Duration Of Neutropenia Research Articles

Evaluation of interleukin-8 levels in the diagnosis of invasive pulmonary aspergillosis in patients with haematological malignancies.

This study aimed to determine the level of interleukin (IL)-8 in diagnosing of invasive pulmonary aspergillosis (IPA). We conducted this study with 50 controls and 25 IPA patients with haematological malignancies. Demographic data, haematological diagnoses, chemotherapy regimen, galactomannan level, fungal culture, and computed tomography findings of the patients were evaluated prospectively. IL-8 levels were studied with the ELISA method. The mean age of patients in the case group was 60.84±15.38 years, while that of the controls was 58.38±16.64 years. Of the patients, 2/25 were classified as having 'proven', 13/25 as 'probable', and 10/25 as 'possible' invasive aspergillosis (IA). Serum IL-8 levels were found to be significantly higher in the case group compared to the controls. There was a negative correlation between serum IL-8 levels and neutrophil counts and a positive correlation with the duration of neutropenia. A significant cutoff value for serum IL-8 parameter in detecting IPA disease was obtained as ≥274 ng/l; sensitivity was 72%; specificity was 64%; PPV was 50%; and NPV was 82%. In the subgroup analysis, there was no significant difference in serum IL-8 levels between the case group and the patients in the neutropenic control group, while a significant difference was found in with the patients in the non-neutropenic control group. Serum IL-8 levels in neutropenic patients who develop IPA are not adequate in terms of both the diagnosis of the disease and predicting mortality. New, easily applicable methods with high sensitivity and specificity in diagnosing IPA are still needed.

Abstract 6327: Impact of G-CSF on safety and efficacy of CAR T-cell therapy in non-Hodgkin lymphoma

Abstract Introduction: Chimeric antigen receptor T-cell (CAR-T) therapy is an established treatment modality for the management of refractory and/or relapsed non-Hodgkin lymphoma (NHL). Despite restrictions on granulocyte colony-stimulating factor (G-CSF) use in registration clinical trials due to potential worsening of cytokine release syndrome (CRS), G-CSF is often prescribed for neutrophil recovery post-CAR-T in clinical practice. We conducted a retrospective study to assess the association between G-CSF use and the safety and efficacy of CAR-T. Methods: Following Institutional Review Board approval, we retrospectively analyzed NHL patients receiving commercial CD19-targeted CAR-T across Mayo Clinic sites (Arizona, Florida, and Minnesota) between October 2017 and May 2023. Demographics, labs, and post CAR-T events were collected. Electronic medical records were reviewed for G-CSF exposure within Day 1 - 100 post-CAR T. Differences by G-CSF status were examined using a Chi-square test and Kruskal Wallis tests. Hazard ratios (HR) and 95% confidence intervals (CI) for overall survival (OS) were calculated using Cox model. Results: Among 270 CAR-T patients; 106 received G-CSF within 30 days and 164 did not. Median age was 56.9 with G-CSF and 58.3 without G-CSF. Most were male (75.2% G-CSF, 62.6% no G-CSF). Diffuse large B cell lymphoma was the predominant NHL subtype (67.0% G-CSF, 65.2% no G-CSF). G-CSF within 30 days was not associated with reduced incidence of neutropenic fever (11.7% G-CSF vs 9.9% no G-CSF, p = 0.6593) or documented infection (22.1% vs 18.3%, p = 0.4439). G-CSF correlated with decreased profound neutropenia duration (ANC < 100 μL, 0 vs 2 days, p < 0.0001) and incidence within 30 days ( 31.7% vs 60.4%, p < 0.0001) as well as incidence of protracted profound neutropenia (> 7 days, 3.8% vs 22.8%, p < 0.0001). G-CSF was associated with a higher incidence of cytopenias between days 30 -100: severe neutropenia (ANC < 500/uL, 28.8% vs 15.2%, p = 0.0075), severe anemia (Hb < 8 g/dL, 21% vs 9.7%, p = 0.0114), and severe thrombocytopenia (Plt < 50 g/L, 35.2% vs 20.9%, p = 0.0099). Logistic regression analysis showed that none of the examined covariates, including prior autologous stem cell transplant, ECOG PS score, and receipt of bridging therapy, were associated with severe neutropenia likelihood. G-CSF was associated with a higher CRS incidence (89.6% vs 79.9%, p = 0.0343), but grade 3 CRS or higher (4.7% vs 3.7%, p = 0.6675) was no different. No difference in complete response rates (66% vs 61.1%, p = 0.4707) or 2-year OS (p = 0.523) was observed between the 2 groups. Conclusion: G-CSF within 30 days was associated with reduced duration and incidence of profound neutropenia without a significant impact on incidence of neutropenic fever or documented infections. There was a signal of association between G-CSF and increased incidence of low-grade CRS and delayed cytopenias (day 30-100) that warrants confirmation in larger studies. Citation Format: Lay She Ng, Claire I. Yee, Radhika Bansal, Mohamed A. Kharfan-Dabaja, Grzegorz S. Nowakowski, Allison C. Rosenthal, Javier Munoz, Januario Castro, Wern Lynn Ng, Hemant S. Murthy, Yi Lin, Matthew R. Buras, Madiha Iqbal, Yucai Wang, Talal Hilal. Impact of G-CSF on safety and efficacy of CAR T-cell therapy in non-Hodgkin lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6327.

Effectiveness and safety of primary prophylaxis of granulocyte colony-stimulating factor during dose-dense chemotherapy for urothelial cancer: Clinical Practice Guidelines for the Use of G-CSF 2022.

Granulocyte colony-stimulating factor (G-CSF) decreases the incidence, duration, and severity of febrile neutropenia (FN); however, dose reduction or withdrawal is often preferred in the management of adverse events in the treatment of urothelial cancer. It is also important to maintain therapeutic intensity in order to control disease progression and thereby relieve symptoms, such as hematuria, infection, bleeding, and pain, as well as to prolong the survival. In this clinical question, we compared treatment with primary prophylactic administration of G-CSF to maintain therapeutic intensity with conventional standard therapy without G-CSF and examined the benefits and risks as major outcomes. A detailed literature search for relevant studies was performed using PubMed, Ichu-shi Web, and Cochrane Library. Data were extracted and evaluated independently by two reviewers. A qualitative analysis of the pooled data was performed, and the risk ratios with corresponding confidence intervals were calculated and summarized in a meta-analysis. Seven studies were included in the qualitative analysis, two of which were reviewed in the meta-analysis of dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) therapy, and one randomized controlled study showed a reduction in the incidence of FN. Primary prophylactic administration of G-CSF may be beneficial, as shown in a randomized controlled study of dose-dense MVAC therapy. However, there are no studies on other regimens, and we made a "weak recommendation to perform" with an annotation of the relevant regimen (dose-dense MVAC).

Effectiveness and safety of primary prophylaxis with G-CSF after induction therapy for acute myeloid leukemia: a systematic review and meta-analysis of the clinical practice guidelines for the use of G-CSF 2022 from the Japan society of clinical oncology

Although granulocyte colony-stimulating factor (G-CSF) reduces the incidence, duration, and severity of neutropenia, its prophylactic use for acute myeloid leukemia (AML) remains controversial due to a theoretically increased risk of relapse. The present study investigated the effects of G-CSF as primary prophylaxis for AML with remission induction therapy. A detailed literature search for related studies was performed using PubMed, Ichushi-Web, and the Cochrane Library. Data were independently extracted and assessed by two reviewers. A qualitative analysis of pooled data was conducted, and the risk ratio with corresponding confidence intervals was calculated in the meta-analysis and summarized. Sixteen studies were included in the qualitative analysis, nine of which were examined in the meta-analysis. Although G-CSF significantly shortened the duration of neutropenia, primary prophylaxis with G-CSF did not correlate with infection-related mortality. Moreover, primary prophylaxis with G-CSF did not affect disease progression/recurrence, overall survival, or adverse events, such as musculoskeletal pain. However, evidence to support or discourage the use of G-CSF as primary prophylaxis for adult AML patients with induction therapy remains limited. Therefore, the use of G-CSF as primary prophylaxis can be considered for adult AML patients with remission induction therapy who are at a high risk of infectious complications.

Chronic disseminated candidiasis in a patient with acute leukemia - an illustrative case and brief review for clinicians

Chronic disseminated candidiasis (CDC) is a severe but rarely seen fungal infection presenting in patients with hematologic malignancies after a prolonged duration of neutropenia. A high index of suspicion is required to diagnose CDC as standard culture workup is often negative. While tissue biopsy is the gold standard of diagnosis, it is frequently avoided in patients with profound cytopenias and increased bleeding risks. A presumptive diagnosis can be made in patients with recent neutropenia, persistent fevers unresponsive to antibiotics, imaging findings of hypoechoic, non-rim enhancing target-like lesions in the spleen and liver, and mycologic evidence. Here, we describe the case of an 18-year-old woman with relapsed B-cell acute lymphoblastic leukemia treated with re-induction chemotherapy who subsequently developed CDC with multi-organ involvement. The diagnosis was made based on clinical and radiologic features with positive tissue culture from a skin nodule and hepatic lesion. The patient was treated for a total course of 11 months with anti-fungal therapy, most notably amphotericin B and micafungin, and splenectomy. After initial diagnosis, the patient was monitored with monthly CT abdomen imaging that showed disease control after 5 months of anti-fungal therapy and splenectomy. The diagnosis, treatment, and common challenges of CDC are outlined here to assist with better understanding, diagnosis, and treatment of this rare condition.

Prognostic Factors for Survival Using a Clinical Severity Staging System Among Patients With Acute Invasive Fungal Sinusitis

Despite the aggressive progression of fulminant acute invasive fungal sinusitis (AIFS), data on prognostic factors have been disparate, hindering the development of a staging system. A composite staging system may improve prognostication for patient counseling and conduct of clinical research. To identify prognostically important factors in AIFS and to incorporate the factors into a comprehensive Functional Severity Staging System and Clinical Severity Staging System. This retrospective cohort study included adult patients diagnosed with pathology-proven AIFS from June 1, 1992, to December 31, 2022, at Washington University Medical Center and Barnes-Jewish Hospital, a tertiary care center in St Louis, Missouri. Data were analyzed from April to July 2023. Sequential sequestration and conjunctive consolidation was used to develop a composite staging system to predict 6-month overall survival. Of 71 patients with pathology-proven AIFS over the 30-year period, the median (range) age of the cohort was 56 (19-63) years, and there were 47 (66%) male patients. The median (range) follow-up time was 2 (0-251) months. There were 28 patients alive within 6 months, for a 39% survival rate. Symptoms, comorbidity burden, and presence and duration of severe neutropenia were associated with 6-month survival and were consolidated into a 3-category Clinical Severity Staging System with 6-month survival of 75% for stage A (n = 16), 41% for stage B (n = 27), and 18% for stage C (n = 28). The discriminative power of the composite staging system was moderate (C statistic, 0.63). This cohort study supports the clinical importance of symptomatology, comorbidity burden, and prolonged severe neutropenia at the time of AIFS presentation. The composite clinical staging system may be useful for clinicians when counseling patients with AIFS and conducting clinical research.

Effectiveness and safety of empegfilgrastim (Extimia®, BIOCAD) in patients with lymphoproliferative diseases receiving cytotoxic therapy: results of LEGERITY, a multicenter retrospective-and-prospective observational post-marketing study

Aim. To evaluate the effectiveness and safety of Extimia® BIOCAD (international non-proprietary name: empegfilgrastim) to reduce the incidence and duration of neutropenia, the incidence of febrile neutropenia (FN) and infections associated with FN in patients with lymphoproliferative diseases receiving myelosuppressive therapy.
 Materials and methods. The paper presents the results of a multicenter retrospective-and-prospective observational post-marketing study of the safety and effectiveness of Extimia® BIOCAD (international non-proprietary name: empegfilgrastim) in patients with lymphoproliferative diseases receiving cytotoxic therapy. Initially, the study was defined as retrospective-and-prospective. However, only 2 of 671 (0.3%) patients were included retrospectively. Thus, the study is based on the evaluation of prospectively collected data. The analysis describes the characteristics and treatment of 671 patients diagnosed with lymphoma who received one or more cycles of chemotherapy in the LEGERITY study. The endpoints of interest included the incidence of grade 3–4 neutropenia, FN, and grade 3–4 infectious complications, the frequency of antibiotic therapy, and the incidence of all adverse reactions in patients who received at least one dose of the study medication.
 Results. A total of 671 patients were enrolled in the study, the majority having B-cell non-Hodgkin lymphoma (428/671, 64%) and Hodgkin lymphoma (211/671, 31%). The mean age was 54 years (18–84); 35% (236/671) of patients were elderly (over 60). The number of injections of empegfilgrastim for the entire observation period was 3093 (n=671). Adverse events were reported in 57/3093 (1.8%) cases. The most common adverse events were mild to moderate ossalgia and myalgia (27/671, 4%), back pain, and arthralgia (12/671, 1.8%), which did not require drug therapy. Two patients developed serious adverse reactions – CTCAE v.5 grade 4 hypotension events. 529 (78.8%) patients received at least 4 courses of chemotherapy. FN was reported in 14 (2.6%) patients and did not require antimicrobial therapy.
 Conclusion. The final analysis results confirm the high clinical efficacy and safety of the Russian original pegylated granulocyte colony-stimulating factor empegfilgrastim (Extimia®) in patients with indolent and aggressive lymphomas. The data obtained from real-world clinical practice demonstrate a favorable safety and tolerability profile of empegfilgrastim in all age groups, including the elderly population.

Serum interleukin-33 and soluble suppression of tumorigenicity 2 in pediatric leukemia with febrile neutropenia.

The purpose of this study was to evaluate the association between interleukin-33 (IL-33) and its receptor Soluble Suppression of Tumorigenicity-2 (sST2) levels and bacterial infections during febrile neutropenia (FN) in pediatric patients with acute lymphoblastic leukemia (ALL). In this prospective, case-control study, participants were divided into 3 groups: ALL patients with FN (Group A), ALL patients without neutropenia and fever (Group B), and healthy children without infection and chronic disease (Group C). There were 30 cases in each group. Blood samples for IL-33 and sST2 have been drawn from patients in Group A before the initiation of treatment and on days 1 and 5 of treatment, and from patients in Groups B and C at initiation. At admission, mean IL-33 level (39.02 ± 26.40ng/L) in Group B and mean sST2 level (185.3 ± 371.49ng/ml) in Group A were significantly higher than the other groups (p = 0.038, p < 0.001, respectively). No difference was observed in the mean IL-33 and sST2 levels in the 5-day follow-up of patients in Group A (p = 0.82, p = 0.86, respectively). IL-33 and sST2 levels were not associated with fever duration, neutropenia duration or length of hospitalization. While C-reactive protein (CRP) was significantly higher in patients with positive blood culture (p = 0.021), IL-33 (p = 0.49) and sST2 (p = 0.21) levels were not associated with culture positivity. Conclusion: IL-33 and sST2 levels were not found valuable as diagnostic and prognostic markers to predict bacterial sepsis in patients with FN. What is Known: • Neutropenic patients are at high risk of serious bacterial and viral infections, but the admission symptom is often only fever. • Febrile neutropenia has a high mortality rate if not treated effectively. What is New: • Febrile neutropenia is not only caused by bacterial infections. Therefore, new biomarkers should be identified to prevent overuse of antibiotics. • Specific biomarkers are needed to diagnose bacterial sepsis in the early phase of febrile neutropenia.

Efbemalenograstim alfa not inferior to pegfilgrastim in providing neutrophil support in women with breast cancer undergoing myelotoxic chemotherapy: results of a phase 2 randomized, multicenter, open-label trial

PurposeEvaluate the safety and efficacy of efbemalenograstim alfa for neutrophil support in breast cancer patients undergoing myelosuppressive chemotherapy in a phase 2, dose-finding, open-label study (NCT01648322, ClinicalTrials.gov, 2012–07-19).Methods232 patients received up to 4 cycles of chemotherapy, 141 patients with docetaxel + cyclophosphamide (TC) and 91 patients with docetaxel + doxorubicin + cyclophosphamide (TAC). Patients were randomized to efbemalenograstim alfa (80, 240, or 320 µg/kg [TC]; 240 or 320 µg/kg [TAC]) or pegfilgrastim (6 mg) on Day 2 of each cycle.ResultsEfbemalenograstim alfa was non-inferior to pegfilgrastim in duration of moderate and severe neutropenia (absolute neutrophil count [ANC] < 1.0 × 109/L) in TAC Cycle 1 (mean [SD] of 2.1 [1.58] and 2.1 [1.46] days for 240 µg/kg and 320 µg/kg efbemalenograstim alfa, respectively, and 1.8 [1.28] days for pegfilgrastim), with a difference (95% CI) of 0.3 (-0.4, 1.1) days. ANC nadir occurred between Days 7–8 of TAC Cycle 1, with mean [SD] of 0.68 [1.064], 0.86 [1.407] and 0.78[1.283] × 109/L for 240 µg/kg, 320 µg/kg efbemalenograstim alfa and pegfilgrastim, respectively. Time to ANC recovery post nadir (defined as an ANC > 2.0 × 109/L after the expected ANC nadir) was 2.0–2.4 and 1.9 days for TAC patients treated with efbemalenograstim alfa and pegfilgrastim, respectively. No significant difference was found between any dose of efbemalenograstim alfa and pegfilgrastim in TAC Cycle 1 for incidence of moderate to severe neutropenia (76%-77% of patients) or incidence of severe neutropenia (ANC < 0.5 × 109/L; 63%-72%). Efbemalenograstim alfa exhibited similar safety profile to pegfilgrastim. Febrile neutropenia occurred in 4 (1.8%) patients, 2 patients each for 320 µg/kg efbemalenograstim alfa and pegfilgrastim, with no event considered related to study drug.ConclusionEfbemalenograstim alfa was comparable to pegfilgrastim in efficacy and safety.ClinicalTrials.gov identifierNCT01648322.

Applying the EHA/EBMT grading for ICAHT after CAR-T: comparative incidence and association with infections and mortality

AbstractCytopenias represent the most common side effect of CAR T-cell therapy (CAR-T) and can predispose for severe infectious complications. Current grading systems, such as the Common Terminology Criteria for Adverse Events (CTCAE), neither reflect the unique quality of post–CAR-T neutrophil recovery, nor do they reflect the inherent risk of infections due to protracted neutropenia. For this reason, a novel EHA/EBMT consensus grading was recently developed for Immune Effector Cell-Associated HematoToxicity (ICAHT). In this multicenter, observational study, we applied the grading system to a large real-world cohort of 549 patients treated with BCMA- or CD19-directed CAR-T for refractory B-cell malignancies (112 multiple myeloma [MM], 334 large B-cell lymphoma [LBCL], 103 mantle cell lymphoma [MCL]) and examined the clinical sequelae of severe (≥3°) ICAHT. The ICAHT grading was strongly associated with the cumulative duration of severe neutropenia (r = 0.92, P < .0001), the presence of multilineage cytopenias, and the use of platelet and red blood cell transfusions. We noted an increased rate of severe ICAHT in patients with MCL vs those with LBCL and MM (28% vs 23% vs 15%). Severe ICAHT was associated with a higher rate of severe infections (49% vs 13%, P < .0001), increased nonrelapse mortality (14% vs 4%, P < .0001), and inferior survival outcomes (1-year progression-free survival: 35% vs 51%, 1-year overall survival: 52% vs 73%, both P < .0001). Importantly, the ICAHT grading demonstrated superior capacity to predict severe infections compared with the CTCAE grading (c-index 0.73 vs 0.55, P < .0001 vs nonsignificant). Taken together, these data highlight the clinical relevance of the novel grading system and support the reporting of ICAHT severity in clinical trials evaluating CAR-T therapies.

Infections in children and adolescents with Acute Leukemia

The incidence and spectrum of infections in pediatric leukemia patients vary depending on the type of leukemia. AML, which involves intensive chemotherapeutic regimes, leads to profound and prolonged neutropenia, making children more susceptible to infection. The intensity of chemotherapy, the duration of neutropenia, and antimicrobial prophylaxis implementation all affect the risk of life-threatening infections. In AML studies have shown that during intensive treatment, children experience more than one episode of infection, with majority being bacteremias. Viridans group Streptococci comprises around 20% of all isolates. Infection related deaths range from 5.4% to 7.3% during chemotherapy being more frequent on intensive phase. Invasive fungal infections (IFI) were highly associated with mortality specially caused by Aspergillus spp. In ALL induction and consolidation phases posing a higher risk for infections due to severe neutropenia. Infection related mortality in ALL is 2–4%, and infections are the main cause of treatment related deaths. IFI are significant concern with risk factors including age and treatment intensity. High risk include older children, delayed response during early induction therapy and corticosteroid administration. In summary, while survival rates for childhood leukemia have improved, the risk of infections, particularly bacterial and fungal infections, remains a significant concern, especially during intensive treatment phases. Ongoing research is needed to better understand and manage these infections in pediatric leukemia patients

The Relation of Baseline Serum Albumin with the Duration of Neutropenia after Induction Chemotherapy in Adult Acute Leukaemia

The Relation of Baseline Serum Albumin with the Duration of Neutropenia after Induction Chemotherapy in Adult Acute Leukaemia

Efbemalenograstim alfa, an Fc fusion protein, long-acting granulocyte-colony stimulating factor for reducing the risk of febrile neutropenia following chemotherapy: results of a phase III trial

PurposeEvaluate the safety and efficacy of efbemalenograstim alfa for reducing the risk of febrile neutropenia in breast cancer patients undergoing myelosuppressive chemotherapy.MethodsA phase III, randomized, double-blind, placebo-controlled study was conducted. A total of 122 subjects received up to 4 cycles of TA chemotherapy (75 mg/m2 docetaxel + 60 mg/m2 doxorubicin). Patients were randomized in a 2:1 ratio to subcutaneously inject a single 20 mg of efbemalenograstim alfa or placebo on day 2 of cycle 1, and all subjects received efbemalenograstim alfa on day 2 of cycles 2, 3, and 4. Duration of severe (grade 4) neutropenia (DSN), depth of neutrophil nadir, incidence of febrile neutropenia (FN), time to neutrophil recovery, and safety information were recorded.ResultsFor the primary endpoint, the mean DSN in cycle 1 was 1.3 days and 3.9 days for efbemalenograstim alfa and placebo respectively (95% CI, 2.3, 3.4). As the lower bound of the 95% CI was > 0, superiority of efbemalenograstim alfa over placebo can be declared. In addition, the incidence of FN in Cycle 1 was lower in efbemalenograstim alfa group than in placebo group (4.8% vs. 25.6%; p = 0.0016). Patients in the efbemalenograstim alfa group required less intravenous antibiotics (3.6% vs. 17.9%; p = 0.0119). Most adverse events were consistent with those expected for breast cancer patient receiving TA chemotherapy.ConclusionEfbemalenograstim alfa is effective and safe for significantly decreasing the duration of severe neutropenia and the incidence of febrile neutropenia in breast cancer patients who are receiving TA chemotherapy.Trial registration.NCT02872103, August 19, 2016.

Different Epidemiology and Characteristics of Invasive Pulmonary Aspergillosis in Acute Lymphoid Leukemia in Comparison with AML: Results of a Prospective Multicentric Observational Study of the Rete Ematologica Lombarda (REL)

Introduction. Invasive pulmonary aspergillosis (IPA) still affects the outcome of acute leukemia (AL) patients (pts). Although this aspect is better defined in acute myeloid leukemia (AML) ( Candoni et al, Mycoses 2020), some reports show a dismal impact also in acute lymphoid leukemia (ALL) ( Cattaneo et al, Leuk Lymphoma 2019). However, data concerning the epidemiology of IPA in adult ALL patients, as well as the best antifungal prophylaxis strategy, are still lacking. Therefore, to describe the incidence of IPA in AL pts and their clinical characteristics, as well as the predisposing factors, we carried out a prospective multicentric observational study within the Rete Ematologica Lombarda (REL). Methods. All consecutive AL patients diagnosed during a 3-year period and treated with curative intent were recorded. Diagnosis of IPA was defined according to EORTC/MSG criteria ( Donnelly et al, Clin Infect Dis 2020). Data concerning age, gender, AL type, chemotherapy (cht) received, complete remission (CR) achievement, antifungal prophylaxis, duration of neutropenia and 30-day mortality were collected. Patient's characteristics were analysed by standard descriptive statistics. The Student's t-test was used to compare continuous values; the Fisher's exact test was used to compare differences in percentage. P values below 0.05 were considered statistically significant. Results. Between 2018 and 2020, 207 AL pts (AML: 165, ALL: 42) were evaluated in five Hospitals participating to the REL. Median age of the whole cohort was 58y, and M/F ratio 112/95. After induction treatment, CR was achieved in 153 of the 200 evaluable pts (76.5%), more frequently in ALL (38/42, 90.5%) than in AML pts (115/158, 72.8%) (p=0.0146). During induction cht, proven/probable (p/p) and possible (poss) IPA were diagnosed in 32/207 pts (15.4%), equally divided in p/p and poss (16 each, 7.7%). P/p IPA were more frequent in ALL than in AML (ALL: 7/42, 16.6% vs AML: 9/165, 5.4%; p= 0.0235); similarly, considering also poss IPA, incidence was higher, even if not significantly (9/42, 21.4% vs 23/165, 13.9%; p=0.2374). Among ALL pts, IPA was more frequent in pts not achieving CR (2/4, 50%) than CR pts (7/38, 18%), whereas in AML CR achievement did not influence IPA frequency (CR group: 15/115, 13%; no CR group: 7/43: 16.5%). ALL pts were uniformly treated with pediatric-like protocols; in AML pts no statistically significant differences in IPA incidence were observed according to cht received (3+7/like: 13/81, 16%; 3+7+midostaurin: 2/27, 7.4%; FLAG-Ida: 3/21, 14.3%; CPX-351: 4/19, 21%). Antimould prophylaxis was protective against IPA in 202 evaluable pts (Yes: 22/171, 12.9%; No: 10/31, 32.3%, p=0.0134). Among ALL pts only 1 out of 15 (6.7%) receiving antimould prophylaxis developed IPA, as compared to 8/27 (29.6%) of those not receiving antimould prophylaxis (p=0.1235). All but two AML pts developing IPA were on posaconazole prophylaxis. Both mean age and duration of neutropenia were significantly lower in ALL than in AML pts (46.02y vs 57.75y, p&amp;lt;0.0001 and 16.66d vs27.96d, p&amp;lt;0.0001); however, an impact of mean duration of neutropenia on IPA incidence was observed only in ALL pts (IPA group: 24.38d; no IPA group: 14.79d, p=0.0359). Only 2 AML pts died at 30d: 1 (3.1%) out of 32 pts with IPA and 1 (0.6%) out of 175 pts without. No early death was observed in ALL pts. Table 1 summarizes the clinical characteristics of AL pts in relation to IPA. Conclusions. Despite younger age, shorter duration of neutropenia and higher percentage of CR achievement, IPA, particularly p/p, was more frequently observed in ALL pts than AML during induction cht. High dose induction cht seems to have no impact in IPA incidence in AML pts. On the other hand, intensive cht ALL protocols, including high doses of dexamethasone, could have a role in IPA development, as well as the lack of antimould prophylaxis, which is confirmed as a predictive factor for IPA. Therefore, studies with antimould agents as prophylaxis against aspergillosis in ALL pts during inductions would be desirable.

Risk Factors and Prognostic Scoring Model for 28-Day Mortality in Hematologic Patients with Stenotrophomonas M altophilia Bacteremia

Objective: Patients with hematologic diseases are at a higher risk for Stenotrophomonasmaltophilia(SM) bacteremia, which poses significant burden on morbidity and mortality. The aim of this study was to evaluate the early predictors of 28-day mortality in hematologic patients with SM bacteremia and to construct a reliable prediction model which can be used to identify patients at higher risk for mortality. Methods: This retrospective analysis of 131 hospitalized patients diagnosed with SM bacteremia was conducted in a tertiary blood disease center in Tianjin, China, from January 2012 to June 2023. Univariate analysis and multivariate logistic regression analysis were used to identify prognostic risk factors and develop a prognostic mortality scoring system and internally validated by bootstrap method (resampling = 1000). Results: The overall 28-day mortality rate in our study was 29.77% (39/131). The mean age was 45 (IQR 30.5-56.0) years and 70 individuals (53.44%) were diagnosed with myeloid malignancies. The existing condition severity-related scores did not perform well in predicting 28-day mortality for the patients in our population (AUROC values: SOFA: 0.842; ECOG: 0.831; APACHE Ⅱ: 0.709; SAPS Ⅱ: 0.675; aCCI: 0.654; Pitt score: 0.629). Through univariate and multivariate analysis, we identified four independent risk factors associated with 28-day mortality: SOFA score (OR = 3.67, 95% CI 1.99-6.78, P &amp;lt; 0.001; score = corresponding SOFA score), age ≥ 60 years (OR = 6.95, 95% CI 1.44-33.55, P = 0.0158; score = 2), bloody sputum or hemoptysis (OR = 5.32, 95% CI 1.08-26.29, P = 0.0402; score = 2) and neutropenia duration ≥ 25 days (OR = 3.92, 95% CI 1.01-15.26, P = 0.0487; score = 1). These factors were used to develop a prognostic scoring model, which yielded good discrimination (AUC = 0.889, 95% CI: 0.829-0.949) and calibration (Hosmer-Lemeshow goodness-of-fit test P = 0.998), with similar performance in the internal bootstrap validation (AUC = 0.888). Furthermore, all patients were divided into the high-risk group (≥ 7 points) and the low-risk group (&amp;lt; 7 points) based on the model and compared using Kaplan-Meier curves and log-rank tests. Additionally, we founded that the use of trimethoprim-sulfamethoxazole (TMP/SMX) after infection was associated with a better prognosis ( P = 0.012). Conclusions: The prediction model, utilizing SOFA score, age, bloody sputum or hemoptysis and neutropenia duration, proves to be an effective tool for early identification of hematologic patients with SM bacteremia at high risk of mortality.

The Impact of Immune Function on Hematopoietic Reconstitution and Infection in Patients with Lymphoma after Autologous Hematopoietic Stem Cell Transplantation

Objective To investigate the impact of immune function on hematopoietic reconstitution and infection in lymphoma patients after autologous hematopoietic stem cell transplantation (auto-HSCT). Methods: A total of 20 patients with lymphoma who underwent auto-HSCT in Chongqing University Cancer Hospital from January 2021 to December 2021 were retrospectively analyzed. According to whether the number of CD4+T cells was greater than or equal to 200 cells /ul, the patients were divided into normal immune function group and immunocompromised group. The hematopoietic reconstitution of the two groups was observed, including the time of neutrophil engraftment and platelet engraftment, as well as the occurrence of infection, including the pathogen could not be identified in some patients with neutropenia, it was necessary to judge according to physical examination, laboratory and imaging examination or empirical antimicrobial treatment was effective. Results 1. Immunocompetent and immunocompromised patients included 10 patients, respectively. The durations of neutrophil engraftment were 9.5 (7-12) days and 12 (8-15) days (P = 0.007), and the durations of grade 3 neutropenia were 1.5 (0-4) days and 3 (1-7) days (P = 0.030), respectively. The duration of grade 4 neutropenia was 9 (5-16) days and 11 (6-20) days, respectively (P = 0.010). There was no significant difference in platelet engraftment time and incidence of grade IV anemia between the two groups (P &amp;gt;0.05). 2. The incidence of febrile neutropenia in immunocompetent group and immunocompromised group was 60% and 80%, respectively, and the median duration of febrile neutropenia was 3.5 (1-10) days and 5 (1-20) days, respectively (P = 0.005). 3. The incidence of infection in immunocompetent group and immunocompromised group was 20% and 30%, and the incidence of bloodstream infection was 20% and 30%. 4. The length of hospital stay in immunocompetent group and immunocompromised group was 31.5 (23-43) days and 37 (25-75) days, respectively (P&amp;lt;0.001). Conclusion The immune function of lymphoma patients before transplantation has a certain impact on hematopoietic reconstitution and infection. Normal immune function is superior to immunocompromised in terms of neutrophil engraftment, shortening the duration of febrile neutropenia, and the incidence of infection after transplantation.

Early Autologous Hematopoietic Stem Cells (AHSC) Boost (HCB) to Overcome Immune Effector Cell-Associated Hematotoxicity (ICAHT) after CAR T-Cell Therapy for Lymphoma: A Single Center Experience

Sustained cytopenias designed as Immune Effector Cell-Associated Hematotoxicity (ICAHT) represent one of the most frequent side effect of CAR-T-cell therapy (30 to 90 % patients in recent real life studies) resulting in significant morbidity, mortality and resources consumption. We report single center experience of early reinjection of previously cryopreserved AHSC (HCB) in that setting. From July 2021 until January 2023, 27 patients received CAR T-cell therapy (25 Axi-Cel, 2 Brexu-Cel) after Fludarabine and Cyclophosphamide lymphodepletion for relapsed/refractory large B-cell lymphomas (24), mantle lymphoma (2), or follicular lymphoma (1). Median age was 62 years (19-75). CAR-HEMATOTOX score was ≥ 2 for 46% of patients. All patients received Filgrastim from D0. Hematopoietic recovery was longitudinally evaluated until D90 or censoring for relapse and/or subsequent cytotoxic treatment: severe (CTAE grade ≥ 3) neutropenia, anemia or thrombopenia occurred respectively for 88, 44 and 76% of patients until D28, and 60, 24 and 60% until D90. Median duration of severe neutropenia was 7 days (0-39) and 28 days for severe thrombocytopenia (0-118). Prolonged neutropenia occurred in 18/25 evaluable patients, mostly with a biphasic course (intermittent recovery and aplastic phenotype for 14 and 4 patients respectively). CAR-HEMATOTOX score was significantly correlated with sustained thrombopenia (p = 0,005) but only marginally with ICAHT (p = 0,054) and not with severe neutropenia (p = 0,44) . We observed significant correlation of severe ICAHT with progressive disease at CAR T-cell infusion (p = 0,015), platelets nadir &amp;lt; 30 giga/l before D28 (p &amp;lt; 0,005) and CAR T-cell expansion (&amp;gt; 200/µl) at D7 (p = 0,023). 7 patients received HCB (no conditioning) at a median D24 (15-41) post CAR T-cell infusion: after D14 for patients with aplastic phenotype, or for cytopenic recurrence for patients with biphasic course. Filgrastim was pursued or reintroduced until neutrophil recovery (&amp;gt; 1 giga/l) which occurred after a median of 10 days (4-16); platelet recovery (&amp;gt; 20 giga/l and &amp;gt; 50 giga/l) occurred after a median of respectively 12 (8-14) and 17 (11-22) days. If we consider D0 as CAR T-cell infusion, neutrophil recovery occurred at median D37 (22-49) and platelet recovery (&amp;gt; 50 giga/l) at median D37 (26-63). Median complete hematopoietic reconstitution (defined as PMNC &amp;gt; 1 giga/l, and Hb &amp;gt; 100 g/l, and PLT &amp;gt; 100 giga/l) was significantly shorter (median 23 days, 14-30) for patients receiving HCB compared with patients with prolonged cytopenia (&amp;gt; 28 days) who do not receive HCB (60 days, p = 0,018). Transfusion and hematopoietic growth factors (HGF) consumption was significantly reduced after HCB but we observe no difference between 2 groups considering hospitalization, EFS or OS. 2 patients receiving HCB experienced late recurrence of cytopenia (after D90) requiring intermittent HGF support but no transfusion or hospitalization. Discussion - Perspectives Recent case series highlighted clinical feasibility and safety and of this approach across a broad population of pediatric and adult patients: we validate this strategy in a more homogeneous and systematic practice. As study population is small, we failed to demonstrate that earlier application of an HCB is associated with superior survival outcomes as shown by others. We agree with recent updated recommendation of experts panel considering application of HCB without prior conditioning chemotherapy for grade ≥ 3 ICAHT beyond D14 (so considered early) if AHSC graft is readily available. Prophylactic AHSC harvest in high-risk candidates has been proposed but collection process may add to already high logistic burden and costs of CAR T-cell therapy in the lymphoma setting. Conversely, cryopreserved ASHC is mainly available for patients with myeloma and this approach would be readily proposed and useful for around 20% patients as recently described. Gagelmann N et al. Hematopoietic stem cell boost for persistent neutropenia after CAR T-cell therapy: a GLA/DRST study. Blood Adv. 2023;7(4):555 Rejeski K et al, Immune Effector Cell-Associated Hematotoxicity (ICAHT): EHA/EBMT Consensus Grading and Best Practice Recommendations. Blood. 2023 doi: 10.1182/blood.2023020578 Davis JA et al. Efficacy and safety of CD34+ Stem Cell Boost for Delayed hematopoietic Recovery After BCMA Directed CAR T-cell Therapy. Transplant Cell Ther. 2023 doi: 10.1016/j.jtct.2023.05.012

Yield of Repeat Blood Cultures in Acute Myeloid Leukemia Patients Following Allogeneic Hematopoietic Stem Cell Transplantation

Introduction: Unnecessary repeat blood culture collection has been demonstrated to increase health care costs, length of stay, duration of antimicrobial exposure, and risk of anemia and result in unnecessary removal of vascular catheters. The aim of this study was to characterize the yield of new pathogen identification in acute myeloid leukemia (AML) patients with known bacteremia in the post-allogeneic hematopoietic stem cell transplant (HSCT) period. Methods: This was a retrospective study of AML patients who underwent allogeneic HSCT at Taussig Cancer Center from January 1 st 2019 to December 31 st 2022. Patients who experienced an occurrence of febrile neutropenia (FN) within 35 days of date of HSCT and had positive initial blood cultures within 24 hours of diagnosis of FN were included in the study. Patients who had at least 1 additional set of repeat cultures drawn following initial blood cultures were included in the study. Blood cultures were collected through a peripheral site via venipuncture or through a central line. The study was approved by the Institutional Review Board. Data were collected on baseline patient characteristics, AML disease characteristics, HSCT characteristics, and infection characteristics. Febrile neutropenia was defined as recorded temperature ≥ 100.4°F with concurrent ANC &amp;lt;1500 cells/uL. Each patient day with a recorded temperature ≥100.4°F and ANC &amp;lt;1500 cells/μL was considered as a day of FN. An episode of FN was considered to be resolved following 72 hours of defervescence. Cultures drawn within 24 hours of onset of FN were considered the initial blood cultures. All subsequent sets of blood cultures were considered repeat blood cultures. A positive set of blood culture was defined as &amp;gt;50% of all blood cultures in that set growing an organism. Cultures drawn from all peripheral and central sites on the same day of FN were considered as one set of blood cultures. All patients received post-HSCT anti-bacterial prophylaxis with bactrim or ciprofloxacin. Results: A total of 154 AML patients who underwent HSCT at Taussig Cancer Center were screened for the study. 50/154 (32.5%) of those patients met inclusion criteria and were included in the study. Among the 50 patients included in the study, there were 50 episodes of FN with positive initial blood cultures that were diagnosed within 35 days of HSCT. There were 120 total days of FN among the 50 episodes of FN with an average of 2.4 days per episode. 50 initial sets of blood cultures and 96 sets of repeat blood cultures were drawn between the 50 episodes of FN with an average of 2.9 total sets of blood cultures per episode. 12/96 (12.5%) of repeat blood cultures sets were positive for a pathogen. 3/96 (3.1%) of repeat blood cultures sets grew a pathogen that differed from the pathogen which grew in the preceding positive blood culture. The median duration of febrile neutropenia at time of repeat positive culture was 3.5 days. 30-day mortality rate from infection was 6.0% (3/50). Conclusion: Even amongst bacteremic AML patients in the post-HSCT period, the yield of repeat blood cultures was low for detecting new pathogen identification. Repeat blood cultures should be guided by thorough evaluation of emerging clinical signs and symptoms.

The Mini-Teddi-R Treatment Demonstrated a High Rate of Remission in Patients with DLBCL Involving the CNS Who Had Previously Been Exposed to BTK Inhibitors

Background: Secondary CNS B-cell lymphomas (SCNSL) are aggressive lymphomas with a bleak prognosis. TEDDI-R has been successful in achieving lasting remission in relapsed/refractory primary DLBCL of the CNS (PCNSL), but the effectiveness of ibrutinib-responsive tumors in SCNSL remains unknown. This study presents initial findings from the use of mini-TEDDi-R in SCNSL. Methods: Efficacy and safety data of mini-TEDDi-R were retrospectively analyzed for patients with DLBCL involving the CNS. All patients experienced relapse in the CNS or/and peripheral region after initial therapy. Brain parenchyma involvement allowed for treatment with MTX, Ara-c, and/or BTK inhibitors. The dosage of the drugs used in the original regimen was reduced, leading to the adoption of the term “mini-TEDDi-R.” Each 21-day cycle involved the following treatments: intravenous rituximab at a dose of 375 mg/m 2/day on days 1-2, oral temozolomide at a dose of 150 mg/m 2/day on days 2-5, intravenous infusion of 30 mg/m 2/day etoposide on days 2-5, intravenous infusion of 25 mg/m 2 of pegylated liposomal doxorubicin on day 2, intravenous infusion of dexamethasone at a dose of 10 mg/m 2/BID on days 1-5, and oral zanubrutinib at a dose of 200mg/BID or oral orelabrutinib at a dose of 150mg/qd or oral ibrutinib at a dose of 560mg/qd from day 1 until neutrophil count &amp;lt;0.5*10^9/L or platelet count &amp;lt;30*10^9/L. Additionally, intrathecal administration of 70 mg of cytarabine occurred on days 1 and 5, All remissions observed on MRI were confirmed through FDG-PET and CSF analysis. Results: Between December 2019 and June 2023, 24 patients with a median age of 53 (range 28-69) received mini-TEDDi-R treatment. All patients had DLBCL, comprising 16 (66.7%) non-GCB, 6 (25%) GCB, and 2 (8.3%) transformed from FL. All patients experienced relapse in the CNS system after a median of 6 (range 1-17) prior therapies, and all (100%) patients received prior anthracycline treatment. A total of 21 patients (87.5%) had received multiple lines of therapy before mini-TEDDi-R. Among them, 19 patients (79.2%) had received HD-MTX based salvage therapy, 11 patients (45.8%) had received HD-Ara-c based salvage therapy, and 14 patients (58.3%) had been exposed to BTK inhibitors. Seven patients (29.2%) showed triple resistance to MTX, Ara-c, and BTK inhibitors. Six patients had previously undergone transplantation, and four patients had experienced failure of CD19 CART treatment. Thirteen patients (54.2%) had isolated CNS disease, while 11 patients (45.8%) had both CNS and peripheral disease. Thirteen patients (54.2%) underwent 1 cycle of mini-TEDDi-R, 8 patients (33.3%) completed 2 cycles, 2 patients (8.3%) finished 3 cycles, and 1 patient (4.2%) completed 4 cycles. The objective remission rate (ORR) was determined to be 70.8%, with a complete remission (CR) rate of 58.3%. Notably, patients (N=14) exposed to BTK inhibitors previously exhibited a similar CR rate compared to patients (N=10) who had not received prior BTK inhibitor treatment (50% vs. 70%, p = 0.348). Patients (N=19) who had undergone HD-MTX based salvage therapy achieved an ORR of 74% and a CR rate of 58%. No significant difference in response rate was observed between patients with peripheral and non-peripheral secondary CNS involvement. In patients who achieved complete remission, only one patient experienced a second CNS relapse. Four patients bridged to auto-HSCT, 2 patients bridged to CART treatment, and 4 patients underwent auto-HSCT combined with CART treatment for consolidation. The median overall survival and median PFS have not been reached within the 11.8-month follow-up period. Toxicity was evaluated over 39 cycles. Grade 3 and 4 neutropenia occurred in 51% and 16% of cycles, respectively, while febrile neutropenia was observed in 10% of cycles. The median duration of neutropenia was 6 days (range 4-10). Three cycles (8%) were complicated by infections graded as ≥G3, but no opportunistic infections (including Aspergillus) were observed. Grade 3 and 4 thrombocytopenia occurred in 26% and 14% of cycles, respectively. The median duration of neutropenia was 7 days (range 3-14). Conclusions: The mini-TEDDi-R regimen demonstrated a favorable remission rate in patients with DLBCL involving the CNS. The treatment was well-tolerated, and patients with tumors that were previously exposed to BTK inhibitors and HD-MTX treatment also showed positive responses to mini-TEDDi-R.

843. Prognostic Association of Liposomal Amphotericin B Doses Above 5 mg/kg in Mucormycosis: A Nationwide Epidemiologic and Treatment Analysis in Japan

Abstract Background Mucormycosis is a fatal fungal infection, and there is limited information on its epidemiology and treatment practices, including the optimal dosage of liposomal amphotericin B. Methods A retrospective nationwide analysis of 82 proven and probable cases of mucormycosis was performed. Cases were collected from 51 hospitals in Japan by hematologists and infectious disease specialists. Variables included annual incidence, site of infection, Mucorales genera, and patient and treatment characteristics. Comparison was made between patients who survived and those who died. Comparative analysis was performed between patients who received a liposomal amphotericin B dose of 5 mg/kg and those who received a dose of &amp;gt;5 mg/kg. Categorical variables were tested for differences using Fisher's exact test or χ-squared test. The association between liposomal amphotericin B dose and prognosis was evaluated using the Kaplan-Meier method, and differences were tested using the log-rank test. A Cox proportional hazards model was used to control for confounding.Figure 1.Patient selection Results The lung was the most commonly involved organ (70.7%), and 35.4% of cases were disseminated. Rhizopus spp., Cunninghamella spp., and Mucor spp. were the most common organisms. No significant differences in infected organs or distribution of Mucorales were observed between the survival and death groups. Longer duration of neutropenia was more common among deaths (p = 0.007). Mortality within 120 days was 54.2%. More cases in the survival group started liposomal amphotericin B before confirmed diagnosis (p = 0.028). Survival did not differ between patients receiving liposomal amphotericin B at 5 mg/kg and those receiving &amp;gt;5 mg/kg (p=0.873). Using Cox proportional hazards models adjusting for confounders, such as age ( &amp;gt;65 years), prolonged neutropenia, and resection of infected lesions, the hazard ratio for the effect of &amp;gt;5 mg/kg liposomal amphotericin B on 120-day prognosis was 0.93 (95% confidence interval, 0.4-2.3, p = 0.870) compared with 5 mg/kg. Conclusion This study provides important insights into the precise epidemiology and treatment practices of mucormycosis among hematologists and infectious disease specialists. There was no difference in prognosis between the 5 mg/kg and &amp;gt;5 mg/kg liposomal amphotericin B groups.Figure 2.Kaplan-Meier estimates of survival in the two groups of mucormycosis treated with different doses of liposomal amphotericin B. Disclosures Masato Tashiro, MD, PhD, Asahi Kasei Pharma Corporation: Advisor/Consultant|Asahi Kasei Pharma Corporation: Honoraria|Sumitomo Pharma Co., Ltd.: Honoraria Hiroshi Kakeya, MD, PhD, Asahi Kasei Pharma Corporation: Honoraria|Merck Sharp &amp; Dohme: Honoraria|Sumitomo Pharma Co., Ltd.: Honoraria Hiroshige Mikamo, M.D, Ph.D, Asahi Kasei Pharma Corporation: Grant/Research Support|Merck Sharp &amp; Dohme: Honoraria|Pfizer Inc.: Grant/Research Support|Pfizer R&amp;D Japan: Honoraria|Sumitomo Pharma Co., Ltd.: Grant/Research Support|Sumitomo Pharma Co., Ltd.: Honoraria Kazutoshi Shibuya, M.D., Ph.D., Sumitomo Pharma Co., Ltd.: Grant/Research Support Koichi Izumikawa, M.D., Ph.D., Asahi Kasei Pharma Corporation: Grant/Research Support|Asahi Kasei Pharma Corporation: Honoraria|Astellas Pharma Inc.: Honoraria|DAIICHI SANKYO COMPANY, LIMITED: Grant/Research Support|DAIICHI SANKYO COMPANY, LIMITED: Honoraria|KYORIN Pharmaceutical Co., Ltd.: Honoraria|Merck &amp; Co., Inc.: Honoraria|Pfizer Japan Inc.: Honoraria|Shionogi &amp; Co., Ltd.: Grant/Research Support|Shionogi &amp; Co., Ltd.: Honoraria|Sumitomo Pharma Co., Ltd.: Grant/Research Support|Sumitomo Pharma Co., Ltd.: Honoraria|TAIHO PHARMACEUTICAL CO., LTD.: Grant/Research Support