Case Studies in Myeloproliferative Neoplasms - Episode 20

Case 3: Disease Progression and Transformation in ET

Stephen Oh, MD, PhD, discusses the nuances of identifying disease progression vs transformation in patients with essential thrombocythemia.

Ruben Mesa, MD: You brought up the L word: leukemia. Leukemia is truly the concern across all 3 of the MPNs [myeloproliferative neoplasms], with the greatest fear being for those who have myelofibrosis [MF], with a challenging and very difficult natural history if acute leukemia transformation occurs. Stephen, how do we make that diagnosis if somebody has progressed? What are some of the stronger predictors of people who might eventually go down that pathway?

Stephen Oh, MD, PhD: I’ll reinforce that, in general, patients with ET [essential thrombocythemia] do very well over the course of many years. The risk of ultimate transformation to myelofibrosis or AML [acute myeloid leukemia] is, to some extent, a time-dependent phenomenon, meaning the longer you have the disease, the higher that risk is. Things that can be a tip-off that something’s happening can be quite subtle. For instance, in the case of ET, let’s say the platelet count is going down. It’s still in the normal range, but you’re finding that you need less and less hydroxyurea to keep it in the ideal range. That seems like a good thing initially because you need less medication, but it’s actually a sign that the platelet count is dropping, and that might go hand in hand with the hemoglobin dropping and developing an anemia. Then you see that the spleen is becoming enlarged, the patient’s not feeling well, and some of the typical signs and symptoms of myelofibrosis. That transition can occur over a relatively long period, but it can show that you’re moving toward myelofibrosis. When you call it myelofibrosis, or when you intervene in terms of work-up or doing a bone marrow biopsy, it’s not necessarily 100% clear in the individual, but it becomes more apparent over time.

The transformation to acute leukemia can be somewhat abrupt, in my experience. The patient is doing just fine and you’re getting a routine CBC [complete blood count] or they’re coming for a checkup, and lo and behold, there’s an increased blast count on the peripheral smear, which would obviously prompt a bone marrow biopsy and additional work-up. There’s not necessarily that same slow transition period as there is with transformation to myelofibrosis. You’re going to be monitoring these patients with periodic visits and CBCs and things like that. Things like cytopenias and increased blast count are going to be the tip-off.

Ruben Mesa, MD: Very well said. As I try to tell my patients, if anything has taught me a lesson over the years of caring for patients with MPN, it’s that biology is not linear. You’re right. There’s probably a more predictable pace of evolution from ET and PV [polycythemia vera] into MF than there is with acute leukemia. It can be abrupt and unexpected. We still don't quite know what that biological switch is. I’m mindful that in the past, when we used to use a much higher degree of leukemogenic therapies in ET and PV, people could jump from ET or PV straight into AML. Fortunately, that is much less common now, having done some of those retrospective chart reviews at the Mayo Clinic, as I’m sure Prithviraj did at [University of Texas] MD Anderson [Cancer Center], and yourselves have. You look back on those charts from the 1960s with people receiving things like radioactive phosphorus. It’s almost tragic. You saw multiple doses of radioactive phosphorus and the next thing you know, they have acute leukemia. Fortunately, now it tends to be these 2 parallel ways of progression: a natural history of ET to progressive MF, and this second track, almost biologically, of movement toward AML that usually has myelofibrosis in the middle.

Jamile, as patients ask you about acute leukemia, what do you tell them about risks if they have ET or PV vs MF? If they ask how likely they are to get acute leukemia, what do you tell them these days?

Jamile M. Shammo, MD: It’s very small. I usually tell them that they have to go through a myelofibrosis phase. That’s probably more likely the case, and then from there on, there’s acute leukemia risk. The transformation from ET or PV to AML directly is much less likely than going through an MF phase. There are data to suggest that in a 10-year course, 4% to 5% could be the transformation risk. I try to stay away from this, because nowadays, the cases we are taking care of are probably vastly different from what has been described in the past. Perhaps the trajectory of what has been described in the past to give you those timeframes is very different from what we deal with today. Maybe we can make the diagnosis earlier. I try to simply say that we have to go through MF before you go to AML. I agree with Stephen when he says that you have to keep an eye on the anemia and the blast percentage that flows into the peripheral blood. Some of it may be related to the treatment you are giving. If you take this treatment down and the patient doesn’t get better, it’s time for a bone marrow biopsy.

Ruben Mesa, MD: I tell patients that the good news is there’s tremendous progress being made. There’s progress being made in new therapies for acute leukemia. There are therapies being developed for MDS [myelodysplastic syndromes], which may end up being relevant for these patients. There are ET and PV therapies being developed. There are MF therapies. Patients may benefit from any number of these, or combinations of them. The lessons learned in 1 myeloid disorder, or even outside of myeloid disorders, may end up benefiting them. There’s a lot for us to be hopeful for as we try to build on the observations that we’ve had.

This has been a wonderful discussion. Let me thank each of you, Jamile, Stephen, and Prithviraj. It’s been a fantastic discussion as we’ve chatted about important clinically relevant things to be considering for PV, ET, and MF. Thank you for your thoughtful case presentations and the great discussion. To the viewing audience, our thanks for joining this Targeted Oncology Virtual Tumor Board® presentation. We hope today’s discussion has been a valuable use of your time and that you’ve acquired some practical knowledge that you can take back to your clinic. Thank you.

This transcript has been edited for clarity.