Neutropenia Grade Research Articles

The Non-Hodgkin Lymphoma Treatment and Side Effects: A Systematic Review and Meta-Analysis.

This paper aims to review studies regarding side effects found during Non-Hodgkin Lymphoma treatment, to suggest the drug class most associated with these effects, as well as the most prevalent side effect grade. This review is registered in PROSPERO (IDCRD42022295774) and followed the PICOS strategy and PRISMA guidelines. The search was carried out in the databases PubMed/MEDLINE, Scientific Electronic Library Online, and DOAJ. Medical Subject Headings Terms were used and quantitative studies with conclusive results regarding side effects during the non-Hodgkin lymphoma treatment were selected. Patent information was obtained from google patents. Monoclonal antibodies were the main drug class associated with side effects during NHL therapy. The combination of Rituximab (Rituxan®; patent EP1616572B) and iInotuzumab (Besponsa®; patent EP1504035B3) was associated with a higher incidence of thrombocytopenia (p<0.05), while the combination of Rituximab and Venetoclax (Venclexta®; patent CN107089981A) was associated with a higher incidence of neutropenia (p<0.05) when compared to Bendamustine combinations (Treanda ™; patent US20130253025A1). Meta-analysis revealed a high prevalence of grade 3-4 neutropenia and thrombocytopenia in men. Finally, Americans and Canadians experienced a higher prevalence of these side effects, when compared to others nationalities (p<0.05). Patents regarding the use of monoclonal antibodies in NHL treatment were published in the last year. Monoclonal antibodies associated with neutropenia (grade 3-4) and thrombocytopenia, especially in North American men treated for NHL, and with an average age of 62 years demonstrated importance in this study.

Population pharmacokinetics and exposure-response analyses for efficacy and safety of upadacitinib in patients with axial spondyloarthritis.

Upadacitinib is an orally administered, selective, Janus kinase inhibitor that is approved for several auto-immune conditions, such as axial spondyloarthritis, an inflammatory rheumatic disease that includes ankylosing spondylitis (AS) and non-radiographic axial spondyloarthritis (nr-axSpA). The approvals of upadacitinib for the treatment of AS and nr-axSpA were based on the safety and efficacy data for upadacitinib 15 mg once-daily compared to placebo from the SELECT-AXIS 1 and SELECT-AXIS 2 studies. Population pharmacokinetic analyses based on data from 244 patients with axSpA showed that the pharmacokinetics of upadacitinib were comparable in subjects with AS and nr-axSpA. Exposure-response relationships were characterized for key efficacy and safety end points using data from 482 patients with axSpA. The exposure-response analyses for efficacy based on Assessment of SpondyloArthritis International Society (ASAS)20 and ASAS40 responses at week 14, showed a clear differentiation from placebo with no evidence of increased responses with increasing upadacitinib plasma exposures. There were no clear exposure-response trends observed for safety end points that included serious infections, herpes zoster, pneumonia, lymphopenia (grade ≥3), neutropenia (grade ≥3), or a greater than 2 g/dL decrease in hemoglobin from baseline through week 14. The exposure-response analyses for efficacy and safety presented here supported the favorable benefit-risk profile with the use of upadacitinib 15 mg once-daily for the treatment of axSpA.

Tolerability of Daratumumab Amongst Asian Patients with Plasma Cell Dyscrasias - A Single Centre Experience.

Daratumumab is increasingly incorporated into the standard treatment regimens for patients with plasma cell dyscrasias in Asia, especially with cost-containment measures implemented by various regional health authorities. This analysis aimed to study daratumumab's tolerability amongst Asian patients. This is a retrospective medical records review of patients who received daratumumab between November 2016 and August 2021 as part of routine clinical care. Sixty-two patients were included in the study: 62.9% had renal impairment, and 27.4% had creatinine clearance (CrCl) \<30ml/min. Forty-five patients (72.6%) received daratumumab combination therapy, with a median 1 line of prior therapy. The median duration of follow-up was 12.4 months, and the median duration patients were on treatment with daratumumab was 12.3 months. Twenty-one of 62 (33.9%) patients experienced infusion-related reactions (IRRs) after the first dose of intravenous daratumumab. Seven developed mostly grades 1 and 2 respiratory events, and 14 showed grades 1 and 2 non-respiratory IRRs. Only one patient experienced a grade 1 IRR with the second infusion, with none developing any IRRs in the third or subsequent infusions. Eight (12.9%) patients were affected by hematological adverse events (AEs), mostly grades 2 and 3, with one experiencing grade-4 neutropenia without sepsis. Six (9.7%) patients experienced non-hematological AEs, the commonest being pneumonia and other infections, with one developing Nocardia pneumonia (grade 4) 14 months after the initiation of daratumumab. In conclusion, daratumumab is tolerable amongst Asian patients, including the elderly, and patients with severe renal impairment and chronic lung diseases.

Dalpiciclib in combination with letrozole/anastrozole or fulvestrant in HR-positive and HER2-negative advanced breast cancer: results from a phase Ib study.

Dalpiciclib is a novel cyclin-dependent kinase 4/6 inhibitor which showed tolerability and preliminary efficacy as monotherapy for pretreated advanced breast cancer (BC). To further assess dalpiciclib with endocrine therapy (ET) in hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative BC. A multicenter, open-label, phase Ib trial. Patients with locally recurrent or metastatic BC were enrolled in five cohorts. Patients without prior treatment for advanced disease (cohorts 1-2) were given dalpiciclib (125 or 150 mg) plus letrozole/anastrozole; patients who progressed after ET (cohorts 3-5) were given dalpiciclib (125, 150, or 175 mg) plus fulvestrant. Dalpiciclib was administered orally once daily in 3-weeks-on/1-week off schedule. The primary endpoint was safety. A total of 58 patients received dalpiciclib with letrozole/anastrozole and 46 received dalpiciclib with fulvestrant. No maximum tolerated dose of dalpiciclib was reached with letrozole/anastrozole or fulvestrant. Across all cohorts, 86.7%-93.8% of patients had a grade ⩾3 adverse event, with the most common being neutropenia (grade 3, 40.0% for dalpiciclib 175 mg and 61.8%-87.5% for lower doses; grade 4, 46.7% and 4.2%-20.6%, respectively) and leukopenia (grade 3, 80.0% for 175 mg and 33.3%-54.2% for lower doses; grade 4, 0% for all doses). At tested dose levels, steady-state areas under the concentration curve and peak concentration of dalpiciclib increased with dose when combined with letrozole/anastrozole and fulvestrant. Dalpiciclib at 150 mg was associated with a numerically higher objective response rate in both patients untreated for advanced disease (67.6%; 95% confidence interval (CI) 49.5-82.6) and patients progressing after ET (53.3%; 95% CI 26.6-78.7); as of July 30, 2022, the median progression-free survival with dalpiciclib 150 mg was 24.1 months (95% CI 16.9-46.0) with letrozole/anastrozole and 16.7 months (95% CI 1.9-24.1) with fulvestrant. Dalpiciclib plus letrozole/anastrozole or fulvestrant showed an acceptable safety profile. The recommended phase III dose of dalpiciclib was 150 mg. ClinicalTrials.gov identifier: NCT03481998.

Gemcitabine/Cisplatin versus docetaxel, cisplatin and 5-fluorouracil as induction chemotherapy in locally advanced nasopharyngeal carcinoma.

Induction chemotherapy followed by concomitant chemoradiation is the standard therapy for patients with locoregionally advanced NPC. There is a limitation of clinical studies that compare different induction regimens. The purpose of this work is to analyze the efficacy of two distinct chemotherapy regimens, docetaxel, cisplatin, and 5-fluorouracil (TPF) and gemcitabine/cisplatin (GP), in treating patients with loco-regionally advanced nasopharyngeal carcinoma (NPC). We analyzed 81 patients initially presented with stage III-IVA NPC from January 2019 to June 2023. Participants were randomized in 1:1 ratio to obtain GP regimen or TPF regimen followed by concurrent CRT. The overall response rate was 97.5% after induction chemotherapy in both groups (In GP arm, 78% of patients achieved complete remission compared to 70% of patients treated with TPF regimen). The satisfactory tumor response to induction chemotherapy was linked with significant enhanced progression free survival [CI (3.37-13.92), HR=2.16, P=0.001] and overall survival [CI (3.717-9.443), HR=1.873, P=0.001]. The GP regimen was both efficacious and well-tolerated. Leucopenia and neutropenia (Grade 3-4) were significantly lower in GP group contrasted to in TPF group. There was no significant difference in the 3-year DFS and OS between GP and TPF protocols.

A Phase 1 Trial of OPB-111077 in Combination with Bendamustine (B) and Rituximab (R) in Patients with Relapsed or Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL): Preliminary Results of Dose-Escalation Stage

Background OPB-111077, a first-in-class small molecule, is an orally available antitumor agent with an inhibitory effect on mitochondrial oxidative phosphorylation (OXPHOS). OPB-111077 inhibits mitochondrial respiratory chain complex I, which leads to inhibition of energy production and activation of the AMPK-mTOR energy stress sensor pathway, as well as inhibition of the signal transducer and activator of transcription (STAT) 3 pathway. In non-clinical studies using cultured cells and murine xenograft models, OPB-111077 showed antitumor effects in a variety of tumor cell lines, including hematological and solid tumors, and OPB-111077 in combination with an alkylating agent has a potential synergistic antitumor effect for malignant lymphoma. Here we report the preliminary results from the dose-escalation (DE) stage of an ongoing phase 1 trial (NCT04049825) of OPB-111077 in combination with bendamustine (B) and rituximab (R) in patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL). Method This trial is composed of 2 stages. OPB-111077 is administered in combination with B in a DE stage and with B and R in a dose-expansion (EX) stage. The DE stage uses a 3+3 design. The objectives of the DE stage are to evaluate the tolerability and safety of OPB-111077 in combination with B and to determine the recommended dose for the EX stage based on dose-limiting toxicity (DLT). A secondary objective is to evaluate efficacy. Response assessment is based on IWG Lugano response criteria for non-Hodgkin lymphoma (NHL) (2014). Key eligibility criteria include age 20 to 80 years (inclusive), at least initial standard treatment, measurable lesions, and Eastern Cooperative Oncology Group performance status score of 0 or 1. OPB-111077 is orally administered once daily on Days 3 to 6, Days 10 to 13, and Days 17 to 20 of each cycle. The duration of each cycle is 21 days, except for Cycle 1, which is 23 days. The dose in the first cohort is 200 mg/day, increasing as appropriate to 400 mg/day in Cohort 2 and then to 600 mg/day in Cohort 3. B is administered intravenously at 120 (or 90) mg/m 2 once daily on Days 1 and 2 of each cycle for up to 6 cycles. Results As of 31 Jan 2023, 16 patients had been treated with OPB-111077 + B (120 mg/m 2) at OPB-111077 doses of 200 mg (Cohort 1, n = 3), 400 mg (Cohort 2, n = 6), and 600 mg (Cohort 3, n = 7). Patients had received 1 to 6 prior lines of chemotherapy, median age was 70.0 (range 54 - 79) years, and 56.3% were male. Median treatment duration was 69.0 days. No DLT was observed in Cohort 1 or in the first 3 patients in Cohort 2. In Cohort 3, 2 patients experienced DLTs of neutropenia (grade 4) and neutropenia (grade 3, dose interruption of ≥21 consecutive days), respectively. As the Efficacy and Safety Evaluation Committee (ESEC) judged the OPB-111077 600-mg dose to be intolerable, in accordance with the scheme for the DE stage, new 3 patients were added to Cohort 2. One of the 6 patients in Cohort 2 experienced DLTs of anorexia (grade 3) and neutropenia (grade 4, dose interruption of ≥21 consecutive days). Based on the ESEC's recommendation, the recommended dose for the EX stage was set at OPB-111077 400 mg + B 120 mg/m 2. The most common (≥90%) treatment-related adverse events of any grade were lymphopenia (93.8%, grade 3: ≥93.8%), leukopenia (93.8%, grade 3: ≥81.3%), and nausea (93.8%, grade 3: ≥18.8%). The overall response rate [complete response (CR) + partial response (PR)] and CR rate were respectively 62.5% and 43.8%. Median progression-free survival was 257.0 days. Conclusion OPB-111077 400 mg + B 120 mg/m 2 combination treatment showed a tolerable safety profile. The preliminary data are encouraging, especially regarding the efficacy of OPB-111077 combination treatment, including CR in patients with DLBCL. The DE stage of the trial is still ongoing and the EX stage, which will evaluate the safety and efficacy of OPB-111077 in combination with B + R, is now recruiting.

Efficacy and Safety of Ino Combined with Reduce Dose R-GDP Regimen in Patients with Relapsed/Refractory B-Cell NHL in China

Background: The combination of immunochemotherapy resulted in satisfactory efficacy and survival for B-cell Non-Hodgkin Lymphoma (NHL). But many patients face no response to combination therapy or the disease progression again. This study aimed to investigate the efficacy and safety of Inotuzumab Ozogamicin (InO) combined with reduce dose R-GDP as a salvage therapy in patients with relapsed/refractory (R/R) B-NLH. Patients and methods: Seven patients with R/R B-NLH or even failure of anti-CD19 and CD22 chimeric antigen receptor (CAR) T cell therapy received InO combined with reduce dose R-GDP combination therapy. All patients received Rituximab (R) 375mg/m 2 intravenously (IV) on day -1, and InO 0.8 mg/m 2 (IV) on day 0. Then Gemcitabine (G) 500-1000mg/m 2(IV), Dexamethasone (D) 40 mg/day (IV) on day 1-4 and Cisplatin (P) 40-75mg/m 2 (IV) on day 1 of each 21-day cycle (±2 days). Treatment was continued for up to two cycles unless progressive disease (PD) or intolerable toxicity occurred. The primary endpoint of this study was the Complete remission (CR) and Overall response rate (ORR). The secondary endpoint of this study was Progression-free survival (PFS), Overall survival (OS) and Adverse events (AE), particularly hematological toxicity. In our study, the response evaluation was detected using computed tomography (CT) or PET-CT. Results: Seven patients with R/R B-NLH received 1-2 cycles of InO combined with reduce dose R-GDP therapy. Three patients did not respond to anti-CD19 and CD22 CAR-T cell therapy or their disease progressed again. The other four patients did not respond to more than 3 lines of combined immunochemotherapy and never achieved Partial response (PR) or CR. Four patients with R/R B-NLH who received 1-2cycles of InO combined with reduce dose R-GDP therapy achieved CR and survived to this day. Three of the four patients had previously received anti-CD19 and CD22 CAR-T cell therapy. Two patients with R/R B-NLH achieved PR after one cycle of InO combined with reduce dose R-GDP therapy, the other one patient achieved Stable disease (SD) only. One R/R B-NLH patient who achieved CR after one cycle of this salvage therapy had a PFS of one year to date without any other treatments. The other three R/R B-NLH patients who achieved CR after 1-2 cycles of this salvage therapy had a PFS of 3-6 months without any other treatments. The other two patients who achieved PR after 1 cycle of this salvage therapy survived 7 months and 2 months, while the only one patient who achieved SD survived one month without any other treatment. The main AE of this study was hematological toxicity. Three patients were defined as 3-4 grade of neutropenia, four patients were defined as 3-4 grade of anemia and three patients were defined as 3-4 grade of thrombocytopenia in this study. Except for one patient who was defined as grade 3 of thrombocytopenia recovered nine months after this salvage therapy, all other patients recovered two to three months after this study. There have been no deaths from severe infections due to hematological toxicity. Conclusions Ino combined with reduce dose R-GDP therapy in patients with R/R B-NLH could be an effective and safety therapy. However, the GDP regimen needs to be reduced appropriately to avoid severe hematological toxicity.

3rd-Generation Tyrosine Kinase-Inhibitors and Azacitidine Are Safe and Effective in Myeloid Blast-Phase Chronic Myeloid Leukaemia and Result in a High Proportion of Subjects in 2 nd Chronic Phase Able to Receive a Transplant

Background Myeloidblast phase of chronic myeloid leukemia (CML-MBP) has a terrible prognosis with a haemopoietic cell transplant the only likely cure. Probability of transplant success is markedly increased if someone can be returned to chronic phase. Purposes Study safety and efficacy of olverembatinib or ponatinib and azacitidine (AZA) in this setting. MethodsCML-MBP was diagnosed according to the WHO 2016 criteria. Ponatinib, 45 mg/d or olverembatinib, 30 mg every other d were combined with azacitidine, 75 mg/mE+2/d for 7 d in 28 d cycles. Subjects achieving 2 nd chronic phase received an allotransplant whereas others continued the therapy specified. 2 nd chronic phase was defined as &amp;lt; 10% blood and bone marrow blasts and no extra-medullary leukaemia for ≥ 4 w. Event-free survival (EFS) was defined as interval from therapy start to no response, progression to accelerated or blast phase or CML-related death. CML-related survival was defined as interval from therapy start to death from blast phase and survival, this interval to death from any cause. Haematologic, cytogenetic and molecular responses were monitored. Targeted DNA sequencing and whole RNA sequencing were done before therapy start. “MOVICS” package in R software was used for multi-omics integrated analyses and molecular sub-type classification. Cox regression models were used to identify co-variates associated with outcomes. The study was registered in Chinese Clinical Trial Registry (ChiCTR2200055887). Results 39 consecutive subjects were registered from October, 2020 to July, 2023. 21 were male. Median age was 50 years (Interquartile range [IQR], 33-54 years). 23 received olverembatinib; 16, ponatinib. Median follow-up was 10 months (mo) (IQR, 3-19 mo). 30 (77%) subjects achieved a 2 nd chronic phase after 1 cycle, 11 of whom received a transplant, 8 progressed to blast phase again; and 9 (23%) others had no response. 25 subjects died of progression (N = 19), transplant-related mortality (N = 3), COVID-19 (N = 2) or heart failure (N = 1). Median EFS, CML-related survival and survival were 4 (95% Confidence Interval [CI], 1-6) months, 12 (8-17) months and 11 (6-15) months. Subjects receiving a transplant had better EFS ( p= 0.03), CML-related survival ( p= 0.009) and survival ( p= 0.04) compared with non-transplant subjects ( Figure 1). Most treatment-related severe adverse events were tolerable and manageable including 25 subjects (65%) developing ≥ 4 grade neutropenia with or without thrombocytopenia except only 1 subject developing early death due to heart failure. In addition, 2 subjects experienced COVID-19 and died subsequently. In adjusted Cox regression analyses of genomic (N = 37) and transcriptomic (N = 34) data KRASmutation was significantly-associated with worse EFS ( p= 0.05), CML-related survival ( p&amp;lt; 0.001) and survival ( p= 0.009). TP53mutation was associated with worse CML-related survival ( p= 0.02) and survival ( p= 0.003). PFKFB3::LINC02649 fusion was associated with better EFS ( p= 0.001), CML-related survival ( p= 0.007) and survival ( p= 0.005). Based on these data 34 subjects were divided into 2 clusters. Subjects in cluster 2 (N = 14) had worse EFS ( p= 0.001), CML-related survival ( p= 0.008) and survival ( p= 0.005) compared with those in cluster 1 (N = 20). In differential gene expression analyses 1,564 genes were up-regulated and 1,000 down-regulated in cluster 2 compared with cluster 1. In KEGG analyses up-regulated genes were enriched in signaling pathways including cytokine-cytokine receptor interaction, cell adhesion molecules, natural-killer (NK) cell mediated cytotoxicity, primary immune deficiency and Toll-like receptor. Down-regulated genes were enriched in cell-cycle and DNA replication pathways. Conclusion s Olverembatinib or ponatinib combined with azacitidine is a safe and effective therapy of CML-MBP allowing many subjects to receive a transplant in 2 nd chronic phase. KRAS and TP53 mutations and PFKFB3::LINC02649 fusions had predictive impact on outcomes. Determining whether adding azacitidine to a 3 rd-generation TKI requires a randomized controlled trial.

Idarubicin Plus Azacitidine + Venetoclax As Induction Therapy Achieved High Remission in Elderly Fit- Acute Myeloid Leukemia Patients: Preliminary Results of a Phase II Study

Background The diagnosed age of de novo acute myeloid leukemia (AML) increased over the years, with a median current age of 68 years old. Elderly AML patients characterized by harboring high-risk mutations and significant comorbidities, usually display resistance to conventional chemotherapy, leading to poor outcomes. Although encouraging results from VIALE-A were reported in these years, over 30% participants had limited responses to the regimen of azacitidine + venetoclax after first-cycle induction. Thus, the selection of initial regimen for elderly AML is worth further exploration, especially for those with good fitness (the fitness was evaluated based on the physical ability, emotional status, cognitive function, and comorbidities). Here, we added idarubicin to azacitidine + venetoclax as the induction regimen (IAV regimen) for elderly fit-AML, and reported the preliminary results of efficacy and safety. Methods This single-center, single-arm, phase II trial (ChiCTR2300070190) was conducted at Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (Shanghai, China). Elderly patients (aged 60-75 years) of newly diagnosed acute myeloid leukemia (AML) were assessed via modified comprehensive geriatric assessment (mCGA) for the fitness. From April 2023, 22 patients have been enrolled for the treatment of IAV regimen (cycle 1: IDA 6 mg/m 2 d1-3, AZA 75 mg/m 2 d1-7, VEN 100 mg d1, 200 mg d2, 400 mg d3-14; cycle 2: IDA 6 mg/m 2 d1-2, AZA 75 mg/m 2 d1-5, VEN 400 mg d1-14). Among them, 19 patients and 13 patients who have completed cycle 1 and cycle 2 treatment, respectively, were available for analyzing the preliminary efficacy and safety in the trial. The primary objective of this study was to access the composite complete remission (cCR: CR + CRi) rate of IAV treatment. The secondary objective was to evaluate the MRD-negative rate, regimen-related toxicity, and safety. The duration of CR, overall survival rate and event-free survival rate would also be further accessed with sufficient follow-up time. Results The median age of currently enrolled patients was 64 (61-69) years old, and males accounted for 68.4%. Detailed baseline characters were summarized in Table 1. Composite complete remission rate after 1-cycle IAV treatment was achieved in 89.5% (17/19) participants, among which 52.9% (9/17) got MRD-negative status. One patient (1/19, 5.26%) got partial remission, with 7.5% blasts remained. After cycle 2 treatment, the CR rate increased to 92.9% (13/14), and 92.3% (12/13) CR participants were MRD-negative (Table 1). Till now, only 1 patient with chromothripsis-associated rearrangements showed no response and died on day 40 after treatment initiation. The median recovery time of neutrophils (ANC &amp;gt; 0.5×10 9/L) and platelet (PLT &amp;gt; 50×10 9/L) was 20.5 (16-30) days and 20.5 (15-43) days, respectively (Table 1). The most frequent grade 3/4 non-hematological adverse events (according to CTCAE version 5.0) were febrile neutropenia (grade 3, n = 14; grade 4, n = 5), pneumonia (grade 3, n = 5) and sepsis (grade 3, n = 2; grade 4, n = 1) (Table 2). Conclusion In this study, IAV regimen showed promising efficacy on elderly fit-AML patients, with high rates of MRD-negative remission. Non-hematological toxicities were tolerable under current observation. Based on the invigorating preliminary results, the efficacy and potential benefit of IAV regimen on elderly fit AML is worthy of follow-up in the future.

Bendamustine Is Less Toxic Than Fludarabine-Cyclophosphamide-Based Lymphodepletion before CD28-Costimulated CART19 through Reduced Inflammatory Cytokines

Introduction: Lymphodepletion (LD) is an integral component of anti-CD19 chimeric antigen receptor T cell (CART19) immunotherapy, creating the proper environment and cytokine milieu for CART engraftment and function. We previously demonstrated that bendamustine (Benda) LD is as effective as standard fludarabine and cyclophosphamide (Flu/Cy) LD prior to 4-1BB-costimulated tisagenlecleucel but is characterized by significantly reduced cytokine-release syndrome (CRS), neurotoxicity (ICANS), and hematological toxicities. However, whether Benda LD is also effective and safe in CD28 costimulated CART19, and the mechanism for the reduced toxicities associated with Benda LD remain unknown. Methods: We retrospectively evaluated the outcomes of 59 consecutive non-Hodgkin lymphoma patients (pts), including large B cell lymphomas (LBCL, n=48) and follicular lymphoma (FL, n=11), treated with commercial CD28 costimulated axicabtagene ciloleucel (axi-cel) at the University of Pennsylvania between January 2018 and March 2023. Data cut-off was June 30 th, 2023. LD regimens were Flu 30 mg/m 2/day and Cy 500 mg/m 2/day x 3 days or Benda 90 mg/m 2/day x 2 days. LD choice was at the treating physician's discretion, partially determined by Flu shortage. Pts were evaluated for 3-month response (Lugano criteria), survival, and toxicities (ASTCT, CTCAE) in the 30 days after axi-cel infusion. For hematological toxicities, we analyzed lymphocyte, neutrophil, platelet, and hemoglobin levels from the first day of LD to 30 days after axi-cel infusion. For long-term hematological toxicities, we retrieved blood values at 6 months in pts with ongoing remission. Moreover, we analyzed serum samples collected pre- and post-LD (CART19 infusion day) for changes in circulating cytokines (Luminex) and metabolites (Liquid Chromatography/Mass Spectrometry) in a second cohort of 32 pts undergoing CART19. Results: Of 59 pts, 37 received Flu/Cy while 22 Benda LD. The two groups were balanced for most clinical features. Responses with Flu/Cy and Benda LD were similar, with complete remission rates of 51.4% and 50.0%, respectively. Progression-free and overall survivals were similar in the two LD groups. However, any-grade CRS occurred in 91.9% of pts who received Flu/Cy versus 72.7% of pts who received Benda LD; any-grade ICANS after Flu/Cy occurred in 43.2% and after Benda LD in 18.2% of pts ( Fig.1A). These results were confirmed in both LBCL and FL cohorts. Both LD regimens induced profound lymphopenia by the time of axi-cel infusion. However, Flu/Cy LD induced a deeper reduction in median lymphocyte counts (Flu/Cy: 0.00x10 9/L; Benda, 0.20x10 9/L). Additionally, Flu/Cy was associated with a higher incidence of neutropenia of grade ≥3 (100.0% vs 54.5%). Consequently, Flu/Cy pts were more likely to develop infections (78.4% vs. 27.3%), and neutropenic fever (78.4% vs. 13.6%) than Benda receiving pts. By evaluating long-term hematological toxicities, 75.0% of Flu/Cy pts did not have lymphocyte recovery to normal values at 6 months compared to 37.5% with Benda LD. Mechanistically, both Flu/Cy (n=7) and Benda (n=25) LD regimens induced an increase in the levels of cytokines facilitating CART proliferation (IL2, IL7, IL15). Overall, Flu/Cy LD pts had a higher increase in inflammatory cytokine levels compared to Benda LD pts, including a higher increase in the levels of cytokines previously associated with CRS and ICANS (IL15, IL8, and MCP1, Fig.1B). Moreover, after LD, several indispensable anabolic metabolites, including carnitine esters, were decreased in pts receiving Flu/Cy. We also found that NADH and nicotinamide riboside, critical elements for cellular redox balance, were reduced in pts exposed to Flu/Cy LD. We speculate that the higher cytotoxicity/cytopenias, induced by Flu/Cy LD, causes a faster utilization of the above-mentioned metabolites in order to reconstitute the hematopoietic cell compartment to physiological levels, resulting in a higher patient susceptibility to additional metabolic stress. Conclusions: In this retrospective comparison,Benda LD is a safer alternative to Flu/Cy for CART19 immunotherapy with similar efficacy and significantly reduced toxicities. Our data can serve as guidance to clinicians for the selection of the best regimen for lymphodepletion. Our conclusions are supported by our mechanistic studies showing reduced inflammatory cytokines after Benda LD.

Phase I/II Clinical Trial Evaluating Azacitidine + Venetoclax + Donor Lymphocyte Infusion in Post-Transplant Relapse Myelodysplastic Syndromes and Acute Myeloid Leukemia: Preliminary Results of Ventograft, a GFM Study

Background: Azacitidine (AZA) is approved for the treatment of patients with high-risk MDS and in combination to Venetoclax (VEN) in AML. Beyond direct cytotoxic/epigenetic effects of AZA and ability to induce remissions even in patients refractory to chemotherapy, AZA has been shown to increase the immunogenicity of AML blasts by reexpression of key antigens [ Schroeder et al. Leukemia 2013]. Moreover, VEN imparts distinct cell death sensitivity and adaptivity patterns in T cells ( Ludwig et al. Cell Death Dis 2021). DLI have shown efficacy to treat or prevent relapse of AML or MDS following allogeneic stem cell transplantation (allo-SCT) in 20-40% of the cases [ Castagna et al. Transfusion and Apheresis 2016]. A german retrospective study showed an overall response rate (ORR) of 33% (including 27% CR and 6% PR), to AZA and DLI following relapse after allo-SCT in AML and MDS [ Schroeder et al. BBMT 2015], a regimen used since in many centers. We present here preliminary results of a phase I/II evaluating the combination of AZA/VEN/DLI in relapse MDS/AML. Patients and Methods: In this open label multicenter phase I/II study, MDS and AML patients relapsing post allo-SCT, without active graft versus host disease (GVHD) and active infections, are treated with VEN during 14 days in combination with AZA at 75 mg/m²/day for 5 days for each cycle (or 50 mg/m²/day for 5 days each cycle if relapse occurs less than 4 months after allo- SCT), and VEN orally at escalating dose (step 1: VEN 100mg/d; step 2: VEN 200mg/d and step 3: VEN 400mg/d) in the phase I part and at maximal tolerated dose (MTD) on days 1-14 of each cycle in the phase II part. Cycles are administered every 28 day (or delayed until day 42 in case of hematological toxicity). DLI are started at least 8 weeks after immunosuppressive therapy discontinuation, if chimerism in &amp;lt;90% recipient, and administered on day 15 every two cycles (C2, C4, C6, C8) in the absence of GVHD. Patients receive at least 8 cycles of AZA/VEN + DLI unless progression occurs. Response is assessed after 4, 6 and 8 cycles. Patients achieving a response receive 12 cycles of AZA + VEN followed by cycles of AZA alone. In the absence of response after 8 cycles, patients stop treatment. Results: From November 2022 to June 2023, 9 patients were included in part 1 of VENTOGRAFT. M/F was 8/1. Median age 57 years (range 18-71). Two patients had MDS and 7 patients had AML at diagnosis. Five patients had MDS (IPSS-R was low (1), intermediate (2) and very high (2)), and 3 patients had AML (ELN2017 was intermediate (1) and unfavorable (2) and molecular relapse (1)) at the time of relapse. Median interval between allo-SCT and relapse was 44 months (range 2-181). At data cut-off, 3 patients had been treated in step 1, 3 patients in step 2 and 3 patients in step 3 (AZA + VEN 400mg/d D1-14)). Median number of AZA + VEN cycles was 3 (range 1-8) and median number of DLI infused was 1 (range 0-3). One dose limiting toxicity (No ANC recovery on D42 and one patient still neutropenic at D28) was observed in step 3 leading to inclusion 3 more patients on this step. Other adverse events observed were grade 1/2 nausea (2 patients), grade 1 skin lesions (1 patient), ALAT increase grade 3 (1 patient), febrile neutropenia grade 3 (2 patients), grade 3 abdominal pain (1 patient) and grade 3 gastrointestinal bleeding (2 patients). GVHD was seen in 1/9 (11%) patients). CMV and EBV reactivation were observed in 0 and 2 patients, respectively. Overall response rate was 6/9 (67%) patients 67% including 22% complete remission (CR), 22% of CR with incomplete recovery (CRi) and 33% of morphologic leukemia-free state (MLFS). Full donor chimerism was obtained in all patients obtaining a response. Conclusion: The combination of AZA at 75mg/m²/d D1-5 and VEN at 100 to 400mg/d D1-D14 (400mg/d ongoing) was safe, showed a promising ORR of 67%. Final results of the phase 1 and first patients treated in this phase 2 will presented at the ASH meeting.

Trifluridine/Tipiracil Plus Bevacizumab for Vulnerable Patients With Pretreated Metastatic Colorectal Cancer: A Retrospective Study (WJOG14520G).

Trifluridine/tipiracil (FTD/TPI) plus bevacizumab has shown clinical benefit for metastatic colorectal cancer (mCRC) refractory to standard therapy. However, few data have been available for patients with pretreated mCRC who are intolerant of intensive therapy (vulnerable). We performed a multicenter retrospective study (WJOG14520G; TWILIGHT) of FTD/TPI plus bevacizumab for vulnerable patients with pretreated mCRC. Eligibility criteria included previous chemotherapy (although patients treated with all key cytotoxic agents, a fluoropyrimidine, oxaliplatin, and irinotecan, were excluded) and intolerance of full-dose combination therapy with oxaliplatin or irinotecan at the start of FTD/TPI plus bevacizumab. The median age of 93 evaluable patients was 79 years (range, 21-90). Intolerance of intensive therapy was attributable to an older age in 60 (65%) patients, serious concomitant disease in 24 (26%) patients, and a poor performance status in 19 (20%) patients. FTD/TPI plus bevacizumab was administered as second-line treatment in 74 (80%) patients and as third- or fourth-line treatment in 19 (20%) patients. The objective response rate was 4.9% (95% confidence interval [CI], 1.4%-12.2%), and the disease control rate was 67.9% (95% CI, 56.6%-77.8%). With a median follow-up time of 21.6 months, median overall survival and progression-free survival were 18.6 months (95% CI, 12.1-23.2) and 6.3 months (95% CI, 5.0-8.3), respectively. Neutropenia of grade ≥3 developed in 50 (54%) patients, whereas 2 (2%) patients experienced febrile neutropenia, and no treatment-related death was observed. Our data show the potential efficacy and acceptable safety profile of FTD/TPI plus bevacizumab for vulnerable patients with pretreated mCRC.

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

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

A Matching-Adjusted Indirect Comparison of Acalabrutinib with and without Obinutuzumab Versus Zanubrutinib in Treatment-Naïve Chronic Lymphocytic Leukemia

Introduction The second-generation Bruton tyrosine kinase inhibitors acalabrutinib (acala) and zanubrutinib (zanu) have not been compared with each other in a head-to-head randomized controlled trial (RCT). Acala with and without obinutuzumab (obin) was evaluated in the ELEVATE-TN RCT in treatment-naïve patients with chronic lymphocytic leukemia (CLL). Zanu was evaluated in treatment-naïve patients with CLL/small lymphocytic leukemia (SLL) in cohorts 1 and 2 of the SEQUOIA RCT. We used an unanchored matching-adjusted indirect comparison (MAIC) to compare the efficacy and safety of acala ± obin versus zanu in patients with treatment-naïve CLL/SLL without del(17p). Datasets were derived from comprehensive individual patient data (IPD) from ELEVATE-TN and published aggregate data from cohort 1 in SEQUOIA. Methods In this unanchored MAIC, we weighted IPD for the acala + obin and acala monotherapy arms from ELEVATE-TN to match zanu baseline data from SEQUOIA. We excluded patients with del(17p) in ELEVATE-TN to match cohort 1 in SEQUOIA, which excluded patients with del(17p). Patients were matched based on variables considered prognostic and/or predictive of investigator-assessed progression-free survival (INV-PFS) in an exploratory multivariate Cox-regression analysis of ELEVATE-TN. These were age, ECOG status, Binet stage, bulky disease, B2 microglobulin, cytopenia, del(11q), trisomy 12, IGHV status,and TP53 mutation. The efficacy analysis assessed INV-PFS in randomized patients (acala + obin, n = 162; acala monotherapy, n = 163; zanu, n = 241) using the Oct 2021 data cut-off (DCO) for ELEVATE-TN and the Oct 2022 DCO for SEQUOIA (median follow-up 58 versus 44 months). Pseudo-IPD for INV-PFS for zanu were obtained from Kaplan-Meier curves. The safety analysis assessed the incidence of adverse events (AEs) and reported the odds ratios (ORs) of AEs in treated patients (acala + obin, n = 162; acala monotherapy, n = 162; zanu, n = 240). To compare the incidence of AEs, the ELEVATE-TN Sep 2020 DCO was used to match the median follow-up from the SEQUOIA Oct 2022 DCO (47 versus 44 months). Results In the efficacy analysis, the acala + obin and acala monotherapy effective sample sizes (ESSs) post-matching were 124 (76%) and 105 (64%), respectively. Matching had little impact on acala + obin and acala monotherapy INV-PFS (Figure 1). Post-matching, 36-month INV-PFS was higher with acala + obin (95%; 95% CI: 90-97) than with zanu (84%; 95% CI: 79-88). The MAIC-weighted Cox hazard ratio (HR) found INV-PFS to be superior with acala + obin versus zanu (HR: 0.41; 95% CI: 0.23-0.74; Figure 1). No evidence of a difference between acala monotherapy post-matching and zanu was found when looking at 36-month INV-PFS (86%; 95% CI: 78-91 versus 84%; 95% CI: 79-88; HR: 0.91; 95% CI: 0.53-1.56). In the safety analysis, the acala + obin and acala monotherapy ESSs post-matching were 123 (76%) and 103 (64%), respectively. There were no significant differences in the odds of having most types of AE with acala + obin versus zanu, except for higher odds of having any grade neutropenia (OR: 2.19; 95% CI: 1.33-3.60) and arthralgia (OR: 2.33; 95% CI: 1.37-3.96). Acala monotherapy showed lower odds of having any grade hypertension (OR: 0.44, 95% CI: 0.20-0.99; Figure 2) and no significant differences in the odds of having other types of AEs versus zanu. Conclusions In this MAIC of ELEVATE-TN and SEQUOIA evaluating patients with treatment-naïve CLL/SLL without del(17p), acala + obin had a longer INV-PFS versus zanu, while there was no evidence of a difference between acala monotherapy and zanu. Acala + obin and acala monotherapy generally had similar safety profiles to zanu. However, acala monotherapy was associated with lower odds of any grade hypertension versus zanu, while acala + obin was associated with higher odds of any grade neutropenia and arthralgia versus zanu. Although the results of MAIC analyses can only be hypothesis-generating, these results address an important data gap by systematically comparing these two commonly used regimens where randomized, prospective data are not available.

Efficacy of Chimeric Antigen Receptor T-Cell Therapy Is Not Impaired By Previous Bispecific Antibody Treatment in Patients with Large B-Cell Lymphoma

Introduction: Potential T-cell exhaustion after bispecific antibody (BsAb) treatment remains an open question, raising the theoretical concern that prior BsAb exposure could affect subsequent chimeric antigen receptor (CAR) T-cell efficacy. Clinical data on CAR T-cell outcomes after prior BsAb treatment in the setting of large B-cell lymphoma (LBCL) are scarce and highly awaited to better define treatment sequencing in relapsed/refractory (R/R) patients. Methods: We conducted a retrospective, international study including R/R LBCL patients treated with CD19-targeted CAR T-cells at 15 centers between July 2018 and January 2023 who had been exposed to BsAbs prior to apheresis. Then, we identified a control cohort from patients included in the DESCAR-T Registry (n=764). We carried out a 1:1 propensity score matching (PSM) to achieve balance between cohorts; 13 baseline covariates were included in the PSM. We compared response rates, survival outcomes and toxicity after CAR T-cell therapy, according to previous BsAb exposure. Results: We identified 47 LBCL patients who received BsAb therapy prior to CAR T-cell apheresis. Median age was 65 years (range 31-82), with a male predominance (66%), and median prior lines of therapy before BsAb were 2 (IQR 2-3) (Table). The BsAbs targeted CD20/CD3 (91%) or CD22/CD3 (9%), either in monotherapy (n=41, 87%) or in combination with other agents (n=6, 13%) (lenalidomide [n=2], polatuzumab [n=1], chemotherapy [n=2], missing [n=1]). The median time on BsAb treatment was 98 days (IQR 56-160) with a best overall (complete) response rate (ORR [CRR]) of 47% (19%). Median progression-free survival (PFS) and duration of response (DOR) were 3.1 months (95% CI 2.7-4.4 months) and 8.8 months (95% CI 2.2-NR), respectively. Cytokine release syndrome (CRS) occurred in 59% of patients (grade 3 in 4%). No neurologic toxicity (NT) was reported. In 26 (55%) patients, bispecific antibody was the last line before CAR T-cell therapy. Median washout between the last BsAb dose and lymphocyte apheresis for CAR T-cell manufacturing was 43 days (range 34-103 days). In terms of the subsequent CAR T-cell therapy, patients received axi-cel (n=22, 47%), tisa-cel (n=20, 43%) or liso-cel (n=5, 11%). Most patients developed CRS after infusion (79%, 6% grade &amp;gt;2), with a low rate of NT (23%, 2% grade &amp;gt;2). Neutropenia and thrombocytopenia grade &amp;gt;2 were reported in 66% and 45% of patients, respectively. Regarding efficacy, ORR after infusion was 83% (CR 43%). Median PFS and overall survival (OS) were 6.6 months (95% CI 2.6-not reached [NR]) and NR (95% CI 9.0-NR), respectively. The rate of overall (complete) response was similar between patients who had previously responded (CR or PR) or not (SD or PD) to BsAb therapy (82% [41%] vs 84% [44%], respectively, p=0.64). However, all 9 patients achieving CR after BsAb achieved subsequent response to CAR T-cells. Given the wide variability in the washout between last BsAb dose and lymphocyte apheresis, we evaluated the impact of this interval on CAR T-cell efficacy. The 6-month PFS and OS of patients previously exposed to BsAb within 45 days of lymphocyte apheresis was similar to patients who had a longer washout (59% vs 47% [p=0.25] and 83% vs 67% [p=0.21], respectively). In the second part of the analysis, we matched our cohort with a control group of CAR T-cell recipients not previously exposed to BsAbs. The final analysis included 2 sets of 42 patients with comparable characteristics. Median follow-up from CAR T-cell infusion was 11.5 months for the BsAb cohort (CI 95% 6.4-19.0 months) and 18.8 months for the control cohort (CI 95% 10.9-23.0 months). Patients with previous BsAb exposure showed a similar PFS (p=0.10, Figure) and OS (p=0.08) after CAR T-cell infusion in comparison to the control group. In terms of toxicity, there were no differences in the incidence of CRS (p=0.41) or NT (p=1.0) after infusion. Conclusions: Previous exposure to bispecific antibody treatment targeting different antigens does not have a negative impact on survival outcomes after CAR T-cell therapy. Lack of response to a previous BsAb does not predict for lower response rates after CAR T-cell infusion.

Safe and Effective Escalation of Evidence-Based Chemotherapy for Mature B Cell Non-Hodgkin's Lymphoma in a Low Resource Setting

BACKGROUND Although high intensity chemotherapy regimens result in &amp;gt;90% long term survival of children with Mature B-cell Non-Hodgkin Lymphoma (MB-NHL), low intensity chemotherapy regimens are used in most Sub-Sahara African (SSA) setting resulting in decades of less than 20% long term survival. This is in part because dose-intense chemotherapy strategies that are standard of care in high income countries (HIC) have not been widely or effectively implemented in low- and middle income countries (LMIC). We investigated the toxicity and outcomes of children with MB-NHL who were treated with a treatment regimen that includes 1g/M2 of methotrexate per dose (mini COPADM) at Mulago National Referral Hospital in Uganda. The objective of this study was to evaluate the safety and effectiveness of an incremental chemotherapy escalation strategy to control treatment-related toxicities and increase response and survival of children treated for MB-NHL at a pediatric oncology center in the SSA setting. METHODS We prospectively collected clinical outcomes on children under 18 years with MB-NHL at Mulago National Referral Hospital (MNRH) in Uganda between January 2020 and July 2023. Overall (OS) and event-free survival (EFS) were calculated using the Kaplan-Meier method. Events in the EFS analysis were: 1) Death; 2) Relapse; or 3) Persistent or progressive disease at the end of Cycle 3. Patients were censored at the earlier of two years from presentation or their last day of follow-up. Descriptive statistics were presented. Toxicities were graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 5. RESULTS We identified 77 patients, among whom 16 (21%) died prior to commencement of the first cycle of chemotherapy and 6 (8%) treated with alternative therapies. The 55 patients who were treated with mini COPADM with 1g/M 2 of methotrexate and are included in this analysis had similar demographics and clinical phenotypes to the 22 that were excluded. The median age was 9.6 years (interquartile range ((IQR) 6.6 - 11.7 years) with 38 (69%) males. Patients were Stage III (53%, 29/55), stage IV (38%, 21/55); and 55%, (30/55) were high-risk. The most common presentations were abdominal mass 43 (78%) and jaw mass 14 (25%). With a median follow-up time of 9 months (IQR 6 - 24 months), the 1-year overall survival (OS) and event free survival (EFS) were 56%; 95% CI (41 - 76) and 41%; 95%CI (27 - 61) respectively. For children with high-risk disease, 1-year OS was 44%; 95%CI (28 - 72) and EFS 25%; 95% CI (12 - 51). Toxicities included febrile neutropenia (83%) and CTCAE grade ≥3 mucositis (44%). For the 12 patients whose cause of mortality was recorded, 1 case (8.3%) was treatment-related and 11 (91.7%) were due to cancer. CONCLUSION: This study establishes baseline response rates, survival, and toxicity for patients with pediatric MB-NHL in Uganda treated with 1g/M2 of methotrexate. Toxicities were consistent with treatment received, perhaps exacerbated by synergy of anthracycline (50 mg/m2) along with intermediate dose MTX. These findings suggest that mini-COPADM with 1g/M 2 of methotrexate can be safely supported with the current clinical resources at MNRH and this low dose regimen accounts for the poor survival of children with MB-NHL in our center. We plan to escalate our therapy to mini-COAPDM with 3g/M2 and addition of Rituximab, with contingent intensification of supportive care to curb treatment-related toxicities.

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

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

Incidence of Infections Associated with the Use of Bispecific Antibodies in B-Cell Non-Hodgkin Lymphomas

Background: Despite recent advances in the treatment of B-cell non-Hodgkin lymphomas (NHL), most patients with relapsed/refractory (R/R) disease are at high risk of dying from their disease. Bispecific antibodies (BsAbs) are novel therapies with favorable response rates in R/R B-cell NHL even after cellular therapies. Mosunetuzumab, epcoritamab, glofitamab, and odronextamab are CD20 targeting BsAbs that have proven efficacy for R/R B-cell NHL. These treatments are generally well tolerated, but the infectious complications are not well described in the literature. Our study aims to quantify the relative incidence of infections associated with B-cell NHL targeted BsAbs. Methods: We conducted a preliminary evaluation, of an ongoing pooled analysis encompassing single agent BsAbs used in B-cell NHL with no prior use of alternate BsAbs. Exclusion criteria included studies reporting the use of BsAbs as part of combination therapy and trispecific antibodies. Results: A total of 546 B-cell NHL patients (number of trials, n=4) were treated with BsAbs in the studied period. Pooled median follow up was 11.7 . Relevant adverse events included all grade neutropenia in 26.9% (n=147/546), grade III/IV neutropenia in 20% (n=109/546), all grade infections in 40.1% (n=219/546), grade III/IV infections in 16.8% (n=92/546), all grade pneumonia in 7.2% (n=17/235), and coronavirus 2019 (COVID-19) in 1.3% (n=3/235). Incidence of grade III/IV and all grade infections of the BsAbs in each study are shown in figure 1. In addition, all grade cytokine release syndrome was seen in 56.4% (n=308/546) and death was reported in 33 patients of which 4 (0.7%) were reported to be secondary to infections. Conclusion: Data from this ongoing analysis better describes the various infectious risks of patients with B-cell NHL receiving BsAbs. Providers should remain vigilant regarding these risks and intervene promptly in such situations. The finalized pooled analysis with a larger sample size may corroborate these findings.

Open-labeled, multicenter phase II study of prophylactic administration of pegylated granulocyte colony-stimulating factor in relapsed or refractory multiple myeloma who received pomalidomide-based regimens (KMM170).

Pegylated granulocyte colony-stimulating factor (G-CSF) has been widely used for preventing febrile neutropenia in various types of cancer treatment. In the present study, we prospectively evaluated the safety and efficacy of pegfilgrastim as a primary prophylaxis of febrile neutropenia and infection among patients with relapsed refractory multiple myeloma (RRMM) treated with pomalidomide-based regimens. Thirty-three patients with RRMM who received pomalidomide and dexamethasone (Pd) with or without cyclophosphamide (PCd) were enrolled in this study. Twenty-eight patients were treated with PCd and 5 patients were treated with Pd. All patients were given pegfilgrastim subcutaneously with a single administration performed on the first day of each cycle as primary prophylaxis until the fourth cycle. The median age of the patients was 75 (range 56-85), and the median prior line of therapy was 2 (range 2-6). Seventeen patients (51.5%) had any grade of neutropenia and 20 (60.6%) had any grade of thrombocytopenia before starting pomalidomide treatment. During the 4 cycles of treatment, grade 3 or more neutropenia occurred in 17 patients (51.5%), and 4 (12.1%) experienced grade 3 or more febrile neutropenia. Grade 3 or more infections occurred in 5 patients (15.2%). Interestingly, the patients with markedly increased ANC of more than 2 x 109/L compared to baseline ANC after 7 days of pegfilgrastim at 1st cycle of treatment showed a significantly lower incidence of grade 3-4 neutropenia. The most common adverse event of pegfilgrastim was fatigue, and all the adverse events caused by pegfilgrastim were grade 1 or 2. And there was no significant change in the immune cell population and cytokines during the administration of pegfilgrastim. Considering that this study included elderly patients with baseline neutropenia, pegylated G-CSF could be helpful to prevent severe neutropenia, febrile neutropenia, or infection in patients with RRMM.

Cost-utility analysis and cross-country comparison of pharmacogenomics-guided treatment in colorectal cancer patients participating in the U-PGx PREPARE study

ObjectivesA cost-utility analysis was conducted to evaluate pharmacogenomic (PGx)-guided treatment compared to the standard-of-care intervention among patients diagnosed with colorectal cancer (CRC) in Italy. MethodsData derived from a prospective, open-label, block randomized clinical trial, as a part of the largest PGx study worldwide (355 patients in both arms) were used. Mortality was used as the primary health outcome to estimate life years (LYs) gained in treatment arms within a survival analysis context. PGx-guided treatment was based on established drug-gene interactions between capecitabine, 5-fluorouracil and irinotecan with DPYD and/or UGT1A1 genomic variants. Utility values for the calculation of Quality Adjusted Life Year (QALY) was based on Visual Analog Scale (VAS) score. Missing data were imputed via the Multiple Imputation method and linear interpolation, when possible, while censored cost data were corrected via the Replace-From-The-Right algorithm. The Incremental Cost-Effectiveness Ratio (ICER) was calculated for QALYs. Raw data were bootstrapped 5000 times in order to produce 95% Confidence Intervals based on non-parametric percentile method and to construct a cost-effectiveness acceptability curve. Cost differences for study groups were investigated via a generalized linear regression model analysis. Total therapy cost per patient reflected all resources expended in the management of any adverse events, including medications, diagnostics tests, devices, surgeries, the utilization of intensive care units, and wards. ResultsThe total cost of the study arm was estimated at €380 (∼ US$416; 95%CI: 195–596) compared to €565 (∼ US$655; 95%CI: 340–724) of control arm while the mean survival in study arm was estimated at 1.58 (+0.25) LYs vs 1.50 (+0.26) (Log Rank test, X2 = 4.219, df=1, p-value=0.04). No statistically significant difference was found in QALYs. ICER was estimated at €13418 (∼ US$14695) per QALY, while the acceptability curve indicated that when the willingness-to-pay was under €5000 (∼ US$5476), the probability of PGx being cost-effective overcame 70%. The most frequent adverse drug event in both groups was neutropenia of severity grade 3 and 4, accounting for 82.6% of total events in the study arm and 65.0% in the control arm. Apart from study arm, smoking status, Body-Mass-Index and Cumulative Actionability were also significant predictors of total cost. Subgroup analysis conducted in actionable patients (7.9% of total patients) indicated that PGx-guided treatment was a dominant option over its comparator with a probability greater than 92%. In addition, a critical literature review was conducted, and these findings are in line with those reported in other European countries. ConclusionPGx-guided treatment strategy may represent a cost-saving option compared to the existing conventional therapeutic approach for colorectal cancer patient management in the National Health Service of Italy.