Multidisciplinary Approach Required for Pulmonary Hypertension in Myelofibrosis

Juan C. Lopez-Mattei, MD, FACC, FASE, FSCCT, FSCMR

Early detection of pulmonary hypertension with a multidisciplinary approach may allow treatment of reversible etiologies in patients with myelofibrosis, explained Juan C. Lopez-Mattei, MD, FACC, FASE, FSCCT, FSCMR.

Pulmonary hypertension, which is rare and typically found in advanced myelofibrosis, has an unknown etiology and early predictors of it may be detected by echocardiogram. A retrospective analysis was recently conducted to evaluate the prevalence of pulmonary hypertension, as determined by echocardiography, in a group of patients with myelofibrosis and to recognize clinical risk factors for pulmonary hypertension.

The analysis looked at 143 patients who received an echocardiograph from October 2015 to May 2017 and 14% of patients had echocardiographic findings consistent with pulmonary hypertension. Findings showed that the female gender was protective (odds ratio [OR], 0.21; 95% CI, 0.049-0.90; P = .035) and N-terminal prohormone brain natriuretic peptide (BNP) was a significant clinical predictor of pulmonary hypertension (OR, 1.07; 95% CI, 1.02 = 1.12; P = .006).

Pulmonary hypertension in myelofibrosis was lower in the examined cohort than previously reported data; however, many patients had cardiac comorbidities. Research suggests that pulmonary hypertension due to left-sided heart disease may be underestimated in patients with myelofibrosis. Therefore, evaluation of respiratory symptoms and elevated N-terminal prohormone BNP should prompt a baseline echocardiogram.

Lopez-Mattei, who is lead author of the analysis, suggested that a multidisciplinary team of oncologists, hematologists, pulmonologists, and cardiologists collaborate when diagnosing and treating patients with myelofibrosis who are experiencing pulmonary hypertension.

“We [as cardiologists] have to work with the oncologist and hematologist,” said Lopez-Mattei. “We have to manage the patient in a multidisciplinary fashion, meaning there are going to be times when we are going to have an accurate way of studying the risk of different treatments.”

In an interview with OncLive, Lopez-Mattei, a multimodality imaging cardiologist and associate professor of cardiology and diagnostic imaging at The University of Texas MD Anderson Cancer Center, discussed the findings of the retrospective analysis of pulmonary hypertension in patients with myelofibrosis and their impact on clinical practice.

OncLive: Could you provide an overview of this retrospective analysis and the findings?

Lopez-Mattei: We have been collaborating with the Department of Lymphoma and Myeloma as well as the Pulmonary Medicine at The University of Texas MD Anderson Cancer Center, managing patients—and we have good collaboration with pulmonary medicine as well. Every time you see a patient with myelofibrosis and pulmonary hypertension, the literature leads you to think pulmonary hypertension is prevalent in these patients with unknown mechanisms or related to their underlying disease.

Our initial question was regarding the age range and the comorbidities of the patients that we're used to seeing, whereas what the most common cause of pulmonary hypertension in patients with myelodysplastic syndromes is, especially myelofibrosis. That question led to us to look retrospectively at our data because, sometimes, there are several limitations.

Usually these patients are not going to be referred for invasive right heart catheterization, unless they have a dramatic value form of hypertension. The way to screen this patient is by echocardiography, but it's not perfect because sometimes you cannot get appropriate measurements of the pulmonary pressures.

Most of our data came from patients who were not referred to our clinic for heart failure, but they had an echocardiogram and results showed elevated pulmonic pressures. We did a deep dive looking at the diastolic parameters, or the relaxation parameters, by echocardiogram to assess whether these patients could have some sort of pulmonary hypertension or secondary to left heart disease (LHD) because of the risk factors of the age range that these patients tend to have. We found that the most common cause of pulmonary hypertension was secondary to LHD or diastolic dysfunction permanently, which is not a surprise based on the comorbidities of the patients in our study.

We want to make the clinicians who take care of these patients more conscious [of pulmonary hypertension] because they might be dealing with some of these cases, including potentially type 5 cases. The pulmonary hypertension that is the most prevalent is going to be type 2 or secondary to LHD, meaning that some of these patients have really stiff ventricles; this is because they were hypertensive or they had other comorbidities.

Were there any limitations to the study?

There are limitations to our study. We did not do invasive assessment on patients at the time of the echocardiogram because there was no stroke indication, patients may have refused, or other reasons. It adds to the literature by showing that [pulmonary hypertension] is more common in patients with myelofibrosis. It's important to reinforce that, especially when you're assessing these patients initially in your clinic.

The other thing we'll be looking for is the etiology of diastolic dysfunction, which can be filtered in disorders, such as hemochromatosis, as patients receive allogeneic transfusion. Perhaps that could be the cause. We didn't look into [hemochromatosis as the cause], but it would be sensible to look and not just assume that it is related to the myelofibrosis. As doctors, we have to do the due diligence and partner with the oncologists to make sure that our patients are receiving the appropriate care.

Previous studies only look at pulmonary hypertension by echocardiogram but did not evaluate thoroughly by assessing the diastolic elevation of these patients. We did that by following the American Society of Echocardiography guidelines for evaluation of diastolic dysfunction. It's important to have that level of complexity added to the evaluation because, as cardiologists, we have a lot of resources in how to partner and how we can help the oncologists in this family of complex diseases.

What patient characteristics were found in patients with myelofibrosis and pulmonary hypertension?

The patients with pulmonary hypertension were older. Some of them had coronary artery disease and comorbidities. In that sense, [the presence of hypertension] is no surprise because when patients without myelofibrosis develop pulmonary hypertension secondary to LDH, these are risk factors for LDH. When you look at the patients with pulmonary hypertension in the comparison, the diastolic performance measurements are significantly higher in patients with pulmonary hypertension. The size of the left atrium was larger in [patients with] pulmonary hypertension. That all fits very well into the narrative.

Patients with pulmonary hypertension and myelofibrosis have similar risk factors to other patients with heart failure who have preserved ejection fraction. However, they also have the parameters that are the surrogates of the diastolic function that are abnormal in the majority of patients with pulmonary hypertension. If you put all of that in context, then you can understand why we have to look at patient risk factors regardless of whether or not they have myelofibrosis, because sometimes they need better blood pressure control. Some patients will require a more extensive workup. The majority of them need to have control of their risk factors, and perhaps that will help their symptoms.

When you use the American Society of Echocardiography guidelines for diastolic dysfunction assessment, you see that the majority of patients with elevated filling pressures had the left atrial fibrillation pressures elevated. That goes along with diastolic dysfunction and therefore the risk factor. These are important data and that was the missing link for us as cardio-oncologists who take care of patients with hematologic and malignant diseases. We now understand that these are the most common causes of [pulmonary hypertension], and we can’t assume that [pulmonary hypertension] is just related to the myelofibrosis.

How is pulmonary hypertension impacting the treatment for patients with myelofibrosis?

From the treatment standpoint, we found a higher mortality signal related to myelofibrosis in patients with pulmonary hypertension. We have to manage that and make sure that the patients do well.

There is not a relationship between pulmonary hypertension and the treatment that patients receive for pulmonary hypertension. We have a case report where 1 patient received treatment for their myelofibrosis and everything seemed better, including improved pulmonary pressures. We have to understand that there will be some cases of pulmonary hypertension related to myelofibrosis and to myeloproliferative neoplasms (MPNs) overall, but in our observations, we feel that this will be quite rare. For example, there were about 6 patients who had normal, nonsubstantial evidence of LDH, but still had high pulmonary pressures. The majority had evidence of some sort of LDH.

In some patients with MPNs, there are some drugs that could cause some cardiovascular adverse events. We did not find that any [drugs] in pulmonary hypertension were tied to worsening outcomes.

What are your current recommendations for treating pulmonary hypertension in this patient population?

The profile for pulmonary hypertension is more related to LDH. There are several things that you can do. If the patient is hypertensive, you have to control their blood pressure and do a thorough workup to make sure there are no other causes, like pulmonary problems, chronic obstructive pulmonary disease, or others. We have a close collaboration with pulmonologists because we both take care of this patient. Our [collaborative] approach has a lot of success in [treating patients with pulmonary hypertension and myelofibrosis] because we have varied perspectives.

When the patient has pulmonary hypertension due to LDH, the cardiologist is going to be the most important resource. You definitely need to involve a cardiologist and there are certain heart failure cardiologists that manage pulmonary hypertension. The pulmonologist must also be involved in caring for the patient. We work together and we collaborate closely. The multidisciplinary aspect is important, and there are several good resources for the oncologist involving cardiologists, pulmonologists, and trying to clarify the etiology [of the pulmonary hypertension].

Are there any next steps to this to this research?

There have been some discussions [regarding continuing research]. Our next manuscript is going to be related to pulmonary hypertension in patients with a different type of malignancy. We have some interesting data [regarding the trends] that we hope to continue. It's going to be exciting and we're going to keep learning from this patient population.

Lopez-Mattei J, Verstovsek S, Fellman B, et al. Prevalence of pulmonary hypertension in myelofibrosis. Ann Hematol. 2020. doi: 10.1007/s00277-020-03962-2