Objectives: PNH clones, also aptly called “escape clones,” are evidence of acquired immune-mediated bone marrow failure and have a high prevalence in patients with aplastic anemia (AA). Several studies have reported contradictory results regarding the impact of PNH clones on AA patients with immunosuppression treatment, and PNH clones have not been confirmed as positive predictors of response in the AA guidelines of the British Society for Standards in Haematology. Methods: We performed a meta-analysis to address this issue by searching for articles in PubMed, EMBASE, The Coch-rane Library, Web of Science, and ClinicalTrials.gov, and for abstracts from the annual meetings of the American Society of Hematology and the European Hematology Association. We included 1,236 participants from 11 cohort-controlled studies. Our primary outcome was the 6-month hematologic response with a secondary outcome of the mortality rate within 3 months. Results: A better response rate was observed in the PNH+ group than in the PNH– group (odds ratio [OR] 2.85; 95% confidence interval [CI] 2.17–3.75; p < 0.00001), and further subgroup analysis strengthened the outcome, with minor heterogeneity in non-Asian countries. In contrast, the early mortality was not significantly different between the PNH+ and PNH– groups (OR 0.54; 95% CI 0.26–1.10; p = 0.09). Conclusions: The meta-analysis suggested an evidence-based role for PNH clones in predicting a better response in AA patients with immunosuppression.

1.
Young
NS
.
Aplastic Anemia
.
N Engl J Med
.
2018
Oct
;
379
(
17
):
1643
56
.
[PubMed]
0028-4793
2.
Mufti
GJ
,
Marsh
JC
.
Somatic mutations in aplastic anemia
.
Hematol Oncol Clin North Am
.
2018
Aug
;
32
(
4
):
595
607
.
[PubMed]
0889-8588
3.
Killick
SB
,
Bown
N
,
Cavenagh
J
,
Dokal
I
,
Foukaneli
T
,
Hill
A
, et al;
British Society for Standards in Haematology
.
Guidelines for the diagnosis and management of adult aplastic anaemia
.
Br J Haematol
.
2016
Jan
;
172
(
2
):
187
207
.
[PubMed]
0007-1048
4.
Bacigalupo
A
.
How I treat acquired aplastic anemia
.
Blood
.
2017
Mar
;
129
(
11
):
1428
36
.
[PubMed]
0006-4971
5.
Vallejo
C
,
Montesinos
P
,
Polo
M
,
Cuevas
B
,
Morado
M
,
Rosell
A
, et al;
Bone Marrow Failure Spanish Study Group (Pethema-GETH)
.
Rabbit antithymocyte globulin versus horse antithymocyte globulin for treatment of acquired aplastic anemia: a retrospective analysis
.
Ann Hematol
.
2015
Jun
;
94
(
6
):
947
54
.
[PubMed]
0939-5555
6.
Afable
MG
 2nd
,
Shaik
M
,
Sugimoto
Y
,
Elson
P
,
Clemente
M
,
Makishima
H
, et al
Efficacy of rabbit anti-thymocyte globulin in severe aplastic anemia
.
Haematologica
.
2011
Sep
;
96
(
9
):
1269
75
.
[PubMed]
0390-6078
7.
Kojima
S
,
Hibi
S
,
Kosaka
Y
,
Yamamoto
M
,
Tsuchida
M
,
Mugishima
H
, et al
Immunosuppressive therapy using antithymocyte globulin, cyclosporine, and danazol with or without human granulocyte colony-stimulating factor in children with acquired aplastic anemia
.
Blood
.
2000
Sep
;
96
(
6
):
2049
54
.
[PubMed]
0006-4971
8.
Führer
M
,
Burdach
S
,
Ebell
W
,
Gadner
H
,
Haas
R
,
Harbott
J
, et al;
German/Austrian Pediatric Aplastic Anemia Working Group
.
Relapse and clonal disease in children with aplastic anemia (AA) after immunosuppressive therapy (IST): the SAA 94 experience
.
Klin Padiatr
.
1998
Jul-Aug
;
210
(
4
):
173
9
.
[PubMed]
0300-8630
9.
Rosenfeld
SJ
,
Kimball
J
,
Vining
D
,
Young
NS
.
Intensive immunosuppression with antithymocyte globulin and cyclosporine as treatment for severe acquired aplastic anemia
.
Blood
.
1995
Jun
;
85
(
11
):
3058
65
.
[PubMed]
0006-4971
10.
Frickhofen
N
,
Kaltwasser
JP
,
Schrezenmeier
H
,
Raghavachar
A
,
Vogt
HG
,
Herrmann
F
, et al;
The German Aplastic Anemia Study Group
.
Treatment of aplastic anemia with antilymphocyte globulin and methylprednisolone with or without cyclosporine
.
N Engl J Med
.
1991
May
;
324
(
19
):
1297
304
.
[PubMed]
0028-4793
11.
Scheinberg
P
,
Wu
CO
,
Nunez
O
,
Young
NS
.
Predicting response to immunosuppressive therapy and survival in severe aplastic anaemia
.
Br J Haematol
.
2009
Jan
;
144
(
2
):
206
16
.
[PubMed]
0007-1048
12.
Maciejewski
JP
,
Risitano
A
,
Sloand
EM
,
Nunez
O
,
Young
NS
.
Distinct clinical outcomes for cytogenetic abnormalities evolving from aplastic anemia
.
Blood
.
2002
May
;
99
(
9
):
3129
35
.
[PubMed]
0006-4971
13.
Holbro
A
,
Jotterand
M
,
Passweg
JR
,
Buser
A
,
Tichelli
A
,
Rovó
A
.
Comment to “Favorable outcome of patients who have 13q deletion: a suggestion for revision of the WHO ‘MDS-U’ designation” Haematologica. 2012;97(12):1845-9
.
Haematologica
.
2013
Apr
;
98
(
4
):
e46
7
.
[PubMed]
0390-6078
14.
Yoshizato
T
,
Dumitriu
B
,
Hosokawa
K
,
Makishima
H
,
Yoshida
K
,
Townsley
D
, et al
Somatic mutations and clonal hematopoiesis in aplastic anemia
.
N Engl J Med
.
2015
Jul
;
373
(
1
):
35
47
.
[PubMed]
0028-4793
15.
Sugimori
C
,
Chuhjo
T
,
Feng
X
,
Yamazaki
H
,
Takami
A
,
Teramura
M
, et al
Minor population of CD55-CD59- blood cells predicts response to immunosuppressive therapy and prognosis in patients with aplastic anemia
.
Blood
.
2006
Feb
;
107
(
4
):
1308
14
.
[PubMed]
0006-4971
16.
Nevill
E
,
Dalal
B
,
Narayanan
S
,
Donna
H
,
Power
M
,
Sanford
D
, et al
The presence of a PNH clone influences the kinetics of response to immunosuppressive therapy (IST) in aplastic anemia (AA) patients. EHA Library. Jun 11,
2016
; 133521
17.
Rahman
K
,
Mittal
N
,
Gupta
R
,
Kumar
S
,
Gupta
T
,
Gupta
A
, et al
Clinicopathological profile of paroxysmal nocturnal haemoglobinuria clone-positive aplastic anaemia paediatric patients-A single centre study from North India
.
Int J Lab Hematol
.
2018
Jun
;
40
(
5
):
604
10
.
[PubMed]
1751-5521
18.
Gurion
R
,
Gafter-Gvili
A
,
Paul
M
,
Vidal
L
,
Ben-Bassat
I
,
Yeshurun
M
, et al
Hematopoietic growth factors in aplastic anemia patients treated with immunosuppressive therapy-systematic review and meta-analysis
.
Haematologica
.
2009
May
;
94
(
5
):
712
9
.
[PubMed]
0390-6078
19.
Ding
SX
,
Chen
T
,
Wang
T
,
Liu
CY
,
Lu
WL
,
Fu
R
.
The risk of clonal evolution of granulocyte colony-stimulating factor for acquired aplastic anemia: a systematic review and meta-analysis
.
Acta Haematol
.
2018
;
140
(
3
):
141
5
.
[PubMed]
0001-5792
20.
Liu
S
,
Li
Q
,
Zhang
Y
,
Li
Q
,
Ye
B
,
Wu
D
, et al
Association of human leukocyte antigen DRB1*15 and DRB1*15:01 polymorphisms with response to immunosuppressive therapy in patients with aplastic anemia: a meta-analysis
.
PLoS One
.
2016
Sep
;
11
(
9
):
e0162382
.
[PubMed]
1932-6203
21.
Yang
N
,
Chen
J
,
Zhang
H
,
Dai
Z
,
Yao
H
,
Ma
X
, et al
Horse versus rabbit antithymocyte globulin in immunosuppressive therapy of treatment-naïve aplastic anemia: a systematic review and meta-analysis
.
Ann Hematol
.
2017
Dec
;
96
(
12
):
2031
43
.
[PubMed]
0939-5555
22.
Hayakawa
J
,
Kanda
J
,
Akahoshi
Y
,
Harada
N
,
Kameda
K
,
Ugai
T
, et al
Meta-analysis of treatment with rabbit and horse antithymocyte globulin for aplastic anemia
.
Int J Hematol
.
2017
May
;
105
(
5
):
578
86
.
[PubMed]
0925-5710
23.
Hong
Y
,
Li
X
,
Wan
B
,
Li
N
,
Chen
Y
.
Efficacy and safety of eltrombopag for aplastic anemia: a systematic review and meta-analysis
.
Clin Drug Investig
.
2019
Feb
;
39
(
2
):
141
56
.
[PubMed]
1173-2563
24.
Wells GA, Shea B, O’Connell D, Peterson J, Welch V, Losos M, Tugwell P. [Internet] The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. 2019. Available from: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp.
25.
Kulagin
A
,
Lisukov
I
,
Ivanova
M
,
Golubovskaya
I
,
Kruchkova
I
,
Bondarenko
S
, et al
Prognostic value of paroxysmal nocturnal haemoglobinuria clone presence in aplastic anaemia patients treated with combined immunosuppression: results of two-centre prospective study
.
Br J Haematol
.
2014
Feb
;
164
(
4
):
546
54
.
[PubMed]
0007-1048
26.
Dunn
DE
,
Tanawattanacharoen
P
,
Boccuni
P
,
Nagakura
S
,
Green
SW
,
Kirby
MR
, et al
Paroxysmal nocturnal hemoglobinuria cells in patients with bone marrow failure syndromes
.
Ann Intern Med
.
1999
Sep
;
131
(
6
):
401
8
.
[PubMed]
0003-4819
27.
Narita
A
,
Muramatsu
H
,
Sekiya
Y
,
Okuno
Y
,
Sakaguchi
H
,
Nishio
N
, et al;
Japan Childhood Aplastic Anemia Study Group
.
Paroxysmal nocturnal hemoglobinuria and telomere length predicts response to immunosuppressive therapy in pediatric aplastic anemia
.
Haematologica
.
2015
Dec
;
100
(
12
):
1546
52
.
[PubMed]
0390-6078
28.
Timeus
F
,
Crescenzio
N
,
Lorenzati
A
,
Doria
A
,
Foglia
L
,
Pagliano
S
, et al
Paroxysmal nocturnal haemoglobinuria clones in children with acquired aplastic anaemia: a prospective single centre study
.
Br J Haematol
.
2010
Aug
;
150
(
4
):
483
5
.
[PubMed]
0007-1048
29.
Tutelman
PR
,
Aubert
G
,
Milner
RA
,
Dalal
BI
,
Schultz
KR
,
Deyell
RJ
.
Paroxysmal nocturnal haemoglobinuria phenotype cells and leucocyte subset telomere length in childhood acquired aplastic anaemia
.
Br J Haematol
.
2014
Mar
;
164
(
5
):
717
21
.
[PubMed]
0007-1048
30.
Piaggio
G
,
Podestà
M
,
Pitto
A
,
Sessarego
M
,
Figari
O
,
Fugazza
G
, et al
Coexistence of normal and clonal haemopoiesis in aplastic anaemia patients treated with immunosuppressive therapy
.
Br J Haematol
.
1999
Dec
;
107
(
3
):
505
11
.
[PubMed]
0007-1048
31.
Yoshida
N
,
Yagasaki
H
,
Takahashi
Y
,
Yamamoto
T
,
Liang
J
,
Wang
Y
, et al
Clinical impact of HLA-DR15, a minor population of paroxysmal nocturnal haemoglobinuria-type cells, and an aplastic anaemia-associated autoantibody in children with acquired aplastic anaemia
.
Br J Haematol
.
2008
Jul
;
142
(
3
):
427
35
.
[PubMed]
0007-1048
32.
Fattizzo
B
,
Alan
D
,
Robin
M
,
Shireen
K
,
Dario
C
,
Deborah
Y
, et al
Prognostic and predictive impact of small PNH clones in a large cohort of patients with myelodysplastic syndromes and aplastic anemia: a single-center experience
.
Blood
.
2018
;
132
Suppl 1
:
3870
. 0006-4971
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.