Помалидомид плюс орелабутиниб и зуберитамаб при нелеченной мантийноклеточной лимфоме

Inclusion Criteria:

• Pathologically confirmed mantle cell lymphoma
• Age 18-80 years, both genders are eligible..
• Untreated MCL.
• At least one measurable lesion. Measurable disease is defined as a tumor mass measurable in one or two dimensions ≥1.5 cm, as well as measurable spleen lesions.
• Any one of the following factors is present:: MIPI intermediate-high risk, ki67≥30%, blastoid/pleomorphic, TP53 abnormality (mutation/deletion) or p53 protein expression >50%, large mass (maximum diameter ≥7.5cm), complex karyotype (≥3 chromosomal abnormalities (excluding t(11; 14)))
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 2.

• Hematologic function is adequate, defined as:

  1. Absolute neutrophil count (ANC) ≥1×109/L, growth factor support must not be used within 7 days prior to testing;
  2. Platelet count ≥75×10⁹/L, or ≥50×10⁹/L (if bone marrow involvement), no use of growth factor support or transfusion allowed within 7 days prior to testing.

• Adequate hepatic function per local laboratory reference range as follow:

  1. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5× the upper limit of normal (ULN);
  2. Bilirubin ≤ 2 × ULN (except for those diagnosed with Gilbert's syndrome, which allows up to 5 × ULN)

• Adequate renal function as demonstrated by:

  1. Creatinine clearance ≥60 mL/min (estimated using the Cockcroft-Gault formula or the glomerular filtration rate [eGFR] estimated using the Modification of Diet in Renal Disease [MDRD] formula)
  2. Serum creatinine ≤1.5×ULN
• International Normalized Ratio (INR) ≤ 1.5 × ULN and Activated Partial Thromboplastin Time (APTT) ≤ 1.5 × ULN
• Life expectancy of more than 3 months.
• Ability to provide written informed consent and understand and comply with study requirements.
• Able to comply with the study visit schedule and other protocol requirements

Exclusion Criteria:

• Current central nervous system involvement or suspected patients and those with a history of this condition
• Previously received systemic treatment for MCL, including BTKi.
• Uncontrolled active systemic fungal, bacterial, or viral infections (defined as persistent signs/symptoms related to the infection despite the use of appropriate antibiotics, antiviral therapy, and/or other treatments with no improvement).

• Known human immunodeficiency virus (HIV) infection, or the following serological status indicating active hepatitis B or C virus infection:

  1. Subjects with positive hepatitis B virus core antibody (HBcAb) and negative surface antigen (HBsAg) must have a negative polymerase chain reaction (PCR) result prior to the first dose. Subjects with positive HBsAg or HBV-DNA:
  2. Subjects with positive hepatitis C antibodies must have an HCV-RNA negative result before the first dose. Subjects with positive hepatitis C PCR results will not be eligible for this study.

• Clinically severe cardiovascular diseases, including:

  1. Myocardial infarction occurring within the 6 months prior to screening;
  2. Unstable angina occurring within 3 months prior to screening;
  3. Clinically significant arrhythmias (e.g., sustained ventricular tachycardia, ventricular fibrillation, torsades de pointes ventricular tachycardia);
  4. QTcF (corrected by Fridericia's formula) > 480 msec;
  5. History of second-degree type II atrioventricular (AV) conduction block or third-degree atrioventricular conduction block;
  6. III or IV congestive heart failure as defined by the New York Heart Association (NYHA)
• History of severe hemorrhagic disorders, such as hemophilia A, hemophilia B, von Willebrand disease, or a history of spontaneous bleeding requiring blood transfusion or other medical interventions.
• History of deep vein thrombosis (DVT) or pulmonary embolism (PE) in the past 12 months
• History of significant cerebrovascular disease/events within 6 months prior to the first administration of the investigational drug, including stroke or intracranial hemorrhage.
• Unable to swallow capsules or having significant gastrointestinal functional disorders, such as malabsorption syndrome, gastric or small intestine resection, symptomatic inflammatory bowel disease, or partial or complete intestinal obstruction.
• Continuous treatment with strong and moderate CYP3A inhibitors or CYP3A inducers is required. If the patient has taken strong or moderate CYP3A inhibitors or inducers within 7 days prior to the first dose of the investigational drug (or has taken these drugs for less than 5 half-lives), they cannot be enrolled. Patients using moderate CYP3A inhibitors can be considered for the study after at least a 7-day washout period.
• Anticoagulation treatment with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon) is required within 7 days after the first dose of the investigational drug or receiving anticoagulation therapy.
• Pregnant or breastfeeding women
• Hypersensitivity to any investigational drug
• Any mental or cognitive impairment that may limit their understanding, execution, and compliance with the informed consent form and the study.
• Subjects with drug abuse and alcoholism