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. I am joined today by two of my colleagues.
Dr. Gabriela Hobbs: I am Gaby Hobbs. I'm an Associate Professor at Harvard Medical School, and I practice at Mass General Hospital in Boston.
Dr. Douglas Tremblay: And I'm Doug Tremblay, I'm an Assistant Professor at Mount Sinai in New York.
Dr. Abdulraheem Yacoub: Thank you very much, Gaby and Doug. Today we will be discussing the treatment and management of high-risk myelofibrosis with three patient case studies. Our final installment will focus on managing myelofibrosis beyond first line.
So our patient is Mr. JP. He's a 70-year-old man with primary myelofibrosis that was diagnosed 2 years ago. He has been receiving ruxolitinib therapy at the dose of 10 mg twice a day with good spleen response and resolution of B symptoms. The dose was limited due to his platelet counts. Now he has relapse and progression of his B symptoms. His labs currently show a white count of 17,000, hemoglobin of 8.1, and platelet counts of 58,000 while on ruxolitinib 10 mg twice a day. Subsequently, ruxolitinib was discontinued due to loss of benefit and the patient is now presented to you for a second opinion regarding his medical management.
On your assessment, the patient has persistent B symptoms without any impact of ruxolitinib discontinuation or withdrawal. His spleen is 8 cm below costal margin, and his labs now off of ruxolitinib show a white count of 55,000 with 3% blasts, hemoglobin of 8.5, and platelet count that has improved marginally to 105,000. His LDH is elevated at 1,300 U/L. So Douglas, what is your next steps in the workup and the treatment for this patient?
Dr. Douglas Tremblay: So this is a challenging case because we know that through multiple different investigations that a patient who discontinues ruxolitinib has a severely compromised survival of around 12 to 16 months. So this is obviously a high-risk patient even regardless of any sort of risk score. And we know that this patient is at a high-risk for poor outcomes. But I think an important assessment at this stage is to really repeat a bone marrow biopsy with the specific aim to see if there is any disease progression to MPN accelerated or blast phase disease with an increased leukemic burden because that needs to be treated separately than what will be treated for someone who is in more chronic phase with myelofibrosis.
I think also repeating a bone marrow biopsy would allow reassessment of next-generation sequencing and to understand if there's any additional targets that could be available for therapeutic reasons. So then the next step I would really consider doing is seeing where we're at with a bone marrow biopsy.
Dr. Abdulraheem Yacoub: Fantastic. So let's do that. So the patient is now being evaluated at a tertiary cancer center/NCI Cancer Center. So he's getting a state-of-the-art assessment for molecular reclassification. So his bone marrow biopsy shows a 30% cellular marrow with atypical megakaryocytes in clusters. He has grade 3 fibrosis, he had a dry tap biopsy and an aspirate could not be obtained. He has 5% by immunohistochemistry on his bone marrow biopsy core. His molecular assessments, so a JAK2 V617F at a high allele burden of 65%. This is significantly higher than his JAK2 at time of diagnosis. He also has acquisition of U2AF1 mutation and EZH2 mutation, both in the allele burden of around 20% to 25%. His karyotype is now abnormal showing a deletion 20q and 8 metaphases. A microarray panel was also performed that showed loss of heterozygosity at chromosome 9, which really explains the likely rise in JAK2 allele burden. And then this really qualifies him as a very high-risk patient on any molecular assay that we would apply in this setting. The patient is 71, subsequently, it's his first assessment at a tertiary center, so he's now referred to the bone marrow transplant team for a consultation. And then meanwhile, what would be your next medical intervention? So, Gaby?
Dr. Gabriela Hobbs: Yeah, so like you said, this patient now has very high-risk myelofibrosis and like Doug very clearly pointed out, regardless of where they fall under the MIPSS score, the fact that they have now progressed past ruxolitinib really also makes me very worried about this gentleman. And so certainly getting them ready for transplant would be the next step. And then I guess the real question is how do we optimize this gentleman to get him to transplant and ensure their success with that. So they still have splenomegaly symptoms and so in the process of working them up for transplant and getting them ready for transplant we have to get them started on a JAK inhibitor from a quality of life perspective, but hopefully also to improve their spleen to prepare them for transplant. We know that getting to transplant with a smaller spleen is helpful for engraftment afterwards and outcomes after transplant. And then of course if we have a JAK inhibitor that we can give that can help with the cytopenias, that would be great as well.
And so for this patient, the conversation really is what are the other JAK inhibitors that we can give? So we have fedratinib, pacritinib, and momelotinib, and I think that based on the anemia we would really spend our debate thinking about between pacritinib and momelotinib, what would be best for somebody like him? I would say that with the platelets being over 100 or around 100, with the white count being elevated, my preference would probably be to start them on momelotinib as this is a slightly more mild suppressive medication that potentially can help to lower the white count a bit and also hopefully help shrink the spleen a bit and improve the hemoglobin. So that would probably be my preferred agent. Again, if there was an option of a clinical trial alongside that, that would be helpful as well as we are definitely in a situation with this patient where there's no clear standard of what is the best next line of therapy. And so if there's a consideration for a trial, I would consider that as well.
Dr. Abdulraheem Yacoub: Excellent. So both of you reiterated that this is a high-risk patient clinically because he progressed on a JAK inhibitor and also molecularly given the acquisition and clonal evolution and in both high-risk mutations and his driver mutation and his chromosome. So obviously this is an unstable and evolving disease. The transplant is the only cure. And what we're doing between now and then is to get him in the optimum shape for a transplant. Hopefully that goes forward with a curative intent.
You mentioned the three JAK inhibitors that are on label for this patient. And honestly even fedratinib seems to be – was studied in exactly the same situation. So we do have three JAK inhibitors, but obviously momelotinib and pacritinib have more advantages in hemoglobin and also in being protective or can be delivered with thrombocytopenia.
Now, Douglas, in your institution generally what other investigational agents can be offered to somebody who progressed on JAK inhibitor? What are some of the hot active clinical trials that you would offer to this patient?
Dr. Douglas Tremblay: So there's many different investigations that are at different stages of development for the treatment of myelofibrosis that has been relapsed/refractory to a JAK inhibitor. I can highlight several of these and they fall into groups that are add-on therapies to someone who's already been on a JAK inhibitor, which we all know is very attractive because it can be very challenging to take someone off a JAK inhibitor. But there's also therapies that can be given just as single agents.
So some investigations that are ongoing in the add-on setting and it include drugs such as nuvisertib, which really has extremely good evidence so far that it can improve some of the cytokine storm that these patients will experience and improve symptoms and spleens. So this trial is something that is exciting for us. There's also therapies that look at implementing inhibition of the MDM2 axis, HDM2 axis, which really evaluates this strategy to try to increase the amount of p53 expression. And this is a drug called navtemadlin, which is being used in the add-on setting, which is something that we're also very excited about. And a lot of the science that's originated from our institution.
I mentioned previously these patients are at a very poor survival with an estimated median overall survival of 12 to 16 months. And a drug that has been approved for MDS that has data from phase II studies suggesting maybe that it could increase the survival of these patients is the telomerase inhibitor imetelstat. And so there is an ongoing exciting trial of imetelstat, a phase III trial, which really asking the question in a very unique way, does imetelstat improve survival in these patients who have stopped the JAK inhibitor? And this trial is something that we are eagerly awaiting the news for to see if we can impact not only the splenomegaly and the constitutional symptoms of these patients, but also improve their survival overall.
Dr. Abdulraheem Yacoub: All right, fantastic. So obviously you're very passionate about it. Obviously you're very excited about offering this patient one of many clinical trials.
Gaby, in your institution, what would be your top choice for a patient in this portfolio and in terms of your active clinical trials?
Dr. Gabriela Hobbs: Yeah, so Doug gave a nice summary of some of the compounds that are currently being studied. I would say for single therapy agents there's also the selective JAK inhibitors of which there are two compounds currently. We have the AJAX study, but there's also an Incyte study trying to target the JAK stat signaling pathway in a more selective way. So that's one where I'm really excited to see the results of, the next generation of JAK inhibitors.
In addition to that, I think the list of add-on drugs are pretty long. So we also have the PIM kinase inhibitor, which has been helpful in monotherapy as well as in combination and is now being studied as an add-on to momelotinib in the upfront setting. And of course there's also selinexor that's also being studied and has so far had some very promising early activity.
Dr. Abdulraheem Yacoub: Fantastic. So really a very dynamic and evolving field. And really that is – I'm going to start with that as my takeaway point. Relapsed/refractory myelofibrosis remains a disease with an unmet need, and many patients will require additional therapy. And the only way to advocate for our patients is to advocate for clinical trials and referral to centers of excellence and access to these trials in order to advance our treatment options.
So myelofibrosis is a progressive disease. Many patients, if not all patients will require multiple lines of therapy. Bone marrow transplantation is the only curative therapy, and it's never too late to refer a patient like this patient to transplantation. There are fortunately multiple JAK inhibitors that are approved beyond first line, and the choice will be personalized based on the patient's preference. And clinical trials should always be emphasized to our patients, which brings us to the end of this case.
Thank you all very much for your attention. Please see the other segments for further discussions about the latest research in myelofibrosis or visit ascopost.com. Thank you.
