Abstract

Emapalumab is a fully human immunoglobulin G1 monoclonal antibody directed against interferon-γ (IFN-γ), which in November 2018 received the first global approval for the treatment of pediatric and adult patients with primary hemophagocytic lymphohistiocytosis (HLH) with refractory, recurrent, or progressive disease or intolerance to HLH therapy. This review will highlight the pathophysiology of primary HLH, the therapeutic rationale for use of IFN-γ–targeting therapy, and potential limitations to its broader use in the treatment of HLH.

REFERENCES

REFERENCES
1.
Allen
CE
,
McClain
KL
.
Pathophysiology and epidemiology of hemophagocytic lymphohistiocytosis
.
Hematology Am Soc Hematol Educ Program
.
2015
;
2015
:
177
-
182
.
2.
Stepp
SE
,
Dufourcq-Lagelouse
R
,
Le Deist
F
, et al
.
Perforin gene defects in familial hemophagocytic lymphohistiocytosis
.
Science
.
1999
;
286
(
5446
):
1957
-
1959
.
3.
Ishii
E
,
Ueda
I
,
Shirakawa
R
, et al
.
Genetic subtypes of familial hemophagocytic lymphohistiocytosis: correlations with clinical features and cytotoxic T lymphocyte/natural killer cell functions
.
Blood
.
2005
;
105
(
9
):
3442
-
3448
.
4.
Sieni
E
,
Cetica
V
,
Hackmann
Y
, et al
.
Familial hemophagocytic lymphohistiocytosis: when rare diseases shed light on immune system functioning
.
Front Immunol
.
2014
;
5
:
167
.
5.
Ramos-Casals
M
,
Brito-Zerón
P
,
López-Guillermo
A
,
Khamashta
MA
,
Bosch
X
.
Adult haemophagocytic syndrome
.
Lancet
.
2014
;
383
(
9927
):
1503
-
1516
.
6.
Emile
JF
,
Abla
O
,
Fraitag
S
, et al;
Histiocyte Society
.
Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages
.
Blood
.
2016
;
127
(
22
):
2672
-
2681
.
7.
Brisse
E
,
Wouters
CH
,
Matthys
P
.
Hemophagocytic lymphohistiocytosis (HLH): a heterogeneous spectrum of cytokine-driven immune disorders
.
Cytokine Growth Factor Rev
.
2015
;
26
(
3
):
263
-
280
.
8.
Henter
JI
,
Samuelsson-Horne
A
,
Aricò
M
, et al;
Histocyte Society
.
Treatment of hemophagocytic lymphohistiocytosis with HLH-94 immunochemotherapy and bone marrow transplantation
.
Blood
.
2002
;
100
(
7
):
2367
-
2373
.
9.
Trottestam
H
,
Horne
A
,
Aricò
M
, et al;
Histiocyte Society
.
Chemoimmunotherapy for hemophagocytic lymphohistiocytosis: long-term results of the HLH-94 treatment protocol
.
Blood
.
2011
;
118
(
17
):
4577
-
4584
.
10.
Al-Salama
ZT
.
Emapalumab: first global approval
.
Drugs
.
2019
;
79
(
1
):
99
-
103
.
11.
Humblet-Baron
S
,
Franckaert
D
,
Dooley
J
, et al
.
IFN-γ and CD25 drive distinct pathologic features during hemophagocytic lymphohistiocytosis
.
J Allergy Clin Immunol
.
2019
;
143
(
6
):
2215
-
2226.e7
.
12.
Binder
D
,
van den Broek
MF
,
Kägi
D
, et al
.
Aplastic anemia rescued by exhaustion of cytokine-secreting CD8+ T cells in persistent infection with lymphocytic choriomeningitis virus
.
J Exp Med
.
1998
;
187
(
11
):
1903
-
1920
.
13.
Jordan
MB
,
Hildeman
D
,
Kappler
J
,
Marrack
P
.
An animal model of hemophagocytic lymphohistiocytosis (HLH): CD8+ T cells and interferon gamma are essential for the disorder
.
Blood
.
2004
;
104
(
3
):
735
-
743
.
14.
Behrens
EM
,
Canna
SW
,
Slade
K
, et al
.
Repeated TLR9 stimulation results in macrophage activation syndrome-like disease in mice
.
J Clin Invest
.
2011
;
121
(
6
):
2264
-
2277
.
15.
Canna
SW
,
Wrobel
J
,
Chu
N
,
Kreiger
PA
,
Paessler
M
,
Behrens
EM
.
Interferon-γ mediates anemia but is dispensable for fulminant toll-like receptor 9-induced macrophage activation syndrome and hemophagocytosis in mice
.
Arthritis Rheum
.
2013
;
65
(
7
):
1764
-
1775
.
16.
Das
R
,
Guan
P
,
Sprague
L
, et al
.
Janus kinase inhibition lessens inflammation and ameliorates disease in murine models of hemophagocytic lymphohistiocytosis
.
Blood
.
2016
;
127
(
13
):
1666
-
1675
.
17.
Albeituni
S
,
Verbist
KC
,
Tedrick
PE
, et al
.
Mechanisms of action of ruxolitinib in murine models of hemophagocytic lymphohistiocytosis
.
Blood
.
2019
;
134
(
2
):
147
-
159
.
18.
Zandvakili
I
,
Conboy
CB
,
Ayed
AO
,
Cathcart-Rake
EJ
,
Tefferi
A
.
Ruxolitinib as first-line treatment in secondary hemophagocytic lymphohistiocytosis: a second experience
.
Am J Hematol
.
2018
;
93
(
5
):
E123
-
E125
.
19.
Slostad
J
,
Hoversten
P
,
Haddox
CL
,
Cisak
K
,
Paludo
J
,
Tefferi
A
.
Ruxolitinib as first-line treatment in secondary hemophagocytic lymphohistiocytosis: a single patient experience
.
Am J Hematol
.
2018
;
93
(
2
):
E47
-
E49
.
20.
Sin
JH
,
Zangardi
ML
.
Ruxolitinib for secondary hemophagocytic lymphohistiocytosis: first case report
.
Hematol Oncol Stem Cell Ther
.
2019
;
12
(
3
):
166
-
170
.
21.
Broglie
L
,
Pommert
L
,
Rao
S
, et al
.
Ruxolitinib for treatment of refractory hemophagocytic lymphohistiocytosis
.
Blood Adv
.
2017
;
1
(
19
):
1533
-
1536
.
22.
Locatelli
F
,
Jordan
MB
,
Allen
CE
, et al
.
Safety and efficacy of emapalumab in pediatric patients with primary hemophagocytic lymphohistiocytosis [abstract]
.
Blood
.
2018
;
132
(
suppl 1
):
LBA
-
6
.
23.
Kaplon
H
,
Reichert
JM
.
Antibodies to watch in 2019
.
MAbs
.
2019
;
11
(
2
):
219
-
238
.
24.
US Food and Drug Administration
. GAMIFANT (emapalumab-lzsg) injection. http://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761107lbl.pdf. Accessed 24 July 2019.
You do not currently have access to this content.