Risk Classification (Specific Issues of Treatment in PV and ET) (Myeloproliferative Neoplasms) Part 2

Leukocyte Number and Function

A prognostic role for leukocytosis in ET, as in PV, has been advocated.Two large cohort studies reported that an increased baseline leukocyte count was an independent risk factor for both thrombosis and inferior survival (Wolanskyj et al. 2006; Carobbio et al. 2007) . In "low-risk" ET patients (i.e. below 60 years and without previous thrombosis), leukocytosis confers a thrombotic risk comparable to that of treated "high-risk" patients without leukocytosis (Carobbio et al. 2007). The role of WBC count in ET was mostly observed on the occurrence of myocardial infarction, as shown in Table 7.2, confirming the data reported above for PV (Carobbio et al. 2008). White blood cell (WBC) counts above 9.5 χ 109/L at diagnosis were independently associated with thrombosis during follow-up (RR = 1.8, P = 0.03) in another study of 187 patients with ET and PV (Caramazza et al. 2009) . These findings were not confirmed in a retrospective study of 407 low-risk patients with ET (Gangat et al. 2009a) . Leukocytosis at the time of diagnosis, defined by a cut-off level of either 15 or 9.4 χ 109/L, did not appear to be predictive of either arterial or venous thrombosis during follow-up. However, in an analysis by Passamonti et al. (2009) of 194 low-risk ET patients, the increase in leukocyte count within 2 years of diagnosis (observed in 9% of patients), rather than leukocytosis at diagnosis, was associated with an higher risk of vascular complications during follow-up.


Table 7.2 Sites of thrombosis according to leukocytosis at diagnosis in 657 patients with ET

7.1 to 10 χ 109/L

More than 10χ109^

White blood cellsa

White blood cellsa

HR (95% CI)

P

HR (95% CI)

P

Major thrombosis

2.21 (1.05-4.65)

0.036

3.27 (1.54-6.95)

0.002

Arterial thrombosis

2.07 (0.83-5.20)

0.121

3.12(1.20-8.08)

0.019

Myocardial infarction

5.82 (0.64-53.2)

0.118

8.08 (1.00-65.5)

0.050

Stroke/TIA

0.88 (0.29-2.67)

0.824

1.32(0.42-4.11)

0.631

Venous thrombosis

1.40 (0.49-4.04)

0.534

2.51 (0.86-7.29)

0.092

Multivariable models adjusted for information collected at diagnosis, including center, sex, standard risk factors, hemoglobin, hematocrit, and platelet count "Reference category: WBC £ 7 χ 109/L

In ET, an in vivo leukocyte activation has been consistently documented in association with signs of activation of both platelets and endothe-lial cells. Interestingly, the presence of the JAK2 mutation is associated with higher platelet and leukocyte activation in these patients (Arellano-Rodrigo et al. 2006). Thus, platelet and leukocyte activation may play a role in the generation of the pre-thrombotic state that characterizes essential thrombocythemia (Falanga et al. 2005; Marchetti and Falanga, 2008) . However, whether leukocy-tosis should be simply considered a marker for vascular disease or whether elevated WBC levels actually contribute directly to causing such disorders should be matter of prospective studies.

Other Risk Factors

The presence of the JAK2 V617F mutation in about 60% of ET patients raised the question whether mutated and non-mutated patients differ in terms of thrombotic risk. The largest prospective study on 806 patients suggested that JAK2 mutation in ET was associated with anamnestic venous but not arterial events (Campbell et al. 2005). An increased risk of thrombosis in JAK2 mutated patients was retrospectively observed by other investigators (Cheung et al. 2005; Finazzi et al. 2007). However, the rate of vascular complications was not affected by the presence of the mutation in two relatively large retrospective studies, including 150 and 130 ET patients, respectively (Antonioli et al. 2005; Wolanskyj et al. 2005) . A systematic literature review was carried out to compare the frequency of thrombosis between JAK2 V617F positive and wild-type patients with essential thrombocythemia (Lussana et al. 2009) . This study showed that JAK2 V617F patients have a twofold risk of developing thrombosis (odds ratio 1.92, 95% confidence interval 1.45-2.53), but a significant heterogeneity between studies should be pointed out. In addition to the prognostic role of JAK2 mutation for the first throm-botic episode, recent data would indicate that the mutation has also a role to predict recurrent thrombotic episodes in patients with ET (De Stefano et al. 2010).

Bone marrow histology is important for an accurate morphologic diagnosis of ET according to WHO criteria and for predicting survival and hema-tological transformations to myelofibrosis or acute leukemia.However, its role as risk factor for thrombosis is controversial. Campbell et al. (2009) have identified increased bone marrow reticulin fibrosis at diagnosis as an independent predictor of subsequent thrombotic and hemor-rhagic complications. However, a recent analysis comparing 891 patients with WHO-diagnosed ET vs. 180 patients clinically presenting like ET but with an histological picture of pre-fibrotic PMF did not show any difference in the rates of arterial (1.21.4% patient-year, respectively) and venous (0.6% patient-year in both groups) thrombotic complications.

Table 7.3 Risk stratification in PV and ET based on thrombotic risk

Risk category

Age > 60 years or history of thrombosis

Low

No

High

Yes

Extreme thrombocytosis (platelet count >1,000 χ 109/L) is a risk factor for bleeding, not for thrombosis Increasing leukocyte count and JAK2 V617F mutation or allele burden have been identified as novel risk factors for thrombosis, but confirmation is required Major thrombosis rate was higher in the highest C-reactive protein tertile (P=0.01) and lower at the highest pentraxin-3 levels (P=0.045). These associations remained significant in multivariable analysis and indicate that these inflammatory biomarkers independently and in opposite ways modulate the risk of cardiovascular events in patients with MPN.

Conclusions

By incorporating this body of knowledge in a clinically oriented scheme (Table 7.3), we have now consistent information to stratify the patients with either PV or ET in a "high-risk" or "low-risk" category according to their age and previous history of thrombosis.Putative novel variables, such as leukocytosis and JAK2 V617F mutational status and allele burden might be incorporated in the risk classification, possibly allowing better definition of the low-risk group, once more information is available and when they have been eventually validated in prospective studies.

Risk Stratification in Pregnancy

Pregnancy in MPN is an increasingly frequent and relevant problem due to improvement in diagnosis and for the trend in modern society towards delaying pregnancy until later life.

Normal pregnant women are at an increased risk of thrombosis, calculated to be approximately six times higher than in non-pregnant women, and the risk is compounded if they also have MPN. As a consequence, women with MPN may present a high incidence not only of pregnancy-related venous thromboembolism but also of other vascular complications of pregnancy involving occlusion of the placental circulation (Harrison 2005; Griesshammer et al. 2006). The paucity of published data, however, makes it difficult to obtain a clear view of the overall risk of these events.

Incidence and Risk Factors for Pregnancy Complications

In the Italian guidelines for the therapy of essential thrombocythemia, the outcomes of 461 pregnancies reported in retrospective and prospective cohort studies were pooled.Most reports dealt with single cases or small numbers, and some suspicion of reporting bias was raised since there is a tendency to describe patients with complications rather than those with an uncomplicated pregnancy.

The mean age at pregnancy was 29 years, with a mean platelet count at the beginning of pregnancy of 1,000 χ 109/L. During the second trimester, a spontaneous decline was registered to a nadir of 599 χ 109/L. This decrease seems larger than the reduction seen in normal pregnancies, which is attributed to an increase in plasma volume. The mechanism is not known, but could involve placental or fetal production of a factor that downregulates platelet production. In the post-partum period, the platelet counts rise back up to their earlier levels, and rebound thrombocy-tosis may occur in some patients. This increases the probability of vascular complications at this time, which is a period of high thrombotic risk, like in other conditions of thrombophilia as well as in normal women. Overall, 50-70% of ET women had successful live births; first-trimester loss occurred in about 25-40% and late pregnancy loss in 10% of cases. This is in agreement with a Mayo Clinic study of 63 pregnancies: 60% ended in live births and 32% in first trimester miscarriages (Gangat et al. 2009b). Abruptio placentae was reported in 3.6% of cases, higher than in the general population (1%).Pre-eclampsia rates were similar to the normal population (1.7%), and intrauterine growth retardation was reported in 4-5%. Recent studies suggested that the presence of JAK2 V617F mutation may increase the risk of pregnancy loss (Passamonti et al. 2007), but adjusting management strategies on this basis is not recommended.

Maternal thrombosis or hemorrhage is uncommon. In the pooled analysis cited above, post-partum thrombotic episodes were reported in 13 patients, occurring in 5.2% of pregnancies, and minor, or major, pre- or post-partum bleeding events in other 13 cases.The maternal vascular risk may be higher in women with previous venous or arterial events or hemorrhages attributed to MPN, independent of whether they occurred in a previous pregnancy or not. Similarly, severe complications in a previous pregnancy, such as >3 first-trimester, or >1 second- or third-trimester losses, birthweight <5th centile of gestation, pre-eclampsia, intrauterine death, or stillbirth, are considered to raise the risk of subsequent events for the mother and the fetus. Other vascular risk factors in pregnant women are age, obesity, immobilization, and other causes of genetic and acquired thrombophilia including antiphospholipid antibodies.

Pregnancy in polycythemia vera (PV) is rarer than in ET. A study reviewed a total of 38 pregnancies in 18 PV patients (Robinson et al. 2005); 22 successful live births were reported (57%). Similar to ET, spontaneous abortion during the first trimester was reported in 22% of cases and pre-term delivery in 13.8%.

Based on the information, consensus recommendations for risk stratification in pregnant women with MPNs have been recently developed by ELN and are summarized in Table 7.4.

Table 7.4 Features consistent with high-risk pregnancy in Ph-neg. classical myeloproliferative neoplasms (MPN)

Previous venous or arterial thrombosis (whether pregnant or not)

Previous hemorrhage attributed to MPN (whether pregnant or not)

Previous pregnancy complication that may have been caused by MPN; e.g.

Unexplained recurrent first trimester loss (three unexplained first trimester losses)

Intrauterine growth restriction (birthweight <5th centile for gestation)

Intrauterine death or still birth (with no obvious other cause, evidence of placental dysfunction and growth restricted fetus)

Severe pre-eclampsia (necessitating pre-term delivery <34 weeks) or development of any such complication in the index pregnancy

Placental abruption

Significant ante- or post-partum hemorrhage

Marked sustained rise in platelet count rising to above 1,500 χ 109/L

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