MOLECULAR MRD STATUS AND OUTCOME AFTER TRANSPLANTATION IN NPM1 MUTATED AML: RESULTS FROM THE UK NCRI AML17 STUDY
Author(s): ,
Richard Dillon
Affiliations:
Department of Medical and Molecular Genetics,King's Collge,London,United Kingdom
,
Robert Hills
Affiliations:
Nuffield Department of Population Health,University of Oxford,Oxford,United Kingdom
,
Sylvie Freeman
Affiliations:
Clinical Immunology Service,University of Birmingham,Birmingham,United Kingdom
,
Nicola Potter
Affiliations:
Department of Medical and Molecular Genetics,King's College,London,United Kingdom
,
Jelena Jovanovic
Affiliations:
Department of Medical and Molecular Genetics,King's College,London,United Kingdom
,
Anju Kanda
Affiliations:
Department of Medical and Molecular Genetics,King's College,London,United Kingdom
,
Manohursingh Runglall
Affiliations:
Department of Medical and Molecular Genetics,King's College,London,United Kingdom
,
Nicola Foot
Affiliations:
Cancer Genetics Service,Viapath,London,United Kingdom
,
Mikel Valganon
Affiliations:
Cancer Genetics Service,Viapath,London,United Kingdom
,
Kavita Raj
Affiliations:
Department of Haematology,Guy's Hospital,London,United Kingdom
,
Asim Khwaja
Affiliations:
Department of Haematology,University College Hospital,London,United Kingdom
,
Jamie Cavenagh
Affiliations:
Department of Haematology,Barts and the London NHS Trust,London,United Kingdom
,
Ruth Spearing
Affiliations:
Haematology Department,Christchurch Hospital,Christchurch,New Zealand
,
Hans Beier Ommen
Affiliations:
Department of Blood Diseases,Aarhus University Hospital,Aarhus,Denmark
,
Ulrik Malthe Overgaard
Affiliations:
Hæmatologisk Afdeling,Rigshospitalet,Copenhagen,Denmark
,
Alan Burnett
Affiliations:
Blackwaterfoot,Isle of Arran,United Kingdom
,
Nigel Russell
Affiliations:
Department of Haematology,University of Nottingham,Nottingham,United Kingdom
David Grimwade
Affiliations:
Department of Medical and Molecular Genetics,King's College,London,United Kingdom
EHA Library. DILLON R. Jun 16, 2019; 267366; S1612
Richard DILLON
Richard DILLON
Contributions
×
Abstract

Abstract: S1612

Type: Oral Presentation

Presentation during EHA24: On Sunday, June 16, 2019 from 08:00 - 08:15

Location: Forum Hall

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.

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.

Session topic: 4. Acute myeloid leukemia - Clinical

Keyword(s): AML, MRD, Prognostic factor

By clicking “Accept Terms & all Cookies” or by continuing to browse, you agree to the storing of third-party cookies on your device to enhance your user experience and agree to the user terms and conditions of this learning management system (LMS).

Cookie Settings
Accept Terms & all Cookies