Baseline Total Lymphocyte Count Research Articles

Radiation-Induced Lymphopenia and Its Impact on Survival in Patients with Brain Metastasis.

Differences in radiation-induced lymphopenia and prognosis between methods of radiotherapy (RT) for brain metastases remain unclear. In this retrospective analysis of patients who underwent whole-brain radiotherapy (WBRT) or stereotactic radiosurgery/radiotherapy (SRS/SRT) for brain metastases, baseline total lymphocyte count (TLC) data were obtained within 2 weeks before RT initiation. Follow-up TLC data were evaluated at 0-2, 2-4, and 4-8 weeks after RT completion. Persistent lymphopenia was defined as <800/μL at any time point. Overall, 138 RT courses in 128 patients were eligible (94 WBRT; 44 SRS/SRT). In the WBRT courses, the median baseline TLC was 1325/μL (IQR: 923-1799). Follow-up TLC decreased significantly to 946/μL (626-1316), 992/μL (675-1291), and 1075/μL (762-1435) (p < 0.001). SRS/SRT courses showed no significant TLC decrease. Multivariate analysis revealed female sex, prior RT, baseline TLC < 800/μL, and WBRT use were significantly associated with persistent lymphopenia. In the WBRT group, overall survival was significantly different between those with and without persistent lymphopenia (median, 2.6 and 6.1 months; p < 0.001). However, there was no significant difference in survival in the SRS/SRT group (p = 0.60). This study suggests SRS/SRT might be preferable for lymphocyte preservation in brain metastasis patients.

Dose and Fractionation Effects on Lymphocyte-Sparing after Stereotactic Body Radiation Therapy in Patients with Pancreatic Cancer

<h3>Purpose/Objective(s)</h3> Radiation-induced lymphopenia (RIL) is caused by exposing the blood pool to radiation therapy and is associated with inferior survival in patients with pancreatic cancer (PC). Dose escalation with stereotactic body radiation therapy (SBRT) is associated with decreased severity of RIL and improved survival compared to conventional chemoradiation, however, there is also increasing appreciation for the need for larger field sizes to treat occult microscopic disease. We retrospectively analyzed patients undergoing SBRT for PC to explore if the number of fractions, BED10 dose, and PTV volume correlated with lymphopenia. <h3>Materials/Methods</h3> Total lymphocyte counts (TLCs) were compared before and up to 2 months after SBRT for 139 patients treated with SBRT for PC at two institutions. Univariate and multivariate analyses (MVA) were used to identify associations between TLC and G2+ lymphopenia (<800/mm^3), number of fractions, total BED10, and PTV. Baseline TLC were compared using Kruskal-Wallis test. PTV threshold for G2+ RIL was determined with receiver operating characteristic analysis. <h3>Results</h3> Median BED10 was 54.8Gy (48-100) (Table 1). Median baseline and post-SBRT ALC were 1.6/uL (0.59-6.09) and 0.85/uL (0.18-1.99), respectively. All groups had similar median baseline TLCs (p=0.567). G2+ lymphopenia was seen in 49/139 (35%) patients after SBRT. Median planning target volume (PTV) and tumor diameter was 85.5 (11.5-381.6) cm³ and 2.5 (0.3-7.8) cm³. On MVA, only PTV volume was associated with decrease in ALC (95% CI 0.24 - 0.95; P=0.001) and with G2+ lymphopenia (95% CI 1.2-12.9; p=0.019). G2+ lymphopenia was more common with PTV ≥ 178 cm^3 (P<0.01). There was no association between ALC or G2+ lymphopenia and age, gender, tumor diameter, tumor location, BED10, treatment with 5 vs 3 fractions, or treatment with 50 Gy in 5 fractions versus 36-39 Gy in 3 fractions. <h3>Conclusion</h3> While previous studies have shown that SBRT has improved RIL compared to conventional CRT, this effect appears to be independent of SBRT fractionation and total BED, but dependent on PTV size, a surrogate for the volume of lymphocytes exposed to RT. Given the association of severe RIL with survival in LAPC, our study suggests that PTV volume may drive development of lymphopenia and survival. Therefore, we demonstrate the need to balance the lymphopenia effect by limiting PTV size with SBRT with expansion of PTVs to include elective nodes at risk of harboring microscopic disease.

Early Onset of Severe Lymphopenia During Definitive Concurrent Chemoradiotherapy Predicts Poor Survival in Patients with Cervical Cancer

To examine the reduction speed of lymphocytes during definitive concurrent chemoradiotherapy and explore its impact on survival in patients with cervical cancer. This is a retrospective analysis of cervical carcinoma patients who received definitive concurrent chemoradiotherapy (CCRT) from January 2015 through January 2019. The FIGO stage distributions were 4, 37, 27, and 4 for stage I, II, III and IV, respectively. All patients received 3D conformal or Rapidarc pelvic external beam radiotherapy plus concurrent weekly cisplatin, followed by image guided brachytherapy. All patients had baseline total lymphocyte count (TLC), then weekly during the course of treatment. The extent of lymphopenia was graded by CTCAE V4.03. Relationships between lymphopenia (onset time and grade) and patient or tumor characteristics were analyzed using Chi-square test, Fisher exact test or t test. The significance of lymphopenia on progression-free survival (PFS) and overall survival (OS) were evaluated by Kaplan-Meier curves and the Cox proportional hazard model. A total of 72 consecutive patients were eligible. The median follow-up was 22.7 months (range 7.1-50.3months). Compared to corresponding pre-treatment values, TLC decreased significantly during CCRT (P< 0.001). The degree of lymphopenia during CCRT were 1 (1.4%), 2 (2.8%), 39 (54.2%), and 30 (41.7%) for grade 1, 2, 3, and 4 lymphopenia, respectively. The median time to the nadir lymphopenia from the start of treatment were 34 days (range 14-51 days). FIGO stage (P = 0.007), pre-treatment lymphocyte (P = 0.001), pre-treatment hemoglobin (P = 0.010) were significantly associated with the lymphopenia during CCRT. Patients with the onset of grade 3-4 lymphopenia during the first 2 weeks had significantly poorer PFS (2-yr 59.7% vs. 87.5%, P = 0.008) and OS (2-yr 73.1% vs. 94.0%, P = 0.037) than those with onset of grade 3-4 lymphopenia beyond 2 weeks. Multivariate analysis showed that onset of grade 3-4 lymphopenia during the first 2 weeks and concurrent cisplatin less than 5 cycles during CCRT were poor prognostic factors for PFS (HR [95%CI] 11.04 [2.54-47.94], P = 0.001 and 13.54 [3.31-55.41], P<0.001; respectively) and OS (HR [95%CI] 4.83 [1.04-22.43], P = 0.044 and 8.14 [1.63-40.65], P = 0.01; respectively). Earlier onset of grade 3-4 lymphopenia during definitive concurrent chemoradiotherapy predicts poor survival in patients with cervical cancer. Prospective evaluations with larger sample sizes are needed to validate this finding.

Prognostic Significance Of Lymphocyte Ratio In Postoperative Radiation Therapy For Cholangiocarcinoma

The aim of this analysis was the treatment outcomes and immune and inflammatory prognostic factors of postoperative radiation therapy (RT) in patients for Cholangiocarcinoma (CCA). The postoperative radiation therapy in patients for CCA is still controversial. We included 59 postoperative CCA patients who received surgery and postoperative RT with curative intent from 2004 to 2019, in this retrospective analysis. Patients received external irradiation at a planned total dose of 50 Gy in 25 fractions with three-dimensional RT. Photon radiation therapy was delivered, using 2 to 4 beams. Fraction size was 1.8–2 Gy and was delivered daily, 5 days per week, using 15 MV X-rays and a shrinking field technique. Overall survival (OS), cause-specific survival (CSS), progression-free survival (PFS), and loco-regional control rate (LRC) rates from the beginning of RT treatment were calculated with Kaplan-Meier curves. Analyses of prognostic factors used univariate and multivariate Cox proportional-hazards regression models. Median follow-up time was 24 (range: 2–183) months. At 2 years, the OS was 59.52% (95% confidence interval [CI]:35.8-62.5), CSS was 62.03% (95% CI:39.2-66.4), PFS was 40.1% (95% CI:28.1-54.5), and LRC was 66.7% (95% CI:51.5-78.8). We analyzed some immune and inflammatory prognostic factors such as pre-RT platelet count, hemoglobin, lymphocyte ratio in white blood cell (WBC), platelet-to-lymphocyte ratio (PLR) or a neutrophil-to-lymphocyte ratio (NLR) or total lymphocyte count (TLC).In univariate analysis, lower lymphocyte ratio was significantly associated with worse PFS (P = 0.0446, Hazard radio: 1.90, 95% CI: 1.02-3.58). There was not significantly different between the median value of the baseline PLR, NLR, TLC, and Platelet. In univariate analysis, age ≥ 75, N+, and chemotherapy after RT were significantly associated with poor OS. In multivariate analysis, age ≥ 75 years was significantly correlated with OS. There were no patients developed severe acute toxicity (≥ Grade 3). Among late toxicity events, 2 patients (3.38%) were suspected of radiation-induced liver disease. To our knowledge, this is the first report to analyze the immune and inflammatory prognostic factor of postoperative radiation therapy in patients for CCA. Lymphocyte ratio before the RT was the immune and inflammatory prognostic factor for postoperative radiation therapy in patients for CCA.

Dose to Heart, Spine, Aorta, and Body Predict for Severe Lymphopenia and Poor Survival in Patients Undergoing Chemoradiation for Esophageal Cancer

Esophageal cancer (EC) patients (pts) undergoing chemoradiation (CRT) may be at increased risk of lymphopenia due to unintentional dose to immune-related organs at risk. We investigated the relationship between grade 4 lymphopenia (G4L) and recurrence-free (RFS) and overall survival (OS) and identified dosimetric constraints that are associated with G4L. All pts who received CRT for stage I-III EC and had accessible total lymphocyte counts (TLC) at a single institution from 2003-2018 were identified. G4L was defined using CTCAE 4.0 criteria (< 200/mm3) during CRT. RFS and OS were evaluated with Kaplan-Meier methods, log rank tests, and Cox proportional hazards regression. We defined optimal DVH cutpoints for G4L using ROC curves, and these were compared across G4L groups with univariate (UVA) and multivariable (MVA) logistic regression. 189 pts were included with a median follow-up of 2.3 years. Demographics included: median age 65 (range 35-84), 84% male, 92% white, 20% never smoker, 31% no alcohol use. Most pts had clinical stage II (34%) or III (60%) disease, distal esophageal/GE junction location (85%), adenocarcinoma (78%), and poorly differentiated tumors (40%). Median RT dose was 50.4 Gy (range 41.4-70.2) delivered with carboplatin/paclitaxel (55%) or 5FU based regimens (40%). 68% of pts underwent surgical resection following CRT. G4L was identified in 85 pts (45%). G4L was associated with lower median RFS (1.8 vs 4.0 years, p=0.02) and lower median OS (2.4 vs 4.0 years, p=0.03). On MVA for OS, stage (III vs I/II, HR 1.79 [1.17, 2.74]), surgery (HR 0.40 [0.24, 0.66]), and G4L (HR 1.55 [1.00, 2.41]) were significant. Dosimetric data were available for 119 pts. On UVA, Heart V15 > 73%, T-spine V5 > 72%, Body V10 > 18%, Total Lung V5 > 50%, and Aorta V5 > 93% were strong predictors of G4L (Table 1, all p<0.05). In multivariable models including baseline TLC and other clinical factors, exceeding DVH cutpoints for heart, T-spine, aorta, and body predicted for G4L (all p<0.05). When included separately in MVA for OS, exceeding cutpoints for heart (HR 2.22 [1.17, 4.24]), T-spine (HR 2.38 [1.15, 4.92]), and aorta (HR 2.20 [1.04, 4.66]) independently predicted for worse OS. Dose to the heart, spine, aorta, and body predict for G4L, which is associated with worse RFS and OS. Achieving planning constraints for these parameters may decrease G4L and improve outcomes.Abstract 2475; Table 1Odds Ratio (95% CI) for G4 Lymphopenia, *p<0.05, **p<0.01.VariableUVAMVA1Baseline TLC (100 lymphocyte increase)1.06* (1.01, 1.11)0.90-0.93* (0.83-0.86, 0.97-0.99)Heart V15 > 73%2.87** (1.33, 6.18)2.39* (1.05, 5.46)T-spine V5 > 72%2.80** (1.32, 5.93)2.76* (1.22, 6.28)Body V10 > 18%7.21* (1.57, 33.16)10.59* (1.28, 87.64)Total Lung V5 > 50%2.50* (1.18, 5.30)2.09 (0.94, 4.65)Aorta V5 > 93%2.71* (1.04, 7.09)3.49* (1.14, 10.66)Spleen V20 > 45%2.06 (0.984, 4.295)1.75 (0.785, 3.92)1 Separate models including baseline TLC, smoking (NS), alcohol hx (NS), and each individual DVH cutpoint. Open table in a new tab

Acute severe lymphopenia by radiotherapy is associated with reduced overall survival in hepatocellular carcinoma.

Radiotherapy (RT) for peripheral organs can affect circulating lymphocytes and cause lymphopenia. We aimed to investigate RT-related lymphopenia in patients with hepatocellular carcinoma (HCC). Medical records of 920 patients who received RT for HCC during 2001-2016 were reviewed. Total lymphocyte count (TLC) were obtained and analyzed for clinical outcome. Acute severe lymphopenia (ASL) was defined as TLC <500/μL within the first 3months of the start of RT. The median TLCs before and 1month after the start of RT were 1120 and 310/μl, respectively, and the TLCs did not recover to their initial level after 1year. Overall, 87.4% of patients developed ASL. The median overall survival was 13.6 and 46.7months for patients with and without ASL, respectively (p < 0.001). ASL was independently associated with poor overall survival with ahazard ratio (HR) of 1.40; 95% confidence interval (CI), 1.02-1.91 (p = 0.035). In the multivariate analysis, larger planning target volume (HR, 1.02; 95% CI, 1.01-1.03; p < 0.001) and lower baseline TLC (HR, 0.86; 95% CI, 0.82-0.91; p < 0.001) were significantly associated with an increased risk of ASL, while hypofractionation (stereotactic body RT: HR, 0.19; 95% CI, 0.07-0.49; p = 0.001) was significantly associated with areduced risk of ASL. Acute severe lymphopenia after RT was associated with poor overall survival in patients with HCC. Stereotactic body RT may reduce the risk of ASL. Further attention to and research on the cause, prevention, and reversal of this phenomenon are needed.

Total lymphocyte count, neutrophil-lymphocyte ratio, and platelet-lymphocyte ratio as prognostic factors in advanced non-small cell lung cancer with chemoradiotherapy.

ObjectiveThe objective of this study was to investigate the prognostic significance and the efficacy evaluation of total lymphocyte count (TLC), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) in advanced non–small cell lung cancer (NSCLC) patients treated with chemoradiotherapy.Patients and methodsA total of 389 advanced NSCLC patients who received chemoradiotherapy from 2011 to 2016 were enrolled in this retrospective study. TLC, NLR, and PLR were analyzed with overall survival (OS). Survival data were identified with the Kaplan–Meier method and optimal cutoff values with receiver operating characteristic curves.ResultsThe median OS for all patients was 18.37 months. Pretreatment and median baseline TLC was 2.47×103/μL (±0.78); NLR, 3.15 (±3.96); and PLR, 143.82 (±91.77); corresponding cutoffs were 2.4, 3.4, and 136.1. Higher TLC was associated with superior median OS (21.78 vs 15.66 months, P<0.001), and higher NLR and PLR with worse median OS (NLR: 14.13 vs 23.8 months, P<0.001; PLR: 15.49 vs 22.04 months, P<0.001).ConclusionThe lymphopenia indicators (TLC, NLR, and PLR) were significant prognostic indicators of survival in advanced NSCLC patients treated with chemoradiotherapy.

MA 01.10 Outcome Based on Baseline Total Lymphocyte Count & Neutrophil-To-Lymphocyte Ratio in Extensive Stage Small-Cell Lung Cancer

MA 01.10 Outcome Based on Baseline Total Lymphocyte Count & Neutrophil-To-Lymphocyte Ratio in Extensive Stage Small-Cell Lung Cancer

Lymphocyte-Sparing Effect of Stereotactic Body Radiation Therapy Compared to Conventional Fractionated Radiation Therapy in Patients With Locally Advanced Pancreatic Cancer

Conventional fractionated radiation therapy (CFRT)-induced lymphopenia has been reported to be associated with compromised survival in patients with glioblastoma, lung cancer, and pancreatic cancer. However, it is unknown if stereotactic body radiation therapy (SBRT) will induce lymphopenia and its relationship with survival outcomes. Due to smaller fields and a faster dose fall off of SBRT, we hypothesize that SBRT will induce less lymphopenia when compared to CFRT, which may lead to improved survival outcomes on patients with locally advanced pancreatic adenocarcinoma. Medical records of patients with locally advanced pancreatic adenocarcinoma treated at UNMC with neoadjuvant or definitive CFRT or SBRT following induction chemotherapy from 2004-2016 were reviewed. Patients who had baseline and follow-up total lymphocyte counts (TLCs) measured at our institution were included in this study. Patients were stratified into 4 groups: 1) CFRT/5-fluorouracil (5FU), 2) SBRT/5FU, 3) SBRT/Nelfinavir (NVF) and 4) SBRT alone. Median CFRT and SBRT prescription doses were 50.4 Gy (range 8 – 50.4 Gy) at 1.8-2 Gy per fraction and 35 Gy (range 25 - 40 Gy) in 5 fractions, respectively. Serial TLCs from day 0 (the first day of RT) to 40 were recorded. Multiple comparisons were performed using the Kruskal–Wallis test and P values were adjusted with Bonferroni method. Linear regression was used to estimate the slope of TLCs change with time. The Kaplan-Meier plot was used for survival analysis. Among 103 patients identified, 28 were treated with CFRT/5FU, 17 SBRT/5FU, 46 SBRT/NVF and 12 SBRT alone. The median pre-RT baseline TLCs were 1.5 (range 0.5-2.8), 1 (range 0.4-3.3), 1.2 (range 0.3-2.6) and 1.5 (range 0.7-2.3) cells/mm3, respectively. There was no difference in median baseline TLCs among 4 groups (p > 0.05). The median slopes of TLCs changed from day 0 to 40 after starting radiation and were increasing in the following sequence: CFRT/5FU (-0.0239) < SBRT/5FU (-0.0042) < SBRT/NFV (-0.0016) < SBRT alone (0.0024). The median lowest TLCs were 0.2 (range 0-1.6), 0.4 (range 0.1-1.5), 0.7 (range 0-1.6) and 1.1 (range 0.3-1.5) cells/mm3, respectively. CFRT patients had significantly lower lowest TLCs than all SBRT subgroups (P <0.001). The median time to lowest TLCs were 30, 26, 28 and 23 days, respectively. There was no difference in time to lowest TLCs among groups (P >0.05). Survival analysis revealed no significant difference in median overall survival among all groups. SBRT is associated with significant less treatment-induced lymphopenia than CFRT. This did not translate into survival benefit. Further study of the effect of radiation technique on immune status is warranted.

Prognostic Significance of Pretreatment Total Lymphocyte Count, Neutrophil-to-Lymphocyte Ratio, and Platelet-to-Lymphocyte Ratio in Limited-Stage Small Cell Lung Cancer

Inflammation and immunity are important in cancer development and progression. We sought reliable inflammatory and immunologic markers of prognosis in patients with limited-stage small cell lung cancer (LS-SCLC). We retrospectively identified and analyzed patients with LS-SCLC who received chemoradiotherapy or radiotherapy at a single institution from 2002 through 2015. Selection criteria were pathologically proven SCLC, clinically LS I‒IIIB disease, receipt of definitive radiation therapy with curative intent, and availability of laboratory data before initiation of curative treatment. Total lymphocyte count (TLC), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) were extracted from pretreatment complete blood counts (CBCs) with differential along with other potential predictors of overall survival (OS) and progression-free survival (PFS). Receiver operating characteristic (ROC) curves were used to determine the optimal cutoff values for pretreatment TLC, NLR, and PLR that would predict survival. The survival function was carried out using Kaplan-Meier estimates. The Cox’s proportional hazard model was used for multivariate analysis to assess the effect of patient, tumor and other predictor factors of significance on the end points. A total of 122 patients met the eligibility criteria. Mean values and standard deviations of pretreatment TLC, NLR, and PLR were 1.86 ± 0.88 × 103/μL, 3.44 ± 3.69, and 170.53 ± 101.56, respectively. Optimal cutoff values for these factors were 1.9 × 103/μL for TLC, 2.9 for NLR, and 140.1 for PLR. Patients with higher pretreatment TLC (≥1.9 × 103/μL) had superior median OS time and 2-year OS rate compared with patients with lower pretreatment TLC (<1.9 × 103/μL) (17.4 vs 15.7 months; 33% vs 29%, P = 0.029). On the other hand, patients with higher pretreatment NLR (≥2.9) and higher PLR (≥140.1) had worse median OS time and 2-year OS rate than did patients with lower pretreatment NLR (<2.9) and PLR (<140.1) (14.9 vs 17.8 months, 29% vs 31%, P = 0.026; and 14.8 vs 18.9 months, 24% vs 37%, P = 0.009, respectively). The final multivariate Cox regression analysis adjusted for age, performance status, and tumor-nodes-metastasis disease stage showed that higher pretreatment TLC (≥1.9 × 103/μL) was associated with superior OS (hazard ratio [HR] = 0.55, 95% confidence interval [CI] = 0.32–0.94, P = 0.028) and higher pretreatment NLR (≥2.9) (HR = 1.76, 95% CI = 1.08–2.87, P = 0.025) and higher PLR (≥140.1) (HR = 1.74, 95% CI = 1.06–2.84, P = 0.028) were associated with inferior OS. Pretreatment baseline TLC, NLR, and PLR were all found to be associated with survival in patients with LS-SCLC. To our knowledge, this is the first study to show that baseline lymphopenia (defined as TLC) is an important indicator of dismal prognosis in patients with LS-SCLC.

Clinical effectiveness and toxicity of second-line irinotecan in advanced gastric and gastroesophageal junction adenocarcinoma: a single-center observational study.

Randomized clinical trials showed improved overall survival (OS) of advanced gastroesophageal adenocarcinoma (GEA) patients treated with second-line taxane or irinotecan. However, most data on irinotecan efficacy in this setting come from large Asian trials. We retrospectively analyzed clinical effectiveness and toxicity of irinotecan in a cohort of patients with advanced GEA treated in our department. Advanced GEA patients who received at least one cycle of second-line irinotecan were eligible for inclusion. Irinotecan was administered every 3 weeks at an initial dose of 250 mg/m2 of body surface area with subsequent gradual (every 50 mg/m2) dose escalation up to 350 mg/m2, in the case of good treatment tolerance. OS was estimated using the Kaplan-Meier method. A multivariate Cox regression analysis was used to examine the association between clinical and laboratory parameters and survival. A total of 48 patients were identified. Median OS was 6.2 months [95% confidence interval (CI): 3.9-7.6]. In multivariate analysis, age < 65 years, baseline total lymphocyte count (TLC) < 1500/µl and presence of peritoneal metastases were associated with shorter OS. Most adverse events were grade 1-2 and included: anemia (52.3%), leukocytopenia (40.9%), neutropenia (59.1%), nausea (25.0%), vomiting (31.8%), diarrhea (31.8%), anorexia (29.5%) and fatigue (43.2%). Febrile neutropenia occurred in three patients (6.8%). Nine patients (20.5%) experienced a toxicity grade 3-4 of any kind. This retrospective analysis confirms clinical effectiveness and manageable toxicity of second-line irinotecan in an unselected cohort of advanced GEA patients. Age < 65 years, baseline TLC < 1500/µl and presence of peritoneal metastases were independent prognostic factors associated with shorter OS.

Lymphocyte Trends During Neoadjuvant Chemoradiation Predict Pathologic Complete Response at Time of Surgical Resection of Locally Advanced Rectal Cancers

While achieving complete pathologic tumor response (ypCR) following neoadjuvant chemoradiation (NCRT) is achievable in up to 25% of patients with locally-advanced rectal cancer, preoperative factors predicting which patients will achieve ypCR at time of definitive surgery are still poorly-elucidated. A number of studies have reported a correlation between peripheral lymphocyte counts and responses to various oncologic therapies and overall survival outcomes in patients with an array of malignancies including rectal cancer. The aim of this study is to determine whether lymphocyte trends at four weeks after initiation of NCRT are associated with complete treatment response in locally-advanced rectal cancers. Patient, tumor, and treatment data was abstracted on patients with T2 N1-2 and T3-4 N0-2 rectal cancers treated with NCRT and subsequent surgical resection at our institution from January 2009 through December 2013, allowing for two-year follow-up. Neoadjuvant chemoradiation for all patients consisted of completion of 4500 cGy to entire pelvis with boost to 5040 cGy to gross disease with concurrent 5-FU or capecitabine chemotherapy. Pathologic evaluation of final surgical specimens following NCRT was recorded as follows: complete response (ypCR), partial response (ypPR) or stable/progressive disease. Univariate analysis was performed to determine whether relative (%) lymphocyte counts at four weeks after initiation of NCRT (4wk RLC) and/or the ratio of 4wk total lymphocyte count (4wk TLC) to pre-treatment baseline total lymphocyte count (bTLC) were associated with the rates of ypCR. Frequencies were compared using the chi-square test. Thirty-one patients were identified who underwent NCRT followed by surgical resection for locally-advanced rectal cancer during the specified time period. Of the 31 post-NCRT surgical specimens reviewed, ypCR was observed in 10 patients (32%) and ypPR was found in 18 patients (58%). When analyzed as a continuous variable, greater 4wk RLC was predictive of ypCR (OR = 1.27, P = 0.065). Area under the ROC curve as a predictor for ypCR for 4wk RLC was 0.71 and for 4wk TLC: bTLC ratio was 0.69. Of patients with 4wk RLC ≤ 9, 3/19 (16%) achieved ypCR compared to 7/12 (58%) with RLC > 9 (P = 0.021). Of patients with 4wk TLC: bTLC ≤ 0.43, 3/17 (18%) achieved ypCR compared to 7/14 (50%) with 4wk TLC: bTLC > 0.43 (P = 0.055). When assessing lymphocyte trends at four weeks after initiation of NCRT, both RLC as well as percent decrease of TLC from baseline were associated with tumor ypCR at time of definitive surgery in patients with locally-advanced rectal cancers. This study underlines the importance of understanding the role of the host immune response in rectal tumor control. Further work characterizing which tumors have the highest response to immune modulation may guide patient selection in future studies investigating immune checkpoint inhibitors.

Lymphocyte-Sparing Effect of Stereotactic Body Radiation Therapy in Patients With Unresectable Pancreatic Cancer

Radiation-induced lymphopenia (RIL) is associated with inferior survival in patients with glioblastoma, lung cancer, and pancreatic cancer. We asked whether stereotactic body radiation therapy (SBRT) decreases severity of RIL compared to conventional chemoradiation therapy (CRT) in locally advanced pancreatic cancer (LAPC). Serial total lymphocyte counts (TLCs) from patients enrolled in a prospective trial of SBRT for LAPC were compared to TLCs from an existing database of LAPC patients undergoing definitive CRT. SBRT patients received 33 Gy (6.6 Gy × 5 fractions). CRT patients received a median dose of 50.4 Gy (1.8 Gy × 28 fractions) with concurrent 5-fluorouracil (77%) or gemcitabine (23%) therapy. Univariate and multivariate analyses (MVA) were used to identify associations between clinical factors and post-treatment TLC and between TLC and survival. Thirty-two patients received SBRT and 101 received CRT. Median planning target volume (PTV) was smaller in SBRT (88.7 cm(3)) than in CRT (344.6 cm(3); P<.001); median tumor diameter was larger for SBRT (4.6 cm) than for CRT (3.6 cm; P=.01). SBRT and CRT groups had similar median baseline TLCs. One month after starting radiation, 71.7% of CRT patients had severe lymphopenia (ie, TLC <500 cells/mm(3) vs 13.8% of SBRT patients; P<.001). At 2 months, 46.0% of CRT patients remained severely lymphopenic compared with 13.6% of SBRT patients (P=.007). MVA demonstrated that treatment technique and baseline TLCs were significantly associated with post-treatment TLC at 1 but not 2 months after treatment. Higher post-treatment TLC was associated with improved survival regardless of treatment technique (hazard ratio [HR] for death: 2.059; 95% confidence interval: 1.310-3.237; P=.002). SBRT is associated with significantly less severe RIL than CRT at 1 month in LAPC, suggesting that radiation technique affects RIL and supporting previous modeling studies. Given the association of severe RIL with survival in LAPC, further study of the effect of radiation technique on immune status is warranted.

IMCT-13LYMPHOPENIA IN ELDERLY PATIENTS WITH GLIOBLASTOMA TREATED WITH RADIATION AND TEMOZOLOMIDE

BACKGROUND: Management of elderly patients with high grade glioma often includes radiation therapy (RT) +/- temozolomide (TMZ). A previous report showed that standard RT/TMZ resulted in severe lymphopenia in 40% of patients (median age of 57) with an associated shorter survival (Grossman, 2011). Similar findings were described in patients with head and neck, non-small cell lung, and pancreatic cancer. This study is designed to evaluate whether elderly patients (age ≥65) with glioblastoma (GBM) develop severe treatment related lymphopenia (TRL) after RT +/- TMZ and whether TRL is associated with reduced survival. METHODS: Elderly patients (age ≥65) newly diagnosed with GBM and followed-up at Washington University (2000-2013) were eligible. Radiation parameters and serial total lymphocyte counts (TLC) were collected. RESULTS: Seventy-seven patients were eligible: median KPS 70, median age 71 years (range 65 - 86) with 57% of patients >70 years, 52% female, 32% received RT <6 weeks, 42% had a baseline TLC <1000 cells/mm3 with 78% taking glucocorticoids. Baseline TLC prior to treatment was 1100 cells/mm3 with a fall by 45% at 2 months (median 600, range 100-2500). At 2 months, 22% of patients had a drop in TLC to <500 cells/mm3 (median 400, range 100-400). Patients with TLC <500 cells/mm3 at 2 months had a shorter survival than those with TLC ≥500 cells/mm3 with a median overall survival of 7.6 vs 10.1 months, respectively. Consistent with literature, an increased survival was found on multivariable analysis with MGMT methylation and gross total resection. We also found that higher baseline TLC was associated with increased survival. CONCLUSIONS: This is the first study to look at the development of TRL and its association with survival in elderly GBM patients. These findings add to the body of evidence that immunosuppression induced by chemoradiation is associated with inferior clinical outcomes.

Clinical and Dosimetric Predictors of Acute Severe Lymphopenia During Radiation Therapy and Concurrent Temozolomide for High-Grade Glioma

Acute severe lymphopenia (ASL) frequently develops during radiation therapy (RT) and concurrent temozolomide (TMZ) for high-grade glioma (HGG) and is associated with decreased survival. The current study was designed to identify potential predictors of ASL, with a focus on actionable RT-specific dosimetric parameters. From January 2007 to December 2012, 183 patients with HGG were treated with RT+TMZ and had available data including total lymphocyte count (TLC) and radiation dose-volume histogram parameters. ASL was defined as TLC of <500/μL within the first 3months from the start of RT. Stepwise logistic regression analysis was used to determine the most important predictors of ASL. Fifty-three patients (29%) developed ASL. Patients with ASL had significantly worse overall survival than those without (median: 12.5 vs 20.2months, respectively, P<.001). Stepwise logistic regression analysis identified female sex (odds ratio [OR]: 5.30; 95% confidence interval [CI]: 2.46-11.41), older age (OR: 1.05; 95% CI: 1.02-1.09), lower baseline TLC (OR: 0.92; 95% CI: 0.87-0.98), and higher brain volume receiving 25 Gy (V25Gy) (OR: 1.03; 95% CI: 1.003-1.05) as the most significant predictors for ASL. Brain V25Gy <56% appeared to be the optimal threshold (OR:2.36; 95% CI: 1.11-5.01), with an ASL rate of 38% versus 20% above and below this threshold, respectively (P=.006). Female sex, older age, lower baseline TLC, and higher brain V25Gy are significant predictors of ASL during RT+TMZ therapy for HGG. Maintaining the V25Gy of brain below 56% may reduce the risk of ASL.

Low Baseline Lymphocyte Count May Predict Poorer Overall Survival in Patients With Head and Neck Cancer Treated With Radiation Therapy

Low total lymphocyte count and lymphocyte to neutrophil ratio have been reported as poor prognostic indicators for multiple cancers at various stages. However, it is unknown whether the baseline complete blood count is associated with overall survival in patients with head and neck malignancies treated with radiation therapy. The objective of this study is to report the correlation that exists between baseline lymphocyte count and overall survival in patients with head and neck cancer treated with radiation based therapy. This is a retrospective analysis of 150 consecutive patients with non-metastatic Stage I-IV head and neck cancer who were treated with radiation therapy from November of 2009 to October of 2013. Pre-treatment complete blood count, demographic, and clinical variables were extracted from medical records and vital status was obtained by using the Social Security Death Index. Variables and outcomes were analyzed. Of the 150 patients reviewed, 104 had baseline complete blood counts (Median age 58, Male 74, Female 30). The median follow-up duration is 17.5 months. We performed 2 sequential analyses of the data. The initial analysis involved the first 82 patients and it was found that higher baseline lymphocyte count was significantly associated with lower mortality (HR: 0.93, p = 0.0443). The subsequent analysis involved 22 additional patients (n = 104). This was consistent with the findings from the initial analysis: i.e. higher baseline total lymphocyte count was associated with increased overall survival (HR 0.57, p = 0.0665). Other variables such as change in lymphocyte count (HR: 6*10-8, p = 0.749), baseline hemoglobin (HR: 0.87, p = 0.355), lymphocyte-to-neutrophil ratio (HR: 0.92, p = 0.306), age, gender, and race were not significantly associated with overall survival. There may be an association between the baseline lymphocyte count and overall survival in patients with head and neck cancers treated with radiation therapy. This result suggests immune function of each patient may be associated with overall survival. A study with larger sample size and longer follow-up is ongoing to validate this finding.

Association between severe treatment‐related lymphopenia and progression‐free survival in patients with newly diagnosed squamous cell head and neck cancer

Severe treatment-related lymphopenia occurs commonly in many cancers and is associated with early tumor progression. Data are lacking as to whether this occurs in squamous cell head and neck cancer. Serial total lymphocyte counts were retrospectively reviewed in patients with newly diagnosed squamous head and neck cancer undergoing chemoradiation and associated with treatment outcomes. The median baseline total lymphocyte count in 56 patients was 1660 cells/mm(3) , which fell by 73% to 445 cells/mm(3) 2 months after initiating chemoradiation (p < .0001). Human papillomavirus negative (HPV-) patients with a total lymphocyte count <500 cells/mm(3) at 2 months had significantly earlier disease progression than those with higher total lymphocyte counts (hazard ratio [HR], 5.75; p = .045). Baseline total lymphocyte counts were normal, but at 2 months approximately 60% of patients had severe treatment-related lymphopenia regardless of HPV status. Severe treatment-related lymphopenia in HPV- patients is independently associated with earlier disease progression. Prospective studies are needed to confirm these findings, which suggest that immune preservation is important in this cancer.

Changes in circulating lymphocyte counts and tumor-infiltrating lymphocyte subpopulations among patients receiving endorectal brachytherapy for rectal adenocarcinoma.

500 Background: Radiation-induced lymphopenia (RIL) is common in patients with rectal cancer and is associated with worse outcomes in rectal cancer and other solid tumors. We investigated whether endorectal brachytherapy (EB) is associated with milder RIL than external radiation treatment (XRT) in patients with rectal cancer and whether EB is associated with altered tumor-infiltrating lymphocyte (TIL) subpopulations. Methods: Records from 11 patients enrolled in a prospective study of EB for T2-3, N0-1 rectal cancer were reviewed; total lymphocyte counts (TLC) at baseline and 2 months after treatment were recorded. EB was given to tumor alone (6.5Gy x 4). XRT was given to the whole pelvis (median dose 50.4Gy). All patients underwent proctectomy after EB/XRT. TLCs from EB patients were compared to 62 rectal cancer patients receiving pelvic XRT + capecitabine. Proctectomy specimens were immunostained for TIL (CD3, CD4, CD8, FoxP3, and CD25) subtypes. Results: Median baseline TLC in EB patients was 1930 vs 1570 cells/uL in XRT patients (p&gt;0.05). Two months after treatment, median TLC was 1550 in EB patients vs 520 in XRT patients (p&lt;0.01). EB patients had higher absolute numbers of CD3, CD4, CD8, and FoxP3+ TILs (Table). Conclusions: EB spares circulating lymphocytes and is associated with increased TIL expression after therapy. Further investigation is needed to determine if there is a causal association between these phenomena and if the increased TIL expression in EB patients is associated with better outcomes in these patients. [Table: see text]

Lymphocyte Phenotype during Therapy for Acute Graft-versus-Host Disease: A Brief Report from BMT-CTN 0302

Although significant strides have been made in understanding the biology of graft-versus-host disease (GVHD) and its prevention over the last 4 decades, little is known about the different populations of lymphocytes and the changes in response to treatment for this condition. BMT-CTN 0302 was a randomized phase II clinical trial in the Blood and Marrow Transplant Clinical Trials Network that assessed the efficacy of combination therapy with steroids plus pentostatin, mycophenolate mofetil, etanercept, or denileukin diftitox in patients with acute GVHD. Patients enrolled in the study underwent blood analysis by flow cytometry on days 0, 14, and 28 of therapy to enumerate the number of total lymphocytes, T cells, B cells, and lymphocytes expressing activation markers. Baseline total lymphocyte counts and subpopulations were similar in the 4 treatment arms. Responding patients had a smaller decrease in total CD45+ cell count (P = .005) compared with nonresponding patients at day 28. On univariate analysis, those who developed chronic GVHD had significantly higher CD8+ cell counts at day 14 compared with those without it (P = .005). There was no significant association between baseline lymphocyte count and survival. On univariate analysis, among the patients with higher lymphocyte counts at days 14 and 28, there was a trend toward better survival at day 180, although this trend did not reach the predetermined threshold for significance. We found no significant differences in lymphocyte total or subpopulation counts among the 4 treatment arms, and no notable influence on outcomes.

Pretransplant lymphocyte count predicts the incidence of infection during the first two years after liver transplantation

Patients with end-stage liver disease (ESLD) show a low absolute number of peripheral blood lymphocyte subpopulations (PBLSs). We investigated if the baseline PBLS could categorize orthotopic liver transplantation (OLT) recipients into groups at high or low risk for infection after transplantation. PBLSs were prospectively studied in 63 consecutive patients (42 males; mean age +/- standard deviation: 53.5 +/- 10.3 years) with ESLD prior to OLT. Thirty-five patients (55.6%) developed a total of 79 infectious episodes during the first 2 years post-OLT. The median total lymphocyte count and PBLS levels [CD3+ T cells, CD4+ T cells, memory (CD45RO+) CD4+ T cells, T cell receptor alphabeta+ and gammadelta+ subsets, and CD19+ B cells] at baseline were significantly lower in patients with an infection compared with those without one (P < 0.05). There was a significant correlation between the risk of development of a post-OLT infection and a baseline total lymphocyte count < 1.00 x 10(3)/microL (P = 0.001), a baseline CD3+ T cell count < 0.75 x 10(3)/microL (P = 0.009), and a baseline CD4+ T cell count < 0.5 x 10(3)/microL (P = 0.008). In the multivariate analysis, this association between the baseline total lymphocyte level and infection remained significant (odds ratio: 10.1; 95% confidence interval: 1.9-39.5). In conclusion, the pre-OLT total lymphocyte count identifies a subset of patients at high risk for infection. PBLS monitoring prior to OLT may offer an opportunity for surveillance, tapering of immunosuppression, and preemptive therapy.