Duration Of Grade Research Articles

A randomized, multicenter phase III Study of once-per-cycle administration of efbemalenograstim alfa (F-627), a novel long-acting rhG-CSF, for prophylaxis of chemotherapy-induced neutropenia in patients with breast cancer

BackgroundF-627 (efbemalenograstim alfa) is a novel long acting granulocyte colony-stimulating factor (G-CSF) that contains two human G-CSF fused to a human immunoglobulin G2 (hIgG2) -Fc fragment with a peptide linker. This studyevaluated the efficacy and safety of F-627, also known as efbemalenograstim alfa (Ryzneuta®) in reducing neutropenia compared with filgrastim (GRAN®).MethodsThis was a multicenter, randomized, open-label, active-controlled non-inferiority study. Two hundred thirty nine (239) patients were enrolled in thirteen centers and received the chemotherapy with epirubicin (100 mg/m2) and cyclophosphamide (600 mg/m2) on day 1 of each cycle for a maximum of four cycles. Patients were randomized to receive either a single 20 mg subcutaneous (s.c.) injection of F-627 on day 3 of each cycle or daily s.c. injection of filgrastim 5 µg/kg/d starting from day 3 of each cycle. The primary endpoint was the duration of grade 3 or 4 neutropenia in cycle 1. The safety profile was also evaluated.ResultsThe mean (SD) duration of grade 3 or 4 neutropenia in cycle 1 was 0.68 (1.10) and 0.71 (0.95) days for the F-627 and the filgrastim groups, respectively. The Hodges-Lehmann estimate of the between-group median difference (F-627 vs filgrastim) in the duration of grade 3 or 4 neutropenia in cycle 1 was 0 day and the upper limit of the one-sided 97.5% CI was 0 day, which was within the prespecified non-inferiority margin of 1-day. Results for all efficacy endpoints in cycles 2 − 4 were consistent with the results in cycle 1, however a trend towards a lower incidence and a shorter duration of grade 3 or 4 neutropenia and grade 4 neutropenia was observed in the F-627 group compared with the filgrastim group. The ANC nadir in the F-627 group was significantly higher than that in the filgrastim group in each cycle. A single fixed dose of F-627 was well tolerated and as safe as standard daily filgrastim.ConclusionsA single fixed dose of 20 mg of F-627 in each cycle was as safe and effective as a daily dose of filgrastim 5 µg/kg/d in reducing neutropenia and its complications in patients who received four cycles of EC.Trial registrationClinicalTrials.gov: NCT04174599, on 22/11/2019.

The efficacy and safety of ulinastatin in the prevention and treatment of radiotherapy-induced oral mucositis in locoregionally advanced nasopharyngeal carcinoma (LA-NPC): A multicenter, open-label, randomized controlled clinical trial.

6105 Background: Severe oral mucositis is a common radiation-induced toxicity in locoregionally advanced nasopharyngeal carcinoma (LA-NPC) patients treated with concurrent chemo-radiotherapy (CCRT). Ulinastatin (UTI) can reduce the inflammatory response by inhibiting the release of inflammatory factors, but its role in radiotherapy-induced oral mucositis (RTOM) is unclear. Therefore, we conducted a multicenter, open-label, randomized controlled clinical trial to investigate the efficacy and safety of UTI in the prevention and treatment of RTOM in LA-NPC patients. Methods: Patients with histologically confirmed LA-NPC who met the eligibility criteria were randomly assigned to UTI group and control group. All patients received radical intensity modulated radiation therapy (IMRT) and concurrent chemotherapy (cisplatin 100 mg/m2/3 weeks for 2 or 3 cycles). UTI of 100,000 units three times daily (5 days/week) was intravenously administrated from day 1 to the end of radiotherapy for UTI Group. The primary endpoint was the incidence of grade ≥ 3 acute RTOM during CCRT (Radiation Therapy Oncology Group, RTOG grading). The secondary endpoints included the cumulative incidence of RTOM, recovery rate (proportion of patients with grade ≥ 3 RTOM who recovered to grade ≤ 2 during CCRT), the onset time and duration of grade ≥ 3 RTOM, oral pain (Numerical rating scale, NRS), safety and survival outcomes. Results: From January, 2018, to December, 2021, 182 patients from 5 hospitals were enrolled. 179 patients were included for efficacy, safety and survival analysis (89 in the UTI group and 90 in the control group). All UTI group patients completed UTI treatment as planned, and both groups completed scheduled CCRT. The incidence of grade ≥ 3 RTOM was significantly lower in UTI group compared with control group (25.8% vs. 41.1%; P = 0.030). The recovery rate in UTI group was higher than that in control group (39.1% vs. 10.8%; P = 0.023). However, the onset time and the duration of grade ≥ 3 RTOM were similar between the two groups (Median [IQR] 26.00 [19.00, 33.00] days vs. 32.00 [20.50, 36.00] days; P= 0.621 and 12.00 [7.00, 18.00] days vs. 15.00 [8.00, 25.50] days; P= 0.209). The incidence of severe oral pain ( NRS score≥ 7 ) was significantly reduced in UTI group compared with the control group (22.5% vs. 36.7; P = 0.038). No UTI related adverse events were observed during treatment. With a median follow-up time of 41.6 months (IQR, 38.2 - 45.0 months), The 3-year OS, LRRFS, DMFS and PFS in UTI group and Control group were 96.5% vs. 94.3%, 91.2% vs. 87.2%, 95.2% vs. 92.1% and 89.9% vs. 85.1%, respectively (all P > 0.05). Conclusions: Our study revealed that UTI can effectively reduce the incidence of graded ≥ 3 RTOM and severe oral pain without increasing adverse events and compromising survivals. Clinical trial information: NCT03387774 .

Changes in T-cell subsets, preexisting cytopenias and hyperferritinaemia correlate with cytopenias after BCMA targeted CAR T-cell therapy in relapsed/refractory multiple myeloma: Results from a prospective comprehensive biomarker study.

Biomarkers for cytopenias following CAR T-cell treatment in relapsed/refractory (RR) multiple myeloma (MM) are not completely defined. We prospectively analysed 275 sequential peripheral blood (PB) samples from 58 RRMM patients treated with BCMA-targeted CAR T cells, and then divided them into three groups: (i) baseline (before leukapheresis), (ii) ≤day+30, and (iii) >day+30 after CAR T-cell therapy. We evaluated laboratory data and performed flow cytometry to determine the (CAR) T-cell subsets. Baseline hyperferritinaemia was a risk factor for long-lasting grade ≥3 anaemia (r = 0.47, p < 0.001) and thrombocytopenia (r = 0.44, p = 0.002) after CAR T-cell therapy. Low baseline haemoglobin (Hb) and PLT were associated with long-lasting grade ≥3 anaemia (r = -0.56, p < 0.001) and thrombocytopenia (r = -0.44, p = 0.002) respectively. We observed dynamics of CAR-negative T-cell subsets following CAR T-cell infusion. In the late phase after CAR T-cell therapy (>day+30), CD4Tn frequency correlated with anaemia (r = 0.41, p = 0.0014) and lymphocytopenia was related to frequencies of CD8+ T cells (r = 0.72, p < 0.001) and CD8Teff (r = 0.64, p < 0.001). CD4Tcm frequency was correlated with leucocytopenia (r = -0.49, p < 0.001). In summary, preexisting cytopenias and hyperferritinaemia indicated long duration of grade ≥3 post-CAR T-cell cytopenias. Prolonged cytopenia may be related to immune remodelling with a shift in the CAR-negative T-cell subsets following CAR T-cell therapy.

Application of Recombinant Human Superoxide Dismutase in Radical Concurrent Chemoradiotherapy for Cervical Cancer to Prevent and Treat Radiation-induced Acute Rectal Injury: A Multicenter, Randomized, Open-label, Prospective Trial

PurposeTo evaluate the efficacy of recombinant human superoxide dismutase (rhSOD) enemas in radiation-induced acute rectal injury (RARI) in patients with locally advanced cervical cancer. MethodsIn this phase III, randomized, open-label trial (NCT04819685) conducted across 14 medical centers in China from June 2021 to August 2023, all patients received concurrent chemoradiotherapy (CCRT). The experimental group was treated with a rhSOD enema during chemoradiotherapy, and the control group had no enema. The Common Terminology Criteria for Adverse Events (version 5.0) was used to evaluate radiotherapy-induced side effects. Endoscopic appearance was assessed using the Vienna Rectoscopy Score. The primary endpoint in the acute phase was the occurrence rate and duration of grade ≥1 (≥G1) diarrhea during CCRT. Secondary endpoints included the occurrence rate and duration of ≥G2 and ≥G3 diarrhea; ≥G1 and ≥G2 diarrhea lasting at least 3 days; and damage to the rectal mucosa due to radiotherapy measured by endoscopy. ResultsTwo-hundred-and-eighty-three patients were randomly divided into the experimental (n = 141) or control group (n = 140). The mean number of ≥G1 and ≥G2 diarrhea days were significantly lower in the experimental group than in the control group (3.5 and 0.8 days vs. 14.8 and 4.5 days, respectively; P<0.001). The incidence of ≥G2 diarrhea decreased from 53.6% to 24.1% when rhSOD enemas were used. Use of antidiarrheals was lower in the experimental group (36.2% vs. 55.7%, P<0.001). Three patients felt intolerable or abdominal pain following rhSOD enema. RARI grades in the experimental group tended to be lower than those in the control group (P=0.061). Logistic regression analysis revealed that rhSOD enema was associated with a lower occurrence rate of ≥G1/2 diarrhea for at least 3 days (P<0.001). ConclusionThe results of this study suggest that rhSOD enema is safe and significantly reduces the incidence, severity, and duration of RARI, protecting the rectal mucosa.

Prolonged Cytopenia Following CAR T-Cell Therapy in Relapsed/Refractory Multiple Myeloma: A Prospective Comprehensive Biomarker Study

Background Chimeric antigen receptor (CAR) modified T-cells are leading to a paradigm shift in the treatment of relapsed/refractory (RR) multiple myeloma (MM). A high proportion of patients treated with CAR T-cells, however, experience prolonged cytopenia, with the mechanism remaining poorly understood. Here, we aimed to explore potential biomarkers that might correlate with cytopenia following CAR T-cell therapy in RRMM. Methods We prospectively collected peripheral blood (PB) of RRMM patients treated with idecabtagen-vicleucel (ide-cel) at the following time points: prior to lymphodepleting chemotherapy (LDC) (baseline), after ide-cel on day 4, 7, 14 and 28, and monthly thereafter. Cytopenia was determined according to the CTCAE version 5.0. Flow cytometry was performed with the following markers: CD45, CD3, CD4, CD8, CD62L, CD45RA, CD19, CD14, CD138, CD38 and a BCMA-CAR-detection marker. Results We included 222 PB samples at different sampling time points from 35 RRMM patients, who were pretreated with a median of 5 therapy lines (range 2-10). All patients were triple-class exposed and, 34 (97%) and 9 (26%) patients underwent autologous and allogeneic stem cell transplant (SCT), respectively. First, we analyzed the relationship between baseline parameters and the duration of grade ≥3 cytopenia after ide-cel (n=35). Notably, patients who received allogeneic SCT or &amp;gt;4 lines of therapy did not develop longer lasting cytopenia than the remaining patients. We found a correlation between the baseline hemoglobin level and the duration of grade ≥3 anemia (r=-0.55, P&amp;lt;0.001). Similarly, low baseline platelet count indicated long duration of grade ≥3 thrombocytopenia (r=-0.48, P=0.003). Moreover, high baseline ferritin level correlated with long duration of grade ≥3 anemia (r=0.52, P&amp;lt;0.001) and thrombocytopenia (r=0.51, P=0.002). Furthermore, the maximum ferritin level after ide-cel was an indicator for long lasting grade ≥3 anemia (r=0.73, P&amp;lt;0.001) and thrombocytopenia (r=0.71, P&amp;lt;0.001). Interestingly, we found significant correlations between the duration of grade ≥3 lymphopenia and baseline CD4+ T-cell frequency (r=0.41, P=0.02), CD8+ T-cell frequency (r=-0.38, P=0.04) and CD4+/CD8+ ratio (r=0.4, P=0.03). Noteworthy, patients with β2-microglobulin level &amp;gt;3.5 mg/l displayed longer duration of grade ≥3 anemia (median: 9 vs 0 day, P=0.007) and neutropenia (median: 43 vs 12 days, P=0.02) compared with the remaining patients, suggesting that high tumor load might be a risk factor for prolonged cytopenia after ide-cel. Second, we divided the follow-up PB samples (n=187) into two groups: early (&amp;lt;d60) and prolonged (≥d60) cytopenia to account for direct toxic effects related to LDC. A high ferritin level was associated with low hemoglobin level (&amp;lt;d60: r=-0.45, P&amp;lt;0.001, ≥d60: r=-0.62, P&amp;lt;0.001) and low platelet count (&amp;lt;d60: r=-0.58, P&amp;lt;0.001, ≥d60: r=-0.81, P&amp;lt;0.001) in both groups. In prolonged cytopenia (≥d60), lymphocyte count correlated with the T-cell count (r=0.7, P&amp;lt;0.001), suggesting that prolonged lymphopenia was mainly attributed to the reduced T-cell count after ide-cel. Of note, the frequency of naïve CD4+ T-cells (CD3+CD4+CD62L+CD45RA+) positively correlated with neutrophil count (r=0.58, P&amp;lt;0.001), hemoglobin level (r=0.37, P=0.03) and white blood cell count (r=0.5, P=0.002) in the ≥d60 group, suggesting that delayed immune reconstruction with reduced naïve CD4+ T-cells might contribute to prolonged cytopenia after ide-cel. Moreover, in the ≥d60 group, lymphocyte count was related with the frequency of CAR+CD4+ (r=-0.58, P&amp;lt;0.001), CAR+CD8+ (r=0.58, P&amp;lt;0.001), CAR-CD4+ (r=-0.72, P&amp;lt;0.001), CAR-CD8+ (r=0.75, P&amp;lt;0.001) T-cells, as well as the ratios of CAR+CD8+/CAR+CD4+ (r=-0.6, P&amp;lt;0.001) and CAR-CD8+/CAR-CD4+ (r=-0.75, P&amp;lt;0.001). Conclusion Here, we present one of the first prospective studies investigating the factors associated with prolonged cytopenia after CAR T-cell therapy in RRMM. High tumor load, preexisting cytopenia and high ferritin level are related with prolonged cytopenia after ide-cel. Delayed immune reconstruction, characterized by reduced naïve CD4+ T-cell count, indicates prolonged cytopenia following ide-cel therapy. Patients with high CD4+/CD8+ ratio are at risk of prolonged lymphopenia (with reduced T-cell count), which may be a risk factor for infectious complications and an issue for subsequent T-cell based immunotherapies.

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

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

Itacitinib for the Prevention of Immune Effector Cell Therapy-Associated Cytokine Release Syndrome: Results from the Phase 2 Incb 39110-211 Placebo-Controlled Randomized Cohort

Introduction: Cytokine release syndrome (CRS) and immune effector cell (IEC)-associated neurotoxicity syndrome (ICANS) are common adverse effects following IEC therapy. Janus kinase (JAK) pathways are important for the signaling of several cytokines involved in CRS pathogenesis. Itacitinib is a potent, selective JAK1 inhibitor with broad anti-inflammatory activity. We describe preliminary results from the randomized, placebo-controlled portion of the study evaluating itacitinib 200 mg twice daily (bid) for the prevention of CRS. Methods: This randomized, placebo-controlled portion of the phase 2 Study INCB 39110-211 (NCT04071366) enrolled patients ≥18 years old planning to receive axicabtagene ciloleucel for relapsed/refractory large B-cell lymphoma (rrLBCL) and follicular lymphoma (rrFL). Participants received oral itacitinib 200 mg bid beginning 3 days before axicabtagene ciloleucel infusion and continued itacitinib through Day 26. Protocol did not allow tocilizumab for treatment of grade 1 CRS unless CRS did not improve after 72 hours of supportive treatment. Patients who received tocilizumab for grade 1 CRS were not censored. Primary endpoint was incidence of CRS grade ≥2 by Day 14 using American Society for Transplantation and Cellular Therapy grading system. Secondary endpoints included incidence of ICANS by Day 28, duration of CRS and ICANS, and itacitinib safety. Results: 47 patients with rrLBCL were randomized to itacitinib (n=23; median age, 66 [range: 29-80] years; male, 65%) or placebo arms (n=24; median age, 64 [range: 31-79] years; male, 71%). Median (range) number of prior regimens was 2 (1-6) and 1.5 (1-4), respectively. No rrFL patients enrolled in the study. Two (8%) patients in the itacitinib arm received platelet transfusions after Day 28; no transfusions were received in the placebo group. A total of 15 (65.2%) patients in the itacitinib arm developed CRS (grade 1, n=11 [47.8%]) compared with 20 (87.0%) patients in placebo arm (grade 1, n=7 [30.4%]; Figure). No hypotension or hypoxia was observed in patients with grade 1 CRS who received tocilizumab. Grade 2 CRS was experienced by 4 (17.4%) and 13 (56.5%) patients, respectively ( P=0.003; 95% CI: 0.14-0.65). There was no grade 3 or 4 CRS in either arm. Median (range) time to any-grade CRS onset was 2 (0-8) days and 3 (0-9) days, respectively; median (range) duration of grade 2 CRS was 2 (1-8) and 2 (1-5) days. Overall, tocilizumab was used for CRS treatment in 4 (17.4%) patients in the itacitinib arm and in 15 (65.2%) patients in the placebo arm, including 2 and 6 patients, respectively, who received tocilizumab for grade 1 CRS. ICANS occurred in 3 (13%; 95% CI: 3-34) patients in the itacitinib arm and 8 (34.8%; 95% CI: 16-57) patients in the placebo arm (Figure). ICANS grade ≥2 was reported in 2 (8.6%; 95% CI: 1-28) and 5 (21.7%; 95% CI: 8-44) patients, respectively. No grade 4 ICANS occurred in either arm. Median (range) time to any-grade ICANS onset was 5 (4-9) days and 6.5 (2-11) days, respectively; median (range) duration was 2 (2-11) and 3.5 (2-13) days. Persistent grade 3 or 4 thrombocytopenia at Day 28 in the itacitinib arm was reported in 8 (38.1%; [grade 4: n=4]) patients; in the placebo arm in 4 (18.2%; [grade 4: n=0]) patients. Persistent grade 3 or 4 neutropenia at Day 28 in the itacitinib arm was reported in 7 (33.3%; [grade 4: n=3]) patients; in the placebo arm in 3 (13.6%; [grade 4: n=0]) patients. Infections grade ≥3 occurred before Day 28 in 2 (8.7%) patients in the itacitinib arm (urinary tract infection [UTI], n=2) and in 3 (12.5%) patients in the placebo arm (sepsis, n=2; UTI, n=1). There were no fatal adverse events. With a minimum follow-up of 28 days, lymphoma best overall response to axicabtagene ciloleucel showed no difference between the 2 arms. Conclusions: Results from the randomized, placebo-controlled portion of Study INCB 39110-211 have shown prophylaxis treatment with itacitinib 200 mg bid to be well tolerated and resulted in a lower rate and grade of CRS and ICANS after lymphoma treatment with axicabtagene ciloleucel. Incidence of grade 3/4 neutropenia and thrombocytopenia not resolved at Day 28 was higher with itacitinib vs placebo. Rates of severe infections were comparable in both arms. Longer follow-up data on lymphoma response will be available upon presentation. Biomarker analyses comparing the effect of itacitinib on CAR-T cells expansion and function are ongoing.

Efficacy and safety of PEG-rhG-CSF versus rhG-CSF in preventing granulocytopenia in sarcoma patients receiving doxorubicin combined with ifosfamide: A prospective, randomized, non-inferiority phase II study.

e24173 Background: Prophylactic use of rhG-CSF is routinely recommended in patients with a high risk of febrile neutropenia (FN) after chemotherapy. Currently, rhG-CSF is mostly used in clinical practice. However, PEG-rhG-CSF tends to be a substitute due to its convenience and long-acting effect. Regarding concerns about its efficacy and safety, whether PEG-rhG-CSF could be prophylactically used after these regimens with a high risk of FN is still in doubt. Doxorubicin combined with ifosfamide is commonly applied in sarcoma patients and is one of the most serious myelosuppressive chemotherapy regimens in solid tumors. We compared the efficacy and safety of PEG-rhG-CSF with rhG-CSF in the prevention of severe granulocytopenia and FN, in patients receiving this representative regimen. Methods: This was a single-center, prospective, randomized, crossover, non-inferiority phase II trial. Patients with sarcoma suitable for doxorubicin combined with ifosfamide treatment were enrolled. All patients received 2 cycles of chemotherapy and were randomly assigned to either the AOB group (PEG-rhG-CSF used in 1st cycle and rhG-CSF in 2nd cycle) or BOA group (rhG-CSF used in 1st cycle and PEG-rhG-CSF in 2nd cycle). Blood monitoring every other day until ANC ≥ 2×109/L in two consecutive tests. The primary endpoints were the frequency and duration of grade 4 granulocytopenia after prophylactic use of PEG-rhG-CSF and rhG-CSF respectively, the secondary endpoints were the frequency and duration of febrile neutropenia, and proportion of antibiotic use. Results: From Jan 1, 2018 to Aug 31, 2021, 70 patients were enrolled, 35 each in AOB and BOA. There were no statistical differences in the incidence and duration of grade 4 granulocytopenia (85.7% vs. 77.0%, p = 0.1; 1.34d vs. 1.41d, p = 0.70), the proportion and duration of febrile neutropenia (12.8% vs. 8.2%, p = 0.77; 0.6d vs. 0.8d, p = 0.74), and the proportion of antibiotics used (19.1% vs. 14.9%, p = 0.79) when comparing PEG-rhG-CSF vs. rhG-CSF in prophylactical use. The incidence of grade 4 granulocytopenia in both groups was comparable in 1st cycle (90.9% vs. 96.0%, p = 0.47), but in 2nd cycle it was significantly lower in AOB than that in BOA (54.5% vs. 88.0%, p = 0.01). The lowest value of ANC was higher in AOB in 2nd cycle (0.32G/L vs. 0.12G/L, p = 0.03). Conclusions: This study demonstrated PEG-rhG-CSF could prevent granulocytopenia and FN in sarcoma patients receiving doxorubicin combined with ifosfamide, with comparable efficacy and toxicities as rhG-CSF. Considering the convenience in use and patient compliance, PEG-rhG-CSF could be an effective and reasonable alternative to rhG-CSF. Clinical trial information: ChiCTR1900021945 .

Platelet decline rate as the indication of using recombinant human thrombopoietin to prevent chemotherapy induced thrombocytopenia: A prospective, randomized, controlled study.

e24171 Background: Doxorubicin combined with ifosfamide is the common regimen for patients with sarcoma, which will induce severe thrombocytopenia. Sarcoma patients especially those with rapid platelet count decline after receiving this regimen could not avoid severe thrombocytopenia, even Recombinant Human Thrombopoietin(rhTPO) was used when the platelet count decreased to 75,000/μL according to current guidelines. The present study aimed to test the efficiency and safety of using rhTPO to prevent severe thrombocytopenia when rapid platelet count decline occurred. Methods: Our previous data showed those patients with rapid platelet count decline more than 40% within 3 days after administration of doxorubicin combined with ifosfamide were more likely to develop severe thrombocytopenia. In this prospective study, 53 patients with this characteristic were randomly assigned to prevention group (starting rhTPO immediately after enrollment) or treatment group (starting rhTPO when platelet count was less than 75,000/μL after chemotherapy). rhTPO was administrated with 300IU/kg·d until the platelet count increased to 100,000/μL or by 50,000/μL. Incidence and duration of grade 3 to 4 thrombocytopenia, proportion of platelet transfusion and adverse reactions were collected and analyzed. Results: The incidence of grade 3 to 4 thrombocytopenia in the prevention group and the treatment group was 63% and 81% respectively (p = 0.224), however the incidence of grade 4 thrombocytopenia in the former was significantly lower than that in the latter(22% versus 50% , p = 0.047).The duration of grade 3 to 4 thrombocytopenia in the prevention group had a declining trend compared with the treatment group( 2.6±2.8d versus 3.7±3.3d, p = 0.198). There was no difference in the proportion of platelet transfusion between the two groups. No rhTPO related toxicities of grade 3 to 4 were observed in both groups. Conclusions: For sarcoma patients treated with doxorubicin combined with ifosfamide, rapid platelet count decline more than 40% within 3 days after chemotherapy can be used as an indicator for the prophylactic administration of rhTPO, which can significantly reduce the probability of grade 4 thrombocytopenia without increasing toxicity. Clinical trial information: ChiCTR1900022667 .

Comparison of Hematotoxicity of Pegylated Recombinant Human Granulocyte Colony-Stimulating Factor (PEG-rhG-CSF) Combined with Dual-Agent Concurrent Chemoradiotherapy and Cisplatin Concurrent Chemoradiotherapy for Locally Advanced Cervical Cancer

<h3>Purpose/Objective(s)</h3> Concurrent chemoradiotherapy (CCRT) with cisplatin is the standard treatment for locally advanced cervical cancer (LACC), but there are still some patients who have poor efficacy. Though dual-agent concurrent chemoradiotherapy (dCCRT) can improve the efficacy, the higher hematotoxicity makes it difficult to be popularized in clinical. PEG-rhG-CSF has been recommended by relevant NCCN guidelines for CCRT of malignant tumors in recent years, however there are few reports in LACC. The aim of this study was to evaluate the effect of PEG-rhG-CSF on reducing hematotoxicity in LACC with dCCRT. <h3>Materials/Methods</h3> This study retrospectively analyzed the clinical data of patients with LACC treated with CCRT in the Affiliated Cancer Hospital of Guizhou Medical University. According to patients' clinical protocol, all patients were divided into three groups, single-agent concurrent chemoradiotherapy group(sCCRT), dCCRT group and PEG-rhG-CSF combined with dCCRT group (PEG+dCCRT). Patients in sCCRT received CCRT with cisplatin 40 mg/m² for four to six cycles and patients in dCCRT were treated with paclitaxel 135-175mg/m²+cisplatin 60-80mg/m² or lobaplatin 30mg/m² for two cycles. Recombinant human granulocyte colony-stimulating factor (rhG-CSF) 5ug/kg/d was given to patients in these two groups according to the instructions. Patients in PEG+dCCRT were received dCCRT, and PEG-rhG-CSF 6mg was given in 24 to 72 hours after chemotherapy each cycle. The incidence and duration of grade 3-4 leukocytopenia and neutropenia and febrile neutropenia (FN) (according to CTCAE, V5.0) were the primary endpoints. The second endpoints were completion rate of chemotherapy and radiotherapy, time to complete radiotherapy. <h3>Results</h3> A total of 192 patients were enrolled between July 2019 and December 2021. 51 patients in sCCRT, 68 patients in dCCRT and 73 patients in PEG+dCCRT. The three groups were respectively compared for primary and second endpoints, and the results were shown below. The incidences of grade 3-4 leukocytopenia and neutropenia of the three groups (sCCRT, dCCRT and PEG+dCCRT) were 41.2%, 67.2%, 27.4% and 27.5%, 48.6%, 13.7%, respectively. The incidences of PEG+dCCRT were lowest in the three groups(P<0.05). In the three groups, the duration of grade 3-4 leukocytopenia and FN of PEG+dCCRT were observably reduced(P<0.05). There was no statistical difference of other primary and second endpoints in the three groups. <h3>Conclusion</h3> Prophylactic use of PEG-rhG-CSF during dCCRT makes hematotoxicity manageable, which may make dCCRT have better promotion and improves efficacy of LACC. However, further prospective studies are needed to confirm the results.

Simultaneous Modulated Accelerated Radiotherapy (SMART) with Dysphagia Aspiration-Related Structures (DARS) Sparing: Do We Have a Role for Dose Condensation in Locally Advanced Head and Neck Cancer

Introduction Concurrent chemotherapy integrated with intensity-modulated radiotherapy (IMRT) is the standard of care for locally advanced head and neck cancer. Simultaneous integrated boost technique has allowed differential doses to primary and normal structures permitting significant toxicity reduction. The current study explores the feasibility of the simultaneous modulated accelerated radiotherapy (SMART) technique to enhance cytoreduction and explore the possibility of dose intensification with radiobiologically targeted treatment condensation. Methods Thirty patients were randomized in an open-labeled study to receive concurrent chemoradiation of 60 Gy in 25 fractions with “SMART” technique or 70 Gy in 35 fractions using conventional intensity-modulated radiotherapy simultaneous integrated boost “IMRT SIB.” The primary endpoints included comparative volumetric cytoreduction between the study and control arm assessed during the course of treatment and final response evaluation. Secondary endpoints involved the assessment of acute toxicity parameters for xerostomia, mucositis, dysphagia, and fatigue. Results The “SMART” study arm showed comparable volumetric cytoreduction to the conventional “IMRT SIB” arm at midtreatment (p-value = 0.225) as well as toward completion (p-value = 0.476). The study arm did observe 94.4% cytoreduction of tumor volume compared with 88.05% in the conventional arm at the time of response evaluation. In spite of treatment condensation, there was no significant increase in toxicity with “SMART.” There was no difference in the frequency or duration of grade 3 mucositis in the “SMART” arm in spite of intensification (p-value = 0.728). In the “SMART” arm, there was a favorable reduction in the duration of grade ⅔ dysphagia; 2.8 weeks versus 4.6 weeks (p-value = 0.002). Even though the xerostomia was comparable in frequency and intensity, the total duration of xerostomia was 50% less (p-value = 0.001). Conclusions The “SMART” technique provides a radiobiologically sound, effective, and safe protocol that has the potential to improve the treatment of locally advanced head and neck cancer. The good tolerability and toxicity profile in the study arm is encouraging and facilitates further research.

Phase 2 pilot trial of RRx-001 as an anti-mucositis agent in patients with head and neck cancer treated with chemoradiation (PREVLAR).

6078 Background: Severe oral mucositis (SOM) is a dose limiting toxicity during radiotherapy and cisplatin for head and neck cancers. The aim of this 4-arm randomized controlled pilot trial was to evaluate the efficacy of different schedules of a novel radioprotectant, RRx-001 versus standard-of-care (SOC), to reduce duration, time to onset and incidence of SOM in patients received cisplatin-based chemoradiotherapy (CRT) for oral cavity or oropharyngeal cancer (OCC). Methods: Patients with locally advanced OCC treated with definitive or postoperative CRT were randomized to receive RRx-001 by 15-minute intravenous infusion in one of three different schedules versus none. The days and severity of mucositis were prospectively evaluated. Oral mucositis was assessed weekly during and after CRT as well as 28 days after completion. The pre-specified efficacy endpoints were duration of grade 3-4 SOM, resolution of SOM, time to onset of SOM and incidence of SOM. Results: A total of 53 patients were enrolled between June 2018 and July 2019 across 11 institutions. Forty-five (out of 53) patients received study drug and were efficacy evaluable. RRx-001 were well tolerated with no associated serious adverse events. All RRx-001 arms numerically outperformed SOC on the pre-specified efficacy measures, and the greatest effect estimate was observed on Arm 1 (RRx-001 pretreatment only + CRT). The following endpoints favored treatment with RRx-001. Median SOM duration by treatment was 22 and 40 days for Arm 1 and SOC respectively. Time to onset of SOM was by 38 days (Arm 1) vs. 26 days (SOC). On Arm 1, 83% of patients had SOM resolution vs 60% on SOC). Gastrostomy requirement was reduced by 45%. No patients on Arm 1 developed grade 4 mucositis vs 30% developed grade 4 mucositis on the SOC arm. Furthermore, the incidence of oropharyngeal dysphagia, which can substantially impair nutrition, was reduced by treatment with RRx-001, occurring at 50% vs 70% for Arm 1 vs SOC respectively. Treatment with RRx-001 resulted in highly significant decrease in the duration of SOM through 60 Gy with a median SOM of 1 day vs 17 days for Arm 1 vs SOC respectively (Wilcoxon rank-sum test p &lt; 0.001). Median cumulative cisplatin dose was significantly greater for RRx-001 Arm 1 than SOC (557.4 mg vs. 438 mg, Wilcoxon p = 0.025). Conclusions: Compared with SOC, SOM among RRx-001-treated patients given 3 different treatment schedules was less severe, of shorter duration, demonstrated delayed time to onset and resolved earlier. Overall, the incidence, duration and severity of SOM and dysphagia was reduced. The safety profile of RRx-001 was similar to SOC. These results will inform the design of a Phase 3 pivotal study of RRx-001 in the prevention of SOM in at-risk cancer patients. Clinical trial information: NCT03515538.

Abstract P5-16-14: A randomized, multicenter phase III study of once-per-cycle administration of efbemalenograstim alfa (F-627), a novel long-acting dimeric rhG-CSF, for prophylaxis of chemotherapy-induced neutropenia in patients with breast cancer

Abstract Background: Neutropenia is common in patients receiving myelotoxic chemotherapy. F-627( efbemalenograstim alfa ), is a novel long acting dimeric granulocyte colony-stimulating factor (G-CSF) that contains two human G-CSF fused to a human immunoglobulin G2 (hIgG2) -Fc fragment with a peptide linker. This study was to evaluate the efficacy and safety of F-627 for reducing chemotherapy-induced neutropenia as compared with filgrastim (GRAN®). Methods: This was a multicenter, randomized, open-label, and active-controlled non-inferiority study. Thirteen centers enrolled 239 patients who received chemotherapy with epirubicin (100mg/m2) and cyclophosphamide (600 mg/m2) (EC therapy) on day 1 of each cycle for a maximum of four cycles. Patients were randomized to receive on day 3 either a single 20 mg subcutaneous (s.c.) injection of F-627 per cycle or daily s.c injections of filgrastim 5 μg/kg/day. The primary endpoint was the duration of grade 3 (ANC &amp;lt;1× 109/L) or 4 (ANC&amp;lt;0.5× 109/L) neutropenia in cycle 1. The safety profile was evaluated. Results: The mean (SD) duration of grade 3 or 4 neutropenia in cycle 1 was 0.67 (1.10) and 0.71 (0.95) days for the F-627 and the filgrastim groups, respectively. The Hodges-Lehmann estimator of the median difference between groups (F-627 − Filgrastim) in the duration of grade 3 or 4 neutropenia in cycle 1 was 0 day and the upper limit of one-sided 97.5% CI was 0 days, which was within the 1-day prespecified non-inferiority margin. Results for all efficacy end points in cycles 2−4 was consistent with the results from cycle 1, however a trend towards a lower incidence and a shorter duration of grade 3 or 4 neutropenia and grade 4 neutropenia was observed with F-627 compared with filgrastim. The nadir in the F-627 group was higher than that in the filgrastim group in each cycle. A single fixed dose of F-627 was well tolerated and as safe as multiple daily doses of filgrastim. The most frequently reported adverse events considered to be related to the study drug were bone pain and back pain. No deaths occurred during the study. 5.0% of F-627 patients and 6.7% of filgrastim patients reported serious adverse events (SAEs). The incidence of SAEs was low in both groups and no SAEs were related to study drugs, and were resolved during the study. Conclusions: A single fixed dose of 20 mg of F-627 was as safe and effective as multiple daily doses of filgrastim 5μg/kg/day in reducing chemotherapy-induced neutropenia and its complications in patients who received four cycles of EC therapy. F-627 provides the Chinese oncologists an alternative for simplifying the management of chemotherapy-induced neutropenia. The study was approved by the National Medical Products Administration of China (registration number: 2017L04033), and was registered on www.chinadrugtrials.org.cn (registration number: CTR20170705) and ClinicalTrials.gov (registration number: NCT04174599). Citation Format: William Daley, Zhimin Shao, Qingyuan Zhang, Hongshen Li, Changshen Ye, Shufang Wang, Langxi Zhang, Gaochong Zhang, Jianmin Chen. A randomized, multicenter phase III study of once-per-cycle administration of efbemalenograstim alfa (F-627), a novel long-acting dimeric rhG-CSF, for prophylaxis of chemotherapy-induced neutropenia in patients with breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-16-14.

Abstract P5-18-06: Proactive diarrhea management improved tolerability of pyrotinib in combination with trastuzumab and docetaxel in patients with HER2+ early or locally advanced breast cancer: Exploratory analysis from randomized, double-blind, phase 3 PHEDRA study

Abstract Background: Diarrhea is a common side effect of many anti-cancer treatments, including chemotherapeutic agents, tyrosine kinase inhibitors, and pelvic radiotherapy. PHEDRA was a randomized, double-blind, multicenter, phase 3 study comparing the efficacy and safety of adding pyrotinib (an irreversible pan-ErbB inhibitor) to trastuzumab and docetaxel (pyrotinib arm) vs placebo, trastuzumab, and docetaxel (placebo arm) as neoadjuvant treatment in women with HER2+ early or locally advanced breast cancer (ClinicalTrials.gov: NCT03588091). We conducted this exploratory analysis to evaluate the effectiveness of proactive diarrhea management (PDM) according to the recommendation from independent data monitoring committee. Methods: Between July 23, 2018 and January 8, 2021, 355 patients were enrolled and randomized, of whom 212 and 143 patients were randomized before and after the implementation of PDM strategy. The diarrhea management strategy was strengthened with the early identification and proactive management of diarrhea, including use of loperamide as first choice of antidiarrheal agents and strict application of loperamide recommended dose (4 mg initially and an additional 2 mg following each diarrhea stool, not exceeding 16 mg/day). Primary prophylaxis with loperamide was not allowed. The incidence, severity, onset, and duration of diarrhea were summarized. The data cutoff date was April 30, 2021. Results: Of all 178 patients with pyrotinib arm, there were 43 (40.6%) and 56 (77.8%) patients applied loperamide as the first choice of antidiarrheal agents before and after the PDM implementation, respectively. The incidence of grade 3 diarrhea has decreased from 50.0% before the PDM implementation to 36.1% after the PDM implementation (Table 1). During neoadjuvant treatment period, grade 3 diarrhea mainly occurred during the first cycle of treatment for both treatment arms (C1: 20.8%), showing a sharp decreased trend during the following cycles (C2: 8.7%; C3: 5.4%; C4: 4.5%). Furthermore, among patients with pyrotinib arm, the incidences of grade 3 diarrhea in the first, second cycle and thereafter were lower in patients enrolled after the implementation of PDM than those enrolled before the PDM implementation (C1: 29.2%. vs 44.3%; C2: 10.1% vs 21.8%; C3: 7.2% vs 14.1%; C4: 4.5% vs 11.1%). Among patients with pyrotinib, compared with those enrolled before the PDM implementation, the median duration per diarrhea episode (4 days [IQR, 2-9] vs 2 days [1-5]), median duration per grade 3 diarrhea episode (2 days [IQR, 2-3] vs 2 days [1-2]), and median cumulative duration of grade 3 diarrhea (6 days [IQR, 3-9] vs 2 [2-5] days) were shortened in those enrolled after the PDM implementation. During neoadjuvant treatment period, 31 (17.4%) patients experienced diarrhea leading to pyrotinib dose reduction, and only 1 (0.6%) patient discontinued study treatment due to diarrhea in the pyrotinib arm. Conclusion: Pyrotinib tolerability was improved with PDM, which reduced the incidence and duration of grade 3 diarrhea. Grade 3 diarrhoea occurred mainly during the first cycle of treatment and reduced in the second cycle and thereafter. Diarrhea in the pyrotinib group was characterized by early onset and short duration and was generally manageable. Table 1.Characteristics of treatment-emergent diarrheaBEFORE the implementation of PDMAFTER the implementation of PDMPyrotinib+Trastuzumab+Docetaxel(N=106)Placebo+Trastuzumab+Docetaxel(N=106)Pyrotinib+Trastuzumab+Docetaxel(N=72)Placebo+Trastuzumab+Docetaxel(N=71)Diarrhea incidence, n (%)All grade106 (100.0)57 (53.8)72 (100.0)36 (50.7)Grade 112 (11.3)32 (30.2)7 (9.7)28 (39.4)Grade 241 (38.7)18 (17.0)39 (54.2)6 (8.5)Grade 353 (50.0)7 (6.6)26 (36.1)2 (2.8)Cycle 147 (44.3)4 (3.8)21 (29.2)2 (2.8)Cycle 222 (21.8)2 (1.9)7 (10.1)0Cycle 314 (14.1)05 (7.2)0Cycle 411 (11.1)2 (1.9)3 (4.5)0Grade 4 or 50000Median time to the first onset, days (IQR)All grade4 (2 to 5)7 (4 to 28)3 (2 to 4)6 (5 to 12)Grade 39 (5 to 11)16 (7 to 24)9 (6 to 12)11 (6 to 16)Median duration per diarrhea episode, days (IQR)All grade4 (2 to 9)2 (2 to 4)2 (1 to 5)2 (1 to 3)Grade 32 (2 to 3)2 (2 to 2)2 (1 to 2)1 (1 to 1)Median cumulative duration, days (IQR)Grade 36 (3 to 9)2 (2 to 3)2 (2 to 5)1 (1 to 1)Median time since the first onset to recovery, days (IQR)All grade7 (3 to 12)2 (2 to 4)3 (1 to 10)2 (1 to 4)Note: PDM, proactive diarrhea management; IQR, interquartile range. Citation Format: Benlong Yang, Jiong Wu, Zhenzhen Liu, Hongjian Yang, Jinhai Tang, Kun Wang, Yunjiang Liu, Haibo Wang, Peifen Fu, Shuqun Zhang, Qiang Liu, Zefei Jiang, Shusen Wang, Jian Huang, Chuan Wang, Shu Wang, Yongsheng Wang, Linlin Zhen, Fei Wu, Shulin Liu, Xiang Lin, Jianjun Zou. Proactive diarrhea management improved tolerability of pyrotinib in combination with trastuzumab and docetaxel in patients with HER2+ early or locally advanced breast cancer: Exploratory analysis from randomized, double-blind, phase 3 PHEDRA study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-18-06.

Abstract OT1-12-03: Phase II study of pyrotinib plus nanoparticle albumin-bound (nab)-paclitaxel as adjuvant therapy for lymph node-negative (N0) or micrometastatic (N1mi), HER2-positive early breast cancer (PHAEDRA)

Abstract Background: Nowadays, dual HER2-targeted therapy has become the mainstay for high-risk HER2-positive breast cancer. However, for low-risk resectable HER2-positive breast cancer, the optimal adjuvant regimen remains inconclusive. Mono anti-HER2 antibody combined with single-agent chemotherapy has become a recommended adjuvant regimen for N0, small HER2-positive tumors, but there is scarcity of evidence on tyrosine kinase inhibitors (TKIs) for low-risk HER2-positive breast cancer. The randomized phase III PHOEBE trial has proved the superiority of pyrotinib, a novel irreversible pan-ErbB receptor TKI targeting HER1, HER2, and HER4, over lapatinib when in combination with capecitabine for HER2-positive metastatic breast cancer. We believe pyrotinib can also show promising activity in early breast cancer. Regarding the chemotherapy backbone, nab-paclitaxel exhibits its therapeutic advantage over solvent-based paclitaxel and is widely used in combination with immunotherapy. This study is conducted to evaluate pyrotinib plus nab-paclitaxel in the adjuvant setting for patients with low-risk HER2-positive breast cancer. Moreover, diarrhea is the most common adverse event of pan-HER TKIs. Given the unknown incidence and severity of diarrhea with pyrotinib plus nab-paclitaxel and no consensus on therapeutic or prophylactic strategy of pyrotinib-related diarrhea, a sub-study is conducted to investigate the effect of different prophylactic strategies with loperamide for diarrhea. Trial design: This is a multicenter, open-label, single-arm phase II study. Patients will receive nab-paclitaxel 260 mg/m2 once every 3 weeks for 12 weeks and pyrotinib 240 mg once daily for one year within 90 days after surgery. In the sub-study, 120 patients will be randomly (1:1) assigned to two cohorts. Cohort A will receive loperamide during cycle 1 of adjuvant therapy with pyrotinib plus nab-paclitaxel, at a dose of 4 mg three times a day on days 1-7 and 4 mg twice a day on days 8-21. Cohort B will receive loperamide during cycles 1 and 2 of adjuvant therapy, at a dose of 4 mg three times a day on days 1-7 and 4 mg twice a day on days 8-42. Eligibility criteria: Women aged 18-75 years with histologically confirmed N0/N1mi, HER2-positive invasive breast cancer, primary tumor ≤3 cm, ECOG performance score of 0 or 1, known hormone receptor status, and adequate bone marrow, hepatic, renal, and cardiac function. Aims: The primary endpoint is invasive disease-free survival (iDFS). Secondary endpoints are safety and tolerability. In the sub-study, the primary endpoint is the incidence of grade ≥3 diarrhea, and secondary endpoints include the incidence and severity of diarrhea during the first 2 cycles of adjuvant therapy, the incidence and severity of constipation, the onset time, frequency and duration of grade ≥3 diarrhea, relationship between diarrhea and study drugs, the incidence of dose reduction, discontinuation and hospitalization due to diarrhea, and quality of life questionnaire score using the Functional Assessment of Cancer Therapy-Breast. Statistical methods: The primary efficacy analysis will be performed in the full analysis set, defined as all patients with at least one dose of study drug. iDFS will be estimated using Kaplan-Meier method. Safety will be analyzed in the safety set, defined as all patients with at least one dose of study drug and at least one safety assessment. Accrual: Target accrual is 261 patients at approximately 5 sites in China. The first patient was enrolled on January 14, 2021. Accrual is ongoing. Citation Format: Changjun Wang, Yidong Zhou, Yan Lin, Feng Mao, Jinghong Guan, Xiaohui Zhang, Songjie Shen, Xuejing Wang, Yanna Zhang, Bo Pan, Ying Zhong, Li Peng, Xi Cao, Ru Yao, Xingtong Zhou, Chi Xu, Ying Xu, Qiang Sun. Phase II study of pyrotinib plus nanoparticle albumin-bound (nab)-paclitaxel as adjuvant therapy for lymph node-negative (N0) or micrometastatic (N1mi), HER2-positive early breast cancer (PHAEDRA) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-12-03.

Abstract P5-18-10: Mecapegfilgrastim for primary prophylaxis of neutropenia in 355 HER2+ breast cancer patients treated with neoadjuvant docetaxel in combination with trastuzumab and/or pyrotinib: Exploratory analysis from randomized, double-blind, phase 3 PHEDRA study

Abstract Background: A dose relationship may exist for both antitumor activity and toxicity of docetaxel in breast cancer (BC) patients, while 86% grade 4 neutropenia and 12% febrile neutropenia (FN) were reported when pretreated advanced breast cancer (ABC) patients received 100 mg/m2 docetaxel monotherapy without hematopoietic support. PHEDRA was a randomized, double-blind, multicenter, phase 3 study comparing the efficacy and safety of adding pyrotinib to trastuzumab and docetaxel as neoadjuvant treatment in women with HER2+ early or locally ABC (ClinicalTrials.gov: NCT03588091). We conducted this exploratory analysis to evaluate the effectiveness of mecapegfilgrastim, a long-acting recombinant human granulocyte colony-stimulating factor (rhG-CSF), as primary prophylaxis for neoadjuvant chemotherapy-induced neutropenia in BC patients. Methods: Patients with HER2-positive early or locally ABC were randomly assigned (1:1) to pyrotinib arm receiving 4 neoadjuvant cycles of docetaxel (100 mg/m2 iv d1 q3w), trastuzumab (8 mg/kg iv, cycle 1 d1, then 6 mg/kg d1 q3w), and pyrotinib (400 mg po qd, d1-21, q3w) or placebo arm with placebo, trastuzumab and docetaxel. Per protocol, patients were required to receive a single, 6-mg fixed dose of mecapegfilgrastim on Day 2 of each cycle. Other G-CSF was permitted if mecapegfilgrastim was unavailable at the local center or patients occurred mecapegfilgrastim intolerance. The incidence of neutropenia, FN, time to first neutropenia onset, duration per neutropenia event and cumulative neutropenia duration during neoadjuvant treatment period; and the incidences of grade 3/4 neutropenia, FN and decreased WBC count in Cycle 1 to 4 (C1-4) were presented. The data cutoff date was April 30, 2021. Results: Between July 23, 2018 and January 8, 2021, 355 patients were randomized (pyrotinib arm, n=178; placebo arm, n=177). Among them, 291 (82.0%) patients received a single, 6-mg fixed dose of mecapegfilgrastim in Cycle 1 and 270 (76.1%) patients received mecapegfilgrastim in each of the 4 cycles. Grade 3/4 neutropenia was reported in 33 (18.5%) patients in the pyrotinib arm and 36 (20.3%) patients in the placebo arm. Five (2.8%) patients in the pyrotinib arm and 2 (1.1%) patients in the placebo arm developed FN (5 FN occurred in C1; 2 FN occurred in C2). Median duration of grade 3/4 neutropenia was 3 days in the pyrotinib group and 3 days in the placebo group. Median cumulative duration of grade 3/4 neutropenia was 4 days and 3 days in the pyrotinib group and the placebo group, respectively. Grade 3/4 neutropenia mainly occurred during the first cycle of treatment for both pyrotinib (13.5%) and placebo arm (15.8%), reduced in the second cycle (5.9% vs 4.0%) and thereafter (C3: 1.8% vs 3.4%; C4: 2.4% vs 1.7%). Similar trends were observed for grade 3/4 WBC count decreased in Cycle 1 to 4. No grade 4 infection occurred. Overview of neutropenia, FN and WBC count decreased was summarized in Table 1. Consistent findings were observed in 291 mecapegfilgrastim treated patients. Conclusion: The exploratory analysis demonstrated 6-mg fixed dose of mecapegfilgrastim was effective when administrated as primary prophylaxis for neoadjuvant chemotherapy-induced neutropenia, which could be considered as a new treatment option for its advantage of once-per-cycle dosing and convenient dose management. Table 1.Overview of neutropenia, febrile neutropenia and WBC count decrease during neoadjuvant treatment period.Docetaxel+Trastuzumab+Pyrotinib(N=178)Docetaxel+Trastuzumab+Placebo (N=177)All randomized patients(N=355)Neutropenia, n (%)Any grade57 (32.0)54 (30.5)111 (31.3)Grade 16 (3.4)5 (2.8)11 (3.1)Grade 218 (10.1)13 (7.3)31 (8.7)Grade 315 (8.4)20 (11.3)35 (9.9)Grade 418 (10.1)16 (9.0)34 (9.6)Median time to first onset (IQR), days7 (6-63)6 (6-49)7 (6-53)Median duration per grade 3 or higher neutropenia, days (range)3 (1-16)3 (2-12)3 (1-16)Median cumulative duration of grade 3 or higher neutropenia, days (range)4 (2-16)3 (2-14)3 (2-16)FN, n (%)5 (2.8)2 (1.1)7 (2.0)Grade 3 or higher neutropenia, n (%) *Cycle 124 (13.5)28 (15.8)52 (14.6)Cycle 210 (5.9)7 (4.0)17 (4.9)Cycle 33 (1.8)6 (3.4)9 (2.6)Cycle 44 (2.4)3 (1.7)7 (2.1)Grade 3 or higher FN, n (%) *Cycle 12 (1.1)2 (1.1)4 (1.1)Cycle 22 (1.2)02 (0.6)Cycle 3000Cycle 4000Grade 3 or higher WBC count decreased, n (%) *Cycle 120 (11.2)20 (11.3)40 (11.3)Cycle 28 (4.7)2 (1.1)10 (2.9)Cycle 32 (1.2)1 (0.6)3 (0.9)Cycle 44 (2.4)2 (1.1)6 (1.8)Note: IQR, interquartile range; FN, febrile neutropenia; WBC, white blood cell.*The denominator indicates number of patients with mecapegfilgrastim for prophylaxis use in this cycle. Citation Format: Min He, Benlong Yang, Jiong Wu, Zhenzhen Liu, Hongjian Yang, Jinhai Tang, Kun Wang, Yunjiang Liu, Haibo Wang, Peifen Fu, Shuqun Zhang, Qiang Liu, Zefei Jiang, Shusen Wang, Jian Huang, Chuan Wang, Shu Wang, Yongsheng Wang, Linlin Zhen, Xiaoyu Zhu, Shulin Liu, Ping Yan, Jianjun Zou. Mecapegfilgrastim for primary prophylaxis of neutropenia in 355 HER2+ breast cancer patients treated with neoadjuvant docetaxel in combination with trastuzumab and/or pyrotinib: Exploratory analysis from randomized, double-blind, phase 3 PHEDRA study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-18-10.

Abstract P5-18-02: Final findings from the CONTROL trial of diarrheal prophylaxis or neratinib dose escalation on neratinib-associated diarrhea and tolerability in patients with HER2+ early-stage breast cancer

Abstract Background: Neratinib (NERLYNX®), an irreversible pan-HER tyrosine kinase inhibitor, is approved for the extended adjuvant treatment of early-stage HER2+ breast cancer following adjuvant trastuzumab-based therapy and in combination with capecitabine for HER2+ metastatic breast cancer. Diarrhea is the most frequently reported on-target side effect associated with neratinib; in the ExteNET adjuvant trial, where no mandatory anti-diarrheal prophylaxis was used, 39.8% of patients reported grade 3 diarrhea and 16.8% of patients discontinued neratinib due to diarrhea. The CONTROL trial (Clinicaltrials.gov: NCT02400476) was designed to investigate pre-emptive antidiarrheal prophylaxis (loperamide alone or in combination with budesonide or colestipol) or neratinib dose escalation (DE) for the prevention of neratinib-associated diarrhea. Data for the loperamide, budesonide and colestipol cohorts have been reported previously [Barcenas et al. Ann Oncol 2020]. The final findings for the two DE regimen cohorts are reported here. Methods: CONTROL is an international, multi-cohort, open-label, phase 2 study. Patients ≥18 years of age with stage I-IIIc HER2+ breast cancer received oral neratinib (240 mg/day for 1 year) after trastuzumab-based adjuvant therapy. Patients were enrolled sequentially into separate cohorts investigating: 1) mandatory loperamide prophylaxis; 2) budesonide + loperamide; 3) colestipol + loperamide; 4) colestipol + loperamide PRN; 5) neratinib DE + loperamide PRN (two cohorts). DE1 schedule: neratinib 120 mg/day for week 1, 160 mg/day for week 2, then 240 mg/day from week 3 onwards to complete 12 months of treatment. DE2 schedule: neratinib 160 mg/day for weeks 1&amp;2, 200 mg/day for weeks 3&amp;4, then 240 mg/day from week 5 onwards up to 12 months. Both DE cohorts included loperamide PRN. Adverse events were graded according to NCI-CTCAE v4.0. Primary endpoint: incidence of grade ≥3 diarrhea. Results: A total of 563 patients were enrolled in CONTROL. All preventive strategies reduced the incidence of grade 3 diarrhea compared with that seen in ExteNET (historical control: 39.8%). Median cumulative duration of grade 3 diarrhea ranged from 2-3.5 days across the CONTROL study cohorts for the entire 12-month treatment period (compared with 5.0 days for ExteNET). The proportion of patients discontinuing neratinib because of diarrhea was decreased in all cohorts compared with ExteNET (16.8%), except for loperamide alone. Adoption of neratinib DE, particularly the 2-week DE schedule (DE1), most markedly reduced the incidence, severity, and duration of neratinib-associated diarrhea in CONTROL compared with ExteNET (see Table). Conclusions: Neratinib DE + loperamide PRN during the first 2 weeks of treatment (DE1 cohort) was associated with the lowest rates of grade 3 diarrhea (13.3%) and diarrhea-related discontinuations (3.3%) compared with all other anti-diarrheal strategies investigated in CONTROL. These final findings from the study show improved tolerability of neratinib with all diarrhea prophylaxis strategies and suggest that neratinib DE1 with loperamide PRN allows patients to stay on treatment longer and receive the full benefit of neratinib therapy. Table. Patient disposition and diarrhea characteristics: ExteNET vs CONTROL DE cohortsExteNET(n=1408)CONTROL DE1 (n=60)CONTROL DE2 (n=62)Patients completing 1 year of neratinib treatment, %617874Median duration of treatment, months (range)11.6 (2.5–11.9)12.0 (0.2–12.4)11.9 (0.3–14.5)Diarrhea, %Grade 339.813.327.4Grade 4&amp;lt;100Median cumulative duration of grade 3 diarrhea,a days52.52Discontinuations due to diarrhea, %16.83.36.5Dose reductions due to diarrhea, %26311Dose holds due to diarrhea, %341213aNo grade 4 diarrhea was reported in CONTROL. Citation Format: Arlene Chan, Manuel Ruiz-Borrego, Gavin Marx, Adam Brufsky, Jo Chien, Michael Thirlwell, Maureen Trudeau, Ron Bose, José A García-Sáenz, Daniel Egle, Barbara Pistilli, Johanna Wassermann, Kerry A Cheong, Christian F Singer, Daniel Hunt, Navid Foruzan, Leanne McCulloch, Carlos H Barcenas. Final findings from the CONTROL trial of diarrheal prophylaxis or neratinib dose escalation on neratinib-associated diarrhea and tolerability in patients with HER2+ early-stage breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-18-02.

Effect of early granulocyte-colony-stimulating factor administration in the prevention of febrile neutropenia and impact on toxicity and efficacy of anti-CD19 CAR-T in patients with relapsed/refractory B-cell lymphoma

Chimeric Antigen Receptor T cells (CAR-T) are an outbreaking treatment option for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are the most common specific toxicities, while severe neutropenia and infections are often observed as well. From March 2020, early G-CSF prophylaxis at day (D) two post-infusion was systematically proposed. We then compared patients treated before that date who did not receive G-CSF or who received late (after D5) G-CSF as control group. Patients administered with early G-CSF had similar duration of grade 4 neutropenia but significantly decreased incidence of febrile neutropenia (58% versus 81%, p = 0.018). Similar rate of toxicities was observed, including overall and grade 3-4 CRS (p = 0.93 and p = 0.28, respectively), and overall and grade 3-4 ICANS (p = 0.62 and p = 0.88, respectively). We observed no difference in the quality of CAR T-cells expansion (p = 0.79, %Cmax), nor in response rate (best ORR, 57.6% vs 61.8%, p = 0.93), nor survival even in a group of patients adjusted by a propensity score. In conclusion, early G-CSF administration was safe and effective in reducing febrile neutropenia without impact on toxicities nor on anti-lymphoma activity of CAR-T.

The Role of Prophylactic Application of Granulocyte Colony Stimulating Factor in Adjuvant Chemotherapy for Epithelial Ovarian Cancer

The goal of this study was to investigate the relative merits of granulocyte colony stimulating factor (G-CSF) prophylaxis for patients with epithelial ovarian cancer (EOC). The Institutional Review Board of the Women's Hospital, Zhejiang University School of Medicine has approved this study (No. IRB-20200132-R) with a waiver of informed consent. Patients with EOC who received the combination of a platinum drug and paclitaxel (TP) chemotherapy regimens in the hospital from January 1, 2016, to November 30, 2020, were included in this retrospective cohort study. To assess clinical effectiveness, patients were categorized into groups who received either long-acting G-CSF or short-acting G-CSF prophylaxis with and without prophylaxis. The incidence of neutropenia and adverse events were compared between groups. All results of chemotherapy were pooled for analysis. Of the identified cases, 128 patients were evaluated. Long-acting G-CSF and short-acting G-CSF were applied in 51 and 41 patients, respectively. The absolute neutrophil count at the nadir was significantly lower in patients with G-CSF prophylaxis than those without G-CSF (p = 0.001). The duration of ANC levels < 2.0 x 109/L in cycles using short-acting G-CSF was longer than that in those receiving long-acting G-CSF (p = 0.045). There were no serious adverse events observed in patients with G-CSF. No significant differences in the incidence of febrile neutropenia (FN) and duration of grade 2 - 4 neutropenia were observed between groups receiving G-CSF prophylaxis and those without. Primary prophylaxis with G-CSF in chemotherapy for epithelial ovarian cancer appears to be of low value in terms of its relationship to the incidence of FN and prognosis.

Efficacy and Safety of Filgrastim and Its Biosimilars to Prevent Febrile Neutropenia in Cancer Patients: A Prospective Study and Meta-Analysis.

Background: The aim of this review and meta-analysis was to identify, assess, meta-analyze and summarize the comparative effectiveness and safety of filgrastim in head-to-head trials with placebo/no treatment, pegfilgrastim (and biosimilar filgrastim to update advances in the field. Methods: The preferred reporting items for systematic reviews and meta-analyses PRISMA statement were applied, and a random-effect model was used. Primary endpoints were the rate and duration of grade 3 or 4 neutropenia, and an incidence rate of febrile neutropenia. Secondary endpoints were time to absolute neutrophil count ANC recovery, depth of ANC nadir (lowest ANC), neutropenia-related hospitalization and other neutropenia-related complications. For filgrastim versus biosimilar filgrastim comparison, the primary efficacy endpoint was the mean difference in duration of severe neutropenia DSN. Results: A total of 56 studies were considered that included data from 13,058 cancer patients. The risk of febrile neutropenia in filgrastim versus placebo/no treatment was not statistically different. The risk ratio for febrile neutropenia was 0.58, a 42% reduction in favor of filgrastim. The most reported adverse event with FIL was bone pain. For pegfilgrastim versus filgrastim, no statistically significant difference was noted. The risk ratio was 0.90 (95% CI 0.67 to 1.12). The overall difference in duration of severe neutropenia between filgrastim and biosimilar filgrastim was not statistically significant. The risk ratio was 1.03 (95% CI 0.93 to 1.13). Conclusions: Filgrastim was effective and safe in reducing febrile neutropenia and related complications, compared to placebo/no treatment. No notable differences were found between pegfilgrastim and filgrastim in terms of efficacy and safety. However, a similar efficacy profile was observed with FIL and its biosimilars.