Advancements made in the field of molecular genetics for patients with myeloproliferative neoplasms may be increasingly incorporated into treatment decisions, according to a presentation by Ann Mullally, MD, during the 2017 SOHO Annual Meeting.
Ann Mullally, MD
Advancements made in the field of molecular genetics for patients with myeloproliferative neoplasms (MPNs) may be increasingly incorporated into treatment decisions, according to Ann Mullally, MD.
In her presentation during the 2017 SOHO Annual Meeting on our current understanding of the molecular genetics of MPNs, she indicated that the strides that have been made in identifying the driver mutations of these diseases has had the greatest impact upon diagnosing a patient with one of the myeloproliferative diseases. However, Mullally, assistant professor of medicine at Harvard Medical School, attending physician of the Leukemia Program at Dana-Farber Cancer Institute, and associate physician of hematology at Brigham and Women’s Hospital, believes that next the field of molecular genetics will impact treatment decision making, such as in patients with a more or less aggressive clinical progression.
In an interview withTargeted Oncology,Mullally discussed how molecular genetics has led to further advancements for patients with MPNs and is contributing to the search for better treatments and combination approaches.
Targeted Oncology:Could you give a summary of the recent updates of molecular genetics in MPNs?
Mullally:We have a good understanding in that we’ve really defined the major genes that drive the development of this disease. We’ve defined the concomitant or coexisting mutations that occur in cooperation with these phenotypic driver mutationsthe 3 beingJAK2, calreticulin (CALR), andMPL.
The most recent advances have been in the understanding of the mechanism by whichCALRcauses MPN, and this is work that my laboratory and other laboratories have worked on over the last few years. When these mutations were identified in 2013, it wasn’t apparent how a gene likeCALRcould cause an MPN because it’s not a signaling gene, there was nothing that associated it with the JAK-STAT pathway and now we know that it causes MPN by physically interacting withMPL, the thrombopoietin receptor, and activating the JAK-STAT signaling. That’s probably been the most significant advance in terms of the understanding of the molecular genetics of MPNs recently.
Are there any other molecular abnormalities other thanJAK2that are being targeted, and if so, have you seen any potential therapies effectively targeting these abnormalities?
The JAK-STAT pathway is central to the pathogenesis of MPN, regardless if you have aJAK2mutation, aCALRmutation, or anMPLmutation. They all converge on activated JAK-STAT signaling, so I think most of the work [revolves around] trying to actually targetJAK2better, and that either means developing better JAK2 inhibitors or mutant-specific inhibitors, and there is a lot of [ongoing work in these areas]. I think there are a lot of clinical trials on using combinations with JAK2 inhibitors to try to look for synergy with inhibiting JAK2 and something else downstream of JAK2.
In terms of entirely novel targets, I think mutantCALRitself may be an interesting target, and particularly from an immunological perspective, so there is some preclinical data to indicate that mutantCALRis immunogenic and I think there are many potential ways that this could be targeted using immunotherapy approaches. There are some clinical trials that are open using PD-1 inhibitors in MPNs, and it will be interesting to see whether the patients who haveCALRmutations who are enrolled in those trials have higher or different types of responses.
Do you see any advancements or improvements in the diagnostic tools in the next few years that will aid in better diagnosing MPNs?
I think that molecular genetics have really helped us a lot here in that they are pretty definitiveyou either have the mutation or you don’t. And, as I said, we have a comprehensive understanding of the key genes that drive the mutation, so I think that has helped us a lot, the molecular genetics. Obviously, we use all the traditional things, like the clinical picture of the patient, the bone marrow biopsy, but I think increasingly, we rely on molecular genetics to help us understand where in the spectrum of myeloid diseases the patient lies.
What I see happening is using molecular genetics more in treatment decisions, so I think we’ll probably be doing a lot more sequential molecular monitoring, where a patient has clinical progression or a change in their clinical status or a change in their blood counts, I think we’ll try to understand what’s happening to the biology of their disease by looking at molecular diagnostic panels and comparing them with prior ones, and using that information to help us make better treatment decisions. For example, if someone has evidence that they’ve had aggressive progression, then you might be more likely to recommend a transplantation for a patient with myelofibrosis rather than changing therapies. So, I think molecular diagnostics has helped us the most in diagnosis and I think that we’ll start to increasingly integrate that into clinical decision making going forward.
What is the clinical utility for ruxolitinib (Jakafi) as of now? Are there any ongoing studies or new findings that are clinically significant?
Ruxolitinib is approved by the FDA for the treatment of patients who have intermediate or advanced-phase myelofibrosis and it’s also approved for patients with polycythemia vera who are resistant to or refractory to hydroxyurea. We know that ruxolitinib is a good drug at reducing blood counts, reducing spleen size, and improving symptoms. As we get more experience with ruxolitinib, what I think we’ve found is that we have a better sense of which patients, particularly with myelofibrosis, who respond better or worse to ruxolitinib, and this again comes back to molecular genetics. A lot of molecular analysis of the ruxolitinib clinical trials has now been done, and we understand which patients respond better and which don’t. For example, if you have a lot of concomitant mutations, you are more likely to have a short duration of response and progress than if you have a small number of concomitant mutations. So, I think we’re starting to understand better the limitations of ruxolitinib.
I mentioned already there’s a lot of clinical trials, combinatorial trials, combining ruxolitinib with various other agents, and I think this is primarily driven by the fact that although ruxolitinib has clinic efficacy, it is not able in any significant way to eliminate the cells that harbor the mutationstheJAK2orCALRmutationsthe cells that harbor those mutations are not preferentially targeted by the drug, and so that raises concerns about its ability to alter the natural history of the disease. I think that is something that needs additional work, and we need better therapies to address that specific point.
Are there any significant challenges that you’d like to see addressed in the next 5 to 10 years?
I think it gets back to this idea of preferentially or selectively targeting the malignant clone, the cells that harbor the mutations. Currently, we know that interferon can eradicate, or at least render patients undetectable, for theJAK2mutation in a minority of patients who have polycythemia vera or essential thrombocythemia, so probably 15% to 20% of patients can become undetectable for that mutation with interferon. As I already mentioned, ruxolitinib is not strongly selective for the mutant cells, so if we look at sequential allelic burdens forJAK2V617F orCALR