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Predictors of recovery from poor graft function
marily as a result of infectious complications. Of the patients who showed blood count recovery, those who initially had poor graft function in one or two lineages had a superior 5-year overall survival rate of 93.8% (95% CI: 82-99) compared to those with trilineage poor graft func- tion who had a 5-year overall survival rate of 53% (95% CI: 34-88) (Figure 2B). The rates or completeness of recov- ery together with their effect upon outcome were similar over time, as identified by comparing patient cohorts receiving CD34+-selected infusions in the early versus late time periods (2000-2009 versus 2010-2018) of the study (data not shown).
Discussion
Poor graft function occurs only in a minority of patients following allogeneic SCT but is associated with a high mortality. Management of such patients is resource-inten- sive with patients requiring multiple hospital visits or pro- longed, inpatient admissions. Our study shows that the majority of patients with poor graft function who are given CD34+-selected infusion without conditioning will subsequently have a hematologic improvement; in more than six of ten patients, the recovery will be permanent and complete, avoiding the need for transfusion or growth factor support. The procedure is safe with low rates of acute and chronic GvHD, consistent with the low doses of T cells contained within the CD34+-selected graft. Our report does, however, highlight that there are subgroups of patients (those with recipient or donor CMV seroposi- tivity, with active infection or with recipient-donor sex mismatching), who respond less favorably and for whom alternative strategies may be required.
Our study differs from other studies that employed CD34+-selected infusion only in patients with full donor chimerism. Reflecting the use of T-cell depletion in 91% of patients in our series, mixed chimerism was evident in 58% of recipients (affecting the T-cell lineage in all patients with or without involvement of B- and/or myeloid-lineages), with none of these patients having evi- dence of disease relapse. Our data confirm that the approach of CD34+-selected infusion is feasible in such patients with recovery rates similar to those of patients with full donor chimerism. Although a small subset of patients with mixed chimerism received a fixed dose of T cells at the time of CD34+-selected infusion, this had no effect upon outcome. To avoid the additional risk of GvHD, we do not routinely give additional T cells in this setting. We were unable to test whether the precise level of donor chimerism correlated with recovery because the analysis methods used to detect chimerism were only semi-quantitative at the time most patients were treated.
The main limitation of our analysis is the lack of a con- trol group so that it is difficult to measure the effect of the CD34+-selected infusion versus the effect of other hematopoietic stem cell (HSC)-intrinsic or -extrinsic fac- tors that lead to eventual recovery. The lack of a control group is particularly relevant to the observed kinetics of recovery with about one in two patients recovering more than 30 days following infusion (although most achieved complete or partial recovery within 3 months). We observed similar kinetics of recovery to those observed by other groups using CD34+-selected infusion without pre- conditioning.7-11 We currently lack a clear framework in
human patients for understanding how niche function and availability found in patients with poor graft function influence the re-populating capacity of infused CD34+- selected cells. While we presume that there are too few endogenous HSC to outcompete the infused HSC in patients with poor graft function, the number of available niches in this clinical setting is unknown and likely to be influenced by multiple factors including prior therapies, host-pathogen interactions and immune dysregulation.
The larger number of patients in this series compared to the numbers in other reports afforded us the opportunity to explore predictors of response in more detail. We found that active infection (identified using the surrogate of antimicrobial therapy) at the time of CD34+-selected infu- sion was the strongest negative predictor of recovery. Of note, lack of recovery was not related to the level of neu- tropenia, a finding that is indicative that other factors independent of the overall severity of poor graft function may prevent a response (data not shown). Under conditions of replicative stress (e.g., allogeneic SCT) chronic inflam- matory signals such as those mediated through Toll-like receptors or pro-inflammatory cytokines (e.g., tumor necrosis factor-a, interferon-γ or interleukin-1) impair HSC self-renewal through induction of apoptosis or by driving myeloid differentiation.17 In humans, similar mechanisms have been invoked for bone marrow failure in the context of chronic infections. Thus, one possibility is that the pro-inflammatory conditions provoked by infection pose a significant barrier to establishing a func- tional HSC pool from infused CD34+-selected cells.
Although the infections in this cohort of patients were heterogeneous, CMV infection had the most noticeable impact on the response to CD34+-selected infusion. Both CMV seropositivity in the donor and/or recipient and a history of CMV re-activation predicted a worse recovery although the majority of patients in both groups achieved complete or partial recovery. We had reasoned that recov- ery would correlate inversely with surrogates of more severe infections (e.g., high peak CMV viremia or greater numbers of re-activations) but this was not the case; these data suggest that either the sample size of our cohort was not sufficiently powered to detect a relationship or that other mechanisms are involved. While the myelosuppres- sive effects of anti-CMV drugs are well described, CMV infection may also impair niche functions and HSC self- renewal by directly infecting bone marrow macrophages and stroma, or indirectly as a consequence of chronic inflammation.18 Currently, it is difficult to conceive new strategies to overcome these issues other than accelerating restoration of anti-CMV immunity through adoptive transfer of CMV-specific or memory T cells, or the use of anti-CMV drugs that cause less myelosuppression (e.g., letermovir). It will be of interest, therefore, to evaluate how the introduction of CMV prophylaxis with leter- movir affects the overall incidence of poor graft function and responses to CD34+-selected infusions. In our view, CMV-seropositive patients or those with CMV re-activa- tion should not be excluded from consideration for CD34+-selected infusion; however, this approach should be considered as part of a broader plan to improve immune reconstitution and avoid excess use of drugs that are toxic to the bone marrow.
Sex matching between the donor and recipient also influenced recovery following CD34+-selected infusions, specifically when the transplant was from a male donor
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