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A comparison of GvHD characteristics in recipients of haploidentical vs matched unrelated donor transplantation

Sep 9, 2020

The limited availability of human leukocyte antigen (HLA)- matched donors for allogeneic hematopoietic stem cell transplantation (HSCT) can prevent patients from receiving potentially life-saving therapy. T-replete HLA-mismatched haploidentical (haplo) HSCT may offer an alternative donor source where matched donors are unavailable. Previous studies indicate that haplo HSCT combined with posttransplant cyclophosphamide (PTCy) can induce survival rates similar to matched related donor (MRD) and matched unrelated donor (MUD) HSCT, with reduced incidence of acute and chronic graft- versus-host disease (a/cGvHD). However, there is limited data on risk factors, as well as aGvHD and cGvHD characteristics, in patients receiving haplo HSCT.

Sohl et al.evaluated the characteristics of a/cGvHD, including organ distribution, severity, and response to treatment, in patients who received haplo HSCT with PTCy versusthose who received MUD HSCT with calcineurin inhibitors (CIs). The results were published in the Biology of Blood and Marrow Transplant, 1 and the GvHD Hub is happy to provide a summary.

Study design

  • The analysis included patients aged ≥ 18 years who received initial HSCT between 2005 and 2017 (N = 394) from
    • 10/10 allele MUD (n = 179) + CI GvHD prophylaxis, or
    • haplo (n = 215) + PTCy GvHD prophylaxis.
  • Primary endpoints: Cumulative incidence of GvHD, time to GvHD onset, and organ involvement.
  • Secondary endpoints: Overall survival, disease free survival, non-relapse mortality, and relapse.

Results

  • Median follow-up: 52.2 months.
  • Patient characteristics are presented in Table 1.

Table 1.Baseline patient characteristics 1

ALL, acute lymphocytic leukemia; AML, acute myeloid leukemia; BM, bone marrow; CLL, chronic lymphocytic leukemia; CML, chronic myelogenous leukemia; DRI, disease risk index;haplo, haploidentical transplantation; HCT-CI, hematopoietic cell transplantation-comorbidity index;HL, Hodgkin lymphoma; HSCT, hematopoietic stem cell transplantation; MDS, myelodysplastic syndrome; MPS, myeloproliferative syndrome; MUD, matched unrelated donor; NHL, non-Hodgkin lymphoma; PBSC, peripheral blood stem cell.

Bold font signifies statistical significance.

Characteristic, % unless stated otherwise

Haplo HSCT

(n = 215)

MUD HSCT

(n = 179)

p

Median age, years (range)

53 (19–75)

56 (20–74)

0.007

Male sex

58

52

0.22

Race                                  

               

               

< 0.001

White

58

93

 

Black                   

38

7

 

Other/unknown

4

1

 

Diagnosis                          

               

               

0.24

AML                     

40

40

 

ALL                       

18

13

 

MDS/MPS/CML 

21

29

 

NHL/HL/CLL     

16

11

 

Cell source       

               

               

0.013

BM          

30

33

 

PBSC        

70

67

 

Intensity                           

               

               

0.34

Myeloablative

46

51

 

RIC/non-myeloablative

54

49

 

DRI

               

               

0.10

Low                     

13

11

 

Intermediate  

49

57

 

High                     

28

18

 

Very high      

5

7

 

N/A                      

5

7

 

HCT-CI

               

               

< 0.001

 0–2                     

53

36

 

≥ 3                        

47

64

 

Incidence and onset of GvHD in patients receiving haplo vsMUD HSCT

  • No differences in cumulative incidence and time to onset of aGvHD was observed between patients who received haplo vsMUD HSCT ( Table 2).
  • Higher incidences and earlier onset of cGvHD were observed in patients who received haplo vsMUD HSCT ( Table 2).

Table 2.Incidences and time to onset of a/cGvHD in patients who received haplo vsMUD HSCT 1

aGvHD, acute graft- versus-host disease; cGvHD, chronic graft- versus-host disease; haplo, T-replete HLA-mismatched haploidentical transplantation; HSCT, hematopoietic stem cell transplantation; MUD, matched unrelated donor; NS, not significant.

Bold font signifies statistical significance.

 

Haplo HSCT

(n = 215)

MUD HSCT

(n = 179)

p

Cumulative incidence of aGvHD, %

 

 

NS

Grade 2–4

40

49

 

Grade 3–4

14

16

 

Cumulative incidence of cGvHD, %

 

 

0.026

All Grade

34

41

 

Moderate–severe

22

31

 

Severe

16

29

0.02

Median time to aGvHD onset, days (range)

 

 

 

Grade 2–4

56 (14–607)

49 (9–1133)

0.23

Grade 3–4

84 (14–447)

70 (14–1133)

0.53

Median time to cGvHD onset, days (range)

 

 

 

All grade cGvHD

217.5 (74–618)

274 (78–1240)

0.012

Moderate–severe cGvHD

213.5 (74–618)

280.5 (107–1240)

0.011

Severe cGvHD

212 (74–728)

300 (107–1281)

0.003

aGvHD

  • Of the patients who received haplo or MUD HSCT, 97 and 94 developedGrade 2–4 aGVHD, respectively.
  • There was no statistical difference in the distribution of most affected organs in patients who developedGrade 2–4 aGVHD. The most affected organs in both groups (haplo vsMUD HSCT) were skin (75% vs71%), gastrointestinal tract (71% vs68%), and liver (14% vs17%).
  • There was no difference in all-cause mortality between groups (23% after haplo HSCT vs19% after MUD HSCT; p = 0.34).
  • Among patients who received haplo HSCT, a number of risk factors were associated with increased risk for developingGrade 2–4 aGVHD:
    • Myeloablative conditioning regimen ( p = 0.0169)
    • Donor age ≥ 38 years ( p = 0.05)
    • Child as donor ( vsparent as donor; p = 0.0253).
  • Among patients who received MUD HSCT, myeloablative conditioning was associated with increased development ofGrade 2–4 aGVHD (HR, 1.48; p = 0.043).

cGvHD

  • In patients who developed cGVHD:
    • Moderatesevere cGvHD was seen after haplo and MUD HSCT in 65% and 77% of patients, respectively
    • Two of the most affected organs, eyes and fasciae, differed significantly with eyes being more affected after MUD HSCT, while involvement of fasciae was more frequently seen after haplo HSCT ( Table 3)
    • A greater proportion of haplo vsMUD recipients were off immunosuppressants at 2 years (63% vs43%, p = 0.03)
    • Onset of cGvHD was later in MUD vshaplo recipients (274 days vs217 days, p = 0.012)
    • No difference in 2-year all-cause mortality was observed between donor types.
  • Risk factors associated with increased development ofcGvHD after haplo HSCT :
    • White race (HR, 1.43; p = 0.029)
    • History of grade 2–4 aGvHD (HR, 2.34; p = 0.002)
    • Year of transplant (20122017 vs20052011; HR, 1.68; p = 0.002)
    • Graft source (PBSC vsBM; HR, 1.41; p = 0.03).
  • Risk factors associated with increased development ofcGvHD after MUD HSCT :
    • Recipient age (≥ 55 vs< 55; HR, 1.55; p = 0.03)
    • Graft source PBSC (HR, 1.69; p = 0.002)
    • Year of transplant 20122017 (HR, 1.48; p = 0.003).

Table 3.O rgans with moderatesevere (stage IIIII) cGvHD in ≥ 10% of patients 1

cGvHD, chronic graft- versus-host disease; GI, gastrointestinal;haplo, T-replete HLA-mismatched haploidentical transplantation; HSCT, hematopoietic stem cell transplantation; MUD, matched unrelated donor.

Bold font signifies statistical significance.

Organ involvement, %

Haplo HSCT (n = 74)

MUD HSCT (n = 75)

p

Skin

46

46

0.65

GI Upper

20

24

0.11

GI Lower

16

14

0.51

Liver

23

18

0.89

Eyes

12

28

< 0.001

Mouth

26

33

0.14

Joints/Fascia

48         

14

0.001

Patient survival outcomes

  • Multivariable analysis identified factors associated with significantly poorer survival outcomes ( Table 4).

Table 4.Risk factors for poorer OS, DFS, NRM and relapse rates 1

aGvHD, acute graft- versus-host disease; cGvHD, chronic graft- versus-host disease; CI, confidence interval; DFS, disease-free survival; DRI, disease risk index; HR, hazard ratio; NRM, non-relapse mortality; OS, overall survival.

Bold font signifies statistical significance.

Variable

HR

95% CI

p

OS

 

 

 

Grade 3–4 aGVHD

1.66

1.11–2.47

0.013

Severe cGVHD

1.79

1.20–2.69

0.005

Age (≥ 55 vs< 55)

1.72

1.23–2.41

0.001

Race (White vsBlack)

1.66

1.08–2.57

0.022

DRI (high/very high vslow/intermediate)

2.08

1.51–2.86

< 0.001

DFS

 

 

 

Grade 3–4 aGVHD

1.53

1.03–2.28

0.038

Severe cGVHD

1.89

1.25–2.87

0.003

Age (≥ 55 vs< 55)

1.65

1.21–2.25

0.002

Race (White vsBlack)

1.70

1.13–2.55

0.01

DRI (high/very high vslow/intermediate)

1.95

1.44–2.64

< 0.001

NRM

 

 

 

Grade 3–4 aGVHD

2.62

1.42–4.81

0.002

Severe cGVHD

4.72

2.49–8.94

<0.001

Age (≥ 55 vs< 55)

2.28

1.34–3.88

0.002

Relapse

 

 

 

Race (White vsBlack)

2.22

1.31–3.76

0.003

DRI (high/very high vslow/intermediate)

2.59

1.78–3.77

< 0.001

Conclusion

Overall, the data suggest that haplo HSCT with PTCy leads to superior outcomes compared to MUD HSCT in patients undergoing their first transplantation. GvHD prophylaxis with PTCy resulted in lower incidences of cGvHD, faster cGvHD onset, and improved responses to immunosuppressive therapy in patients who received haplo HSCT. cGvHD organ distribution differed significantly between the two treatment groups, and the study highlighted a number of risk factors for patient survival outcomes following HSCT, such as development of severe aGvHD or cGvHD, higher age, White race, and high DRI, which were irrespective of donor type.

Limitations:

  • The transplanting physician had the final decision on certain factors, including donor type, regimen intensity, and graft source.
  • MUD HSCT was accompanied by CI-based GvHD prophylaxis as the most commonly used regimen (rather than PTCy, which accompanied haplo HSCT), so differences between arms may also be due to GvHD prophylaxis.

  1. Solh MM, Baron J, Zhang X, et al. Differences in graft-versus-host disease characteristics between haploidentical transplantation using post-transplantation cyclophosphamide and matched unrelated donor transplantation using calcineurin inhibitors. Biol. Blood Marrow Transplant. 2020. Online ahead of print. DOI: https://doi.org/10.1016/j.bbmt.2020.07.035