aGvHD,   cGvHD,  GvHD Prophylaxis

Haploidentical transplantation versus unrelated donor hematopoietic stem cell transplantation

The gold standard donor for hematopoietic stem cell transplantation (HSCT) is a matched sibling donor (MSD), but for most, the only available option is HSCT from a human leukocyte antigen (HLA) matched unrelated donor (MUD), and increasingly from a related haploidentical donor. Haploidentical donors are defined as being at least 50% HLA-identical to the recipient and are usually first-degree relatives. The introduction of post-transplant cyclophosphamide (PTCy) to prevent graft-versus-host disease (GvHD) has greatly improved the outcome of haploidentical HSCT.1

Leonardo Javier Arcuri from the Insitituto Nacional de Câncer, Centro de Transplante de Medula Óssea, Rio de Janeiro, Brazil, and colleagues performed a systematic review2 to compare overall survival (OS), non-relapse mortality (NRM), GvHD (acute [aGvHD] and chronic [cGvHD]) and relapse rates in patients with hematological malignancies treated with either haploidentical HSCT with PTCy or standard unrelated donor (URD) HSCT. In their Biology of Blood and Marrow Transplantation publication (August 2019) they detail their searches of the PubMed and Cochrane databases for studies comparing haploidentical HSCT with PTCy against URD HSCT indexed between 1st January 2008 and 1st January 2019. The group screened 113 abstracts, before reviewing 46 full texts for eligibility. There were 20 observational studies remaining after eligibility checks, which totalled 1,783 haploidentical HSCT recipients and 6,077 URD HSCT recipients. One study was not included in the meta-analysis due to a lack of extractable data on standard deviations. Study characteristics and a summary of results are detailed in Tables 1 and 2 respectively.

Results

OS: The study found no difference in overall survival between the two different donor HSCT treatments (hazard ratio (HR) 0.98 (95% CI, 0.88–1.08) and risk difference (RD) for death of 4 percentage points (pp) (95% CI, -8 to +1 pp).

Relapse: There was also no difference for relapse risk which was 2 pp higher (95% CI, -2 to +6 pp) in the haploidentical donor HSCT group and the hazard ratio was 1.06 (95% CI, 0.95–1.19). This was also true when only patients with active or high-risk disease were analyzed.

NRM: In studies in which all haploidentical donor HSCTs used a PTCy approach, NRM was lower for haploidentical donor transplantation by 6 pp (95% CI, -10 to -3) and had a HR of 0.85 (95% CI, 0.72–1.00).

GvHD: In terms of aGvHD, both grade II-IV and grade III-IV were lower in the haploidentical HSCT groups (grade II-IV: RD, -12 pp [95% CI, -17 to -7 pp]; HR, 0.52 [95% CI, 0.47–0.82] and grade III-IV: RD, -9 pp [95% CI, -13 to -5 pp]; HR, 0.66 [95% CI, 0.48–0.92]).

The RD of cGvHD was 12 pp lower in the haploidentical donor HSCT group (95% CI, -20 to -4 pp). However, the team reported a high heterogeneity (Ι2 = 86%) and found that this was associated with the use of peripheral blood stem cells (PBSCs) and the proportional difference between the two donor groups (31% of participants in the haploidentical donor HSCT group received PBSCs vs 85% in the URD HSCT group). Meta-regression analysis found an association of PBSC transplantation with cGvHD in the haploidentical donor HSCT groups (cGvHD was 3.7 pp lower in the haploidentical donor HSCT group for each 10-pp PBSC proportion difference [< 0.001; R2 = 70%]).

 

Discussion

The meta-analysis found that there is no difference in OS between the two donor types. The team also reported no evidence of higher relapse rates in the haploidentical donor HSCT group, and this finding was upheld even when analying only high-risk disease studies.

However, the incidence rates of all forms of GvHD and NRM are lower with haploidentical donor HSCT compared to URD HSCT. The team point out that this could be partially explained by the use of PTCy-based GvHD prophylaxis for haploidentical donor HSCT as well as the lower use of PBSCs in this group.

The finding that haploidentical donor HSCT is comparable with URD HSCT in terms of OS and relapse rate, while showing lower rates of NRM and GvHD, encouraged the authors to recommend performing haploidentical donor HSCT with PTCy in patients who are being treated in experienced centers, and cannot wait 2–3 months for identification of an URD. This would allow speeding up of the donor identification process, especially for patients with hematologic malignancy with a high risk of relapse.

Arcuri and colleagues highlight some limitations of their study, such as incomplete data extraction from included studies, all of the studies included were retrospective, outcomes of studies were sometimes reported as cumulative incidence with no confidence intervals, and HRs either reported with inadequate reference categories or not reported at all. They also note that they were unable to find any randomized controlled trials comparing these donor transplantations.

 

Table 1: Study Characteristics

Study

Multi
center

Disease

Number

 

% PBSC

% MAC

GVHD Prophylaxis, %

Age, year

Active or High-risk Disease, %

 

 

 

 

 

Haplo

URD

 

 

Haplo

URD

% MMURD

Haplo

URD

Haplo

URD

PTCy

PTCy or in vivo TCD

Haplo

URD

Haplo

URD

Burroughs et al, 2008 (3)

Yes

Hodgkin
Lymphoma

28

24

25

0

100

0

0

100

0

32

28

43

38

Di Stasi et al, 2014 (4)

No

AML/MDS

19

26

0

5

62

0

0

100

100

55

62

0

0

Di Stasi et al, 2014 (4)

No

AML/MDS

13

82

0

0

51

0

0

100

100

52

62

100

100

Raiola et al, 2014 (5)

No

Malignant

92

43

0

0

40

77

72

100

100

45

42

58

42

Raiola et al, 2014 (5)

No

Malignant

92

43

100

0

35

77

72

100

100

45

47

58

56

Ciurea et al, 2015 (6)

Yes

AML

88

737

0

13

89

0

0

100

39

78%
>50

95%>50

16

22

Ciurea et al, 2015 (6)

Yes

AML

104

1245

0

18

81

100

100

100

 

23

42%
>50

43%>50

34

25

Garciaz et al, 2015 (7)

Yes

NHL

26

 

28

12

50

100

0

0

100

100

53

61

43

29

Baker et al, 2016 (8)

No

Malignant

54

59

39

56

68

0

 

100

91

50.5

57

44

51

Bashey et al, 2016 (9)

No

 

Malignant

116

178

0

45

82

40

51

100

28

51

53

40

31

Blaise et al, 2016 (10)

No

Malignant

31

63

0

87

95

0

0

100

100

62

64

39

30

Gaballa et al, 2016 (11)

No

Malignant
and
non
malignant

60

46

100

3

17

0

0

100

100

45

51

38

40

Kanate et al, 2016 (12)

Yes

Lymphoma

185

241

0

13

91

0

0

100

100

55

55

6

18

Kanate et al, 2016 (12)

Yes

Lymphoma

185

491

0

13

94

0

0

100

0

55

55

6

11

Rashidi et al, 2016 (13)

No

AML

52

88

0

100

100

44

44

100

0

54

63

42

41

How et al, 2017(14)

No

Refractory
AML

24

43

19

100

98

67

79

100

24

54

55

100

100

Martinez et al, 2017 (15)

Yes

Hodgkin
Lymphoma

98

273

0

39

88

10

31

100

74

31

32

15

16

McCurdy et al, 2017 (16)

No

Malignant

372

120

0

0

0

0

100

100

100

55

50

19

29

Bashey et al, 2018 (17)

No

Malignant

33

57

4

48

79

6

30

100

4

66

65

17

24

Brissot et al, 2018 (18)

Yes

AML,
relapsed/
refractory

199

1111

0

53

94

54

42

100

78

52

52

100

100

Brissot et al, 2018 (18)

Yes

AML,
relapsed/
refractory

199

383

100

53

92

54

38

100

88

52

52

100

100

Devillier et al, 2018 (19)

No

AML

33

30

10

94

97

0

17

100

97

64%
>65

50%>65

24

7

Dulery et al, 2018 (20)

Yes

Refractory
malignant

27

29

24

78

100

78

79

100

100

42

63

100

100

Lorentino et al, 2018 (21)

Yes

AML,
adverse
karyotype

48

433

0

62

81

53

49

100

76

49

53

100

100

Lorentino et al, 2018 (21)

Yes

AML,
adverse
karyotype

48

123

100

62

83

53

54

100

86

49

51

100

100

Pagliardini et al, 2018 (22)

No

Malignant

81

81

0

73

96

17

28

100

100

50

50

32

25

MMURD indicates mismatched unrelated donor; TCD, T cell depletion; MAC, myeloablative conditioning; AML, acute myelogenous leukemia; MDS, myelodysplastic syndrome; NHL, non-Hodgkin lymphoma.

 

 

Table 2: Summary of pooled results

Outcome

Risk Difference (95% CI) in percentage points (pp)*

Number of published studies (number of actual comparisons)

Hazard Ratio (95% CI)

Number of published studies (number of actual comparisons)

OS

-4 (-8 to +1)

11 (15)

0.98 (0.88–1.08)

11 (15)

Relapse

+2 (-2 to +6)

12 (16)

1.06 (0.95–1.19)

10 (13)

NRM

-6 (-10 to -3)

10 (14)

0.85 (0.72–1.00)

10 (13)

aGVHD grade II-IV

-12 (-17 to -7)

10 (14)

0.52 (0.47–0.82)

7 (9)

aGVHD grade III-IV

-9 (-13 to -5)

10 (13)

0.48 (0.32–0.72)

6 (8)

cGVHD, all

-12 (-20 to -4)

12 (16)

0.25 (0.17–0.38)

3 (4)

cGVHD, moderate

-5 (-14 to +4)

4 (5)

0.55 (0.31–0.99)

5 (5)

* For Risk Difference, negative values favor haploidentical donor HSCT and positive values favour URD HSCT

High heterogeneity

Statistically significant results in bold

References
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