In order to clarify the association between hyperglycemia during the early period after allogeneic stem cell transplantation (allo-SCT) and adverse outcomes, we retrospectively analyzed 563 consecutive patients who underwent allo-SCT at our institute between 2008 and 2015. Patients were categorized into three groups according to mean fasting blood glucose levels on days 0–7 (normoglycemia group<110 mg/dL, n=347; mild hyperglycemia group 110–149 mg/dL, n=192 and moderate/severe hyperglycemia group≥150 mg/dL, n=24). The median follow-up was 2.7 years. Patients in the moderate/severe hyperglycemia group had significantly worse characteristics. The cumulative incidences of 2-year non-relapse mortality (NRM) and the probabilities of 2-year overall survival (OS) in the normoglycemia, mild hyperglycemia and moderate/severe hyperglycemia groups were 7.5%, 19% and 29%, respectively (P<0.01), and 69%, 53% and 33%, respectively (P<0.01). In multivariate analyses, hyperglycemia was an independent predictor of high NRM (vs normoglycemia; mild hyperglycemia, hazard ratio (HR) 2.56, 95% confidence interval (CI) 1.56–4.18; moderate/severe hyperglycemia, HR 4.46, 95% CI 1.92–10.3) and poor OS (vs normoglycemia; mild hyperglycemia, HR 1.54, 95% CI 1.14–2.07; moderate/severe hyperglycemia, HR 1.61, 95% CI 0.89–2.91). In conclusion, hyperglycemia on days 0–7 after allo-SCT was associated with inferior outcomes.
Allogeneic stem cell transplantation (allo-SCT) is an effective therapy for hematological malignancies and other diseases. Although previous studies showed that the risk of non-relapse mortality (NRM) has decreased significantly over the past several decades, post-transplant complications such as infectious diseases and GvHD remain significant issues.1, 2, 3
Hyperglycemia is known to be associated with a higher risk of mortality in critically ill patients.4, 5, 6, 7 The Leuven studies of patients in intensive care units showed that intensive blood glucose (BG) control, especially of long duration, improved clinical outcomes,8, 9 but other multicenter randomized controlled studies failed to reproduce such beneficial findings.10, 11
There is a paucity of data available on hyperglycemia in allo-HSCT recipients, although we commonly encounter hyperglycemia after allo-SCT.12 Pretransplant diabetes mellitus (DM), one of the factors in the hematopoietic cell transplantation-comorbidity index (HCT-CI), increases the risk of NRM after allo-SCT.13, 14 Post-transplant hyperglycemia after allo-SCT was also reported to be associated with an increased risk of adverse outcomes. Our group previously reported that the presence of hyperglycemia before engraftment increased the risk of subsequent acute GvHD and NRM.15 Gebremedhin et al.16 showed that hyperglycemia on days 1–10 was associated with a significantly increased risk of acute GvHD, in particular, in patients without pretransplant hyperglycemia. Hammer et al.17 reported that hyperglycemia on days 0–100 was associated with an increased risk of NRM.
After our initial report on the impact of hyperglycemia after allo-SCT,15 we conducted several prospective studies relating to nutritional support (one study was reported previously18 and others were not reported yet (UMIN000001189, UMIN000003884)), and simultaneously changed our general practice of nutritional support in 2008, including the use of parenteral nutrition and glucose control as described previously.18 In our general clinical practice, the target glucose level is <150 mg/dL (8.3 mmol/L) after allo-SCT, except for patients who were enrolled in a study of intensive glucose control (target 80–110 mg/dL (4.4–6.1 mmol/L)). The patients in this study were treated according to this practice.
In this study, we retrospectively analyzed a contemporary cohort at our institute assessing the impact of glucose levels during the early period after allo-SCT on subsequent clinical outcomes.
Patients and methods
A total of 594 allo-SCTs were performed at our institute between January 2008 and September 2015. Exclusion criteria were death before day 7 post transplant and lack of data on BG levels for four consecutive days between days 0 and 7. In addition, we excluded allo-SCTs that were performed as rescue for graft failure. Excluding these cases, 563 patients were included in our analyses. If two allo-SCTs in the same patient were eligible for analysis, the procedures were regarded as individual cases.
The general management of hyperglycemia at our institute is as follows: insulin is mixed in bags of parenteral nutrition and the insulin dose is adjusted based on fasting BG levels (determined during routine laboratory testing) to keep fasting blood BG<150 mg/dL. In cases with poor BG control, we combine pre-meal BG level monitoring and sliding-scale insulin. Almost all patients were treated in non-ICU settings, so the monitoring and management of BG were not intensive ones, which were generally provided in ICU settings. In terms of the dose of parenteral nutrition, when the oral caloric intake becomes insufficient to meet the target caloric intake, we start parenteral nutrition irrespective of the type of conditioning regimen.
Patients were categorized into three groups according to the mean value of each fasting BG level on days 0–7, as follows: normoglycemia, <110 mg/dL (6.1 mmol/L); mild hyperglycemia, 110–149 mg/dL (6.1–8.2 mmol/L) and moderate/severe hyperglycemia, ≥150 mg/dL (8.3 mmol/L). This grouping was used in our previous report and another report.15, 19 The study endpoints included overall survival (OS), GvHD, NRM and relapse. Definitions of acute and chronic GvHD were based on established criteria.20 OS was defined as time to death from any cause. NRM was defined as death from any cause in continuous CR or no progression. Relapse was defined as the time to onset of hematologic recurrence or disease progression. Data on cumulative doses of glucose and insulin in parenteral nutrition and of corticosteroids were collected from the medical records of our institute. The mean doses of glucose and prednisolone-equivalent corticosteroid on days 0–7 were calculated for each patient. At our institute, 200 mg of hydrocortisone is administered prior to stem cell transfusion. Acetaminophen is generally used as an antipyretic, but 50–100 mg of hydrocortisone is administered to control acetaminophen-resistant fever. For the purposes of this study, when insulin was administered IV the dose was recorded and the glucose–insulin ratio in parenteral nutrition was calculated.
A descriptive statistical analysis was performed to assess patient characteristics. Medians and ranges are provided for continuous variables, and percentages are shown for categorical variables. Patient characteristics were compared using the χ2 test for categorical variables and the Mann–Whitney U-test or Kruskal–Wallis test for continuous variables. The probability of OS was calculated by the Kaplan–Meier method. Cox proportional hazard regression models were used to examine risk factors associated with overall mortality. The cumulative incidences of NRM and GvHD were evaluated using the cumulative incidence method, and the Fine and Gray model was used for univariate and multivariate analyses. In the analysis of GvHD, relapse and death before onset of GvHD were defined as competing risks. In the analysis of NRM, relapse was defined as a competing risk. For each cause-specific NRM, relapse and NRM due to other causes were defined as competing risks. The cumulative incidences of documented bacterial or fungal infections after day 7 were evaluated for patients who did not have such infections on day 7. Factors that were associated with a two-sided P-value <0.10 in the univariate analysis were included in a multivariate analysis. The final model was determined by backward stepwise selection. A two-sided P-value <0.05 was considered statistically significant. The variables evaluated in these analyses were as follows: donor/recipient combination (female to male vs other), patient age at the time of allo-HSCT (age≥40 years vs age<40), ECOG performance status (0–1 vs 2–4),21 body mass index (continuous value, BMI<18.5 vs 18.5≤BMI<25, 25≤BMI<30 vs BMI≥30),22 conditioning regimen (TBI-based myeloablative vs non-TBI-based myeloablative vs reduced-intensity conditioning), stem cell source (bone marrow vs PBSC vs cord blood), HLA disparity as assessed by allelic typing of HLA-A, B, and C and DRB1 (8/8 match vs others), baseline BG level (<110 mg/dL vs 110–149 mg/dL vs ≥150 mg/dL, defined as the lowest level between days –18 and –14), HCT-CI score (0 vs 1–2 vs ≥3),13 and disease risk (low vs intermediate vs high vs very high, as defined by the Disease Risk Index23). All statistical analyses were performed with EZR ver 1.30 (Saitama Medical Center, Jichi Medical University, Tochigi, Japan),24 which is a graphical user interface for R (The R Foundation for Statistical Computing, version 3.2.2).
This retrospective study was approved by the Institutional Review Board of the National Cancer Center in Japan. It was conducted in accordance with the international ethical recommendations stated in the Declaration of Helsinki and Japanese Good Clinical Practice Guidelines.
Patient characteristics are shown in Table 1. Patients were grouped into three groups as follows: 347 (61.6%) in the normoglycemia group, 192 (34.1%) in the mild hyperglycemia group and 24 (4.3%) in the moderate/severe hyperglycemia group. There was no significant difference in the numbers of BG monitoring per patient in days 0–7 among the 3 groups (7.76 in the normoglycemia group, 7.74 in the mild hyperglycemia group and 7.83 in the moderate/severe hyperglycemia group, P=0.83). Median duration of follow-up of surviving patients was 2.7 years. The proportion of patients grouped into the moderate/severe hyperglycemia group was limited in this study, reflecting the change in our institute’s nutritional management in 2008. Patients in the moderate/severe hyperglycemia group included more patients with adverse characteristics, such as age ≥40 years, high body mass index, unrelated donor, higher BG level before allo-SCT, higher HCT-CI, DM as comorbidity and higher disease risk. The incidence of hypoglycemia (BG<70 mg/dL) on days 0–7 was low (4.3% in the normoglycemia group, 1.6% in the mild hyperglycemia group, and 0% in the moderate/severe hyperglycemia group), with no significant difference among the three groups.
Table 2 shows the doses of glucose, insulin and corticosteroids on days 0–7. Groups with higher BG received significantly higher doses of intravenous parenteral nutrition glucose and corticosteroids. PN was started significantly earlier in groups with higher BG (P<0.01), although the median day when PN was started was 1day after allo-HSCT in all 3 groups. The proportion of patients who did not receive any PN including partial PN during days 0–7 were significantly fewer in higher BG groups (normoglycemia: 51 pts (15%), mild hyperglycemia: 10 pts (5.2%), moderate/severe hyperglycemia: 1 pts (4.2%) P<0.01). As one surrogate marker of inflammatory status after allo-HSCT, we assessed the maximal level of C-reactive protein on days 0–7. The mild and moderate/severe hyperglycemia groups had a significantly higher level of C-reactive protein compared with the normoglycemia group (normoglycemia, 1.9 mg/dL; mild hyperglycemia, 5.1 mg/dL; moderate/severe hyperglycemia, 5.9 mg/dL; P<0.01).
Figures 1a–d show the cumulative incidences of acute GvHD and chronic GvHD. In the normoglycemia, mild hyperglycemia and moderate/severe hyperglycemia groups, the cumulative incidences of grade II–IV acute GvHD were 34%, 39% and 33%, respectively (P=0.62), whereas those of grade III–IV acute GvHD were 7.8%, 9.9% and 13%, respectively (P=0.58). In the normoglycemia, mild hyperglycemia and moderate/severe hyperglycemia groups, the cumulative incidences of chronic GvHD at 2 years were 44%, 44% and 39%, respectively (P=0.92), whereas those of extensive chronic GvHD were 34%, 35% and 39%, respectively (P=0.85). There was no significant impact of BG level on the incidence of chronic GvHD.
Figure 2a shows the cumulative incidences of NRM. The cumulative incidences of 2-year NRM in the normoglycemia, mild hyperglycemia and moderate/severe hyperglycemia groups were 7.5%, 19% and 29%, respectively (P<0.01). The cumulative incidences of cause-specific NRM are shown in Figures 2b and c. The cumulative incidences of infection-related NRM at 2 years in the normoglycemia, mild hyperglycemia and moderate/severe hyperglycemia groups were 1.5%, 7.4% and 8.3%, respectively (P<0.01, Figure 2b), whereas those of organ failure-related NRM at 2 years in each group were 2.6%, 7.9% and 8.3%, respectively (P=0.01, Figure 2c). The risks of all-cause and cause-specific NRM were significantly higher in the mild and moderate/severe hyperglycemia groups.
Figure 3a shows the cumulative incidences of relapse. The cumulative incidences of relapse/progression at 2 years in the normoglycemia, mild hyperglycemia and moderate/severe hyperglycemia groups were 36%, 33% and 40%, respectively (P=0.69). Figure 3b shows the probabilities of OS grouped according to mean BG levels. The probabilities of OS at 2 years in the normoglycemia, mild hyperglycemia and moderate/severe hyperglycemia groups were 69%, 53% and 33%, respectively (P<0.01).
The summaries of univariate and multivariate analyses of NRM and OS are shown in Table 3. In the multivariate analyses, hyperglycemia on days 0–7, poor PS, HCT-CI and disease risk were independent risk factors for poor OS and only hyperglycemia on days 0–7 and HCT-CI were independent risk factors for NRM (Table 4). Exclusion of patients with DM as comorbidity before transplant did not affect the significance of these independent risk factors (Supplementary Table 1). We also conducted multivariate analyses considering mean BS level as a continuous variable. The mean BG level was an independent risk factor for NRM and OS (OS: HR 1.01, 95% CI (1.00–1.02), P<0.01; NRM: HR 1.02, 95% CI (1.01–1.03), P<0.01, Supplementary Table 2). We evaluated the univariate relation between HR and individual mean BG level, and found a linear increase of HR with increasing glucose level (Figure 4).
Our data clearly showed that hyperglycemia on days 0–7 after allo-SCT was a statistically significant risk factor for inferior clinical outcomes. Our current results using a recent cohort basically reproduced the results of our previous study, in which patients with hyperglycemia during the early phase after allo-SCT had inferior outcomes.15
Hyperglycemia is caused by various mechanisms after allo-HSCT, including conditioning regimen-related factors, infection, total parenteral nutrition and immunosuppressive drugs. Therefore, hyperglycemia itself might reflect the intensity of the conditioning regimen or the severity of complications such as mucosal damage and infection. However, hyperglycemia itself is well-known to have harmful effects through various mechanisms such as neutrophil dysfunction, endothelial dysfunction, cytokine production and electrolyte disturbance.25, 26 Such adverse effects could be relevant in patients after allo-SCT as they are already at high risk of infection, GvHD, organ failure and endothelial dysfunction, in particular, during the neutropenic period when the risk of infection is increased.27 Our data support this hypothesis as patients with hyperglycemia had a higher risk of NRM, particularly infection-related and organ failure-related NRM. However, the detailed mechanism, whereby hyperglycemia early after allo-HSCT might increase the risk of NRM, remains unclear. Previous research reported that post-transplant hyperglycemia might affect the phenotype of regulatory T cells,28 and another recent report suggested that post-transplant hyperglycemia was associated with an activated IL-33/ST-2 axis that predicts post-transplant complications.29 More research is needed to clarify the association between hyperglycemia and post-transplant complications.30, 31 Considering the increasing prevalence of DM globally, in particular in Western countries it would be reasonable to pay more attention to BG levels in the context of allo-SCT. Great attention should be paid to the impact of hyperglycemia in the field of allo-SCT in countries with a high prevalence of DM.
The significance of the inferior OS in the moderate/severe group diminished in multivariate analyses. We assume that it was due to the small number of patients in the group (only 4.3%). The small number of patients in that group rather reflected the fact that our clinical practice regarding parenteral nutrition and BG control (targeting<150 mg/dL) was standardized during the study period. The proportion of patients with moderate/severe hyperglycemia was remarkably small in this study compared to our previous report (15%)15 and a study at another center,16 which made it difficult to analyze the impact of moderate/severe hyperglycemia on the clinical outcomes at our institute.15, 16 Furthermore, as our BG control targets <150 mg/dL, we would expect that patients with >150 mg/dL were in poor condition, which in turn makes it challenging to control BG levels. Therefore, it might be difficult to determine the direct effects of moderate/severe hyperglycemia on clinical outcomes using our cohort. Significant differences in clinical outcomes between the normoglycemia and mild hyperglycemia groups and the strong linear associations between glucose levels and clinical outcomes support the idea that stricter glucose control, i.e., <110 mg/dL, further improves the outcomes; this possibility should be further investigated in prospective studies.
In the current analyses, there was no association between the incidence of acute GvHD and hyperglycemia, which is inconsistent with previous studies.15, 16 Hyperglycemia during the early phase after allo-SCT was found to be caused mainly by inflammation secondary to the conditioning regimen and infection associated with the use of parenteral nutrition.12 Therefore, patients with hyperglycemia have profound inflammation, and this inflammatory milieu is believed to increase the risk of subsequent acute GvHD. However, we controlled BG levels by insulin, which changed the relationship between the degree of inflammation and BG levels and could obscure the impact of BG levels themselves on the risk of acute GvHD.
There are several limitations to this study. Due to its retrospective design, the number and characteristics of patients were not well balanced. As the study was conducted at a single institute, the relationship between hyperglycemia and adverse outcomes might differ at other institutes that use different management strategies, including parenteral nutrition and glucose control. In addition, we did not have sufficient follow-up data of the incidence of post-transplant DM (PTDM), metabolic syndrome and cardiovascular diseases. Thus, we were not able to assess the impact of early hyperglycemia on the incidence of PTDM. It should be determined whether early hyperglycemia has a significant impact on the post-transplant outcome independently of the development of PTDM, metabolic syndrome and cardiovascular diseases in future studies. Finally, we did not have any data about the concentration of insulin and inflammatory cytokines due to the retrospective nature of this study, which made it difficult to assess the status of insulin resistance. Although our previous study suggests the presence of insulin resistance during the early period after allo-HSCT, the impact of insulin resistance on the clinical outcome should be also assessed in future studies.
Although we clearly showed that hyperglycemia during the early phase after allo-SCT was associated with a subsequent inferior outcome, the causation between hyperglycemia and poor outcomes is still unclear. Thus, our result does not necessarily mean that better BG control can overcome the adverse impact of hyperglycemia. As shown in the ICU setting, intensive glucose control (IGC) is not a simple procedure. In both Leuven studies,8, 9 70% of the patients in the intensive glucose control group achieved the target BG level (80–110 mg/dL), compared to less than 50% in the NICE-SUGAR study, suggesting the difficulty of standardizing BG measurements and of performing adequate training of the nursing staff in a large multicenter trial.10 A multicenter clinical trial incorporating IGC for patients treated with allo-HSCT using a myeloablative conditioning regimen is being conducted in Japan (UMIN000001189). The results of this study should give us additional information about the clinical impact of IGC after allo-SCT.
In conclusion, hyperglycemia on days 0–7 after allo-SCT was an independent risk factor for OS and NRM. Prospective clinical trials assessing the beneficial impact of intensive glucose control after transplantation are warranted.
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This work was supported by Grants from the National Cancer Research and Development Fund (26-A-26) and the Advanced Clinical Research Organization.
AK and SF designed this study and analyzed the data; all authors wrote the manuscript.
The authors declare no conflict of interest.
Statement of prior presentation: Presented in abstract form at the 77th annual meeting of the Japanese Society of Hematology, Kanazawa, Japan on October 18, 2015.
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Kawajiri, A., Fuji, S., Tanaka, Y. et al. Clinical impact of hyperglycemia on days 0–7 after allogeneic stem cell transplantation. Bone Marrow Transplant 52, 1156–1163 (2017) doi:10.1038/bmt.2017.27
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