Non-neutropenic Fever Research Articles

Prospective External Validation of the Esbenshade Vanderbilt Models Accurately Predicts Bloodstream Infection Risk in Febrile Non-Neutropenic Children With Cancer.

The optimal management of fever without severe neutropenia (absolute neutrophil count [ANC] ≥500/µL) in pediatric patients with cancer is undefined. The previously proposed Esbenshade Vanderbilt (EsVan) models accurately predict bacterial bloodstream infections (BSIs) in this population and provide risk stratification to aid management, but have lacked prospective external validation. Episodes of fever with a central venous catheter and ANC ≥500/µL occurring in pediatric patients with cancer were prospectively collected from 18 academic medical centers. Variables included in the EsVan models and 7-day clinical outcomes were collected. Five versions of the EsVan models were applied to the data with calculation of C-statistics for both overall BSI rate and high-risk organism BSI (gram-negative and Staphylococcus aureus BSI), as well as model calibration. In 2,565 evaluable episodes, the BSI rate was 4.7% (N = 120). Complications for the whole cohort were rare, with 1.1% (N = 27) needing intensive care unit (ICU) care by 7 days, and the all-cause mortality rate was 0.2% (N = 5), with only one potential infection-related death. C-statistics ranged from 0.775 to 0.789 for predicting overall BSI, with improved accuracy in predicting high-risk organism BSI (C-statistic 0.800-0.819). Initial empiric antibiotics were withheld in 14.9% of episodes, with no deaths or ICU admissions attributable to not receiving empiric antibiotics. The EsVan models, especially EsVan2b, perform very well prospectively across multiple academic medical centers and accurately stratify risk of BSI in episodes of non-neutropenic fever in pediatric patients with cancer. Implementation of routine screening with risk-stratified management for non-neutropenic fever in pediatric patients with cancer could safely reduce unnecessary antibiotic use.

Post Hematopoietic Cell Transplantation Maintenance Therapy with Low-Dose Azacitidine in a Pediatric Population with High-Risk Myeloid Neoplasms

Patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) undergoing allogeneic hematopoietic cell transplantation (HCT) remain at risk for relapse. Children with relapsed AML and high-risk features including prior HCT, early relapse, and high-risk cytomolecular features experience survival of ≈30%. Given the even more dismal survival and limited therapy options for post-HCT relapse, azacitidine (aza) has been explored as post-HCT maintenance therapy based on potential disease targeting activity and enhancement of graft versus leukemia. Studies to date suggest that this approach is safe with signals of favorable survival. A phase 3 trial in adults did not show a survival benefit, although results were confounded by a high rate of withdrawal and a minority of patients received all intended cycles. We performed a descriptive analysis of all patients with high-risk myeloid neoplasms who underwent allogeneic HCT at Seattle Children's Hospital (SCH) from November 2017 to January 2023 and received post-HCT maintenance aza. Patients were considered high-risk if they had undergone prior HCT, measurable residual disease at HCT, ≥CR2, or high-risk cytomolecular features. Patients received myeloablative conditioning according to standard protocols. All patients were in remission prior to aza initiation. Aza 36-50 mg/m 2 was administered as IV or subcutaneous infusions daily for 5 consecutive days on a 28-day cycle with intention to continue therapy with cycles beginning through 1-year post-HCT. Nineteen patients began aza therapy at a median of 109 days (range 66-263) post-HCT. Demographics and disease information plus the primary high-risk feature for consideration of post-HCT aza are reported in Table 1. Following aza initiation, 9 (47.4%) patients continued subsequent aza cycles at their referring institution with concurrent remote management by SCH as needed. Median post-HCT follow-up was 30.4 months (range 7-66). The median number of completed aza cycles was 8 (range 3-12) and 14 (73.7%) patients received all intended cycles through 1 year following HCT. In 3 patients, aza cycles were delayed >4 weeks due to non-neutropenic fever or infection; de-escalation to 36 mg/m 2 for subsequent courses in the 2 patients who were receiving 50 mg/m 2 led to no further delays. There were no delays due to marrow suppression, no increased transfusion needs, and no hospitalizations attributed to aza. Fourteen (73.7%) patients had grade II acute graft versus host disease (GVHD) prior to initiation of aza. Two (10.5%) of these patients subsequently developed chronic oral GVHD, 1 diagnosed incidentally during their last aza cycle and 1 diagnosed after completion of aza. Two (10.5%) patients experienced ≤ grade II acute GVHD flares while tapering systemic immunosuppressive treatment (IST) and receiving aza, prompting escalation of same systemic IST (n=1) or addition of topical IST (n=1). Seventeen of 18 patients who were in remission at 1-year post-HCT were tapering or off IST. Five (26.3%) patients discontinued aza before 1 year post-HCT: 2 due to relapse, 2 per family preference, and 1 for inflammatory process with persistent dual chimerism from double cord HCT. Three-year estimates for overall and relapse free survival were 92% (95% CI 54-99) and 76% (95% CI 46-91), respectively, and cumulative incidence of relapse was 24% (95% CI 7-48) (Figure 1). The 6 patients with history of prior HCT are all are alive with ongoing remission at ≥3 years following second HCT with aza maintenance. Our experience demonstrates that post-HCT maintenance therapy with low-dose aza for high-risk pediatric AML/ MDS is tolerable with limited toxicity and without significant impact on marrow suppression or GVHD. The ability to successfully implement a post-HCT aza regimen in partnership with local institutions allowed families to return home, potentially reducing emotional hardship and financial toxicity due to travel/ housing and supporting feasibility. Outcomes in this cohort were improved compared to historical controls; this was especially notable in patients undergoing 2 nd HCT and in patients ≥CR2. Our findings suggest a potential role for post-HCT low-dose aza in children with high-risk AML/ MDS but further prospective pediatric studies are needed to define optimal dosing and evaluate for benefit.

Phase 1 Study of SC291, a Hypoimmune, Allogeneic CD19-Directed CAR T Cell Therapy for Relapsed/Refractory B-Cell Malignancies (ARDENT) - Initial Clinical Data

ARDENT is a phase 1 study evaluating safety and tolerability of SC291, a hypoimmune (HIP), allogeneic, CD19-directed CAR T cell therapy in subjects with Non-Hodgkin's Lymphoma and Chronic Lymphocytic Leukemia (CLL). SC291 is derived from healthy donor CD4+ and CD8+ T cells that are genetically engineered to disrupt function of CD3 and HLA class I/II, overexpress CD47, and express a CD19-directed CAR. A primary obstacle for allogeneic CAR T cell approaches remains their immune recognition and rejection. Patient immune responses prevent durable allogeneic CAR T clinical responses despite the use of enhanced lymphodepletion (LD) regimens. We therefore developed hypoimmune CAR T cells that avoid immune recognition and have the potential to deliver clinical efficacy while using a standard LD chemotherapy regimen (as defined by approved autologous CAR T products). The HIP engineering approach involves the depletion of HLA class I/II to prevent adaptive immune rejection and the overexpression of CD47 to prevent innate immune rejection, which has previously demonstrated alloimmune protection in preclinical models ( Nat Biotechnol 2019;37(3):252-258; Proc Natl Acad Sci U S A 2021;118(28):e2022091118; J Exp Med. 2021;218(3):e20200839; Nat Biotechnol. 2023; doi: 10.1038/s41587-023-01784-x, and Nat Commun. 2023;14(1):2020). The initial patient, a 74-year-old male with CLL (unmutated IGHV, del(11q), BTK C481S mutation) and 3 prior lines of therapy (FCR, ibrutinib, venetoclax + rituximab), received a LD regimen of cyclophosphamide 500 mg/m 2 and fludarabine 24 mg/m 2 (daily for 3 days) followed by a starting dose of 60 million CAR+ SC291 cells (of which approximately 80% are fully HIP engineered cells). SC291 was well tolerated with no observed CRS or ICANS. The patient developed non-neutropenic fever after LD (prior to SC291 infusion). At the Day 28 visit post-SC291 infusion, the patient had a partial response (per iwCLL 2018 criteria), along with significant (99%) B-cell reduction and improvements in platelet levels. Analysis of cellular kinetics is ongoing. SC291 is a mixture of T cells, in which portions are partially or fully HIP-engineered. As such, we evaluated the initial patient's immune response against SC291 subpopulations using a panel of previously described in vitro assays. Blood samples from the patient were taken pre-treatment (Day -5) and at the Day 13 and Day 28 visits following SC291 treatment and were assessed for immune evasion. The patient's PBMCs were sorted into CD3+ T cells and CD3-CD56+ NK cells and incubated with the following subpopulations sorted from SC291 drug product (DP): (i) fully HIP engineered (CD19 HIP CAR T cells), (ii) HLA I/II negative T cells without CD47 overexpression (DKO), and (iii) HLA I/II positive CAR T cells overexpressing CD47 (WT CD19 CAR T cells). Patient serum from Day -5 and the Day 28 visit were used for donor-specific antibody analyses, complement-dependent cytotoxicity (CDC), and antibody-dependent cellular cytotoxicity (ADCC) against the DP subpopulations. At Day -5, T cell EliSpot assays showed no immune responses against any of the SC291 sorted subpopulations, but by Days 13 and 28, these assays produced high and increasing IFN-g spot frequencies against the WT CD19 CAR T cells. Similar results were shown with T cell cytotoxicity assays (Fig. 1B). In contrast, no T cell activation and no T cell killing was observed with DKO and CD19 HIP CAR T cells at any time point. As expected, patient NK cells vigorously killed DKO T cells at all time points but spared WT CD19 CAR T and CD19 HIP CAR T cells (Fig. 1B). No antibodies against any sorted subpopulation were detected at Day -5, but IgG antibody binding of the WT CD19 CAR T population was observed at Day 28. These antibodies did not bind to DKO or CD19 HIP CAR T cells, and there was no CDC or ADCC response against these subpopulations. Interestingly, with the LD regimen used, we observed a 95% and 99% reduction of CD19+ cells on Days 0 and 28, respectively, while T cells rebounded from an 88% reduction on day 0 to pretreatment levels on Day 28 (Fig. 1A). These data demonstrate the preliminary safety and tolerability of SC291 in the initial treated patient. Immune assays demonstrated that the CD19 HIP CAR T cell subpopulation effectively evades the host adaptive and innate immune responses and could overcome the allogeneic barrier in humans. Additional data from the ARDENT study will be presented at the time of the conference.

Clinical outcomes of liposomal irinotecan in advanced pancreatic adenocarcinoma patients previously treated with conventional irinotecan-based chemotherapy: a real-world study.

The efficacy of combination chemotherapy beyond the first-line setting remains modest in patients with advanced pancreatic adenocarcinoma (PAC). Evidence from recent clinical studies has shown that liposomal irinotecan (nal-IRI) plus 5-fluorouracil (5-FU) and leucovorin (LV) resulted in survival benefits in patients with advanced pancreatic adenocarcinoma (APAC) after progression on gemcitabine-based treatment. However, the survival benefits of nal-IRI in the third and later lines, in which limited options are available, have yet to be extensively studied. Also, some studies have shown conflicting results regarding the impact of prior treatment with conventional IRI on patient outcomes following treatment with nal-IRI. Therefore, this real-world study aimed to evaluate the efficacy and safety of nal-IRI plus 5FU-LV in advanced PAC patients who progressed on conventional IRI-containing regimens. A retrospective chart review was conducted between November 2016 to December 2022 on 30 patients diagnosed with advanced PAC who completed at least one cycle of nal-IRI plus 5-FU- LV and were previously treated with conventional IRI. Data regarding survival outcomes were retrieved. Thirty patients met the inclusion criteria. Overall, 76.7% of the patients received at least two lines of therapy prior to nal-IRI. The median overall duration of nal-IRI treatment was 2.0 months (IQR: 1.3 - 3.9 months). One patient (3.3%) had a partial response, and seven patients (23.3%) had stable disease as their best response. The median progression-free survival (PFS) was 1.9 months (95% CI 1.6 - 2.0) and the 6-month PFS rate was 20.0%. The median overall survival (OS) was 5.0 months (95% CI 3.4 - 7.0), and the 6-month OS rate was 36.7%. An interval between conventional IRI and nal-IRI ≥5.5 months was significantly associated with prolonged OS of 10.2 months (95% CI 3.3 - 12.1) versus 4.3 months (95% CI 2.1 - 5.9; p =0.003). Ten patients (33.3%) experienced grade 3 adverse events, most commonly nausea, fatigue, diarrhea, and non-neutropenic fever. Nal-IRI plus 5FU/LV had modest survival benefits and an acceptable safety profile in patients with prior conventional IRI. A longer interval between conventional IRI and nal-IRI was associated with increased survival outcomes.

P04 Urinary tract infections in HSCT: how big is the problem?

Abstract Objectives Urinary tract infections (UTIs) in HSCT recipients are understudied. We aimed to describe the incidence, clinical and laboratory findings of patients with UTIs during HSCT. Methods This was a retrospective analysis of all patients admitted for HSCT between 1 January 2020 and 31 December 2022 in a large London tertiary centre. Patient-level data were collected from the electronic medical record. Results There was a total of 400 admissions for HSCT during the study period, 56.25% (227/400) for autografts and 43.25% (173/400) for allografts. Median age was 55 years (IQR 43–62) and 59% of patients were male. A total of 588 infection episodes were recorded (mean 1.43 episodes per patient, 95% CI 1.39–1.56). Almost all patients (96.75%, 387/400) developed at least one infection episode during their inpatient stay for HSCT. The most common sources of infection were neutropenic fever (56.1%, 330/588) and non-neutropenic fever (17%, 100/588), followed by central line-associated bloodstream infections (10.2%, 60/588) and hospital- or ventilator-associated pneumonias (7%, 41/588). UTIs accounted for only 2% (12/588) of the total infection episodes. Only two UTIs (16.7%, 2/12) were associated with bacteraemia. A total of 1307 urine cultures were sent for all patients (3.23 per patient) and 93.5% of all patients had at least one urine culture. Growth of a specific pathogen was observed in 50/1307 cultures (3.8% positivity rate). The most common isolates included Escherichia coli (50%, 25/50) and Enterococcus spp. (22%, 11/50). The most common clinical syndrome for patients with positive cultures was neutropenic fever 40%, 20/50), followed by UTI (22%, 11/50) and non-neutropenic fever (6%, 3/50). 32% of positive samples (16/50) were considered to represent colonization. Pyuria was uncommon (8%, 4/50), including in patients with UTIs (18.2%, 2/11), as was haematuria (10%, 5/50 for all patients, 9.1%, 1/11 for patients with UTI). Conclusions UTIs account for a small proportion of infections in HSCT recipients during their inpatient stay. Urine culture results are challenging to interpret, as they are often associated with undifferentiated fever syndromes or represent colonization. Urine microscopy results are unreliable in HSCT patients and should not be used to rule in or rule out UTI.

Use of antibiotics and outcomes of patients presenting to emergency department with non-neutropenic fever and/or suspected infection.

e18693 Background: Current guidelines are clear about antibiotic choices for cancer patients presenting to emergency department (ED) with febrile neutropenia. However, there is little known about antibiotic use and outcomes of cancer patients who present to ED with non-neutropenic fever. The objective of this study was to identify antibiotic prescribing pattern of patients with solid tumor malignancies who presented to Juravinski Hospital (JH) emergency department (ED) with non-neutropenic fever or/and suspected infection. Methods: A retrospective cohort review was completed. All patients with solid tumor malignancies followed by an oncologist at Juravinski Cancer Centre (JCC) who presented to JH ED with non-neutropenic fever or suspected infection from July 1 to December 31, 2020 were identified from an electronic database. Patients’ baseline characteristics, antibiotics used, and outcome information were collected. The primary outcome was proportion of patients who received broad spectrum antibiotic(s) (either Piperacillin and Tazobactam, a Carbapenem, or/and Cefepime) during ED visit or hospital admission. Results: A total of 581 patients were identified and 275 met inclusion criteria. Median age was 71 years, with 46% male. Most common cancer types were breast (21%), lung (18%), gastrointestinal (16%), and genitourinary (13%). Most patients had advanced cancer [stage 4 (59%), stage 3 (14%)], and 37% were on active systemic treatment at the time of ED presentation. A source of infection was identified in 68% of patients, which included 83/187 (44%) respiratory, 32/187 (17%) cutaneous or soft tissue, 24/187 (13%) genitourinary, 20/187 (11%) gastrointestinal, 14/187 (5%) hepatobiliary, and 12/187 iatrogenic (4%). Majority of ED visits (73%) resulted in hospital admission. Median duration of hospital stay was 6 days, and death occurred in 12% of the admitted patients. Broad-spectrum intravenous antibiotics were used in 47% of patients, and most of the time (78%) was the first antibiotic type given after arrival in ED. Conclusions: In our single-centre study, nearly half of patients with solid tumor malignancies who presented to ED with non-neutropenic fever or/and suspected infection received broad spectrum intravenous antibiotics typically recommended in febrile neutropenia protocols. These data suggest a need for quality improvement strategies to improve antibiotic stewardship for patients with solid tumour malignancies presenting to ED with non-neutropenic fever.

Under Recognized Respiratory Tract Infections in Non-Neutropenic Fever Children with Cancer: Real-World Insights from Mass Religious Gatherings and Influenza Seasons

Background: No existing research has addressed respiratory tract infections (RTIs) in children with non-neutropenic fever (NNF) who are present during seasons of religious mass gatherings (Hajj, Ramadan), especially if this coincides with the influenza season. The treatment approach for RTI cases in NNF children during mass religious gatherings may not be applicable in the normal season.
 Methods: This study includes a retrospective analysis of RTI in NNF children who were present during mass religious gathering seasons and/or flu season, and who were being treated for malignancy at Princess Noorah Oncology Center from May 1, 2016 through December 2017.
 Results: A total of 4599 spikes in fever were identified in 124 non-neutropenic children in whom 455 spikes (9.9%, 455 out of 4599) were documented during mass religious gatherings and/or the flu season. NNF secondary to RTIs was documented in 59.7% of patients during the study seasons with a total of 245 fever spikes recorded. Ceftriaxone-based therapy was the main treatment approach for NNF including the RTI cases that were associated with 50% of subsequent hospitalization for further management. Among all the examined risk factors, a prolonged fever of more than three days was significantly associated with NNF secondary to RTI during mass religious gatherings if coincident with the flu season, OR=0.034 [95% CI, 0.013 - 0.09] P-value <0.001.
 Conclusions: The present study showed that the prevalence rate of NNF of RTI in NNF children increased during periods of mass gathering. There is need therefore for a national consensus to address NNF management during mass religious gatherings, particularly if coincident with the flu season.

Effects of primary granulocyte-colony stimulating factor prophylaxis on neutropenic toxicity and chemotherapy dose delivery in Chinese patients with breast cancer who received adjuvant docetaxel plus cyclophosphamide chemotherapy: a retrospective cohort study.

This study was performed to examine the effects of primary granulocyte-colony stimulating factor (G-CSF) prophylaxis on neutropenic toxicity, chemotherapy delivery, and hospitalisation among Chinese patients with breast cancer in Hong Kong. This retrospective study included patients with breast cancer who received adjuvant docetaxel plus cyclophosphamide chemotherapy from November 2007 to October 2013 at Princess Margaret Hospital. Data were collected regarding the usage of G-CSF prophylaxis; incidences of grade 3 or 4 neutropenia, febrile neutropenia, non-neutropenic fever, and infection; hospital admissions, and chemotherapy dose delivery. Patients who began to receive G-CSF prophylaxis during the first cycle of chemotherapy and continued such prophylaxis in subsequent cycles were regarded as the primary G-CSF prophylaxis group. In total, 231 female Chinese patients with breast cancer were included in the analysis. Overall, 193 (83.5%) patients received primary G-CSF prophylaxis. The demographics and tumour characteristics were comparable between patients with and without primary G-CSF prophylaxis. Primary G-CSF prophylaxis significantly reduced febrile neutropenia incidence from 31.6% to 14.5% (relative risk=0.45, 95% confidence interval=0.25-0.81). Primary G-CSF prophylaxis also significantly reduced the incidence of grade 3 or 4 neutropenia from 57.9% to 24.7% (relative risk=0.43, 95% confidence interval=0.30-0.62) and the incidence of febrile neutropenia-related hospital admission from 31.6% to 12.4% (P=0.025). Finally, it enabled more patients to receive adequate chemotherapy dose delivery. Primary G-CSF prophylaxis effectively reduced the incidences of grade 3 or 4 neutropenia and febrile neutropenia, while enabling adequate chemotherapy dose delivery and reducing hospital admissions among Chinese patients with breast cancer who received adjuvant docetaxel plus cyclophosphamide chemotherapy.

Non‐neutropenic fever in children with cancer: Management, outcomes and clinical decision rule validation

Fever and infection are an important complication of childhood cancer therapy. Most research and guideline development has focussed on febrile neutropenia, with a paucity directed at non-neutropenic fever (NNF). We describe the clinical presentation, management and outcomes of NNF in children with cancer, and externally validate the Esbenshade Vanderbilt (EsVan) clinical decision rules (CDR) to predict bacteraemia. Using a prospective database, retrospective data were collected on consecutive NNF episodes (fever ≥38.0°C and absolute neutrophil count >1.0cells/mm3 ). Sensitivity, specificity and area under the receiver operator characteristic curve (AUC-ROC) of the CDR were compared to derivation study. There were 203 NNF episodes occurring in 125 patients. Severe sepsis was uncommon (n=2, 1%) and bacteraemia occurred in 10 (4.9%, 95% confidence interval [CI]: 2.7%-8.8%) episodes. A confirmed or presumed bacterial infection requiring antibiotics occurred in 31 (15%) patients. Total 202 (99%) episodes received at least one dose of intravenous broad-spectrum antibiotic and 141 (70%) episodes were admitted to hospital. Six (3%) episodes required intensive care unit (ICU)-level care and there were no infection-related deaths. The EsVan 1 rule had an AUC-ROC of 0.67, 80% were identified as low risk, and sensitivity and specificity were 50% and 81.5%, respectively, for a risk threshold of 10%. Serious infection and adverse outcome are uncommon in children with NNF. Many children did not have a bacterial cause of infection identified, but were still treated with broad-spectrum antibiotics and admitted to hospital. National clinical practice guidelines should be developed for this important cohort to enable risk stratification and optimise antibiotic management. Further research is required to determine appropriateness of EsVan CDR in our cohort.

Treating patients with dihydropyrimidine dehydrogenase (DPD) deficiency with fluoropyrimidine chemotherapy since the onset of routine prospective testing—The experience of a large oncology center in the United Kingdom

Fluoropyrimidine chemotherapy is used across many tumor types and settings. The incidence of severe adverse events (SAEs) is around 20%. Mortality is 0.5%-1%. Dihydropyrimidine dehydrogenase (DPD) plays a key role in fluoropyrimidine inactivation. Key DPYD mutations are linked to a high risk of SAEs. Pretreatment DPD screening was mandated by EMA guidelines in April 2020 and widely adopted thereafter. Uncertainty remains regarding optimal dosing practice. We retrospectively examined records of all 23 patients with DPYD mutation who started chemotherapy between April and November 2020. Our center tests for the mutations considered clinically actionable by Clinical Pharmacogenetics Implementation Consortium and uses the Gene Activity Score (GAS) to guide dose reduction. Most patients started on a 50% dose. One started on 100% and experienced mild diarrhea after cycle 2; DPD was tested belatedly, subsequent cycles were reduced to 50% and he remained well. Three patients receiving chemo-radiotherapy started on 76% dose; 50% was felt to be subtherapeutic. One of them had no toxicities; another had grade 2 nausea and a hospital attendance with non-neutropenic fever; the third was admitted for 6 weeks with pancolitis. Seven patients did not have toxicities above grade 1 and no hospital attendances. Five patients had further dose reductions. None had dose escalation. As our experience shows, patients with DPD deficiency are heterogeneous. Worryingly, SAEs occur despite dose reduction according to GAS. Others had minimal toxicity and may be under-dosed by GAS. There are clearly many factors at play other than the 4 DPYD variants. The DPD result must be available and inform first cycle dosing. Dose should be cautiously titrated up if tolerated; this was not done at our center due to clinician caution. Further research is needed to guide this. Patients should be reviewed frequently, counselled regarding their DPD status, and empowered to seek advice promptly when they feel unwell.

The CAR-Hematotox Identifies Patients at High Risk for Prolonged Neutropenia, Infectious Complications and Prolonged Hospitalization Following CD19-CART in R/R LBCL

The CAR-Hematotox Identifies Patients at High Risk for Prolonged Neutropenia, Infectious Complications and Prolonged Hospitalization Following CD19-CART in R/R LBCL

Routine Prophylaxis of Pneumocystis Pneumonia from the Fourth Cycle of R-CHOP Regimen in DLBCL Patients

▪Introduction: In our previous report, approximately 10% of diffuse large B cell (DLBCL) patients experienced non-neutropenic fever (NNF) during R-CHOP chemotherapy, and interstitial pneumonitis comprised approximately 55% of NNF cases. Pneumocystis jirovecii is one of the most common pathogens causing interstitial pneumonia, and increasing evidences suggest that R-CHOP may increase the risk of PJP with reported incidence of 5%.Method: A total of 404 patients with newly diagnosed DLBCL between Jan 2012 and Aug 2016 who were registered in the prospective study and were treated with R-CHOP were analyzed in this study. Before Mar 2014, primary prophylaxis for Pneumocystis jirovecii pneumonia (PJP) was not performed, whereas, bactrim (1 table daily) was dosed from the initiation of 4th cycle of R-CHOP chemotherapy thereafter. With this change of institutional strategy, we hypothesized that the incidence of PJP may differ by prophylaxis strategy.Results: The median age was 56 years (range, 20-85) and 297 patients (73.5%) completed 6 cycles of R-CHOP chemotherapy. The rest completed 1 (n=18, 4.5%), 2 (n=4, 1.0%), 3 (n=23, 5.7%), 4 (n=37, 9.2%), 5 (n=14, 3.5%), 7 (n=3, 0.7%) and 8 (n=8, 2.0%) cycles of treatment. Overall, 3 (0.7%) and 9 patients (2.2%) were diagnosed with definite and probable PJP during the period, and the incidence of definite plus probable PJP was 5.4%. Of 404 patients in the cohort, 220 (54.5%) patients were the candidates for routine prophylaxis with Bactrim. The incidence of definite and probable PJP before prophylaxis was 4.9% (9 out of 184 patients), which was decreased to 1.4% (3 out of 220 patients) after routine prophylaxis with bactrim (p=0.038). In the era of prophylaxis, 3 cases of PJP were all occurred before the 4th cycle and there was no PJP cases after the 4th cycle, while 6 PJP cases before Mar 2014 were noticed after 4-6 cycles of R-CHOP (0% vs 3.3%, p=0.007).Conclusion: Routine prophylaxis with bactrim during later cycles of R-CHOP regimen significantly reduces the incidence rate of PJP in DLBCL patients. DisclosuresKim:Novartis: Research Funding; Donga: Research Funding; Takeda: Research Funding; J&J: Research Funding; Kyowa-Kirin: Research Funding; Celltrion, Inc: Consultancy, Honoraria; Mundipharma: Research Funding; Roche: Research Funding.

Phase II trial of GVDexa (gemcitabine, vinorelbine and dexamethasone) regimen in relapsed/refractory Hodgkin’s lymphoma.

e19519 Background: Gemcitabine, vinorelbine and liposomal doxorubicin (GVD) is an effective regimen in relapsed/refractory Hodgkin’s lymphoma (RRHL). Conventional second-line chemotherapy is still required as the cost of immunotherapy and antibody-drug conjugates are prohibitive to Indian patients. We report the results of a phase II, open-label, single-arm, single centre interventional study in RRHL where dexamethasone replaced liposomal doxorubicin. Methods: Adult patients (≥18 years) with RRHL at first or second relapse were included. GVDex was delivered as outpatient once in 3 weeks (Gemcitabine 1000 mg/m2 IV over 30 min on D1,8; Vinblastine 25 mg/m2 IV fast infusion on D1,8; Dexamethasone 40 mg PO D1-4) for two cycles followed by interim PET CT assessment by Cheson’s criteria and Deauville scoring. The primary endpoint was the objective response rate (ORR = complete response + partial response). The sample size was calculated using Fleming’s 2-stage model (α error: 0.05 and power: 0.8). Twenty patients were required in the first stage. If there were ≥16 responses, the null hypothesis would be rejected and the study stopped. Results: Between May 2016, and December 2020, 26 patients with RRHL were screened, and 20 were enrolled: primary resistant HL-8 patients (40%) and relapsed HL- 12 patients (60%). The median age was 35 years (range:20-52). Six patients (30%) presented with limited stage and 14 patients (70%) with advanced stage HL at relapse. GVdex was delivered as a first salvage regimen in 18 patients (90%) and second in 2 patients. After 2 cycles of GVDex, 16 (80%) had responded [partial response: 12 (60%); complete response: 4 (20%)]. Median number of cycles of GVDex: 3 (range: 1-4). Five patients (25%) required dose reductions due to chemotherapy-related toxicities. The median duration of objective response was 13.4 months. Eleven patients (55%) underwent high-dose chemotherapy supported by autologous stem cell rescue. After a median follow-up of 25 months (95% CI: 5.9-44.5), the median progression-free survival (PFS) was 24.7 months, and the median overall survival (OS) has not been reached. The estimated 2-year PFS was 44%, and the 2-year OS was 79%. The most common treatment-related adverse events were anemia (100%), neutropenia (70%, 14/20) and fatigue (70%, 14/20). Grade 3 or 4 treatment-related AEs occurred in 14 patients (70%). Grade ≥3 neutropenia occurred in 9 patients (45%) and febrile neutropenia in 3 patients (15%). Serious adverse events were reported in 3 patients (15%). One patient developed Ficat and Arlet classification stage III avascular necrosis of the femoral head. One patient died due to suspected COVID-19 pneumonia (non-neutropenic fever) before cycle 2 of chemotherapy. Conclusions: GVDex it is an effective salvage regimen with acceptable toxicity in patients with RRHL. Clinical trial information: CTRI/2017/04/008361.

Infectious Outcomes of Pediatric Acute Lymphoblastic Leukemia Patients Presenting with Non-Neutropenic Fever

Background: Despite advances in cure rates for pediatric acute lymphoblastic leukemia (ALL), infections remain a significant cause of treatment-related morbidity and mortality. Patients with a central venous catheter (CVC) who develop fever while severely neutropenic (absolute neutrophil count (ANC) < 500) are known to be at high risk for serious infections such as blood stream infections (BSIs). However, on Children's Oncology Group (COG) ALL protocols, the majority of a patient's therapy course is in the maintenance phase, during which patients are typically not severely neutropenic. While the BSI rate in all pediatric oncology patients presenting with non-neutropenic fever has been reported to be around 5 to 10% (Allaway et al Pediatr Blood Cancer 2019), minimal data are available regarding BSI and other infections in pediatric ALL patients with non-neutropenic fever. Objective: The objective of this study was to describe the infectious outcomes of children with ALL who developed non-neutropenic fever. Methods: A single institution retrospective chart review collected data on all non-neutropenic pediatric ALL patients (age 0-25 years) with a CVC who were evaluated for fever (temperature ≥ 38ºC) and had a blood culture drawn at the time of presentation from April 2019 through June 2020. Febrile events occurring within 7 days of a prior febrile episode, during administration of empiric or treatment antibiotics, and in patients within 30 days after stem cell transplant (SCT) were excluded. The primary outcome was documented infection from the day of fever evaluation including BSI, positive respiratory viral panel (RVP) result, or other clinically identified infection. The following demographic and clinical variables were abstracted to evaluate risk factors for infection: age, sex, race, ethnicity, CVC type, maximum presenting temperature, ANC, exposure to chemotherapy agents known to be associated with fever (cytarabine or anti-thymocyte globulin), patient location at presentation, history of SCT, sedation event within the prior 24 hours, and COG ALL protocol risk stratification. Institutional review board approval was obtained. Descriptive and inferential statistics, including chi-square or Fisher's exact test as appropriate, were calculated. Analyses were performed using SAS Enterprise Guide v7.1. Results: Data were collected on 299 non-neutropenic febrile episodes experienced by 150 patients. Eighty-eight (29.4%) episodes (61 patients) had at least one identified infection. Thirteen (14.8%) infections were a BSI; the overall BSI rate was 4.3%. Seven BSIs were gram-positive organisms and the remainder were gram-negative organisms. The other infections included 57 (64.8%) respiratory viral infections, 15 (17.0%) pneumonias, 6 (6.8%) ear, nose and throat infections, 3 (3.4%) gastrointestinal infections, and 5 (5.7%) other infections. There was more than one identified infection in 11 episodes (12.5% of infectious episodes) with respiratory viral infection and pneumonia as the most common co-infections (n=6). Presenting temperature ≥ 39ºC was associated with having an identifiable infection (p=0.003). Documented infections occurred less frequently in patients with an exposure to a drug associated with fever (p=0.004), who were inpatient at presentation (p=0.042), or who had a sedation in the prior 24 hours (p=0.003). Conclusion: In this single institution cohort of children with ALL, 29.4% of non-neutropenic febrile episodes were due to a documented infection. The BSI rate of 4.3% is similar to other published reports of pediatric oncology patients with a CVC who developed non-neutropenic fever. Not surprisingly, the most common type of infection was respiratory viral infection. Notably, infections occurred more frequently in patients with a presenting temperature ≥ 39ºC while having had a sedation event within the past 24 hours or having received a chemotherapy agent associated with development of fever were less likely to be associated with an infection. These results provide data that may be useful in determining need for empiric antimicrobial therapy in pediatric ALL patients with non-neutropenic fever based on height of fever and recent treatment exposures. Further evaluation of these initial results in larger, multi-institutional studies are ongoing in order to guide future approaches to treatment of children with ALL who develop non-neutropenic fever. Disclosures No relevant conflicts of interest to declare.

Universal: An Allogeneic First-in-Human Study of the Anti-Bcma ALLO-715 and the Anti-CD52 ALLO-647 in Relapsed/Refractory Multiple Myeloma

Universal: An Allogeneic First-in-Human Study of the Anti-Bcma ALLO-715 and the Anti-CD52 ALLO-647 in Relapsed/Refractory Multiple Myeloma

Retrospective Chart Review of Emergency Department Patients with Cancer and Non-Neutropenic Fever

Increasingly, acute care for cancer patients is occurring in emergency departments (ED). Observational data reveal that approximately 60% of the estimated 4.5 million annual ED visits result in admission. Many of these ED visits are in the setting of a febrile illness. Unfortunately, the current literature provides limited guidance on how to treat non-neutropenic febrile patients with cancer. This report’s objective is to characterize key clinical outcomes of non-neutropenic febrile patients with cancer presenting to an academic, Comprehensive Cancer Center affiliated ED.

Outcomes and Disposition of Oncology Patients With Non-neutropenic Fever and Positive Blood Cultures.

Children with cancer and non-neutropenic fever (NNF) episodes are often treated as outpatients if they appear well. However, a small subset have bloodstream infections (BSIs) and must return for further evaluation. These patients may be directly admitted to inpatient units, whereas others are first evaluated in outpatient settings before admission. The best practice for securing care for patients discovered to have outpatient bacteremia are unclear. To determine outcomes and compare time to antibiotics between the 2 disposition, we retrospectively reviewed all NNF initially treated as outpatients and later had positive blood cultures from 2012 to 2016. Of 845 NNF cases initially treated in outpatient settings, 48 episodes (n=43 patients) had BSIs. Of those, 77.1% (n=37) were re-evaluated as outpatients and admitted; 14.6% (n=7) were direct admissions. The median time to antibiotic did not significantly differ between outpatient re-evaluations (119 min) and direct admissions (191 min), P=0.11. One patient met sepsis criteria upon return and required intensive care unit admission for vasopressor support. No patient died within 1 week of the febrile episode. Most patients with NNF and BSIs initially discharged are stable upon return. Institutions should evaluate their patient flows to ensure that patients receive timely care.

A clinical approach to non-neutropenic fever in children with cancer.

There are a limited number of studies that address non-neutropenic fever episodes in children with cancer, and no standard approach exists. We opt to retrospectively analyze the efficacy of the current clinical approach for management of non-neutropenic fever episodes and the associated risk factors among children with cancer at the Princess Noorah Oncology Center from May 2016 through December 2017. A total of 480 non-neutropenic fever episodes were identified in 131 children, of which 62 episodes were triaged as high-risk non-neutropenic fever and 418 as low-risk non-neutropenic fever. Of those 480 non-neutropenic fever, 361 episodes (75.2%) were associated with the presence of central venous catheters. The overall failure rate of ceftriaxone mono-therapy was observed in 75.6% (11.7% in high-risk non-neutropenic fever with a mean C-reactive protein level of 21.1 (±23.2) mmol/L and 63.9% in low-risk non-neutropenic fever with a mean C-reactive protein level of 17.6 (±53.9) mmol/L). The overall bacteremia rate was 14.4%. The type of organisms isolated was mainly high-risk organisms in 59 non-neutropenic fever episodes (85.5%), OR 1.78 (95% CI: 0.45-7.04) p = 0.41. Of note, all bacteremia were associated with the presence of central venous catheter (100%). Of all the examined risk factors of outpatient treatment failure in low-risk non-neutropenic fever, only prolonged fever of more than three days were significantly associated with bacteremia OR 8.107 [95% CI: 1.744-37.691], p = 0.008. Noteworthy is that almost 43% of non-neutropenic fever episodes were associated with respiratory symptoms. This study provides a baseline for future prospective research assessing the pattern of non-neutropenic fever by focusing on associated risk factors.

Beyond CAR T-Cell Therapy: Continued Monitoring and Management of Complications.

Chimeric antigen receptor (CAR) T-cell therapy has recently emerged as a groundbreaking treatment for CD19-expressing hematologic malignancies and received rapid approval by the U.S. Food & Drug Administration. Tisagenlecleucel and axicabtagene ciloleucel are now widely available at CAR T-cell therapy centers around the United States. Many patients have achieved complete response or remission despite failing multiple previous lines of therapy, but some patients endure the severe risks of cytokine release syndrome, neurotoxicity, and other immunologic effects. As more patients receive this therapy, they will present to their primary oncologists in the community setting for continued follow-up. Oncology-trained advanced practitioners must then have a working knowledge of CAR T-cell therapy, its toxicities, and follow-up care. This review presents the CAR T-cell therapy development and infusion process with associated immediate management. In addition, patient assessment and disease monitoring, relevant diagnostics, unique grading systems to CAR T-cell therapy toxicities, indications for hospitalization, infection prophylaxis, and management of nonneutropenic and neutropenic fever are presented.

Adjuvant recombinant thrombomodulin therapy for hepatopathy induced by vincristine, actinomycin D, and cyclophosphamide in pediatric rhabdomyosarcoma: A case report.

Hepatopathy induced by vincristine, actinomycin D and cyclophosphamide (VAC) is a potentially lethal complication of VAC chemotherapy for pediatric malignancy, which is managed by conventional anticoagulation and liver-supporting treatment alone. We report a case of VAC-induced hepatopathy with coagulopathy and severe inflammation. A 15-year-old male with rhabdomyosarcoma receiving adjuvant chemotherapy presented with refractory thrombocytopenia, followed by abdominal tenderness and non-neutropenic fever. Hepatic dysfunction and coagulopathy subsequently emerged with persistent fever. This condition indicated disseminated intravascular coagulation. A diagnosis of 'very severe' sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) was established in accordance with the European Society for Blood and Marrow Transplantation diagnostic criteria for hepatic SOS/VOD in children. Early administration of recombinant thrombomodulin (rTM) (380 U/kg/day) and prednisolone (1.8 mg/kg/day) successfully controlled the condition. Serum concentrations of pro-inflammatory cytokines increased with hepatopathy development but immediately decreased after drug initiation. rTM administration may be promising for the control of inflammatory VAC-induced hepatopathy.