Decrease In Absolute Lymphocyte Count Research Articles

Assessment of Repeated Electrocardiogram Findings in Pediatric Multisystem Inflammatory Syndrome Associated with COVID-19

Background: Cardiac involvement, stemming from the novel multisystem inflammatory syndrome in children (MIS-C) associated with coronavirus disease-2019 (COVID-19), leads to common and severe complications. Objectives: The aim of this study is to compare and evaluate repetitive electrocardiogram (ECG) results and laboratory indicators in children diagnosed with MIS-C upon their initial hospital admission. Methods: This prospective, single-center study, conducted between December 2020 and October 2022, included repeated electrocardiographic and laboratory tests. Changes in the ECG over the course of the disease were regularly recorded for three months. Results: This study included 72 patients, 25 of whom were female. Mitral regurgitation and left ventricular systolic dysfunction were observed in 25% of the patients. Statistically significant differences (P < 0.05) were detected among the serial measurements of absolute neutrophil-lymphocyte count, CRP, procalcitonin, ESR, D-dimer, troponin T, pro-BNP, ferritin, and interleukin-6. Significant differences were also observed in heart rate, PR interval, QRS duration, QT duration, Fredericia QTc, JT interval, presence of sinus tachycardia, presence of first-degree AV block, presence of wide QRS, abnormal QRS axis, abnormal T axis, long QTc, and ST-T changes (P < 0.05). Additionally, significant differences were noted in the absolute lymphocyte count, troponin levels, and ferritin levels between patients with prolonged abnormal ECG findings and those whose ECG findings were normal or had returned to normal. Furthermore, statistically significant differences were observed in absolute lymphocyte count, ferritin, and fibrinogen levels among the other four groups (P < 0.05). Conclusions: Electrocardiogram findings in patients measured serially appear to improve over time. Since patients with MIS-C may experience ECG abnormalities that could lead to arrhythmias, close monitoring and the establishment of standardized approaches are essential. Long-term ECG abnormalities were associated with a decrease in absolute lymphocyte count and elevated levels of troponin, ferritin, and fibrinogen.

Abstract 4081: rhIL-7-hyFc (efineptakin-alfa, NT-I7) increases tumor-specific CD8+ T cells despite FOLFOX cytotoxicity effect

Abstract rhIL-7-hyFc (efineptakin-alfa; NT-I7) is a potent T cell amplifier, comprised of two molecules of interleukin-7 (IL-7) fused to the hybrid Fc domain of IgD/IgG4 immunoglobulin. NT-I7 safely, significantly, and persistently increases the absolute lymphocyte counts (ALC) in humans in a dose-proportional manner. Importantly, this increase is primarily due to an increase in T cells (1). Previous studies have shown that NT-I7 not only significantly increases the number of CD8+ T cells in peripheral blood but also dramatically boosts the presence of tumor-infiltrating CD8+ T cells, including both tumor-specific (p15E+PD-1+) and tumor non-specific (PD-1-) CD8+ T cells in mice (2). FOLFOX is a chemotherapy regimen composed of 5-fluorouracil, leucovorin, and oxaliplatin that inhibits DNA duplication and eradicates rapidly dividing cells (3). Although the mechanism of FOLFOX results in direct tumor killing, it also has the potential to kill newly dividing lymphocytes during NT-I7 treatment (4-6). Therefore, in this study, we aimed to evaluate the feasibility of combining FOLFOX with NT-I7 in a syngeneic MC38 mouse tumor model. Our results show that NT-I7 improves the efficacy of FOLFOX, irrespective of the timing of NT-I7 administration: simultaneous administration or delayed 3 hours, or 2 days after FOLFOX administration. This improvement persists despite a significant decrease in ALC for the first 6 days, which was significantly lower than the ALC observed with FOLFOX alone. FOLFOX decreases the absolute numbers of tumor non-specific CD8+ T cells. However, adding FOLFOX does not affect the NT-I7-driven increase of tumor-specific CD8+ T cells within the tumor. Taken together, our data demonstrate that FOLFOX does not compromise NT-I7’s ability to increase tumor-specific T cells within the tumor and the combination enhances the anti-tumor response irrespective of the timing of NT-I7 administration. Citation Format: Soung-Min Lee, Miyoung Kim, Sara Ferrando-Martínez, Sun-Kyoung Im, Mankyu Ji, Donghoon Choi. rhIL-7-hyFc (efineptakin-alfa, NT-I7) increases tumor-specific CD8+ T cells despite FOLFOX cytotoxicity effect [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4081.

Early Initiation of Oral Therapy with Cyclosporine and Eltrombopag for Treatment Naïve Severe Aplastic Anemia: Interim Results of a Phase II Trial

Introduction: Severe aplastic anemia (SAA), a life-threatening bone marrow failure disease, is treated with allogeneic bone marrow transplantation or immunosuppression (IST). Pancytopenia meeting “Camitta” criteria and an empty bone marrow (<30% cellularity) establish the diagnosis of SAA. However, neither diagnosis nor therapeutic interventions are straightforward, resulting in delays of therapy. SAA must be differentiated from hematologic malignancy, and constitutional forms should be excluded by functional or genetic testing. Administration of IST usually occurs at a tertiary care center, and in younger patients' evaluation for BMT is first required. Ongoing immune mediated destruction of stem cells further depletes marrow reserve and increases regenerative stress with such delays. In this phase II study, we tested the feasibility and safety of early initiation of cyclosporine (CSA) to block T cells and eltrombopag (EPAG) to stimulate hematopoiesis followed by standard of care therapies to expedite treatment (NCT04304820). Methods: Twenty-six patients with treatment-naive SAA were enrolled since 2020. Patients were 3 years or older and median age was 35 years. Exclusion criteria included a diagnosis or high clinical suspicion for inherited disease or evidence of myeloid neoplasm. To ensure rapid initiation of therapy, enrollment was not dependent on pending specialized tests (telomere length, chromosomal breakage, cytogenetics, or genomics). Lower dose CSA (2mg/kg) and full dose EPAG were initiated after confirming eligibility. Upon completion of evaluation and confirmation of acquired SAA diagnosis, all subjects received standard IST (horse ATG, CSA, and EPAG; Figure 1A). Primary feasibility endpoint assessed a composite measure of misdiagnosis, non-compliance, and treatment-related serious adverse events (TRSAE) during oral therapy. Secondary endpoints were efficacy at 6 months, relapse, clonal evolution, and overall survival. Results were compared to a historical cohort of 139 patients treated with hATG, CSA, and EPAG initiated the same day (NCT01623167). Results: All patients completed the protocol-defined treatment period, with median time on oral therapy of 17 days (range 0 - 86 days). All subjects ultimately were confirmed to have acquired SAA (no misdiagnoses), all tolerated oral treatment well without any TRSAE, and patients were compliant with local and study-site follow-up. Thus, there were zero events for the primary feasibility endpoint. A single SAE during oral treatment occurred in subject #1, enrolled at the height of the COVID pandemic and was severely ill with persistently positive COVID-19 PCR and recurrent ileitis requiring hospitalization care; his time to standard IST was the longest (86 days). There was significant increase in absolute neutrophil count (ANC; median 0.315x10 3/mL vs 0.570, p=0.041) in a brief interval of oral therapy prior to receiving hATG. There was also a trend towards improvement in absolute reticulocyte count (29x10 3/mL vs. 35.8) and a decrease in absolute lymphocyte count (1.5x10 3/mL vs. 1.3; Figure 1B). Compared to historical cohort, less patients (19% vs 52%) had very SAA (ANC <200 K/uL); age, sex, race, and pre-treatment blood counts were similar in two cohorts. Hematologic response occurred in 68% at 6 months with 45% complete responses, rates similar to the historical cohort (80% and 40%, respectively). Time to platelet and red blood cell transfusion independence was 43 and 51 days, respectively. Only age (18-40 years) was predictive for 6 month response. With median follow-up of 396 days, the cumulative incidence of relapse at 2 years was 17%, lower than in the historical cohort (27%). Clonal evolution to secondary myeloid malignancy was not increased compared to historical cohort; one subject had myelodysplastic syndrome with excess blasts 1 with deletion 20q, and two had transient trisomy 8 without dysplasia. Overall survival was 96.2%; no deaths occurred during study treatment period of oral medications only. Conclusion: Early initiation of CSA and EPAG is a feasible and safe approach to rapidly treat patients with SAA as a bridge to standard therapies and it may lead to improved blood counts, in turn, decreasing early infectious complications. Hematologic response was comparable to our historic cohort. Rates of long-term complications need to be confirmed in a larger cohort with ongoing study enrollment.

Impact of Salvage Versus Palliative Dose Bridging Radiation Therapy on Local Control and Overall Survival in Patients with DLBCL Receiving CD19 CAR T Cell Therapy.

In patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), radiation therapy (RT) can be used to "bridge" patients during the period of chimeric antigen receptor T cell (CAR T) manufacturing. Although RT has been shown to improve local control (LC) in patients who receive RT versus do not, it is unknown whether there is an optimal dose. This was a retrospective study of patients with DLBCL who received bridging RT and CAR T cell therapy between 8/2021 and 12/2022 at a single institution (IRB #202103122). Patient, disease, and treatment characteristics were abstracted. PET/CT and laboratory data were collected at various time points. RT data including dose, planning target volume (PTV), and body volume receiving 2Gy and 4 Gy were tested for associations with LC, overall survival (OS), cytokine release syndrome (CRS) and immune effect cell-associated neurotoxicity syndrome (ICANS). Statistical tests were performed using Python libraries. Twenty-two patients with DLBCL were included for analysis. The median patient age was 68 (range 35-82) and the median prior lines of failed therapies was two. All patients had successful apheresis and subsequent CAR T manufacturing. No patients died before CAR T infusion. All patients had a pre-radiation PET/CT scan that showed Deauville 5 disease. Patients with limited stage disease received salvage dose RT (EQD2∼40Gy, n = 8) while patients with advanced disease received palliative dose RT (n = 14). The median PTV volume was 1332 cm3. With a median follow-up of 156 days (IQR 63 - 252 days) from CAR T infusion, 10 patients had died and six progressed at an RT target. A higher salvage RT dose was not associated with LC at the day 30 PET or day 90 PET time points. In a Cox regression model, no independent variable, including RT dose, was significantly associated with LC or OS, but post-RT residual target SUV trended toward an association with OS (HR 6.2, 95% CI 0.9 - 471.0, p = 0.06). Post-RT LDH was associated with CRS grade (ρ = -0.39, p = 0.05). Other non-significant associative trends were noted between CRS grade and post-RT absolute lymphocyte count (ALC) (ρ = - 0.33, p = 0.09) and residual target SUV max (ρ = - 0.37, p = 0.08) and between ICANS grade and pre- to post-RT LDH change (ρ = -0.38, p = 0.06) and post-RT lymphocyte count (ρ = 0.36, p = 0.07). In an exploratory analysis of body volume receiving integral doses of 4Gy or 2Gy and pre- and post-RT ALC change, it appeared that higher integral dose did lead to larger decreases in ALC (ρ = -0.32, p = 0.15 and ρ = -0.3, p = 0.18, respectively). In this small series of patients with r/r DLBCL treated with bridging RT prior to CAR T therapy, RT dose was not associated with LC. However, higher post-RT target residual SUV was associated with worse OS. The impact of post-RT LDH on CRS and ICANS grades should be explored further.

Prognostic impact of radiotherapy-induced-lymphopenia in patients treated with breast-conservative surgery

We investigated a prognostic impact of radiotherapy-induced lymphopenia (RIL) in breast cancer patients treated with breast-conservative surgery (BCS). We included 531 breast cancer patients who were treated with BCS and adjuvant radiotherapy. None of these received (neo)adjuvant chemotherapy. Pre- and post- absolute lymphocyte counts (ALC) were reviewed before and after radiotherapy. The primary endpoint was to evaluate recurrence-free survival (RFS) according to the pre-to-post ALC ratio. Binary logistic regression model was used to identify risk factors for RIL. Either continuous or categorical (> 2.4) pre-to-post ALC ratio was associated with RFS. In 531 patients receiving whole breast irradiation (WBI) and regional nodal irradiation (RNI), RFS was significantly reduced in the patients with high pre-to-post ALC ration (> 2.4). In multivariable analysis, low pre-to-post post ALC ratio was significantly related to decreased RFS in the multivariable analysis (HR 2.293, 95% CIs 1.110–4.735, P = 0.025). In 452 patients treated with WBI alone, high pre-to-post ALC ratio was still significantly associated with decreased RFS in the multivariable analysis (HR 2.708, 95% CIs 1.016–7.218, P = 0.046). In binary logistic regression analysis, RNI was only significant risk factor for clinically meaningful RIL. Our findings show that a markedly decrease in ALC during radiotherapy has a negative prognostic impact.

PATTERNS OF CIRCULATING NK CELL DYSFUNCTION IN PATIENTS WITH LYMPHOMA

Background: Cancer is a recognized condition of secondary immunosuppression. Lymphoma patients often show a decrease in absolute lymphocyte counts and in peripheral blood gamma-globulin levels. However, less is known about how NK cells are altered in lymphoma patients. The aim of this study was to evaluate the patterns of circulating NK cell dysfunction in lymphoma patients. Methods: We performed a cross-sectional study of patients with a recent diagnosis of nodal lymphoproliferative disorder. Patients with active anticancer treatment or steroid use were excluded. Peripheral blood samples in EDTA were analyzed by multicolor flow cytometry. A custom panel of 30 markers was applied to all samples to test for major subpopulations, maturation, and functional markers. Results were compared to healthy controls. Clinical data were obtained from the electronic database. This study was approved by the institutional IRB and Clinical Ethics Committee. Results: A total of 30 patients were examined between October 2021 and November 2022. The median age was 62 years (range 15–88) and 45.7% were female (16). Patients had the following subtypes: large B-cell lymphoma (LBCL; 9), follicular lymphoma (FL; 9), Hodgkin lymphoma (HL; 5), mantle cell lymphoma (MCL; 4), marginal zone lymphoma (MZL; 2), Waldenström macroglobulinemia (WM; 1). Most patients had advanced stage disease (20). Compared to healthy controls (n = 10), lymphoma patients showed a significant decrease in absolute NK cell counts (ANKC, 319.7 vs. 131.1 cells/mm3; p < 0.0001). MCL patients had the lowest ANKC (68.8) and Hodgkin patients the highest (165.6). Advanced stage disease correlated with lower ANKC compared to localized disease (99.85 vs. 148.9; p = ns). The pattern of maturation was altered in lymphoma patients compared to controls (p = 0.0092). Patients had a higher proportion of immature CD56-bright NK cells (4.97% vs. 2.88%) and lower levels of CD16 expression in the mature CD56-dim subpopulation (68.12% vs. 85.94%). Lymphoma patients also showed dysfunctional expression of receptors and activation markers (Figure). There was a significant increase in the levels of FAS-L, IFNg, CD49b, CD57, CD96, and CD107a, while the levels of TIGIT and NKG2D were significantly decreased. Differences in the expression of immune checkpoints (PD-1, LAG-3, TIM-3), as well as additional activating, inhibitory, and chemokine receptors were not significant. 22 of 30 patients (73.3%) achieved a complete response. All patients with ANKC above 135 cells/mm3 at diagnosis achieved sustained complete remission. The research was funded by: Fondecyt 11200805 Clínica Alemana de Santiago ID1025 Keyword: diagnostic and prognostic biomarkers No conflicts of interests pertinent to the abstract.

Systemic inflammatory markers in elderly patients undergoing transcatheter aortic valve replacement.

Transcatheter aortic valve replacement (TAVR) provokes an early injury response, partially represented by dynamic changes in inflammatory markers. TAVR greatly benefits the elderly and we aimed to determine whether increased inflammatory markers post-TAVR in octagenerians were different than their younger counterparts and whether it was associated with adverse clinical outcomes. Patients with severe symptomatic aortic stenosis who underwent transfemoral TAVR from January 2010 to December 2021 were enrolled. Total white blood cells (WBC) count and subpopulation dynamics were evaluated. Five-hundred and seven patients were finally included in the study, 65% of these patients were 80 or more years old (54% female, median age 84 [82-87]) years, with severe symptomatic aortic stenosis. In patients aged above 80 years (patients ≥ 80), we noticed significant kinetic changes in the WBC and their differential cellular subpopulations (P < 0.0001) between admission and early days post-procedure. This was evident by a significant increase in total WBC (median 7.1 to 9.4) and absolute neutrophil count (median 4.7 to 7.4), neutrophil-lymphocyte (NL) ratio (median 2.82 to 7.21), and a meaningful decrease in absolute lymphocyte count (median 1.5 to 1.0). Implantation of self-expandable valves (SEVs) was associated with a more pronounced inflammatory response than balloon-expandable valves (BEVs). Higher WBC and neutrophil counts were associated with higher mortality and major vascular complications at 30 days, in addition, higher neutrophil counts and NL ratios were found to be correlated to arrhythmia at 30 days with P values of 0.04 and 0.028, respectively. This is the first description of a differential age-related inflammatory response in patients after TAVR, which shows an association between inflammatory markers post procedure and clinical outcome. Nevertheless, survival rates were similar in the elderly population and in younger patients, despite the presence of comorbid conditions.

Red Cell Distribution Width and Absolute Lymphocyte Count Associate With Biomarkers of Inflammation and Subsequent Mortality in Rheumatoid Arthritis.

Morbidity and mortality in rheumatoid arthritis (RA) is partly mitigated by maintaining immune and hematologic homeostasis. Identification of those at risk is challenging. Red cell distribution width (RDW) and absolute lymphocyte count (ALC) associate with cardiovascular disease (CVD) and mortality in the general population, and with disease activity in RA. How these variables relate to inflammation and mortality in RA was investigated. In a retrospective single Veterans Affairs (VA) Rheumatology Clinic cohort of 327 patients with RA treated with methotrexate (MTX)+/- a tumor necrosis factor (TNF) inhibitor (TNFi), we evaluated RDW and ALC before and during therapy and in relation to subsequent mortality. Findings were validated in a national VA cohort (n = 13,914). In a subset of patients and controls, we evaluated inflammatory markers. In the local cohort, high RDW and low ALC prior to MTX treatment was associated with subsequent mortality over 10 years (both P < 0.001). The highest mortality was observed in those with both high RDW and low ALC. This remained after adjusting for age and comorbidities and was validated in the national RA cohort. In the immunology cohort, soluble and cellular inflammatory markers were higher in patients with RA than in controls. ALC correlated with age, plasma TNF receptor II, natural killer HLA-DR mean fluorescence intensity, and CD4CM/CD8CM HLA-DR/CD38%, whereas RDW associated with age and ALC. MTX initiation was followed by an increase in RDW and a decrease in ALC. TNFi therapy added to MTX resulted in an increase in ALC. RDW and ALC before disease-modifying antirheumatic drug therapy are associated with biomarkers of monocyte/macrophage inflammation and subsequent mortality. The mechanistic linkage between TNF signaling and lymphopenia found here warrants further investigation.

Abstract 1971: Lymphocyte kinetics, frailty and survival outcomes in HNSCC

Abstract Lymphopenia is associated with decreased survival outcomes in head and neck squamous cell carcinoma (HNSCC). This is a significant concern especially for frail individuals who are more vulnerable to immunological dysregulations. A robust analysis is needed to understand whether we should expend efforts to limit treatment-related hematological toxicities in HNSCC. First, we would like to understand the prognostic significance for baseline (BL) vs. treatment-related lymphopenia (TRL). We want to know if lymphopenia is merely a reflection of the patient’s frailty at baseline, or if this is iatrogenic and therefore can be a target for treatment modifications in a bid to improve survival. Here, we identified 222 newly diagnosed M0 HNSCC patients treated with radiation ± systemic therapy in 2015-2018 at our institution. Clinical frailty is defined by age ≥ 65 or KPS ≤ 70. Using Kaplan Meier estimates and Cox regression with dichotomous variables, we performed multivariate analysis for both overall survival (OS) and progression-free survival (PFS). Important predictors included frailty (p ≤ 0.002) and ≥ 2K/mm3 decrease in absolute lymphocyte counts (ALC) (p ≤ 0.006). BL did not significantly impact OS or PFS (p ≤ 0.37). For TRL, ALC decrease had greater prognostic significance compared with ALC nadirs (p ≤ 0.45). Next, we simplified our survival model to include only frailty and TRL. Overall, fit patients with modest ALC decline (&amp;lt; 2K/mm3) achieved excellent survival outcomes while frail patients with severe ALC decline (≥ 2K/mm3) had inferior outcomes (3-year OS 95% vs. 56%, p &amp;lt; 0.0001; 3-year PFS 84% vs. 42%, p = 0.002). On subgroup analyses, similar outcomes were also identified for HPV+ HNSCC (n = 172, 3-year OS 96% vs. 71%, p = 0.002; 3-year PFS 89% vs. 54% p = 0.03). Finally, we want to know if ALC decline is determined primarily by treatment intensity, or if frail patients are naturally predisposed to greater ALC decline during treatment. In our data, frail patients had more modest ALC decline when compared to fit patients (1.26 ± 0.57 vs. 1.54 ± 0.58 K/mm3 p = 0.0006). In our survival model, we did not observe any first-order interactions between frailty and ALC decline (p = 0.54). The extent of ALC decline was also higher for patients with concurrent administrations of cisplatin (as opposed to radiation alone, p &amp;lt; 0.0001). Thus, we postulate that the extent of ALC decline is determined primarily by treatment intensity. It is possible that frail patients with severe ALC decline have inferior survival outcomes because they cannot maintain immunological balance and respond poorly when there is significant TRL. This opens opportunities to re-evaluate if the risk of TRL is modifiable by limiting the number of concurrent cycles of chemotherapy administered, and by considering radiation dose de-intensification especially for HPV-associated HNSCC. Lastly, TRL becomes an important consideration when immunotherapeutics are grafted onto existing CRT treatment paradigms. Citation Format: Carmen Kut, Todd McNutt, Carole Fakhry, Theodore DeWeese, Harry Quon. Lymphocyte kinetics, frailty and survival outcomes in HNSCC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1971.

Outcomes and Toxicities of Modern Combined Modality Therapy with Atezolizumab Plus Bevacizumab and Radiation Therapy for Hepatocellular Carcinoma.

Simple SummaryHepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide with slow progress in the development of effective therapies. The breakthrough IMbrave150 trial established atezolizumab plus bevacizumab as the standard of care first-line therapy for patients with unresectable/advanced HCC, demonstrating improved overall survival. Radiation therapy (RT) is a locoregional treatment that may prevent morbidity from tumor-related vascular compromise and associated liver failure. There is no documented evidence yet describing the safety and outcomes of combination RT and atezolizumab/bevacizumab. In the retrospective review of our experience, we identified 21 patients with advanced HCC who underwent liver-directed RT with atezolizumab/bevacizumab. From our findings, the treatment is well-tolerated, safe, and does not potentiate liver failure. There were uncommon autoimmune or GI bleeding events in some patients, mostly unrelated to RT. Post-RT absolute lymphocyte counts (ALC) improved more quickly with atezolizumab/bevacizumab than they did without, which may be a favorable treatment prognosticator.Atezolizumab plus bevacizumab has become frontline therapy for unresectable HCC. The compatibility of atezolizumab/bevacizumab with liver-directed RT has not been reported. Methods: HCC patients treated with liver-directed RT and atezolizumab/bevacizumab between 1/2020–11/2021 were included. Toxicity and outcomes were retrospectively recorded. For ALCs, we matched the analysis to a previously cohort of RT-treated HCC patients who did not receive atezolizumab/bevacizumab. Survival and time-to-liver-failure were analyzed using Kaplan–Meier. Results: Of 21 patients, with a median follow-up of 9.5 months, the median OS was 16.1 months. Post-RT, all patients had reduced tumors or treatment response. There were no ≥Grade 3 RT-related toxicities. Autoimmune complications occurred in two patients (9.5%), and GI bleeding in three patients (14.3%). Liver function remained stable post-RT. There was a marked decrease in ALCs immediately post-RT (post-RT/pre-RT ratio 47.3%, p < 0.0001), restored by 1 month to pre-treatment baseline (1-month post-RT/pre-RT ratio 95.1%, n.s.). Compared to HCC patients treated with RT alone, post-RT ALC recovery was faster with atezolizumab/bevacizumab (p = 0.009). Conclusion: In this first reported experience of RT with modern systemic therapy for HCC, combination therapy is safe and well-tolerated. As a favorable prognosticator, there appears to be faster recovery of ALC among patients who received RT with atezolizumab/bevacizumab.

Prognostic value of serum/plasma neurofilament light chain for COVID-19-associated mortality.

ObjectiveGiven the continued spread of coronavirus 2, the early predictors of coronavirus disease 19 (COVID‐19) associated mortality might improve patients' outcomes. Increased levels of circulating neurofilament light chain (NfL), a biomarker of neuronal injury, have been observed in severe COVID‐19 patients. We investigated whether NfL provides non‐redundant clinical value to previously identified predictors of COVID‐19 mortality.MethodsWe measured serum or plasma NfL concentrations in a blinded fashion in 3 cohorts totaling 338 COVID‐19 patients.ResultsIn cohort 1, we found significantly elevated NfL levels only in critically ill COVID‐19 patients. Longitudinal cohort 2 data showed that NfL is elevated late in the course of the disease, following the two other prognostic markers of COVID‐19: decrease in absolute lymphocyte count (ALC) and increase in lactate dehydrogenase (LDH). Significant correlations between ALC and LDH abnormalities and subsequent rise of NfL implicate that the multi‐organ failure is the most likely cause of neuronal injury in severe COVID‐19 patients. The addition of NfL to age and gender in cohort 1 significantly improved the accuracy of mortality prediction and these improvements were validated in cohorts 2 and 3.InterpretationA substantial increase in serum/plasma NfL reproducibly enhanced COVID‐19 mortality prediction. Combined with other prognostic markers, such as ALC and LDH that are routinely measured in ICU patients, NfL measurements might be useful to identify the patients at a high risk of COVID‐19‐associated mortality, who might still benefit from escalated care.

Early predictive risk factors for dimethyl fumarate-associated lymphopenia in patients with multiple sclerosis

BackgroundLymphopenia is a major concern in MS patients treated with dimethyl-fumarate (DMF) as it increases the risk of progressive multifocal leukoencephalopathy. A pronounced reduction in absolute lymphocyte counts (ALCs) early after treatment initiation has been suggested to be associated with the occurrence of lymphopenia thereafter. ObjectivesTo identify risk factors for DMF-induced lymphopenia and evaluate whether the degree of decrease in the ALCs three months after initiation of DMF treatment is a predictor of the subsequent development of lymphopenia. MethodsIn this real-world Spanish prospective multicenter study conducted in MS patients who started DMF between 2014 and 2019, we analyzed the association between DMF-related lymphopenia and the percentage of early ALCs decline using regression models, considering both, significant lymphopenia (grades 2 + 3) and severe lymphopenia (grade 3). The cutoff values of early ALCs declines were obtained using the ROC curve. ResultsAmong 532 MS patients treated with DMF, 193 (36.3%) developed any grade of lymphopenia. Older age and lower ALCs at treatment onset predicted the risk for lymphopenia but the best predictive risk factor was the reduction of ALCs within the three first months of treatment. Specifically, a reduction in ALCs≥21.2% was associated with a 6.5-fold higher risk of developing significant lymphopenia, and a decrease in ALCs≥40.2% with a 12.7-fold higher risk of developing severe lymphopenia. ConclusionsA pronounced reduction in ALCs early after initiation of DMF in MS patients is the best predictive risk factor for the subsequent development of significant lymphopenia.

Positioning Ozanimod in Ulcerative Colitis: Restoring Leukocyte Traffic Under Control

Positioning Ozanimod in Ulcerative Colitis: Restoring Leukocyte Traffic Under Control

Preliminary Safety and Efficacy Data from Patients (Pts) with Relapsed/Refractory (R/R) B-Cell Malignancies Treated with the Novel B-Cell Lymphoma 2 (BCL2) Inhibitor BGB-11417 in Monotherapy or in Combination with Zanubrutinib

Preliminary Safety and Efficacy Data from Patients (Pts) with Relapsed/Refractory (R/R) B-Cell Malignancies Treated with the Novel B-Cell Lymphoma 2 (BCL2) Inhibitor BGB-11417 in Monotherapy or in Combination with Zanubrutinib

Assessing the Spleen as an Organ at Risk in Radiation Therapy and Its Relationship With Radiation-Induced Lymphopenia: A Retrospective Study and Literature Review

PurposeWe conducted a systematic review and a retrospective study to investigate the relationship between spleen irradiation and lymphocyte toxicity. Methods and MaterialsForty-six patients diagnosed with locally advanced gastric, esophageal, and pancreatic cancer who underwent radiation therapy were included in this study. The spleen was contoured for each patient. Volumes that received 5 up to 40 Gy (5 Gy increments), minimum, mean, and maximum dose were considered along with lymphocyte count to determine toxicity. Comprehensive and systematic literature searches were performed using PubMed, SCOPUS, Cochrane Central Databases, and Google Scholar. ResultsLiterature review on spleen unintended irradiation and lymphocyte toxicity resulted in 408 patients from 5 studies. In our study, univariate and multivariate linear regressions found an association between V15 (chemotherapy as controlling factor) and nadir lymphocyte count (P = .04) and between DMAX and nadir lymphocyte count (P = .046). An increase of 1 Gy in mean splenic dose was associated with a 1% decrease in absolute lymphocyte count at nadir. ConclusionsAlthough there is no consensus regarding lymphopenia spleen dose volume threshold, all studies found that higher splenic dose increases the risk of lymphopenia. Our study's results suggest that spleen unintentional V15 and maximum dose irradiation were associated with lymphopenia during chemoradiation therapy.

Peripheral Blood Biomarkers for Early Diagnosis, Severity, and Prognosis of Checkpoint Inhibitor-Related Pneumonitis in Patients With Lung Cancer.

BackgroundCheckpoint inhibitor-related pneumonitis (CIP) is a potentially fatal immune-related adverse event that occurs during treatment with immune checkpoint inhibitors (ICIs). However, the roles played by peripheral blood parameters in CIP development remain unclear. Here, we aimed to identify which blood biomarkers correlated with the development and prognosis of CIP in patients with lung cancer.MethodsWe conducted a retrospective analysis of 87 patients with CIP (CIP group) and 87 patients without CIP (control group). Cytokines, blood routine, lactate dehydrogenase (LDH) and albumin (ALB) were collected at baseline (before ICIs), at onset of pneumonitis (in the CIP group), and before the last dose of ICI (in the control group). We compared the baseline values and changes over time in various blood parameters between the CIP and control groups. The CIP outcomes were collected and compared according to the median values of these parameters.ResultsSquamous carcinoma (odds ratio [OR]: 3.02; p = 0.004) and ICI monotherapy (OR: 6.56; p = 0.004) correlated with a high risk of CIP. In the CIP group, interleukin (IL)-6 and platelet-to-lymphocyte ratio (PLR) at CIP were significantly increased relative to baseline. By contrast, IL-6 and PLR reduced over time in the control group. Significant decrease in absolute lymphocyte count (ALC) and increases in IL-10, neutrophil to lymphocyte ratio (NLR), and LDH levels were observed from baseline to CIP. No significant change in these parameters was observed in the control group relative to baseline. ALB decreased in both groups, but the decrease in the CIP group was greater (9.21% vs. 2.44%; p = 0.020). High IL-6 levels (OR: 5.23, 95% confidence interval [CI]: 1.15–23.86; p = 0.033), and low levels of ALB (OR: 0.16, 95% CI: 0.04–0.64; p = 0.009) measured at the time of CIP symptom onset were associated with severe pneumonitis. Low concentration of IL-6 (hazard ratio [HR]: 0.17, 95% CI: 0.03–0.95; p = 0.044) and high ALB levels (HR: 0.28, 95% CI: 0.08–0.94; p = 0.040) were correlated with favorable overall survival in CIP.ConclusionsIncrease in IL-6, IL-10, NLR, PLR, and LDH levels or reduced ALC and ALB levels were associated with the occurrence of CIP in lung cancer patients. High IL-6 and low ALB levels at onset of CIP were related to severe grade and poor prognosis of CIP.

Immunophenotyping Reveals Longitudinal Changes in Circulating Immune Cells During Radium-223 Therapy in Patients With Metastatic Castration-Resistant Prostate Cancer.

BackgroundRadium-223 improves overall survival (OS) in men with bone metastatic castration-resistant prostate cancer (mCRPC). While the exact mechanism behind this survival benefit remains unclear, radium-induced immunological mechanisms might contribute to the OS advantage. We performed a comprehensive evaluation of the immunological changes in mCRPC patients by phenotyping the peripheral blood mononuclear cells (PBMCs) during radium-223 therapy.Materials and MethodsIn this prospective, single-arm, exploratory study, PBMCs of 30 mCRPC patients were collected before, during, and after treatment with radium-223. Lymphocyte and monocyte counts were analyzed to get insight into general immune cell trends. Next, we analyzed changes in T cell subsets, myeloid-derived suppressor cells (MDSCs), and immune checkpoint expression using linear regression models. Per subset, the 6-month change (% of baseline) was determined. Bootstrapped 95% confidence intervals were used to measure the degree of uncertainty of our findings.ResultsWe observed a substantial decrease in absolute lymphocyte counts (-0.12 * 10^9 cells/L per injection, 95% CI: -0.143 - -0.102). Simultaneously, an increase was observed in the proportion of T cells that expressed costimulatory (ICOS) or inhibitory (TIM-3, PD-L1, and PD-1) checkpoint molecules. Moreover, the fraction of two immunosuppressive subsets – the regulatory T cells and the monocytic MDSCs – increased throughout treatment. These findings were not more pronounced in patients with an alkaline phosphatase response during therapy.ConclusionImmune cell subsets in patients with mCRPC changed during radium-223 therapy, which warrants further research into the possible immunological consequences of these changes.

Abstract 13352: Decreased Absolute Lymphocyte Count and Increased Neutrophil Lymphocyte Ratio With Immune Checkpoint Inhibitors-associated Myocarditis

Introduction: Myocarditis due to immune checkpoint inhibitor (ICI) therapy is a potentially fatal immune-related adverse event (irAE). Hypothesis: Limited data have suggested an association between baseline and on-treatment absolute lymphocyte count (ALC) and neutrophil lymphocyte ratio (NLR) and the development of other irAEs; there are no data characterizing the role of ALC and NLR in ICI-associated myocarditis. Methods: This was a case control study of 55 patients with ICI myocarditis and 55 controls without any post-ICI irAEs. We leveraged clinical testing where patients underwent routine serial blood counts before and with each ICI cycle to compare the baseline and change in ALC and NLR between cases and controls. The association between the change in these parameters with clinical variables and major adverse cardiac events (MACE) was also tested. Results: In those who developed myocarditis, there was a decrease in ALC from baseline (1.6 K/μL, IQR 1.1-1.9) to admission (1.1 K/μL, IQR 0.7-1.3, p&lt;0.001, Panel A). Similarly, among those who developed myocarditis, there was an increase in NLR from baseline (3.5, IQR 2.3-5.4) to admission (6.6, IQR 4.5-14.1, p&lt;0.001, Panel B). There was no change in patients treated with an ICI who did not develop myocarditis. Among those who developed myocarditis, a greater decrease in ALC or increase in NLR was associated with a higher heart rate and a lower blood pressure at admission. In follow-up, there were 20 events; larger decreases in ALC or increases in NLR were associated with MACE (Panel C and D). Conclusions: A reduction in ALC and an increase in NLR was seen with ICI myocarditis. A greater decrease in ALC or increase in NLR were associated with subsequent MACE.

Decreased Absolute Lymphocyte Count and Increased Neutrophil/Lymphocyte Ratio With Immune Checkpoint Inhibitor-Associated Myocarditis.

BackgroundMyocarditis attributable to immune checkpoint inhibitor (ICI) therapy is a potentially fatal immune‐related adverse event. Limited data have suggested an association between baseline and on‐treatment absolute lymphocyte count (ALC) and neutrophil/lymphocyte ratio (NLR) and the development of other immune‐related adverse events; there are no data characterizing the role of ALC and NLR in ICI‐associated myocarditis.Methods and ResultsThis was a case control study of 55 patients with ICI myocarditis and 55 controls without any post‐ICI immune‐related adverse events. We leveraged clinical testing, where patients underwent routine serial blood counts before and with each ICI cycle to compare the baseline and change in ALC and NLR between cases and controls. The association between the change in these parameters with clinical variables and major adverse cardiac events was also tested. In cases, there was a statistically significant decrease in ALC with myocarditis from baseline (1.6 thousands per cubic milliliter (K/μL); interquartile range, 1.1–1.9 K/μL) to admission (1.1 K/μL; interquartile range, 0.7–1.3 K/μL; P<0.001). Similarly, there was an increase in NLR from baseline (3.5; interquartile range, 2.3–5.4) to admission (6.6; interquartile range, 4.5–14.1; P<0.001). There was no statistically significant change in controls. In follow‐up, there were 20 events; larger decreases in ALC (44.6% versus 18.2%; P<0.001) or increases in NLR (156.5% versus 65.1%; P=0.019) were associated with major adverse cardiac events.ConclusionsA reduction in ALC and an increase in NLR was seen with ICI myocarditis. A greater decrease in ALC or increase in NLR was associated with subsequent major adverse cardiac events.

Venetoclax Has Modest Efficacy in the Treatment of Patients with Relapsed T-Cell Prolymphocytic Leukemia

Venetoclax Has Modest Efficacy in the Treatment of Patients with Relapsed T-Cell Prolymphocytic Leukemia