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NEW ORLEANS -- Patients with relapsed or refractory acute myeloid leukemia (AML) achieved similar outcomes with allogeneic hematopoietic stem-cell transplant (allo-HCT) whether they went to transplant as soon as possible or underwent intensive salvage chemotherapy first, the randomized ASAP trial suggested.

At day 56 post-transplant, complete remission (CR) rates were a similar 84.1% for patients who went directly to transplant -- with most receiving just watchful waiting beforehand -- as compared with 81.3% in control-arm patients who first received salvage chemotherapy, according to a per-protocol analysis reported by Johannes Schetelig, MD, of the University of Dresden in Germany.

"We missed statistical significance. However, given the results of this trial, the probability that the true success rate in the experimental arm is below the non-inferiority margin is only 4.7%," Schetelig said during a press briefing at the American Society of Hematology annual meeting.

Patients who went directly to transplant could also receive low-dose cytarabine or single doses of mitoxantrone as clinically needed before conditioning therapy (disease-control arm), while the control arm received standard high-intensity chemotherapy prior to conditioning therapy.

Leukemia-free survival at 1 year among the patients who achieved the primary endpoint was no different between arms (about 70% in each group), Schetelig reported. In the intent-to-treat population, overall survival from randomization was not significantly different between the disease-control and intensive salvage groups, both at 1 and 3 years:

• 1 year: 69% vs 72%, respectively
• 3 years: 51% vs 54%

"Patients with poor response after first induction chemotherapy or first relapse of AML do not benefit from salvage chemotherapy with high-dose cytarabine plus anthracycline prior to transplantation," Schetelig concluded. "Watchful waiting and sequential conditioning prior to allogeneic transplantation results in comparable CR rates and overall survival, and may be the preferred option whenever the stem-cell donor is readily available."

Furthermore, he said, patients who went straight to transplant spent less time in the hospital and also experienced fewer adverse events (AEs).

The study "completely changes how we've traditionally thought about acute myeloid leukemia," said press briefing moderator Mikkael Sekeres, MD, of the Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine. "When we have a patient who's relapsed or has refractory AML, that person is in a very difficult situation -- the mortality among those sorts of patients is incredibly high."

"Traditionally, we've given them really high doses of chemotherapy to try to reduce the tumor burden -- at least that's been the theory -- to then get them successfully to a transplant," he explained. "This completely upends that if these results hold."

Average time in hospital leading up to transplant was far shorter in the disease-control arm, where a full 76% of patients underwent watchful waiting (19 vs 42 days, P<0.001), and grade ≥3 AEs between randomization and conditioning therapy were far less frequent in patients heading to transplant as soon as possible (23% vs 64%, P<0.001).

"We no longer have to hospitalize these patients and give them very aggressive chemotherapy," said Sekeres. "We don't introduce all the morbidity from giving them very high-dose chemotherapy, which can actually prevent a transplant from happening if they get sick enough, and we can get them to a transplant quicker."

Median time to transplant was 4 weeks in the disease-control arm and by 16 weeks, 97% had undergone allo-HCT. In the control arm, median time to transplant was 8 weeks, with 93% undergoing allo-HCT by week 17. Post-transplant discharge from hospital by day 28 was similar between arms: 75% in the study arm and 73% in the control arm.

Schetelig argued that "the benefit of any treatment aiming at better results after allogeneic transplantation by inducing a CR prior to transplantation should be demonstrated in prospective clinical trials."

Asked to reconcile past studies suggesting benefit of high-intensity chemotherapy before transplant, Schetelig noted that most were retrospective and that most often, residual disease at the time of transplant reflects disease biology rather than a need to induce CR before transplant.

He also cautioned that the results do not indicate that chemotherapy is unnecessary before transplant. "Sequential conditioning regimens contain chemotherapy -- AML-type chemotherapy -- it is important to debulk," he said. "The next step, and the next series of trials, is how much dose-intensity do we need for active disease?"

Study Details

The ASAP trial was conducted by the Study Alliance Leukemia and the German Cooperative Transplant study group. Overall, 281 patients in Germany with non-favorable-risk AML were randomized to either the disease control or intensive salvage therapy.

Disease-control consisted of watchful waiting (recommended) or low-dose cytarabine with or without single doses of mitoxantrone as necessary, followed by sequential conditioning therapy and allo-HCT. Intensive salvage therapy consisted of high-dose cytarabine twice daily on days 1-3 plus mitoxantrone on days 3-5, followed by conditioning therapy and transplant.

Schetelig noted that half of the patients achieved a CR with intensive chemotherapy, but highlighted that most patients in the control group proceeded to transplant whether or not they achieved a remission.

To be eligible for the trial, patients needed to be in poor response after first induction chemotherapy (two-thirds of patients) or in first untreated relapse, be fit enough for salvage chemotherapy and transplant, and have a compatible donor.

Median age was 61, more than half were men, and 88% or more had an Eastern Cooperative Oncology Group performance status of 0-1. Three-fourths had de novo AML.

Mortality at 28 days from randomization occurred in 3.6% of patients in the investigational arm and 1.5% of those in the control arm. In-hospital death prior to day 56 occurred in 2.2% and 0.8%, respectively.

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