Intensive salvage therapy with the goal of achieving complete remission prior to allogeneic hematopoietic cell transplantation (alloHCT) may not be necessary in some patients with relapsed or refractory acute myeloid leukemia (AML), according to the results of the phase III ASAP trial presented at the 2022 American Society of Hematology (ASH) Annual Meeting and Exposition.1 In this study, watchful waiting followed by sequential conditioning prior to alloHCT achieved similar overall survival and leukemia-free survival compared with intensive remission induction chemotherapy in patients with relapsed or refractory AML.
Transplantation is generally considered the only opportunity for cure in these patients, but typically transplantation is offered only to patients who achieve complete remission. Thus, the findings of this study run counter to current practice. The results suggest that many patients may be able to omit the additional step of salvage chemotherapy and the attendant toxicity before undergoing transplantation.
“Our hypothesis was that salvage chemotherapy would not provide a net benefit for patients with high-risk AML. Our conclusions are that patients with a poor response after first induction chemotherapy or first relapse of AML do not benefit from salvage chemotherapy with high-dose cytarabine plus an anthracycline prior to transplantation,” said senior author Johannes Schetelig, MD, MSc, of the University Hospital TU Dresden, Germany. “Watchful waiting and sequential conditioning prior to allogeneic transplantation results in comparable complete response rates and overall survival and may be the preferred option whenever a stem cell donor is readily available.”
Johannes Schetelig, MD, MSc
Matthias Stelljes, MD
Dr. Schetelig called the 56-day results “astonishing” at a press conference during the meeting. The first author of the presentation was Matthias Stelljes, MD, of the University of Muenster, Germany.
Prior to having the results of the ASAP trial, it was unclear whether patients with a poor response to induction therapy and have relapsed or refractory disease would benefit from intensive salvage therapy. Sequential conditioning with high-dose cytarabine or melphalan followed by reduced-intensity conditioning and alloHCT has achieved long-term disease control for this population.
Study Details and Results
To test the hypothesis that intensive high-dose chemotherapy would not improve outcomes in relapsed or refractory AML, the noninferiority randomized ASAP trial enrolled 281 adults with unfavorable-risk AML following first induction therapy or first untreated relapse who were fit for intensive chemotherapy and alloHCT. About one-third had relapsed disease, and about two-thirds were not in complete remission following cycle 1 of induction therapy. Patients were required to have a matched sibling donor, a human leukocyte antigen (HLA)-compatible unrelated donor, or an ongoing donor search with two potential unrelated donors and an HLA-matching probability of at least 90%.
Study participants were randomly assigned 1:1 to the remission induction strategy arm or the disease control arm. Those in the remission induction strategy arm received salvage chemotherapy with cytarabine at 3 g/m2 (1 g/m2 for those older than age 60) twice daily on days 1 to 3 plus mitoxantrone at 10 mg/m2 on days 3 to 5 followed by alloHCT. In the disease control arm, watchful waiting was recommended, but a less intensive approach using low-dose cytarabine and single doses of mitoxantrone was allowed for disease control; this was followed by sequential conditioning and alloHCT.
The primary endpoint of the trial was treatment success defined as disease-free survival at day 56 following alloHCT. Secondary endpoints were overall survival from the time of randomization and leukemia-free survival from day 65.
The median age in both arms was 61 years. Less than half of patients were female, and most patients had an Eastern Cooperative Oncology Group performance status of 0 or 1.
In the disease control arm, the median time to transplantation was 4 weeks, and notably, 76% of patients were managed by watchful waiting only during that period. Sixteen weeks from randomization, 97% of the intention-to-treat population had undergone transplantation. In the remission induction strategy arm, the median time to transplantation was 8 weeks.
“I would like to highlight that most patients who had not achieved a complete response still proceeded to transplantation—72% after sequential conditioning,” said Dr. Schetelig.
The primary endpoint of disease-free survival at day 56 was met by 84.1% of the disease control arm (n = 138) and 81.3% of those in the remission induction strategy arm (n = 134), meeting the prespecified threshold for noninferiority.
“Although this just missed statistical significance, the probability that the true success rate in the investigative arm is below the noninferiority margin is only 4.7%,” said Dr. Schetelig. He acknowledged that disease-free survival at day 56 is not an accepted surrogate endpoint following transplantation. At a median follow-up of 37 months, no differences between the disease control and remission induction strategy arms were seen in leukemia-free survival from day 56 or overall survival from the time of randomization (P = .61).
[P]atients with poor response after first induction chemotherapy or first relapse of AML do not benefit from salvage chemotherapy with high-dose cytarabine plus an anthracycline [to achieve complete remission] prior to transplantation.— Johannes Schetelig, MD, MSc
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Patients who were in complete remission at day 56 had similar rates of leukemia-free survival at 1 year: 71.5% in the disease control arm and 69.9% in the remission induction strategy arm. The 3-year overall survival from randomization analyzed according to the intention-to-treat was about 70% in both arms at year 1 and about 50% in both arms at 3 years after randomization.
Safety
The incidence of grade 3 or higher adverse events was significantly lower in the disease control arm vs the remission induction strategy arm, at 23% and 64%, respectively (P < .001). Importantly, patients assigned to the disease control arm also spent less time in the hospital prior to transplantation compared with those in the remission induction strategy arm: median of 19 days vs 42 days (P < .001). The day 28 mortality rate from the time of randomization in the disease control vs remission induction strategy arms was 3.6% vs 1.5%, respectively.
In the disease control arm, four patients did not undergo transplant, compared with six patients in the remission induction strategy arm. Reasons for not proceeding to transplant in the disease control arm were death due to sepsis (n = 2), leukemia (n = 1), and patient refusal (n = 1). In the remission induction strategy arm, six patients did not go on to alloHCT; three patients died, one due to intracranial bleeding, one due to refractory AML, and one refused transplant. Time to discharge and in-hospital mortality did not differ between the two arms.
“A more general conclusion and forward-looking statement is that the benefit of any treatment aimed at better results after allogeneic transplantation by inducing a complete response prior to transplantation should be demonstrated in prospective clinical trials,” Dr. Schetelig said.
Comment on Study
“This study finds that patients with relapsed or refractory AML do not derive extra benefit from undergoing intensive chemotherapy ahead of a stem cell transplant, suggesting that many can proceed directly to a transplant,” said ASH Committee on Communications Chair Mikkael Sekeres, MD, Chief of Hematology and Professor of Medicine at Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine. “If true, this completely changes how we view relapsed/refractory AML.”
Mikkael Sekeres, MD
Dr. Sekeres continued: “The mortality is very high for these patients. Traditionally, we give them high-dose chemotherapy to get them to a transplant. This study completely upends that, indicating we no longer have to give then high-dose chemotherapy. All the morbidity from high-dose chemotherapy can actually prevent transplant from happening. Theoretically, we can get these patients to transplant more quickly. The debate will ensue about whether it is now okay to stop giving high-dose chemotherapy before transplant.”
DISCLOSURE: Dr. Schetelig has received honoraria from BeiGene, BMS, Janssen, AstraZeneca, and AbbVie; and is employed by DKMS. Dr. Stelljes has served as a consultant to MSD, Kite, Novartis, Amgen, and Pfizer; and has received honoraria or research funding from MSD, Jazz, Kite, Medac, Novartis, and Pfizer. Dr. Sekeres has served as a consultant or advisor to Celgene and Novartis.
REFERENCE
1. Stelljes M, Middeke JM, Bug G, et al: In patients with relapsed/refractory AML sequential conditioning and immediate allogeneic stem cell transplantation (allo-HCT) results in similar overall and leukemia-free survival compared to intensive remission induction chemotherapy followed by allo-HCT: Results from the randomized phase III ASAP trial. 2022 ASH Annual Meeting and Exhibition. Abstract 4. Presented December 11, 2022.
