Abstract

HLA-haploidentical hematopoietic stem cell transplantation is now one of the most commonly employed alternative donor techniques, with most centers applying T-cell–replete strategies such as that developed by the Baltimore group using high-dose posttransplant cyclophosphamide. HLA-haploidentical hematopoietic stem cell transplantation using posttransplant cyclophosphamide is associated with low rates of severe graft-versus-host disease and nonrelapse mortality and does not require graft manipulation or storage, which results in a low graft acquisition cost. Its remarkable safety when used with reduced-intensity conditioning has been demonstrated in patients up to 75 years old with outcomes similar to those of patients in their 50s. Several large, registry-based retrospective studies have confirmed the efficacy of HLA-haploidentical hematopoietic stem cell transplantation with posttransplant cyclophosphamide, achieving results comparable to those of HLA-matched hematopoietic stem cell transplantation. In this article, we describe our approach to this rapidly available and clinically simple platform and address some of the key clinical questions associated with its use.

References

References
1.
Luznik
L
,
O’Donnell
PV
,
Symons
HJ
, et al
.
HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide
.
Biol Blood Marrow Transplant
.
2008
;
14
(
6
):
641
-
650
.
2.
McCurdy
SR
,
Kanakry
JA
,
Showel
MM
, et al
.
Risk-stratified outcomes of nonmyeloablative HLA-haploidentical BMT with high-dose posttransplantation cyclophosphamide
.
Blood
.
2015
;
125
(
19
):
3024
-
3031
.
3.
Ciurea
SO
,
Zhang
MJ
,
Bacigalupo
AA
, et al
.
Haploidentical transplant with posttransplant cyclophosphamide vs matched unrelated donor transplant for acute myeloid leukemia
.
Blood
.
2015
;
126
(
8
):
1033
-
1040
.
4.
Ringdén
O
,
Labopin
M
,
Ciceri
F
, et al
.
Is there a stronger graft-versus-leukemia effect using HLA-haploidentical donors compared with HLA-identical siblings?
Leukemia
.
2016
;
30
(
2
):
447
-
455
.
5.
Gu
Z
,
Wang
L
,
Yuan
L
, et al
.
Similar outcomes after haploidentical transplantation with post-transplant cyclophosphamide versus HLA-matched transplantation: a meta-analysis of case-control studies
.
Oncotarget
.
2017
;
8
(
38
):
63574
-
63586
.
6.
McCurdy
SR
,
Kasamon
YL
,
Kanakry
CG
, et al
.
Comparable composite endpoints after HLA-matched and HLA-haploidentical transplantation with post-transplantation cyclophosphamide
.
Haematologica
.
2017
;
102
(
2
):
391
-
400
.
7.
Passweg
JR
,
Baldomero
H
,
Bader
P
, et al
.
Use of haploidentical stem cell transplantation continues to increase: the 2015 European Society for Blood and Marrow Transplant activity survey report
.
Bone Marrow Transplant
.
2017
;
52
(
6
):
811
-
817
.
8.
Kanakry
CG
,
Fuchs
EJ
,
Luznik
L
.
Modern approaches to HLA-haploidentical blood or marrow transplantation [published correction appears in
Nat Rev Clin Oncol
.
2016
;
13
(
2
):
132
].
Nat Rev Clin Oncol. 2016;13(1):10-24
.
9.
Wang
Y
,
Chang
YJ
,
Xu
LP
, et al
.
Who is the best donor for a related HLA haplotype-mismatched transplant?
Blood
.
2014
;
124
(
6
):
843
-
850
.
10.
McCurdy
SR
,
Zhang
MJ
,
St Martin
A
, et al
.
Effect of donor characteristics on haploidentical transplantation with posttransplantation cyclophosphamide
.
Blood Adv
.
2018
;
2
(
3
):
299
-
307
.
11.
McCurdy
SR
,
Fuchs
EJ
.
Selecting the best haploidentical donor
.
Semin Hematol
.
2016
;
53
(
4
):
246
-
251
.
12.
Lorentino
F
,
Labopin
M
,
Fleischhauer
K
, et al
.
The impact of HLA matching on outcomes of unmanipulated haploidentical HSCT is modulated by GVHD prophylaxis
.
Blood Adv
.
2017
;
1
(
11
):
669
-
680
.
13.
Solomon
SR
,
Aubrey
MT
,
Zhang
X
, et al
.
Selecting the best donor for haploidentical transplant: impact of HLA, killer cell immunoglobulin-like receptor genotyping, and other clinical variables
.
Biol Blood Marrow Transplant
.
2018
;
24
(
4
):
789
-
798
.
14.
Gladstone
DE
,
Zachary
AA
,
Fuchs
EJ
, et al
.
Partially mismatched transplantation and human leukocyte antigen donor-specific antibodies
.
Biol Blood Marrow Transplant
.
2013
;
19
(
4
):
647
-
652
.
15.
Ciurea
SO
,
Thall
PF
,
Milton
DR
, et al
.
Complement-binding donor-specific anti-HLA antibodies and risk of primary graft failure in hematopoietic stem cell transplantation
.
Biol Blood Marrow Transplant
.
2015
;
21
(
8
):
1392
-
1398
.
16.
Vago
L
,
Perna
SK
,
Zanussi
M
, et al
.
Loss of mismatched HLA in leukemia after stem-cell transplantation
.
N Engl J Med
.
2009
;
361
(
5
):
478
-
488
.
17.
McCurdy
SR
,
Iglehart
BS
,
Batista
DA
, et al
.
Loss of the mismatched human leukocyte antigen haplotype in two acute myelogenous leukemia relapses after haploidentical bone marrow transplantation with post-transplantation cyclophosphamide
.
Leukemia
.
2016
;
30
(
10
):
2102
-
2106
.
18.
Crucitti
L
,
Crocchiolo
R
,
Toffalori
C
, et al
.
Incidence, risk factors and clinical outcome of leukemia relapses with loss of the mismatched HLA after partially incompatible hematopoietic stem cell transplantation
.
Leukemia
.
2015
;
29
(
5
):
1143
-
1152
.
19.
Rashidi
A
,
Hamadani
M
,
Zhang
MJ
, et al
.
Outcomes of haploidentical vs matched sibling transplantation for acute myeloid leukemia in first complete remission
.
Blood Adv
.
2019
;
3
(
12
):
1826
-
1836
.
20.
Versluis
J
,
Labopin
M
,
Ruggeri
A
, et al
.
Alternative donors for allogeneic hematopoietic stem cell transplantation in poor-risk AML in CR1
.
Blood Adv
.
2017
;
1
(
7
):
477
-
485
.
21.
Santoro
N
,
Labopin
M
,
Giannotti
F
, et al
.
Unmanipulated haploidentical in comparison with matched unrelated donor stem cell transplantation in patients 60 years and older with acute myeloid leukemia: a comparative study on behalf of the ALWP of the EBMT
.
J Hematol Oncol
.
2018
;
11
:
55
.
22.
Perales
MA
,
Tomlinson
B
,
Zhang
MJ
, et al
.
Alternative donor transplantation for acute myeloid leukemia in patients aged ≥50 years: young HLA-matched unrelated or haploidentical donor? [published online ahead of print 17 May 2019]
.
Haematologica
.
doi:10.3324/haematol.2018.215202
.
23.
Robinson
TM
,
Fuchs
EJ
,
Zhang
MJ
, et al
;
Acute Leukemia Working Party of the European Society for Blood and Marrow Transplant and the Center for International Blood and Marrow Transplant Research
.
Related donor transplants: has posttransplantation cyclophosphamide nullified the detrimental effect of HLA mismatch?
Blood Adv
.
2018
;
2
(
11
):
1180
-
1186
.
24.
Bashey
A
,
Zhang
MJ
,
McCurdy
SR
, et al
.
Mobilized peripheral blood stem cells versus unstimulated bone marrow as a graft source for T-cell–replete haploidentical donor transplantation using post-transplant cyclophosphamide
.
J Clin Oncol
.
2017
;
35
(
26
):
3002
-
3009
.
25.
Savani
BN
,
Labopin
M
,
Blaise
D
, et al
.
Peripheral blood stem cell graft compared to bone marrow after reduced intensity conditioning regimens for acute leukemia: a report from the ALWP of the EBMT
.
Haematologica
.
2016
;
101
(
2
):
256
-
262
.
26.
Rashidi
A
,
DiPersio
JF
,
Westervelt
P
, et al
.
Comparison of outcomes after peripheral blood haploidentical versus matched unrelated donor allogeneic hematopoietic cell transplantation in patients with acute myeloid leukemia: a retrospective single-center review
.
Biol Blood Marrow Transplant
.
2016
;
22
(
9
):
1696
-
1701
.
27.
Kasamon
YL
,
Luznik
L
,
Leffell
MS
, et al
.
Nonmyeloablative HLA-haploidentical bone marrow transplantation with high-dose posttransplantation cyclophosphamide: effect of HLA disparity on outcome
.
Biol Blood Marrow Transplant
.
2010
;
16
(
4
):
482
-
489
.
28.
McCurdy
SR
,
Muth
ST
,
Tsai
HL
, et al
.
Improved event-free survival and higher incidence of early fever associated with mismatches at HLA-DRB1 after nonmyeloablative HLA-haploidentical transplantation [abstract]
.
Biol Blood Marrow Transplant.
2017
;
23
(
3 suppl
):
S106
.
29.
Rimando
J
,
Slade
M
,
DiPersio
JF
, et al
.
HLA epitope mismatch in haploidentical transplantation is associated with decreased relapse and delayed engraftment
.
Blood Adv
.
2018
;
2
(
24
):
3590
-
3601
.
30.
Lin
CH
,
Su
YJ
,
Hsu
CY
,
Wang
PN
,
Teng
CJ
.
Haploidentical allogeneic hematopoietic stem cell transplantation increases the risk of cytomegalovirus infection in adult patients with acute leukemia
.
Transpl Infect Dis
.
2019
;
21
(
4
):
e13096
.
31.
Crocchiolo
R
,
Castagna
L
,
Furst
S
, et al
.
The role of donor CMV serostatus on outcome after T-cell replete haplo-SCT and post-transplant cyclophosphamide: a cohort analysis on 207 consecutive adult patients [abstract]
.
Blood
.
2015
;
126
(
23
):
4401
.
32.
Hammerstrom
AE
,
Lombardi
LR
,
Pingali
SR
, et al
.
Prevention of cytomegalovirus reactivation in haploidentical stem cell transplantation
.
Biol Blood Marrow Transplant
.
2018
;
24
(
2
):
353
-
358
.
33.
Ljungman
P
,
Schmitt
M
,
Marty
FM
, et al
.
A mortality analysis of letermovir prophylaxis for cytomegalovirus (CMV) in CMV-seropositive recipients of allogeneic hematopoietic-cell transplantation [published online ahead of print 8 June 2019]
.
Clin Infect Dis
.
doi:10.1093/cid/ciz490
.
34.
Bastida
JM
,
Cabrero
M
,
Lopez-Godino
O
, et al
.
Influence of donor age in allogeneic stem cell transplant outcome in acute myeloid leukemia and myelodisplastic syndrome
.
Leuk Res
.
2015
;
39
(
8
):
828
-
834
.
35.
Kollman
C
,
Howe
CW
,
Anasetti
C
, et al
.
Donor characteristics as risk factors in recipients after transplantation of bone marrow from unrelated donors: the effect of donor age
.
Blood
.
2001
;
98
(
7
):
2043
-
2051
.
36.
Kollman
C
,
Spellman
SR
,
Zhang
MJ
, et al
.
The effect of donor characteristics on survival after unrelated donor transplantation for hematologic malignancy
.
Blood
.
2016
;
127
(
2
):
260
-
267
.
37.
Canaani
J
,
Savani
BN
,
Labopin
M
, et al
.
Donor age determines outcome in acute leukemia patients over 40 undergoing haploidentical hematopoietic cell transplantation
.
Am J Hematol
.
2018
;
93
(
2
):
246
-
253
.
38.
Elmariah
H
,
Kasamon
YL
,
Zahurak
M
, et al
.
Haploidentical bone marrow transplantation with post-transplant cyclophosphamide using non-first-degree related donors
.
Biol Blood Marrow Transplant
.
2018
;
24
(
5
):
1099
-
1102
.
39.
Chiusolo
P
,
Bug
G
,
Olivieri
A
, et al
.
A modified post-transplant cyclophosphamide regimen, for unmanipulated haploidentical marrow transplantation, in acute myeloid leukemia: a multicenter study
.
Biol Blood Marrow Transplant
.
2018
;
24
(
6
):
1243
-
1249
.
40.
Solomon
SR
,
Sizemore
CA
,
Sanacore
M
, et al
.
Total body irradiation-based myeloablative haploidentical stem cell transplantation is a safe and effective alternative to unrelated donor transplantation in patients without matched sibling donors
.
Biol Blood Marrow Transplant
.
2015
;
21
(
7
):
1299
-
1307
.
41.
Huselton
E
,
Slade
M
,
Trinkaus
KM
,
DiPersio
JF
,
Westervelt
P
,
Romee
R
.
Propensity score analysis of conditioning intensity in peripheral blood haploidentical hematopoietic cell transplantation
.
Biol Blood Marrow Transplant
.
2018
;
24
(
10
):
2047
-
2055
.
42.
Brunstein
CG
,
Fuchs
EJ
,
Carter
SL
, et al
;
Blood and Marrow Transplant Clinical Trials Network
.
Alternative donor transplantation after reduced intensity conditioning: results of parallel phase 2 trials using partially HLA-mismatched related bone marrow or unrelated double umbilical cord blood grafts
.
Blood
.
2011
;
118
(
2
):
282
-
288
.
43.
Anasetti
C
,
Logan
BR
,
Lee
SJ
, et al
;
Blood and Marrow Transplant Clinical Trials Network
.
Peripheral-blood stem cells versus bone marrow from unrelated donors
.
N Engl J Med
.
2012
;
367
(
16
):
1487
-
1496
.
44.
Vigorito
AC
,
Marques Júnior
JF
,
Aranha
FJP
,
Oliveira
GB
,
Miranda
ECM
,
De Souza
CA
.
A randomized, prospective comparison of allogeneic bone marrow and peripheral blood progenitor cell transplantation in the treatment of hematologic malignancies: an update
.
Haematologica
.
2001
;
86
(
6
):
665
-
666
.
45.
Blaise
D
,
Kuentz
M
,
Fortanier
C
, et al
.
Bone marrow (BMT) versus lenograstim-primed blood cell (BCT) allogeneic transplantation: a randomized trial from the Societe Francaise de Greffe de Moelle [abstract]
.
J Clin Oncol
.
2000
;
18
(
3
):
537
.
46.
Ringdén
O
,
Labopin
M
,
Beelen
DW
, et al
;
Acute Leukaemia Working Party of European Group for Blood and Marrow Transplantation (EBMT)
.
Bone marrow or peripheral blood stem cell transplantation from unrelated donors in adult patients with acute myeloid leukaemia, an Acute Leukaemia Working Party analysis in 2262 patients
.
J Intern Med
.
2012
;
272
(
5
):
472
-
483
.
47.
Champlin
RE
,
Schmitz
N
,
Horowitz
MM
, et al
;
IBMTR Histocompatibility and Stem Cell Sources Working Committee and the European Group for Blood and Marrow Transplantation (EBMT)
.
Blood stem cells compared with bone marrow as a source of hematopoietic cells for allogeneic transplantation
.
Blood
.
2000
;
95
(
12
):
3702
-
3709
.
48.
Holtick
U
,
Albrecht
M
,
Chemnitz
JM
, et al
.
Bone marrow versus peripheral blood allogeneic haematopoietic stem cell transplantation for haematological malignancies in adults
.
Cochrane Database Syst Rev
.
2014
;(
4
):
CD010189
.
49.
Castagna
L
,
Crocchiolo
R
,
Furst
S
, et al
.
Bone marrow compared with peripheral blood stem cells for haploidentical transplantation with a nonmyeloablative conditioning regimen and post-transplantation cyclophosphamide
.
Biol Blood Marrow Transplant
.
2014
;
20
(
5
):
724
-
729
.
50.
Bradstock
K
,
Bilmon
I
,
Kwan
J
, et al
.
Influence of stem cell source on outcomes of allogeneic reduced-intensity conditioning therapy transplants using haploidentical related donors
.
Biol Blood Marrow Transplant
.
2015
;
21
(
9
):
1641
-
1645
.
51.
Ruggeri
A
,
Labopin
M
,
Bacigalupo
A
, et al
.
Bone marrow versus mobilized peripheral blood stem cells in haploidentical transplants using posttransplantation cyclophosphamide
.
Cancer
.
2018
;
124
(
7
):
1428
-
1437
.
52.
McCurdy
SR
,
Kanakry
CG
,
Tsai
HL
, et al
.
Grade II acute graft-versus-host disease and higher nucleated cell graft dose improve progression-free survival after HLA-haploidentical transplant with post-transplant cyclophosphamide
.
Biol Blood Marrow Transplant
.
2018
;
24
(
2
):
343
-
352
.
53.
Ciurea
SO
,
de Lima
M
,
Cano
P
, et al
.
High risk of graft failure in patients with anti-HLA antibodies undergoing haploidentical stem-cell transplantation
.
Transplantation
.
2009
;
88
(
8
):
1019
-
1024
.
54.
Chang
YJ
,
Zhao
XY
,
Xu
LP
, et al
.
Donor-specific anti-human leukocyte antigen antibodies were associated with primary graft failure after unmanipulated haploidentical blood and marrow transplantation: a prospective study with randomly assigned training and validation sets
.
J Hematol Oncol
.
2015
;
8
:
84
.
55.
Bramanti
S
,
Calafiore
V
,
Longhi
E
, et al
.
Donor-specific anti-HLA antibodies in haploidentical stem cell transplantation with post-transplantation cyclophosphamide: risk of graft failure, poor graft function, and impact on outcomes
.
Biol Blood Marrow Transplant
.
2019
;
25
(
7
):
1395
-
1406
.
56.
Gladstone
DE
,
Bettinotti
MP
.
HLA donor-specific antibodies in allogeneic hematopoietic stem cell transplantation: challenges and opportunities
.
Hematology Am Soc Hematol Educ Program
.
2017
;
2017
:
645
-
650
.
57.
Leffell
MS
,
Jones
RJ
,
Gladstone
DE
.
Donor HLA-specific Abs: to BMT or not to BMT?
Bone Marrow Transplant
.
2015
;
50
(
6
):
751
-
758
.
58.
Ciurea
SO
,
Al Malki
MM
,
Kongtim
P
, et al
.
The European Society for Blood and Marrow Transplantation (EBMT) consensus recommendations for donor selection in haploidentical hematopoietic cell transplantation
.
Bone Marrow Transplant
.
2019
;
54
(
5
):
784
.
59.
Kasamon
YL
,
Ambinder
RF
,
Fuchs
EJ
, et al
.
Prospective study of nonmyeloablative, HLA-mismatched unrelated BMT with high-dose posttransplantation cyclophosphamide.
Blood Adv
.
2017
;
1
(
4
):
288
-
292
.
60.
Canaani
J
,
Labopin
M
,
Huang
XJ
, et al
.
Minimal residual disease status predicts outcome of acute myeloid leukaemia patients undergoing T-cell replete haploidentical transplantation: an analysis from the Acute Leukaemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT)
.
Br J Haematol
.
2018
;
183
(
3
):
411
-
420
.
61.
Brissot
E
,
Labopin
M
,
Ehninger
G
, et al
.
Haploidentical versus unrelated allogeneic stem cell transplantation for relapsed/refractory acute myeloid leukemia: a report on 1578 patients from the Acute Leukemia Working Party of the EBMT
.
Haematologica
.
2019
;
104
(
3
):
524
-
532
.
62.
Kasamon
YL
,
Fuchs
EJ
,
Zahurak
M
, et al
.
Shortened-duration tacrolimus after nonmyeloablative, HLA-haploidentical bone marrow transplantation
.
Biol Blood Marrow Transplant
.
2018
;
24
(
5
):
1022
-
1028
.
63.
O’Donnell
P
,
Raj
K
,
Pagliuca
A
.
High fever occurring 4 to 5 days post-transplant of haploidentical bone marrow or peripheral blood stem cells after reduced-intensity conditioning associated with the use of post-transplant cyclophosphamide as prophylaxis for graft-versus-host disease
.
Biol Blood Marrow Transplant
.
2015
;
21
(
1
):
197
-
198
.
64.
Arango
M
,
Combariza
JF
.
Fever after peripheral blood stem cell infusion in haploidentical transplantation with post-transplant cyclophosphamide
.
Hematol Oncol Stem Cell Ther
.
2017
;
10
(
2
):
79
-
84
.
65.
McCurdy
SR
,
Muth
ST
,
Tsai
HL
, et al
.
Early fever after haploidentical bone marrow transplantation correlates with class II HLA-mismatching and myeloablation but not outcomes
.
Biol Blood Marrow Transplant
.
2018
;
24
(
10
):
2056
-
2064
.
66.
Abboud
R
,
Keller
J
,
Slade
M
, et al
.
Severe cytokine-release syndrome after T cell-replete peripheral blood haploidentical donor transplantation is associated with poor survival and anti-IL-6 therapy is safe and well tolerated
.
Biol Blood Marrow Transplant
.
2016
;
22
(
10
):
1851
-
1860
.
67.
Luznik
L
,
O’Donnell
PV
,
Fuchs
EJ
.
Post-transplantation cyclophosphamide for tolerance induction in HLA haploidentical BMT
.
Semin Oncol
.
2012
;
39
(
6
):
683
-
693
.
68.
Kanakry
CG
,
Bolaños-Meade
J
,
Kasamon
YL
, et al
.
Low immunosuppressive burden after HLA-matched related or unrelated BMT using posttransplantation cyclophosphamide
.
Blood
.
2017
;
129
(
10
):
1389
-
1393
.
69.
Zeidan
AM
,
Forde
PM
,
Symons
H
, et al
.
HLA-haploidentical donor lymphocyte infusions for patients with relapsed hematologic malignancies after related HLA-haploidentical bone marrow transplantation
.
Biol Blood Marrow Transplant
.
2014
;
20
(
3
):
314
-
318
.
70.
Ghiso
A
,
Raiola
AM
,
Gualandi
F
, et al
.
DLI after haploidentical BMT with post-transplant CY
.
Bone Marrow Transplant
.
2015
;
50
(
1
):
56
-
61
.
71.
Imus
PH
,
Blackford
AL
,
Bettinotti
M
, et al
.
Major histocompatibility mismatch and donor choice for second allogeneic bone marrow transplantation
.
Biol Blood Marrow Transplant
.
2017
;
23
(
11
):
1887
-
1894
.
72.
Toffalori
C
,
Zito
L
,
Gambacorta
V
, et al
.
Immune signature drives leukemia escape and relapse after hematopoietic cell transplantation
.
Nat Med
.
2019
;
25
(
4
):
603
-
611
.
73.
Vago
L
,
Ciceri
F
.
Choosing the alternative
.
Biol Blood Marrow Transplant
.
2017
;
23
(
11
):
1813
-
1814
.
You do not currently have access to this content.