Severe Hyperglycemia Immediately After Allogeneic Hematopoietic Stem-Cell Transplantation is Predictive of Acute Graft-Versus-Host Disease

Abstract

Background Stress hyperglycemia and acute graft versus host disease (GVHD), the major early complication of hematopoietic stem-cell transplantation (HSCT), are both associated with excessive release of inflammatory cytokines. We investigated whether new-onset hyperglycemia immediately after HSCT predicts acute GVHD. Methods We studied nondiabetic adult recipients of human leukocyte antigen(HLA)-matched HSCT (peripheral blood stem-cells) for acute leukemia. Using mean morning serum glucose on Day 1–10, we classified hyperglycemia as: mild (6.11–8.33 mmol/L), moderate (8.34–9.98), severe (minimum 9.99). Subjects GVHD-free on Day 10 were followed Day 11–100 for grade II-IV acute GVHD or competing event (relapse or death). Evaluation utilized cumulative incidence-based proportional hazards regression. Results Subjects (n=328) were age 18–74, median 49 years. Per body mass index (BMI), 25.0% were obese (BMI 30–48), 33.8% overweight (25–<30), 30.8% normal weight (21–;<25), and 10.4% lean (18–;<21). Mild, moderate, or severe hyperglycemia occurred Day 1–10 in 50.0%, 21.3%, and 16.8% of subjects, respectively. Cumulative incidence on Day 100 was 44.8(±2.8)% acute GVHD and 7.9(±1.5)% competing event. Among normal-to-overweight subjects (n=212), severe hyperglycemia developed in 14.2% (n=30) and more than doubled the risk of acute GVHD (hazards ratio, HR, 2.71, 95% CI 1.58–4.65, adjusted for donor/recipient characteristics, prophylactic regimen, and mucositis). In contrast, among obese subjects (n=82), severe hyperglycemia developed in 30.5% (n=25) but did not significantly affect risk of GVHD. (No lean subjects (n=34) developed severe hyperglycemia.) Hyperglycemia that was less than severe had an effect indistinguishable from normoglycemia. Conclusions In nondiabetic patients, severe hyperglycemia immediately after allogeneic HSCT indicates increased likelihood of acute GVHD. This association is absent in obese patients, who may be primed by obesity-induced inflammation to develop severe hyperglycemia even without experiencing the cytokine storm that is essential to GVHD pathogenesis.

How do I manage hyperglycemia/post-transplant diabetes mellitus after allogeneic HSCT

“…60 Several retrospective studies consistently showed that post-transplant hyperglycemia was associated with an increased risk of subsequent morbidity and mortality after HSCT. [61][62][63][64][65] Patients with hyperglycemia during the neutropenic period after allo-HSCT had an increased risk of subsequent GVHD and NRM. 62 Similarly, an increased risk of GVHD was observed in patients with severe hyperglycemia (⩾180 mg/dL) during the early period after allo-HSCT.…”

“…62 Similarly, an increased risk of GVHD was observed in patients with severe hyperglycemia (⩾180 mg/dL) during the early period after allo-HSCT. 64 Substantial elevation of glucose levels during the early period after allo-HSCT may reflect inflammation-induced insulin resistance, which could possibly be associated with subsequent acute GVHD development. 60,62,64 Hammer et al 61 reported the adverse impact of hyperglycemia between days 0 and 100, which was associated with an increased risk of infectious diseases and NRM.…”

“…64 Substantial elevation of glucose levels during the early period after allo-HSCT may reflect inflammation-induced insulin resistance, which could possibly be associated with subsequent acute GVHD development. 60,62,64 Hammer et al 61 reported the adverse impact of hyperglycemia between days 0 and 100, which was associated with an increased risk of infectious diseases and NRM. Patients receiving systemic glucocorticoids as GVHD treatment are at higher risk to develop hyperglycemia, which is associated with inferior clinical outcome.…”

Blood glucose control using a computer-guided glucose management system in allogeneic hematopoietic cell transplant recipients

“…Our earlier study demonstrated that glucose values above 200 mg/dL were associated with twofold or more increase in NRM, compared with BG values between 101 and 150 mg/dL. 24 Similarly, Fuji et al 25 demonstrated an association between hyperglycemia and increased risk of organ dysfunction, grade II-IV acute GvHD and NRM in adult patients treated by myeloablative allogeneic HCT, and Gebremedhin et al 26 demonstrated that severe hyperglycemia immediately after allogeneic HCT was predictive of acute GvHD. There is, therefore, interest in improving glycemic control in the hope of improving transplant outcome.…”

“…1,2,5,8,[14][15][16][18][19][20][31][32][33][34][35][36] Our team and others have previously demonstrated the association between malglycemia (hyperglycemia, hypoglycemia and increased glycemic variability) and increased NRM and infections in HCT patients. [24][25][26] In addition, adverse clinical consequences of hyperglycemia from total parenteral nutrition exposure during HCT were reported. 37 These findings raised the hypothesis that stringent glycemic control with prevention of hypoglycemia and glucose variability may improve transplant outcome.…”