The impact of pre-transplantation diabetes and obesity on acute graft-versus-host disease, relapse and death after allogeneic hematopoietic cell transplantation: a study from the EBMT Transplant Complications Working Party

Patient characteristics and prevalence of pre-transplantation diabetes and obesity

A total of 36 539 patients were included, of which 5228 (14%) had obesity (without co-existing diabetes), 1415 (4%) had diabetes (without co-existing obesity), and 688 (2%) had obesity + diabetes prior to transplant. Table 1 shows the patient characteristics according to pre-transplantation diabetes and obesity. The majority of patients received a peripheral blood stem cell transplant (89.5% of the control group, 92.6% of patients with obesity, 92.2% of patients with diabetes, and 96.6% of patients with obesity + diabetes). The most common donor was a 10/10 HLA-matched unrelated donor (used in 40.4% of the control group, 40.9% of patients with obesity, 41.4% of patients with diabetes, and 44.9% of patients with obesity + diabetes), and the most common indication was acute myeloid leukemia (58.8% of the control group, 57.2% of patients with obesity, 55.6% of patients with diabetes, and 54.4% of patients with obesity + diabetes). Reduced intensity conditioning was used in 49.2% of the control group, 51.5% of patients with obesity, 61.4% of patients with diabetes, and 63.4% of patients with obesity + diabetes.

Table 1 Patient characteristics according to pre-transplantation diabetes and obesity.

With regards to clinically relevant differences between the groups of interest, patients with diabetes and obesity + diabetes were older (median [inter-quartile range (IQR)] age 61.5 [55.1–66.4] years and 59.5 [53.8–64.2] years, respectively) than patients with obesity and the control group (median [IQR] age 53.8 [43.2–61.5] years and 54.3 [41.4–62.7] years, respectively), and they were more likely to be male (71.2% and 65.7% males in patients with diabetes and obesity + diabetes, respectively, versus 57.9% and 58.5% males in patients with obesity and the control group, respectively), and have a Karnofsky performance score <90 (38.3% and 34.2% of patients with diabetes and obesity + diabetes, respectively, versus 26.6% and 27.7% of patients with obesity and the control group, respectively).

The median follow-up was 32.7 months in the control group, 31.0 months in patients with obesity, 32.6 months in patients with diabetes, and 31.9 months in patients with obesity + diabetes.

Acute GvHD

Figure 1 shows the cumulative incidence of grade II–IV acute GvHD according to pre-transplantation obesity and diabetes status. At day +100, the cumulative incidence of grade II–IV acute GvHD was 26.6% (CI: 25.4–27.9%) in patients with obesity, 25.7% (CI: 23.4–28.0%) in patients with diabetes, 25.8% (CI: 22.5–29.2%) in patients with obesity + diabetes, compared with 27.3% (CI: 26.8–27.9%) in the control group of patients without pre-transplantation obesity and diabetes. Similar results were seen at day +180 (Table 2).

Fig. 1: Patients with missing data on acute GvHD status were excluded.figure 1

Cumulative incidence of grade II–IV acute graft-versus-host disease according to pre-transplantation obesity and diabetes status.

Table 2 Cumulative incidence [with 95% confidence interval] of acute and chronic GvHD, NRM, relapse, and OS according to pre-transplantation obesity and diabetes status.

In multivariable analysis, the adjusted HR of grade II–IV acute GvHD—using the control group as reference—was 1.00 (CI: 0.94–1.06, p = 0.89) for patients with obesity, 0.95 (CI: 0.85–1.07, p = 0.43) for patients with diabetes, and 0.96 (CI: 0.82–1.13, p = 0.63) for patients with obesity + diabetes (Table 3).

Table 3 Estimates of the impact of pre-transplantation obesity and diabetes on grade II–IV acute graft-versus-host disease and other transplant outcomes from multivariable cause-specific Cox proportional hazard regression models.Chronic GvHD

The 2-year cumulative incidence of chronic GvHD (both limited and extensive) was 34.9% (CI: 33.5–36.3%) in patients with obesity, 33.0% (CI: 30.4–35.7%) in patients with diabetes, 36.6% (CI: 32.6–40.6%) in patients with obesity + diabetes, compared with 34.4% (CI: 33.8–35.0%) in the control group. The 2-year cumulative incidence of extensive chronic GvHD was 15.2% (CI: 14.1–16.3%) in patients with obesity, 15.3% (CI: 13.3–17.5%) in patients with diabetes, 19.0% (CI: 15.8–22.4%) in patients with obesity + diabetes, compared with 15.8% (CI: 15.3–16.2%) in the control group.

The adjusted HR, compared with the control group, for chronic GvHD (limited and extensive) was 1.04 (CI: 0.98–1.10, p = 0.17) for patients with obesity, 1.02 (CI: 0.92–1.14, p = 0.68) for patients with diabetes, and 1.07 (CI: 0.93–1.25, p = 0.34) for patients with obesity + diabetes. For extensive chronic GvHD alone, the adjusted HR was 1.00 (CI: 0.92–1.08, p = 0.92) for patients with obesity, 1.07 (CI: 0.92–1.25, p = 0.37) for patients with diabetes, and 1.18 (CI: 0.97–1.44, p = 0.10) for patients with obesity + diabetes (Table 3).

NRM, relapse and OS

Figure 2 shows the incidence of NRM according to pre-transplantation obesity and diabetes status. The 1-year NRM was 14% (CI: 13.6–14.4%) in the control group, 15.5% (CI: 14.5–16.5%), in patients with obesity, 23.9% (CI: 21.6–26.3%) in patients with diabetes, and 20.0% (CI: 16.9–23.3%) in patients with obesity + diabetes. Similar differences were observed at 2-years (Table 2). In multivariable analysis, the adjusted HR (using the control group as reference) for NRM was 1.08 (CI: 1.00–1.17, p = 0.047) for patients with obesity, 1.40 (CI: 1.24–1.57, p < 0.0001) for patients with diabetes, and 1.38 (CI: 1.16–1.64, p = 0.0003) for patients with obesity + diabetes (Table 3).

Fig. 2: Patients with missing data on relapse status were excluded.figure 2

Non-relapse mortality according to pre-transplantation obesity and diabetes status.

The cumulative incidence of relapse (Fig. 3) at 2-years was 28.2% (CI: 26.9–29.6%) in patients with obesity, 28.4% (CI: 25.8–31.0%) in patients with diabetes, and 27.7% (CI: 24.0–31.5%) in patients with obesity + diabetes, compared with 28.7% (CI: 28.2–29.3%) in the control group. The adjusted HR for relapse was 1.02 (CI: 0.96–1.08, p = 0.53) for patients with obesity, 1.08 (CI: 0.96–1.20, p = 0.20) for patients with diabetes, and 0.96 (CI: 0.81–1.13, p = 0.61) for patients with obesity + diabetes (Table 3).

Fig. 3: Patients with missing data on relapse status were excluded.figure 3

Cumulative incidence of relapse according to pre-transplantation obesity and diabetes status.

OS (Fig. 4) at 2-years was 63.9% (CI: 62.5–65.3%) in patients with obesity, 50.1% (CI: 47.4–53.0%) in patients with diabetes, and 55.0% (CI: 51.1–59.2%) in patients with obesity + diabetes, compared with 63.3% (CI: 63.0–64.2%) in the control group. The adjusted HR for OS was 1.02 (CI: 0.97–1.08, p = 0.38) for patients with obesity, 1.29 (CI: 1.18–1.40, p < 0.0001) for patients with diabetes, and 1.23 (CI: 1.09–1.39, p = 0.001) for patients with obesity + diabetes (Table 3).

Fig. 4figure 4

Overall survival after allogeneic hematopoietic cell transplantation according to pre-transplantation obesity and diabetes status.

Survival after acute GvHD

Figure 5 shows the OS according to pre-transplantation obesity and diabetes from the date of first occurrence of grade II–IV acute GvHD in the group of patients who experienced this within the first 180 days after allogeneic HCT (N = 9555). At 24-months after the first occurrence of grade II–IV acute GvHD, the OS of patients with pre-transplantation obesity (56.7%, CI: 54.0–59.6%) was similar to that in the control group (56.1%, CI: 54.9–57.3%), whereas patients with pre-transplantation diabetes and patients with pre-transplantation obesity + diabetes had a lower OS of 38.3% (CI: 33.2–44.1%) and 43.3% (CI: 36.1–52.1%), respectively.

Fig. 5: Only patients who experienced grade II-IV acute GvHD within day +180 were included.figure 5

Overall survival after diagnosis of grade II–IV acute graft-versus-host disease according to pre-transplantation obesity and diabetes status.

In multivariable analysis (Table 3), having pre-transplantation diabetes was associated with poorer OS after a diagnosis of grade II–IV acute GvHD compared to patients without pre-transplantation diabetes or obesity (HR 1.46, CI: 1.25–1.70, p < 0.0001). We did not find support for an inferior survival—in comparison to the control group—in patients with pre-transplantation obesity (HR 1.02, CI: 0.93–1.13, p = 0.65) or with pre-transplantation obesity + diabetes (HR 1.18, CI: 0.95–1.47, p = 0.14).

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