Paper Details

ABSTRACT

It is uncertain what the optimal consolidation is for fit older adults with acute myeloid leukemia (AML) who attain an MRD negative remission (MRD-) after induction. There is also currently a lack of data to determine the benefit from allogeneic transplant in CR1 (CR1-allo) in this group.  These questions were evaluated in  the NCRI AML18 trial for older patients (>60yrs) fit for intensive chemotherapy.

Methods

AML18 undertook a number of post induction randomisations to  optimize outcome of patients in remission (CR/CRi) following course 1 of daunorubicin (60mg/m2 x 3 and AraC (100mg/m2 bd sc x 10 days) (DA,3+10) +/- gemtuzumab ozogamicin (GO).  Median Follow-up was  70 months.

Between October 2015 and September 2018, patients in MRD- remission by flow cytometry after course 1 were directed to DA 3+8 as second induction followed by a course 3 randomisation comparing DA 2+5 with  intermediate dose AraC (1gm/m² od x 5 days, IDAC).  Primary endpoints were overall survival (OS), supportive care requirements and toxicity with a median follow-up of 64 months.

Patients who were in remission but MRD positive (MRD+, threshold >0.05% by flow cytometry)  or unknown could enter a course 2 randomisation for treatment intensification with either DA plus cladribine (DAC) or FLAG-Ida versus DA alone as previously reported. Patients could also enter a post course-1 randomisation to receive quizartinib (AC220) or not. Patients without favourable risk cytogenetics were recommended for CR1-allo based on health status and donor availability.

Results

Of patients in remission post course 1 (PC1), 497 were categorised as MRD- and  305 MRD+.  PC1 MRD- patients had numerically higher 5yr OS compared to  MRD+ patients (35% vs 30%, HR 0.86, 95%CI 0.72-1.02, P= 0.086.).  However, within the  MRD+  group,  those patients who received course 2 intensification as per MRD-directed randomisation (n=164) achieved a 5yr OS of 35%, equivalent  to the MRD- patients, versus 24% in the others (n=142).     

Following recovery from course 2 DA, 285 PC1 MRD- patients were randomised between course DA (n=143) and IDAC (n=142). Baseline characteristics and prior treatment were similar between the IDAC and DA arms and comparable to those PC1 MRD- patients not entering the randomisation. Cytogenetics were intermediate in 85%  and adverse in 9%; 26% had FLT3 mutations, 46%  NPM1. The median interval between trial entry and random assignment was 3 months (range, 2-7 months).  There was no significant difference in favour of IDAC versus DA with respect to 5yr OS (38% v 36%, P=0.766) or relapse-free-survival (26% v 29%, P=0.491).  This was also the case when survival was censored at transplant in the 78 (27%) patients who received a CR1 transplant (37% v 38%, P=0.834). Outcomes were not affected by any of the patients’ baseline characteristics or induction treatments although there was a trend favoring IDAC in FLT3mutated patients (P =0.08). Count recovery was equivalent between arms but usage of blood product and IV antibiotics was significantly higher with IDAC. IDAC was associated with increased liver toxicity but otherwise there was no difference in adverse events including cardiac.

Overall, of patients in remission PC1, CR1-allo was performed in 132(27%) PC1 MRD- and 113(37%) PC1 MRD+ patients In a time dependent (Mantel-Byar) analysis, CR1-allo was associated with a significant 5yr survival benefit in the MRD+ patients (HR 0.72, 95%CI 0.53-0.99, P =0.040).  Notably CR1-allo  provided no significant survival advantage for MRD- patients (HR 0.81, 95%CI 0.62-1.06, P =0.131).

Conclusion

 In this  large trial cohort of older adults undergoing intensive chemotherapy for AML, MRD-guided course 2 intensification resulted in MRD positive patients achieving equivalent outcomes to MRD negative patients. For MRD negative patients, IDAC instead of DA consolidation increased resource usage with no survival or toxicity benefit. Interestingly, post course 1 MRD status may stratify older adults who most benefit from CR1 allogeneic transplant as a significant survival advantage was only observed in MRD positive patients.  This suggests that some older adults with early MRD negativity  may be spared transplant and that post treatment MRD monitoring and maintenance can be considered instead.