New AML approvals changing the treatment landscape

With a recent flurry of new drug approvals, the treatment landscape for acute myeloid leukemia has expanded, raising new questions about how to incorporate those drugs into patient care.

Until about a decade ago, advances in AML therapy centered mainly around iterations of daunorubicin and cytarabine. Now, novel and targeted agents, many specifically going after mutational byproducts, are yielding some great results and raising hopes for better survival outcomes, Jeffrey Lancet, MD, said in an interview.

“When I go to sleep at night, I often dream about ... 10-year survival rates in the 80% range. And then I wake up ... and I realize this is actually [the survival curve for chronic myeloid leukemia]. This is where we’d like to be [with AML].” Those outcomes are a long way off, but appreciable incremental gains may lie ahead with the recent advances in AML therapy, said Dr. Lancet, chair of the department of malignant hematology at Moffitt Cancer Center in Tampa.

In addition to the new approvals, 16 drugs are in late stage clinical development and will likely contribute to an AML market that is expected to surpass $1.5 billion by 2026, according to projections by the market intelligence company GlobalData.

Vyxeos

The liposome-encapsulated combination of daunorubicin and cytarabine (Vyxeos) was approved in August by the Food and Drug Administration for the treatment of therapy-related AML and AML with myelodysplasia-related changes.

In a phase 3 randomized trial, the fixed-dose combination product was associated with median overall survival of 9.6 months, compared with 5.9 months with a standard combination of cytarabine and daunorubicin (7+3).

“I would envision that Vyxeos will hold and become the primary standard of care for fit chemotherapy-suitable older patients, or any patients for that matter, who are dealing with secondary-like AML or high-risk AML, based on the phase 3 results that we demonstrated,” Dr. Lancet, the principal investigator for the trial, said in an interview.

Asked whether the improved survival with Vyxeos is primarily related to more patients becoming transplant eligible or to significant reductions in disease burden, Dr. Lancet remarked that it’s likely a mixture of both.

The high remission rate with Vyxeos vs. standard 7+3 therapy means Vyxeos has the ability to stand on its own, and “the potential to send more patients to transplant and to get better results.”

“Transplant is part of the continuum of care of AML, including in older patients, and Vyxeos is going to become a standard part of that care,” he remarked. But transplant outcomes were not a predesignated component of the phase 3 trial, and further study will be needed to determine Vyxeos’ role as a bridge to transplant. “At this stage I can reasonably state that it has a role in the upfront therapy of secondary and high-risk AML, regardless of whether the patient is being considered for transplant.”

The early stages of working Vyxeos into the therapeutic mix come with some challenges, however, according to Donna Capozzi, PharmD.

Dr. Donna Capozzi

Vyxeos is a fixed-dose combination that comes in vials containing 44 mg daunorubicin and 100 mg cytarabine encapsulated in liposomes. Patient dosing is based on the daunorubicin component and calculated based on body surface area (mg/m²), meaning the cytarabine dose does not need to be calculated. There are both pros and cons to this approach, she explained.

Benefits include a longer half-life with Vyxeos vs. standard 7+3, and the fact that during induction the drug is delivered on days 1, 3, and 5 for 90 minutes rather than continuously for 7 days as with 7+3, Dr. Capozzi said.

The main concern relates to ensuring that the dosing is calculated based on the proper component, she said.

“We had our first patient last week. It was very time consuming, with double and triple checking to make sure everything was correct,” she said. Preparing the drug is also time-consuming, as it involves multiple steps, such as warming, which is not required with standard 7+3; the additional labor factors will have to be built into workflow, she noted.

“The other piece not fully in place right now is building [the use of Vyxeos] into electronic health records,” she said, adding that safeguards put into place through EHRs will also help to streamline the administration process.

For example, cardiac toxicity is a known effect of daunorubicin; the EHR will help track lifetime cumulative dosing of that component, which is otherwise challenging, especially when using a combination product, she said.

The process will get easier over time, as use of Vyxeos becomes more prevalent in practice, she added. “None of these are insurmountable issues.”

Cost is another matter. Based on average wholesale prices, the cost per cycle is approximately $40,000 with Vyxeos vs. about $4,300 for conventional 7+3 therapy, Dr. Capozzi said. Given the differential, there will be a great deal of debate as to which patients will derive the most benefit from Vyxeos, she said.

Also, it will take time to figure out the extent of adverse events. “For liposomal products in general, rash-type side effects can be really significant. Hand-foot syndrome was not reported in the initial trials, but we’ll keep our eyes open to see how that plays out,” she said noting that the one patient treated so far at the University of Pennsylvania is doing very well. “We will learn more with real world experience.”