Pulmonary Hypertension in Chronic Myeloproliferative Disorders

EPIDEMIOLOGY

The incidence of CMPD is rare and estimated between 6 and 9 new cases per 100,000 per year, most commonly occurring between 40 and 60 years of age.67 There have been several publications showing that prevalence of PH in CMPD ranges from 13% to 48% (Table 1), but exact prevalence is unknown.8–16 Two factors may account for this wide range.

Table 1. Prevalence of PH in CMPDs

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The first is the different diagnostic methods used for PH diagnosis. The largest report on the association of PH and CMPD is from Dingli et al. Diagnosis codes were utilized to identify patients with both CMPD and PH. PH was defined as right ventricular systolic pressure (RVSP) >35 mm Hg on Doppler transthoracic echocardiography (TTE) or mPAP >25 mm Hg on RHC or pulmonary angiography.16 Because of the search strategy utilized, a prevalence rate could not be calculated, but the authors found that 26 patients met inclusion criteria (CMPD plus PH unexplained by other medical conditions). They concluded that given the rarity of idiopathic pulmonary arterial hypertension (PAH) in the general population (expected to see <1 case of idiopathic PAH in their entire CMPD cohort), the 2 diseases were likely related. Of the 26 patients in their cohort, 22 (92%) received treatment for CMPDs, which included therapy with hydroxyurea, anagrelide, or busulfan. PH was diagnosed a median of 8 years after recognition of the CMPD.

In a subsequent prospective study, Chebrek and coworkers evaluated 103 consecutive patients with CMPDs for the presence of PH, defined as an RVSP >35 mm Hg by echocardiography. Five patients were found to have an unexplained elevation in pulmonary artery (PA) pressure (<5%),15 and another 3 patients were found to have elevated pulmonary pressures in association with a known cause (left heart disease and/or chronic pulmonary embolism [PE]). Finally, Gupta et al reported one of the highest prevalences of PH, with 52% (14/27) of patients with CMPD having elevated PA pressures by echocardiogram.11 Two patients had a reduced left ventricular ejection fraction and were excluded from further analysis; the remaining patients had no other known risk factor for PH. Among these 12 patients, 7 had essential thrombocytosis (ET) and 5 had polycythemia vera (PV). Diagnosis of PH was based on measurements obtained by TTE with Doppler study and was established if RVSP was estimated >35 mm Hg.

Given that PH in the majority of patients in these studies was diagnosed based on Doppler TTE and not confirmed by RHC, the rate of PH may be inaccurate. Alternatively, because clinical signs of PH appear at advanced stages of the disease and chronic hypoxemia can confound the diagnosis of CMPD, the prevalence of PH may also be underestimated. Either way, the lack of a uniform diagnostic method appears to be one factor that leads to a wide range in incidence.

The second factor likely contributing to the variable prevalence rate is that CMPD is not a single entity, but rather includes a spectrum of disorders. Higher rates of PH may be seen in one disorder when compared to another, changing the overall incidence in a cohort, which includes all CMPDs. For example, Altintas and colleagues reported a diagnosis of PH in 22/46 patients (47.8%) with essential thrombocytosis.10 Dingli et al and Tefferi report that among CMPDs, myelofibrosis with myeloid metaplasia (MMM) appears to be most frequently associated with PH.1617

PATHOGENESIS

Three distinct forms of PH associated with CMPD (PH-CMPD) have been identified: chronic thromboembolic pulmonary hypertension (CTEPH), which is often diagnosed at an early stage of CMPD; precapillary PH mimicking PAH, often occurring later in the course of CMPD; and drug-induced-PH.1819 Guilpain et al, in their case series of 6 patients, describes the differing time course of CTEPH vs PAH-like conditions. In this series, all 6 cases of CTEPH were made at the same time as the diagnosis of MPDs, and the authors concluded that CTEPH could be the first manifestation of the MPD, particularly for PV. In contrast, for the 4 patients with precapillary PH mimicking PAH, Guilpain et al found that PH developed later in the course of the disease, with a median of 162 months (range: 120–140) after the diagnosis of CMPD.13 Similarly, Dingli et al found that precapillary PH was diagnosed a mean of 8 years after recognition of the MPD.16

The mechanism of development of CTEPH in CMPD is multifactorial. In PV and in ET, it is characterized by thrombophilic states that can lead to microcirculatory disturbances and subsequent arterial and venous thrombosis. Marvin and Spellberg have also suggested that thrombocytosis may cause PH mediated by pulmonary capillary obstruction due to cellular components, involving platelet aggregation, microthrombosis, stasis, and vasoconstrictor effects.20 Additionally, high hematocrit values seen in PV lead to blood hyperviscosity, which increases risk for thrombosis.2122 Specifically, JAK-2 mutations in PV predisposes to polymorphonuclear cell activation, platelet aggregation and activation, and subsequent development of thrombosis.23

Precapillary PH mimicking PAH also has several pathogenic mechanisms, including portal hypertension, cytotoxic chemotherapies, megakaryocyte embolism, and enhanced angiogenesis.13 Portal hypertension is a well-known complication of myeloid metaplasia and myelofibrosis, which can lead to PAH.1726 Cytotoxic chemotherapy may result in pulmonary damage or promote pulmonary veno-occlusive disease.25 Megakaryocyte embolism of pulmonary vessels may be caused by translocation of megakaryocytes from the bone marrow, spleen, or liver to the lungs, in patients with progressive myeloproliferative syndrome, finally leading to PH. In addition, they secrete vasoactive cytokines, which propagate the development of PH.26 Finally, a possible pathogenic link between CMPDs and PH has been found in the peripheral blood and bone marrow, because of an enhanced angiogenesis. In that study, patients with primary myelofibrosis and PH had higher bone marrow microvessel density and vascular endothelial growth factor levels, suggesting the presence of a proangiogenic phenomenon.12

More recently, pathologic mechanisms for development of PH have been described in relationship to medications used for treatment of CMPD for both dasatinib and anagrelide. In the largest case series published to date, dasatinib, a tyrosine kinase inhibitor, was noted to cause incident PH in 9 patients reported in the French PH registry between November 2006 and September 2010. Clinical, functional, or hemodynamic improvements were observed within 4 months of dasatinib discontinuation in all but 1 patient. The authors concluded that dasatinib may induce severe precapillary PH, fulfilling the criteria of PAH, thus suggesting a direct and specific effect of dasatinib on pulmonary vessels.27 This is supported by work published by Nagaraj and coworkers, who demonstrated that tyrosine kinase is crucial for potassium channel function in human pulmonary arteries. Under physiological conditions, a low pulmonary vascular tone is maintained by Src family tyrosine kinase (SrcTK), and that inhibition of SrcTK will lead to vasoconstriction of pulmonary resistance arteries and thus to an increase in PA pressure.29 The concern over dasatinib leading to drug- and toxin-induced PAH is reflected in the updated PH guidelines from the 2013 WSPH, which now include dasatinib in the list of drugs that can result in PAH (Group 1.3 of the WSPH).

Anagrelide is an oral imidazoquinazoline agent with an anticyclic adenosine monophosphate (AMP) phosphodiesterase activity, and inhibits platelet aggregation in both humans and animals. It has been shown to have potent platelet-reducing activity in ET and related disorders. The introduction of anagrelide was suggested to be, at least in part, involved in the pathogenesis of biopsy proven pulmonary veno-occlusive disease (PVOD) in a 66-year-old female with myelodysplastic syndrome (MDS).30 Overall, there is less literature to support a relationship between anagrelide and PH. Dingli and coworkers reported that 7 of 26 patients with PH were exposed to anagrelide, but only 3 of them had received it prior to their diagnosis of PH.16

DIAGNOSIS

CLINICAL IMPLICATIONS

The clinical implications for CMPD patients that develop PH are quite severe. Specifically, it has been demonstrated that once a CMPD patient exhibits clinically significant PH, the patient's life expectancy is shortened. Dingli et al reported on a cohort of 26 patients in which there were 21 deaths with the median survival time after PH diagnosis of 18 months. Neither antiplatelet agents nor cytoreductive therapies were shown to delay the progression of PH, and the majority of deaths were a result of a cardiopulmonary cause.16

Additionally, Garcia-Manero et al found that the interval between the development of dyspnea (leading to the diagnosis of PH) and death was <7 months in 5 out of 6 patients.14 Precapillary PH (PAH-like) also generally occurs late in the course of CMPD, and the more advanced underlying disease may also contribute to the poor prognosis. In contrast, for patients with CTEPH who are amenable to pulmonary thromboendarterectomy, there may be reversal of PH and improved prognosis.19 Spontaneous improvement of severe PAH in CMPD after withdrawal of dasatinib has been described in several isolated case reports and case series.41–45 Montani and colleagues reported that hemodynamics improved after dasatinib withdrawal in 7 of 8 patients, but no patient demonstrated complete normalization of pulmonary hemodynamic indices.28 The role for PAH therapies remains unclear; Groeneveldt et al reported that PAH-specific therapies were not effective in dasatinib-associated PAH,36 while in the series by Montani et al, PAH-specific therapy was attempted in 2 patients simultaneous with dasatinib withdrawal, making assessment of efficacy difficult.27

MANAGEMENT

There is little guidance regarding the appropriate management of the 3 distinct forms of PH associated with CMPD. Currently, no data specific to CTEPH associated with CMPD are available. However, pulmonary endarterectomy is the first choice treatment in patients with WHO Group 4, CTEPH. In CTEPH patients with inoperable disease, medical therapy including diuretics, anticoagulants, and PAH-specific therapy should be considered.19

For example, the 2008 BENEFiT trial randomized 157 patients with inoperable CTEPH or recurrent PH after endarterectomy to receive placebo or bosentan, an endothelial receptor antagonist. Bosentan demonstrated a statistically significant positive treatment effect on hemodynamics. However, no improvements were observed in exercise capacity.37 Among patients with technically inoperable CTEPH, riociguat, a soluble guanylate cyclase stimulator, was shown to improve exercise capacity, PVR, WHO functional class, and levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) in patients with inoperable CTEPH or recurrent PH after pulmonary endarterectomy,38 and riociguat has been approved by the US Food and Drug Administration (FDA) for this indication. Unfortunately, there are no specific studies to address CTEPH specifically associated with CMPD. An additional challenge is that the currently approved pharmacological therapies for PAH do not have a specific indication for Group 5 disease states.

Clinical trial data to support routine use of pulmonary vasodilators in precapillary PH associated with CMPD are also lacking, including endothelin receptor antagonists, prostacyclin analogues, or phosphodiesterase-type 5 inhibitors. Whether treatment of the underlying disease is beneficial also remains unclear. For example, Tabarroki et al described 15 patients with myelofibrosis and PH treated with ruxolitinib, and in 66% of the patients, an improvement of PA pressure and RV function measured by echocardiography was observed.39 In contrast, a recent case report by Low and coworkers detailed an association between worsening PAH and ruxolitinib, with improvement on withdrawal of the drug on 2 separate occasions in a 57-year-old woman with progressive myelofibrosis.40 Further data would be required to support the use of any current FDA-approved PAH-specific therapy or CMPD-specific therapy for the purpose of treating PH associated with CMPD.

CONCLUSION

Three distinct clinical forms of PH-CMPD have been described: CTEPH, precapillary PH, and drug-induced PAH; however, the exact incidence and prevalence in CMPDs is poorly defined. Nonetheless, new-onset or progressively increasing dyspnea in a patient with CMPD should prompt clinicians to investigate for PH. A definitive diagnosis of PH associated with CMPD must include an RHC. Unfortunately, when PH is present it portends a poor prognosis and is associated with an increased risk of mortality, and as of yet, data about the current use of specific PAH therapies in this group of patients are still not available. Therefore, clinical judgment must be employed to successfully manage patients with PH-CMPD.