All content on this site is intended for healthcare professionals only. By acknowledging this message and accessing the information on this website you are confirming that you are a Healthcare Professional.

The GvHD Hub uses cookies on this website. They help us give you the best online experience. By continuing to use our website without changing your cookie settings, you agree to our use of cookies in accordance with our updated Cookie Policy

A phase III study of calcineurin inhibitor-free chronic GvHD prophylaxis in patients undergoing HLA-matched myeloablative HSCT

Jan 10, 2022
Share:

The standard approach to prevent graft-versus-host disease (GvHD) in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) is the use of a combination therapy including calcineurin inhibitors (CNIs).1 However, CNIs need regular pharmacokinetic monitoring, may increase the risk of renal toxicity and thrombotic microangiopathy, and their prolonged use may predispose patients to infections and reduce graft-versus-tumor effects, ultimately precluding the effectiveness of post-HSCT therapies. Chronic GvHD (cGvHD) is common post HSCT, affecting 3555% of transplantation survivors, with higher rates and severity in peripheral blood stem cell (PBSC) compared with bone marrow (BM) grafts. More recently, CNI-free approaches using donor T-cell depletion of PBSC grafts with an intensified myeloablative conditioning regimen or in vivo post-transplantation cyclophosphamide (PTCy) as a single agent have shown promising results for GvHD prophylaxis.1

Here, we summarize the key findings published by Luznik et al.1 in Journal of Clinical Oncology of a phase III trial (NCT02345850) comparing CD34+ selected PBSCs, PTCy after a BM graft, or tacrolimus (Tac) + methotrexate (MTX) after a BM graft in patients with acute myeloid leukemia or myelodysplastic syndromes with a human leukocyte antigen (HLA)-matched donor.

Study design

This was a three-arm, phase III, multicenter, open-labelled, randomized controlled study performed by the Blood and Marrow Transplant Clinical Trial Network (BMT-CTN). The study compared HSCT approaches among patients aged ≤65 years undergoing HLA-matched myeloablative HSCT for acute leukemia in complete remission, complete remission with incomplete hematologic recovery, or myelodysplastic syndromes with <5% blasts in the BM. Patients were enrolled from 26 centers across Germany and the USA. HLA-matched related or unrelated donors were defined as 8 out of 8 matches. Patients were randomly allocated to one of the three treatment arms (Figures 1 and 2).

Figure 1. Treatment allocation*

BM, bone marrow; Cy, cyclophosphamide; GCSF, granulocyte colony stimulating factor; HSCT, hematopoietic stem cell transplantation; IV, intravenous; MTX, methotrexate; PBSC, peripheral blood stell cell; Tac, tacrolimus.

*Data from Luznik et al.1

Figure 2. Consort diagram*

MTX, methotrexate; PTCy, post-transplantation cyclophosphamide; Tac, tacrolimus.

*Adapted from Luznik et al.1

Excluding patients who withdrew from the study, died, or were lost to follow up.

The primary endpoint was a composite of moderate to severe cGvHD, disease relapse, and chronic relapse-free survival (CRFS). Secondary endpoints included overall survival (OS), acute GvHD (aGvHD), cGvHD, disease relapse, relapse-free survival, transplant-related mortality (TRM), immunosuppression-free survival, hematologic recovery, toxicities, infections, and health-related quality of life.

The primary analysis was performed using the intent-to-treat population, with estimates of CRFS described for each group along with pairwise comparisons.

Results

Baseline characteristics

A total of 346 patients were enrolled, of which 327 underwent transplantation. The median age was 51 years (range, 13−66 years) and the median time from diagnosis to HSCT was 5 months (range, 1.3−231 months). Treatment non-compliance rates were 14.4%, 8.2%, and 2.6% in the CD34+, PTCy, and Tac + MTX arms, respectively. Patient characteristics are shown in Table 1.

Table 1. Baseline characteristics*

Characteristics, %

CD34+ selected graft
(n = 114)

PTCy
(n = 114)

Tac + MTX
(n = 118)

Male

54.4

62.3

54.2

Age group, years

 

 

 

              1−18

0.0

0.0

1.7

              19−40

25.4

24.6

23.7

              41−60

55.3

60.5

64.4

              >60

19.3

14.9

10.2

Lansky or Karnofsky score

 

 

 

              70−80

44.7

36.8

48.3

              90−100

55.3

63.2

51.7

Primary disease

 

 

 

              ALL

26.3

23.7

19.5

              AML

55.3

64.9

63.6

              MDS

16.7

9.6

13.6

              CMML

0.9

0.9

0.8

Disease stage for AML and ALL

 

 

 

              First CR

72.0

68.4

78.6

              ≥ Second CR

17.3

20.8

16.3

              CRi

2.1

6.9

0.0

MDS status

 

 

 

              No prior treatment

52.6

81.8

56.3

              Hematologic improvement

5.3

18.2

6.3

              No response or SD

42.1

0.0

25.0

Donor type

 

 

 

              Related

37.7

37.7

38.1

              Unrelated

62.3

62.3

61.9

              Post-transplant maintenance therapy

12.3

11.4

5.1

              Tyrosine kinase inhibitor

50.0

46.2

66.7

              FLT3 inhibitor

50.0

53.8

33.3

DRI

 

 

 

              Low or moderate

58.8

58.8

60.2

              High

31.6

34.2

33.9

HSCT comorbidity index

 

 

 

              0

36.5

37.6

38.6

              1−2

35.6

39.4

43.0

              ≥3

27.9

22.9

18.4

Pre-transplant status

 

 

 

              Positive

43.3

49.5

50.0

              Negative

56.7

50.5

50.0

Donor CMV status

 

 

 

              Positive

29.8

49.5

37.7

              Negative

70.2

50.5

62.3

Stem cell source

 

 

 

              Peripheral blood

94.2

10.1

10.5

              BM

5.8

89.9

89.5

Conditioning regimen

 

 

 

              TBI + Cy + thiotepa + rATG

26.0

0.0

0.0

              Bu + Mel +Flu + rATG

65.4

0.0

0.0

              Bu + Cy

3.8

37.6

27.2

              Bu + Flu

2.9

35.8

52.6

              Cy + TBI

1.0

24.8

19.3

ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; BM, bone marrow; Bu, busulfan; CMML, chronic myelomonocytic leukemia; CMV, cytomegalovirus; Cy, cyclophosphamide; DRI, disease risk index; Flu, fludarabine; GvHD, graft-versus-host disease; HSCT, hematopoietic stem cell transplantation; MDS, myelodysplastic syndrome; Mel, melphalan; MTX, methotrexate; PTCy, post-transplantation cyclophosphamide; rATG, rabbit antithymocyte-globulin; SD, stable disease; Tac, tacrolimus; TBI, total body irradiation.
*Adapted from Luznik et al.1

Primary outcomes

CRFS was 50.6%, 48.1%, and 41.0% in the CD34+, PTCy, and Tac + MTX arms, respectively (Table 2).

  • Compared with the Tac + MTX arm, the hazard ratios (HRs) for CRFS were 0.80 and 0.86 in the CD34+ and PTCy arms, respectively, and the HR was 0.93 comparing the CD34+ and PTCy arms (Table 3).
  • The HR was 1.43 (p = 0.026) for CRFS in patients aged ≥50 years compared with younger patients.

Table 2. Primary and secondary outcomes*

Outcomes, % (95% CI)

CD34+ selected graft

PTCy

Tac + MTX

p value

CRFS at 2 years

50.6
(40.8−60.0)

48.1
(38.5−57.1)

41.0
(32−49.9)

0.224

OS at 2 years

60.1
(50.1−68.8)

76.2
(67.1−83.1)

76.1
(67.2−83)

0.006

Moderate to severe cGvHD at 2 years

8.9
(4.3−15.5)

27
(18.7−36)

33.7
(25.1−42.5)

<0.001

TRM at 2 years

21.5
(14.1−30.0)

15.7
(9.6−23.2)

7.9
(3.9−13.8)

0.020

Relapse at 2 years

21.4
(14.0−29.8)

13.9
(8.1−21.2)

25.6
(17.9−33.9)

0.076

RFS at 2 years

57.1
(46.9−66.0)

70.3
(60.7−78.0)

66.5
(56.9−74.3)

0.029

Grade II−IV aGvHD at 100 days

16.3
(9.9−24.1)

37.6
(28.5−46.6)

29.8
(21.7−38.4)

0.026

Grade III−IV aGvHD at 100 days

2.9
(0.8−7.5)

10.1
(5.3−16.6)

3.5
(1.1−8.1)

0.037

IFS at 1 year

57.8
(48.3−67.4)

67.6
(58.8−76.4)

57.9
(48.8−67.0)

0.24

Delayed engraftment

2.9
(0.6−8.2)

8.3
(3.8−15.1)

3.5
(1.0−8.7)

0.13

Secondary graft failure

2.9
(0.8−7.5)

0

0.9
(0.1−4.3)

0.15

CMV reactivation by 180 days

11.6
(6.3−18.6)

9.2
(4.7−15.5)

9.6
(5.1−15.9)

0.97

EBV reactivation by 180 days

12.5
(7.0−19.7)

0.9
(0.1−4.6)

0.9
(0.1−4.3)

<0.001

aGvHD, acute graft-versus-host disease; cGvHD, chronic graft-versus-host disease; CI, confidence interval; CMV, cytomegalovirus; CRFS, chronic relapse-free survival; EBV, Epstein-Barr virus; HR, hazard ratio; IFS, immunosuppressive-free survival; MTX, methotrexate; OS, overall survival; PTCy, post-transplant cyclophosphamide; RFS, relapse-free survival; Tac, tacrolimus; TRM, transplant-related mortality.
*Adapted from Luznik et al.1
Values in bold are statistically significant.

Secondary outcomes

  • The 2-year OS was 60.1%, 76.2%, and 76.1% in the CD34+, PTCy, Tac + MTX arms, respectively (Table 2).
    • Compared with the Tac + MTX arm, the HRs for OS were 1.74 and 1.02 in the CD34+ and PTCy arms, respectively, and the HR was 1.77 comparing the CD34+ and PTCy arms (Table 3).
  • For overall mortality, patients aged ≥50 years compared with younger patients had a HR of 1.75 (p = 0.01), and high disease risk index compared with low or moderate was associated with a HR of 1.80 (p = 0.01).
  • Cumulative incidences of moderate to severe cGvHD at 2 years was highest in the Tac + MTX arm compared with the CD34+ and PTCy arms (p < 0.001) (Table 2).
    • Patients in the CD34+ arm showed lower moderate to severe cGvHD compared with those in the PTCy arm (p = 0.02).
  • Cumulative incidence of TRM at 2 years was highest among patients in the CD34+ arm compared with the PTCy and Tac + MTX arms (p = 0.020) (Table 2).
    • TRM was higher in patients aged ≥50 years compared with younger patients (HR, 3.29; p < 0.01).
  • PTCy was associated with comparable cGvHD and survival outcomes to Tac + MTX, showing a trend toward lower disease relapse (p = 0.037) (Table 3).
  • Cumulative incidences of Grade III infections at 2 years were 29.8%, 20.2%, and 14% for the CD34+, PTCy, and Tac + MTX arms, respectively (p = 0.014).
  • Disease relapse was the most common cause of death; occurring in 45.2%, 48.1%, and 73.4% of patients in the CD34+, PTCy, and Tac + MTX arms, respectively.

Table 3. Pairwise treatment comparison*

Outcomes

CD34+ vs Tac + MTX

PTCy vs Tac + MTX

CD34+ vs PTCy

HR (95% CI)

p value

HR (95% CI)

p value

HR (95% CI)

p value

CRFS at 2 years

0.80
(0.56−1.15)

0.237

0.86
(0.61−1.23)

0.413

0.93
(0.64−1.35)

0.717

OS at 2 years

1.74
(1.09−2.80)

0.020

1.02
(0.60−1.72)

0.953

1.77
(1.09−2.88)

0.019

Moderate to severe cGvHD at 2 years

0.25
(0.12−0.52)

<0.001

0.79
(0.48−1.29)

0.342

0.32
(0.15−0.69)

0.002

TRM at 2 years

2.86
(1.32−6.20)

0.008

1.88
(0.84−4.21)

0.127

1.53
(0.81−2.89)

0.188

Relapse at 2 years

0.89
(0.51−1.54)

0.672

0.52

(0.28−0.96)

0.037

1.76
(0.91−3.39)

0.091

RFS at 2 years

1.35
(0.88−2.09)

0.172

0.84
(0.52−1.34)

0.463

1.64
(1.04−2.59)

0.034

Grade II−IV aGvHD at 100 days

0.54
(0.30−0.96)

0.036

1.43
(0.91−2.26)

0.120

0.40
(0.23−0.71)

0.002

Grade III−IV aGvHD at 100 days

0.82
(0.18−3.67)

0.798

2.95
(0.94−9.28)

0.064

0.28
(0.08−0.99)

0.050

aGvHD, acute graft-versus-host disease; cGvHD, chronic graft-versus-host disease; CI, confidence interval; CRFS, chronic relapse-free survival; HR, hazard ratio; MTX, methotrexate; OS, overall survival; PTCy, post-transplant cyclophosphamide; RFS, relapse-free survival; Tac, tacrolimus; TRM, transplant-related mortality.
*Adapted from Luznik et al.1
Values in bold are statistically significant.

Conclusion

This phase III study demonstrated that CD34+ selection or PTCy were not superior to Tac + MTX with BM in patients with HLA-matched transplantation. CD34+ selection showed significant reduction in cGvHD, however had higher rates of TRM. Although TRM, cGvHD, CRFS, and OS were similar for PTCy and Tac + MTX, PTCy was associated with more aGvHD. However, PTCy showed a trend towards improved relapse rate and relapse-free survival in comparison to Tac + MTX and CD34+ selection, respectively. Therefore, PTCy may be a transplant option in patients contraindicated to CNI or who require a CNI-free approach. Interestingly, this study demonstrated better TRM and OS for Tac + MTX compared with the experimental arms, but it was associated with the highest rate of cGvHD. Tac + MTX or PTCy and a BM graft offer improved survival rates >75% and should be considered the new standard approach for patients with hematologic malignancies. Further studies are warranted that focus on improving cGvHD and disease relapse using Tac + MTX, as well as investigating the effectiveness of PTCy + Tac + mycophenolate mofetil and anti-thymocyte globulin + Tac + MTX.

  1. Luznik L, Pasquini MC, Logan B, et al. Randomized phase III BMT CTN trial of calcineurin inhibitor-free chronic graft-versus-host disease interventions in myeloablative hematopoietic cell transplantation for hematologic malignancies. J Clin Oncol. 2021. Online ahead of print. DOI: 1200/JCO.21.02293

Share: