Absolute Neutrophil Count Nadir Research Articles

Impact of 10% Dose Reductions and Duration of Treatment Delays in the Management of Chemotherapy-Induced Neutropenia in Dogs Treated With Common Chemotherapy Protocols: A Single-Centre Experience.

Neutropenia is a common chemotherapy-associated adverse event (AE) in dogs and a significant cause of decreased relative dose intensity. Dose reductions (DRs) and treatment delays (TDs) are frequently applied to decrease the risk of further neutropenic events (NEs) and AEs, but there is no standardised approach. The two main objectives of this retrospective study were to determine: (1) the failure rate of a 10% DR to prevent a subsequent inadequate absolute neutrophil count (ANC), defined as a nadir ANC <0.75 × 109/L or pretreatment ANC <1.5 × 109/L; and (2) if the duration of TDs due to pretreatment neutropenia affects the occurrence of subsequent NEs. A total of 1056 chemotherapy treatments were recorded for 128 dogs that developed at least one NE. In 75 of 124 (60.5%, 95% CI: 51.2%-69%) evaluable NEs, a nadir ANC of ≥0.75 × 109/L and pretreatment ANC of ≥1.5 × 109/L were achieved after a single 10% chemotherapy DR, while a 10% DR failed to prevent a subsequent inadequate ANC in the remaining 49/124 (39.5%, 95% CI: 30.1%-48.3%). The only variable associated with failure was the drug prescribed. DR failure occurred in 22/39 (56.4%, 95% CI: 40.9%-70.6%) lomustine DRs, 14/27 (51.9%, 95% CI: 33.9%-69.2%) cyclophosphamide DRs, but only 2/22 (9.1%, 95% CI: 2.5%-27.8%) doxorubicin DRs and 2/24 (8.3%, 95% CI: 2.3%-25.8%) vincristine DRs. Seventy-three evaluable TDs (mean: 5 days, SD ± 2.2 days) were prescribed. There was no association between TD duration and subsequent NEs (p = 0.11).

Dose-Volume Parameters of Spared Magnetic Resonance Imaging-Defined Active Bone Marrow Predict Hematologic Toxicity in Pelvic Malignancies Patients Undergoing Radiotherapy: A Cohort Study.

Background: The objective of this investigation is to evaluate the superiority of dose-volume parameters relying on magnetic resonance imaging (MRI)-defined active bone marrow (ABM) over those based on total bone marrow (TBM) contoured via CT in the prediction of hematologic toxicity (HT) occurrence among patients with pelvic malignancies undergoing radiotherapy. Methods: The clinical data of 116 patients with pelvic malignancies treated with pelvic radiotherapy were analyzed retrospectively. The ABM areas on T1-weighted MRI were contoured. The statistical significance between TBM and ABM dose-volume measures was assessed through the utilization of either Student's t-test or Wilcoxon signed rank test. Logistic and linear regression models were employed to analyze the correlation between dose-volume parameters (V5-V50) and HT occurrence in pelvic ABM and TBM. Receiver operating characteristic (ROC) curves were used to compare predictors of HT2+. Results: There were significant differences in dosimetric parameters between ABM and TBM. Logistic regression analysis showed that ABM V5, ABM V10, ABM V15, ABM V20, and TBM V5 were significantly associated with the occurrence of HT2+ in pelvic malignancies. Linear regression analysis showed that ABM V5, ABM V10, and ABM V15 were significantly associated with white blood cell (WBC), absolute neutrophil count (ANC), hemoglobin (Hb), and lymphocyte (Lym) nadir. ABM V5, ABM V10, ABM V15, and ABM V30 were predictive of HT2+. Conclusions: More accurate prediction of HT in patients receiving pelvic radiotherapy may be achieved by relying on dose-volume parameters of MRI-based ABM. Further prospective studies are needed to confirm this.

Analysis of the Risk of Infection Stratified By Absolute Neutrophil Counts during Deferiprone-Associated Severe Neutropenia or Agranulocytosis

Introduction Patients with transfusional iron overload receiving iron chelation therapy with deferiprone may experience a decrease in absolute neutrophil counts (ANC) that range from mild (ANC &amp;lt;1.5 x 10 9/L) to severe neutropenia/agranulocytosis (typically defined as ANC &amp;lt;0.5 x 10 9/L), and which put them at risk for infections. In patients taking deferiprone, the risk of infection and/or mortality associated with ANC of &amp;lt;0.2 or &amp;lt;0.1 x 10 9/L is unknown. Our objective was to analyze data from patients taking deferiprone in clinical trials and the postmarketing setting to determine the incidence and severity of infection stratified by ANC levels. s Methods The clinical trial setting involved patients with systemic iron overload who had thalassemia, sickle cell disease, or other anemias and received deferiprone across 15 clinical trials. Data associated with episodes of severe neutropenia/agranulocytosis in patients who had been treated with at least 1 dose of deferiprone were reviewed. For the postmarketing setting, all individual case safety reports since the first market approval of deferiprone on August 25, 1999 to August 31, 2021, were reviewed; cases coded to agranulocytosis were extracted; cases without any reported ANC were removed; and cases with at least 1 ANC value were analyzed. Obtaining confirmed ANC value was not always possible in the postmarketing setting. All infections occuring within ±2 weeks of agranulocytosis onset were identified, graded for severity, and classified as serious, including fatal or life-threatening. Serious events were defined as any event that resulted in death, was life-threatening, required hospitalization or prolonged existing hospitalization, caused disability or permanent damage, caused congenital anomaly, or was classified as an important medical event. Infection events associated with ANC values were categorized into 3 groups based on the nadir ANC (all x 10 9/L): Group A, ANC ≥0.2 to &amp;lt;0.5; Group B, ANC ≥0.1 to &amp;lt;0.2; or Group C: ANC &amp;lt;0.1. Results A total of 977 patients with systemic iron overload received deferiprone in sponsored clinical trials. Among those, 9 patients were in Group A, 3 in Group B, and 10 in Group C. Of the 12 patients in Groups A and B, none had serious, severe, or fatal infections ( Table 1). Three of the 10 (30.0%) patients in Group C experienced serious or severe infections that included (1) parvovirus infection accompanied by diarrhea, a maculopaular rash, and pyrexia resulting in hospitalization; (2) a severe but nonserious respiratory tract infection with esophageal candidiasis in a patient with a history of neutropenia prior to initiating deferiprone; and (3) a fatal case of Pseudomonal sepsis in a patient who had a history of multiple cardiac and pulmonary comorbidities. Deferiprone was permanently discontinued in all 3 patients. From postmarketing data, of a total of 238 adverse reactions that were coded as agranulocytosis, 176 had at least 1 ANC value. Among those, 65 reactions were in Group A, 20 in Group B, and 91 in Group C. Among the reactions in Group A, 5/65 (7.7%) had serious infections and 3 of them (4.6%) had fatal outcomes due to sepsis ( Table 2). Among the reactions in Group B, 2/20 (10.0%) had serious infections, with a fatal outcome in one of them (5.0%); the death was from sepsis and the life-threatening infection involved pneumonia with multiple pulmonary complications. Among the reactions in Group C, 12/91 (13.2%) had serious infections and 8 of them (8.8%) had fatal outcomes; the 8 deaths were associated with sepsis. The 4 serious non-fatal infections involved sepsis; pancytopenia with ANC nadir of 0 accompanied by oropharyngeal pain, fever, and diarrhea that required hospitilization; angioinvasive mucormycosis; and disseminated herpes simplex accompanied by sepsis, resulting in hospitalization. Conclusion Patients receiving deferiprone who become neutropenic are generally at a higher risk of infections or mortality with lower neutrophil levels (ie, ANC &amp;lt;0.2 or &amp;lt;0.1 x 10 9/L compared with ANC ≥0.2 to &amp;lt;0.5 x 10 9/L). Our findings are consistent with the recently published guidelines from the European Hematology Association and the European Network for Innovative Diagnosis and Treatment of Chronic Neutropenias that used agranulocytosis to describe events with ANC of ≤0.2 x 10 9/L in association with a high risk of severe and life-threatening infections.

Population Pharmacokinetic-Pharmacodynamic Modeling of Neutrophil and Platelet Count for Lower-Intensity Therapy of CPX-351 Combined with Venetoclax in Acute Myeloid Leukemia

Background: Improved survival outcomes and a comparable safety profile with CPX-351 (a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio) vs conventional 7+3 chemotherapy in a pivotal phase 3 trial led to the approval of CPX-351 for newly diagnosed therapy-related acute myeloid leukemia (tAML) or AML with myelodysplasia-related changes (AML MRC) in adults and pediatric (aged ≥1 year) patients in the United States and in adults in Europe. The approved induction dose is 1-2 cycles of CPX-351 100 units/m 2 (daunorubicin 44 mg/m 2 and cytarabine 100 mg/m 2) as a 90-minute intravenous infusion on days 1, 3, and 5 (days 1 and 3 for second induction). In this study, we developed a population pharmacokinetic-pharmacodynamic (PK-PD) model of absolute neutrophil count (ANC) and platelet count to determine the optimal dose for a lower-intensity therapy (LiT) of CPX-351 combined with venetoclax. Methods: The CPX-351 population PK-PD analysis was based on data collected from 3 clinical studies (phase 1 study [NCT00389428; J Clin Oncol 2011; 29(8):979-85];phase 2 study [NCT02238925; Cancer Chemother Pharmacol 2019; 84(1):163-73];phase 3 study [NCT01696084; J Clin Oncol 2018; 36(26):2684-92]) in patients with newly diagnosed high-risk/secondary AML. Venetoclax population PK-PD analysis was based on data from a comprehensive safety analysis of venetoclax monotherapy ( Clin Cancer Res 2018; 24(18):4371-9). ANC and platelet data used in the analysis were from 94 patients for CPX-351 and 272 patients for venetoclax. Generalized semi-mechanistic population PK-PD analyses were performed using non-linear mixed-effects modeling to characterize the time-course of ANC and platelet count following administration of CPX-351 and venetoclax monotherapy. The majority of system parameters were shared across the 2 therapies and a limited number of treatment-specific parameters were estimated by fitting CPX-351 and venetoclax PK time-courses simultaneously. An R Shiny app was developed for the simulation of different dosing regimens with favorable safety profiles to guide optimal dose selection for LiT of CPX-351 combined with venetoclax, assuming the 2 drug effects on ANC and platelet count were additive. Results: The generalized PK-PD model included multi-compartment transit models for ANC and platelet count with separate semi-mechanistic compartments to represent proliferating, maturing, and circulating cells. The model fitted CPX-351 and venetoclax PK-PD data with shared system parameters except for the drug-specific parameter IC 50 (concentration producing 50% of maximal inhibition of cell proliferation). For ANC, the estimated IC 50 values for CPX-351 and venetoclax were 295 μM (relative standard error [RSE]: 8.96%) and 120 μM (RSE: 18.0%), respectively; the shared mean transit time (MTT) estimate for ANC maturation was 66.6 h (RSE: 4.95%), and shared maximal inhibition of cell proliferation (I max) was fixed to 1. For platelet count, the estimated IC 50 values for CPX-351 and venetoclax were 0.0109 μM (RSE: 50.2%) and 16.5 μM (RSE: 8.73%); the shared MTT estimate for platelet maturation was 87.2 h (RSE: 9.01%) and shared I max estimate was 0.313 (RSE: 11.2%). Simulations with different doses of CPX-351 in combination with 400 mg venetoclax were performed. The simulated mean nadir ANC were 2.1, 1.5, 1.1, and 0.6 × 10 9/L for CPX-351 doses of 20, 40, 60, and 100 units/m 2, respectively, when administered on days 1 and 3 and combined with venetoclax 400 mg daily for 28 days. The simulated mean nadir platelet counts were 31.0, 30.3, 30.0, and 29.7 × 10 9/L for CPX-351 doses of 20, 40, 60, and 100 units/m 2, respectively, when administered on days 1 and 3 and combined with venetoclax 400 mg daily for 28 days. Model-based simulated outcomes of ANC and platelet count were consistent with the observed trial data. C onclusions: A generalized semi-mechanistic population PK-PD model was developed to adequately describe the time-courses of ANC and platelet counts in patients with AML following the administration of CPX-351 and venetoclax monotherapy and was used to infer the impact on ANC and platelet count when given in combination. Model-based simulations supported initial dose selection in the phase 1b study of combined CPX-351 LiT plus venetoclax as first-line treatment for patients with AML who are unfit for intensive chemotherapy (NCT04038437).

Early Identification of Patients at Risk of Cabazitaxel-induced Severe Neutropenia

BackgroundCabazitaxel frequently causes severe neutropenia. A higher cabazitaxel systemic exposure is related to a lower nadir absolute neutrophil count (ANC). ObjectiveTo describe the effect of cabazitaxel systemic exposure on ANC by a population pharmacokinetic/pharmacodynamic (POP-PK/PD) model, and to identify patients at risk of severe neutropenia early in their treatment course using a PK threshold. Design, setting, and participantsData from five clinical studies were pooled to develop a POP-PK/PD model using NONMEM, linking both patient characteristics and cabazitaxel systemic exposure directly to ANC. Outcome measurements and statistical analysisA PK threshold, predictive of severe neutropenia (grade ≥3), was determined using a receiver operating characteristic curve. Results and limitationsNinety-six patients were included with a total of 1726 PK samples and 1081 ANCs. The POP-PK/PD model described both cabazitaxel PK and ANC accurately. A cabazitaxel plasma concentration of >4.96 ng/ml at 6 h after the start of infusion was found to be predictive of severe neutropenia, with a sensitivity of 76% and a specificity of 65%. ConclusionsEarly cabazitaxel plasma levels are predictive of severe neutropenia. Implementation of the proposed PK threshold results in early identification of almost 76% of all severe neutropenias. If prospectively validated, patients at risk could benefit from prophylactic administration of granulocyte colony stimulating factors, preventing severe neutropenia in an early phase of treatment. Implementation of this threshold permits a less restricted use of the 25 mg/m2 dose, potentially increasing the therapeutic benefit. Patient summaryTreatment with cabazitaxel chemotherapy often causes neutropenia, leading to susceptibility to infections, which might be life threatening. We found that a systemic cabazitaxel concentration above 4.96 ng/ml 6 h after the start of infusion is predictive of the occurrence of severe neutropenia. Measurement of systemic cabazitaxel levels provides clinicians with the opportunity to prophylactically stimulate neutrophil growth.

Incidence and Risk Factors for Neutropenia After Intra-Arterial Chemotherapy for Retinoblastoma

Intra-arterial chemotherapy (IAC) has quickly gained popularity as a mainstay of treatment for retinoblastoma. Intra-arterial chemotherapy has been described as having several advantages over systemic chemotherapy, including reducing systemic toxicity and neutropenia; however, studies on the risk of neutropenia after IAC remain limited. To estimate the incidence of neutropenia after IAC, as well as identify risk factors associated with the development of neutropenia. This case series included pediatric patients with unilateral or bilateral retinoblastoma who were treated with IAC at a single quaternary care center from July 13, 2013, to January 6, 2023. All patients were treated with IAC and underwent multiple IAC cycles depending on treatment response. The primary chemotherapy agent used was melphalan, but topotecan or carboplatin could be used along with melphalan. Melphalan doses were kept to 0.4 mg/kg or less per cycle. After each IAC cycle, complete blood cell counts were obtained within 10 to 12 days and repeated until the absolute neutrophil count (ANC) was greater than or equal to 1000/μL. The primary outcome was the minimum ANC after each IAC cycle. The secondary outcome was the development of severe (grade 3 or 4) neutropenia (ANC <1000/μL). Regression analyses were used to identify associations between variables and outcomes. Receiver operating characteristic curves were used to calculate threshold dose for each chemotherapy agent potentially associated with the development of severe neutropenia. A total of 64 eyes of 49 patients (mean [SD] age, 1.7 [1.2] years; 25 females [51.0%]) with retinoblastoma were treated with 171 cycles of IAC. The mean (SD) nadir ANC was 1325.3 (890.7)/μL and occurred a median (IQR) of 10 (10-14) days (range, 6-28 days) after IAC administration. The frequency distribution of post-IAC neutropenia grades 0, 1, 2, 3, 4, and missing was 31 (18.1% of cycles), 25 (14.6%), 40 (23.4%), 37 (21.6%), 26 (15.2%), and 12 (7.0%), respectively. Factors weakly correlated with a lower ANC were higher melphalan dose (β = -2356 [95% CI, -4120.6 to -611.2]; adjusted R2 = 0.251; P = .01) and higher topotecan dose (β = -4056 [95% CI, -7003.6 to -1344.5]; adjusted R2 = 0.251; P = .006). In this case series of patients with retinoblastoma, the incidence of severe neutropenia after IAC was nearly 40%, which is higher than previously reported. Extended laboratory monitoring may aid in capturing previously overlooked cases of neutropenia. Topotecan may be associated with the development of neutropenia; limiting topotecan doses, especially in the setting of a high melphalan dose, may be beneficial in reducing the risk of neutropenia.

Absolute neutrophil count nadir in healthy pediatric patients with the Duffy-null phenotype

Absolute neutrophil count nadir in healthy pediatric patients with the Duffy-null phenotype

Model-based approach to identify predictors of paclitaxel-induced myelosuppression in "real-world" administration.

Taxanes are currently the most frequently used chemotherapeutic agents in cancer care, where real-world use has focused on minimizing adverse events and standardizing the delivery. Myelosuppression is a well-characterized, adverse pharmacodynamic effect of taxanes. Electronic health records (EHRs) comprise data collected during routine clinical care that include patients with heterogeneous demographic, clinical, and treatment characteristics. Application of pharmacokinetic/pharmacodynamic (PK/PD) modeling to EHR data promises new insights on the real-world use of taxanes and strategies to improve therapeutic outcomes especially for populations who are typically excluded from clinical trials, including the elderly. This investigation: (i) leveraged previously published PK/PD models developed with clinical trial data and addressed challenges to fit EHR data, and (ii) evaluated predictors of paclitaxel-induced myelosuppression. Relevant EHR data were collected from patients treated with paclitaxel-containing chemotherapy at Inova Schar Cancer Institute between 2015 and 2019 (n = 405). Published PK models were used to simulate mean individual exposures of paclitaxel and carboplatin, which were linearly linked to absolute neutrophil count (ANC) using a published semiphysiologic myelosuppression model. Elderly patients (≥70 years) constituted 21.2% of the dataset and 2274 ANC measurements were included in the analysis. The PD parameters were estimated and matched previously reported values. The baseline ANC and chemotherapy regimen were significant predictors of paclitaxel-induced myelosuppression. The nadir ANC and use of supportive treatments, such as growth factors and antimicrobials, were consistent across age quantiles suggesting age had no effect on paclitaxel-induced myelosuppression. In conclusion, EHR data could complement clinical trial data in answering key therapeutic questions.

Grade 4 Neutropenia Frequency as a Binary Risk Predictor for Adverse Clinical Consequences of Chemotherapy‑Induced Neutropenia: A Meta-analysis

Neutropenia is the major toxicity of myelosuppressive cancer chemotherapy. Grade 4 neutropenia (Gr4N) is a measure of chemotherapy-induced neutropenia (CIN) severity. We conducted a meta-analysis of CIN data. Gr4N incidence was significantly correlated with febrile neutropenia (FN), days of severe neutropenia (DSN), and nadir absolute neutrophil count (ANC), which are all important predictors of morbidity. With a Gr4N threshold of 65%, both FN and DSN were below levels for low risk of adverse CIN outcomes. Gr4N was highly predictive for adverse CIN outcomes, and a 65% threshold demarcated low vs. high risk for FN and other adverse CIN outcomes.

Real-world effectiveness of prophylactic granulocyte colony-stimulating factor (G-CSF) early (week 1) and late (weeks 2-3) in the cycle for the prevention of febrile neutropenia (FN) among patients (pts) with breast cancer (BC) after high FN–risk chemotherapy (chemo).

599 Background: G-CSF mitigates chemotherapy-induced neutropenia (CIN) and reduces FN risk. G-CSF moves the nadir of absolute neutrophil count (ANC) earlier (to week 1) in the chemo cycle and shortens nadir duration (Crawford, NEJM 1991), suggesting the potential for suboptimal CIN protection early (week 1) in the chemo cycle. The relative FN risk in week 1 vs. weeks 2-3 of the cycle with G-CSF is unknown and was analyzed compared with no G-CSF in the real-world setting with high FN risk chemo. Methods: Using a database of administrative claims representing 100% of fee-for-service Medicare, we analyzed BC pts who initiated docetaxel (T), doxorubicin (A), or cyclophosphamide (C) monotherapy or combination therapy between 01/01/2015 – 12/31/2019. Sample pts included adults aged ≥ 65 years with continuous coverage in Medicare Parts A, B, and D for 6 months before and 20 days after chemo initiation. Pts were categorized as receiving vs. not receiving G-CSF therapy within 3 days after chemo. Rate of FN events starting in week 1 vs. weeks 2-3 in cycle 1 was calculated. We defined FN as an inpatient admission with a primary or secondary diagnosis of neutropenia and measured the interval between chemo initiation and FN admission. Results: Among 18,788 Medicare beneficiaries with BC treated with T, A, and/or C, 72% received G-CSF therapy. More pts receiving G-CSF were treated with ≥ 2 of T, A, and/or C compared to pts who did not receive G-CSF (71% vs. 51%). Overall FN incidence in cycle 1 was significantly lower among pts receiving G-CSF (4.0%; n=546) compared to pts not receiving G-CSF (8.8%; n=462) (p&lt;0.0001). In pts with G-CSF, 81% (440/546) of all 1st-cycle FN events started in week 1 vs. 19% (106/546) in weeks 2-3. In pts not receiving G-CSF, the start of 1st-cycle FN events was more equally distributed: 41% (190/462) started in week 1 vs. 59% (272/462) in weeks 2-3. Results were robust to sensitivity analyses restricted to pts receiving ≥ 2 of T, A, and/or C. The rates of 1st-cycle FN events starting in weeks 1 and 2-3 with and without G-CSF following chemo initiation is shown below. Conclusions: Prophylactic G-CSF was highly effective for the prevention of FN in weeks 2-3, but relatively ineffective in week 1 of cycle 1 in the real-world setting, leaving pts largely unprotected during the first week. This represents an unmet medical need in week 1 of the cycle, despite use of G-CSF. Clinical trial information: NCT03294577. [Table: see text]

Delayed Neutropenia in Heart Transplant Recipients Following COVID-19 Diagnosis

Introduction`Neutropenia is observed after heart transplantation due to medication effects and viral infections. SARS-CoV-2 infection, which causes Covid-19 illness, can uncommonly cause neutropenia in non-transplant recipients. Delayed neutropenia following SARS-CoV-2 infection in heart transplant recipients (HTRs) has not been described.Case ReportCase 1: A 45 year old male combined heart and liver transplant recipient was diagnosed with Covid-19 17 months after transplant. Neutropenia had been noted six months after transplant in the setting of valganciclovir and mycophenolate mofetil (MMF) use, which resolved with discontinuation of those medications. At the time of his Covid-19 diagnosis, his immunosuppression regimen included tacrolimus with a target level 8-10 ng/mL and prednisone 5 mg once daily, and he had an asymptomatic course. His absolute neutrophil count (ANC) four weeks prior to Covid-19 diagnosis was 1,690/uL. The ANC obtained nine weeks after Covid-19 diagnosis was 890/uL. Testing for cytomegalovirus was negative and no neutrophil-depleting medications were identified. He received two doses of granulocyte colony stimulating factor (G-CSF). The subsequent ANC two days after the second dose was 3,600/uL. Case 2: A 66 year old male HTR was diagnosed with Covid-19 31 months after transplant. His symptoms included fever, cough, and diarrhea and he was admitted for inpatient care. Immunosuppression at the time of diagnosis included tacrolimus with a target level of 8-10 ng/mL and MMF 1000 mg twice daily, which was later decreased to 500 mg twice daily. The ANC nadir during his acute illness was 1310/uL. Six weeks after Covid-19 diagnosis, his ANC was 420/uL. Testing for cytomegalovirus was negative. The patient required a total of six doses of G-CSF over six weeks due to persistent neutropenia. MMF was discontinued. He was referred to a hematologist for persistent neutropenia. A bone marrow biopsy showed normal neutrophil production, and increased peripheral neutrophil consumption was hypothesized.SummaryAcute viral infections including SARS-CoV-2 can cause neutropenia, but delayed neutropenia is rare and has not been described in HTRs. Careful monitoring of the complete blood count (with differential) may be useful in this population following a Covid-19 diagnosis. Modulation of immunosuppression and G-CSF administration can support neutrophil recovery.

Dosimetric parameters and absolute monocyte count can predict the prognosis of acute hematologic toxicity in cervical cancer patients undergoing concurrent chemotherapy and volumetric-modulated\xa0arc\xa0therapy

PurposeTo explore clinical and dosimetric predictors of acute hematologic toxicity (HT) in cervical cancer patients treated with concurrent chemotherapy and volumetric-modulated arc therapy (VMAT).Methods and materialsWe retrospectively reviewed the clinical data of 184 cervical cancer patients who had concurrent chemotherapy and VMAT. Hematological parameters were collected during the treatment period. The total pelvic bone (TPB) was delineated retrospectively for dose-volume calculations. To compare the differences between two groups, the normality test findings were used to run a paired-samples t-test or Wilcoxon signed-rank test. Pearson's correlation analysis or Spearman's correlation was used to testing the correlation between the two variables. Binary logistic regression analysis was used to analyze associations between HT and possible risk factors. The receiver operating characteristic curve(ROC) was used to evaluate the best cut-off point for dosimetric planning constraints.ResultsThe nadir of absolute monocyte count (AMC) was found to be positively correlated with the nadir of absolute white blood cells (WBC) count (r = 0.5378, 95% CI 0.4227–0.6357, P < 0.0001) and the nadir of absolute neutrophil count(ANC) (r = 0.5000, 95% CI 0.3794–0.6039, P < 0.0001). The AMC decreased and increased before the ANC and WBC. In multivariate logistic regression analysis, the chemotherapy regimens and the TPB_V20 were independent risk factors for developing grade ≥ 3 HT. The optimal TPB_V20 cut-off value identified by ROC curves and the Youden test was 71% (AUC = 0.788; 95% CI 0.722–0.845; P value < 0.001).ConclusionsThe changing trend of AMC can be used as an effective predictor for the timing and severity of the ANC/WBC nadirs and prophylactic G-CSF administration. Maintain TPB_V20 < 71% and selecting single-agent cisplatin or carboplatin could significantly reduce grade ≥ 3 HT in cervical cancer patients undergoing concurrent chemoradiotherapy.

Outcomes of granulocyte colony-stimulating factor use in pediatric kidney transplant recipients: A Pediatric Nephrology Research Consortium study.

Neutropenia is common in the first year after pediatric kidney transplant and is associated with an increased risk of infection, allograft loss, and death. Granulocyte colony-stimulating factor (G-CSF) increases neutrophil production, but its use in pediatric solid organ transplant recipients remains largely undescribed. We performed a multicenter retrospective cohort study of children with neutropenia within the first 180days after kidney transplant. Multivariable linear regression and Poisson regression were used to assess duration of neutropenia and incidence of hospitalization, infection, and rejection. Of 341 neutropenic patients, 83 received G-CSF during their first episode of neutropenia. Median dose of G-CSF was 5mcg/kg for 3 (IQR 2-7) doses. G-CSF use was associated with transplant center, induction immunosuppression, steroid-free maintenance immunosuppression, hospitalization, and decreases in mycophenolate mofetil, valganciclovir, and trimethoprim-sulfamethoxazole dosing. Absolute neutrophil count nadir was also significantly lower among those treated with G-CSF. G-CSF use was not associated with a shorter duration of neutropenia (p=.313) and was associated with a higher rate of neutropenia relapse (p=.002) in adjusted analysis. G-CSF use was associated with a decreased risk of hospitalization (aIRR 0.25 (95%CI 0.12-0.53) p<.001) but there was no association with incidence of bacterial infection or rejection within 90days of neutropenic episode. G-CSF use for neutropenia in pediatric kidney transplant recipients did not shorten the overall duration of neutropenia but was associated with lower risk of hospitalization. Prospective studies are needed to determine which patients may benefit from G-CSF treatment.

Bendamustine Is a Safe and Effective Regimen for Lymphodepletion before Tisagenlecleucel in Patients with Large B-Cell Lymphomas

Bendamustine Is a Safe and Effective Regimen for Lymphodepletion before Tisagenlecleucel in Patients with Large B-Cell Lymphomas

Incidence, Risk Factors and Outcomes of Pancytopenia Following Chimeric Antigen Receptor (CAR)-T Cell Therapy in Relapsed Refractory Diffuse Large B Cell Lymphoma

Introduction: CD19 directed CAR-T cell therapy has changed treatment paradigm of relapse refractory diffuse large B cell lymphoma (DLBCL). It is associated with certain unique toxicities including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), B-cell aplasia and hypogammaglobulinemia. However, the information on hematologic toxicity including neutropenia, thrombocytopenia and anemia is limited.Methods: We retrospectively evaluated patients who received CAR-T cell therapy for relapsed refractory DLBCL to estimate incidence, risk factors and outcomes of hematological toxicity especially pancytopenia. We also evaluated the impact of prophylactic G-CSF administration on incidence and duration of neutropenia, and infectious complications.Results: Between April 2018 and December 2020, 30 adult patients received CAR-T cell therapy (AxiCel=22, TisaCel=8). Median age of the population was 57 years (range, 23-81). Median time from diagnosis to CAR-T cell therapy was 674 days. Four patients each had double expressor and double hit subtypes. Seventy percent patients had extra-nodal disease, 60% of patients received three or more lines of therapy, 27% of patients received prior autologous stem cell transplant (autoSCT), and 23% patients received bridging therapy. All patients received Fludarabine and Cyclophosphamide (Flu/Cy) as a lymphodepleting therapy. CRS and ICANS were noted in 83% and 37% patients, respectively. One-year progression-free and overall survival were 49.76% and 85.91%, respectively.After CAR-T cell therapy, 93% (28/30) patients developed neutropenia with 17 (57%) experiencing absolute neutrophil count (ANC) <100/mm3, 9 (30%) developing ANC 100-500/mm3, and two (7%) with ANC 500-1000/mm3. Median ANC nadir was zero (range, 0-2800/mm3). The median time to ANC <1500/mm3, ANC <1000/mm3, ANC <500/mm3 and ANC <100/mm3 was 1 day, 2 days, 4 days, and 7 days post-CAR-T cell therapy, respectively. At day+30, the cumulative incidences of ANC <1500/mm3, ANC <500/mm3, ANC <100/mm3 were 93.3%, 90%, and 56.7%, respectively. The median duration of ANC <1500/mm3, ANC <500/mm3, and ANC <100/mm3 was 24 days, 6 days, and 3 days, respectively. At day +30, 3.7% of patients had persistent neutropenia with ANC <500/mm3, whereas 23.21% of patients experienced mild neutropenia (ANC <1500/mm3) at day +80 following CAR-T cell therapy. Nineteen patients received prophylactic G-CSF and 11 patients did not. No difference in infectious complications, and ICU admission was noted between both groups.Following CAR-T cell therapy, 86% (26/30) patients developed thrombocytopenia with two (7%) experiencing platelets <10,000/µL, 12 (40%) developing platelets 10,000-50,000/µL, and 12 (40%) with platelets 50,000-150,000/µL. Median platelet nadir was 57,000/µL (range, 2000-194,000). The median time to platelets <150,000/µL, <50,000/µL, and <10,000/µL was 1 day, 6 days, and 20 days post-CAR-T cell therapy, respectively. At day+30, the cumulative incidences of platelets <150,000/µL, platelets <50,000/µL, and platelets <10,000/µL were 83.3%, 40%, and 6.67%, respectively. The median duration of platelets <50,000/µL was 28.5 days and <150,000/µL was 192 days. At day +30, 50% of patients had persistent thrombocytopenia with platelets <50,000/µL, and 80.77% of patients had thrombocytopenia with platelets <150,000/µL. Sixty-one percent patients still experienced platelets <150,000/µL at day +80 following CAR-T cell therapy.Univariable analyses revealed that high dose of CAR-T cell was associated with decreased incidence of neutropenia (HR, 0.63; p=0.02), while absence of extra-nodal disease was associated with increased incidence of neutropenia (HR, 3.19; p=0.02). Moreover, patients with prior autoSCT had a lower likelihood of resolution of neutropenia (HR, 0.33; p=0.03), and those with multiple prior therapies had a lower likelihood of resolution of thrombocytopenia (HR, 0.36; p=0.002).Conclusion: Our study shows that a proportion of patients experienced prolonged hematological toxicity, and prior autoSCT and multiple lines of therapy were identified as risk factors. Prophylactic G-CSF did not appear to have any benefit on the prevention of neutropenia or infectious complications. [Display omitted] DisclosuresDeol: Kite, a Gilead Company: Consultancy. Modi: Genentech: Research Funding; Seagen: Membership on an entity's Board of Directors or advisory committees; MorphoSys: Membership on an entity's Board of Directors or advisory committees.

1709P Prediction of febrile neutropenia (FN), hospitalization (Hosp) rates, and infection (Inf) rates in chemotherapy-induced neutropenia (CIN) patients (pts) treated with the plinabulin and pegfilgrastim combination (Plin+Peg) using a meta-analysis (MA)-based tool

Plin is a non-G-CSF small molecule, with anti-cancer activity, and prevents CIN as single agent and in combination with Peg. In the phase (Ph) III trial PROTECTIVE-2 (NCT03294577), the Plin+Peg combination had superior CIN preventive efficacy versus (vs) Peg alone for Grade 4 neutropenia (Gr4N) (86% vs 68% for Peg alone, p<0.0015), for days of severe neutropenia (DSN, p=0.03), absolute neutrophil count (ANC) nadir (p=0.0002) (Blayney ASCO 2021). We evaluated the impact of the observed reduction in Gr4N from 86% with Peg alone to 68% with Plin+Peg on CIN outcomes using a MA.

Abstract 1358: Model-based evaluation of pegfilgrastim effects on chemotherapy-induced neutropenia in infants with CNS tumors

Abstract Pegfilgrastim (PG), a pegylated recombinant form of human granulocyte colony-stimulating factor (G-CSF), is used to shorten the duration of chemotherapy-induced neutropenia. Previous studies have characterized the neutrophil response to PG exposure in adults, but little information is available for the infant population (&amp;lt;1-year-old). This study aims to develop a pharmacokinetic/pharmacodynamic (PK/PD) model to characterize PG PK, the chemotherapy-induced neutropenia, and the neutrophil response to PG in infants and young children with brain tumors. PG concentration-time data and absolute neutrophil counts (ANC) were obtained from 21 children including 13 infants (median [range] age 0.96 [0.4-2.9] years) with newly diagnosed atypical teratoid rhabdoid tumors, enrolled in a phase 2 study (NCT02114229). Patients received multiple cycles of age- and risk-adapted chemotherapy. A single dose of 100 µg/kg PG was given SC 24-48h after the last doses of chemotherapy of each cycle, i.e., cisplatin 75 mg/m2 and high-dose cyclophosphamide (CTX) 1.5 g/m2. A total of 37 PG PK studies were performed for up to 12 days post-dose, and serum PG concentrations were analyzed using a validated ELISA test, with a limit of quantification of 39 pg/mL. The ANC was monitored routinely throughout the cycles. Population PK/PD modeling was performed using Monolix 2019R2. The model included four components: PG PK, neutrophil dynamics, CTX PK, and endogenous G-CSF dynamics. PG data were adequately described with a one-compartment model with linear delayed absorption, and dual linear ANC-dependent and saturable non-specific elimination processes. CTX-induced neutropenia was well captured with a classic myelosuppression model, in which PG and endogenous G-CSF stimulated the neutrophil proliferation and maturation. PG concentrations were inversely correlated with ANC. Median (range) PG AUC0-∞ was 39,917 (7,233-66,410) h·ng/mL, with no significant differences between infants and older children. The ANC profiles exhibited pre-nadir peaks higher than post-nadir peaks, which was captured by the model with the addition of transit compartments to include a delay in the chemotherapy effect. The ANC nadir was reached 7.0±1.1 days post-CTX dose and was below 10 cells/mm3 for 88% of patients. The ANC recovered above 500 cells/mm3 13.4±4.0 days post-CTX dose. PG effects were described using concentration-dependent slopes (mean 0.089 and 0.044 per ng/mL for stimulation of neutrophil proliferation and maturation, respectively). No association was found between patient age and PG effects. Further investigations will be performed to explore the effects of patient covariates, ANC baseline before treatment, and timing of PG administration. As such, the model may be a useful tool for optimization of chemotherapy and PG treatment to minimize the risk of severe neutropenia occurring in infants and young children. Citation Format: Olivia Campagne, Abigail Davis, Santhosh A. Upadhyaya, Clinton F. Stewart. Model-based evaluation of pegfilgrastim effects on chemotherapy-induced neutropenia in infants with CNS tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1358.

Bvgp: A Novel Protocol for Hodgkin's with Excellent Response, Minimal Acute Toxicities and Reduced Risk of Late Effects

Pediatric and Young Adult Hodgkin lymphoma (HL) has a five-year survival rate over 90%. The downside is use of chemotherapy with a lifetime risk of cardiac deaths, second malignancies, pulmonary disease and infertility. Because of effective salvage therapy, ultimate outcomes may be improved by using effective but less toxic initial therapy. To this end, we have piloted a regimen in low and intermediate risk HL using agents not known to be associated with significant late effects. The BVG regimen {bortezomib 1.3 mg/m2 IV day 1,4,8,11; vinorelbine (25 mg/m2 IV day 1,8); gemcitabine (1000 mg/m2 IV day 1,8) every 21 days} was derived from BIGEV [Ding 2009] with elimination of ifosfamide, etoposide and prednisone. Initial use was to consolidate 3 patients after ABVE-PC. Subsequently we treated 5 newly diagnosed patients with non-bulk stage IIA (n=4) or IIB (n=1) HD. Two received BVG and 3 received BVGP with the addition of prednisone (20 mg/m2/dose PO BID x 11 days). Nausea was mild and controlled with 5HT3 antagonists and scopolamine patch. Pegfilgrastim was not necessary due the high absolute neutrophil count nadir (median 1.16 & minimum 0.56 x 109/L). There were no episodes of febrile neutropenia, infections or need for transfusions. There were no significant abnormalities in electrolytes, renal or liver function tests. No patients had any hair loss. One patient developed sensory neuropathy, after dose 8 of bortezomib, that responded to gabapentin and a switch to subcutaneous administration. Newly diagnosed patients were all PET negative after 1 or 2 cycles and remained PET negative at the end of four cycles of therapy. Status of the five newly diagnosed patients ages 10 to 18 is: one is still on therapy; three in remission at 158, 312, 1015 days; one relapsed at 861 days in previous disease sites. This retrospective chart review was approved by Children's Minnesota IRB. For each patient an in depth discussion was held on the benefits and risks of BVGP vs. standard therapy. The chief barrier to use of the protocol was insurance coverage for bortezomib in patients under the age of 18. We hope this abstract will provide early evidence to allow expansion of this pilot experience leading to a randomized trial comparing BVGP with current chemotherapy for low and intermediate Young Adult and Pediatric HL. DisclosuresNo relevant conflicts of interest to declare.

Chimeric Antigen Receptor Induced Cytopenia Differs from Chemotherapy Induced Myelosuppression

▪Background: Cytopenias are a potential complication of chimeric antigen receptor (CAR) therapy. The specific degree, duration, or implication of these cytopenias is not well established, and is further confounded by baseline cytopenias in heavily pre-treated patients with active leukemia. Preclinical models suggest that these cytopenias may be due to a cytokine rich milieu which may contribute to nonspecific suppression of marrow progenitors-independent of the CAR target (Sauter, ASH 2016, abstract 3357); which differs from standard cytotoxic chemotherapy based myelosuppression. We systematically analyzed CAR-related cytopenias on our phase I dose-escalation study of CD22 CAR.Design: Children and young adults with relapsed/refractory CD22+ acute lymphoblastic leukemia (ALL) treated on our phase I dose escalation anti-CD22 CAR therapy protocol (NCT02315612) were evaluated for time to neutrophil and platelet recovery (defined by absolute neutrophil count (ANC) of > 500 k/mcL x 3 days and achievement of transfusion independent platelet count > 20 k/mcL, respectively). All patients had bone marrow evaluations by morphology and flow cytometry at baseline, prior to lymphodepleting chemotherapy (Fludarabine 25 mg/m2 x 3 days and Cyclophosphamide 900 mg/m2 x 1 day) and again at day 28 (+/- 4 days) post-CAR. Infections were closely monitored for. All patients were on anti-fungal prophylaxis and were empirically treated for fever during periods of neutropenia.Results: From December 2014 to July 2017, 30 patients with ALL were treated on study at 3 dose levels. All patients had active bone marrow involvement at baseline with the majority (n=21) having an M2 marrow (>5% blasts) or higher. Twenty-six patients had prior transplants, and 21 patients had prior CD19-directed CAR therapy. Cytokine release syndrome (CRS) was seen in 24/30 (80%), with most patients having grade 1-2 CRS. 18/30 patients (60%) attained a complete remission following CD22 CAR therapy. Baseline hematologic parameters for responders prior to lymphodepletion included grade 2-4 neutropenia and grade 2 and 3 thrombocytopenia, with five patients requiring platelet transfusions (Table 1). Amongst complete responders, the bone marrow at day 28 demonstrated a median cellularity of 28% with trilineage hematopoiesis noted in 16/18 patients. The median CAR T cell % in bone marrow at 1 month was 30%. The median time to ANC nadir was 15 days post CAR infusion (range:10-23 days).17/18 patients had ANC recovery >500 k/mcL, at a median of 22 days post-infusion (range: 15-44 days). One patient had ANC recovery to 260 k/mcL but subsequently developed disease relapse. Eight patients received intermittent GCSF, with clinically relevant responses seen in seven of these patients with a median increase in ANC of 2,180 k/mcL (range: 850-4,100 k/mcL) with limited dosing. The median number of days of GCSF administration to time of ANC recovery was 4, with 3 patients requiring only 1 injection to achieve robust ANC response. Interestingly, only 1/18 patient (6%) had a new onset of infection (clostridium difficile colitis) during the period of CAR associated neutropenia, which was confounded by administration of intravenous antibiotic therapy for fevers that was initiated 24 hours prior to onset of diarrhea. There was no new development of fungal infections or worsening of any pre-existing infections. Platelet recovery to > 20 k/mcL was at a median of 36 days (range: 21-55) post-CAR and was seen in 16 of 18 responders. Two patients who remained platelet transfusion dependent post-CAR included one patient who was later found to have donor-cell monosomy 7 MDS and another patient whose disease relapsed prior to recovery.Conclusion: In contrast to chemotherapy associated myelosuppression, CAR-therapy associated peripheral blood cytopenias existed despite evidence for trilineage hematopoiesis on the bone marrow. Although the period of CAR associated neutropenia is substantial, with prophylactic antifungals and intermittent growth factor support, this heavily pre-treated population was not at an increased risk of developing serious bacterial or fungal infections over baseline. The rapid response to G-CSF is suggestive of an alternative modality of bone marrow inhibition distinct from chemotherapy induced cytotoxicity. Further evaluation in the context of multiple CAR targets and constructs are needed to further explore this complication. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

History of whole pelvis plus para-aortic radiation is a risk factor associated with febrile neutropenia during chemotherapy for recurrent cervical cancer.

Radiation-based therapy is widely used for advanced cervical cancer. Prior radiation-based therapy is a potential risk factor for febrile neutropenia (FN). However, the effect of irradiation field size on the incidence of FN during recurrent cervical cancer treatment is unclear. This study aimed to investigate the relationship between prior irradiation field size and FN development during recurrent chemotherapy. This retrospective, observational study included cervical cancer patients who received recurrent chemotherapy between November 2006 and June 2020. The patients were classified into two groups based on the area of irradiation fields. The first group included patients with a history of whole pelvis (WP) irradiation (WP group). The second group had patients who underwent WP plus para-aortic lymph node (PAN) irradiation (WP + PAN group). The incidences of hematological toxicities and FN during the recurrent chemoradiotherapy were compared between the two groups. The FN incidence was significantly higher in the WP + PAN group than in the WP group (32.1% vs. 0%, P < 0.001). The incidence of Grade 4 neutropenia was not significantly different between the WP + PAN and WP groups. The nadir absolute neutrophil counts were significantly lower and the dose reduction or discontinuation rate of chemotherapy was significantly higher in the WP + PAN group than in the WP group. History of WP plus PAN radiation is a risk factor for developing FN during recurrent cervical cancer chemotherapy.