Molecular MRD status and outcome after transplantation in NPM1-mutated AML

Abstract

Relapse remains the most common cause of treatment failure for patients with acute myeloid leukemia (AML) who undergo allogeneic stem cell transplantation (alloSCT), and carries a grave prognosis. Multiple studies have identified the presence of measurable residual disease (MRD) assessed by flow cytometry before alloSCT as a strong predictor of relapse, but it is not clear how these findings apply to patients who test positive in molecular MRD assays, which have far greater sensitivity. We analyzed pretransplant blood and bone marrow samples by reverse-transcription polymerase chain reaction in 107 patients with NPM1-mutant AML enrolled in the UK National Cancer Research Institute AML17 study. After a median follow-up of 4.9 years, patients with negative, low (<200 copies per 105ABL in the peripheral blood and <1000 copies in the bone marrow aspirate), and high levels of MRD had an estimated 2-year overall survival (2y-OS) of 83%, 63%, and 13%, respectively (P < .0001). Focusing on patients with low-level MRD before alloSCT, those with FLT3 internal tandem duplications(ITDs) had significantly poorer outcome (hazard ratio [HR], 6.14; P = .01). Combining these variables was highly prognostic, dividing patients into 2 groups with 2y-OS of 17% and 82% (HR, 13.2; P < .0001). T-depletion was associated with significantly reduced survival both in the entire cohort (2y-OS, 56% vs 96%; HR, 3.24; P = .0005) and in MRD-positive patients (2y-OS, 34% vs 100%; HR, 3.78; P = .003), but there was no significant effect of either conditioning regimen or donor source on outcome. Registered at ISRCTN (http://www.isrctn.com/ISRCTN55675535).

Graphical abstract

Figure 1.

CONSORT diagram showing the number of patients in each part of the trial, therapy given before transplant, and outcomes in each group. CT, chemotherapy; MRD, measurable residual disease; NRM, nonrelapse mortality; REL, relapse; UNK, unknown cause of death.

Figure 2.

OS from date of transplant according to pretransplant molecular MRD status. Panels A to C show the difference in survival between patients with positive and negative MRD (A) overall, (B) in the peripheral blood, and (C) in the bone marrow. Panels D to F show the difference in survival between patients with negative, low, and high levels of MRD (D) in the peripheral blood using a cutoff at 200 copies per 10⁵ ABL, (E) in the bone marrow with level of more than 1000 copies, and (F) with either, defining high-level MRD. Percentages indicate estimated 2y-OS.

Figure 3.

Effect of FLT3-ITD on outcome according to pretransplant MRD status. (A) HR and 95% CIs for FLT3-ITD mutation in each group. (B-D) OS from transplant for patients with high (B), low (C), and negative (D) pretransplant MRD. Percentages indicate estimated 2y-OS.

Figure 4.

OS from transplant according to the risk group. The risk group was derived from FLT3-ITD status and pretransplant MRD level. Patients with high levels of MRD and those with low levels who had the FLT3-ITD mutation were allocated to the high-risk group. All other patients were allocated to the low-risk group. Percentages indicate estimated 2y-OS.

Figure 5.

Effect of transplant-related factors on OS. Panels A to C show the effect of transplant-related variables in the entire cohort; panels D to F show their effect in patients who were MRD-positive before transplantation. (A,D) Effect of donor source. (B,E) Effect of conditioning type. (C,F) Effect of T-cell depletion.