Therapeutic Response with JAK Inhibition in Myelofibrosis
Insights From: Srdan Verstovsek, MD, PhD, University of Texas MD Anderson Cancer Center; Daniel J. DeAngelo, MD, PhD, Dana-Farber Cancer Institute; Kim-Hien T. Dao, DO, PhD, Oregon Health & Science University
Srdan Verstovsek, MD, PhD: Ruxolitinib has a very good chance in helping patients in myelofibrosis that have symptomatic splenomegaly or general systemic symptoms. In a great majority of the patients, these two aspects will be markedly improved. In fact, one of the analyses of the COMFORT II study, one of the two large prospective randomized studies, showed that more than 90% of the patients on ruxolitinib have a certain degree of spleen reduction. I would say that 10% or more spleen reduction is clinically relevant because these people did not just have a smaller spleen but felt better. It’s not really about having a 50% reduction or any other percent. One has to combine the benefits together.
Spleen reduction and quality of life improvements together really is the aim of the therapy, and that is achievable in the great majority of the patients. This can be done in patients who have anemia or are transfusion dependent. That can be done in patients who do develop anemia as a consequence of the therapy. Dose adjustments are in order, transfusions can be given, but anemia is not a contraindication to therapy, nor does the anemia that develops on therapy require stopping the therapy. It can be expected, with dose adjustments, anemia will improve. And there is also now clear knowledge that there is a rebound in the production of red blood cells on therapy, even without dose adjustments, within the first 6 months. So, in my own practice, I’m not too worried about anemia that develops, at the very beginning in particular. My goal is to decrease the spleen as much as I can in a safe way, monitoring platelets in particular, but not much of the red blood cells. Ultimately, the overall outcome of the patients depends, to a greater deal, on a degree of spleen reduction and not really at all on the presence of anemia.
Kim-Hien T. Dao, DO, PhD: For patients who are on ruxolitinib, the way to monitor their response is to use some of these tools that are available to quantify their symptom burden, such as the MPN-SAF (Myeloproliferative Neoplasm Symptom Assessment Form), which is available online and through the papers that were published by Dr. Mesa and also Dr. Scherber. Using that scoring system, you can monitor how patients respond to ruxolitinib before and after, and compare whether their symptom burden overall has reduced. The COMFORT I and COMFORT II studies showed, very clearly, that there was a major symptom benefit by treating patients with ruxolitinib. So, this is something that I look for in monitoring patients for response. In terms of the spleen response, I palpate their spleen and record that in their chart notes. I also determine whether they are having improved symptoms from the spleen, which includes improved appetite, and also reduced mechanical effects of the splenomegaly, such as early satiety and abdominal pain.
Daniel J. DeAngelo, MD, PhD: The goal of JAK inhibitor use in patients with chronic myelofibrosis is to initiate a response and, in hopes of having some disease modification of their outcome, that it improves survival. It’s what we always want for our patients. It’s hard to know that on a case-by-case basis. And, in terms of measuring response, the easiest one to measure is whether or not the spleen is being reduced. Of course, there are patients who may have already had a splenectomy, but there are patients for whom their spleen may not be the reason why the agent was initiated. But, if a patient does have splenomegaly, an enlarged spleen, measuring the response or the reduction in the size of the spleen is a very easy physical exam characteristic that can be used to assess response. I think the most important way of assessing response is, how does a patient feel? If a patient initiated therapy with symptoms such as night sweats, are those night sweats gone? Has the patient been troubled with pruritus? Is the pruritus improved? Fatigue? Weight? I follow the patient’s weight. I actually map out the weight and see if there’s an improvement in their weight. I find that is the most useful of the vital sign assessment. What’s not useful is anemia. All patients will develop anemia on ruxolitinib and many of the JAK inhibitors, and you should not use that as an indication for disease progression. That is an on-target hit or an on-target side effect. And so, you need to use development or the improvement in constitutional symptoms—specifically weight, night sweats, pruritus, as well as reduction in spleen—as assessment for response.
Kim-Hien T. Dao, DO, PhD: Ruxolitinib has a known effect of reducing platelet count in patients who start the drug, and this is something that’s been well documented in the COMFORT I and COMFORT II study, but definitely can be safely managed. And, in fact, most patients did not have to stop ruxolitinib due to low platelet count. As long as the providers are aware of this initial response that happens within the first 3 months of treatment, this can be managed safely.
In addition, for patients who start with very low platelets to begin with, let’s say, 50,0000 to 100,000 platelets per mm3, those patients can actually start at a lower dose of ruxolitinib, for example, 5 mg twice a day and over time. Then, they can titrate that dose up. And that has been shown in one study to be very effective in terms of symptom control and splenomegaly response. And so, there is a strategy for dosing ruxolitinib in patients with low platelets.
I’d like to give you two examples of patients that really responded well to ruxolitinib. The first patient was relatively young, a female in her 40s, who developed myelofibrosis. She didn’t have all the high-risk features and ended up being an intermediate-1 DIPSS score. So, in that situation, I think ruxolitinib is optional. I could have considered hydroxyurea. However, she was already beginning to lose weight from her splenomegaly and she had a very active life, exercising very frequently. Her spleen was very enlarged, and also her job requires her to be very physically active to basically make a living. And so, in her case, after reviewing potentially starting hydroxyurea or ruxolitinib, we decided to go with ruxolitinib. She had a dramatic response in her spleen volume, but also her symptoms really improved. And she even stated that she didn’t realize how bad her symptoms were until she started ruxolitinib because then she noticed a significant improvement in fatigue and energy.
Another patient that I had is a patient actually that was on the COMFORT I study. He was a 68-year-old gentleman who had polycythemia vera and then developed myelofibrosis after many years of having polycythemia vera. He had a very enlarged spleen, approximately 3 liters, and they were considering splenectomy in his case. However, the surgical morbidity and mortality was very concerning, especially because his spiritual belief did not allow him to receive blood transfusions. Luckily, we were able to get him on the study. He’s one of the last few patients who got on the study, and basically that really improved his quality of life and symptoms. He even stated that, in his case, had he not been on the trial, he felt like he was dying. He felt like the treatment really turned his life around, and he’s still on ruxolitinib today after 4 years of being on it.