PURPOSE: MT-3724, a novel engineered toxin body comprised of an anti-CD20 single-chain variable fragment genetically fused to Shiga-like Toxin A subunit, is capable of binding to and internalizing against CD20, inducing cell killing via permanent ribosomal inactivation. This study evaluated MT-3724 in patients with relapsed/refractory B-cell Non-Hodgkin lymphoma (r/rNHL). METHODS: This open-label, multiple-dose Phase 1a/b trial included a dose escalation in patients with r/rNHL according to a standard 3+3 design. Primary objectives were to determine the maximum tolerated dose (MTD) and pharmacokinetics/pharmacodynamics. In a dose expansion study at MTD in serum rituximab-negative patients with diffuse large B-cell lymphoma (DLBCL), primary objectives were safety, tolerability, and pharmacokinetics/pharmacodynamics. RESULTS: Twenty-seven patients enrolled. MTD was 50 µg/kg/dose with 6000 µg/dose cap. Thirteen patients experienced at least one Grade ≥3 treatment-related adverse events; the most common Grade ≥3 event was myalgia (11.1%). Two patients (75 µg/kg/dose) experienced Grade 2 treatment-related capillary leak syndrome. Overall objective response rate was 21.7%. In serum rituximab-negative patients with DLBCL or composite DLBCL (n=12), overall response rate was 41.7% (complete response, n=2; partial response, n=3). In patients with detectable baseline peripheral B-cells, treatment resulted in dose-dependent B-cell depletion. The proportion of patients with anti-drug antibodies (ADAs) increased during treatment and the majority appeared to be neutralizing based on an in vitro assay; nevertheless, tumor regression and responses were observed. CONCLUSIONS: MT-3724 demonstrated efficacy at the MTD in this population of previously treated patients with r/rDLBCL, with mild-to-moderate immunogenic safety events.

<p>Supplementary Table 1. Additional Study Eligibility Criteria. Supplementary Table 2. Pharmacokinetic Serum Sample Collection. Supplementary Table 3. Summary of Adverse Events and Discontinuations. Supplementary Table 4. Summary of Serum MT-3724 PK Parameters by Treatment on Cycle 1 Day 1. Supplementary Table 5. Summary of Serum MT-3724 PK Parameters by Treatment on Cycle 1 Day 12. Supplementary Table 6. Best Overall Response, Objective Response Rate, and Disease Control Rate (FAS). Supplementary Table 7. Summary of ADA Incidence by Actual Dose. Supplementary Figure 1. Study Design for Dose Escalation and Dose Expansion. Supplementary Figure 2. CONSORT diagram. Supplementary Figure 3. Individual CD19+ Nadir Percent Change from Baseline.</p>

<div><p>MT-3724, a novel engineered toxin body comprised of an anti-CD20 single-chain variable fragment genetically fused to Shiga-like Toxin A subunit, is capable of binding to and internalizing against CD20, inducing cell killing via permanent ribosomal inactivation. This study evaluated MT-3724 in patients with relapsed/refractory B-cell non-Hodgkin lymphoma (r/rNHL). This open-label, multiple-dose phase Ia/b trial included a dose escalation in patients with r/rNHL according to a standard 3+3 design. Primary objectives were to determine the MTD and pharmacokinetics/pharmacodynamics. In a dose expansion study at MTD in serum rituximab-negative patients with diffuse large B-cell lymphoma (DLBCL), primary objectives were safety, tolerability, and pharmacokinetics/pharmacodynamics. Twenty-seven patients enrolled. MTD was 50 μg/kg/dose with 6,000 μg/dose cap. Thirteen patients experienced at least one grade ≥3 treatment-related adverse events; the most common grade ≥3 event was myalgia (11.1%). Two patients (75 μg/kg/dose) experienced grade 2 treatment-related capillary leak syndrome. Overall objective response rate was 21.7%. In serum rituximab-negative patients with DLBCL or composite DLBCL (<i>n</i> = 12), overall response rate was 41.7% (complete response, <i>n</i> = 2; partial response, <i>n</i> = 3). In patients with detectable baseline peripheral B cells, treatment resulted in dose-dependent B-cell depletion. The proportion of patients with anti-drug antibodies (ADA) increased during treatment and the majority appeared to be neutralizing based on an <i>in vitro</i> assay; nevertheless, tumor regression and responses were observed. MT-3724 demonstrated efficacy at the MTD in this population of previously treated patients with r/rDLBCL, with mild-to-moderate immunogenic safety events.</p>Significance:<p>This work describes the safety and efficacy of a new pharmaceutical pathway that could provide a treatment option for a subset of patients with a critical unmet therapeutic need. The study drug, MT-3724, is capable of targeting B-cell lymphomas via a unique, potent cell-killing mechanism that appears to be promising.</p></div>

<p>Supplementary Table 1. Additional Study Eligibility Criteria. Supplementary Table 2. Pharmacokinetic Serum Sample Collection. Supplementary Table 3. Summary of Adverse Events and Discontinuations. Supplementary Table 4. Summary of Serum MT-3724 PK Parameters by Treatment on Cycle 1 Day 1. Supplementary Table 5. Summary of Serum MT-3724 PK Parameters by Treatment on Cycle 1 Day 12. Supplementary Table 6. Best Overall Response, Objective Response Rate, and Disease Control Rate (FAS). Supplementary Table 7. Summary of ADA Incidence by Actual Dose. Supplementary Figure 1. Study Design for Dose Escalation and Dose Expansion. Supplementary Figure 2. CONSORT diagram. Supplementary Figure 3. Individual CD19+ Nadir Percent Change from Baseline.</p>

Введение. Острый лимфобластный лейкоз (ОЛЛ) у взрослых проявляет экспрессию гена BCR-ABL1 у 25-40% пациентов, непредсказуемость прогноза и неблагоприятное социально-экономическое воздействие в резистентных случаях. Целью исследования было сравнительное описание результатов лечения и прогноза в клинических случаях с BCR-ABL1+ и BCR-ABL1-негативным (BCR-ABL1–) ОЛЛ. Материалы и методы. Представлен анализ трёх женщин в возрасте 31, 43 и 67 лет с ОЛЛ, которые проходили лечение в Институте онкологии Молдовы в период с 2012 по 2021 гг. Диагнозы подтвердили с помощью иммунофенотипирования и количественной ПЦР образцов костного мозга (КМ) и периферической крови (ПК) в режиме реального времени. Результаты. Пациентка 43 лет с 3-летним анамнезом излеченного рака левой молочной железы обратилась в гематологическое отделение с умеренной гепатоспленомегалией, лейкоцитозом 75000/мкл, повышением лактатдегидрогеназы до 570 U/Lв ПК и количества бластных клеток L3 до 55% в КМ. Транскрипт p210 химерного гена BCR-ABL1 составлял 44,65%. У пациенток с BCR-ABL1– ОЛЛ были незначительная гепатоспленомегалия, нормальные уровни лактатдегидрогеназы в ПК. У больной 31 года выявлены лейкоцитоз 14000/мкл и 70% бластных клеток в КМ. У пациентки 67 лет обнаружены лейкопения 1900/мкл, лимфоцитоз 69% в ПК и 83,3% бластных клеток в КМ. В качестве терапии первой линии применялась схема ALL-BFM. Полный гематологический ответ был достигнут при BCR-ABL1– ОЛЛ. Пациентка с BCR-ABL1+ ОЛЛ была переведена на лечение по протоколу AVAMP в сочетании с иматинибом, с достижением нестабильного частичного гематологического ответа. Заключение. Результаты лечения пациенток с ОЛЛ позволяют рассматривать более выраженную сплено- и гепатомегалию, высокий лейкоцитоз и уровень лактатдегидрогеназы в ПК, вариант L3 и положительный транскрипт р210 химерного гена BCR-ABL1, как неблагоприятные прогностическиие факторы.