Dr. Abdulraheem Yacoub: Hello and welcome to The ASCO Post Roundtable Series: Expert Perspectives on the Treatment of High-Risk Myelofibrosis. I'm Dr. Abdulraheem Yacoub. I'm a Professor of Medicine at the University of Kansas, and I'm joined today by two of my colleagues.
Dr. Gabriela Hobbs: Hi, I'm Gaby Hobbs. I'm an Associate Professor of Medicine at Harvard Medical School, and I practice at Massachusetts General Hospital in Boston.
Dr. Douglas Tremblay: And I’m Doug Tremblay. I am an Assistant Professor of Medicine at Mount Sinai in New York City.
Dr. Abdulraheem Yacoub: Thank you very much, Gaby and Doug. Today we'll be discussing the treatment and management of high-risk myelofibrosis with three patient case studies. Our second installment will focus on some of the challenges associated with first-line JAK inhibition for myelofibrosis and the importance of recognizing cytopenias and comorbidities.
So our patient, Mr. AJ, is 71-year-old man who presents with weight loss, drenching night sweats, and cytopenias. He has had a mitral valve replacement and has been on anticoagulation with warfarin. He has stage 2 chronic kidney disease. On exam, he has splenomegaly that is 17 cm below the costal margin. His labs show a white cell count of 13,000. His hemoglobin is 8.3 g/dL. His platelets are 78,000. He has less than 1% blast circulating, and his LDH is 450 U/L. His bone marrow biopsy shows a hypercellular marrow with maturation of all three lines, atypical megakaryocytes in clusters, and no increase in blasts.
His bone marrow reticulum fibrosis shows a grade 2 out of 3 fibrosis. He has a normal karyotype, and his myeloid NGS panel shows an isolated mutation of MPL at an allele burden of 35%. Additional diagnostic workup shows a serum erythropoietin level of 750. The patient has normal iron studies without evidence of iron deficiency, B12, or folate deficiency. He has no schistocytes. He has an absolute retic count that is 25,000. He had extensive GI evaluation without evidence of GI bleeding, and his abdominal imaging identified massive splenomegaly, which is consistent with his examination. So for Gaby and Douglas, what do you think should be our next step in diagnostic and therapeutic discussions?
Dr. Gabriela Hobbs: So this is a challenging case, right, because we have somebody that has significant cytopenias but also really significant splenomegaly. So both the cytopenia aspect and the splenomegaly aspect as well as the symptoms need to be addressed. So usually when I meet somebody for the first time, the next thing that I do is to risk stratify them because that really helps to inform the conversation and determine whether or not a patient needs to be considered for transplant or needs to be managed medically without the option of transplant in the future. And so when we look at the different risk scores for a patient like this one, undoubtedly this is somebody that's going to fall under a higher risk category. And so that's really where I would go next in terms of the conversation with this patient.
Dr. Abdulraheem Yacoub: Fantastic. So to recap on that, the patient does have an increased risk. So his IPSS score shows intermediate-2 risk. His dynamic IPSS also is concordant – with an intermediate-2 risk. And his MIPSS70 version 2.0 is consistent with high-risk disease. So this is, to recap, a 71-year-old man with now a primary myelofibrosis diagnosis and high-risk features. He also presents with significant B symptoms, significant spleen and cytopenias. And his comorbidities include the prosthetic heart valve in which he's committed to a lifelong therapy with warfarin, as well as chronic kidney disease. So on initial assessment, he was referred to the bone marrow transplant colleagues and he was found to be ineligible given the constellation of his medical comorbidities. And then the decision was to start a first-line JAK inhibitor therapy. So, Douglas, what would be your leading decision in this patient for his medical therapy?
Dr. Douglas Tremblay: Sure. So in 2025, we have a few choices now with JAK inhibitor therapy in the front line. And specifically—while in a prior case we discussed, ruxolitinib was decided to be the optimal JAK inhibitor in this case—in a patient who is moderately thrombocytopenic and moderately anemic as well too, I don't think ruxolitinib is the optimal JAK inhibitor for this patient. Specifically in someone who has a platelet count of 78 and a hemoglobin of 8.3, you may have to employ a lower dose of a JAK inhibitor like ruxolitinib that doesn't really produce the same sort of efficacy that you see with higher doses of ruxolitinib. So in this specific case, I think the options really come down to pacritinib, which is the JAK2/IRAK1/ACVR inhibitor, and momelotinib the JAK1/2 and ACVR1 inhibitor.
And the patient that is presented here, the fact that they have a hemoglobin of 8.3 and 78 means both of these options are available. But in this particular patient, I think the fact that they have some cardiac comorbidities and specifically are on anticoagulation with warfarin would lead me to stay away from pacritinib, which does have some concern regarding concurrent anticoagulation use. And the fact that momelotinib can be given in someone who has moderate or severe thrombocytopenia and also has very well demonstrated anemia benefits would lead me to consider momelotinib as a choice for a JAK inhibitor in this patient in the front line.
Dr. Abdulraheem Yacoub: Gaby, do you agree with this decision and how do you select between the two contenders, pacritinib and momelotinib, in this setting?
Dr. Gabriela Hobbs: Yeah, no, I agree with everything that Doug said here, and I think the only thing that I would add is when strictly following the NCCN guidelines, pacritinib is reserved for patients with platelets of less than 50. So it makes it easier to choose momelotinib. But I think Doug's rationale was excellent. And I think for patients with platelets between 50 and 100, it's still kind of hard to know what the optimal JAK inhibitor would be. Outside of the considerations of anticoagulation or cardiac comorbidities, pacritinib is probably still efficacious in that group of patients, and it was studied in that group of patients as well in the PERSIST studies.
But its approval is really for patients in first line with platelet count of less than 50. But we all know that if you have somebody with a platelet count of 60 or 70 and you start them on therapy, there's a possibility that their platelets are going to go down lower. And so sometimes it's not that obvious to know which of the two to choose. But in this case, I would say that momelotinib is the obvious first choice, and I would start with that as well.
Dr. Abdulraheem Yacoub: Excellent. So a therapy with the JAK inhibitor in this patient would help both addressing his myelofibrosis domains of reducing the spleen, improving symptoms, and the specific choice of which JAK inhibitor, we're all advocating for agents that might not worsen the hemoglobin, if you actually mean improve the hemoglobin and also be gentle with the platelet counts and not challenge that too much. So in this patient, his own anticoagulation and really thrombocytopenia or anemia, both are not going to be something he can tolerate medically very well. So obviously patients come in with their diagnosis, but they also have comorbidities and their own active therapy. So the other thing we did not discuss is drug-drug interactions. So again, momelotinib is also favorable with less drug-drug interactions with Coumadin and has other advantages in this unique setting. But there are two options for patients with cytopenias.
So really some of the key takeaways that I learned from this patient is that thrombocytopenia and anemia are common in myelofibrosis—they're usual challenges. And in addition to being prognostic, they're also influential in our choice of how we treat our patients and how do we choose our JAK inhibitors. We do need to evaluate for all causes of anemia or reversible causes that we can address and try to optimize that. But we are fortunate that we have JAK inhibitors that are still effective as JAK inhibitors, but more favorable for the hemoglobin and platelet count responses.
So 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.
