Inotuzumab Research Articles

Inotuzumab Ozogamicin and Low-Intensity Chemotherapy in Older Patients With Newly Diagnosed CD22+ Philadelphia Chromosome-Negative B-Cell Precursor Acute Lymphoblastic Leukemia.

The use of inotuzumab ozogamicin (InO), a conjugated anti-CD22 monoclonal antibody, is becoming a promising frontline treatment for older patients with ALL. EWALL-INO is an open-label prospective multicenter phase II trial (ClinicalTrials.gov identifier: NCT03249870). Patients age 55 years and older with newly diagnosed CD22+ Philadelphia chromosome-negative (Ph-) B-cell precursor (BCP) ALL were eligible. After a prephase, a first induction consisting of vincristine, dexamethasone, and three injections of InO (0.8 mg/m2 day 1, 0.5 mg/m2 day 8/day 15) was followed by a second induction combining cyclophosphamide, dexamethasone, and two injections of InO (0.5 mg/m2 day 1/day 8). Responders received up to six cycles of chemotherapy consolidation and 18-month chemotherapy maintenance. Allotransplant was allowed after three consolidations. The primary end point was 1-year overall survival (OS). Between December 2017 and March 2022, 131 patients (median age 68 years) were included. Three patients died during induction 1 (n = 130), two from multiple organ failure and one from hemorrhage, and none during induction 2 (n = 120). After induction 2, 90% of the patients achieved complete remission (CR) or CR with incomplete platelet recovery (CRp) and 80% had measurable residual disease (MRD2) <10-4. Among responders (n = 119), 47 relapsed and 14 died in CR/CRp. One-year OS, relapse-free survival (RFS), and cumulative incidence of relapse (CIR) rates were 73.2%, 66%, and 25%, respectively. High-risk cytogenetics and lower CD22 expression (<70%) were associated with worse OS, while both high-risk cytogenetics and MRD2 ≥10-4 were associated with lower RFS and higher CIR. The 10 allotransplanted patients had very favorable outcomes (90% 2-year OS/RFS and no relapse). Only one nonfatal sinusoidal obstructive syndrome was documented during the study. Our results support InO's use in first-line regimens for older patients with CD22+ Ph- BCP-ALL.

Inotuzumab Ozogamicin in Indian Patients with B-Cell Acute Lymphoblastic Leukemia

Inotuzumab Ozogamicin in Indian Patients with B-Cell Acute Lymphoblastic Leukemia

Bone marrow necrosis and hyperinflammation after treatment with inotuzumab ozogamicin for B-cell acute lymphoblastic leukaemia

Bone marrow necrosis and hyperinflammation after treatment with inotuzumab ozogamicin for B-cell acute lymphoblastic leukaemia

Development of Inotuzumab Ozogamicin and Blinatumomab for Frontline Treatment of Older Patients with Ph-Negative B-Cell Acute Lymphoblastic Leukemia

Development of Inotuzumab Ozogamicin and Blinatumomab for Frontline Treatment of Older Patients with Ph-Negative B-Cell Acute Lymphoblastic Leukemia

Impact of prior inotuzumab ozogamicin treatment on brexucabtagene autoleucel outcomes in adults with B-cell ALL

AbstractThe effect of prior inotuzumab ozogamicin (InO) treatment on brexucabtagene autoleucel (brexu-cel) outcomes remains unclear in adults with acute lymphoblastic leukemia (ALL), particularly the influence of previous InO response and the timing of administration. We conducted a retrospective multicenter analysis of 189 patients with relapsed/refractory ALL treated with brexu-cel. Over half of the patients received InO before brexu-cel (InO exposed). InO-exposed patients were more heavily pretreated (P = .02) and frequently had active marrow disease before apheresis (P = .03). Response rate and toxicity profile after brexu-cel were comparable for InO-exposed and InO-naïve patients; however, consolidation therapy after brexu-cel response was used at a higher rate in InO-naïve patients (P = .005). With a median follow-up of 11.4 months, InO-exposed patients had inferior progression-free survival (PFS; P = .013) and overall survival (OS; P = .006) in univariate analyses; however, prior InO exposure did not influence PFS (hazard ratio, 1.20; 95% confidence interval, 0.71-2.03) in multivariate models. When InO-exposed patients were stratified according to prior InO response, InO responders had superior PFS (P = .002) and OS (P < .0001) relative to InO-refractory patients. The timing of administering InO did not affect brexu-cel outcomes, with comparable PFS (P = .51) and OS (P = .86) for patients receiving InO as bridging therapy or before apheresis. In conclusion, although InO exposure was associated with inferior survival outcomes after brexu-cel in unadjusted analyses, these associations were no longer significant in multivariate analyses, suggesting it is unlikely that InO negatively affects brexu-cel efficacy. Our data instead imply that InO-exposed recipients of brexu-cel tend to be higher-risk patients with intrinsic adverse leukemia biology.

Impact of Age on Pharmacogenomics and Treatment Outcomes of B-Cell Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia (ALL) can occur across all age groups, with a strikingly higher cure rate in children compared with adults. However, the pharmacological basis of age-related differences in ALL treatment response remains unclear. Studying 767 children and 309 adults with newly diagnosed B-cell ALL enrolled on frontline trials at St Jude Children's Research Hospital, MD Anderson Cancer Center, the Alliance for Clinical Trials in Oncology, and the ECOG-ACRIN Cancer Research Group, we determined the ex vivo sensitivity of leukemia cells to 21 drugs. Twenty-three ALL molecular subtypes were identified using RNA sequencing. We systematically characterized the associations between drug response and ALL genomics in children, adolescents and young adults, and elderly adults. We evaluated the effect of age-related gene expression signature on ALL treatment outcomes. Seven ALL drugs (asparaginase, prednisolone, mercaptopurine, dasatinib, nelarabine, daunorubicin, and inotuzumab ozogamicin) showed differential activity between children and adults, of which six were explained by age-related differences in leukemia molecular subtypes. Adolescents and young adults showed similar patterns of drug resistance as older adults, relative to young children. Mercaptopurine exhibited subtype-independent greater sensitivity in children. Transcriptomic profiling uncovered subclusters within CRLF2-, DUX4-, and KMT2A-rearranged ALL that were linked to age and cytotoxic drug resistance. In particular, a subset of children had adult-like ALL on the basis of leukemia gene expression patterns across subtypes, despite their chronological age. Resistant to cytotoxic drugs, children with adult-like ALL exhibited poor prognosis in pediatric ALL trials, even after adjusting for age and minimal residual diseases. Our results provide pharmacogenomic insights into age-related disparities in ALL cure rates and identify leukemia prognostic features for treatment individualization across age groups.

Prediction of Response to FDA-Approved Targeted Therapy and Immunotherapy in Acute Lymphoblastic Leukemia (ALL).

Acute lymphoblastic leukemia (ALL) represents the predominant cancer in pediatric populations, though its occurrence in adults is relatively rare. Pre-treatment risk stratification is crucial for predicting prognosis. Important factors for assessment include patient age, white blood cell (WBC) count at diagnosis, extramedullary involvement, immunophenotype, and cytogenetic aberrations. Minimal residual disease (MRD), primarily assessed by flow cytometry following remission, plays a substantial role in guiding management plans. Over the past decade, significant advancements in ALL outcomes have been witnessed. Conventional chemotherapy has remarkably reduced mortality rates; however, its intensive nature raises safety concerns and has led to the emergence of treatment-resistant cases with recurrence of relapses. Consequently, The U.S. Food and Drug Administration (FDA) has approved several novel treatments for relapsed/refractory ALL due to their demonstrated efficacy, as indicated by improved complete remission and survival rates. These treatments include tyrosine kinase inhibitors (TKIs), the anti-CD19 monoclonal antibody blinatumomab, anti-CD22 inotuzumab ozogamicin, anti-CD20 rituximab, and chimeric antigen receptor (CAR) T-cell therapy. Identifying the variables that influence treatment decisions is a pressing necessity for tailoring therapy based on heterogeneous patient characteristics. Key predictive factors identified in various observational studies and clinical trials include prelymphodepletion disease burden, complex genetic abnormalities, and MRD. Furthermore, the development of serious adverse events following treatment could be anticipated through predictive models, allowing for appropriate prophylactic measures to be considered. The ultimate aim is to incorporate the concept of precision medicine in the field of ALL through valid prediction platform to facilitate the selection of the most suitable treatment approach.

Inotuzumab ozogamicin in adult acute lymphoblastic leukemia: Development, current status, and future directions.

Inotuzumab ozogamicin (InO) is an antibody-drug conjugate approved for the treatment of relapsed/refractory B-cell acute lymphoblastic leukemia (ALL). Several clinical trials are investigating InO in combination with low-intensity chemotherapy or other anti-ALL-targeted therapies in the salvage and frontline settings, notably in older adults who often cannot tolerate intensive chemotherapy and tend to have higher-risk disease. InO is also increasingly used to bridge patients to hematopoietic stem cell transplantation (HSCT), in sequence with chimeric antigen receptor T-cell therapy, to eliminate measurable residual disease and to prevent post-HSCT relapse. Veno-occlusive disease/sinusoidal obstruction syndrome is a potential complication of InO treatment, particularly when followed by HSCT. Herein, the authors review the historical development and current status of InO, strategies for mitigating the risk of InO-related veno-occlusive disease/sinusoidal obstruction syndrome, and future directions for InO research and clinical use.

Evolving Horizons in Pediatric Leukemia: Novel Insights, Challenges, and the Journey Ahead.

Pediatric leukemia, encompassing acute lymphoblastic leukemia (ALL) and acute myeloid leukemia, remains a formidable challenge despite significant treatment advancements. This review examines recent developments in immunotherapy, chemotherapy, and bone marrow transplantationfor pediatric leukemia through a comprehensive analysis of recent literature, focusing on critical studies and clinical trials. Immunotherapy, including monoclonal antibodies, such as blinatumomab and inotuzumab ozogamicin, and chimeric antigen receptor T-cell therapies, such as tisagenlecleucel and brexucabtagene autoleucel, have demonstrated promising results in relapsed or refractory B-cell ALL (B-ALL), achieving notable remission rates with manageable side effects. Chemotherapy continues to be the primary treatment, utilizing multiphase regimens tailored to individual risk profiles. Bone marrow transplantation, especially allogeneic stem cell transplantation, offers potential cures for high-risk or relapsed cases, though it poses risks including graft-versus-host diseaseand infections. Despite these advancements, treatment resistance, toxicity, and accessibility persist. This review also discusses the long-term outcomes among pediatric leukemia survivors, focusing on late-onset side effects associated with treatments such as chemotherapy and bone marrow transplantation, encompassing secondary malignancies, organ dysfunction, and neurocognitive impacts. Ongoing research and clinical trials are crucial to refine these therapies, enhance their efficacy, and reduce adverse effects, ultimately improving young patients' survival and quality of life.

Population Pharmacokinetics of Inotuzumab Ozogamicin in Pediatric Relapsed/Refractory B-Cell Precursor Acute Lymphoblastic Leukemia: Results of Study ITCC-059.

Inotuzumab ozogamicin is an antibody-drug conjugate approved for treating relapsed/refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in adults. Pediatric pharmacokinetic data of inotuzumab ozogamicin are lacking. This study is the first to examine the population pharmacokinetics of inotuzumab ozogamicin in pediatric patients with relapsed/refractory BCP-ALL. From 531 adult patients with B-cell non-Hodgkin's lymphoma, 234 adult patients with BCP-ALL, and 53 pediatric patients with BCP-ALL, 8924 inotuzumab ozogamicin serum concentrations were analyzed using non-linear mixed-effects modeling. A published adult inotuzumab ozogamicin population-pharmacokinetic model, a two-compartment model with linear and time-dependent clearance, was adapted to describe the pediatric data. Modifications in this analysis, compared to the published adult model, included: (i) re-estimating pharmacokinetic parameters and covariate effects; (ii) modifying covariate representation; and (iii) introducing relevant pediatric covariate effects (age on the decay coefficient of time-dependent clearance and ALL effect (disease type and/or different bioanalytical analysis methods) on initial values of time-dependent clearance). For patients with relapsed/refractory BCP-ALL, increasing age was associated with a decreasing decay coefficient of time-dependent clearance, reflecting that the target-mediated drug clearance declines more rapidly in children. In pediatric BCP-ALL, the median [interquartile range] cumulative area under the concentration-time curve was significantly higher among responders (n = 42) versus non-responders (n = 10) at the end of the first cycle (26.1 [18.9-35.0] vs 10.1 [9.19-16.1], × 103 ng*h/mL, p < 0.001). From simulations performed at the recommended pediatric phase II dose, inotuzumab ozogamicin exposure reached a similar level as observed in responding pediatric trial participants. The pharmacokinetic profile of inotuzumab ozogamicin in pediatric patients with relapsed/refractory BCP-ALL was well described in this study. No dose adjustment is required clinically for pediatric patients with BCP-ALL based on the simulated inotuzumab ozogamicin exposure at the recommended pediatric phase II dose, promising efficacy and acceptable tolerability.

MRD in Philadelphia Chromosome-Positive ALL: Methodologies and Clinical Implications.

Measurable residual disease (MRD) is integral in the management of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). This review discusses the current methods used to evaluate MRD as well as the interpretation, significance, and incorporation of MRD in current practice. New molecular technologies have allowed the detection of MRD to levels as low as 10- 6. The most used techniques to evaluate MRD are multiparametric flow cytometry (MFC), quantitative reverse transcription polymerase chain reaction (RT-qPCR), and high-throughput next-generation sequencing (NGS). Each method varies in terms of advantages, disadvantages, and MRD sensitivity. MRD negativity after induction treatment and after allogeneic hematopoietic cell transplantation (HCT) is an important prognostic marker that has consistently been shown to be associated with improved outcomes. Blinatumomab, a new targeted therapy for Ph + ALL, demonstrates high efficacy in eradicating MRD and improving patient outcomes. In the relapsed/refractory setting, the use of inotuzumab ozogamicin and tisagenlecleucel has shown promise in eradicating MRD. The presence of MRD has become an important predictive measure in Ph + ALL. Current studies evaluate the use of MRD in treatment decisions, especially in expanding therapeutic options for Ph + ALL, including tyrosine kinase inhibitors, targeted antibody therapies, chimeric antigen receptor cell therapy, and HCT.

Naked antibodies and antibody-drug conjugates: targeted therapy for childhood acute lymphoblastic leukemia.

The treatment of childhood acute lymphoblastic leukemia (ALL) has reached overall survival rates exceeding 90%. The present and future challenges are to cure the remainder of patients still dying from disease, and to reduce morbidity and mortality in those who can be cured with standard-of-care chemotherapy by replacing toxic chemotherapy elements while retaining cure rates. With the novel therapeutic options introduced in the last years, including immunotherapies and targeted antibodies, the treatment of ALL is undergoing major changes. For B-cell precursor ALL, blinatumomab, an anti-CD19 bispecific antibody, has established its role in the consolidation treatment for both high- and standard-risk first relapse of ALL, in the presence of bone marrow involvement, and may also have an impact on the outcome of high-risk subsets such as infant ALL and Philadelphia chromosome-positive ALL. Inotuzumab ozogamicin, an anti-CD22 drug conjugated antibody, has demonstrated high efficacy in inducing complete remission in relapsed ALL, even in the presence of high tumor burden, but randomized phase III trials are still ongoing. For T-ALL the role of CD38-directed treatment, such as daratumumab, is gaining interest, but randomized data are needed to assess its specific benefit. These antibodies are currently being tested in patients with newly diagnosed ALL and may lead to major changes in the present paradigm of treatment of pediatric ALL. Unlike the past, lessons may be learned from innovations in adult ALL, in which more drastic changes are piloted that may need to be translated to pediatrics.

Inotuzumab Ozogamicin: First Pediatric Approval.

Inotuzumab ozogamicin (BESPONSA™) is a CD22-targeted monoclonal antibody drug conjugate (ADC) developed by Pfizer for the treatment of CD22-postive B-cell precursor acute lymphoblastic leukaemia (ALL). Inotuzumab ozogamicin comprises a humanized IgG4 anti-CD22 monoclonal antibody covalently linked to the potent DNA-binding cytotoxic agent N-acetyl-gamma-calicheamicin dimethylhydrazide (CalichDMH) via a linker. Inotuzumab ozogamicin binds to CD22-expressing tumour cells, facilitating the delivery of conjugated CalichDMH, which after intracellular activation induces double strand DNA breaks, ultimately leading to cell cycle arrest and apoptotic cell death. Inotuzumab ozogamicin is approved in the USA, Europe and several countries worldwide for the treatment of relapsed or refractory CD22-positive B-cell precursor ALL in adults. On 6 March 2024, inotuzumab ozogamicin received its first pediatric approval in the USA for this indication in patients aged ≥1 years. Inotuzumab ozogamicin has since been approved in Japan in March 2024 for the same indication in pediatric patients. This article summarizes the milestones in the development of inotuzumab ozogamicin leading to this first approval for the treatment of relapsed or refractory CD22-positive B-cell precursor ALL in pediatric patients.

Combining inotuzumab ozogamicin with PARP inhibitors olaparib and talazoparib exerts synergistic cytotoxicity in acute lymphoblastic leukemia by inhibiting DNA strand break repair.

Inotuzumab ozogamicin (IO), a novel therapeutic drug for relapsed or refractory acute lymphoblastic leukemia (RR)‑(ALL), is a humanized anti‑cluster of differentiation (CD) 22 monoclonal antibody conjugated with calicheamicin that causes DNA single‑ and double‑strand breaks. Although the efficacy of IO is significantly improved compared with that of conventional chemotherapies, the prognosis for RR‑ALL remains poor, highlighting the need for more effective treatment strategies. The present study examined the role of DNA damage repair inhibition using the poly (ADP‑ribose) polymerase (PARP) inhibitors olaparib or talazoparib on the enhancement of the antitumor effects of IO on B‑ALL cells in vitro. The Reh, Philadelphia (Ph)‑B‑ALL and the SUP‑B15 Ph+ B‑ALL cell lines were used for experiments. Both cell lines were ~90% CD22+. The half‑maximal inhibitory concentration (IC50) values of IO were 5.3 and 49.7 ng/ml for Reh and SUP‑B15 cells, respectively. The IC50 values of IO combined with minimally toxic concentrations of olaparib or talazoparib were 0.8 and 2.9 ng/ml for Reh cells, respectively, and 36.1 and 39.6 ng/ml for SUP‑B15 cells, respectively. The combination index of IO with olaparib and talazoparib were 0.19 and 0.56 for Reh cells and 0.76 and 0.89 for SUP‑B15 cells, demonstrating synergistic effects in all combinations. Moreover, the addition of minimally toxic concentrations of PARP inhibitors augmented IO‑induced apoptosis. The alkaline comet assay, which quantitates the amount of DNA strand breaks, was used to investigate the degree to which DNA damage observed 1 h after IO administration was repaired 6 h later, reflecting successful repair of DNA strand breaks. However, DNA strand breaks persisted 6 h after IO administration combined with olaparib or talazoparib, suggesting inhibition of the repair processes by PARP inhibitors. Adding olaparib or talazoparib thus synergized the antitumor effects of IO by inhibiting DNA strand break repair via the inhibition of PARP.

Inotuzumab ozogamicin as a bridging therapy to allogeneic hematopoietic stem cell transplantation in children with refractory/relapsed B-cell acute lymphoblastic leukemia

Inotuzumab ozogamicin as a bridging therapy to allogeneic hematopoietic stem cell transplantation in children with refractory/relapsed B-cell acute lymphoblastic leukemia

Cardiovascular adverse events associated with antibody-drug conjugates (ADCs): a pharmacovigilance study based on the FAERS database.

As a novel drug formulation, antibody drug conjugates (ADCs) are widely used in various types of cancer. However, clinically, there is a lack of attention to the CVD produced by them, as well as a lack of research on the real-world situation. Using the Food and Drug Administration Adverse Event Reporting System (FAERS) database, to ensure its clinical safety application, we analyzed post-marketing data on antitumor ADCs to identify risk factors and drugs associated with the risk of cardiovascular events. We used OpenVigil 2.1 to conduct a database query for adverse events (AEs) reported to the FAERS database between the time the drug was launched and the second quarter of 2023. Cardiovascular adverse events (AEs) were grouped into fourteen narrow categories using the Standardized Medical Dictionary for Regulatory Activities (MedDRA) Queries (SMQs), and the reporting odds ratio (ROR) and the proportional reporting ratio (PRR) for reporting the association between different drugs and cardiovascular disease (CVD) risk were calculated. In the FAERS database, 1863 AEs associated with CVD we studied were identified in patients receiving ADC therapy. Most reports came from people aged ≥65, but a significant number of cases were found to be unknown. The number of patients with antibody-drug conjugates (ADCs)-related CVD cases aged <18years, 18-64years, and≥ 65years was 52 (2.79%), 586 (31.45%), and 613 (32.90%), respectively. The proportion of female patients (834, 44.77%) was higher than that of male patients (752, 40.37%). Death (770 reports), disability (9 reports), Hospitalization initial or prolonged (407 reports), and life-threatening reactions (187 reports). Of the 770 deaths reported, 103 (31.7%) were associated with brentuximab vedotin, 10 (24.4%) with sacituzumab govitecan, 22 (19.3%) with enfortumab vedotin, and 35 (34.7%) with trastuzumab emtansine.49 (41.2%) cases were associated with polatuzumab vedotin, 62 (29%) with trastuzumab deruxtecan, 423 (54.3%) with gemtuzumab ozogamicin, and 66 (38.8%) with inotuzumab ozogamicin. In a disproportionate number of SMQS, cardiac failure (n = 277) and embolic and thrombotic events, venous (n = 446) were the most frequently reported CVD-related AEs in ADCs. By mining the FAERS database, we provided relevant information on the association between ADC use and cardiovascular-associated AEs. ADCs were associated with increased cardiovascular toxicity, deserving distinct monitoring and appropriate management. Further research is needed to confirm these findings and assess causality.

Antibody-drug conjugate adverse effects can be understood and addressed based on immune complex clearance mechanisms

AbstractNumerous antibody-drug conjugates (ADCs) are being developed for cancer immunotherapy. Although several of these agents have demonstrated considerable clinical efficacy and have won Food and Drug Administration (FDA) approval, in many instances, they have been characterized by adverse side effects (ASEs), which can be quite severe in a fraction of treated patients. The key hypothesis in this perspective is that many of the most serious ASEs associated with the use of ADCs in the treatment of cancer can be most readily explained and understood due to the inappropriate processing of these ADCs via pathways normally followed for immune complex clearance, which include phagocytosis and trogocytosis. We review the key published basic science experiments and clinical observations that support this idea. We propose that it is the interaction of the ADC with Fcγ receptors expressed on off-target cells and tissues that can most readily explain ADC-mediated pathologies, which therefore provides a rationale for the design of protocols to minimize ASEs. We describe measurements that should help identify those patients most likely to experience ASE due to ADC, and we propose readily available treatments as well as therapies under development for other indications that should substantially reduce ASE associated with ADC. Our focus will be on the following FDA-approved ADC for which there are substantial literatures: gemtuzumab ozogamicin and inotuzumab ozogamicin; and trastuzumab emtansine and trastuzumab deruxtecan.

Association of leukemic molecular profile with efficacy of inotuzumab ozogamicin in adults with relapsed/refractory ALL

AbstractThe phase 3 INO-VATE trial demonstrated higher rates of remission, measurable residual disease negativity, and improved overall survival for patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) who received inotuzumab ozogamicin (InO) vs standard-of-care chemotherapy (SC). Here, we examined associations between genomic alterations and the efficacy of InO. Of 326 randomized patients, 91 (InO, n = 43; SC, n = 48) had samples evaluable for genomic analysis. The spectrum of gene fusions and other genomic alterations observed was comparable with prior studies of adult ALL. Responses to InO were observed in all leukemic subtypes, genomic alterations, and risk groups. Significantly higher rates of complete remission (CR)/CR with incomplete count recovery were observed with InO vs SC in patients with BCR::ABL1–like ALL (85.7% [6/7] vs 0% [0/5]; P = .0076), with TP53 alterations (100% [5/5] vs 12.5% [1/8]; P = .0047), and in the high-risk BCR::ABL1– (BCR::ABL1–like, low-hypodiploid, KMT2A-rearranged) group (83.3% [10/12] vs 10.5% [2/19]; P < .0001). This retrospective, exploratory analysis of the INO-VATE trial demonstrated potential for benefit with InO for patients with R/R ALL across leukemic subtypes, including BCR::ABL1–like ALL, and for those bearing diverse genomic alterations. Further confirmation of the efficacy of InO in patients with R/R ALL exhibiting the BCR::ABL1–like subtype or harboring TP53 alterations is warranted. This trial was registered at www.ClinicalTrials.gov as #NCT01564784.

Abstract 541: Establishment of Inotuzumab ozogamicin resistant leukemia cell lines; Focusing on p-gp and DNA damage repair for overcoming drug resistance

Abstract Introduction: Inotuzumab Ozogamicin (IO) is a humanized anti-CD22 monoclonal antibody conjugated with chalicheamicin, which causes single- and double-strand DNA breaks. Although IO shows a high CR/CRi rate in relapsed/refractory CD22-positive B-cell acute lymphoblastic leukemia (ALL), the duration of remission is short due to early acquisition of resistance. Therefore, the present study attempted to enhance the cytotoxicity of IO by focusing on polyadenosine diphosphate-ribose polymerase (PARP) inhibition. Furthermore, IO-resistant cell lines were newly established to investigate the mechanism of IO resistance. Methods: Reh cell line derived from Ph-negative B-ALL cells was used. To establish IO-resistant cell lines, Reh cells were long-term exposed to IO, followed by limiting dilution. FACS analysis evaluated the CD22 positivity and the induction of apoptosis. WTS assay determined the cell growth inhibition effects. The Comet assay quantitatively assessed DNA damage. Gene expression profiles were determined by using DNA microarray. Results: The 50%-inhibitory concentration (IC50) of IO was 2.1 ng/mL in Reh cells. Reh cells were synergistically sensitized to IO by the addition of non-toxic concentrations of PARP inhibitors, olaparib or talazoparib, with the Combination Index of 0.19 and 0.42, respectively. Moreover, these combinations augmented the induction of apoptosis (23.5% in IO alone, 51.7% in IO + olaparib, 66.1% in IO + talazoparib). The Comet assay demonstrated that DNA strand breaks observed 1h after IO administration were repaired 6h later. In the combination of IO with olaparib or talazoparib, DNA damage remained even at 6h, suggesting the inhibition of DNA repair by PARP inhibitors. Next, six IO-resistant cell lines were established with IC50 more than 60-fold that of parental cells. All these cell lines kept CD22 expression. These cell lines were also resistant to apoptosis induced by IO. In addition of olaparib or talazoparib to IO, the IC50 of IO decreased by 40% to 70% in 6 IO-resistant cells. These combinations also augmented the induction of apoptosis (24.2% in IO alone, 45.3% in IO+olaparib, and 56.8% in IO+talazoparib). DNA microarray was performed to compare gene expression profiles between parental and IO-resistant cell lines. ABCB1 (p-gp), a drug efflux pump that causes multi-drug resistance, was overexpressed in resistant cell lines. Moreover, the addition of p-gp inhibitor, PSC-833, to IO enhanced the cell growth inhibition and induction of apoptosis due to more DNA strand break. Conclusion: The present study demonstrated that the combination of IO with PARP inhibitors exerted synergistic cytotoxicity via the inhibition of DNA repair. In addition, it was suggested that overexpression of p-gp caused IO resistance, which was partially reversed with the combination of PARP inhibitors or a p-gp inhibitor. Citation Format: Naoko Ida, Miyuki Okura, Naoko Hosono, Takahiro Yamauchi. Establishment of Inotuzumab ozogamicin resistant leukemia cell lines; Focusing on p-gp and DNA damage repair for overcoming drug resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 541.

A pharmacovigilance study on antibody-drug conjugate (ADC)-related neurotoxicity based on the FDA adverse event reporting system (FAERS).

Background: Antibody-drug conjugates (ADCs) are a relatively new class of anticancer agents that use monoclonal antibodies to specifically recognize tumour cell surface antigens. However, off-target effects may lead to severe adverse events. This study evaluated the neurotoxicity of ADCs using the FDA Adverse Event Reporting System (FAERS) database. Research design and methods: Data were extracted from the FAERS database for 2004 Q1 to 2022 Q4. We analysed the clinical characteristics of ADC-related neurological adverse events (AEs). We used the reporting odds ratio (ROR) and proportional reporting ratio (PRR) for the disproportionality analysis to evaluate the potential association between AEs and ADCs. Results: A total of 562 cases of neurological AEs were attributed to ADCs. The median age was 65years old [(Min; Max) = 3; 92]. Neurotoxic signals were detected in patients receiving brentuximab vedotin, enfortumab vedotin, polatuzumab vedotin, trastuzumab emtansine, gemtuzumab ozogamicin, inotuzumab ozogamicin, and trastuzumab deruxtecan. The payloads of brentuximab vedotin, enfortumab vedotin, polatuzumab vedotin, and trastuzumab emtansine were microtubule polymerization inhibitors, which are more likely to develop neurotoxicity. We also found that brentuximab vedotin- and gemtuzumab ozogamicin-related neurological AEs were more likely to result in serious outcomes. The eight most common ADC-related nervous system AE signals were peripheral neuropathy [ROR (95% CI) = 16.98 (14.94-19.30), PRR (95% CI) = 16.0 (14.21-18.09)], cerebral haemorrhage [ROR (95% CI) = 9.45 (7.01-12.73), PRR (95% CI) = 9.32 (6.95-12.50)], peripheral sensory neuropathy [ROR (95% CI) = 47.87 (33.13-69.19), PRR (95% CI) = 47.43 (32.93-68.30)], polyneuropathy [ROR (95% CI) = 26.01 (18.61-36.33), PRR (95% CI) = 25.75 (18.50-35.86)], encephalopathy [ROR (95% CI) = 5.16 (3.32-8.01), PRR (95% CI) = 5.14 (3.32-7.96)], progressive multifocal leukoencephalopathy [ROR (95% CI) = 22.67 (14.05-36.58), PRR (95% CI) = 22.52 (14.01-36.21)], taste disorder [ROR (95% CI) = 26.09 (15.92-42.76), PRR (95% CI) = 25.78 (15.83-42.00)], and guillain barrier syndrome [ROR (95% CI) = 17.844 (10.11-31.51), PRR (95% CI) = 17.79 (10.09-31.35)]. The mortality rate appeared to be relatively high concomitantly with AEs in the central nervous system. Conclusion: ADCs may increase the risk of neurotoxicity in cancer patients, leading to serious mortality. With the widespread application of newly launched ADC drugs, combining the FAERS data with other data sources is crucial for monitoring the neurotoxicity of ADCs. Further studies on the potential mechanisms and preventive measures for ADC-related neurotoxicity are necessary.