Background: BCL-2 inhibition with venetoclax has proved to be highly effective treatment for patients with CLL. However, when administered to patients with CLL who have a high tumor burden, venetoclax is associated with an elevated risk of tumor lysis syndrome (TLS). Because of this risk, venetoclax is initiated with a gradual, 5-week dose ramp-up, requiring close laboratory monitoring over an extended period. Lisaftoclax (APG-2575) is a novel, potent, selective BCL-2 inhibitor under clinical development for hematologic malignancies (HMs). Preliminary data in 18 patients with CLL treated in a first-in-human study suggested the feasibility of an abbreviated ramp-up of lisaftoclax that might also result in a lower incidence of neutropenia (Ailawadhi et al, J Clin Oncol 39, 2021; abstr 7502). Methods: This new study is a global, open-label, multicenter, two-part phase 1b dose escalation and dose expansion study to assess the safety and tolerability of lisaftoclax (Part 1) and lisaftoclax combined with rituximab or acalabrutinib (Part 2), including dose-limiting toxicity (DLT) and maximum tolerated dose (MTD). The trial is enrolling adults with (1) histologically confirmed CLL/SLL (by 2018 iwCLL criteria) that is relapsed or refractory to ≥ 1 prior therapy and requires treatment (also by 2018 iwCLL criteria); (2) adequate bone marrow function (in the absence of growth factors), including absolute neutrophils ≥ 1.0 × 10 9/L in patients without bone marrow involvement (not required in CLL/SLL patients with bone marrow involvement); and (3) adequate renal and hepatic function. Exclusion criteria: (1) recent history of allogeneic stem cell transplantation or CAR T-cell therapy (< 90 days); (2) prior treatment with a BCL-2 inhibitor (unless patient discontinued such therapy without disease progression); (3) treatment with vitamin K anticoagulants or previous discontinuation of treatment due to acalabrutinib toxicity (in acalabrutinib plus lisaftoclax cohort); (4) active Richter's syndrome; (5) infection (e.g. HIV, hepatitis); (6) CNS involvement; (7) prior cancer that has recurred within 2 years of screening and requires treatment (apart from adequately treated cervical or breast carcinoma in situ); (8) uncontrolled and other serious concomitant illnesses, including cardiovascular disease and diabetes; (9) failure to recover adequately after surgical procedures; and (10) active graft-vs-host disease or a requirement for immunosuppressive treatment. In a standard "3+3" dose escalation design (Part 1), lisaftoclax is being administered orally once daily in a 28-day cycle, with full doses of 200 to 1,200 mg (by 200-mg increments at 4 dose levels (400, 600, 800, and 1,000 mg) in parallel. The ramp-up is performed in the hospital with close monitoring for TLS and consists of the following doses and days of lisaftoclax treatment: 20 mg on Day 1, 50 mg on Day 2, 100 mg on Day 3, 200 mg on Day 4, 400 mg on Day 5, 600 mg on Day 6, 800 mg on Day 7, and 1,000 mg on Day 8. Patients who experience TLS on any of these days have their dose held until resolution of TLS before proceeding to the next dose. Part 2 includes a further standard 3+3 dose escalation of lisaftoclax combined with rituximab or acalabrutinib (in separate cohorts), with a further planned dose expansion at recommended phase 2 doses of these combination regimens. Primary outcome measures are (1) DLTs observed during cycle 1; and (2) MTD (measured over the same interval). DLT criteria are defined as grade 4 thrombocytopenia or neutropenia lasting > 7 days, grade 3 ≥ thrombocytopenia with bleeding, grade 4 febrile neutropenia, or grade 3 ≥ non-hematologic toxicities. As of July 19, 2021, 71 patients have been enrolled (of 144 planned). Clinicaltrial.gov identifier: NCT04215809. Disclosures Davids: Ascentage Pharma: Consultancy, Research Funding; Astra-Zeneca: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; MEI Pharma: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; Surface Oncology: Research Funding; AbbVie: Consultancy; Adaptive Biotechnologies: Consultancy; BeiGene: Consultancy; Celgene: Consultancy; Eli Lilly and Company: Consultancy; Janssen: Consultancy; MEI Pharma: Consultancy; Merck: Consultancy; Research to Practice: Consultancy; Takeda: Consultancy. Siddiqi: Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Juno therapeutics: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Other: DSM Member, Speakers Bureau; PCYC: Speakers Bureau; Jannsen: Speakers Bureau; Dava Oncology: Honoraria; ResearchToPractice: Honoraria. Pagel: Gilead: Consultancy; AstraZeneca: Consultancy; BeiGene: Consultancy; Incyte/MorphoSys: Consultancy; Epizyme: Consultancy; Kite, a Gilead Company: Consultancy; Actinium Pharmaceuticals: Consultancy; MEI Pharma: Consultancy; Pharmacyclics/AbbVie: Consultancy. Pylypenko: Communal nonprofit enterprise "Cherkasy regional oncology dispensary of Cherkasy oblast council: Current Employment. Kriachok: Takeda, Roche, Abbivie, Janssen, MSD: Consultancy; Takeda, Roche, Abbvie, Janssen, MSD, Pfizer: Honoraria, Speakers Bureau. Usenko: Abbvie: Honoraria; Acerta: Honoraria; Ascentage: Honoraria; AstraZeneca: Honoraria; Celgene: Honoraria; Il Yang: Honoraria; Janssen: Honoraria; Karyopharm: Honoraria; Oncopeptides: Honoraria; Rigel: Honoraria; Takeda: Honoraria; UCB: Honoraria. Chen: Ascentage Pharma (Suzhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company. Huang: Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment, Current equity holder in publicly-traded company. Li: Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment, Current equity holder in publicly-traded company. Ahmad: Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company. Mudenda: Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company. Yang: Ascentage Pharma (Suzhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding. Zhai: Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding; Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding.

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Background. Modern immunochemotherapy (ICT) and infusion therapy (IT) in the treatment of malignant lymphomas, further supportive and concomitant therapy require constant and reliable vascular access. Today, the hematology clinic uses both short-term and minimally invasive methods of vascular access (venipuncture, peripheral catheters) and long-term options (peripherally inserted central catheter, subclavian vein catheterization). The choice of the optimal method of access to vessels, its preservation and care, and the avoidance of complications associated with the functioning of such access require the joint efforts of many specialists. Objective. To outline the indications for the establishment, advantages and disadvantages of the use of implanted port systems (IPS) in hematological patients. Materials and methods. 8 patients with newly diagnosed malignant lymphomas and established IPS who received volumetric and long-term IT during antilymphoma treatment were observed. 7 patients were diagnosed with primary mediastinal large B-cell lymphoma (PMBCL), and 1 patient was diagnosed with Hodgkin’s lymphoma (HL). Gender distribution was the following: 7 women and 1 man. Age of patients ranged from 26 to 48 years (median – 29.8 years). Patients were implanted with one of the two IPS available on the Ukrainian market (U-port 6.6/8.4 Fr or B-Braun Celsite® ST301 6.5/8.5 Fr). Catheterization of the right or left subclavian vein was performed in the operating room using local anesthesia and under X-ray control. IPS began to be used immediately after implantation. Results and discussion. Patients who were scheduled for long-term and volumetric infusions for the treatment of malignant lymphomas, or who had problems with short-term vascular access, were suggested to have IPS. As a result 7 patients with PMBCL received ICT, which involved a continuous 96-hour infusion of antilymphoma drugs and concomitant IT, the total volume of which was 5.0-6.5 liters per day. In 2 patients before the initiation of ICT there were significant obstacles to the establishment of short-term vascular access (phlebitis, postphlebotic changes in peripheral veins), another 1 patient had similar problems after the second course of ICT. The patient with HL at the time of chemotherapy had a poor condition of peripheral veins, which did not allow their frequent and prolonged catheterization, and the mode of application of antilymphoma drugs (every 2 weeks, 12 injections) made it inexpedient to catheterize the subclavian vein. Eventually, the presence of IPS has greatly simplified the permanent vascular access and care for the port system itself. In all of our patients, IPS ensured the continuity of the infusion and the planned volume. In the intercourse period, IPS did not require special care: patients followed their normal lifestyle, including taking a shower. Subsequently, in the long term (up to 24 months) IPS appeared to be functionally complete and with regular care (every 2-4 weeks) allowed for maintenance and concomitant therapy. One patient had a hematoma in the pocket area of the reservoir of the port system, which resolved spontaneously. No infection around the port area and no cases of catheter induced sepsis were observed. To date, IPS has been removed without complications in 5 patients, one continues ICT, and in another one IPS was decided not to be removed. Conclusions. The use of IPS in hematological patients has shown its benefits in long-term and large-scale ICT and IT regimens to ensure persistent, multiple and safe access to blood vessels. The use of IPS is also indicated for patients with vascular lesions, venous diseases or their unsatisfactory condition. The medical staff avoids the constant search for “working vessels” for the placement of peripheral catheters or special care for the central catheter. IPS provides the opportunity to conduct initial, supportive and concomitant therapy for months with minimal care for vascular access. Complications during the installation and operation of IPS are extremely rare and minor. IPS placement can be considered an integral part of ICT and IT in the hematological practice.

Background. Chronic lymphocytic leukemia (CLL) is one of the most frequent malignant blood disorders in adult patients. For the last several decades treatment of CLL made its way from simple chemotherapy agents (chlorambucil, cyclophosphamide, fludarabine) to highly technological innovative medications (monoclonal antibodies, targeted agents, CAR T-cell therapy). Despite quite high rate of remissions induced by the novel treatment methods significant proportion of the patients develop infectious mostly bacterial complications in the long term. Various infections often become the cause of mortality in CLL patients in remission. They develop in about 70 % of the patients and become severe in about 30 % of them (requiring inpatient hospitalization and/or intravenous antibacterial treatment). Novel agents for treatment of CLL influencing the immune B-cells lead to immune suppression (secondary hypogammaglobulinemia, immunoglobulin G (IgG) deficiency), distribution and severity of infectious complications. Substitutive treatment with intravenous IgG changed clinical course of the secondary hypoimmunoglobulinemia reducing significantly incidence of the infectious events in CLL patients as well as in patients undergoing immunochemotherapy (ICT) and immunosuppressive treatment. Objective. To determine the necessity for immunocorrection in patients with CLL requiring ICT. Materials and methods. Patients with the diagnosis of CLL undergoing ICT within hematology department developing infectious complications were observed. Results and discussion. Patients with CLL undergoing ICT were tested and analyzed and according to the results in 31 of these patients hypogammaglobulinemia and reduced levels of IgG were revealed. In 8 of the patients reduction of IgG was detected already at the primary diagnosis of CLL (Binet stages B and C). Depending on the performed treatment of CLL frequency of infectious complications differed and was the highest in subjects with progressive course of leukemia and in those who were treated with RFC (rituximab, fludarabine and cyclophosphamide) ICT. Levels of IgG ranged from 0.86 to 5.55 g/L (median – 3.49 g/L, lower-upper quartile – 2.62-4.76 g/L). Levels of hypogammaglobulinemia in the whole group ranged from 4.49 to 16.87 g/L (median – 12.11 g/L, lower-upper quartile – 11.44-12.88 g/L). Patients underwent the substitutive treatment with intravenous immunoglobulin with the dose of 0.4 g/kg every month. The medication was administered according to standard recommendations. There were no side effects registered within 24 h of infusion. Additionally, patients with infectious complications were treated with antibacterial, antifungal and antiviral agents. After application of intravenous immunoglobulin general condition of the patients improved, body temperature normalization and reduction of recurrent infectious events were observed. The mean time from the diagnosis of persistent hypogammaglobulinemia to complete resolution of infectious complications was 12.5 months (ranging from 3.6 to 27 months). Our results suggested that patients with IgG deficiency without signs of infection responded better to this treatment. Levels of IgG increased from 6.57 to 13.5 g/L (median – 9.35 g/L, lower-upper quartile – 7.57-10.70 g/L) and levels of γ-globulin grew from 14.4 to 17.69 g/L (median – 16.70 g/L, lower-upper quartile – 15.96-17.30 g/L). Conclusions. Secondary hypogammaglobulinemia and deficiency of the serum IgG often develop in patients with blood malignancies, especially in those involving clonal proliferation of the B-cells, like in CLL. According to our study immunocorrection by intravenous immunoglobulin resulted in resolution of infectious complications in all cases of confirmed immunodeficiency. In order to prevent severe infections in CLL patients it is expedient to perform screening of the humoral immunity status before initiation of ICT and in case of development of febrile conditions.