Impact of graft CD4/CD8 ratio on HSCT outcomes with different GvHD-prophylaxis regimens

A high CD4/CD8 T-cell ratio in the hematopoietic stem cell transplant (HSCT) allograft is associated with increased risk of graft-versus-host disease (GvHD) and mortality. An optimal GvHD prophylaxis regimen may mitigate this risk; however, the impact of the CD4/CD8 ratio in the graft has not yet been systematically compared using different GvHD prophylaxis regimens.¹

To address this knowledge gap, Nikoloudis et al. ¹ aimed to analyze the risks associated with a high (i.e., above 75th percentile) CD4/CD8 ratio in HSCT allografts in three different cohorts within a single center, stratified by the applied GvHD prophylactic platforms. Here, we summarize the key findings.

Methods¹

This retrospective monocentric study from an Austrian EBMT center included all consecutive HSCTs performed with peripheral blood stem cells between January 21, 2000, and June 29, 2021. The impact of the graft CD4/CD8 ratio was analyzed in the following three cohorts defined by GvHD prophylaxis:

• Cyclosporine A with methotrexate (CSA/MTX; n = 185);
• CSA with mycophenolate mofetil (CSA/MMF; n = 294); and
• Posttransplant cyclophosphamide combined with tacrolimus and MMF (PTCy/TAC/MMF; n = 113).

The impact of the CD4/CD8 ratio was analyzed for endpoints including overall survival (OS), incidence of non-relapse mortality, acute GvHD (aGvHD), chronic GvHD (cGvHD), aGvHD-associated mortality, relapse incidence, and progression-free survival.

Results¹

The cohort was stratified according to GvHD prophylaxis regimen. Compared to the CSA/MMF and PTCy-TAC/MMF cohorts, recipients in the CSA/MTX cohort were younger and a higher proportion of patients had a diagnosis of AML or ALL, matched-related donors, and myeloablative conditioning regimens. The key patient and transplant characteristics are summarized in Table 1.

Table 1. Patient characteristics*

ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; ATG, antithymocyte globulin; CSA, cyclosporine; MAC, myeloablative conditioning; MDS, myelodysplastic syndrome; MMF, mycophenolate-mofetil; MTX, methotrexate; PTCy, posttransplant cyclophosphamide; RIC, reduced-intensity conditioning; TAC, tacrolimus. *Adapted from Nikoloudis, et al.1
Characteristic, % (unless otherwise stated)	CSA/MMF (n = 294)	CSA/MTX (n = 185)	PTCy-TAC/MMF (n = 113)	p value
Median age of recipient (range), years	53.68 (19.55–73.04)	43.96 (18.05–74.65)	56.96 (19.36–74.90)	<0.001
Median age of donor (range), years	38.40 (18.31–76.99)	37.16 (18.29–67.44)	36.90 (18.54–63.61)	0.77
Diagnosis
MDS	25.9	15.7	22.1	0.03
AML	40.1	54.6	46.9
Lymphoma	20.1	10.8	17.7
ALL	12.9	16.2	11.5
Nonmalignant,               immunodeficiency	1.0	2.7	1.8
Donor type
Matched related	44.2	53.5	0	<0.01
Unrelated	55.8	46.5	8.8
Haploidentical               related	0	0	91.2
Conditioning
MAC	43.5	80	63.7	<0.001
RIC	56.5	20	36.3
ATG
No	23.1	40.5	—	<0.001
Yes	76.9	59.5	—
Median CD4/CD8 ratio (range)	1.88 (0.52–6.00)	1.90 (0.33–8.26)	1.88 (0.40–6.69)	0.91
Median CD3 cell dose (range), 107/kg	25.54 (3.40–87.15)	24.80 (5.60–71.11)	32.47 (2.87–82.91)	<0.001

In the CSA/MMF cohort, a high CD4/CD8 ratio was associated with significantly decreased OS, increased non-relapse mortality, and GvHD-associated mortality (Figure 1). In the PTCy/TAC/MMF cohort, a high CD4/CD8 ratio was associated with significantly lower OS and Grade 3–4 aGvHD. By contrast, a high CD4/CD8 ratio had no significant impact on any of the investigated endpoints in the CSA/MTX cohort (Figure 1).¹

aGvHD, acute GvHD; cGvHD, chronic GvHD; CSA, cyclosporine; GRFS, GVHD and relapse-free survival; GvHD, graft-versus-host disease; MMF, mycophenolate mofetil; MTX, methotrexate; NRM, non-relapse mortality; PTCy, post-transplant cyclophosphamide; TAC, tacrolimus.
*Adapted from Nikoloudis, et al.^1
†Sub-hazard ratio > 1 indicates increased probability of an event with high CD4/CD8 ratio compared with low CD4/CD8 ratio.
^‡p = 0.01.
^§p = 0.04.
^ǁp = 0.005.
^¶p = 0.02.

In recipients of a HLA-matched transplant who had a top-quartile CD4/CD8 ratio with either an MTX or MMF prophylaxis regimen (n = 116), MTX-based prophylaxis was associated with better OS versus MMF-based prophylaxis. In contrast, in recipients with a lower CD4/CD8 ratio (quartiles 1–3; n = 363), outcomes were identical with MTX versus MMF (Figure 2).

GvHD, graft-versus-host disease; HSCT, hematopoietic stem cell transplant; MMF, mycophenolate-mofetil; MTX, methotrexate; OS, overall survival.
*Adapted from Nikoloudis et al.¹

No differences were observed in the impact of high CD4/CD8 ratio on OS when the entire cohort was stratified by median age, conditioning regimen, or median CD3 cell dose. Also, the adverse effect of a high CD4/CD8 ratio was independent of the use of anti-T-lymphocyte globulin and vice versa.

Conclusion¹

This study revealed that a high CD4/CD8 ratio in the graft can adversely impact HSCT outcomes, particularly in recipients with post-grafting CSA/MMF and PTCy/TAC/MMF, while MTX-based prophylaxis may largely alleviate this risk factor. Clinical implementation of these results could mean the addition of a short course of MTX (e.g., Day +1 and Day +3) instead of, or in addition to MMF in recipients of grafts with a high CD4/CD8 ratio. Further prospective studies are warranted to better understand the optimal prophylaxis platform for reduced intensity conditioning-based HLA-identical transplants.