Dr. Abdulraheem Yacoub: Hello. Welcome to The ASCO Post Roundtable Series: Expert Perspectives on the Treatment of High-Risk Myelofibrosis. I'm Dr. Adbulraheem Yacoub. I'm a Professor of Medicine at the University of Kansas. I am joined today by two of my colleagues.
Dr. Gabriela Hobbs: Hi, I am Gaby Hobbs. I'm an Associate Professor at Harvard Medical School and practice at Mass General in Boston.
Dr. Douglas Tremblay: And I'm Douglas Tremblay. I'm an Assistant Professor at Mount Sinai in New York City.
Dr. Abdulraheem Yacoub: Thank you very much, Doug and Gaby. Today we'll be discussing the treatment and management of high-risk myelofibrosis with three patient case studies. Our first installment will focus on initial management of a patient with high-risk myelofibrosis. So this is a patient of mine who is now 67 years old. She was diagnosed with ET at the age of 57. When she turned 60, she started on pharmacological cytoreduction with hydroxyurea and she's been on that since then. Now she's 67 and has developed anemia, normal platelet counts despite discontinuation of hydroxyurea, and ETC.
She has lost 15 lbs in the last 3 months and now has drenching night sweats. On exam, she has a spleen that is enlarged and palpable at 8 cm below the left costal margin. And on laboratory assessment, the patient has a white count of 29,000. Her hemoglobin is down to 10.5 g/dL. Her platelets are 350,000, and she has 2% circulating blasts and an LDH that is increased at 600 U/L. She underwent a bone marrow examination that showed a hypercellular marrow with atypical megakaryocytes in clusters without increased blasts and with evidence of grade 3 fibrosis. Her karyotype remains normal and her mutational analysis confirmed a JAK2 mutation with an allele burden of 75%, as well as acquisition of TET2 mutation and ASXL-1 mutation. Gaby, what do you think is going on with this patient?
Dr. Gabriela Hobbs: Great case. So this is one of those cases where normalization of counts or having good blood counts only tells parts of the story. So clearly this is somebody that progressed from underlying essential thrombocythemia to now secondary myelofibrosis, and there's several things that are concerning in this patient's presentation. First, sounds like she's pretty symptomatic with night sweats, with splenomegaly, not feeling well and the spleen is easily palpable. And then second, in addition to having the normal platelets, she has an elevated white blood cell count and anemia, as well as circulating blasts, and she's acquired an ASXL-I mutation, which is always concerning in the setting of myelofibrosis.
Dr. Abdulraheem Yacoub: Thank you very much. So obviously this is a patient that would be of concern to us treating oncologists, and after confirming her diagnosis, we apply our prognostic tools and based on her prognostic risk scores – so her IPSS is concordant with her DIPPS+, both showing intermediate two risk, with definitely significant decrement in her survival. And then with the MIPS-70 version 2.0, given her ASXL-I mutation, she scores as high-risk disease.
So obviously this is a patient who has need for immediate action and immediate therapy. So as a standard approach to patients who are in generally healthy status and good fitness, she was referred to our bone marrow transplant colleagues and she has a full-matched, unrelated donor. But for personal reasons, she would like to defer her transplant for at least 12 months. Meanwhile, she would like medical therapy as a bridge to her transplant. So the decision was to start with a first-line JAK inhibitor. So Doug, what do you think would be your next move in treating this patient?
Dr. Douglas Tremblay: Clearly, as Gaby had mentioned, there is a need to initiate therapy because of the symptoms and the splenomegaly that the patient's experiencing. And there are several options, but I think it's very clear to say that while JAK inhibitor therapy can offer symptom relief and shrink spleen, it won't necessarily delay the disease from progressing and is by no way a cure of myelofibrosis. So definitely preparing the patient for transplant is an important goal to really try to achieve. And to do that with a JAK inhibitor is a fantastic way to both ameliorate symptoms and reduce spleen size to help prepare a patient for transplant. And now in 2025, we have several options for JAK inhibitor therapy, which include ruxolitinib, momelotinib, pacritinib and fedratinib. And in this patient in particular because the platelet count is adequate at 350 and the hemoglobin is above 10, a standard approach would really be to use ruxolitinib in this case, to try to improve symptoms and shrink spleen size in a patient without significant anemia and without thrombocytopenia, ruxolitinib is generally agreed to be the frontline therapy.
Dr. Abdulraheem Yacoub: Fantastic. So going by your advice, we started ruxolitinib, and per label, she would start on a full dose of 20 mg twice a day, which is what she did, and she continued to undergo frequent evaluation. So now on ruxolitinib therapy, she has complete resolution of her B symptoms. The weight loss, the drenching night sweats have completely been relieved. The spleen is no longer palpable. Now we're six months into therapy. However, the patient has worsening hemoglobin. So now her hemoglobin is 7.6. She's starting to feel symptoms, particularly dyspnea on exertion. Has not required transfusions yet. So with this patient with an excellent control of her disease, but anemia as a side effect likely from her therapy, what would be your considerations to address the anemia? Let's start with Gaby.
Dr. Gabriela Hobbs: Yeah. So I think that this is a great time in the patient's care to kind of go back to the beginning and remind her that although she's had an excellent response to ruxolitinib in terms of splenomegaly and symptoms, and although we know that the anemia that comes from being treated with ruxolitinib doesn't have such a negative prognostic impact as having anemia de novo from disease or disease progression, it still is a time to remind her that really where she needs to be is she needs to be preparing herself for transplant.
And so although we know that the anemia from ruxolitinib is not as bad from a prognostic perspective, it really is still significant from a quality of life perspective. And so for a patient like this, we need to think, if she really does not want to go to transplant still, although I would really encourage her to consider that now, because now is a good time to do that when she has an optimal spleen response, then we can think about either switching her to another JAK inhibitor or adding a medication to her ruxolitinib to help ameliorate the anemia.
And personally, I would say that it's difficult to get patients that are on a pretty good dose of ruxolitinib onto another JAK inhibitor while preserving that spleen response. But I don't know what experience either of you have had in the switching of patients from full-dose or nearly full-dose rux like her to another JAK inhibitor. So my preference for her would probably be to add something else.
Dr. Abdulraheem Yacoub: Excellent. And Douglas, would there be any additional data or information that would help you choose to switch her to a different JAK inhibitor versus add a different drug? Can you walk us through that diagnostic process and how do you make the decision between the two options?
Dr. Douglas Tremblay: Yeah, absolutely. And I share Gaby's concern about switching someone from ruxolitinib 20 mg twice a day to a different JAK inhibitor and compromising spleen or symptom control. I think it's an important time to also discuss that anemia and myelofibrosis is multifactorial, and, in this case, it's pretty clear that JAK inhibitor with ruxolitinib contributed to the state we're in. But there's other causes of anemia in myelofibrosis patients. There can be sequestration in the spleen of red blood cells and in this patient, the spleen has shrunk, so that may not be relevant. But there's also iron deficiency anemia or B12 anemia, which can contribute and should be really evaluated as well.
And myelofibrosis patients occasionally can also have things like GI bleeding as well too. So evaluating all of those different causes, to really make sure there's not a secondary cause of anemia is very important. Another data point that's extremely helpful, especially as we discussed, like Gaby mentioned, adding on another therapy is the endogenous EPO level. And that's particularly relevant if you're thinking about adding an erythropoietin stimulating agent, because someone who has a high endogenous EPO level is unlikely to respond to exogenous erythropoietin stimulating agent. So checking an EPO level can be very helpful diagnostically, but more so to try to figure out what therapeutic options are available to the patient.
Dr. Abdulraheem Yacoub: Fantastic. So based on your advice, we've done additional diagnostic workups. So her serum erythropoietin level is actually low at 100 U/L. She does not have iron deficiency. Her GI evaluation has been negative for GI source of blood loss. Her other nutritional assessments have been normal. So with that, we do have a low serum EPO level in this patient.
So this really kind of takes us into this new era in which we're really fortunate that we have options for our patients. And you mentioned two different strategies and sometimes it's a good place to have more than one option to offer to this patient. So recently the NCCN guidelines were updated in which some guidance was provided based on how do we address JAK inhibitors in patients with myelofibrosis and factor in anemia?
So in this woman in which she's on a successful therapy with ruxolitinib at a really high dose that is really as both of you showed reluctance at discontinuing or interrupting, and she's meeting all her disease milestones. She has complete resolution of the spleen, complete resolution of symptoms, it's really hard to bring this patient away from this therapy. This is not a failing therapy obviously. However, the only caveat is the anemia. So maybe in these patients, addressing the anemia with anemia-directed therapy seems to be a preferred course of action. In a similar situation in which the same patient is also struggling with controlling the spleen or controlling the symptoms and has anemia, you probably would jump the ship and move on to a different JAK inhibitor. So that guidance from the NCCN seems to be very contributory in this case in how we address this patient. What do you guys think about that?
Dr. Gabriela Hobbs: Yeah, no, I agree. I mean it seems like the NCCN definitely reflects what Doug and I would've done in practice. If you have a patient with adequately controlled spleen and symptoms on their JAK inhibitor, well then don't move them from there. As you said, Abe, they're not failing that therapy, so keep him on the ruxolitinib. But then the NCCN gives you the option of adding a few different things.
And so for this person, because of their EPO level, you can add an erythropoietin stimulating agent. Of course, we also have the option of danazol, which is an easy add-on, especially for those patients that don't want to come to clinic and get their blood counts checked or don't want to administer ESA. And then off-label, although included in the NCCN guidelines, if those options don't fail, we can use luspatercept and I guess the other point to mention here as well is that if there is a clinical trial available, this would also be a good opportunity for considering a clinical trial.
Dr. Abdulraheem Yacoub: Fantastic.
Dr. Douglas Tremblay: And I would also add that this scenario is still an area of high unmet need where the response rates to any of these additional add-on therapies are still generally less than 50%. So clinical trial I think is a great option if clinical trial is available to the patient, because this is clearly a situation that is going to negatively affect this patient's quality of life. And any new therapies that are out there, including luspatercept, need to be really evaluated. And I think it's an opportunity to really put a patient on a trial.
Dr. Abdulraheem Yacoub: All right, well, thank you both very much. I'm going to summarize our takeaways from this patient, is that really allogeneic stem cell transplantation is the only curative therapy for myelofibrosis and should be emphasized early on and during therapy, especially if the patient is doing well with therapy. That should not really obviate the need for a bone marrow transplantation. Ruxolitinib remains a key first-line therapy in many patients with preserved counts, but cytopenia and particularly anemia remains a challenge with these patients. Anemia and these patients are multifactorial. You still need to do the doctor thing. You need to evaluate for other causes for anemia and also tackle anemia with all the tricks that we have. If serum EPOs level, then ESA is an option. Many agents in development, luspatercept, danazol, IMiDs, have roles in this situation. And also there are JAK inhibitors with preferred efficacy in patients with anemia, that can be an option.
So thank you very much. This brings us to the end of this case. Please see the other segments for further discussions about the latest research in myelofibrosis or visit ascopost.com. Thank you.
