Median Absolute Lymphocyte Count Research Articles

Immune Reconstitution and Infection Patterns Following CAR T-Cell Therapy in Patients with Aggressive Lymphoma

Introduction: Chimeric antigen receptor T-cell therapy (CAR T) is an effective therapy in relapsed/refractory (R/R) large B-cell lymphoma (LBCL) but is associated with prolonged cytopenias, persistently low CD4 T-cells, and hypogammaglobulinemia (defined as serum IgG <500 mg/dL) resulting in an immunocompromised state post CAR T [Logue 2021]. Prophylactic antimicrobials and intravenous immunoglobulin (IVIG) have been utilized to mitigate infectious complications, but practices are not standardized. We sought to examine patterns of immune reconstitution and their impact on incidence, timing, and management of infection following CAR T. Methods: We identified patients (pts) with R/R LBCL treated with CAR T between 2015 - 2022 across 13 academic institutions. Data on measures of immune recovery and infections were captured post CAR T. Time-to-event curves were established by Kaplan-Meier method. Results: 582 pts were included with a median age of 62 yrs (range 19-89). Pts were heavily pretreated with 3 median lines (range 1-18), and 26% with prior autologous transplant. Median time to ANC > 500 cells/mm3 was 11 days (D); median CD4 counts were 155 and 223 cells/mm 3 at 6 and 12 mo, respectively. Median absolute neutrophil and lymphocyte counts at 6 mo were 2300 and 690 cells/mm 3, respectively. At D90 post-CAR T, 61.5% (136/221) of pts had hypogammaglobulinemia (HGG) that persisted in 62.1% (90/145) at 1yr and 48.3% (56/116) at 2yrs. Data for D90-2 yrs post CAR T were analyzed to characterize late effects of CAR T as follows: Figure 1 describes time to first infection by organism of interest. 66.8% (193/389) of pts developed bacterial infections; median time to infection was 6.7 mo. Most common organisms were Pseudomonas (n =33), E. Coli (n=24), S. Aureus (n=22), C. Diff (n=26), Klebsiella (n= 18). HGG at D30 and D90 was associated with increased risk of bacterial infection, p = 0.002 (OR 2.5) and p= 0.013 (OR 2.1), respectively. Low CD4 counts and neutropenia at any time point within 2 years, did not correlate with increased rate of bacterial infection. Excluding COVID, 31.2% (138/443) of pts developed viral infections; median time to infection was 5.4 mo. Most common organisms were COVID (n=49), Rhinovirus (n= 20), CMV (n= 21), and Influenza (n= 13). Median time to COVID infection was 15.6 mo (range 0.2- 33.1). Neither neutropenia, nor low CD4 counts within 2 yrs post CAR T correlated with increased rate of viral infection. HGG at any time point within 6 mo post CAR T was associated with increased risk of viral infections, including COVID (p = 0.04, OR 2.2). Fungal and PJP infections were infrequent, occurring in 19 and 6 pts, respectively. Median time to fungal infection was 1.7 mo. For infection risk mitigation: 98.4% (496/504) of pts received prophylactic antivirals for median duration of 9.0 mo (0.2- 80.0) and 74.5% (371/498) received PJP prophylaxis for median duration of 6.3 mo (0.2-62.6). IVIG was administered in 34.3% (192/560) of pts with median time to initiation of 3.9 mo post CAR T. Pts with infection D90- 2 yrs were more likely to receive IVIG than those without infection (43.5% vs 26.9% respectively, p= 0.001). Median follow-up in living pts was 35.3 mo with median OS of 27.8 mo (CI 21.2-34.5). Ninety-six (16.5%) pts received salvage therapy post CAR T. Infection of all types <90 days post- CAR T was associated with inferior OS (16 mo vs 43.3 mo, p=0.001). Infection >90 days-2 yrs post CAR T was not associated with worse OS. Presence of HGG at any time point did not impact OS (p = 0.218). However, median OS was not reached in pts who received IVIG vs 16.9 mo in pts who did not (Figure 2, p= 0.001). Furthermore, in pts with HGG, lack of IVIG utilization at D90 was associated with worse OS (p <0.001). Conclusions: Immune suppression is a long-term toxicity of CAR T. Bacterial infections were common and most occurred within ~ 7 mo of infusion while viral infections were less frequent and occurred earlier. Both were associated with prolonged HGG. These observations should inform use of early antimicrobial prophylaxis. The majority of pts received anti-viral and PJP prophylaxis which may have contributed to lower rates of these infections. Pts with infection were more likely to receive IVIG with administration of IVIG improving survival. Our results support continued use of antiviral and PJP prophylaxis and the consideration of empiric IVIG within 30 days following CAR T to mitigate risk of infection and improve survival following CAR T.

Time-Limited Therapy with Zanubrutinib Plus Rituximab in Treatment-Naïve Chronic Lymphocytic Leukemia: Early Results of an Ongoing Phase 2 Trial

Introduction: The Bruton tyrosine kinase inhibitor (BTKi) zanubrutinib has recently been approved for treatment of chronic lymphocytic leukemia (CLL). Zanubrutinib induces durable remissions in most patients with CLL, and treatment is typically given as continuous monotherapy, until disease progression or toxicities prohibit further use. We developed time-limited therapy with zanubrutinib in combination with rituximab as an alternative to long-term BTKi monotherapy. Here, we report early results from the first 17 treatment-naïve patients with CLL who enrolled in this ongoing phase 2 trial (NCT04458610) between July 2020 and April 2023 at MD Anderson Cancer Center. Patients and Study Design: Patients with treatment-naïve CLL requiring therapy per iwCLL criteria receive zanubrutinib 160 mg orally twice daily and rituximab (375 mg/m 2 intravenously) on days 1, 8, 15, 22 of cycle 1, and then on day 1 of cycles 2 - 6 (one cycle is 28 days). Patients who achieve a complete remission (CR) by iwCLL 2018 criteria after 6 cycles of combination therapy continue with zanubrutinib alone for another 6 cycles. Patients who achieve a partial remission (PR) or stable disease (SD) after 6 cycles continue for another 6 cycles of the combination. Patients who achieve a CR after 12 cycles will receive 6 additional cycles of zanubrutinib alone, and then stop treatment. Patients who achieve a PR or SD after 12 cycles will continue zanubrutinib alone for 12 cycles and the stop therapy after a total of 24 cycles. After this time-limited therapy, patients transition to observation and can resume therapy if they relapse and fulfill iwCLL criteria for salvage therapy. The primary objective of the trial is to determine the proportion of patients who have treatment-free remission 6 months after discontinuation of zanubrutinib. Secondary objectives are to determine the length of treatment-free remission, identify clinical factors associated with long versus short remissions, and to evaluate the efficacy of re-treatment with zanubrutinib plus rituximab in patients who relapse. Results: The median age of the patients was 68 years (range, 54 - 77 years), 47% had unmutated IgHV and 41% advance stage disease (RAI stage III and IV). The median baseline absolute lymphocyte count (ALC) and β2 microglobulin were 51.9x10 9/L (range, 1.7 - 231.0x10 9/L) and 3.9 mg/L (range, 2.5 - 6.8 mg/L), respectively. After a median follow-up of 13 months (range, 0.5 - 29 months), all patients remain on study, and the estimated one-year progression-free (PFS) and overall survival (OS) is 100%. Seven patients completed therapy (1 patient after 12 cycles, 6 patients after 24 cycles) and have moved on to observation (median observation time post-therapy 4.5 months). So far, we have not observed any progression events after treatment discontinuation. Overall response rate is 100%, with 9% CR and 91% PR after 6 months (n=11), 11% CR and 89% PR after 12 months (n=9), and 33% CR and 67% PR after 24 months of therapy (n=6). The median levels of bone marrow involvement by CLL cells, quantified by flow cytometry, declined from 81.6% at baseline (range, 25.8 - 93.2%, n=16) to 20.3% after 6 cycles (range, 0.07 - 82%, n=11, p<0.0001), to 12.1% after 12 cycles (range, 0.04 - 55.60%, n=9, p<0.0001), and to 7.23% after 24 cycles (range, 0.2 - 41.4%, n=6, p=0.001). Grade ≥3 adverse events (AE) were observed in 9 patients (52.9%), which included hypertension (n=4) and decreased neutrophil counts (n=3). The most frequent grade 1-2 AE were decreased neutrophil (59%) and platelet counts (47%), bruising (41%), chills, increased creatinine, arterial hypertension, nausea (35% each), fatigue, and headache (29% each). No atrial fibrillation events were observed. Conclusion: This early analysis indicates that time-limited therapy with zanubrutinib and rituximab is well tolerated and induces remissions with a major reduction in bone marrow disease burden in patients with treatment-naïve CLL. The first 7 patients who stopped therapy so far have not progressed, but longer follow-up in more patients is needed to determine the durability of responses after therapy discontinuation, and how those compare to more intensive CLL combination regimens.

CAR T-Related Toxicities Based on Dynamic Proteomic Profiles Identifies Risk Factors for Cytokine Release Syndrome (CRS) and Immune Effector Cell -Associated Neurotoxicity Syndrome (ICANS)

TK and SM are Co-first authors INTRODUCTION Treatment with chimeric antigen receptor (CAR) T-cells significantly improved outcomes in relapsed/refractory non-Hodgkin lymphoma (NHL) and multiple myeloma (MM). CAR-T activation and anti-tumor cytotoxicity are associated with bystander inflammatory reactions resulting in CRS and/or ICANS. Due to complex cytokine profiles, disease heterogeneity, and variability between commercial CAR-T products, identification of risk factors associated with CRS and/or ICANS has been challenging. In this study, we used plasma proteomic profiling at different timepoints to identify possible inflammatory mediators associated with CRS and ICANS METHODS We prospectively collected plasma samples from patients who received CAR-T cells therapy between 9/2021 to 12/2022 at several time points - before lymphodepletion chemotherapy on day -5 (relative to CAR-T cell infusion), prior to CAR T-cell infusion on day 0, and post CAR T-cell therapy on days 1, 2, 3, and 7. Protein profiling analyses were conducted at Eve Technologies (Calgary, Alberta, Canada) using an assay measuring 71 total cytokines and chemokines. Proteins levels were compared across different time points used Wilcoxon rank test, while features associated with CRS/ICANS were identified using logistic regression. Receiver operating characteristic (ROC) analysis used to identify variables predictive for CRS. Area under the curve (AUC) of at least 0.8 was used and best cutoffs were determined according to Youden index. P-values <0.05 were considered statistically significant. This study was supported in part by The Frederick A. Deluca Foundation. RESULTS Overall, 56 patients with available cytokine assays at all time points were included. The median age was 65 years (IQR: 57-74) and 70% were men. Of all patients, 26 (46%) had diffuse large B-cell lymphoma (DLBCL), 23 (41%) MM, 4 (7%) mantle cell lymphoma, and 3 (6) follicular lymphoma. Ide-cel (39%), liso-cel (36%), and axi-cel (17%) were the most used CAR-T cell products. All patients received lymphodepleting chemotherapy with fludarabine/cyclophosphamide. In total, 35 (63%) patients developed CRS (grade 1, 89%; grade 2, 8%; grade 3, 3%) and 18 (32%) patients developed ICANS (grade 1, 72%; grade 2, 22%; grade 3, 6%). Compared to patients who did not develop CRS, patients with CRS had lower median absolute lymphocyte counts at day -5 (0.02 x10 9/L vs. 0.05, p=0.0146), higher baseline CRP (13 vs. 4 mg/L, p=0.0005), and higher ferritin (914 vs. 442 mg/L, p=0.048). No differences in the type of CAR-T products (p=0.090), percentages of DLBCL or MM (p=0.270) were observed between CRS and no CRS cohorts ( Panel-A). First, we investigated the proteomic profiles at baseline for CRS odds. Hemoglobin (odd ratio [OR]: 0.6, 95%CI: 0.4-0.8) was associated with lower odds for CRS while IL6 (2.0, 1.2-3.3) and stem cell factor (scf 2.2, 1.2-4.2) were associated with higher odds of CRS. We then analyzed the differences in cytokine levels between day 0 and day 3 to select cytokines with significant changes for further analysis ( Panel-B). At day 3, groa (1.9, 1.1-3.3), IL3 (1.6, 1.2-2.1), IL5 (1.5, 1.2-1.9), IL6 (1.7, 1.3-2.3), IL10 (2.0, 1.3-3.0), TNFα (2.0, 1.1-3.6), and mcp2 (2.5, 1.2-5.3) were all associated with higher odds for CRS. Based on ROC analysis at day 3, best cutoff points to estimate CRS (value, sensitivity/specificity) for IL3 (3, 80%/90%), IL5 (197, 74%/85%), IL6 (11, 70%/85%), and IL10 (53, 74%/85%) were identified. Based on that, elevated IL3 (OR:24, 95%CI: 6-105), IL5 (11, 3-40), IL6 (21, 5-95), and IL10 (12, 3-46) were associated with higher odds for CRS. For ICANS, day 3 IL3 (1.5, 1.2-1.9), IL6 (1.2, 1.1-1.5), IL8 (2.1, 1.4-3.3), and IL10 (1.7, 1.3-2.4) were associated with higher odds for ICANS. Best cutoff points to estimate ICANS at day 3 (value, sensitivity/specificity) for IL3 (5, 78%/76%), IL6 (115, 78%/78%), IL10 (130, 81%/80%), and IL8 (21, 83%/81%) were identified. Based on that, elevated IL3 (OR:10, 95%CI: 3-37), IL6 (11, 3-43), IL10 (13, 3-51), and IL8 (19, 4-81) were associated with higher odds for ICANS. CONCLUSIONS In our comprehensive plasma proteomic profiles analysis, we identified cutoffs for IL3, IL6, IL5 and IL10 that may be predictive for CRS and ICANS regardless of CAR-T cell product. Our results are clinically applicable and may be used to recognize patients at risk for CRS and/or ICANS who may be eligible for prophylactic therapies.

Radiation-Associated Lymphopenia in Advanced Prostate Cancer Treated with Contemporary Radiation Techniques.

Lymphocytes play a critical role in the immune system as primary effector cells for cancer control, often depleted by external beam radiation therapy (EBRT). Radiation-associated lymphopenia (RAL) has been shown to be a poor prognostic factor in the management of multiple solid tumors. We hypothesize RAL is similarly observed in advanced prostate cancer (PC) RT with contemporary techniques. We identified patients with advanced PC (high-risk or clinical/pathologic node-positive) receiving EBRT including lymph node/prostatic lesion boost on a prospective collection protocol for whom 1 baseline and ≥2 subsequent complete blood count (CBC) with differential samples were available, collected at RT end, 3-, 6-, and 12-months post-RT. Clinicopathological characteristics were retrieved from chart review. Common Terminology Criteria for Adverse Events (CTCAE)v5 was used to grade absolute lymphocyte count (ALC); RAL was defined as CTCAEv5 grade ≥2. As these patients received pelvic nodal irradiation, they were pooled with low/intermediate-risk PC cohort treated with high dose-rate (HDR) brachytherapy or prostate alone EBRT with similar CBC timepoints for univariable analysis to understand RT field size effect on RAL. Between 2019 and 2022, among 17 patients in the low/intermediate-risk PC cohort, 6 patients had grade ≥2 lymphopenia. Among 25 patients in the advanced PC cohort, all received androgen deprivation therapy (ADT), 6 received lymph node boost, and 5 received prostatic lesion boost. At RT end, leukopenia was prominently observed (median nadir count 75.1% of baseline), with ALC as major driver (median nadir count 27.3% of baseline). Grade ≥2 lymphopenia was observed in 76% of patients (n = 19) Of 19 advanced PC patients who reached 6 months post-RT follow-up, median ALC was 53.0% of baseline, and Grade ≥2 lymphopenia remained in 37% (n = 7) of patients. Of 8 advanced PC patients who reached 12 months post-RT follow-up, median ALC was 55.6% of baseline. When evaluating whether RT dose or field size contributed to lower nadir ALC counts, combining the low/intermediate-risk and advanced PC cohorts (n = 42), univariable analysis demonstrated Gleason grade group (p = 0.009), RT field size (p = 0.020), ADT use (p = 0.020), baseline ALC (p = 0.037), and baseline hemoglobin (p = 0.009) were independent predictors of Grade ≥2 lymphopenia. Age, prostatic lesion/lymph node boost, and equivalent dose in 2 Gy/fraction (EQD2) were nonsignificant. Grade ≥2 RAL was observed in patients with advanced PC at end of RT, irrespective of age, RT boost, or EQD2. Lymphocyte recovery from baseline can be prolonged even at 12 months post-RT. Ongoing analyses include expanding data with additional serial CBC, increasing cohort size, and integrating effect of additional systemic therapies. RAL has downstream implications for future chemotherapy/radiopharmaceuticals.

Adrenal Stereotactic Body Radiation Therapy: Do Dosimetric Factors Predict for Grade 2+ Lymphopenia?

Recent studies suggest improvement in outcomes in multiple oligometastatic tumor sites with immunotherapy (IO) and radiation therapy (RT). However, RT may induce lymphopenia that can be immunosuppressive and dosimetric consensus is lacking on parameters predicting grade ≥2 lymphopenia. In this study, we evaluated lymphopenia post receipt of stereotactic body RT (SBRT) for adrenal metastases to see if we could identify any modifiable treatment planning factors. Patients with adrenal oligometastases who were treated with conventional SBRT or MRI-guided (MRgSBRT), had absolute lymphocyte count (ALC) and white blood cell count (WBC) data available within 6 weeks before and after their radiation treatment, and had contouring data available for review were included in this IRB approved retrospective study. Lymphopenia was graded for ALC as: Grade 1 (1.0-0.8 no/ul), Grade 2 (<0.8 - 0.5 no/ul), Grade 3 (<0.5-0.2 no/ul), Grade 4 (<0.2 no/ul). The vertebral bodies (VB), at the level of the planning treatment volume (PTV) and one above and below, and the spleen were contoured. Dosimetric variables of interest included spleen and VB mean dose (Gy) as well as V2.5-20 Gy in 2.5 Gy increments. Regression analyses were used to identify dosimetric variables associated with absolute and relative difference in ALC post-SBRT. A total of 30 patients were identified with a slight male predominance (N = 17, 57%) and most commonly left adrenal (N = 17) versus right adrenal (N = 10, 33%) or bilateral metastases (N = 3, 10%). Grade 2+ lymphopenia was observed in N = 7 patients pre-SBRT (23%) and N = 17 patients post-SBRT (57%). N = 26 (87%) of the patients had previous chemotherapies and N = 17 (57%) had previous immunotherapy. Multiple primary tumor types were represented with the most common non-small cell lung cancer (N = 14, 47%), followed by melanoma (N = 4, 13%) and small cell lung cancer (N = 3, 10%). Most patients were treated with non-MRgSBRT (N = 19, 63%) vs MRgRT (N = 11, 37%) and all received SBRT in 5 fractions with median dose 50 Gy (Range: 25 - 60 Gy). The median pre-SBRT ALC was 1.13 (Range: 0.39 - 2.96) and median post-SBRT ALC was 0.72 (Range: 0.11 - 4.15). On linear regression analysis, there was no significant association between post SBRT ALC nor lymphopenia grade with splenic or vertebral body dose, treatment laterality, or SBRT dose. In this retrospective series of predominately metastatic lung cancer patients treated with adrenal SBRT, we observed high rates of post SBRT grade 2+ lymphopenia, yet no dosimetric parameter was predictive, not even for left-sided lesions. Future work includes clinical validation of these findings in a larger population, likely with multi-institutional collaboration, and further study of the investigation of the IO/RT sequencing issues in such heavily pre-treated patients.

A Risk Prediction Model for Severe Radiation Induced Lymphopenia in Patients with Pancreatic Cancer Treated with Concurrent Chemoradiotherapy

In pancreatic cancer, radiation induced lymphopenia (RIL) is associated with a poor prognosis. However, normal tissue complication probability (NTCP) models predicting RIL in pancreatic cancer treated with concurrent chemoradiotherapy (CCRT) have yet to be developed. This study aims to develop a least absolute shrinkage and selection operator (LASSO)-based multivariate NTCP model to predict severe RIL in patients with pancreatic cancer during CCRT and to validate the model internally. We retrospectively reviewed patients with localized pancreatic cancer who underwent CCRT using three-dimensional conformal radiation therapy from 2013 to 2021. The exclusion criteria were patients with distant metastasis; patients who did not complete RT due to tumor progression; patients who did not have absolute lymphocyte count (ALC) data available before or during RT. An ALC of < 0.5 K/μL during CCRT was defined as severe RIL. A NTCP model of severe RIL was developed by LASSO-based multivariate analysis. We used age, sex, Karnofsky performance status, maximum tumor size, carbohydrate antigen 19-9 level before RT, ALC before RT, volume of planning target volume (PTV), and dosimetric parameters for surrounding organs (including spleen, vertebrae, liver, bilateral kidneys, gastrointestinal tracts) as variables for LASSO. In addition, internal validation was performed by the bootstrap method. The predictive performance of the model was evaluated by the area under the curve (AUC) of the receiver operating characteristic curve and scaled Brier score. Of the 131 patients included in the study, the median age was 68 years (range, 42-84), and 55% were male. The median ALC before RT was 1.37 K/µL (0.52-3.50). The median PTV volume was 315.4 ml (86.3-1079.3). The median dose of radiotherapy was 50.4 Gy (16.2-50.4), with 1.8 Gy per fraction. Combination chemotherapy was S-1 in 99 cases (75.6%) and gemcitabine in 32 cases (24.4%). Induction chemotherapy before CCRT was performed in 39 patients (29.8%). Severe RIL was observed in 84 (63.6%) patients. The LASSO showed that low baseline ALC (p = 0.0002), large PTV volume (p < 0.0001), and a large kidney V5 defined as the percentage of bilateral kidneys receiving 5 Gy or more (p = 0.0338) were selected as parameters of the prediction model for severe RIL (AUC = 0.917) and scaled Brier score was 0.511. As a result of internal validation by the bootstrap method, the average AUC was 0.918 (95% confidence interval, 0.849-0.954). Severe RIL occurred frequently during CCRT for pancreatic cancer, and a NTCP model for severe RIL developed and validated internally in this study showed good predictive performance. External validation is needed before this NTCP model can be used as a benchmark for treatment planning to reduce the risk of severe RIL and for considering future treatment approaches.

Clinico-Haematological Profile Of Chronic Lymphoproliferative Disorders In Patients Presenting With Lymphocytosis.

To assess the spectrum and clinico-haematological profile of chronic lymphoproliferative disorders in patients presenting with lymphocytosis. The cross-sectional, retrospective study was conducted at the Aga Khan University Hospital, Karachi, and comprised data related to cases of bone marrow aspirate and trephine from January to November 2020. Patients for whom the bone marrow was done for lymphocytosis were studied for the presence of lymphoproliferative disorders, sub-types and patients'characteristics. The diagnosis and classification were based on the World Health Organisation criteria for tumours of haematopoietic and lymphoid tissues. Data was analysed using SPSS 21. Of the 3,334 bone marrow specimenstested, 103(3%) were related to lymphocytosis. Of these, 84(82%) were diagnosed with lymphoproliferative disorders, while diagnosisremained undetermined in 19(18%) cases. Male:female ratio was 3.6:1 and median age was 60 years (range: 21-85 years). Constitutional symptoms were found in 61(73%) patients. Median absolute lymphocyte count was 45x109/L (range: 5.3-480). All 84(100%) patients were classified as B-cell lymphoproliferative disorder. Chronic lymphocytic leukaemia wasthe most common form, 61(73%), and 31(51%) of them presented with advanced stage disease. A huge majority of patients presenting with lymphocytosis had underlying lymphoproliferative disorders of which B-cell chronic lymphocytic leukaemia was found to be the most common.

Outcome of COVID-19 and tolerance of Remdesivir in patients with renal failure: a single center experience from Pakistan

Introduction: Coronavirus disease-19 (COVID-19) is known to cause severe disease in chronic kidney disease and maintenance dialysis patients. We aim to report the outcome of COVID-19 and the adverse effects of Remdesivir (RDV) in patients with renal failure. Methodology: A retrospective observational study included all admitted patients with COVID-19 who received Remdesivir. Clinical characteristics and outcomes were compared in patients with renal failure (RF) and non-renal failure (NRF). We also evaluated RDV-associated nephrotoxicity and observed renal functions during antiviral treatment. Results: A total of 142 patients received RDV, 38 (26.76%) in RF and 104 (73.23%) in the non-RF group. The median absolute lymphocyte count was low while C-reactive protein, ferritin, and D-dimer were significantly high on admission in the RF group. A significant number of patients in the RF group required ICU admission (58% vs. 35% p = 0.01) and expired (29% vs. 12.5 p = 0.02). Among survivors and non-survivors in the RF group, raised inflammatory markers and low platelet count on presentation were significantly associated with high mortality. Median serum creatinine (mg/dL) was 0.88 on admission, remained at 0.85 in the NRF group, and improved from 4.59 to 3.87 (mg/dL) after receiving five days of RDV in the RF group. Conclusions: COVID-19 in renal failure has a high risk for ICU admissions leading to increased mortality. Multiple comorbidities and raised inflammatory markers are predictors of poor outcomes. We observed no significant drug-related adverse effects, and none of our patients required discontinuation of RDV due to worsening renal function.

Impact of fludarabine exposure on the depth and duration of lymphopenia and CAR T-cell outcomes.

10033 Background: Chimeric antigen receptor (CAR) T-cells are highly effective for patients with relapsed or refractory B-ALL. Lymphodepletion has been paramount to CAR T-cell expansion and efficacy. Recent data identified an association of fludarabine exposure with reduced relapse rates, longer leukemia free survival, and more prolonged B-cell aplasia following tisagenlecleucel. However, the relationship of fludarabine exposure to lymphopenia and the mechanism by which dosing impacts outcomes following CAR T-cells remains unknown. Methods: We conducted a retrospective review of children and young adults with B-ALL who received fludarabine for lymphodepletion (LD) prior to infusion of anti-CD19, anti-CD22, or anti-CD19/22 bispecific CAR T-cells. The primary objective of this study was to investigate the impact of fludarabine on the depth and duration of lymphopenia. Secondary objectives included examining the impact of fludarabine exposure on: 1) overall clinical response, and 2) CAR T-cell expansion. All patients in the analysis cohort received fludarabine 25 mg/m2/day x 3 days ( = 75 mg/m2 cumulative dosing). Fludarabine exposure (AUC per dose) for each patient was predicted using a validated population PK model and analyzed with various responses/endpoints using the 3-day cumulative exposure/patient. Results: Of 137 children and young adults, the median cumulative AUC was 8.3 mg*hr/mL (range, 3.00-13.83 mg*hr /mL). The overall complete response (CR) rate was: 67.9% (93/137). The median duration of lymphopenia (defined as an absolute lymphocyte count (ALC) £ 150 K/uL) was 5 days (range, 0-15); and the median ALC on Day 0 was 80 K/uL (range, 0-1250 K/uL). When stratified by the median fludarabine exposure, there was no difference in depth or duration of lymphopenia or CAR T-cell expansion collectively or per trial. The median fludarabine exposure also did not differ between responders and non-responders. However, depth and duration of lymphopenia did differ in the CD22 CAR T-cell trial. Specifically, in those achieving CR, the duration of lymphopenia was longer than in non-responders (7 days versus 4 days, p = 0.030). Similarly, CAR T-cell expansion was higher if lymphopenia duration was greater than 5 days (p = 0.019). These findings were not seen across our less persistent CD19 or CD19/22 CAR T-cell trials. Conclusions: Although lymphodepletion impacts CAR T-cell response, we did not find an association between CR rate, depth of lymphopenia, or duration of lymphopenia with varying fludarabine exposures. This raises additional questions regarding the impact of LD therapy on CAR T-cell outcomes—especially since a more prolonged lymphopenia was associated with high CR rates and greater peak expansion in at least one of our studies (CD22 CAR T-cells). Future analysis will evaluate the impact of fludarabine on Day 0 cytokines and other immune parameters. Clinical trial information: NCT03448393 .

Pneumocystis jirovecii Infections Among COVID-19 Patients: A Case Series and Literature Review.

Pneumocystis jirovecii pneumonia (PCP) is a serious, emerging complication of coronavirus disease 2019 (COVID-19). We performed a systematic review of published cases. We describe 6 new cases of PCP/COVID-19 coinfection. Among our cases (n = 6) and those in the literature (n = 69) with available data, the median age (interquartile range [IQR]) was 59 (44-77) years (n = 38), 72% (47/65) were male, and the mortality rate was 30.9% (21/68). Long-term corticosteroid use was noted in 45.1% (23/51), advanced HIV infection (defined as a CD4 count <200 cells/μL) in 17.6% (9/51), and antineoplastic chemotherapy in 13.7% (7/51), consistent with known PCP risk factors. Notably, 56.7% (38/47) had verifiable risk factors for PCP (high-dose corticosteroids, immunosuppressive therapy, and HIV infection) before COVID-19 infection. A median absolute lymphocyte count (IQR) of 0.61 (0.28-0.92) ×103 cells/mm3 (n = 23) and CD4 count (IQR) of 66 (33-291.5) cells/mm3 (n = 20) were also discovered among the study population. These findings suggest a need for greater attention to PCP risk factors among COVID-19 patients and consideration of PCP prophylaxis in these high-risk populations.

Prognostic impact of the simple L-index and absolute lymphocyte count early after allogeneic hematopoietic stem cell transplantation

Background aimsThe L-index, designed as a quantitative parameter to simultaneously assess the duration and severity of lymphopenia, and absolute lymphocyte count (ALC) have a prognostic impact after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, discrepancies have been reported in the impact of ALC, and limited information is currently available on the L-index. MethodsTo search for a better clinical tool, the authors retrospectively compared the simple L-index at 30 days (sL-index(30)), which aims to make the original L-index more compact, and ALC at 30 days (ALC(30)) after allo-HSCT in 217 patients who underwent allo-HSCT at the authors’ institutions. ResultsMedian sL-index(30) was 11 712 (range, 4419–18 511) and median ALC(30) was 404 (range, 0–3754). In a multivariate analysis, higher sL-index(30) was associated with a significantly higher cumulative incidence of relapse (CIR) (hazard ratio [HR], 1.01, 95% confidence interval [CI], 1.00–1.02, P = 0.02 for every increase of 100 in sL-index(30)) as well as non-relapse mortality (NRM) (HR, 1.02, 95% CI, 1.00–1.03, P = 0.01 for every increase of 100 in sL-index(30)). Although higher ALC(30) was associated with significantly lower CIR (HR, 0.94, 95% CI, 0.89–1.00, P = 0.04 for every increase of 100/μL in ALC(30)), it was not extracted as an independent risk factor for NRM (HR, 0.96, 95% CI, 0.88–1.05, P = 0.39). Higher sL-index(30) was associated with a slightly higher rate of grade 3–4 acute graft-versus-host disease (GVHD) (HR, 1.02, 95% CI, 1.00–1.04, P = 0.12 for every increase of 100 in sL-index(30)) but not chronic GVHD (HR, 1.00, 95% CI, 0.99–1.01, P = 0.63). ALC(30) was not associated with rates of grade 3–4 acute GVHD (HR, 1.02, 95% CI, 0.88–1.17, P = 0.81) or chronic GVHD (HR, 1.02, 95% CI, 0.98–1.06, P = 0.34). In a receiver operating characteristic curve, the cutoff values of sL-index(30) and ALC(30) for CIR were 9000 and 500, respectively, and the cutoff value of sL-index(30) for NRM was 12 000. ConclusionssL-index(30) is a promising tool that may be applied to various survival outcomes. A large-scale prospective study is needed to clarify whether medical interventions based on sL-index(30) values will improve the clinical prognosis of patients.

Infectious Complications of B-Cell Maturation Antigen (BCMA)-Targeted Therapies for Relapsed/Refractory Multiple Myeloma

Background: Recently, therapeutics targeting B-cell Maturation Antigen (BCMA), including CAR T cells, bispecific antibodies (bsAbs) and antibody-drug conjugates (ADCs), have shown promise in improving outcomes in RRMM patients (pts). However, targeting BCMA can impair natural humoral immunity and increase infection risk. It remains unknown if BCMA-targeted therapies predispose pts to infection at higher frequency or with different characteristics than non-BCMA-targeted therapies in this RRMM population, or if the frequency and characteristics of infections differ amongst the various BCMA-targeted modalities. Methods: We conducted a single-center retrospective study of RRMM pts who started BCMA-targeted therapies (CAR T, bsAb, or ADC) or a selinexor-based treatment between Nov. 2015 and May 2021. We extracted data on patient demographics, MM characteristics, prior lines of therapy, neutrophil and lymphocyte counts, and response to therapy, as well as frequency, type, and severity of infections, quantitative immunoglobulins, and use of intravenous immunoglobulin (IVIG). Pts who had received serial BCMA-targeted therapies, or both a BCMA-targeted therapy and selinexor were excluded from analysis. Results: There were 134 pts included in the analysis: 112 who received a BCMA-targeted treatment (36 CAR T, 29 bsAb, and 47 ADC) and 22 who received selinexor-based treatment. Overall pt characteristics, including age, median lines of therapy, and %triple- and penta-refractory, were similar between the anti-BCMA therapy and selinexor groups, as well as amongst pts receiving the different anti-BCMA modalities. However median duration of therapy differed between groups, longest in the bsAb group and shortest for selinexor (Table 1). Of pts receiving BCMA-targeted treatment, 63 (56%) experienced at least 1 infectious complication (75% of CAR T, 48% of bsAb, and 47% of ADC pts), compared to 6 pts (27%) in the selinexor group. These 69 pts had a total of 146 infections (mean of 2.0, 2.9, 2.1, and 1.0 infections per infected pt in the CAR T, bsAb, ADC, and selinexor groups, respectively) (Table 2). Of the infections in the BCMA-treated pts, 70% were considered low-severity (no treatment or oral treatment alone) and 30% were high-severity (hospitalization, life-threatening, or fatal), with similar frequency of high-severity infections amongst pts getting CAR T, bsAb or ADC. Four of 6 infections (67%) in the selinexor group were high-severity. Most (66%) of the low-severity were upper respiratory tract infections, while most high-severity were lower respiratory tract infections (54%) or bacteremia (22%). Low-severity infections were most commonly viral, while high-severity infections were more likely bacterial. Fungal infections were rare (n=2, both in CAR-T patients). Median time to onset of high-severity infections was 59 days in the CAR T cohort compared to 278 days and 124 days in the bsAb and ADC groups, respectively, and 205 days in the selinexor group. Only 12 of the 146 infections (8%) occurred while pts were neutropenic. Median absolute lymphocyte counts (ALC) were low in all groups pre-treatment; amongst pts still on therapy at 3 months, median ALC had increased in all 3 BCMA-treated groups (Table 1). Regarding hypogammaglobulinemia we focused on pts with non-IgG myeloma to limit confounding effects of the monoclonal IgG protein. Amongst non-IgG pts receiving BCMA-targeted treatments (n=50), 70% had IgG<400 pre-treatment, which increased to 87% by 3 months. For non-IgG selinexor pts (n=9), these numbers were 67% and 71%, respectively. At least 1 dose of IVIG was given in 31% of BCMA-treated pts (22% of CAR T, 59% of bsAb, and 21% of ADC). Conclusions: RRMM pts treated with BCMA-targeted therapies are at high risk of developing an infectious complication, regardless of treatment modality, with many patients having multiple infections, and up to 30% developing high-severity infections. Infection frequency in this study appeared higher for anti-BCMA-treated pts than for selinexor-treated patients, though this finding is confounded by the small numbers and shorter duration of therapy in the selinexor group. Further analyses of the impact of response, ALC, immunoglobulin levels, and IVIG use on infection risk and severity are ongoing. These data demonstrate a need for optimizing strategies to prevent and treat infectious complications in RRMM pts receiving BCMA-targeted therapies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Chronic Lymphocytic Leukemia Treatment: Single Center Experience

Background: Chronic lymphocytic leukemia (CLL) is relatively uncommon in the Middle East, with a younger age at diagnosis and different clinical characteristics compared to the West. There is little research on CLL in this region. This study aims to evaluate widely used prognostic markers and examine treatment outcomes of CLL patients in the Kuwait Cancer Control Center (KCCC), the only cancer center in Kuwait. Methods: This is a retrospective analysis of unselected 141 CLL patients receiving treatment in the KCCC. Diagnostic and treatment guidelines in our center were in accordance with the International Workshop on CLL criteria. Results: The median age of those patients at diagnosis was 58 years (IQR, 51-65), with 60% of patients under the age of 60. The male to female ratio in this group was 3.3:1. Median absolute lymphocyte count was 51x109/L (IQR, 51-65), and the median hemoglobin and platelet count were 11.8 g/dL (IQR, 10.1-13.8) and 170x109/L (IQR, 129-222). FISH analysis was performed in 118 patients, of which 9% (11) demonstrated del17p. Del13q and trisomy 21 were detected in 31% (36) and 26% (31) patients, respectively. IGHV mutational status was determined in 80 patients, 25% (20) were mutated, and 75% (60) were unmutated. When it comes to treatment, 47% (65) of patients were on FCR regimen, while 11% (15) and 12% (16) were receiving BR and CR, respectively. Approximately 15% (21) of patients in our study were on a BTKi. In 105 patients, the median progression-free survival (PFS) was 44.2 months [95% CI: 36-61.5], with a PFS rate of 48% and 32% at 25 and 50 months, respectively. In 121 patients with no history of progression or treatment in our study cohort, 41.5% and 21% progressed or received treatment at 25 and 50 months, respectively, with a median time to first progression or treatment around 37.6 months [95% CI: 29.1-49.5]. Examining 103 patients with prior history of progression or treatment, 34% and 13% progressed again or required a second course of treatment at 25 and 50 months, respectively, with a median time to second progression or treatment around 65.5 months [95% CI: 40.5-NA]. Those receiving chemoimmunotherapy exhibited a higher median PFS of 93 months [95% CI: 83-NA] compared to those receiving a BTKi with a median PFS of 42 months [95% CI: NA-NA]. However, the difference was not statistically significant (p=0.34). IGHV mutation status was significantly associated with OS (p=0.044) but not PFS (p=0.28). Those with unmutated IGHV had an inferior outcome compared to their mutated counterparts with OS rates at 50 months, around 15% and 25%, respectively, PFS rates were also lower in the unmutated compared to a mutated group, 21% vs. 31% at 50 months, respectively, and PFS medians around 49 [95% CI: 36.4-NA] and 94.5 [95% CI: 94.5-NA], respectively. Multivariate cox regression analysis on OS was not significant (p=0.160). None of the individual treatment regimens were significant predictors of OS compared to the reference (BR), except FCR. Treatment with FCR was associated with a hazard ratio of 0.11 (p = 0.011). Unmutated IGHV status, presence of del17p, and age greater than 60 were all associated with greater hazard ratios, but none were significant predictors of OS. Conclusion: Our CLL treatment group is younger. Unmutated IGHV was associated with a poor prognosis, consistent with the literature. However, treatment with BTKis was not associated with superior outcomes compared to CIT; however, this study is not powered to detect a difference between the two arms. Those receiving FCR had the best survival outcome compared to those receiving other therapies. Keywords: Chronic Lymphocytic Leukemia, Treatment Outcomes, Kuwait, Middle East Funding Agency: Kuwait Foundation for the Advancement of Science, Grant number: PR1713MM03 Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Immune checkpoint inhibitor therapy and outcomes from SARS-CoV-2 infection in patients with cancer: a joint analysis of OnCovid and ESMO-CoCARE registries

BackgroundAs management and prevention strategies against COVID-19 evolve, it is still uncertain whether prior exposure to immune checkpoint inhibitors (ICIs) affects COVID-19 severity in patients with cancer.MethodsIn a joint analysis...

Lymphocyte Nadir Following Radiation for Soft-Tissue Sarcoma: Defining Key Dosimetric Parameters and Outlining Clinical Significance

<h3>Purpose/Objective(s)</h3> Lymphopenia following radiotherapy (RT) is associated with worse oncologic outcomes in numerous cancers, but its incidence and effects are unknown in soft-tissue sarcomas (STS). Our goals were to determine the dosimetric parameters associated with development of lymphopenia and evaluate the impact of lymphopenia on overall survival (OS) and disease-free survival (DFS). <h3>Materials/Methods</h3> We retrospectively reviewed 51 patients who underwent either preoperative, postoperative, or definitive RT for STS at our institution between April, 2010 and May, 2021. Absolute lymphocyte count (ALC) nadir was defined as lowest lymphocyte value within one year after RT, and lymphopenia grading was by CTCAE v5.0. Dosimetric parameters were evaluated for associations with ALC nadir, including PTV size as well as mean and volumetric doses (V10, V20, V30) of body, bone, heart, and lung. <h3>Results</h3> Median follow-up was 1.9 years (range 0.3-9.7 years). Stage I cancer was present in 15.7%, Stage II in 11.8%, Stage III in 68.6%, Stage IV in 3.9% (for N1). Grade 1 disease was found in 6.5%, Grade 2 in 6.5%, Grade 3 in 78.4%, and unknown in 9.8%. Chemotherapy was delivered to 35.3%. Median RT dose was 50 Gy (range 45-78 Gy) and IMRT was used for 70.6%. Time to ALC nadir was within 6 months of RT for 86% of patients. Median ALC at baseline was 1400 cells/mm³ (range 600 to 3400 cells/mm³) and at nadir was 900 cells/mm³ (range 40 to 2400 cells/mm³). Strongest correlations with ALC nadir were body V10 (r_s = 0.435, p = 0.002), mean bone (r_s = 0.632, p = 0.001), bone V10 (r_s = 0.632, p <0.001), and bone V20 (r_s = 0.562, p <0.001). Significant but weaker correlations included mean body, body V20, body V30, and bone V30. Lung and heart parameters as well as total dose did not show significant correlations. On multivariable linear regression controlling for disease grade, surgical resection, and chemotherapy use, strongest correlations with ALC nadir were body V10 (β = 0.468, p < 0.001) and bone V10 (β = 0.479, p < 0.001). Distribution of lymphopenia was: grade 1 (17.6%), grade 2 (13.7%), grade 3 (19.6%), and grade 4 (5.9%). Grade 2-4 lymphopenia was associated with inferior OS (HR 5.82, p = 0.01) and DFS (HR 3.85, p=0.002). Lower ALC nadir was also associated with worse OS (HR = 1.95, p = 0.014) and DFS (HR = 1.15, p = 0.001). On multivariate regression, only Grade 3-4 lymphopenia remained associated with worse OS and DFS. <h3>Conclusion</h3> Lower ALC nadir and development of Grade 2-4 lymphopenia were associated with worse OS and DFS in STS. Despite the heterogenous location of STS presentation, lower ALC nadir showed strong correlations with increasing body V10 and bone V10, consistent with the known radiosensitivity of lymphocyte cell lines. Our study supports efforts to reduce treatment-related hematopoietic toxicity as a move to improve oncologic outcomes. This work also raises the hypothesis that radiation effects on lymphocyte progenitors in the bone marrow dominate those of circulating lymphocytes for treatments with minimal contribution to heart and lung.

Modeling Potential Lymphocyte-Sparing Effect of Involved-Field Radiotherapy in Rectal Cancer

<h3>Purpose/Objective(s)</h3> Radiation-induced lymphopenia (RIL) is associated with worse disease-free and overall survival in solid tumors including rectal cancer, as well as lower response rates to checkpoint inhibitors. Large elective nodal volumes, as are utilized in whole-pelvis radiotherapy (WPRT) for rectal cancer, are associated with high RIL risk, while involved-field radiotherapy (IFRT) reduces planning target volume (PTV) size, potentially sparing circulating lymphocytes. In rectal cancer, effective use of IFRT may be facilitated by advances in imaging and high response rates to doublet/triplet chemotherapy regimens such as FOLFOX and FOLFIRINOX. We investigated the potential for IFRT to spare circulating lymphocytes in rectal cancer patients by comparing predicted absolute lymphocyte count (ALC) depletion rates associated with WPRT vs. IFRT. <h3>Materials/Methods</h3> Seventy-five rectal cancer patients who underwent chemoradiotherapy (CRT) were selected. Two different CTVs were contoured in all patients, CTV_(WP) containing traditional at-risk RTOG nodal volumes and CTV_(IF) incorporating primary tumor with a 1-2cm margin, entire mesorectum including a 1cm anterior margin, and any grossly enlarged lymph nodes with a 1cm margin. Two different PTVs, PTV_(WP) & PTV_(IF), were generated using a 0.8-cm isotropic expansion. Wilcoxon signed-rank test was used to compare the two different PTV volumes. Median PTV volume from each data set was used to compute the probability of ALC depletion resulting from PTV_(WP) & PTV_(IF). The equation used to calculate the ALC decay constant k_ALC was: k_ALC = 0.058 + (0.056 * PTV volume/total blood volume) * (dose per fraction)². The computed k_ALC was then used to calculate predicted end-treatment ALC for each field design. Predicted rate of CTCAE v5.0 Grade 3-4 lymphopenia was also computed for these cohorts. <h3>Results</h3> Of the 75 patients, 45 had node positive disease, and 6 patients had pelvic sidewall lymph node/s. 59 patients had T3 disease. Median PTV volume was 1330 cc (IQR: 1200,1534) for PTV_(WP) and 802 cc (IQR: 697,969.8) for PTV_(IF) (ΔPTV 41%, p<0.0001). In summary, PTV_(IF) was 41% smaller than the PTV_(WP). Assuming a baseline ALC of 1800 cells/μL, the predicted median ALC at the end of RT was 360.2cells/μL for PTV_(WP), and 483.0cells/μL for PTV_(IF)(p<0.0001). Grade 3 lymphopenia was predicted in all patients in the PTV_(WP) cohort, whereas it was predicted for only 60% if PTV_(IF) were to be used. <h3>Conclusion</h3> In rectal cancer patients undergoing neoadjuvant CRT, involved-field RT results in a significantly lower median PTV volume when compared to whole-pelvis RT (ΔPTV 41%). This in turn led to improved predicted lymphocyte-sparing and 40% absolute reduction in the risk of predicted grade 3 lymphopenia. These results will be validated in a larger cohort and will help design a prospective study investigating lymphocyte-sparing radiotherapy for rectal cancer patients.

PJP pneumonia in brentuximab vedotin recipients.

e19533 Background: Pneumocystis pneumonia (PJP) is a catastrophic infection seen in the context of low CD4 counts. Brentuximab vedotin (BV) is a drug antibody conjugate targeting CD30 and is used to treat patients with Hodgkin’s lymphoma (HL) and T-cell lymphoma (TCL). PJP prophylaxis is not currently recommended for patients receiving BV-based treatment despite co-expression of CD30 on CD4 cells. The frequency of PJP following BV remains poorly defined. Methods: We evaluated patients who received BV between January 1, 2011 and October 31, 2021 at Mayo Clinic for the development of PJP. Patient demographics and clinical characteristics including underlying disease, chemotherapy regimen, absolute lymphocyte count (ALC), and steroid exposure were collected. Patients who developed PJP more than 3 months after their last BV exposure were excluded. Results: Of 402 BV recipients identified, 63 received PJP prophylaxis and were omitted. Fourteen of the 339 (4.1%) not on prophylaxis developed PJP following BV. Those infected had a median age of 61 (22-87), 71% were male. The most common diagnoses were HL, TCL, and primary mediastinal B-cell lymphoma at rates of 57%, 21%, and 14% respectively. Therapy regimens included BV monotherapy, BV-CHP, and BV-AVD at rates of 43%, 21%, and 14% respectively. BV represented median 2nd line of therapy (1-10) and patients received median of 3 doses (1-10) prior to PJP diagnosis. Patients with PJP had median ALC of 620 (370-3500). 71.4% (10/14) had an ALC less than 750 and among those with ALC greater than 1000, 75% (3/4) had underlying diagnosis of HL. Three patients had CD4 count measured at time of PJP diagnosis with median value of 157 (5-175). 57.1% (8/14) had no steroid exposure beyond the treatment regimen. 14.3% (2/14) were on chronic doses of 5mg prednisone for autoimmune conditions. Short bursts of steroids (prednisone 40 mg) prior to PJP were seen in 21.4% (3/14) with median exposure of 8 days (7-10). One patient had prolonged steroid exposure but was weaned off 17 days prior to PJP diagnosis. 71.4% were older than 50 years at time of PJP. Conclusions: We observed rates of PJP above the commonly accepted threshold of 3.5% for recommending prophylaxis. Among patients with an ALC greater than 1000, 75% had HL raising the question of a qualitative defect in immunity. Close ALC monitoring is recommended for patients receiving BV with a low threshold to institute PJP prophylaxis, especially amongst those older than 50 or with a diagnosis of HL.[Table: see text]

Coinfections in hospitalized COVID-19 patients are associated with high mortality: need for improved diagnostic tools

Background: Hospitalized patients with COVID-19 often receive antimicrobial therapies due to concerns for bacterial and fungal coinfections. We analyzed patients admitted with COVID-19 to our VA facility to understand antimicrobial use, frequency of coinfections, and outcomes in our population. Methods: This retrospective study included veterans who were 18 years or older and hospitalized with COVID-19 from March 10, 2020, to March 9, 2021 at the Louis Stokes VA Medical Center in Cleveland, Ohio. We identified antimicrobials administered and coinfections with bacterial or fungal pathogens. Patients were deemed to have coinfection if there was supporting microbiological data and a consistent clinical course upon review of clinical records. Urinary tract infections were excluded because of difficulty determining infection. Odds ratios (ORs) and 95% confidence intervals (CIs) for 30-day mortality were derived using multivariate logistic regression models that included age, Charlson comorbidity index (CCI), corticosteroid use, and time of infection. Results: In our cohort of 312 patients, the median age was 70 years and 97% of the patients were male. The mean CCI was 3.7 (SD, 3.0), and 111 patients (35.6%) had a score ≥5. Oxygen was administered to 250 patients (80.1%), and 20 (6.4%) required mechanical ventilation. Antimicrobials were administered to 164 patients (52.6%) (Fig. 1). Of 20 patients (6.4%) with coinfection, 11 (3.5%) had a bloodstream infection (BSI) and 9 (2.9%) had bacterial pneumonia (Fig. 2). The overall 30-day mortality rate was 12.5% (39 of 312). Among patients with coinfection, the 30-day mortality rate was 45% (9 of 20). Diagnoses of BSI (OR, 6.35; 95% CI, 1.41–26.30) and bacterial pneumonia (OR, 9.34; 95% CI, 2.01–46.34) were associated with increased mortality. Of the data available, 12 (63%) of 19 patients with coinfection had elevated procalcitonin levels (ie, &gt;0.50). At the time of COVID-19 diagnosis, the median absolute lymphocyte count in patients who died was 0.7 K/mm3 (95% CI, 0.6–1.12) in comparison to 1 K/mm3 (95% CI, 0.7–1.4) in patients who survived at 30 days. Conclusions: Our analysis of hospitalized COVID-19 patients with advanced age and underlying comorbid conditions demonstrated that coinfections were infrequent but that they were independently associated with increased mortality. This finding highlights the need for better tools to diagnose the presence or absence of bacterial and fungal coinfection in COVID-19 patients. Our findings also emphasize the need for judicious use of antimicrobials while discerning which patients are at risk of critical illness and mortality.Funding: NoneDisclosures: None

Association between the pharmacokinetics of rabbit anti-thymocyte globulin and acute graft-versus-host disease in patients who received haploidentical hematopoietic stem cell transplantation.

Anti-thymocyte globulin (ATG) is an important prophylactic drug against acute graft-versus-host disease (aGVHD) after haploidentical hematopoietic stem cell transplantation (haplo-HSCT). This study analyzed the pharmacokinetics of rabbit ATG 2.5mg/kg and its effect against aGVHD in 24 patients undergoing unmanipulated haplo-HSCT. All patients had hematological malignancies not in remission. The median absolute lymphocyte count (ALC) before rabbit ATG administration was 9.5/µL (range 0-41/µL). The grade ≥ II aGVHD group had a significantly lower median rabbit ATG concentration on days 0 (C0) and 7 (C7) and areas under the curve on days 0-7 (AUC0-7) and 0-32 (AUC0-32) than the grade 0-I aGVHD group. Among the four parameters, C0 was the most optimal for predicting aGVHD according to the receiver-operating characteristic (ROC) analysis (area under the ROC curve 0.893; 95% confidence interval 0.738-1.000). The high C0 (≥ 27.8µg/mL) group had significantly lower cumulative incidence of grade ≥ II aGVHD on day 100 than the low C0 (< 27.8µg/mL) group (13.8% vs. 88.9%, p < 0.001). In haplo-HSCT, the C0 of rabbit ATG is a good predictor of grade ≥ II aGVHD, even though ALC before rabbit ATG administration is not a predictor of aGVHD.

Antibody Responses to COVID-19 Vaccination in Left Ventricular Assist Devices

PurposeLeft ventricular assist device (LVAD) implantation is associated with immune dysregulation and common occurrence of major infections. Whether humoral responses to COVID-19 vaccination are protective and durable in LVAD patients is uncertain.MethodsWe conducted a prospective single-center cohort study in LVAD patients without prior COVID-19 infection, who received 2 doses of BNT162b2 (Pfizer) or mRNA-1273 (Moderna) or 1 dose of Ad26.COV2.S (J&J) COVID-19 vaccines. Serologic testing was performed at 3, 6, and 9 months after COVID-19 vaccination using the Roche Elecsys anti-SARS-CoV-2 spike enzyme immunoassay (range <0.4 to >2500 U/mL [positive ≥0.8]), which tests for antibodies against the spike protein's receptor-binding domain (RBD).ResultsIn March 2021, 45 LVAD patients (80% HeartMate 3) were enrolled and 24 (53%) received Pfizer vaccines, 17 (38%) Moderna, and 4 (9%) J&J at a median duration of LVAD support of 34 months (1-114). Most were male (89%) and white non-Hispanic (71%) persons with median age 62 years (23-78); 26 (58%) had diabetes, 16 (36%) had chronic kidney disease (CKD), and 3 (7%) were on immunosuppressive medications. Median absolute lymphocyte count (ALC) at the time of their vaccine was 1.26 K/uL (0.54-3.41). All patients developed a detectable anti-RBD antibody after vaccination, which began to wane after 3 months. The median anti-RBD IgG titers were 1132 U/mL, 360 U/mL, and 286 U/mL at 3, 6, and 9 months, respectively, post-vaccination (Figure). Age > 60 years, ALC < 1.5 K/uL, and history of CKD were associated with lower median anti-RBD IgG titers at 3, 6, and 9 months. Moderna vaccine recipients had the highest and J&J the lowest anti-RBD IgG titers at 3-months. In the 9-month study period, there were no vaccine-related serious adverse events or breakthrough COVID-19 infections.ConclusionLVAD patients exhibit a robust humoral response to COVID-19 vaccination without breakthrough infection. Further research to evaluate cellular responses to COVID-19 vaccination in LVAD patients is warranted.