Continuous Maintenance Therapy Research Articles

The value and indications for surgery in pancreatic cancer with synchronous liver metastases.

714 Background: Over half of pancreatic cancer patients present with advanced disease and distant metastases, primarily in the liver, at initial diagnosis. Although systemic combination therapies have improved outcomes, the role of surgery remains contentious. This study seeks to pinpoint prognostic factors for patients with synchronous liver metastatic pancreatic cancer (sPDACLM) who receive effective treatments, and to identify patients likely to benefit from surgery. Methods: This is a retrospective cohort study. Included patients received first-line chemotherapy (AG/mFOLFIRINOX), with efficacy assessed every 4-6 cycles through imaging and biochemical evaluations. Imaging assessments were conducted according to RECIST 1.1 criteria, while biochemical evaluation focused on the reduction of CA19-9 (calculating cutoff values). Patients with good responses were considered for curative surgery, while those with minor responses decided between surgical treatment or continued maintenance therapy after being fully informed. Results: From May 2017 to February 2024, a total of 48 patients with sPDACLM who met the inclusion criteria were recruited for this study. The prognosis of patients with resectable or borderline resectable primary tumors was significantly superior to unresectable cases (18 months vs 11 months, p = 0.0011). Multivariate analysis revealed independent favorable prognostic factors: surgery (HR 0.22; p = 0.026), partial response (PR) per RECIST 1.1 criteria (HR 0.09, p = 0.040), and tumor marker reduction >85% (HR 27.99; p = 0.005). Achieving conversion effectiveness, as defined by imaging and biochemical criteria, was associated with a significantly improved prognosis compared to cases where conversion was ineffective (28 months vs. 12 months, p = 0.0086). Notably, effective surgery patients had a median survival of 49 months and a 5-year survival rate of 33%. Conversely, for patients who did not respond to systemic therapy, surgery did not confer any significant impact on overall survival; however, the corresponding survival curve indicated a trend towards shorter survival compared to those who did not undergo surgery. Conclusions: Patients with sPDACLM fulfill both imaging and biochemical criteria, exhibit improved prognoses; additionally, surgery has been shown to significantly prolong their median overall survival times. Research indicates that accurate screening for cases suitable for conversion surgery can significantly improve the survival rates of sPDACLM. Overall survival time and survival rates in patients with synchronous liver metastatic pancreatic cancer undergoing conversion therapy. OS 1-year survival rate 2-year survival rate 3-year survival rate 5-year survival rate Effective group Surgery 49 months 100% 88% 66% 33% Non-surgery 18 months 80% 20% - - Non-effective group Surgery 11 months 33% - - - Non-surgery 12 months 36% - - - OS, overall survival time.

CAR T-cell therapy to treat multiple myeloma: current state and future directions.

Chimeric antigen receptor (CAR) T-cell therapy represents a transformative advancement in treating relapsed or refractory multiple myeloma (MM) in both early- and late-line settings. MM, a plasma cell malignancy, traditionally requires ongoing complex drug regimens, posing significant burdens on patients. In contrast, CAR T-cell therapy offers a one-time treatment option without the need for continuous maintenance therapy. CAR T-cell therapy leverages engineered T-cells to target specific antigens on tumor cells, leading to their elimination. Current approved therapies target B-cell maturation antigen (BCMA); new targets are under investigation, such as G-protein-coupled receptor class C group 5 member D (GPRC5D). Despite its efficacy, CAR T-cell therapy is associated with serious toxicities such as cytokine release syndrome (CRS) and immune-effector cell-associated neurotoxicity syndrome (ICANS), necessitating careful management. The review will provide an overview of the design and manufacturing of CAR T-cells and current FDA indications, as well as challenges and future directions of CAR-T therapy for MM treatment.

Potential Risks Associated With Long-term Use of Proton Pump Inhibitors and the Maintenance Treatment Modality for Patients With Mild Gastroesophageal Reflux Disease.

Gastroesophageal reflux disease (GERD) significantly affects the health-related quality of life and healthcare costs. The prevalence of this disease is increasing in Asia, leading to a rapid increase in the demand of proton pump inhibitors (PPIs). Despite effective symptom management during initial treatment, relapse rates after PPI cessation remain high in patients with GERD, warranting longterm maintenance therapy. Concerns regarding potential side effects related to the long-term use of PPIs are escalating with increased usage. Studies have reported diverse side effects of PPIs, such as increased fracture risk, cardiovascular concerns, enteric infections, neurological diseases, and potential associations with gastric cancer. However, definitive causal relationships remain unclear. This review comprehensively summarizes the latest knowledge on the potential risks associated with long-term use of PPIs. Continuous or noncontinuous therapy can be used as a maintenance treatment modality for GERD. For patients with mild GERD, including those with nonerosive and mildly erosive reflux disease, on-demand therapy following a sufficient period of continuous maintenance therapy is recommended as a long-term maintenance treatment option.

Phase II/III study of paclitaxel/carboplatin alone or combined with either trastuzumab and hyaluronidase-oysk or pertuzumab, trastuzumab, and hyaluronidase-zzxf in HER2 positive, stage I-IV endometrial serous carcinoma or carcinosarcoma (NRG-GY026).

TPS5641 Background: Uterine serous carcinoma and uterine carcinosarcoma are rare, high-risk uterine cancer subtypes that overexpress HER2 in up to 40% and 10% of cases, respectively. Phase II data demonstrated a benefit in adding trastuzumab in HER2 positive advanced and recurrent uterine serous carcinoma. Dual anti-HER2 therapy has the potential for further improvement in survival. Methods: This is a non-blinded, three-arm randomized phase II/III study. The primary objective is to evaluate the efficacy of trastuzumab and hyaluronidase-oysk (HERCEPTIN HYLECTA) or a fixed dose combination of pertuzumab, trastuzumab, and hyaluronidase-zzxf (PHESGO) in combination with paclitaxel/carboplatin in patients with HER2 positive uterine serous carcinoma or carcinosarcoma. The primary outcome of the phase II component is PFS. Depending on the phase II results, the study will progress to a phase III study of either two or three study arms. Patients in the control arm (Arm 1) receive carboplatin and paclitaxel every 3 weeks for 6 cycles. Patients on Arm 2 receive carboplatin and paclitaxel with trastuzumab and hyaluronidase-oysk every 3 weeks for 6 cycles plus one year of maintenance trastuzumab and hyaluronidase-oysk. Patients enrolled on Arm 3 receive carboplatin and paclitaxel with trastuzumab, pertuzumab, and hyaluronidase-zzxf every 3 weeks for 6 cycles plus one year of maintenance trastuzumab, pertuzumab, and hyaluronidase-zzxf . Those with an ongoing partial response may continue maintenance therapy for up to three years. Patients are eligible if they are diagnosed with chemo-naïve, non-recurrent stage IA-IVB myoinvasive uterine serous or carcinosarcoma. All tumors must be HER2 positive as defined by the ASCO/CAP Breast Cancer 2018 guidelines (testing performed locally). Tumors may also be HER2 positive based on next generation sequencing testing. Patients may have measurable, non-measurable, or no measurable disease and may have a plan for vaginal brachytherapy . Key exclusion criteria include severe heart disease or interstitial lung disease. The phase II portion of this study is open and enrolling. Clinical trial information: NCT05256225 .

Symptom clusters and their impact on quality of life in multiple myeloma survivors: Secondary analysis of BMT CTN 0702 trial.

Autologous haematopoietic cell transplantation (autoHCT) and continuous post-transplant maintenance therapy are the standard of care in transplant-eligible multiple myeloma (MM) patients. We sought to describe symptom burden and identify symptom clusters occurring in MM patients after autoHCT using data from the BMT CTN 0702 randomized controlled trial comparing the outcomes of three treatment interventions after an autoHCT in 758 MM patients. We analysed individual transplant-related symptoms assessed via the FACT-BMT questionnaire at enrolment and annually for 4-year post-autoHCT. We also described the effect the individual symptoms and symptom clusters have on quality of life (QoL). We identified three stable symptom clusters: malaise symptom cluster (lack of energy, feeling ill, having pain, experiencing nausea, loss of appetite), physical symptom cluster (having skin problems, tremors, worsening eyesight, change in taste, shortness of breath, frequent colds) and emotional symptom cluster (feeling sad, being nervous, experiencing sleep problems). Malaise and emotional symptom clusters have a greater impact on QoL than the physical symptoms cluster. Identifying these symptoms warrant additional support in terms of psychosocial support, in addition to treatment of the physical symptoms themselves.

COST PER REMISSION FOR MIRIKIZUMAB VS USTEKINUMAB IN THE MAINTENANCE PHASE FOR MODERATELY-TO-SEVERELY ACTIVE ULCERATIVE COLITIS TREATMENT FROM THE UNITED STATES COMMERCIAL PAYER PERSPECTIVE

Abstract BACKGROUND In phase 3 studies, mirikizumab (MIRI), an IL-23p19 antibody, demonstrated efficacy vs placebo in adult patients with moderately-to-severely active ulcerative colitis (UC). It is being developed for the United States Food and Drug Administration approval for the treatment of UC. Ustekinumab (USTE), an IL-12/23p40 antibody, is currently the most utilized second line treatment in UC patients. Physicians may prescribe MIRI in a similar placement to USTE, and payers may compare them when making formulary decisions for IL-23 inhibitors. Given the need for continued maintenance therapy to manage UC, it is of interest to evaluate the relative cost-efficiency of MIRI vs USTE. We estimated and compared the cost of MIRI vs USTE for achieving remission in one additional patient during the maintenance phase in biologic/Janus kinase inhibitor (JAKi)-experienced patients with UC. METHODS This study used a network meta-analysis (NMA) of published randomized controlled trials of maintenance phase therapy to derive the number needed to treat (NNT) for achieving clinical remission among those who responded to induction therapy. In NMA, clinical remission was defined as a total Mayo score of ≤2 points, with no individual sub-score >1. An Excel-based analytic model was developed to estimate cost per additional patient achieving clinical remission at the end of maintenance trial period. The model included the cost of maintenance therapy from a US commercial payer perspective and the NNT of achieving clinical remission for MIRI and USTE in the biologic/JAKi-experienced population. Wholesale Acquisition Cost (WAC) of USTE was taken from Micromedex Redbook. A scenario with USTE biosimilar was also considered where NNT was considered the same as USTE, but the WAC was considered 50% lower than the current WAC of USTE. RESULTS The costs per biologic/JAKi-experienced patient achieving clinical remission during the maintenance phase were $501,472 and $1,027,799 for MIRI and USTE. The lower cost per remission for MIRI in maintenance was the result of both lower relative NNT and lower anticipated WAC of MIRI compared to USTE. The scenario also resulted in a comparable cost per remission for MIRI vs a USTE biosimilar. CONCLUSION MIRI is projected to have a lower cost per remission during maintenance therapy compared to USTE. Given the need for long-term treatment for this chronic condition, MIRI appears to be a cost-efficient treatment option based on its lower NNT and anticipated acquisition cost in the maintenance phase.

Combination of Mitoxantrone Hydrochloride Liposome with Tislelizumab in Patients with Relapsed or Refractory NK/T Cell Lymphoma: A Phase Ib/Ⅱ Clinical Trial

Background : Extranodal NK/T cell lymphoma (ENKTL) is a highly aggressive malignancy associated with Epstein-Barr virus (EBV) infection, and remains a high unmet clinical need for improving prognosis. Mitoxantrone hydrochloride liposome (PLM60) is a nano-drug that has been approved as the first treatment option for relapsed/refractory (r/r) PTCL, and has shown certain efficacy and safety in a pivotal phase Ⅱ study. Tislelizumab is a humanized immunoglobulin G4 variant monoclonal antibody against PD-1. This trial aims to investigate the safety and efficacy of combining PLM60 with tislelizumab in patients (pts) with r/r ENKTL. Methods: Pts with r/r ENKTL were recruited in this ongoing, prospective, multicenter, open-label phase Ib/Ⅱ study (NCT05464433). Phase Ib was 3+3 design with two dose levels of PLM60 (d1, 16 mg/m 2 and 20 mg/m 2) plus tislelizumab 200 mg (d1, Q4W) induction therapy for up to 6 cycles, then tislelizumab 200 mg (Q3W) to continue maintenance therapy until disease progression, discontinuation, withdrawal or one year of therapy (including induction therapy period). Phase II was a dose expansion at the recommended phase II dose (RP2D). The primary endpoints were to assess the tolerability (i.e. dose-limiting toxicity (DLT)) and explore RP2D of PLM60 in phase Ib, and the objective response rate (ORR) of phase II. Secondary endpoints were complete response (CR) rate, ORR, disease control rate (DCR) and safety of phase Ib, and DCR, progression-free survival (PFS), overall survival (OS) and safety of phase II. Results: At data cut-off on 11 July 2023, 13 eligible pts were enrolled (phase Ib, n=6 and phase II, n=7). 6 pts of phase Ib were evaluable for response with a median age of 29.5 (range, 22-47) years, and 5 pts (83.3%) were ECOG 1. 3 pts (50.0%) had advanced stage III or IV (Ann Arbor). No DLT occurred at 16 mg/m 2 and 20 mg/m 2in phase Ib study. RP2D was PLM60 20 mg/m 2 plus tislelizumab 200 mg. The CR rate, ORR and DCR were 33.3% (2/6, 95% CI 4.3%-77.7%), 100.0% (6/6, 95% CI 54.1%-100.0%) and 100.0% (6/6, 95% CI 54.1%-100.0%), respectively. At data cutoff, the phase II study is being enrolled. Overall, the 11 pts evaluated in phase Ib and phase II had an ORR of 81.8% (9/11) (Figure 1). Furthermore, a decrease in EBV viral load was observed during treatment with PLM60 and tislelizumab except for one pt who experienced viral load rebounded and disease progression after 3 cycles of therapy (Figure 2). With a median follow-up of 2.1 (range, 1.0-5.6) months currently, the median PFS and OS will be reported after long-term follow-up. Treatment-related adverse events (TRAEs) of any grade occurred in all 13 enrolled pts, in which 7 (53.8%) pts were grade 3/4. The common grade 3/4 TRAEs were leucopenia (38.5%), neutropenia (30.8%), lymphocyte count decreased (30.8%), thrombocytopenia (7.7%), alanine aminotransferase increased (7.7%) and diarrhea (7.7%). Three patients had treatment delayed because of AEs. Moreover, no adverse cardiac events occurred during this study. Conclusions: PLM60 plus tislelizumab proves an encouraging efficacy in r/r ENKTL pts with manageable safety profiles.

Blinatumomab Therapy for Low Level Minimal Residual Disease Detected By Next-Generation Sequencing in Adult B-Cell Acute Lymphoblastic Leukemia

Introduction: Blinatumomab, a bi-specific T-cell engager, has shown clinical benefit in patients with relapsed-refractory and hematologic complete remission with minimal residual disease (MRD)-positive Acute Lymphoblastic Leukemia (ALL). The BLAST trial (Gökbuget N et al., Blood. 2018) demonstrated improved overall survival (OS) and disease-free survival (DFS) in patients with MRD-positive disease (≥0.1%) who achieved MRD response with Blinatumomab. We sought to evaluate the utility of Blinatumomab in low levels of MRD (<0.1%) using clonoSEQ with a sensitivity of (0.0001%). Methods: Adult (18+) B- ALL patients that underwent treatment for B-cell ALL at Norris Comprehensive Cancer Center (NCCC) between 2016 and 2022 who had residual disease tracked using the Next Generation Sequencing (NGS)-based clonoSEQ assay (Adaptive Biotechnologies, Seattle, WA) were included. Patients who received Blinatumomab for MRD positivity were included only if they had a tracked clonoSEQ sequence within one month before starting treatment. Patients who didn't receive Blinatumomab were included if they had an MRD-positive clonoSEQ report. Those who were relapse/refractory when found to be MRD positive were excluded. Cumulative incidence of relapse (CIR) was evaluated using competing risk regression (Fine-Gray method), with death as a competing outcome. At the same time, OS and DFS were analyzed using Cox proportional hazards model. The start time was set to the date of the MRD report, and patients were censored until the last follow-up. Confounder-adjusted KM curves were calculated using direct standardization. Results: 47 patients were included with a median age at diagnosis of 45 years (range: 21-70). Most were Hispanic (N = 33, 70.2%), and the median follow-up time was 12 months. The 3-year OS, DFS, and CIR were 95.4% (95% CI 89.3-100%), 75.1% (95% CI 60.4-93.5%), and 20.3% (95% CI 7.2-38.0%). Twenty-six patients were treated with Blinatumomab (median two cycles, range 1-9), with most (N= 14, 53.8%) having low levels of MRD (<0.1%). Fourteen patients (53.8%) achieved MRD negativity with a median time to MRD negativity of 3.1 months. There were no relapses or death in patients who achieved MRD negativity in the treated group. However, non-responders with Blinatumomab had one death and two relapses. All patients continued Maintenance therapy after receiving Blinatumomab and did not proceed with the transplant. The patients who received Blinatumomab were more likely to be MRD positive on multiparameter flow cytometry (MFC) (60.0% vs. 28.6%, P = 0.042) but had a similar distribution of patient age, treatment type, and receipt of transplant. Additionally, there was a trend toward increased median percent residual cells on clonoSEQ (0.018% vs. 0.003% P =0.244) and flow (0.02% vs 0% P =0.066) in the Blinatumomab treatment group. On univariate analysis, significant predictors of CIR and DFS were flow percent (DFS: HR = 1.54; 95% CI 1.07-2.23; P = 0.019; CIR: HR = 1.83; 95% CI 1.38-2.41; P<0.001) and clonoSEQ residual cell count(DFS: HR = 1.58; 95% CI 1.04-2.41; P = 0.031, CIR: HR = 1.88; 95% CI 1.18-2.97 P=0.008). When controlling for the number of residual cells on close, patients who received Blinatumomab had significantly better CIR(HR = 0.11; 95% CI 0.02-0.69; P = 0.019) and a trend towards improved DFS(HR = 0.21; 95% CI 0.04-1.28; P = 0.092), but no difference in OS. On subgroup analysis of the 31 patients with low levels of MRD (<0.1%), there was no improvement in DFS for patients who were treated with Blinatumomab (HR = 0.41; 95% CI 0.04-3.91; P = 0.44). Of those with low levels of MRD, only two relapsed, and both did not receive Blinatumomab. Conclusions: In B cell ALL, Blinatumomab may offer a CIR benefit to patients with low levels of MRD as detected on clonoSEQ.

THU353 Late Onset Of Immune Checkpoint Inhibitor-Related Diabetes After 3 Years

Abstract Disclosure: S. Avula: None. A. Ahmed: None. M. Salim: None. Z.J. Anderson: None. A. Kumar: None. A. Estrada: None. Background: Immune checkpoint inhibitor-induced diabetes mellitus (ICI-DM) is characterized by acute onset of dramatic hyperglycaemia with severe insulin deficiency following exposure to PD-1/PD-L1 inhibitors. The frequency of type 1 diabetes related to ICIs is estimated to be ∼3.5%. Endogenous insulin secretion is depleted within a few weeks of the clinical onset of diabetes. Moreover, the positive rate for islet-related autoantibodies varies from 5% to 50%. Case: 51-year-old male with a PMH of stage 4 adenocarcinoma of the lung with metastasis to brain, bone, and kidneys was sent to the ED for a POC BG above 700 mg/dl. He was diagnosed with stage 4 lung adenocarcinoma three years prior to the current presentation. He received stereotactic radiotherapy for the brain metastases, Carboplatin/pemetrexed/pembrolizumab x4 cycles, then continued maintenance therapy of pemetrexed/pembrolizumab with the last dose given 3 weeks prior. He had recent evidence of progression, so chemotherapy adjustment was planned, and he started dexamethasone 4mg on the day prior to presentation. Upon ED presentation, he reported new onset polyuria and polydipsia for 1 week accompanied by 10% weight loss over the last 3 months. His vitals were stable. Physical examination was unremarkable. Serum glucose level was found to be 726 mg/dl, Bicarbonate level 28 mEq/L (22-30), creatinine 1.99 mg/dl (baseline 1.2), venous blood PH was 7.29, Bicarbonate 24 mEq/L (24-28), anion gap 15 mEq/L (8-16), B-hydroxybutyrate 2.91 mmol/L (0.02-0.27), sodium 127 mEq/L(135-148) and HbA1c 6.3%. He received normal saline boluses and NPH insulin 15 units SQ, after which his repeat BG level was 426 mg/dl. Given prediabetic Hba1c with recent dexamethasone therapy he was thought to have steroid-induced hyperglycaemia. He was discharged on NPH 15 units daily with Novolog sliding scale. Upon clinic follow-up 1 week later, his BGs did not improve significantly despite stopping steroids. His C-peptide level was low at 0.22 ng/ml (1.10-4.40) with BG 443mg/dl, and GAD -65 antibodies were negative. He continued to have hyperglycaemia while on NPH /Novolog regimen, thus he was switched to Lantus and Novolog regimen with better glycaemic control. He continues to have significant insulin requirements 3 months later. Conclusion: Although the mean interval between the first ICI administration and T1DM development was found to be 201 ± 187 days, the development of type 1 DM may occur with longer intervals from initiating the ICI therapy. In our case, the patient developed new-onset diabetes with low C-peptide after 1,095 days from receiving the first dose of pembrolizumab. On the previous case reports, the presence of GAD-65 antibodies is typically associated with shortened intervals between receiving the ICI therapy and the development of DM. Presentation: Thursday, June 15, 2023

Immunophenotypic correlates of sustained MRD negativity in patients with multiple myeloma

The role of the immune microenvironment in maintaining disease remission in patients with multiple myeloma (MM) is not well understood. In this study, we comprehensively profile the immune system in patients with newly diagnosed MM receiving continuous lenalidomide maintenance therapy with the aim of discovering correlates of long-term treatment response. Leveraging single-cell RNA sequencing and T cell receptor β sequencing of the peripheral blood and CyTOF mass cytometry of the bone marrow, we longitudinally characterize the immune landscape in 23 patients before and one year after lenalidomide exposure. We compare patients achieving sustained minimal residual disease (MRD) negativity to patients who never achieved or were unable to maintain MRD negativity. We observe that the composition of the immune microenvironment in both the blood and the marrow varied substantially according to both MRD negative status and history of autologous stem cell transplant, supporting the hypothesis that the immune microenvironment influences the depth and duration of treatment response.

PHASE 1/2A CLINICAL TRIAL OF BI‐1206, A MONOCLONAL ANTIBODY TO CD32B (FCGRIIB), IN COMBINATION WITH RITUXIMAB IN SUBJECTS WITH INDOLENT B‐CELL LYMPHOMA

Introduction: Anti-CD20 antibodies, such as rituximab, are an essential therapy resource in patients with B-cell lymphomas. However, approximately 15% of patients are refractory to treatment, and 25% relapse within 3 years following treatment. Non-clinical and retrospective clinical data indicate that the inhibitory Fc receptor CD32b promotes resistance through mechanisms acting on tumor and immune effector cells. Expressed on tumor B cells, CD32b triggers rituximab internalization, and tumor CD32b expression correlates inversely with response to rituximab or rituximab-containing therapy in MCL, FL, and DLBCL. BI-1206 is a human recombinant anti-CD32b (FcγRIIB) antagonistic IgG1 antibody that blocks rituximab internalization and, in non-clinical experimental models, enhances efficacy and overcomes rituximab resistance. During early clinical development of BI-1206, frequent infusion-related reactions were observed after intravenous (IV) administration. The development of a novel pre-medication regimen using two doses (16–24 h and 1 h) of corticosteroids prior to IV administration, as well as of a subcutaneous (SC) administration, have been shown to improve the tolerability of BI-1206 significantly, and both methods of administration are evaluated in the current trial. Methods: The current phase 1/2a multicenter clinical trial includes relapsed or refractory B-cell lymphoma, including FL (except FL grade 3B), MZL, and MCL. This trial will evaluate the safety and tolerability of IV and SC BI-1206 administered in combination with rituximab. The ivRP2D has been established, and enrollment of patients to SC BI-1206 to establish scRP2D has started. Ph2a of the trial will consist of cohorts of at minimum 6 and maximum 12 subjects each, receiving ivRP2D, scRP2D, and potential additional dose levels of interest. During induction therapy, patients receive one dose of single-agent rituximab (375 mg/m2) followed by dosing of BI-1206 with subsequent rituximab on weeks 2, 3, and 4. Patients showing clinical benefit (complete response [CR], partial response [PR], or stable disease [SD]) at week 6 are eligible for continued maintenance therapy with dosing of BI-1206 and rituximab every 8 weeks for up to 7 cycles. The research was funded by: BioInvent Keywords: Combination Therapies, Immunotherapy, Ongoing Trials Conflicts of interests pertinent to the abstract. M. Jerkeman Honoraria: Gilead, Janssen, Roche, AstraZeneca, Abbvie, BMS Research funding: Gilead, Janssen, Roche, AstraZeneca, Abbvie, BMS P. Abrisqueta Costa Consultant or advisory role Janssen, Roche, Abbvie, BMS, Astrazeneca, Gilead, Beigene Honoraria: Janssen, Roche, Abbvie, BMS, Astrazeneca, Gilead Educational grants: Janssen, Abbvie J. M. Sancho Cia Consultant or advisory role Roche, Janssen, Novartis, BMS-Celgene, Kite-Gilead, Beigene, Lilly, Incyte, Miltenyi Biomedicine Honoraria: Roche, Janssen, Novartis, BMS-Celgene, Kite-Gilead, Takeda, Incyte M. Bastos-Oreiro Consultant or advisory role Roche, Kite, Novartis, Takeda, Janssen, Incyte Honoraria: Roche, Kite, Novartis, Takeda, Janssen, Incyte Research funding: Roche Educational grants: Roche, Kite, Novartis, Takeda, Janssen, Incyte J. B. Cohen Consultant or advisory role Janssen, Astra Zeneca, BeiGene, Loxo/Lilly, Gilead, ADCT Research funding: Genentech, Takeda, Novartis, Celgene, BioInvent, LAM Therapeutics, Loxo/Lilly, Astra Zeneca R. Cordoba Mascunano Consultant or advisory role Roche, Abbvie, Janssen, Astra Zeneca, Beigene, Lilly, Kite, Incyte, Takeda, Kiowa-Kirin E. Domingo Domenech Consultant or advisory role TAKEDA Honoraria: TAKEDA Educational grants: TAKEDA, BMS S. Novelli Canales Honoraria: Mundipharma Research funding: Novartis M. Borggren Employment or leadership position: BioInvent Stock ownership: BioInvent B. Frendeus Employment or leadership position: BioInvent Stock ownership: BioInvent I. Karlsson Employment or leadership position: BioInvent Stock ownership: BioInvent L. Mårtensson Employment or leadership position: BioInvent Stock ownership: BioInvent S. Patel Employment or leadership position: BioInvent Stock ownership: BioInvent I. Teige Employment or leadership position: BioInvent Stock ownership: BioInvent J. E. Wallin Employment or leadership position: BioInvent, Lilly Keywords: combination therapies, immunotherapy, ongoing trials Stock ownership: BioInvent, Lilly A. Mc Allister Employment or leadership position: BioInvent Stock ownership: BioInvent

Management of suspected and known eosinophilic esophagitis-anationwide survey in Austria.

Eosinophilic esophagitis (EoE) is achronic immune-mediated disease of the esophagus with increasing incidence and dysphagia as the main symptom. The management of suspected or known EoE by Austrian endoscopists has not been investigated yet. Aweb-based survey with 13questions about the management of EoE was sent to endoscopists via the Austrian Society of Gastroenterology and Hepatology (ÖGGH). Atotal of 222 endoscopists (74% gastroenterologists, 23% surgeons, and 2% pediatricians; 68% working in ahospital) from all 9states participated. In patients with dysphagia but anormal appearing esophagus, 85% of respondents reported always taking biopsies; however, surgeons were less likely to obtain biopsies compared to gastroenterologists ("always" 69% vs. 90%, "sometimes" 29% vs. 10%, "never" 2% vs. 0%, p < 0.001). The approved budesonide orodispersible tablet is the preferred first-line drug used in EoE, ahead of proton pump inhibitors (PPI). Only 65% of participants monitor the patients by endoscopy and histology after 12weeks of induction therapy, 26% do not continue maintenance therapy, and 22% monitor patients only when symptomatic. The vast majority of Austrian endoscopists adhere to the European and US guidelines in cases of suspected EoE. In contrast, despite the chronic disease course, asignificant percentage of providers indicate not to use maintenance therapy and monitor the patients routinely.

Methadone Maintenance Therapy after Aneurysmal Subarachnoid Hemorrhage: A Case Report

There is limited information on the effects of continued methadone maintenance therapy following aneurysmal subarachnoid hemorrhage (aSAH). However, with the increasing incidence of opioid use disorder (OUD) in the US, there is a need to define best practices for the management of pain and prevention of acute withdrawal syndrome in patients with pre-existing OUD who develop aSAH. In this case report, we describe the use of MMT in a patient with aSAH and discuss important considerations, including sedation or confusion that might mimic acute neurologic changes seen in cerebral vasospasm or delayed cerebral ischemia, cardiac complications related to QTc prolongation, and liver or kidney interactions associated with aSAH routine treatment. Our patient recovered from her aSAH without any adverse events and, with increased monitoring and collaborative team-based care, including input from those with expertise in OMD or aSAH, we believe MMT can be safely continued in most aSAH patients.

Systematic literature review of quality-of-life questionnaires in Waldenström macroglobulinaemia-need for a disease-specific tool.

Systematic literature review of quality-of-life questionnaires in Waldenström macroglobulinaemia-need for a disease-specific tool.

P433 Efficacy of risankizumab by baseline clinical, biochemical, and endoscopic disease severity in moderately to severely active Crohn's disease

Abstract Background Risankizumab (RZB), a p19-anti-interleukin-23 monoclonal antibody, has demonstrated efficacy as induction and maintenance therapy in patients with moderately to severely active Crohn’s disease (CD). This post hoc analysis evaluates the efficacy of induction and maintenance RZB therapy by baseline clinical, biochemical, and endoscopic disease severity. Methods In the ADVANCE (NCT03105128) and MOTIVATE (NCT03104413) studies, patients with moderately to severely active CD and intolerance/inadequate response to ≥ 1 biologic (both studies) and/or conventional therapy (ADVANCE) were randomized to receive intravenous (IV) RZB induction therapy or placebo (PBO) for 12 weeks. Patients achieving stool frequency and/or abdominal pain score clinical response to 12 weeks of induction therapy were rerandomized in the FORTIFY (NCT03105102) study to receive subcutaneous (SC) maintenance RZB (180 mg or 360 mg) or PBO (withdrawal). Clinical and endoscopic endpoints were evaluated by baseline disease characteristics (Crohn’s Disease Activity Index [CDAI: ≤ 300, &amp;gt; 300], highsensitivity C-reactive protein [hs-CRP: &amp;lt; 10 mg/L, ≥ 10 mg/L], and Simple Endoscopic Score for Crohn’s Disease [SES-CD: 6−15, &amp;gt; 15]). Induction analyses included patients who received RZB 600 mg or PBO; data from the ADVANCE and MOTIVATE studies were pooled. Nonresponder imputation incorporating multiple imputation to handle missing data due to COVID-19 was used. Results The induction analysis included 527 patients who received RZB 600 mg IV and 362 patients who received PBO. Patients treated with RZB 600 mg IV achieved significantly higher response rates vs PBO at week 12, regardless of subgroup (P &amp;lt; .05 for all; Figure 1). In the maintenance study, patients treated with SC RZB continued to achieve higher response rates vs the PBO (withdrawal) group at week 52 regardless of subgroup (P was not &amp;lt; .05 for all; Figure 2). Improvements in clinical and endoscopic outcomes were generally observed from weeks 12 to 52 with RZB treatment across all subgroups. Response rates were generally similar across subgroups in both induction and maintenance studies; endoscopic remission and ulcer-free endoscopy (resolution of ulcer) rates were numerically lower for patients with increased inflammation (hs-CRP &amp;gt; 10 mg/mL) and higher endoscopic activity (SES-CD &amp;gt; 15). Conclusion RZB induction therapy resulted in higher response rates for clinical and endoscopic outcomes compared with PBO at week 12, regardless of baseline clinical, biochemical, and endoscopic disease severity. RZB also showed durable efficacy with continued RZB maintenance therapy, supporting the long-term use of RZB for patients across a range of baseline disease severity and activity.

Dynamic Response Assesment Combining Liquid Biopsy MRD and PET/CT in Follicular Lymphoma Patients Including CAR-T Cell Therapy

INTRODUCTION: Follicular lymphoma (FL) is considered an indolent disorder with a relatively favorable course. However, some patients have a more aggressive course and a poorer outcome. Chimeric antigen receptor (CAR) T-cell therapy has improved outcomes for R/R non-Hodgkin lymphomas (NHL). However, nearly 60% of patients will either fail to respond or relapse after CAR T-cell therapy. Currently, PET/CT is used to assess response in FL. Circulating tumor DNA (ctDNA), as a minimal residual disease (MRD) biomarker, has been validated in other NHL, but never in FL. METHODS: A total of 58 FL patients were included. Of them, 37 received first-line therapy, 14 a non-CAR T-cell salvage treatment, and seven salvage CAR-T cell therapy. By PET/CT, 42 patients achieved CR, five PR and 11 EE or progression. Genomic profiling to identify somatic mutations suitable for liquid Biopsy MRD monitoring (LiqBioMRD) was performed at baseline on DNA from FFPE lymph node biopsies and/or cfDNA from peripheral blood plasma samples. Then, the previously described NGS-MRD method (Onecha, E et al. Hematologica 2019) was applied to 175 cfDNA follow-up samples. Of them, 27 were screened at mid-induction and 49 at the end of treatment (EOT) and presented a paired PET/CT scan (month_3 and month_6 for CAR-T patients). A mean of 81.7 ng, (rank 3.5 - 943.8 ng) were analyzed with the LiqBioMRD test with a cut-off of 1E-4. In CAR-T patients, cfDNA was obtained on day_7 (n=4), day_28 (n=6), day_90 (n=6), day_180 (n=6) and day_365 (n=4). For those patients, PET/CT examinations were performed on day_90, day_180, and day_365. PET/CT was considered positive when DS was 4 or 5. RESULTS: The most frequently mutated genes at baseline were CREBBP (78%) KMT2D (69%), BCL2 (43%) and TNFRSF14 (37%). The mean number of MRD biomarkers analyzed per patient was 3.8 (rank 1 -12). After a median follow-up of 26 months, 16 patients relapsed with a median time to relapse of 10 months. A higher risk of progression was observed with the LiqBioMRD test (HR 14.6, 95% CI 5.1-42.2 p < 0.001) and PET/CT (HR 5.4, 95% CI 2.0-14.2, p = 0.001). The sensitivity (SE) of the LiqBioMRD test for the last TP available was 71%, with a specificity (SP) of 98%, being SE=62% and SP=86% for PET/CT. When both tests were combined, progression in less than 24 months was identified with 80% SE and 100% SP. Regarding the 15 patients with discordant results (26%), 11 were incorrectly classified by PET/CT, and only 4 were by LiqBio-MRD (Figure panel A). More importantly, of the 42 patients with concordant results, only two were misclassified. These two patients progressed despite being negative on both tests during the first six months after treatment. The first patient progressed after 12 months from CAR T-cell infusion. At this time point, both PET and liqBio-MRD were positive (Figure panel B). The second patient negative by both tests becomes positive in a sequential cfDNA sample obtained under rituximab maintenance after RCHOP, five months before progression. Of note, this patient continued maintenance therapy, achieving a complete response a few months later. Considering only CAR T-cell patients, all patients achieved CR by day_90 PET/TC evaluation. After a median follow-up of 21 months, only 1 of 7 patients progressed 12 months after infusion, presenting an MRD positive test at this point. The other six patients remain in CR. Regarding the 24 samples obtained from those patients after CAR-T infusion, at day_7, 4 of 4 samples were LiqBio-MRD positive, at day_28 only 1 of 6 remained positive. All samples at day_90 and day_180 (n=12) presented a negative LiqBioMRD result. Only one sample was positive at day_365, corresponding to the time point of progression of this patient (Figure panel B). CONCLUSIONS: Our preliminary results suggest that the combination of imaging with the LiqBio-MRD test during the first six months of treatment is a robust approach to identifying patients with a high risk of relapse independently of the therapy line. This combination presented an unprecedented sensitivity and specificity, and should be considered in future response-adapted clinical trials. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

De-escalation or discontinuation of tyrosine kinase inhibitor in patients with chronic myeloid leukemia: A multicentral, open-label, prospective trial in China.

Background: Long-term treatment-free remission (TFR) represents a new goal for chronic myeloid leukemia (CML). Optimizing dose of tyrosine kinase inhibitors (TKIs) in the CML treatment maybe a new challenge to maintain effective and improving patients' quality of life. We hypothesized that administration of low-dose TKIs does not compromise major molecular response (MMR) in patients with CML who have a deep molecular response (DMR). Methods: We did an open-label, randomized trial at eight hospitals in China. Eligible CML-CP patients (aged 18-70 years) had shown continuous response to TKI more than 5 years and maintained MR4.5 (BCR-ABLIS ≤ 0.0032%) in recent 18 months. Patients were randomly assigned (1:1) to the TKI de-escalation group or the discontinuation group. Randomization was done with permuted blocks (block size four) and implemented through an interactive web-based randomization system. Recurrence was defined as the single sample with real time Quantitative PCR (RT-qPCR) measurement greater than 0.1% (MMR). The primary endpoint was 12-month MMR rate in patients who received de-escalation or discontinuation of TKIs. This study was registered at ClinicalTrials.gov (NCT04143087). Results: Around 125 patients were enrolled between October 23, 2019 and October 31, 2020, 62 patients received dose de-escalation of TKIs, while 63 patients in the discontinuation group. In the de-escalation group, molecular recurrence-free survival at 12 months was 88.32% (95% CI 79%-98%), whereas molecular recurrence-free survival in the discontinuation group at 12 months was 59.98% (95% CI 47-73). No progressions occurred at the data cut-off date. All 29 recurrence cases restart TKI treatment returned to MMR. Cytolytic NK cells as a proportion of lymphocyte cells were significantly increased from baseline after 6 months whether in the de-escalation or TKIs cessation group (P=0.048, 0.001, respectively); compared with the relapsing patients, Tregs proportion was decreased (P=0.003), and higher proportion of NK cells were found in non-relapsing patients whetherin TKI de-escalation or discontinuation group (P=0.011, 0.007, respectively). We also found that the de-escalation group showed better disease-specific HRQOL in regards to its impact on emotional functioning, fatigue, pain, and financial difficulties. Conclusion: With 88.32% MMR in 12-months follow-up after de-escalation TKIs' treatment, dose-halving could become a new treatment paradigm for CML patients who with DMR under continuing maintenance therapy with TKIs.

Higher serum infliximab concentrations during induction predict short-term endoscopic response in patients with inflammatory bowel disease.

Measuring of serum infliximab (IFX) induction concentrations might reduce primary non-response rates in inflammatory bowel diseases (IBD), but optimal target concentrations are unclear. We investigated whether IFX induction concentrations predict short-term endoscopic response at week 12 or treatment persistence at week 52. Sixty-nine IBD patients (Crohn's disease, n=24; ulcerative colitis, n=45) received standard IFX induction of 5 mg/kg bodyweight at weeks 0, 2, and 6. Responders continued maintenance therapy and underwent follow-up until week 52 or treatment discontinuation. We measured IFX concentrations at weeks 2, 6, and 12, and evaluated treatment response around week 12 with endoscopy or with clinical scores and fecal calprotectin. Using the receiver operating characteristic analysis, we determined optimal IFX concentration thresholds associated with treatment response. We further compared IFX induction concentrations between patients persisting on IFX at week 52 and patients discontinuing treatment due to insufficient response. Responders (74%, 51 out of 69 patients) had significantly higher median IFX concentrations than non-responders at weeks 6 (25.06 vs. 19.68 µg/ml; P = 0.04) and 12 (18.03 vs. 10.02 µg/ml; P = 0.03), but not at week 2 (33.12 vs. 34.20 µg/ml; P = 0.97). Optimal IFX concentration thresholds for induction response were 21.33 and 5.13 µg/ml at weeks 6 and 12, respectively. Fifty-three patients continued IFX maintenance therapy until week 52. Induction concentrations failed to predict persistence on IFX therapy at week 52. Higher IFX induction concentrations predict endoscopic short-term response. However, induction concentrations failed to predict long-term persistence on IFX treatment.

Clinical efficacy and safety of pemetrexed with or without either Bevacizumab or Pembrolizumab in patients with metastatic nonsquamous non-small cell carcinoma.

Pemetrexed was approved by United States Food and Drug Administration (US FDA) in combination with platinum for the treatment of advanced nonsquamous non-small cell lung carcinoma (NSCLC) and malignant mesothelioma. Bevacizumab and pembrolizumab can be added to chemotherapy for patients with nonsquamous NSCLC with benefits but there has not been any dedicated head-to-head comparison between pembrolizumab-pemetrexed-platinum (PAC) and bevacizumab-pemetrexed-platinum (BAC) on their efficacy and safety. This was a retrospective single-center cohort study conducted in Queen Mary Hospital in Hong Kong. The study included 451 patients with advanced stage nonsquamous NSCLC that received first-line pemetrexed and platinum with or without bevacizumab or pembrolizumab. Patients who received pemetrexed-platinum (AC) were compared with those who received PAC and BAC. The primary endpoint was the progression-free survival (PFS). The median PFS for patients that received PAC was significantly longer than those who received BAC and AC (9months vs. 6.8months vs. 4.8 months, p<0.05 among all three groups), with OR of 0.578 (95% CI, 0.343-0.976; p=0.040) and 0.430 (95% CI, 0.273-0.675; p<0.001) when compared to BAC and AC, respectively. Patients who received PAC also had a higher disease control rate and higher likelihood to receive continuation maintenance therapy than those on AC. There is no statistically significant difference in the grade 3 to 4 toxicity among the three treatment groups. Although both regimens are superior to pemetrexed-platinum alone, data fromthis retrospective single center study suggestedabetter PFS in advanced stage nonsquamous NSCLC patient treated with first-linepembrolizumab-pemetrexed-platinumthan bevacizumab-pemetrexed-platinum without an obvious increase in significant toxicity.

Efficacy and safety analysis of bevacizumab combined with capecitabine in the maintenance treatment of RAS-mutant metastatic colorectal cancer.

What is known and objectivesThe optimal strategy for maintenance therapy in patients with metastatic colorectal cancer (mCRC) remains controversial. Considering that, beyond progression, co‐therapy with bevacizumab and cytotoxic chemotherapy showed less toxicity and a significant disease control rate. We aimed to investigate the differences in efficacy and safety between bevacizumab combined with capecitabine maintenance therapy and capecitabine monotherapy for RAS‐mutant mCRC （as defined by mutations in KRAS and NRAS exons 2–4）controlled by bevacizumab plus FOLFIRI chemotherapy for at least 12 weeks.MethodsWe retrospectively analysed patients with RAS‐mutant mCRC admitted to the Department of Oncology, Huizhou Municipal Central Hospital from December, 2015 to December, 2020. All patients were first treated with bevacizumab combined with FOLFIRI for at least 12 weeks of induction therapy. 154 patients whose disease was brought under control then continued maintenance therapy. 78 patients were in the observation group (bevacizumab plus capecitabine) and 76 patients were in the control group (capecitabine alone). The efficacy and adverse effects of maintenance treatment were compared between the two groups. The clinicopathological characteristics such as sex, age, performance status (PS) score, primary tumour site, degree of pathological differentiation, baseline carcinoembryonic antigen (CEA) level, microsatellite instability (MSI) status, number of metastatic tumour sites and efficacy of induction treatment were compared in terms of prognosis.Results and discussionThe median progression‐free survival (mPFS)of patients was 9.0 months (95% CI 8.0–10.0) in the observation group and 7.2 months (95% CI 6.0–8.4) in the control group, with a statistically significant difference (p < 0.05). The baseline CEA level was an independent prognostic factor. Both groups tolerated the toxic side effects.What is new and conclusionBevacizumab combined with capecitabine was well tolerated and contributed to a longer PFS time than capecitabine alone, and it is worthy of popularization in clinical practice.