inotuzumab

Numerous antibody-drug conjugates (ADC) are being developed for cancer immunotherapy. Although several of these agents have demonstrated considerable clinical efficacy and have won FDA approval, in many instances they have been characterized by adverse side effects (ASE) which can be quite severe in a fraction of treated patients. The key hypothesis in this perspective is that many of the most serious ASE associated with the use of ADC in the treatment of cancer can be most readily explained and understood due to the inappropriate processing of these ADC via pathways normally followed for immune complex clearance, which include phagocytosis and trogocytosis...

The 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...

Philadelphia chromosome-positive acute lymphoblastic leukemia (PH + ALL) is the most common cytogenetic abnormality of B-ALL in adults and is associated with poor prognosis. Previously, the only curative treatment option in PH + ALL was allogeneic hematopoietic stem cell transplantation (Allo-HSCT). Since 2000, targeted therapy combined with chemotherapy, represented by the tyrosine kinase inhibitor Imatinib, has become the first-line treatment for PH + ALL. Currently, the remission rate and survival rate of Imatinib are superior to those of simple chemotherapy, and it can also improve the efficacy of transplantation...

Inotuzumab ozogamicin (InO) is an antibody-drug conjugate that delivers calicheamicin to CD22-expressing cells. In a retrospective cohort of InO-treated patients with B-cell acute lymphoblastic leukemia, we sought to understand the genomic determinants of response and resistance to InO. Pre- and post-InO patient samples were analyzed by whole genome, exome, and/or transcriptome sequencing. Acquired CD22 mutations were observed in 11% (3/27) of post-InO relapsed tumor samples, but not in refractory samples (0/16)...

Outcomes of patients with B-acute lymphoblastic leukemia (B-ALL) have improved remarkably in the past decade. This has largely been due to the development and introduction of novel immunotherapies such as blinatumomab, inotuzumab ozogamicin, chimeric antigen receptor T (CAR-T) cells, highly potent tyrosine kinase inhibitors, and improved risk stratification, including better understanding of high risk genomic subgroups and better methods of measurable residual disease (MRD) detection. Historically, allogeneic stem cell transplant (allo-SCT) has been the consolidative treatment of choice in first complete remission for fit adults with B-ALL...

A 25-year-old woman with a history of B-cell acute lymphoblastic leukemia over ten years ago was referred to our hospital with a chief complaint of leukoblastosis. She was participating in a JPLSG (Japanese Pediatric Leukemia/Lymphoma Study Group) clinical study at that time. We diagnosed ALL relapse by multi-color flow cytometric analysis of bone marrow samples at admission, with reference to previous JPLSG data. Because her leukemic cells were resistant to conventional cytotoxic agents, she proceeded to lymphocyte apheresis for chimeric antigen receptor T-cell (CAR-T, Tisagenlecleucel [Tisa-cel])...

B-cell acute lymphoblastic leukaemia (B-cell ALL) is a common haematologic cancer in children and adults. About 10 percent of children and 50 percent of adults fail to achieve a histological complete remission or subsequently relapse despite current anti-leukaemia drug therapies and/or haematopoietic cell transplants. Several new immune therapies including monoclonal antibodies and chimeric antigen receptor (CAR)-T-cells are proved safe and effective in this setting. We review data on US Food and Drug Administration (FDA)-approved immune therapies for B-cell ALL in children and adults including blinatumomab, inotuzumab ozogamicin, tisagenlecleucel, and brexucabtagene autoleucel...

Survival rates for pediatric acute lymphoblastic leukemia (pALL) have improved dramatically; relapsed/refractory (r/r) acute lymphoblastic leukemia (ALL) remains challenging. Immunotherapies are rapidly evolving treatments for r/r ALL with limited cost-effectiveness data. This study identifies existing economic evaluations of immunotherapy in pALL and summarizes cost-effectiveness. Medline, Embase, and other databases were searched from inception to October 2022. Cost-effectiveness analyses evaluating immunotherapy in pALL were included...

Here we report on the first prospective study evaluating the safety and long-term survival when an escalating dose of inotuzumab ozogamicin (INO) (0.6, 1.2, or 1.8 mg/m2 on day 13) was added to one alkylator-containing conditioning regimen in patients with relapsed CD22 (+) lymphoid malignancies who were candidates for hematopoietic stem cell transplantation (HSCT). Twenty-six patients were enrolled. Six (23%) of these patients entered the phase 1 study: four were treated at an INO dose of 0.6 mg/m2 and two at dose of 1...

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)...

Acute lymphoblastic leukemia (ALL) is one of the most rapidly changing hematological malignancies with advanced understanding of the genetic landscape, detection methods of minimal residual disease (MRD), and the development of immunotherapeutic agents with good clinical outcomes. The annual incidence of adult ALL in Korea is 300-350 patients per year. The WHO classification of ALL was revised in 2022 to reflect the molecular cytogenetic features and suggest new adverse- risk subgroups, such as Ph-like ALL and ETP-ALL...

BACKGROUND: The combination of low-intensity chemotherapy and inotuzumab ozogamicin (INO), with sequential blinatumomab, is highly effective in older adults with newly diagnosed B-cell acute lymphoblastic leukemia (ALL) and in relapsed or refractory B-cell ALL. Earlier, "dose-dense" administration of blinatumomab could lead to earlier and deeper measurable residual disease (MRD) responses and better outcomes. PATIENTS AND METHODS: We performed a retrospective analysis of the safety and efficacy of a dose-dense regimen of mini-hyper-CVD (mini-hyperfractionated cyclophosphamide, vincristine, and dexamethasone alternating with mini-methotrexate and cytarabine), INO, and blinatumomab in patients with B-cell ALL...

Preclinical studies suggest that Bcl-2 inhibition with venetoclax has antileukemic activity in acute lymphoblastic leukemia (ALL) and may synergize with conventional chemotherapy. We designed a phase 1/2 clinical trial to evaluate the safety and efficacy of low-intensity chemotherapy in combination with venetoclax in adults with relapsed or refractory ALL. Patients received the mini-hyper-CVD regimen in combination with venetoclax (200 mg or 400mg daily) on days 1-14 in cycle 1 and on days 1-7 in consolidation cycles...

The integration of immune and targeted therapies into the treatment of acute lymphoblastic leukemia (ALL) has significantly improved outcomes, reduced the intensity and duration of chemotherapy, and the reliance on allogeneic stem cell transplantation (SCT). In younger patients with Philadelphia chromosome (Ph)-negative ALL, treatment with Hyper-CVAD and blinatumomab +/- inotuzumab has improved the 3-year overall survival (OS) to above 85%. In older patients, using less intensive chemotherapy (mini-Hyper-CVD) in combination with inotuzumab and blinatumomab has improved the 5-year OS rate to 50%...

Inotuzumab Ozogamicin (InO) is a CD22-directed antibody conjugated with calicheamicin. The Phase 1B of the ITCC-059 trial tested InO combined with chemotherapy in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Relapsed /refractory CD22+ BCP-ALL pediatric patients were enrolled. The primary objective was to establish the Recommended Phase 2 Dose (RP2D). Secondary objectives included preliminary efficacy and tolerability. InO was combined with 1.5 mg/m2 of vincristine (days 3, 10, 17, 24), 20 mg/m2 of dexamethasone (two 5-day blocks, then amended), and intrathecal therapy...

Objective: To observe the treatment response of a two-dose regimen of inotuzumab ozogamicin (inotuzumab), a monoclonal antibody targeting CD22, for patients with heavily treated relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL), including those failed or relapsed after chimeric antigen receptor (CAR) -T-cell therapy. Methods: Pediatric and adult patients who received two doses of inotuzumab and who were evaluated after inotuzumab treatment were included. Antibody infusions were performed between March 2020 and September 2022...

Older adults (≥55 years old) with B-cell acute lymphoblastic leukemia (B-ALL) have dismal outcomes with standard chemotherapy as the result of low treatment efficacy and considerable risks for treatment-related morbidity and mortality. There has been a recent success with the introduction of novel therapies, such as blinatumomab and inotuzumab, in the frontline therapeutic paradigm in older adults with B-ALL. However, these agents have their own challenges including the limited durability of remission, the need for additional concurrent chemotherapy and the prolonged course of treatment, and limited efficacy in the setting of extramedullary disease...

Adult B-lineage acute lymphoblastic leukemia (B-ALL) with t(4;11)(q21;q23) is very rare. It is characterized by mixed-lineage leukemia and has the potential for lineage switching during the treatment course. We report the disease course of a patient with B-ALL with t(4;11)(q21;q23) to demonstrate that close monitoring of cell morphology and immunophenotyping is necessary to capture the lineage switch at an early stage. Cell morphology, immunophenotyping, and cytogenetics were used to evaluate the patient's disease status...

The curative potential of allogeneic hematopoietic transplant (alloHCT) in patients with acute lymphoblastic leukemia (ALL) is hampered by relapse. Inotuzumab ozogamicin (INO) is an anti-CD22 monoclonal antibody bound to calicheamicin which has significant activity against ALL. We hypothesized that low-dose INO would be safe and feasible post alloHCT. Therefore we conducted a phase I study to determine the dose and safety in this setting. Patients were eligible if they were aged 16-75, had undergone alloHCT for CD22+ALL, were in complete remission (CR) after alloHCT, had high-risk of recurrence, were between day 40 and 100 post-alloHCT with adequate graft function, and did not have a history of hepatic veno-occlusive disease (VOD)...

In pediatric Acute Lymphoblastic Leukemia (ALL), mutations/deletions affecting the TP53 gene are rare at diagnosis. However, at relapse about 12% of the patients show TP53 aberrations, predicting a very poor outcome. Since p53-mediated apoptosis is an endpoint for many cytotoxic drugs, loss of p53 function frequently leads to therapy failure. In this study, we show that CRISPR/Cas9-induced loss of TP53 drives resistance to a large majority of drugs used to treat relapsed ALL, including novel agents such as inotuzumab ozogamicin...