Dr Raajit Rampal assesses whether frontline treatment with ruxolitinib was appropriate in the presented patient case with supporting data from the COMFORT-I and -II clinical trials.
Case: A 67-Year-Old Man With Myelofibrosis
RF is a 67 y/o man who visits his primary care physician for his yearly checkup. He reports having fatigue and bone pain for the last few months. More recently, he’s been complaining of abdominal discomfort which he thinks is probably related to the big Thanksgiving dinner party, he and his wife hosted.
He enjoys spending time working on antique cars in his garage, but his wife says he becomes tired after just an hour.
RF has not noticed any changes in his eating habits, but his wife mentions he doesn’t eat as much as he used too. Upon examination, RF has lost close to 13 lbs. since this last yearly exam.
Primary myelofibrosis diagnosed about 1 year ago
Diabetes (controlled with diet and exercise)
SMH: Smoked 3 packs/day but quit 5 years ago; he drinks occasionally
PE: abdominal exam reveals spleen palpable 5cm below left coastal margin, visible bruising
Platelet count: 184 x 109/L
WBC: 34 x 109/L
Bone Marrow Biopsy
Shows an increase in megakaryocytes
Bone Marrow Fibrosis
JAK-V617F mutation: positive
Patient was started on ruxolitinib 10mg BID when initially diagnosed
One year later, RF reports increasing fatigue and abdominal pain)
Platelet count: 57 x 109/L
WBC count: 29 x 109/L
Raajit Rampal, MD, PhD: Let's talk a little bit about his initial presentation and the decision concerning management. First, let's talk about the data to support the use of ruxolitinib. Ruxolitinib was studied in two phase 3 trials, the COMFORT-I and the COMFORT-II trials. The COMFORT trials randomized patients to ruxolitinib or either placebo or the best available therapy depending on which COMFORT study in particular one is referring to. The primary end points of these studies were to look at the spleen volume reduction by 35% as well as the total symptom score reduction by 50%. In both trials ruxolitinib was superior either to best available therapy or to placebo at the primary end point time point. In that, approximately 30% to 40% of patients had a spleen volume reduction of 35% or more and certainly had a significantly improved symptom burden compared to placebo or best available therapy. Based on this data, the drug, of course, was approved by the FDA [United States Food and Drug Administration]. In this patient and this particular vignette, is the use of ruxolitinib supported by the data? The answer is yes. This patient has a symptom burden with fatigue being the main culprit. The patient has early satiety and unexpected weight loss as well. The patient does have a palpable spleen. With regards to dosing ruxolitinib, the COMFORT studies looked at patients with a platelet count of 100,000 or greater. Certainly with a baseline platelet count of 184,000, this patient fits into those parameters. Per the FDA label, ruxolitinib is labeled for an indication of a platelet count of 50,000 and higher for myelofibrosis [MF]. But the dose is attenuated based on the platelet count. Starting at 10 mg twice daily is very much appropriate in this case and is supported by the COMFORT data.
Now what about the diagnosis? What are the things that we have to think about in this patient's case or any patient's case when it comes to diagnostic criteria? There are several considerations. One is that a bone marrow examination is absolutely essential for making the diagnosis of myelofibrosis. That has to be used in conjunction with clonal markers such as a driver mutation. Most typically, these are mutations in the JAK-STAT pathways such as JAK2, MPL, or CALR. It's important to note that still in about 10% to 15% of cases, a mutation is not identified as 1 of these 3 driver mutations. But certainly, there are a host of other mutations that can occur in these patients. In some percentages of patients with MF, patients can have up to 5 mutations, actually. Identification of a clonal marker is essential for making the diagnosis. Cytogenetic abnormalities are another important factor in helping to make the diagnosis. They do have prognostic implications so getting this information is important. The amount of fibrosis in the marrow can be informative with regards to prognosis and certainly as part of the diagnostic criteria, as is excluding any other potential cause for the patient's blood counts or bone marrow findings. A review of the peripheral blood smear is also essential here as we typically see a look-over for a blast picture from the blood smear looking at other markers such as the LDH [lactate dehydrogenase]. Those are some of the major things that we need to consider when diagnosing a patient with myelofibrosis. But it's also important to consider other assessments, such as the symptom burden. This of course can be done conventionally by asking the patient about their symptoms, or more formally using something such as total symptom score. Tools are available which allows one to quantitate and follow the symptom burden over time. Of course, in our patient's case, he meets all of these diagnostic criteria, thus the diagnosis of myelofibrosis was established.
Transcript edited for clarity.