• The ruxolitinib response–based stratified therapy achieved CR in 73.1% of HLH patients, with a 12-month survival of 86.4%.

  • Ruxolitinib, as a first-line agent, had a rapid efficacy for pediatric HLH and led to sustained CR in 42.3% of patients with good tolerance.

Hemophagocytic lymphohistiocytosis (HLH) is a lethal disorder characterized by hyperinflammation. Recently, ruxolitinib (RUX), targeting key cytokines in HLH, has shown promise for HLH treatment. However, there is a lack of robust clinical trials evaluating its efficacy, especially its utility as a frontline therapy. In this study (www.chictr.org.cn, ChiCTR2000031702), we designed ruxolitinib as a first-line agent for pediatric HLH and stratified the treatment based on its early response. Fifty-two newly diagnosed patients were enrolled. The overall response rate (ORR) of ruxolitinib monotherapy (day 28) was 69.2% (36/52), with 42.3% (22/52) achieving sustained complete remission (CR). All responders achieved their first response to ruxolitinib within 3 days. The response to ruxolitinib was significantly associated with the underlying etiology at enrollment (P = .009). Epstein-Barr virus (EBV)-HLH patients were most sensitive to ruxolitinib, with an ORR of 87.5% (58.3% in CR). After ruxolitinib therapy, 57.7% (30/52) of the patients entered intensive therapy with additional chemotherapy. Among them, 53.3% (16/30) patients achieved CR, and 46.7% (14/30) patients dominated by chronic active EBV infection-associated HLH (CAEBV-HLH) developed refractory HLH by week 8. The median interval to additional treatment since the first ruxolitinib administration was 6 days (range, 3-25 days). Altogether, 73.1% (38/52) of the enrolled patients achieved CR after treatment overall. The 12-month overall survival (OS) for all patients was 86.4% (95% confidence interval [CI], 77.1% to 95.7%). Ruxolitinib had low toxicity and was well tolerated compared with intensive chemotherapy. Our study provides clinical evidence for ruxolitinib as a frontline agent for pediatric HLH. The efficacy was particularly exemplified with stratified regimens based on the early differential response to ruxolitinib. This study was registered in the Chinese Clinical Trials Registry Platform (http://www.chictr.org.cn/) as ChiCTR2000031702.

1.
Canna
SW
,
Marsh
RA
.
Pediatric hemophagocytic lymphohistiocytosis
.
Blood.
2020
;
135
(
16
):
1332
-
1343
.
2.
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
.
3.
Bergsten
E
,
Horne
A
,
Aricó
M
, et al
.
Confirmed efficacy of etoposide and dexamethasone in HLH treatment: long-term results of the cooperative HLH-2004 study
.
Blood.
2017
;
130
(
25
):
2728
-
2738
.
4.
Locatelli
F
,
Jordan
MB
,
Allen
C
, et al
.
Emapalumab in children with primary hemophagocytic lymphohistiocytosis
.
N Engl J Med.
2020
;
382
(
19
):
1811
-
1822
.
5.
Canna
SW
,
Girard
C
,
Malle
L
, et al
.
Life-threatening NLRC4-associated hyperinflammation successfully treated with IL-18 inhibition
.
J Allergy Clin Immunol.
2017
;
139
(
5
):
1698
-
1701
.
6.
Bami
S
,
Vagrecha
A
,
Soberman
D
, et al
.
The use of anakinra in the treatment of secondary hemophagocytic lymphohistiocytosis
.
Pediatr Blood Cancer.
2020
;
67
(
11
):
e28581
.
7.
Dufranc
E
,
Del Bello
A
,
Belliere
J
,
Kamar
N
,
Faguer
S
;
TAIDI (Toulouse Acquired Immune Deficiency and Infection) study group
.
IL6-R blocking with tocilizumab in critically ill patients with hemophagocytic syndrome
.
Crit Care.
2020
;
24
(
1
):
166
.
8.
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
.
9.
Maschalidi
S
,
Sepulveda
FE
,
Garrigue
A
,
Fischer
A
,
de Saint Basile
G
.
Therapeutic effect of JAK1/2 blockade on the manifestations of hemophagocytic lymphohistiocytosis in mice
.
Blood.
2016
;
128
(
1
):
60
-
71
.
10.
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
.
11.
Sin
JH
,
Zangardi
ML
.
Ruxolitinib for secondary hemophagocytic lymphohistiocytosis: first case report
.
Hematol Oncol Stem Cell Ther.
2019
;
12
(
3
):
166
-
170
.
12.
Broglie
L
,
Pommert
L
,
Rao
S
, et al
.
Ruxolitinib for treatment of refractory hemophagocytic lymphohistiocytosis
.
Blood Adv.
2017
;
1
(
19
):
1533
-
1536
.
13.
Zhao
Y
,
Shi
J
,
Li
X
, et al
.
Salvage therapy with dose-escalating ruxolitinib as a bridge to allogeneic stem cell transplantation for refractory hemophagocytic lymphohistiocytosis
.
Bone Marrow Transplant.
2020
;
55
(
4
):
824
-
826
.
14.
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
.
15.
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
.
16.
Wang
J
,
Zhang
R
,
Wu
X
, et al
.
Ruxolitinib-combined doxorubicin-etoposide-methylprednisolone regimen as a salvage therapy for refractory/relapsed haemophagocytic lymphohistiocytosis: a single-arm, multicentre, phase 2 trial
.
Br J Haematol
2021
;
193
(
4
):
761
-
768
.
17.
Boonstra
PS
,
Ahmed
A
,
Merrill
SA
,
Wilcox
RA
.
Ruxolitinib in adult patients with secondary hemophagocytic lymphohistiocytosis
.
Am J Hemtaol
2021
;
96
(
4
):
E103
-
E105
.
18.
Ahmed
A
,
Merrill
SA
,
Alsawah
F
, et al
.
Ruxolitinib in adult patients with secondary haemophagocytic lymphohistiocytosis: an open-label, single-centre, pilot trial
.
Lancet Haematol.
2019
;
6
(
12
):
e630
-
e637
.
19.
Zhang
Q
,
Wei
A
,
Ma
HH
, et al
.
A pilot study of ruxolitinib as a front-line therapy for 12 children with secondary hemophagocytic lymphohistiocytosis
.
Haematologica.
2021
;
106
(
7
):
1892
-
1901
.
20.
Keenan
C
,
Nichols
KE
,
Albeituni
S
.
Use of the JAK inhibitor ruxolitinib in the treatment of hemophagocytic lymphohistiocytosis
.
Front Immunol.
2021
;
12
:
614704
.
21.
Henter
JI
,
Horne
A
,
Aricó
M
, et al
.
HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis
.
Pediatr Blood Cancer.
2007
;
48
(
2
):
124
-
131
.
22.
Lévy
R
,
Fusaro
M
,
Guerin
F
, et al
.
Efficacy of ruxolitinib in subcutaneous panniculitis-like T-cell lymphoma and hemophagocytic lymphohistiocytosis
.
Blood Adv.
2020
;
4
(
7
):
1383
-
1387
.
23.
Goldsmith
SR
,
Saif Ur Rehman
S
,
Shirai
CL
,
Vij
K
,
DiPersio
JF
.
Resolution of secondary hemophagocytic lymphohistiocytosis after treatment with the JAK1/2 inhibitor ruxolitinib
.
Blood Adv.
2019
;
3
(
23
):
4131
-
4135
.
24.
Vouloumanou
EK
,
Rafailidis
PI
,
Falagas
ME
.
Current diagnosis and management of infectious mononucleosis
.
Curr Opin Hematol.
2012
;
19
(
1
):
14
-
20
.
25.
Marsh
RA
.
Epstein-Barr virus and hemophagocytic lymphohistiocytosis
.
Front Immunol.
2018
;
8
:
1902
.
26.
Sawada
A
,
Inoue
M
.
Hematopoietic stem cell transplantation for the treatment of Epstein-Barr virus-associated T- or NK-cell lymphoproliferative diseases and associated disorders
.
Front Pediatr.
2018
;
6
:
334
.
27.
Dunmire
SK
,
Verghese
PS
,
Balfour
HH
Jr
.
Primary Epstein-Barr virus infection
.
J Clin Virol.
2018
;
102
:
84
-
92
.
28.
Arai
A
.
Chronic active Epstein-Barr virus infection: the elucidation of the pathophysiology and the development of therapeutic methods
.
Microorganisms.
2021
;
9
(
1
):
180
.
29.
Chaturvedi
V
,
Lakes
N
,
Tran
M
,
Castillo
N
,
Jordan
MB
.
JAK inhibition for murine HLH requires complete blockade of IFN-γ signaling and is limited by toxicity of JAK2 inhibition
.
Blood.
2021
;
138
(
12
):
1034
-
1039
.
30.
Meyer
LK
,
Verbist
KC
,
Albeituni
S
, et al
.
JAK/STAT pathway inhibition sensitizes CD8 T cells to dexamethasone-induced apoptosis in hyperinflammation
.
Blood.
2020
;
136
(
6
):
657
-
668
.
31.
Huarte
E
,
Peel
MT
,
Verbist
K
, et al
.
Ruxolitinib, a JAK1/2 inhibitor, ameliorates cytokine storm in experimental models of hyperinflammation syndrome
.
Front Pharmacol.
2021
;
12
:
650295
.
32.
Loh
ML
,
Tasian
SK
,
Rabin
KR
, et al
.
A phase 1 dosing study of ruxolitinib in children with relapsed or refractory solid tumors, leukemias, or myeloproliferative neoplasms: a Children’s Oncology Group phase 1 consortium study (ADVL1011)
.
Pediatr Blood Cancer.
2015
;
62
(
10
):
1717
-
1724
.
33.
Niswander
LM
,
Loftus
JP
,
Lainey
É
, et al
.
Therapeutic potential of ruxolitinib and ponatinib in patients with EPOR-rearranged Philadelphia chromosome-like acute lymphoblastic leukemia
.
Haematologica.
2021
;
106
(
10
):
2763
-
2767
.
34.
Ding
YY
,
Stern
JW
,
Jubelirer
TF
, et al
.
Clinical efficacy of ruxolitinib and chemotherapy in a child with Philadelphia chromosome-like acute lymphoblastic leukemia with GOLGA5-JAK2 fusion and induction failure
.
Haematologica.
2018
;
103
(
9
):
e427
-
e431
.
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