CONFERENCE UPDATE: ASH 2022
Favorability of sequential conditioning over intensive remission induction chemotherapy prior to allo-HCT
In the 64th American Society of Hematology (ASH) Annual Meeting and Exposition 2022, Dr. Johannes Schetelig, on behalf of the Study Alliance Leukemia and the German Cooperative Transplant Study Group, presented his group’s study to prove their hypothesis that salvage chemotherapy before allogeneic hematopoietic cell transplantation (allo-HCT) would not provide a net benefit.1
Presently, intensive salvage chemotherapy courses result in the complete remission (CR) rates of 35%-50% in high/intermediate risk acute myeloid leukemia (AML).1 AML relapse and refraction are classified by increased clonal complexity and chemotherapy resistance.1 When compared with the standard of care, allo-HCT in aplasia after first chemotherapy induction is more effective for high-risk AML.1 Sequential conditioning regimens constructed for active AML patients, which combine the AML-type chemotherapy with lower intensity conditioning and transplantation within 2 weeks, may prevent recovery of more aggressive clones and potentially lead to a cure.1 Such effective sequential regimens in a series of trials in patients with active diseases prompted to question of the advantages of salvage chemotherapy before transplantation.1
The ASAP was a randomized phase 3 trial, focusing on a hypothesis that salvage chemotherapy before allo-HCT does not present a net benefit, whereby patients (n=276) were randomized 1:1 into standard remission induction (RIST) and disease control (DisC).1 Patients in the RIST arm received high dose cytarabine and mitoxantrone, and were subsequently referred for transplantation following remission assessment.1 Conditioning intensity was altered and adapted to the level of residual AML and the patient’s condition.1 Patients in the DisC arm were maintained with watching waiting, or given low-dose cytarabine, or single-dose mitoxantrone as clinically required, while being transferred to transplantation as soon as possible.1 All patients in this arm were scheduled for sequential conditioning.1 Two-thirds of patients had poor induction response and one-third with relapsed AML at baseline (p=0.8).1 In the DisC arm, the median time to transplantation was 4 weeks, and at 16-week, 97% of the intention-to-treat (ITT) population had transplantation, with most of them gaining a CR.1 In the RIST arm, the median time to transplantation was 8 weeks, with every second patient having a CR after salvage chemotherapy.1 However, most patients who did not receive a CR opted for transplantation (72%).1
The primary endpoint of disease-free survival (DFS) at day 56 post-transplantation were 84.1% and 81.3% in the DisC arm and the RIST arm (p=0.047), respectively.1 The type I error of the trial of 4.7% showed that the probability of the true success rate in the experimental arm was lower than the non-inferiority margin.1 However, there was no long-term significant difference between the 2 arms, in terms of overall survival (OS) and leukemia-free survival (LFS) from day 56, with 37 months of median follow-up post-randomization.1
According to the European LeukemiaNet (ELN) 2022 criteria, AML biology was the most important risk factor for failure at the primary endpoint.1 With respect to OS, age, female, performance status, and HCT comorbidity index (HCT-CI) were factors predictive of outcomes.1 Types of treatment approach were equally effective across the population, with none significant at the 10% OR, except patients ≤60 years benefiting more from a DisC regimen before transplantation.1
Adverse events (AEs) grade ≥3 were less common in the DisC arm, compared with the RIST arm (23% vs. 64%; p<0.001).1 In addition, HCT-CI in the DisC arm was better, with HCT-CI at HCT worse in 25%, as compared with the RIST arm with HCT-CI at HCT worse in 39%.1 Most noticeably, the number of days spent in the hospital before HCT was lower in the DisC arm (19 days vs. 42 days; p<0.001).1
In summary, there was no benefit in salvage chemotherapy with high-dose cytarabine and anthracycline to induce CR before allo-HCT in patients with the poor response following first induction therapy or relapsed AML.1 As such, watchful waiting and sequential conditioning before allo-HCT led to similar CR rates and OS with fewer grade ≥3 AEs and less time in hospital, and therefore might be favored when a stem cell donor is accessible.1 The consequences of morphological CR upon allo-HCT were less important than predicted, with the minimal disease burden at admission for HCT unpredictive of positive long-term outcomes after allo-HCT.1 Any long-term treatment goals through inducing a CR before transplantation should focus on prospective intention-to-transplant trials.1
