosis
Neonatal
Inappropriate EPO secretion
Bartter syndrome
Renal cysts, hydronephrosis
Other Causes
EPO receptor hypersensitivity
Congenital erythrocytosis
Androgen therapy
Adrenal tumors
Autotransfusion (blood doping), self injection of EPO
Polycythemia vera*
*EPO levels in PV may be either low or normal; high EPO levels are not consistent with PV.
Treatment
Treatment goals are to (i) relieve the clinical symptoms that result from an elevated red cell mass, (ii) decrease thrombotic risk, and (iii) slow or prevent leukemic transformation. The efficacy of therapies must be balanced against their toxicities.
The international Polycythemia Vera Study Group (PVSG) began to organize large randomized trials in 1967. Patients were randomly assigned to phlebotomy, chlorambucil, or P32. The thrombosis rate for patients treated with phlebotomy alone was 37.3%, significantly higher than for those treated with chlorambucil or P32. However, there were an excess number of deaths secondary to leukemia in the chlorambucil and P32 arms of the study. The PVSG08 study showed that hydroxyurea significantly lowered the risk of thrombosis compared with phlebotomy alone, but patients who received hydroxyurea exhibited a trend toward increase in the risk of leukemic transformation. The European Collaboration on Low-Dose Aspirin in PV (ECLAP) trial followed a cohort of 518 patients with PV without a contraindication to aspirin therapy who received low-dose aspirin and were undergoing phlebotomy; major thrombosis was decreased by 60% in this cohort compared to controls, without a significant increase in bleeding.15
Therapy in PV is based on risk of thrombohemorrhagic complications. Current risk stratification is outlined below:
Low Risk
Age <60 years, and
No history of thrombosis
Low Risk with Extreme Thrombocytosis
Low risk with platelet count >1 million/µL
High Risk
Age ≥60 years, or
Previous history of thrombosis
Phlebotomy is the treatment of choice for most patients. The hematocrit should be maintained at <45% in men, 42% in women, and <37% in late pregnancy. Additionally, for patients aged 60 years or older, myelosuppression is recommended to decrease the thrombotic risk. Paradoxically, the initiation of phlebotomy is transiently associated with an increase in thrombotic risk and is greatest in the elderly. Interferon-α has also been used for cytoreduction in younger patients, and during pregnancy. Busulfan or P32 may be used in the elderly who may be unable to tolerate hydroxyurea. A suggested treatment algorithm is seen in Figure 8.2.
Additional therapies may be required for other complications related to PV. Low-dose aspirin appears effective for alleviation of microvascular sequelae including headache, vertigo, visual disturbances, distal paresthesias, and erythromelalgia. The safety and benefits of low-dose aspirin in PV have been investigated in a multicenter project (ECLAP)10,20: aspirin lowered the risk of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and total mortality; treatment nonsignificantly increased major bleeding. Aspirin should not be used in patients with a history of hemorrhage. All PV patients with extreme thrombocytosis (more than 1 million platelets/µL) should be assessed for acquired von Willebrand syndrome with a ristocetin cofactor activity level, and aspirin should be avoided in those with ristocetin cofactor levels of <30%.
Pruritis is a problem in 40% to 50% of patients with PV. Variably effective measures include reduction of water temperature and the use of antihistamines. Other agents of uncertain efficacy for these symptoms include cholestyramine, psoralen + UVA (PUVA), and interferon-α. The selective serotonin reuptake inhibitors paroxetine (20 mg every day) or fluoxetine (10 mg every day) have been shown to provide relief in many patients suffering from prurits.21
Patients with PV undergoing surgery are at high risk of postoperative complications. Elective procedures should be postponed until the hematocrit has normalized for more than 2 months.
Fibrotic transformation occurs on average 10 years after the initial diagnosis and is heralded by the development of cytopenias and splenomegaly. Hydroxyurea and interferon-α may alleviate cytopenias due to splenomegaly. Although splenectomy may provide some relief from these symptoms, hepatomegaly secondary to extramedullary hematopoiesis may be a consequence. Low-dose splenic irradiation usually provides only short-term relief.
FIGURE 8.2 Treatment algorithm for polycythemia vera. *Phlebotomy HCT goals are <45% in men, <42% in women, and <37% in 3rd trimester pregnancy.
Stem cell transplantation remains an option for advanced PV and can be curative. Outcomes are more favorable in those transplanted in fibrotic transformation than in those after evolution to acute leukemia.22
ESSENTIAL THROMBOCYTOSIS
ET was first described by Epstein and Goedel in 1934 and called hemorrhagic thrombocythemia. Dameshek classified it as one of the myeloproliferative disorders in 1951.
Epidemiology
The annual incidence of ET is estimated at 1 to 2.5 per 100,000. Most patients are between age 50 and 60 at presentation, and there is no gender predilection. A second peak occurs around age 30 when females are more often affected. Prevalence is higher in women than men 1.5–2:1. The median survival of ET is more than 10 years.4 Most patients with ET have a normal life expectancy without disease-related complications. The etiology of the disease is unknown.
Pathophysiology
Although ET has been traditionally described as a clonal disorder, X-chromosome inactivation studies suggest polyclonal hematopoiesis in some patients.23 JAK2V617F is found in 55% of patients with ET; the mutation is associated with elevated hemoglobin and neutrophil counts, lower EPO levels, and increased progression to polycythemia.24 One percent of patients with ET have a mutation in the gene encoding the TPO receptor (c-MPL 515), and in many cases this is found with the JAK2 mutation. Patients with ET tend to have normal to high TPO levels and many have low TPO receptor (c-MPL) levels.25The rate of clonal cytogenetic abnormalities in ET is approximately 5%.
Clinical Features
As many as half of the patients are asymptomatic at presentation. Vasomotor symptoms occur in approximately 40% of patients and include visual disturbances, light-headedness, headaches, palpitations, atypical chest pain, erythromelalgia, livedo reticularis, and acral paresthesias. Thrombosis occurs in 15% of cases at presentation and in 10% to 20% during the course of the disease. Associated thrombotic events include DVT and PE, digital ischemia, portal vein thrombosis, and cerebrovascular and coronary ischemia. Major hemorrhage occurs in 5% to 10% of patients during the disease course. Other disease associations include recurrent first trimester abortions greater than the unaffected population and palpable splenomegaly, which is present in less than 50% of patients. The risk of leukemic transformation is low in the first decade after diagnosis but increases with each subsequent decade, but overall it is less than for other MPNs.
Diagnostic Testing
ET is characterized by persistent nonreactive thrombocytosis. WHO diagnostic criteria are shown in Table 8.2. The differential diagnosis includes reactive thrombocytosis and other MPNs, as well as chronic myeloid disorders. Causes of thrombocytosis other than ET are listed below:
Asplenia
Acute hemorrhage
Infections
Hemolysis
Postthrombocytopenic rebound
Cancer
Inflammatory states (infection, collagen vascular disorders)
Iron deficiency
Pregnancy
MPN (Note that most of the MPN may present with isolated thrombocytosis.)
Often a careful patient history will exclude reactive thrombocytosis. In addition to JAK2 mutational analysis, other laboratory testing to assist in diagnosis include:
Iron studies to exclude iron deficiency.
C reactive protein (CRP), erythrocyte sedimentation rate (ESR), and fibrinogen to rule out an occult inflammatory or malignant process.
Blood smear: Howell-Jolly bodies indicate anatomic or functional asplenia.
Bone marrow morphology.
Cytogenetics including fluorescence in situ hybridization (FISH) or PCR for BCR/ABL to exclude chronic myeloid leukemia (CML).
Decreased megakaryocyte c-MPL expression and increased granulocyte PRV1 and endogenous erythroid colony formation can be seen in both PV and ET and do not distinguish between them.26 When a definitive diagnosis is not initially possible, later periodic evaluation may be revealing.
Treatment
The decision to treat must be based on risk-based management because life expectancy in this disease is nearly normal. High-risk patients are those over 60 years or older or those who have a history of thrombosis. Low-risk patients are younger than 60 years old with no history of thrombosis and may have extreme thrombocytosis (platelet count >1 million/µL).
Choice of therapy is based on efficacy and toxicity.16 Therapeutic options include mechanical reduction of counts using plateletpheresis (in acute situations), myelosuppressive agents (alkylating agents, hydroxyurea, or radiophosphorus), maturation modulators (interferon-α or anagrelide), or antiplatelet agents (Table 8.5). Treatment should be focused on a platelet count goal of less than 400,000/µL.
Table 8.6 Essential Thrombocytosis Treatment Algorithm
Low risk: Low-dose aspirin therapy
Low risk with extreme thrombocytosis: Low-dose aspirin for patients in whom von Willebrand syndrome has been excluded
High risk: Low-dose aspirin and cytoreductive therapy
The treatment algorithm for ET is shown in Table 8.6. All patients older than age 60 are high risk. All ET patients with extreme thrombocytosis (more than 1 million platelets/µL) should be tested for acquired von Willebrand syndrome with a ristocetin cofactor activity level. Low-dose aspirin can be used if ristocetin cofactor level is greater than 30%. Women of childbearing age not using birth control should be treated with interferon-α based on anecdotal evidence of safety in pregnancy.
Low-risk patients (with or without extreme thrombocytosis) should be observed and not treated with cytoreductive therapy unless they develop high risk features. Cytoreductive therapy should be administered to high-risk patients. Hydroxyurea is usually the first choice in high-risk patients, with interferon-α or busulfan used as the second line.
As in PV, low-dose aspirin is safe, and may even lower thrombotic complications in patients who do not have a significant bleeding risk.27,28 Aspirin is efficacious for treating vasomotor symptoms. Aspirin is contraindicated in patients who have experienced bleeding episodes, and in those with acquired von Willebrand syndrome.
Alkylating agents are generally avoided because of the risk of leukemia but are useful in the very elderly whose comorbidities make them intolerant to other therapies.
Hydroxyurea decreases thrombotic complications in patients with ET16 but can cause bone marrow suppression. Questions remain as to its leukemogenic potential in the absence of controlled randomized clinical trials. Hydroxyurea is contraindicated in women of childbearing age.
Anagrelide acts by interfering with platelet maturation but is associated with toxicities including fluid retention, headache, and palpitations and is extremely expensive compared to hydroxyurea. Most side effects abate within 2 to 4 weeks after initiation of therapy, so it is prudent to slowly titrate the dose. Anagrelide should be avoided in patients with cardiovascular comorbidities because of its side effect profile. In a trial where randomized patients received aspirin plus hydroxyurea or anagrelide, there were lower rates of venous thromboembolism in the anagrelide arm, but arterial thrombosis, hemorrhage, and marrow fibrosis were increased.29
Interferon-α is effective in reducing platelet count but is associated with significant side effects including flu-like symptoms and depression.
Plateletpheresis is used in emergent thrombosis where abrupt decrease in platelet count is mandated.
All patients with ET should be instructed to avoid smoking and to avoid nonsteroidal anti-inflammatory drugs.
PRIMARY MYELOFIBROSIS
Myelofibrosis was first described in 1879 by Hueck and was first included as one of the myeloproliferative diseases by Dameshek in 1951.1
Epidemiology
The annual incidence of PMF is 0.5 to 1.5 per 100,000. The median age at presentation is 67 years. The male to female ratio is 1:1. PMF has the worst prognosis among the MPNs, with a median survival of 3 to 5 years. The etiology of the disease is unknown, but a familial occurrence has been reported in rare kindreds.4 A high incidence of PMF was observed in individuals exposed to radiation at Hiroshima.
PMF that develops in late-stage PV or ET is referred to as postpolycythemic metaplasia (PPMM) or postthrombocythemic myeloid metaplasia (PTMM), respectively. De novo PMF is referred to as idiopathic myelofibrosis.
Pathophysiology
PMF is characterized by marrow fibrosis and extramedullary hematopoiesis. The marrow fibroblasts in PMF are not derived from the abnormal clone. Increased levels of platelet derived growth factor (PDGF), transforming growth factor (TGF)β, and other cytokines produced by megakaryoctyes may be responsible for the marrow fibrosis. Cytogenetic abnormalities are seen in approximately 50% of patients and include 13q, 20q, 12p, trisomy 8, and trisomy 9. High levels of CD34+ cells and of hematopoietic colony forming cells are typical in the circulation of patients with PMF and appear to correlate with the extent of myeloproliferation.30
The JAK2V617F mutation is found in 65% of patients. The MPL 515 mutation, also identified in ET, is present in approximately 5% of these patients. Other somatic mutations currently being investigated are LNK, TET2, ASXL1, IDH1/IDH2, EZH2, DNMT3A, CBL, IKZF1, TP53, and SF3B1.3,16
Clinical Features
Approximately one third of patients are asymptomatic at diagnosis. Presenting complaints include profound fatigue, symptoms of anemia, abdominal discomfort, early satiety, or diarrhea caused by splenomegaly, bleeding, weight loss, and peripheral edema. The constitutional symptoms of fever and night sweats occur in most patients during the course of the disease. Splenomegaly is common in PMF and may be marked. Episodic left upper quadrant pain can occur secondary to splenic infarction. Palpable hepatomegaly is found in the majority of cases. Extramedullary hematopoiesis may occur in almost any organ.
Laboratory abnormalities in patients with PMF may include leukocytosis or leukopenia, and thrombocytosis or thrombocytopenia. The classic blood smear shows leukoerythroblastosis but bone marrow morphologic findings vary from mild to marked fibrosis.31 Osteosclerosis and periostitis can cause severe bone pain. Elevations of LDH, serum B12, and alkaline phosphatase are commonly seen. Transformation to acute leukemia occurs in approximately 20% of patients during the first decade after diagnosis.
Diagnostic Testing
The WHO diagnostic criteria for PMF are listed in Table 8.2. The bone marrow is often inaspirable, a “dry tap.” The classic peripheral smear shows teardrop-shaped red cells, nucleated red cells and granulocyte precursors (leukoerythroblastosis). However, other marrow infiltrative processes can cause a similar picture and must be excluded (Table 8.7). Absence of splenomegaly should make the diagnosis of PMF suspect. Many benign and malignant conditions mimic PMF, including metastatic cancer, granulomatous disease, connective tissue disease, lymphoma, systemic mast cell disease, hypereosinophilic syndrome, and other myeloid disorders. Both ET and PV can transform to PMF. Cytogenetics and FISH or PCR for BCR/ABL should be performed to exclude fibrotic CML.
Staging and Prognostic Features
PMF often progresses to marrow failure. Features associated with decreased survival include the following:
Advanced age
Hypercatabolic symptoms*
Anemia (hemoglobin less than 10 g/dL)**
Leukopenia (white cell count <4,000/mm3)**
Leukocytosis (white cell count >30,000/mm3)
Abnormal cytogenetics or the presence of circulating granulocyte precursors or blasts*
(*May be an indication for splenectomy or **transplantation.)
Splenic irradiation may provide short-term improvement in patients with symptoms referable to organomegaly who are not surgical candidates.
Median survival in high-risk patients is less than 2 years, while patients with low-risk features have median survivals of over 10 years. Up to 30% of patients may progress to acute myeloid leukemia (AML), and this is thought to be more common after splenectomy.
A number of prognostic scoring systems have been developed for PMF. The International Prognostic Scoring Scale (IPSS) developed by the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) is based on five adverse prognostic features noted on multivariate analysis: presence of constitutional symptoms, age greater than 65 years, hemoglobin less than 10 g/dL, leukocyte count greater than 25,000/µL, and circulating blast greater than or equal to 1%.32 Each category received one point and subjects with zero (low risk), one (intermediate risk-1), two (intermediate risk-2), or greater than or equal to 3 (high risk) at presentation had median survivals of 135, 95, 48, and 27 months, respectively. A dynamic IPSS (DIPSS) score has been developed, which can be used at any time during the disease course, and a more recent scoring system called DIPSS-plus incorporates the previous factors plus platelet count, red cell transfusion need, and unfavorable karyotype.33
Treatment
Treatment for PMF is largely palliative. Approximately 30% of patients with anemia will show improvement with a combination of androgen (oxymethalone 50 mg 4 times per day or fluoxymesterone 10 mg 3 times per day) and prednisone (30 mg/day) therapy. Responses are usually brief in duration. EPO is most often ineffective. In patients with a more favorable prognosis who require transfusions for symptomatic anemia, timely initiation of chelation therapy is warranted.
Hydroxyurea, busulfan, interferon, or melphalan may be used to control thrombocytosis, leukocytosis, or organomegaly. Lower doses of hydroxyurea are used in PMF than in ET or PV (start at 20 to 30 mg/kg two or three times per week). None of these agents is effective in preventing disease progression or improving survival. Anagrelide and imatinib are not effective. Thalidomide and prednisone may treat anemia and lenalidomide can be used if there is a deletion 5q abnormality.34 JAK2 inhibitors have shown significant reduction in splenic size and relief of symptoms in some patients. The JAK2 inhibitor ruxolitinib has been approved for the treatment of intermediate and high-risk myelofibrosis.35 There are ongoing studies using mTOR kinase inhibitors and proteasome inhibitors.
Allogeneic stem cell transplantation remains the only treatment with curative potential for patients with PMF.36 Debate continues as to the value of splenectomy prior to transplantation. Concerns about graft failure because of marrow fibrosis have proven unwarranted and, in fact, successful transplantation is associated with resolution of marrow fibrosis. In both the European multicenter cooperative studies and Seattle single institution trials, overall survival after myeloablative transplantation was 60%. Reduced intensity conditioning is under exploration for older patients and for those who are not candidates for myeloablative protocols.
CHRONIC MYELOMONOCYTIC LEUKEMIA
Epidemiology
The annual incidence of CMML is estimated at 4 cases per 100,000. There is a male predominance of 1.5–3:1. The median age at presentation is 70 years. Median survival is estimated at 12 to 18 months. The etiology of the disease is unknown.
Pathophysiology
The WHO classification places CMML in the category labeled myelodysplastic/myeloproliferative, which is appropriate because the marrow cells in this disease show dysplastic features, and there are many characteristics of myeloproliferation as well. The spleen, liver, and lymph nodes are the most common sites of extramedullary involvement. Clonal cytogenetic abnormalities are present in 20% to 40% of CMML and include trisomy 8, deletion 7q, and translocations involving 5q31–35; the latter activate the platelet derived growth factor receptor β (PDGFRβ) and are associated with eosinophilia4,37,38Mutational spectrum analysis has demonstrated the heterogeneity of CMML with various mutations in TET2, ASXL1, CBL, IDH1/2, KRAS, NRAS, JAK2V617F, UTX, DNMT3A, and EZH2. A recent study of 72 patients with CMML found at least 1 mutation in 86% of cases.39 Studies evaluating prognostic significance are currently ongoing.
Clinical Features
CMML frequently presents with fatigue, fever, weight loss, or night sweats. There is risk of infection because of neutropenia and of bleeding secondary to thrombocytopenia. In approximately 50% of patients, the white count at presentation may be normal or decreased, while in the remainder it is elevated. In all cases there is persistent peripheral blood monocytosis, the defining feature of the disease. Progression to acute leukemia occurs in 15% to 30% of cases.40
Diagnostic Testing
WHO diagnostic criteria include the following:
Persistent peripheral blood monocytosis (greater than 1 × 109 per liter for more than 3 months)
Absence of the Philadelphia chromosome or BCR/ABL fusion gene
Less than 20% blasts in the blood or bone marrow
Dysplasia of one or more myeloid lineages
Clonal cytogenetic abnormality
If dysplasia is absent, the diagnosis can be made if there is a clonal abnormality and no other causes of monocytosis.
Staging and Prognostic Features
Based on peripheral blood leukocyte counts, the French American British (FAB) group proposed dividing CMML into a dysplastic and a proliferative form with a white count over 13,000/mm3. Attempts to evaluate the prognostic value of these distinctions have yielded disparate results. Recent analysis of CMML diagnosed based on FAB classification identified the following factors as independently associated with shorter survival: hemoglobin <12 g/dL; lymphocyte count >2,500/mm3; medullary blast count 10% or more, and presence of circulating immature myeloid cells. Median survival was 12 months.41 A recent investigation of 414 patients revealed an abnormal karyotype was associated with poorer overall survival and a higher risk of leukemic transformation. Low-risk category included a normal karyotype or loss of the Y chromosome as single anomaly; high-risk patients had trisomy 8, abnormalities of chromosome 7, or complex karyotype. All other abnormalities were intermediate risk. 5-year overall survival for low, intermediate, and high-risk cytogenetics were 35%, 26%, and 4%, respectively.42
Treatment
Treatment approaches are all experimental, and none has proven effective in modifying the natural course of the disease. Evaluation of treatment responses of patients with CMML specifically is difficult, because they have historically been grouped under the myelodysplastic syndromes. Growth factors have been used in an attempt to treat cytopenias and low-dose chemotherapy during the pre-leukemic phase of the disease. Hydroxyurea is effective in controlling cell counts in the proliferative phase. Although many patients respond initially to chemotherapy, complete responses are rare and remissions generally short lived. A variety of low-dose chemotherapeutic agents including cytarabine, topotecan, fludarabine, oral idarubicin, and oral etoposide have showed little success in altering long-term survival rates. Imatinib mesylate is effective in the rare CMML patients who have PDGFRβ translocations.43,44Hypomethylating agents can induce complete or partial remissions in subsets of patients. Stem cell transplantation has proved successful in a small number of cases and remains the only option for cure.
References