Granulocyte Colony-stimulating Factor Support Research Articles

Real-world status of treatment for lymphoid neoplasms developed during the course of myeloproliferative neoplasms in Japan

ABSTRACT Objectives: Patients with myeloproliferative neoplasms (MPNs) are at higher risk of developing secondary malignancies. In this study, we focused on patients with MPNs that complicated lymphoid neoplasms. To analyze the real-world status of lymphoid neoplasm treatment in patients with pre-existing MPNs in Japan, we conducted a multicenter retrospective study. Methods: Questionnaires were sent to collect the data on patients who were first diagnosed with either polycythemia vera, essential thrombocythemia or myelofibrosis and who later were complicated with lymphoid neoplasms defined as malignant lymphoma, multiple myeloma, or chronic lymphocytic leukemia/small cell lymphoma. Results: Twenty-four patients with MPNs complicated by lymphoid neoplasms were enrolled (polycythemia vera, n = 8; essential thrombocythemia, n = 14; and primary myelofibrosis, n = 2). Among these, diffuse large B-cell lymphoma (DLBCL) was the most frequently observed (n = 13, 54.1%). Twelve (92.3%) of the patients with DLBCL received conventional chemotherapy. Among these 12 patients, regarding cytoreductive therapy for MPNs, 8 patients stopped treatment, one continued treatment, and two received a reduced dose. Consequently, most patients were able to receive conventional chemotherapy for DLBCL with a slightly higher dose of granulocyte colony-stimulating factor support than usual without worse outcomes. All 3 patients with multiple myeloma received a standard dose of chemotherapy. Conclusion: Our data indicate that if aggressive lymphoid neoplasms develop during the course of treatment in patients with MPNs, it is acceptable to prioritize chemotherapy for lymphoma.

Granulocyte Transfusions in Neutropenic Infections: Insights From a Single-Center Study.

Introduction Despite the development of modern antibiotic and antifungal therapies, neutropenic infections remain life-threatening. Granulocyte transfusion (GTX) is a less frequently used treatment modality in patients with refractory neutropenic infections. The role of donor GTX remains controversial, partly because of the lack of proper clinical trials. This study aimed to contribute to the literature by evaluating the efficacy and side effects of granulocyte transfusions in our center. Methods Eight febrile neutropenic patients with confirmed infections received granulocyte transfusions from ABO-compatible related and unrelated donors. Donors received filgrastim and dexamethasone stimulation, and granulocyte suspensions were irradiated and administered within six hours. Monitoring, antibiotic therapy, and granulocyte colony-stimulating factor (G-CSF) support were maintained. Results Our study observed a 28-day survival rate of 25%, which was lower than that reported in previous literature. The median number of transfusions was 3, with an average eight-day duration post-infection diagnosis, and no side effects were observed. Conclusion While some patients benefited from GTX, overall survival rates remained modest, indicating the need for further research. Prospective, well-powered randomized controlled trials are essential to address patient selection, dosing, and duration to determine the clinical utility of GTX. This study underscores the complexity of GTX in real-world clinical practice and provides insight into the ongoing debate regarding its efficacy in treating severe neutropenic infections.

Drug-induced pneumonitis risk in diffuse large B-cell/follicular lymphoma patients treated with R-CHOP-like regimen is associated with the use of granulocyte colony-stimulating growth factors.

Rituximab-based combinations are the standard of care in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). Despite being on market for over 20 years, some of the adverse effects associated with the use of rituximab are not well known. Drug-induced interstitial pneumonitis (DIP) is a potentially fatal complication of the treatment. Granulocyte colony-stimulating factors (G-CSF) are supportive agents commonly used to prevent neutropenic infections. G-CSF are reported to have pulmonary toxicity, but the risk of DIP is greater when used in combination with other potentially pulmotoxic agents. In this retrospective study, we reported the G-CSF use and risk of DIP in 234 DLBCL patients and 87 FL patients receiving R-CHOP-type immunochemotherapy. In 72% of patients, the treatment included a G-CSF support. The overall incidence of treatment-induced pneumonitis was 6.9% in this patient group. All the DIP cases (n = 16) were among patients receiving G-CSF support (p = 0.03). Older age (over 60 years) and higher disease stage (Ann Arbor 3-4) also increased the risk of DIP. These findings suggest that the use of G-CSF increases the risk of DIP, when used in combination with rituximab-containing regimen.

The Double Antibody Drug Conjugate (DAD) phase I trial: sacituzumab govitecan plus enfortumab vedotin for metastatic urothelial carcinoma

The antibody-drug conjugates sacituzumab govitecan (SG) and enfortumab vedotin (EV) are standard monotherapies for metastatic urothelial carcinoma (mUC). Given the different targets and payloads, we evaluated the safety and efficacy of SG+ EV in a phase I trial in mUC (NCT04724018). Patients with mUC and Eastern Cooperative Oncology Group performance status ≤1 who had progressed on platinum and/or immunotherapy were enrolled. SG+ EV were administered on days 1+ 8 of a 21-day cycle until progression or unacceptable toxicity. Primary endpoint was the incidence of dose-limiting toxicities during cycle 1. The number of patients treated at each of four pre-specified dose levels (DLs) and the maximum tolerated doses in combination (MTD) were determined using a Bayesian Optimal Interval design. Objective response, progression-free survival, and overall survival were secondary endpoints. Between May 2021 and April 2023, 24 patients were enrolled; 1 patient never started therapy and was excluded from the analysis. Median age was 70 years (range 41-88 years); 11 patients received ≥3 lines of therapy. Seventy-eight percent (18/23) of patients experienced grade ≥3 adverse event (AE) regardless of attribution at any DL, with one grade 5 AE (pneumonitis possibly related to EV). The recommended phase II doses are SG 8 mg/kg with EV 1.25 mg/kg with granulocyte colony-stimulating factor support; MTDs are SG 10 mg/kg with EV 1.25 mg/kg. The objective response rate was 70% (16/23, 95% confidence interval 47% to 87%) with three complete responses; three patients had progressive disease as best response. With a median follow-up of 14 months, 9/23 patients have ongoing response including 6 responses lasting over 12 months. The combination of SG+ EV was assessed at different DLs and a safe dose for phase II was identified. The combination had encouraging activity in patients with mUC with high response rates, including clinically significant complete responses. Additional study of this combination is warranted.

Neutropenia - when is GCSF support indicated?

Many systemic treatments used in genitourinary oncology negatively affect haematopoiesis, thus leading to neutropenia. Neutropenic patients are vulnerable to bacterial, and other infections. Often fever is the only symptom in these patients. Neutropenic fever is a major threat for these patients, as it may lead to life-threatening therapy complications that significantly impair the patient's quality of life, Moreover, it may also worsen the prognosis due to therapy delays or necessary dose modifications. Granulocyte colony stimulating factors (GCSF), which can improve neutrophil granulocyte formation, are used both for supportive treatment in febrile neutropenia and for its prophylaxis. The correct indication for such GCSF support depends on the general risk of febrile neutropenia of the therapy used, as well as on individual patient factors and the treatment intent (palliative vs. curative). Based on the current recommendations both of the German and international guidelines, this article aims to provide an up-to-date and practice-oriented overview of the use of GCSF in uro-oncology.

TROPHY-U-01 Cohort 4 (C4): Sacituzumab govitecan (SG) in combination with cisplatin (cis) as first-line (1L) therapy, followed by maintenance avelumab plus (+) SG or zimberelimab (zim) + SG in patients (pts) with treatment (Tx)-naïve metastatic urothelial cancer (mUC).

TPS4611 Background: SG is a Trop-2–directed antibody-drug conjugate. In the TROPHY-U-01 study, SG monotherapy showed a 27% objective response rate (ORR) and 10.9 months median overall survival (OS) with an overall manageable safety profile in pts with mUC who received platinum (PT)-containing chemotherapy and a checkpoint inhibitor (CPI), resulting in accelerated FDA approval in this population. PT-based chemotherapy followed by avelumab maintenance is standard 1L therapy in pts with Tx-naïve mUC. Zim (anti–PD-1) is a CPI under clinical investigation for antitumor activity. C4 of TROPHY-U-01 will evaluate safety, tolerability, and clinical activity of SG+cis followed by maintenance avelumab+SG or zim+SG in cis-eligible pts with Tx-naïve mUC. Methods: TROPHY-U-01 (NCT03547973) is a multicohort, open-label, global, phase 2 study. C4 will evaluate 1L SG in combination with cis in pts with cis-eligible mUC or unresectable locally advanced disease. Eligibility requirements include ECOG PS 0-1; no prior anticancer monoclonal antibody within 4 weeks of study drug initiation; no history of active interstitial lung disease or noninfectious pneumonitis; adequate hematologic and hepatic function. Pts will be treated with cis at 70 mg/m2 on D1 of 21-D cycles (if creatinine clearance [CrCl] ≥60 mL/min) or at an optional split dose of 35 mg/m2 on D1 and D8 of 21-D cycles (if CrCl 50-59 mL/min), followed by SG (5, 7.5, or 10 mg/kg, based on 10-pt safety lead-in of a 3+3 design) on D1 and D8 of 21-D cycles. Granulocyte colony-stimulating factor support is not allowed in the safety lead-in but was permitted during escalation and expansion. SG+cis will continue for up to 6 cycles, followed by maintenance (4 to 8 wk after last induction dose of SG+cis and when RP2D is determined) in the absence of progression. Dose escalation maintenance consists of avelumab 800 mg q2w, then SG 10 mg/kg on D1 and D8 of 21-D cycles. Dose expansion maintenance consists of zim 360 mg (D1 of a 21-D cycle) and SG 10 mg/kg (D1 and D8 of 21-D cycles) and will begin once safety lead-in of 6-8 pts receiving zim+SG of a 21-D cycle in Cohort 5 is deemed safe and completed. Pts will continue Tx until progression, unacceptable toxicity, or loss of clinical benefit. Primary endpoint is ORR per RECIST v1.1 by central review. Secondary endpoints include progression-free survival, duration of response, and clinical benefit rate per central review and investigator assessment. OS and safety will also be evaluated. All statistical analyses will be performed using a two-sided hypothesis test approach at the overall 5% level of significance. Time to event endpoints will be assessed via the Kaplan-Meier method. Enrollment is ongoing; up to 57 pts expected across ~120 sites in North America and Europe. Clinical trial information: NCT03547973 .

Randomized Phase III Trial of Pemetrexed Versus Docetaxel in Patients With Non-Small-Cell Lung Cancer Previously Treated With Chemotherapy.

To compare the efficacy and toxicity of pemetrexed versus docetaxel in patients with advanced non-small-cell lung cancer (NSCLC) previously treated with chemotherapy. Eligible patients had a performance status 0 to 2, previous treatment with one prior chemotherapy regimen for advanced NSCLC, and adequate organ function. Patients received pemetrexed 500 mg/m2 intravenously (IV) day 1 with vitamin B12, folic acid, and dexamethasone or docetaxel 75 mg/m2 IV day 1 with dexamethasone every 21 days. The primary end point was overall survival. Five hundred seventy-one patients were randomly assigned. Overall response rates were 9.1% and 8.8% (analysis of variance P = .105) for pemetrexed and docetaxel, respectively. Median progression-free survival was 2.9 months for each arm, and median survival time was 8.3 versus 7.9 months (P = not significant) for pemetrexed and docetaxel, respectively. The 1-year survival rate for each arm was 29.7%. Patients receiving docetaxel were more likely to have grade 3 or 4 neutropenia (40.2% v 5.3%; P < .001), febrile neutropenia (12.7% v 1.9%; P < .001), neutropenia with infections (3.3% v 0.0%; P = .004), hospitalizations for neutropenic fever (13.4% v 1.5%; P < .001), hospitalizations due to other drug related adverse events (10.5% v 6.4%; P = .092), use of granulocyte colony-stimulating factor support (19.2% v 2.6%, P < .001) and all grade alopecia (37.7% v 6.4%; P < .001) compared with patients receiving pemetrexed. Treatment with pemetrexed resulted in clinically equivalent efficacy outcomes, but with significantly fewer side effects compared with docetaxel in the second-line treatment of patients with advanced NSCLC and should be considered a standard treatment option for second-line NSCLC when available.

Safety, tolerability, and pharmacokinetics of Aurora kinase B inhibitor AZD2811: a phase 1 dose-finding study in patients with advanced solid tumours

BackgroundAZD2811 is a potent, selective Aurora kinase B inhibitor. We report the dose-escalation phase of a first-in-human study assessing nanoparticle-encapsulated AZD2811 in advanced solid tumours.MethodsAZD2811 was administered in 12 dose-escalation cohorts (2-h intravenous infusion; 15‒600 mg; 21-/28-day cycles) with granulocyte colony-stimulating factor (G-CSF) at higher doses. The primary objective was determining safety and maximum tolerated/recommended phase 2 dose (RP2D).ResultsFifty-one patients received AZD2811. Drug exposure was sustained for several days post-dose. The most common AZD2811-related adverse events (AEs) were fatigue (27.3%) at ≤200 mg/cycle and neutropenia (37.9%) at ≥400 mg/cycle. Five patients had dose-limiting toxicities: grade (G)4 decreased neutrophil count (n = 1, 200 mg; Days 1, 4; 28-day cycle); G4 decreased neutrophil count and G3 stomatitis (n = 1 each, both 400 mg; Day 1; 21-day cycle); G3 febrile neutropenia and G3 fatigue (n = 1 each, both 600 mg; Day 1; 21-day cycle +G-CSF). RP2D was 500 mg; Day 1; 21-day cycle with G-CSF on Day 8. Neutropenia/neutrophil count decrease were on-target AEs. Best overall responses were partial response (n = 1, 2.0%) and stable disease (n = 23, 45.1%).ConclusionsAt RP2D, AZD2811 was tolerable with G-CSF support. Neutropenia was a pharmacodynamic biomarker.Clinical trial registrationNCT02579226.

Durable Engraftment and Excellent Overall Survival After CD34-Selected Peripheral Blood Stem Cell Boost in Pediatric Patients With Poor Graft Function Following Allogeneic Stem Cell Transplantation

Poor graft function (PGF) is a life-threatening complication after allogeneic stem cell transplantation (alloSCT). Historically, outcomes of patients with PGF have been very poor, and there are no standardized approaches to treatment. Furthermore, few outcomes after CD34-selected stem cell boost (CD34+SCB) for PGF in pediatric alloSCT recipients have been reported. Here we report on a single center experience with CD34+SCB for PGF after alloSCT in patients treated on the Pediatric Transplant and Cellular Therapy Service at MSK Kids, Memorial Sloan Kettering Cancer Center. A retrospective analysis of patients transplanted for malignant and nonmalignant disorders who received a CD34+SCB between 2008 to 2020 for treatment of PGF defined as the need for granulocyte colony-stimulating factor (G-CSF) and/or packed red blood cell or platelet transfusion support with bone marrow donor chimerism ≥85%. Peripheral blood stem cells from the original donor were the source for CD34+SCB. Durable complete recovery (durable CR) was defined as recovery of peripheral blood counts without recurrent need for G-CSF or transfusion support. The main outcomes of interest were recovery of hematopoiesis and overall survival. Development of graft versus host disease (GVHD) was an additional outcome of interest. Fourteen patients with PGF received a boost. Six patients had no known infection, while 8 patients had PGF associated with an infection. The probability of CR at 60 days was 79% (95% confidence interval [CI], 57%-100%). The overall survival at both 2 and 5 years was 78% (95% CI, 56%-100%). One patient developed GVHD, which was fatal. No other CD34+SCB-related toxicities were observed. While including patients with PGF as recently defined by the American Society for Transplantation and Cellular Therapy, as well as PGF in patients with concomitant infections, we demonstrate that CD34+SCB is safe and can provide for durable trilineage hematopoietic recovery and long-term survival in pediatric patients after alloSCT.

T087: Brentuximab vedotin (Bv) Demonstrates Superior Event-Free Survival in Pediatric High-Risk Hodgkin Lymphoma

Figure 1: Event Free Survival (EFS) by study arm: The hazard for events of progression, death or second malignant neoplasm (SMN) was 0.41 (95% CI 0.25, 0.67), in favor of Bv-AVE-PC. No. of first events: Bv-AVE-PC, n=23; ABVE-PC, n=51 Background: The use of the anti-CD30 antibody drug conjugate, Brentuximab vedotin (Bv) has not been established as first line therapy for Hodgkin lymphoma (HL) in children or adolescents. We compared the efficacy and safety of Bv with doxorubicin, vincristine, etoposide, prednisone and cyclophosphamide (Bv-AVE-PC) to the standard pediatric dose intensive regimen ABVE-PC, inclusive of bleomycin. Methods: This multicenter randomized, open-label phase 3 study enrolled patients 2–21 years (yrs) with previously untreated HL, stages IIB + bulk, IIIB, IVA, IVB (NCT02166463). Patients were randomized to 5 cycles of either ABVE-PC or Bv-AVE-PC given every 21 days with granulocyte colony-stimulating factor support. Centrally reviewed PET-CT after 2 cycles (iPET) defined slow responding lesions (SRL) by 5-point score (PS) >3. Involved site radiotherapy (ISRT) was given to bulky mediastinal adenopathy and SRL. The primary objective was EFS. Results: 600 participants were enrolled across 153 Children’s Oncology Group institutions from March 2015 to August 2019; 587 were eligible. Median age was 15.6 yrs (range 3.4–22). Patient and disease characteristics were balanced across study arms. Stage distribution: 20.6% IIB-bulk; 19.3% IIIB; 28.5% IVA; 31.7% IVB. At a median follow-up of 42.1 mos (0.1–80.9), 3-year EFS (95%CI) by intent-to-treat analyses was 92.1% (88.4, 94.7) with Bv-AVE-PC vs. 82.5% (77.4, 86.5) with ABVE-PC (HR 0.41 (0.25, 0.67), p=0.0002). Cumulative incidence of relapse was 7% with Bv-AVE-PC and 17% following ABVE-PC. iPET+ rates were comparable (ABVE-PC 19% vs. Bv-AVE-PC 18%, p=0.8), but iPET+ patients who received Bv-AVE-PC had a significantly higher 3yr-EFS (90.7%) compared to ABVE-PC (68.3%) (HR 0.28 [0.10, 0.76]). As-treated ISRT receipt did not differ (ABVE-PC 55.7% vs. Bv-AVE-PC 52.7%, p=0.69). No difference was noted in grade 3/4 adverse events; myelosuppression, reflected in a 32% incidence of > grade 3 febrile neutropenia, did not differ by arm (p=0.67). Only 19% of patients experienced > grade 2 neuropathy by the Balis pediatric neuropathy scale, with no difference between arms (p=0.86). Conclusion: Bv with AVE-PC in a dose intensive regimen has superior efficacy to ABVE-PC for pediatric patients with high-risk HL. A 9.6% improvement in EFS was achieved with no increase in toxicity and with fewer patients receiving RT compared to prior pediatric trials for high-risk HL.

Dose modification rules and availability of growth factor support: A cross-sectional study of head-to-head cancer trials used for US FDA approval from 2009 to 2021

Aim of the studyDifferent drug modification rules or growth factor support guidance may affect the results in oncology randomised controlled trials. We aimed to estimate the prevalence of unequal rules for dose modification rules or the use of myeloid growth factors in head-to-head registration Food and Drug Administration trials. MethodsThis cross-sectional analysis included all head-to-head registration randomised controlled trials leading to a US Food and Drug Administration approval between 2009 and 2021. Trials examined anti-cancer drugs in the advanced or metastatic setting where a comparison could be made between arms regarding either dose modification rules or myeloid growth factors recommendations. Sixty-two registration trials met inclusion criteria. Information abstracted for each trial included tumour type, setting, phase, and type of sponsor. We assessed, according to pre-specified rules, imbalance in drug modification rules, myeloid growth factors recommendations or both. ResultsWe find 40 of 62 (65%) selected trials have unequal rules for dose medication, granulocyte colony-stimulating factor (G-CSF) use or both. Six trials (10%) had rules favouring the control arm, while 55% of selected trials (34/62) favoured the experimental arm. Among these, 50% (17/34) had unequal drug modification rules, 41% (14/34) had unequal G-CSF rules and 9% contained both (3/34). ConclusionWe find that 55% of trials testing anti-cancer drugs against each other used protocol rules that favoured the experimental arm. This leaves open the question of whether new molecules are truly superior to older molecules or if instead different outcomes are due to more aggressive dosing or growth factor support. Trials should utilise equal rules for dose medication and G-CSF support.

The effect of G-CSF used after allogeneic hematopoietic stem cell transplantation on engraftment times and platelet suspension replacement numbers

BackgroundWith the use of granulocyte colony stimulating factor (G-CSF) after allogeneic hematopoietic stem cell transplantation (HSCT), the duration of neutrophil engraftment and hospitalization were shortened. However, there is no consensus on the effect of G-CSF on platelet engraftment time. The primary aim of our study is to determine the effect of G-CSF use on platelet engraftment time after HSCT. Secondary purposes are to determine the number of platelet suspension, number of erythrocyte suspension and incidence of acute graft versus disease after HSCT. Material and methodsPatients who had allogeneic stem cell transplantation at our center between 01.01.2011 and 01.01.2022 were retrospectively analyzed. Patients were divided into 2 groups as those who received and did not receive G-CSF after transplantation. ResultsA total of 64 patients were included. While 32 patients were given post-HSCT G-CSF support, the other 32 patients were not given. Neutrophil engraftment time and length of hospital stay were shorter in the group receiving G-CSF (p < 0.05). Platelet engraftment time was shorter in the group that did not receive G-CSF (p < 0.05). The incidence of acute GVHD of the patients in group 1 tended to be higher than the patients in group 2 (40.6 % vs 15.6 %, p = 0.052). Post-HSCT platelet suspension was less in the group that did not receive G-CSF, but this difference was not statistically significant (p = 0.173). ConclusionWhile the positive effect of post HSCT G-CSF use on duration of neutrophil engraftment and hospitalization is evident, its effects on platelet engraftment need to be investigated.

Efficacy and safety of lurbinectedin as second-line therapy in Chinese patients with small cell lung cancer: Preliminary results of a phase 1 study.

8580 Background: Lurbinectedin (Zepzelca), a selective inhibitor of oncogenic transcription, was granted accelerated approval on June 15, 2020, by the FDA for adult patients (pts) with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy, based on the results from SCLC cohort in PM1183-B-005-14 trial. Here we report the preliminary results of a phase 1 study (LY01017/CT-CHN-101) which aimed to evaluate the safety, tolerability, pharmacokinetics (PK) characters and preliminary efficacy of lurbinectedin in Chinese pts with advanced solid tumors including relapsed SCLC. Methods: In the dose-escalation stage, 10 pts with advanced solid tumors received lurbinectedin (2.5-3.2 mg/m2) as 1-hour i.v. infusion q3wk in a classical 3+3 design, without primary granulocyte colony-stimulating factor (G-CSF) prophylaxis during Cycle 1. In the dose-expansion stage, 22 pts with relapsed SCLC after first-line platinum-based chemotherapy were treated with single-agent lurbinectedin at the recommended dose (RD) defined in the dose-escalation stage, with or without G-CSF support. Endpoints included safety (CTCAE v5.0), tolerability, PK, and confirmed objective response rate (ORR; RECIST v1.1). The data cutoff was January 13, 2022. Results: No dose-limiting toxicity (DLT) was observed in the first 3 pts treated at 2.5 mg/m2, while 1/7 pts treated at 3.2 mg/m2 had DLT (grade 4 neutropenia lasting ≥3 days) in Cycle 1, thus 3.2mg/m2 without G-CSF prophylaxis was defined as the RD of the dose-expansion stage. At cutoff, 22 SCLC pts treated in the dose-expansion stage were still ongoing, with 21 and 22 pts evaluable for efficacy and safety, respectively. The investigator-assessed confirmed ORR was 42.9% (9/21, partial responses). The duration of response (DOR) is pending. The most common grade 3-4 treatment-related adverse events (TRAEs) were neutropenia (16 [72.7%]), leukopenia (13 [59.1%]), thrombocytopenia (9 [40.9%]), increased ALT (4 [18.2%]), anemia (3 [13.6%]), and increased AST (2 [9.1%]). Serious treatment-related adverse events, including neutropenia (5 [22.7%]), leukopenia (4 [18.2%]), thrombocytopenia (3 [13.6%]), increased ALT (2 [9.1%]), increased AST (2 [9.1%]), vomiting (2 [9.1%]), febrile neutropenia (1 [4.5%]), and edema (1 [4.5%]), were reported in 10 pts (45.5%). No cases of infection, sepsis and Hy’s law were reported. A total of 40.9% (9/22) had dose delay and 31.8% (7/22) had dose reduction, mainly attributed to hematological toxicities. No discontinuations occurred due to AEs. No treatment-related deaths were reported. Conclusions: Lurbinectedin at the RD (3.2mg/m2) shows promising efficacy as second-line therapy in Chinese pts with SCLC, with acceptable tolerability and manageable safety profile. Clinical trial information: NCT04638491.

Brentuximab vedotin and association with event-free survival (EFS) in children with newly diagnosed high-risk Hodgkin lymphoma (HL): A report from the Children's Oncology Group phase 3 study AHOD1331 (NCT 02166463).

7504 Background: The anti-CD30 antibody drug conjugate, Brentuximab vedotin (Bv) is approved for adults with advanced stage HL but its use has not been established in children or adolescents. We compared the efficacy and safety of Bv with doxorubicin, vincristine, etoposide, prednisone and cyclophosphamide (Bv-AVE-PC) to the standard pediatric dose intensive regimen ABVE-PC, inclusive of bleomycin. Methods: This multicenter randomized, open-label phase 3 study enrolled patients 2-21 years (yrs) with previously untreated HL, stages IIB + bulk, IIIB, IVA, IVB. Patients were randomized to 5 cycles of either ABVE-PC or Bv-AVE-PC given every 21 days with granulocyte colony-stimulating factor support. Centrally reviewed PET-CT after 2 cycles (PET2) identified slow responding lesions (SRL) defined as Deauville score &gt; 3. Involved site radiotherapy (ISRT) was given to bulky mediastinal adenopathy and SRL. The primary objective was 3-year EFS; events include relapse/progression, second malignant neoplasm (SMN) or death. Final data cutoff was 31 December 2021. Results: 600 participants were enrolled across 151 institutions from March 2015 to August 2019; 587 were eligible. Median age was 15.6 yrs (range 3.4-21). Patient and disease characteristics were balanced across study arms. Histology was nodular sclerosing in 76.5%. Stage distribution: 20.6% IIB-bulk; 19.3% IIIB; 28.5% IVA; 31.7% IVB. At a median follow-up of 42.1 mos (0.1-80.9), 3-year EFS (95%CI) by intent-to-treat analyses was 82.5% (77.4, 86.5) with ABVE-PC and 92.1% (88.4, 94.7) with Bv-AVE-PC (HR 0.41 (0.25, 0.67), p = 0.0002). Median time to 1st event was 9.4 months for both arms but the range differs by arm (3.6-57.8 ABVE-PC; 1.3, 25.8 Bv-AVE-PC). Relapse rate was 17% following ABVE-PC and 7% with Bv-AVE-PC. One SMN is noted in each arm: thyroid cancer at 57.8 mos and acute myeloid leukemia at 20.3 mos. 3-year overall survival (95%CI) was 98.5% (96.0, 99.4) for ABVE-PC and 99.3% (97.3, 99.8) for Bv-AVE-PC (p = 0.38). PET2 SRL rates were comparable (ABVE-PC 19% vs. Bv-AVE-PC 18%, p = 0.8). As-treated ISRT receipt did not differ (ABVE-PC 55.7% vs. Bv-AVE-PC 52.7%, p = 0.69). No difference in grade 3/4 adverse events was observed; myelosuppression, reflected in a 32% incidence of &gt; grade 3 febrile neutropenia, did not differ by arm (p = 0.67). Only 19% of patients experienced &gt; grade 2 neuropathy by the Balis pediatric neuropathy scale, with no difference between arms (p = 0.86). Conclusions: Brentuximab vedotin with AVE-PC in a dose intensive regimen has superior efficacy to ABVE-PC for pediatric patients with high-risk HL. A 59% risk reduction in EFS was achieved with no increase in toxicity and with fewer patients receiving ISRT compared to prior pediatric trials for high-risk HL. Clinical trial information: 02166463.

Efficacies of FAEV and EMA/CO regimens as primary treatment for gestational trophoblastic neoplasia.

Guidelines recommend etoposide, methotrexate, actinomycin D (EMA)/cyclophosphamide, vincristine (CO) as first-line treatment for high-risk gestational trophoblastic neoplasia (GTN). However, the floxuridine, actinomycin D, etoposide and vincristine (FAEV) regimen is commonly used to treat these patients in China. We conducted a randomised controlled trial to compare the efficacies and toxicities of FAEV and EMA/CO. Ninety-four patients with GTN were enrolled between May 2015 and April 2019 and randomly assigned to the FAEV or EMA/CO regimen. The rates of complete remission and relapse and the toxicities were compared in August 2021. Five patients were excluded from the analysis. There were 46 patients in the FAEV group and 43 patients in the EMA/CO group. The complete remission rates following primary treatment were 89.1% and 79.1% (P = 0.193), respectively. The relapse rates were 8.7% and 9.3% (P = 0.604). The apparent incidences of grade 4 myelosuppression were 60.9% and 32.6% (P = 0.008), respectively; however, they became both 32.6% (P = 0.996) after granulocyte colony-stimulating factor support. Other adverse reactions were similar in the two groups. No patient died of disease. FAEV has comparable efficacy and toxicity to EMA/CO as the primary treatment for high-risk GTN, and may thus be another first-line choice of chemotherapy. chictr.org.cn: ChiCTR1800017423.

Tumor board presentation of a woman with metastatic, hormone receptor‐positive, mismatch repair‐deficient endometrial cancer

Tumor board presentation of a woman with metastatic, hormone receptor‐positive, mismatch repair‐deficient endometrial cancer

Phase 1/dose expansion trial of brentuximab vedotin and lenalidomide in relapsed or refractory diffuse large B-cell lymphoma

AbstractNew therapies are needed for patients with relapsed/refractory (rel/ref) diffuse large B-cell lymphoma (DLBCL) who do not benefit from or are ineligible for stem cell transplant and chimeric antigen receptor therapy. The CD30-targeted, antibody-drug conjugate brentuximab vedotin (BV) and the immunomodulator lenalidomide (Len) have demonstrated promising activity as single agents in this population. We report the results of a phase 1/dose expansion trial evaluating the combination of BV/Len in rel/ref DLBCL. Thirty-seven patients received BV every 21 days, with Len administered continuously for a maximum of 16 cycles. The maximum tolerated dose of the combination was 1.2 mg/kg BV with 20 mg/d Len. BV/Len was well tolerated with a toxicity profile consistent with their use as single agents. Most patients required granulocyte colony-stimulating factor support because of neutropenia. The overall response rate was 57% (95% CI, 39.6-72.5), complete response rate, 35% (95% CI, 20.7-52.6); median duration of response, 13.1 months; median progression-free survival, 10.2 months (95% CI, 5.5-13.7); and median overall survival, 14.3 months (95% CI, 10.2-35.6). Response rates were highest in patients with CD30+ DLBCL (73%), but they did not differ according to cell of origin (P = .96). NK cell expansion and phenotypic changes in CD8+ T-cell subsets in nonresponders were identified by mass cytometry. BV/Len represents a potential treatment option for patients with rel/ref DLBCL. This combination is being further explored in a phase 3 study (registered on https://clinicaltrials.org as NCT04404283). This trial was registered on https://clinicaltrials.gov as NCT02086604.

Real World Prospective Observational Multicenter Trial of Venetoclax-Based Therapy for Patients with AML Reveals Unique Patterns of Patient Selection and Treatment Utilization - Revive Study

Real World Prospective Observational Multicenter Trial of Venetoclax-Based Therapy for Patients with AML Reveals Unique Patterns of Patient Selection and Treatment Utilization - Revive Study

Decreased Chimeric Antigen Receptor T-Cell Efficacy with Severe or Prolonged Post-Infusion Cytopenias

INTRODUCTIONProlonged cytopenias following Chimeric Antigen Receptor (CAR) T-cell therapy are common. The cytopenias are mainly due to the genotoxic effects of conditioning chemotherapy and systemic inflammatory insult to hematopoietic stem and progenitor cells from CAR T-cell activity. Tocilizumab, an anti-IL6 receptor antibody, reduces cytokine release syndrome (CRS), a clinical manifestation of CAR T inflammatory toxicity. We sought to determine if prophylactic tocilizumab can decrease the risk and/or severity of CRS. We secondarily hypothesized that decreasing the inflammatory injury to hematopoietic stem cells could improve bone marrow function after CAR T. Lastly, we analyzed the association between cytopenias and CAR T efficacy generally.METHODSIn this single-institution, retrospective cohort study, we examined all patients who had received axicabtagene ciloleucel for relapsed/refractory diffuse large B cell lymphoma (DLBCL) between March 2018 and April 2021 (Table 1). Each patient was evaluated for prolonged cytopenias, defined as requiring granulocyte-colony stimulating factor (G-CSF), red blood cell or platelet transfusion beyond day 28 after CAR T infusion. After CAR T infusion, no patient was given any anti-lymphoma therapy prior to collection of blood count data. We compared response to CAR T 6 weeks post-infusion, progression-free survival (PFS), and overall survival (OS) for patients with and without prolonged cytopenias. A univariate regression analysis was performed, and between group differences were calculated using Chi-squared, Fisher's exact tests, and Cox Proportional hazard regression model. Kaplan-Meier and log-rank analyses were used to evaluate the PFS and OS. We also compared patients who did and did not receive prophylactic tocilizumab 36 hours after CAR T infusion for differences in prolonged cytopenias, PFS, OS, and development and severity of CRS and neurotoxicity. CRS and neurotoxicity were graded using the ASTCT consensus grading system.RESULTSThe study included 54 patients, 31 (57.4%) met criteria for prolonged cytopenias. 1 (1.9%) patient died of progressive disease prior to day 28 and was excluded from analysis. All patients who died in this study did so on the basis of progressive lymphoma. Likelihood of no response to CAR T at 6 weeks was higher in patients who needed G-CSF support past day 28 (HR 2.20, p = 0.048), had a hemoglobin nadir less than 8 g/dL (HR 2.61, p = 0.031), were still requiring platelet transfusions after day 28 (HR 2.26, p = 0.038), or had a platelet nadir less than 25,000 per µl during the first 28 days (HR 4.01, p = 0.013, Table 2). For patients who had neutrophil counts below the median at day 28, the median PFS was 4.5 months vs. 17.9 months (HR 2.07, p = 0.035) compared to those above the median. In patients with a platelet nadir less than 25,000 per µl or below the median at day 28 (Figure 1), the median PFS was 4.5 months vs. not reached (HR 3.12, p = 0.003) and 3.9 months vs. not reached (HR 3.85, p = 0.0004) respectively. Median OS was 9.44 months in patients who required G-CSF support past day 28 (HR 2.79, p = 0.022) vs. not reached in those who didn't receive G-CSF past day 28. For patients with an ANC below the median on day 28, median OS was 19.87 months vs not reached (HR 2.65, p = 0.022). In patients with a platelet nadir less than 25,000 per µl or below the median at day 28, the median OS were 7.8 months vs not reached (HR 3.72, p = 0.006) and 7.79 months vs not reached (HR 3.39, p = 0.007) respectively. Among patients who received prophylactic tocilizumab, 12 (54.5%) had prolonged bone marrow failure compared to 19 (57.6%) among those who did not (p = 0.82). PFS, OS, and rates and severity of CRS and neurotoxicity did not differ between the prophylactic tocilizumab groups.CONCLUSIONSIn this study of patients with relapsed/refractory aggressive B-cell lymphomas receiving a CD28 domain-containing CAR T product, severe short-term or prolonged cytopenias were associated with an increased risk of lymphoma progression and death. This effect was not ameliorated by administration of prophylactic tocilizumab, which also did not affect the development or severity of CAR T inflammatory toxicities. Further study is required to determine the mechanistic nature of the relationship between post-infusion cytopenias and CAR T efficacy. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

A Quantitative Systems Pharmacology Framework for Optimal Doxorubicin Granulocyte Colony-Stimulating Factor Regimens in Triple-Negative Breast Cancer

Introduction: To mitigate the risk of neutropenia during chemotherapy treatment of triple-negative breast cancer, prophylactic and supportive therapy with granulocyte colony-stimulating factor (G-CSF) is administered concomitant to chemotherapy. The proper timing of combined chemotherapy and G-CSF is crucial for treatment outcomes. Methods: Leveraging our established mathematical model of neutrophil production by G-CSF, we developed quantitative systems pharmacology (QSP) framework to investigate how modulating chemotherapy dose frequency and intensity can maximize antitumour effects. To establish schedules that best control tumour size while minimizing neutropenia, we combined Gompertzian tumour growth with pharmacokinetic/pharmacodynamic models of doxorubicin and G-CSF, and our QSP model of neutrophil production. Results: We optimized a range of chemotherapeutic cycle lengths and dose sizes to establish regimens that simultaneously reduced tumour burden while minimizing neutropenia. Our results suggest that cytotoxic chemotherapy with doxorubicin 45 mg/m2 every 14 days provides effective control of tumour growth while mitigating neutropenic risks. Conclusion: This work suggests future avenues for optimal regimens of chemotherapy with prophylactic G-CSF support. Importantly, the algorithmic approach that we developed can aid in balancing the anticancer and the neutropenic effects of both drugs, and therefore contributes to rational considerations in clinical decision-making in triple-negative breast cancer.