Influence of Hyperglycemia on the Prognosis of Patients with Diffuse Large B-Cell Lymphoma

Figures & data

Table 1 Baseline Clinical Characteristics of 1767 DLBCL Patients with or Without Hyperglycemia

Clinical Characteristics	DLBCL and Hyperglycemia (n=732)	DLBCL and Non-Hyperglycemia (n=1035)	F/ X2	P value
Age	64.38± 12.45	58.11± 15.54	57.97	<0.001*
Gender			0.11	0.741
Male	369(50.4%)	530(51.2%)
Female	363(49.6%)	505(48.8%)
BMI	24.92± 3.76	24.05± 3.84	0.61	<0.001*
Ann-Arbor Staging			28.46	<0.001*
III–IV	486(66.4%)	556(53.7%)
I–II	246(33.6%)	479(46.3%)
IPI score			98.40	<0.001*
3–5 score	349(47.7%)	258(24.9%)
0–2 score	383(52.3%)	777(75.1%)
LDH			12.44	<0.001*
>250U/L	335(45.8%)	387(37.4%)
≤250U/L	397(54.2%)	648(62.6%)
β2 micro-globulin			3.80	0.051
>2.8ug/mL	274(37.4%)	341(32.9%)
≤2.8ug/mL	458(62.6%)	694(67.1%)
B symptoms			3.62	0.057
Yes	308(42.1%)	389(37.6%)
No	424(57.9%)	646(62.4%)
Pathological diagnosis			0.02	0.897
GCB	316(43.2%)	450(43.5%)
Non-GCB	416(56.8%)	585(56.5%)
Extranodal involvement			2.38	0.120
Yes	470(64.2%)	701(67.7%)
No	262(35.8%)	334(32.3%)
Bulky disease			61.64	<0.001*
Yes	238(32.5%)	171(16.5%)
No	494(67.5%)	864(83.5%)
Comorbidities			30.42	<0.001*
Yes	307(41.9%)	303(29.3%)
No	425(58.1%)	732(70.7%)
Ki-67			1.99	0.370
≥90%	140(19.1%)	198(19.1%)
0–90%	566(77.3%)	812(78.5%)
Negative	26(3.5%)	25(2.4%)
BCL-2			0.01	0.919
Positive	526(71.8%)	746(72%)
Negative	206(28.2%)	289(28%)
BCL-6			2.55	0.111
Positive	521(71.1%)	772(74.6%)
Negative	211(28.9%)	263(25.4%)
C-MYC			1.21	0.547
≥40%	239(32.6%)	313(30.2%)
0–40%	264(36.1%)	382(36.9%)
Negative	229(21.3%)	340(32.9%)

Notes: Categorical variables were compared by Pearson chi-square and represented by X² value, continuous variables were compared by analysis of variance and represented by F value. *P value less than 0.05 was considered statistically significant.

Abbreviations: DLBCL, diffuse large B-cell lymphoma; BMI, body mass index; IPI, international prognostic index; LDH, lactate dehydrogenase; GCB, germinal center B cell.

Table 2 Baseline Clinical Characteristics of 732 Patients with DLBCL with Hyperglycemia and 1035 Patients with DLBCL and Non-Hyperglycemia

Clinical Characteristics	DLBCL with Primary Hyperglycemia (n=466)	DLBCL with Secondary Hyperglycemia (n=266)	DLBCL with Non-Hyperglycemia (n=1035)	F/ X^2	P value
Age	65.94±12.53	61.65±11.83	58.11± 15.54	*0.11	*<0.001^†
				^#29.41	^#0.001^†
Gender				*0.20	*0.655
Male	232(49.8%)	137(51.5%)	530(51.2%)	^#0.01	^#0.931
Female	234(50.2%)	129(48.5%)	505(48.8%)
BMI	24.97±3.82	24.83± 3.66	24.05± 3.84	*0.05	*0.641
				^#0.54	^#0.003^†
Ann-Arbor Staging				*0.18	*0.672
III–IV	312(67.0%)	174(65.4%)	556(53.7%)	^#11.75	^#0.001^†
I–II	154(33.0%)	92(34.6%)	479(46.3%)
IPI score				*3.31	*0.069
3–5 score	234(50.2%)	115(43.2%)	258(24.9%)	^#34.67	^#<0.001^†
0–2 score	232(49.8%)	151(56.8%)	777(75.1%)
LDH				*0.00	*0.967
>250U/L	213(45.7%)	122(45.9%)	387(37.4%)	^#6.38	^#0.012^†
≤250U/L	253(54.3%)	144(54.1%)	648(62.6%)
β2 micro-globulin				*7.78	*0.005^†
>2.8ug/mL	192(41.2%)	82(30.8%)	341(32.9%)	^#0.43	^#0.510
≤2.8ug/mL	274(58.8%)	184(69.2%)	694(67.1%)
B symptoms				*0.09	*0.765
Yes	198(42.5%)	110(41.4%)	389(37.6%)	^#1.27	^#0.260
No	268(57.5%)	156(58.6%)	646(62.4%)
Pathological diagnosis				*0.56	*0.454
GCB	206(44.2%)	110(41.4%)	450(43.5%)	^#0.39	^#0.532
Non-GCB	260(55.8%)	156(58.6%)	585(56.5%)
Extranodal involvement				*0.99	*0.320
Yes	293(62.9%)	177(66.5%)	701(67.7%)	^#0.14	^#0.710
No	173(37.1%)	89(33.5%)	334(32.3%)
Bulky disease				*1.14	*0.290
Yes	145(31.1%)	93(35.0%)	171(16.5%)	^#44.49	^#<0.001^†
No	321(68.9%)	173(65.0%)	864(83.5%)
Comorbidities				*3.24	*0.070
Yes	207(44.4%)	100(37.6%)	303(29.3%)	^#6.85	^#0.009^†
No	259(55.6%)	166(62.4%)	732(70.7%)
Ki-67				*1.05	*0.591
≥90%	90(19.3%)	51(19.2%)	198(19.1%)	^#0.04	^#0.979
0–90%	357(77.6%)	208(78.2%)	812(78.5%)
Negative	19(4.1%)	7(2.6%)	25(2.4%)
BCL-2				*1.37	*0.241
Positive	328(70.4%)	198(74.4%)	746(72%)	^#0.59	^#0.442
Negative	138(29.6%)	68(25.6%)	289(28%)
BCL-6				*0.00	*0.956
Positive	332(71.2%)	189(71.1%)	772(74.6%)	^#1.37	^#0.242
Negative	134(28.8%)	77(28.9%)	263(25.4%)
C-MYC				*6.69	*0.035^†
≥40%	164(35.2%)	75(28.2%)	313(30.2%)	^#2.1	^#0.350
0–40%	152(32.6%)	111(41.7%)	382(36.9%)
Negative	150(32.2%)	80(30.1%)	340(32.9%)
Metformin				*40.41	*<0.001^†
Yes	126(27.0%)	20(7.5%)	–	–	–
No	340(73%)	246(92.4%)	–

Notes: Categorical variables were compared by Pearson chi-square and represented by X² value, continuous variables were compared by analysis of variance and represented by F value. *DLBCL with primary hyperglycemia VS DLBCL with secondary hyperglycemia. ^#DLBCL with secondary hyperglycemia VS DLBCL with non-hyperglycemia. ^†P value less than 0.05 was considered statistically significant.

Abbreviations: DLBCL, diffuse large B-cell lymphoma; BMI, body mass index; IPI, international prognostic index; LDH, lactate dehydrogenase;GCB, germinal center B cell.

Table 3 Univariate and Multivariate Analysis of PFS in 1767 Patients with DLBCL

	Univariate Analysis	Multivariate Analysis
	HR (95% CI) P value	HR (95% CI) P value
Hyperglycemia (Yes, No)	1.83 (1.53–2.18) <0.001*	1.41 (1.16–1.70) <0.001*
Gender (Male, Female)	1.21 (1.01–1.44) 0.036*	1.18 (0.99–1.41) 0.071
Age (>60,≤60)	1.97 (1.62–2.41) <0.001*	1.48 (1.19–1.82) <0.001*
BMI (≥24kg/m2,<24kg/m2)	0.74 (0.62–0.88) 0.001*	0.76 (0.63–0.91) 0.003*
Ann-Arbor Staging (III˜ V, I˜II)	2.77 (2.24–3.42) <0.001*	1.54 (1.20–1.98) 0.001*
IPI score (3˜5,0˜2)	3.35 (2.80–4.01) <0.001*	1.74 (1.39–2.19) <0.001*
B symptoms (Yes, No)	1.65 (1.38–1.97) <0.001*	1.23 (1.02–1.48) 0.032*
Pathological diagnosis (GCB, Non-GCB)	0.77 (0.64–0.92) 0.005*	0.90 (0.75–1.08) 0.261
LDH (>250 U/L,≤250 U/L)	2.93 (2.00–2.86) <0.001*	1.42 (1.15–1.75) 0.001*
β2 micro-globulin (>2.8ug/mL,≤2.8ug/mL)	2.32 (1.94–2.77) <0.001*	1.36 (1.12–1.66) 0.002*
Extranodal involvement (Yes, No)	1.04 (0.86–1.25) 0.710	1.35 (1.11–1.64) 0.002*
Bulky disease (Yes, No)	1.26 (1.04–1.54) 0.020*	1.13 (0.93–1.39) 0.026*
Comorbidities (Yes, No)	0.99 (0.82–1.19) 0.932	–
Ki-67(≥90%,<90%)	1.02 (0.82–1.28) 0.840	–
BCL-2(Positive, Negative)	1.39 (1.34–1.71) 0.002*	1.26 (1.02–1.55) 0.035*
BCL-6(Positive, Negative)	0.94 (0.78–1.14) 0.550	–
C-MYC (≥40%,<40%)	1.30 (1.08–1.57) 0.006*	1.12 (0.92–1.35) 0.264

Note: *P value less than 0.05 was considered statistically significant.

Abbreviations: PFS, progression-free survival; HR, hazard ratio; BMI, body mass index; GCB, germinal center B cell; IPI, international prognostic index; LDH, lactate dehydrogenase.

Table 4 Univariate and Multivariate Analysis of OS in 1767 Patients with DLBCL

	Univariate Analysis	Multivariate Analysis
	HR (95% CI) P value	HR (95% CI) P value
Hyperglycemia (Yes, No)	1.75 (1.46–2.09) <0.001*	1.33 (1.09–1.61) 0.004*
Gender (Male, Female)	1.19 (1.00–1.43) 0.051	1.16 (0.97–1.39) 0.106
Age (>60,≤60)	1.93 (1.58–2.35) <0.001*	1.48 (1.20–1.83) <0.001*
BMI (≥24kg/m2,<24kg/m2)	0.74 (0.62–0.88) 0.001*	0.76 (0.64–0.92) 0.004*
Ann-Arbor Staging (III˜IV, I˜II)	2.64 (2.14–3.27) <0.001*	1.46 (1.13–1.87) 0.003*
IPI score (3˜5,0˜2)	3.30 (2.76–3.95) <0.001*	1.76 (1.40–2.21) <0.001*
B symptoms (Yes, No)	1.68 (1.41–2.01) <0.001*	1.25 (1.04–1.50) 0.020*
Pathological diagnosis (GCB, Non-GCB)	0.78 (0.65–0.93) 0.006*	0.92 (0.76–1.10) 0.361
LDH (>250 U/L,≤250 U/L)	2.43 (2.03–2.91) <0.001*	1.48 (1.21–1.83) <0.001*
β2 micro-globulin (>2.8ug/mL,≤2.8ug/mL)	2.33 (1.95–2.78) <0.001*	1.39 (1.14–1.70) 0.001*
Extranodal involvement (Yes, No)	1.06 (0.88–1.29) 0.526	1.39 (1.15–1.70) 0.001*
Bulky disease (Yes, No)	1.28 (1.05–1.55) 0.016*	1.16 (0.95–1.42) 0.153
Comorbidities (Yes, No)	0.95 (0.79–1.14) 0.588	–
Ki-67(≥90%,<90%)	0.98 (0.79–1.23) 0.862	–
BCL-2(Positive, Negative)	1.38 (1.13–1.70) 0.002*	1.24 (1.00–1.53) 0.047*
BCL-6(Positive, Negative)	1.03 (0.85–1.26) 0.749	–
C-MYC (≥40%,<40%)	1.39 (1.15–1.68) 0.001*	1.21 (1.00–1.47) 0.055

Note: *P value less than 0.05 was considered statistically significant.

Abbreviations: OS, overall survival; HR, hazard ratio; BMI, body mass index; GCB, germinal center B cell; IPI, international prognostic index; LDH, lactate dehydrogenase.

Table 5 Univariate and Multivariate Analysis of PFS in 732 Patients with DLBCL and Hyperglycemia

	Univariate Analysis	Multivariate Analysis
	HR (95% CI) P value	HR (95% CI) P value
Metformin (Yes, No)	0.71 (0.52–0.99) 0.044*	0.69 (0.49–0.96) 0.028*
Secondary hyperglycemia (Yes, No)	1.35 (1.04–1.75) 0.026*	1.31 (1.00–1.72) 0.046*
Gender (Male, Female)	1.01 (0.79–1.28) 0.968	–
Age (>60,≤60)	1.38 (1.04–1.83) 0.026*	1.12 (0.83–1.51) 0.479
BMI (≥24kg/m2,<24kg/m2)	0.71 (0.56–0.91) 0.006*	0.79 (0.62–1.02) 0.070
Ann-Arbor Staging (III˜IV, I˜II)	2.25 (1.67–3.04) <0.001*	1.31 (0.92–1.86) 0.137
IPI score (3˜5,0˜2)	2.82 (2.18–3.65) <0.001*	2.06 (1.49–2.85) <0.001*
B symptoms (Yes, No)	1.44 (1.13–1.83) 0.003*	1.09 (0.84–1.43) 0.506
Pathological diagnosis (GCB, Non-GCB)	0.81 (0.64–1.04) 0.097	0.86 (0.67–1.11) 0.250
LDH (>250 U/L,≤250 U/L)	1.84 (1.44–2.31) <0.001*	1.15 (0.86–1.53) 0.349
β2 micro-globulin (>2.8ug/mL,≤2.8ug/mL)	1.71 (1.34–2.17) <0.001*	1.19 (0.91–1.56) 0.199
Extranodal involvement (Yes, No)	1.09 (0.84–1.40) 0.528	–
Bulky disease (Yes, No)	1.20 (0.94–1.54) 0.151	1.25 (0.97–1.61) 0.090
Comorbidities (Yes, No)	1.92 (0.86–1.39) 0.474	–
Ki-67(≥90%,<90%)	1.18 (0.88–1.58) 0.263	–
BCL-2(Positive, Negative)	1.12 (0.85–1.46) 0.423	–
BCL-6(Positive, Negative)	0.84 (0.65–1.08) 0.170	0.86 (0.65–1.12) 0.265
C-MYC (≥40%,<40%)	1.34 (1.03–1.73) 0.027*	1.33 (1.02–1.74) 0.038*

Note: *P value less than 0.05 was considered statistically significant.

Abbreviations: PFS, progression-free survival; HR, hazard ratio; BMI, body mass index; IPI, international prognostic index; GCB, germinal center B cell; LDH, lactate dehydrogenase.

Table 6 Univariate and Multivariate Analysis of OS in 732 Patients with DLBCL and Hyperglycemia

	Univariate Analysis	Multivariate Analysis
	HR (95% CI) P value	HR (95% CI) P value
Metformin (Yes, No)	0.70 (0.51–0.97) 0.034*	0.68 (0.49–0.95) 0.024*
Secondary hyperglycemia (Yes, No)	1.36 (1.05–1.77) 0.021*	1.35 (1.03–1.77) 0.030*
Gender (Male, Female)	0.99 (0.78–1.26) 0.910	–
Age (>60,≤60)	1.37 (1.03–1.82) 0.029*	1.15 (0.86–1.56) 0.348
BMI (≥24kg/m2,<24kg/m2)	0.69 (0.54–0.89) 0.003*	0.75 (0.59–0.97) 0.026*
Ann-Arbor Staging (III˜IV, I˜II)	2.12 (1.57–2.86) <0.001*	1.24 (0.87–1.77) 0.277
IPI score (3˜5,0˜2)	2.69 (2.08–3.48) <0.001*	1.94 (1.41–2.68) <0.001*
B symptoms (Yes, No)	1.49 (1.17–1.89) 0.001*	1.13 (0.87–1.48) 0.351
Pathological diagnosis (GCB, Non-GCB)	0.87 (0.68–1.11) 0.245	–
LDH (>250 U/L,≤250 U/L)	1.86 (1.46–2.37) <0.001*	1.24 (0.93–1.66) 0.144
β2 micro-globulin (>2.8ug/mL,≤2.8ug/mL)	1.73 (1.36–2.20) <0.001*	1.23 (0.93–1.61) 0.143
Extranodal involvement (Yes, No)	1.06 (0.82–1.36) 0.665	–
Bulky disease (Yes, No)	1.14 (0.88–1.46) 0.318	–
Comorbidities (Yes, No)	1.07 (0.84–1.36) 0.610	–
Ki-67(≥90%,<90%)	1.15 (0.86–1.54) 0.355	–
BCL-2(Positive, Negative)	1.10 (0.84–1.44) 0.476	–
BCL-6(Positive, Negative)	0.93 (0.72–1.20) 0.563	–
C-MYC (≥40%,<40%)	1.44 (1.11–1.86) 0.006*	1.39 (1.07–1.80) 0.014*

Note: *P value less than 0.05 was considered statistically significant.

Abbreviations: OS, overall survival; HR, hazard ratio; BMI, body mass index; IPI, international prognostic index; GCB, germinal center B cell; LDH, lactate dehydrogenase.

Figure 1 Kaplan–Meier survival curve of the two cohorts. Description: (A) PFS regarding non-hyperglycemia group and hyperglycemia group. (B) OS regarding non-hyperglycemia group and hyperglycemia group.

Figure 2 Kaplan–Meier survival curve of the three cohorts. Description: (A) PFS regarding primary hyperglycemia group, secondary hyperglycemia group and non- hyperglycemia group. (B) OS regarding primary hyperglycemia group, secondary hyperglycemia group and non-hyperglycemia group.

Figure 3 Kaplan–Meier survival curve of the two cohorts. Description: (A) PFS regarding the metformin group and the non-metformin group. (B) OS regarding the metformin group and the non-metformin group. Metformin group refers to taking single-drug metformin or metformin combined with other hypoglycemic drugs, non-metformin group refers to never taking metformin (other hypoglycemic drugs are not excluded).