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T-cell costimulation blockade with abatacept for acute GvHD: Results of the ABA2 trial with subanalysis from the TCT 2021 Meeting

Mar 12, 2021
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There are still no approved agents for preventing severe acute (a) graft-versus-host disease (GvHD), which is a major cause of non-relapse mortality (NRM). For patients undergoing hematopoietic stem cell transplantation, especially human leukocyte antigen (HLA)-mismatched unrelated donor transplant (MMUD), severe aGvHD remains a significant cause of morbidity and mortality.

In an article published in the Journal of Clinical Oncology, Benjamin Watkins and colleagues describe the results of the phase II ABA2 trial (NCT01743131), which investigated adding abatacept, a T-cell costimulation blocker currently approved for rheumatoid arthritis, to a calcineurin inhibitor and methotrexate (CNI/MTX) for GvHD prophylaxis.1

A subanalysis was presented by Muna Qayed at the Transplantation and Cellular Therapy (TCT) 2021 Meetings of ASTCT and CIBMTR comparing the outcome of abatacept treatment in patients with MMUD transplant with placebo-treated patients who had received a matched unrelated donor (MUD) transplant.2

Study design

Patients and treatment

Three cohorts were included in this study (see also Table 1). Patients undergoing transplant with stem cells from 8/8 HLA-matched unrelated donors (MUD study cohort, n = 148 enrolled) were randomly assigned (1:1) to receive CNI/MTX plus placebo or abatacept. Patients transplanted with 7/8 HLA-mismatched donor stem cells (MMUD study cohort, n = 46 enrolled) received CNI/MTX plus abatacept, and these were compared with a prespecified control cohort from the Center for International Blood and Marrow Transplant Research (CIBMTR).

Patients were given:

  • Four doses of abatacept: 10 mg/kg on Days -1, +5, +14, and +28, and/or
  • CNI (tacrolimus or cyclosporine): given as standard through Day +100 and weaned between Days +100–180 as tolerated, plus
  • MTX: 15 mg/m2 on Day +1 and 10 mg/m2 on Days +3, +6, and +11.

Key endpoints

  • Primary endpoint: Cumulative incidence of severe (Grade III–IV) aGvHD at Day +100.
  • Secondary endpoint: Day +180 severe aGvHD-free survival (SGFS).

Other endpoints included Grade III–IV aGvHD at Day +180; Grade II–IV aGvHD at Days +100 and +180; cGvHD at 1 year; NRM; relapse; relapse-free survival (RFS); overall survival (OS); cytomegalovirus reactivation and disease; Epstein-Barr virus reactivation and post-transplant lymphoproliferative disease; hematologic recovery; and donor engraftment.

Patient and transplant characteristics

Table 1. Baseline patient and transplant characteristics1

Characteristic

MMUD

MUD

Aba
(n = 38)*

CIBMTR control
(n = 127)

Aba
(n = 73)

Placebo
(n = 69)

Median age, years (range)

36.7 (6.6−76.5)

45 (6.0−74.4)

44.1 (6.9−71.9)

41 (7.6−74.2)

Age > 21 years, %

57.9

69.3

78.1

75.4

White ethnicity, %

68.4

82.7

86.3

87.0

Performance scores > 90%, %

76.3

74.8

71.2

75.4

CIBMTR disease stage, %

Advanced

13.2

15.7

15.1

20.3

Intermediate

15.8

14.2

19.2

23.2

Early

68.4

69.3

64.4

55.0

Chemosensitive

2.6

0.8

1.3

1.4

Conditioning intensity, %

MAC

73.7

68.5

75.3

71.0

RIC

26.3

31.5

24.7

29.0

CNI, %

Tacrolimus

68.4

75.6

84.9

84.1

Cyclosporine

31.6

24.4

15.1

15.9

Graft type, %

Peripheral blood

47.4

62.2

54.8

62.3

Bone marrow

52.6

37.8

45.2

37.7

Aba, abatacept; CIBMTR, Center for International Blood and Marrow Transplant Research; CNI, calcineurin inhibitor; MAC, myeloablative conditioning; MMUD, mismatched unrelated donor; MUD, matched unrelated donor; RIC, reduced intensity conditioning.

*Data from patients matched to the CIBMTR control group.

The most common malignancy experienced in this patient population was acute myeloid leukemia, followed by acute lymphoid leukemia and myelodysplastic syndromes. As listed in Table 1, most patients received myeloablative conditioning. Controls were well matched for patient characteristics, and the majority of patients received tacrolimus as CNI – this was especially prominent in the 8/8 cohort.  

Sex matching of donors and recipients was achieved in roughly 50% of patients across all groups, and graft source was split between peripheral blood and bone marrow across the whole population. However, in the historical CIBMTR control group, data on sex matching was missing in 28% of patients and data on the donor-recipient Epstein-Barr virus status was not available.

Key points

  • Abatacept was administered in combination with CNI/MTX to 43 patients in the MMUD cohort and 73 patients in the MUD group.
  • To compare data between MMUD transplanted patients, a group of 38 patients out of 43 who had received abatacept was matched to the CIBMTR control group.
  • Addition of abatacept significantly reduced the incidence of severe (Grade III−IV) aGvHD in MMUD transplanted patients when compared to the historical CIBMTR controls (p < 0.001).
    • Interestingly, improvement in Grade III−IV aGvHD with abatacept was only significant for patients who had been transplanted with MMUD.
  • A benefit was also seen in the MUD cohort randomized to abatacept for reduced incidence of aGvHD Grades II−IV (p = 0.006)(Table 2).
  • Similarly, improvements in RFS, NRM, and OS after 2 years were significantly different in the MMUD groups comparing patients treated with abatacept versus historical matched controls. No difference was found for the MUD cohorts, possibly because the study was not powered to show a difference for these outcomes.
  • Early treatment failure was assessed by investigating SGFS at Day +180. Again, addition of abatacept significantly improved outcomes in both MMUD and MUD transplanted patients when compared with a historical control/placebo group (MMUD, p < 0.001; MUD, p = 0.05)

Table 2. Outcome of treatment1

Outcomes

MMUD

MUD

Aba
(n = 38)

CIBMTR
(n = 127)

p value

Aba
(n = 73)

Placebo
(n = 69)

p value

Acute GvHD at Day 100, % (80% CI)

Grade II−IV

39.5 (29.2−49.6)

53.2 (47.3−58.7)

0.06

43.1 (35.5−50.6)

62.1 (53.9−69.3)

0.006

Grade III-IV

0 (0−0)

30.2 (25.0−35.5)

< 0.001

6.8 (3.7−11.3)

14.8 (9.7−20.8)

0.13

Acute GvHD at Day 180, % (80% CI)

Grade II−IV

39.5 (29.2−49.6)

57.4 (51.3−62.9)

0.03

44.8 (37−52.3)

63.7 (55.5−70.8)

0.006

Grade III−IV

0 (0−0)

32.1 (26.7−37.5)

< 0.001

6.8 (3.7−11.3)

14.8 (9.7−20.8)

0.13

Chronic GvHD at 1 year, % (80% CI)

Mild-severe

62.2 (50.0−72.2)

45.9 (39.6−51.9)

0.74

51.9 (43.8−59.3)

45.3 (36.8−53.3)

0.55

Mod-severe

N/A

44.6 (36.8−52.2)

36 (28.2−44)

0.32

Other outcome measures, % (80% CI)

SGFS at Day 180

100 (100−100)

58.7 (52.7−64.2)

< 0.001

93.2 (88.2−96.1)

82 (75−87.2)

0.05

Relapse

7.9 (3.4−14.8)

21.4 (16.7−26.5)

0.21

21.5 (15.4−28.1)

23.6 (17.2−30.5)

0.66

RFS at 2 years

75.9 (64.1−84.1)

38.3 (32.4−44.1)

0.001

65.7 (57.8−72.5)

60.3 (52.2−67.5)

0.28

NRM at 2 years

16.3 (8.5−26.3)

40.3 (34.4−46.1)

0.01

12.8 (8.2−8.5)

16.1 (10.9−22.3)

0.45

OS at 2 years

76.9 (64.4−85.2)

45.3 (39.3−51.1)

0.002

74.3 (66.9−80.4)

64 (55.9−71)

0.15

Aba, abatacept; CI, confidence interval; CIBMTR, Center for International Blood and Marrow Transplant Research control group; GvHD, graft-versus-host disease; MMUD, mismatched unrelated donor; mod, moderate; MUD, matched unrelated donor; NRM, non-relapse mortality; OS, overall survival; RFS, relapse free survival; SGFS, severe aGvHD-free survival.

Significant values are highlighted in bold.

  • Addition of abatacept did not affect the incidence or severity of chronic (c) GvHD, with a comparable percentage of patients experiencing mild−severe symptoms in both the treatment and control/placebo groups (MMUD: HR, 1.26; 80% CI, 0.97−1.64; p = 0.74 and MUD: HR, 1.17; 80% CI, 0.85−1.61; p = 0.55).
  • Successful donor engraftment, neutrophil and platelet restoration, and leukocyte reconstitution were achieved in all cohorts. In addition, there was no significant difference in cytomegalovirus or Epstein-Barr virus reactivation in MUD transplanted patients. These data were unavailable for the MMUD cohorts.
  • There was no significant difference in the rate of relapse in the abatacept group and control/placebo group (MMUD: HR, 0.45; 80% CI, 0.22−0.91; p = 0.21 and MUD: HR, 0.86; 80% CI, 0.54−1.35; p = 0.66).
  • Using flow cytometry following treatment levels, investigators found that GvHD prophylaxis with abatacept significantly preserved the proportions of naïve T cells.

Subanalysis in Black patients reported at the TCT 2021 Meeting

The focus of this subanalysis was to compare safety of 43 abatacept-treated patients with MMUD transplant with 69 placebo-treated patients who had received an MUD transplant in the ABA2 trial.2 This subanalysis confirmed that the MMUD cohort treated with abatacept showed a significantly reduced risk of aGvHD Grade II−IV compared with the MUD cohort treated with placebo (p = 0.013). This significant reduction was also seen for severe aGvHD (Grade III−IV) with a cumulative incidence of 2.3% for the MMUD cohort vs 14.8% for the MUD cohort (p = 0.033). As in the main analysis, no impact was seen on the incidence of cGvHD following abatacept treatment. No statistical difference was found between both cohorts for TRM, survival outcomes, relapse, engraftment, immune reconstitution, and viral reactivation.

The subanalysis concluded that due to the reduced risk of severe aGvHD in MMUD transplanted patients receiving abatacept, the disadvantages of using MMUD can be overcome. This may mitigate the racial/ethnic differences in outcomes following HSCT which are partly due to the decreased availability of MUD for Black people. Muna Qayed also reported on the initiation of a trial (NCT04380740) to investigate the impact of extending the duration of treatment of abatacept on cGvHD.

Conclusion

Safe and effective GvHD prophylaxis strategies for patients without HLA-matched sibling donors are desperately needed. In ABA2, abatacept was shown to reduce the incidence of aGvHD in patients receiving MMUD and MUD transplants and greatly improve survival outcomes for the MMUD cohort when compared to a matched historical control. The safety profile for this treatment was also shown to be acceptable. However, using a four-dose regimen of abatacept in this trial was not shown to have any impact on the incidence of chronic GvHD. In order to assess if a longer dosing schedule would improve the risk of cGvHD development, further trials are necessary.

  1. Watkins B, Qayed M, McCracken C, et al. Phase II trial of costimulation blockade with abatacept for prevention of acute GVHD. J Clin Oncol. 2021. Online ahead of print. DOI: 1200/JCO.20.01086
  2. Qayed M, Watkins BK, Gillespie S, et al. Comparable outcomes for matched and mismatched unrelated donor (URD) transplantation with the addition of abatacept to standard graft versus host disease prophylaxis. Transplantation and Cellular Therapy. 2021;27(Issue 3, Supplement):S32-S33. DOI: 1016/S2666-6367(21)00059-2

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