Introduction
Patient communication represents an important element of the clinical work of the treating physicians, with this especially applying to individuals with neoplastic diseases, as it is the case of the myeloproliferative neoplasms (MPNs). In the current Internet era, an increasing number of patients seek for information in the network, and, very often, misinterpretation of the information found raises additional doubts and creates more uncertainties. In MPN patients, concerns about the nature of the disease, the symptoms and complications that can derive from it, and the prognosis and life expectancy are common, as well as the possibility that the disease could be inherited. Once they are informed on these important aspects, they usually want to know on the available therapeutic options, if progress is being made in the understanding of their disease and if this will eventually translate into the availability of better treatment options in the next future. Moreover, since a substantial proportion of MPN patients are young individuals and, for most of them, the expected survival is close to normal, information on the possibility of creating a family and the risks associated with this process is a frequent request. The present topic tries to summarize the more relevant information to be provided to MPN patients.
Patient Information Before Planning Therapy
The first topic to address in an interview with a patient that has been diagnosed with a myelopro-liferative neoplasm (MPN) and his or her family could be to explain the neoplastic nature of these diseases. This having been said, it is advisable to explicitly distinguish these disorders from leukemia, a much more feared condition, and this especially applies to patients with polycythemia vera (PV) or essential thrombocythemia (ET), two disorders that, when properly managed, are associated with a life expectancy not substantially different from that of the general population (Passamonti et al. 2004) . Beside, the lack of a causative agent in most MPNs cases must also be highlighted. Patients might be interested in knowing that the annual incidence of ET and PV is low, from one to three new cases per 100,000 inhabitants per year, whereas primary myelofibrosis (PMF) is even less frequent (Johansson et al. 2004). However, because life expectancy, particularly in patients with ET and PV, is long, the prevalence of these diseases is severalfold higher.
A typical concern of a MPN patient is the possibility that the disease might be heritable. This issue can be clarified by indicating that the MPNs originate from an acquired somatic mutation in the hematopoietic stem cells, not present therefore in the germ line (Campbell and Green 2006), and that the majority of cases of MPNs are of sporadic appearance. However, it can be added that there is occasional occurrence of MPNs among members of the same family and that an increased incidence of MPNs has been observed among first-degree relatives of patients with MPNs (Landgren et al. 2008; Rumi et al. 2007). This does not mean that specific laboratory tests should be performed to the patient’s relatives in order to rule out the presence of one such disorder, unless indicated by a history suggesting an MPN (for instance, being aware of persistent thrombocytosis or polyglobulia, or a history of aquagenic pruritus, microvascular disturbances or recurrent thrombosis). Moreover, if the patient asks about the existence of biological data supporting a predisposition to develop an MPN, it can be said that an increased frequency of a special genetic background, the so-called haplotype 46/1 of the JAK2 gene, has been recently found in MPN patients and their first-grade relatives (Jones et al. 2009) but, again, no specific test to screen for this haplotype should be performed to the patient’s relatives out of the research setting.
Information on the genetic abnormalities most commonly encountered in MPNs can also be disclosed, but always making it clear that genetic is not synonymous of hereditary, since, as already mentioned, the genetic abnormalities typical of the MPNs are acquired and, as such, while they are present in the hematopoietic cells, they are not in the cells of other organs or tissues of the patient. In this sense, it can be indicated that the most frequent molecular abnormality in the MPNs consists of a mutation in the JAK2 gene, which is detected in around 95% of PV patients and in 50% to 60% of patients with ET or PMF.In addition, that activating mutations in the MPL gene are found in about 4% of patients with ET and in 10% of those with PMF, but not in PV.Of note, it can be mentioned that, for the time being, there is no universal agreement on the possibility that the presence of the JAK2 or MPL mutations might affect the thrombotic risk, the patients’ survival, or the frequency of leukemic transformation of the disease.
The onset of the MPNs is often a gradual process, with many patients (especially those with ET and, to a lesser extent, PV) being currently diagnosed by chance while having blood tests done for other reasons. Because of this, it might be helpful to educate the patient on identifying the signs and symptoms that could be related to the MPN. Thus, patients should be aware of the possibility of suffering microvascular disturbances either at diagnosis or during the disease evolution, including dizziness, transient ischemic attacks or other neurological symptoms, transient visual abnormalities, acral paresthesia, erythromelalgia, or others. These manifestations should not be overlooked, since they are generally sensitive to low-dose aspirin and might precede a major thrombotic event. Large vessel thrombosis and mucocutaneous bleeding can occur in all three MPNs, but they appear mainly in PV and ET (Landolfi et al. 2008) . With regard to bleeding, patients must be recommended to avoid the intake of aspirin at standard dosage in order to minimize the risk of this complication (Tartaglia et al. 1986; Willoughby and Pearson 1998). PMF patients are more often symptomatic at diagnosis, with roughly one-third of them complaining of either constitutional symptoms, anemic symptoms, and discomfort or pain in the upper left part of the abdomen due to the splenomegaly, respectively. Pruritus, typically exacerbated by hot water, is a particularly distressing symptom that preferentially occurs in patients with PV but can also be noted in a minority of patients with ET and PMF.
Prognostic Information
The prognosis of MPNs should be underscored to patients as soon as the diagnosis is established. In this sense, while PMF is associated with a substantial reduction in life expectancy, it must be stressed that ET affects more the patients’ quality of life than their survival, whereas PV is associated with both a substantial morbidity derived from thrombosis but also with a certain reduction in the patients’ life expectancy (Passamonti et al. 2004; Rozman et al. 1991; Wolanskyj et al. 2006). When the survival of PMF patients has been compared with that of age-and sex-matched individuals from the general population, a substantial reduction in life expectancy has been observed (Cervantes et al. 2009; Rozman et al. 1991), mainly due to evolution to acute leukemia, infection, bleeding, portal hypertension, and heart failure. Despite this, life expectancy of PMF patients is widely variable and younger patients without adverse prognostic factors (anemia, constitutional symptoms, circulating blast cells) can be reassured by telling them that their predicted outcome is favorable (Cervantes et al. 1997). Patients with PV and ET have to understand that their life expectancy is mainly affected by vascular complications, especially thrombosis, although there is also a small risk of transformation to either myelofibrosis or leukemia, particularly in PV. Transformation to acute leukemia in PV and ET is exceedingly infrequent in cytoreductive treatment-naïf patients and can increase slightly depending on the treatment administered (Kiladjian et al. 2006; Murphy et al. 1997). With regard to thrombosis, in PV, the incidence is 18 per 1,000 person-years, being about 5 per 1,000 person-years for the evolution to myelofibrosis and leukemia, whereas in ET, it is 12 per 1,000 person-years, being 1.6 per 1,000 person-years for evolution to myelofibrosis and 1.2 per 1,000 person-years for leukemic transformation (Passamonti et al. 2004). Therefore, given that thrombosis is the more frequent complication of PV and ET, patients must be informed that the treatment strategy is based on their thrombosis risk (and, to a lesser extent, their bleeding risk), with advanced age and a previous history of thrombosis being the two major predictors for such complication. In this regard, a point to be stressed in order to minimize the risk of thrombosis is the importance of an appropriate control of generic cardiovascular risk factors, including arterial hypertension, diabetes mellitus, hyperlipidemia, and obesity, as well as strict smoking cessation. Patients, particularly those managed without cytoreductive drugs, should understand that the platelet count per se does not correlate with the risk of thrombosis. However, they should know that extreme thrombocytosis (>1.500 χ 109/L) is used as an indication for cytoreductive therapy, due to the bleeding tendency associated with the appearance of acquired von Willebrand disease (Buss et al. 1985).
Examinations Needed for Prognostic Stratification and Treatment Monitoring
A detailed history of the patient’s health habits, comorbidities, and concomitant therapies is mandatory. In particular, direct inquisition about the possible presence of the above-mentioned cardiovascular risk factors and past history of throm-bohemorrhagic complications is essential since such information constitutes the basis for risk stratification in treatment decision-making for these patients.A thorough investigation of the family history should be part of the initial work-up, in order to evaluate potential familial predisposition to the MPNs, as well as the possibility of inherited thrombophilia, which would highly increase the thrombotic risk (Ruggeri et al. 2002). Attention should also be paid to collect relevant information on prognostic clinical factors, such as presence of constitutional symptoms (including weight loss, night sweats, and more rarely, low-grade temperature) in PMF and PV or the need for red blood cell transfusions in PMF.
Table 5.1 Definition of clinicohematologic response in ET and PV according to the criteria of the European LeukemiaNet
|
Response grade |
Essential thrombocythemia |
Polycythemia vera |
|
Complete response (CR) |
1. Platelet count £400 χ 109/L |
1. Hematocrit <45% without phlebotomy |
|
2. No disease-related symptoms |
2. Platelet count £400 χ 109/L |
|
|
3. Normal spleen size on imaging |
3. Leukocyte count £10 χ 109/L |
|
|
4. Leukocyte count £10 χ 109/L |
4. Normal spleen size on imaging |
|
|
5. No disease-related symptoms |
||
|
Partial response (PR) |
In the absence of CR, platelet count £600 χ 109/L or decrease >50% from baseline |
In the absence of CR, hematocrit <45% without phlebotomy or response in 3 or more of the other criteria |
|
No response |
Any response that does not satisfy PR |
Any response that does not satisfy PR |
Physical examination will assess the patient’s general clinical condition and check for possible signs of the disease, such as facial plethora or enlarged spleen or liver. Complete blood counts with a manual differential will provide prognostic information on variables potentially increasing the thrombotic risk (leukocytosis), or associated with higher bleeding risk (extreme thrombocytosis) or shorter survival (anemia, excessive leukocytosis, circulating blood blasts) (Cervantes et al. 2009). Although detection of JAK2 or MPL mutations is very important for the diagnosis of the MPNs, their prognostic value has not been fully established yet.Cytogenetic studies are not usually required in PV and ET at presentation, since abnormalities are rarely found in these two diseases (Diez-Martin et al. 1991; Gangat et al. 2009), but they can provide relevant prognostic information in PMF. In this sense, an abnormal karyotype is observed in about a third of PMF patients at diagnosis, and a negative influence on survival has been noted for trisomy 8, deletion of 12p, and abnormalities in chromosomes 5, 7, and 17, while, on the contrary, the sole detection of deletions of 13q and 20q is associated with an outcome comparable to that of patients with a normal diploid karyotype (Hussein et al. 2010; Tam et al. 2009). A bone marrow biopsy is not usually required to establish the diagnosis of PV, but it is mandatory for PMF and is also essential to differentiate ET from PMF. Moreover, an increase in the reticulin fiber content at ET diagnosis has been associated with a higher incidence of myelofibrotic transformation (Campbell et al. 2009).
Treatment monitoring should adopt the European LeukemiaNet criteria for PV and ET, which were proposed for defining the clinicohematologic response (Table 5.1) (Barosi et al. 2009), and the criteria established by the International Working Group for Myeloproliferative Neoplasms Research and Treatment for myelofibrosis.Complete blood counts and regular biochemical tests should be frequently obtained during the first 3 months of initiation of treatment to allow for drug dose titration. There is no formal indication to routinely monitor JAK2 allele burden during treatment, unless the therapeutic intervention may induce molecular responses (i.e., interferon-a or hemopoietic stem cell transplantation). Similarly, bone marrow studies are not required for response assessment (with the exception of allogeneic transplantation or trials with experimental drugs in myelofibrosis), although they may be performed during follow-up if clinically indicated, such as in case of suspicion of transformation to myelofibrosis of PV or ET.
General Information on Therapy
Although several drugs are currently available to effectively control the MPNs, for the time being, none of them have curative potential. However, patients should understand that the current goal of treatment is not to cure the MPN but to avoid the development of complications and to improve the patients’ quality of life by relieving the disease-related symptoms. To date, the only curative strategy for the MPNs is allo-geneic stem cell transplantation, but its utility is limited by the relatively high treatment-related mortality and morbidity (Kroger et al. 2009). For this reason, transplantation is only an option for patients with myelofibrosis (either PMF or post-PV/ET myelofibrosis) with intermediate-2 or high-risk features either at diagnosis (Cervantes et al. 2009) or during follow-up (Gangat et al. 2011), whenever their clinical condition is reasonably good and an appropriate donor is available.
Table 5.2 International Working Group (IWG) consensus criteria for treatment response in myelofibrosis
|
Complete remission (CR) |
1. Complete resolution of disease-related symptoms and signs including palpable hepatosplenomegaly 2. Peripheral blood count remission (Hb > 110 g/L, platelet count >100 χ 109/L, neutrophil count >1.0 χ 109/L). AH 3 blood counts should be no higher than the upper normal limit 3. Normal leukocyte differential including disappearance of nucleated red blood cells, blasts, and immature myeloid cells in the peripheral smear, in the absence of splenectomya 4. Bone marrow histologic remission defined as the presence of age-adjusted normocellularity, no more than 5% myeloblasts, and an osteomyelofibrosis grade no higher than oneb |
|
Partial remission (PR) |
All of the above criteria for CR except bone marrow histologic remission A repeat bone marrow biopsy is required in the assessment of PR |
|
Clinical improvement (CI) |
Requires one of the following in the absence of both disease progression and CR/PR assignment (CI response is validated only if it lasts for no fewer than 8 weeks): 1. A minimum 20 g/L Hb increase or becoming transfusion independent (applicable only for patients with baseline Hb < 100 g/L)c 2. Either a minimum 50% reduction in palpable splenomegaly of a spleen that is at least 10 cm at baseline or a spleen that is palpable at more than 5 cm at baseline becomes not palpabled 3. A minimum 100% increase in platelet count and an absolute platelet count of at least 50 χ 109/L (applicable only for patients with baseline platelets <50 χ 109/L) 4. A minimum 100% increase in neutrophil count and neutrophils of at least 0.5 χ 109/L (applicable only for patients with baseline absolute neutrophil count <1 χ 109/L) |
|
Progressive disease (PD) |
Requires one of the followinge: 1. Progressive splenomegaly defined by the appearance of a previously absent splenomegaly that is palpable at greater than 5 cm below the left costal margin or a minimum 100% increase in palpable distance for baseline splenomegaly of 5-10 cm or a minimum 50% increase in palpable distance for baseline splenomegaly of greater than 10 cm 2. Leukemic transformation confirmed by a bone marrow blast count of at least 20% 3. An increase in peripheral blood blast percentage of at least 20% that lasts for at least 8 weeks |
|
Stable disease (SD) |
None of the above |
|
Relapse |
Loss of CR, PR, or CI |
aCR does not require absence of morphologic abnormalities of red cells, platelets, and neutrophils
bIn patients with CR, a complete cytogenetic response is defined as failure to detect a cytogenetic abnormality in cases with a preexisting abnormality. A partial cytogenetic response is defined as 50% or greater reduction in abnormal meta-phases. In both cases, at least 20 bone marrow- or peripheral blood-derived metaphases should be analyzed. A major molecular response is defined as the absence of a specific disease-associated mutation in peripheral blood granulocytes of previously positive cases. In the absence of a cytogenetic/molecular marker, monitoring for treatment-induced inhibition of endogenous myeloid colony formation is encouraged. Finally, baseline and posttreatment bone marrow slides are to be stained at the same time and interpreted at one sitting by a central review process
cTransfusion dependency is defined by a history of at least 2 units of red blood cell transfusions in the last month for a hemoglobin level of less than 85 g/L that was not associated with clinically overt bleeding. Similarly, during protocol therapy, transfusions for a hemoglobin level of 85 g/L or more are discouraged unless it is clinically indicated
dIn splenectomized patients, palpable hepatomegaly is substituted with the same measurements
eA decrease in hemoglobin level of 20 g/L or more, a 100% increase in transfusion requirement, and new development of transfusion dependency, each lasting for more than 3 months after the discontinuation of protocol therapy, can be considered disease progression
In general, treatment is dictated by the baseline or evolutive risk factors of the MPN, as well as by the patient’s age and general condition. The different therapeutic options must be discussed with the patient, along with comments regarding how both the disease and its treatment might affect the patient’s quality of life.All patients should be reinforced to follow a healthy diet and exercise regularly, whenever possible. A strict control of cardiovascular risk factors is strongly encouraged, with this including smoking cessation. Combined oral contraceptive pill must be avoided since this drug has been associated with an increased risk of venous thrombosis in women with ET, particularly thromboses that involve splanchnic sites (Gangat et al. 2006 ) . By contrast, hormone replacement therapy seems safe in this setting (Gangat et al. 2006). Aquagenic pruritus can occasionally be controlled by avoidance of precipitating conditions, but several drugs may be effective to manage the more disabling cases, mainly antihista-mines, paroxetine, interferon-a, and the currently in clinical trials JAK2 inhibitors.
It is worthy to remind PV patients not to take iron supplements, as this will cause the hemoglobin level to rise rapidly. Low-dose aspirin is routinely used in PV and ET to prevent clotting from overactive platelets, unless contraindicated. Patients should understand that aspirin does not reduce the number of platelets but inactivate them for a period of 5-7 days. Therefore, they should be aware of the need to contact his or her hema-tologist in case of active bleeding or surgery while receiving this drug. In patients who must undergo surgery, antiplatelet therapy must be stopped 7-10 days before. A high incidence of thrombotic and hemorrhagic complications has been observed in MPN patients submitted to surgical procedures (Ruggeri et al. 2008). Therefore, to minimize the risk of such complications, in case of elective surgery, normalization of the hematocrit and the platelet counts by cytoreduc-tive therapy is recommended and, for all patients, prophylaxis of postoperative thrombosis with low molecular weight heparin (LMWH) mandatory. A particularly risky intervention is splenec-tomy in PMF since, even in experienced hands, it has been associated with a perioperative mortality of 9%, mainly derived from hemoperitoneum, infection, or thrombosis (especially in the spleno-portal vein tract).In this setting, treatment with heparin or antiplatelet drugs had no apparent effect on adverse outcomes, although there was a trend for heparin efficacy in the prevention of venous thromboembolism.
Treatment of arterial and venous thrombosis in MPN subjects should not differ from that recommended in the general population (Landolfi et al. 2008) . However, the optimal duration of anticoagulation is uncertain, due to the lack of studies addressing this issue in the MPNs. An exception to this would be splanchnic vein thrombosis, for which long-life anticoagulation is usually recommended.
Hydroxyurea is currently the most effective drug for preventing thrombosis in high-risk ET and PV patients (Cortelazzo et al. 1995; Fruchtman et al. 1997) . However, some patients may be reluctant to use this drug due to fear regarding its possible leukemogenicity. In this sense, it must be remarked that, whereas the potential leukemogenic effect of hydroxyurea in MPN patients remains a matter of controversy, to date, no data supporting such hypothesis in either ET or PV are available from controlled studies (Finazzi et al. 2005; Harrison et al. 2005) .
Information on Pregnancy
Information on the management of pregnancy in the setting of MPNs is limited (Harrison 2005) . Despite this, the available data indicate that there is an increased risk of miscarriage and thrombosis during pregnancy in ET and PV, including preeclampsia, placental abruption, intrauterine death or stillbirth, and intrauterine growth retardation; venous thrombosis may also occur, especially in the postpartum period (Passamonti et al. 2007). However, a successful outcome may still be achieved in about a half of the patients with correct planning and close follow-up. On the contrary, due to reduced survival and risk of disease progression in the midterm, pregnancy is not recommended for women with PMF. If a properly informed patient is willing to become pregnant, a preconception meeting should be held to delineate the overall management of pregnancy, which should include a multidisciplinary team. Some factors might help to identify women at high risk of pregnancy-related complications, such as previous major thrombosis, a history of severe pregnancy or obstetric complications or having genetic thrombophilia.
Treatment options include no therapy, phlebotomy, aspirin, LMWH, and interferon-a. Although evidence for therapeutic guidelines is limited, management recommendations on this topic are available. In brief, low-risk pregnancy can be managed with phlebotomies in PV to maintain normal hematocrit values, low-dose aspirin throughout the pregnancy (unless contraindi-cated), and LMWH during the weeks following delivery, while management of high-risk pregnancy must be more aggressive, including LMWH during the pregnancy and postdelivery, low-dose aspirin in the absence of a bleeding history, and cytoreduction with interferon in case of previous major thrombosis, recurrent miscarriage, serious obstetric problems, or marked thrombocytosis. It is important to inform the patient that chemotherapy (in practice, hydroxyurea) and anagrelide are contrain-dicated during pregnancy due to their teratogenic potential. For this reason, interferon-a is the drug of choice for those women wishing pregnancy who require administration of cytoreduc-tive therapy.
