Stone Highlights Emerging Treatment Options for Older Patients With AML

Richard M. Stone, MD

A plethora of additional agents has given physicians more options for the treatment of older patients with acute myeloid leukemia (AML), explained Richard M. Stone, MD, although the optimal combinations and settings have yet to be discerned.

In terms of combinations, venetoclax (Venclexta) and hypomethylating agents (HMAs) have shown strong signals of activity. In a phase II trial reported at the 2018 ASH Annual Meeting, the combination of venetoclax and 10 days of decitabine induced a complete response (CR) rate or a CR with incomplete hematologic recovery of 92% in patients >60 years with newly diagnosed AML and 71% of patients with secondary AML.

“The therapeutic algorithm has changed from 7 + 3 chemotherapy for fit patients and azacitidine or decitabine for unfit patients to a more personalized approach,” said Stone, director of the Adult Leukemia Program at Dana-Farber Cancer Institute.

Additional agents include midostaurin (Rydapt) for patients with FLT3-mutant AML, gemtuzumab ozogamicin (Mylotarg) for patients with t(8;21) or inv(16), and CPX-351 (Vyxeos) for patients with therapy-related AML or AML from myelodysplastic syndrome (MDS), with a carrier type similar to MDS, or with MDS-related dysplastic changes.

This departure from a chemotherapy approach is due in large part to refined patient assessments and a better understanding of the biology of AML.

“We can’t stop now. We have to keep working to find out how to use them, make them less toxic, and more effective,” Stone said. “Our older adults need that.”

OncLive: How has the management of elderly patients with AML evolved in recent years?

In an interview with OncLive, Stone, who is also a professor of medicine at Harvard Medical School, discussed the therapeutic landscape for elderly patients with AML.Stone: Thanks to the amazing number of newly FDA-approved drugs in AML, we have new options for older patients with the disease. We’ve seen the impact of genetics on prognosis and maybe even choice of therapy in certain cases.

Could you elaborate on patient assessment?

Before we get to the new drugs, I want to make sure that people realize that there are different ways to assess the patient and the disease right now. In terms of patient assessment, we have to be good communicators and make sure we transmit what we know to the patient and their family. These are very stressed patients who can’t really hear what we say, so we have to avoid medical jargon when possible. Patients inflate what we tell them because the devastating news about their leukemia is hard to put into one’s own psyche.Patient assessment includes more than just performance status or whether we think they’re fit or unfit. A lot of research led by the late Arti Hurria, MD, of City of Hope, used something called the geriatric assessment scale. That may be better than [another test] that looks at the patient’s ECOG performance status or Karnofsky scales to assess their fitness for chemotherapy. Preliminary work has shown that the geriatric assessment, which is a battery of questions about social functioning, ability to do tasks, and physical tests, can predict a patient’s likelihood of success or failure with chemotherapy.

On the other hand, we [also have] these new tests that stress the [importance of] genetics. From work done by R. Coleman Lindsley, MD, PhD, of Dana-Farber Cancer Institute, we know that mutations can guide the prognosis and perhaps help us choose therapy. You can bucket these patients into 3 categories. When I say “these patients,” I mean older adults who don’t appear to have a history of myelodysplasia or other cancers before their AML.

One bucket would be those with p53 mutations. Another bucket would be those with MDS-type mutations or secondary mutations—–epigenetic mutations such as ASXL1. The third bucket would be those who have what we tend to call pan-AML mutations or more secondary, singling-type mutations in the RAS or FLT3 pathway. The latter group are the ones with de novo mutations in the singling pathway who do pretty well with 7 + 3 chemotherapy. Patients with p53 and secondary mutations don’t do very well.

Could you expand on some of these newer options?

We need new therapies for those patients. In 2019, we have slightly better therapies for that adverse group and unfit patients—which is exciting. For example, we have the addition of venetoclax to either azacitidine or decitabine or possibly low-dose cytarabine [LD-AraC] if we don’t have access to the HMAs.There are several newer options, 1 of which is midostaurin for the occasional older patient with FLT3-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 regimen is the combination of an HMA plus venetoclax. There have been no prospective randomized data with that regimen compared with the other 3 drugs that have been mentioned; however, the phase II data are so strikingly positive, and the combination is pretty tolerable. [The combination] is more myelosuppressive, so you have to watch for neutropenia, but in general, the responses have been very high. Of course, this has to be confirmed by the recently completed phase III trial comparing azacitidine alone to azacitidine plus venetoclax in patients aged 75 or older or those with bad comorbidities.

What are the unmet needs that still need to be addressed in these populations?

It should be pointed out that this trial did not include patients with intrinsically difficult disease, such as those with p53 or secondary mutations. It makes sense that those patients who aren’t going to do well with 7 + 3 [may tolerate] azacitidine and venetoclax, but it remains unproved. Moreover, they’re not going to go into remission with [this combination], or very unlikely so. Of course, we need a [randomized] trial to prove that azacitidine and venetoclax is better than 7 + 3 in some of these groups, but the data are pretty striking. I would consider using it quite broadly with this older age population.There are many unmet needs. We’re still not curing people, and we’re still making people sick with our therapy. [With] p53[-mutated disease], although there are some bright spots, it is still a horrible disease. Being able to bring transplant, which has its own advantages and disadvantages, to older adults [is an area of investigation], but we don’t really know how many patients can tolerate it in this age group. We need new drugs, and we need to know how to fit in the available drugs. The hedgehog inhibitors don’t seem to have a huge niche to fill right now. Maybe in combination we’ll understand who should get what. For example, should a patient who is eligible for azacitidine and venetoclax and CPX-351 get 1 or the other? How are we going to make these decisions? There are a lot of questions [that still need to be answered].

[In my presentation], we also talked a lot about IDH1/2 inhibitors and how they should be used. They’re [FDA] approved for use in patients with IDH-mutant AML in the relapsed setting, but do they have a role either alone or in combination with azacitidine or 7 + 3 in up-front setting? Moreover, can we dose IDH1/2 inhibitors in combination with LD-AraC in unfit patients? If a patient with an IDH1/2 mutation is unfit, can they receive an IDH1/2 inhibitor plus LD-AraC, or should they get an IDH1/2 inhibitor plus an HMA? Or should they get venetoclax plus an HMA? [Those questions] just scratch the surface of the research.

Research helps. There was a desert [in terms of drug development] in AML for 40 years, and now we have an explosion of new drugs. We didn’t give in; we kept trying new things. Our understanding of the biology of the disease has blossomed, which has helped with the [development of] targeted therapies.

Maiti A, DiNardo CD, Cortes JE, et al. Interim analysis of phase II study of venetoclax with 10-day decitabine (DEC10-VEN) in acute myeloid leukemia and myelodysplastic syndrome. Presented at: 2018 American Society of Hematology Annual Meeting; December 1-4, 2018; San Diego, CA. Abstract 286. ash.confex.com/ash/2018/webprogram/Paper113749.html.