Evolution of Myelofibrosis and Efficacy & Toxicity of Therapy
Moshe Talpaz, MD: Myelofibrosis is a lethal disease. Patients who do not receive any specific treatment will succumb to their disease over a period that can be as short as 1 year for the high-risk patients or…14 years or longer for the low-risk patients. The reason for the mortality is either disease progression, the disease itself progresses, or the disease transforms to acute leukemia. Acute leukemia develop—at least now I will refer to my personal experience because we analyzed it. In my personal experience at Michigan Medicine at the University of Michigan, when we looked retrospectively at our results, a quarter of the patients progressed to acute leukemia over time. And this is an acute leukemia that is extremely difficult to treat that is known, a development of leukemia after an antecedent disease that tends to be more difficult to treat.
We have learned that about a quarter of the patients progress with a symptom of general wasting, weight loss, muscle loss, or progression of liver disease that looks very much like cirrhosis. Another group of patients develop a bone marrow failure. The fibrosis progresses to such an extent that the normal production of bone marrow cells is being affected. The patients tend to develop very severe thrombocytopenia or low platelets and severe anemia. Many of these patients require up to weekly transfusions, and this stage also tends to be lethal. Another situation, which has been under-reported but that we have seen as part of the progression of the disease, is the development of pulmonary hypertension, increased pressure in the blood vessels of the lungs and subsequently shortness of breath, requirement of oxygen, and another stage that tends to be lethal. This poses also a lot of problems with therapy because of this very different outcome. Patients can go either way, and the diseasecan progress either way. So the question is how to deal with it and how to apply specific approaches to each one of these settings, and that’s still a problem we are grappling with.
John Mascarenhas, MD: So unfortunately, myelofibrosis is chronic and potentially progressive in most patients. In some patients it progresses in terms of big spleen or symptom burden, or cytopenias, or high white blood cell count. But other patients can develop a clonal progression, a clonal evolution to an acute myeloid leukemia, which we believe is driven by the acquisition of mutations and other epigenetic events that promote this transition from a chronic type of leukemia to an acute leukemia. This happens probably in about 10% to 20% of patients with myelofibrosis over the first decade of diagnosis.
A clinician needs to be aware of that and needs to monitor for that, and the way you monitor that is really by seeing the patient on a regular basis, by examining the blood smear to see if there’s an accumulation of myeloblast leukemia cells, and determining if there are changes in the patient’s clinical status, whether it’s the emergence of night sweats, fevers, or weight loss—things that could signify progression of disease.
Well, I think with any agent one needs to be aware of the potential toxicities to start out with. So for example, if you’re using pacritinib or fedratinib, in the future one needs to be aware that GI [gastrointestinal] toxicity could be an issue, needs to prepare the patient for it, needs to be aware that antiemetics or even antidiarrheals may be used, particularly up front to help patients early on. And even deciding whether the drug should be taken on a full stomach or an empty stomach, and that’s tailored to the patient. So I think being aware of the toxicity profile, so you can anticipate and in a dynamic fashion deal with emerging toxicities, is very important.
Toxicities even with ruxolitinib are possible. So for example, myelosuppression is not uncommon. Preparing the patient for the need to be monitored more frequently when they start ruxolitinib, and the potential for the hemoglobin to drop usually nadirs within the first 2 to 3 months, and to treat through that. So we often encourage patients and physicians alike to not withdraw the drug immediately if the anemia is an issue up front, because it often will settle down over time. Usually after 3 months the hemoglobin will rest, typically about 1 gram per deciliter below the starting hemoglobin.
The platelets will usually drop about 40% when you start ruxolitinib, so you have to be prepared for that. And in some cases transfused patients do that rather than consider it a failure.
Moshe Talpaz, MD: All the therapies, as I stated earlier, have activity and toxicity. Let’s refer to ruxolitinib as the gold standard. It is not the gold standard, but it’s the gold standard of care at this time. We have a problem with adverse effects such as anemia, and at the same time, the patient feels better. So we ask ourselves, what do we do? Do we compromise the dose? We lower the dose and then we maybe reduce the anemia, but we have the risk of having a less efficacious treatment. So it’s a difficult scenario and not easy to manage. And each one has to find his own way how to manage the patient. To a large extent, it has to do with the quality of life of the patients that we are trying to manage and maintain. If anemia is the biggest issue and the patient requires a lot of transfusions, obviously we have to lower the dose, compromise the dose, and at times we have to stop ruxolitinib altogether.
The problem that we encounter is what do we do with a patient who stops responding to ruxolitinib altogether. These patients have poor prognosis. By definition, they have a very bad outlook. They tend to live about a year after they stop to respond to ruxolitinib, and that’s a situation that requires the development of new treatments. And that’s a situation that also is subject to testing of new JAK2 [Janus kinase 2] inhibitors and to seeing if they do have activity as second-line treatment in patients that already failed the first line. And can we create a situation in which these patients, who have very bad outlook otherwise, can we create a situation in which they will benefit from new forms of therapy.