GvHD Prophylaxis

Impact of ATG on post-allo-HSCT outcomes by pre-transplant MRD status

Measurable residual disease (MRD)-positive status prior to allogeneic hematopoietic stem cell transplantation (allo-HSCT) is associated with an increased relapse incidence (RI) and reduced overall survival (OS) in patients with acute myeloid leukemia (AML). Testing MRD status prior to transplant may help assess a patient’s disease risk and predict outcome.1

Anti-thymocyte globulin (ATG) is able to effectively deplete T-cells in vivo and is often used to prevent graft-versus-host disease (GvHD) – a major cause of non-relapse mortality (NRM) post-allo-HSCT.2 Some studies have shown that the use of ATG is associated with improved transplant outcomes, however since ATG can eliminate alloreactive donor T-cells, it may also reduce the graft-versus-leukemia effect resulting in increased RI and reduced OS.1,3 There is also a particular concern that ATG may increase RI in patients who are MRD-positive. Therefore, the optimal setting where ATG can be used without impacting leukemia-free survival (LFS) is currently undetermined.1

To assess whether the use of ATG impacted post-transplant outcomes, specifically in relation to pre-transplant MRD status, Arnon Nagler, Bhagirathbhai Dholaria, Myriam Labopin, and colleagues conducted a retrospective analysis of patients with AML who underwent allo-HSCT in first complete remission (CR1), stratified by MRD status. The results were recently published in Leukemia and are summarized in this article.

Study design1
  • Retrospective, multicenter analysis using the data set of the Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT)
  • Adult patients (N= 1,509), with de novo AML who underwent allo-HSCT in CR1 between 2006 and 2017 were selected
  • Transplants were received from:
    • Matched sibling donors (MSD): 59% (n= 855) or
    • 10/10 matched unrelated donors (MUD): 41% (n= 624)
  • MRD-status was assessed using molecular and/or immunophenotyping criteria. Sensitivity thresholds were:
    • Mutations-specific polymerase chain reaction (PCR): ranging from 10−3 to 10−6
    • Multiparameter flowcytometry: ranging from 10−3 to 10−6
    • Next-generation sequencing (NGS): ranging from 10−2 to 10−3,
Patient characteristics1
  • Median patient age (range): 51 (18–73) years
  • Median time from diagnosis to allo-HSCT (range): 4.7 (1.4–12.9) months
  • Adverse cytogenetics: 15%
  • FLT3 internal tandem duplication (ITD; FLT3-ITD): 51%
  • NPM1 mutation: 56%
  • MRD status:
    • MRD-negative: 1,083 patients
    • MRD-positive: 426 patients
  • Median year of allo-HSCT: 2014
  • Graft source, peripheral blood (PB): 82%
  • Conditioning:
    • Myeloablative (MAC): 58%
      • Most commonly busulfan/fludarabine (BuFlu): 53%
    • Reduced intensity (RIC): 42%
      • Most commonly busulfan/cyclophosphamide (BuCy): 40%
    • GvHD prophylaxis:
      • Cyclosporin (CsA)/methotrexate (MTX): 51%
      • CsA/mycophenolate mofetil (MMF): 24%
      • Post-transplant cyclophosphamide (PTCy) was only given to 3% of patients
    • ATG usage (MRD-negative versus MRD-positive): 52% (n= 561) vs 58% (n= 239)
      • Patients who received transplants from MUDs were more likely to receive ATG
      • ATG was more frequently used with PB grafts and RIC regimens
      • Patients who had not received ATG tended to have a longer follow up.
Results1

Total cohort results are shown in Table 1.

Table 1. Survival and GvHD rates for the total cohort (N= 1,509)

Factor

%

95% CI

Grade II–IV aGvHD in first 100 days post-allo-HSCT

24

22.1–26.6

Two-year incidence of grade II–IV cGvHD

38

34.6–40.4

Two-year incidence of extensive cGvHD

20

17.6–23.0

Two-year NRM

11

8.9–12.5

Two-year LFS

62

59.3–65.0

Two-year OS

62

59.3–65.0

aGvHD, acute graft-versus-host disease; allo-HSCT, allogeneic hematopoietic stem cell transplantation; cGvHD, chronic graft-versus-host disease; CI, confidence interval; LFS; leukemia-free survival; NRM, non-relapse mortality; OS, overall survival

Univariate analysis (two year results; entire study population)

  • ATG versus no-ATG: GvHD-free relapse-free survival (GRFS) was significantly higher in patients receiving ATG (p< 0.01) and the two-year incidence of chronic GvHD (cGvHD) and extensive cGvHD was significantly lower (p< 0.01 for both)
  • Intermediate vs adverse cytogenetics: patients with adverse cytogenetics had a significantly lower OS compared to those with intermediate cytogenetics (p< 0.01)
  • FLT3-ITD negative vs positive: patients with FLT3-ITD had a significantly higher relapse rate (p< 0.01), lower LFS (p< 0.01), OS (p< 0.01), and GRFS (p< 0.01). They also had a lower rate of cGvHD (p= 0.03) and extensive cGvHD (p< 0.01)
  • MRD-negative vs positive: patients who were MRD-negative had a significantly lower incidence of relapse (p< 0.01) and higher LFS, OS and GRFS (all p< 0.01)

Multivariate analysis

Multivariate analysis was conducted to evaluate the individual effect of baseline patient and transplant characteristics on outcome measures. The impact of ATG on post-transplant patient outcome in MRD-negative patients is shown in Table 2. The use of ATG led to a reduced rate of grade II–IV acute GvHD (aGvHD), cGvHD and extensive GvHD whilst improving LFS, OS and GRFS and without impacting RI.

Table 2. Impact of ATG on post-transplant patient outcome in MRD-negative patients

Factor

Effect

HR

95% CI

P value

RI

None

0.80

0.59–1.1

0.17

Grade II–IV aGvHD

Reduced

0.71

0.51–0.99

0.04

Grade III–IV aGvHD

Reduced

0.37

0.20–0.66

<10-3

cGvHD

Reduced

0.55

0.41–0.72

<10-4

Extensive cGvHD

Reduced

0.42

0.27–0.64

<10-4

NRM

Reduced

0.66

0.43–1.0

0.05

LFS

Improved

0.74

0.58–0.95

0.02

OS

Improved

0.69

0.53–0.92

0.01

GRFS

Improved

0.62

0.50–0.77

<10-3

aGvHD, acute graft-versus-host disease; cGvHD, chronic graft-versus-host disease; CI, confidence interval; GRFS, GvHD-free relapse-free survival; LFS, leukemia-free survival; NRM, non-relapse mortality; OS, overall survival; RI, relapse incidence

In MRD-positive patients, the use of ATG did not impact RI, but did lead to a reduction in the rate of cGvHD and extensive cGvHD (Table 3). NRM, LFS, OS and GRFS were unaffected by the use of ATG in this population of patients.

Table 3. Impact of ATG on post-transplant patient outcome in MRD-positive patients

Factor

Effect

HR

95% CI

P value

RI

None

1.03

0.64–1.65

0.92

Grade II–IV aGvHD

None

0.89

0.53–1.50

0.66

Grade III–IV aGvHD

Reduced

0.58

0.22–1.48

0.25

cGvHD

Reduced

0.56

0.33–0.95

0.03

Extensive cGvHD

Reduced

0.4

0.20–0.80

0.01

NRM

None

0.55

0.21–1.46

0.23

LFS

None

0.93

0.61–1.42

0.74

OS

None

0.81

0.51–1.23

0.36

GRFS

None

0.87

0.61–1.24

0.43

aGvHD, acute graft-versus-host disease; cGvHD, chronic graft-versus-host disease; CI, confidence interval; GRFS, GvHD-free relapse-free survival; LFS, leukemia-free survival; NR, not reported; NRM, non-relapse mortality; OS, overall survival; RI, relapse incidence

In the regression analysis, other variables were found to be significantly associated with outcome. These are summarized below:

  • FLT3-ITD: In both MRD-negative and MRD-positive patients, the presence of FLT3-ITD was associated with a higher RI (p< 0.01 for both)
  • Cytogenetics: adverse risk cytogenetics were associated with poor OS in both MRD-negative and MRD-positive patients
  • Age: older age was associated with a poor OS in the MRD-negative group, predominantly due to an increase in NRM (p< 0.01)
  • Conditioning: the use of RIC was linked to a higher RI in MRD-positive patients (p< 0.01), leading to a poor OS (p= 0.04), though NRM was unaffected

Causes of death

  • The most common causes of death (given as ATG vs no ATG) were:
    • Relapse: 43.92% vs 54.36%
    • GvHD: 17.46% vs 23.08%
    • Infection: 16.93% vs 12.31%

Study limitations

  • Retrospective analysis
  • Lack of uniformity in MRD-assessment platforms and sensitivity thresholds
  • Lack of information on brand of ATG used
Conclusion1

In patients with AML undergoing allo-HSCT in CR1, ATG use was found to reduce the risk of GvHD and did not increase RI, even in patients who were MRD-positive prior to transplant. In MRD negative patients the use of ATG was also associated with improved LFS, OS, and GRFS. The authors concluded that ATG should be incorporated into standard pre-transplant regimens for patients with AML, irrespective of MRD-status and conditioning regimen intensity.

References
  1. Nagler A., Dholaria B., Labopin M. et al., The impact of anti-thymocyte globulin on the outcomes of Patients with AML with or without measurable residual disease at the time of allogeneic hematopoietic cell transplantation. Leukemia. 2019 Nov 14. DOI: 10.1038/s41375-019-0631-5
  2. Kumar A. et al., Antithymocyte globulin for graft-versus-host disease prophylaxis: an updated systematic review and meta-analysis. Bone Marrow Trans. 54, 1094–1106 (2019). DOI: 10.1038/s41409-018-0393-0
  3. Baron F. et al., Anti-thymocyte globulin as graft-versus-host disease prevention in the setting of allogeneic peripheral blood stem cell transplantation: a review from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Haematologica. 2017;102(2):224–234. DOI: 10.3324/haematol.2016.148510
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