Severe Treatment-related Lymphopenia Research Articles

Impact of Lymphopenia Recovery After Chemoradiotherapy on Durvalumab Consolidation Therapy in Stage III NSCLC

IntroductionDurvalumab maintenance therapy after definitive concurrent chemoradiotherapy (CRT) is the standard treatment modality for stage III NSCLC. Although severe treatment-related lymphopenia (TRL) during CRT may impair the efficacy of subsequent durvalumab therapy, data on the effect of TRL recovery on consolidation durvalumab therapy are lacking. MethodsThis retrospective study evaluated patients with unresectable stage III NSCLC treated with durvalumab after concurrent CRT. The patients were enrolled across nine institutes throughout Japan between August 2018 and March 2020. The effect of TRL recovery on survival was evaluated. The patients were divided into two groups on the basis of their lymphocyte recovery status: the recovery group involved patients who did not experience severe TRL or experienced TRL but exhibited lymphocyte count recovery at durvalumab initiation, and the nonrecovery group involved patients who experienced severe TRL and did not exhibit lymphocyte count recovery on durvalumab initiation. ResultsAmong the 151 patients evaluated, 41 (27%) and 110 (73%) patients were classified into the recovery and the nonrecovery groups, respectively. The nonrecovery group had significantly worse progression-free survival than the recovery group (21.9 mo versus not reached, p = 0.018). Recovery from TRL (p = 0.027) and high pre-CRT lymphocyte count (p = 0.028) independently influenced progression-free survival. ConclusionsBaseline lymphocyte count and recovery from TRL at the start of durvalumab therapy were predictive factors for survival outcomes in patients with NSCLC treated with durvalumab consolidation after concurrent CRT.

Association of severe lymphopenia and disease progression in unresectable locally advanced non-small cell lung cancer treated with definitive chemoradiation and immunotherapy

BackgroundDefinitive chemoradiation with consolidative immunotherapy offers the best chance for cure in patients with unresectable, locally advanced non-small cell lung cancer (NSCLC). However, treatment-related lymphopenia (TRL) may negatively impact outcomes. MethodsPatients definitively treated with chemoradiation and immunotherapy from 2015 to 2019 at a single tertiary academic center were identified. Severe lymphopenia was defined as <0.5 × 109 cells/L. Progression-free survival (PFS) was calculated by Kaplan Meier methodology. Univariate and multivariate Cox Proportional Hazard modeling was used to correlate clinical variables with disease outcome. Immune-related adverse events (irAEs) were assessed according to CTCAE version 5.0 criteria. ResultsSeventy-eight patients were included in the final cohort. The median age was 66 years (IQR: 58−73), 55 % were males, and 88 % had a KPS of >70. At baseline, 90 % (n = 70/78) of patients had a normal ALC and one patient had severe lymphopenia. After chemoradiation, the median ALC decreased from 1.52 × 109cells/L (IQR: 1.23–1.98) to 0.72 × 109cells/L (IQR: 0.52−0.94) (p < 0.001), 22 % (n = 17/78) of patients had a normal ALC, and 23 % (n = 18/78) of patients developed severe lymphopenia. Patients who initiated consolidative immunotherapy with severe lymphopenia had worse PFS than those who did not (median 217 days [IQR: 120–434] vs. 570 days [IQR: 401-NR], p < 0.001). On multivariate modeling, severe lymphopenia at the time of immunotherapy initiation remained an independent predictor of worse PFS (HR 4.90, p < 0.001). ConclusionsThis is the first report to associate severe TRL with disease progression in patients with locally advanced NSCLC receiving consolidative immunotherapy. Factors associated with development of lymphopenia and strategies to mitigate lymphopenic effects should be considered.

Effect of a novel long-acting interleukin-7 agonist, NT-I7, on survival in mouse models of glioma.

e13516 Background: Glioblastoma is one of the most devastating cancers, with a 5-year overall survival &lt; 10%. Patients are routinely treated with radiation therapy (RT) and temozolomide (TMZ). These treatments can cause prolonged severe lymphopenia which is associated with shorter survival. Interleukin-7 (IL-7) is a cytokine that preferentially supports growth and survival of CD4+ and CD8+ lymphocytes. IL-7 levels were inappropriately low in glioblastoma patients treated with chemoradiation who developed severe treatment-related lymphopenia (TRL). NT-I7 (rhIL-7-hyFc, from NeoImmuneTech, Inc.) is a long-acting cytokine consisting of recombinant human IL-7 fused to a hybrid Fc (hyFc) region of IgD and IgG4. Similarly to murine IL-7, human IL-7 also induces proliferation of murine cell lines. Consequently, NT-I7 can be studied using comparable dosing in both mice and humans. We hypothesized that administration of NT-I7 could mitigate TRL and improve survival. Methods: We developed a murine glioma model with chemoradiation induced lymphopenia. The C57BL/6 mice were injected intracranially with mouse glioma cells (GL261) expressing luciferase. Tumor-bearing mice were treated with clinically-relevant RT (2 Gy for 5 consecutive days) and concomitant TMZ (33mg/kg daily during RT) to induce lymphopenia. NT-I7 was given subcutaneously at 10 mg/kg one day after completion of RT/TMZ. Peripheral blood samples were collected on days 1, 3, 7, 14- and 28-days post-RT/TMZ. Lymphocyte counts including CD3, CD4, CD8, and CD19 were analyzed by flow cytometry. Tumor growth was monitored by bioluminescence imaging and mouse survival was monitored daily. Results: We found that 1) NT-I7 significantly improved lymphocyte count recovery post RT/TMZ; 2) mice receiving NT-I7 lived significantly longer than controls. Presently, we are elucidating the mechanisms of survival benefit found by NT-I7 administration. Conclusions: Overall, our data suggest that NT-I7 may be a feasible solution for immune reconstitution and may synergize anti-tumor effect with standard chemoradiation in glioma. Further studies are ongoing to confirm these findings in a different glioma model and to evaluate whether NT-I7 can alter tumor micro-environment.

Irradiation-Related Lymphopenia for Bone Metastasis from Hepatocellular Carcinoma

Background/Aim: In the era of immunotherapy, treatment-related lymphopenia (TRL) is gaining attention. In this study, TRL was investigated in patients with bone metastasis from hepatocellular carcinoma (HCC) treated with radiotherapy (RT). Methods: Clinical data of 302 patients receiving RT for 511 bone metastases from HCC between 2005 and 2018 were reviewed. Data on absolute lymphocyte count (ALC) from pre-RT to 12 months post-RT were collected. Severe TRL was defined as ALC <500 cells/mm³ and evaluated using ALC 2 months after initiating RT. Factors associated with TRL were analyzed, which include the amount of active bone marrow within the RT field. The amount of active bone marrow included in the RT field was calculated as the product of the percentage of the bone compartment included in the RT field and the active bone marrow percentage of the bone compartment. Results: Overall, 33.4% of patients developed TRL 2 months after initiating RT. The mean ALC decreased after initiating RT and remained persistently low during 12 months of observation. Overall survival (OS) was significantly worse in patients with TRL than in those without (median OS: 3.7 vs. 6.5 months, p < 0.001). In the prognostic factor analysis, TRL was an independent prognostic factor of OS (p = 0.036), along with known prognostic factors of HCC. The percentage of active bone marrow within the RT field was the only significant factor associated with TRL (p < 0.001). Conclusion: TRL was observed in patients receiving RT for bone metastasis from HCC, and it was associated with poor survival. The percentage of active bone marrow within the RT field significantly affected TRL development. The results suggest that a new strategy is required to prevent TRL.

Treatment-Related Lymphopenia is an Independent Predictor of Survival in Patients with Lung Cancer Treated via Stereotactic Body Radiation Therapy

Treatment-related lymphopenia (TRL) is frequently associated with radiation therapy. Multiple prior studies have shown associations between TRL and inferior outcomes in various solid tumors, including patients treated with conventionally fractionated radiation therapy for lung cancer. TRL was recently shown to occur in patients with lung cancer treated with stereotactic body radiation therapy (SBRT), but the survival impact of TRL in this setting remains unknown. We seek to evaluate the impact of severe TRL in the setting of lung cancer treated with SBRT on overall survival and evaluate potential strategies to minimize TRL. We retrospectively identified 346 patients treated with thoracic SBRT between 2008 and 2016. Of these patients, 137 had complete blood counts with differentials within 12 months preceding and following SBRT. This was further refined to exclude patients who received prior radiation therapy to the head, neck or thorax; patients who received chemotherapy; and patients with pre-treatment absolute lymphocyte counts less than 500x106 cells/L. The remaining 91 patients were included in the analyses. All patients were treated with 5 fraction regimens, following RTOG 0813 or 0915 as appropriate. We defined severe TRL as an absolute lymphocyte count less than 500x106 cells/L. Kaplan-Meier curves, log-rank analysis and cox regression were performed to assess for survival differences associated with severe TRL using statistical software. Of the 91 included patients, median age was 71.9 years, 55% were female, and 39% had central lung lesions. Planning target volumes ranged from 4.3-183 cm3. Patients with severe TRL had worse overall survival (log rank, 2=7.62, p=0.006). On univariate cox regression, minimum absolute lymphocyte count was directly related to survival, with a hazard ratio of 0.353 (p=0.002). Flattening filter free-arcs were associated with less lymphocyte depletion compared to step and shoot IMRT, with a mean difference in depletion of 211x106 cells/L between modalities (p=0.04). PTV size also had a statistically significant positive correlation with lymphopenia. Severe TRL after lung cancer SBRT is associated with worse overall survival. The use of flattening filter free-arcs reduced lymphocyte depletion compared to step and shoot IMRT.

Severe Treatment-Related Lymphopenia in Patients with Newly Diagnosed Rectal Cancer

Background: Although treatment-related lymphopenia (TRL) is common in many cancers no data exists in rectal cancer. Methods: Serial lymphocyte counts were analyzed retrospectively in patients with newly diagnosed rectal cancer, serial blood counts, and complete records at Johns Hopkins Hospital. Results: Fifty-seven patients with normal pretreatment lymphocyte counts were studied. Two months after beginning chemoradiation, 35% of these patients developed grade III-IV lymphopenia [median lymphocyte counts fell from 1590 to 490 cell/mm3 (p < 0.001)] which persisted throughout one year of observation. Conclusion: Severe and prolonged TRL is common in rectal cancer. Further studies are required to determine TRL’s relationship to survival.

Association between treatment-related lymphopenia and overall survival in elderly patients with newly diagnosed glioblastoma.

Management of patients with glioblastoma (GBM) often includes radiation (RT) and temozolomide (TMZ). The association between severe treatment-related lymphopenia (TRL) after the standard chemoradiation and reduced survival has been reported in GBM patients with the median age of 57. Similar findings were described in patients with head and neck, non-small cell lung, and pancreatic cancers. This retrospective study is designed to evaluate whether elderly GBM patients (age ≥65) develop similar TRL after RT/TMZ and whether such TRL is associated with decreased survival. Serial total lymphocyte counts (TLC) were retrospectively reviewed in patients (age ≥65) with newly diagnosed GBM undergoing RT/TMZ and associated with treatment outcomes. Seventy-two patients were eligible: median KPS 70, median age 71 years (range 65-86) with 56 % of patients >70 years, 53% female, 31% received RT ≤45 Gy. Baseline median TLC was 1100 cells/mm(3) which fell by 41% to 650 cells/mm(3) 2 months after initiating RT/TMZ (p < 0.0001). Patients with TLC <500 cells/mm(3) at 2 months had a shorter survival than those with higher TLCs with a median overall survival of 4.6 versus 11.6 months, respectively. Multivariate analysis revealed a significant association between TRL and survival (HR 2.76, 95% CI 1.30-5.86, p = 0.008). Treatment-related lymphopenia is frequent, severe, and an independent predictor for survival in elderly patients with GBM. These findings add to the body of evidence that immunosuppression induced by chemoradiation is associated with inferior clinical outcomes. Prospective studies are needed to confirm these findings suggesting that immune preservation is important in this cancer.

Immune Control Despite Protracted Lymphopenia After Chemoradiation in an Elite Controller.

Elite controllers are human immunodeficiency virus-1–positive individuals capable of sustaining undetectable viral loads without treatment. We present the case of an elite controller diagnosed with extensive stage small cell lung cancer who maintained a viral load of <20 copies/mL despite the development of severe treatment-related lymphopenia.

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.

Survival in Patients With Severe Lymphopenia Following Treatment With Radiation and Chemotherapy for Newly Diagnosed Solid Tumors.

The immune system plays an important role in cancer surveillance and therapy. Chemoradiation can cause severe treatment-related lymphopenia (TRL) (<500 cells/mm3) that is associated with reduced survival. Data from 4 independent solid tumor studies on serial lymphocyte counts, prognostic factors, treatment, and survival were collected and analyzed. The data set included 297 patients with newly diagnosed malignant glioma (N=96), resected pancreatic cancer (N=53), unresectable pancreatic cancer (N=101), and non-small cell lung cancer (N=47). Pretreatment lymphocyte counts were normal in 83% of the patient population, and no patient had severe baseline lymphopenia. Two months after initiating chemoradiation, 43% developed severe and persistent lymphopenia (P=.001). An increased risk for death was attributable to TRL in each cancer cohort (gliomas: hazard rate [HR], 1.8; 95% CI, 1.13-2.87; resected pancreas: HR, 2.2; 95% CI, 1.17-4.12; unresected pancreas: HR, 2.9; 95% CI, 1.53-5.42; and lung: HR, 1.7; 95% CI, 0.8-3.61) and in the entire study population regardless of pathologic findings (HR, 2.1; 95% CI, 1.54-2.78; P<.0001). Severe TRL was observed in more than 40% of patients 2 months after initiating chemoradiation, regardless of histology or chemotherapy regimen, and was independently associated with shorter survival from tumor progression. Increased attention and research should be focused on the cause, prevention, and reversal of this unintended consequence of cancer treatment that seems to be related to survival in patients with solid tumors.

The Association Between Chemoradiation-related Lymphopenia and Clinical Outcomes in Patients With Locally Advanced Pancreatic Adenocarcinoma

Lymphopenia is a common consequence of chemoradiation therapy yet is seldom addressed clinically. This study was conducted to determine if patients with locally advanced pancreatic cancer (LAPC) treated with definitive chemoradiation develop significant lymphopenia and if this affects clinical outcomes. A retrospective analysis of patients with LAPC treated with chemoradiation at a single institution from 1997 to 2011 was performed. Total lymphocyte counts (TLCs) were recorded at baseline and then monthly during and after chemoradiation. The correlation between treatment-induced lymphopenia, established prognostic factors, and overall survival was analyzed using univariate Cox regression analysis. Important factors identified by univariate analysis were selected as covariates to construct a multivariate proportional hazards model for survival. A total of 101 patients met eligibility criteria. TLCs were normal in 86% before chemoradiation. The mean reduction in TLC per patient was 50.6% (SD, 40.6%) 2 months after starting chemoradiation (P<0.00001), and 46% had TLC<500 cells/mm. Patients with TLC<500 cells/mm 2 months after starting chemoradiation had inferior median survival (8.7 vs. 13.3 mo, P=0.03) and PFS (4.9 vs. 9.0 mo, P=0.15). Multivariate analysis revealed TLC<500 cells/mm to be an independent predictor of inferior survival (HR=2.879, P=0.001) along with baseline serum albumin (HR=3.584, P=0.0002), BUN (HR=1.060, P=0.02), platelet count (HR=1.004, P=0.005), and radiation planning target volume (HR=1.003, P=0.0006). Severe treatment-related lymphopenia occurs frequently after chemoradiation for LAPC and is an independent predictor of inferior survival.

Feasibility of lymphocyte harvesting and reinfusion in patients with newly diagnosed high-grade gliomas.

2094 Background: Standard radiation (RT), temozolomide (TMZ), and dexamethasone cause severe treatment-related lymphopenia (TRL) (total lymphocyte counts (TLC) <500 cells/mm3) two months after init...

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.

Stereotactic Body Radiation Therapy Results in Less Severe Treatment-Related Lymphopenia than Conventional Chemoradiation Therapy in Patients With Locally Advanced Pancreatic Cancer

Stereotactic Body Radiation Therapy Results in Less Severe Treatment-Related Lymphopenia than Conventional Chemoradiation Therapy in Patients With Locally Advanced Pancreatic Cancer

The association between severe treatment-related lymphopenia and progression-free survival in patients with newly diagnosed squamous cell head and neck cancer.

6068 Background: Severe treatment-related lymphopenia (TRL) occurs in 50% of glioblastoma and pancreatic cancer patients and is associated with early death from tumor progression. We sought to determine if similar findings were seen in head and neck squamous cell carcinoma (HNSCC). Methods: Eligible patients for this retrospective study had: 1) HNSCC cancer diagnosed in 2007-2009, 2) good performance status, 3) platinum-based chemoradiation, and 4) follow-up at Johns Hopkins. Serial total lymphocyte counts (TLC), overall survival (OS) and progression-free survival (PFS) were analyzed accounting for known prognostic factors. Results: Fifty-six adults met eligibility criteria: median age: 57 years, female: 21%, HPV+: 61%, surgery prior to chemoradiation: 16%, stage IVA-IVB: 77%, T stage 3-4: 40% and N stage 2b-3: 56%. Changes in TLC are shown below (Table). 14/56 patients (25%) had tumor recurrence and 9 (16%) died of their tumor. HPV+ patients had longer PFS (p=0.01) and OS (p=0.006) than HPV- patients. 10/22 HPV- patients had disease progression and 7 died. HPV- patients who developed grade III-IV TRL two months after beginning chemoradiation had a strikingly higher hazard rate for disease progression than those whose TLC remained higher (multivariate analysis HR 6.2, 95%CI: 1.1-35.2; p=0.039). Too few events occurred in the HPV+ cohort for analysis. Conclusions: TLCs were normal before chemoradiation. However, two months after chemoradiation ~60% of patients had severe TLC regardless of HPV status. HPV- patients with severe TRL were much more likely to have disease progression than those without TRL. Prospective studies are needed to confirm these findings which are similar to those reported in other cancers. Preservation of the immune system during chemoradiation may be important to improving PFS and OS. [Table: see text]

Abstract 2420: The association between severe treatment-related lymphopenia and progression free survival in patients with newly diagnosed squamous cell head and neck cancer.

Abstract Background: Severe treatment-related lymphopenia (TRL) occurs in 50% of glioblastoma and pancreatic cancer patients and is associated with early death from tumor progression. We sought to determine if similar findings were seen in head and neck squamous cell carcinoma (HNSCC). Patients and Methods: Eligible patients for this retrospective study had: 1) HNSCC cancer diagnosed in 2007-2009, 2) good performance status, 3) platinum-based chemoradiation, and 4) follow-up at Johns Hopkins. Serial total lymphocyte counts (TLC), overall survival (OS) and progression-free survival (PFS) were analyzed accounting for known prognostic factors. Results: Fifty-six adults met eligibility criteria: median age: 57 years, female: 21%, HPV+: 61%, surgery prior to chemoradiation: 16%, stage IVA-IVB: 77%, T stage 3-4: 40% and N stage 2b-3: 56%. Changes in TLC are shown below: Median TLC:Baseline Median TLC: 2 months post-Rx % with TLC &amp;lt;500: 2 months post-Rx Overall 1660 448 61% HPV- (n = 22) 1770 550 36% HPV+ (n = 34) 1610 320 76% 14/56 patients (25%) had tumor recurrence and 9 (16%) died of their tumor. HPV+ patients had longer PFS (p=0.01) and OS (p=0.006) than HPV- patients. 10/22 HPV- patients had disease progression and 7 died. HPV- patients who developed grade III-IV TRL two months after beginning chemoradiation had a strikingly higher hazard rate for disease progression than those whose TLC remained higher (multivariate analysis HR 6.2, 95%CI: 1.1-35.2; p=0.039). Too few events occurred in the HPV+ cohort for analysis. Conclusion: TLCs were normal before chemoradiation. However, two months after chemoradiation ∼60% of patients had severe TLC regardless of HPV status. HPV- patients with severe TRL were much more likely to have disease progression than those without TRL. Prospective studies are needed to confirm these findings which are similar to those reported in other cancers. Preservation of the immune system during chemoradiation may be important to improving PFS and OS. Citation Format: Jian L. Campian, Guneet Sarai, Xiaobu Ye, Shanthi Marur, Stuart A. Grossman. The association between severe treatment-related lymphopenia and progression free survival in patients with newly diagnosed squamous cell head and neck cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2420. doi:10.1158/1538-7445.AM2013-2420 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.

Abstract 1242: The association between treatment-related lymphopenia and survival in patients with solid tumors.

Abstract Background: This retrospective review was conducted to determine: 1) the frequency and severity of treatment related lymphopenia (TRL) in solid tumors, 2) its association with survival accounting for prognostic variables, and 3) its relationship to radiation or chemotherapy. Methods: Serial lymphocyte counts (pre-treatment and monthly for one year), prognostic factors, treatment details, and survival were retrospectively reviewed in 338 newly diagnosed patients with 1) high grade glioma, 2) resected pancreatic cancer, 3) unresectable pancreatic cancer, 4) stage III lung cancer, and 5) HPV- head and neck cancer in this IRB approved study. Severe TRL was defined as grade III-IV lymphopenia (&amp;lt;500 cells/mm3). Results: The findings in each patient cohort are similar: 1) About 40% of patients develop severe TRL two months after initiating radiation and this persists for many months, 2) There is an association between TRL at two months and shorter survival from tumor progression, and 3) The hazard ratio for reduced survival is high after adjusting for known prognostic factors. Lung cancer patients treated with neoadjuvant chemotherapy did not experience TRL until after radiation was initiated. Conclusions: Severe TRL is common, severe, long-lasting and associated with earlier death from tumor progression in patients with solid tumors receiving radiation and chemotherapy. These studies suggest that radiation likely plays a major role in the development of TRL and that novel approaches to protect and/or restore immunologic function in patients with solid tumors are critical. NeoplasmTotal number patientsPatients developing grade III-IV TRLMedian Survival &amp;lt;500 vs &amp;gt;500 lymphocytes (months)Multivariate association with reduced survival:HR, (CI), pvalueHigh grade glioma9640%13 vs 19.7 (p = 0.002)OS: 1.66, (1.05–2.64), 0.03Pancreatic resected5345%14 vs 20 (p = 0.048)OS: 2.2, (1.17–4.12), 0.01Pancreatic unresectable12074%9.2 vs 14.6 (p = 0.013)OS: 1.34, (0.09–2.0), 0.15NSCLC Stage III4750%21.8 vs 28.3 (p = 0.38)OS: 1.7, (0.8–3.6), 0.17HEENT (HPV)2236%PFS onlyPFS: 6.2, (1.1–35.2), 0.04 Citation Format: Stuart A. Grossman, Susannah Yovino, Jian Campian, Aaron Wild, Joseph Herman, Daniel Laheru, Malcolm Brock, Shanthi Marur, Ani Balmanoukian, Xiaobu Ye. The association between treatment-related lymphopenia and survival in patients with solid tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1242. doi:10.1158/1538-7445.AM2013-1242

The Etiology of Treatment-related Lymphopenia in Patients with Malignant Gliomas: Modeling Radiation Dose to Circulating Lymphocytes Explains Clinical Observations and Suggests Methods of Modifying the Impact of Radiation on Immune Cells

Purpose: Severe treatment-related lymphopenia (TRL) occurs in 40% of patients with high grade gliomas (HGG) receiving glucocorticoids, temozolomide, and radiation. This occurs following radiation, persists for months, and is associated with reduced survival. As all three treatment modalities are lymphotoxic, this study was conducted to estimate the radiation dose that lymphocytes receive passing through the radiation field and if this could explain the observed TRL. Materials and Methods: A typical glioblastoma plan (8-cm tumor, 60 Gy/30 fractions) was constructed using the Pinnacle™ radiation planning system. Radiation doses to circulating cells (DCC) were analyzed using MatLab™. The primary endpoints were mean DCC and percent of circulating cells receiving ≥0.5 Gy. The model was also used to study how changes in target volumes (PTV), dose rates, and delivery techniques affect DCC. Results: The modeling determined that while a single radiation fraction delivered 0.5 Gy to 5% of circulating cells, after 30 fractions 99% of circulating blood had received ≥0.5 Gy. The mean DCC was 2.2 Gy and was similar for IMRT, 3D-conformal techniques, and different dose rates. Major changes in PTV size affected mean DCC and percent of circulating cells receiving ≥0.5 Gy. Conclusions: Standard treatment plans for brain tumors deliver potentially lymphotoxic radiation doses to the entire circulating blood pool. Altering dose rates or delivery techniques are unlikely to significantly affect DCC by the end of treatment. Novel approaches are needed to limit radiation to circulating lymphocytes given the association of lymphopenia with poorer survival in patients with HGG.

Modeling radiation dose to circulating lymphocytes during brain tumor treatment: Effects of target volume, dose rate, and treatment technique.

2017 Background: Severe treatment-related lymphopenia (TRL) occurs in 40% of glioblastoma patients despite minimal radiation (RT) doses to bone marrow or nodal sites. In glioblastoma, TRL is associated with decreased survival. To explain the lymphopenia, we sought to estimate radiation doses received by circulating lymphocytes during partial brain RT. Methods: An in-house computer program linked to treatment planning software was used to calculate the mean radiation dose to circulating blood (DCB) and the fraction of blood receiving &gt;0.5 Gy. The model also studied the impact of different target volumes (PTV), dose rates (DR), and delivery techniques (IMRT, 3D-CRT). Results: The mean DCB for a 60-Gy course (8-cm diameter PTV, dose rate 600 MU/minute) was 2.2 Gy. With this the entire blood pool receives a lymphotoxic dose of &gt;0.5 Gy. DCB is correlated with fraction number, PTV size, and DR. Regardless of dose rate or delivery technique, the percent of circulating blood receiving &gt;0.5 Gy approached 100% as the number of fractions increased. Changing dose rate had minimal effects on mean DCB (3.1Gy for 300 MU/min vs 2.2 Gy for 1200 MU/min). Smaller PTV size reduced the percent of blood receiving &gt;0.5 Gy (15% for 2-cm diameter PTV vs 100% for 8-cm PTV). Conclusions: Standard RT for brain tumors delivers a lymphotoxic radiation dose to circulating blood. Altering dose rate may initially affect DCB, but advantages disappear over the course of 30 fractions. Marked reductions in target size appear to be the best way to avoid radiation injury to normal circulating lymphocytes. Other novel approaches are needed to limit radiation exposure to circulating lymphocytes given evidence associating lymphopenia with poorer outcomes in cancer patients.

Incidence, severity, and etiology of treatment-related lymphopenia in patients with stage III non-small cell lung cancer (NSCLC).

e17552 Background: Severe treatment-related lymphopenia (TRL) is associated with shorter survival in patients with glioblastoma and pancreatic cancer treated with concurrent chemotherapy and radiation (chemo/RT). This retrospective study sought to determine if patients with stage III NSCLC develop TRL and if this results from chemotherapy or radiation. Methods: Patients selected for this retrospective analysis had newly diagnosed stage III NSCLC, Karnofsky performance status &gt;60, and chemo/RT and follow-up blood counts at Johns Hopkins Hospital. Patients were divided into those who received neoadjuvant chemotherapy followed by chemo/RT and those who received only chemo/RT. Serial lymphocyte counts were analyzed. Results: Forty-six adults met the above eligibility criteria. Their median age was 62 years (range 43-79), 65% were female, 74% were stage IIIA and 26% were IIIB, 72% had adenocarcinoma, and 68% were poorly differentiated. Surgery included pneumonectomy (7%), lobectomy (43%), wedge resection (7%), or biopsy (43%). Twenty patients received neoadjuvant chemotherapy consisting of 2 cycles of taxol/carboplatin (85%) or gemcitabine/carboplatin (15%). Their mean total lymphocyte count (TLC) prior to chemotherapy was 1416 cells/mm3 (SD 899). TLC remained unchanged after the neoadjuvant chemotherapy (mean 1519, SD 553). These patients then received concurrent chemo/RT (mean dose 58.4 Gy). TLC fell 68% at two months from a mean of 1519 (SD 553) to 490 (SD 305) (p&lt;0.00001) with 55% having TLC ≤500 cells/mm3. The remaining 26 patients received only concurrent chemo/RT. Their initial TLCs were normal (mean 1807, SD 644) but two months later had fallen by 70% (mean 545, SD 397) (p&lt;0.00001) with 54% having TLC ≤500 cells/mm3. Reductions in TLCs occurred irrespective of the chemotherapy administered with RT. Conclusions: TLCs are normal in patients with newly diagnosed stage III NSCLC and are unaffected by 2 cycles of neoadjuvant chemotherapy. However, with the addition of radiation TLCs drop in ~50% of patients to levels associated with severe immunosuppression. Further studies are needed to determine if this is associated with reduced survival as reported in other malignancies.