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Posttransplant cyclophosphamide for GvHD prophylaxis after allogeneic hematopoietic stem cell transplantation

Aug 14, 2020

Prevention of graft- versus-host disease (GvHD) represents the most important factor in the success of allogeneic hematopoietic stem cell transplantation (allo-HSCT), and posttransplant cyclophosphamide (PTCy) is an effective prophylactic treatment for GvHD after haploidentical (haplo) HSCT.

Two retrospective studies, published in September last year, suggested that PTCy represents a good alternative to the standard GvHD prophylaxis with antithymocyte globulin (ATG) in the human leukocyte antigen (HLA)-mismatched, unrelated donor (9/10 MMUD) allo-HSCT setting, and may improve outcomes in a HLA disparity transplant setting. However, there is not much information on the impact of donor types using PTCy prophylaxis.  

In May 2020, two retrospective studies were published evaluating the impact of donor type on the outcome of patients with acute leukemia who underwent allo-HSCT, using PTCy for GvHD prophylaxis. The first study, published in the Journal of Hematology & Oncologyby Jaime Sanz and colleagues, investigated the outcomes of patients with acute myeloid leukemia (AML) in first complete remission (CR1) who received allo-HSCT, with PTCy for GvHD prophylaxis, from matched sibling donors (MSD), matched unrelated donors (MUD), and haplo donors. 1The second study, published in Leukemiaby Francesca Lorentino and colleagues, compared the outcomes of patients with acute leukemia receiving 10/10 or 9/10 HLA allele-matched unrelated donors HSCT (UD-HSCT) with PTCy-based GvHD prophylaxis. 2

Study design

The main designs of both studies are highlighted in Table 1.

Table 1.Study design

 

Sanz et al. 1

Lorentino et al. 2

aGvHD, acute GvHD; ALL, acute lymphoblastic leukemia; ALWP, acute leukaemia working party; AML, acute myeloid leukemia; cGvHD, chronic GvHD; CR1, first complete remission; EBMT, European Society for Blood and Marrow Transplantation; GRFS, graft- versus-host disease and relapse-free survival; GvHD, graft- versus-host disease; haplo, haploidentical; HSCT, hematopoietic stem cell transplantation; LFS, leukemia-free survival; MSD, matched sibling donor; MUD, matched unrelated donor; NRM, non-relapse mortality; OS, overall survival; PTCy, posttransplant cyclophosphamide; UD, unrelated donor

*Haplo defined as recipient-donor number of human leukocyte antigen (HLA) mismatches ≥ 2

Study

Retrospective registry-based analysis on behalf of the ALWP of the EBMT

Retrospective registry-based study on behalf of the ALWP and the Cellular Therapy and Immunobiology Working Party of the EBMT

Eligibility criteria

Adult (≥ 18 years) patients with AML in CR1 at transplantation, who underwent first allogeneic HSCT, from haplo*, MUD, or MSD donors between 2010 and 2017, using PTCy either alone or in combination with other immunosuppressive drugs as GvHD prophylaxis

Adult (≥ 18 years) patients with AML or ALL at all disease stages, who received a first allogeneic HSCT from 10/10 or 9/10 UD between 2010 and 2017, using PTCy either alone or in combination with other immunosuppressive drugs as GvHD prophylaxis

Primary endpoint

LFS

LFS

Secondary endpoints

Neutrophil engraftment, aGvHD and cGvHD, relapse incidence, NRM, GRFS, and OS

aGvHD, cGvHD, NRM, relapse, OS and GRFS

Patient characteristics

Patient characteristics from both studies are summarized in Table 2. In both studies, the vast majority of patients received PTCy combined with one or two additional immunosuppressive drugs as GvHD prophylaxis, while PTCy without any additional immunosuppressive drug was adopted only in a small number of patients.

Table 2.Patient characteristics

 

 

Characteristic

Sanz et al. 1(N = 1239)

Lorentino et al. 2(N = 464)

MSD

(n = 215)

MUD

(n = 235)

Haplo

(n = 789)

10/10 UD

(n = 305)

9/10 UD

(n = 159)

ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; GvHD, graft- versus-host disease; haplo, haploidentical; MAC, myeloablative conditioning; MSD, matched sibling donor; MUD, matched unrelated donor; PTCy, posttransplant cyclophosphamide; RIC, reduced intensity conditioning; UD, unrelated donor

Median age, years (range)

48 (18–71)

47 (18–74)

54 (18–75)

41 (18–76)

47 (19–73)

Diagnosis, n (%)

 

 

 

 

 

AML

 

 

 

218 (71.0)

113 (71.0)

ALL

 

 

 

87 (29.0)

46 (29.0)

Conditioning, n (%)

 

 

 

 

 

RIC

87 (42.0)

115 (50.0)

298 (38.0)

144 (47.0)

70 (44.0)

MAC

122 (58.0)

116 (50.0)

487 (62.0)

161 (53.0)

89 (56.0)

Missing

6

4

4

 

 

Cell source, n (%)

 

 

 

 

 

Bone Marrow

62 (29.0)

22 (9.0)

341 (43.0)

36 (12.0)

19 (12.0)

Peripheral blood

152 (71.0)

213 (91.0)

448 (57.0)

269 (88.0)

140 (88.0)

GvHD prophylaxis, n (%)

 

 

 

 

 

PTCy + 2 drugs

56 (26.0)

111 (47.0)

730 (93.0)

165 (54.0)

113 (71.0)

PTCy + 1 drug

108 (50.0)

111 (47.0)

46 (6.0)

111 (36.0)

38 (24.0)

PTCy only

51 (24.0)

13 (6.0)

13 (2.0)

24 (8.0)

4 (2.5)

Other

 

 

 

5 (2.0)

4 (2.5)

Results

Engraftment

  • Sanz et al. found that the cumulative incidence of neutrophil recovery at 60 days was 94% (95% confidence interval [CI], 92–95), 98% (95% CI, 95– 99), and 98% (95% CI, 94–99; p = 0.12), the median time of neutrophil recovery was 19 days (range, 2–63), 20 days (range, 2–48), and 19 days (range, 5–64) for haplo, MUD, and MSD, respectively 1
  • In the study by Lorentino et al., the rate of engraftment was 98% and 95% after 10/10 and 9/10 HLA-matched UD-HSCT, respectively (p = 0.25) 2

Transplant outcomes

Univariate analysis

The results from the univariate analysis of transplant outcomes are reported in Table 3.

Table 3. Univariate analysis of transplant outcomes

 

Outcome, % (95% CI)

Sanz et al. 1

Lorentino et al. 2

MSD

MUD

Haplo

p value

10/10 UD

9/10 UD

p value

aGvHD, acute graft- versus-host disease; cGvHD, cronic graft- versus-host disease; CI, confidence interval; GRFS, graft- versus-host disease and relapse-free survival; Haplo, haploidentical; LFS, leukemia-free survival; MSD, matched sibling donor; MUD, matched unrelated donor; NRM, non-relapse mortality; OS, overall survival; UD, unrelated donor

100-day cumulative incidence of aGvHD

 

 

 

 

 

 

 

Grades II–IV

17 (12–23)

28 (22–34)

26 (23–29)

0.03

28 (23–33)

28 (21–35)

0.84

Grades III–IV

6 (4–10)

8 (5–11)

9 (7–12)

0.2

10 (7–14)

8 (5–13)

0.51

2-year cumulative incidence of:

 

 

 

 

 

 

 

cGvHD

 

 

 

 

 

 

 

Overall

34 (26–41)

32 (25–39)

30 (26–33)

0.3

35 (28–42)

44 (34–54)

0.21

Extensive type

14 (9–20)

18 (13–25)

10 (8–13)

0.003

21 (15–27)

20 (12–28)

0.60

NRM

10 (6–15)

14 (9–19)

23 (20–26)

< 0.001

20 (15–26)

16 (9–24)

0.15

Relapse

33 (26–40)

25 (19–31)

23 (20–26)

0.02

24 (19–30)

28 (21–37)

0.42

2-year probability of:

 

 

 

 

 

 

 

 

OS

64 (56–72)

68 (62–75)

61 (58–65)

0.1

62 (55–69)

59 (49–69)

0.86

LFS

57 (49–65)

62 (55–69)

54 (51–58)

0.2

56 (49–62)

56 (46–65)

0.64

GRFS

45 (37–53)

42 (35–50)

46 (42–50)

0.9

40 (33–47)

43 (33–52)

0.33

 Lorentino et al. found no difference in the outcome of the 10/10 and 9/10 HLA-matched UD groups stratifying for the total number of immunosuppressive drugs used for GvHD prophylaxis. 2

Multivariate analysis

The multivariate analysis of transplant outcomes showed that:

  • In the study by Sanz et al. 1
    • Haplo, when compared with MSD, was associated with
      • increased risk of aGvHD grades II–IV (Hazard ratio [HR], 1.6; 95% CI, 1.08–2.37; p = 0.02) and of non-relapse mortality (NRM) (HR, 2.6; 95% CI, 1.5–4.49; p < 0.001)
      • lower risk of relapse (HR, 0.67; 95% CI, 0.48–0.93; p = 0.02)
    • Standard or intermediate risk cytogenetics, compared with poor risk, were associated with
      • decreased risk of relapse (HR, 0.58; 95% CI, 0.43–0.78; p < 0.001)
      • better leukemia-free survival (LFS) (HR, 0.73; 95% CI, 0.58–0.92; p = 0.007) and overall survival (OS) (HR, 0.7; 95% CI, 0.54–0.9; p = 0.005)
      • improved GvHD and relapse-free survival (GRFS) (HR, 0.78; 95% CI, 0.63–0.96; p = 0.02)
    • Myeloablative conditioning (MAC), compared with reduced intensity conditioning (RIC), was associated with
      • lower risk of relapse (HR, 0.56; 95% CI, 0.43–0.77; p < 0.001)
      • better LFS (HR, 0.71; 95% CI, 0.58–0.88; p = 0.001) and OS (HR, 0.76; 95% CI, 0.6–0.96; p = 0.02)
      • improved GRFS (HR, 0.79; 95% CI, 0.66–0.95; p = 0.01)
    • The use of peripheral blood as the stem cell source, when compared with bone marrow, was associated with
      • higher risk of aGvHD grades II–IV (HR, 1.93; 95% CI, 1.39–2.67; p < 0.001) and grades III–IV (HR, 1.86; 95% CI, 1.1–3.15; p = 0.02), and higher risk of overall cGvHD (HR, 1.71; 95% CI, 1.23–2.39; p = 0.001) and extensive cGvHD (HR, 1.86; 95% CI, 1.15–3.01; p = 0.01)
      • lower risk of relapse (HR, 0.74; 95% CI, 0.45–0.99; p = 0.04)
  • In the study by Lorentino et al. 2
    • Recipients of 9/10 UD-HSCT when compared with 10/10 UD-HSCT had a higher risk of cGvHD (HR, 1.6; 95% CI, 1–2.5; p = 0.05)
    • Disease status (active vsCR1) was associated with:
      • higher risk of NRM (HR, 2.4; 95% CI, 1.3–4.5; p = 0.005) and relapse (HR, 2.6; 95% CI, 1.5–4.7; p = 0.001)
      • worse OS (HR, 2.6; 95% CI, 1.7–4; p < 0.001), LFS (HR, 2.5; 95% CI, 1.6–3.7; p < 0.001), and GRFS (HR, 2; 95% CI, 1.4–2.9; p < 0.001)
    • RIC regimen, compared with MAC, was associated with lower risks of NRM (HR, 0.5; 95% CI, 0.3–0.9; p = 0.02)

Conclusions

Sanz et al. showed that the use of PTCy for GvHD prophylaxis, in patients with AML in CR1 receiving HSC from haplo donors, led to higher rates of aGVHD and NRM but lower relapse incidence, compared with MSD. Although all patients received PTCy prophylaxis, only a very small number of patients in the haplo group received PTCy alone. In fact, the vast majority of patients (93%) in the haplo group received PTCy plus two additional immunosuppressive drugs and this might have enhanced the effect of PTCy, leading to a reduction in the risk of severe cGvHD. In conclusion, haplo-HSCT offers a good alternative to matched donor transplants but, when available, HLA-matched donors should remain the first choice.

Lorentino and colleagues, found a higher risk of cGvHD in the 9/10 compared with the 10/10 HLA-matched group but similar survival outcomes between the two groups. These results could have important implications, since they could allow a donor pool expansion for high-risk patients who lack an identical sibling or a well-matched UD.

Both studies had the limitations of retrospective studies. In addition, although all patients received PTCy prophylaxis, conditioning regimens were heterogeneous and different immunosuppressive drugs were added to PTCy.

  1. Sanz J, Galimard J-E, Labopin M, et al. Post-transplant cyclophosphamide after matched sibling, unrelated and haploidentical donor transplants in patients with acute myeloid leukemia: a comparative study of the ALWP EBMT. J Hematol Oncol. 2020;13(1):46. DOI: 10.1186/s13045-020-00882-6
  2. Lorentino F, Labopin M, Ciceri F, et al. Post-transplantation cyclophosphamide GvHD prophylaxis after hematopoietic stem cell transplantation from 9/10 or 10/10 HLA-matched unrelated donors for acute leukemia. Leukemia. 2020. DOI: 1038/s41375-020-0863-4