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. 2020 Sep;22(9):503-510.
doi: 10.1016/j.jcyt.2020.05.005. Epub 2020 Jul 1.

Early CD4+ T cell reconstitution as predictor of outcomes after allogeneic hematopoietic cell transplantation

Ichelle van Roessel  1 , Susan Prockop  2 , Elizabeth Klein  3 , Farid Boulad  3 , Andromachi Scaradavou  3 , Barbara Spitzer  3 , Andrew Kung  3 , Kevin Curran  3 , Richard J O'Reilly  3 , Nancy A Kernan  3 , Maria Cancio  3 , Jaap Jan Boelens  3
Affiliations

Early CD4+ T cell reconstitution as predictor of outcomes after allogeneic hematopoietic cell transplantation

Ichelle van Roessel et al. Cytotherapy. 2020 Sep.

Abstract

Background: An association between early CD4+ T cell immune reconstitution (CD4+ IR) and survival after T-replete allogeneic hematopoietic cell transplantation (HCT) has been previously reported. Here we report validation of this relationship in a separate cohort that included recipients of ex vivo T-cell-depleted (TCD) HCT. We studied the relationship between CD4+ IR and clinical outcomes.

Methods: A retrospective analysis of children/young adults receiving their first allogeneic HCT for any indication between January 2008 and December 2017 was performed. We related early CD4+ IR (defined as achieving >50 CD4+ T cells/µL on two consecutive measures within 100 days of HCT) to overall survival (OS), relapse, non-relapse mortality (NRM), event-free survival (EFS) and acute graft-versus-host disease (aGVHD). Fine and Gray competing risk models and Cox proportional hazard models were used.

Results: In this analysis, 315 patients with a median age of 10.4 years (interquartile range 5.0-16.5 years) were included. The cumulative incidence of CD4+ IR at 100 days was 66.7% in the entire cohort, 54.7% in TCD (N = 208, hazard ratio [HR] 0.47, P < 0.001), 90.0% in uCB (N = 40) and 89.6% in T-replete (N = 47) HCT recipients. In multi-variate analyses, not achieving early CD4+ IR was a predictor of inferior OS (HR 2.35, 95% confidence interval [CI] 1.46-3.79, P < 0.001) and EFS (HR 1.80, 95% CI 1.20-2.69, P = 0.004) and increased NRM (HR 6.58, 95% CI 2.82-15.38, P < 0.001). No impact of CD4+ IR on relapse or aGVHD was found. Within the TCD group, similar associations were observed.

Conclusion: In this HCT cohort, including recipients of TCD HCT, we confirmed that early CD4+ IR was an excellent predictor of outcomes. Finding strategies to predict or improve CD4+ IR may influence outcomes.

Keywords: CD4 T Cells; Hematopoietic transplant; Pediatric; T-cell reconstitution; immune reconstitution.

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Conflict of interest statement

Conflict of Interest: None of authors has relevant financial interest related to this topic. Some of authors have non-related financial interest: JJB consulting Magenta, Advanced clinical, Bluebird bio, Bluerock, Omeros, Takeda, Avrobio, CK consulting Mesoblast, Novartis, SP consulting

Figures

Figure 1.
Figure 1.
Outline of patients included and excluded from analysis
Figure 2.
Figure 2.
A. Cumulative incidence (CI) CD4+ T cell reconstitution according to transplant type / manipulation (cell source). CD4+ IR was defined as having greater than or equal to 50×106 CD4+ T cells/L in 2 consecutive measurements within 100 days after SCT. B. Cumulative incidence of CD4+ T cell reconstitution according to TCD technique: “Isolex/E- and SBA-E-- combined‟ versus CliniMACS, Miltenyi.
Figure 3.
Figure 3.
A. Cumulative incidence CD4+ T cell reconstitution according to median age in whole cohort. B. Cumulative incidence CD4+ T cell reconstitution according to HLA-matching in patients undergoing HCT with a TCD graft.
Figure 4.
Figure 4.
A Continuous CD4+ T cell recovery (x106 T cells) within 100 days after transplantation, according to CD 4 reconstitution (no CD4+IR in red line “0” and CD4+IR in blue line “1”) . B. Continuous values of CD8+ T cell recovery (x106 T cells) within 100 days after transplantation, according to CD 4 reconstitution (no CD4+IR in red line “0” and CD4+IR in blue line “1”)
Figure 5.
Figure 5.
Outcomes according to CD4+ T cell IR. Plots on the left (A, C, E) show results in all (whole cohort) patients. Plots on the right (B, D, F) show results in T cell depleted patients. Red lines show patients without CD4 IR, green lines patients with CD4 IR. Dotted lines show adjusted curves; curves for NRM, OS and EFS are adjusted for significant predictors from multivariate analysis (Table 2). (A) NRM according to CD4 IR. (B) NRM according to CD4 IR in TCD. (C) OS according to CD4 IR. (D) OS according to CD4 IR in TCD. (E) EFS according to CD4 IR. (F) EFS according to CD4 IR in TCD. (G) aGvHD according to CD4 IR. (H) aGvHD according to CD4 IR in TCD. (I) cGvHD (all) according to CD4 IR. (J) cGvHD (all) according to CD4 IR in TCD.
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