Abstract

Graft-versus-host disease (GVHD) remains a major limitation of allogeneic hematopoietic stem cell transplantation. Only half of patients with severe acute GVHD respond to first-line treatment with corticosteroids and, for several decades, there was no optimal second-line treatment of patients with corticosteroid-refractory acute GVHD. Ruxolitinib was recently approved for the treatment of corticosteroid-refractory acute GVHD in adult and pediatric patients 12 years and older. Thus, it is important to define the patient population that would now be considered as refractory to ruxolitinib vs ruxolitinib dependent. Here, we propose to define ruxolitinib-refractory acute GVHD as disease that shows: (1) progression of GVHD compared with baseline after at least 5 to 10 days of treatment with ruxolitinib, based either on objective increase in stage/grade, or new organ involvement; (2) lack of improvement in GVHD (partial response or better) compared with baseline after ≥14 days of treatment with ruxolitinib; or (3) loss of response, defined as objective worsening of GVHD determined by increase in stage, grade, or new organ involvement at any time after initial improvement. GVHD manifestations that persist without improvement in patients who had a grade ≥3 treatment-emergent and ruxolitinib-attributed adverse event that did not resolve within 7 days of discontinuing ruxolitinib would serve as a clinical indication for additional treatment. In addition, absence of complete response or very good partial response at day 28 after ruxolitinib could be considered as an eligibility criterion.

REFERENCES

REFERENCES
1.
Niederwieser
D
,
Baldomero
H
,
Szer
J
, et al
.
Hematopoietic stem cell transplantation activity worldwide in 2012 and a SWOT analysis of the Worldwide Network for Blood and Marrow Transplantation Group including the global survey
.
Bone Marrow Transplant
.
2016
;
51
(
6
):
778
-
785
.
2.
Ruutu
T
,
Gratwohl
A
,
de Witte
T
, et al
.
Prophylaxis and treatment of GVHD: EBMT-ELN working group recommendations for a standardized practice [published correction appears in Bone Marrow Transplant. 2014;49:319]
.
Bone Marrow Transplant
.
2014
;
49
(
2
):
168
-
173
.
3.
Zeiser
R
,
Blazar
BR
.
Acute graft-versus-host disease: biologic process, prevention, and therapy
.
N Engl J Med
.
2017
;
377
(
22
):
2167
-
2179
.
4.
Martin
PJ
,
Rizzo
JD
,
Wingard
JR
, et al
.
First- and second-line systemic treatment of acute graft-versus-host disease: recommendations of the American Society of Blood and Marrow Transplantation
.
Biol Blood Marrow Transplant
.
2012
;
18
(
8
):
1150
-
1163
.
5.
Jagasia
M
,
Zeiser
R
,
Arbushites
M
,
Delaite
P
,
Gadbaw
B
,
Bubnoff
NV
.
Ruxolitinib for the treatment of patients with steroid-refractory GVHD: an introduction to the REACH trials
.
Immunotherapy
.
2018
;
10
(
5
):
391
-
402
.
6.
van Groningen
LF
,
Liefferink
AM
,
de Haan
AF
, et al
.
Combination therapy with inolimomab and etanercept for severe steroid-refractory acute graft-versus-host disease
.
Biol Blood Marrow Transplant
.
2016
;
22
(
1
):
179
-
182
.
7.
Arai
S
,
Margolis
J
,
Zahurak
M
,
Anders
V
,
Vogelsang
GB
.
Poor outcome in steroid-refractory graft-versus-host disease with antithymocyte globulin treatment
.
Biol Blood Marrow Transplant
.
2002
;
8
(
3
):
155
-
160
.
8.
Van Lint
MT
,
Milone
G
,
Leotta
S
, et al
.
Treatment of acute graft-versus-host disease with prednisolone: significant survival advantage for day +5 responders and no advantage for nonresponders receiving anti-thymocyte globulin
.
Blood
.
2006
;
107
(
10
):
4177
-
4181
.
9.
Westin
JR
,
Saliba
RM
,
De Lima
M
, et al
.
Steroid-refractory acute GVHD: predictors and outcomes
.
Adv Hematol
.
2011
;
2011
:
601953
.
10.
MacMillan
ML
,
Weisdorf
DJ
,
Wagner
JE
, et al
.
Response of 443 patients to steroids as primary therapy for acute graft-versus-host disease: comparison of grading systems
.
Biol Blood Marrow Transplant
.
2002
;
8
(
7
):
387
-
394
.
11.
Malard
F
,
Huang
XJ
,
Sim
JPY
.
Treatment and unmet needs in steroid-refractory acute graft-versus-host disease
.
Leukemia
.
2020
;
34
(
5
):
1229
-
1240
.
12.
Przepiorka
D
,
Luo
L
,
Subramaniam
S
, et al
.
FDA approval summary: ruxolitinib for treatment of steroid-refractory acute graft-versus-host disease
.
Oncologist
.
2020
;
25
(
2
):
e328
-
e334
.
13.
Martin
PJ
.
How I treat steroid-refractory acute graft-versus-host disease
.
Blood
.
2020
;
135
(
19
):
1630
-
1638
.
14.
US Food and Drug Administration
.
FDA approves ruxolitinib for acute graft-versus-host disease.
https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ruxolitinib-acute-graft-versus-host-disease. Accessed 27 May 2020.
15.
Jagasia
M
,
Perales
MA
,
Schroeder
MA
, et al
.
Ruxolitinib for the treatment of steroid-refractory acute GVHD (REACH1): a multicenter, open-label phase 2 trial
.
Blood
.
2020
;
135
(
20
):
1739
-
1749
.
16.
Zeiser
R
,
von Bubnoff
N
,
Butler
J
, et al;
REACH2 Trial Group
.
Ruxolitinib for Glucocorticoid-Refractory Acute Graft-versus-Host Disease
.
N Engl J Med
.
2020
;
382
(
19
):
1800
-
1810
.
17.
Zeiser
R
,
Burchert
A
,
Lengerke
C
, et al
.
Ruxolitinib in corticosteroid-refractory graft-versus-host disease after allogeneic stem cell transplantation: a multicenter survey
.
Leukemia
.
2015
;
29
(
10
):
2062
-
2068
.
18.
Liu
S
,
Zhao
J
,
Xu
L
, et al
.
Ruxolitinib is an effective salvage treatment for multidrug-resistant graft-versus-host disease after allogeneic hematopoietic transplantation
.
Blood
.
2019
;
134
(
suppl 1
):
5670
.
19.
Escamilla Gómez
V
,
García-Gutiérrez
V
,
López Corral
L
, et al;
Grupo Español de Trasplante Hematopoyético (GETH)
.
Ruxolitinib in refractory acute and chronic graft-versus-host disease: a multicenter survey study
.
Bone Marrow Transplant
.
2020
;
55
(
3
):
641
-
648
.
20.
Abedin
S
,
McKenna
E
,
Chhabra
S
, et al
.
Efficacy, toxicity, and infectious complications in ruxolitinib-treated patients with corticosteroid-refractory graft-versus-host disease after hematopoietic cell transplantation
.
Biol Blood Marrow Transplant
.
2019
;
25
(
8
):
1689
-
1694
.
21.
Martin
PJ
,
Bachier
CR
,
Klingemann
H-G
, et al
.
Endpoints for clinical trials testing treatment of acute graft-versus-host disease: a joint statement
.
Biol Blood Marrow Transplant
.
2009
;
15
(
7
):
777
-
784
.
22.
Inamoto
Y
,
Martin
PJ
,
Storer
BE
,
Mielcarek
M
,
Storb
RF
,
Carpenter
PA
.
Response endpoints and failure-free survival after initial treatment for acute graft-versus-host disease
.
Haematologica
.
2013
;
99
(
2
):
385
-
391
.
23.
Major-Monfried
H
,
Renteria
AS
,
Pawarode
A
, et al
.
MAGIC biomarkers predict long-term outcomes for steroid-resistant acute GVHD
.
Blood
.
2018
;
131
(
25
):
2846
-
2855
.
You do not currently have access to this content.