Baykoyanni, Giorgos

Cater, Daniel T.

Moser, Elizabeth A.S.

Paczesny, Sophie

Rowan, Courtney M.

Teagarden, Alicia M.

English

IUPUIScholarWorks

Early high plasma ST2, the decoy IL-33 receptor, inchildren undergoing hematopoietic cell transplantation is associated with the developmentof post-transplant diabetes mellitusPost-transplant diabetes mellitus (PTDM) occurs in60% of adults post-allogeneic hematopoietic cell trans-plant (post-HCT) and has a negative impact on survival.1Soluble Stimulation-2 (sST2), the decoy IL-33 receptor, isthe most validated predictor of refractory acute graft-versus-host disease (aGvHD) and death post-HCT.2In adults, day +14 plasma sST2 concentration was elevat-ed in those who develop PTDM.3 There are no studiesevaluating the incidence of PTDM and its relationship tosST2 in pediatric hematopoietic cell transplant (HCT)recipients. Here, we describe the incidence of PTDM inchildren. We also relate its diagnosis to complicationspost-HCT (aGvHD, veno-occlusive disease, and pediatricintensive care unit [PICU] admission), and day +100 post-HCT and overall survival. Furthermore, we correlatedday +14 plasma sST2 with the development of PTDM.  Institutional review board approval was obtained priorto the start of this study. Fifty-five HCT recipients, age ≤21 years, were prospectively accrued and plasma sampleswere collected at day +14 post-HCT. PTDM was definedas no pre-existing diabetes, a first fasting blood sugar≥126 mg/dL or random blood sugar ≥200 mg/dL duringthe first 100 days post-HCT.1 Cumulative incidence func-tion used the cohort median (23 ng/mL) of day +14 sST2as a cut-off for risk categorization into high (above) andlow (below).  Unadjusted and adjusted hazard ratios (HR)using Akaike’s Information Criterion (AIC) for multivari-able selection were calculated. Time-dependent receiveroperating characteristic (ROC) curves for day +14 sST2were generated to evaluate the area under the curve(AUC) for risk of developing PTDM by days +30 and+100 post-HCT. Death was used as a competing risk.haematologica 2020; 105:e249LETTERS TO THE EDITORTable 1. Demographics and patient characteristics stratified by the development of post-transplant diabetes mellitus.                                                                                             PTDM                                      No PTDM                                         P                                                                                             (n=17)                                       (n=38)                                            DemographicsSex (female)                                                                                          5 (29)                                                13 (34)                                                0.7260Age (years)                                                                                      7.7 (0.8, 16.0)                                   10.0 (4.9, 13.8)                                         0.3769DiagnosesLymphoid malignancy                                                                         7 (41)                                                 9 (24)Myeloid malignancy                                                                            3 (18)                                                14 (38)                                                0.2315Nonmalignant                                                                                       7 (41)                                                15 (39)                                                     Disease Risk Index score                                                              3.0 (2.0, 5.0)                                      3.0 (3.0, 5.0)                                           0.3930Conditioning regimenFull                                                                                                             15                                                        25Reduced                                                                                                     2                                                         10                                                    0.2830Nonmyeloablative                                                                                    0                                                           3                                                           Total body irradiation                                                                           6 (35)                                                15 (39)                                                0.7642Donor sourceBone marrow                                                                                       6 (35)                                                26 (68)Cord blood                                                                                           10 (59)                                                9 (24)                                                 0.0363Peripheral blood                                                                                  1 (6)                                                   3 (8)                                                        Donor statusMatched related                                                                                 3 (18)                                                18 (47)Matched unrelated                                                                             7 (41)                                                12 (32)                                                0.3219Mismatched unrelated                                                                      7 (41)                                                 8 (21)                                                       2nd transplant                                                                                          3 (18)                                                  0 (0)                                                  0.0259Body mass index at transplant                                                  19.1 (16.4, 21.6)                                17.7 (15.8, 22.4)                                        0.8275Time to PTDM (median, range)                                                 19.0 (3.0, 44.0)                                             na                                                        naTime to acute GvHD (median, range)                                     60.0 (32.0, 70.0)                                14.0 (14.0, 14.0)                                          na*High dose corticosteroids use prior to the development of                                                              4 (24)                                                 5 (13)                                                 0.4348PTDM or any time during the first 100 days post HCT                                                                              Time to corticosteroids (median, range)                                9.5 (0.0, 19.0)                                     2 (0.0, 21.0)                                            0.9999Values displayed are frequencies with (%) for categorical variables and were compared using c2 or Fisher’s Exact test where appropriate.  % are rounded to the nearestwhole number.  Continuous variables are displayed in medians (interquartile ranges) and were compared with Wilcoxon rank sum test. *P-value not obtained due to onlyone data point for time to aGvHD for the no PTDM group.  PTMD: post-transplant diabetes mellitus; aGvHD: acute graft-versus-host disease; na: not analysed. PTDM was diagnosed in 31% of children.  The medianday to development of PTDM was day +19 post-HCT(range: 3.0, 44.0 days). Demographics including sex, age,malignant diagnosis, matched or related donor status, dis-ease risk index, high-dose corticosteroids ( ≥1 mg/kgmethylprednisolone equivalent for at least 72 hours), andbody mass index did not differ significantly (Table 1).Those who received a cord blood transplant were morelikely to develop PTDM (P=0.0363). All patients (n=3)who underwent a second transplant developed PTDM(P=0.0259). Outcomes were worse in those who devel-oped PTDM (Table 2).  Univariate analysis showed thosewith PTDM had increased rates of aGvHD (P=0.0085).Four patients diagnosed with PTDM also had aGvHDgrade I-IV with a median time to development of 60 days(range: 32-70 days) (Table 1). Only three of these patientshad a maximum grade II-IV aGvHD.  Two of these threepatients were diagnosed with aGvHD prior to the PTDMdiagnosis (two and three days prior respectively). Onepatient was diagnosed with aGvHD 36 days after the diag-nosis of PTDM. There was no difference in the use of highdose steroids and the median time to steroid use was notstatistically different (Table 1). Those with PTDM werealso more likely to be admitted to the intensive care unit(71% vs. 8%, P<0.0001) and more likely to receivemechanical ventilation (53% vs. 5%, P=0.001).  Finally,those with PTDM also had decreased survival at 100 days(P=0.0070) as compared to patients who did not developPTDM. While not reaching statistical significance, morepatients with PTDM died of non-relapsed mortality(NRM) than those who did not develop PTDM (P=0.14).Those who developed PTDM had a higher mean sST2level at day +14 post HCT: 95.1±90.0 compared to thosewho did not develop PTDM: 28.2±28.7, P=0.0002.  Also,examining sST2 as a continuous variable, we found ahigher risk for PTDM (hazard ratio [HR]=1.013, 95%haematologica 2020; 105:e250LETTERS TO THE EDITORFigure 1. sST2 measured on day +14 post-allogeneic hematopoietic cell transplant is associated with the development of post-transplant diabetes mellitusand survival. (A) Cumulative incidence function graphs for risk based on sST2 level at day +14 post-allogeneic hematopoietic cell transplant (post-HCT).Cumulative incidence of the development of post-transplant diabetes mellitus (PTDM) comparing those at high risk (sST2 > cohort median of 23 ng/mL) to thoseat low risk (sST2 < cohort median of 23 ng/mL). Death was used as a competing risk. (B) Time dependent receiver operating characteristic curve for sST2 meas-ured at day +14 post-HCT. Time dependent receiver operating characteristic curves using sST2 levels measured on day +14 post-HCT to determine the risk ofdeveloping PTDM by day 30 and 100 post-HCT. Death was used as a competing risk. (C) Survival curve by PTDM status. Survival stratified by the developmentof PTDM.  Those in who developed PTDM (n=17), illustrated in red, had worse 1-year survival that those who did not developed PTDM (n=38), illustrated in blue.Log-rank P-value=0.0035. (D) Survival curve by high and low sST2 . Survival stratified by high sST2 (above the cohort median of 23 ng/mL) and low sST2 (below23 ng/mL).  Those with a high sST2 on day +14 had a worse probability of survival at 1 year than those who had a low sST2. Log-rank P-value=0.0072.A BC Dconfidence interval [CI]: 1.01-1.02, P<0.0001). We then,in an effort to identify a clinically useful cutpoint, catego-rized patients into high and low risk, using the mediansST2 level as a cutpoint.  Illustrated with cumulative inci-dence function graphs (Figure 1A), those with high sST2on day +14 had a higher risk of developing PTDM (HR=3.92, 95% CI: 1.42-10.84, unadjusted P=0.0085).Using death as a competing risk and adjusting for donorsource and second transplant, high sST2 was still strong-ly associated with PTDM occurrence within 100 dayspost-HCT (HR=4.06, 95% CI: 1.55-10.62, adjustedP=0.0043). A time-dependent ROC curve, with a com-peting risk of death, demonstrated that sST2 had anexcellent ability to discriminate the development ofPTDM by 30 (AUC=0.86) and 100 days (AUC=0.80)post-HCT (Figure 1B). Survival curves, estimated byKaplan-Meier curves method, showed that patients withPTDM had significantly lower survival than those whodid not, log-rank P-value for the difference of 0.0035(Figure 1C). Those with a high sST2 also had a lower sur-vival, similar to the survival curve by PTDM status, log-rank P-value of 0.0072 (Figure 1D). To examine if sST2was different even earlier in the transplant course, weinvestigated samples at day -7 (pre-HCT) on 10 noPTDM versus 18 PTDM patients. In this small samplesize, the mean +/- standard error of the mean (SEM) was23.3±6.7 for those with PTDM compared to 30.3±13.7 inthose who did not develop PTDM, the P-value=0.7184was not statistically significantly different. This is one of the first studies reporting the incidenceof PTDM in children post-HCT, which unexpectedlyappears common. Furthermore, to our knowledge, this isthe first manuscript to report an association betweensST2 and PTDM in a pediatric cohort. In adults withhyperglycemia post-HCT, studies have found increasedrisk for aGvHD and nonrelapsed mortality.4,5 Our studyfound similar results in a pediatric population. Childrenwith PTDM have increased aGvHD and the need for crit-ical care, and subsequently decreased overall survival.Surprisingly, but similar to a recent adult study,6 therewas not an association of the use of high dose corticos-teroids with PTDM. This suggests that HCT acutelymodifies glucose homeostasis in recipients too young tohave changes induced by age and other common factors.Perhaps, as suggested in non-transplant diabetes, PTDMis induced by inflammation resulting in insulinresistance.7 Supporting this is our finding that childrenwith high plasma sST2, as early as 14 days post-HCT,had a significantly higher risk to develop PTDM. This issimilar to adults with type-2 diabetes and PTDM.1,8Importantly, in our cohort, similar to the adult cohort, thebest statistical model did include high day +14 sST2 butnot aGvHD.3 These data suggest that the ST2/IL-33 path-way plays a role in maintaining the metabolic equilibri-um after HCT. Fasting pre-HCT glucose levels have beenshown to identify PTDM susceptibility in adults6 andtesting for it pre-HCT is crucial. However, fasting glucoselevels are sometimes difficult to perform in childrenyounger than 10 years and we believe that early testingof sST2 levels may help identify those at higher risk forPTDM development and help guide the frequency ofblood glucose monitoring, particularly in this youngerpopulation. As our adult patients, we recommend testingfor pre-HCT fasting glucose levels in children. In addi-tion, early testing of sST2 levels may help identify thoseat higher risk for PTDM development in children difficultto evaluate by pre-HCT fasting glucose levels with thegoal of early prevention and treatment of peripheralinsulin resistance, which may improve survival.Courtney M. Rowan,1 Alicia M. Teagarden,1 Daniel T. Cater,1Elizabeth A.S. Moser,2 Giorgos Baykoyannis2and Sophie Paczesny11Department of Pediatrics, Indiana University School of Medicineand 2Department of Biostatistics, Indiana University, Indianapolis, IN,USACorrespondence: COURTNEY ROWAN - coujohns@iu.edu  SOPHIE PACZESNY - sophpacz@iu.edu doi:10.3324/haematol.2019.222992.Information on authorship, contributions, and financial & other dis-closures was provided by the authors and is available with the onlineversion of this article at www.haematologica.org.haematologica 2020; 105:e251LETTERS TO THE EDITORTable 2. Outcomes and multivariate analyses of sST2 levels based on post-transplant diabetes mellitus status.                                                                          PTDM                                              No PTDM                                                  P                                                                          (n=17)                                               (n=38)                                                      HCT Outcomes, n (%)aGvHD grade I-IV                                                         5 (29)                                                            1 (3)                                                              0.0085Veno-occlusive disease                                              5 (29)                                                            3 (8)                                                              0.0908Survival Outcomes, n (%)Survival 100 days post-HCT                                       13 (77)                                                        38 (100)                                                          0.0070Survival 1 year post-HCT                                           10 (59)                                                         34 (90)                                                           0.0239Overall survival                                                             9 (53)                                                          32 (84)                                                           0.0208Causes of DeathRelapsed Mortality                                                      3 (38)                                                           5 (83)                                                               0.14Nonrelapsed Mortality*                                             5 (63)                                                           1 (17)Day +14 sST2 Biomarker > 23 ng/mLUnadjusted HR (95% CI)                                  3.92 (1.42-10.84)                                              reference                                                         0.0085Adjusted HR (95% CI)                                       4.06 (1.55-10.62)                                              reference                                                         0.0043Values displayed are frequencies with (%) for categorical variables and were compared using Chi Squared or Fisher’s Exact test where appropriate.  % are rounded to thenearest whole number.  HR: hazard ratio and CI: confidence interval were adjusted based on Akaike’s Information Criterion (AIC) for second transplant and donorsource.*Causes of non-relapsed mortality (NRM) included infection (n=1), acute graft-versus-host disease (aGVHD) (n=2), and SOS (n=2) in the PTDM group and pul-monary hemorrhage in the group with no PTDM. HCT:  hematopoietic cell transplant; n: number.References1. Griffith ML, Jagasia MH, Misfeldt AA, et al. Pretransplantation C-Peptide level predicts early posttransplantation diabetes mellitus andhas an impact on survival after allogeneic stem cell transplantation.Biol Blood Marrow Transplant. 2011;17(1):86-92.2. Vander Lugt MT, Braun TM, Hanash S, et al. ST2 as a marker for riskof therapy-resistant graft-versus-host disease and death. N Engl JMed. 2013;369(6):529-539.3. Johnpulle RA, Paczesny S, Jung DK, et al. Metabolic complicationsprecede alloreactivity and are characterized by changes in suppres-sion of tumorigenicity 2 signaling. Biol Blood Marrow Transplant.2017;23(3):529-532.4. Fuji S, Kim SW, Mori S, et al. Hyperglycemia during the neutropenicperiod is associated with a poor outcome in patients undergoingmyeloablative allogeneic hematopoietic stem cell transplantation.Transplantation. 2007;84(7):814-820.5. Sheean PM, Freels SA, Helton WS, Braunschweig CA. Adverse clini-cal consequences of hyperglycemia from total parenteral nutritionexposure during hematopoietic stem cell transplantation. Biol BloodMarrow Transplant. 2006;12(6):656-664.6. Engelhardt BG, Savani U, Jung DK, et al. New-onset post-transplantdiabetes mellitus after allogeneic hematopoietic cell transplant is ini-tiated by insulin resistance, not immunosuppressive medications.Biol Blood Marrow Transplant. 2019;25(6):1225-1231.7. Esser N, Legrand-Poels S, Piette J, Scheen AJ, Paquot N. Inflammationas a link between obesity, metabolic syndrome and type 2 diabetes.Diabetes Res Clin Pract. 2014;105(2):141-150.8. Fousteris E, Melidonis A, Panoutsopoulos G, et al. Toll/interleukin-1receptor member ST2 exhibits higher soluble levels in type 2 dia-betes, especially when accompanied with left ventricular diastolicdysfunction. Cardiovasc Diabetol. 2011;10:101.haematologica 2020; 105:e252LETTERS TO THE EDITOR

Early high plasma ST2, the decoy IL-33 receptor, in children undergoing hematopoietic cell transplantation is associated with the development of post-transplant diabetes mellitus

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Early high plasma ST2, the decoy IL-33 receptor, in children undergoing hematopoietic cell transplantation is associated with the development of post-transplant diabetes mellitus

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