VEGF Levels Aid Prediction of Chemotherapy Induced Myeloid Toxicity and Presence of Extranodal Disease in Diffuse Large B-Cell Lymphoma (DLBCL).
Authors: Rajan Sandeep K. , Thakoor Kaveri , Yang Terk J. , Gao Fei 
Published: October 2019

Myeloid toxicity and their complications after chemotherapy for diffuse large B-cell lymphoma (DLBCL) are frequent and can be dose limiting. Most predictive models have focused on neutropenia and neutropenic fever. In our study we studied the role of conventional clinical factors & baseline vascular endothelial growth factor (VEGF) on all 3 lineage cytopenia i.e. thrombocytopenia, anemia and neutropenia.

Methods: 106 newly diagnosed DLBCL patients between 2001 to 2005 had evaluation of their baseline white blood count (WBC), absolute neutrophil count (ANC), platelet count (PLT), hemoglobin (HB), serum albumin (ALB), creatinine (CRE), age, stage, presence of B-symptoms, high-LDH, performance status, bone marrow involvement (BM+). VEGF levels were performed in peripheral blood of 38 cases using Human VEFG Immunoassay Kit (Biosource International). All patients received standard CHOP chemotherapy +/− immunotherapy with rituximab. The clinical and laboratory factors were correlated with day-21 HB, PLT, ANC & cycle-1 neutropenic fever (NEU-FVR). Statistical analysis was done using SPSS v 11.5 software.

Results: 106 patients had age distribution from 18–78-y (median 47.9y). 38 were >60y & 27>65y. Male: Female ratio was 67:39. Stage distribution was I=15, II=50, III=29& IV=12. 57 presented with B-symptoms. Only 11 had b-WBC (baseline) <4.0k/μl. 59 had b-HB <12g% and 17 <10g%. 13 had b-PLT <150K/μl. 25 developed neutropenic fever after first cycle of chemotherapy. Number of patients with D-21 HB<10g%, ANC<1.5 K/μl & PLT <100K/μl were respectively 30, 31 & 21. By linear regression analysis the significant predictors of D-21 Hb <10g% were BM+, baseline anemia & thrombocytopenia (p<0.05) and age >65y, ALB<35g/L & presence of B-symptoms (p<0.01). By backward stepwise methods of linear regression D-21 HB was predicted by (p<0.01) baseline anemia, thrombocytopenia, B-symptoms, low albumin & BM+. Similarly d-21 ANC was predicted by (p<0.001) advanced age, low albumin, basal anemia & thrombocytopenia. Thrombocytopenia and high LDH predict D-21 PLT<100K (p<0.001). By logistic regression neutropenic fever (NEU-FVR) after first cycle were predicted by low albumin, leukopenia (WBC<4.0K/μl) and age > 65 (all p <0.05). Baseline VEGF levels varied from 5–643pg/ml. Levels over 100pg/ml predicted baseline HB <12g%, extranodal disease, d-21 HB<10g% and d-21 ANC <1.5K/μl as shown in Table-1. A simple model based on age, baseline counts, albumin and VEGF correctly predicted D-21 counts & neutropenic fever with an accuracy of 96%.

Conclusions: In our series clinical variables such as advanced age, baseline cytopenia and low albumin were important clinical variables for predicting myeloid toxicity and neutropenic fever (Table 2). Serum VEGF levels as a single parameter shows promise in predicting myeloid recovery before next chemotherapy. Its incorporation along with clinical variables presents an attractive predictive model for myeloid toxicity.

Table 1: Elevated VEGF compared to important clinical parameters Parameter VEGF <100pg/ml VEGF >100pg/ml p-value Chi square test performed in all. NS-Not significant Baseline HB <12g% 15/27 11/11 0.008 Extranodal disease 4/27 11/11 <0.001 Day-21 Hb <10g% 6/27 8/11 <0.01 Day-21 ANC <1.5K 7/27 7/11 <0.05 Day-21 PLT <100K 5/27 3/11 NS Cycle-1 NEU-FVR 7/27 4/11 NS Table 2: Significant predictors of myeloid toxicity Age Low albumin Basal HB Basal PLT Basal WBC Hi-LDH VEGF D-21 HB + + + + − − + D-21-PLT − − − + − + − D-21 ANC + + + + − − + NEU FVR + + − − + − −