Hematologic Adverse Events Research Articles

Phase I dose escalation and pharmacokinetics clinical trial of mitoxantrone hydrochloride liposome in children with relapsed and refractory solid tumors.

10047 Background: Compared with solvent-based mitoxantrone, mitoxantrone hydrochloride liposome has been found to reduce bone marrow toxicity. This open-label, muti-center, single-arm phase I clinical trial aims to evaluate the safety and efficacy of mitoxantrone hydrochloride liposome in pediatric with solid tumors. Methods: The study was divided into Phase Ia and Ib. Phase Ia was the dose escalation study, with a "3+3" design. Patients received mitoxantrone hydrochloride liposome at three dose levels (16 mg/m2, 20mg/m2, 24mg/m2, d1) in combination with irinotecan (50mg/m2, d1-5) and vincristine (1.5mg/m2, d1) every 3 weeks. Pharmacokinetic studies were conducted simultaneously. The primary endpoint of Phase Ia was the maximum tolerated dose (MTD). In phase Ib, patients received the combination therapy of mitoxantrone hydrochloride liposome at the MTD dose. The primary endpoint of Phase Ib was the incidence and severity of hematological adverse events. Secondary endpoints in both phases included objective response rate (ORR), pharmacokinetic (PK) parameters, and others. Results: From October 2022 to January 2024, a total of 51 pediatric patients with relapsed and refractory solid tumors were enrolled, 28 patients in Phase Ia and 23 patients in Phase Ib. The median age was 10.0 years (range: 3, 21). All Patients could be evaluated for toxicity and 40 for efficacy. The MTD of mitoxantrone hydrochloride liposome was determined to be 24mg/m2. The results of pharmacokinetic analysis were not returned. Highest incidence of hematological and non-hematological adverse events (AEs) were anaemia (88.2%), diarrhea (84.3%). The newly found or aggravated TnIUtra, BNP value abnormality and lower LV function after medication were 4 (11.8%), 5 (14.3%) and 0 (0.0%), respectively. The overall ORR and DCR were 50.0% (95% CI: 33.8% - 66.2%) and 90.0% (95% CI: 76.3% -97.2%). 13 patients (25.0%) treated with mitoxantrone hydrochloride liposome combination regimen received the opportunity of surgery. Conclusions: The mitoxantrone hydrochloride liposome combination regimen has demonstrated an acceptable toxicity profile and promising clinical efficacy in pediatric patients with solid tumors, especially in sarcomas. Clinical trial information: NCT05620862 .

Safety analysis for BH009 vs docetaxel from a bioavailability study.

e13129 Background: BH009 is a novel polysorbate 80-free formulation of docetaxel (DXT) that could eliminate hypersensitivity reactions associated with polysorbate 80. In a bioavailability study of BH009 vs docetaxel (Taxotere), we reported that the ratios for the total DXT and free-DXT fraction Cmax, AUC0-t, and AUC0-∞ of BH009 and docetaxel were within 80% to 125% (90% confidence intervals). Here, we report the safety analysis from the same study population. Methods: This multicenter, randomized, open-label, 2-way crossover study compared the pharmacokinetics and safety of BH009 and docetaxel (Winthrop docetaxel injection, an authorized generic of Taxotere). A total of 46 patients with breast, head and neck, lung, stomach, ovarian, or cervical cancers were randomized, of which 43 patients were treated with BH009 and 44 patients were treated with docetaxel. Patients received a single dose of 75 mg/m2 BH009 or Taxotere IV over 60 min, with ≥21-d washout between doses. Safety evaluation included treatment-emergent adverse events (TEAEs) and serious adverse events. Results: In all, 198 TEAEs were reported during the study: 94 after the administration of BH009 and 104 after the administration of docetaxel. No serious adverse events or deaths occurred. The only grade 3/4 toxicities that occurred for both arms during this study were hematologic. Overall, the incidence of grade 3/4 hematologic toxicity was significantly lower in the BH009 group than in the docetaxel group (2.3% vs 15.9%). Only one patient in BH009 arm experienced grade 3 anemia; no additional grade 3/4 hematologic adverse events were seen in the BH009 group. The incidence of grade 3/4 leukopenia, neutropenia, and lymphopenia in the Taxotere group was 6.8%, 4.6%, and 2.3%, respectively. The overall safety profile in the BH009 group was better than that in the Taxotere group. Conclusions: A better safety profile was observed in the study when BH009 group was compared to docetaxel group in grade 3/4 hematologic toxicity. Clinical trial information: NCT04889599 . [Table: see text]

First-in-human trial of M9140, an anti-CEACAM5 antibody drug conjugate (ADC) with exatecan payload, in patients (pts) with metastatic colorectal cancer (mCRC).

3000 Background: CEACAM5 is a cell surface protein with limited expression in adult healthy tissues, but high expression in various adenocarcinomas, particularly in CRC (>90% of pts). M9140 is the first anti-CEACAM5 ADC with a topoisomerase 1 inhibitor (Top1i) payload (exatecan). The ß-glucuronide linker connecting the M9140 antibody backbone to the payload is highly stable in circulation (drug-to-antibody ratio=8). In preclinical models, M9140 has demonstrated strong potency, antitumor activity, and a bystander effect. Methods: This Phase 1 trial (NCT05464030) investigated the safety, tolerability, pharmacokinetics (PK), and preliminary clinical activity of M9140 as monotherapy (Q3W [Day 1 of 21-day cycles]; IV) in adults with CRC (ECOG PS ≤1) who had received ≥2 prior lines of treatment. The primary objectives of Part 1A were to determine the maximum tolerated dose (MTD) and/or recommended dose(s) for expansion (RDE). Results: At data cutoff (19 Jan 2024), 40 pts from the US, EU, and Japan were treated across 7 dose levels (DLs): 0.6 mg/kg, 1.2 mg/kg (n=3, each), 2.4 mg/kg (n=7), 2.6 mg/kg (n=4), 2.8 mg/kg (n=12), 3.0 mg/kg (n=4), and 3.2 mg/kg (n=7, including 3 pts with primary G-CSF prophylaxis). Most pts were heavily pretreated (80% had ≥3 lines of prior treatment; 100% received irinotecan). Overall, 6 pts experienced dose-limiting toxicities (DLTs); the majority were hematological adverse events at DLs 3.0 and 3.2 mg/kg; 1 patient (at 2.8 mg/kg) experienced a Grade 5 sepsis. The most frequently reported Grade ≥3 treatment-emergent adverse events (TEAEs) were neutropenia in 16 (40.0%) pts, thrombocytopenia and anemia in 11 (27.5%) pts each, and WBC decreased in 10 (25.0%) pts. No events of ocular toxicity/interstitial lung disease (ILD) were reported. The best objective response per RECIST v1.1 was partial response (PR) in 4 (10.0%) pts (3 confirmed) (all at DLs ≥2.4 mg/kg); stable disease (SD) in 17 (42.5%), including 6 (15.0%) lasting for ≥100 days and progressive disease (PD) in 6 (15.0%) pts. For a total of 13 (32.5%) pts, the best overall response was not evaluable, including 6 (15.0%) who had no on-treatment tumor assessment yet. The preliminary median progression-free survival (PFS) was 6.7 months (95% CI: 4.6, 8.4). As of data cutoff, 15 (37.5%) pts are continuing treatment. Based on the safety, tolerability, preliminary clinical activity, PK, and PK/pharmacodynamics modeling data, 2.8 mg/kg was declared as the MTD, and 2.4 mg/kg and 2.8 mg/kg were chosen as the RDEs and have been taken forward into a randomized expansion study. Conclusions: M9140 demonstrated encouraging activity in heavily pretreated pts with advanced CRC, with a manageable and predictable safety profile. Contrary to approved ADCs with Top1i payloads, no ILD or ocular toxicities were observed. Evaluation of M9140 in mCRC continues in the dose expansion part of this study. Clinical trial information: NCT05464030 .

A phase Ib, open-label study of add-on therapy with CK0804 in participants with myelofibrosis and suboptimal response to ruxolitinib.

6580 Background: Suboptimal response to JAK2 inhibitor ruxolitinib in patients with myelofibrosis (MF) remains a major unmet medical need. Deregulated inflammatory pathways including CXCR4/CXCR12 axis might limit the therapeutic efficacy of ruxolitinib and contribute to disease progression. In preclinical studies, cord blood-derived, CXCR4 enriched T regulatory cells [CK0804; T-regs] showed ability to suppress inflammatory cytokines playing major role in MF (Huang et al., Cytotherapy, 2023). Methods: This phase Ib study evaluates the safety and activity of up to 6 doses of CK0804 (non-HLA matched, Cryopreserved) T-regs therapy, fixed dose of 100 million cells, added every 28 days to ruxolitinib. Patients with MF on ruxolitinib for ≥12 weeks and stable dose for ≥8 weeks, who have palpable splenomegaly, symptoms, or grade 2 cytopenia are eligible. Primary objective is safety, secondary objective is overall response per IWG-MRT criteria at 24 weeks. Present analysis includes cohort of initial run-in safety phase. Results: Nine patients of median age 68 years (range, 55-84) were enrolled, 44% were males. Median blood counts [range] showed while blood cells 10.6 [3.1-70.4] x10^9/L, hemoglobin 8.8 [7.8-11.5] g/dL, platelets 177 [148-311] x10^9/L. Three patients were transfusion dependent. Median spleen volume was 1449 cubic centimeters (176-5609), 7 patients (78%) had clinically worsening splenomegaly. Median symptoms score (MPN-SAF TSS) was 23 (20-40). Six (67%) had diploid karyotype, 5 (56%) had JAK2 mutation and 8 (89%) had additional no-driver mutations. Median duration of prior ruxolitinib was 35 months (range, 10-132), all patients were on ≥ 10 mg twice daily dose with no dose change throughout the study. Four patients received all six doses of CK0804, three patients have ongoing treatments. One patient experienced infusion reaction to second dose of CK0804 likely due to the excipient dimethylsulfoxide and withdrew consent. One patient died of unrelated cause prior to the infusion 6. There were no nonhematologic or hematologic adverse events. Two transfusion dependent patients who were evaluable for response had decreased monthly need for transfusions by the end of the sixth cycle: 4 to 2.8 units and 1.2 to 0.8 units, respectively. All patients noticed symptoms improvement; median best decline in MPN-SAF TSS was -38% (range, -20% to -71%); with ≥ 50% reduction in 3 patients. One patient achieved ≥ 35% spleen volume reduction at week 12. Longitudinal analysis of markers of inflammation is in progress and will be presented at the conference. Conclusions: This preliminary analysis of run-in phase of study evaluating CXCR4 enriched T regs cell therapy as addition to ruxolitinib shows initial safety with no myelosuppressive adverse events and promising clinical activity. Active enrollment of participants to the expansion cohort is ongoing. Clinical trial information: NCT05423691 .

Trilaciclib use for prevention of hematological adverse events in chemotherapy: A meta-analysis of real-world studies and clinical trials.

e24130 Background: Trilaciclib, a cyclin-dependent kinase (CDK)-4 and -6 inhibitor, is the only FDA-approved agent that preemptively protects hematopoietic stem cells from chemotherapy-induced myelosuppression (CIM) without compromising efficacy. It transiently arrests hematopoietic stem cells in the G1 phase, thus temporarily blocking progression through the cell cycle and protecting progenitor cells from cytotoxicity. It has been approved for use in extensive-stage small-cell lung cancer (SCLC). Limited real-world evidence of its efficacy exists owing to its recent approval. We sought to enhance our understanding and evaluate the preventive effect of trilaciclib through a combined meta-analysis of clinical trials and retrospective studies. Methods: A systematic literature search was performed on PubMed, Embase, Cochrane, and Scopus from inception until December 2023. Retrospective cohort studies and randomized-controlled trials with trilaciclib and non-trilaciclib arms were included. The primary outcomes of interest were CIM-related grade ≥3 hematological adverse events, and secondary outcomes included supportive care interventions to remedy CIM. Quantitative meta-analyses were conducted using the random-effects model on STATA v17. Results: The meta-analysis comprised seven studies, including four clinical trials and three real-world retrospective studies, including 6537 patients with extensive SCLC or locally recurrent or metastatic breast cancer. Chemotherapy regimens in SCLC patients included the combination of etoposide/platinum (E/P), E/P/PD-L1 inhibitors, or topotecan, and gemcitabine/carboplatin in patients with breast cancer. The mean age of the patients was 63.28 ± 5.31 years, and 49.21% were males. Administration of trilaciclib led to a reduction in the incidence of febrile neutropenia (2.41% vs. 7.56% OR = 0.35), severe neutropenia (21.76% vs. 41.91% OR = 0.57), anemia (18.02% vs. 32.41% OR = 0.51), and thrombocytopenia (20.06% vs. 31.25% OR = 0.62). Utilization of cytopenia-supportive therapies, including granulocyte colony-stimulating factor use (40.47% vs. 81.01% OR = 0.61) and RBC transfusions (16.66% vs. 18.25% OR = 0.59) were significantly lower in the trilaciclib cohort as compared to control. The overall response rate (mean difference = 1.09,95% CI = 0.74–1.60) and overall survival (OR = -0.02 95% CI = -0.95-0.92) were similar, and progression-free survival was noted to be longer in the trilaciclib group (mean difference = 1.75, 95% CI = 0.75-2.75). Conclusions: Trilaciclib use consistently demonstrated efficacy in reducing CIM, thus lowering cytopenia-related healthcare utilization without compromising treatment efficacy in trials and real-world settings. Its novel mechanism of action offers great promise, and further studies with larger sample sizes on various cancers will corroborate existing evidence.

Safety and Efficacy of Mycophenolate Mofetil Associated With Tacrolimus for Kidney-pancreas and Kidney Transplantation: A Systematic Review and Meta-Analysis of Randomized Studies

IntroductionThis study evaluated the efficacy and safety of mycophenolate mofetil (MMF) associated with tacrolimus (TAC) in patients undergoing kidney-pancreas and kidney transplants, in comparison with cyclosporine (CyA), azathioprine (AZA), everolimus (EVL), sirolimus (SRL), manitimus (MAN), mizoribine (MZR), and enteric-coated mycophenolate sodium (ECMPS) in combination or monotherapy. MethodsA systematic review and meta-analysis of randomized clinical trials was performed. The outcomes comprised acute rejection, graft loss, and adverse events. ResultsThirty studies were included. The main adverse events related to the TAC+MMF scheme were infection (36%; 95%CI: 26%-46%), including cytomegalovirus (CMV) (14%; 95%CI: 8%-20%); anemia (20%; 95%CI: 2%-37%); leukopenia (18%; 95%CI: 3%-33%); nausea (20%; 95%CI: 1%-39%); and diarrhea (26%; 95%CI:13%-40%). TAC+MMF was compared to the schemes AZA+TAC, CyA+AZA, CyA+MMF, CyA+SRL, ECMPS, EVL, MAN+TAC, MMF+SRL, MZR, TAC+AZA, TAC+EVR, TAC+MZR, TAC +SRL and TAC. TAC+MMF was associated with a lower risk of rejection than MMF monotherapy (RD: -0.24; 95%CI -0.46; -0.02). Comparing TAC+MMF with the other regimens, no significant difference was found for graft loss. TAC+MMF was associated with a higher risk of infections than MZR (RD: 0.174; 95%CI: 0.25; 0.323) and TAC monotherapy (RD: 0.07; 95%CI 0.003; 0.138). ConclusionGastrointestinal and hematological adverse events and infections are the most common with TAC+MMF for kidney-pancreas and kidney. TAC+MMF effectively prevents acute cellular rejection, and alternatives with AZA, CyA, SRL, ECMPS, EVL, MAN, and MSR have similar efficacy and safety profiles. TAC monotherapy and MZR may be associated with a lower risk of infections.

Preliminary efficacy and safety of total neoadjuvant therapy combined with PD-L1 blockade in pMMR/MSS locally advanced rectal cancer (ESTIMATE): A prospective, single-arm, phase II trial.

e15602 Background: Patients with locally advanced rectal cancer (LARC) experience benefits from total neoadjuvant therapy (TNT). This study aims to explore the efficacy and safety of combining TNT with immunotherapy for pMMR/MSS LARC patients. Methods: ESTIMATE is a prospective, single-center, phase II study (ChiCTR2400079718) enrolling pMMR/MSS LARC patients with tumors located 10cm away from the anal margin. Treatment involved induction chemotherapy with immunotherapy ([mFOLFOX6, days 1-2 + Envafolimab 200mg, ih, day 1]; q2w; 2 cycles), long-course concurrent chemoradiotherapy (LCRT) with immunotherapy ([IMRT, 50Gy/25f, 2Gy + Cape 825mg/m2, bid]; 5w + Envafolimab 200mg, ih, day 1; q2w; 3 cycles), consolidation chemotherapy with immunotherapy ([mFOLFOX6 + Envafolimab; 2 cycles), and then total mesorectal excision (TME) 3 weeks later or watch and wait (W&W). The primary endpoint is the pathological complete response (pCR) rate. Results: Until Nov. 16th, 2023, 35 patients were enrolled, with 28 completing the TNT regimen. The efficacy analysis revealed that out of 28 patients, 12 (42.9%) achieved clinical complete response (cCR), with 7 individuals choosing the W&W strategy. 21 patients underwent TME, yielding 8 with a tumor regression grade (TRG) of 0, 7 with TRG of 1, and 6 with TRG of 2. The rates of pCR, major pathological response (MPR), and complete response (CR) were 38.1% (8/21), 71.4% (15/21), and 53.6% (15/28), respectively. 25 (89.3%) patients experienced treatment-related adverse events (AEs) of any grade. Non-hematological AEs included decreased appetite, fatigue, nausea, and vomiting, while hematological AEs mainly comprised thrombocytopenia, anemia, and leukopenia or neutrophilia. Grade III AEs were primarily leukopenia or neutrophilia (2/28, 7.1%). Additionally, circulating tumor DNA (ctDNA) levels were measured in 7 patients who chose the W&W strategy after achieving cCR. Of these, 6 tested negative for minimal residual disease (MRD), while 1 had a positive MRD result (ctDNA: 0.56 MTM/ml). As of Jan. 26th, 2024, with a median follow-up of 5 months (range: 3-6), no recurrence was observed in any of the patients. Conclusions: The TNT approach, integrating LCRT with mFOLFOX6 and PD-L1 blockade, demonstrated a favorable CR rate and acceptable tolerability, offering a potential avenue for organ preservation in low rectal cancer patients with pMMR/MSS. Long-term benefits need validation through further follow-up. Clinical trial information: ChiCTR2400079718. [Table: see text]

Perioperative therapy for resectable and borderline resectable pancreatic adenocarcinoma: An AGICC clinical trial.

4175 Background: Patients (pts) with pancreatic adenocarcinoma (PDAC) who are candidates for surgery are anatomically segregated into two groups: those with resectable tumors (R-PDAC), and those with borderline resectable tumors (BR-PDAC). For each group, complete surgical resection with no visible or microscopic disease left behind (R0 resection) is generally accepted as the path to cure. Neoadjuvant therapy (NAT) has been used to improve the R0 resection rate. However, the optimal role and type of NAT that will improve R0 resection rate and overall survival (OS) remains controversial. The Academic Gastrointestinal Cancer Consortium (AGICC) evaluated a perioperative strategy with combination chemotherapy and preoperative stereotactic radiation therapy (SBRT) to improve the R0 resection rate. Methods: This prospective, multicenter open label, single arm phase 2 clinical trial conducted among 5 member AGICC institutions enrolled pts with R-PDAC and BR-PDAC. Treatment included 3 cycles of gemcitabine (1000mg/m2) and nab-paclitaxel (125 mg/m2) (GEM/NAB) on days 1, 8 and 15 of a 28-day cycle prior to SBRT (33Gy: 6.6Gy daily x 5) followed by surgery and 3 cycles of adjuvant GEM/NAB. Accrual goal was 20 R-PDAC and 30 BR-PDAC pts selected by central radiology review. Primary objective was to estimate the R0 resection rate for each cohort. Secondary objectives included safety and tolerability of neoadjuvant treatment and OS. Results: Eighty-six pts signed consent and after radiologic screening, 20 R-PDAC patients and 29 BR-PDAC patients were found eligible to begin treatment. One R-PDAC and two BR-PDAC pts did not initiate therapy. 14 (70%) and 19 (66%) R-PDAC and BR-PDAC pts, respectively, completed all neoadjuvant chemotherapy.14 R-PDAC (70%) and 17 BR-PDAC (59%) pts completed SBRT. 11 R-PDAC pts (55%) and 11 (38%) BR-PDAC, underwent surgery. 8 R-PDAC pts (40%) had an R0 resection. One R-PDAC pt had a complete pathologic response (pCR). 8 BR-PDAC pts (28%) had an R0 resection. 19% (3/16) pts undergoing an R0 resection are alive (47-73+ mos). 16 pts (32%) had at least one grade ≥ 3 non-hematologic adverse event (AE); 25 patients (51%) had at least one grade ≥ 3 hematologic AE. 8 pts, 4 R-PDAC and 4 BR-PDAC were hospitalized prior to surgery. One pt (2%) died during NAT. There were no deaths due to surgery. Conclusions: R0 resection rates and survival in R-PDAC and BR-PDAC were low despite a perioperative approach of systemic therapy and SBRT. The lack of survival benefit of GEM/NAB as an adjuvant regimen, as well as SBRT pre-operatively (both shown in studies subsequent to this one) may explain the disappointing results. While an R0 resection for localized PDAC is recognized as essential, our results demonstrate that an R0 resection is not sufficient to cure the majority of PDAC pts who receive NAT with GEM/NAB + SBRT. Future NAT therapy trials should aim to markedly improve the pCR rates associated with R0 resection. Clinical trial information: NCT02723331 .

Long-term follow-up from the phase 1/2 MajesTEC-1 trial of teclistamab in patients with relapsed/refractory multiple myeloma.

7540 Background: Teclistamab, the first approved B-cell maturation antigen × CD3 bispecific antibody (BsAb) with weight-based dosing for the treatment of patients (pts) with triple-class exposed relapsed/refractory multiple myeloma (RRMM), demonstrated rapid, deep, and durable responses in the pivotal MajesTEC-1 study. Here, we report updated results from MajesTEC-1. Methods: Eligible pts received teclistamab at the recommended phase 2 dose (RP2D; 1.5 mg/kg subcutaneous QW preceded by step-up dosing) with the option to switch to Q2W dosing if a partial response or better after ≥4 cycles of therapy (phase 1) or complete response or better (≥CR) for ≥6 mo (phase 2) was achieved; pts not in ≥CR could switch due to adverse events (AEs). Pts could subsequently switch to less frequent dosing if they continued to demonstrate a response. The primary endpoint was overall response rate (ORR) assessed by independent review committee per International Myeloma Working Group 2016 criteria. AEs were graded per Common Terminology Criteria for Adverse Events v4.03. Cytokine release syndrome (CRS) was graded per American Society for Transplantation and Cellular Therapy guidelines. Results: At median follow-up of 30.4 mo, 165 pts had received teclistamab at the RP2D. ORR was 63.0%, and responses continued to deepen, with 46.1% achieving ≥CR. 85.7% (48/56) of MRD-evaluable pts were MRD negative (10-5 threshold). Median duration of response (mDOR) increased to 24.0 mo; median progression-free survival (mPFS) and overall survival (mOS) improved to 11.4 and 22.2 mo, respectively. For pts with ≥CR, mDOR, mPFS, and mOS were not yet reached, and estimated 30-mo DOR, PFS, and OS rates were 60.8%, 61.0%, and 74.2%, respectively. Of the 38 pts who remain on treatment, 37 have switched to a less frequent dosing schedule (eg, Q2W), all of whom maintained responses. Hematologic AEs (any grade/grade 3/4) included neutropenia (72%/65%), anemia (55%/38%), thrombocytopenia (42%/23%), and lymphopenia (36%/35%). Infections occurred in 79% of pts (55% grade 3/4). Of grade 5 infections, 18/22 were due to COVID-19, reflecting study conduct during the COVID-19 pandemic. Onset of new grade ≥3 infections generally decreased over time, which aligned approximately with the median time of switch to Q2W dosing; other factors, such as increasing use of IVIG, may also contribute to this trend. AEs leading to dose reduction (n=1) or discontinuation (n=8; 5 due to infection) were infrequent. No new safety signals were reported. Conclusions: With the longest follow-up of any BsAb in MM, teclistamab continues to demonstrate deep and durable responses, including in pts who switch to less frequent dosing. The safety profile of teclistamab remains consistent with that of BCMA-targeted bispecific therapies, with a notable decrease in new onset of severe infections with time. Clinical trial information: NCT03145181 / NCT04557098 .

Adverse events in real-world patients (pts) with metastatic pancreatic ductal adenocarcinoma (mPDAC) who received FOLFIRINOX (FFX) or gemcitabine with nab-paclitaxel (GnP) in the first line (1L).

e16321 Background: FFX and GnP are the most common 1L treatments for mPDAC. Each regimen is associated with a different profile of toxic effects that impact quality of life. However, the regimens have not been directly compared for safety or efficacy in a randomized controlled trial. RW studies of the frequency of adverse events (AEs) under each regimen have reported inconsistent results. Supportive care such as granulocyte colony-stimulating factor (G-CSF) also affects the rate of hematologic AEs. We assessed AEs and G-CSF use in a RW cohort of mPDAC pts treated with FFX or GnP in the 1L. Methods: This retrospective observational study utilized the Ontada Clinical Data View: Pancreatic Cancer database. Adult pts diagnosed with mPDAC between November 2018 and November 2022 who initiated treatment with 1L FFX or GnP within 90 days of their diagnosis for metastatic disease were included in the study. Diarrhea, fatigue, nausea and vomiting, and neuropathy were available in the data as ungraded AEs abstracted from clinician notes. Assessment of hematologic and hepatic AEs were based on observed lab values and were graded according to the Common Terminology Criteria for AEs version 5. Results: 2,918 pts met study inclusion criteria: 1,703 received 1L GnP and 1,215 received 1L FFX. For the GnP vs. FFX cohorts, the median age at 1L initiation was 71yr (IQR: 64–76) vs. 65yr (IQR: 58–71), 52% vs. 57% were male, 65% vs. 68% were white, 9% vs. 15% had an ECOG score of 0, and 40% vs. 39% had an ECOG score of 1. GnP pts had a statistically significantly greater rate of grade 1/2 and 3/4 neutropenia (26% vs. 15%, p = .001; 25% vs. 17%, p = .014), grade 1/2 thrombocytopenia (25% vs. 20%, p < .001), grade 1/2 and 3/4 anemia (87% vs. 68%, p < .001; 19% vs. 6%, p = .001), grade 1/2 elevated ALT (62% vs. 44%, p < .001), grade 1/2 elevated AST (68% vs. 50%, p < .001), and grade 1/2 elevated ALP (68% vs. 58%, p < .001). For GnP vs. FFX, there was no statistically significant difference in grade 3/4 thrombocytopenia (9% vs. 5%, p < .001), grade 3/4 elevated ALT (6% vs. 5%, p = .367), grade 3/4 elevated AST (9% vs. 5%, p = .170), grade 3/4 elevated ALP (11% vs. 11%, p = .417), and grade 1/2 and 3/4 hypokalemia (32% vs. 34%, p = .241; 7% vs. 13%, p = .060). There were not statistically significant differences for GnP vs. FFX for AEs reported in clinician notes including diarrhea (12% vs. 18%, p = .074), fatigue (15% vs. 12%, p = .187), nausea and vomiting (10% vs. 11%, p = .399), and neuropathy (15% vs. 12%, p = .219). G-CSF was used by 19% vs. 57% of GnP vs. FFX patients (p < .001), with median time to first use of G-CSF 14 days (IQR: 7–35) vs. 0 days (IQR: 0–14). Conclusions: In a RW cohort of mPDAC pts treated with 1L GnP or FFX, pts experienced a variety of serious AEs. The burden of AEs was higher among the RW GnP cohort than the RW FFX cohort. G-CSF was more prevalent and began earlier in the FFX cohort, indicating prophylactic use.

Neoadjuvant S-1 plus cisplatin-based chemoradiotherapy compared with surgery alone for locally advanced gastric cancer: Randomized, phase II trial.

4076 Background: Patients with locally advanced gastric cancer (LAGC), are known to have a high risk of recurrence even after surgery. This study was designed to delineate whether neoadjuvant concurrent chemoradiotherapy (CCRT) using the S-1/Cisplatin (SP) regimen can effectively downstage the T stage in patients with clinically T4 stage compared with surgery alone (OP). Methods: This is a randomized phase II open label trial and gastric cancer patients with initial clinical T4 were enrolled. Patients were randomized into neoadjuvant CCRT or OP. For the CCRT group, S-1 (20 mg/m2 twice daily, 2 weeks on and 1 week off) and cisplatin (30 mg/m2/day, first day of week 1, 2, 4, and 5) were administered concurrent with radiotherapy (day 1-5 for 5 weeks, total 45 Gy/25 fractions,). Surgery was performed within 3 to 6 weeks after the completion of CCRT. For the OP group, curative surgery was performed within 3 weeks after randomization. Post-operative adjuvant chemotherapy was chosen as S-1 monotherapy or combination of Capecitabine, and Oxaliplatin according to the physician’s choice. The primary objective of this study was to compare the downstaging rates between the groups (65% and 40% for the CCRT and OP group). Using a type I error rate of 0.10 and a power of 0.80, the planned sample size was 51 patients per group but the study was closed prematurely. Results: Between November 2016 and August 2021, 49 patients with T4 were enrolled. Of those, 26 (CCRT) and 23 (OP) patients were randomized but diagnostic laparoscopy for preoperative screening revealed peritoneal seeding in some patients. Finally, 23 (CCRT) and 17 (OP) patients were evaluable and clinicopathologic characteristics were well balanced between the two groups in per protocol analysis. For CCRT, 19 out of 23 (82.61%) patients satisfied downstage, while among 8 out of 17 (47.06%) patients in OP group satisfied downstage ( P=0.038). The median disease-free survival (DFS) was 27.91 months in CCRT group, and 45.96 months in OP group ( P=0.985). The median overall survival (OS) was not reached in CCRT group, and 51.2 months in OR group ( P=0.335). There were no statistically significant differences between neoadjuvant CCRT and surgery group in the aspect of both hematologic and non-hematologic adverse events. Conclusions: In this study, neoadjuvant SP based CCRT significantly increased downstaging in T stage compared than OP alone. The prespecified genomic analysis with transcriptomic sequencing will be available at the meeting. Clinical trial information: NCT03814759 .

Long-term efficacy of high-dose imatinib in Hispanic patients without access to second-generation tyrosine kinase inhibitors treated in LATAM centers.

6512 Background: Treatment for patients with chronic myeloid leukemia (CML) had a benchmark with the introduction of imatinib, a tyrosine kinase inhibitor (TKI). Nevertheless, resistance due to genetic mutations in the BCR::ABL1 kinase receptor remains relatively common for many patients, leading to failure, lack of response, or suboptimal response. Ideally, to bypass genetic resistance, guidelines recommend switching to a second-generation TKI, but for many developing countries, socioeconomic barriers hinder the possibility of switching medication. Despite this scenario, scarce information is available to evaluate the clinical prognosis of these patients. Methods: We conducted a retrospective cohort analysis to compare the overall mortality of patients with CML who developed a suboptimal response to standard-dose imatinib and were treated with either high-dose imatinib or a second-generation TKI. We created a marginal structural model with inverse probability weighting and stabilized weights and depicted the survival curves and median using the Kaplan-Meier estimator. Our primary outcome was overall survival (OS) at 150 months, defined as the number of deaths once patients had reached treatment response based on parameters of the European Leukemia Net Guidelines for CML. Our secondary outcomes were disease-free survival (DFS) at 150 months, defined as the number of months after patients achieved either major molecular response or deep molecular response, and adverse events that included gastrointestinal, dermatologic, hematologic, and others. Results: The cohort included 148 patients, of which 32 received high-dose imatinib and 116 a second-generation TKI. While we found no difference in the 150-month risk in both OS and DFS (Table), patients receiving second-generation TKI had an increase in median survival of OS ( p-value = 0.009). No difference was found in the median survival of DFS ( p-value = 0.55). No difference was found in either hematologic, gastrointestinal, dermatologic, or other adverse events (p-values of 0.39, 0.94, 0.24, and 0.33, respectively). Conclusions: Ideally, patients who develop a suboptimal response to imatinib should be switched to a second-generation TKI. However, If impossible, our findings suggest that patients treated with high-dose imatinib have a similar OS and DFS prognosis to those receiving a second-generation TKI. [Table: see text]

Patient-reported fatigue and risk of treatment-related adverse events (AEs) in patients receiving systemic therapy in cancer clinical trials.

11015 Background: Fatigue in patients with cancer is common and negatively impacts quality of life. Patient-reported outcomes (PROs) assess a patient’s direct report of their symptoms and well-being; research has highlighted their potential to predict cancer outcomes. We examined whether fatigue prior to treatment was associated with AEs. Methods: We analyzed 18 phase II and III cancer treatment clinical trials with baseline fatigue data conducted by SWOG between 1988-2018. The Common Terminology Criteria for Adverse Events was used. Symptomatic AEs were defined as those aligned with the NCI’s PRO-CTCAE; laboratory-based or measurable AEs were designated as objective (hematologic v nonhematologic). Thirteen symptomatic and 14 objective AE categories were examined. Fatigue was derived from multiple scales (e.g., FACT, EORTC QLQ-C30 and PROMIS-Fatigue 7a). Each measure was mapped to a 5-point Likert scale. Binary categories were compared (e.g., < some vs. > = some fatigue). Generalized estimating equations were used with a binomial distribution and logit link, adjusting for age, sex, race, and BMI, with clustering by study. Results: We examined N = 8,040 patients receiving systemic therapy. Among 18 trials (prostate, 5; lung, 3; colorectal, 2; lymphoma, 2; breast, 2; bladder, 1; melanoma, 1; ovarian, 1, pancreas, 1), n = 108,059 AEs were examined. Patient fatigue was present at levels of “a little” or greater in 75.8%, “some” or greater in 42.8%, and “quite a lot” or “very much” in 17.7%. Patients with some or greater fatigue were nearly twice as likely to have severe or worse toxicity (OR = 1.92, 95% CI, 1.53-2.40, p < .001) or life-threatening toxicity (OR = 1.93, 95% CI, 1.44-2.59, p < .001) and nearly threefold more likely to have fatal toxicity (OR = 2.76, 95% CI, 1.37-5.53, p = .004). Similar patterns were seen at a threshold of “quite a lot”. A dose response pattern was evident; patients reporting quite a lot/very much compared to no fatigue were > 5 times more likely to experience fatal toxicity (OR = 5.63, p = .002). These patterns were consistent in symptomatic, objective hematologic, and objective non-hematologic AEs. Conclusions: Baseline fatigue was highly predictive of subsequent risk of AEs. These findings suggest that in an era of precision medicine, patient-reported fatigue may be an important component of determining toxicity risk and could aid in treatment decision making.[Table: see text]

The Effecacy and Safety of Daratumumab Based Regimens in Relapsed/Refractory Multiple Myeloma: A Single-Center Real-World Data Analysis

To investigate the efficacy and safety of daratumumab based regimens in relapse and/or refractory multiple myeloma (RRMM) in the real world, as well as the impact of daratumumab on stem cell collection and engraftment. The clinical data of patients with RRMM who received daratumumab in hematology department of the First Affiliated Hospital of Xiamen University from February 2019 to March 2023 and had evaluable efficacy were retrospective analysis. All 43 RRMM patients were treated with daratumumab-based combination regimens, including Dd, DVd, DRd, Dkd, DId, and Dara-DECP. With median follow-up time 10.1 (2.1-36.6) months, the best overall response rate (ORR) was 74.4% and a best complete response rate (CR) was 25.6%. 1-year overall survival rate (OS) was 84.5%. The most common severe hematologic adverse events (Grade>3) are 3/4 grade leukopenia（18.6%）, and the most common severe non-hematologic adverse events were infusion-related reactions (IRRs， 20.9%) and infections（7.0%）. Multivariate prognostic analysis showed that extramedullary infiltration was an independent adverse prognostic factor affecting OS （P =0.004）. The use of daratumumab has no effect on stem cell collection, or engraftment. Daratumumab is safe and effective in RRMM.

Efficacy and safety of GPRC5D-based monotherapies for relapsed/refractory multiple myeloma: A systematic review and meta-analysis.

e19503 Background: G protein-coupled receptor family C group 5 member D (GPRC5D), a highly expressed receptor in myeloma cells, is one of the novel emerging targets for relapsed/ refractory (R/R) multiple myeloma (MM). Among the GRPC5D therapies, currently one agent talquetamab has been approved while CAR-T therapies are under development. Methods: A literature search using electronic databases Pubmed, Embase, Scopus, Web of Science and Cochrane, including major conference abstracts was conducted from inception to December 31, 2023 focusing on GPRC5D therapies in MM. For multiple reports of the same study, the latest available report of the study describing the efficacy or safety was selected. Only GPRC5D based monotherapies were included, and combination regimens were excluded for this review. Data on safety and efficacy were extracted, evaluated and systematically analyzed using Comprehensive Meta-analysis 3.3. The study protocol was registered with PROSPERO (CRD42024497933). Results: After screening 562 articles, and removing duplicates, total seven studies with 581 patients were included (5 GPRC5D-CAR T studies with 137 patients and 2 GPRC5D-BsAb studies with 444 patients). The pooled overall response rate (ORR) for GRPC5D therapies in this cohort was 77.4%, with best response rate [very good partial response (VGPR) or better] of 59.2%. The pooled incidence rate of cytokine release syndrome (CRS), any grade and Immune effector cell-associated neurotoxicity syndrome (ICANS), any grade, was 78.8% and 9.6% respectively. Grade 3/4 hematological adverse events included neutropenia being the most common (69.6%), followed by thrombocytopenia (36.8%) and anemia (34.2 %). Subgroup analysis was performed for GPRC5D therapies- CAR T and BsAb as shown in the table. Conclusions: GPRC5D based therapies showed high response rates in R/R MM with distinct side effect profile including CRS and cytopenias. Further studies along with follow up of the ongoing trials is needed to understand the long-term outcomes. [Table: see text]

Efficacy of a Daltuzumab-containing Regimen in Patients with mSMART High-Risk Multiple Myeloma

To investigate the efficacy and safety of a treatment regimen based on daratumumab in patients with high-risk relapsed refractory multiple myeloma(MM) with mSMART 3.0 score. Clinical data were collected from 16 patients with mSMART3.0 score high-risk relapsed refractory MM treated at the Affiliated Hospital of Shandong University of Traditional Chinese Medicine from May 2020 to May 2023, all of whom received daltezumab-based regimen (regimen drugs including dexamethasone, isazomib, bortezomib, lenalidomide). The efficacy and safety of the treatment were retrospectively analyzed. The median age of 16 patients was 63.5 (47-70) years old, including 10 cases of IgG type, 2 cases of IgA type, and 4 cases of light chain type. The curative efficacy was judged in all 16 patients, with an overall response rate of 93.75% (15/16), including 4 cases of strict complete remission (sCR), 1 case of complete remission (CR), 2 case of very good partial remission (VGPR), partial remission (PR) in 5 cases, and minor remission (MR) in 3 cases. The median follow-up time was 11(2-30) months, and the median progression-free survival and median overall survival were not achieved in 16 patients at the median follow-up period. The hematologic adverse effects of the treatment regimen using daratumumab-based were mainly neutropenia, and the non-hematologic adverse effects were mainly infusion-related adverse reactions and infections. Daratumumab-based regimen for the treatment of relapsed refractory MM patients with high risk of mSMART3.0 score has better efficacy and safety.

Real-world analysis of belantamab mafodotin (belamaf): Care patterns in relapsed/refractory multiple myeloma.

e19507 Background: Belamaf is an anti-B cell maturation antigen immunoconjugate for relapsed/refractory multiple myeloma that has shown efficacy and safety in the DREAMM clinical trials. Additional long-term real-world data on its use patterns, efficacy, and tolerability are needed. Methods: This retrospective review (NCT05986682) analyzed adults with multiple myeloma receiving ongoing care at Duke Cancer Institute who began belamaf monotherapy (not in a clinical trial) between 8/5/2020 and 11/22/2022. We abstracted data for 30 patients through 9/18/2023. We described baseline clinical characteristics, disease response (per International Myeloma Working Group [IMWG] criteria, as possible given available marrow biopsy data), belamaf use patterns, and ocular adverse events (AEs) (per the Keratopathy Visual Acuity [KVA] scale). Results: Our sample was 53% (n=16) female, 47% (14) White, and 47% (14) Black; median age was 68 years at the beginning of belamaf therapy. 67% (20) had ≥4 prior lines of therapy (median: 4, min-max: 2-19), 87% (26) were triple-/quad-/penta-refractory, and 23% (7) had high-risk cytogenetics (per IMWG). Overall response rate (ORR) was 67% (11 very good partial response, 9 partial response). Median (min-max) time to best response was 1.5 (0.7-9.9) months. Median (min-max) response duration was 9.8 (1.1-20.2) months. Progression occurred in 73% (22) of patients; median progression-free survival (PFS) was 8.4 months (95% CI 6.6-12.7). Median overall survival was not reached. Median (min-max) number of cycles was 6.5 (2-13). 63% of patients (19) had a dose reduction from 2.5 to 1.9 mg/kg; 65% (13) were due to corneal AEs and 30% (6) due to hematologic AEs. 93% (28) had ≥1 cycle delay, and the median (min-max) number of delays was 5 (1-14); 85% of delays (n=153) were due to corneal AEs. Cycle length changed for 33% (10) from every 3 weeks to every 4 (1) or 6 (9) weeks; 91% (n=10) of cases were due to corneal AEs. 93% (28) had keratopathy (any grade); among all events (n=323), 2% were grade ≥3. Median (min-max) time to resolution of grade ≥2 keratopathies was 6 (2-22) weeks. 90% (27) experienced a visual acuity change; among all events (n=244), 3.3% were grade ≥3. Median (min-max) time to resolution of grade ≥2 visual acuity events was 6 (2.9-53) weeks. The most common ocular symptoms were blurry vision (53% of symptoms), dry eyes (17%), and photophobia (14%). Belamaf was discontinued in 13% (4) due to ocular AEs and 20% (6) to patient/physician choice or other reason. Median (min-max) time to last dose/discontinuation was 9.3 (0.7-21.6) months. Conclusions: In our study, ORR and median PFS were greater than other real-world studies. Corneal AEs were also more common, but severity was consistent with these and DREAMM-3 findings. Despite a higher rate of dose reductions and delays than other real-world studies, our study adds promise to the benefit of belamaf over an extended time with dose modifications.

Efficacy and safety of SHR-2554 in advanced epithelioid sarcoma: A phase 2 trial.

11549 Background: Epithelioid sarcoma (ES) is a rare and aggressive subtype of soft-tissue sarcoma. The loss of SMARCB1 (INI1) expression which leads to oncogenic dependence on the transcriptional repressor EZH2 has been observed in over 90% of ES. Patients (pts) with metastatic ES have a poor prognosis. We investigated the efficacy and safety of SHR-2554, an oral selective EZH2 inhibitor, in pts with refractory ES. Methods: To be eligible for inclusion, pts had to fulfill the following criteria: 8 years or older; histologically confirmed advanced or metastatic ES with loss of INI1 or upregulated mRNA level of EZH2; progressive disease after at least one line of doxorubicin-containing chemotherapy; the presence of measurable disease according to RECIST 1.1; an ECOG performance status of 0-1. Pts received SHR2554 (350 mg, bid, po) until disease progression or unacceptable toxicity. The primary endpoint was progression-free rate at 12 weeks. A Simon two-stage design was applied. If there were 3 pts remaining progression-free at 12 weeks within the first 9 pts, the cohort would expand to 17 pts and the outcome would be positive if more than 7 pts remained progression-free at 12 weeks. Results: Between Jul 2021 and Dec 2023, a total of 17 pts were enrolled and received at least 1 dose of SHR-2554. The median age was 32 years (range 8-57) and 41.2% were males. 9 (52.9%) pts had received immunotherapy targeting PD-1/L1 and 6 (35.3%) pts had received anti-angiogenesis therapy before enrollment. The median line of previous treatment was 2 (range 1-4). Loss of INI1 was confirmed in 14 (82.4%) pts. Tumor response was evaluated in 14 pts at data cutoff. 9 (64.3%) of 14 pts remained progression-free at 12 weeks. The primary endpoint was met. Based on investigator assessment, 3 (21.4%) of 14 pts achieved partial response and 8 (57.1%) pts had stable disease as best response. Adverse events (AEs) were generally mild. The most common treatment-related hematological AEs were anaemia, platelet count decreased and hyperuricaemia. Conclusions: SHR-2554 showed promising efficacy and an acceptable safety profile in pts with refractory ES, warranting further investigation. Clinical trial information: ChiCTR2100046099.

Efficacy and safety of stem cell transplantation for multiple sclerosis: a systematic review and meta-analysis of randomized controlled trials

Multiple sclerosis (MS) is a common autoimmune neurological disease affecting patients’ motor, sensory, and visual performance. Stem Cell Transplantation (SCT) is a medical intervention where a patient is infused with healthy stem cells with the purpose of resetting their immune system. SCT shows remyelinating and immunomodulatory functions in MS patients, representing a potential therapeutic option. We conducted this systematic review and meta-analysis that included randomized control trials (RCTs) of SCT in MS patients to investigate its clinical efficacy and safety, excluding observational and non-English studies. After systematically searching PubMed, Web of Science, Scopus, and Cochrane Library until January 7, 2024, nine RCTs, including 422 patients, were eligible. We assessed the risk of bias (ROB) in these RCTs using Cochrane ROB Tool 1. Data were synthesized using Review Manager version 5.4 and OpenMeta Analyst software. We also conducted subgroup and sensitivity analyses. SCT significantly improved patients expanded disability status scale after 2 months (N = 39, MD = − 0.57, 95% CI [− 1.08, − 0.06], p = 0.03). SCT also reduced brain lesion volume (N = 136, MD = − 7.05, 95% CI [− 10.69, − 3.4], p = 0.0002). The effect on EDSS at 6 and 12 months, timed 25-foot walk (T25-FW), and brain lesions number was nonsignificant. Significant adverse events (AEs) included local reactions at MSCs infusion site (N = 25, RR = 2.55, 95% CI [1.08, 6.03], p = 0.034) and hematological disorders in patients received immunosuppression and autologous hematopoietic SCT (AHSCT) (N = 16, RR = 2.33, 95% CI [1.23, 4.39], p = 0.009). SCT can improve the disability of MS patients and reduce their brain lesion volume. The transplantation was generally safe and tolerated, with no mortality or significant serious AEs, except for infusion site reactions after mesenchymal SCT and hematological AEs after AHSCT. However, generalizing our results is limited by the sparse number of RCTs conducted on AHSCT. Our protocol was registered on PROSPERO with a registration number: CRD42022324141.

BeEAM vs. BEAM: evaluating conditioning regimens for autologous stem cell transplantation in patients with relapsed or refractory DLBCL.

To evaluate whether BeEAM is an alternative to BEAM for autologous stem cell transplantation (ASCT) in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). Data of 60 patients with relapsed or refractory DLBCL who underwent ASCT from January 2018 to June 2023 in our center, including 30 patients in the BeEAM group and 30 patients in the BEAM group, were retrospectively analyzed. The time to hematopoietic reconstitution, treatment-related adverse events, number of hospitalization days, hospitalization cost, and survival benefit were compared between the two groups. The clinical characteristics of the patients did not significantly differ between the two groups. The median number of reinfused CD34 + cells was 5.06 × 106/kg and 5.17 × 106/kg in the BeEAM and BEAM groups, respectively, which did not significantly different (p = 0.8829). In the BeEAM and BEAM groups, the median time to neutrophil implantation was 10.2 and 10.27 days, respectively (p = 0.8253), and the median time to platelet implantation was 13.23 and 12.87 days, respectively (p = 0.7671). In the BeEAM and BEAM groups, the median hospitalization duration was 30.37 and 30.57 days, respectively (p = 0.9060), and the median hospitalization cost was RMB 83,425 and RMB 96,235, respectively (p = 0.0560). The hospitalization cost was lower in the BeEAM group. The most common hematologic adverse events were grade ≥ 3 neutropenia and thrombocytopenia, whose incidences were similar in the two groups. The most common non-hematologic adverse events were ≤ grade 2 and the incidences of these events did not significantly differ between the two groups. Median overall survival was not reached in either group, with predicted 5-year overall survival of 72.5% and 60% in the BeEAM and BEAM groups, respectively (p = 0.5872). Five-year progression-free survival was 25% and 20% in the BeEAM and BEAM groups, respectively (p = 0.6804). As a conditioning regimen for relapsed or refractory DLBCL, BeEAM has a desirable safety profile and is well tolerated, and its hematopoietic reconstitution time, number of hospitalization days, and survival benefit are not inferior to those of BEAM. BeEAM has a lower hospitalization cost and is an alternative to BEAM.