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Serial assessment of toxicity after hematopoietic SCT can discern kinetics of transplant-related organ injury and patterns of recovery

Objective assessment of organ toxicity that occurs after hematopoietic SCT (HSCT) typically employs grading schemes that describe peak toxicities in individual organs using validated severity scores.1, 2, 3, 4 In addition, global measures of transplant-related toxicity may include total length of hospital admission, the need for transfer to intensive care5 and non-relapse mortality at 100 days. None of these toxicity measures, however, provide insight regarding the timing or the recovery from organ damage. Herein, we describe the use of serial toxicity assessments as a tool to assess the toxicity as well as the rate and extent of functional recovery following HSCT.

Consecutive patients undergoing HSCT at the Ottawa Hospital between April and August 2009 and who provided consent were included in the study. Patients undergoing allogeneic HSCT received MTX on days 1, 3, 6 and 11, and calcineurin inhibitors after transplant to prevent GVHD unless contraindicated. Patients undergoing unrelated donor allogeneic HSCT also received antithymocyte antiglobulin 2.5 mg/kg, as GVHD prophylaxis. Patients receiving TBI as part of the conditioning regimen received keratinocyte growth factor before transplantation to reduce oral mucositis (OM).6 The severity of transplant-related organ toxicity was assessed in accordance with previously published severity scales1 and determined daily beginning on the first day after stem cell infusion and continued until hospital discharge or death.

A total of 57 patients were enrolled (39 autologous and 18 allogeneic HSCT recipients). The characteristics of the patient population are presented in Table 1. The most common toxicities were OM, gastrointestinal, hepatic injury and renal impairment. Severe OM (grade 2) was more common in the allogeneic group (P<0.0001), and the incidence of hepatic (P=0.0002) and renal injury (P=0.022) of any grade was also greater in allogeneic recipients. The kinetics of OM, gastrointestinal tract toxicity, and liver and kidney injury are presented separately for the autologous and the allogeneic transplant recipients in Figure 1. The mean grade of toxicity for each organ system was determined for each day following hematopoietic stem cell infusion to provide an estimate of the severity of toxicity at each time point in the post-transplant period.

Table 1 Patient characteristics
Figure 1
figure1

Mean toxicity grade among allogeneic (solid line) and autologous (dashed line) recipients at each day following transplantation.

OM was the most severe organ toxicity observed with a mean toxicity grade >0.5 between days 5 and 13 for the autologous transplant recipients and a mean toxicity grade >1.5 between days 9 and 20 for the allogeneic transplant recipients. The difference in the mean toxicity score was significantly greater for days 8–23 in the allogeneic group (P<0.05). The peak severity of toxicity occurred earlier in the autologous transplant patients, although the overall severity was markedly less in comparison with allogeneic transplant patients. Recovery of OM can be observed in the autologous cohort as hematopoieteic engraftment begins, whereas the severity of OM in the allogeneic group persists beyond the start of hematopoietic engraftment. Hepatic toxicity was significantly greater in the allogeneic cohort compared with autologous recipients between days 5 and 15 post-transplant (P<0.05). Hepatotoxicity persisted throughout the post-transplant period in both the groups and did not resolve immediately following hematopoietic engraftment. Gastrointestinal toxicity was similar for the allogeneic and autologous groups, peaking between days 5 and 10 with gradual resolution by the time of hematopoietic engraftment. Likewise, renal toxicity was similar between the autologous and allogeneic groups, although it appeared that renal toxicity persisted throughout the post-transplant period at low levels following allogeneic transplant, perhaps owing to the use of MTX and calcineurin inhibitors as GVHD prophylaxsis. A re-emergence of renal toxicity after hematopoietic engraftment in the autologous group was observed.

Serial assessment of toxicity grades provides a novel yet simple tool for assessing the onset and duration of organ toxicity in multiple organ systems following HSCT and provides a means for quantifying differences between various transplant strategies. Although we compared patterns following autologous and allogeneic HSCT in a heterogenous cohort to highlight patterns that are commonly appreciated, new strategies to prevent GVHD or other interventions could easily be assessed in a similar manner. Likewise, serial assessments of toxicity could be performed using different toxicity grading systems. The use of serial toxicity assessments may be useful particularly in comparing different reduced intensity transplant regimens and for evaluating strategies or supportive measures employed to reduce the toxicity of HSCT.7 It was interesting to note in our cohort that the pattern of toxicity appeared to be organ specific, including the onset, timing of peak severity and the kinetics of recovery. In some cases, organ recovery is concomitant with hematopoietic engraftment, suggesting that cellular repair may have an important role. In other types of organ injury, the repair may not occur until the causative agents are stopped such as nephrotoxic or hepatotoxic drugs. Studies in large numbers of patients are needed to refine our initial observations and to better characterize the kinetics of tissue injury and recovery in organ systems with a low incidence of significant toxicity. Moreover, a comparison using alternative toxicity scoring systems such as the Common Terminology Criteria for Adverse Events of the National Cancer Institute4 would be insightful as an alternative means of grading organ injury.

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Chou, A., Guo, M., Tay, J. et al. Serial assessment of toxicity after hematopoietic SCT can discern kinetics of transplant-related organ injury and patterns of recovery. Bone Marrow Transplant 47, 1375–1376 (2012). https://doi.org/10.1038/bmt.2012.27

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