Rate Of Febrile Neutropenia Research Articles

A Phase 1b Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of an Investigational Microbiome Therapeutic, SER-155, in Adults Undergoing Hematopoietic Stem Cell Transplantation

Background: In patients undergoing allogeneic hematopoietic cell transplantation (HCT), loss of gastrointestinal microbial diversity is associated with risk of bloodstream infections (BSI), acute graft-versus-host disease (aGvHD), and death. SER-155 is an investigational cultivated microbiome therapeutic rationally designed to improve clinical outcomes in HCT by restoring colonization resistance to potential pathogens, promoting epithelial barrier integrity, and reducing colonic inflammation. SER-155-001 is a Phase 1b study to evaluate the efficacy, safety, and pharmacokinetics (PK) of SER-155 in adults undergoing HCT that is currently enrolling at 4 sites. Study Design and Methods: This study will enroll approximately 70 subjects ≥ 18 years in an open-label Cohort 1 (n = 10) followed by a double-blind, placebo-controlled Cohort 2 (n = 60) randomized 1:1 to SER-155 or placebo and stratified by conditioning regimen intensity. Exclusion criteria include history of severe colitis or active inflammatory bowel disease or total colectomy, umbilical cord blood or ex vivo T-cell depletion, exposure to fecal microbiota transplant or any live microbial therapeutic within 3 months prior to screening, and evidence of relapse or progression of hematologic malignancy (minimal residual disease is allowed). Following screening, subjects in both cohorts will receive 2 treatment courses (before and after HCT), each comprised of microbiome conditioning with oral vancomycin or placebo followed by SER-155 or placebo, and a conditional 3rd treatment course if the subject receives antibiotics (Table 1; Figure 1). Safety outcomes will be followed through 52 weeks post HCT. The primary endpoint is to evaluate the incidence and severity of adverse events, serious adverse events, and adverse events of special interest. Secondary endpoints include rates of BSI, gastrointestinal infections, aGvHD, febrile neutropenia and overall survival in placebo vs SER-155 arms. Microbiome related endpoints include engraftment of SER-155 bacterial strains in the gastrointestinal tract (PK endpoint) and fecal microbiome diversity, composition and metabolites. In April 2022, the SER-155 Data and Safety Monitoring Committee met as part of a planned review of available safety data from Cohort 1 and supported continuation of Cohort 1 enrollment. Summary: In this Phase 1b study, the feasibility, safety, and clinical efficacy of SER-155 is being assessed in the setting of allogeneic HCT. This trial will add to the expanding clinical experience of microbiome-directed interventions in allogeneic HCT recipients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Clinical Outcomes, Prognostic Factors and Therapeutic Management in Extranodal Natural-Killer/T-Cell Lymphoma, Nasal-Type (ENKTL-NT) - Results of the Multicenter T-Cell Brazil Project

Introduction: Extranodal natural-killer/T-cell lymphoma, nasal-type (ENKTL-NT) is an aggressive, angiocentric, and extensively necrotic malignancy, universally associated with Epstein-Barr virus (EBV) infection. Although highly prevalent in South America, few studies involving cohorts from this region have been published. Brazil is the largest and most populous country in South America, but Brazilian data on ENKTL-NT are extremely scare. In order to fill this gap, the current study aims to describe clinical and laboratory characteristics, assess clinical outcomes, determine predictors of survival and compare responses between different therapeutic modalities applied in a multicenter cohort of Brazilian patients with ENKTL-NT. Methods: This is a retrospective, observational and multicenter study, involving 98 patients with ENKTL-NT diagnosed and treated at 20 different Brazilian institutions between January 2000 and December 2021. Endpoints included overall response rate (ORR), overall survival (OS) and progression-free survival (PFS). Survival curves were constructed using the Kaplan-Meier method and the Log-Rank test was used to assess the relationship between variables and outcomes. Univariate analysis was performed using the semi-parametric Cox test and multivariate analysis by Cox regression method or proportional ratios model. The results were presented in hazard ratio (HR) and 95% confidence interval (95% CI) and a p-value ≤ 0.05 was considered statistically significant. Results: The median age was 50 years (IqR 40-58) and 60.2% (59/98) were male. Sixty-three percent (62/98) had B-symptoms, 26.5% (26/98) had ECOG ≥ 2, 16.3% (16/98) had extranasal disease, 34.7% had advanced-stage III/IV, and 30.2% (29/98) had high-risk PINK score [Table 1A]. Table 1B summarizes the main therapeutic modalities, responses and associated adverse event profile among the 89/98 patients undergoing up-front treatment. With a median follow-up of 49.0 months (95% CI: 35.8-62.3), the estimated 2-year OS and PFS were 51.1% (95% CI: 40.4-61.6) and 17.7% (95% CI: 4.5-30.8), respectively. Among early-stage disease (IE/IIE) patients, the estimated 2-year OS were 81.3% (95% CI: 64.8-97.7) for SCRT (sequential chemoradiotherapy) followed by CHOP-like, 53.2% (95% CI: 29.3-77.1) for CCRT (concurrent chemoradiotherapy) followed by VIPD, and 50.5% (95% CI:21.4-79.5) for SCRT followed by asparaginase-based regimens, p=0.221 [Figure 1B]. CCRT-VIPD was associated with higher early-mortality (p=0.034), and higher rates of neutropenia (p=0.075), febrile neutropenia (p=0.043) and mucositis (p<0.001) [Table 1B]. Among advanced-stage (III/IV) disease, the estimated 2-year OS were 37.0% (95% CI: 8.9-65.0) for asparaginase-based regimens and 33.0% (95% CI: 1.9-68.5) for anthracycline-based regimens, p=0.851 [Figure 1C]. Chemoradiotherapy (CRT) was associated with benefit for OS (p=0.001) and PFS (p=0.007) compared to chemotherapy alone [Figure 1D and 1E]. In multivariate analysis, anemia (HR 2.052, p=0.038), lymphopenia [HR 3.600, p=0.012], advanced- stage disease (III/IV) [HR 3.101, p=0.007], bone marrow infiltration [HR 5.406, p=0.034] and omission of RT in up-front therapy [HR 2.791, p=0.023] were independent factors associated with decreased survival. Conclusion: High-dose EF-RT proved to be the cornerstone for the treatment of early-stage ENKTL-NT, and omission of this therapeutic modality was associated with decreased OS and PFS in Brazilian patients. In our real-life study, CCRT-VIPD regimen was poorly tolerated, and surprinsingly protocols based on anti-MDR agents were not associated with increased survival either in early- or advanced-stage disease. We also found that anemia, lymphopenia, advanced-stage (III/IV) and bone marrow involvement were independent predictors associated with poor clinical outcomes. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Obinutuzumab Versus Rituximab Based First-Line Chemoimmunotherapy for Follicular Lymphoma - a Real-World Multicenter Retrospective Cohort Study

Introduction - The recent GALLIUM study showed an advantage of 7% in progression free survival in favor of obinutuzumab (G) vs. rituximab (R) based immunochemotherapies as first line therapy in follicular lymphoma (FL) patients. Yet, the toxicity appears to be increased with obinutuzumab based therapy. Methods - To assess for toxicity we compared treatment for FL in the era before the approval of obinutuzumab by the Israeli health authorities on 1/1/2018 (rituximab-based therapy) to the era post approval (obinutuzumab-based therapy). This is a multicenter retrospective cohort study comprising five medical centers in Israel. All adult FL patients treated with first line chemo-immunotherapy were included. Comparison of G vs. R based chemo-immunotherapy was performed in order to assess real life toxicity profile between the two anti-CD20 monoclonal antibodies (R- and G-groups). Primary outcome was any infection recorded during the induction and 6 months post induction period. Secondary outcomes included rates of febrile neutropenia, severe infections defined as grade 3-4 infections, infections requiring intravenous (IV) antibiotics, life threatening infections or fatal infections, as well as rates of other non-hematological and hematological toxicities and treatment discontinuation. Response rates at the end of induction therapy were also recorded. Results - A total of 156 patients, treated between 1/1/2016-1/1/2019, were included in the analysis - 78 patients in each group. Most patients received bendamustine (n= 92, 59%) or CHOP (n=49, 31.4%) as the adjacent chemotherapy regimen. Baseline characteristics of patients were comparable between groups, apart from a higher incidence of diabetes mellitus and hypertension in the R-group. Any infection occurred in 69 patients (44.2%) of the cohort, and a total of 106 infectious episodes were recorded. Patients in the R- and G-groups had similar rates of any infection (44.8% and 43.5%, p=1), severe infections (43.3% vs. 47.8%, p=0.844), febrile neutropenia (15% vs. 19.6%, p=0.606) and treatment discontinuation (14.1% vs. 19.2%). Characteristics of the 106 infection episodes according to the R- versus G- groups are described in Table 1. Most other adverse events recorded, including hematological and non-hematological toxicities, were also comparable between groups, apart from higher rates of nausea and vomiting (30.7% vs. 11.5%, p=0.029) and fever from a non-infectious origin (32% vs. 10%, p=0.032) in the R-group. Overall, no statistically significant difference was evident in adverse events of grades 3 to 5 (hematological and non-hematological) between R and G-based treatments (76.9% vs. 82%, p=0.427) nor in complete remission rates at the end of induction therapy (79.5% vs. 84.6%, p=0.147). Baseline factors significantly associated with any infection in univariate analysis included female gender, chronic obstructive pulmonary disease, use of GCSF prophylaxis, elevated LDH, beta2 microglobulin and lower levels of hemoglobin before `treatment commencement. None of the parameters was found to be significantly associated with any infection in multivariable analysis, albeit gender and LDH values had a trend towards significance. Conclusions - In this first and largest real-life study of first line treated patients with follicular lymphoma, we did not observe excess toxicity with G- compared to R- based therapy during the induction and 6 months post induction period. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Effects of a Guideline-Informed Clinical Decision Support System Intervention to Improve Colony-Stimulating Factor Prescribing

Colony-stimulating factors are prescribed to patients undergoing chemotherapy to reduce the risk of febrile neutropenia. Research suggests that 55% to 95% of colony-stimulating factor prescribing is inconsistent with national guidelines. To examine whether a guideline-based standing order for primary prophylactic colony-stimulating factors improves use and reduces the incidence of febrile neutropenia. This cluster randomized clinical trial, the Trial Assessing CSF Prescribing Effectiveness and Risk (TrACER), involved 32 community oncology clinics in the US. Participants were adult patients with breast, colorectal, or non-small cell lung cancer initiating cancer therapy and enrolled between January 2016 and April 2020. Data analysis was performed from July to October 2021. Sites were randomized 3:1 to implementation of a guideline-based primary prophylactic colony-stimulating factor standing order system or usual care. Automated orders were added for high-risk regimens, and an alert not to prescribe was included for low-risk regimens. Risk was based on National Comprehensive Cancer Network guidelines. The primary outcome was to find an increase in colony-stimulating factor use among high-risk patients from 40% to 75%, a reduction in use among low-risk patients from 17% to 7%, and a 50% reduction in febrile neutropenia rates in the intervention group. Mixed model logistic regression adjusted for correlation of outcomes within a clinic. A total of 2946 patients (median [IQR] age, 59.0 [50.0-67.0] years; 2233 women [77.0%]; 2292 White [79.1%]) were enrolled; 2287 were randomized to the intervention, and 659 were randomized to usual care. Colony-stimulating factor use for patients receiving high-risk regimens was high and not significantly different between groups (847 of 950 patients [89.2%] in the intervention group vs 296 of 309 patients [95.8%] in the usual care group). Among high-risk patients, febrile neutropenia rates for the intervention (58 of 947 patients [6.1%]) and usual care (13 of 308 patients [4.2%]) groups were not significantly different. The febrile neutropenia rate for patients receiving high-risk regimens not receiving colony-stimulating factors was 14.9% (17 of 114 patients). Among the 585 patients receiving low-risk regimens, colony-stimulating factor use was low and did not differ between groups (29 of 457 patients [6.3%] in the intervention group vs 7 of 128 patients [5.5%] in the usual care group). Febrile neutropenia rates did not differ between usual care (1 of 127 patients [0.8%]) and the intervention (7 of 452 patients [1.5%]) groups. In this cluster randomized clinical trial, implementation of a guideline-informed standing order did not affect colony-stimulating factor use or febrile neutropenia rates in high-risk and low-risk patients. Overall, use was generally appropriate for the level of risk. Standing order interventions do not appear to be necessary or effective in the setting of prophylactic colony-stimulating factor prescribing. ClinicalTrials.gov Identifier: NCT02728596.

Can order entry systems improve oncology practice? The TrACER Experience.

339 Background: Primary prophylactic colony stimulating factors (PP-CSF) are prescribed to patients undergoing chemotherapy to reduce the risk of febrile neutropenia (FN). Prior research suggested poor adherence to PP-CSF prescribing relative to national guidelines. Accordingly, the objective of the TrACER study was to examine whether a guideline-based standing order entry (SOE) system for PP-CSF improves use and reduces FN. TrACER also included a substudy to evaluate the effectiveness of PP-CSF for patients receiving intermediate risk chemotherapy, where evidence of benefit is weaker. Methods: We conducted a patient-informed, cluster randomized trial among 32 oncology clinics from the NCI Community Oncology Research Program. Patients age ≥18 with breast, colorectal or non-small cell lung cancer initiating cancer therapy were enrolled. Clinics were randomized 3:1 to the implementation of a guideline-based PP-CSF SOE or usual care. Automated orders for PP-CSF were added for high-risk regimens and an alert not to use PP-CSF was included for low-risk regimens. Risk was based on National Comprehensive Cancer Network guidelines. A secondary 1:1 randomization for intermediate risk-regimens assigned 16 intervention sites to either SOE to prescribe or an alert to not prescribe PP-CSF. Results: 2,946 patients were enrolled (2287 intervention, 659 usual care). PP-CSF use among high-risk patients was high and not significantly different between arms (89.2% SOE; 95.8% usual care). FN rates for the SOE and usual care arms were 6.1% and 4.2% and not significantly different. The FN rate among high-risk patients not receiving PP-CSF was 14.9%. Among the 585 patients receiving low-risk regimens, PP-CSF use was low and not different between arms (6.3% SOE, 5.5% usual care). FN rates did not differ between the SOE system (1.5%) and usual care (0.8%). In contrast, for the intermediate risk substudy, rates of PP-CSF use were substantially higher among sites randomized to SOE (37.1% vs 9.9%, OR = 5.91(95% CI 1.77-19.70; p = 0.0038), and rates of FN were low and identical between arms (3.7% vs 3.7%). Similarly, FN rates did not differ between intermediate-risk patients that did or did not receive PP-CSF, irrespective of assignment. Conclusions: Implementation of a guideline-informed SOE system did not impact PP-CSF use or FN rates in high- and low-risk patients, where evidence supporting PP-CSF is stronger, and had a significant impact on PP-CSF use but not FN rates among intermediate risk patients, where evidence of benefit is weak. Overall, adherence to PP-CSF for low- and high-risk chemotherapy was much better than predicted based on evidence available at trial design. SOE interventions may be more useful in situations where more uncertainty of benefit exists. The pragmatic trial design provides high-quality evidence that had previously been lacking on the use and performance of PP-CSF in real world settings across the spectrum of FN risk. Clinical trial information: NCT02728596.

AML-119 The Impact of Post-Remission Granulocyte Colony-Stimulating Factor (G-CSF) Use (G-CSFu) in the Phase 3 Studies of Venetoclax (Ven) Combination Treatments in Patients (Pts) With Newly Diagnosed Acute Myeloid Leukemia (AML)

In VIALE-A (NCT02993523) and VIALE-C (NCT03069352), Ven+azacitidine (Aza) and low-dose cytarabine (LDAC), respectively, improved outcomes in pts with intensive chemotherapy (IC)-ineligble newly diagnosed AML. To explore outcomes in pts with G-CSFu. VIALE-A/C, dosing and treatment schedule were previously described. G-CSFu was given per institutional practice. Pts who achieved complete remission (CR) or CR with incomplete hematologic recovery (CRi) were analyzed by G-CSFu. In VIALE-A/C, baseline demographics were similar in Ven-treated pts regardless of G-CSFu. In VIALE-A, 190/286 pts (66%) treated with Ven+Aza and 41/145(28%) pts treated with placebo (PBO)+Aza achieved CR/CRi; 93(49%) and 10(24%) pts with CR/CRi received G-CSF (median time to first G-CSFu[range], 36d[2-483] and 35d[4-127]), respectively. Median duration of response (mDOR) for CR/CRi (95% CI) was not reached (NR; 17.5-NR) and 12.9mo(7.9-17.3) in the Ven+Aza+G-CSF and Ven+Aza+non-G-CSF groups, respectively; DOR at 12mo was 67% and 53%. Among 164 evaluable pts, measurable residual disease response (MRD<10-3) was achieved by 67, of whom 38(57%) had G-CSFu. Median overall survival (mOS[95% CI) was NR(NR-NR) with Ven+Aza+G-CSF and was 21.1mo(15.2-NR) with Ven+Aza+non-G-CSF; 12-mo OS rates were 83% and 71%. Post-remission Gr ≥3 neutropenia and febrile neutropenia (FN) rates were 33%(n=31) and 39%(n=36) with Ven+Aza+G-CSF, and 29%(n=28) and 20%(n=19) with Ven+Aza+non-G-CSF, respectively. Median durations of post-remission Gr ≥3 neutropenia and FN were 12.5d and 8d (Ven+Aza+G-CSF), and 16d and 10.5d (Ven+Aza+non-G-CSF). In VIALE-C, 69/143 pts (48%) treated with Ven+LDAC and 9/68(13%) pts treated with PBO+LDAC achieved CR/CRi; 30(43%) and 2(22%) received G-CSF (median time to first G-CSFu[range], 30d[2-459] and 229d[169-289]), respectively. mDOR was 10.8(4.9-17.8) and 11.8mo(5.9-NR) in the Ven+LDAC+G-CSF and Ven+LDAC+non-G-CSF groups, respectively; DOR at 12mo was 45% and 49%. mOS was 20.8mo(11.9-NR) with Ven+LDAC+G-CSF and 13.7mo(10.8-NR) with Ven+LDAC+non-G-CSF; 12-mo OS were ~68% and ~57%; 9/64 evaluable pts achieved MRD<10-3, of whom 6(67%) had G-CSFu. Post-remission Gr ≥3 neutropenia and FN rates were 53%(n=16) and 23%(n=7) with Ven+LDAC+G-CSF, and 51%(n=20) and 8%(n=3) with Ven+LDAC+non-G-CSF, respectively. Median durations of post-remission Gr≥3 neutropenia and FN were 15d and 6d(Ven+LDAC+G-CSF), and 12.5d and 29d(Ven+LDAC+non-G-CSF). Gr ≥3 neutropenia and FN with G-CSFu trended towards shorter duration, without negative impact on DOR or OS.

CLINICAL OUTCOMES, PROGNOSTIC FACTORS AND THERAPEUTIC MANAGEMENT IN EXTRANODAL NATURAL-KILLER/T-CELL LYMPHOMA, NASAL-TYPE (ENKTL-NT) – RESULTS OF THE MULTICENTER T-CELL BRAZIL PROJECT

Extranodal natural-killer / T-cell lymphoma, nasal-type (ENKTL-NT) is an aggressive, angiocentric, and extensively necrotic malignancy, universally associated with Epstein-Barr virus (EBV) infection. Although highly prevalent in South America, few studies involving cohorts from this region have been published. Brazil is the largest and most populous country in South America, but Brazilian data on ENKTL-NT are extremely scare. In order to fill this gap, the current study aims to describe clinical and laboratory characteristics, assess clinical outcomes, determine predictors of survival and compare responses between different therapeutic modalities applied in a multicenter cohort of Brazilian patients with ENKTL-NT. This is a retrospective, observational and multicenter study, involving 98 patients with ENKTL-NT diagnosed and treated at 20 different Brazilian institutions between January 2000 and December 2021. Endpoints included overall response rate (ORR), overall survival (OS) and progression-free survival (PFS). Survival curves were constructed using the Kaplan-Meier method and the Log-Rank test was used to assess the relationship between variables and outcomes. Univariate analysis was performed using the semi-parametric Cox test and multivariate analysis by Cox regression method or proportional ratios model. The median age was 50 years (IqR 40-58) and 60.2% (59 / 98) were male. Sixty-three percent (62 / 98) had B-symptoms, 26.5% (26 / 98) had ECOG ≥ 2, 16.3% (16 / 98) had extranasal disease, 34.7% had advanced-stage III / IV, and 30.2% (29 / 98) had high-risk PINK score. With a median follow-up of 49.0 months (95% CI: 35.8-62.3), the estimated 2-year OS and PFS were 51.1% (95% CI: 40.4-61.6) and 17.7% (95% CI: 4.5-30.8), respectively. Among early-stage disease (IE / IIE) patients, the estimated 2-year OS were 81.3% (95% CI: 64.8-97.7) for SCRT (sequential chemoradiotherapy) followed by CHOP-like, 53.2% (95% CI: 29.3-77.1) for CCRT (concurrent chemoradiotherapy) followed by VIPD, and 50.5% (95% CI:21.4-79.5) for SCRT followed by asparaginase-based regimens, p = 0.221. CCRT-VIPD was associated with higher early-mortality (p = 0.034), and higher rates of neutropenia (p = 0.075), febrile neutropenia (p = 0.043) and mucositis (p < 0.001). Among advanced-stage (III / IV) disease, the estimated 2-year OS were 37.0% (95% CI: 8.9-65.0) for asparaginase-based regimens and 33.0% (95% CI: 1.9-68.5) for anthracycline-based regimens, p = 0.851. Chemoradiotherapy (CRT) was associated with benefit for OS (p = 0.001) and PFS (p = 0.007) compared to chemotherapy alone. In multivariate analysis, anemia (HR 2.052, p = 0.038), lymphopenia [HR 3.600, p = 0.012], advanced- stage disease (III / IV) [HR 3.101, p = 0.007], bone marrow infiltration [HR 5.406, p = 0.034] and omission of RT in up-front therapy [HR 2.791, p = 0.023] were independent factors associated with decreased survival. High-dose EF-RT proved to be the cornerstone for the treatment of early-stage ENKTL-NT, and omission of this therapeutic modality was associated with decreased OS and PFS in Brazilian patients. In our real-life study, CCRT-VIPD regimen was poorly tolerated, and surprinsingly protocols based on anti-MDR agents were not associated with increased survival either in early- or advanced-stage disease. We also found that anemia, lymphopenia, advanced-stage (III/IV) and bone marrow involvement were independent predictors associated with poor clinical outcomes.

Concurrent Chemoradiotherapy With Docetaxel, Cisplatin, and 5-Fluorouracil (DCF-RT) for Patients With Potentially Resectable Esophageal Cancer.

We evaluated the long-term outcome of docetaxel, cisplatin, and 5-fluorouracil as combination chemoradiotherapy (DCF-RT) for patients with potentially resectable esophageal cancer (EC) in clinical settings. Twenty-eight patients with potentially resectable thoracic EC were included in this study. Chemotherapy consisted of intravenous docetaxel at 50 mg/m2 (day 1), CDDP at 60 mg/m2 (day 1), and 5-FU at 600 mg/m2 (days 1 to 4), repeated every four weeks for two cycles along with radiotherapy (60 Gy in 30 fractions). Potentially resectable esophageal cancer was defined as clinical stage (cStage) I, II, III, and IV with supraclavicular lymph node metastasis [M1(Lym)]. The overall complete response (CR) rate was 88.5%. The 5-year overall survival (OS) rates for cStage I, cStage II-III, and IV [M1(lym)] patients were 79.5%, 76.2%, and 50.0%, respectively. The most frequent grade 3 or 4 acute toxicities were leucopenia (85.7%), neutropenia (78.5%), and febrile neutropenia (FN) (21.4%). The rate of any grade 3 or 4 late toxicity was 7.7%. DCF-RT demonstrated a satisfactory CR rate and OS with a higher rate of FN for potentially resectable thoracic EC patients. Prophylactic treatment with granulocyte-colony-stimulating factor and antibiotics may be appropriate supportive care for patients undergoing DCF-RT.

Real-world outcomes of cisplatin, capecitabine, and gemcitabine with either epirubicin (PEXG) or docetaxel (PDXG) as first-line palliative treatment in metastatic or unresectable locally advanced pancreatic adenocarcinoma.

First-line palliative chemotherapy regimens in advanced pancreatic adenocarcinoma include triplet chemotherapy with 5-fluorouracil, oxaliplatin, and irinotecan, and the doublet of nab-paclitaxel plus gemcitabine. Use of triplet chemotherapy in real-world populations is limited by tolerability and nab-paclitaxel is not universally available. Regimens using the combination of cisplatin, capecitabine, gemcitabine, and either epirubicin or docetaxel may be better tolerated, more widely available, and similarly effective, but no published real-world data exist. A retrospective cohort review of patients with metastatic or unresectable locally advanced pancreatic adenocarcinoma treated with first-line palliative cisplatin, capecitabine, gemcitabine, and either epirubicin or docetaxel chemotherapy at Auckland City Hospital between July 1, 2013 and July 30, 2020. The primary outcome was overall survival (OS). Secondary outcomes were rates of grade 3 or 4 hematological toxicity, rate of febrile neutropenia, number of cycles received, and reasons for discontinuation. Eighty-eight patients were included. Median age was 66years (range 39-79), 28.4% had unresectable, locally advanced disease and 71.6% metastatic disease. Median OS was 8.5months. Patients stopped treatment due to disease progression (53.4%), completing 12 cycles (19.3%), or toxicity (10.2%). Grade 4 neutropenia was experienced by 21.6%; 10.2% had febrile neutropenia. There were four treatment-related deaths. This retrospective study in a real-world population demonstrates that chemotherapy with cisplatin, capecitabine, and gemcitabine with epirubicin (PEXG) or docetaxel (PDXG) had similar effectiveness to more commonly used combination regimens. PDXG/PEXG are viable alternatives to nab-paclitaxel plus gemcitabine in countries that have restricted drug funding.

1615P The association of social distancing and obligatory face masks during COVID-19 era with the rates of febrile neutropenia in patients with solid tumors receiving antineoplastic therapy

Febrile neutropenia (FN) is a major complication of anti-neoplastic therapy, with significant morbidity and mortality. While granulocytes colony stimulating factors (G-CSF) and hand sanitation are proven preventive measurements, facial mask is not routinely recommended. COVID-19 pandemic led to obligatory social distancing and use of masks in public places. We aimed to assess whether these preventive measurements were associated with reduced rate of FN in patients receiving chemotherapy.

Infectious complications of cyclin-dependent kinases 4 and 6 inhibitors in patients with hormone-receptor-positive metastatic breast cancer: a systematic review and meta-analysis.

The combination of cyclin-dependent kinase 4 and 6 (CDK 4/6) inhibitors plus endocrine therapy (ET) improved the survival outcomes and became the standard of care in the treatment of metastatic hormone-positive breast cancer. However, these combinations increased the risk of neutropenia compared with ET alone. While the infection-related mortalities did not seem to be increased, the exact risk of infections with CDK 4/6 inhibitor and ET combinations is relatively understudied. Therefore, we performed a meta-analysis of CDK 4/6 inhibitor clinical trials to assess the infection risk of adding CDK4/6 inhibitors to ET. We systemically searched the PubMed database for relevant clinical trials. For each study, all grade and grade 3 or higher infections, upper respiratory tract infections (URTI), urinary tract infections (UTI), pneumonia, and febrile neutropenia rates were recorded whenever available. The hazard ratios (HR) with a 95% confidence interval (CI) of infection risk were calculated via the generic inverse-variance method with a random-effects model. Nine eligible studies were included in the analyses (MONALEESA-2,3,7, MONARCH-2,3, MONARCH plus, PALOMA-1,2,3). In the meta-analysis of these studies, CDK 4/6 inhibitors plus ET arms were associated with increased all grade infections (HR 1.77, 95% CI 1.56-2.01, p < 0.00001), grade 3 or higher infections, (HR 1.77, 95% CI 1.28-2.43, p = 0.0005), UTIs (HR 1.59, 95% CI 1.19-2.12, p = 0.002), and febrile neutropenia (HR 4.28, 95% CI 1.73-10.62, p = 0.002). In this meta-analysis, we observed that adding CDK4/6 inhibitors to ET significantly increased the risk of all grade, grade 3 or higher infections, and urinary tract infections. We propose that closer follow-up for infections should be considered for metastatic breast cancer patients using CDK 4/6 inhibitors. This may help clinicians to recognize infections earlier which prevents early death from infection.

Decreased incidence of febrile neutropenia in Michigan following masking and social distancing orders for the COVID-19 pandemic: A population based cohort study.

BACKGROUNDIt has been theorized that 75%-80% of febrile neutropenia (FN) is caused by endogenous pathogens, while up to 20% of cases are thought to be caused by a viral infection. It is unknown if precautions such as masking and social distancing reduce the risk of FN in susceptible populations.AIMTo determine whether coronavirus disease 2019 (COVID-19) infection mitigation efforts, namely masking and social distancing, were associated with a reduction in the incidence of FN.METHODSThis was a retrospective population based cohort study comparing the incidence of FN in the 13 mo prior to (Year 0) and 13 mo following (Year 1) the public health executive orders (PHEO) in Michigan. Data was queried for all emergency department (ED) visits from April 1, 2019 to March 31, 2021 from the National Syndromic Surveillance Program, a program which collects data that is voluntarily submitted by approximately 89% of Michigan EDs. The primary study outcome was the incidence of FN as a proportion of ED visits in the 13-mo before and 13-mo after COVID-19 mitigations efforts, namely masking and social distancing. We hypothesized that there would be a significant decrease in the incidence of FN in the period following the PHEO aimed at reducing the spread of the severe acute respiratory syndrome coronavirus 2 virus.RESULTSThere was a total of 8979221 total ED visits captured during the study period. In Year 0 there were 5073081 recorded ED visits and 3906140 in Year 1. There was a significant reduction in the proportion of total ED visits with a diagnosis of FN, decreasing 13.3% across periods (0.15% vs 0.13%, P = 0.036). In patients with a hematologic malignancy a more impressive reduction in the incidence of FN was evident following PHEO (22% vs 17%, P = 0.02).CONCLUSIONWe found a significant association between social distancing and mask guidelines implemented on a large public scale with decreased rates of FN, particularly in those with a hematologic malignancy. These findings may be useful in the design of future research and recommendations regarding the prevention of FN.

The effect of cryopreserved and noncryopreserved stem cells on the outcome of autologous stem-cell transplantation in multiple myeloma patients

Background The CD34+ stem cells are either noncryopreserved (non-CP) or cryopreserved (CP) in autologous stem-cell transplantation (ASCT). Some retrospective studies have shown that engraftment failure and engraftment rate are similar in CP cells and infusion reactions are lower in CP cells due to the absence of dimethyl sulfoxide. Objective In this study, we presented our clinical experience comparing the outcomes and safety of ASCT with CP and non-CP stem cells. Patients and methods A total of 163 patients were enrolled between January 2019 and June 2021. Duration of neutrophil/platelet engraftment, rates of infusion-related reactions, febrile neutropenia, and duration of hospitalization were compared between the CP and non-CP groups. Results Fifty five (33.7%) received CP cells, 108 (66.3%) received non-CP cells. The median dose of CD34+ cells was similar in both groups (P=0.755). The median duration of neutrophil and platelet engraftment was not statistically significantly different in CP and non-CP groups (P=0.896 and 0.183, respectively). No statistical difference was observed in the median duration of hospitalization between the two groups [CP: 16 (13–26) vs. non-CP: 15 (11–31) days, P=0.124]. The febrile neutropenia rate was higher in the CP group, but there was no statistical difference between the two groups (CP: 56.4% vs. non-CP, 48.1%, P=0.301). The rates of infusion-related reaction such as nausea, vomiting, and rash were higher in the CP group (21.8 vs. 12%), with no statistically significant difference (P=0.159). Conclusion Non-CP cells have similar outcomes to CP cells and lower toxicity than CP cells, which are safe and effective in ASCT.

Effectiveness and cost-effectiveness of trastuzumab emtansine in women with HER2-positive locally advanced or metastatic breast cancer: A systematic review and meta-analysis.

Trastuzumab emtansine (T-DM1) is a human epidermal growth factor receptor-2 targeted antibody-drug conjugate that contains a monoclonal antibody, trastuzumab, covalently linked to DM1, a small molecule cytotoxin. We conducted a systematic review and meta-analysis of published trials to examine the efficacy and safety of T-DM1 for patients with HER2-positive metastatic breast cancer. In addition, we systematically reviewed existing economic evaluations of T-DM1. An electronic literature search of online databases (Medline, CENTRAL, and Embase) was performed. Randomized controlled trials that compared T-DM1 with other active treatment agents were eligible for inclusion. In addition, studies that involved T-DM1 as one of the treatment comparators in an economic evaluation were included. Four trials with a total of 2462 participants were included in this meta-analysis. Pooled results showed T-DM1 substantially improved overall survival (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.67-0.85; I2 = 0%) and progression-free survival (HR, 0.67; 95% CI, 0.52-0.85; I2 = 75%). In addition, T-DM1 showed greater association with severe thrombocytopenia and liver dysfunction than other regimens, but a lower rate of neutropenia, leukopenia, febrile neutropenia, asthenia, and diarrhea. All four trials included in the meta-analysis overall had a low risk of bias. Two cost-utility analyses involving T-DM1 were identified, and the overall quality was high. T-DM1 is effective for the treatment of patients with HER2-positive metastatic breast cancer, and it demonstrates a tolerable safety profile compared with other active controls. Little evidence was available regarding the cost-effectiveness of T-DM1 so no conclusions can be drawn.

Does castration status affect docetaxel-related adverse events? :Identification of risk factors for docetaxel-related adverse events in metastatic prostate cancer.

Docetaxel-related adverse events (AEs) such as neutropenia and febrile neutropenia (FN) can be life-threatening. A previous in vivo study raised the hypothesis that the castration status affects the rate of hematologic AEs. We aimed to investigate the impact of castration status on the incidence of docetaxel-related AE in metastatic prostate cancer (mPCa) patients. We retrospectively analyzed the records of 265 mPCa patients treated with docetaxel, comprising 92 patients with metastatic hormone-sensitive prostate cancer (mHSPC) and 173 patients with metastatic castration-resistant prostate cancer (mCRPC) between January 2015 and December 2021. Common terminology Criteria for Adverse Events (CTCAE) was applied to evaluate AEs. We analyzed the differential incidences between mHSPC and mCRPC, and risk factors of hematologic and nonhematologic AEs using a logistic regression model. The rate of patients who received primary prophylaxis against neutropenia was higher in those with the mHSPC compared with those with the mCRPC (7.5% vs. 33%, p < 0.001). Among the patients without primary prophylaxis, incidence rates of severe neutropenia (CTCAE ≥ Grade3) and FN were 89% and 16% in patients with mCRPC compared to 81% and 18% in those with mHSPC. Logistic regression analysis revealed that age ≥ 75 years and failure to provide primary prophylaxis were independent risk factors of severe neutropenia (odds ratio [OR]: 2.39, 95% confidential interval [CI]: 1.10-5.18 and OR: 15.8, 95% CI: 7.23-34.6, respectively). Eastern Cooperative Oncology Group Performance Status (ECOG-PS) ≧ 1 was an independent risk factor of FN (OR: 2.26, 95% CI: 1.13-4.54). Castration status (mHSPC vs. mCRPC) was not associated with the risks of severe neutropenia and FN. Castration status did not affect the risk of severe neutropenia or FN in mPCa patients treated with docetaxel regardless of the disease state. Failure to provide primary prophylaxis and advanced patient age are independent risk factors of severe neutropenia; while patients with poor PS are more likely to develop FN. These findings may help guide the clinical decision-making for proper candidate selection of docetaxel treatment.

S207: EFFICACY AND SAFETY OF A THIRD GENERATION CD20 CART (MB-106) FOR TREATMENT OF RELAPSED/REFRACTORY FOLLICULAR LYMPHOMA (FL)

Background: Follicular lymphoma (FL) is incurable and novel treatments with high efficacy and low toxicity are needed. Chimeric antigen receptor T-cells (CAR-T) targeting CD19 are effective, and axicabtagene ciloleucel is currently approved by FDA for treatment of patients (pts) with relapsed FL, but toxicities like cytokine-release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) may limit its use. MB-106 is a fully human 3rd-generation CD20-targeted CAR-T product with both 4-1BB and CD28 costimulatory domains. Aims: We present the results of the FL cohort from our ongoing phase I/II clinical trial investigating MB-106 for B-cell lymphoma/CLL. Methods: Pts with R/R B-cell malignancies including FL were eligible after confirmation of CD20 expression. Prior treatment with CD19 CAR-T is permitted. Lymphodepletion (LD) consists of cyclophosphamide (Cy) ± fludarabine (Flu). CAR-T cells are administered at one of 4 dose levels (DL): DL1: 3.3x105, DL2: 1x106, DL3: 3.3x106, DL4: 1x107 CAR T cells/kg. A continual reassessment method dose escalation design was used to find the maximally tolerated dose. CAR-T was infused in the outpatient setting except for the first pt of each dose cohort (overnight observation). Initial treatment response is assessed on day 28 and best response is reported here. CRS and ICANS are graded per ASTCT. Results: Between Dec 2019 and Dec 2021, 16 pts with FL were treated and had day 28 assessment. Median age was 61.5 years (range: 45 – 81). High-risk features included pts with progression of disease within 24 months of first-line chemotherapy (POD24) (n=11; 69%), history of histologic transformation (n=3; 19%), prior treatment with a CD19 targeted CAR-T (n=1; 6%). 6 pts (37.5%) had a PI3 kinase inhibitor. Median time between leukapheresis and LD was 15 days (range: 9-21) and 2 pts received bridging therapy with lenalidomide (1) and high-dose corticosteroids (1). All DLs were reached (DL0=1, DL1=1, DL2=4, DL3=7, DL4=2), with no dose-limiting toxicities. All CRS events were grade 1 (n=4; 25%) or grade 2 (n=1; 6%), with no grade ≥ 3 CRS events. There was no occurrence of ICANS of any grade. No pts had tumor lysis syndrome or Gr 3-4 infections. In the first 28 days, thrombocytopenia (Gr 3-4: 12.5%) and neutropenia (Gr 3-4: 94%) were common but there were no bleeding complications, and the rate of febrile neutropenia was 25%. Overall response (ORR) rate was 94% (15/16) and a complete response (CR) rate was 75% (12/16). Pts who received DL3 or DL4, had an ORR 100% and CR rate of 89%. The single patient who had previously been treated with a CD19 targeted CAR-T achieved a CR. With median follow-up of 10 months, one patient died, from complications of myelodysplastic syndrome (MDS) while still in remission; the MDS was attributed to the prior treatments (7 lines of chemo-based therapy and radioimmunotherapy). Most of the remissions are ongoing and 4 pts have relapsed during the follow-up median 7 months after treatment (range 3-10.5). CAR T cells were detectable by flow cytometry at last available timepoint (up to 2 years) for 15 of 16 patients. One patient had undetectable CAR T cells by day 201. Summary/Conclusion: Treatment with MB-106, a third generation CD20 targeting CAR-T, resulted in high ORR and CR rates and CAR-T persistence in FL pts and was associated with favorable safety profile with no occurrence of Gr 3 or Gr 4 CRS and no ICANS event of any grade. A multicenter trial for treatment of B-cell malignancies including FL will start enrollment in 2022.

Real-world febrile neutropenia rates with same-day versus next-day pegfilgrastim after myelosuppressive chemotherapy.

Aim: To compare the incidence of febrile neutropenia (FN) after same-day versus next-day pegfilgrastim. Materials & methods: This single-institution, real-world, retrospective electronic health record-based study included patients who received chemotherapy and prophylactic same-day or next-day pegfilgrastim/pegfilgrastim-cbqv. Results: In cycle 1,117 patients received same-day pegfilgrastim and 180 patients received next-day pegfilgrastim. FN episodes in cycle 1 occurred in 6.0versus 6.7% of patients with same-day versus next-day pegfilgrastim, respectively (p=0.814). Across all cycles, 8.5and 9.4% of patients experienced ≥1 FN episode after same-day versus next-day pegfilgrastim, respectively (p=0.793). In the breast cancer patient subgroup, FN occurred 3.2% of same-day pegfilgrastim cycles versus 1.8% of next-day pegfilgrastim cycles (p=0.938). Conclusion: No significant differences were detected between same-day and next-day pegfilgrastim administration.

A pragmatic cluster-randomized trial of a standing physician order entry intervention for colony stimulating factor use among patients at intermediate risk for febrile neutropenia (SWOG S1415CD).

1518 Background: Primary prophylactic colony stimulating factors (PP-CSF) are prescribed to patients undergoing chemotherapy to reduce the risk of febrile neutropenia (FN) but their benefit for regimens with intermediate FN risk is uncertain. Within a pragmatic, randomized trial of a standing order entry (SOE) intervention for prescribing PP-CSF, we designed a substudy to evaluate the effectiveness of PP-CSF for patients receiving therapy with intermediate FN risk. Methods: TrACER was a cluster randomized trial where NCI community Oncology Research Program practices were randomized to usual care (UC) or a guideline-based SOE intervention. In the primary study, sites were randomized 3:1 to a SOE of automated PP-CSF orders for NCCN-designated high FN risk chemotherapy regimens and alerts against PP-CSF orders for low FN risk regimens (intervention) versus usual care. A secondary randomization assigned intervention sites to a SOE intervention either to prescribe or not prescribe PP-CSF for patients receiving intermediate FN risk regimens. Clinicians were allowed to override the SOE. Patients age ≥18 with either breast, colorectal or non-small cell lung cancer were enrolled and followed for 12 mo. PP-CSF was defined as initiation within 24-72 hours after systemic chemotherapy. Sample size calculations were based on an FN risk reduction from 15% to 7.5%, and provided 80% power at a planned enrollment of 90 patients per site. Mixed effect logistic regression models were used to test differences between sites randomized to prescribe or not prescribe PP-CSF. Results: Between January 2016 and April 2020, 24 sites (2,287 patients) were randomized to the intervention. Among intervention sites, 12 were randomized to either SOE to prescribe or an alert to not prescribe PP-CSF for the 542 patients receiving intermediate FN risk regimens. Rates of PP-CSF use were higher among sites randomized to prescribe PP-CSF (37.1% vs 9.9%, OR = 5.90 (95% CI 1.72-20.20; p = 0.0048)). Overall, the rates of FN were low and identical between PP-CSF and no PP-CSF arms (3.7% vs 3.7%). Among patients who did not receive PP-CSF, rates of FN were also low and similar between arms (3.8% vs 4.1%). Conclusions: While implementation of a SOE intervention for PP-CSF significantly increased PP-CSF use among patients receiving intermediate risk regimens, FN rates did not differ between arms. Despite SOE, 63% of patients assigned to receive PP-CSF did not receive it. FN rates overall were lower than expected and did not differ between patients that did or did not receive PP-CSF. Although this guideline-informed SOE influenced prescribing, the results suggest that neither the SOE nor PP-CSF itself provide sufficient benefit to justify their use for persons receiving intermediate FN risk regimens. Clinical trial information: NCT02728596.

The impact of COVID-19 lockdown measures on rates of febrile neutropenia in a cohort of Irish patients receiving chemotherapy.

e18784 Background: Febrile neutropenia in patients receiving chemotherapy is a life-threatening condition requiring prompt attention. This condition may also result in dose reductions, delays, or discontinuations of chemotherapy which compromise patient outcomes. This study seeks to evaluate the impact of COVID19 “lockdown” public health measures in Ireland on the incidence of febrile neutropenia in patients who were receiving cytotoxic chemotherapy regimens. Methods: All patients receiving chemotherapy at the Bon Secours Hospital Cork who were admitted with neutropenia and fever during two separate time periods were included in the study: 1st April 2018 to 31st March 2019 (“pre-pandemic year”) and 1st April 2020 to 31st March 2021 (“pandemic year”). The pandemic year selected equates to a period of heightened infection control measures in Irish society, featuring public health advice re social distancing, routine mask wearing in public and successive lockdown waves. Retrospective chart review was performed on all patients admitted to the oncology inpatient ward who had blood cultures on admission to determine the number of these patients who were neutropenic at the time of blood culture draw. Similarly, pharmacy records were accessed to determine the number of unique chemotherapy items dispensed in each year in order to establish a rate of febrile neutropenia episodes per 100 chemotherapy items dispensed for each period. The incident rate ratio was calculated using the Exact Poisson Test. Results: During the pre-pandemic year there were 57 individual admissions with febrile neutropenia compared with 32 admissions during the pandemic year. There were 4581 chemotherapy units dispensed during the pre-pandemic year compared to 4628 during the pandemic year. The rate of febrile neutropenia episodes per 100 chemotherapy units dispensed was 1.24 (95% CI 0.94, 1.61) in the pre-pandemic year and 0.69 (95% CI 0.47, 0.98) in the pandemic year. The incident rate ratio is 1.80 (95% CI 1.14, 2.87, two-sided P = 0.007). 9 of 57 (16%) admissions in the pre-pandemic year were associated with positive blood cultures compared with 4 of 32 (13%) in the pandemic year (not significant by Fisher's exact test). Conclusions: Increased precautionary infection control measures during the COVID19 pandemic public health restrictions correlated with a significant reduction in the rate of febrile neutropenia amongst patients receiving cytotoxic chemotherapy. This suggests that there may be a role for similar measures for this patient cohort in the post-pandemic period. Options which patients may consider to employ include social distancing, wearing face-coverings and restricting social contacts while at risk of neutropenia from cytotoxic chemotherapy regimens.

A pragmatic cluster-randomized trial of a computerized clinical decision support system to improve colony stimulating factor prescribing for patients with cancer receiving myelosuppressive chemotherapy (SWOG S1415CD).

1525 Background: Primary prophylactic colony stimulating factors (PP-CSF) are prescribed to patients undergoing chemotherapy to reduce the risk of febrile neutropenia (FN). Prior studies have shown that 55-95% of CSF prescribing is inconsistent with practice guidelines. We conducted a cluster randomized trial to determine if guideline-informed standing orders for PP-CSF improved prescribing and reduced the incidence of FN. Methods: Patients age ≥18 with breast, colorectal or non-small cell lung cancer initiating first cancer-directed therapy with NCCN-recommended regimens were eligible. The intervention consisted of automated PP-CSF orders for high FN risk chemotherapy regimens and an alert not to use PP-CSF for low FN risk regimens. Regimen FN risk was based on NCCN guidelines. Clinicians could override the orders. Primary and secondary outcomes were PP-CSF use among patients receiving high and low risk regimens FN incidence within 6 months of initial therapy. Sample size estimates assumed an FN risk of 25% for high-risk chemotherapy. 32 NCI Community Oncology Research Program (NCORP) practices randomized 3:1 to the order entry system (intervention) versus usual care (UC) provided 90% power to detect a 50% reduction in FN at a planned enrollment of 90 patients per site. Mixed effect logistic regression models were used to test differences among randomized sites. 13 practices with pre-existing PP-CSF order sets enrolled in a parallel cohort study. Patients and other stakeholder groups informed study design, conduct and reporting. Results: Between January 2016 and April 2020, 2,946 patients were randomized (2287 intervention, 659 UC); 718 were enrolled in the cohort. Mean age across arms was 58.1. 77% of patients were female; 61% diagnosed with breast cancer. Among patients receiving high-risk regimens, PP-CSF use did not differ between arms (89.2% intervention; 95.8% UC, adjusted p = 0.21) and was similar to the cohort patients (93.0%). The FN rate for high-risk patients was 5.7% in intervention clinics and 4.2% in UC clinics (adjusted p = 0.26); FN was 14.9% among high-risk patients who did not receive PP-CSF. Among patients receiving low-risk regimens, PP-CSF use did not differ between arms (intervention 6.3%, UC 5.5%, adjusted p = 0.74) and was slightly lower than the cohort (8.3%). FN rates did not differ between low risk groups (intervention 1.5%, UC 0.8%, adjusted p = 0.51). Conclusions: Guideline-informed standing orders did not increase PP-CSF use in high-risk patients, nor did it decrease use in low-risk patients. Adherence to guidelines in both risk groups exceeded historical reports. FN rates among patients not receiving PP-CSF were substantially below those reported in CSF guidelines. Automated standing orders for PP-CSF do not appear to be helpful or necessary. Clinical trial information: NCT02728596.