Apatinib in Patients with Relapsed or Refractory Diffuse Large B Cell Lymphoma: A Phase II, Open-Label, Single-Arm, Prospective Study

Figures & data

Figure 1 Trial protocol.

Table 1 Baseline Characteristics

Characteristics	N	%
Gender
Male	19	59.4
Female	13	40.6
Age
<60y	17	53.1
≥60y	15	46.9
ECOG
0~1	24	75.0
≥2	8	25.0
Serum LDH
Normal	16	50.0
Increased*	16	50.0
Serum β2 microglobulin
Normal	17	53.1
Increased*	15	46.9
B symptoms
Absent	14	43.8
Present	18	56.3
Bone marrow involvement
Absent	25	78.1
Present	7	21.9
Ann Arbor clinical stage
I-II	12	37.5
III-IV	20	62.5
COO
ABC	19	59.3
GCB	11	34.4
NOS	2	6.3
EBER
Negative	27	84.4
Positive	5	15.6
Double/triple-hit
Absent	29	90.6
Present	3	7.4
Previous treatment lines
=2	11	34.4
>2	21	65.6
Baseline of major function	n	95% CI
ANC (10^9/L)	3.6	2.7–4.3
HB (g/L)	110.4	98.1–120.7
PLT (10^9/L)	105.6	89.9–127.3
TB (μmol/L)	15.5	12.4–18.8
ALT (U/L)	35.3	32.7–38.8
AST (U/L)	34.8	29.3–41.5
Cr (μmol/L)	72.2	56.1–86.4
Ccr (mL/mins)	104.4	94.6–115.3

Notes: Double/triple-hit lymphoma refers to lymphoma with rearrangements of MYC and BCL-2 or/and BCL-6, which is also described as high-grade B cell lymphoma (HGBL). Among all of the 32 patients enrolled in this study, two patients lack of EBER results were considered EBER negative, and five patients lack of BCL-2/MYC/BCL-6 FISH results were considered absent of double/triple-hit. *In this study, increased serum LDH level was defined as higher than 245U/L, and increased Serum β2 microglobulin level was defined as higher than 3 mg/L.

Abbreviations: ECOG, Eastern Cooperative Oncology Group; COO, cell of origin; GCB, germinal center B-cell-like; EBER, Epstein-Barr virus-encoded small RNA; ANC, absolute neutrophil count; HB, haemoglobin; PLT, platelet count; LDH, lactic dehydrogenase; TB, total bilirubin; ALT, alanine aminotransferase; AST, aspartate aminotransferase; Cr, creatinine; Ccr, creatinine clearance rate.

Figure 2 Kaplan–Meier estimates of progression-free survival (PFS) and overall survival (OS).

Figure 3 Waterfall plot of best percentage changes from baseline. Waterfall plot of the best percentage changes from baseline of target tumor size is shown for each patient. Dashed line at −50% represents the threshold of partial response, and another dashed line at 50% represents the threshold of progressive disease. One patient had tumor shrinkage despite of progressive disease. One patient had no tumor size change from baseline.

Table 2 Treatment-Related Adverse Events Occurred in More Than One Patient

Adverse Events	All (%)	Grade 1–2 (%)	Grade 3 (%)	Grade 4 (%)
General status
Fatigue	12 (37.5)	10 (31.2)	2 (6.3)	0
Hematological system
Leukopenia	13 (40.6)	10 (31.2)	2 (6.3)	1 (3.1)
Neutropenia	10 (31.2)	9 (28.1)	1 (3.1)	0
Anemia	7 (21.8)	5 (15.6)	1 (3.1)	0
Thrombocytopenia	5 (15.6)	4 (12.5)	1 (3.1)	0
Cardiovascular system
Hypertension	20 (62.5)	16 (50.0)	4 (12.5)	0
Skin and subcutaneous tissue
Hand-foot syndrome	13 (40.6)	10 (31.2)	3 (9.4)	0
Mucositis	3 (9.4)	3 (9.4)	0	0
Gastrointestinal system
Abdominal pain	3 (9.4)	3 (9.4)	0	0
Diarrhea	4 (12.5)	4 (12.5)	0	0
Anorexia	11 (34.3)	10 (31.2)	1 (3.1)	0
Fecal occult blood	4 (12.5)	3 (9.4)	1 (3.1)	0
Nausea	5 (15.6)	5 (15.6)	0	0
Urinary system
Proteinuria	17 (53.1)	16 (50.0)	1 (3.1)	0
Blood biochemistry
AST/ALT increase	7 (21.8)	6 (18.7)	1 (3.1)	0
Bilirubin increase	5 (15.6)	4 (12.5)	1 (3.1)	0
Hypoproteinemia	3 (9.4)	3 (9.4)	0	0
Mental and nervous system
Headache	3 (9.4)	3 (9.4)	0	0

Table 3 Dose Adjustments and First Dose Interruption Since Entry

Dose	n (%) or Time (days)
Dose Adjustments
No dose adjustments (500 mg)	15 (46.9)
Dose level −1 (500 mg and 250 mg on alternate days)	13 (40.6)
Dose level −2 (250 mg)	4 (12.5)
Dose interrupted temporarily	26 (81.2)
Dose interrupted permanently	1(3.1)
First dose interruption since entry(days)
Median (IQR)	17 (13, 22)

Table 4 Comparison Between No Dose Reduction Group and Dose Reduction Group

Outcome	No Dose Reduction (n=15)		Dose Reduction (n=17)		P value (2-Tailed)
	Mean	SD	Mean	SD
PFS (m)	6.8	2.6	6.9	2.8	>0.05
OS (m)	7.8	2.7	8.0	3.0	>0.05