Febrile Neutropenia Events Research Articles

Adverse Event Profile of Atezolizumab, Bevacizumab, Carboplatin, and Paclitaxel Combination Therapy Based on JADER.

There have been advances in the development of immune checkpoint inhibitors for monotherapy and combination therapy with other anticancer agents in recent years. The combination of bevacizumab, carboplatin, and paclitaxel with atezolizumab, an anti-programmed death ligand 1 antibody (ABCP therapy), has been reported to be effective for treating non-small cell lung cancer. However, reports on its adverse events are limited. In this study, a survey and disproportionality analysis based on the Japanese Adverse Drug Event Report (JADER) database was conducted to elucidate the adverse event profile of ABCP therapy. The reporting odds ratio (ROR) and information component were used as indicators for the disproportionality analysis. The ROR was also used to assess the changes in the reporting intensity with combination therapy, and the mutual exclusivity of the 95% confidence interval between the compared groups was considered. The reported adverse events of ABCP therapy mirrored those of the individual drugs that constituted it. ABCP therapy enhanced the reporting intensity of adverse events related to leukocytes and the skin, while decreased those related to interstitial lung disease and hepatic function abnormality as immune-related adverse events caused by atezolizumab, and gastrointestinal perforation caused by bevacizumab. Our analysis of data from the JADER database has revealed the adverse event profile of ABCP therapy. Our findings emphasize the importance of effectively managing febrile neutropenia and skin-related adverse events in ABCP therapy.

Safety and Efficacy of the Combination Lurbinectedin plus Doxorubicin from a Phase 1b Trial in Patients with Advanced/Metastatic Soft-Tissue Sarcoma.

While cytotoxic chemotherapy is the standard first-line treatment for patients with metastatic soft-tissue sarcoma (STS), clinical outcomes remain suboptimal. Our prior study showed lurbinectedin plus doxorubicin is well tolerated with promising clinical activity in STS. We designed this phase 1b trial to optimize dosing as the basis for a randomized trial in leiomyosarcoma and to further explore the safety profile and efficacy signal. Patients had advanced/metastatic STS and no prior anthracycline/lurbinectedin/trabectedin. Escalation followed a 3 + 3 design with 3-week cycles: lurbinectedin (3.2 mg/m2 day 1) and two doxorubicin levels (DL1, 25 mg/m2 day 1; DL2, 25 mg/m2 days 1 and 8). The primary objectives were to identify the maximum tolerated dose and recommended dose for subsequent randomized trials. Ten patients were enrolled in a 6-month period. The most common treatment-emergent adverse events were grade (G) 2 fatigue and nausea, and G2 cytopenias with no febrile neutropenia events. There were two dose-limiting toxicities (DLTs) at DL2 [day 8 (G2 alanine aminotransferase [ALT]/aspartate aminotransferase increase, G3 neutropenia)], and one DLT in DL1 (G3 ALT increase). These were reversible and all patients continued the study. DL1 was chosen for further study. At the time of data cutoff, the estimated median progression-free survival is 16.5 months [95% confidence interval (CI), 6.0-ND]. The objective response rate was 60% (6/10 confirmed partial responses). In this phase 1b study, the recommended dose is lurbinectedin 3.2 mg/m2 in combination with doxorubicin 25 mg/m2 every 3 weeks. The study combination was well tolerated and demonstrated intriguing clinical activity.

Brentuximab Vedotin, Nivolumab, Doxorubicin, and Dacarbazine (AN+AD) for Early-Stage Classical Hodgkin Lymphoma (SGN35-027 Part C)

Introduction Brentuximab vedotin (BV) with AVD is approved in classical Hodgkin lymphoma (cHL) and has demonstrated statistically significant improvement in 6-year overall survival (OS) as compared with ABVD; associated neuropathy and neutropenia may be related to overlapping mechanisms of BV and vinblastine (Ansell 2022). A study in nonbulky early-stage cHL showed preserved efficacy with improved safety when omitting vinblastine in the BV-AD regimen (Abramson 2023). Here, we present results of a phase 2 trial adding nivolumab to the BV-AD regimen without radiation in patients (pts) with nonbulky early-stage cHL (SGN35-027 Part C). Methods SGN35-027 (NCT03646123) Part C enrolled pts with Ann Arbor stage I or II cHL without bulky disease, defined as those with a single node or nodal mass with a <10-cm diameter on computed tomography imaging. Pts received 4 cycles of AN+AD (BV 1.2 mg/kg [A], nivolumab 240 mg [N], doxorubicin 25 mg/m 2 [A], and dacarbazine 375 mg/m 2 [D] intravenously on days 1 and 15 of each 28-day cycle). Per protocol, G-CSF prophylaxis was not required for subjects receiving the treatment regimen. The primary endpoint is complete response (CR) rate at end of treatment (EOT). Secondary endpoints include progression-free survival (PFS), overall response rate (ORR), duration of response (DOR), and duration of complete response (DOCR), as well as safety and tolerability. The Lugano Classification Revised Staging System for malignant lymphoma (Cheson 2014) incorporating Lymphoma Response to Immunomodulatory Therapy Criteria (LYRIC) for nodal non-Hodgkin and Hodgkin Lymphomas (Cheson 2016) per investigator was used to assess disease response and progression. Exploratory endpoints include baseline and longitudinal circulating tumor DNA analysis on a subset of pts. Results Part C has completed enrollment with 154 pts having received at least 1 dose of study treatment. The majority of treated pts were white (84%), aged <65 years (92%), and female (55%), and presented with nonbulky stage I (11%) or II (89%) cHL. Median age was 31.0 years (range, 18-77). All findings were based on a data cutoff of 22 May 2023. Among 150 efficacy evaluable pts, the ORR was 98% (95% CI, 94.3-99.6) and the CR rate was 93% (95% CI, 87.3-96.3) at EOT (Table 1). Among all pts treated (N = 154), the ORR was 95% (95% CI, 90.9-98.2) and the CR rate was 90% (95% CI, 84.4-94.4) at EOT. With a median follow-up of 15.2 months, 3 of 154 pts (2%) had progressive disease (at 12.5, 16.4, and 24.0 months) and no deaths occurred. The PFS rate at 12 months was 100% (95% CI, 100-100) (Figure 1). A total of 99.2% of pts (95% CI, 94.3-99.9) had a DOR of least 12 months, and 97.2% (95% CI, 91.5-99.1) had a DOCR of at least 12 months. The planned treatment course of 4 cycles was completed by 94% of pts. Forty-four percent received G-CSF, primarily for primary prophylaxis, for 1 or more cycles. Three percent of pts discontinued treatment (all drugs) due to treatment-emergent adverse events (TEAEs). No events of febrile neutropenia were reported. Thirty four percent of pts experienced grade ≥3 treatment-related TEAEs, and 3% experienced grade ≥3 treatment-related peripheral sensory neuropathy. The most common grade ≥3 treatment-related TEAEs were neutropenia (9%), increased alanine aminotransferase (ALT) (7%), and increased aspartate aminotransferase (5%). Treatment-emergent immune-mediated adverse events (IMAEs) occurred in 22% of pts, and grade ≥3 treatment-emergent IMAEs occurred in 7% of pts. The most common treatment-emergent IMAE of any grade was hypothyroidism (6%). Twelve percent of pts experienced treatment-related serious TEAEs. The most common treatment-related serious TEAEs were pyrexia (3%), increased ALT (1%), and peripheral sensory neuropathy (1%). Conclusions Results from SGN35-027 Part C show promising efficacy and an acceptable safety profile for BV and nivolumab in combination with chemotherapy (AN+AD) for pts with nonbulky early-stage cHL. Pts had high ORR (98%) and CR rates (93%) at EOT, and a 12-month PFS of 100% with a median follow-up of 15.2 months. There was a low incidence of grade 3 or higher neuropathy and there were no cases of febrile neutropenia. AN+AD demonstrates encouraging efficacy in nonbulky early-stage cHL and may avoid toxicities associated with radiation, bleomycin, and vinblastine. Follow-up of Part C is ongoing with 92% of pts in long-term follow-up.

A prospective, real-world, multinational study of febrile neutropenia (FN) occurrence in oncology patients receiving chemotherapy with intermediate risk of FN: a MASCC Neutropenia, Infection, and Myelosuppression Study Group initiative

PurposeLimited knowledge is available on the incidence of febrile neutropenia (FN) in intermediate-risk patients and the rationale for use of granulocyte colony-stimulating factor (G-CSF) in these patients. We aimed to estimate the rate at which patients associated with intermediate risk (10–20%) of FN would develop ≥ 1 episode of FN with a commonly used chemotherapy regimen in clinical practice.MethodsThis prospective, real-world, observational, multinational, multicenter study (December 2016–October 2019) recruited patients with solid tumors or Hodgkin’s/non-Hodgkin’s lymphoma. Patients receiving chemotherapy with intermediate risk of FN, but not G-CSF as primary prophylaxis were included and observed for the duration of the chemotherapy (≤ 6 cycles and ≤ 30 days after the last chemotherapy administration).ResultsIn total, 364 patients (median age, 56 years) with 1601 cycles of chemotherapy were included in the analysis. The incidence of FN was 5% in cycle 1, 3% in cycles 2–3, and 1% in cycles 4–6. The rate of patients with ≥ 1 episode of FN was 9%, and 59% of FN events were reported during cycle 1. The rate of grade 4 neutropenia in cycle 1 was 11%, and 15% of patients experienced ≥ 1 episode of grade 4 neutropenia.ConclusionsOverall, the incidence of FN was low, with a high incidence in cycle 1 and a decrease in the subsequent cycles. These results provide the real FN risk for common chemotherapy regimens in patients generally excluded from clinical trials. Prophylactic G-CSF in intermediate-risk patients could be considered as per clinician’s judgement.

An observational, prospective, open label, multicenter study to evaluate the safety and effectiveness of pegfilgrastim as secondary prophylaxis to decrease the incidence of febrile neutropenia in Korean female patients with breast cancer

PurposePegfilgrastim is a widely used long-acting granulocyte colony-stimulating factor (G-CSF) that prevents febrile neutropenia (FN) in patients with breast cancer receiving chemotherapy. This study aimed to evaluate the incidence of chemotherapy-related FN events and other adverse events (AEs) during chemotherapy in Korean patients with breast cancer treated with pegfilgrastim as secondary prophylactic support. Materials and methodsThis was a multicenter, open-label, prospective, observational study. A total of 1255 patients were enrolled from 43 institutions. The incidence of FN was evaluated as the primary endpoint. The secondary endpoints included (1) incidence of bone pain, (2) proportion of patients with a relative dose intensity (RDI) of ≥85%, and (3) proportion of patients with AE. ResultsPegfilgrastim administration reduced FN by 11.8–1.6%. The highest incidence of bone pain was observed at the time point of the 1st day after the administration and mild bone pain was the most common of all bone pain severity. The mean RDI was 98.5 ± 7.3%, and the proportion of the patients with and RDI≥85% was 96.9% (1169/1233). AEs were reported in 52.6% of the patients, and serious drug reactions occurred in only 0.7%. ConclusionThe use of pegfilgrastim as secondary prophylaxis was effective and safe for preventing FN in patients with breast cancer who were treated with chemotherapy.

Cost-effectiveness of granulocyte colony-stimulating factors (G-CSFs) for the prevention of febrile neutropenia (FN) in patients with cancer

PurposeClinical practice guidelines recommend the use of all approved granulocyte colony-stimulating factors (G-CSFs), including filgrastim and pegfilgrastim, as primary febrile neutropenia (FN) prophylaxis in patients receiving high- or intermediate-risk regimens (in those with additional patient risk factors). Previous studies have examined G-CSF cost-effectiveness by cancer type in patients with a high baseline risk of FN.This study evaluated patients with breast cancer (BC), non-small cell lung cancer (NSCLC), or non-Hodgkin’s lymphoma (NHL) receiving therapy who were at intermediate risk for FN and compared primary prophylaxis (PP) and secondary prophylaxis (SP) using biosimilar filgrastim or biosimilar pegfilgrastim in Austria, France, and Germany.MethodsA Markov cycle tree-based model was constructed to evaluate PP versus SP in patients with BC, NSCLC, or NHL receiving therapy over a lifetime horizon. Cost-effectiveness was evaluated over a range of willingness-to-pay (WTP) thresholds for incremental cost per quality-adjusted life year (QALY) gained. Sensitivity analyses evaluated uncertainty.ResultsResults demonstrated that using biosimilar filgrastim as PP compared to SP resulted in incremental cost-effectiveness ratios (ICERs) well below the most commonly accepted WTP threshold of €30,000. Across all three countries, PP in NSCLC had the lowest cost per QALY, and in France, PP was both cheaper and more effective than SP. Similar results were found using biosimilar pegfilgrastim, with ICERs generally higher than those for filgrastim.ConclusionsBiosimilar filgrastim and pegfilgrastim as primary prophylaxis are cost-effective approaches to avoid FN events in patients with BC, NSCLC, or NHL at intermediate risk for FN in Austria, France, and Germany.

An analysis of the resource use and costs of febrile neutropenia events in pediatric cancer patients in Australia.

Febrile neutropenia (FN) in children with cancer generally requires in-hospital care, but low-risk patients may be successfully managed in an outpatient setting, potentially reducing the overall healthcare costs. Updated data on the costs of FN care are lacking. A bottom-up microcosting analysis was conducted from the healthcare system perspective using data collected alongside the Australian PICNICC (Predicting Infectious Complications of Neutropenic sepsis In Children with Cancer) study. Inpatient costs were accessed from hospital administrative records and outpatient costs from Medicare data. Costs were stratified by risk status (low/high risk) according to the PICNICC criteria. Estimated mean costs were obtained through bootstrapping and using a linear model to account for multiple events across individuals and other clinical factors that may impact costs. The total costs of FN care were significantly higher for FN events classified as high-risk ($17,827, 95% confidence interval [CI]: $17,193-$18,461) compared to low-risk ($10,574, 95% CI: $9818-$11,330). In-hospital costs were significantly higher for high-risk compared to low-risk events, despite no differences in the cost structure, mean cost per day, and pattern of resource use. Hospital length of stay (LOS) was the only modifiable factor significantly associated with total costs of care. Excluding antineoplastics, antimicrobials are the most commonly used medications in the inpatient and outpatient setting for the overall period of analysis. The FN costs are driven by in-hospital admission and LOS. This suggests that the outpatient management of low-risk patients is likely to reduce the in-hospital cost of treating an FN event. Further research will determine if shifting the cost to the outpatient setting remains cost-effective overall.

Brentuximab-vedotin in combination with cyclophosphamide, doxorubicin, prednisolone for the treatment of aggressive CD30-positive cutaneous T-cell lymphomas

Aggressive CD30-positive cutaneous T-cell lymphomas (CD30+CTCL) are associated with unfavorable prognosis. Anthracycline-based polychemotherapy (CHOP) and brentuximab-vedotin (BV) monotherapy are related to poor outcomes in case of extracutaneous involvement or rapidly-progressing disease. Our objective was to assess the effectiveness of BV + CHP in aggressive CD30+CTCL. We included 7 patients treated with BV + CHP from April 2015 to January 2022: 4 had mycosis fungoides with large-cell transformation, 2 had primary cutaneous anaplastic large-cell lymphoma, and 1 harbored a primary cutaneous aggressive epidermotropic CD8-positive T-cell lymphoma. After a median [IQR] follow-up of 17.2 [13.2–21.0] months, 6/7 patients achieved an ORR lasting ≥4 months. The median [IQR] duration of response was 9.5 [5.9–11.1] months and the median [IQR] progression free survival was 14.9 [11.6–16.4] months. Four patients displayed progression with a median (range) time to next treatment of 15.8 (6.5–16.3) months. Two grade-3 adverse events were reported: febrile neutropenia and thromboembolic event. BV + CHP displayed substantial antitumor activity and favorable safety profile in 7 patients with aggressive CD30+CTCL.

Thiopurine Methyltransferase Intermediate Metabolizer Status and Thiopurine-Associated Toxicity During Maintenance Therapy in Childhood Acute Lymphoblastic Leukemia.

Mercaptopurine is a cornerstone of maintenance chemotherapy in childhood acute lymphoblastic leukemia (ALL). Its cytotoxic effects are mediated by 6-thioguanine nucleotides (TGNs) incorporation into lymphocyte DNA. Thiopurine methyltransferase (TPMT) inactivates mercaptopurine, and deficiency resulting from genetic variants increases TGN exposure and hematopoietic toxicity. Although mercaptopurine-dose reduction reduces toxicity risk without compromising relapse rate in patients with TPMT deficiency, dosing recommendations for those with moderately reduced activity (intermediate metabolizer (IM)) are less clear and their clinical impacts have yet to be established. This cohort study assessed the effect of TPMT IM status on mercaptopurine-associated toxicity and TGN blood exposure in pediatric patients with ALL initiated on standard dose mercaptopurine. Of 88 patients studied (mean age 4.8 years), 10 (11.4%) were TPMT IM, and all had undergone ≥ 3 cycles of maintenance therapy (80% completed). A larger proportion of TPMT IM than normal metabolizers (NM) had febrile neutropenia (FN) during the first two cycles of maintenance, reaching significance in the second cycle (57% vs. 15%, respectively; odds ratio=7.33, P < 0.05). Compared to NM, FN events occurred more frequently and with prolonged duration in IM in cycles 1 and 2 (adjusted P < 0.05). IM had a 2.46-fold increased hazard ratio for FN, and about twofold higher TGN level than NM (P < 0.05). Myelotoxicity was more common in IM than NM (86% vs. 42%, respectively) during cycle 2 (odds ratio=8.2, P < 0.05). TPMT IM initiated at a standard mercaptopurine dose are at greater risk for FN during early cycles of maintenance therapy, thus our findings support genotype-guided dose adjustment to reduce toxicity.

The reliability of FEbrile Neutropenia after ChEmotherapy (FENCE) scores in predicting granulocyte colony-stimulating factor breakthrough febrile neutropenia among patients with lymphoma undergoing first-cycle chemotherapy: A prospective observational study.

A tool for estimating risk of febrile neutropenia (FN) after chemotherapy, namely the FEbrile Neutropenia after ChEmotherapy (FENCE) score, has been developed but has not been widely validated. This study aimed to validate the FENCE score as a tool for predicting granulocyte colony-stimulating factor (G-CSF) breakthrough FN among patients with lymphoma who underwent chemotherapy. This was a prospective observational study of treatment-naive adult patients with lymphoma who underwent their first cycle of chemotherapy between 2020 and 2021. The patients were followed up until the next cycle of chemotherapy to identify any infection events. Among the 135 patients with lymphoma, 62 (50%) were men. In a comparison of the value of each FENCE parameter for predicting G-CSF breakthrough infection, the parameter of advanced-stage disease showed high sensitivity of 92.8%, and receipt of platinum chemotherapy showed high specificity of 95.33%. With a FENCE score of 12 as a cutoff for low risk, analysis across all patients with lymphoma resulted in a high AUROCC of 0.63 (95% CI = 0.5-0.74%; p = 0.059), and analysis across only patients with diffuse large B-cell lymphoma (DLBCL) resulted in an AUROCC of 0.65 (95% CI = 0.51-0.79%; p = 0.046). With a cutoff point of 12, FENCE score can predict breakthrough infection events at 30.0% (95% CI = 17.8-47.4%). This study divided patients with lymphoma into risk groups according to FENCE score, showing that this instrument has discriminatory ability in predicting FN events, these being more likely to occur in patients in the intermediate- and high-risk groups. Multicenter studies are needed to validate this clinical risk score.

Risk of chemotherapy-induced febrile neutropenia in intermediate-risk regimens: Clinical and economic outcomes of granulocyte colony-stimulating factor prophylaxis.

BACKGROUND: Chemotherapy-induced neutropenia increases the risk of febrile neutropenia (FN) and infection with resultant hospitalizations, with substantial health care resource utilization (HCRU) and costs. Granulocyte-colony stimulating factor (GCSF) is recommended as primary prophylaxis for chemotherapy regimens having more than a 20% risk of FN. Yet, for intermediate-risk (10%-20%) regimens, it should be considered only for patients with 1 or more clinical risk factors (RFs) for FN. It is unclear whether FN prophylaxis for intermediate-risk patients is being optimally implemented. OBJECTIVE: To examine RFs, prophylaxis use, HCRU, and costs associated with incident FN during chemotherapy. METHODS: This retrospective study used administrative claims data for commercial and Medicare Advantage enrollees with nonmyeloid cancer treated with intermediate-risk chemotherapy regimens during January 1, 2009, to March 31, 2020. Clinical RFs, GCSF prophylaxis, incident FN, HCRU, and costs were analyzed descriptively by receipt of primary GCSF, secondary GCSF, or no GCSF prophylaxis. Multivariable Cox regression analysis was used to examine the association between number of RFs and cumulative FN risk. RESULTS: The sample comprised 13,937 patients (mean age 67 years, 55% female). Patients had a mean of 2.3 RFs, the most common being recent surgery, were aged 65 years or greater, and had baseline liver or renal dysfunction; 98% had 1 or more RFs. However, only 35% of patients received primary prophylaxis; 12% received secondary prophylaxis. The hazard ratio of incident FN was higher with increasing number of RFs during the first line of therapy, yet more than 54% of patients received no prophylaxis, regardless of RFs. Use of GCSF prophylaxis varied more by chemotherapeutic regimen than by number of RFs. Among patients treated with rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride (doxorubicin hydrochloride), vincristine, and prednisone, 76% received primary prophylaxis, whereas only 22% of patients treated with carboplatin/paclitaxel received primary prophylaxis. Among patients with a first line of therapy FN event, 78% had an inpatient stay and 42% had an emergency visit. During cycle 1, mean FN-related coordination of benefits-adjusted medical costs per patient per month ($13,886 for patients with primary prophylaxis and $18,233 for those with none) were driven by inpatient hospitalizations, at 91% and 97%, respectively. CONCLUSIONS: Incident FN occurred more often with increasing numbers of RFs, but GCSF prophylaxis use did not rise correspondingly. Variation in prophylaxis use was greater based on regimen than RF number. Lower health care costs were observed among patients with primary prophylaxis use. Improved individual risk identification for intermediate-risk regimens and appropriate prophylaxis may decrease FN events toward the goal of better clinical and health care cost outcomes. DISCLOSURES: This work was funded by Sandoz Inc., which participated in the design of the study, interpretation of the data, writing and revision of the manuscript, and the decision to submit the manuscript for publication. The study was performed by Optum under contract with Sandoz Inc. The author(s) meet criteria for authorship as recommended by the International Committee of Medical Journal Editors. The authors received no direct compensation related to the development of the manuscript. Dr Li is an employee of Sandoz Inc. Drs Bell and Lal and Mr Peterson-Brandt were employees of Optum at the time of the study. Ms Anderson and Dr Aslam are employees of Optum. Dr Lyman has been primary investigator on a research grant from Amgen to their institution and has consulted for Sandoz, G1 Therapeutics, Partners Healthcare, BeyondSpring, ER Squibb, Merck, Jazz Pharm, Kallyope, Teva; Fresenius Kabi, Seattle Genetics, and Samsung.

Influence of a biliary stent in patients with advanced pancreatic cancer treated with modified FOLFIRINOX.

Endoscopic biliary drainage is the recommended 1st-line treatment for malignant biliary obstruction. Although a high incidence of febrile neutropenia has been reported in patients treated with FOLFIRINOX and a biliary stent, it remains unknown whether the biliary stent contributes to patient survival. Thus, we aimed to elucidate the effects of biliary stents on the survival of patients with advanced pancreatic cancer treated with modified FOLFIRINOX (mFFX). We retrospectively reviewed medical charts of patients with advanced pancreatic cancer treated with mFFX between January 2014 and April 2020. We compared the overall survival (OS) of patients with and without biliary stent during mFFX treatment and examined the independent effect on mortality using propensity score matching. Overall, we included 89 patients (stent group, n = 24; non-stent group, n = 65). The proportion of patients with pancreatic head cancer was significantly higher in the stent group than in the non-stent group (P < .01). Stratification analysis in patients with pancreatic head cancer revealed that OS was significantly shorter in the stent group than in the non-stent group (P = .03). After propensity score matching, 19 pairs of patients in each group were analyzed. The stent group revealed a significantly shorter survival than the non-stent group (median OS, 10.3 vs 24.9 months; P < .01). The incidences of febrile neutropenia (P = .01) and biliary tract-related events that required biliary stenting or stent replacement (P < .01) were significantly higher in the stent group than in the non-stent group. Stent insertion was an independent risk factor for overall mortality. Biliary stents may reduce survival in patients with advanced pancreatic cancer. The rate of febrile neutropenia was higher in the stent group than in the non-stent group. There is a need to assess the patient's condition with discretion and develop a treatment strategy with short prognosis in mind after stent insertion.

Safety and Tolerability of AZD0466 As Monotherapy for Patients with Advanced Hematological Malignancies. Preliminary Results from an Ongoing Phase I/II Trial

Background: Anti-apoptotic proteins of the BcL-2 family such as Bcl-2 and Bcl-xL are critical to tumor survival and are associated with resistance to anticancer therapy. Specific Bcl-2 inhibition using venetoclax is beneficial in patients with acute myeloid leukemia (AML), but resistance often develops due to upregulation of anti-apoptotic proteins such as Bcl-xL and Mcl-1. Dual inhibition of Bcl-2 and Bcl-xL therefore has potential for broader activity than is observed with Bcl-2-specific inhibitors such as venetoclax. AZD0466 is a drug-dendrimer conjugate in which the Bcl-2/xL dual inhibitor AZD4320 is covalently conjugated to a pegylated poly-L-lysine dendrimer and gradually released by hydrolysis. Release of AZD4320 results in lower peak plasma levels compared to direct infusion of AZD4320 at similar concentrations, reducing the potential for the on-target toxicity associated with Bcl-xL inhibition (Balachander et al. Clin Cancer Res 2020; Patterson et al. Commun Biol 2021). AZD0466 has shown preclinical efficacy in solid (Arulananda et al. Cell Death Discov 2021) and hematological malignancies (Balachander et al. Clin Cancer Res 2020; Patterson et al. Commun Biol 2021). Preliminary results from the first-in-human study (NCT04214093) in advanced solid malignancies indicated that AZD0466 is well tolerated; no dose-limiting toxicities (DLTs) were reported. Here, we present preliminary data from an ongoing phase I trial of AZD0466 in patients with advanced hematological malignancies (NCT04865419). Methods: NIMBLE (drug deNdrIMer targeting BCL2/xL in acute LEukemias) is a modular, non-randomized phase I/II trial. Module 1 is evaluating the safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of AZD0466 as monotherapy in adults with relapsed/refractory AML, acute lymphocytic leukemia (ALL), or higher risk myelodysplastic syndrome who have received ≥1 prior line of therapy, have no standard-of-care treatment available, and have no active CNS involvement. No minimum platelet count at study entry was specified and transfusions were permitted as part of supportive care. Module 1, Part A is a dose escalation study evaluating the safety and tolerability of AZD0466 monotherapy. The selected starting dose is AZD0466 300 mg IV; decisions on escalation and de-escalation are based on a mTPI-2 design (Guo et al. Contemp Clin Trials 2017;58:23-33). AZD0466 administration starts with a dose ramp-up with administration on days 1, 4, and 8 of cycle 1, followed by weekly IV administration at the target dose. The duration of Cycle 1 is 35 days, while subsequent cycles of 28 days. All patients are treated until progressive disease, unacceptable toxicity, or withdrawal of consent. The primary objectives of Module 1A are DLT (according to predefined criteria and occurring during cycle 1), maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D). Secondary objectives include assessment of PK parameters for total and released plasma AZD4320. Results: As of May 31, 2022, 9 patients had been treated (55% male; median age, 70 years). Patients received AZD0466 at target doses of 300 mg (n=4), 600 mg (n=4), or 1200 mg (n=1). The safety analysis set consists of 9 patients and the DLT-evaluable set of 7 patients. No DLTs have been observed. All patients experienced at least one adverse event (AE). Five patients experienced AEs possibly related to treatment (grade 3 febrile neutropenia event, n=1; grade 3 gamma-glutamyltransferase increase, n=1; grade 2 sinus tachycardia, n=1; grade 1 aspartate aminotransferase increase, n=3; grade 1 alanine aminotransferase increase, n=2; grade 1 abnormal coagulation test, lactate dehydrogenase increase and alkaline phosphatase increase, all n=1). Four serious AEs occurred, none of which was treatment related. No AZD0466 discontinuations due to AEs have been observed. There were no thrombocytopenia events considered related to AZD0466 at the doses given. Following IV infusion, released AZD4320 exhibited a dose-proportional increase in area under the concentration time curve (AUC) and maximum serum concentration (Cmax), moderate PK variability (≈50% coefficient of variation), and a half-life of ≈18 hours. Conclusions: AZD0466 has been well tolerated, with no DLTs to date and no discontinuations due to treatment-related AEs. The trial continues to enroll, further dose escalation is planned, and updated data will be presented.

CREST-UK: CPX-351 Real-World Effectiveness and Safety Study for the Treatment of Newly Diagnosed Therapy-Related AML and AML with Myelodysplasia-Related Changes in the UK

Background: In the UK, CPX-351 (Vyxeos® liposomal) has been licensed since August 2018 for adults with newly diagnosed, therapy-related AML (t-AML) or AML with myelodysplasia-related changes (AML-MRC), primarily based on favorable outcomes for CPX-351 versus 7+3 chemotherapy in a phase 3 trial in adults aged 60 to 75 y with newly diagnosed, high-risk/secondary AML. However, the phase 3 trial population did not reflect the full CPX-351 licensed population. As a complement to the phase 3 trial and to address important data gaps, CREST-UK was performed to assess the effectiveness and safety of CPX-351 in routine clinical practice in the UK and observe the impact of COVID-19 infection in these patients (pts). Methods: CREST-UK is a retrospective, noninterventional, multicenter, single-arm, observational study (NCT05169307) that collected pseudonymized pt data abstracted from the medical records of adults aged ≥18 y with newly diagnosed t-AML or AML-MRC (per WHO 2016 criteria) who received ≥1 infusion of CPX-351 in routine practice; pts who received CPX-351 in a clinical trial were excluded. The primary objective was to describe complete remission (CR or CRi) and overall survival (OS). Key secondary objectives described pt and disease characteristics, frequency of hematopoietic cell transplantation (HCT), OS landmarked from the HCT date, and the CPX-351 safety profile. Median follow-up for OS was 10.6 mo (interquartile range [IQR]: 4.5, 18.4). Results: A total of 147 pts who received their first CPX-351 induction from November 2018 to March 2022 were included from 15 centers. Median age was 64 y (range: 18, 83), with 17 (12%) pts aged <45 y, 39 (27%) aged 45-59 y, 64 (44%) aged 60-69 y, and 27 (18%) aged ≥70 y. Overall, 35 (24%) pts had t-AML and 112 (76%) had AML-MRC (n=43 with prior MDS, n=9 with prior CMML, n=41 with MDS-related cytogenetics, and n=19 with multilineage dysplasia alone); 13 (9%) had received prior azacitidine. The majority (90%) of pts had an ECOG performance status ≤1. Disease risk by European LeukemiaNet 2017 criteria was favorable for 13 (9%) pts, intermediate for 39 (27%), adverse for 66 (45%), and unknown for 29 (20%) due to limited mutational data. Complex karyotype, monosomal karyotype, and/or abn(17p) were reported for 37 (25%) pts. TP53 mutations were reported for 15/66 (23%) pts with evaluable data. A best response of CR+CRi was achieved by 73/138 (53%) evaluable pts, and overall response (CR+CRi+MLFS+PR) was achieved by 88/138 (64%) pts. Post induction, 19/37 (51%) pts in CR or CRi with a known measurable residual disease (MRD) status achieved MRD negativity; 3 additional pts achieved MRD negativity at a later time point. Kaplan-Meier median OS was 12.85 mo (95% CI: 9.2, 15.4; Fig 1), with 2- and 3-y OS estimates of 36% and 34%, respectively. Fifty (34%) pts proceeded to HCT; median OS landmarked from the HCT date was not reached (Fig 2), with a 2-y OS estimate of 71%. Among pts in CR or CRi, median recovery (IQR) to neutrophils ≥500/μL was 33 d (28, 43) and to platelets ≥50,000/μL was 34 d (27, 48) during the first induction. Grade ≥3 treatment-related adverse events (TRAEs) of interest included febrile neutropenia (36%; n=1 grade 5), infections (29%; n=6 grade 5), bleeding (4%; n=1 grade 5), and gastrointestinal events (3%). Cardiac TRAEs of any grade were reported for 5% of pts, with grade ≥3 events in 3% (n=1 grade 5). No extravasation was reported. Estimated all-cause mortality was 7% at 30 d and 14% at 60 d. This study included pts who were diagnosed and treated for AML during the COVID-19 pandemic. A total of 26 COVID-19 infections happened at variable time intervals pre- or post-AML treatment. In this cohort, 2 deaths were directly linked to COVID-19; both were assessed by the site investigator as unrelated to CPX-351 treatment. Conclusion: CREST-UK, a real-world study in the context of the COVID-19 pandemic, confirmed the efficacy and safety of CPX-351 in a broad population that included substantial proportions who were aged <60 y or ≥70 y and/or had adverse-risk disease. CR or CRi with MRD negativity and/or proceeding to HCT was achieved in proportions consistent with clinical trials and other real-world studies. Survival outcomes were also consistent with other real-world studies. No new safety concerns with CPX-351 were identified. These data provide new insights into the use of CPX-351 in routine clinical practice in the UK and support its continued use in adults with newly diagnosed t-AML and AML-MRC. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Phase II Trial of Venetoclax (Ven) in Combination with Azacitidine (AZA) As Maintenance Therapy for High-Risk Acute Leukemia Following Allogeneic Stem Cell Transplantation (SCT)

Introduction: Allogeneic SCT remains the only potentially curative therapy for acute leukemia patients but with inferior outcomes for high-risk patients. Prior data on maintenance therapies, including AZA, have yielded conflicting results on its efficacy to improve outcomes. Considering the clinical efficacy of VEN in acute myeloid and lymphoid leukemia (AML/ALL) with its known tolerability when used with AZA, we thought VEN and AZA might be an attractive maintenance strategy to improve outcomes after SCT. Methods: This is a single center, open label, Phase II clinical trial to assess the safety and efficacy of VEN with AZA as maintenance therapy after SCT. Inclusion criteria was 1) high risk AML or B cell and T cell ALL or mixed phenotype leukemia, 2) absolute neutrophil count >/= 1.0 x 109/L and platelet >/= 30 x 109/L without any support, 3) absence of active graft versus host disease (GvHD) and infection, 4) absence of minimal residual disease at enrollment. Treatment consisted of up to 12 cycles of VEN 100 mg on Days 1-7 with AZA 32 mg/m 2/day IV/SC on Days 1-5 every 28 days. VEN dosing was adjusted for patients on concomitant CYP3A inhibitors or those with severe cytopenias. After the first 11 patients enrolled, due to myelosuppression observed, VEN dose was changed to 50 mg on days 1-7 if patients were on posaconazole. Treatment delays, up to 70 days, were allowed by toxicity. The primary objectives are relapse-free survival (RFS) after initiation of VEN and AZA and the safety and tolerability of the combination. The study has been ongoing. Results: The study enrolled a total of 30 patients (27 AML, 3 ALL). Demographics across all AML patients included mean age 52 years (range: 40-74), 67% males, 15% second SCT, 48% in first complete remission (CR1) at SCT, 41% adverse risk by European Leukemia Net classification. The majority (63%) received a myeloablative intensity conditioning regimen using intravenous busulfan. The three ALL patients were younger with mean age of 35 and all were in CR1 at SCT. The median time to start the maintenance treatment was 70.5 days (range, 42-103). As of the data cutoff date of 13 July 2022, patients completed a median of 4 cycles (range, 1-12) of study treatment with 9 patients (30%) remaining on study treatment. The primary reasons for study treatment discontinuation among 21 patients were complications like myelosuppresssion, infections and GvHD in 11, relapse in 6 and completion of 12 cycles of treatment in 4. The median follow-up time was 8.67 months (95% CI, 7.23 to 13.6).The median RFS and OS were not reached. The estimates of RFS and OS at 1-year were 69.2% (95% CI, 52.1% to 91.8%) and 90.2% (95%CI, 78% to 100%), respectively, after the initiation of VEN and AZA maintenance (Figure 1&2). Assuming a Bayesian Poisson-Gamma Model with a Gamma (1,1) prior; the mean number of grade≥3 treatment related adverse events (AEs) per patient was estimated. The mean number of AEs were 1.87 (range, 0-8) for decreased white blood cell count; 1.68 (range, 0-7) for decreased absolute neutrophil count; 1.06 (range, 0-6) for decreased platelet count; 0.55 (range, 0-6) for anemia; 0.13 (range, 0-1) for pneumonia and 0.06 (range 0-1) for each event of febrile neutropenia, maculopapular rash, respiratory failure and secondary graft failure (GF). The secondary GF was observed in one patient after the 4th cycle of treatment leading to discontinuation of study treatment. No patient died to due to treatment related AEs. Due to frequent and prolonged myelosuppression observed, 9 patients (30%) required dose reduction of VEN; mostly right after the first cycle of treatment (6 of 9 patients). After the protocol amendment for VEN to be given as 50 mg on days 1-7 on posaconazole, the requirement for dose changes decreased though still some patients required lower doses of VEN (as 30 mg on days 1-5) on subsequent cycles. Conclusion: Post-SCT maintenance therapy with VEN/AZA was safe and tolerable with favorable results in patients with high-risk AML and ALL. The majority of reported AEs was related to myelosuppression which is a known complication of VEN. Many patients required dose modification of VEN and treatment delays between cycles, highlighting the importance of monitoring these patients very closely. On the other hand, the observed RFS and OS data were highly encouraging compared to the historical outcomes for this high-risk group of patients although longer follow-up is needed. The study has been ongoing. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Management of chemotherapy-induced febrile neutropenia and use of granulocyte colony-stimulating factor in patients with soft tissue or bone sarcoma.

Febrile neutropenia, an oncological complication related to myelosuppressive chemotherapy, can lead to unplanned hospitalization, morbidity, mortality, and changes in the oncological therapeutic plan. The present study aimed (1) to determine the prevalence of chemotherapy-induced febrile neutropenia requiring hospitalization and the use of granulocyte colony-stimulating factor and (2) to evaluate its consequences for the oncological treatment of patients with soft tissue or bone sarcomas. This is a cross-sectional and retrospective study (January 2018 to December 2019) carried out in a reference oncology hospital in the Brazilian public health system. Inpatients diagnosed with chemotherapy-induced febrile neutropenia, older than the age of 18 years, and treated with granulocyte colony-stimulating factor were included in the study. Twenty-nine chemotherapy-induced febrile neutropenia events were identified, involving 25 patients. Among the febrile neutropenia events, 90% were grade 4, and 59% occurred during palliative chemotherapy. Among patients with febrile neutropenia, 31% had arterial hypertension or/and diabetes mellitus comorbidities, 34% had infectious skin sites, such as compression ulcers and tumor wounds, and 31% had infections with defined etiologic agents. Treatment of hospitalized patients was performed with cefepime in combinations or alone (97%) and filgrastim. The outcomes related to chemotherapy-induced febrile neutropenia were chemotherapy dose reduction (31%), chemotherapy cycle delays (21%), chemotherapy treatment suspension (17%), deaths (7%), and other associated complications (10%). Granulocyte colony-stimulating factor prophylaxis was prescribed in 72.41% of febrile neutropenia events. The frequency of febrile neutropenia concerning total chemotherapy cycles was 2.15%. Even with granulocyte colony-stimulating factor prophylaxis, an overall prevalence of 2.15% of febrile neutropenia associated with hospitalization was observed, causing negative outcomes in chemotherapy treatment of patients.

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

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

AML-295 AGILE: A Global, Randomized, Double-Blind, Phase 3 Study of Ivosidenib + Azacitidine Versus Placebo + Azacitidine in Patients With Newly Diagnosed Acute Myeloid Leukemia With an IDH1 Mutation

Isocitrate dehydrogenase 1 (IDH1) mutations are oncogenic drivers in acute myeloid leukemia (AML), with 6-10% of AML patients harboring mutant IDH1 (mIDH1). Ivosidenib (IVO) is a small molecule mIDH1 inhibitor that silences the oncogenic pathways activated by this mutation. Assess efficacy/safety of IVO+azacitidine (AZA) as frontline therapy for AML patients ineligible for intensive chemotherapy (IC). Randomized, placebo (PBO)-controlled, global phase 3 study. Patients with untreated AML, centrally confirmed mIDH1 status, ineligible for IC. Once daily IVO 500 mg (or PBO) plus AZA 75 mg/m2 for 7 days in 28-day cycles. Event-free survival (EFS), overall survival (OS), response rates, blood counts, transfusion dependence, health-related quality of life (HRQoL), and adverse events (AEs). 146 patients were randomized to IVO+AZA (n=72) and PBO+AZA (n=74). Median age was 76.0 and 75.5 years, respectively. EFS was significantly in favor of IVO+AZA (HR=0.33; 1-sided P=0.0011). Median OS was 24.0 vs 7.9 months for IVO+AZA vs PBO+AZA, respectively (HR=0.44; 1-sided P=0.0005). Complete response rates were 47.2% and 14.9% for IVO+AZA vs PBO+AZA, respectively (P<0.0001). During 2 weeks after treatment initiation, only the IVO+AZA treatment group showed an increase in absolute neutrophil count (from 0.99×109/L at baseline to 2.05×109/L at week 2). Significantly more patients in the IVO+AZA group became RBC and platelet transfusion independent (2-sided P=0.006). IVO+AZA preserved or improved HRQoL from treatment cycles 5 to 19, with few clinically meaningful improvements with PBO+AZA. Grade ≥3 AEs occurring in >20% of patients receiving IVO+AZA vs PBO+AZA included febrile neutropenia (28.2% vs 34.2%), anemia (25.4% vs 26.0%), thrombocytopenia (23.9% vs 20.5%), pneumonia (22.5% vs 28.8%), and infections (21.1% vs 30.1%). In patients with IC-ineligible, newly diagnosed mIDH1 AML, IVO+AZA significantly improved EFS, OS, and clinical response compared with PBO+AZA. Blood counts rapidly recovered in patients given IVO+AZA, patients were less dependent on RBC/platelet transfusion than those given PBO+AZA, with HRQoL improvements in the IVO+AZA group. The safety profile of IVO+AZA was favorable, with fewer febrile neutropenia and infection events with IVO+AZA vs PBO+AZA.

A comparative assessment of neutropenia events, healthcare resource use, and costs among cancer patients treated with lipegfilgrastim compared with pegfilgrastim in Germany

We assessed the occurrence of neutropenia and febrile neutropenia (FN) and the associated healthcare resource in cancer patients receiving myelosuppressive chemotherapy in combination with pegfilgrastim versus lipegfilgrastim. This is a retrospective analysis using a German health insurance claims database. Adults receiving chemotherapy with a prescription code for pegfilgrastim (n = 734) or lipegfilgrastim (n = 346) were observed over a 1-year follow-up period. Patient subgroups were analyzed according to cancer type and FN risk. FN risk was based on the chemotherapy regimen and any additional neutropenia risk factors. Outcomes were adjusted via regression analysis. Most patients were classified as high FN risk (70.0% pegfilgrastim; 65.6% lipegfilgrastim cohort). The mean age was 58.2years in the pegfilgrastim cohort and 58.0years in the lipegfilgrastim cohort, with more female patients than male patients (77.3% vs 79.8%, respectively), and the majority had breast cancer (64.9% and 68.8%, respectively). Overall, 10.0% and 10.4% of patients receiving pegfilgrastim or lipegfilgrastim experienced a neutropenia event (p = 0.82), with 4.4% and 3.5% of patients experiencing a FN event (p = 0.49). The mean neutropenia event-related healthcare costs were €604 and €441 for the pegfilgrastim and lipegfilgrastim cohorts; among patients with lymphoma, these costs were significantly greater (p = 0.03) with pegfilgrastim (€1,612) versus lipegfilgrastim (€382). The mean all-cause hospitalizations were significantly (p < 0.01) higher for lymphoma patients receiving pegfilgrastim (2.76) versus lipegfilgrastim (1.60). Overall, patients treated with pegfilgrastim and lipegfilgrastim were comparable in terms of neutropenia occurrences in the 1-year follow-up. In patients with lymphoma, neutropenia event-related healthcare costs and all-cause hospitalizations were significantly higher with pegfilgrastim compared with lipegfilgrastim in this study; however, this should be interpreted with caution in light of the limited sample size and the absence of clinical information.

Effects of primary granulocyte-colony stimulating factor prophylaxis on the incidence of febrile neutropenia in patients with germ cell tumors.

Testicular germ cell tumors (GCTs) are the most common solid malignancy in males aged 15–35 years. Febrile neutropenia (FN) is a serious complication of chemotherapy that frequently occurs in patients with GCTs. The present retrospective study aimed to evaluate the effect of primary granulocyte-colony stimulating factor (G-CSF) prophylaxis on the incidence of FN in patients with GCTs. The present study included a review of the medical records of patients diagnosed with GCTs treated with first-line/adjuvant chemotherapy between January 2000 and December 2017 at the National Cancer Institute (Bratislava, Slovakia). In January 2006, a decision was made to administer G-CSF prophylaxis (filgrastim or pegfilgrastim) to patients after every cycle of chemotherapy. The present study included 385 patients, and out of these, 264 patients received primary G-CSF prophylaxis, while 121 patients did not. A total of 71 patients (18.4%) suffered from FN events. In the subgroup that did not receive primary prophylaxis, 42 patients exhibited FN, while only 29 patients with primary prophylaxis suffered from FN (34.7 vs. 11.0%; P=0.00000003). According to the subgroup analysis, FN incidence was decreased in all groups that received primary prophylaxis, except for patients with stage I GCT receiving adjuvant chemotherapy, without affecting overall survival. Primary G-CSF prophylaxis was associated with markedly reduced FN incidence in patients treated with first-line chemotherapy for metastatic disease. Therefore, the results of the present study suggested that primary G-CSF prophylaxis should be considered in patients with GCT receiving first-line chemotherapy.