Response: Still a need for more robust evidence that FLT3/ITD status should influence the decision to proceed to transplantation in AML patients

We welcome the contribution from Bornhäuser and colleagues on the impact of a FLT3/ITD in acute myeloid leukemia (AML) patients treated with different types of consolidation therapy in the AML 96 study of the DSIL. There is general agreement that the presence of a FLT3/ITD is a poor prognostic factor associated with a higher relapse rate, but the controversial issue is whether the demonstration of this poor prognosis is an indication for a transplantation.

In our published series of 970 non–acute promyelocytic leukemia AML patients entered into the UK MRC AML 10 or 12 trials who achieved complete remission,¹  we found that, for patients receiving standard chemotherapy consolidation, those who were FLT3/ITD positive had a significantly higher relapse rate than those who were FLT3/ITD negative (76% versus 53%, respectively; odds ratio [OR] = 2.41; 95% confidence interval [CI] = 1.85-3.13). In those who received an autograft, the relapse rate was lower, but the difference between those who had a FLT3/ITD and those who did not was of a similar magnitude to the chemotherapy recipients (56% versus 35%, respectively; OR = 2.39; CI = 1.24-4.63). In the allograft recipients, the relapse rate was lower still, and there was little difference between those who were FLT3/ITD positive and FLT3/ITD negative (31% versus 25%, respectively; OR = 1.31; CI = 0.56-3.06). This might suggest that allografting was a good idea but, crucially, the analysis of heterogeneity showed no significant difference in the impact of a FLT3/ITD between the 3 types of consolidation. The results in the patients receiving an allograft may be due to the small cohort size of 170 patients, of whom only 35 were FLT3/ITD positive, and we therefore advised a cautious interpretation of our data.

Bornhäuser et al report on 376 patients with intermediate-risk cytogenetics who achieved remission, of whom 132 subsequently had chemotherapy consolidation, 141 an autograft, and 103 an allograft. They found a significant impact of a FLT3/ITD in the chemotherapy consolidation group, in accord with our data. They also found an impact of a FLT3/ITD on the relapse rate in the allograft recipients but not the autografted patients, but as no tests of heterogeneity are provided it is not possible to comment on the significance of these differences. Furthermore, the findings in the autograft and allograft groups were the opposite of what we observed, again raising concerns about small numbers.

It is also worth noting that the presence of a FLT3/ITD predicts for early relapse (P = .03 for trend in our cohort). If patients in whom a transplantation is intended relapse before the procedure can be carried out and are then omitted from the transplantation series, this will decrease the difference between the FLT3/ITD-positive and -negative groups. If these early relapses are considered in the chemotherapy-only group, then the impact of the FLT3/ITD in chemotherapy recipients will be exaggerated.

A large meta-analysis might help resolve this important clinical issue, but will still not be a substitute for a well-powered randomized trial. We do not support the view of Bornhäuser et al that all patients with a FLT3/ITD “should be scheduled for an autologous or allogeneic SCT [stem-cell transplantation] within a controlled clinical study” unless by this they mean a randomized trial.