Incidence Of Neutropenia Research Articles

The Role of the Intestinal Microbiome in Antibiotic Associated Neutropenia

Prolonged antibiotic administration has been associated with bone marrow suppression in approximately 10-15% of patients. The mechanisms that underlie the association between prolonged antibiotic therapy and bone marrow suppression, including neutropenia, remain poorly understood. Our recent studies in murine models demonstrated that prolonged broad-spectrum antibiotics suppress hematopoiesis by depletion of the intestinal microbiota. Furthermore, oral administration of the microbial metabolites nucleotide-binding oligomerization domain-containing protein 1 ligand (NOD1L) and desaminotyrosine (DAT) was sufficient to restore normal hematopoiesis in antibiotic-treated mice. Additionally, Type I IFN signaling in hematopoietic cells was noted to be critical for the intestinal microbiota to promote hematopoiesis, as administration of IFNα during antibiotic therapy rescued normal hematopoiesis. These findings support a paradigm in which products of the intestinal microbiota enter the bloodstream and travel to the bone marrow where they promote the production of growth cytokines that support normal hematopoiesis. To elucidate whether changes in the microbiome similar to those observed in mice also occur in humans treated with prolonged courses of antibiotics, we carried out a multicenter non-treatment, non-intervention study. We enrolled patients aged 0-17 years receiving long-term (>2 weeks) intravenous (IV) or oral (PO) antibiotic courses across two tertiary children's hospitals. We excluded patients with history of abnormal blood counts, bone marrow failure, gastrointestinal infection / syndromes / abnormalities, immunodeficiency, malignancy, severe malnutrition, use of prophylactic antibiotics or use of antibiotics immediately before admission. Patients noted to develop neutropenia while receiving antibiotics were enrolled in the retrospective arm. A stool sample was collected at 2 timepoints: at the start and at the completion of antibiotics for the prospective arm of the study; at the onset of neutropenia while on antibiotics and at resolution of neutropenia after completion of antibiotics for the retrospective arm. Here, we report an interim analysis performed for an initial cohort of 5 patients with antibiotic-associated neutropenia and 10 controls matched for age and race/ethnicity. For clinical data analysis, we assessed continuous variables using parametric and non-parametric tests when appropriate while using χ2 or Fisher's exact tests for categorical variables. Stool samples were sent for 16s rDNA sequencing to determine whether there are significant changes in the composition (individual microbial taxa) and diversity (both alpha and beta) of the gut microbiome between groups; as well as for untargeted metabolomic profiling to assess whether changes in the relative abundance of specific microbiome-related metabolites, including but not limited to NOD1L and DAT, are associated with the development of neutropenia with prolonged antibiotic treatment. Analyses of these data are currently ongoing. Neutropenia occurred in 9.4% of our prospective patient samples (3 out of 32 patients). Median age was 13y (range 6 mo. - 17y) for the neutropenic group and 11y (range 1-15y) for the control group. Forty percent of patients were female in both groups (Table 1). Total length of IV antibiotic and ICU admission were positively correlated with neutropenia in this cohort (Table 2). To our knowledge, this is the first clinical study linking changes in the intestinal microbiota with antibiotic associated neutropenia. The incidence of antibiotic-associated neutropenia was comparable to what has been previously reported. The analysis of stool samples from this cohort through 16sDNA sequencing and untargeted metabolomic profiling will outline specific changes in microbiome load, diversity, as well as specific taxa and metabolites potentially related to the development of neutropenia. Altogether, we hope to utilize an improved understanding of the molecular pathways, mediators and receptors by which the microbiome sustains normal hematopoiesis to prevent and treat antibiotic-associated bone marrow suppression. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Pegfilgrastim Versus Filgrastim in the Supportive Care of Heavily Pretreated Multiple Myeloma in Treatment with Pomalidomide-Dexamethasone

The objective of this study was to compare the efficacy and safety of pegfilgrastim in patients affected by heavily pretreated MM, treated with pomalidomide-dexamethasone, in order to determine whether a single subcutaneous injection of pegfilgrastim is as effective as daily injections of standard filgrastim, in terms of haematological toxicity, febrile neutropenic episodes, antibiotic usage and hospedalization duration. 57 patients (31 M and 26 F) were enrolled, median age at diagnosis 69 years (r. 52-84), and median age at start of treatment 76 years (r.56-90) treated with several lines of treatments (median 7, r. 2-12), every refractory to all the drugs previously received, received Pomalidomide-Dexamethasone (P 4 mg for 21 days, D 40 mg days 1,8,15,22, pegfilgrastim day +8) every 28 days, until progression. Since first course, received in domestic setting, with a very good compliance, patients performed blood counts once weekly and received, from day +8 to day +19, prophylactic oral chinolonic antibiotics and anti-fungal drugs. During neutropenia after first cycle, Filgrastim (5 μgr/kg/day for 3 days) was given if neutrophils count was <1500 x 10^9 cells/L. Median number of filgrastim administrations was 4.6 (r. 3-6); nadir neutropenia was registered after a median of 10.4 days (r. 7-14); median of nadir neutrophil count was 1.13 x 10^9 cells/L (r.0.3 - 1.5), with maximum duration of 14 days. From the second course, all patients switched to prophylaxis with pegfilgrastim (6 mg), injected subcutaneously with a single administration on day +3 independently from the neutrophil count at that time. During pegfilgrastim, neutropenia was never longer than 8 days, with a consequent reduction of neutropenia-related infections. Median nadir neutrophil count, evaluated for every patients for at least three courses of therapy (r. 3-6) registered at day +11, was 1.28 (r.0.9-2.2). Only 4 patients needed a supplement of 3 administrations of filgrastim. Pegfilgrastim was well tolerated in all patients: main side effects in our patients were mild fever and bone pain (21.2%). In patients affected by heavily pretreated MM treated with pomalidomide-dexamethasone, pegfilgrastim seems to reduce the incidence of severe neutropenia and infections and may increase the possibility to maintain the scheduled time of treatment.

Evaluation of Infection in Patients with Myelodysplastic Syndromes Treated with Hypomethylating Agents: A Systematic Review

BACKGROUND: Myelodysplastic syndromes (MDS) are a heterogeneous group of disorders associated with cytopenias and risk of febrile neutropenia and infection. Hypomethylating therapy, such as azacitidine and decitabine, form the backbone of outpatient chemotherapy for many patients with MDS. Current literature reports heterogeneous and variable frequency, location, and severity of infections among patients receiving this treatment. Further, the relationship between infection and neutropenia is not well established. OBJECTIVE: To facilitate evidence-informed supportive care therapy, we evaluated the incidence and severity of infection and neutropenia among patients with MDS treated with hypomethylating therapy. We also aimed to evaluate the relationship between neutropenia and infection (CRD42022339150). POPULATION: Adult patients (age ≥ 18 years) with MDS (≥80% of the study population) treated with hypomethylating agents. OUTCOMES: Our primary outcome was febrile neutropenia, as per the National Cancer Institute's Common Toxicity Criteria for Adverse Events (NCI-CTCAE). Secondary outcomes included infection of any grade, grade 3 or 4 infections, death due to infection, microbial and clinical infection subtype, frequency of grade 3 or 4 neutropenia, duration of neutropenia, and use of antimicrobial prophylaxis. METHODS: We identified randomized controlled trials (RCT) from Medline, Embase, CENTRAL, and CINAHL from inception to April 2021. RCTs were included if they evaluated hypomethylating therapy in patients with MDS and reported at least one outcome of interest. We used Freeman-Tukey transformation to calculate the weighted summary proportion using a random effects model. RESULTS: We included 21 unique trials enrolling 1380 patients. 14 trials evaluated azacitidine (n=946 patients) and 8 trials studied decitabine (n=434 patients). The median patient age was 70, and 56% were male. 10 trials (n=729 patients) reported risk by International Prognostic Scoring System, of which 5% were low risk, 30% were intermediate-1 risk, 41% were intermediate-2 risk, and 24% were high risk. 49% of patients had grade 3 or 4 neutropenia (95% confidence interval (CI) 34%-63%, n=10 trials, n=697 patients). Febrile neutropenia was reported in 22% of patients (95% confidence interval (CI) 16% to 29%; n=16 trials, n=1124 patients). Grade 3 or 4 infection was reported in 33% of patients (95% CI 0% to 67%; n=3 trials, n=294 patients). Death due to infection occurred in 7% of patients (95% CI 4%-10%; n=9 trials, n=528 patients). Reporting of infection location was inconsistent, and uninterpretable on a per-patient basis. Microbial subtype of infection, duration of neutropenia, and antimicrobial prophylaxis use were not reported. CONCLUSION: In patients with MDS treated with hypomethylating therapy, grade 3 or 4 neutropenia, febrile neutropenia, and grade 3 or 4 infection were common, yet reported rates were heterogeneous between trials. Limited information was available to define the relationship between neutropenia and infection, as well as the use of antimicrobial prophylaxis. Trials commonly reported infection events in the absence of patient-specific risk estimates. Comprehensive reporting of febrile neutropenia, infection and use of antimicrobial prophylaxis is needed to direct evidence-informed care.

Population Pharmacokinetics (PPK) and Exposure-Response to Support Body Surface Area (BSA)-Based Dosing of Brentuximab Vedotin in Pediatric Patients with Advanced-Stage Newly-Diagnosed Hodgkin Lymphoma (HL)

Introduction Brentuximab vedotin is an antibody-drug conjugate (ADC), consisting of antibody cAC10 specific to human CD30 and the antimicrotubule agent monomethyl auristatin E (MMAE), conjugated by a protease-cleavable linker. PPK models were developed to identify factors impacting the pharmacokinetics of ADC and MMAE, and exposure-response analyses were performed to assess the risk-benefit profiles of brentuximab vedotin combined with doxorubicin, vinblastine, and dacarbazine (A+AVD) to support BSA-based dosing of brentuximab vedotin in pediatric patients with advanced-stage newly-diagnosed HL. Methods Data from two open-label phase 1/2 pediatric studies were included in the PPK analysis: study C25002 (NCT01492088), which was a dose-escalation study (brentuximab vedotin 1.4-1.8 mg/kg every 3 weeks) in patients with relapsed or refractory systemic anaplastic large cell lymphoma or HL, and study C25004 (NCT02979522) in patients with advanced-stage, newly-diagnosed HL (brentuximab vedotin 48 mg/m2 every 2 weeks [Q2W] +AVD; A 25 mg/m2, V 6 mg/m2, D 375 mg/m2). Samples for measuring ADC and MMAE concentrations and immunogenicity assessment were collected. Sources of brentuximab vedotin pharmacokinetic variability were quantified using nonlinear mixed-effects modeling. ADC exposures achieved by BSA-based dosing of brentuximab vedotin in pediatric patients were compared to those in adults who received weight-based dosing of brentuximab vedotin in the ECHELON-1 trial (NCT01712490). Exposure-response analyses included patients in study C25004 treated with brentuximab vedotin 48 mg/m2 Q2W in combination with AVD. Relationships between ADC/MMAE exposures, progression-free survival (PFS), and incidence of adverse events (AEs) were analyzed by logistic regression in patients receiving A+AVD. Results Data from 95 patients (6-17 years) informed pharmacokinetics models of ADC (linear 3-compartment with zero-order input and first-order elimination) and MMAE (2-compartment with first-order elimination and formation of MMAE from ADC). BSA (0.79-2.03 m2) and albumin level (23-51 g/L) were significant covariates for clearance of ADC and MMAE. Age, body weight, sex, and race were not identified as covariates for ADC and MMAE pharmacokinetics. Albumin concentrations did not result in clinically meaningful change in clearance of ADC and MMAE. BSA-based brentuximab vedotin dosing resulted in similar systemic exposures of ADC and MMAE across age groups (<12 [n=23], 12-16 [n=56], and >16 years [n=16]). In exposure-response analyses (n=59), steady-state ADC exposures (area under the curve [AUC]) with BSA-based dosing of brentuximab vedotin at 48 mg/m2 Q2W in pediatric patients were comparable to those with weight-based dosing of brentuximab vedotin at 1.2 mg/kg Q2W in adults in the ECHELON-1 trial (Figure). A significant increase (p<0.05) in the incidence of febrile neutropenia was related to increasing exposure of MMAE, consistent with what has been observed in adult patients. No apparent relationship was identified between ADC exposure and the incidence of peripheral neuropathy, grade ≥3 neutropenia, febrile neutropenia, or grade ≥3 treatment-emergent AEs, or between ADC/MMAE exposure and PFS. Conclusions PPK and exposure-response analyses support brentuximab vedotin 48 mg/m2 Q2W in combination with AVD as a treatment option for pediatric patients with advanced-stage newly-diagnosed HL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Evaluation of Infection in Patients with Acute Myeloid Leukemia Treated with Hypomethylating Agents: A Systematic Review

BACKGROUND: Acute myeloid leukemia (AML) is characterized by bone marrow failure, cytopenias, and complications related to bleeding and infection. In many adults with AML, hypomethylating agents (e.g., azacitidine, decitabine) comprise the backbone of outpatient chemotherapy. Due to underlying disease and/or treatments, patients with AML frequently have severe and prolonged neutropenia, which increases risk of infectious complications. The frequency and severity of infectious complications have not been well defined for patients receiving treatment with hypomethylating agents, either alone or in combination with venetoclax. OBJECTIVE: To inform optimal supportive care therapy to minimize infection risk, we evaluated the incidence and severity of neutropenia, febrile neutropenia, and infections among patients with AML treated with hypomethylating therapy. We also aimed to study the incremental risk with combination hypomethylating therapy, and the reported use of antimicrobial prophylaxis (CRD42022339158). POPULATION: Adult patients (age ≥ 18 years) with AML (≥80% of the study population) treated with hypomethylating agents. OUTCOMES: Our primary outcome was febrile neutropenia, as per the National Cancer Institute's Common Toxicity Criteria for Adverse Events (NCI-CTCAE). Secondary outcomes included infection of any grade, grade 3 or 4 infections, death due to infection, microbial and clinical infection subtype, frequency of grade 3 or 4 neutropenia, duration of neutropenia, and use of antimicrobial prophylaxis. METHODS: We searched Medline, Embase, CENTRAL and CINAHL from inception to April 2021. We included randomized controlled trials if they evaluated hypomethylating therapy in patients with AML and reported at least one outcome of interest. We used Freeman-Tukey transformation to calculate the weighted summary proportion using a random effects model. RESULTS: From 13,225 citations, we included 18 unique trials (published between 2010 and 2021), enrolling 2,788 patients. Azacitidine was evaluated in 8/18 trials (n = 984 patients) while 6/18 trials (n = 877 patients) evaluated decitabine, and 4/18 trials (n = 927 patients) evaluated combination therapy with hypomethylating agents and venetoclax. The median patient age was 74 years (interquartile range 72 to 76 years); males represented 53% of the population. 31% of patients had grade 3 or 4 neutropenia (95% confidence interval (CI) 21% to 41%; n = 9 trials; 1,407 patients). Febrile neutropenia affected 31% patients receiving single agent hypomethylating therapy (95% CI 26% to 37%; n = 11 trials; 1,382 patients), with increased risk among patients treated with the combination of hypomethylating therapy and venetoclax (46%; 95% CI 35% to 57%; n = 2 trials; 398 patients). 45% of AML patients reported infection (95% CI 33% to 57%; n = 11 trials; 1,232 patients). The most frequent infections were respiratory infections (31%), bacteremias (24%), skin and soft tissue infections (18%), and urinary tract infections (11%). Infection-related death occurred in 8% of patients with AML (95% CI 6% to 11%; n = 9 studies; 898 patients). Microbial subtype of infection and duration of neutropenia were not reported. Antimicrobial prophylaxis was reported in only one trial. CONCLUSION: Neutropenia and infection occur commonly in patients with AML treated with hypomethylating agents, with increased risk with venetoclax combination therapy. Reported risks were heterogenous among trials, and limited data was available to evaluate the relationship between neutropenia and infection. Antimicrobial prophylaxis was rarely reported. Clinical trials are needed to inform optimal supportive care interventions to decrease infection risk in this high-risk patient population.

Safety and Tolerability of Anti-CD38 Monoclonal Antibodies (mAb) in Multiple Myeloma

Introduction: Patients with multiple myeloma are mostly older and with co-morbidities. Although clinical trials have confirmed an improved response rate with the addition of anti-CD38 mAbs to the immunomodulatory agents and proteasome inhibitors in patients with multiple myeloma, the safety of such an addition remains a concern. This meta-analysis aims to evaluate the safety and tolerability of anti-CD38 mAbs in both newly diagnosed (NDMM) and relapsed/refractory multiple myeloma(RRMM). Method: A systematic search of Pubmed and Cochrane databases was conducted and all randomized controlled clinical trials reporting adverse events (AEs) of anti-CD 38 mAbs, daratumumab (Dara) and isatuximab (Isa) were reviewed. Pooled odds ratios (OR) and 95% confidence intervals (CI) were calculated by employing the random-effects model, Mantel-Hazel method. Review Manager (RevMan) Version 5.4, Cochrane Collaboration 2020 was used for analysis. Results: A total of 13 studies (11 Dara and 2 Isa) were identified. Both Isa studies were conducted in patients with RRMM, 5 Dara studies were in RRMM, and 6 Dara studies were in NDMM. The pooled incidences of infusion-related reactions of grade 3 and above were low in both groups, 4.02% in the Dara group and 1.52% in the Isa group. Treatment discontinuation due to adverse events was less common in the Dara group compared to the control group [OR 0.72 (95% CI 0.58-0.92), p=0.009], but the treatment-emergent adverse event (TEAE)-related deaths were not different [OR 0.89 (0.58-1.36), p=0.60]. Similarly, treatment discontinuation was less common in the Isa group compared to control group [OR 0.55 (95% CI 0.32-0.95), p=0.03], but (TEAE)-related deaths were not different [OR 0.88 (0.28-2.72), p=0.82]. The pooled incidences of common grade 3 and above AEs were summarized in the table. Discussion: This meta-analysis confirms the safety and tolerability of Anti-CD38 mAbs and highlights the key differences in their AE profiles, with more pronounced thrombocytopenia, pneumonia and diarrhea noted with Dara while both agents resulted in a higher incidence of neutropenia and fatigue. Understanding the AEs of these agents can assist the clinicians in counseling their patients and taking the necessary prophylactic or therapeutic measures to minimize these events. In addition, it can help clinicians in selecting the appropriate agent based on their patients' comorbidities. This study has multiple limitations with the most important one being the low number of Isa clinical trials available to be included in this meta-analysis. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Pooled Safety Analysis from Phase I-III Studies for Patients with Hematological Malignancies Treated with the PI3K Inhibitor Copanlisib

Introduction: As of 2021, four phosphatidylinositol 3-kinase (PI3K) inhibitors had received accelerated approval by the FDA for treatment of patients (pts) with indolent follicular lymphoma (FL) having received ≥2 systemic therapies. Recently, during confirmatory studies, three of the PI3K inhibitors have been voluntarily withdrawn over concerns for toxicities impacting overall survival and this issue was the focus of an Oncologic Drugs Advisory Committee (ODAC) meeting in April 2022. Copanlisib is the only PI3K inhibitor currently available for treatment of FL and is distinguished by being administered intravenously on an intermittent schedule. We report here a comprehensive pooled analysis of copanlisib safety with long-term follow-up from 10 completed Phase I-III studies in pts with hematologic malignancies. Methods: Pts with hematologic malignancies treated with copanlisib monotherapy in completed open-label Phase I or II studies and a randomized, placebo-controlled Phase III in combination with rituximab were included. Copanlisib 60 mg (i.v.) was administered intermittently on days 1, 8, and 15 of a 28-day cycle until disease progression or unacceptable toxicity. AEs were reported using MedDRA version 24.1 and assessed by duration of treatment in 6-month intervals or time of onset (worst grade or new AEs occurring ≤180 days [d], 181-360 d, 361-540 d, 541-720 d, or ≥721 d). Results: A total of 684 pts received copanlisib and were evaluable for safety (data cut-off Feb 2022). Median age was 64 years (range 22-93). A total of 51% of pts had a history of FL, 14% MZL, and 10% DLBCL. More than half (54%) were treated with copanlisib for less than 6 months, whereas 27% were treated for >12 months and 13% >2 yrs. The mean overall duration of treatment was 10.9 months (range 0.2-80 months). 24% of pts had at least one dose reduction and 73% had at least one dose interruption or delay (mean duration 3 days). Copanlisib-related treatment-emergent AEs (TEAEs) were reported in 92% of pts; 55% of pts had TEAEs of worst grade [g] 3, and 24% had TEAEs of worst g4. The most common reasons for discontinuation were progression (41%), AE not associated with clinical disease progression (29%) and withdrawal by subject (11%). The most common (≥10%) copanlisib-related TEAEs (% all-grade/g3/g4) were hyperglycemia (58/37/6), hypertension (42/33/0), diarrhea (23/4/0), neutrophil count decreased (20/7/7), neutropenia (19/8/7), nausea (17/0.3/0), white blood cell count decreased (13/5/0.6), fatigue (13/1/0), and anemia (11/3/0). Hyperglycemia and hypertension, both of which were infusion related and transient, had the highest incidence in the first 180 days of treatment. For diarrhea, pts treated for longer duration were more likely to have experienced diarrhea, but g3 events were constant per 6-month onset of event interval (2.2/2.5/3.2/0.8/3.3%). For AEs of interest, the incidence of colitis was low (0.9%; 6 pts: 2 g1, 3 g3 and 1 g4) as was the overall incidence of pneumonitis (6/2/0.6; one g5) with all the g4 events occurring <180 days. The occurrence of late onset AEs of increasing severity has been an issue with orally administered PI3K inhibitors. The greater exposure of pts to copanlisib with longer treatment notwithstanding, we examined the incidence and severity of AEs in pts treated ≤6 months, 6-12 months and >12 months, by overall duration of treatment and by interval of onset (Table) to ascertain the timing and severity of AEs. For hyperglycemia and hypertension, the overall incidence rate was similar for pts treated ≤6 months, 6-12 months and >12 months but was mostly accounted for higher rates day 1-180. Diarrhea was higher in pts treated >12 months, but mostly due to low grade events. There was a trend for a higher incidence of neutropenia and/or neutrophil count decrease depending on treatment duration, but infections remained low. A total of 50 (7%) pts died within 35 days of discontinuing copanlisib, with 18 (2.6%) due to progressive disease (PD) and 9 (1.3%) AEs related to PD, and 20 (2.9%) AEs not associated with clinical progression. Copanlisib-related g5 (death) TEAEs were reported in 10 pts (1.5%), with 8 events in pts treated <6 months; infection-related AEs reported in 5 pts. Conclusions: Based on this expanded safety dataset with long-term treatment of copanlisib, there is no evidence of late-onset toxicities or worsening of severity of TEAEs. No new or unexpected safety issues were identified. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Decreased febrile neutropenia during inpatient chemotherapy for urologic cancer during coronavirus disease 2019 pandemic.

Since 2020, the COVID‐19 pandemic has led to the widespread practice of hand hygiene and wearing face masks, not only among healthcare workers, but also among the general public. Thus, there is a need to verify the impact of the COVID‐19 pandemic on the incidence of febrile neutropenia (FN). This study aimed to examine the incidence of FN in hospitalized chemotherapy patients at Kanazawa University Hospital. Among inpatients at the Department of Urology receiving chemotherapy, we compared the incidence of FN between 317 cases in 2018–2019 and 276 cases in 2020. We retrospectively analyzed the factors of FN via binominal logistic regression analysis based on patient characteristics and the characteristics of primary diseases, with statistical significance set at p < 0.05. FN occurred in 20/317 cases in 2018–2019, but only in 1/276 cases in 2020, with a significant decrease in the latter (p = 0.005). On multivariate analysis, we identified the following independent risk factors for FN: non‐COVID‐19 era (p = 0.005), first course of therapy (p = 0.005), malnutrition (p = 0.032), and past history of FN (p = 0.018). Due to the COVID‐19 pandemic, hygiene policies for healthcare workers and quarantine measures for patients were thoroughly implemented. As a result, the incidence of FN in 2020 decreased to 1/15 of the previous incidence. Thus, hygiene measures for healthcare workers and patients during the expected period of chemotherapy‐induced neutropenia are important for FN prevention.

290P Use of PEG G-CSF is associated with decreased myelotoxicity in dexrazoxane-used aggressive non-Hodgkin lymphoma patients

Dexrazoxane (DXZ) is indicated as a cardioprotective agent for elderly aggressive lymphoma receiving doxorubicin. Several studies reported an apparent increase in the severity of myelosuppression when dexrazoxane was used. Prophylactic use of pegylated granulocyte colony stimulating factor (PEG G-CSF) is known to reduce the incidence of both neutropenia and febrile neutropenia. We conducted a retrospective study to evaluate prophylactic effect of PEG G-CSF in elderly aggressive lymphoma treated with CHOP-based regimen and cardioprotective dexrazoxane.

Efficacy and safety of lenalidomide in diffuse large B-cell lymphoma: a meta-analysis of randomized controlled trials.

As an immunomodulatory agent with antitumor activity, lenalidomide has been evaluated for its value in diffuse large B-cell lymphoma (DLBCL). We performed a meta-analysis to gain a better understanding of the efficacy and safety of lenalidomide in DLBCL. PubMed, Cochrane Library, and Embase were searched up to March 2022 for potential studies. The pooled hazard ratio (HR) and relative risk (RR) with 95% confidence interval (CI) were estimated by the fixed/random effects model. Overall, 6 randomized controlled trials including 1938 patients were included. The complete response rate (CRR) of the group containing lenalidomide was 47.7% (95%CI 28.5-67.2%), which was higher than the 37.8% (95%CI 16.7-61.5%) of the control group without lenalidomide (RR = 1.11, 95%CI 1.03-1.20, P = 0.008). The overall estimation of survival showed a benefit for progression-free survival (PFS) (HR = 0.77, 95%CI 0.66-0.90, P = 0.001) but not overall survival (OS) or event-free survival (EFS). The lenalidomide group had a significant incidence of grade ≥ 3 hematological adverse events (AEs) involving neutropenia (RR = 1.56, 95%CI 1.15-2.11, P = 0.004) and febrile neutropenia (RR = 1.81, 95%CI 1.31-2.49, P < 0.001), with the incidence of neutropenia (48.3%, 95%CI 37.5-59.1%) being highest. In conclusion, addition of lenalidomide results in a higher CRR and better PFS but a higher incidence of grade ≥ 3 hematological AEs involving neutropenia and febrile neutropenia.

Impact of oral hygiene on febrile neutropenia during breast cancer chemotherapy.

Oral hygiene is crucial in the management of oral and febrile complications during chemotherapy for cancer. This study aimed to investigate the impact of oral hygiene on the incidence of febrile neutropenia (FN) throughout the course of chemotherapy for breast cancer. A total of 137 patients with breast cancer who underwent four cycles of adjuvant chemotherapy with docetaxel and cyclophosphamide (TC) combination therapy or docetaxel alone were assessed for oral hygiene by quantifying the number of oral bacteria they harbored. These patients received professional oral health care (POHC). Eighteen patients underwent primary prophylaxis with granulocyte colony-stimulating factors. The relationship between oral bacteria count and FN incidence was retrospectively assessed. The FN incidence rate was 47.4% throughout all treatment cycles (32.8%, 13.5%, 14.3%, and 14.4% in cycles 1, 2, 3, and 4, respectively). The oral bacteria count decreased with each treatment cycle (cycle 1: 9.10 × 106 colony-forming units (CFU)/mL, cycle 2: 5.89 × 106CFU/mL, cycle 3: 4.61 × 106CFU/mL, cycle 4: 5.85 × 106CFU/mL, P = 0.004). Among 281 treatment cycles, FN occurred in 63 (22.4%). In the treatment cycle-based analysis, high oral bacteria count was an independent risk factor for FN. FN incidence decreased with each treatment cycle and was associated with changes in oral bacteria counts. The oral bacterial count was one of risk factors for FN development in breast cancer.

Rituximab Toxicity after Preemptive or Therapeutic Administration for Post-Transplant Lymphoproliferative Disorder

Rituximab is commonly used as prevention, preemption, or therapeutically for post-transplant lymphoproliferative disorder (PTLD) after hematopoietic cell transplantation (HCT). Although it is generally assumed that rituximab toxicity (ie, infections resulting from hypogammaglobulinemia and neutropenia) is negligible in relation to mortality due to PTLD, limited evidence supports the validity of this assumption. We sought to determine the impact of rituximab on immunoglobulin levels, neutrophil count, infection density, and mortality outcomes. This study retrospectively analyzed 349 HCT recipients, 289 of whom did not receive rituximab and 60 of whom received rituximab preemptively or therapeutically at a median of 55 days post-transplantation. IgM, IgG, and IgA levels at 6 months and 12 months post-transplantation were lower in patients who received rituximab compared with those who did not (significant at P < .05 for IgM and IgA at 6 months and for IgM and IgG at 12 months). Rituximab recipients also had a higher incidence of severe neutropenia (<.5/nl) between 3 and 24 months (subhazard ratio [SHR], 2.3; P=.020). Regarding non-Epstein-Barr viral infections/PTLD, the rituximab group had a higher infection density between 3 and 24 months compared with the no-rituximab group (3.8 versus 1.6 infections per 365 days at risk; incidence rate ratio, 2.2; P < .001). The rituximab group also had a higher incidence of fatal infections (SHR, 3.1; P=.026), higher nonrelapse mortality (SHR, 2.4; P=.006), and higher overall mortality (hazard ratio, 1.7; P=.033). There were no significant between-group differences in the incidence of clinically significant graft-versus-host disease, graft failure, or relapse. Based on this study, rituximab given for PTLD is associated with substantial morbidity and mortality. Whether the benefit of preemptive rituximab outweighs the risk remains to be determined. © 2022 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Differences in Prevalence of Haematological Abnormalities on Presentation to Hospital in COVID-19-Infected Adult and Paediatric Patients: A Retrospective Multicentre Descriptive Study

Background: It is well known that COVID-19 infection affects multiple systems in the body. Reports have documented many changes in the hematopoietic system in the pathophysiology of the disease, and many haematological markers like lymphopenia and high d dimer have been linked to worse outcomes after COVID-19 infection in adult patients. Aim: The aim of the study was to find out the prevalence and any significant difference in routine haematological parameters on presentation in paediatric and adult patients with COVID-19 infection. Methodology: We conducted a multicentre retrospective descriptive observational study and investigated the prevalence of haematological abnormalities at the presentation of 1,000 PCR swab-confirmed COVID-19-infected randomly selected adult and paediatric patients admitted to 3 tertiary hospitals in Dubai from 15 March–30 May 2020. Data were gathered through their electronic medical records, and all analysis was done using the Statistical Package for the Social Sciences software (SPSS). Results: The prevalence of at least one abnormal haematological parameter was 95.1% (794/835) on the first presentation to the hospital. After adjusting of age and gender, the prevalence of any white cell abnormality was 34.7% (290/835) (5.7% leukopenia, 9.6% leucocytosis, 25.4% lymphopenia, 5.5% neutropenia, 16.4% neutrophilia, 7.3% monocytosis, and 1.2% eosinopenia). A prevalence of 15.3% (128/835) anaemia, 9.5% (79/835) thrombocytopenia, and 4.3% (36/835) thrombocytosis was also observed. The prevalence of other abnormal blood parameters was C-reactive protein 69.5% (573/835), D dimer 57.5% (280/835), high lactate dehydrogenase 52% (383/835), high ferritin 72.1% (452/835), high international normalized ratio 5.1% (38/835), prolonged prothrombin time 32.2% (240/835), and prolonged activated partial thromboplastin time 35.6% (264/835). A significant difference in the prevalence of these abnormalities was evident between adult and paediatric populations, and these abnormalities were much more prevalent in adults but interestingly paediatric population tended to have a higher incidence of neutropenia, eosinophilia, and monocytosis (p < 0.001). Conclusion: COVID-19 infection tends to be milder and has better outcomes in the paediatric population. The immune system responds differently to the infection in these populations. The response is exaggerated in adults reflected by the increased prevalence of haematological abnormalities like raised inflammatory markers and other white cell abnormalities and has been linked with increased severity of infection and mortality.

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.

CART CELL THERAPY BLACK SHADOW IN HEMATOLOGICAL DISORDERS : SYSTEMIC REVIEW WITH META-ANALYSIS

To determine the effect of CART therapy on hypogammaglobulinemia and bone marrow aplasia, and to determine the probable medications in management of hypogammaglobulinemia with other associated risk factors and complications. Systematic search was conducted in 4 databases using the terms CART therapy, haematological malignancies, and hypogammaglobulinemia. Articles including patients with any haematological malignancies undergone CART therapy and assessment done on hypogammaglobulinemia were included. Following screening and selection of the articles, narrative synthesis, quality assessment, and meta-analysis were conducted 1197 citations , 9 were finally included for meta-analysis comprising of 425 patients who were affected due to any haematological malignancies and had undergone CART therapy. The overall incidence rate was 35.35%. In all the studies, hypogammaglobulinemia was managed using IgG. Most of the patients across the studies had infection due to reduction in WBC count. The overall incidence of neutropenia following CART therapy was 59% lymphopenia was 82%,and B-cell aplasia was 49.5%. The effective way for management of hypogammaglobulinemia was using IgA antibody. The overall incidence of hypogammaglobulinemia and WBCs was difficult to conclude as majority of the studies were of low and fair quality and were collected at different time points after administration of CART therapy. Thus, good quality clinical trials, open label trials or RCT are required. Hypogammaglobulinemia increases with a decrease in neutrophils, lymphocytes, and B-type cells leading to variable infection.

MM-499 Pegfilgrastim Versus Filgrastim in the Supportive Care of Heavily Pretreated Multiple Myeloma in Treatment With Pomalidomide-Dexamethasone

Pegfilgrastim is a pegylated long-acting recombinant form of G-CSF that extends the half-life and allows for once-per-cycle dosing, requiring less frequent dosing than nonpegylated G-CSF. The objective was to compare the efficacy and safety of pegfilgrastim in heavily pretreated MM, treated with pomalidomide-dexamethasone, in order to determine whether a single subcutaneous injection of pegfilgrastim is as effective as daily filgrastim. 57 patients (31 M and 26 F) were enrolled, median age at diagnosis 69 years (r. 52-84), and median age at start of treatment 76 years (r. 56-90) treated with several lines of treatments (median 7, r. 2-12), refractory to all drugs previously received. They received pomalidomide-dexamethasone (P 4 mg for 21 days, D 40 mg days 1, 8, 15, 22, pegfilgrastim day +8) every 28 days, until progression. In the first course in domestic setting, patients' blood counts were drawn once weekly and they received, from day +8 to day +19, prophylactic oral chinolonic antibiotics and anti-fungal drugs. During neutropenia after first cycle, filgrastim (5 µgr/kg/day for 3 days) was given if neutrophils count was <1500 × 109 cells/L. Median number of filgrastim administrations was 4.6 (r. 3-6); nadir neutropenia was registered after a median of 10.4 days (r. 7-14); median of nadir neutrophil count was 1.13 × 109 cells/L (r.0.3 - 1.5), with maximum duration of 14 days. For the second course, all patients switched to prophylaxis with pegfilgrastim (6 mg), injected subcutaneously with a single administration on day +3 independently from the neutrophil count at that time. During treatment with pegfilgrastim, neutropenia was never longer than 8 days, with a consequent reduction of neutropenia-related infections. Median nadir neutrophil count, evaluated for every patient for at least three courses of therapy (r. 3-6) registered at day + 11, was 1.28 (r.0.9-2.2). Only 4 patients needed a supplement of 3 administrations of filgrastim. Pegfilgrastim was well tolerated in all patients: main side effects in our patients were mild fever and bone pain (21.2%). In MM treated with pomalidomide-dexamethasone, pegfilgrastim seems to reduce the incidence of severe neutropenia and infections and may increase the possibility to maintain the scheduled time of treatment.

An exploratory comparative effectiveness analysis of febrile neutropenia incidence among patients with cancer receiving granulocyte colony stimulating factors.

408 Background: We conducted an exploratory comparative effectiveness analysis comparing various G-CSF (pegfilgrastim/filgrastim) products to each other in incidence of febrile neutropenia (FN) among patients with breast, lung, colon, pancreatic, ovarian cancers or non-Hodgkin’s lymphoma (NHL) in the Biologics and Biosimilars Collective Intelligence Consortium’s (BBCIC) Distributed Research Network. Methods: We included patients aged &gt; = 20 years who, in 2015-2019, per insurance claims, received any pegfilgrastim or filgrastim products as febrile neutropenia (FN) prophylaxis during the first cycle of chemotherapy posing a high or intermediate FN risk per National Comprehensive Cancer Network guidelines. We compared the FN risk starting at day 5 following day 1 of chemotherapy receipt between products using Poisson regression model with standardized inverse probability weights and robust variance to estimate the Relative Risk (RR) and 95% Confidence intervals (CI). Results: A total of 15,941 patients received a pegfilgrastim product in cycle 1 of chemotherapy: 15,115 (95%) pegfilgrastim, 484 (3%) pegfilgrastim_cbqv, 342 (2%) pegfilgrastim_jmdb. 565 patients received a filgrastim product: 284 (50%) filgrastim, 201 (36%) filgrastim_sndz, 80 (14%) tbo-filgrastim. FN events by product were: 346 pegfilgrastim (2.3% of users), 11 pegfilgrastim_cbqv (2.3%), 8 pegfilgrastim_jmdb (2.3%), 13 filgrastim (4.6%), 5 filgrastim_sndz (2.5%), 2 tbo-filgrastim (2.5%). We found no difference in FN incidence when comparing pegfilgrastim_cbqv to pegfilgrastim (RR 0.83, 95% CI 0.41-1.69), pegfilgrastim_jmdb to pegfilgrastim (RR 1.03, 95% CI 0.56-1.92), and pegfilgrastim_jmdb to pegfilgrastim_cbqv (RR 1.11, 95% CI 0.45-2.74). Similarly, we found no difference in FN incidence when comparing filgrastim_sndz to filgrastim (RR 0.46, 95% CI 0.17-1.28), tbo-filgrastim to filgrastim (RR = 0.30, 95% CI 0.06-1.36), or tbo-filgrastim to filgrastim_sndz (RR 0.54, 95% CI 0.10-2.77). Adverse events were rare, with similar rates observed among all products. Conclusions: We observed no significant difference in FN incidence among patients when comparing various G-CSF products, including when biosimilars were compared to their reference counterparts.

ABCL-322 Retrospective Analysis of Real-World Outcomes in Older Adult Patients With Diffuse Large B-Cell Lymphoma

Treatment of older adult patients with diffuse large B-cell lymphoma (DLBCL) seeks to achieve disease remission while minimizing treatment-related toxicities. The use of anthracycline in older adults is associated with increased risk of cardiotoxicity and myelosuppression. Non-anthracycline-based regimens have commonly been used in patients ineligible or at risk of severe toxicities to anthracyclines. To analyze the treatment outcomes of patients with DLBCL aged ≥60 years and compare R-CHOP and R-CEOP regimens. Retrospective study, median follow-up: 22.71 months (IQR 8.55-39.24 months). Single institution, tertiary care cancer center. Those aged ≥60 years and newly diagnosed with DLBCL between January 2014 and December 2018 were included. Of a total of 218 patients, 71 patients received the R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) and 137 received R-CE(etoposide)OP chemotherapy. The decision to substitute etoposide for doxorubicin was based on physician's discretion depending on the patient's performance status, cardiac comorbidities, frailty, and available resources for supportive care. Two-year progression-free survival (PFS), 2-year overall survival (OS), Grade III/IV toxicities. The 2-year PFS rate in the R-CHOP group was higher than that in the R-CEOP group (79.1% vs. 49.6%, P-value<0.001); this superiority of R-CHOP was seen in both early and advanced disease. The 2-year OS rate in the overall cohort was significantly higher in the R-CHOP group (86.2% vs. 70.6%, P-value=0.016), and the age group of 60-65 years showed significantly better outcomes with the anthracycline-based regimen. The incidence of febrile neutropenia and grade III/IV hematological toxicities was significantly higher in the R-CHOP group in the age group of 60-65 years. Multivariate analysis showed that ECOG-PS, NCCN-IPI, and chemotherapy regimen were significant factors for 2-year PFS, and NCCN-IPI and chemotherapy regimen were significant factors for 2-year OS. An anthracycline-based regimen should be used in fit older adult patients without absolute cardiac contraindications with careful monitoring for toxicities and access to supportive care. Geriatric assessment tools should be used for better objective assessment of fitness to deliver optimal therapy and lessen the risks of toxicities.

603. NEOADJUVANT DCF VERSUS CRT IN COMPLEX TREATMENT OF LOCALLY ADVANCED ESOPHAGEAL SQUAMOUS CELL CANCER

Abstract Both neoadjuvant chemotherapy and neoadjuvant chemoradiotherapy improve tumor resectability, lead to downstaging of tumor process and increase overall and disease-free survival rates. This study investigates the efficacy and outcomes after neoadjuvant chemotherapy with DCF regimen and chemoradiotherapy for patients with locally advanced esophageal squamous cell carcinoma. We retrospectively analyzed the results of 130 patients from 2013 to 2018 who received preoperative DCF chemotherapy (docetaxel 70 mg/m2 on day 1, cisplatin 70 mg/m2 on day1, 5-FU 750 mg/m2 on days 1-5, total 4 courses) followed by surgery or chemoradiotherapy (paclitaxel 175 mg/m2 on day 1, cisplatin 75 mg/m2 on day 1, 5-FU 750 mg/m2 on days 1-5 and 46 Gy) followed by surgery. Surgery included both open and minimal invasive esophagectomy with regional lymphadenectomy. Data, surgical results, treatment related complications and long-term results were compared in two groups. Patient characteristics did not differ between the two groups. Incidence of &amp;gt; grade 2 complications were higher in the DCF group. Incidence of neutropenia was in 72.3% versus 30.7% in the CRT group, febrile neutropenia 18.4% and 7.7%, respectively. The R0 resections were similar (98.3%). Chylothorax was noted only in two patients in the CRT group (3.0%). Complete pathological response in the CRT group was in 35.3% versus 20.0% in the DCF group. 3-year overall survival in the DCF and CRT groups was 70.7% and 64.6%, and 3-year disease-free survival was 60.0% and 49.2%, respectively (p&amp;lt;0,05). Thus, 4 courses of DCF is not inferior compared to CRT in terms of survival rates and becomes an alternative to CRT in the complex treatment of locally advanced squamous cell carcinoma of the esophagus.

Pegfilgrastim Biosimilars in US Supportive Oncology: A Narrative Review of Administration Options and Economic Considerations to Maximize Patient Benefit.

Granulocyte colony-stimulating factor (G-CSF) biologics, such as pegfilgrastim, are a standard of care in supportive cancer treatment that are administered once per chemotherapy cycle to reduce the incidence of febrile neutropenia. The high cost of these biologics in the United States can be a limiting factor to accessing care; however, lower-cost pegfilgrastim biosimilars have been available for several years for patients requiring prophylaxis of febrile neutropenia. Different options for pegfilgrastim administration are also now available to accommodate specific patient preferences. As patients may want to minimize the risk of both neutropenia and SARS-CoV-2 infection, same-day administration is a pertinent option during the present COVID-19 pandemic. Therefore, individualized, patient-centered approaches and risk-management strategies should be considered when selecting the treatment and administration method for prophylaxis of febrile neutropenia. Three methods of administration would minimize hospital or clinic visits while also providing the prophylactic effect of G-CSF: same-day administration after chemotherapy, use of the US Food and Drug Administration–approved on-body injector delivering pegfilgrastim approximately 27 h after chemotherapy, or self-administration by the patient or caregiver > 24 h after chemotherapy. Choice of the specific administration option should be based on the patient’s specific needs, while also considering mitigating factors, such as the economic burden associated with biologic medications and the risk of COVID-19. Pegfilgrastim biosimilars can minimize the additional financial burden on patients and the health care system during this pandemic and beyond.