Impact of standard-dose dipeptidyl peptidase-4 inhibitors on the incidence of graft-versus-host disease among diabetes mellitus patients undergoing allogeneic hematopoietic cell transplantation: a KSGCT multicenter retrospective study

doi:10.21203/rs.3.rs-2038009/v1

Download PDF

Article

Impact of standard-dose dipeptidyl peptidase-4 inhibitors on the incidence of graft-versus-host disease among diabetes mellitus patients undergoing allogeneic hematopoietic cell transplantation: a KSGCT multicenter retrospective study

https://doi.org/10.21203/rs.3.rs-2038009/v1

This work is licensed under a CC BY 4.0 License

You are reading this latest preprint version

This study aimed to evaluate the impact of standard-dose dipeptidyl peptidase-4 inhibitors (DPP-4i) on the incidence of graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT). We retrospectively evaluated 207 diabetes mellitus patients undergoing allogeneic HCT between 2010 and 2019. The 100-day cumulative incidences (CI) of grade II–IV acute GVHD (aGVHD) in patients who took DPP-4i from day − 1 to 14, those who did not, and those who discontinued DPP-4i within 10 days after HCT because of difficulty taking the medicine were 33.9%, 32.8%, and 60.0% (P = 0.063), respectively. With regard to chronic GVHD (cGVHD), taking DPP-4i between days 21 and 60 was associated with a trend toward lower incidence of cGVHD (1-year CI: 25.4% vs. 35.6%, P = 0.094). In a multivariate analysis, the administration of DPP-4i between days 21 and 60 was significantly associated with lower incidence of cGVHD (hazard ratio 0.53, 95% confidence interval 0.30–0.96, P = 0.035). It was difficult to interpret the impact of standard-dose DPP-4i on the development of aGVHD since an inability to continue oral medication was significantly associated with higher incidence of aGVHD. On the other hand, taking DPP-4i over days 21–60 may suppress the development of cGVHD.

dipeptidyl peptidase-4 inhibitor

diabetes mellitus

graft-versus-host disease

allogeneic hematopoietic cell transplantation.

The prophylactic administration of high-dose sitagliptin, a dipeptidyl peptidase 4 (DPP-4) inhibitor, was reportedly associated with a low incidence of acute graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT).¹ Since DPP-4 inhibitors affect glucose regulation, they have been originally used for the treatment of diabetes mellitus.² DPP-4, also known as CD26, is expressed on T lymphocytes and has a costimulatory function in T-cell activation.³ Therefore, DPP-4 inhibitors may also regulate T cell-mediated immune responses. In addition to GVHD prophylaxis, some previous studies reported that DPP-4 inhibitors were associated with lower risk of autoimmune disorders in type 2 diabetes mellitus patients.^4–6

Until now, it has not been investigated how standard-dose DPP-4 inhibitors affect the development of GVHD in allogeneic HCT recipients. In this study, we retrospectively analyzed the impact of standard-dose DPP-4 inhibitors on the development of acute and chronic GVHD in diabetes mellitus patients undergoing allogeneic HCT at institutions participating in the Kanto Study Group for Cell Therapy (KSGCT).

Study patients

We conducted a multicenter retrospective study to evaluate the impact of standard-dose DPP-4 inhibitors on the development of acute and chronic GVHD in allogeneic HCT recipients. Patients with a comorbidity of diabetes mellitus who underwent allogeneic HCT between 2010 and 2019 at participating institutions in KSGCT were included in this study. Patients who died within 30 days after HCT and those who experienced primary engraftment failure were excluded. By using a clinical research form, information on the treatment for diabetes mellitus including DPP-4 inhibitors and other hypoglycemic agents until 100 days after HCT was collected from each participating center. Registration data were obtained from the KSGCT data center, and all patients provided informed consent for data reporting. This study was approved by the Institutional Review Board of Jichi Medical University Saitama Medical Center and each participating institution in accordance with the Declaration of Helsinki.

Definitions

Donor types were classified into HLA-A, B, and DR serologically 6/6-matched related donors (MRD), HLA serologically mismatched related donors (MMRD), HLA-A, B, C, DRB1 allele 8/8-matched unrelated donors (MUD), HLA allele mismatched unrelated donors (MMUD) and cord blood (CB) donors. Bone marrow (BM), peripheral blood (PB) and CB were used as stem cell sources. With regard to cytomegalovirus (CMV) serostatus, CB was considered to test negative for CMV by definition. The disease risk index (DRI) and hematopoietic cell transplantation-specific comorbidity index (HCT-CI) were calculated as previously reported.^{7, 8} Since all patients had a comorbidity of diabetes mellitus, their HCT-CI was at least 1. Patients were divided into two groups with HCT-CI 1–2 or ≥ 3. Performance status (PS) was evaluated based on the Eastern Cooperative Oncology Group (ECOG) scoring system. PS of 0 or 1 was defined as good, whereas scores of 2 through 4 were defined as poor.

Conditioning regimens were classified as myeloablative conditioning (MAC) if they included total body irradiation (TBI) > 8 Gy, melphalan > 140 mg/m², oral busulfan ≥ 9 mg/kg or intravenous busulfan ≥ 7.2 mg/kg.⁹ Other regimens were classified as reduced-intensity conditioning (RIC). In vivo T-cell depletion was defined as the inclusion of anti-thymocyte globulin (ATG), anti-lymphocyte globulin or alemtuzumab in the conditioning regimen for GVHD prophylaxis.

Neutrophil engraftment was defined as the first of 3 consecutive days with a neutrophil count > 500 /µl. Acute and chronic GVHD were diagnosed and graded as previously described.^10–12.

Statistical considerations

Dichotomous and continuous variables were compared using Fisher’s exact test and the Mann-Whitney U test, respectively. Kaplan-Meier curves were used to estimate survival probabilities. The cumulative incidence of GVHD was estimated and compared by Gray’s method while treating death as a competing event. In risk factor analyses for acute and chronic GVHD, the Cox proportional hazard regression model was used. Acute GVHD was treated as a time-dependent covariate in a risk factor analysis for chronic GVHD. The hazard ratio (HR) of the administration of DPP-4 inhibitors was adjusted for variables with a P-value < 0.15 in a univariate analysis. Statistical significance was defined as a two-tailed P-value < 0.05. All statistical analyses were performed with EZR version 1.55 (Jichi Medical University Saitama Medical Center, accessed 24 December 2021; available at http://www.jichi.ac.jp/saitama-sct/SaitamaHP.files/statmedEN.html).¹³

Study patients and transplantation outcomes

A total of 207 HCTs in 15 institutions were evaluated in this study (Table 1). In 7 patients, both their first and second HCTs were included. In these patients, the follow-up of the first HCT was censored at the second HCT. The median follow-up period for survivors was 1,351 days (range, 82–4,263 days). The 5-year OS was 41.8% (95% confidence interval [CI], 34.6–48.7%). Neutrophil engraftment was achieved at a median of 19 days (range, 9–69 days) after HCT. Grade II–IV and grade III–IV acute GVHD were observed in 77 (37.2%) and 19 (9.2%) patients at a median of 34 days (range, 9–226 days) and 34 days (range, 9–122 days) after HCT, respectively. Overall chronic GVHD and extensive chronic GVHD were observed in 61 and 38 patients at a median of 145 days (range, 23–841 days) and 135.5 days (range, 23–34 days) after HCT, respectively, among those who survived at least 100 days after HCT (n = 182).

Table 1

Patient characteristics of overall cohort
Factors		Total (n = 207)		DPP-4i [baseline] (n = 89)		No DPP-4i [baseline] (n = 118)		P-value
Age, years	Median (range)	57	(18–69)	60	(26–69)	55	(18–67)	< 0.001
	< 50 >= 50	49 158	(23.7) (76.3)	13 76	(14.6) (85.4)	36 82	(30.5) (69.5)	0.008
Sex	Male Female	154 54	(74.4) (25.6)	73 16	(82.0) (18.0)	81 37	(68.6) (31.4)	0.036
Disease	AML ALL MDS CML/MPN ML Others	94 39 32 11 23 8	(45.4) (18.8) (15.5) (5.3) (11.1) (3.9)	44 20 15 1 8 1	(49.4) (22.5) (16.9) (1.1) (9.0) (1.1)	50 19 17 10 15 7	(42.4) (16.1) (14.4) (8.5) (12.7) (5.9)
Disease risk index	Low / Intermediate High / Very High	10 / 100 74 / 23	(4.8 / 48.3) (35.7 / 11.1)	47 42	(52.8) (47.2)	63 55	(53.4) (46.6)	1.00
Number of allogeneic HCTs	1 2 3	180 19 8	(87.0) (9.2) (3.9)	80 5 4	(89.9) (5.6) (4.5)	100 14 4	(84.7) (11.9) (3.4)	0.29
PS	0–1 >= 2	185 22	(89.4) (10.6)	83 6	(93.3) (6.8)	102 16	(86.4) (13.6)	0.17
HCT-CI	1–2 >= 3 NA	127 79 1	(61.7) (38.3)	58 30 1	(65.9) (34.1)	69 49	(58.5) (41.5)	0.31
Donor	MRD MMRD MUD MMUD CB	34 26 49 47 51	(16.4) (12.6) (23.7) (22.7) (24.6)	15 10 21 21 22	(16.9) (11.2) (23.6) (23.6) (24.7)	19 16 28 26 29	(16.1) (13.6) (23.7) (22.0) (24.6)	0.99
CMV Ab Patient / Donor	+ / + + / - - / + - / - NA	76 92 8 14 17	(40.0) (48.4) (4.2) (7.4)	32 43 2 4 8	(39.5) (53.1) (2.5) (4.9)	44 49 6 10 9	(40.4) (45.0) (5.5) (4.9)	0.46
Conditioning	MAC RIC	81 126	(39.1) (60/9)	33 56	(37.1) (62.9)	48 70	(40.7) (59.3)	0.67
	TBI > 8Gy T-cell depletion Post-CY	30 42 1	(14.5) (20.3) (0.5)	12 15 0	(13.5) (16.9)	18 27 1	(15.3) (22.9) (0.8)	0.84 0.30 0.43
Insulin therapy		95	(45.9)	20	(22.5)	75	(63.6)	< 0.001
Patients were divided into two groups depending on the administration of DPP-4i before HCT: a No DPP-4i [baseline] group and a DPP-4i [baseline] group.
DPP-4i, dipeptidyl peptidase-4 inhibitors; AML, acute myeloid leukemia; ALL, acute lymphoblastic leukemia; MDS, myelodysplastic syndrome; CML, chronic myeloid leukemia; MPN, myeloproliferative neoplasm; ML, malignant lymphoma; HCT, hematopoietic cell transplantation; PS, performance status; HCT-CI, hematopoietic cell transplantation-specific comorbidity index; NA, not available; MRD, HLA-matched related donor; MMRD, HLA-mismatched related donor; MUD, HLA-matched unrelated donor; MMUD, HLA-mismatched unrelated donor; CB, cord blood; CMV Ab, cytomegalovirus antibody; MAC, myeloablative conditioning; RIC, reduced-intensity conditioning; TBI, total body irradiation; CY, cyclophosphamide.

The treatments used for diabetes mellitus before allogeneic HCT are summarized in Supplementary Tables 1 and 2. Eighty-nine patients had been taking DPP-4 inhibitors (DPP-4i [baseline]) and 118 had not (No DPP-4i [baseline]). There was no significant difference in patient backgrounds between the two groups with exception for age, sex and insulin therapy (Table 1).

Impact of DPP-4 inhibitors on the development of acute GVHD

From 1 day before to 20 days after HCT, 79 patients took DPP-4 inhibitors for at least 1 day. Among these patients, 27 patients discontinued DPP-4 inhibitors within 20 days because of difficulty taking the medicine. Patients were divided into three groups depending on the administration period of DPP-4 inhibitors from day − 1 to 14 after HCT: those who did not take DPP-4 inhibitors (No DPP-4i [D-1 to 14]; n = 128), those who took them for 12 days or longer (Long DPP-4i [D-1 to 14]; n = 59), and those who took them for less than 12 days (Short DPP-4i [D-1 to 14]; n = 20). We used 12 out of 16 days as a cut-off value, since 78% of the patients received 80% or more of the planned high-dose sitagliptin in the previous study.¹ The 100-day cumulative incidence of grade II–IV acute GVHD was 32.8% in the No DPP-4i [D-1 to 14] group, 33.9% in the Long DPP-4i [D-1 to 14] group, and 60.0% in the Short DPP-4i [D-1 to 14] group (P = 0.063) (Fig. 1A). With regard to grade III–IV acute GVHD, the 100-day cumulative incidences were 7.0%, 10.2% and 15.0%, respectively (P = 0.55) (Fig. 1B).

Under the assumption that patient conditions which precluded the intake of oral medications might have affected the incidence of acute GVHD, we also evaluated the impact of administration of oral hypoglycemic agents other than DPP-4 inhibitors within 20 days after HCT on the development of acute GVHD. The 100-day cumulative incidence of grade II–IV acute GVHD was 36.8% in patients who did not take oral hypoglycemic agents other than DPP-4 inhibitors (n = 163), 23.3% in those who took oral hypoglycemic agents other than DPP-4 inhibitors without discontinuation (n = 30), and 50.0% in those who discontinued oral hypoglycemic agents other than DPP-4 inhibitors within 20 days after HCT because of difficulty taking the medicine (n = 14) (P = 0.22) (Supplementary Fig. 1A). The same analysis was performed after excluding patients who took DPP-4 inhibitors within 20 days after HCT, which showed similar results (Supplementary Fig. 1B).

Impact of DPP-4 inhibitors on the development of chronic GVHD

We performed an analysis of chronic GVHD among patients who survived for 100 days or longer after HCT (Table 2). Involved organs in chronic GVHD are summarized in Supplementary Table 3. We evaluated the relationship between the development of chronic GVHD and the administration of DPP-4 inhibitors either within 14 days after HCT or between days 21 and 60 after HCT. Two patients who developed chronic GVHD within 60 days after HCT were excluded from the chronic GVHD analysis. Neither of these patients took a DPP-4 inhibitor throughout the clinical course.

Table 2

Patient characteristics of the chronic GVHD cohort in patients with and without administration of DPP-4 inhibitors between days 21 and 60 after HCT
Factors		Total (n = 180)		DPP-4i [D21 to 60] (n = 61)		No DPP-4i [D21 to 60] (n = 119)		P-value
Age, years	Median (range)	57	(18–69)	56	(26–69)	57	(18–69)	0.63
	< 50 >= 50	45 135	(25.0) (75.0)	15 46	(24.6) (75.4)	30 89	(25.2) (74.8)	1.00
Sex	Male Female	131 49	(72.8) (27.2)	72 9	(85.2) (14.8)	79 40	(66.4) (33.6)	0.008
Disease risk index	Low / Intermediate High / Very High	99 81	(55.0) (45.0)	30 31	(49.2) (50.8)	69 50	(58.0) (42.0)	0.27
Number of allogeneic HCTs	1 2 3	158 16 6	(87.8) (8.9) (3.3)	55 3 3	(90.2) (4.9) (4.9)	103 13 3	(86.6) (10.9) (2.5)	0.34
PS	0–1 >= 2	168 12	(93.3) (6.7)	56 5	(91.8) (8.2)	112 7	(94.1) (5.9)	0.54
HCT-CI	1–2 >= 3	113 66	(63.1) (36.9)	42 19	(68.3) (31.7)	72 47	(60.5) (39.5)	0.33
Donor	MRD MMRD MUD MMUD CB	31 20 44 42 43	(17.2) (11.1) (24.4) (23.3) (23.9)	11 6 15 16 13	(18.0) (9.8) (24.6) (26.2) (21.3)	20 14 29 26 30	(16.8) (11.8) (24.4) (21.8) (25.2)	0.95
CMV Ab Patient / Donor	+ / + + / - - / + - / - NA	65 79 7 13 16	(39.6) (48.2) (4.3) (7.9)	20 28 2 4 7	(37.0) (51.9) (3.7) (7.4)	45 51 5 9 9	(40.9) (46.4) (4.5) (8.2)	0.95
Conditioning	MAC RIC	70 110	(38.9) (61.1)	24 37	(38.7) (61.3)	46 73	(38.7) (61.3)	1.00
	TBI > 8Gy T-cell depletion	28 33	(15.6) (18.3)	10 11	(16.4) (18.0)	18 22	(15.1) (18.5)	0.83 1.00
aGVHD	Grade II–IV Grade III–IV	67 12	(37.2) (6.7)	23 2	(37.7) (3.3)	44 10	(37.0) (8.4)	1.00 0.34
Patients were divided into two groups depending on the administration of DPP-4i between days 21 and 60 after HCT: those who did not take DPP-4 inhibitors or took them for less than 10 days (No DPP-4i [D21 to 60]) and those who took them for 10 days or longer (DPP-4i [D21 to 60]).
DPP-4i, dipeptidyl peptidase-4 inhibitors; HCT, hematopoietic cell transplantation; PS, performance status; HCT-CI, hematopoietic cell transplantation-specific comorbidity index; NA, not available; MRD, HLA-matched related donor; MMRD, HLA-mismatched related donor; MUD, HLA-matched unrelated donor; MMUD, HLA-mismatched unrelated donor; CB, cord blood; CMV Ab, cytomegalovirus antibody; MAC, myeloablative conditioning; RIC, reduced-intensity conditioning; TBI, total body irradiation; aGVHD, acute graft-versus-host disease.

The 1-year cumulative incidences of overall chronic GVHD in the Long DPP-4i [D-1 to 14], No DPP4i [D-1 to 14] and Short DPP4i [D-1 to 14] groups were 30.1%, 33.0%, and 33.3%, respectively (P = 0.71) (Supplementary Fig. 2A). The 1-year cumulative incidences of extensive chronic GVHD in these treatment groups were 20.4%, 20.1%, and 27.8%, respectively (P = 0.74) (Supplementary Fig. 2B).

Then, we evaluated the relationship between the administration of DPP-4 inhibitors between days 21 and 60 after HCT and the development of chronic GVHD. Patients were divided into two groups: those who did not take DPP-4 inhibitors (n = 115) or took them for less than 10 days (n = 4) (No DPP-4i [D21 to 60] group, n = 119) and those who took them for 10 days or longer (DPP-4i [D21 to 60] group, n = 61) (Table 2). The 1-year cumulative incidence of chronic GVHD was 25.4% in the DPP-4i [D21 to 60] group and 35.6% in the No DPP-4i [D21 to 60] group (P = 0.094) (Fig. 2A). The 1-year cumulative incidence of extensive chronic GVHD was 15.3% in the DPP-4i [D21 to 60] group and 23.9% in the No DPP-4i [D21 to 60] group (P = 0.14) (Fig. 2B). On the other hand, the administration of oral hypoglycemic agents other than DPP-4 inhibitors between days 21 and 60 after HCT did not have an impact on the development of chronic GVHD (Supplementary Fig. 3A). This was also true after excluding patients who took DPP-4 inhibitors between days 21 and 60 after HCT (Supplementary Fig. 3B).

Risk factor analysis for the development of chronic GVHD

We performed risk factor analyses for overall and extensive chronic GVHD (Table 3). As for the administration of DPP-4 inhibitors, patients were divided into two groups: a DPP-4i [D21 to 60] group and a No DPP-4i [D21 to 60] group. In a univariate analysis, the DPP-4i [D21 to 60] group (HR 0.55; 95%CI: 0.31–10.99), RIC (HR 0.67; 95%CI: 0.40–1.11) and grade II–IV acute GVHD (HR 1.56; 95%CI: 0.93–2.61) were associated with the incidence of chronic GVHD with at least borderline significance. In a multivariate analysis, inclusion in the DPP-4i [D21 to 60] group (HR 0.53; 95%CI: 0.30–0.96; P = 0.035) was identified as a significant risk factor for reduced incidence of chronic GVHD. Similarly, the DPP-4i [D21 to 60] group (HR 0.54; 95%CI: 0.26–1.15), RIC (HR 0.49; 95%CI: 0.26–0.93) and grade II–IV acute GVHD (HR 1.86; 95%CI: 0.97–3.54) were associated with the incidence of extensive chronic GVHD with at least borderline significance in a univariate analysis. In a multivariate analysis, RIC (HR 0.50; 95%CI: 0.26–0.95; P = 0.035) was identified as a significant factor associated with a reduced risk of extensive chronic GVHD. The DPP-4i [D21 to 60] group (HR 0.52; 95%CI: 0.25–1.11; P = 0.093) tended to be associated with lower incidence of extensive chronic GVHD, but the association was not statistically significant in a multivariate analysis.

Table 3

Risk factors for chronic GVHD
Factors		Univariate analysis			Multivariate analysis
		HR	95%CI	P-value	HR	95%CI	P-value
Chronic GVHD
Age, years	>= 50	0.78	0.44–1.38	0.39
Sex	Male	0.90	0.51–1.58	0.70
Disease risk index	High / Very High	1.12	0.67–1.89	0.67
Number of allogeneic HCTs	>= 2	1.21	0.57–2.55	0.62
PS	>= 2	1.77	0.76–4.13	0.18
HCT-CI	>= 3	0.88	0.51–1.52	0.65
Donor	MRD MMRD MUD MMUD CB	1.00 1.40 1.23 0.94 1.08	0.51–3.86 0.52–2.87 0.39–2.28 0.46–2.54	0.91 ^§ 0.52 0.64 0.89 0.86
Female donor to male patient		1.27	0.72–2.23	0.41
CMV Ab, Patient / Donor	+ / + + / - - / + - / -	1.00 0.84 0.97 0.18	0.48–1.47 0.23–4.12 0.02–1.32	0.39 ^§ 0.53 0.96 0.09
Conditioning	RIC	0.67	0.40–1.11	0.12	0.66	0.39–1.10	0.11
	TBI > 8Gy	1.25	0.65–2.42	0.50
	T cell depletion	0.80	0.40–1.64	0.55
aGVHD2-4 ^#		1.56	0.93–2.61	0.089	1.59	0.95–2.67	0.077
DPP-4i [D21 to 60]		0.55	0.31–0.99	0.047	0.53	0.30–0.96	0.035
Extensive chronic GVHD
Age, years	>= 50	0.80	0.39–1.65	0.55
Sex	Male	0.78	0.39–1.54	0.47
Disease risk index	High / Very High	1.21	0.63–2.31	0.57
Number of allogeneic HCTs	>= 2	1.19	0.46–3.04	0.72
PS	>= 2	1.40	0.43–4.55	0.58
HCT-CI	>= 3	0.83	0.42–1.66	0.60
Donor	MRD MMRD MUD MMUD CB	1.00 1.36 1.02 1.01 0.58	0.41–4.46 0.37–2.81 0.37–2.79 0.19–1.81	0.70 ^§ 0.61 0.97 0.98 0.35
Female donor to male patient		1.07	0.52–2.21	0.86
CMV Ab, Patient / Donor	+ / + + / - - / + - / -	1.00 0.62 0.55 < 0.01	1.65–3.07 0.15–1.12 0.00-Inf	0.58 ^§ 0.18 0.56 1.00
Conditioning	RIC	0.49	0.26–0.93	0.030	0.50	0.26–0.95	0.035
	TBI > 8Gy	1.85	0.87–3.93	0.11
	T cell depletion	1.23	0.49–2.56	0.78
aGVHD2-4 ^#		1.86	0.97–3.54	0.060	1.79	0.94–3.43	0.077
DPP-4i [D21 to 60]		0.54	0.26–1.15	0.11	0.52	0.25–1.11	0.093
^§Overall comparison; ^#time-dependent covariate. HR, hazard ratio; 95%CI, 95% confidence interval; GVHD, graft-versus-host disease; HCT, hematopoietic cell transplantation; PS, performance status; HCT-CI, hematopoietic cell transplantation-specific comorbidity index; MRD, HLA-matched related donor; MMRD, HLA-mismatched related donor; MUD, HLA-matched unrelated donor; MMUD, HLA-mismatched unrelated donor; CB, cord blood; CMV Ab, cytomegalovirus antibody; RIC, reduced-intensity conditioning; TBI, total body irradiation; aGVHD2-4, grade II–IV acute graft-versus-host disease; DPP-4i, dipeptidyl peptidase-4 inhibitors; DPP-4i [D21 to 60], patients who took DPP-4i for 10 days or longer between days 21 and 60 after HCT.

In previous studies, the administration of a high-dose DPP-4 inhibitor early after HCT was associated with remarkably lower risk of acute GVHD in allogeneic HCT recipients.^{1, 14, 15} In this study, there was no difference in the incidence of grade II–IV or grade III–IV acute GVHD between patients who took standard-dose DPP-4 inhibitors from day − 1 to day 14 after HCT and those who did not take them. It was striking that the incidence of grade II–IV acute GVHD was high in patients who discontinued DPP-4 inhibitors due to difficulty taking them. In addition, there was a non-significant trend toward higher incidence of acute GVHD in patients who discontinued oral hypoglycemic agents other than DPP-4 inhibitors. These results suggested that the conditions of patients which led them to discontinue medicines because of oral or gastrointestinal mucositis may have affected the development of acute GVHD. This was consistent with a proposed mechanism in which danger-associated molecular patterns (DAMPS) released from damaged tissue cause and perpetuate a non-infectious inflammatory response, which leads to the development of acute GVHD.¹⁶ Taking these results into consideration, it was difficult to evaluate the impact of standard-dose DPP-4 inhibitors on the development of acute GVHD in this retrospective study.

To the best of our knowledge, this is the first study to show a significant association between DPP-4 inhibitors and the development of chronic GVHD. The administration of standard-dose DPP-4 inhibitors between days 21 and 60 after HCT reduced the incidence of chronic GVHD. Since the administration of oral hypoglycemic agents other than DPP-4 inhibitors during the same period did not affect the incidence of chronic GVHD, we considered that the immunosuppressive effects of the DPP-4 inhibitors themselves had an impact on the incidence of chronic GVHD. While acute GVHD is mediated primarily by mature donor T cells in the stem cell product, chronic GVHD is a more complex immune reaction presenting with a variety of clinical signs and symptoms resembling autoimmune diseases.^17–19 Donor-derived effector T cells and B cells both contribute to the immune pathology of chronic GVHD, and regulatory elements within the T- and B-cell lineages play important roles in the development and maintenance of immune tolerance after allogeneic HCT.

In an experimental model of autoimmune encephalomyelitis, which is a well-known CD4⁺ T cell-mediated autoimmune disease leading to central nervous system inflammation and demyelination, a DPP-4 inhibitor was shown to significantly decrease and delay clinical and neuropathological signs.²⁰ In several large-scale retrospective observational studies, a DPP-4 inhibitor was associated with a lower incidence of autoimmune diseases in type 2 diabetes mellitus patients.^4–6 Although the underlying mechanisms of these prophylactic effects have not been fully elucidated, it is known that DPP-4 inhibitors suppress T cell proliferation and cytokine production.^{2, 21} The in vitro inhibition of the DPP-4 enzymatic activity in T cells induces intracellular signals that lead to suppression of the production of activating cytokines and an enhanced production of cytokine transforming growth factor-β (TGF-β). The action of the immune-inhibitory TGF-β could partially explain the effect of DPP-4 inhibitors on T cell proliferation and on cytokine production. In addition, a previous study in systemic sclerosis patients reported that DPP-4 expression characterizes a population of activated fibroblasts, and regulates TGF-β induced fibroblast activation and tissue fibrosis.²²

The dose and administration timing are also important factors. In previous studies in allogeneic HCT recipients, high-dose sitagliptin was administered (600–1200 mg/day versus the standard 50–100 mg/day dose for diabetes mellitus).^{1, 14, 15} When sitagliptin 600 mg was administered twice daily, maximal plasma DPP-4 inhibition was observed at 2 hours and 4 hours after dosing with a mean nadir plasma DPP-4 of 22 ± 10% and 22 ± 5%, respectively. Plasma DPP-4 inhibition was sustained with a mean trough residual activity of 29 ± 8%.¹ In a pharmacokinetics and pharmacodynamics study in healthy subjects, sitagliptin doses of 50 mg or higher produced at least 80% inhibition of DPP-4 activity over a 12-hour period, and doses of 100 mg or higher produced 80% inhibition over a 24-hour period.²³ Therefore, a standard dose of sitagliptin could produce clinically significant inhibition of DPP-4. With regard to the administration timing, high-dose sitagliptin early after HCT suppressed the development of acute GVHD in previous studies.^{1, 14, 15} In our study, the administration of DPP-4 inhibitors between days 21 and 60 had an impact on the development of chronic GVHD, which suggests that inhibition of DPP-4 around and early after engraftment might efficiently suppress the development of chronic GVHD.

In this study, RIC was identified as one of the factors significantly associated with a lower risk of extensive chronic GVHD. Impact of conditioning intensity on GVHD has been investigated in previous studies.^{24, 25} Although MAC and/or TBI have been identified as significant factors associated with higher incidence of acute GVHD in most studies,^24–26 conditioning intensity has not been associated with chronic GVHD.^{24, 27} The association between RIC and lower incidence of chronic GVHD in this study might be partly explained by the association between the intensity of the conditioning regimen and acute GVHD, because a prior history of acute GVHD is one of the most important risk factors for developing extensive chronic GVHD.²⁸

This study has some limitations. First, there was a heterogeneity among study patients in terms of underlying disease, type of donors and GVHD prophylaxis. In addition, there may have been a difference in the severity of diabetes mellitus between the patients with and without DPP-4 inhibitors, since the proportion of patients who had been receiving insulin therapy was higher in those without DPP-4 inhibitors. Second, chronic GVHD was diagnosed by the traditional criteria, since National Institutes of Health (NIH) criteria were not available from the database.^{29, 30} Third, the condition of patients—i.e., whether they could continue taking medicines—might have had an impact on the results in the chronic GVHD cohort, although we tried to evaluate the impact of the DPP-4 inhibitors themselves by focusing on survivors for 100 days or longer after HCT and evaluating the effect of oral hypoglycemic agents other than DPP-4 inhibitors. Finally, since this study included only patients with diabetes mellitus, it is still unclear whether the results are applicable to HCT recipients in general.

In conclusion, it was difficult to interpret the impact of standard-dose DPP-4 inhibitors on the development of acute GVHD, since the ability or inability of patients to continue oral medication was significantly associated with the incidence of acute GVHD in this retrospective study. On the other hand, the administration of DPP-4 inhibitors between days 21 and 60 after HCT might suppress the development of chronic GVHD. Further studies are warranted to evaluate the impact of standard-dose DPP-4 inhibitors on the development of acute GVHD, and to evaluate the appropriate dose of DPP-4 inhibitors and the optimal timing of administration for prevention of chronic GVHD.

Funding

None to declare.

Conflict of interest

S-IK has received personal fees from Asahi Kasei, Sumitomo Dainippon Pharma, Merck Sharp & Dohme, Astellas, Pfizer, Kyowa Kirin, Chugai Pharmaceutical Co., Ltd., Bristol-Myers Squibb, Ono Pharmaceutical Co., Ltd., Eisai Co., Ltd., Takeda Pharmaceutical Co., Ltd., SymBio Pharmaceuticals Ltd., Amgen Co., Ltd., Meiji Seika Pharma Co., Ltd., and Nippon Kayaku. MS received research support from Nippon Shinyaku and owns stock in Celaid Therapeutics. HN has received honoraria from Takeda Pharmaceutical, Otsuka Pharmaceutical, Bristol-Myers Squibb, Pfizer, Novartis, Janssen Pharmaceutical, Eisai, Chugai Pharmaceutical, Sanofi, and Nippon Shinyaku. TT reports service on speakers bureaus from Otsuka, Novartis, Pfizer, MSD, abbvie, and Amgen, outside the submitted work. YKanda received honoraria from Merck Sharp & Dohme, Pfizer, Astellas Pharma, Janssen, Chugai Pharma, Otsuka, Sumitomo Dainippon Pharma, Eisai, Novartis, Kyowa Hakko Kirin, Bristol-Myers Squibb, Takeda Pharmaceuticals, Alexion Pharmaceuticals, Shire, Daiichi Sankyo, Ono Pharmaceutical, Nippon Shinyaku, Mochida Pharmaceutical, Mundipharma, Sanofi and Meiji Seika Kaisha, and research funding from Astellas Pharma, Eisai, Otsuka, Kyowa Hakko Kirin, Sanofi, Shionogi, Taiho Pharmaceutical, Chugai Pharma, Nippon Shinyaku and Pfizer. The other authors have no conflicts to declare.

Acknowledgements

The authors are grateful for the work of all of the physicians and data managers at the centers that contributed valuable data on transplantation to the KSGCT. We would also like to thank Toyohiro Kawano and all members of the KSGCT data center for their dedicated data management.

Author contributions

S-IK designed the study, analyzed data, and wrote the manuscript. HS, TM, MS, STanoue, KK, CO, KY, HN, TO and KS advised on methods and revised the manuscript. TT, KH, KO, YKimura, SS, ND, MT, YH and STakahashi collected data and revised the manuscript. YKanda designed the study, advised on the methods, wrote the manuscript, and was responsible for the project of the KSGCT.

Farag SS, Abu Zaid M, Schwartz JE, Thakrar TC, Blakley AJ, Abonour R et al. Dipeptidyl Peptidase 4 Inhibition for Prophylaxis of Acute Graft-versus-Host Disease. N Engl J Med 2021; 384(1): 11–19.
Lambeir AM, Durinx C, Scharpe S, De Meester I. Dipeptidyl-peptidase IV from bench to bedside: an update on structural properties, functions, and clinical aspects of the enzyme DPP IV. Crit Rev Clin Lab Sci 2003; 40(3): 209–294.
Hatano R, Ohnuma K, Yamamoto J, Dang NH, Morimoto C. CD26-mediated co-stimulation in human CD8(+) T cells provokes effector function via pro-inflammatory cytokine production. Immunology 2013; 138(2): 165–172.
Kim SC, Schneeweiss S, Glynn RJ, Doherty M, Goldfine AB, Solomon DH. Dipeptidyl peptidase-4 inhibitors in type 2 diabetes may reduce the risk of autoimmune diseases: a population-based cohort study. Ann Rheum Dis 2015; 74(11): 1968–1975.
Seong JM, Yee J, Gwak HS. Dipeptidyl peptidase-4 inhibitors lower the risk of autoimmune disease in patients with type 2 diabetes mellitus: A nationwide population-based cohort study. Br J Clin Pharmacol 2019; 85(8): 1719–1727.
Chen YC, Chen TH, Sun CC, Chen JY, Chang SS, Yeung L et al. Dipeptidyl peptidase-4 inhibitors and the risks of autoimmune diseases in type 2 diabetes mellitus patients in Taiwan: a nationwide population-based cohort study. Acta Diabetol 2020; 57(10): 1181–1192.
Armand P, Kim HT, Logan BR, Wang Z, Alyea EP, Kalaycio ME et al. Validation and refinement of the Disease Risk Index for allogeneic stem cell transplantation. Blood 2014; 123(23): 3664–3671.
Sorror ML, Maris MB, Storb R, Baron F, Sandmaier BM, Maloney DG et al. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood 2005; 106(8): 2912–2919.
Giralt S, Ballen K, Rizzo D, Bacigalupo A, Horowitz M, Pasquini M et al. Reduced-intensity conditioning regimen workshop: defining the dose spectrum. Report of a workshop convened by the center for international blood and marrow transplant research. Biol Blood Marrow Transplant 2009; 15(3): 367–369.
Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant 1995; 15(6): 825–828.
Shulman HM, Sale GE, Lerner KG, Barker EA, Weiden PL, Sullivan K et al. Chronic cutaneous graft-versus-host disease in man. Am J Pathol 1978; 91(3): 545–570.
Sullivan KM, Shulman HM, Storb R, Weiden PL, Witherspoon RP, McDonald GB et al. Chronic graft-versus-host disease in 52 patients: adverse natural course and successful treatment with combination immunosuppression. Blood 1981; 57(2): 267–276.
Kanda Y. Investigation of the freely available easy-to-use software 'EZR' for medical statistics. Bone Marrow Transplant 2013; 48(3): 452–458.
Farag SS, Srivastava S, Messina-Graham S, Schwartz J, Robertson MJ, Abonour R et al. In vivo DPP-4 inhibition to enhance engraftment of single-unit cord blood transplants in adults with hematological malignancies. Stem Cells Dev 2013; 22(7): 1007–1015.
Farag SS, Nelson R, Cairo MS, O'Leary HA, Zhang S, Huntley C et al. High-dose sitagliptin for systemic inhibition of dipeptidylpeptidase-4 to enhance engraftment of single cord umbilical cord blood transplantation. Oncotarget 2017; 8(66): 110350–110357.
Zeiser R. Advances in understanding the pathogenesis of graft-versus-host disease. Br J Haematol 2019; 187(5): 563–572.
MacDonald KP, Hill GR, Blazar BR. Chronic graft-versus-host disease: biological insights from preclinical and clinical studies. Blood 2017; 129(1): 13–21.
Lee SJ. Classification systems for chronic graft-versus-host disease. Blood 2017; 129(1): 30–37.
Cutler CS, Koreth J, Ritz J. Mechanistic approaches for the prevention and treatment of chronic GVHD. Blood 2017; 129(1): 22–29.
Steinbrecher A, Reinhold D, Quigley L, Gado A, Tresser N, Izikson L et al. Targeting dipeptidyl peptidase IV (CD26) suppresses autoimmune encephalomyelitis and up-regulates TGF-beta 1 secretion in vivo. J Immunol 2001; 166(3): 2041–2048.
Kahne T, Lendeckel U, Wrenger S, Neubert K, Ansorge S, Reinhold D. Dipeptidyl peptidase IV: a cell surface peptidase involved in regulating T cell growth (review). Int J Mol Med 1999; 4(1): 3–15.
Soare A, Gyorfi HA, Matei AE, Dees C, Rauber S, Wohlfahrt T et al. Dipeptidylpeptidase 4 as a Marker of Activated Fibroblasts and a Potential Target for the Treatment of Fibrosis in Systemic Sclerosis. Arthritis Rheumatol 2020; 72(1): 137–149.
Herman GA, Stevens C, Van Dyck K, Bergman A, Yi B, De Smet M et al. Pharmacokinetics and pharmacodynamics of sitagliptin, an inhibitor of dipeptidyl peptidase IV, in healthy subjects: results from two randomized, double-blind, placebo-controlled studies with single oral doses. Clin Pharmacol Ther 2005; 78(6): 675–688.
Mielcarek M, Martin PJ, Leisenring W, Flowers ME, Maloney DG, Sandmaier BM et al. Graft-versus-host disease after nonmyeloablative versus conventional hematopoietic stem cell transplantation. Blood 2003; 102(2): 756–762.
Nakasone H, Fukuda T, Kanda J, Mori T, Yano S, Kobayashi T et al. Impact of conditioning intensity and TBI on acute GVHD after hematopoietic cell transplantation. Bone Marrow Transplant 2015; 50(4): 559–565.
Jagasia M, Arora M, Flowers ME, Chao NJ, McCarthy PL, Cutler CS et al. Risk factors for acute GVHD and survival after hematopoietic cell transplantation. Blood 2012; 119(1): 296–307.
Flowers ME, Inamoto Y, Carpenter PA, Lee SJ, Kiem HP, Petersdorf EW et al. Comparative analysis of risk factors for acute graft-versus-host disease and for chronic graft-versus-host disease according to National Institutes of Health consensus criteria. Blood 2011; 117(11): 3214–3219.
Ratanatharathorn V, Ayash L, Lazarus HM, Fu J, Uberti JP. Chronic graft-versus-host disease: clinical manifestation and therapy. Bone Marrow Transplant 2001; 28(2): 121–129.
Jagasia MH, Greinix HT, Arora M, Williams KM, Wolff D, Cowen EW et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group report. Biol Blood Marrow Transplant 2015; 21(3): 389–401 e381.
Shulman HM, Cardona DM, Greenson JK, Hingorani S, Horn T, Huber E et al. NIH Consensus development project on criteria for clinical trials in chronic graft-versus-host disease: II. The 2014 Pathology Working Group Report. Biol Blood Marrow Transplant 2015; 21(4): 589–603.

Yes

KSGCTDPP4iSuplementaryBMT.docx

Download PDF

Reviewer #3 agreed at journal
13 Sep, 2022
Review #2 received at journal
11 Sep, 2022
Reviewer #2 agreed at journal
11 Sep, 2022
Reviewer #1 agreed at journal
10 Sep, 2022
Reviewers invited by journal
10 Sep, 2022
Submission checks completed at journal
07 Sep, 2022
Editor assigned by journal
06 Sep, 2022
First submitted to journal
06 Sep, 2022

You are reading this latest preprint version

Impact of standard-dose dipeptidyl peptidase-4 inhibitors on the incidence of graft-versus-host disease among diabetes mellitus patients undergoing allogeneic hematopoietic cell transplantation: a KSGCT multicenter retrospective study

Status:

Version 1

Abstract

Figures

Introduction

Methods

Study patients

Definitions

Statistical considerations

Results

Study patients and transplantation outcomes

Impact of DPP-4 inhibitors on the development of acute GVHD

Impact of DPP-4 inhibitors on the development of chronic GVHD

Risk factor analysis for the development of chronic GVHD

Discussion

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1