Intensive remission induction chemotherapy prior to allogeneic haematopoietic cell transplantation does not confer survival advantage in R/R AML
The phase III ASAP trial is the first randomised controlled trial which questioned the benefit of intensive remission induction chemotherapy prior to allogeneic haematopoietic cell transplantation (alloHCT) for patients with relapsed or refractory acute myeloid leukaemia. Chemotherapy with high-dose cytarabine and mitoxantrone before alloHCT did not result in a higher overall success rate and did not confer a survival advantage. Watchful waiting followed by sequential conditioning and alloHCT resulted in comparable overall complete response rates and survival.
Current intensive salvage chemotherapy regimens lead to complete remission (CR) rates of 35-50% in high/intermediate risk acute myeloid leukaemia (AML). However, whether patients with relapsed or refractory (R/R) AML benefit from an attempt to induce CR with intensive chemotherapy prior to allogeneic haematopoietic cell transplantation (alloHCT) is unknown. Sequential conditioning within 12 days prior to alloHCT with high-dose cytarabine or melphalan followed by reduced intensity conditioning leads to good results as well. Therefore, researchers asked whether intensive remission induction chemotherapy prior to alloHCT really improves outcome compared to immediate alloHCT after sequential conditioning without attempt to induce a CR before transplantation.
Study design
Adult patients with poor responsive non-favourable AML after first induction therapy or AML relapse, eligible for intensive chemotherapy and alloHCT, with either a matched sibling donor, an HLA-compatible (≥9/10) unrelated donor (UD) or ongoing donor search with two potential UD with ≥90% HLA-matching probability were enrolled. Patients were randomised 1:1 to a remission induction strategy (RIST-arm) with 3 g/m2 cytarabine (1 g/m2 for patients >60 years) twice daily on days 1-3 plus 10 mg/m2 mitoxantrone on days 3-5 and subsequent alloHCT (remission induction strategy, RIST-arm) or to disease control (DISC-arm) prior to sequential conditioning and alloHCT. In the DISC-arm watchful waiting was recommended, but low-dose cytarabine (LDAC) and single doses of mitoxantrone were permitted for disease-control. The primary endpoint was treatment success, defined as complete remission at day 56 after alloHCT. Statistically, the goal was to show non-inferiority for the DISC-arm with a non-inferiority margin of 5% and a one-sided alpha of 2.5%. Major secondary endpoints were overall survival from randomisation and leukaemia-free survival from CR at day 56.
Results
In total, 276 patients were enrolled in the ITT population (N= 139 in the DISC-arm and N= 137 in the RIST-arm). Baseline patient characteristics were well balanced between the two study arms. Patients had a median age of 61 years (range 18-75). The bone marrow blasts at study inclusion was 30% in both arms, two thirds of patients entered the trial with poor induction response and one third had relapsed AML.
In the DISC-arm, the median time to transplantation was 4 weeks. Notably, 76% of patients were bridged by watchful waiting during this period. At 16 weeks, 97% of the intention-to-treat population were transplanted and the majority achieved a CR after transplantation. In the RIST-arm, median time to HCT was 8 weeks and every second patient achieved CR after salvage chemotherapy. However, most patients who had not achieved a CR still proceeded to transplantation. At 16 weeks, 93% had been transplanted. The primary endpoint of CR at day 56 after alloHCT was reached by 84.1% of patients in the DISC-arm and 81.3% of patients in the RIST-arm (test for non-inferiority, p= 0.047). Furthermore, leukaemia-free survival of patients who met the primary endpoint was not different for patients treated in the DISC- or RIST-arm (p= 0.61) and overall survival from randomisation in the ITT population was not different between arms (p= 0.47). AML biology is a strong risk factor for DFS at day 56 and overall survival. Finally, treatment effect was consistent across subgroups. However, patients below 60 years old seemed to benefit more from a disease control strategy prior to scheduled transplantation. The number of patients with adverse events (AEs) of grade ≥3 was significantly lower in the DISC-arm than in the RIST-arm (23% vs. 64%, p< 0.001). Most notably, before transplantation patients spent on average 23 days less in hospital in the DISC-arm (19 vs. 42 days, p< 0.001). Yet, time to discharge and in-hospital mortality after transplantation did not differ.
Conclusion
Patients with poor response after first induction therapy or relapsed AML do not benefit from salvage chemotherapy with high-dose cytarabine plus anthracycline administered for CR induction prior to alloHCT. Watchful waiting and sequential conditioning prior to alloHCT results in comparable CR rates and overall survival and may be the preferred option whenever a stem cell donor is readily available. Patients spent less time in hospital with disease control compared to remission induction and experienced fewer adverse events of grade ≥3.
Reference
Stelljes M, 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. Presented at ASH 2022; Abstract 4.
