Dr. Srdan Verstovsek:
Welcome to The ASCO Post Roundtable Series on Updates in Myeloproliferative Neoplasms. I am Srdan Verstovsek, Professor of Medicine in the Leukemia Department at MD Anderson Cancer Center in Houston, Texas. Joining me today is one of my good friends and colleagues from Kansas.
Dr. Abdulraheem Yacoub:
Hello, my name is Abdulraheem Yacoub. I'm an associate professor at the University of Kansas Cancer Center and a clinical investigator in the field of myeloproliferative neoplasms.
Dr. Verstovsek:
Well, Abe, thank you for joining me today. In this installment, we will be discussing the role of anemia in selecting initial therapy for myelofibrosis and how to manage patients with anemia as a presenting symptom of myelofibrosis. Let's get to the case. We have a 68-year-old female who comes as a consult, because she's short of breath. She has some fatigue and complaints of significant night sweating and weight loss. We do the physical exam, we find enlarged spleen. It measures about 7 centimeters below left costal margin. Then, we do the CBC, a blood count and chemistry. We find actually that she has some abnormalities. Hemoglobin 8.7 g/dL, hematocrit 26.1%, white cell count elevation at 22 x 109/L and platelets at 122 x 109/L, slightly below normal. She has 2% blasts in the peripheral blood among all these white blood cells. LDH is very high at more than 1500 U/L, and erythropoietin level is slightly elevated as well at 35 mU/mL.
We do the bone marrow biopsy, and bone marrow biopsy shows clusters of a dysplastic megakaryocytes with marked reticulin fibrosis corresponding to MF-2 of the World Health Organization Histological Grading. We grade from zero to three. She also has a JAK2 V617F mutation in the test. And so, we make a diagnosis of myelofibrosis. And of course, the first thing that I usually think about, is that patient a candidate for a bone marrow transplant, but the patient tells me right away she's not interested in transplant at all right in this moment. What is the best next step? And Abe, how would you approach this case?
Dr. Yacoub:
Well, thank you very much, Serge. This represents a common challenge in our field for patients who present with myelofibrosis and have medical needs. To start with, this patient presents with a relatively higher risk disease with her advanced age, her constitutional symptoms and her significant anemia. She will qualify as an intermediate-2 or high-risk disease in which early therapy might be necessary and therapy needs to be tailored to the patient's needs. I always try to consult patients and try to clarify their needs and their priorities upfront. We like to focus on controlling disease symptoms. We would like to focus on improving the blood counts and also provide therapy that could provide more benefits such as survival data or disease control or disease modification going forward. We need to have a discussion with the patient regarding all these goals and highlight which ones are more immediate and if we can achieve many of them at the same time, that'll be definitely a favorable intervention. That would be a discussion starter with the patient.
Dr. Verstovsek:
Yeah, I agree. You see, we think first about the curative potential of a bone marrow transplant as an option, but this is not usually my first approach and it's usually last approach. Patients really don't want to do it right away. What is the reason for treatment? We want to look first of all at the symptoms. I agree 100% with you. After prognostication, which leads to a referral for a transplant. The first question to my mind is why do I need to treat the patients and what for? It's quality-of-life improvement and that would then eliminate those systemic symptoms. But even if the symptoms are related to the spleen, I would like to make that spleen as small as possible. If the anemia is present, not to worsen it too much, so that there is no need for transfusions. In this way, I would reason to perhaps even combine the therapies that would be on one hand for the spleen and symptoms, and on the other hand for anemia, because there are overlapping problems here. That's common, as you said. What do you think? What would reasonably happen in your hands?
Dr. Yacoub:
So again, this patient represents the classic dilemma in myelofibrosis where many of the active therapies, particularly ruxolitinib, which is a first line therapy in this disease, can result in significant improvement in symptoms and in spleen as well as cachexia, which this patient is manifesting. But that could result in worsening of her anemia, and that's always going to be the balance that we have to tackle as we treat this patient. So this patient has clinical needs that shows weight loss, which we can definitely improve on, as well as night sweats. Both are symptoms that can be very well managed with ruxolitinib therapy, as well as this therapy can result in improving her overall survival based on the published data. That has to be balanced with a risk that we might increase the severity of the anemia and/or require transfusions on the short term, but that can be mitigated with supportive care measures as well as transfusions or other supportive measure we can offer to the patient going forward.
Dr. Verstovsek:
Yes, I agree with you in that aspect that first of all we want to have efficacy and we want to control the symptoms. We're going to control the size of the spleen to make it smaller, the symptoms go away if there are some, but then we need to focus on the anemia as well. But anemia is not a contraindication for JAK inhibitor use. In the first-line setting I typically use, if the platelets are above 50 x 109/L, ruxolitinib. If the patients have a platelet count below 50 x 109/L, a few months ago here in United States we had approval of a different medication [pacritinib] for that group of people, which is rather small. With ruxolitinib you do get a good control of spleen and symptoms. Anemia does worsen during the first 3 to 4 months, but then it comes up even without those adjustments. And I tell you from my own experience, the anemia measurements improve after about 4 to 6 months.
You actually get to what I would consider a baseline. Of course, I do add anemia drugs, if the anemia is present. We have danazol, an anabolic steroid. I measure erythropoietin level. In this case for example, I could add erythropoietin level because the level is below 500 mU/mL. Sometimes even low-dose thalidomide or prednisone. With that, I allow the anemia to be present for a while and count on increase in the anemia measurements after 4 or 6 months of overall therapy. And the most important part is that anemia does not affect the ability of patients to respond in the symptoms and the spleen. Anemia, you would think may worsen these symptoms. But no, we learn from experience that the symptoms actually improve because the JAK inhibitors are anti-inflammatory agents, and these systemic symptoms are much more related to the inflammation in the body than to anemia. What's your experience?
Dr. Yacoub:
Yeah, I fully agree with you, Serge. So our clinical experience matches a lot of the published data from the COMFORT studies in which patients with a successful ruxolitinib therapy do experience a significant improvement in their symptom burden and in their quality-of-life despite worsening hemoglobin. And although the hemoglobin can eventually improve, the initial drop in hemoglobin has not been associated with patients’ reported quality of life decrements or discontinuation of therapy on those studies. So that actually mirrors a lot of my experience in that we do need to support our patients a lot more closely at the beginning, you need to run frequent labs, you might need to supplement transfusions.
In this patient, she's an excellent candidate for ESA along with ruxolitinib in which we support our patients through the initial phase of therapy. And once patients have a steady state, once they're been on therapy for a few months, once they experience clinical improvement in their spleens and their weights and their constitutional symptoms, their hemoglobin tends to kind of plateau at a new baseline, might not be as good as their initial baseline, but at a baseline that is compatible with a good quality-of-life and no anemia-related symptoms, which again has been the findings on the clinical trials as well.
Dr. Verstovsek:
And importantly you said that the survival benefit of JAK inhibitors and on the label for use of ruxolitinib since 2014, we have that survival benefit acknowledged by the FDA. Importantly, the anemia related to ruxolitinib is not a bad prognostic factor. So therapy-related anemia is something that we can manage, but it does not affect the ability of patients to live longer with the good control of the signs and symptoms. But still anemia is a problem. So we have witnessed that development of alternative dosing regimen starting with the ruxolitinib at the lower dose and building it up. How do we go about that?
Dr. Yacoub:
So I always like to explore the therapy for myelofibrosis as a marathon. And this is not a quick win. This is a strategic therapy in which you would like to achieve results and then build on them. So one strategy would be to start with a lower dose of ruxolitinib and allow patients to benefit from that and then keep challenging them with dose escalation and dose titration over weeks to come until we get to the optimum dose and the maximum tolerated dose in which patients can get the most benefit.
So again, this is definitely a long-term strategy that requires strategically modifying the doses and supporting the patients as we go further. And with that approach, most patients can reach their target dose and get the full benefit of ruxolitinib. We already have good track records of data that show that patients on ruxolitinib who can maintain a dose of 10 mg twice a day, have had improvements in their quality of life, in splenic volume reduction as well as in their overall survival. And that’s why we would like to continue to challenge our patients and slowly and steadily to escalate to that dose level and maintain them on it for as long as possible.
Dr. Verstovsek:
Very good. So I think it’s safe to say that avoiding or delaying JAK inhibitor therapy due to baseline anemia is unnecessary. This is totally unnecessary. We need to introduce the therapy when we have symptoms, and patients benefit from and tolerate ruxolitinib with a low discontinuation rate actually due to anemia as evidenced in the literature. I would, as you said, combine the JAK inhibitors with an anemia drug. In this case erythropoietin makes sense, a lot, but there are future strategies that are in development as anemia drugs and hopefully we'll have some of them for our patients in the near future like luspatercept, momelotinib, perhaps KER-050, and some other unusual, you would say, non-JAK inhibitor therapies.
So I think the future is bright, we need to learn, certainly how to optimize the care. In that sense, I would actually thank you very much for your lovely discussion today because this brings us to the end of this case. Please see the other segments for further discussion about the latest data in myeloproliferative neoplasms or visit ascopost.com. Thank you all very much and thank you Abe.
Dr. Yacoub:
Thank you very much Serge for the kind invitation.
