Tag Archive for: BCR-ABL

Advances in Research | Emerging MPN Therapies on the Horizon

Advances in Research | Emerging MPN Therapies on the Horizon from Patient Empowerment Network on Vimeo.

The pace of research in myeloproliferative neoplasms (MPNs) is advancing rapidly, but what do patients need to know? MPN specialist and researcher Dr. Naveen Pemmaraju shares an update on the latest research and his optimism for the future of MPN care.

Dr. Naveen Pemmaraju is Director of the Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) Program in the Department of Leukemia at The University of Texas MD Anderson Cancer Center. Learn more about Dr. Pemmaraju.


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Katherine Banwell:

Dr. Pemmaraju, as a researcher, what are new and emerging therapies on the horizon in MPN care?  

Dr. Pemmaraju:

Well, Katherine, I’m glad you asked because I’m proud to tell you here, at the end of 2023, that we’ve now entered a new golden era of therapies for MPNs. Your group, and others, have led the way in advocating, but for so many years, honestly, we didn’t have many breakthroughs or new medicines. And now we literally have something we’re hearing about once a month. I think this golden era is divided into four buckets, Katherine, and that’s why I’m so excited for our patients and their caregivers. Number one is novel JAK inhibitors. So, beyond the approved ruxolitinib, fedratinib, and now pacritinib, we have a fourth one that’s under consideration, that’s called momelotinib.  Hopefully, we’ll have that approved by the end of the year. 

 [Editor’s Note: Momelotinib (Ojjaara) was approved by the U.S. Food and Drug Administration (FDA) on Sept 15, 2023 for the treatment of intermediate- or high-risk myelofibrosis, in adults with anemia.] 

And there are actually other drugs around the world. So, not just in the U.S. and North America that are being developed as a further JAK inhibitor. So, just like we’ve seen in CML with the TKIs for BCR-ABL after the imatinib (Gleevec) medicine, hopefully, we have seven to 10 choices for our patients.  

Number two is the combinatorial approach of a JAK inhibitor plus something else. And that’s a field that I’m personally very involved in and helping to lead. The concept there is you take the known workhorse drug, the JAK inhibitor, use it as the backbone, and then add in the second agent. We started to do those studies in patients who were already starting to lose a response and we added in the second agent, those were called suboptimal studies. And then now we’re moving those drugs into the frontline setting in international global randomized studies. So, stay tuned, let’s see how those go.

But the concept is, can you take a new agent, whether it’s a BET inhibitor, a bromodomain inhibitor, a Bcl-xL inhibitor, PI3 Kinase, et cetera, and combine it with the JAK inhibitor? The third bucket that’s even more exciting to many people is that of novel agents standing alone by themselves. Now you’ve had either a JAK inhibitor or some other therapy for your myelofibrosis. That didn’t work for whatever reason. Now you’re looking for a completely new strategy.   

An explosion of research, not just in the lab, which we’ve had for the last 10 years, but over the last three or four years, amazingly, even despite the COVID pandemic. I would say dozens, really dozens of trials that are what you would consider beyond or non-JAK inhibitor therapy. Some of them include telomerase inhibition, with the imetelstat agent, for example.

And so the concept here is, can you now hit the myelofibrosis in a completely different pathway? And the answer clearly is yes. And those results have been tested now in the lower stages, the earlier stages, Phase I and II. And you’re starting to see those drugs enter into the phase two and phase three. We eagerly await those results if there can be a viable beyond JAK inhibitor. And then finally, if that wasn’t exciting enough, there’s a fourth bucket, which is thinking about specifically the anemia myelofibrosis. We’ve never really historically done that. We’ve had older drugs, danazol (Danocrine), steroids, growth factor shots, blood transfusions.  

But now here you see both pharmaceutical interest, as well as academic interest, in developing agents that either specifically target the anemia of MF or both, the MF and the anemia. And that could be a game changer for our patients in the next five years. So, Katherine, a wealth of exploding research that I’m personally very excited about that gives me and our field hope, momentum, and enthusiasm going into 2024.   

Myeloproliferative Neoplasms Defined: What Are ET, PV, and MF?

Myeloproliferative Neoplasms Defined: What Are ET, PV, and MF? from Patient Empowerment Network on Vimeo.

What are essential thrombocythemia (ET) , polycythemia vera (PV), and myelofibrosis (MF) exactly? Dr. Naveen Pemmaraju explains how each of these blood disorders manifests along with the symptoms observed in these MPN patients.

Dr. Naveen Pemmaraju is Director of the Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) Program in the Department of Leukemia at The University of Texas MD Anderson Cancer Center. Learn more about Dr. Pemmaraju, here.

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Katherine Banwell:    

Can you help us understand the differences between ET, PV, and MF?

Dr. Pemmaraju:         

Yeah, this is very important because we toss these words around as if there’s some big definition that was given, and oftentimes, that never happens. So, let’s pause to do that. So, this goes back to the 1950s when William Damashek, who really postulated the modern MPDs at that time as they were known – myeloproliferative disorders – really thought that there were four diseases that were similar at some level and then presented differently. So, that’s polycythemia vera, essential thrombocytosis, myelofibrosis, and CML, chronic myeloid leukemia.

Then, as the modern era comes in, CML is divided off because of the Philadelphia chromosome, BCR-ABL, which is present in 100 percent of those patients.

So, now we know CML is its own thing. And now we have the big three, sort of non-Philadelphia chromosome MPNs, as they’re now known, because neoplasm – cancer – instead of disorder. Within the subtype, and this is important, the subtypes that you mentioned are the most common.

So, polycythemia vera – poly meaning many, cythemia, cells, vera is Latin for true.

This is the designation for the patient who has a higher than expected blood red cell mass or hematocrit. And it actually, interestingly, Katherine, most patients with P vera have an increase in all three of their blood lines, so the red cells, hemoglobin, hematocrit, platelets, and white count. Those patients with PV are especially at risk for both bleeding and clotting, transformation to myelofibrosis, and even transformation to acute leukemia in maybe 5 to 7 percent of patients.

So, the usual treatment there, Katherine, is to bring off the blood mass. That’s the phlebotomy.

And then in the patient who is above the age of 60 or has a prior blood clot, to give some form of chemotherapy, hydroxyurea (Hydrea), or interferon, for example.

Now, the second grouping is ET, essential thrombocytosis. Again, this word vera or essential, meaning not reactive, not benign, not from a regular cause like a surgery or a trauma or an inflammation. So, it means a cancerous cause, an autonomous cause, something that’s coming on its own.

Thrombocythemia or thrombocytosis, meaning too many platelets. So, usually, patients with ET have too many platelets as their predominant manifestation. But again, as with P vera, patients can get into problems with that. Very, very high platelets, usually a million-and-a-half or higher, can actually lead to bleeding. Not necessarily clotting, but extra bleeding. And then patients with any platelet levels, because the platelet level doesn’t exactly correlate, can have either bleeding or clotting. So, that’s usually the predominant factor. And again, the underlying problem with these MPNs is that they can transform to the other ones – PV, MF, even acute leukemia.

And then, finally, myelofibrosis, which we could spend the whole hour on just by itself, is the more advanced state out of these.

So, it can either arise out of the PV or ET or stand alone. And really here, this is an advanced bone marrow failure state with bone marrow scarring or fibrosis. And now, usually, most patients, their blood counts, rather than high are now low because the bone marrow is unable to produce enough cells. And then, therefore, the sequela of the disease – anemia, thrombocytopenia. So, low blood, low platelets.

Then you need transfusions. The liver and the spleen get larger because they remember how to make blood cells. People can have a wasting away appearance. And then here, more than the PV or ET, this is more of an acute disease for many where if you have intermediate to high stage, these patients can transform more readily to leukemia and have a decreased overall survival.