Key Points

  • The benefit of GO in non-CBF AML patients with favorable or intermediate ELN 2017 risk is restricted to those with signaling mutations.

  • Higher CD33 expression levels on non-CBF AML blasts correlate with the presence of activating signaling mutations.

Abstract

Acute myeloid leukemia (AML) is a highly heterogeneous disease both in terms of genetic background and response to chemotherapy. Although molecular aberrations are routinely used to stratify AML patients into prognostic subgroups when receiving standard chemotherapy, the predictive value of the genetic background and co-occurring mutations remains to be assessed when using newly approved antileukemic drugs. In the present study, we retrospectively addressed the question of the predictive value of molecular events on the benefit of the addition of gemtuzumab ozogamicin (GO) to standard front-line chemotherapy. Using the more recent European LeukemiaNet (ELN) 2017 risk classification, we confirmed that the benefit of GO was restricted to the favorable (hazard ratio [HR], 0.54, 95% confidence interval [CI], 0.30-0.98) and intermediate (HR, 0.57; 95% CI, 0.33-1.00) risk categories, whereas it did not influence the outcome of patients within the adverse risk subgroup (HR, 0.93; 95% CI, 0.61-1.43). Interestingly, the benefit of GO was significant for patients with activating signaling mutations (HR, 0.43; 95% CI, 0.28-0.65), which correlated with higher CD33 expression levels. These results suggest that molecular aberrations could be critical for future differentially tailored treatments based on integrated genetic profiles that are able to predict the benefit of GO on outcome.

REFERENCES

REFERENCES
1.
Döhner
H
,
Estey
E
,
Grimwade
D
, et al
.
Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel
.
Blood
.
2017
;
129
(
4
):
424
-
447
.
2.
Meyer
SC
,
Levine
RL
.
Translational implications of somatic genomics in acute myeloid leukaemia
.
Lancet Oncol
.
2014
;
15
(
9
):
e382
-
e394
.
3.
Walasek
A
.
The new perspectives of targeted therapy in acute myeloid leukemia
.
Adv Clin Exp Med
.
2019
;
28
(
2
):
271
-
276
.
4.
Castaigne
S
,
Pautas
C
,
Terré
C
, et al;
Acute Leukemia French Association
.
Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study
.
Lancet
.
2012
;
379
(
9825
):
1508
-
1516
.
5.
Burnett
AK
,
Hills
RK
,
Milligan
D
, et al
.
Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial
.
J Clin Oncol
.
2011
;
29
(
4
):
369
-
377
.
6.
Burnett
AK
,
Russell
NH
,
Hills
RK
, et al
.
Addition of gemtuzumab ozogamicin to induction chemotherapy improves survival in older patients with acute myeloid leukemia
.
J Clin Oncol
.
2012
;
30
(
32
):
3924
-
3931
.
7.
Hills
RK
,
Castaigne
S
,
Appelbaum
FR
, et al
.
Addition of gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia: a meta-analysis of individual patient data from randomised controlled trials
.
Lancet Oncol
.
2014
;
15
(
9
):
986
-
996
.
8.
Renneville
A
,
Abdelali
RB
,
Chevret
S
, et al
.
Clinical impact of gene mutations and lesions detected by SNP-array karyotyping in acute myeloid leukemia patients in the context of gemtuzumab ozogamicin treatment: results of the ALFA-0701 trial
.
Oncotarget
.
2014
;
5
(
4
):
916
-
932
.
9.
Olombel
G
,
Guerin
E
,
Guy
J
, et al
.
The level of blast CD33 expression positively impacts the effect of gemtuzumab ozogamicin in patients with acute myeloid leukemia
.
Blood
.
2016
;
127
(
17
):
2157
-
2160
.
10.
Pollard
JA
,
Alonzo
TA
,
Loken
M
, et al
.
Correlation of CD33 expression level with disease characteristics and response to gemtuzumab ozogamicin containing chemotherapy in childhood AML
.
Blood
.
2012
;
119
(
16
):
3705
-
3711
.
11.
Ruminy
P
,
Marchand
V
,
Buchbinder
N
, et al
.
Multiplexed targeted sequencing of recurrent fusion genes in acute leukaemia
.
Leukemia
.
2016
;
30
(
3
):
757
-
760
.
12.
Döhner
H
,
Weisdorf
DJ
,
Bloomfield
CD
.
Acute myeloid leukemia
.
N Engl J Med
.
2015
;
373
(
12
):
1136
-
1152
.
13.
Itzykson
R
,
Duployez
N
,
Fasan
A
, et al
.
Clonal interference of signaling mutations worsens prognosis in core-binding factor acute myeloid leukemia
.
Blood
.
2018
;
132
(
2
):
187
-
196
.
14.
Paul
SP
,
Taylor
LS
,
Stansbury
EK
,
McVicar
DW
.
Myeloid specific human CD33 is an inhibitory receptor with differential ITIM function in recruiting the phosphatases SHP-1 and SHP-2
.
Blood
.
2000
;
96
(
2
):
483
-
490
.
15.
Vitale
C
,
Romagnani
C
,
Puccetti
A
, et al
.
Surface expression and function of p75/AIRM-1 or CD33 in acute myeloid leukemias: engagement of CD33 induces apoptosis of leukemic cells
.
Proc Natl Acad Sci USA
.
2001
;
98
(
10
):
5764
-
5769
.
16.
Lajaunias
F
,
Dayer
J-M
,
Chizzolini
C
.
Constitutive repressor activity of CD33 on human monocytes requires sialic acid recognition and phosphoinositide 3-kinase-mediated intracellular signaling
.
Eur J Immunol
.
2005
;
35
(
1
):
243
-
251
.
17.
Balaian
L
,
Zhong
RK
,
Ball
ED
.
The inhibitory effect of anti-CD33 monoclonal antibodies on AML cell growth correlates with Syk and/or ZAP-70 expression
.
Exp Hematol
.
2003
;
31
(
5
):
363
-
371
.
You do not currently have access to this content.