Keywords

Introduction

The myeloproliferative neoplasms (MPNs) are clonal hematological diseases characterized by overproduction of mature blood cells and, in general, a chronic course [1].The World Health Organisation has recently modified the nomenclature from myeloproliferative disorder to neoplasm to reflect the malignant nature of these diseases [2]. MPNs include polycythemia vera (PV), primary myelofibrosis (PMF) and essential thrombocythemia (ET), and the rarer entities, chronic neutrophilic leukemia, chronic eosinophilic leukemia and chronic myeloproliferative neoplasm, unclassifiable as well as mast cell diseases as summarised in Table 6.1. Here, we consider the commoner so-called classical Philadelphia-negative MPNs: ET, PV and PMF. In these entities which were all described in the last 200 years the proliferation of a single cell type defines disease phenotype: erythrocytes in PV, platelets in ET and fibroblasts in PMF.

Table 6.1 WHO defined myeloproliferative neoplasms
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Over the past two centuries our understanding of myeloproliferative neoplasms has evolved from their original clinical and hematopathological observations to an increasing appreciation of the molecular mechanisms underpinning the neoplastic process and their interplay with clinical phenotype and therapy. The disorders including chronic myeloid leukemia (CML), PV, and PMF were all identified as clinical and pathological entities in the nineteenth century. ET was delineated later by Epstein and Goedel in 1934, post-PV MF was described by Hirsch in 1935, and so during the first half of the twentieth century the inter-relationship between these disorders began to be defined. Dameshek however was the first author to formally articulate the idea of a common ‘myeloproliferative’ heritage in his landmark publication of 1951 stating: “It is possible that… ‘myeloproliferative disorders’ – are all… variable manifestations of proliferative activity of the bone marrow cells, perhaps due to a hitherto undiscovered stimulus” [3]. Dameshek thus importantly postulated not only the possibility of transition between these disorders, but more interestingly a common primary mechanism for all MPNs. Dameshek’s proposal of a common underlying pathology began to bear fruition during the 1980s with growing evidence that tyrosine kinase (TK) activity provided the molecular mechanism for CML which is not formally discussed further in this chapter.

An acquired point mutation in the JAK 2 (JAK2 V617F) gene occurs in most patients with PV and almost half of those with ET or PMF and less prevalent mutations have been described in exon 12 of JAK2 and the transmembrane domain of the thrombopoietin receptor cMPL as well as others [4]. The JAK2 V617F mutation disrupts the secondary structure of the pseudokinase domain and then enables constitutive, cytokine-independent activation of signal transduction pathways, enhancing cell proliferation. The functional consequences of the mutations effecting exon 9 of CALR are not yet clear and they are beginning to be integrated into diagnostics. This has revolutionized the investigation and diagnosis of these conditions and has been incorporated into standard diagnostic pathways in a rational manner [5]. There have only been four large clinical trials, ECLAP [6], PT1 [7] and the COMFORT studies [8, 9] in these conditions to date, these have enabled hematologists to refine evidence-based management further, while current clinical trials focus upon novel agents used alone and in combination [10]. Each of the three commonest entities will now be considered in turn.

Polycythemia Vera

Clinical Features and Epidemiology

PV or Vasquez disease is characterized by raised red cell mass (erythrocytosis) usually but not always in combination with thrombocytosis and/or neutrophilia; pruritus, gout and splenomegaly are classical clinical features. The median age at presentation of PV is 55–60 years. Clinical events include arterial and to a lesser extent venous thromboses often at atypical sites (e.g. abdominal venous thrombosis) or rarely bleeding. Over 10–15 years, myelofibrosis occurs in 10–15 % and acute myeloid leukemia (AML) in 5–10 % of patients with this disease and as demonstrated in the ECLAP study AML is more common in patients who are older (over 65 years), treated with drugs known to increase this risk such as alkylating agents, and smokers [11].

A packed cell volume (PCV or hematocrit) persistently greater than 0.52 in a male, or 0.48 in a female, should trigger investigation, however there is a wide differential diagnosis of potential causes of an erythrocytosis as summarised in Table 6.2. Assessment of patients suspected of an erythocytosis should include a thorough history and examination, full blood count/film, haematinics, renal/liver profile, urate, JAK2 V617F screen, urinalysis and chest X-ray (especially for smokers). In the absence of an obvious secondary cause and no detectable JAK2 V617F mutation, a red cell mass may be required to identify an absolute erythrocytosis (i.e. a truly raised red cell count). Additional tests include serum erythropoietin level (suppressed in PV), bone marrow biopsy, screening for mutations in exon 12 of JAK2, truncated erythropoietin receptor, proline dehydroxylase abnormalities, abdominal ultrasound, sleep studies and screening for a high-affinity haemoglobin. The diagnostic criteria for PV are shown in Table 6.3.

Table 6.2 Causes of an erythrocytosis
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Table 6.3 Diagnostic criteria for the MPNs
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Worldwide estimates of the incidence of PV vary greatly, with the incidence thought to be between 2 and 2.8 per 100,000, with a slightly higher male preponderance.

One of the largest studies of a cohort of PV patients, the European Collaboration on Low-dose Aspirin in PV (ECLAP) over a median period of 2.8 years, revealed that the mortality of patients with PV was 2.1 times higher that of the standard population, with cardiovascular complications playing a significant role [11]. A predominance of arterial events and non-hemorrhagic cerebral vascular events was noted. Abdominal venous thrombosis such as Budd-Chiari syndrome, and obstruction of the portal, mesenteric and splenic systems have often been seen in patients with PV. A previous history of thrombotic events and a rising age are felt to independently increase the risk of further thrombotic events in this sub-group of individuals. These results were corroborated by the results of the ECLAP study whereby those over the age of 65 years and with a prior history of a thrombotic event were noted to have the highest risk of cardiac complications.

Leucocytosis appears to be another independent risk factor, whereby individuals with a WCC >15 × 109 are at a higher risk of vascular events. This has been attributed to endothelial and platelet activation, leading to acceleration of arteriosclerosis [12]. Hypertension, hypercholesterolaemia, smoking and diabetes are independently associated with atherosclerosis, and in the context of their presence in patients with PV should be managed aggressively [13].

Management and Prognosis of PV

The risk of vascular events in treated PV patients remains raised at approximately 1.6 times normal despite optimal modern management [11]. Transformation to either Myelofibrosis or AML following PV are treated as per myelofibrosis (see below) or usually supportively, as the outlook is extremely poor; stem cell transplantation is an option in a minority of suitably fit patients who transform. Reversible factors for cardiovascular disease should be managed aggressively and low-dose aspirin considered unless contraindicated, e.g. active or previous peptic ulcer disease, prominent bleeding symptoms and presence of acquired von Willebrand’s disease. The European Collaboration on Low-dose Aspirin in PV (ECLAP) study found low-dose aspirin was effective in reducing the number of thrombotic events as well as micro vascular symptoms such as erythromelagia which is associated with the spontaneous aggregation of platelets. Treatment includes repeated venesection or cytoreductive therapy to keep the PCV below 0.45 in males, and females, and in some patients the platelets less than 400 × 109/l. The target for venesection was recently confirmed in a prospective study [14].

Cytoreduction is clearly indicated if patients are intolerant of venesection or indeed if they develop thrombocytosis, symptomatic splenomegaly or a thrombosis [13]. Hydroxyurea (or hydroxycarbamide, HC) is the cytoreductive drug of first choice. Concern that it might increase the risk of leukemia is not proven but the use of phosphorus-32 (P32) or busulfan is restricted because of their well-defined leukemogenic potential. Interferon alpha (IFN) is a non-leukemogenic alternative and recent data suggest that pegylated IFN may reduce JAK2 V617F levels, potentially eradicating the abnormal clone. Intermittent busulphan or P32 can be used in the very frail, in whom regular out-patient visits are not practical or compliance is an issue, bearing in mind their leukemogenic potential. Investigational agents include JAK inhibitors and Histone Deacetylase Inhibitors which are currently being assessed in clinical trial. A current trial is directly comparing IFN and HC.

Therapuetic Options and Considerations for the Elderly Patient with PV

Therapeutic options in managing elderly patients with PV is dependent on the use of the appropriate agent, taking into consideration the phase of the disease, age of the patient as well as their ability to tolerate or comply with therapy. Treatment affects overall survival, with those that remain untreated having an average survival of 18 months, with thrombotic events being the predominant cause of morbidity and mortality. Those who are treated have on average a median survival of 10–15 years.

The aim of cytoreduction in PV is to minimise the overall risk of thrombotic events, control disease-related symptoms and reduce the risk of disease progression. The needs of older patients are often different from those of younger patients. In particular, the impact of reduced physiological reserve as well as multiple-morbidities needs to be taken into account. Elderly patients commonly have multiple pathologies leading to polypharmacy, in addition to altered pharmacokinetics as well as pharmacodynamics. In this sub-group of patients, optimisation of their existing therapies, looking into their ability to tolerate various available therapies, and optimisation of their ability with compliance of therapy needs careful forethought. In such scenarios, a dedicated review by the elderly care team with close liaison with the treating hematologist can play a vital role in optimisation of drug use amongst this high-risk group.

Essential Thrombocythemia

Clinical Features and Epidemiology of ET

ET is characterized by a persistent thrombocytosis and recent WHO criteria suggest patients with platelets persistently over 450 × 109/l merit investigation (see also Table 6.3) [2]. Clinical features are very similar to PV. Microvascular events are said to predominate here including erythromelalgia (asymmetric erythema, congestion and burning pain in the hands and feet) which may progress to ischaemia and gangrene, migrainous-like headaches and transient ischaemic attacks. The long-term risk of myelofibrosis and leukemia is perhaps lower than that with PV. ET is perhaps one of the most common myeloproliferative neoplasms and is thought to have an annual incidence of between 1 and 2.5 per 100,000 individuals according to the WHO. It is often identified as an incidental finding. It is predominantly diagnosed in patients between 50 and 60 years, with what appears to be an even distribution between both male and females though in younger patients there is a female preponderance [15].

The differential diagnosis of an isolated thrombocytosis includes other MPNs and reactive thrombocytosis, the causes of the latter include iron deficiency anemia, infection, chronic inflammation (e.g. rheumatoid arthritis or inflammatory bowel disease), splenectomy, acute hemorrhage and malignant disease. Such conditions may coexist with ET especially of course in the elderly, making the diagnosis difficult [16]. Investigations include full blood count/film, haematinics, renal and liver profile, C-reactive protein (CRP), anti nuclear antibody (ANA) and rheumatoid factor (RF), screening for JAK2 V617F Calreticulin [30]. MPL W515L/K mutations, chest X-ray, abdominal ultrasound scan and bone marrow examination (see Table 6.3).

Management and Prognosis of ET

Thrombosis is the major cause of morbidity and mortality for patients with ET. Hemorrhage occurs less commonly and is particularly associated with platelet counts of more than 1,500 × 109/l and acquired von Willebrand’s disease. Most patients have a near normal life expectancy. Cytoreductive agents should be used for patients with a high risk of thrombosis (any patient of age >60 years, platelet count >1,500 × 109/l, prior disease-related thrombosis or hemorrhage, treated diabetes or hypertension) [13, 16]. The total leucocyte count and allele burden of JAK2V617F are potentially useful future risk factors for thrombosis, as well as degree of reticulin deposition (fibre present in the marrow) Calreticulin [30] mutations appear to be associated with lower thrombotic risk.

In common with PV, patients with ET should be screened and aggressively managed for reversible factors for cardiovascular disease and low-dose aspirin given unless contraindicated. HC is the gold standard cytoreductive drug as has been demonstrated in the PT1 trial where it was compared with anagrelide see below [7]. Alternatives include 32P and busulfan, although these agents are more leukemogenic. IFN and anagrelide have the advantage that they are probably non-leukemogenic and do not affect fertility [16]. Both control the platelet count in most patients but are poorly tolerated, with up to 30 % being unable to continue treatment in the long term. The MRC-PT1 study made a direct comparison between hydroxycarbamide and anagrelide in patients with ET at high risk of thrombosis. The results suggested that hydroxycarbamide + aspirin is a more effective first-line therapy than anagrelide + aspirin, which was associated with a higher rate of arterial thrombosis, hemorrhage and myelofibrotic transformation [7]. In those who do not respond to a single cytoreductive agent, they can be switched to an alternative combination therapy can be used where appropriate. In circumstances whereby hydroxycarbamide is used with leukemogenic agents such as Busulfan, it has the potential to potentiate the leukemogenicity of either agent. Systemic anticoagulation should be considered in individuals over the age of 60 years in those with a venous thrombosis history.

Therapuetic Options and Considerations for the Elderly Patient with ET

The comments recorded for elderly PV patients (see above) apply equally to those for elderly ET patients. Indeed a recent paper examined the management of patients over the age of 80 years with ET in total 395 patients >80 years old with ET were followed as a subgroup of an observational study the authors concluded that “Well-tolerated and effective cytoreductive therapy has been achieved in patients aged >80 years by following individual treatment modalities that appear in agreement with the recent European LeukemiaNet (ELN) guidelines” [17].

Myelofibrosis

MF may present de novo when it is known as PMF or progress from an antecedent ET or PV when it is referred to as Post-ET or Post-PV myelofibrosis [18], collectively we will refer to these conditions as MF. Fibrosis is a hallmark feature of this condition and was identified in the first description of MF by Huek in 1872 along with massive splenomegaly. This fibrosis is thought to arise from an interaction between diseased megakaryocytes, leukocytes, and bone marrow stroma which release mitogens such as platelet-derived growth factor and transforming growth factor β. The proliferating fibroblasts are polyclonal and the primary disorder affects the hematopoetic stem cell. A range of molecular abnormalities have been described in patients with MF and these are beginning to be incorporated into prognosis for these patients more so that for patients with ET or PV for example [19].

Clinical Features and Epidemiology of MF

Individuals with MF often have a significant disease burden with diverse, debilitating symptoms that are progressive in nature and severely impact on the quality of life [20, 21]. Constitutional symptoms including fevers, night sweats, pruritus and bone pain can be a prominent feature of the disease and impact significantly on quality of life. Progression to AML occurs in up to 25 % of patients. Other MPNs (PV, ET, CML) and disorders in which marrow fibrosis can develop as a secondary feature (e.g. metastatic carcinoma, lymphoma, irradiation, tuberculosis, leishmaniasis) should be excluded. Most therapies are mainly targeted at alleviating and managing symptoms though until the introduction of JAK inhibitors they were not very effective, with a delay in disease progression to the leukemic phase is the primary aim [13, 18]. The yearly calculated incidence of primary myelofibrosis (PMF) ranges from 0.4 to 1.4 per 100,000 people. A slight male preponderance exists for PMF in adults, the median age at diagnosis is 65 years and about 20 % of affected patients are aged <55 years [15].

A positive screen for JAK2 V617F Calreticulin [30] MPL W515L/K mutations is helpful in confirming the diagnosis of MF but it is important to exclude other conditions as many other conditions may be associated with marrow fibrosis including for example myelodysplasia, CML, Hodgkin’s disease and other non-neoplastic conditions such as tuberculosis and leishmaniasis.

Management and Prognosis of MF

Therapeutic decisions in primary myelofibrosis depend on the stage of the disease as well as overall prognosis, whilst looking at the patient’s clinical status and co-morbidities as a whole. For the vast majority, medical management is the management choice. Supportive therapy with red cell transfusions and treatment of infection is often a mainstay, with androgens or erythropoietin therapy for some. (9) Several risk stratification scores have been developed for MF although they have only been validated in PMF. Of these IPSS is used at diagnosis and both DIPSS and DIPSS-Plus are the most widely used during the course of disease (these scores are discussed in detail in recent British Guidelines [18]). The overall score predicts progression and survival, and can enable a decision regarding the appropriate choice of treatment. In particular for those patients eligible for bone marrow transplantation these scores are extremely useful since international guidelines recommend consideration of this therapy when prognosis is less than 5 years and indeed outcome from transplant has been linked to IPSS as well as DIPSS [13, 22]. Transplantation has generally not been recommended for elderly patients but is being increasingly explored [22].

Conventional non-transplant related therapies for MF are diverse and are targeted usually at specific aspects of disease. Hydroxycarbamide which we have discussed in the context of ET and PV is also widely used particularly in patients with symptomatic splenomegaly and proliferative counts, with an overall response rate of ~45 % seen in a retrospective study [23]. However it may not affect prognosis. Careful dose titration is often required till clinical effect is observed. However it in itself requires patients to have regular follow up monitoring, for side effects such as cytopenias. A combination of steroids and thalidomide has been shown to be effective in some or the use of Lenalidomide in the context of those who are anaemic but have a platelet count >100 × 109 [18]. Splenectomy is very hazardous for these patients [24] yet is sometimes effective; it is not recommended for all, and certainly in the elderly there is an added risk of complications with significant morbidity and mortality in view of existing underlying co-morbidities. Radiotherapy may be an option in those with intractable bone pain, those with evidence of extramedullary hemopoiesis in other organs or symptomatic splenomegaly deemed not suitable for surgical intervention [18]. Anemia can be managed with blood transfusions and in certain individuals with moderate anemia in the context of an erythropoietin level of <125 u/l, may benefit from recombinant treatment. Androgens such as Danazol have been seen to be an option in transfusion dependent anemia, however monitoring of liver function and prostate cancer for men is required.

The therapeutic landscape for patients with MF has been radically altered with the arrival of JAK inhibitors which have been evaluated in Phase III clinical trials (reviewed in [10, 25]). The first such agent, Ruxolitinib is now approved for use in Intermediate and high risk MF in the United States and for symptoms of MF and/or splenomegaly in the EU. Ruxolitinib has proven to be effective at relieving symptoms and reducing splenomegaly with approximately 30 % of patients achieving a 50 % or greater reduction in palpable spleen size compared to best available therapy. Exactly how these agents exert their mode of action and the relevance of trial endpoints has been debated, none of these drugs is specific to the JAK2 V617F mutation and to date they all appear equally active in patients whether they test positive for the mutation or not [26, 27]. Nonetheless there is emerging and strengthening evidence of a survival benefit and perhaps of disease modification at least with Ruxolitinib while data with other agents is thus far immature [9, 28, 29].

Therapuetic Options and Considerations for the Elderly Patient with MF

The elderly patients with MF can present a difficult challenge disease progress is inexorable and co-morbidities can rule out consideration of curative therapy such as transplantation or even clinical trials with novel agents which is an area of intense interest in this particular field. Fortuitously the JAK inhibitors are extremely well-tolerated and can be given in patients with renal, cardiac and liver impairment though with due caution.

Conclusions

The MPN are chronic neoplastic conditions characterised by a preponderance of mature blood cells, they have a central common pathogenesis with JAK/STAT activation, frequently associated with mutations in JAK2 in particular JAK2 V617F. The description of this mutation in 2005 has substantially modified management from diagnosis and is now influencing treatment approaches for these patients. These conditions are more prevalent in the elderly; their clinical phenotype is dominated by risk of thrombosis (so for all of them aggressive vascular risk management is mandatory); and development of either MF, after one of the more benign entities (ET or PV), or AML (which occurs after any MPN but more frequently MF). For each MPN advanced age has been shown to be a poor prognostic factor. There have been several large studies of these patients but none have systematically evaluated care for the elderly cohort. Notwithstanding these facts the evidence to date is that most elderly patients with MPN can be managed with standard therapies to which they respond as well as younger patients. The most important challenge here remaining to identify these diseases before the occurrence of a thrombosis or hemorrhage.