aGvHD,   cGvHD

EBMT 2019 | Results from the PBMTC 1202/ABLE study: biological differences between pediatric late aGvHD and cGvHD by biomarker analysis

Late acute GvHD (aGvHD) and chronic GvHD (cGvHD) can be defined clinically according to the NIH consensus criteria, and represent leading causes of morbidity and mortality after allogeneic hematopoietic stem cell transplant (allo-HSCT). However, the differences in their biology are still not fully understood and hamper the development of predictive biomarkers and targeted therapies.

Kirk R Schultz from the University of British Columbia, Vancouver, CA, presented the results from the PBMTC 1202 / ABLE study (NCT02067832) during the 45th Meeting of the European Society for Blood and Marrow Transplantation (EBMT) in Frankfurt, Germany, on Tuesday 26 March 2019.1

The PBMTC 1202 / applied biomarkers in late effects of childhood cancer treatment (ABLE) study was conducted across 26 centers in Canada, the United States (US) and Europe. It aimed to investigate the biological difference between aGvHD and cGvHD by assessing biomarker levels at day 100 post- allo-HSCT.

Study design and patient characteristics

  • Pediatric patients (≤18 years) were enrolled at the time of allo-HSCT, prior to conditioning treatment beginning (N = 302) and 234 patients were available for day +100 assessment and sufficient follow up.
  • Data collected prospectively for 1-year post-HSCT
  • Two subgroups:
    • Control group: patients who did not develop cGvHD (n=123)
    • Experimental group: patients developing cGvHD (n=44) or late aGvHD (n=58)
  • Testing for prognostic cGvHD biomarkers occurred:
    • Within 96 hours of starting the conditioning regimen
    • On day +100 (+/- 14 days)
    • At 6 months and 12 months post-transplant
    • At the onset of cGvHD (no further samples were taken if cGvHD was detected between day 100 and 1-year post-transplant)
  • Definitions followed the 2005 NIH consensus criteria:
    • Patients not evaluable were excluded for many reasons, the most common (in ≥10 patients) were; toxic mortality (n = 16), non-engraftment (n = 14) and relapse (n = 11)
  • A marker was deemed significant if it had:
    • P value ≤ 0.05, AUC ≥60 and effect ratio ≥ 1.3 or ≤ 0.75, compared to controls
    • Cell populations or biomarkers only meeting 1 or 2 of the above criteria are not included/shown in the analysis below

Table 1: B-cell populations in cGvHD

 

P value

AUC

Effect ratio

Unswitched memory B-cells (MZ-like)

0.005

0.67

2.7

Classic switched memory B-cells

0.03

0.63

3.0

CD19+ B-cells

0.0005

0.71

0.45

T3 transitional B-cells (anergic naïve)

0.0003

0.68

0.69

T2 transitional B-cells (naïve mature)

0.03

0.64

0.72

Autoimmune/chronic activation B-cells, CD21low

0.03

0.72

0.46

Table 2: B-cell populations in late aGvHD

 

P  value

AUC

Effect ratio

Unswitched memory B-cells (MZ-like)

0.006

0.63

2.5

Classic switched memory B cells

0.01

0.61

2.4

CD19+ B-cells

NS

NS

NS

T3 transitional B-cells (anergic naïve)

0.0006

0.66

0.75

T2 transitional B-cells (naïve mature)

NS

NS

NS

Autoimmune/chronic activation B-cells, CD21low

NS

NS

NS

*Not Significant (NS)

Table 3: T-cells and cytolytic natural killer (NK) cell populations in cGvHD*

 

P value

AUC

Effect ratio

Activated T-cells

0.003

0.70

1.6

Peripheral naïve TH-cells

0.01

0.65

1.5

Follicular TH-cells

0.05

0.63

3.8

Activated cytolytic NK-cells

0.0003

0.70

1.6

Recent thymic emigrants (RTE) naïve TH-cells

0.04

0.61

0.63

RTE naïve TREG-cells

0.02

0.63

0.55

NKREG

0.005

0.65

0.74

* No significant associations were found in the equivalent analysis in late aGvHD

Table 4: Plasma marker analysis in cGvHD and late aGvHD

 

cGvHD

 

 

Late aGvHD

 

 

 

P value

AUC

Effect ratio

P value

AUC

Effect ratio

ST2

0.0002

0.69

1.5

0.006

0.60

1.7

MMP3

0.01

0.65

2.6

NS

NS

NS

CXCL9

0.03

0.60

1.8

NS

NS

NS

Aminopeptidase N (CD13)

0.006

0.64

1.4

NS

NS

NS

Table 5: Summary of changes in cell levels and plasma marker expression in late aGvHD and cGvHD

 

Late aGvHD

cGvHD

B-cells

 

Increase in switched and unswitched memory B-cells

 

 

Decrease in T3 transitional B-cells (anergic naïve)

 

Decrease in transitional B-cell populations (anergic naïve, naïve mature and autoimmune CD21low B-cells)

 

T- and NK-cells

 

 

No significant changes

 

Increased numbers of activated T-cells, naïve TH cells and follicular TH cells

 

 

Loss of RTE TH cells, RTE TREG cells, and NKREG cells

 

Plasma markers

Increased biomarkers: ST2

 

Increased biomarkers: ST2, MMP3, CXCL9 and aminopeptidase N (CD13)

 

Conclusion 

The study concluded that in both late aGvHD and cGvHD, transitional B-cell populations decrease, memory B-cells increase and ST2 expression levels are elevated. cGvHD, however, displays more complex abnormalities, with a loss of regulatory function (decreased RTE TREG cells and NKREG cells) and an increase in additional cytokines and follicular TH cells. Therefore, therapeutic targets may differ between late aGvHD and cGvHD. A further prospective validation study in 500 children is ongoing/planned.

References
  1. Shultz K. et al. Biological differences between pediatric late acute graft-versus-host disease (aGvHD) and chronic GvHD (cGvHD) identified by day 100 biomarker analysis: results of the PBMTC 1202/ABLE studies. Abstract OS7-5. 2019 Mar 26. 45th Annual Meeting of the European Society of Blood and Marrow Transplantation (EBMT), Frankfurt, DE
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