To assess the efficacy of new protein-based B cell depletion with glyco-engineered anti-CD20 antibody obinutuzumab (OBI) and the CD19/CD3 T cell engager blinatumomab (BLI) in patients with autoimmune diseases (AIDs) in comparison to rituximab (RTX) and CD19 chimeric antigen receptor (CAR) T cell therapy. Sequential inguinal lymph node biopsies were taken before and after treatment with OBI-, BLI-, RTX- and CD19-CAR T cells in patients with AID. CD19+ and CD20+ B cells, plasma cells, T cells and macrophages were analysed by immunohistochemistry. Changes in follicular architecture (follicular dendritic cells, T follicular helper cells, proliferation) were also assessed. Baseline and follow-up lymph node biopsies from 24 patients with AID (OBI, 4; BLI, 4; RTX, 4; CD19-CAR T cells, 12) were analysed. B cell depletion was confirmed in all CD19-CAR T cell-treated patients but only in 1 (OBI) out of 12 protein-based B cell-treated patients. Likewise, follicular architecture was disrupted in all CD19-CAR T cell-treated patients but only in 1 (OBI) out of 12 protein-based B cell-treated patients. B cell depletion efficacy in the lymph nodes was 100% for CD19-CAR T cells, 92% for OBI, 86% for RTX and 69% for BLI. Plasma cells were reduced but not depleted in all treatment approaches. CD3+ T cells and CD68+ macrophages remained unaffected. Peripheral blood B cell depletion occurred in all but 1 BLI-treated patient. B cell depletion was associated with stable drug-free remission, whereas a reduction in B cell numbers without depletion required retreatment with immunomodulatory drugs. Protein-based B cell depletion reduces but usually does not deplete B cells in lymph nodes leaving the follicular architecture intact and being associated with disease recurrence.

Pre-transplant blinatumomab and/or inotuzumab ozogamicin therapy for relapsed/refractory acute lymphoblastic and B/myeloid mixed phenotype acute leukemia in adults.

Efficacy and Tolerability of Blinatumomab in Clinical Trial Ineligible Patients with CD19+ Leukemias

Acute Lymphoblastic Leukemia (ALL) Outcomes after Allogeneic Blood or Marrow Transplantation (alloBMT) with High-Dose Post-Transplantation Cyclophosphamide (PTCy) in the Era of More Effective Pre-Transplant Therapy

Real-World Experience of Efficacy and Toxicity Issues of Inotuzumab Ozogamicin in Adult Patients with Relapsed or Refractory Acute Lymphoblastic Leukemia

Background. Despite the successes achieved in the treatment of B-cell acute lymphoblastic leukemia (B-ALL), overcoming the toxicity of standard chemotherapy regimens and the treatment of relapsed/refractory (r/r) forms of the disease remains relevant. The most promising option is to use immunotherapy (IT), including a monoclonal antibody blinatumomab (BM). The purpose of the study. To analyze indications of using, as well as efficacy and tolerability of BM in children with V-ALL. Materials and methods. From April 2016 to January 2024 a retrospective assessment of using of BM in children with B-ALL in the chemotherapy department of oncohematological diseases and TCM for children in Almazov National Medical Research Centre was performed. Results. The study included 53 patients, including 28 (53 %) girls and 25 (47 %) boys with median age of 7,7 (2,08–19,8) years. Indications for using of BM were as follows: (1) consolidation of remission (CR) with primary ALL (n = 17, 32 %); (2) persistence of minimal residual disease (MRD) (n = 23, 43 %) after completion of chemotherapy (CT) induction or before the stage of allogeneic haematopoietic stem cell transplantation (alloHSCT); (3) replacement of the standard CR due to the previous toxicity of СT or other contraindications to its implementation (n = 12, 23 %); (4) salvage therapy for r/r ALL (n = 1, 1,9 %). The status of MRD-negative remission after the 1st course of IT was achieved in 89 % of cases. Therapy using BM in a patient with the r/r ALL and total blast infiltration of the bone marrow was effective and facilitated reducing the tumor population to 7,2% by day 15 of therapy, however, there was a fatal outcome due to development and progression of preexisted severe infection. The most common variants of grade III–IV toxicity were leuko-/neutropenia (28 %) and neurotoxicity (3,7 %). BM dose reduction for the purpose of relieving toxicity was required in 19 % of patients, while the median days of therapy with dose reduction was 4. Corticosteroids were used for this purpose in 11 % of cases, antibacterial therapy — in 13 %. At the time of results evalution, there were no relapses of the disease in the study group. The article analyzes the international experience of using BM in patients with B-ALL.Conclusion. Our experience and the presented literature data demonstrate a reasonable expansion of indications for using of BM in children with B-ALL with high efficacy and satisfactory toxicity profile.

Chemotherapy-Sparing Induction Followed By Consolidation and Maintenance with Blinatumomab and Concurrent Oral Tyrosine Kinase Inhibitor Therapy for Newly-Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: Primary Endpoint Results from the Blissphall Study

Exploring the Heterogeneity of Response to Blinatumomab in High-Risk Philadelphia-Negative B-Cell Precursor Acute Lymphoblastic Leukemia: An Analysis from the QUEST Sub-Study of the Graall-2014/B Trial

In-Depth Immune Profiling in Children with BCP-ALL within the AIEOP-BFM ALL 2017 Study

Incidence of Central Nervous System Toxicity and Cytokine Release Syndrome in Leukemia Patients Treated with Blinatumomab

PurposeChildren and young adults with relapsed or refractory (r/r) acute lymphoblastic leukemia (ALL) have poor survival due to ineffective therapy options. The newly approved chimeric antigen receptor T-cell (CAR-T) therapy, tisagenlecleucel, has demonstrated improved survival but at a high up-front cost. The study aims to evaluate the cost-effectiveness and budget impact of tisagenlecleucel versus salvage chemotherapy regimen (SCR) or blinatumomab (BLN) for the treatment of pediatric and young adult patients with relapsed/refractory B-cell ALL from the Singapore healthcare system perspective.Patients and MethodsA three-health state partitioned survival model was constructed to analyze the cost-effectiveness of tisagenlecleucel vs SCR/BLN with/without allogenic hematopoietic stem cell transplantation (allo-HSCT) over a lifetime period. Clinical efficacy for tisagenlecleucel, SCR and BLN were based on pooled data from ELIANA, ENSIGN and B2101J trials, the study by von Stackelberg et al 2011, and MT103-205 respectively. Medical costs from pre-treatment until terminal care, including treatment, side effects, follow-up, subsequent allo-HSCT and relapse, were considered. Incremental cost-effectiveness ratios (ICERs) were estimated as the incremental costs per quality-adjusted life-year (QALY) gain. Additionally, the financial impact of tisagenlecleucel introduction in Singapore was estimated, comparing the present treatment scenario (without tisagenlecleucel) with a future scenario (with tisagenlecleucel), over 5 years.ResultsIn the base-case analysis, tisagenlecleucel treatment demonstrated cost-effectiveness with an ICER of S$45,840 (US$34,762) per QALY (vs SCR) and S$51,978 (US$39,315) per QALY (vs BLN). The estimated budget ranges from S$477,857 (US$361,438) to S$1.4 million (US$1.05 million) annually for the initial 5 years.ConclusionTisagenlecleucel is likely to be a cost-effective treatment option with limited budget implications while treating r/r ALL patients who have failed at least 2 lines of prior therapies.

Anticancer effects of a single intramuscular dose of a minicircle DNA vector expressing anti-CD3/CD20 in a xenograft mouse model

IntroductionDespite currently available treatments for adults with relapsed/refractory acute lymphoblastic leukemia (R/R ALL), survival outcomes remain poor, highlighting the need for new therapeutic strategies. This study estimates the cost-effectiveness of KTE-X19 to treat adults with R/R ALL from a US payer perspective.MethodsThe model had two components: a decision-tree, where pre-infusion costs for patients who ultimately did not receive KTE-X19 are accounted for, followed by a partitioned survival analysis, where all KTE-X19 infused patients would enter the three-state (pre-progression, progressed disease, death) model. Comparators included current standard of care treatments, i.e., blinatumomab (BLIN), inotuzumab ozogamicin (INO), and salvage chemotherapy (CHEMO). Both standard parametric and mixture cure models were used to model survival. Efficacy, safety, healthcare resource utilization, and health state utility inputs were derived from the ZUMA-3 trial (NCT02614066) and literature. Cost inputs were derived from literature or publicly available sources. Outcomes and costs were discounted 3% annually. Results of KTE-X19 versus comparators are reported as total and incremental life-years (LYs), quality-adjusted life-years (QALYs), costs, and resulting incremental cost-effectiveness ratio (ICER). Deterministic and probabilistic sensitivity analyses (PSA) and key scenario analyses were also performed.ResultsIn the base case, incremental QALYs for KTE-X19 were 2.44, 3.26, and 4.61 versus BLIN, INO, and CHEMO, respectively. Incremental costs were $50,913, $251,532, and $432,027, respectively, resulting in ICERs of $20,843/QALY (versus BLIN), $77,271/QALY (versus INO), and $93,768/QALY (versus CHEMO). Deterministic sensitivity analysis results were most sensitive to subsequent allogeneic stem cell transplant rates and post-progression utilities. PSA found that KTE-X19 is 78.4%, 74.0%, and 75.4% likely to be cost-effective versus BLIN, INO, and CHEMO, respectively. Across most scenarios, at a willingness-to-pay (WTP) threshold of $150,000/QALY, KTE-X19 was cost-effective versus all treatments.ConclusionsCompared to current options for adults with R/R ALL, KTE-X19 is cost-effective, driven primarily by improved survival.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-022-02201-6.

Treatment of Relapsed or Refractory Acute Lymphoblastic Leukemia in Real-World US Practices

BackgroundThe outcomes of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) can improve with allogeneic hematopoietic stem cell transplantation (HSCT) during the first complete remission after treatment with a tyrosine kinase inhibitor (TKI) combined with chemotherapy. However, frail patients who are not eligible for allogeneic HSCT or those with TKI-resistant mutations within the BCR–ABL kinase domain have a poor clinical course. Blinatumomab (BLIN) is a bispecific T-cell engager antibody construct that directs cytotoxic T cells to CD19-expressing B-ALL cells. To date, only a few studies have shown the safety and efficacy of Blinatumomab (BLIN) + TKI combination therapy for relapsed/refractory (R/R) Ph+ ALL. Here we report the case of two patients with R/R Ph+ ALL who were treated with BLIN + TKI with durable molecular response.Case presentationPatient 1: A 69-year-old Japanese male with R/R Ph+ ALL was treated with conventional chemotherapy and dasatinib in April 2016. In May 2018, he developed molecular relapse due to the acquisition of T315I during dasatinib maintenance therapy. Thereafter, he achieved molecular complete remission (mCR) after switching from dasatinib to ponatinib. However, he developed a second relapse after the emergence of triple compound mutations (G250E/D276G/T315I) in November 2018. He subsequently received a total of nine cycles of BLIN and ponatinib combination therapy, which resulted in sustained mCR without any adverse events. Patient 2: A 69-year-old Japanese female with R/R Ph+ ALL was treated with chemotherapy and imatinib in April 2008. She developed molecular relapse due to the emergence of the T315I mutation in October 2017. She achieved mCR after switching from imatinib to ponatinib. However, she developed a second relapse after acquiring ABL exon4 skipping in addition to T315I. She subsequently received a total of seven cycles of BLIN and ponatinib combination therapy, which resulted in sustained mCR.ConclusionIn our two cases, BLIN + ponatinib combination therapy was highly effective for R/R Ph+ ALL without any incidence of severe adverse events. Further studies with larger cohorts are warranted to validate the safety and efficacy of this potent combination therapy.

Phase II Study of Blinatumomab and Concurrent Oral Tyrosine Kinase Inhibitor Therapy As Consolidation and Maintenance Therapy for Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Following Chemotherapy-Sparing Induction

Evaluation of Biomarkers As Predictors of Blinatumomab Toxicity and Real-World Management of Blinatumomab Toxicity in B-Acute Lymphoblastic Leukemia Patients

e18359 Background: To estimate Incremental CE Ratio (ICER) of BLIN vs INO in adults with R/R S0/S1 ALL based on matching-adjusted indirect comparison (MAIC) of TOWER and INO-VATE trials from a UK healthcare perspective. Methods: CE was estimated by a partitioned-survival model with outcomes based on published aggregate data from INO-VATE (cutoff: 01/05/2017) and individual patient data from TOWER weighted to match patients in INO-VATE using MAIC. Five analyses were conducted based on alternative approach for the MAIC (anchored through Standard of Care [SOC] vs unanchored), proportional hazard (PH) assumptions, and reference overall survival (OS) distributions. Rates of complete remission and HSCT, utilities, duration of therapy, and use of subsequent therapies also were MAIC adjusted. Due to inconsistent definitions of event-free survival (EFS) between the trials, EFS was assumed to be equal for BLIN and INO complete responders. Costs were estimated from published sources and included those of medicine and administration, key adverse events, HSCT, salvage therapy, and terminal care. Utilities were based on EORTC-8D values derived from EORTC QLQ-C30 assessments in TOWER. A 50-year time horizon was used. Results: In all analyses, BLIN was more costly and more effective than INO. The ICER for BLIN vs INO ranged from £4,014 to £13,371 per QALY. Conclusions: For various approaches for conducting MAIC of BLIN vs INO, BLIN was highly cost effective vs INO in R/R ALL adults with S0/S1 from a UK healthcare perspective. [Table: see text]

e18511 Background: In the phase 3 TOWER study (NCT02013167), blinatumomab (BLIN) significantly improved overall survival in adults with Ph- R/R BCP ALL, and these patients (pts) also reported better HRQoL (EORTC QLQ-C30 measures) compared with standard of care (SOC) chemotherapy. This analysis assessed the impact of grade 3+ infection, which was reported in 34.1% of BLIN pts vs 52.3% of SOC pts, on HRQoL in TOWER. Methods: Pts were stratified into two groups: those with infection vs those without infection, between baseline and Day 8, Day 15, and Day 29. A difference-in-difference (DID) model investigated the impact of infection on HRQoL. A 5-point change is considered the minimum clinically important difference in the EORTC QLQ-C30 for between group comparisons (King et al. 1996). Results: In total, 342 pts (n = 247 BLIN; n = 95 SOC) had a non-missing baseline and ≥1 post-baseline HRQoL score for any scale. Grade 3+ infection was reported in 15 (4.5%) pts before Day 8, 49 (14.5%) pts before Day 15, and 76 (22.6%) pts before Day 29. Pts with grade 3+ infection reported clinical meaningful deterioration in global health status (GHS) score and in almost all functional subscales across timepoints assessed (Table). At Day 29, grade 3+ infection was associated with statistically significant and clinically meaningful deterioration in GHS and most functional scales (Table). Similar but smaller effects were also observed for symptom scales/items (data not shown). Conclusions: Grade 3+ infection in pts with Ph- R/R BCP ALL was associated with clinically meaningful deterioration in HRQoL. The lower incidence of infection in pts treated with BLIN vs SOC may have contributed to the improved HRQoL for pts treated with BLIN. Clinical trial information: NCT02013167. [Table: see text]

Conventional treatment for cancer such as surgical resection and chemotherapy can cause damage in cases with advanced cancers. Moreover, the identification of tumor-specific targets has great importance in T-cell therapies. For decades, T cell activity has been stimulated to improve anti-tumor activity. Bispecific antibodies have attracted strong interest from pharmaceutical companies, for their diagnostic and therapeutic use. Blinatumomab is a first-in-class bispecific T engager antibody for the treatment of relapsed or refractory precursor B- cell acute lymphoblastic leukemia. But, it can benefit several cases with CD19+ malignancies in the future. PhiC31 integrase-based vectors could selectively integrate therapeutic transgenes into pseudo-attP sites in CHO genome. In this study, production of Blinatumomab in CHO cells using this type of vectors was investigated. We evaluated the effects of histone deacetylases (HDACs) inhibitors such as sodium butyrate and valproic acid, on specific productivity and cell viability of antibody expressing cells. Although sodium butyrate increased specific productivity about 1.7-fold and valproic acid about 1.4-fold, valproic acid was found more efficient because of its less cytotoxic effect on cell growth. We examined the efficacy of expressed Blinatumomab at various effector to target (E/T) ratios. A dose-response analyses of calcein-acetoxymethyl release assay illustrated that the effective dose of expressed mAb required for antibody mediated cytotoxicity was 100 ng/ml and the expressed mAb was more effective at E/T ratios of 10:1 and 5:1. Results of this study indicated that the expressed blinatumomab can be useful for enhancing the cytotoxicity of CD3+ T-cells against CD19 + target cells in vitro.