Q: Why are disease-related symptoms so important in MPN?

The symptoms of MPN are an important biologic aspect of the disease, and they represent the significant burden that patients face. We believe that these symptoms are linked to inflammation and cytokine activity; in myelofibrosis in particular, symptoms may be prognostic of worse outcomes. A goal of therapy is to eradicate symptoms, and a key part of assessing the efficacy of therapy is determining its effect on symptoms. How much is the patient still suffering with the disease? Severe pruritus can be quite disturbing; in fact, some patients have even committed suicide because their pruritus was so intractable. Symptom assessment is an important aspect of evaluating the response to treatment. Persistence or worsening of symptoms is a sign of treatment failure. Do we need to change therapy, or should we alter the dose to achieve better symptom relief? Symptoms are an important biomarker of the underlying disease. Inadvertent weight loss and cachexia, for example, can be a sign of progressive disease and may share biologic underpinnings with the disease process. There is a misconception that simply asking patients how they are feeling is somehow an appropriate substitute for a more structured intake, and, unfortunately, it is not. Additionally, a more structured approach need not undermine a practice’s workflow or efficiency. We administer a simple, 10-point symptom questionnaire to patients in our waiting area. It serves as the springboard for organizing our discussions with patients, and it has been helpful at our institution.

Symptom burden is a significant issue for patients with MPN. Symptoms are also biologically linked with the disease, so they relate to outcomes. The constitutional symptoms of patients with MPN are risk factors for poor outcomes and drive the changes in an individual’s functional status, particularly in those with myelofibrosis. Symptoms such as fatigue and bone pain can be quite limiting to a patient’s function, and our risk models incorporate constitutional symptoms as indicators of worse outcomes. One of the challenges with some of these constitutional symptoms is evaluating them more objectively in a busy clinical practice. Another challenge arises when patients with myelofibrosis are precluded from potentially curative therapies such as allogeneic stem cell transplantation because of a very poor performance status; and yet, when you evaluate these patients, you find that it is all disease related. Part of the benefit of treatment with Janus kinase 2 inhibition, in addition to the survival advantage that was indirectly observed in the studies, is an improvement in functioning and performance status and fewer disease-related complications. These end points are in contrast to altering the natural history of the disease or reversing fibrosis. Thus, I think that the constitutional symptoms are key, and those patients with advanced or progressive MPN are often quite symptomatic.    

We need to remember that symptoms have the greatest impact on a patient’s daily life. When we tell our patients that they have a chronic disease with a particular expected prognosis, they are usually most concerned about how their symptoms and treatment side effects will interfere with their ability to enjoy time with their friends and family. To some patients, coming to terms with their illness is as important as gaining control of their symptoms. Our center, along with many other hematology-oncology centers, uses intake forms that cover many of the constitutional symptoms associated with MPN, such as fatigue, loss of appetite, and night sweats. They include general questions, and the forms are relevant to nearly all of our patients. There are different levels of symptom assessment, and some, such as the ones used in clinical trials, may be more robust than others. There are occasions when symptoms guide therapy more so than laboratory findings. That is, in many patients with MPN, we reach a point where the laboratory goals have been met but the patient has ongoing symptoms. At this time, we would consider changing the type of therapy (eg, switching from phlebotomy and hydroxyurea to ruxolitinib in a patient with polycythemia vera). Our goal in this case would be to gain control of the symptoms while maintaining the laboratory responses.