StemCell Therapy

ORLANDO, Florida For the first time, there is a maintenance therapy for patients with acute myeloid leukemia (AML) in remission that can improve overall survival a new oral formulation of an old drug, azacitidine, known as CC-486 (Celgene).

Dr Andrew Wei

"Oral azacitidine represents a new therapeutic standard for patients with AML in remission," said lead author Andrew H. Wei, MBBS, PhD, from the Alfred Hospital in Melbourne, Australia.

"It's not too hard to get these patients into remission," commented another expert. "The problem comes in keeping them in remission."

Wei noted that standard treatment with intensive induction chemotherapy (IC) for AML induces complete remission (CR) in 60% to 80% of patients aged 60 years or younger and in 40% to 60% of patients aged 60 years or older.

However, the majority of patients who attain CR will eventually relapse, and relapse is the primary obstacle to long-term survival, he said.

Despite various attempts, there has been no success over the past 30 years in defining maintenance treatment for these patients, Wei said.

The new results suggest that oral azacitidine could be an effective maintenance therapy.

Wei presented the results here at the American Society of Hematology 2019 annual meeting. They come from the QUAZAR AML-001 study, conducted in 472 patients with poor-risk AML in first remission.

The results show that CC-486 significantly improved outcomes compared with placebo plus best supportive care in terms of median overall survival (24.7 vs 14.8 months) and median relapse-free survival (10.2 vs 4.8 months).

The trial was funded by Celgene, which said it will be submitting the data for regulatory approval for the new oral formulation of azacitidine, CC-486.

Experts approached for comment agreed that maintenance oral azacitidine will become the new standard of care for patients with AML in first remission.

"Unlike therapy for acute lymphoblastic leukemia (ALL), maintenance therapy has not been part of the treatment algorithm for AML patients in first remission," Harry P. Erba, MD, PhD, director of the Leukemia Program at the Duke Cancer Institute, Durham, North Carolina, told Medscape Medical News.

He explained that trials for maintenance after first remission in AML have failed. Recently, Erba noted, the HOVON97 trial with injectable azacitidine demonstrated improvement in relapse-free survival compared with observation for older AML patients achieving remission after induction therapy. "However, there was no improvement in overall survival," he said.

"Remission in AML is short lived," Erba said. Oral azacitidine represents the first maintenance therapy in AML that has shown both significant and clinically meaningful improvements in overall and relapse-free survival and will represent a new standard of care for patients with AML in remission, Erba said. "Maintenance oral azacitidine will be practice changing," he predicted.

HOVON97 was a small study of injectable azacitidine used as maintenance therapy for 12 months, but it was slow to accrue and did not meet its accrual target.

"In HOVON97, at 12 months, only one third of patients received less than the 12 cycles of therapy," Wei said. He explained that with injectable azacitidine, patients have to come into the hospital/clinic for 7 days a month, 84 days a year. Oral azacitidine is more convenient as patients do not have to come into the clinic, he said.

Wei pointed out that about 40 patients in the QUAZAR study, which started in 2013, are still on maintenance therapy, with one patient now having received 80 cycles of therapy (approximately 7 years). "Long-term maintenance therapy with azacitidine is possible," he said.

Another expert was also impressed by the new results. "This is an important clinical trial that addresses an unmet need in AML care," said John Mascarenhas, MD, director of the Adult Leukemia Program and leader of clinical investigation within the Myeloproliferative Disorders Program at Mount Sinai's Tisch Cancer Institute in New York City.

"Older patients can often receive induction chemotherapy but frequently do not ultimately do well, as the disease relapses and survival is limited," he explained.

"This large, randomized, double-blind, controlled study of intermediate or poor risk AML patients over the age of 55 years supports the use of maintenance oral azacitidine after initial remission to extend overall and relapse-free survival in older AML patients not eligible for transplant," Mascarenhas said.

"This is still not a curative approach," Wei said, but added that it prolongs relapse-free survival for older patients while maintaining a quality of life for as long as possible.

The QUAZAR phase 3 study enrolled patients with poor- or intermediate-risk cytogenetics who had an Eastern Cooperative Oncology Group performance status 3 and who had achieved complete remission (CR) or complete remission with incomplete count recovery (CRi) after induction therapy with or without consolidation therapy. In addition, patients were not candidates for stem cell transplants.

Patients had predominantly de novo AML (89%). Other baseline characteristics of note:

85% of patients had intermediate-risk and 15% had poor-risk cytogenetics

79% achieved CR and 21% achieved CRi after induction therapy

78% received at least one cycle of consolidation therapy

43% of patients had MRD-positive disease

Patients were randomized to receive oral azacitidine 200 mg daily on days 1 to 14 of a repeat 28-day cycle (n = 278) or matching placebo (n = 274). Treatment was continued indefinitely until blast count was more than 15% or patients experienced unacceptable toxicity or went on to transplant.

At a median follow up of over 41.2 months (3 years, 5 months), median OS was significantly longer for patients receiving oral azacitidine at 24.7 months vs 14.8 months for placebo (P < .0009; hazard ratio [HR], 0.69).

Relapse-free survival was also significantly prolonged, to 10.2 months for patients on oral azacitidine vs 4.8 months for placebo (HR, 0.65; P < .0001).

Patients on oral azacitidine reported more grade 1 and 2 gastrointestinal (GI) adverse events, such as nausea (65% vs 24% on placebo), vomiting (60% vs 10%) and diarrhea (50% vs 22%), and also had more cytopenia. The most common grade 3 or 4 adverse events were neutropenia (41% with oral azacitidine vs 24% on placebo), thrombocytopenia (23% vs 22%), and anemia (14% vs 13%).

Although Erba supported the use of oral azacitidine as maintenance therapy, he pointed out that it was hard to convince patients, especially older ones, to continue on maintenance therapy indefinitely. "The toxicities of continuing on a drug indefinitely are real issues," he said, explaining that most elderly patients cannot cope with even grade 1 or 2 nausea, diarrhea, and vomiting over the long term.

But he noted that regardless of the higher incidence of some adverse events with oral azacitidine, the health-related quality-of-life of patients on oral azacitidine was similar to those on placebo.

Both experts said that longer-term follow-up is needed.

"We need a longer follow-up to see how the curves plateau," Erba said. He would also like to see a comparative analysis of the data in patients who are minimal residual disease (MRD)-negative vs those who are MRD-positive.

"The final results of this study, including the impact of measurable residual disease on outcome in this setting, will potentially have practice-changing implications," said Mascarenhas.

At the press conference, Wei pointed out that based on the data from QUAZAR, oral azacitidine is likely to be evaluated in the front-line setting of AML. "The elderly make up about two thirds of all AML patients, and oral azacitidine will be a better option than 7 days per month for chemotherapy treatment in the clinic," he said. "Oral azacitidine in the future may also be the backbone for other combinations."

The study was funded by Celgene.

Wei receives honoraria from AbbVie, Macrogenics, Pfizer, Astellas, Janssen, Servier, Celgene, Amgen, AstraZeneca, Novartis, and Genentech; is on the Board of Directors or serves on the advisory committees for AbbVie, Macrogenics, Pfizer, Astellas, Servier, Celgene, Amgen, Novartis, and Genentech; and receives research funding from AbbVie, Servier, Celgene, Amgen, AstraZeneca, and Novartis. As a former employee of the Walter and Eliza Hall Institute, Wei receives a fraction of its royalty stream related to venetoclax.

A partial list of Erba's conflict of interest includes consulting with Agios, Novartis, Daiichi Sankyo, MacroGenics, Jazz Pharmaceuticals, Seattle Genetics, GlycoMimetics, Amgen, Pfizer, Celgene, AbbVie, Covance, Immunogen, Astellas Pharma, Incyte; on the Speakers Bureau/lecture fees from Agios, Novartis, MacroGenics, Jazz Pharmaceuticals, Celgene; receiving research funding from Novartis, Daiichi Sankyo, MacroGenics, GlycoMimetics, Celgene; on the Data and Safety Monitoring board of GlycoMimetics; and Chair on independent review boards for several trials across several companies.

American Society of Hematology (ASH) 2019 Annual Meeting: Abstract LBA 3. Presented December 10, 2019.

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Oral Azacitidine: First Maintenance Therapy for AML - Medscape

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