S1612 MOLECULAR MRD STATUS AND OUTCOME AFTER TRANSPLANTATION IN NPM1 MUTATED AML: RESULTS FROM THE UK NCRI AML17 STUDY
Authors: Dillon R. , Hills R. , Freeman S. , Potter N. , Jovanovic J. , Kanda A. , Runglall M. , Foot N. , Valganon M. , Raj K. , Khwaja A. , Cavenagh J. , Spearing R. , Ommen H.B. , Overgaard U.M. , Burnett A. , Russell N. , Grimwade D. 
Published: June 2019

Background:

Relapse remains the primary cause of treatment failure for patients with acute myeloid leukaemia (AML) who undergo allogeneic stem cell transplantation (alloSCT) and carries a grave prognosis. Multiple studies have identified the presence of minimal residual disease (MRD) assessed by flow cytometry or next‐generation sequencing prior to 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.

Aims:

We aimed to correlate pre‐transplant molecular MRD status with outcome in patients with NPM1 mutant AML to identify clinically relevant MRD thresholds, evaluate interaction with established prognostic factors and examine the effect of transplant type.

Methods:

We analysed pre‐transplant blood and bone marrow samples by reverse‐transcription polymerase chain reaction (RT‐qPCR) in 107 patients with NPM1 mutant AML enrolled in the UK NCRI AML17 study for younger adults eligible for intensive chemotherapy.

Results:

After a median follow up of 4.9 years from transplant, estimated 5‐year overall survival (5y‐OS) was 65% for patients transplanted in 1st remission and 54% for those transplanted after a molecular or morphological relapse (p = 0.3). Evaluable pre‐SCT PB and BM samples were available for 103 and 78 patients.

In total, 57 (53%) patients were MRD negative prior to SCT; 5y‐OS was 76% vs 46% for patients who were MRD positive. A threshold of 200 copies/105 ABL in the PB and 1000 copies in the BM provided maximal discrimination. Patients with negative, low (positive below the defined thresholds) and high levels of MRD had 2y‐OS of 83%, 63% and 13% respectively (p < 0.0001).

Presence of a FLT3 ITD at diagnosis was associated with a poorer outcome only in patients with a low level of MRD (hazard ratio 7.14, p = 0.04, fig 1a). There was no impact in patients who were MRD negative or who had high levels of MRD. Peripheral blood MRD status after second induction cycle (PC2, previously identified as a powerful prognostic factor) was also associated with poor outcome in the MRD low group (5y OS 82% vs 45%, p = 0.033) but had no effect in patients who had negative or high levels of MRD. These variables retained prognostic power in multivariate analysis and combining these could divide patients into two groups with 2y OS of 10% and 81% (adjusted hazard ratio 7.70, p < 0.0001, figure 1b).

We investigated the effect of donor source, conditioning regimen and T‐depletion on outcome. In the MRD negative group, none of these factors correlated with outcome. In the MRD positive group, T‐depletion was significantly associated with inferior survival (34% vs 100% for patients who did not undergo T‐depleted transplant, p = 0.002). No effect of donor source or conditioning protocol was detected.

Summary/Conclusion:

In contrast to patients who are MRD positive by flow cytometry or NGS, patients who test positive for NPM1 mutant transcripts prior to alloSCT do not have a universally poor outcome. Adverse outcome is predicted in patients with high levels of MRD (above 200 copies / 105 ABL in the PB or 1000 copies in the BM). For patients with MRD positivity below these levels, FLT3 ITD and post‐induction PB status are strongly associated with poor outcome. We observed no effect of transplant conditioning regimen for any MRD group however use of T‐depletion was associated with adverse outcome in patients who were MRD positive. These findings may help inform peri‐transplant management and the design of future interventional studies.

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