Richard M. Stone, MD, discusses the emerging agents for older patients with AML, as well as the importance of patient assessment and the identification of select mutations.
Richard M. Stone, MD
Treatment options in acute myeloid leukemia (AML) had been lacking over the last 2 decades, with limited options available for older, unfit patients. However, the recent explosion of new therapies in the field is allowing physicians to take a more personalized approach when selecting treatments for older patients, according to Richard M. Stone, MD.
With the addition of newer agents into the treatment paradigm for AML, patient assessment and identification of select mutations has become more important. Use of a geriatric assessment scale can help in identifying whether patients are fit or unfit for an intensive therapy. Patients can also be grouped into 3 categories based on their genetic mutations, which can help in determining the best treatment option for an individual patient.
The categories are classified by 3 different types of mutations:P53mutations, secondary mutations, and de novo mutations. These classifications can help in determining how a patient may respond to a specific therapy. For example, those with de novo mutations may respond well to 7+3 chemotherapy, while those withP53mutations or secondary mutations are likely to do poorly on this treatment.
“Our understanding of the disease biology has blossomed, which has certainly helped, but we can’t stop now. We have to keep learning how to use them, make them less toxic, more effective, and keep going. Our older adults need that,” said Stone.
In an interview withTargeted Oncology,Stone, chief of staff and director of Translational Research and the Adult Leukemia Program at Dana-Farber Cancer Institute, and a professor of medicine at Harvard Medical School, discussed the emerging agents for older patients with AML as well as the importance of patient assessment and the identification of select mutations.
TARGETED ONCOLOGY:Can you start by highlighting the biggest changes to the treatment landscape in AML?
Stone:Thanks to the amazing number of newly approved drugs in AML over the past few years, we have new options, but my main point is that the therapeutic algorithm has changed from a time when we had 2 options 7+3 for fit patients and azacitidine for unfit patients – to a more personalized approach.
Before we even get into the new drugs, I want people to understand that there are different ways to assess both the patient and the disease right now. In terms of the patient assessment, we have to be good communicators to the best of our ability to transmit what we know to the patient and their family. These are very stressed patients that can’t really hear what we say, and we have to avoid medical jargon when possible. They always inflate what we tell them because the devastating news about their leukemia is hard to put into one’s own psyche.
Of course, regarding the new methods of assessment, chromosomes have been around for a while and are still very important, but now the impact of genetics on prognosis and maybe even on choice therapy in several cases is definitely there.
TARGETED ONCOLOGY:How do you assess these patients?
Stone:Assessment of the patient potentially includes more than just the performance status and whether we think, by walking in the room, they are fit or unfit for chemotherapy. There’s research done and led by the late Arti Hurria, MD, of City of Hope, using the geriatric assessment scale, which may be a better way than just the eye test, the doctor’s eyes just looking at the patient, or performance status by ECOG or Karnofsky scales to assess the patient’s fitness for chemotherapy. Preliminary work has shown that geriatric assessment, which is a battery of questions about their social functioning, their ability to do tasks, and physical tasks, could predict people’s likelihood of success or failure with chemotherapy.
On the other hand, we do have these new tests that I want to stress the genetic issues of. We now know from work done by Coleman Lindsley, MD, PhD, at Dana-Farber, that mutations can really guide the prognosis and perhaps help us choose therapy. For example, you can bucket people into 3 categories. When I say people, I mean old adults that don’t appear to have a history of myelodysplasia or other cancers before their AML.
One bucket would be people who haveP53mutations, which is very bad. Another bucket would be people who have myelodysplastic syndrome (MDS)-type mutations, or secondary mutations, epigenetic mutations,IZH1,IZH2, etc. The third bucket would be people that don’t have those who tend to have what we can pan-AML, or more secondary single-type mutations in the RAS pathway or the FLT3. The latter group, the ones with the de novo mutations of the single pathway mutations can do pretty well with 7+3 chemotherapy. The other groups withP53and secondary mutations don’t do very well.
We need new therapies for those people, and I think that one of the exciting things is that now in 2019 we have slightly better therapies for that adverse group for people that aren’t fit, and those would receive the addition of venetoclax (Venclexta) to either azacitidine or perhaps decitabine (Dacogen) or possibly low-dose cytarabine for those around the country that don’t have access to the hypomethylating agents.
TARGETED ONCOLOGY:What are these newer treatment options in AML?
Stone:There are several newer options, 1 of which is midostaurin for the occasional older patient withFLT3-mutant disease, or gemtuzumab ozogamicin for the rare, fit, older patient who has inv(16) or t(8;21). We also have CPX-351, which is a better version of 7+3 and proved superior to 7+3 in patients between the ages of 60 and 75. However, the [FDA] approval is for all patients who have a history of MDS, cytogenetics like MDS, or a history of cancer chemotherapy.
The most exciting, I would say, would be the combination of the hypomethylating agent plus venetoclax (Venclexta). It’s very interesting that I say that because there’s been no prospective randomized data as there has been for the other 3 things I mentioned. It’s just that the phase II data is just so strikingly positive that the drug combination of venetoclax with either low-dose cytarabine, azatadine, or decitabine is pretty tolerable, though it is more myelosuppressive and you have to watch out for fever and neutropenia. However, in general the responses have been very high. Of course, this has to be confirmed in the context of a recently completed phase III trial comparing azacitidine alone to azacitidine plus venetoclax in a specified group of patients. The specified group of patients being those with age greater than 75 or those with a bad comorbid disease like bad lung function or heart function. It should be pointed out that that does not include people with intrinsically difficult diseases likeP53or secondary mutations. Yet, I think, and I’m proven, that azacitidine/venetoclax makes a lot of sense in those people who aren’t going to do well with the 7+3, who may be able to tolerate it, but they won’t go into remission with it, very likely. We need the phase III trial to prove that azacitidine/venetoclax is better than 7+3 in some of these groups, but the phase II data has been pretty striking, and I would consider using it quite broadly in this older patient population.
TARGETED ONCOLOGY:What are the unmet needs that still exist in this patient population, and how do you see these challenges being overcome?
Stone:There are many unmet needs, and we are still not curing people. People are sick without therapy. InP53, though, there are some bright spots even though this may be a horrible disease, being able to bring transplantation which has its own advantages and disadvantages, to the older adults has been helpful to a certain degree, but we don’t really know how many people can tolerate it in this age group.
We need new drugs, still. We need to know how to fit in the available drugs, like these hedgehog inhibitors, which really don’t seem to have a huge niche to fit into right now. With combinations, we need to understand who should get what. [For example], should a patient who is eligible for both azacitidine/venetoclax and CPX-351 get one or the other. How do we make these decisions? There’s a lot of questions and a lot of unmet need. We are still not curing these people in the numbers that we need to.
TARGETED ONCOLOGY:What are the key takeaways on the management of older patients with AML?
Stone:The key takeaway is that research helps, that’s what I would say. There was a great desert of new drugs in AML for 40 years and now we have, in the vernacular, an explosion of new drugs. We didn’t give up; we kept trying new things. Our understanding of the disease biology has blossomed which has certainly helped, but we can’t stop now. We have to keep learning how to use them, make them less toxic, more effective, and keep going. Our older adults need that.
TARGETED ONCOLOGY:Is there anything else you would like to highlight?
Stone:We talked a lot about the use of IDH inhibitors and how they should be used. Whether they were approved for mutantIDH-AML in the relapsed setting. Do they have a role either alone or in combination with azacitidine or 7+3 in the upfront setting? There’s a lot of open questions. I think that was a key takeaway as we are just beginning to learn how to use these agents.