Venetoclax Combined With ATRA and ATO in Hyperleukocytic Acute Promyelocytic Leukemia

Venetoclax Plus All-Trans Retinoic Acid and Arsenic Trioxide in Newly Diagnosed Acute Promyelocytic Leukemia With Hyperleukocytosis: A Prospective Single-Arm Study

This study aims to evaluate the safety and effectiveness of combining venetoclax with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) in patients with newly diagnosed acute promyelocytic leukemia (APL) who have very high white blood cell counts. APL is a rare type of blood cancer, and patients with high white blood cell levels often face serious complications. Current treatments with ATRA and ATO are effective, but the outcomes for patients with high white blood cells remain poor. This study will test whether adding venetoclax, a drug that helps leukemia cells die, can improve treatment results.

PRIMARY OBJECTIVE 1. To evaluate the efficacy of the venetoclax + ATRA + ATO regimen, as defined by complete remission (CR), complete remission with incomplete hematologic recovery (CRi), and morphological leukemia-free state (MLFS).

________________________________________ SECONDARY OBJECTIVES

1. To evaluate long-term effectiveness and durability of the regimen, as defined by 1-year overall survival (OS), 1-year event-free survival (EFS), and overall response rate (ORR).

2. To evaluate the safety of the regimen, as defined by Grade 3-4 clinical adverse events (AEs), incidence of laboratory abnormalities, differentiation syndrome, and treatment-related mortality (TRM).

3. To assess transfusion requirements (red blood cells and platelets) during induction.

   ________________________________________ OUTLINE

   • Newly diagnosed hyperleukocytosis group: Patients with baseline WBC >10 × 10⁹/L will receive venetoclax + ATRA + ATO as induction therapy.
   • Secondary hyperleukocytosis group: Patients who develop WBC >10 × 10⁹/L for ≥3 consecutive days during therapy will receive venetoclax added dynamically to ATRA + ATO.

   Induction regimen:

   • Venetoclax (VEN): 100 mg orally once daily on days 1-7. For patients with WBC >100 × 10⁹/L, administer 50 mg on days 1-2, then escalate to 100 mg on days 3-7.
   • All-Trans Retinoic Acid (ATRA): 25 mg/m² orally per day (divided doses), on days 1-28.
   • Arsenic Trioxide (ATO): 0.15 mg/kg intravenously once daily, on days 1-28.

   Assessment:

   • Complete blood counts monitored regularly.
   • Bone marrow evaluation on days 14 and 28.
   • One treatment cycle lasts 28 days.

   Response evaluation:

   • On day 21 of the first cycle, bone marrow assessment will be performed.
   • If CR, CRi, or MLFS is not achieved, induction with the same regimen will continue for one additional cycle.
   • Patients failing to achieve remission after two cycles will be withdrawn from the study.
   • Patients achieving remission will proceed to consolidation and maintenance therapy according to investigator's discretion.

Inclusion Criteria:

1. Patients diagnosed with acute promyelocytic leukemia (APL) according to bone marrow morphology and immunophenotyping, consistent with the WHO 2016 diagnostic criteria.

2. Age ≥14 years, both male and female patients are eligible.

3. Adequate organ function, defined as:

   3.1 Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) ≤3 × upper limit of normal (ULN);

   3.2 Total serum bilirubin ≤1.5 × ULN;

   3.3 Creatinine clearance ≥30 mL/min;

   3.4 Serum cardiac enzymes <2.0 × ULN.

4. Signed informed consent obtained from the patient or a legally authorized representative.

5. White blood cell (WBC) count >10 × 10⁹/L at initial diagnosis, or WBC >10 × 10⁹/L during treatment.

Exclusion Criteria:

1. Diagnosis of acute non-promyelocytic leukemia, myeloid sarcoma, or chronic myeloid leukemia in accelerated or blast phase.

2. Known hypersensitivity to any drug included in the study regimen.

3. Pregnant or breastfeeding women, and women of childbearing potential who are unwilling to use effective contraception during the study treatment period.

4. Presence of organic heart disease, such as uncontrolled or symptomatic arrhythmia, congestive heart failure, or myocardial infarction within 6 months prior to screening that resulted in clinical symptoms or impaired cardiac function (NYHA class ≥III).

5. Concurrent malignancies, except for:

   5.1 Malignancies treated with curative intent (e.g., hematopoietic stem cell transplantation) and with no known active disease for ≥5 years before enrollment;

   5.2 Adequately treated non-melanoma skin cancer or malignant lentigo without evidence of disease, even if diagnosed <3 years before enrollment;

   5.3 Adequately treated carcinoma in situ without evidence of disease, even if diagnosed <3 years before enrollment.

6. Patients with acquired immunodeficiency syndrome (AIDS) or syphilis, or those with active hepatitis B (detectable HBV DNA) or active hepatitis C infection.

7. Any concurrent medical condition or disease that may interfere with study procedures or outcomes, or that may pose an unacceptable risk to the participant as determined by the investigator (e.g., active systemic infection).

8. Inability to understand or comply with the study protocol.

9. Participation in another clinical study within 1 month prior to enrollment.