We are witnessing here a relatively young gentleman with myelofibrosis. The bone marrow shows increased reticulin fibrosis. There is the presence of anemia, and there are abnormalities in white cell types. The patient has the symptoms and an enlarged spleen. These are all clues that would lead one to combine them together and make a diagnosis of a myelofibrosis.

There is one clinical relevant factor here that is of concern on blood cell count, and this is significant anemia. There is another one, which is symptomatic splenomegaly. So, this is a patient who is in the need of therapy actually. Once we have a diagnosis, we would assess his risk of dying, then consider referral to a bone marrow therapist, and then assess a need for introduction of certain medications to counteract clinically irrelevant abnormalities in his blood cell count on physical exam.

We would usually first start with testing the prognosis of the patient. This is done with the International Prognostic Scoring System, or IPSS. There are 5 factors that are involved: age over 60; white cell count over 25,000; blast in blood; hemoglobin less than 10; and systemic symptoms. And with the systemic symptoms, there are 3 in particular: significant weight loss, night sweating, and low-grade fevers.

If we apply these 5 factors, we would divide patients in 4 different groups: without any, that would be a low-risk patient; with 1, intermediate-1 risk patient; with 2 out of 5, intermediate-2 risk patient; and 3 or 4 or 5 out of 5, that&rsquo;s a high-risk patient for early untimely death. This particular case appears to have intermediate-1 risk disease because there is only significant anemia from the 5 factors.

The patient with intermediate-1 risk disease has projected survival from diagnosis of about 8 years. This is in comparison, for example, to intermediate-2, which is about 4 years&rsquo; median survival, or high-risk patients that have a 2-years median survival. Low-risk patients have a median survival of 11 years. This is important knowledge because we would like to refer patients that have a survival of less than 5 years to a bone marrow transplant. This is an intermediate-1 grade patient. Therefore, it is not quite clear that there would be immediate benefit to refer this patient for the bone marrow transplant. It would be perhaps wiser to treat patients for clinical relevant abnormalities with medications and only upon a progression of the disease to refer to a transplant.

Risk assessment is usually assessed by traditional ways of looking at the symptoms, blood cell count, and age of the patient. This is the so-called International Prognostic System, or IPSS. There are variations, like the Dynamic International Prognostic Scoring System, or DIPSS, where we can add some additional factors from blood, like low platelets, or transfusion requirements, or even cytogenetic or chromosomal abnormalities. However, at this time and age when we can, relatively with some ease, test patients for different genetic abnormalities that are known to contribute to the aggressiveness of the disease, the question is how to combine the traditional way of prognostication, with IPSS, with the genetical amount that is relatively easy and accessible to us, at least in academic centers.

There are other known genetic abnormalities that would lead patients to progress faster. There is no quite clear way to combine that information that we can gather from genetic testing with traditional prognostication. For example, in this particular case, this is an intermediate-1 group patient who would have a projected survival of about a year. Let&rsquo;s say that we do genetic prognostication in this case. In my particular center, we test for about 50 different mutations other than driver mutations. And let&rsquo;s say that this patient has one of the bad prognostic factors. This is, for example, IDH1, IDH2, EZH2 or ASXL1. If the patient has 1 or 2 of those 4, that is bad prognosis for him. How do we combine genetic prognostication with traditional prognostication? Whether we should refer this patient with the intermediate-1 prognosis to transplant is an open question and a debate in the MPN circles.

Working in academic centers makes me see patients that are more advanced. The knowledge about the biology prognostication and therapy of mild thrombosis is markedly increasing in a community setting now that we have opportunity to do something about the disease to treat patients successfully. So, my colleagues in the community setting are eager to learn more. The referral pattern, therefore, for me in an academic center, is that I see patients that will not do wellwith the more aggressive features or a shorter life expectancy. If you talk about prognosis, that would be the majority of the patients that are intermediate to high risk. About 60% would be between these 2 groups, and only 40% would be low-risk or intermediate-1.

The Prognosis of Myelofibrosis

The underlying biology of all myeloproliferative neoplasms is the same. It&rsquo;s a hyperactivity of the intracellular signaling path of the JAK/STAT pathway. However, there are many other mutations, other than those, that activate the JAK/STAT pathway. And in myelofibrosis in particular, there are 3. This is

mutations. But apart from those, because they are also present in essential thrombocythemia, for example, we know that many other factors lead to different clinical scenarios. So, myelofibrosis appears to be more aggressive among the myeloproliferative neoplasms because of additional genetic abnormalities, or chromosomal abnormalities, that lead to a more aggressive clinical picture and untimely death.

Diagnostic criteria of myeloproliferative neoplasms, MPN, are based on similar factors that need to be combined. Usually, that is a clinician who does the combination of the factors, and the crucial one is the bone marrow exam. You need to have a presence of the myelofibrosis disease and no other disease that would cause fibrosisfor example, overt myelofibrosis. But there are other genetic factors, presence of all of the driver mutations&mdash;the

mutation, or calreticulin mutation. Then there is a need for having some of the analysis in blood cell count: anemia, or very high white blood cell counts, or physical exam abnormalities. I&rsquo;m talking about the big spleen, all leuko-erythroblastosis, another factor in the blood cell count. And finally, there is also a need to have abnormalities in chemistry, which is abnormality in LDH, or lactate dehydrogenase. So, a combination of the chemistry, blood cell count, a physical exam, and a bone marrow exam are leading one to diagnose a myelofibrosis.

There are many other conditions that can cause a fibrosis in the bone marrow. The most common ones are autoimmune problems, like rheumatoid arthritis, or some other autoimmune or inflammatory conditions that can actually lead to inflammatory fibrosis in a bone marrow. In the disease itself, it appears that fibrosis in the bone marrow in myelofibrosis is a reactive process. So, there is a high degree of inflammation present in myelofibrosis, and one cannot easily distinguish between fibrosis related to autoimmune process, for example, from this disease itself. There are infections that can cause fibrosis. There are other diseases of the bone marrow, like hairy cell leukemia, a disease of lymphocytes, that can cause fibrosis. So, there is a whole area of other conditionsfrom benign to infectious, from autoimmune to malignant ones&mdash;that can cause fibrosis, and one needs to be cautious not to associate just the presence of fibers with the disease called myelofibrosis.

Acute myeloid leukemia is the most common cause, as a single cause, over that of patients with myelofibrosis. However, overall, only about 20% of the patients will transform to acute myeloid leukemia. The rest of the patients, 80% of the patients, die from complications of having myelofibrosis. Because it&rsquo;s the most common cause, the question is whether we can prognosticate who can actually expect to progress and whether we can do anything about it. This is not that easy.

There are some factors that are associated with a high risk that come from, for example, looking at their blood cell count. Low platelets are known to be a factor. Increased risk of blasts, particularly over 10% in the blood or bone marrow, would lead one to progress to acute myeloid leukemia. Or, for example, there&rsquo;s transfusion dependency. If you turn to the biology, then abnormalities in chromosomesparticularly either from 17 and certain genetic abnormalities like ASXL1, EZH2, IDH1, and IDH2, and several others, like p53, for example&mdash;are associated with a high risk of progression or progressive events on its own to acute myeloid leukemia. These are easy to access in every day management, and if we see those, perhaps there is a need to push patients to do the transplant sooner rather than later. Once the patient transforms to acute myeloid leukemia, this is a very difficult situation to treat.

Myelofibrosis: Understanding the Biology and Diagnosis

When we see patients with myelofibrosis in the clinic, we usually look at the prognosis of the patients to be able to refer them to a bone marrow transplant. Beyond that, we look at the clinically relevant abnormalities that we can correct to control the patient&rsquo;s quality of life. So, we are really talking about control of signs and symptoms of the disease. There are 3 major areas of concern. One is failing bone marrow that leads to anemia, in particular. So, anemia is a target for therapy. The second one is progressive splenomegaly and the liver enlargement in many of the patients. About 80% of the patients will have very big spleens, many times the size of normal, with a lot of symptoms. And area number 3 of concern is poor quality of lifeinability to work, bone aches and pains, night sweating, itching, and low-grade fevers. For these 3 areas, we have medications that we can implement. When these problems are clinically relevant, they affect the patients. So, for anemia, we have anemia-directed therapies like Danazol, erythropoietin, thalidomide, or lenalidomide. For symptoms in the spleen, we have a JAK inhibitor, ruxolitinib, as the first ever approved therapy for this condition. And perhaps there are some other more traditional ways of looking, such as hydroxyurea, cladribine, or lenalidomide use for the spleen.

Undertherapy of patients with myelofibrosis is quite problematic because traditionally we did not have much to offer to the patient. Therefore, we were waiting for patients to really be in such a dire situation only to be able to provide palliative care when the patient was in a dying mode. However, we now know that new ways of therapyJAK inhibitors, in particular&mdash;can provide survival benefit of the patients. Therefore, if the patient had symptomatic spleen or symptoms from the disease in general&mdash;loss of weight, night sweating, low-grade fevers, itching, fatigue, weakness&mdash;these are good reasons to initiate therapy earlier, rather than later, in patients with myelofibrosis, which controls those symptoms and signs, and we did prolong survival. That is the main message that I try to project in a community setting: not to wait until the patient is so debilitated from the disease, but to initiate therapy when we see, first, a compromised quality of life.

It is important to appreciate the disease. Myelofibrosis does change over time, and that can be seen in different ways. That can be seen as progressive splenomegaly, that can be seen as worsening bone marrow failure with anemia, or disability that comes from weight loss, inability to walk, night sweating, and bone aches and pains. But these issues usually are not associated with age. It is really a natural way of progression of the disease, by possible acquisition of different genetic abnormalities that leads to progressive features. Age has little to do with initiation of the therapy, and the spleen size usually does not have the direct correlation with the need to intervene. It is really the symptomatic splenomegaly that is important, that needs to be treated, rather than its size per se.

Ruxolitinib is a JAK inhibitor that inhibits the super-active JAK/STAT pathway. The hyperactive JAK/STAT pathway is an underlying biological problem in myelofibrosis. With that, we have antiproliferative and anti-inflammatory effects on the body of the person. That means that there is a smaller spleen and there is also improvement in quality of life. People gain weight and work more. They&rsquo;re able to live longer, with control of symptoms and signs of the disease. We are not eliminating the diseasethat&rsquo;s an important distinction. There is no complete response. There is just very good control of signs and symptoms. The body composition improves, the weight goes up, and, therefore, people live longer.

These are results that we have now confirmed by looking back in time at the outcome of the patients from the 2 randomized studies that led ruxolitinib to be approved. These are called the COMFORT-I and COMFORT-II studies, where ruxolitinib was compared to other very good medications that have activity in this condition or placebo. And even in those studies where these patients in the control arms were allowed to cross over and be given ruxolitinib, we witnessed prolongation of life in the patients that were treated with ruxolitinib from the very beginning. That leads me conclude, and others in the field agree, that we should not really wait for patients to be very advanced with the features of advanced myelofibrosis for us to treat them. Patients that are symptomatic or have symptomatic splenomegaly at any stage of their disease are good candidates for therapy with ruxolitinib, with JAK inhibitors, and with potential to extend their life, too.

The field of myelofibrosis is rapidly changing. We established the disease name 10 years ago and the factors that would mean that the patient is responding to new therapies. With this backbone, we were able to develop new medications, and now we are in the situation where patients even live longer, with good control of signs and symptoms of the disease. So, the diagnostic process, prognostication, therapeutic decision making, and improvements in our ability to target new biological markers in this disease are rapidly evolving. Hopefully, in the next couple of years, we&rsquo;ll have another 1 or 2 medications approved to help our patients with myelofibrosis.

Underlying Treatment of Myeloproliferative Neoplasms

The Prognosis of Myelofibrosis

Myelofibrosis: Understanding the Biology and Diagnosis

Initiating Treatment in Myelofibrosis