GvHD Prophylaxis

GvHD prophylaxis in mismatched, unrelated allogeneic stem cell transplant: a comparison of post-transplant cyclophosphamide and anti-thymocyte globulin

Anti-thymocyte globulin (ATG) is considered the standard graft-versus­-host disease (GvHD) prophylaxis for human leukocyte antigen (HLA)-mismatched, unrelated, donor (9/10 MMUD) allogeneic stem cell transplant (allo-SCT). However, it’s use has been associated with an increased risk of infection, delayed immune reconstitution and relapse. In contrast, post-transplant cyclophosphamide (PtCy) has also been shown to be an effective prophylaxis treatment for GvHD after haploidentical allo-SCT, however, it has not been well studied in the MMUD allo-SCT setting. Patients undergoing MMUD allo-SCT typically have poor survival outcomes related to the high rates of GvHD and non-relapse mortality (NRM). Therefore, there is a requirement to improve GvHD prophylaxis treatments in order to overcome current limitations of HLA mismatched allo-SCT.1,2 This article forms part of the GvHD monthly educational theme of GvHD prophylaxis. 

In September, two studies comparing ATG to PtCy in MMUD allo-SCT were published. The first study by Giorgia Battipaglia, Hospital Saint-Antoine, Paris, FR, and colleagues, utilized registry data from the Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT) to conduct a retrospective, matched-pair analysis of ATG and PtCy in patients after 9/10 MMUD transplant.1 The second, by Charlotte Nykolyszyn, Institut Paoli-Calmettes, Marseille, FR, and colleagues was a historical comparison of comparing PtCy and ATG in the MMUD transplant setting from a single center.2

Study design and patient characteristics

Highlighted below, in Table 1, are the main designs of both studies, including patient characteristics and any significant differences between patients at baseline.

Table 1. Study design and patient characteristics for both studies

 

Battipaglia et al.,1

Nykolyszyn et al.,2

Patient population

Homogenous population of adult patients with acute myeloid leukemia (AML) undergoing first allo-SCT from 9/10 MMUD source between 2011 and 2017

Patients undergoing first allo-SCT for treatment of a hematological malignancy using peripheral blood stem cells (PBSCs) as donor source between; 2015–2018 (PtCy) and 2010–2014 (ATG)

Size

Multicenter

Single center

Study design

Retrospective

Matched pair analysis

Retrospective

Historical comparison

 

ATG

PtCy

ATG

PtCy

N

179

93

40

22

Median age at transplant (years)

53 (19–75)

51 (20–73)

51

49

Female patients

60%

45%

Not reported (NR)

NR

Type of malignancy

(%, lymphoid vs myeloid)

0 vs 100

0 vs 100

33 vs 68

18 vs 82

HLA class I mismatches

75%

73%

NR

NR

Patients in first complete remission (CR1, total)

55%

NR

Year of transplant (range)

2014

2011-2017

2015

2011-2017

NR

NR

Median follow-up (months)

27

14

68

24

PBSCs as source (%)

92

91

100

100

Most frequently used myeloablative conditioning (MAC) regimen

Busulfan and cyclophosphamide

Busulfan and fludarabine-based

Busulfan and fludarabine-based

Thiotepa + busulfan-based

Most frequently used reduced intensity conditioning (RIC) regimen

Busulfan and fludarabine-based

Busulfan and fludarabine-based

Busulfan and fludarabine-based

Fludarabine, cyclophosphamide and total body irradiation

Engraftment rate

96%

95%

NR

NR

Median time to neutrophil engraftment (days)

17

19

NR

NR

Graft failure (n)

37

4

NR

NR

GvHD analysis and survival outcomes

Rates of acute GvHD (aGvHD) and chronic (cGvHD) as shown in Table 21,2

  • In the study by Battipaglia et al.,:1
    • The use of PtCy led to a lower incidence of grade III–IV aGvHD compared to ATG, p< 0.04, hazard ratio (HR): not reported (NR)
    • However, aGvHD grade II–IV, cGvHD of any grade, and extensive cGvHD were not different between the two groups
  • In the study by Nykolyzsyn et al., :2
    • Rates of grade II–IV (p= 0.01) and III–IV (p= 0.011) aGvHD were lower in the PtCy group. This was confirmed in multivariate analysis (HR: 0.12, p= 0.002)
    • No significant difference in cumulative incidence of cGvHD on uni- or multi-variate analysis

Survival outcomes as shown in Table 21,2

  • In the Battipaglia et al., study:1
    • Use of PtCy was associated with:
      • Higher probability of leukemia-free survival (LFS, p< 0.05, HR: NR)
      • A trend towards increased overall survival (OS, p< 0.07, HR: NR)
      • Significantly higher GvHD/relapse-free survival (GRFS) at two-years with PtCy (p<0.03, HR: NR)
    • No difference in NRM or relapse incidence (RI) based on GvHD prophylaxis
    • Subgroup analysis confirmed these results when looking at:
      • Patients receiving cyclosporine and mycophenolate mofetil as additional immunosuppressive agents
      • Patients in CR at time of transplant
      • Patients receiving PBSC as source
  • In Nykolyzsyn et al.:2
    • PtCy was associated with an improved:
      • Two-year progression-free survival (PFS), p= 0.007, HR: NR
      • Two-year OS, p= 0.035, HR: NR
      • Two-year GRFS, p= 0.009, HR: NR
    • These were confirmed in multivariate analysis
      • PFS: HR: 0.22, p= 0.006
      • OS: HR: 0.24, p= 0.026
      • GRFS: HR: 0.37, p= 0.011

Table 2. Rates of GvHD and survival outcomes in the two studies1,2

Battipaglia et al.,1

Nykolyszyn et al.,2

 

ATG (n= 179), %

(95% CI)

PtCy (n= 93), %

(95% CI)

 

ATG (n= 40), %

(95% CI)

PtCy (n= 22), %

(95% CI)

Grade II–IV aGvHD (100 days)

32 (26–40)

30 (21–40)

Grade II–IV aGvHD (100 days)*

35 (23–53)

14 (5–39)

Grade III–IV aGvHD (100 days)*

19 (13–25)

9 (14–16)

Grade III–IV aGvHD (100 days)*

18 (9–34)

0

Any grade cGvHD (two-years)

36 (28–44)

39 (26–51)

Any grade cGvHD (two-years)

26 (15–44)

29 (15–58)

Extensive cGvHD (two-years)

20 (14–28)

17 (9–28)

Moderate–severe cGvHD (two-years)

26 (15–44)

20 (8–48)

LFS*

34 (27–42)

55 (43–66)

PFS*

45 (32–63)

81 (65–100)

OS

38 (30–46)

56 (43–68)

OS*

56 (42–74)

85 (71–100)

GRFS*

21 (14–28)

37 (25-49)

GRFS*

27 (17–45)

60 (42–87)

NRM

29 (22–36)

16 (9–25)

NRM

22 (13–40)

5 (1–31)

RI

37 (29–44)

29 (20–40)

RI

32 (21–51)

15 (5–43)

* Statistically significant

Advantages and limitations of studies

Table 3. Advantages and limitations of the two studies

 

Battipaglia et al.,1

Nykolyszyn et al.,2

Advantages

  • Homogenous population of patients with AML
  • Multicenter analysis
  • Largest series to date comparing PtCy to ATG in the 9/10 MMUD allo-SCT setting
  • Subgroup analysis possible  
  • Focus on patients who received PBSC as graft source
  • Results conformed in a multivariate analysis

Limitations

  • Retrospective
  • Short follow-up period in PtCy group
  • No data on infectious complications
  • No data on disease biology
  • Retrospective
  • Single center experience
  • Patients with different hematological malignancies
  • Small patient sample (subgroup analysis not possible)
  • Patients treated over different time periods
  • Short follow-up period in PtCy group
  • Conditioning regimens were not the same in both groups
Conclusion

The use of PtCy was associated with lower rates of grade III–IV aGvHD in both studies, comparable rates of cGvHD and superior survival outcomes (LFS/PFS and GRFS).These results suggest that PtCy represents a viable alternative to ATG for GvHD prophylaxis in the 9/10 MMUD allo-SCT setting (with PBSCs as donor source) and may improve outcome in a HLA disparity transplant setting. However, prospective trials are required to confirm the results.1,2

References
  1. Battipaglia G. et al., Posttransplant cyclophosphamide vs antithymocyte globulin in HLA-mismatched unrelated donor transplantation. Blood. 2019 Sep 12. DOI: 10.1182/blood.2019000487
  2. Nykolyszyn C. et al., Posttransplantation cyclophosphamide vs. antithymocyte globulin as GVHD prophylaxis for mismatched unrelated hematopoietic stem cell transplantation. Bone Marrow Trans. 2019 Sep 18. DOI: 10.1038/s41409-019-0682-2
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