Dexamethasone palmitate for patients with engraftment syndrome is associated with favorable outcome for children with hematological malignancy

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Engraftment syndrome (ES) is an early complication of hematopoietic stem cell transplantation (HSCT), characterized by non-infectious high-grade fever, skin eruptions in the absence of infection or drug toxicity, non-cardiac pulmonary infiltrate, body weight gain, diarrhea and/or jaundice.1 Although the pathogenesis of ES is poorly understood, activated macrophages have crucial roles in both the innate and acquired immune pathways during the peri-engraftment period.2, 3 Several reports have demonstrated that immune suppressive agents, such as corticosteroids, could control the peri-engraftment immune reactions after HSCT, but ES has been associated with a higher prevalence of acute GvHD and higher non-relapse mortality (NRM).4, 5, 6, 7, 8, 9 In particular, viral infections as a consequence of long-term steroid administration after HSCT often have fatal outcomes. Liposome-incorporated dexamethasone or dexamethasone palmitate (DP), which is readily taken up by macrophages via phagocytosis and strongly retained in the cytoplasm, is known to suppress macrophage activation.10 Nishiwaki et al.11 reported that DP reduced the number of primary human macrophages in vitro more rapidly and profoundly than dexamethasone sodium phosphate, and that DP treatment suppressed the activity of macrophages and prevented the engraftment failure in three patients with hemophagocytic syndrome after HSCT.

To assess the efficacy and feasibility of DP treatment for ES and to evaluate the clinical impact on transplantation outcomes, we reviewed the cases of 95 consecutive children with allogeneic HSCT for hematological malignancy treated at our institute between 2006 and 2014.

Details regarding the materials and methods employed are given in the Supplementary Information. DP treatment (2.5 mg/m2 per day IV for 3 consecutive days) was indicated for all patients with ES; refractory cases received on-demand DP treatment. We analyzed the incidence of ES according to the modified Spitzer’s criteria and clinical outcomes of DP treatment for ES.

Patient characteristics are summarized in Supplementary Table 1. Median follow-up for survivors was 52 months. Thirty-five patients (37%) were diagnosed with ES, with a median interval from HSCT until the onset of ES of 14 days (range, 7–22 days; Supplementary Figure 1a). No covariates were found to be associated with ES development using Gray’s test (Supplementary Table 1). Clinical symptoms of patients with ES are shown in Supplementary Table 2. Eleven of the 35 patients with ES presented with all three major criteria; the other 24 patients showed two major criteria and at least one minor criterion. Ten of the 32 patients with erythrodermatous rash underwent skin biopsy and the absence of infection or drug toxicity was confirmed by our pathologist. All 35 patients in the ES group were treated with DP for 3 days. The median interval from DP initiation to defervescence was 2 days (range, 0–39 days). Of the 35 patients with ES, 17 (49%) required additional DP treatment (median, 2 days; range, 1–8 days). ES resolved in 30 of 35 cases without additional other steroid treatment.

Of the 35 patients with ES, graft failure was concomitantly observed in three patients with donations from siblings (n=1) or unrelated cord blood (n=2). Cumulative incidence rates of engraftment at day +42 after bone marrow transplantation (BMT)/cord blood transplantation (CBT) were 99%/96% for the ES group and 100%/99% for the non-ES group, respectively. Median time to engraftment after BMT/CBT was 19/22 days for the ES group and 17/21 days for the non-ES group, respectively. No significant differences were apparent between groups (Supplementary Figures 1b and c).

Although the cumulative incidence of CMV antigenemia was significantly higher in the ES group than in the non-ES group (16/35 for the ES group and 14/60 for the non-ES group), CMV infection developed in zero patients in the ES group and two patients in the non-ES group. EBV viremia occurred in three patients in the ES group and six patients in the non-ES group; none of these patients developed post-transplant lymphoproliferative disease. Human herpesvirus 6 viremia occurred in six and two patients, and hemorrhagic cystitis developed in two and three patients in the ES and non-ES groups, respectively; all of these patients recovered spontaneously with supportive care.

The incidence of grade II–IV acute GvHD among patients with ES was comparable to that among patients without ES (14% versus 12% at day +100, P=0.70; Figure 1a), whereas the incidence of limited and extensive chronic GvHD was higher in the ES group than in the non-ES group (25% versus 8% at 4 years, P=0.03; Figure 1b). The incidence of NRM among the ES group was comparable to that among the non-ES group (6% versus 5% at 4 years, P=0.91; Figure 1c); on the other hand, the former group showed a significantly lower relapse rate (29% versus 51% at 4 years, respectively, P=0.03; Figure 1d; among high-risk patients, 33% versus 70% at 4 years, respectively, P=0.02; Supplementary Figure 2a). Finally, disease-free survival/overall survival (OS) rates were superior in the ES group compared with the non-ES group (59%/77% versus 43%/57% at 4 years, respectively, P=0.08/P=0.08; Figures 1e and f), even among high-risk patients (56%/57% versus 29%/31% at 4 years, respectively, P=0.05/P=0.09; Supplementary Figures 2b and c). Causes of death were disease relapse or progression (n=5) and bacterial infection (n=1) in the ES group, and disease relapse or progression (n=21), bacterial infection (n=2), acute respiratory distress (n=1) and thrombotic microangiopathy (n=1) in the non-ES group. Multivariate analyses for HSCT outcomes are summarized in Table 1. Multivariate analysis identified high-risk clinical status as an unfavorable predictor for relapse and ES development as a predictor for reduced risk of relapse. Moreover, the strongest negative predictor of OS was high-risk clinical status, followed by age at HSCT >10 years old; ES development was identified as a predictor of favorable OS.

Figure 1
figure1

Incidences of acute GvHD, chronic GvHD, non-relapse mortality, relapse, disease-free survival and overall survival. (a) Cumulative incidences of grade II–IV acute GvHD at day +100 were 14% (95% confidence interval (CI), 5–28%) for the engraftment syndrome (ES) group (black line) and 12% (95% CI, 5–21%) for the non-ES group (gray line). (b) Cumulative incidences of chronic GvHD at 4 years were 25% (95% CI, 12–41%) for the ES group (black line) and 8% (95% CI, 3–17%) for the non-ES group (gray line). (c) Cumulative incidences of non-relapse mortality at 4 years were 6% (95% CI, 1–18%) for the ES group (black line) and 5% (95%CI, 1–14%) for the non-ES group (gray line). (d) Cumulative incidences of relapse at 4 years were 33% (95% CI, 17–49%) for the ES group (black line) and 52% (95% CI, 38–64%) for the non-ES group (gray line). (e) Probabilities of disease-free survival at 4 years after hematopoietic stem cell transplantation (HSCT) were 59% (95% CI, 40–74%) for the ES group (black line) and 43% (95%CI, 30–56%) for the non-ES group (gray line). (f) Probabilities of overall survival at 4 years after HSCT were 77% (95% CI, 58–89%) for the ES group (black line) and 55% (95% CI, 39–68%) for the non-ES group (gray line).

Table 1 Multivariate analysis

Although the Spitzer criteria remain the most accepted definition, recent studies have tended to use broader time ranges than those prescribed by Spitzer, and do not distinguish pre-ES from ES.6, 7, 8 We included patients with Spitzer’s ES manifestations even before engraftment in the indication for DP treatment and added phagocytosis detected via bone marrow aspiration (BMA) to the minor criteria. Regarding our results, the cumulative incidence of ES in the current study was 37%, similar to the incidences (13–48%) reported in the literature for pediatric allogeneic HSCT.5, 6, 7, 8 As several investigators have proposed their own criteria, the incidence of ES strictly according to Spitzer’s criteria in a pediatric population within an allogeneic setting would have been ~20%.5, 6, 7, 8 Indeed, the incidence of ES in our cohort would have been 19% (18/95) according to Spitzer’s criteria. These patients diagnosed using unmodified Spitzer’s criteria showed similar outcomes to our own ES group. As in previous reports describing children with allogeneic HSCT, incidences of hepatic dysfunction, renal insufficiency and transient encephalopathy were very low in our cohort.5, 6, 7, 8 Signs of phagocytosis and activated macrophage proliferation were observed more frequently during BMA examination in our ES group (60%, 21 of 35); these signs occurred in 9 of 18 patients (50%) meeting Spitzer’s criteria. Our findings suggest that phagocytosis in BMA examination might be a sensitive marker of developing ES.

A report from the University of Michigan revealed that ES patients exhibited a significantly higher incidence of acute GvHD and higher NRM, resulting in poorer OS despite early recognition of ES and treatment with systemic corticosteroid.8 In the current study, patients with ES prospectively received DP treatment for 3 consecutive days, with good resolution, which was associated with an equivalent incidence of acute GvHD and NRM in comparison with patients without ES. Goral et al.4 reported that systemic corticosteroid treatment led to the rapid resolution of ES, but NRM was significantly higher because of the prevalence of uncontrolled systemic infection in ES patients. Systemic corticosteroid is thus convenient, but not without danger, particularly for immune-compromised patients. On the other hand, the present study found no differences in the rates of viral, bacterial or fungal infections between the ES and non-ES groups, confirming that our DP treatment for ES does not increase the incidence of infection in recipients after allogeneic HSCT.

Several studies have described associations between chronic GvHD and a lower incidence of relapse after allogeneic HSCT, reflecting the close relationship between chronic GvHD and the GvL effect.12, 13, 14 Our analyses identified the surprising finding that DP treatment could not only control ES and prevent the development of acute GvHD but also maintain the immune reactions important for the GvL effect; this led to a higher incidence of chronic GvHD, a lower relapse rate and better OS in the ES group compared with the non-ES group. These findings were conserved in the high-risk cohort and were supported by multivariate analyses.

Although the current study has several limitations, including the small number of patients, the one-arm design, absence of laboratory work and a single institutional setting, DP was found to effectively suppress acute allogeneic reactions, but not later immune reactions inducing the GvL effects that improve the outcomes of children with hematological malignancies.

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Acknowledgements

We wish to thank all of the staff who contributed to patient care at our institute. This study was partially supported by a grant from the National Center for Child Health and Development (grant number 26-14), Tokyo, Japan.

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Correspondence to H Sakaguchi.

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The authors declare no conflict of interest.

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Supplementary Information accompanies this paper on Bone Marrow Transplantation website

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