There have been a number of improvements made in the field of UCB transplantation over recent years, particularly in defining a critical infused cell dose needed for sustained neutrophil recovery and in developing approaches to overcome this limitation(15
). Despite the progress in recognizing a critical cell dose for engraftment, TRM and relapse remain significant causes of treatment failure for UCB recipients. TRM is especially distressing since it occurs in patients that might otherwise be cured from their disease. The ability to identify patients at increased risk for early death could lead to interventions directed toward preventing these negative outcomes. This single institution analysis of 360 patients who received UCB transplantation for hematologic malignancies, shows that early rapid lymphocyte recovery, after either myeloablative or RIC transplantation is an independent parameter associated with superior survival.
In this analysis, patients who received either a MA or RIC UCB transplant and had an ALC >200 ×106
/L at day 30 or 42 respectively, had superior OS and PFS. Similar findings of improved outcomes for BM and PBSC recipients have been reported (6
), but this issue has not yet been examined in UCB transplantation. The exact explanation for these findings is unknown, but may reside in the cells that make up the ALC at these early time points. NK cells recover to normal amounts rapidly after transplant (28
), however, these cells are functionally impaired (29
). Despite this, two prior studies correlating high ALC with improved transplant outcomes have implicated natural killer (NK) cells as being significantly associated with improved outcomes (30
). Thus, perhaps the numbers of NK cells in the graft or levels of endogenous cytokine (i.e., IL-15) after transplant may differentially influence NK expansion and account for these findings. Alternatively, even though the number of T cells at day 30–60 after transplant are low, reconstitution is actively occurring and rapid recovery of the T cell compartment might also account for these observations. Both thymic independent (homeostatic proliferation) and dependent pathways of T cell reconstitution have been described (reviewed in (32
)). The early increases in T cells after transplant are thought to be mainly due to homeostatic T cell proliferation, where a limited repertoire of T cells emerge in response to alloantigen stimulation and high serum cytokine concentrations. Whether these T cells are protective against relapse or infectious organisms remains an open question in humans, but both have been hypothesized (32
). Perhaps in support of this, Hamza et al. showed that patients with rapid lymphoid recovery after UCBT and MUD BMT had a lower risk of infections (12
). In contrast, IFN-γ producing CD8+ CMV reactive T cells could be detected in the blood of UCB recipients early after transplant (week 8), but their appearance did not correlate with CMV control (34
). Alternatively, rapid lymphocyte recovery may reflect a more robust thymic dependent T cell production. In support of this Komanduri et al. showed that UCB recipients who had high numbers of CD4+ T cells that co-expressed CCR7+ (found on naïve and central memory cells) at day 30 UCB had superior survival, suggesting that new T cell formation and intact immune responses were critical to survival (13
). In our analysis, MA patients with a day 30 ALC ≤ 200 ×106
/L had significantly more early infections compared to patients >200 ×106
/L, but this was not seen for late infections or for RIC patients (early or late infections) based on their day 42 ALC. Unfortunately, for a significant proportion of patients in our study, we do not have detailed lymphocyte subset data available to determine the composition of the patient’s ALC and this will be addressed in future studies.
Several prior studies that report the benefit of high ALC early after transplant show that the improvement in survival is due to lower relapse rates (6
). For instance, in studies of patients transplanted with ALL(10
) or a mixture of hematological diseases(11
), a high day 21 ALC was strongly correlated with a reduction in relapse and an improved DFS following matched sibling donor transplant. Similar results were shown by Savani et al. for T cell depleted sibling donor transplants for AML at day 30, but not for ALL (31
). These findings by Savani et al., prompted us to perform a similar subgroup analysis (based on disease type) in our myeloablative and RIC patient cohorts. However, for both subgroups of diseases in patients undergoing myeloablative (ALL and AML) or RIC UCB transplantation (leukemia/MDS and lymphoma), we were unable to identify a significant impact of ALC on disease relapse in multivariate analysis (data not shown). In contrast to other reports on early lymphocyte recovery following BM or PBSC transplantation (6
), our results in UCB transplantation show that a low ALC after MA allo-HCT was associated with significantly higher TRM, with no impact on relapse. The early TRM identified in these patients may have been a competing risk to relapse, thus explaining these results. While it is tempting to speculate that high ALC early after transplant is somehow related to graft versus tumor reactions, the association of ALC on relapse is not limited to the allogeneic graft vs. tumor effect, since similar findings have been found after autologous transplant for non-Hodgkin’s lymphoma(36
), Hodgkin’s disease(37
), multiple myeloma(38
) and Ewing sarcoma(39
All prior studies investigating ALC on allo-HCT outcomes have been in the myeloablative setting (6
). The time to lymphocyte recovery in our myeloablative UCB recipients are relatively similar to the studies in BM or PBSC recipients reported by others (6
). This is remarkable considering that UCB recipients receive 10–50× fewer MNCs/kg and that these cells have been cryopreserved and thawed, which negatively affects viability. Thus, these results might suggest that the proliferation kinetics and/or the homing properties of UCB lymphocytes differ compared to BM/PBSC.
Here, we also report the first large series of ALC data in patients undergoing RIC conditioning (n=189). In these patients, day 42 was the first time that ALC was significantly predictive for transplant associated outcomes. Based on our prior studies, the majority of patients show full donor lymphocyte chimerism at this time point (18
). Although the kinetics of immune recovery are relatively similar between MA and RIC recipients (40
), an explanation for the difference in time (day 30 vs. day 42) between MA and RIC in terms of an ALC of ≤200 x106
/L predicting outcome may be the result of residual host cells competing with lymphoid growth factors in RIC patients. Alternatively, after RIC, the niches for stem cells and lymphoid engraftment may still be occupied with residual host cells which might also delay donor lymphocyte recovery.
While TRM remains a significant barrier to the success of UCB transplantation, there have been very few measures to identify patients at risk for this complication. For instance, Sorror and colleagues described the HCT-specific co-morbidity index (41), but such measures have only been partially validated in the UCBT setting, since they are predictive for TRM after myeloablative, but not RIC transplantation in adult recipients (42). Here we show that patients with hematologic malignancies receiving a MA or RIC UCBT and fail to achieve an ALC >200 ×106/L at day 30 or day 42 respectively, have a significantly inferior OS and PFS. These results may allow for interventions aimed at preventing mortality. Considering that the majority of deaths after UCB transplantation are within 180 days and are related to multi-organ failure and/or infectious complications, day 30 or 42 ALC may be useful to identify MA or RIC UCBT recipients at risk for early mortality. The findings presented here also suggest that limiting treatments that delay- or instituting approaches that accelerate lymphocyte recovery might have a significant impact on transplant outcomes. Potential strategies could include improved antimicrobial prophylaxis, or the use of agents that promote the recovery and survival of T cells (i.e., IL-7 (43)) and/or NK cells (i.e., IL-15 (44–45)). Lastly, agents aimed at protecting structures involved in de novo T cell production, including thymic epithelial protectants and/or stimulants have considerable promise (46). Further analyses investigating the impact of ALC following MA and RIC UCBT for hematologic malignancies are warranted to confirm these findings.