Baseline Absolute Neutrophil Count Research Articles

Anti-Thymocyte Globulin as a Therapy for Chronic Lung Allograft Dysfunction: A Single-Center Experience.

Anti-thymocyte globulin (ATG) is a polyclonal antibody formulation which has been used as a second-line therapy for chronic lung allograft dysfunction (CLAD).Limited data exist evaluating its efficacy; however, several single-center retrospective studies have variably demonstrated either improvement or stabilization of spirometry parameters after administration of ATG.ATG has been in use at UT Southwestern for treatment of CLAD since at least 2010; here, we seek to evaluate the effectiveness of this intervention at our center. METHODS: A retrospective chart review was conducted of a total of 136 patients who underwent lung transplantation at UT Southwestern Medical Center between 2010 and 2022. Of these, 72 patients had received ATG specifically for treatment of CLAD, and the remaining 64 had never received ATG. Two separate analyses were performed: in the first, among those who received ATG for CLAD, spirometry data from the 6 months preceding and following ATG administration were reviewed and rates of change in FEV1 were calculated for each time period. Descriptive statistics were performed to summarize the baseline clinical characteristics and outcomes after ATG, with patients classified as having either a full response (positive rate of change in FEV1) or partial response (>20% attenuation in rate of FEV1 decline) to ATG. In the second analysis, survival was described among those who received ATG for CLAD and comparison was provided between propensity-score matched cohorts from the ATG and non-ATG groups. Of the 63 patients who received ATG for treatment of CLAD (and had adequate spirometry measurements available to trend FEV1), 49 (77.8%) had at least a partial response to therapy; 8 (12.7%) experienced an overall improvement in FEV1. Response to ATG was found to be associated with a more rapid rate of pre-ATG decline in FEV1; no other baseline parameters were found to be predictive of a response to ATG. Median post-CLAD graft survival was 31.7 months among those who received ATG, and only baseline absolute neutrophil count was found to be associated with worse post-CLAD graft survival among this group. Anti-thymocyte globulin therapy, when given for CLAD, was associated with at least a modest attenuation in rate of FEV1 decline in most patients but only rarely preceded an absolute improvement in FEV1. Further study is warranted to better define the role for ATG in treatment of CLAD, a challenging disease state with limited therapeutics available.

Baseline monocyte count predicts symptom improvement during intravenous ketamine therapy in treatment-resistant depression: a single-arm open-label observational study.

Neuroinflammatory processes in depression are associated with treatment resistance to conventional antidepressants. Ketamine is an effective new therapeutic option for treatment-resistant depression (TRD). Its well-established immunomodulatory properties are hypothesized to mediate its antidepressant effect. In this context, higher levels of inflammation may predict a better treatment response. However, conclusive evidence for this hypothesis is lacking. We thus investigated whether standard peripheral inflammatory cell markers and C-reactive protein (CRP) levels could predict symptom improvement during intravenous ketamine therapy in TRD patients. 27 participants with TRD were treated with six weight-adjusted intravenous ketamine infusions (0.5 mg/kg bodyweight) over three weeks. Baseline assessments included CRP, absolute monocyte count (AMC), and absolute neutrophil count (ANC). Depression severity was measured using the Montgomery-Åsberg Depression Rating Scale (MADRS) at baseline (D1), after the first (D3) and before the last ketamine infusion (D18). Raters were blinded for the baseline laboratory assessments. 13 participants responded to ketamine treatment, and 8 participants partially responded. Baseline AMC showed a strong negative correlation with MADRS change at D3 (r=-0.57, p=0.002) and at D18 (r =-0.48, p=0.010), indicating that a high baseline AMC was associated with greater symptom improvement. A generalized linear model confirmed the association of baseline AMC with symptom improvement during ketamine treatment when additionally accounting for age, sex, and body mass index. Specifically, baseline AMC demonstrated predictive value to discriminate responders and partial responders from non-responders, but lacked discriminative ability between partial responders and responders. Baseline ANC correlated with the MADRS changes at D3 (r=-0.39, p=0.046), while CRP values did not correlate at all. Our prospective single-arm open-label observational study demonstrated that baseline AMC reliably predicted symptom improvement during intravenous ketamine treatment in TRD patients. AMC could therefore serve as a simple and easily accessible marker for symptom improvement during ketamine therapy in daily clinical practice. Future studies with larger sample sizes and a more detailed longitudinal assessment of AMC subtypes are needed to better understand the specific relationship between monocytes and the neuromodulatory effects of ketamine.

Clonal Hematopoiesis is Associated With Severe Cytokine Release Syndrome in Patients Treated With Chimeric Antigen Receptor T-Cell (CART) Therapy

Among patients receiving CD19 or B-cell maturation antigen (BCMA) CAR T therapy, inflammation pre- and post-CAR T infusion is implicated in the development of toxicities including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and likely contributes to prolonged cytopenias. Clonal hematopoiesis (CH), the clonal expansion of hematopoietic stem cells harboring somatic mutations, has been associated with inflammasome upregulation. Herein, we examined the prevalence of pre-CAR T CH in a predominantly transplant-naïve cohort of recipients with non-Hodgkin lymphoma (NHL) or multiple myeloma (MM), and assessed the relationship between the presence of CH mutations and CAR T-related outcomes including CRS, ICANS, prolonged cytopenia, progression-free survival (PFS), and overall survival (OS). This study included 62 patients with NHL or MM who underwent CD19 or BCMA CAR T therapy from 2017 to 2022 at City of Hope and had available pre-CAR T cryopreserved peripheral blood mononuclear cells (PBMCs). DNA was isolated with QIAamp DNA Mini Kit (Qiagen) from PBMC samples (94% collected <30d of CART infusion), on which we performed targeted exome sequencing (108 pre-defined gene panel with 1000x sequencing depth) to determine the presence of CH (variant allele frequency [VAF] ≥2%). Multivariable logistic regression was used to examine the association between CH and absolute neutrophil count (ANC) recovery at day +30 and +60, maximum grade CRS and ICANS, grade <2 versus 2+, and OS and PFS at 1y. Covariates considered were age at CART, baseline ANC, sex, race, CAR-HEMATOTOX, LDH, bridging therapy (Y/N), and number of prior lines of therapy. Fifteen (24%) patients had at least one pathogenic CH mutation; 2 (13%) had ≥2 CH mutations concurrently. DMT3A mutations were the most common; 29% of mutations had VAFs >10%. Patients with CH were significantly more likely to develop grade ≥2 CRS (60% versus 28%, p = .03) compared to those without CH (odds ratio [OR] 3.9, 95% CI 1.2-13.2; p = .027). Accounting for baseline ANC (which was higher among the CH cohort and associated with delayed ANC recovery, p = .02) patients with CH did not have a significantly different rate of delayed ANC recovery compared to those without CH (adjusted OR 0.37, 95% CI 0.09-1.5; p = .17). There was no association between CH and ICANS, nor with 1y PFS or OS. CH was frequent (24%) in this cohort of CAR T recipients and was associated with a higher risk of development of grade ≥2 CRS after CAR T. Additional validation studies are currently underway, which may set the stage for consideration of pre-CAR T CH as a biomarker for risk stratification towards more proactive CRS prophylaxis. Translational studies could aim to prove a direct relationship between CH-mutated myeloid cells and CRS.

Model-Based Prediction of Irinotecan-Induced Grade 4 Neutropenia in Cancer Patients: Influence of Incorporating Germline Genetic Factors in the Model.

Neutropenia is the major dose-limiting toxicity of irinotecan-based therapy. The objective of this study was to assess whether inclusion of germline genetic variants into a population pharmacokinetic/pharmacodynamic model can improve prediction of irinotecan-induced grade 4 neutropenia and identify novel variants of clinical value. A semimechanistic population pharmacokinetic/pharmacodynamic model was used to predict neutrophil response over time in 197 patients receiving irinotecan. Covariate analysis was performed for demographic/clinical factors and 4,781 genetic variants in 84 drug response- and toxicity-related genes to identify covariates associated with neutrophil response. We evaluated the predictive value of the model for grade 4 neutropenia reflecting different clinical scenarios of available data on identified demographic/clinical covariates, baseline and post-treatment absolute neutrophil counts (ANCs), individual pharmacokinetics, and germline genetic variation. Adding 8 genetic identified covariates (rs10929302 (UGT1A1), rs1042482 (DPYD), rs2859101 (HLA-DQB3), rs61754806 (NR3C1), rs9266271 (HLA-B), rs7294 (VKORC1), rs1051713 (ALOX5), and ABCB1 rare variant burden) to a model using only baseline ANCs improved prediction of irinotecan-induced grade 4 neutropenia from area under the receiver operating characteristic curve (AUC-ROC) of 50-64% (95% confidence interval (CI), 54-74%). Individual pharmacokinetics further improved the prediction to 74% (95% CI, 64-84%). When weekly ANC was available, the identified covariates and individual pharmacokinetics yielded no additional contribution to the prediction. The model including only ANCs at baseline and at week 1 achieved an AUC-ROC of 78% (95% CI, 69-88%). Germline DNA genetic variants may contribute to the prediction of irinotecan-induced grade 4 neutropenia when incorporated into a population pharmacokinetic/pharmacodynamic model. This approach is generalizable to drugs that induce neutropenia and ultimately allows for personalized intervention to enhance patient safety.

What Is the Impact of Baseline Inflammatory and Hemostatic Indicators with the Risk of Mortality in Severe Inpatients with COVID-19: A Retrospective Study.

The purpose of the study was to investigate baseline inflammatory, hemostatic indicators and new-onset deep vein thrombosis (DVT) with the risk of mortality in COVID-19 inpatients. In this single-center study, a total of 401 COVID-19 patients hospitalized in Sir Run Run Shaw Hospital, Zhejiang University School of Medicine were enrolled from December 1, 2022 to January 31, 2023. The basic information, first laboratory examination results, imaging examination, and outcome-related indicators were compared between patients in the moderate and severe subgroups. We found that baseline D-dimer and baseline absolute neutrophil count (ANC) levels were associated with new-onset DVT and death in severe hospitalized patients with COVID-19. The odds ratio (OR) of baseline D-dimer and baseline ANC with mortality was 1.18 (95% confidence interval [CI], 1.08-1.28; P < .001) and 1.13 (95% CI, 1.06-1.21; P < .001). Baseline ANC was associated with the risk of death in severe hospitalized COVID-19 patients, irrespective of the DVT status. In addition, a significantly higher serum neutrophil activity was observed in severe COVID-19 inpatients with DVT or those deceased during hospital stay. New-onset DVT partially mediated the association between baseline D-dimer (indirect effect: 0.011, estimated mediating proportion: 67.0%), baseline ANC (indirect effect: 0.006, estimated mediating proportion: 48.7%), and mortality in severe hospitalized patients with COVID-19. In summary, baseline D-dimer and baseline absolute neutrophil count (ANC) levels were associated with the mortality in severe hospitalized patients with COVID-19, especially DVT inpatients. New-onset DVT partially mediated the association between baseline D-dimer, baseline ANC, and mortality in severe hospitalized patients with COVID-19.

Duffy-Null Patients with Sickle Cell Disease Are at Risk for Low Neutrophil Counts with HU Treatment

Introduction The Duffy blood group consists of two main antigens, Fya and Fyb, and is encoded by the atypical chemokine receptor 1 ( ACKR1) gene. About 60% of Black individuals have the Duffy null phenotype, Fy(a-b-) characterized by absence of expression of the Fya and Fyb antigens on red cells. The Duffy null phenotype in Black individuals is caused by homozygosity for a SNP (rs2814778; T&amp;gt;C; CC) in the ACKR1 gene promoter. This polymorphism results in the disruption of a binding site for the GATA1 erythroid transcription factor and silences expression of the Duffy antigens. There is a strong correlation between the Duffy null phenotype and the lower range of absolute neutrophil counts (ANC) observed in some Black individuals. The impact of Fy(a-b-) status on clinical outcomes in individuals with sickle cell disease (SCD) is not well studied. Neutropenia is a common toxicity with hydroxyurea (HU) in the treatment for SCD. We hypothesized that SCD patients with the Duffy null phenotype are at risk for lower ANCs with HU treatment, and potentially have different clinical outcomes compared to Duffy-positive patients. Methods Pediatric patients with SCD (HbSS and HbSB 0-thalassemia) treated with HU and enrolled in the St. Jude Children's Research Hospital observational cohort study, the Sickle Cell Clinical Research and Intervention Program (SCCRIP) were eligible. Patients who had available Duffy genotype and reached a maximal tolerated dose (MTD) of HU before 12/31/2021 were included. The MTD based on neutrophil counts was considered to be achieved at a dose when the ANC was between 1000 and 3000 /mm 3. Multivariate generalized linear regression model was used for association analysis after adjusting for age at HU initiation, sex, and 5 principal components. Mediation analysis was conducted to evaluate indirect effect of the Duffy null phenotype on time to MTD via baseline ANCs. Results A total of 250 patients met the inclusion criteria. One hundred eighty (72%) patients were Duffy null, and 70 (28%) patients were positive for at least one of Duffy antigen. The average patient age at starting HU was 5.9 ± 4 years old. Female patients accounted for 44.8% (n= 112) of the study population. The mean MTD of HU was 28.0 ± 5.5 mg/kg/day, the time to MTD was 2.3 ± 2.7 years, and there was no significant difference between Duffy-null and Duffy-positive patients. The Duffy null phenotype was associated with a significantly lower baseline ANCs (Duffy-null: 3800 ± 2684 /mm 3 vs. Duffy-positive: 4702 ± 3015 /mm 3; p = 0.005; Figure A), and more frequent episodes of ANC &amp;lt;1500 /mm 3 in the first two years after starting HU (Duffy-null: 1.2 ± 2.3 times/patent vs. Duffy-positive: 0.5 ± 1.2 times/patient; p = 0.006; Figure B). Although the Duffy null phenotype did not have a direct effect on the time to MTD, it affected the time to MTD indirectly via baseline ANC (mediation indirect effect test p = 0.01) since the higher the baseline ANCs were, the longer it took to reach MTD (p = 0.0002). We did not find the Duffy null phenotype associated with Hgb, MCV and HbF at base line, one or two years after starting HU. In addition, there was no association of Duffy status on frequencies of vaso-occlusive crisis and acute chest syndrome within 2 years after HU initiation. Notably, MCV increased significantly after HU initiation (Baseline: 83.5 ± 7.6 fl; two-year post HU: 99.0 ± 12.0 fl; p &amp;lt;0.00001), the increases were similar between Duffy-null and Duffy-positive patients (p = 0.36), suggesting similar HU adherence. Conclusion Patients with SCD and the Duffy null phenotype have more frequent episodes of lower ANC with HU treatment. However, Duffy status was not associated with risks for other adverse clinical outcomes.

Outcomes of Antithymocyte Globulin and Cyclosporine for Severe Aplastic Anemia

Background: Aplastic anemia (AA) is mediated by T cell destruction of hematopoietic stem and progenitor cells causing pancytopenia and bone marrow hypoplasia. The current standard of care for severe aplastic anemia (SAA) is hematopoietic stem cell transplantation (HSCT) or immunosuppressive therapy (IST) with antithymocyte globulin (ATG) plus cyclosporine (CsA) with or without eltrombopag (Epag), a thrombopoietin receptor agonist. HSCT is preferred for SAA in young adults as a curative option, but only a small proportion of patients have histocompatible siblings and mortality increases with age. The IST plus CsA combination with or without Epag has led to survival rates comparable with those observed with HSCT recipients. However, complete hematologic remission is rare with IST and there is a considerable risk of clonal complications, including PNH evolution and progression to MDS. The aim of this study was to evaluate outcomes of ATG plus CsA therapy in a large cohort of SAA patients. Methods: We retrospectively analyzed medical records of 156 patients with SAA, aged ≥2 years treated with ATG plus CsA with or without Epag at our institution between July 2000 and January 2023. Hematologic responses were evaluated at 3-, 6- and 12-months post therapy initiation. Super response (SR) was defined as hemoglobin ≥12 g/dL, platelet count ≥150x10 9/L and absolute neutrophil count (ANC) ≥1.0x10 9/L; complete response (CR) was defined as hemoglobin ≥10 g/dL, platelet count ≥100x10 9/L and ANC ≥1.0x10 9/L. Partial response (PR) was defined as not meeting the criteria for CR and SAA. Overall response encompassed SR, CR, and PR. Statistical analyses were performed with the use of Chi-squared test and Kaplan Meier method. Results: The median age at diagnosis was 52 (IQR 30-66) years, 47% were male, and 86% were Caucasian. Twenty three percent of the cohort had coexisting paroxysmal nocturnal hemoglobinuria. Most patients were treated with ATG plus CsA (92%), the remaining 8% additionally received Epag. Overall response rates were 70%, 67%, and 77% at 3-, 6- and 12-months post-treatment initiation, respectively. CR was achieved in 10%, 15%, and 18% at 3-, 6- and 12-months, respectively. SR was achieved in 16.3% of patients at 12 months, as shown in Figure 1. Patients who achieved SR were young with median age at diagnosis of 28 years, while those who achieved PR or no response had a median age of 54 and 56 years, respectively. Patients who responded to the ATG + CsA therapy had significantly higher baseline ANC (p=0.04), absolute reticulocyte count (ARC) (p&amp;lt;0.001) and absolute lymphocyte count (ALC) (p&amp;lt;0.001). Pre-treatment median values of ANC, ARC and ALC were higher for patients who achieved SR compared to the rest of responders. With a median follow up time of 4.5 years, the estimated median relapse free survival was 9.2 years (95% CI, 3.2 - not reached [NR]) (Figure 2). Of the entire cohort, 21 (13%) patients progressed to acute myeloid leukemia or myelodysplastic syndrome. At data cut off, a total of 66 patients had died; the estimated median OS was 11.6 years (95% CI, 8.4 - NR). In particular, 30 patients died within the first 12-months, 13 within 3-months of ATG initiation from treatment-related complications, 6 from pneumonia and the rest from unknown causes. Conclusion: The findings of our study demonstrate that ATG plus CsA is an effective and safe treatment option for patients with SAA, especially in the older patient population where HSCT-related toxicities can lead to high mortality. Those with higher baseline ALC, ANC and ARC were more likely to respond to therapy compared to those with lower counts. A small percentage of patients progressed to myeloid neoplasia. Mortality within the first 12-months was high, indicating the need for close monitoring to avoid treatment-related mortality.

Clonal Hematopoiesis Is Associated with Severe Cytokine Release Syndrome in Patients Treated with Chimeric Antigen Receptor T-Cell (CAR-T) Therapy

Background: Among patients receiving CD19 or B-cell maturation antigen (BCMA) CAR-T therapy, inflammation pre- and post-CAR-T infusion is attributed in the development of toxicities such as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and prolonged cytopenias. Clonal hematopoiesis (CH), the clonal expansion of hematopoietic stem cells with somatic mutations, has been associated with inflammatory disorders such as rheumatoid arthritis and graft-versus-host disease, as well as clonal cytopenias of undetermined significance. In the setting of CAR-T, others have reported an association between CH and both ICANS and treatment-associated myeloid neoplasms. Herein, we examined the prevalence of pre-CAR-T CH in a predominantly transplant-naïve cohort of recipients with non-Hodgkin lymphoma (NHL) or multiple myeloma (MM), and assessed the relationship between CH and CAR-T related outcomes including CRS, ICANS, prolonged cytopenia, progression-free survival (PFS), and overall survival (OS). Methods: This study included 62 patients with NHL or MM who underwent CD19 or BCMA CAR-T therapy from 2017 to 2022 at City of Hope and had available pre-CAR-T cryopreserved peripheral blood mononuclear cells (PBMCs). DNA was isolated with QIAamp DNA Mini Kit (Qiagen) from PBMC samples (94% collected &amp;lt;30d of CAR-T infusion), on which we performed targeted exome sequencing (108 pre-defined gene panel with 1000x sequencing depth) to determine the presence of CH (variant allele frequency [VAF] ≥2%). Multivariable logistic regression was used to examine the association between CH (Yes/No) and absolute neutrophil count (ANC) recovery at day +60 (Y/N), maximum grade CRS and ICANS, grade &amp;lt;2 vs 2+, and OS and PFS at 1y. Covariables considered were age at CAR-T, baseline ANC, sex, race, CAR-HEMATOTOX (Rejeski et al. 2021), bridging therapy (Y/N), and number of prior lines of therapy. ANC recovery was defined as grade 2 or better for 3 measurements without growth factor support &amp;gt;2 weeks. Those without ANC recovery and who started new treatment before day +60 were excluded from that analysis. Results: Overall, the median age was 64y (range 21y-85y); 37 (60%) had de novo diffuse large B-cell lymphoma, 17 (27%) had transformed follicular lymphoma, 2 (3%) had MM, 2 (3%) had mantle cell lymphoma, and the remaining patients had other transformed indolent lymphomas. Median prior lines of therapy was 3 (1-12), and only 6% had previously undergone autologous hematopoietic cell transplantation. Systemic bridging therapy prior to CAR-T was required in 27 (44%), and 8 (13%) received radiation as bridging. All received fludarabine and cyclophosphamide for lymphodepleting chemotherapy. Axicabtagene ciloleucel was the most common (76%) CAR-T product, followed by tisagenlecleucel in 16% of patients. Overall, 51 (82%) and 29 (47%) patients experienced CRS and ICANS, respectively. had delayed ANC recovery. One-year PFS was 50% and 1y OS was 73%. Clonal hematopoiesis: 15 (24%) patients had at least one pathogenic CH mutation; 4 (6.5%) had ≥2 CH mutations. Of the 28 CH mutations identified, the most common were DNMT3A (18%), CHEK2 (11%), PMS2 (7%) and ASXL1 (7%); 29% of mutations had VAFs &amp;gt;10%. Outcomes after CAR-T: Patients with CH were significantly more likely to develop grade ≥2 CRS (60% vs. 28%, p=0.03) compared to those without CH (odds ratio [OR] 3.9, 95% CI 1.2-13.2; p=0.027). Accounting for baseline ANC (which was unexpectedly higher among the CH cohort and associated with delayed ANC recovery, p=0.02) patients with CH did not have a significantly different rate of delayed ANC recovery compared to those without CH (adjusted OR 0.37, 95% CI 0.09-1.5; p=0.17). There was no association between CH and ICANS, nor with 1y PFS and OS. Conclusion: CH was frequent (24%) in this cohort of CAR-T recipients and was associated with a higher risk of ≥2 CRS after CAR-T. Additional validation studies are currently underway, which may set the stage for consideration of pre-CAR-T CH as a biomarker for risk stratification towards more proactive CRS prophylaxis Acknowledgements: Funding through the CoH Hematological Malignancies Program Pilot Project Award. The authors acknowledge the work provided by CoH Center for Informatics, notably Research Informatics, and the utilization of the POSEIDON platform and the Honest Broker process.

When a Number Is Just a Number: Duffy-Null Blood Group Phenotype, Absolute Neutrophil Count, and Incidence of Neutropenic Fever and Chemotherapy Dose Reductions in Patients Treated for Plasma Cell Dyscrasias

Introduction: A single nucleotide polymorphism in the promoter region of the Duffy antigen/chemokine receptor (DARC) gene results in the red blood cell (RBC) Duffy-null phenotype, which is present in up to 80% of individuals of Sub-Saharan ancestry. Duffy-null phenotype is associated with lower peripheral absolute neutrophil counts (ANC) with preserved myeloid maturation and neutrophil function. The impact of Duffy-null phenotype on patients with hematologic malignancies is largely unknown; however, lower ANC (both at baseline and during treatment) may lead to the receipt of less intense treatment (with lower upfront dosing as well as more treatment interruptions/dose reductions). Lower ANC also pose challenges in enrollment in clinical trials due to ANC cutoffs for eligibility criteria. Herein, we evaluated the impact of Duffy phenotype status on the incidence of neutropenic fever and chemotherapy dose reductions in a cohort of patients treated for multiple myeloma (MM) or light chain (AL) amyloidosis at the largest safety net hospital in New England, USA. Methods: In this retrospective study, we identified patients treated for MM or AL amyloidosis at Boston University Medical Center (BMC) who underwent phenotyping for the RBC Duffy antigen. Patients were categorized as Duffy-null phenotype, i.e., Fy (a-b-) or non-Duffy-null phenotype including Duffy heterozygous, i.e., Fy (a-b+ or a+b-) or Duffy positive, i.e., Fy (a+b+). We collected data from medical charts including patient demographics; clinical characteristics (including malignancy and treatment regimens); incidence of neutropenia (defined as ANC &amp;lt;1,800/µL); incidence of neutropenic fever (excluding peri-stem cell transplantation [SCT] neutropenia); and chemotherapy dose adjustments. This research was approved by the BMC Institutional Review Board. Results: Between 06/2020 and 06/2023, 136 patients had a Duffy phenotype evaluation; mean age at the time of first chemotherapy was 65 (± 11.3) years and 62/136 (46%) were female. The most common self-identified race/ethnicity was non-Hispanic Black (74/136, 54%), followed by non-Hispanic White (34/136, 25%), Hispanic (18/136, 13%), and other (10/36, 7%), and other (10/136, 6%). Plasma cell dyscrasias included MM (94/136, 69%), AL amyloidosis (34/136, 25%) (Table 1). Duffy-null Fy (a-b-) phenotype was seen in 52/136 (38%) patients, while 84/136 (62%) were non-Duffy-null, including 73/136 (54%) with Duffy heterozygosity Fy (a-b+ or a+b-) and 11/136 (8%) with Duffy positivity Fy (a+ b+). Number of lines of treatment did not differ by Duffy status (Table 1): 35/136 (26%) received 2 lines of treatment; 56/136 (41%) received ≥ 3 lines; and 28/136 (21%) received high-dose chemotherapy and autologous SCT. Among those with known baseline ANC, we observed a higher frequency of neutropenia before receipt of any chemotherapy in patients with Duffy-null status (17/50, 34%) compared to those with non-Duffy-null status (8/79, 10%), p= 0.0009. Similarly, the incidence of treatment-related neutropenia (excluding the peri-SCT period) was higher in Duffy-null patients (44/52, 85%) compared to non-Duffy-null (39/82, 48%) patients, p&amp;lt;0.0001. Overall, the incidence of febrile neutropenia in our cohort was low; all 7 patients who experienced a febrile neutropenic event were non-Duffy-null (7/84, 8%). None of the patients in the Duffy-null cohort (0/52, 0%) had febrile neutropenia, despite higher incidences of both baseline and treatment-related neutropenia. Treatment interruptions/delays or dose reductions due to any cause were observed in 95/136 (70%) of all patients and did not differ by Duffy phenotype status (Table 1). The proportion of patients initiated on upfront reduced-dose pomalidomide or lenalidomide was 62/106 (59%) and also did not differ by Duffy phenotype status. Conclusion: In this retrospective study, we found that compared to patients with non-Duffy-null phenotype, patients with Duffy-null phenotype treated for plasma cell dyscrasias did not have a higher incidence of neutropenic fever, treatment interruptions or dose reductions, despite having higher frequencies of both baseline and treatment-related neutropenia. Prospective validation of our results could help to inform the creation and implementation of guidelines for the management of patients with lower ANC related to Duffy-null phenotype who undergo treatment for plasma cell dyscrasias.

BIOM-28. PROGNOSTIC BIOMARKERS IN GLIOBLASTOMA PATIENTS TREATED WITH TEMOZOLOMIDE

Abstract OBJECTIVE Identifying blood biomarkers that predict favorable outcomes for patients with glioblastoma treated with temozolomide (TMZ). BACKGROUND Glioblastoma is the most aggressive primary brain tumor. The standard of care is maximum safe resection, then radiation plus oral TMZ, followed by six months of cyclic oral TMZ. Previous studies have revealed that TMZ-induced myelosuppression is associated with improved overall survival. METHODS Adults with glioblastoma who completed radiation therapy and received temozolomide for at least 6-months at Beth Israel Deaconess Medical Center between 2018-2021 were identified. Baseline and nadir white blood cell count, absolute neutrophil count, absolute lymphocyte count, red blood cells, and platelets were collected retrospectively. Additionally, IDH1 R132H, MGMT promoter methylation, progression free survival (PFS), and overall survival (OS) were also collected retrospectively. Data was combined with that of Vaios et al. and Ho et al. Kaplan-Meier analysis and multivariate testing were performed. RESULTS Leukopenia is associated with increased overall survival (p = 0.008) and progression free status (p = 0.02). Grade 3 thrombocytopenia is associated with decreased PFS (p = 0.0005) and OS (p = 0.0006). Grade 1 &amp; 2 lymphopenia is associated with increased progression free survival (p = 0.01 and p = 0.03). Lower baseline absolute lymphocyte count is associated with improved OS (p = 0.007). Higher baseline absolute neutrophil count is associated with worse OS (p = 0.002). CONCLUSION Cytopenia may serve as a prognostic biomarker for OS and PFS. Leukopenia may reflect adequate temozolomide dosing, anti-tumor activity, or changes in the tumor micro-environment. Peripheral biomarker monitoring may improve prognostic stratification and lead to personalized treatment with improved outcomes.

Prevalence of Duffy Null Status and Its Impact on Hydroxyurea Dosing in Young Children with Sickle Cell Disease in the United States

Background: Sickle cell disease (SCD) affects approximately 100,000 Americans and causes many morbidities mediated by inflammation. Hydroxyurea (HU), the primary SCD therapy, demonstrates superior outcomes with dose-escalation. While HU induces fetal hemoglobin, it also reduces absolute neutrophil counts (ANC) and inflammation. However, ANC is used to determine if HU can be dose-escalated. Thus, a lower baseline ANC has potential to limit dose escalation and outcomes. The Duffy null phenotype, ubiquitous among West Africans, reduces ANC through neutrophil egress from the blood into tissues.While this does not increase infection risk, its prevalence and impact on ANC, HU dosing, and outcomes among children with SCD in the U.S. are unknown. Thus, the primary objective of this study was to determine prevalence of Duffy null among children with SCD (any genotype) receiving care and who had erythrocyte phenotyping performed at a large, Midwestern SCD center between 2010-2022. We also aimed to compare baseline ANC of children with SCD and Duffy null and to children with SCD and Duffy positive phenotypes at their one-year hematology visit (overall and by genotype severity). Finally, in those who initiated HU, we aimed to compare ANC, HU dosing, and the frequency of acute healthcare utilization for SCD complications between groups during the first year of HU use. Methods: This was a retrospective study of children with SCD. Subjects were identified using a list of those who had phenotyping performed at the center and confirmed to have SCD in their electronic health records. Individuals with Fy a-Fy b- were considered to be Duffy null. Data abstracted included demographics (e.g., age, race) and laboratory studies (e.g., hemoglobin (Hb), ANC). HU prescribing information and emergency department and/or admissions among those who used HU for ≥1year were also recorded. Descriptive statistics (median and interquartile range (IQR)) were used and Chi-squared, Fisher's exact, and Wilcoxon rank sum were used to compare categorical and continuous groups; p-value &amp;lt;0.05 was considered statistically significant. Results: Of 187 children with SCD who had phenotyping; 147 (78.6%) had Duffy null (Table 1) and were compared to Duffy positive children with SCD (Figure 1). A subset of 72 children with Duffy null and 22 with Duffy positive initiated HU;59 with Duffy null and 15 with Duffy positive remained on HU for ≥1 year. Median HU doses at initiation (p=0.72) and at one year (p=0.35) did not significantly differ between groups. Median ANC at HU initiation was 4.0 mm 3 (IQR 3.3.-5.9) in the Duffy null group and 5.0 mm 3 (IQR 3.2-6.8) in the Duffy positive group but this difference was not significantly different (p=0.21), nor was median ANC at one year between groups (2.0 mm 3, IQR 1.9-4.2 vs. 3.7 mm 3, IQR 2.8-4.9, p=0.07). Median number of acute visits did not differ between the Duffy null (0, IQR 0-1) and Duffy positive (0, IQR 0-1) groups (p=0.65). Discussion: We identified that Duffy null, while not ubiquitous, was present in more than three fourths of young children with SCD in the Midwest and was associated with having a lower ANC at one year of life. Given that HU dose-escalation improves outcomes, it was reassuring that those with Duffy null on HU did not have a significantly lower ANC and were not prescribed lower dose HU than Duffy positive children at either point. However, it is notable that these may be because few children in both groups had ANC low enough to preclude HU initiation or escalation based on dosing guidelines and because acute visits were infrequent. Limitations include the retrospective design, small number of those who initiated and remained on HU for ≥1 year, and short time interval that clinical and laboratory outcomes were compared. Also, it is possible that some did not have phenotyping completed, but standard practice at our center is to complete phenotyping on all with SCD. In conclusion, Duffy null is highly prevalent in young children with SCD in the U.S. While this does not appear to have an impact on HU dosing of young children with SCD early in their HU course, subsequent longitudinal studies of older children are needed to explore if Duffy null has an impact on longer-term HU dosing and outcomes.

Inflammatory Biomarkers and Outcomes in Multiple Myeloma Patients after CAR T-Cell Therapy

Introduction: CAR T-cell therapy is an effective tool for the treatment of multiple myeloma but produces a systemic inflammatory response which can manifest as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS) and other neurologic toxicities, and hyperferritinemia. Understanding the factors associated with these complications can help clinicians better evaluate their patients' candidacy for CAR T-cell therapy. In this study, we assessed whether baseline values of inflammatory biomarkers were associated with outcomes after CAR T-cell therapy. Methods: We retrospectively reviewed multiple myeloma patients who underwent CAR T-cell therapy with commercial products or on clinical trials at The Mount Sinai Hospital between 2017 and 2023. We gathered data on lab parameters that we felt were indicative of patients' baseline inflammatory status including C-reactive protein (CRP), ferritin, D-dimer, fibrinogen, absolute lymphocyte count (ALC), and absolute neutrophil count (ANC). Baseline data were collected prior to lymphodepletion. Outcomes of interest were occurrence and maximum grade of CRS and ICANS, occurrence of delayed neurotoxicity, attainment of peak ferritin ≥5000 within 30 days of infusion, progression-free survival (PFS), and overall survival (OS). Univariate logistic regression was used to assess the association between baseline labs and CRS, ICANS, delayed neurotoxicity, and peak ferritin ≥5000. Ordinal logistic regression was used to assess the baseline labs' association with maximum grade of CRS and ICANS, while proportional cox regression was used to assess their association with OS and PFS. The percentage of bone marrow plasma cells pre-CAR T, which we used as a surrogate for tumor burden, was included as a covariate on multivariable analyses. Results: A total of 101 patients treated with CAR T cells were included - 45 with ciltacabtagene autoleucel, 37 with idecabtagene vicleucel, and 19 with other products on clinical trials. Median age was 63 (range 37-82), median baseline marrow plasma cells percentage was 5% (range 0%-95%), and median follow-up was 11.9 months. Patients had a median (IQR) CRP of 4.0 mg/L (1.8, 11.8), ferritin of 174 ng/mL (68, 364), D-dimer of 0.6 mcg/L (0.4, 1.2), fibrinogen of 397.0 mg/dL (334.0, 477.5), ALC of 0.8 x10 3/µL (0.5, 1.1), and ANC of 2.7 x10 3/µL (1.9, 3.6). CRS occurred in 88.2% of patients (3.9% grade ≥3), ICANS in 15.7% (all grade &amp;lt;3), and delayed neurotoxicity in 5.9% (all grade &amp;lt;3). Increased baseline fibrinogen and ferritin were significantly associated with inferior OS even after adjusting for covariates (p-values 0.031 and 0.010, respectively). Every 143 mg/dL increase in fibrinogen increased the hazard of death by 83.7%, while every 500 ng/mL increase in ferritin increased the hazard of death by 27.5%. Patients with higher baseline CRP had a trend towards inferior OS (30.2% increased hazard of death per 20 mg/L CRP increase, p = 0.055). Baseline CRP, D-dimer, fibrinogen, ferritin, ALC, and ANC were not associated with PFS. Higher baseline ALC was associated with both increased odds of ICANS (110.2% increased odds of ICANS for every 0.5 x10 3/µL increase in ALC, p = 0.019 on multivariable analysis) and increased grade of ICANS (p = 0.023 on multivariable analysis). None of the assessed biomarkers were associated with peak ferritin ≥5000 (aside from baseline ferritin), occurrence of CRS, maximum grade of CRS, or delayed neurotoxicity. Conclusion: Although CAR T-cell therapy is a highly effective treatment option for patients with multiple myeloma, outcomes of infused patients can be highly variable. Serologic biomarkers like fibrinogen and ferritin are routinely assessed in patients undergoing CAR T-cell therapy and could offer value as predictors of outcomes. We found that higher fibrinogen and ferritin values at baseline were associated with inferior OS after CAR T-cell therapy, even after controlling for tumor burden. Higher baseline ALC was also associated with higher risk of ICANS and higher grade of ICANS, an important toxicity to consider for patients receiving CAR T. Baseline fibrinogen, ferritin, and ALC may be incorporated into assessments of the risk of CAR T-cell therapy for multiple myeloma patients.

Semimechanistic pharmacokinetic-pharmacodynamic model of tripegfilgrastim for pediatric patients after chemotherapy.

Tripegfilgrastim is a long-acting granulocyte colony-stimulating factor (G-CSF) that has been used to prevent chemotherapy-induced neutropenia in adults. This study aimed to establish a pharmacokinetic (PK)-pharmacodynamic (PD) model to explore the impact of chemotherapy and tripegfilgrastim on absolute neutrophil counts (ANCs) and to further propose a fixed-dose regimen in pediatric patients. Because neutrophils affect the clearance of tripegfilgrastim, the semimechanistic PK-PD model was developed simultaneously by using data from 40 healthy adults and 27 pediatric patients with solid tumors. Tripegfilgrastim PK and ANC dynamics were described with a pharmacodynamics-mediated drug disposition model assuming quasi-equilibrium with five transit compartments mimicking neutrophil granulopoiesis. The effect of chemotherapy on neutrophils was included by stimulating the elimination of the G-CSF receptor at the mitotic cells. Healthy adult and pediatric patients showed significantly different value for dissociation constant of the tripegfilgrastim-G-CSF receptor complex (Kd ) and apparent volume of distribution (Vd /F). Patients treated with chemotherapy had a higher Vd /F and 62% lower Kd than healthy adults. As the age increased, the absorption rate of tripegfilgrastim was decreased. Body weight affected the G-CSF receptor-mediated internalization of tripegfilgrastim, and the baseline ANC value impacted the production rate of G-CSF receptors. Simulations from the developed model suggested that 1.5, 2.5, 4, and 6 mg single subcutaneous tripegfilgrastim doses for the respective weight groups of 10-20, 21-30, 31-44, and more than 45 kg significantly reduced the duration of Grade 4 neutropenia similar to tripegfilgrastim weight-based treatment with 100 μg/kg.

How Asian Breast Cancer Patients Experience Unequal Incidence of Chemotherapy Side Effects: A Look at Ethnic Disparities in Febrile Neutropenia Rates.

The majority of published findings on chemotherapy-induced febrile neutropenia (FN) are restricted to three ethnic groups: Asians, Caucasians, and African Americans. In this two-part study, we examined FN incidence and risk factors in Chinese, Malay, and Indian chemotherapy-treated breast cancer (BC) patients. Hospital records or ICD codes were used to identify patients with FN. In both the Singapore Breast Cancer Cohort (SGBCC) and the Joint Breast Cancer Registry (JBCR), the time of the first FN from the start of chemotherapy was estimated using Cox regression. Multinomial regression was used to evaluate differences in various characteristics across ethnicities. FN was observed in 170 of 1014 patients in SGBCC. The Cox model showed that non-Chinese were at higher risk of developing FN (HRMalay [95% CI]:2.04 [1.44-2.88], p < 0.001; HRIndian:1.88 [1.11-3.18], p = 0.018). In JBCR, FN was observed in 965 of 7449 patients. Univariable Cox models identified ethnicity, a lower baseline absolute neutrophil count, non-luminal A proxy subtypes, and anthracycline-containing regimens as risk factors. Disparities across ethnicities' risk (HRMalay:1.29 [1.07-1.54], p = 0.006; HRIndian:1.50 [1.19-1.88], p < 0.001) remained significant even after further adjustments. Finally, an age-adjusted multinomial model showed that Malays (p = 0.006) and Indians (p = 0.009) were significantly more likely to develop multiple episodes of FN during treatment. Ethnic differences in chemotherapy-induced FN among BC patients exist. Further studies can focus on investigating pharmacogenetic differences across ethnicities.

Cytopenia after CAR‑T cell therapy: Analysis of 63patients with relapsed and refractory B‑cell non‑Hodgkin lymphoma.

The present study aimed to determine the clinical characteristics of cytopenia in patients with relapsed and refractory B-cell non-Hodgkin lymphoma (B-NHL) who were treated with chimeric antigen receptor T-cell (CAR-T) therapy. Thus, a total of 63 patients with relapsed and refractory B-NHL who underwent CAR-T therapy between March 2017 and October 2021 were retrospectively selected for analysis. Neutropenia, anemia and thrombocytopenia at grade ≥3 occurred in 48 (76.19%), 16 (25.39%) and 15 (23.80%) cases, respectively. The results of a multivariate analysis demonstrated that the baseline absolute neutrophil count (ANC) and hemoglobin concentration were independent risk factors for grade ≥3 cytopenia. A total of 3 patients died early and were therefore excluded from the present study. Furthermore, cell recovery was examined at day +28 after infusion; 21 patients (35%) did not recover from cytopenia and 39 patients (65%) recovered. A multivariate analysis demonstrated that the baseline ANC <2.29×109/l, baseline hemoglobin <114.50 g/l and baseline IL-6 >21.43 pg/l were independent risk factors affecting hemocyte recovery. In conclusion, patients with relapsed and refractory B-NHL exhibited an increased incidence of grade ≥3 hematologic toxicity following CAR-T cell therapy, while baseline blood cell and IL-6 levels are independent risk factors for hemocyte recovery.

Utility of the Brixia CXR score, C-Reactive Protein and Absolute Neutrophil Count in Predicting the Need for Invasive Mechanical Ventilation, Length of Hospital Stay, and Mortality in Moderate to Severe COVID-19 Patients

Background: The Brixia Chest X-ray (CXR) score, C-reactive protein (CRP), and the absolute neutrophil count (ANC) have been useful to predict outcomes in Coronavirus disease 2019 (COVID-19 patients). We studied the utility of the Brixia CXR score, CRP, and ANC in predicting the outcomes in terms of the need for invasive mechanical ventilation, length of stay, and mortality in moderatesevere COVID-19 patients. Materials and Methods: This was a single-centre, retrospective, study on 122 COVID -19 patients. Brixia CXR score, CRP, and ANC on admission to the hospital and the fifth day of hospital stay were noted along with the need for invasive mechanical ventilation (IMV), prolonged length of stay (LOS) ≥ 14 days, and mortality. Results: 122 patients were included for analysis. The median and interquartile range (IQR) for baseline CRP was 81.50 (39 -151) mg/L and 11.0 (4-30) mg/L (p &lt; 0.001) on the fifth day. The median and IQR for baseline Brixia score was 10.0 (7-13), and on the fifth day was 7 (4-11) (p &lt;0.001). The receiver operating characteristic curve (ROC) showed that the baseline CRP ≥ 52.5mg/L predicted both the need for IMV, with an area under the curve (AUC) of 0.628, and prolonged LOS with an AUC of 0.608. The ROC curve depicted that the baseline ANC &gt;8500/μL predicted IMV requirement with an AUC of 0.657. The fifth day CRP ≥ 32 mg/L, ANC ≥ 11,000/ μL and Brixia CXR score ≥ 7 predicted a higher mortality in hospitalized patients. Conclusion: Baseline CRP (&gt; 52.5mg/L) predicts the need for IMV and a prolonged LOS, but not mortality. Baseline ANC (&gt; 8500/μL) predicted the need for IMV. CRP, Brixia CXR score, and ANC on the fifth day were not useful to predict LOS or mortality, though there was a significant reduction in CRP and Brixia CXR score on the fifth day compared to baseline after treatment. The fifth day CRP ≥ 32 mg/L, ANC ≥ 11,000/ μL and Brixia CXR score ≥ 7 predicted a higher mortality.

Model-based approach to identify predictors of paclitaxel-induced myelosuppression in "real-world" administration.

Taxanes are currently the most frequently used chemotherapeutic agents in cancer care, where real-world use has focused on minimizing adverse events and standardizing the delivery. Myelosuppression is a well-characterized, adverse pharmacodynamic effect of taxanes. Electronic health records (EHRs) comprise data collected during routine clinical care that include patients with heterogeneous demographic, clinical, and treatment characteristics. Application of pharmacokinetic/pharmacodynamic (PK/PD) modeling to EHR data promises new insights on the real-world use of taxanes and strategies to improve therapeutic outcomes especially for populations who are typically excluded from clinical trials, including the elderly. This investigation: (i) leveraged previously published PK/PD models developed with clinical trial data and addressed challenges to fit EHR data, and (ii) evaluated predictors of paclitaxel-induced myelosuppression. Relevant EHR data were collected from patients treated with paclitaxel-containing chemotherapy at Inova Schar Cancer Institute between 2015 and 2019 (n = 405). Published PK models were used to simulate mean individual exposures of paclitaxel and carboplatin, which were linearly linked to absolute neutrophil count (ANC) using a published semiphysiologic myelosuppression model. Elderly patients (≥70 years) constituted 21.2% of the dataset and 2274 ANC measurements were included in the analysis. The PD parameters were estimated and matched previously reported values. The baseline ANC and chemotherapy regimen were significant predictors of paclitaxel-induced myelosuppression. The nadir ANC and use of supportive treatments, such as growth factors and antimicrobials, were consistent across age quantiles suggesting age had no effect on paclitaxel-induced myelosuppression. In conclusion, EHR data could complement clinical trial data in answering key therapeutic questions.

Abstract CT242: A phase I study of ruxolitinib in combination with abemaciclib for patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis

Abstract Introduction: Patients (pts) with primary and secondary myelofibrosis (MF) have a reduced life expectancy. While several oral Janus Kinase (JAK)-1/2 inhibitors such as ruxolitinib (RUX) have demonstrated improvements in symptom burden and spleen volume reduction compared to physician choice of best available therapy leading to their approval by the US FDA, responses to these agents are generally time-limited. Additionally, these agents are not considered to be disease-modifying and survival in pts after RUX discontinuation is poor with a median survival of 11-14 months. Thus, novel mechanism-based therapies for pts with suboptimal response or progression on RUX are needed. Preclinical Rationale: JAK2 V617F mutations promote transition from G1 to S-phase of the cell cycle via increased expression of CDC25A in preclinical models and CDC25A expression is upregulated in primary MPN patient samples. Additional cell cycle regulators such as CDK6 and Cyclin D also play a role in MF pathogenesis and drive myeloproliferation. Finally, combination of the CDK4/6 inhibitor ribociclib and RUX demonstrated reduction in spleen and liver size when compared to RUX alone in murine models, suggesting synergy (Rampal et al., CCR 2021). Methods: This multicenter, phase I dose-escalation trial evaluates the safety of RUX + the CDK4/6 inhibitor abemaciclib in pts with primary or secondary MF with intermediate-1/2 or high-risk disease by DIPSS who require treatment and had an inadequate response to RUX. An inadequate response will be defined by (I) palpable splenomegaly ≥5 cm below the left costal margin at study entry AND/OR (II) active MPN symptoms [presence of 1 symptom score ≥5 or 2 symptom scores ≥3 using the screening MPN-SAF TSS. This study follows a conventional “3+3” dose-escalation design, in which pts on a stable dose of RUX (10mg or 15mg BID) with sufficient baseline platelet and absolute neutrophil count will be treated with increasing doses of abemaciclib. Abemaciclib was chosen due to less myelosuppression compared with other CDK4/6 inhibitors. The pre-study dose of ruxolitinib will be maintained to determine the maximum tolerated dose of the combination of RUX+ abemaciclib. The primary endpoint is to determine the safety and tolerability, and to identify the recommended phase II dose of abemaciclib in MF pts on a stable dose of RUX. Secondary endpoints include overall response rate, progression-free and overall survival, and duration of response per the modified International Working Group - Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and the European Leukemia Net (ELN) 2013 consensus definitions. Correlative studies are planned to identify biomarkers predictive of response to RUX + abemaciclib, mechanisms of resistance (e.g., MAP kinase pathway activation), and any disease-modifying effects of combination therapy. Citation Format: Jan P. Bewersdorf, Srdan Verstovsek, Andriy Derkach, Lucia Masarova, Naveen Pemmaraju, Eytan M. Stein, Michael Mauro, Raajit Rampal, Prithviraj Bose. A phase I study of ruxolitinib in combination with abemaciclib for patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT242.

The predictive value of hematological markers in renal cell carcinoma.

621 Background: Renal cell carcinoma (RCC), which accounts for about 3% of adult malignancies, is regarded as a major cause of morbidity and mortality. The neutrophil-lymphocyte ratio (NLR) is a simple, reliable, and cost-effective biomarker of systemic inflammation that has been linked to oncologic outcomes in a variety of malignancies. The objective of this study is to determine whether NLR, along with other hematological parameters such as absolute neutrophil count (ANC), absolute lymphocyte count (ALC), absolute eosinophil count (AEC), absolute monocyte count (AMC), monocyte-lymphocyte ratio (MLR), platelet-lymphocyte ratio (PLR), and the Systemic Immune-Inflammation Index (SII; defined as neutrophils counts X platelets counts divided by lymphocyte count), are related to baseline distant metastases and overall survival (OS) in RCC patients. Methods: Clinical data from 203 RCC patients treated at King Hussein Cancer Center (Amman, Jordan) were retrospectively reviewed. We examined the relationship between age, sex, ANC, AMC, ALC, AEC, NLR, MLR, PLR, and SII with baseline distant metastasis and patients’ OS. Results: Of the 203 patients, 97 patients (48.5%) were stage 4 at the time of diagnosis. Univariate analysis showed that patients with high baseline ANC (&gt;5400), AMC (&gt;600), AEC (&gt;120), NLR (&gt;4.36), MLR (&gt;0.33), PLR (&gt;140.44), WBC count (&gt;8.2), SII (&gt;757.7) and low baseline ALC (≤1900) had more baseline metastasis. (p-value: &lt;0.001, 0.007, 0.020, &lt;0.001, &lt;0.001, &lt;0.001, 0.006, &lt;0.001, and 0.004, respectively). On multivariate analysis, patients who had elevated NLR (&gt;4.36) were more likely to have distant metastasis at the time of diagnosis (p-value = 0.0076, odds ratio (OR): 4.45, CI: 1.49–13.33). Moreover, univariate and multivariate analysis showed that patients with elevated NLR (&gt;4.36) were associated with poorer OS (p-value: &lt;0.0001 and 0.0065, respectively). In addition, patients with elevated baseline ANC, AMC, MLR, PLR, SII, WBC count, and low ALC values were associated with poorer OS (p-value: &lt;0.0001, 0.0234, &lt;0.0001, &lt;0.0001, &lt;0.0001, 0.0290, and &lt;0.0001, respectively). Conclusions: The results of this study indicate a substantial correlation between several hematological parameters, including NLR, with the presence of distant metastases at the time of diagnosis and OS. Further research is required to uncover whether these hematological markers may be used to identify patients who are more likely to develop metastases and predict treatment response.

Comparison of ATG-Based Immunosuppressive Treatment and Allogeneic Hematopoietic Stem Cell Transplantation for Patients with Transfusion-Dependent Non-Severe Aplastic Anemia: A Single Center, Retrospective Analysis

Transfusion-dependent non-severe aplastic anemia (TD-NSAA) refers to aplastic anemia (AA) that is dependent on blood transfusion but does not fulfilling the criteria for severe AA (SAA). It has been clear that allogeneic hematopoietic stem cell transplantation (HSCT) and anti-thymocyte globulin (ATG)-based immunosuppressive therapy (IST) is the front line for the treatment of SAA, but there is no consensus on the treatment timing and strategy for TD-NSAA. The natural history observation reported that the progress-free survival (PFS) of TD-NSAA at 60 months after diagnosis is around 62%, but decreased significantly to 22% at 120 months. In China, the practical guideline recommends cyclosporine-based IST with or without hematopoietic stimulating regimes (such as androgens) as initial treatment, and further treated as SAA if no response was observed after 6 months management. As reported, the hematopoietic response of ATG-based IST was much better than CsA-based IST (75% Vs. 55.8%, 6-month) for TD-NSAA, however, the relapse and clonal expansion are still the unavoidable events. For HSCT, the long-term PFS is much better than IST for SAA, but the complications (including graft versus host disease, various infection, etc.), transplantation related mortality, as well as donor availability still limited its application. At present, there is limited data compared the efficiency of HSCT and IST for TD-NSAA. With the development of haplo-identical transplantation in China, most TD-NSAA own a donor, and we also performed HSCT for those young patients after informed consent. Herein, we respectively compared the efficiency of ATG-based IST and HSCT for TD-NSAA, and also analyzed the risk factors that contribute to the overall survival (OS) as well as event free survival (EFS). During Jul 2011 to Dec 2019, 97 TD-NSAA patients were diagnosed in our cohort, among them, 5 only received supportive treatment, 30 received CsA-based IST with or without androgen, and the other 62 patients received HSCT or ATG-based IST therapy. We further analyzed the efficiency and prognosis of 55 patients aged 16-60 years old who received HSCT or ATG-based IST therapy. Among them, 27 (49.09%) patients received ATG-based IST, and the others performed HSCT (including 14 from sibling donor, 7 from haplo-identical donor and 7 from unrelated donor) (the baseline information showed in Table1). Results showed that the 12-month overall response rate (ORR) of ATG-based IST and HSCT were 48.1% (with 18.52% CR) and 78.57% (with 60.71% CR), respectively (P=0.04, Fig A). The median time of achieving transfusion-free was 94(35-205) and 24(11-139) days, respectively in ATG-based IST and HSCT group (P<0.001, Fig B). The 5-year OS and EFS rates were 54.9±13.3% and 34.5±12.1% in ATG-based IST group respectively, and 70.0±9.0% and 62.6±9.6% in HSCT group, while no statistically differences was observed (Fig C and D). To explore the possible influencing factors of 5-year OS and EFS, we performed COX regression analysis based on age, disease duration, baseline absolute neutrophil count (ANC), hemoglobin (HB), platelet count (PLT), serum ferritin (SF), lymphocyte percentage, and CD4/CD8 ratio. Univariate analysis showed that disease duration, baseline HB, SF, and ANC may affect OS and EFS of patients in ATG-based IST group (Table 2), and multivariate analysis showed that SF≧1000ng/ml was an independent risk factor for OS in ATG-based IST group. While in the HSCT group, patients with disease duration≧20 months had a higher risk of events (Table 3). The subgroup analysis showed that in HSCT group, patients with disease duration of 6 to 20 months had a lower risk of events (HR=0.196, 95%CI: 0.046-0.832); the HR of the group <6 months and ≥20 months were not statistically significant (Fig E). TD-NSAA patients with disease duration between 6 months and 20 months had a higher EFS rate in HSCT group than that in ATG-based IST group (Fig F). The subgroup analysis of mortality was not statistically significant (Fig G). To conclusion, TD-NSAA patients should be actively treated, patients with shorter disease duration and no iron overload may achieve a better response. The 12-month ORR in the HSCT group was higher than that in the IST group, but there was no significant difference in OS rate and EFS rate, even there is a great difference tendency. For TD-NSAA patients with a disease duration between 6 to 20 months, HSCT has a higher EFS rate than IST, which may be a better choice. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal