Low Absolute Neutrophil Count Research Articles

Clinical Risk Factors for High-Dose Methotrexate-Induced Oral Mucositis Following Individualized Dosing.

Oral mucositis affects about 20% of children undergoing high-dose methotrexate (HDMTX) for acute lymphoblastic leukemia (ALL), despite existing management strategies. Personalized HDMTX dosing, adjusted by pharmacokinetics and leukemia risk, has reduced mucositis incidence, but variations still occur with similar 24-h methotrexate levels. This retrospective study investigated risk factors for oral mucositis under individualized methotrexate protocols. Data from patients with ≥ Grade 2 oral mucositis (CTCAE v4.0) were analyzed from the St. Jude Children's Research Hospital total 16 trial. A 1:1 case-control matching method considered age, sex, risk classification, immunophenotype, and methotrexate course. McNemar's, Bowker's symmetry, and Wilcoxon signed-rank tests were used for statistical analyses. Risk factors for recurrent mucositis were identified in a case-only analysis. The study found significant associations between methotrexate-induced mucositis and new-onset skin rashes (p = 0.0027), fever (p = 0.0016), neutropenic fever (p = 0.0008), lower absolute neutrophil count (p < 0.0001), acute kidney injury (AKI) (p = 0.0164), delayed methotrexate clearance (p = 0.0133), and higher 42-h methotrexate levels (p = 0.0179). In the standard/high-risk group, mercaptopurine dose was also linked to mucositis (p = 0.0495). Multivariable analysis showed that skin rashes (OR 6.5, p = 0.0016), fever (OR 2.8, p = 0.009), and neutropenia (OR 2.3, p = 0.0106) were independent risk factors for mucositis. Female sex (OR 7.12, p = 0.015) and AKI (OR 3.819, p = 0.037) were associated with recurrent mucositis. Fever, skin rashes, AKI, delayed methotrexate clearance, and higher 42-h methotrexate levels were key risk factors for HDMTX-induced oral mucositis. Skin rashes, fever, and neutropenia were independent predictors, while female sex and AKI were linked to recurrent mucositis.

Prophylactic Antimicrobials for Prevention of Febrile Neutropenia in Tumour-Bearing Dogs Treated With Lomustine.

CCNU (1-[2-chloroethyl]-3-cyclohexyl-1-nitrosurea), lomustine, is an oral alkylating agent in the nitrosourea subgroup. The dose-limiting toxicity of CCNU is neutropenia most frequently documented 7 days after its administration. Use of prophylactic antimicrobials to prevent chemotherapy-related febrile neutropenia (FN) and its associated morbidity and mortality has been well-documented in human oncology, but this information is limited in the veterinary literature. The purpose of this multi-institutional retrospective study was to assess whether antimicrobial prophylaxis reduced the risk of FN approximately 7 days after CCNU administration in tumour-bearing dogs. A secondary goal was to identify risk factors for fever development in neutropenic dogs. Two hundred dogs were included in the study. One hundred and fifty-three dogs (76.5%) were neutropenic at the first post-CCNU recheck. One hundred and six (69.3%) dogs received prophylactic antimicrobials and 47 (30.7%) did not. Of the 106 dogs on prophylactic antimicrobials, 8 (7.5%) developed FN. Of the 47 dogs in the no-prophylactic antimicrobials group, 4 (8.5%) developed FN. Use of prophylactic antimicrobials did not reduce the risk of development of FN (p = 0.84). Older age (> 9 y), lower weight and body surface area, and pre-treatment with chemotherapy or radiation therapy were significantly associated with development of FN (p = 0.009, p = 0.023, p = 0.015 and p = 0.01). Patients with a lower absolute neutrophil count, and a higher VCOG-CTCAE v2 neutropenia grade were also at an increased risk of developing FN (p = 0.01, p < 0.001). Additional studies may help establish guidelines for antimicrobial prophylaxis in dogs treated with CCNU, especially for those at high-risk for FN.

Low leucocyte, neutrophil and lymphocyte count (tri-low phenotype) in melioidosis: A predictor of early mortality

IntroductionMelioidosis is a bacterial disease caused by Burkholderia pseudomallei, a gram-negative bacillus endemic to parts of Asia and Northern Australia. This study aimed to identify the role of total and differential leucocyte count in predicting 48-h mortality in patients with melioidosis. MethodologyThis retrospective cohort study included patients diagnosed with culture-proven melioidosis at Kasturba Medical College between 2017 and 2023. Total leucocyte count (TLC), absolute neutrophil count (ANC), and absolute lymphocytic count (ALC) were classified into low (first quartile), medium (second and third quartile) and high (last quartile). The chi-square test was used to compare each group's early (48-h) mortality. ResultsOf the 170 patients with culture-confirmed melioidosis, 24 patients died within 48 h. The mortality was significantly higher in those with low TLC, ANC and ALC. When all three parameters were found to be low (tri-low phenotype), the specificity in predicting mortality was 93.2 %. ConclusionLow TLC, ANC and ALC are significant predictors of mortality among melioidosis patients. There is a need to explore new strategies to improve clinical outcomes among melioidosis patients with tri-low phenotype.

Abstract C019: Peripheral Absolute Lymphocyte Count and Breast Cancer Mortality among Racially Diverse Women

Abstract Background: Among patients with triple-negative breast cancer (TNBC), higher tumor infiltrating lymphocytes (TILs) are associated with increased overall mortality (OM) and breast cancer-specific mortality (BCSM). We previously found that low peripheral absolute lymphocyte count (ALC) is associated with increased OM and BCSM in a sample of mostly non-Hispanic White (NHW) patients with TNBC. Here, we investigated the association between low ALC and mortality (OM and BCSM) across different breast cancer subtypes and whether the association is potentially modified by race and ethnicity. Methods: We used the Oncoshare database, which links electronic medical records (EMRs) data to the California Cancer Registry (CCR), and assessed women diagnosed with stage I-III breast cancer between 2000-2017, who had at least one ALC measurement and treated at two healthcare systems in California. Patient and tumor characteristics were obtained from the CCR and laboratory testing from EMRs. Patients with metastatic disease and chemotherapy receipt after one year of diagnosis were excluded. Multivariable logistic models assessed factors associated with “low ALC” (&amp;lt;1 K/µL, ever vs. never). We applied Cox models to evaluate the association between “min ALC” (lowest ALC value after diagnosis) and OM and BCSM within each breast cancer subtype (Luminal A, HER2-enriched, and TNBC), and further explored the interaction between min ALC and race and ethnicity. All models adjusted for low absolute neutrophil count, demographics, and tumor features. Results: Among 10,750 women analyzed, the risk of “low ALC” was associated with TNBC vs Luminal A (odds ratio (OR) 1.22, p=0.0098), older age (OR 1.01 per year, p&amp;lt;0.001), higher grade (grade 3 vs. 1, OR 1.15, p=0.042), higher stage (stage III vs. I, OR 1.81, p&amp;lt;0.001), and public vs. private health insurance (OR 1.29, p&amp;lt;0.001). Cox models showed that higher min ALC was associated with lower OM across breast cancer subtypes (Luminal A: HR 0.37, HER2-enriched: HR 0.32, TNBC: HR 0.22; all p&amp;lt;0.001) and BCSM (Luminal A: HR 0.29, HER2-enriched: HR 0.23, TNBC: HR 0.19; all p&amp;lt;0.001). Interaction analysis showed that race and ethnicity modified the association between min ALC and OM (interaction-p &amp;lt;0.001) and BCSM (interaction-p &amp;lt; 0.001) in the overall cohort; compared to NHW women (HR 0.38, 95% confidence interval [0.34-0.43]), the association between min ALC and OM was stronger among Hispanic (HR 0.24, [0.18-0.33]), Asian (HR 0.19, [0.14-0.25]), and Black (HR 0.21, [0.13-0.35]) women. Similar results were observed for BCSM. Conclusions: Low peripheral ALC, a routinely measured clinical lab result, strongly predicts higher BCSM and OM across breast cancer subtypes, beyond TNBC. The association between min ALC and BCSM/OM was stronger among Black and Asian women vs. NHW women, suggesting that maintaining normal ALC during breast cancer treatment may reduce BCSM and OM, especially for women from racial and ethnic minoritized groups. Future research should investigate differences in ALC, immune response, and BCSM in diverse populations. Citation Format: Candice N. Thompson, Ingrid Luo, Mina Satoyoshi, Lidia Schapira, Esther M. John, Summer S. Han, Allison W. Kurian. Peripheral Absolute Lymphocyte Count and Breast Cancer Mortality among Racially Diverse Women [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C019.

Cancer Trial Eligibility and Therapy Modifications for Individuals With Duffy Null–Associated Neutrophil Count

Absolute neutrophil counts (ANCs) are used to determine cancer clinical trial (CCT) eligibility and systemic anticancer therapy (SACT) dose modifications. Duffy null-associated ANC (DANC) is a nonpathologic phenotype associated with lower ANC and most frequently seen in individuals with African and Middle Eastern ancestry. It is unclear whether CCTs exclude or SACT regimens modify doses for individuals with ANC within the DANC reference range. To investigate CCT exclusions and SACT dose modifications for ANC within the DANC reference range. This cross-sectional study of contemporary CCTs and SACT regimens included adult, interventional, phase 3 CCTs for the 5 most prevalent cancers in the US and United Kingdom (prostate, breast, melanoma, colorectal, and lung cancers) testing SACTs with start dates between November 1, 2021, and November 1, 2023, and that were registered on ClinicalTrials.gov. Preferred curative-intent SACT regimens were listed in National Comprehensive Cancer Network guidelines. Cancer clinical trial exclusions and SACT regimen modifications. Proportions of CCTs that exclude and SACT regimens that modify doses for individuals with an ANC within the DANC reference range. For CCTs, 289 of 382 trials (75.7%) were eligible, of which 221 (76.5% [95% CI, 71.1%-81.2%]) excluded patients with ANC values within the DANC reference range. Colorectal CCTs had the highest (38 of 44 [86.4% (95% CI, 72.6%-94.8%)]) and prostate CCTs had the lowest (11 of 23 [47.8% (95% CI, 26.8%-69.4%)]) proportions of exclusions. Of CCTs testing cytotoxic chemotherapy, 116 of 142 (81.7% [95% CI, 74.3%-87.7%]) had exclusions; 93 of 123 (75.6% [95% CI, 67.0%-82.9%]) CCTs testing targeted therapies alone and 12 of 24 (50.0% [95% CI, 29.1%-70.9%]) testing hormonal therapies alone had exclusions. Among the 113 US- and UK-based trials, exclusions were present in 89 (78.8% [95% CI, 70.1%-85.9%]). Of 71 SACT regimens, 38 (53.5% [95% CI, 41.3%-65.5%]) included dose modifications for ANC values within the DANC reference range. Lung cancer regimens had the highest (23 of 31 [74.2% (95% CI, 55.4%-88.1%)]) and prostate cancer had the lowest (0 of 12 [0 (95% CI, 0%-26.4%)]) proportions of modifications. Regimens including chemotherapy had modifications in 32 of 44 (72.7% [95% CI, 57.2%-85.0%]); 11 of 20 (55.0% [95% CI, 31.5%-76.9%]) of targeted therapy regimens and 0 of 16 (0% [95% CI, 0%-20.6%]) of hormonal therapy regimens had modifications. Among regimens including chemotherapy and/or targeted therapy, modifications were present in 38 of 55 (69.1% [95% CI, 49.7%-73.2%]). In this cross-sectional study, substantial proportions of CCTs excluded and SACT regimens modified doses for patients with ANCs in the DANC reference range. These practices structurally discriminate against patients of African and Middle Eastern ancestry. While determining optimal SACT dose modifications requires further study, CCT exclusion criteria should be revised.

Autopsy findings from patients diagnosed with COVID-19 demonstrate unique morphological patterns in bone marrow and lymph node

AimsThe identification of haemophagocytosis in bone marrow (BM) is recurrently identified in patients with severe COVID-19. These initial COVID-19 autopsy studies have afforded valuable insight into the pathophysiology of this...

A retrospective study on the analysis of influencing factors of neutropenia in endometrial cancer with adjuvant chemoradiotherapy

ObjectiveThis retrospective study aimed to investigate the factors influencing the occurrence of neutropenia in patients with endometrial cancer (EC) following adjuvant chemoradiotherapy (CRT).MethodsRetrospective analysis of EC patients who underwent adjuvant CRT from January 2012 to June 2023 in the Department of Gynecology and Oncology of the First Affiliated Hospital of Shandong First Medical University. Neutropenia was defined as an Absolute Neutrophil Count (ANC) of peripheral blood neutrophils below 2 × 109/L. Factors affecting neutropenia in EC patients treated with CRT using Generalized Estimating Equation (GEE), and Logistic regression was used to further analyze the effect of adding radiotherapy to different chemotherapy cycles on neutropenia, so that patients receive optimal adjuvant CRT while the risk of neutropenia is appropriately controlled.ResultsA total of 144 patients met the inclusion criteria. They underwent 330 cycles of adjuvant chemotherapy, of whom 96 (66.7%) developed neutropenia, which occurred 140 times. The results of one-way GEE analysis showed that before CRT, White Blood Cell (WBC) (OR = 0.827; 95%CI, 0.701–0.976), ANC (OR = 0.749; 95%CI, 0.586–0.957), Absolute Monocyte Count (AMC) (OR = 0.047; 95%CI, 0.008–0.283), Blood Urea Nitrogen (BUN) (OR = 0.857; 95%CI, 0.741–0.991), platinum and docetaxel (platinum/docetaxel) dosing regimen (OR = 2.284; 95%CI, 1.130–4.618) were associated with neutropenia with adjuvant CRT for EC (p < 0.05), results of multifactorial GEE analysis showed that before adjuvant CRT ANC (OR = 0.552; 95%CI, 0.973–2.231), AMC (OR = 0.047; 95%CI, 0.004–0.052), platinum/docetaxel (OR = 2.437; 95%CI, 1.087–5.464) were an independent influence on neutropenia in adjuvant CRT for EC (p < 0.05). Multifactorial Logistic regression shows addition of radiotherapy to the first cycle of chemotherapy (OR = 4.413; 95%CI, 1.238–18.891) was an independent influence of neutropenia (p < 0.05).ConclusionsPatients with low pre-CRT ANC and AMC, platinum/docetaxel dosing regimens need to be closely monitored during each cycle of CRT. Also, the concurrent addition of radiotherapy should be avoided during the first cycle of chemotherapy.

Significance of absolute neutrophil count before allogeneic hematopoietic stem cell transplantation in adult patients with aplastic anemia.

The impact of absolute neutrophil count (ANC) before allogenic hematopoietic stem cell transplantation (HSCT) on the outcomes for patients with aplastic anemia (AA) remains unclear. We retrospectively evaluated the relationship between ANC before transplantation and patient outcomes, involving 883 adult Japanese patients with AA who underwent allogeneic HSCT as their first transplantation between 2008 and 2020. Patients were divided into three groups based on ANC: 0/µL (n = 116); 1-199 (n = 210); and ≥ 200 (n = 557). In the low ANC groups (ANC < 200), patient age was higher, previous anti-thymocyte globulin (ATG) treatments were infrequent, duration from diagnosis to transplantation was shorter, hematopoietic cell transplantation-comorbidity index (HCT-CI) was higher, ATG-based conditioning was used infrequently, and peripheral blood stem cell from related donor and cord blood were used frequently. In multivariate analysis, patient age, previous ATG treatment, HCT-CI, stem cell source, and ANC before transplantation were significantly associated with 5-year overall survival (OS) ("ANC ≥ 200": 80.3% vs. "ANC 1-199": 71.7% vs. "ANC 0": 64.4%). The cumulative incidence of bacterial infection, invasive fungal disease, and early death before engraftment were significantly higher in the low ANC groups. Among patients with ANC of zero before transplantation, younger patient age, shorter duration from diagnosis to transplantation, HCT-CI of 0, and bone marrow from related donor as stem cell source were significantly associated with better OS. Consequently, ANC before allogeneic HSCT was found to be a significant prognostic factor in adult patients with AA. Physicians should pay attention to ANC before transplantation.

Neutropenia Occurs More Often Under Carbimazole than Under Methimazole Treatment in Pediatric Graves' Disease Patients.

Background: Agranulocytosis is a rare antithyroid drug treatment (ATD) side effect seen in children suffering from Graves' disease (GD). Neutropenia is a recognized adverse event associated with ATD but has also been reported as pre-treatment neutropenia in GD. Methods: We performed a retrospective cohort study to analyze the longitudinal clinical and biochemical data of 161 pediatric patients with GD who received either methimazole (MMI) or carbimazole (CBZ) as ATD. The inclusion criteria were elevated free thyroxine (fT4 >25 pmol/L), suppressed thyrotropin (TSH <0.05 mlU/mL), and elevated thyrotropin receptor antibodies (TSHRAbs >2.5 IU/L). Absolute neutrophil count (ANC) was used to define neutropenia (ANC <1800/µL) and agranulocytosis (ANC <500/µL). Results: Nine of the 161 patients had neutropenia at diagnosis (ANC: 1348/µL ± 250) without further deterioration under ATD. In this subgroup, we found higher levels of free triiodothyronine (fT3: 31.45 pmol/L ± 3.99) at diagnosis in comparison with those who developed neutropenia (26.29 pmol/L ± 12.96; p = 0.07) and those without neutropenia before and during therapy (23.12 pmol/L ± 13.7; p = 0.003). Thirty-eight patients (23.6%) became neutropenic (ANC: 1479/µL ± 262) while receiving ATD. Neutropenia occurred after a mean of 551.8 (range: 10-1376) days, mostly without further deterioration. Two of these 38 patients developed agranulocytosis and underwent emergency thyroidectomy. The patients with neutropenia were significantly younger (p = 0.031). Neutropenia occurred significantly more often in patients receiving CBZ (50%; n = 20/40) than in those receiving MMI (16.5%; n = 18/110; p = 0.001). The minimum ANC was significantly lower in the CBZ (1971/µL ± 1008) than in the MMI group (2546 ± 959); p = 0.004. Conclusions: Neutropenia occurred significantly more often under CBZ than MMI. As this is potentially due to higher immunogenicity, we suggest that children with GD should be treated with MMI. Frequent measurements of ANC may be needed to detect severe agranulocytosis, although low pre-treatment ANC may not necessarily be a contraindication to ATD treatment. Young age may be potentially associated with an increased risk of reduced ANC. Further investigation is necessary to fully understand risk factors for neutropenia in children with GD.

Abstract PO1-12-06: Is it appropriate to select patients for primary prophylactic use of pegfilgrastim based on the risk of febrile neutropenia?

Abstract Background: Febrile neutropenia (FN), a major hematologic adverse event in perioperative chemotherapy for breast cancer, is more prevalent among Asians than in Caucasian populations. Four main guidelines, i.e., ASCO, EORTC, NCCN, and ESMO, provide recommendations regarding the appropriate use of hematopoietic growth factors. These guidelines recommend primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) based on the estimated incidence of FN, primarily defined by the chemotherapy regimen. G-CSF administration is recommended when the incidence of FN is ≥20% or 10–20% with risk(s). However, the incidence of FN varies depending on the trial and design, and patient-specific risk factors for FN remain unclear. We previously performed a multicenter prospective cohort study in Japan, the CSPOR-BC FN study, evaluating the incidence of FN during perioperative chemotherapy for breast cancer. Herein, we conducted an additional analysis to explore thresholds of patient-specific risk factors for FN that could be evaluated before chemotherapy. We analyzed the risk factors for FN and verified the appropriateness of patient selection for prophylactic G-CSF administration. Methods: The previously reported CSPOR-BC FN study (PubMed ID=33631458) consecutively enrolled 1005 patients with stage I–III breast cancer between August 2015 and July 2017. In the current additional analysis, we intended to have 477 patients in the visiting group that evaluated true-FN, defined as ≥37.5℃ and grade 4 neutropenia. Multivariate analysis of risk factors for FN was performed, followed by the determination of cutoff values for age and pretreatment absolute neutrophil count (ANC) as risk factors. Results: Chemotherapy regimens administered were FEC (fluorouracil, epirubicin, and cyclophosphamide) in 170 patients (36%), E(A)C (epirubicin (doxorubicin) + cyclophosphamide) in 165 patients (35%), and TC (docetaxel + cyclophosphamide) in 142 patients (30%). The incidence of FN was 28.7% (N = 137). To evaluate the risk factors for FN, we predefined regimens, age, performance status (PS), stage, chemotherapy or radiotherapy history, infectious wounds, open wounds, ANC, and renal and liver dysfunction as potential risk factors. Multivariate analysis of risk factors for FN identified regimen (TC), age (≥65), low pretreatment ANC, treatment setting, and no primary pegfilgrastim prophylaxis as significant risk factors. Two patient-specific risk factors (age and pretreatment ANC) were analyzed. Logistic regression analysis revealed that age≥65 years was a significant risk factor (odds ratio=2.24, 95% confidence interval: 1.34–3.75). Applying a cutoff of 65 years (age) to predict FN, the sensitivity and specificity were 28.4 and 83.8%, respectively, which were inaccurate. Despite applying a cutoff of 67 years optimized from the receiver operating characteristic (ROC) curve, the sensitivity (22.4%), specificity (90.7%), and area under the curve (0.519) indicated low discrimination for predicting FN. The incidence of FN by age group was as follows: &amp;lt; 45 years, 30.8%; 45–55 years, 26.4%; 55–64 years, 20.9%; ≥65 years, 39.6%. Additionally, applying a cutoff of 2436/µL (pretreatment ANC) optimized from the ROC curve, the observed sensitivity (27.6%) and specificity (83.8%), and area under the curve (0.558) also indicated low discrimination for predicting FN. The incidence of FN by stratum of pretreatment ANC was as follows: &amp;lt; 2000, 33.3%; 2000–3000, 30.7%; 3000–4000, 29.9%; and &amp;gt;4000, 24.6. Accordingly, setting a cutoff value to predict FN incidence using age and/or pretreatment ANC was deemed inappropriate. Conclusion: Selecting patients for primary prophylactic G-CSF based on the existing FN risk can be challenging. Primary prophylactic G-CSF would be considered for every patient undergoing perioperative chemotherapy for breast cancer, especially Asians. ROC curve for FN and age. The AUC was 0.519. ROC curve for FN and neutrophil count. The AUC was 0.558. Citation Format: Kazutaka Narui, Takashi Ishikawa, Ikumi Takashima, Kosuke Kashiwabara, Yukari Uemura, Yuichiro Kikawa, Naruto Taira, Hirofumi Mukai. Is it appropriate to select patients for primary prophylactic use of pegfilgrastim based on the risk of febrile neutropenia? [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-12-06.

Patterns of lower risk myelodysplastic syndrome progression: factors predicting progression to high-risk myelodysplastic syndrome and acute myeloid leukemia.

The patterns of low-risk myelodysplastic syndrome (MDS) progression and the clinical and molecular features of those patterns have not been well described. We divided our low-risk (LR) MDS patients (N=1,914) into 4 cohorts: 1) patients who remained LR-MDS (LR-LR; N=1,300; 68%), 2) patients who progressed from LR to high-risk (HR) MDS (LR-HR) without transformation into acute myeloid leukemia (AML) (N=317; 16.5%), 3) patients who progressed from LR to HR MDS and then AML (LR-HR-AML; N=124; 6.5%), and 4) patients who progressed from LR MDS directly to AML (LR-AML; N=173; 9%). Risk factors for progression included: male gender, low absolute neutrophil count (ANC), low platelet count, high bone marrow (BM) blasts, ferritin >1000 mcg/L, albumin <3.5 g/dL, multi-lineage dysplasia (MLD), and lack of ring sideroblasts. Among patients with marked BM fibrosis (N=49), 18% progressed directly to AML. Somatic mutations (SM) associated with an increased risk of direct or indirect AML progression included SRSF2 and NRAS. SM in IDH1, IDH2 and NPM1 were more common in patients with direct AML transformation. SM associated with progression to higher risk disease only, without AML transformation, were ASXL1, TP53, RUNX1, and CBL. SF3B1 mutation was associated with less progression. About 171 patients (13.1% of all LR-LR patients) died within two years of diagnosis of LR-MDS without disease progression. Among the 61 cases with documented cause of death, 18 patients (29.5%) died from cytopenia and MDS-related complications. Identifying patterns of disease progression of LR MDS patients and their predictive factors will be crucial to be able to tailor therapy accordingly.

Evaluation of Absolute Neutrophil Count in the Perioperative Setting of Sarcoma Resection.

Limb salvage surgery (LSS) is the preferred surgical treatment for bone sarcomas. Preoperatively, many patients receive chemotherapy and may develop neutropenia. No study has evaluated the effect of a low preoperative absolute neutrophil count (ANC) on postoperative outcomes following LSS. This was a retrospective review of 114 patients who underwent LSS for bone sarcoma from 2010 to 2020. Preoperative lab values were analyzed by logistic regression to identify the risk of developing surgical complications within 30 days, surgical site infection (SSI), and reoperation. Three (2.6%) patients experienced a surgical complication within 30 days. Twelve (10.53%) patients experienced postoperative SSI. Twenty-nine (25.4%) required reoperation. Preoperative ANC was not a significant predictor of surgical complications within 30 days, SSI, or reoperation. The only independent predictor of worse overall survival was the presence of a pathologic fracture at the time of surgery. This is the first study to evaluate preoperative ANC on postoperative outcomes following LSS. We report no significant differences in surgical complications within 30 days, SSI, or reoperation with low preoperative ANC. Future studies with larger cohorts of neutropenic patients are needed to evaluate these outcomes, as our cohort had very few neutropenic patients due to selection bias.

The der(1;7)(q10;p10) defining a distinct profile from -7/del(7q) in myelodysplastic syndromes: Asystematic review and meta-analysis.

Myelodysplastic syndromes (MDS) are myeloid neoplasms characterized by ineffective hematopoiesis due to stem cell abnormalities. Monosomy 7q aberrations are a common cytogenetic abnormality in MDS. Specifically, an unbalanced translocation der(1;7)(q10;p10) [der(1;7)] has been identified in MDS patients, which is a monosomy 7q aberration variant like -7/del(7q). However, knowledge of der(1;7)'s features remains limited. Existing studies have compared the clinical and genetic characteristics of der(1;7) to those of -7/del(7q) but yielded inconsistent findings. Accordingly, we conducted meta-analyses comparing der(1;7) to -7/del(7q). Publications were searched from the following databases up to January 10, 2023: Pubmed, Web of Science, Embase, Cochrane, and ClinicalTrials.gov. Eligible studies were assessed for risks of bias. Relevant data were extracted from included studies and analyzed using random-effects models. Publication bias was evaluated and sensitivity analyses were performed. The comparative meta-analyses included 405 MDS patients with der(1;7) from nine studies. The analysis revealed that der(1;7) was associated with a greater male preponderance (86.1% vs. 68.3%, Odds Ratios (ORs) 2.007, p < 0.01) than -7/del(7q), lower platelets counts compared to del(7q), higher hemoglobin levels than -7, lower absolute neutrophil counts, and higher percentage of patients with non-excess blasts (66.9% vs. 41.3%, ORs 2.374, p = 0.01) in comparison with -7/del(7q). The der(1;7) existed more as a sole karyotype aberration (55.6% vs. 37.0%, ORs 2.902, p = 0.02), co-occurred more often with +8 (22.7% vs. 4.2%, ORs 5.714, p = 0.04) whereas less -5/del(5q) (1.5% vs. 41.3%, ORs 0.040, p < 0.01) and complex karyotype (7.3% vs. 54.8%, OR 0.085, p < 0.01). The der(1;7) was associated with higher frequencies of RUNX1 (40.8% vs. 12.3%, ORs 4.764, p < 0.01), ETNK1 (28.1% vs. 2.5%, ORs 42.106, p < 0.01) and EZH2 (24.8% vs. 6.9%, ORs 3.767, p = 0.02) mutations, but less TP53 mutation (2.4% vs. 45.3%, ORs 0.043, p < 0.01). Moreover, der(1;7) patients had longer time to progression (Hazard Ratios (HRs) 0.331, p = 0.02), better overall survival (OS) than -7 patients (HRs 0.557, p < 0.01), but similar OS with del(7q) patients (HRs 0.837, p = 0.37). The findings revealed distinct clinical, cytogenetic, and molecular characteristics distinguishing der(1;7) from -7/del(7q), indicating der(1;7) defines a unique subtype within MDS with monosomy 7q. These findings support classifying der(1;7) as a separate MDS entity in future.

Baseline Circulating Blood Cell Counts and Ratios and Changes Therein for Predicting Immune-Related Adverse Events during Immune Checkpoint Inhibitor Therapy: A Multicenter, Prospective, Observational, Pan-Cancer Cohort Study with a Gender Perspective.

Several factors have been associated with the occurrence of immune-related adverse events (irAEs) induced by immune checkpoint inhibitor (ICI) therapy. Despite their availability, the predictive value of circulating blood cell parameters remains underexplored. Our aim was to investigate whether baseline values of and early changes in absolute neutrophil count (ANC), absolute lymphocyte count (ALC), other blood cell counts, and lymphocyte-related ratios can predict irAEs and whether sex may differentially influence this potential predictive ability. Of the 145 patients included, 52 patients (35.8%) experienced at least one irAE, with a 1-year cumulative incidence of 41.6%. Using Fine and Gray competing risk models, we identified female sex (hazard ratio (HR) = 2.17, 95% confidence interval (CI) = 1.20-3.85), high ALC before ICI initiation (HR = 1.63, 95% CI = 1.09-2.45), and low ANC after ICI initiation (HR = 0.81, 95% CI = 0.69-0.96) as predictors of irAEs. However, ALC and ANC may only have an impact on the risk of irAEs in women (stratified for female sex, ALC-related HR = 2.61, 95% CI = 1.40-4.86 and ANC-related HR = 0.57, 95% CI = 0.41-0.81). Priority should be given to developing models to predict ICI-related toxicity and their validation in various settings, and such models should assess the impact of patient sex on the risk of toxicity.

Effect of delayed cell infusion in patients with large B-cell lymphoma treated with chimeric antigen receptor T-cell therapy.

Complications occurring after lymphodepleting chemotherapy (LDC) may delay chimeric antigen receptor (CAR) T-cell infusion. The effect of these delays on clinical outcomes is unclear. We performed a retrospective analysis of 240 patients with relapsed/refractory large B-cell lymphoma treated with standard-of-care axicabtagene ciloleucel (axi-cel) and identified 40 patients (16.7%) who had delay in axi-cel infusion. Of these, 85% had delay due to infection. At time of LDC initiation, patients with delayed infusion had lower absolute neutrophil count (P=0.006), lower platelets (P=0.004), lower hemoglobin (P<0.001) and higher C-reactive protein (P=0.001) than those with on-time infusion. Patients with delayed infusion had lower day 30 overall response rates (59.0% vs. 79.4%; P=0.008) and shorter median progression-free survival (PFS) (3.5 vs. 8.2 months; P=0.002) and overall survival (7.8 vs. 26.4 months; P=0.046) than those with on-time infusion. The association with PFS was maintained on multivariate analysis. There was also an association between extent of delay and survival, with shorter median PFS in patients who had delays of 2-5 days (1.8 vs. 8.2 months; P=0.001) and >5 days (4.6 vs. 8.2 months; P=0.036), but not 1 day (5.7 vs. 8.2 months; P=0.238). Following propensity score matching, patients with delayed infusion continued to have shorter median PFS (3.5 vs. 6.0 months; P=0.015). Levels of pro-inflammatory cytokines on day of infusion were significantly higher in patients with delayed infusion. Together, these findings suggest that delays in CAR T-cell administration after initiation of LDC are associated with inferior outcomes. Further studies are needed to guide strategies to improve efficacy in such patients.

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.

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.

Risk Factors and Outcomes for Hematotoxicity Following Tisagenlecleucel for Pediatric B-Acute Lymphoblastic Leukemia

Background: Hematotoxicity following chimeric antigen receptor (CAR) T-cell therapy is increasingly recognized as a distinct adverse event. The CAR-HEMATOTOX score has been developed as a prognostic tool for subsequent development of prolonged cytopenias in adults with lymphoma. However, risk factors in children and young adults (CAYA) with B-acute lymphoblastic leukemia (B-ALL) receiving CAR T cell therapy are less well-defined. We sought to describe incidence, outcomes, and risk factors for prolonged severe neutropenia in CAYA treated with tisagenlecleucel. Methods: This was a multi-institutional retrospective study involving CAYA ≤26 years of age with B-ALL treated with tisagenlecleucel who underwent leukapheresis and manufacturing between August 2017 and March 2020, with data collected through the Pediatric Real World CAR Consortium (PRWCC). Of 185 patients infused, 41 patients were excluded from analysis due to missing data (n=10), refractory disease/death from leukemia (n=27) or non-relapse mortality (n=4) prior to day 35 post-CAR T. Severe prolonged neutropenia was defined as absolute neutrophil count (ANC) &amp;lt;500 cells/mm 3 for ≥30 days. For those with severe neutropenia pre-CAR T, day 0 of severe neutropenia was considered the day of CAR T-cell infusion. Statistical analyses included comparisons using Mann-Whitney and Fisher's exact tests, receiver operating characteristic (ROC) curves to determine cut points with optimal sensitivity and specificity, univariate logistic regression, Kaplan-Meier curves for recovery from neutropenia, overall survival (OS) and relapse free survival (RFS). Results: Of 144 patients, 23 (15.9%) met the definition of severe prolonged neutropenia and 121 (84%) did not. For lymphodepleting chemotherapy, 139 (96.5%) received standard fludarabine (30mg/m 2/dose x 4) and cyclophosphamide (500mg/m 2 x 2). Pre- and post-infusion characteristics are shown in Table 1. Pre-infusion, higher pre-infusion C-reactive protein (CRP), ferritin, bone marrow disease burden, and lower ANC and platelet counts were associated with severe prolonged neutropenia. Post-infusion, any grade cytokine release syndrome (CRS), severe CRS, CRS with hemophagocytic lymphohistiocytosis (HLH)-like manifestations, any grade neurotoxicity, peak CRP and ferritin, use of tocilizumab and steroids, and presence of infections within 30 days were associated with severe prolonged neutropenia. With univariate logistic regression, pre-infusion inflammatory markers, cytopenias, and bone marrow disease burden associated with severe prolonged neutropenia and of these, disease burden &amp;gt;15% had the highest odds ratio (Figure 1). Post-infusion infections and inflammatory toxicities, particularly CRS with HLH-like toxicities, as well as peak CRP, and peak ferritin, were associated with severe prolonged neutropenia. Peak ferritin &amp;gt;3800 ng/ml had the highest odds ratio. In patients with severe prolonged neutropenia, OS was inferior (p&amp;lt;0.0001) and RFS trended towards being inferior (p=0.052), compared to those without. Groups with or without severe prolonged neutropenia were also subdivided into &amp;gt;15% or ≤15% pre-infusion bone marrow disease burden subgroups. OS was similar between patients without severe prolonged neutropenia that had &amp;gt;15% or ≤15% pre-infusion disease burden, but patients with severe prolonged neutropenia and &amp;gt;15% disease burden had inferior OS, suggesting prolonged severe neutropenia may have independent prognostic value. Conversely, RFS was inferior in patients in the subgroups with &amp;gt;15% disease burden compared to those with ≤15%, regardless of occurrence of severe prolonged neutropenia. Discussion/Conclusions: We describe incidence, risk factors and outcomes for the development of severe prolonged neutropenia in CAYA with B-ALL following tisagenlecleucel. While there are similarities in risk factors with the CAR-HEMATOTOX score that has been validated in adults, in CAYA with B-ALL high disease burden pre-infusion and severe inflammation post-infusion were identified as the strongest risk factors for prolonged neutropenia. Identification of risk factors unique to the CAYA B-ALL population allows for tailored risk mitigation in higher risk patients and may help improve outcomes in CAYA at increased risk of prolonged severe neutropenia following tisagenlecleucel.

The ELEMENT-MDS Trial: A Phase 3 Randomized Study Evaluating Luspatercept Versus Epoetin Alfa in Erythropoiesis-Stimulating Agent-Naive, Non-Transfusion-Dependent, Lower-Risk Myelodysplastic Syndromes

Background and Significance: Anemia is a common and debilitating symptom in patients with myelodysplastic syndromes (MDS), frequently leading to dependence on red blood cell (RBC) transfusions. Transfusion-dependent (TD) patients have worse overall survival and quality of life, and repeat transfusions are associated with complications, including iron overload. Erythropoiesis-stimulating agents (ESAs) are the standard treatment for anemia in patients with lower-risk (LR)-MDS, but many patients are ineligible for or refractory to ESAs, and responses are limited. Luspatercept, a late-stage erythroid maturation agent, is approved to treat TD patients with LR-MDS after ESA failure. In the phase 3 COMMANDS study, in ESA-naive patients with LR-MDS requiring transfusions, a significantly higher proportion of patients receiving luspatercept than epoetin alfa achieved RBC transfusion independence for ≥ 12 weeks with concurrent hemoglobin (Hb) increase ≥ 1.5 g/dL (weeks 1-24) (Platzbecker U, et al. Lancet 2023. doi: 10.1016/S0140-6736(23)00874-7). The potential of luspatercept to improve moderately severe chronic anemia and reduce RBC transfusion dependence has not yet been investigated in the majority non-transfusion-dependent (NTD) LR-MDS patient population. Preventing transfusion dependence is crucial for improving LR-MDS patient outcomes. The aim of this actively enrolling, phase 3, randomized, multicenter study is to compare the safety and efficacy of luspatercept versus epoetin alfa in reducing progression to RBC transfusion dependence in ESA-naive, NTD adult patients with anemia due to LR-MDS. Study design and methods: The ELEMENT-MDS study includes a 5-week screening period, a 96-week treatment period, an extension phase, and a post-treatment follow-up period (Figure). Target enrollment is 360 patients with anemia due to Revised International Prognostic Scoring System (IPSS-R) Very low-, Low-, or Intermediate-risk MDS. Eligible patients are ≥ 18 years of age with a confirmed MDS diagnosis, baseline serum erythropoietin (sEPO) levels ≤ 500 U/L, and symptomatic anemia defined as a score of moderate or worse on ≥ 1 Patient Global Impression of Severity (PGI-S) item (fatigue, shortness of breath, weakness, or dizziness). Participants must be RBC transfusion-independent per International Working Group 2018 criteria (no RBC transfusions within 16 weeks prior to randomization) and have baseline Hb ≤ 9.5 g/dL. Patients will be excluded if they have a del(5q) cytogenetic abnormality, unclassifiable MDS or myelodysplastic/myeloproliferative neoplasms, anemia due to reasons other than MDS, bleeding disorders, low absolute neutrophil or platelet counts, uncontrolled hypertension, previous acute myeloid leukemia diagnosis, or history of recent malignancies, among other reasons. Participants will be randomized 1:1 to receive luspatercept or epoetin alfa. Stratification factors include baseline sEPO levels, ring sideroblast status, and IPSS-R risk category. Patients will receive luspatercept once every 3 weeks at a starting dose of 1.0 mg/kg (escalation up to 1.75 mg/kg allowed) or epoetin alfa once a week at a starting dose of 450 IU/kg (escalation up to 1050 IU/kg allowed). The primary endpoint will compare the proportion of patients becoming TD (defined as requiring ≥ 3 RBC units/16 weeks) during any continuous 16-week interval in weeks 1-96. The key secondary endpoint is a Hb increase ≥ 1.5 g/dL sustained for ≥ 16 weeks during weeks 1-48. Additional secondary endpoints include time to RBC transfusion dependence, transfusion-free survival, time to achieve modified hematologic improvement-erythroid response, transfusion independence ≥ 24 weeks, and quality of life assessment. Safety endpoints include type and severity of adverse events and relationship to treatment, overall survival, and progression to high-risk MDS and acute myeloid leukemia. Summary: The results of this phase 3 study will determine the efficacy and safety of luspatercept as a therapy for ESA-naive NTD patients with LR-MDS, who have limited treatment options for anemia. The study is registered at ClinicalTrials.gov (NCT05949684) and EudraCT (2022-500430-29-00).

Grndad and Disease Modifying Therapy (DMT): Shifts in Dmt Are Seen at the Adolescent/Young Adult Transition in Sickle Cell Disease in a Multi-Site Prospective Registry

The ability to characterize the modern person living with SCD in the US has been limited by the lack of a well-curated longitudinal registry. The Globin Research Network for Data and Discovery ( GRNDaD) registry aims to overcome this challenge by collecting data from the now 53 IRB-approved centers across the US in collaboration with the National Alliance of Sickle Cell Centers (NASCC) and the HRSA-funded Sickle Cell Disease Treatment Demonstration Project Grant. Here, we describe the use of disease-modifying therapy in (actively consented) adults and children with Hgb SS/ SB 0 thalassemia (SCA) from 37 sites. Methods: Each site consents subjects and enters extensive baseline data including SCD complications and labs, subjects also complete patient-reported outcomes (PROs)-both at baseline and annually. Each subject is expected to have an annual follow-up where data is extracted from the Electronic Health Record (EHR). All data is stored in REDCap and, for this abstract, data were extracted into R on all active subjects (data entry in the last two years) who have complete minimum data collected. Median values were compared using Mann-Whitney U tests. Disease-modifying therapy (DMT) in this study comprises hydroxyurea (HU), chronic red blood cell (RBC) transfusions, crizanlizumab, L-glutamine, and voxelotor. Results: There are 2501 active patients in GRNDaD. Twenty-six percent of subjects are pediatric &amp;lt;/= 18 years of age, 55.5% are female and 66.7% have HgbSS or HgbSB 0 thalassemia (SCA). Here, we report data on people with SCA only, whose minimum data were complete (n=1272). Table 1 shows DMT by age. 187 (21%) adults and 31 (8.5%) children were not on DMT. Figure 2 is a box plot of the absolute neutrophil count (ANC) comparing adults and children who are and are not taking HU. Adults on HU had significantly lower ANCs than those not on HU (median = 4.4 (IQR: 3.07, 6.3) v 6.6 (IQR:4.07, 8.14), p&amp;lt;0.001) (Figure). Similar findings were observed for children ( median = 3.5 (IQR:2.5, 5.7) Vs 8.1 (5.8, 12.8) , p =0.04) Both children and adults on HU had higher MCVs than those not on HU (median for peds: 91.5 (IQR: 85.1, 98.75) v 86 (IQR: 83.3, 86.1), p=0.05, median for adults: 96.5 (IQR: 89, 107) v 90 (IQR: 86.1, 95.1), p&amp;lt;0.001). We compared hemoglobin for those on and off HU, and on and off voxelotor, excluding patients on chronic transfusion therapy. There was a statistically significant difference in hemoglobin when comparing on or off of HU (median 8.9 g/dl (IQR 7.95, 9.9) v 8.2 g/dl (IQR: 7.2, 9.7, p =0.047)). There were no statistically significant differences in hemoglobin when comparing subjects on or off of voxelotor (median = 8.4 g/dl (IQR: 7.5, 9.6) vs 7.9 (IQR: 7.4, 9.8), p =0.57). In the adults, there were statistically significantly more males than females on HU, but there were no differences seen in the pediatric cohort. Examining DMT by age group, chronic RBC transfusion use doubled from the 11-17 age group to the 18-29-year age group (12% to 25%) and HU use decreased (83%-59%) over this same period. Limitations: This cohort may over-represent those on DMT as those enrolled in GRNDaD were more likely to have clinic visits. Discussion: GRNDaD has doubled the number of sites consenting subjects and entering data over the last year. The number is expected to increase again in the next 12 months, as an additional 15 sites are already IRB-approved with a goal to include all SCD centers in NASCC. This cross-sectional description of the current population of people living with SCD and treated in NASCC-recognized SCD centers in the US shows that the majority of those with SCA are receiving DMT. There is a noticeable decrease in HU use during the transition period with an increase in the use of chronic transfusion therapy. Newer DMT has had limited uptake in this cohort. The next steps will be to provide longitudinal data on this population and examine associations of DMT and important clinical outcomes including PROs.