Haematology & Oncology News: Volume 9

Minimal residual disease a powerful prognostic factor in AML

BY PATRICE WENDLING

Frontline Medical News

From the New England

Journal of Medicine

he presence of minimal re-

sidual disease predicts relapse

in patients with NMP1-mutated

acute myeloid leukaemia and is su-

perior to currently used molecular

genetic markers in determining

whether these patients should be

considered for stem cell transplanta-

tion, a new study has found.

At 3 years, patients with mini-

mal residual disease (MRD) had a

significantly greater risk of relapse

than those with no MRD (82%

vs 30%; univariate hazard ratio,

4.80; P < 0.001) and a lower rate

of survival (24% vs 75%; univariate

HR, 4.38; P < 0.001), Adam Ivey

of King’s College London reported.

In an editorial that accompanied

the study Dr Michael J. Burke from

the Children’s Hospital of Wiscon-

sin in Milwaukee wrote, “Time will

tell, but this moment may prove to

be a pivotal one in the assessment

of minimal residual disease to assign

treatment in patients with AML”.

In adult AML, assessment of

MRD has taken a back seat to analy-

ses of cytogenetic and molecular le-

sions in determining a patient’s risk

and treatment strategy. Typically,

allogeneic stem cell transplantation

is used for patients with high-risk

features such as chromosome 3,

5, or 7 abnormalities or the FLT3-

internal tandem duplication (ITD)

mutation, while chemotherapy alone

is used for low-risk disease.

The role of transplantation is

unclear, however, for cytogeneti-

cally standard-risk patients, which

includes those with a mutation in

the gene encoding nucleophosmin

(NPM1).

To address this issue, the investi-

gators used a reverse-transcriptase

quantitative polymerase chain re-

action assay to evaluate 2569 bone

marrow and peripheral-blood sam-

ples from 346 patients with NPM1

mutations who had completed two

cycles of induction chemotherapy in

the UK National Cancer Research

Institute AML17 trial.

MRD, defined as persistence of

NPM1-mutated transcripts in pe-

ripheral blood, was present in 15%

of patients after the second chemo-

therapy cycle.

Patients with MRD were sig-

nificantly more likely than those

without MRD to have a high UK

Medical Research Council clinical

risk score and to carry the FLT3-ITD

mutation.

On univariate analysis, the risk of

relapse was significantly higher with

the presence of MRD in peripheral

blood, an increased white cell count,

and with the DNMT3A and FLT3-

ITD mutations.

Only the presence of MRD and an

elevated white cell count significantly

predicted survival, Mr Ivey reported.

“We could find no specific mo-

lecular subgroup consisting of 10

patients or more that had a rate of

survival less than 52%; in contrast,

the rate in the group with the pres-

ence of minimal residual disease was

24%,” he observed.

In multivariate analysis, the

presence of MRD was the only sig-

nificant prognostic factor for relapse

(HR, 5.09; P < 0.001) or death (HR,

4.84; P < 0.001).

The results were validated in an in-

dependent cohort of 91AML17 study

patients. It confirmed that MRD in

peripheral blood predicts worse out-

come at 2 years than the absence of

MRD, with a cumulative incidence of

relapse of 70% vs 31% (P = 0.001) and

overall survival rates of 40% vs 87%

(P = 0.001), reported the investiga-

tors, including senior author Professor

David Grimwade, also from King’s

College London.

The clinical implications of these

results “are substantive” because

NPM-1 mutated AML is the most

common subtype of AML and be-

cause of the uncertainty over the

best treatment strategy for patients

typically classified as standard risk,

editorialist Dr Burke observed.

“Now with the ability to reclassify

standard-risk or low-risk patients as

high-risk on the basis of the persis-

tent expression of mutant NPM1

transcripts, it may be possible that

stem-cell transplantation is a better

approach in patients who otherwise

would be treated with chemotherapy

alone and that transplantation may

be avoidable in high-risk patients

who have no evidence of minimal

residual disease,” he wrote. “Such

predictions will need to be tested

prospectively.”

The presence of MRD is also

known to be an important inde-

pendent prognostic factor in acute

lymphoblastic leukaemia, but since

AML has a greater molecular heter-

ogeneity, routine MRD assessment

has not been as quickly adopted in

AML, Dr Burke noted.

The Children’s Oncology Group,

however, recently adopted MRD

assessment by flow cytometry to

further stratify children with newly

diagnosed AML after first induction

therapy into low-risk or high-risk

groups.

The study was supported by grants

from Bloodwise and the National In-

stitute for Health Research. Mr Ivey

and Dr Burke reported having no

disclosures.

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Date of preparation 16 December 2015.

References: 1.

Furman RR

et al. N Engl J Med

2014;370:997–1007.

Sharman JP SE

et al.

Second Interim Analysis of a Phase 3 Study of Idelalisib (ZYDELIG ) Plus Rituximab (R) for Relapsed Chronic

Lymphocytic Leukemia (CLL): Efficacy Analysis in Patient Subpopulations with Del(17p) and Other Adverse Prognostic Factors. The American Society of Hematology (ASH) 56th Annual Meeting, 6–9

December 2014, San Francisco, CA, USA: Abstract 330.

Coutre SE

et al.

Second interim analysis of a phase 3 study evaluating idelalisib and rituximab for relapsed CLL.

J Clin Oncol

2014;32(Suppl):

Abstract 7012.

Gopal AK

et al. N Engl J Med

2014;370:1008–18

Salles G

et al.

Idelalisib efficacy and safety in follicular lymphoma patients from a phase 2 study.

J Clin Oncol

2015;33(Suppl):

Abstract 8529.

Zydelig Product Information, 16 December 2015.

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