Reduced Risk Of Relapse Research Articles

Oral corticosteroid dosage and taper duration at onset in myelin oligodendrocyte glycoprotein antibody-associated disease influences time to first relapse

BackgroundWe sought to identify an optimal oral corticosteroid regimen at the onset of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), which would delay time to first relapse while minimising cumulative corticosteroid...

Resilience and relapse risk in Emirate adult patients with substance use disorder: a national cross-sectional study from the United Arab Emirates.

The United Arab Emirates is among the countries affected by substance use disorders (SUDs), which have economic and social impacts. Relapse after successful rehabilitation is a major issue in the treatment of SUD. Several factors increase the risk of relapse in patients with SUD, such as craving and negative social experiences. Resilience could empower patients struggling with SUD. This study aims to explore levels of resilience and relapse risk in adult Emirati patients diagnosed with SUD, and also the possible correlation between the two variables. Two hundred eighty-six Emirati adult patients with SUD completed a self-administered questionnaire for demographics, resilience (Connor and Davidson Resilience Scale), and relapse risk (Stimulant Relapse Risk Scale). Descriptive statistics (frequency, percentage, mean, SD, etc.) were used to describe study participants and variables. Inferential statistics were used to analyze the relationships, associations, and correlations between resilience and relapse risk, the main variables, and the participants demographics. Participants' mean total score for resilience was 72.92 out of a maximum possible score of 100 (SD = 16.99), while their mean total score for relapse risk was 59.07 out of a maximum possible score of 105 (SD = 12.23). Furthermore, examining the correlation between the resilience subscales and the relapse risk subscales revealed similar significant, negative, low-to-moderate correlations between all the subscales (r = -0.486). Protective and risk factors to enhance resilience and reduce relapse risk in patients with SUD were discussed.

Psychosocial functioning and its influencing factors in patients with depression post-remission: Implications for assessment and interventions

Background: Enhancing psychosocial functioning is crucial for reducing relapse in depression, but methods for monitoring and recovery are unclear. MethodA 1-year follow-up study assessed psychosocial functioning in 182 patients with remitted depression at baseline (T0) as well as at 1, 2, 6, 9, and 12 months post-remission (T1–T5). Using generalized estimating equations (GEE) and multiple linear regression (MLR), we analyzed the impact of changes in psychosocial functioning on relapse/recurrence risk, and assessed the influence of various factors. ResultsAn increase in psychosocial functioning significantly lowered relapse/recurrence odds by 54.2 %, averaging a risk reduction of 3.1 %. GEE analyses indicated subjective depressive symptoms (β = −0.315) most significantly impacted psychosocial functioning, followed by social support (β = 0.236), positive coping (β = 0.225), and negative automatic thoughts (β = −0.183). Negative coping and expressed emotion exhibited non-significant effects. MLR revealed that the impact of negative automatic thoughts was most significant at initial remission, but the relative importance of residual subjective depressive symptoms, positive coping, and social support on psychosocial functioning remained stable over time. LimitationsPredetermined follow-up assessments may not fully capture psychosocial functioning at relapse/recurrence, and the inclusion of factors might not be sufficiently comprehensive. ConclusionsRecovery of psychosocial functioning significantly reduces relapse risk in post-remission patients with depression more than residual subjective depressive symptoms. The degree of influence of factors on psychosocial functioning can change with the length of remission time.

A randomised, two-arm (1:1 ratio), double blind, placebo controlled phase III trial to assess the efficacy, safety, cost and cost-effectiveness of Rituximab in treating de novo or relapsing NS in patients with MCD/FSGS (TURING)

BackgroundMinimal Change Disease (MCD) and Focal Segmental Glomerulosclerosis (FSGS) are a spectrum of disease causing the nephrotic syndrome (NS), characterised by proteinuria with debilitating oedema, as well as a high risk of venous thromboembolic disease and infection. Untreated, 50–60% patients with FSGS progress to end stage kidney disease after 5 years. These diseases respond to immunosuppression with high dose glucocorticoids, but 75% will relapse as the glucocorticoids are withdrawn, leading to significant morbidity associated with prolonged use. In children, the B cell depleting monoclonal antibody rituximab reduces relapse risk, but this drug has not been tested in randomised controlled trial in adults.Methods130–150 adults with new or relapsing MCD/FSGS, from UK Renal Units, are being randomised to receive either rituximab (two 1 g infusions two weeks apart) or placebo. Partipicipants are recruited when they present with nephrosis, and all are treated with glucocorticoids as per KDIGO guidelines. Once in remission, prednisolone is withdrawn according to a pre-specified regimen. If in remission at 6 months, participants receive a further dose of trial drug. If they relapse, they are unblinded, and if they have received placebo, they are offered open label rituximab with protocolised prednisolone as in the main phase of the trial. The primary end point is time from remission to relapse. A number of secondary endpoints will be assessed including the effect of rituximab on: (1) NHS and societal resource use and hence cost: (2) safety: (3) other measures of efficacy, such as achievement of partial and complete remission of NS and the preservation of renal function: (4) health status of participant.Trial RegistrationTURING received ethical approval on 14 Jun 2019 - REC reference: 19/LO/0738. It is registered on EudraCT, with ID number: 2018-004611-50, with a start date of 2019-06-14.

Study protocol for a randomised, phase II, double-blind, experimental medicine study of obinutuzumab versus rituximab in ANCA-associated vasculitis: ObiVas

IntroductionRelapses in ANCA-associated vasculitis (AAV) increase the incidence of end-organ damage and their prevention requires prolonged immunosuppressive therapy. Rituximab, a type I anti-CD20 B cell depleting monoclonal antibody, is the...

Benefit of consolidative radiation in patients with extranodal limited-stage diffuse large B-cell lymphoma: a multicenter retrospective study in China.

Approximately 40% of limited-stage (stage I and II) diffuse large B-cell lymphoma (LS-DLBCL) presents with extranodal disease. Extranodal LS-DLBCL may have significant biological differences and associated with worse outcomes than nodal disease. Although rituximab based chemoimmunotherapy is standard of first-line treatment, the role of consolidative radiotherapy (RT) in this particular subgroup is controversial. In this multicenter retrospective study, we evaluated the survival benefit of consolidative RT in patients diagnosed with extranodal LS-DLBCL and received rituximab-based chemoimmunotherapy with or without consolidative RT. A total of 328 patients were included, 129 patients (39.3%) received chemoimmunotherapy and consolidative RT, and 199 patients (60.7%) received chemoimmunotherapy alone. With a median follow-up of 5.1 years (range, 0.3-14.8 years), 5-year progression-free survival (PFS) and overall survival (OS) for all patients were 75.4% and 83.9%, respectively. In multivariate analyses, the addition of consolidative RT was associated with superior OS (P = 0.004) and PFS (P = 0.005). High stage-modified International Prognosis Index (SM-IPI) risk predicted worse OS (P = 0.001) and PFS (P = 0.005). Also, propensity score-matched analyses showed RT improved both OS (hazard ratio [HR] 0.228, 95% confidence index [CI] 0.111-0.467, P < 0.001) and PFS (HR 0.308, 95% CI 0.167-0.566, P < 0.001). Among patients who achieved CR, 49 patients (16.6%) developed disease relapse, of which 30.6% relapsed at local sites. Consolidative RT significantly reduced relapse risk (P = 0.002). Our results demonstrated that consolidative RT significantly improved outcomes in patients with extranodal LS-DLBCL in the rituximab era.

EFFECTIVENESS OF CBT BASED RELAPSE PREVENTION THERAPY IN REDUCING RELAPSE RISK AND CRAVING AMONG INDIVIDUALS WITH SUBSTANCE USE DISORDER

Present study explored the effectiveness of Cognitive Behavioral Therapy with Relapse Prevention Techniques (CBT-BRPT) in reducing relapse risk and craving among individuals with substance use disorder (SUD). Drawing from a comprehensive literature review, the study addressed the pressing need for evidence-based interventions to combat SUD and its associated challenges. Present study employed a Pre-Experimental Research Design with a one-group pretest-posttest approach, utilized the purposive sampling to recruit a sample of 50 male participants seeking treatment for SUD. The instruments utilized include the Stimulant Relapse Risk Scale (SRRS), the Brief Substance Craving Scale (BSCS), and a Demographic Information Form. Results demonstrated significant reductions in both craving and relapse risk among participants who received CBT-BRPT intervention. These findings underscore the importance of CBT-BRPT as a viable treatment option for individuals with SUD, offering promising implications for clinical practice and substance abuse treatment programs. Despite limitations such as sample size and absence of a control group, the study's findings advocate for the integration of CBT approaches into existing treatment modalities and call for further research to validate the efficacy of CBT interventions in addressing substance use disorders comprehensively.

Changing vistas of psychosis and antipsychotic drug dosing toward personalized management of antipsychotics in clinical practice.

To discuss current evidence on tapering antipsychotic drugs in view of changing vistas of psychosis, suggesting a provisional framework for safely tapering antipsychotic drugs to an optimal low dose, in collaboration with patients and their relatives, to promote functional recovery while preventing relapse. Paradigm shifts during recent years regarding the nature of psychotic disorders and the role of the dopamine system are discussed, including the positive effects of dopamine blockade in acute psychosis and the limitations and drawbacks of dopamine blockade regarding negative and cognitive symptoms after remission of positive symptoms. Recent advances in tapering strategies and upcoming ways to solve the dilemma between the need to prevent relapses with antipsychotics on the one hand and the need to minimize side effects by tapering these drugs on the other are presented. Modern tapering strategies appear to reduce relapse risk to acceptable levels and offer a feasible personalized option to find the least effective dose to treat and prevent positive symptoms without redundant side effects and functional incapacity. These findings need replication, and several trials that might provide more certainty are on their way. Preliminary evidence and clinical experience indicate that personalized dose reduction of antipsychotics is feasible and safe if carried out in close collaboration with patients and their relatives, according to a provisionally suggested framework presented here. These preliminary directions still must be confirmed, revised, and adjusted according to upcoming trial results. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Strategies to reduce relapse risk in patients undergoing allogeneic stem cell transplantation for acute myeloid leukaemia.

Allogeneic stem cell transplantation is a centrally important curative strategy in adults with acute myeloid leukaemia; however, relapse occurs in a significant proportion of patients and remains the leading cause of treatment failure. The prognosis for patients who relapse post-transplant remains poor, and the development of new strategies with the ability to reduce disease recurrence without increasing transplant toxicity remains a priority. In this review, within the context of our understanding of disease biology and the graft-versus-leukaemia (GVL) effect, we will discuss established, evolving and novel approaches for increasing remission rates, decreasing measurable residual disease pretransplant, future methods to augment the GVL effect and the opportunities for post-transplant maintenance. Future progress depends upon the development of innovative trials and networks, which will ensure the rapid assessment of emerging therapies in prospective clinical trials.

203 Assessing social determinants of health and psychosocial factors critical to sustaining recovery among pregnant and parenting women with opioid use disorder

OBJECTIVES/GOALS: This study explored personal recovery support, including social determinants of health and psychosocial needs to understand factors for sustaining recovery among parenting and pregnant women with opioid use disorder. METHODS/STUDY POPULATION: This study used a mixed method quantitative/qualitative design and recruited women from residential/transitional facilities in an urban area. We used the Accountable Health Communities Health-Related Social Needs tool to assess social determinants of health factors, level of physical activity, family/community support, and mental health (stress). Through focus groups, we interviewed women to describe challenges to recovery and to resources including access to providers, housing, childcare, and food assistance from lived experiences. RESULTS/ANTICIPATED RESULTS: Survey analysis showed social determinants of health factors such as food and transportation were partially mitigated by residential living; however, parenting and pregnant women with opioid use disorder remained concerned about housing and finances; and encountered low levels of physical activity and significant stress. Preliminary results from the focus groups revealed a theme of positive recovery and retention experiences from residential living. DISCUSSION/SIGNIFICANCE: Evidence from studies suggests focused interventions for recovering women to reduce relapse risk factors and adverse maternal outcomes. Opportunities for improving personal recovery capital are accessible in residential facilities, however, further exploration of unmet social determinants of health factors are needed for recovery retention.

Medication choice and psychosis Hospital readmissions: A two-year comparative study

IntroductionHospital readmissions in psychosis are a critical concern, with medication choice playing a vital role. Oral antipsychotics, though common, rely on patient adherence and can lead to relapses if not followed. Long-acting injectable atypical antipsychotics (LAIAs) provide an alternative, ensuring consistent medication release and reducing relapse risk due to missed doses. Studies indicate that LAIAs result in fewer readmissions due to improved adherence. Tailoring treatment to individual needs is essential. Medication choice significantly influences hospital readmission prevention in psychosis. LAIAs, which could offer greater adherence to treatment and symptom control, present a promising option. Individualized treatment decisions are a priority for long-term recovery.ObjectivesThis study aimed to compare the hospital readmission rates within two years post-discharge among two groups of patients diagnosed with schizophrenia and other psychotic disorders who received either oral antipsychotic treatment or LAIAs.MethodsWe collected sociodemographic and hospitalization data from 155 patients, 90 receiving oral antipsychotics and 65 receiving LAIAs, following their discharge from a psychiatric unit.ResultsThere were 90 patients in the oral treatment group, and 65 in the LAIA group, with 67.6% receiving paliperidone and 26.1% receiving aripiprazole. There were no significant differences in age or gender between the two groups. However, patients in the LAIA group had longer stays in the hospital (M=14.7; SD=10.2 vs M=11.1; SD=6.4; t(153)=2.67; p&lt;.01) and a higher number of prior admissions (M=3.2; SD=3.7 vs M=1.3; SD=3.5; t(153)=2.41; p&lt;.01) compared to the oral antipsychotic group. Additionally, a higher percentage of patients in the LAIA group were diagnosed with schizophrenia (60%) compared to the oral antipsychotic group (24%) (X2(1, N = 155)= 20.4, p&lt;.01). After two years, readmission rates were 66.6% for the oral antipsychotic group and 61.5% for the LAIA group (X2(1, N = 155)= 8.5, p &gt; .05). However, the time to readmission was shorter for patients on oral antipsychotics (M=172.4; SD=162.0) compared to those on LAIAs (M=326.2; SD=211.4; t(153)=3.05; p&lt;.01). Notably, 86.6% of patients on oral antipsychotics were readmitted within the first year, while only 52% of those on LAIAs experienced readmission during the same period (X2(1, N = 155)= 8.5, p = .001).ConclusionsLong-acting injectable antipsychotics (LAIAs) appear to reduce hospital readmissions, with a more pronounced effect in the first few months post-discharge. However, after two years, the readmission rates between LAIAs and oral antipsychotics become comparable. This data suggests that while LAIAs may reduce early readmissions, their long-term effectiveness is on par with oral antipsychotics.Disclosure of InterestNone Declared

Revised HLA-DP TCE-Core Permissiveness Model Better Defines Relapse Risk and Survival following Haploidentical Transplant

The presence of an HLA-DPB1 nonpermissive mismatch (NPMM) by the TCE-3 model has been associated with improved survival following haploidentical donor transplantation (HIDT) using post-transplantation cyclophosphamide (PTCy). With the development of a revised model (TCE-Core) that further separates TCE-3 "group 3" alleles into "core" (C) and "noncore" (NC) alleles, a formerly permissive mismatch (PMM) resulting from group 3 alleles in both donor and recipient is now considered a C-NPMM if 1 or more of those alleles is NC. We aimed to study the additional effect of HLA-DPB1 C-NPMM according to the TCE-Core algorithm, as well as the directional vector of the mismatch, on outcomes following HIDT. To this end, we analyzed 242 consecutive HIDT recipients with acute leukemia or myelodysplastic syndrome who underwent transplantation between 2005 and 2021 (median age, 51 years; range, 19 to 80 years). The median follow-up was 62 months (range, 23 to 199 months). Of the 136 HIDTs classified as PMM by TCE-3, 73 were reclassified as a C-NPMM by the TCE-Core algorithm, of which 36 were in the graft-versus host (GVH) vector (37 were host-versus-graft [HVG] only). Given comparable survival between conventional NPMM and C-NPMM, GVH/bidirectional were analyzed together (nonpermissive). HVG-only C-NPMM were combined with HLA-DPB1-matched and PMM (permissive) because of similar outcomes. The presence of a TCE-Core-defined nonpermissive HLA-DP mismatch resulted in superior 5-year overall survival (OS) (66% versus 47%) and disease-free survival (DFS) (60% versus 43%). Compared to the conventional TCE-3 algorithm, TCE-Core identified a higher percentage of nonpermissive transplants (38% versus 23%) and better discriminated outcomes between nonpermissive and permissive status, with a larger difference in survival outcomes using TCE-Core compared to TCE-3 (OS Δ, 18.3% versus 12.7%; DFS Δ, 16.5% versus 8.5%). In multivariable analysis (MVA), a nonpermissive TCE-Core mismatch led to improved OS (hazard ratio [HR], .54; P = .003) and DFS (HR, .62; P = .013), largely due to decreased relapse risk (HR, .63; P = .049). In contrast, nonrelapse mortality (NRM) and graft-versus-host disease (GVHD) outcomes were not significantly impacted. In summary, the presence of nonpermissive TCE-Core HLA-DP mismatch strongly predicts survival following PTCy-based HIDT, owing to a reduction in relapse risk without a corresponding increase in GVHD or NRM. As a donor selection tool, TCE-Core appears to better discriminate HIDT outcomes while at the same time identifying a larger percentage of the potential donor pool.

Reinfusion of CD19 CAR T cells for relapse prevention and treatment in children with acute lymphoblastic leukemia

AbstractRelapse after CD19-directed chimeric antigen receptor (CAR)–modified T cells remains a substantial challenge. Short CAR T-cell persistence contributes to relapse risk, necessitating novel approaches to prolong durability. CAR T-cell reinfusion (CARTr) represents a potential strategy to reduce the risk of or treat relapsed disease after initial CAR T-cell infusion (CARTi). We conducted a retrospective review of reinfusion of murine (CTL019) or humanized (huCART19) anti–CD19/4-1BB CAR T cells across 3 clinical trials or commercial tisagenlecleucel for relapse prevention (peripheral B-cell recovery [BCR] or marrow hematogones ≤6 months after CARTi), minimal residual disease (MRD) or relapse, or nonresponse to CARTi. The primary endpoint was complete response (CR) at day 28 after CARTr, defined as complete remission with B-cell aplasia. Of 262 primary treatments, 81 were followed by ≥1 reinfusion (investigational CTL019, n = 44; huCART19, n = 26; tisagenlecleucel, n = 11), representing 79 patients. Of 63 reinfusions for relapse prevention, 52% achieved CR (BCR, 15/40 [38%]; hematogones, 18/23 [78%]). Lymphodepletion was associated with response to CARTr for BCR (odds ratio [OR], 33.57; P = .015) but not hematogones (OR, 0.30; P = .291). The cumulative incidence of relapse was 29% at 24 months for CR vs 61% for nonresponse to CARTr (P = .259). For MRD/relapse, CR rate to CARTr was 50% (5/10), but 0/8 for nonresponse to CARTi. Toxicity was generally mild, with the only grade ≥3 cytokine release syndrome (n = 6) or neurotoxicity (n = 1) observed in MRD/relapse treatment. Reinfusion of CTL019/tisagenlecleucel or huCART19 is safe, may reduce relapse risk in a subset of patients, and can reinduce remission in CD19+ relapse.

Anti-aquaporin-4 immune complex stimulates complement-dependent Th17 cytokine release in neuromyelitis optica spectrum disorders

Proinflammatory cytokines, such as (IL: interleukin) IL-6 and IL-17A, and complement fixation are critical in the immunopathogenesis of neuromyelitis optica spectrum disorders (NMOSD). Blocking the IL-6 receptor or the C5 complement pathway reduces relapse risk. However, the role of interleukin (IL)-6 and complement in aquaporin-4 (AQP4) autoimmunity remains unclear. To investigate the role of the anti-AQP4 immunoglobulin (AQP4-IgG)/AQP4 immunocomplex on the induction and profile of ex vivo cytokine and surface marker expression in peripheral blood mononuclear cells (PBMC) culture. Isolated PBMCs obtained from 18 patients with AQP4-IgG-seropositive-NMOSD (8 treatment-naive, 10 rituximab-treated) or ten healthy controls were cultured with AQP4-immunocomplex with or without complement. Changes in PBMC surface markers and cytokine expression were profiled using flow cytometry and ELISA. PBMCs derived from treatment-naive NMOSD patients stimulated with a complex mixture of serum complement proteins produced significant elevations of IL-17A and IL-6. Rituximab-treated patients also exhibited higher IL-6 but not IL-17A release. IL-6 and IL-17A elevations are not observed without complement. Co-stimulation of PBMCs with AQP4-IgG/AQP4 immunocomplex and complement prompts a Th17-biased response consistent with the inflammatory paradigm observed in NMOSD. A possible inflammation model is proposed via antigen-specific autoreactive peripheral blood cells, including NK/NKT cells.

Impact of Natural Killer Cell-Associated Factors on Acute Leukemia Outcomes after Haploidentical Hematopoietic Stem Cell Transplantation with αβ T Cell Depletion in a Pediatric Cohort

The technique of αβ T cell depletion (αβTCD) is a well-established method of hematopoietic stem cell transplantation (HSCT) for children with acute leukemia owing to the low rates of graft-versus-host disease and nonrelapse mortality (NRM). The graft-versus-leukemia effect is generally ascribed to natural killer (NK) cells conserved within the graft. It is not known whether NK-related factors affect the outcome of αβTCD HSCT, however. The aim of this retrospective study was to explore the impact of NK alloreactivity (based on donor-recipient killer immunoglobulin-like receptor [KIR] mismatch), graft NK cell dose, and blood NK cell recovery on day +30 post-HSCT on the incidences of leukemia relapse and NRM. The pediatric acute leukemia cohort comprised 295 patients who underwent their first HSCT from a haploidentical donor in complete remission. During post hoc analysis, the total cohort was divided into subcohorts by diagnosis (acute lymphoblastic leukemia [ALL]/acute myeloid leukemia [AML]), NK alloreactivity prediction (KIR match/KIR mismatch), graft NK cell dose (less than versus greater than the median value), and blood NK cell recovery on day +30 post-HSCT (less than versus greater than the median value). We also investigated the influence of serotherapy (antithymocyte globulin [ATG] group) versus abatacept + tocilizumab combination [aba+toci] group) on relapse risk in the context of KIR mismatch. The risks of relapse and NRM were calculated by the cumulative risk method, and groups were compared using the Gray test. Multivariate analysis revealed no apparent impact of predicted NK alloreactivity or any other studied NK cell-related factors for the entire cohort. For patients with AML, a significantly higher relapse risk associated with high NK cell graft content on the background of no predicted KIR mismatch (P = .002) was shown. Multivariate analysis confirmed this finding (P = .018); on the other hand, for the KIR-mismatched patients, there was a trend toward a lower risk of relapse associated with high NK cell dose. The use of ATG was associated with a trend toward reduced relapse risk (P = .074) in the AML patients. There was no significant impact of NK-related factors in the ALL patients. Overall, the evaluated NK-related factors did not show a clear and straightforward correlation with the key outcomes of HSCT in our cohort of children with acute leukemia. In practice, the data support prioritization of KIR-mismatched donors for patients with AML. Importantly, a potential interaction of KIR ligand mismatch and NK cell content in the graft was identified. Indirect evidence suggests that additional cellular constituents of the graft could influence the function of NK cells after HSCT and affect their role as graft-versus-leukemia effectors.

AMPLIFY-7P: Phase 1 and randomized phase 2 study of amphiphile immunotherapy ELI-002 7P as adjuvant treatment for subjects with G12D, G12R, G12V, G12C, G12A, G12S and G13D Kirsten rat sarcoma (KRAS)-mutated pancreatic ductal adenocarcinoma.

TPS720 Background: KRAS mutations occur in 25% of human tumors, frequently in pancreatic where over 85% relapse after locoregional treatment. ELI-002 7P is a lymph node targeted immunotherapy comprised of Amphiphile (Amph)-modified G12D, G12R, G12V, G12C, G12A, G12S and G13D mutant KRAS peptides together with an Amph-modified CpG oligonucleotide adjuvant. In the first in human AMPLIFY-201 study, a two peptide G12D/G12R formulation increased KRAS-specific T cells in 87% of patients, and T cell responses 13-fold or higher over baseline correlated with outcomes including reduction in risk of relapse or death. The AMPLIFY-7P study hypothesizes that adjuvant administration of ELI-002 7P will be safe and will delay relapse compared to observation in patients with KRAS mutated pancreatic cancers who have completed curative intent locoregional treatment. Methods: This open-label, phase 1 and randomized phase 2 study is evaluating ELI-002 7P in patients with KRAS mutated pancreatic adenocarcinoma following standard of care chemotherapy and surgery. In phase 2, patients are randomized 2:1 to ELI-002 7P versus observation with crossover of the observation arm permitted at the time of confirmed radiographic relapse via iRECIST. Eligible patients must be within 6 months of completion of locoregional treatment for up-front resectable pathologically confirmed pancreatic cancer (Stage I-III) with radiographic NED (no evidence of disease). Phase 2 patients are included regardless of biomarker evidence of recurrent disease, however, those who have not recovered absolute lymphocytes to the normal range following cytotoxic therapy are excluded. The primary phase 2 objective is to compare the efficacy of ELI-002 7P versus observation, with primary endpoint disease-free survival per investigator. Secondary objectives compare biomarker response (reduction or clearance of ctDNA or if ctDNA was not detectable, serum tumor antigen CA19-9) in the subset with positive baseline values, OS, safety, and iRECIST response rate in the crossover subset. Exploratory endpoints include immunogenicity, the association of immunogenicity with high resolution HLA typing, and evaluation of tumor-infiltrating T cells and the tumor microenvironment in the event biopsy tissue is available. An Independent Data Monitoring Committee reviewed phase 1 data and recommended opening phase 2. Subsequent patients will receive up to 10 doses of Amph-peptides 7P 700 mcg each (4.9 mg total), together with Amph-CpG-7909 (10.0 mg) administered over a five-month treatment period. In Phase 2, approximately 135 patients will be enrolled in the United States. An interim analysis is planned using group sequential design for control of overall alpha 0.10. Clinical trial information: NCT05726864 .

Post-Allograft Romidepsin Maintenance Mitigates Relapse Risk and Stimulates the Graft-Versus-Malignancy Effect through Enhanced NK-Cell Cytotoxicity in Patients with T-Cell Malignancies: Final Results of a Phase I/II Trial

Background: For patients with high risk, and relapsed/refractory T-cell malignancies allogeneic stem cell transplant (allo-SCT) is the only available potentially curative therapy. The efficacy of allo-SCT is limited in this population by high rates of relapse, with rates up to 55-60% post-allo-SCT. We designed a phase I/II trial, evaluating the combination of the histone deacetylases inhibitor romidepsin (rom) with busulfan/fludarabine (BuFlu) conditioning, followed by romidepsin maintenance (m-rom) in patients receiving allo-SCT for T-cell malignancies (NCT02512497). Here we present final clinical results of this therapeutic approach, including an evaluation of the stimulatory effects of m-rom on the graft-versus-malignancy effect through NK-cells post-allo-SCT. Methods: This was a phase I/II clinical trial. Eligible patients had: a diagnosis of T-cell leukemia (including T-acute lymphoblastic leukemia) or T-cell lymphoma (TCL, cutaneous or peripheral) in at least a partial remission requiring an allo-SCT, &amp;lt;70 years of age, with a matched sibling/unrelated donor. Patients received myeloablative (20K) or reduced intensity (16K) BuFlu with rom, followed by standard tacrolimus/methotrexate GVHD prophylaxis and anti-thymocyte globulin for unrelated donors (MUD). An expansion cohort of up to 30 patients (total) was included. M-rom was initiated between day +28 and +100 for 1 year (2 nd year optional), with built in dose reductions for toxicity. An efficacy endpoint of 20% reduction in relapse risk at 1-year in the whole cohort or any individual disease cohort was set based upon historical/CIBMTR (Center for Blood and Marrow Transplant Research) controls was pre-specified. The effect of m-rom on NK-cell cytotoxicity was assessed on samples taken pre-transplant, and 1, 3, 6, 12 months post allo-SCT. NK cytotoxicity was assessed by isolating mononuclear cells from patient samples at each timepoint, comparing those on m-rom (n=13) versus those who did BuFlu controls who did not receive m-rom (n=16). Cells were targeted against K562 targets using the calcein-AM assay. K-M and Fine-Gray models were used to estimate PFS, OS, and cumulative incidence, and compare survival across groups. Results: 28 patients were enrolled on this trial (Table). With a median follow-up time of 15 months, the median OS is 3.3 years (95% CI: 0.85-not reached), with a 1 and 3 year OS probability of 68% and 54%. The median PFS is 2.3 years (95% CI: 0.6-not reached), with 1 and 3-year PFS of 61% and 41%. Cumulative incidence (CI) of NRM at day 100 and 1 year were 14.3% and 21.4%. CI of grade II-IV aGHVD and extensive cGVHD were 46.4% and 38%. The CI of relapse (CIR) was 18.1% at 1 year and 33% at 3 -years. There was no difference between PFS among patients with MRD versus those without MRD prior to transplant (p=0.43). The CIR of patients with TCL was 9.3% at 1 and 3 years, whereas the CIR of patients with leukemia was 25% at 1 year and 48% at 3 years. No patients with PTCL relapsed, 1/2 patients with CTCL relapsed, and 4/6 patients with T-PLL are alive, disease free. Pre-specified general CIR was 55% for all patients. With an overall CIR of 18% at 1 year, and 33% at 3-years, this trial met its pre-specified endpoint of decreasing relapse by 20% at 1-year, and performed well compared to published CIBMTR control populations. Matched propensity score analysis across disease subsets with CIBMTR controls will be presented. 18/28 (64%) of patients received m-rom with a median number of 13 cycles (range 1-47). 8 patients experienced grade 3/4 adverse events (AE), and 1 patient discontinued m-rom due to toxicity, unlikely related to romidepsin (loss of CD3 chimerism). When NK-cytotoxicity was assessed between the two groups after starting maintenance, NK-cytotoxicity in the m-rom group was significantly higher than in those without m-rom (p&amp;lt;0.0001) (Figure). Conclusions: BuFluRom with m-rom is effective at decreasing relapse in patients with T-cell malignancies, with 1-year CI relapse below expected relapse rates for this set of diseases, meeting the pre-specified efficacy endpoint. NK-cell cytotoxicity data in a large sample set of trial patients demonstrates that m-rom enhances NK-cell cytotoxicity post allo-SCT, augmenting the GVL effect and likely accounting for at a minimum, some of the decrease in relapse seen on this trial. M-rom should be considered a new option post allo-SCT to mitigate relapse in patients with T-cell malignancies.

Dynamic Changes in ABL1 Kinase Domain Mutations and Comparative Efficacy of Third-Generation Tyrosine Kinase Inhibitors across Different Stages in Acute Lymphoblastic Leukemia and Chronic Myeloid Leukemia Blast Crisis Patients

*Drs.Zixuan Li and Danyue Peng contributed equally. Drs.Mei Hong and Qiuling Wu are co-corresponding authors Background The development of first-generation and second-generation tyrosine kinase inhibitors (TKIs) has played a crucial role in the treatment of Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) and chronic myeloid leukemia (CML). However, the emergence of mutations in the kinase domain (KD) of BCR-ABL1 has increasingly compromised the efficacy of TKIs and become the primary cause of TKI resistance. Testing BCR-ABL1 KD mutations in early phase accurately is of great value in predicting response and guiding therapeutic decisions. Next-generation sequencing (NGS) provided a more comprehensive and elaborate understanding of mutation status. Third-generation (3G) TKI has been designed to overcome resistance problems caused by BCR-ABL1 KD mutations, and it exhibited unique pharmacological profiles and response patterns relative to different mutations and disease characteristics. Therefore, the potential clinical relevance of mutations detected by NGS and the efficacy of 3G TKI are worth exploring. Methods NGS was used to analyze the dynamic changes of both clinically unreported mutations and reported resistant mutations in the ABL1 KD during three stages of the disease course (pretreatment, remission, and relapsed periods) in Ph+ ALL (n = 97) and chronic myeloid leukemia blast crisis (CML-BP) (n = 21) patients. Meanwhile, the comparative efficacy of three generations of TKIs in Ph+ ALL (n = 92) and CML-BP (n = 23) and the relationship between ABL1 KD mutations and different TKI selection were analyzed. Results In Ph+ ALL patients, single ABL1 KD unreported mutations were detected in 30.49% of patients before therapy and 39.73% in remission, which accounted for the highest proportion among other mutation types. Conversely, single ABL1 KD resistant mutations were found to be the most prevalent (54.5%) in relapsed patients ( P &amp;lt; 0.0001). Logistic analysis revealed that the presence of F401V/L in untreated Ph+ ALL patients was associated with a higher risk of relapse ( P &amp;lt; 0.1). Furthermore, through analyzing patients who received TKI treatment, we observed that 3G TKIs like olverembatinib exhibited advantages in prognosis, including achieving deep molecular response, rapid remission reduction, and decreased relapse probability, for both newly diagnosed and relapsed Ph+ ALL patients. Notably, 3G TKIs not only demonstrated strong inhibition against the T315I mutation, as previously reported, but also displayed superior effectiveness against certain ABL1 KD unreported mutations, such as R516L, K262T, and F401V. Similar trends were observed in CML-BP, although statistical significance was not reached likely due to the limited number of patients. Conclusion Overall, our findings indicate the prevalence and impact of ABL1 KD mutations in Ph+ ALL and CML-BP patients, highlighting the necessity for effective therapies targeting these mutations. The promising outcomes observed with 3G TKIs suggest their potential as a treatment option for both newly diagnosed and relapsed Ph+ ALL patients, offering advantages in terms of molecular response depth, rapid remission, and reduced relapse risk. Further investigations are warranted to explore the clinical significance of unreported ABL1 KD mutations and validate the effectiveness of 3G TKIs against them.

Full CD34 Donor Chimerism Following CD34 Chimerism Directed Donor Lymphocyte Infusion Results in Reduced Relapse and Superior Overall Survival Compared with Mixed Chimerism Status in Allogeneic Haemopoietic Stem Cell Transplant Recipients

Introduction Peripheral blood CD34 donor chimerism (DC) is a clinically valuable method for detecting relapse of myeloid malignancies following allogeneic hematopoietic stem cell transplantation (alloHSCT). Our institution has recently shown that CD34 DC ≤80% was superior to CD3 DC for predicting relapse (1). While pre-emptive DLI has demonstrated efficacy in preventing relapse in the setting of falling whole unfractionated and CD3 DC, little has been reported about its utility in falling CD34 DC. Methods We conducted a retrospective analysis of consecutive patients who received DLI at the Alfred Hospital in Melbourne, Australia between January 2012 and January 2023. Peripheral blood CD34 DC was monitored in alloHSCT patients transplanted for myeloid malignancies or acute lymphoblastic leukaemia (ALL). CD34+ cells were enriched using magnetic beads and DC measured using an STR-PCR method, which had a sensitivity of 1%. DLI was administered to patients with CD34 ≤80% that did not respond to immunosuppression taper. DLI doses were based on donor type and recipient weight, with subsequent doses administered incrementally according to a predefined protocol. Starting doses were 3x10 6/kg for sibling donors, 1x10 6/kg for unrelated donors and 0.5x10 6/kg for haploidentical donors. DLI was discontinued upon achieving full DC (FDC) defined as CD34 DC &amp;gt; 95%, clinically significant graft-versus-host disease (GVHD), disease progression, or lack of available donor cells. Results One hundred and six patients received DLI between 2012 and 2023. Twenty-five of these patients received DLI for CD34 DC ≤80% without morphologic relapse. Eleven of 25 (44%) patients received DLI alone, while 14 (56%) patients received it in combination with other therapies, primarily a hypomethylating agent. At the time of DLI, 5 (20%) of the 25 patients had concurrent decreased CD3 DC ≤ 80%. The median follow-up period was 1.84 years (range 0.58 to 8.43 years). Sixteen of 25 (66.7%) patients achieved CD34 FDC while 8 (33.3%) had persistent CD34 mixed DC (CD34 MDC). One patient could not be assessed due to death from infection. Patient characteristics and outcomes according to response to DLI are presented in Table 1. The cumulative incidence of relapse was significantly lower in the CD34 FDC group (12.5% vs 75% at 2 years, p&amp;lt;0.001). Patients achieving CD34 FDC had improved progression-free survival (PFS) and overall survival (OS) compared to the CD34 MDC group (PFS median years not reached [95% CI 1.94-ND] vs 0.29 years [95% CI 0.09-ND], p&amp;lt;0.001; OS median years not reached vs 0.68 years [95% CI 0.58-ND], p=0.003; Figure 1). Rates of grade II-IV acute graft-versus-host-disease (aGVHD) post-DLI were 12.5% in those achieving FDC and MDC (Table 1). A significant proportion of patients (37.5%) achieving FDC developed moderate-severe cGVHD while the MDC group did not survive long enough to develop cGVHD (Table 1). The non-relapse mortality observed in the CD34 FDC group was 12.5% at 3 years post-DLI. Conclusion Our centre experience demonstrated that CD34-directed DLI reduced relapse risk and improved overall survival when FDC is restored in alloHSCT patients, with an acceptable toxicity profile. Only 20% of patients with CD34 MDC had concurrent CD3 MDC, highlighting the additional value of CD34 monitoring in guiding salvage DLI administration. In patients with CD34 MDC ≤80%, the target of DLI should be to achieve FDC (&amp;gt;95%) given the clear association with improved outcomes in this group. References 1/ Das TP, North D, Fleming SA, Tan JLC, Ivey A, Cummings NJ, Spencer A, Patil SS, Widjaja JML, Swain MI, Bourke C, O'Brien ME, Kliman DS, Curtis DJ. Peripheral Blood CD34 Donor Chimerism has Greater Clinical Utility Than CD3 for Detecting Relapse after Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia or Myelodysplastic Syndrome. Transplant Cell Ther. 2023 Jul;29(7):454.e1-454.e8. doi: 10.1016/j.jtct.2023.03.025.

A Phase 2, Single-Arm, Multicohort, Open Label, Multicenter Trial of Off-the-Shelf Natural Killer Cells (SAR445419) in Patients with High-Risk Myeloid Malignancies Undergoing Allogeneic HSCT

Background and Significance: Relapse remains the leading cause of treatment failure for patients with high-risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although the risk depends on parameters such as age and conditioning intensity, relapse is experienced in 30-50% of patients after conventional HSCT in high-risk AML/MDS. Initial safety and post-HSCT relapse risk reduction results were reported in a phase I study of haploidentical (haplo) donor-derived natural killer (NK) cells expanded ex vivo on feeder cells expressing IL-21 and 4-1BBL in conjunction with haplo-HSCT (Ciurea et al, Leukemia, 2022). This study supported exploring SAR445419 (SAR'419), an off-the-shelf (OTS) product, derived from universal donor NK cells and expanded ex vivo in a feeder cell-free system using plasma membrane particles bearing membrane-bound IL-21 and 4-1BBL. Here, we aim to test whether SAR'419 can mediate an effective anti-leukemia response and reduce post-transplant relapse rate when administered in the peri-transplant period. Study Design and Methods: In this multicenter, multicohort, phase 2, single-arm trial (NCT05726682), patients with high-risk AML/MDS planned for allo-HSCT from matched sibling, matched unrelated or haplo donors will be enrolled in 2 cohorts. Cohort A will comprise patients aged 18‒65 years undergoing myeloablative conditioning with hematopoietic cell transplantation comorbidity index ≤3 and cohort B will comprise patients aged 18‒75 years undergoing reduced intensity conditioning. Patients with prior allogeneic transplantation or AML beyond first complete remission will be excluded from the study. Patients will undergo HSCT conditioning starting on Day ‒7 and will receive a peripheral blood stem cell graft on Day 0. Prophylaxis for Graft-versus-host disease (GVHD) using cyclophosphamide, mycophenolate mofetil, and tacrolimus will start on Day +3. SAR'419 will be administered as adjunctive therapy to the HSCT on Day ‒2, Day +7, and Day +28. To confirm the anticipated safety profile of SAR'419, a safety run-in will be conducted in 6‒12 patients in each cohort prior to open enrollment. Patients will be enrolled until 51 and 44 patients in cohorts A and B, respectively, receive at least the first 2 doses of SAR'419 at the target dose confirmed during safety run-in. In total, approximately 107 patients will be enrolled. The primary endpoint, relapse free survival (RFS), will be assessed at 12 months post-HSCT. Additional primary endpoints include frequency of graft failure, life-threatening infusion-related reactions or cytokine release syndrome, tumor lysis syndrome, immune cell-associated neurotoxicity syndrome, acute GVHD, overall mortality at 100 days post-HSCT, non-relapse mortality, and cytomegalovirus reactivation/infection. Secondary endpoints are safety, tolerability, and the impact of SAR'419 on HSCT outcomes, stem cell engraftment, GVHD, infection, and quality of life. Exploratory assessments include evaluation of the impact of SAR'419 on immune reconstitution, cytomegalovirus seroconversion, minimal residual disease, resource utilization, SAR'419 immunogenicity and persistence and their impact on outcomes in whole blood (including serum and plasma) and bone marrow aspirates. RFS will be reported as the percentage of patients who are relapse free and alive at 12 months from the date of HSCT and who received at least the first 2 planned doses of SAR'419. Adverse events will be graded by the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0 and will be summarized using descriptive statistics.