The Efficacy and Safety of Third-generation TKIs Combined With Azacitidine and Bcl-2 Inhibitor in Patients With CML-MBP

The Efficacy and Safety of Third Generation Tyrosine Kinase Inhibitors Combined With Azacitidine and B-cell Lymphoma-2 Inhibitor in Patients With Myeloid Blast Phase Chronic Myeloid Leukemia

This is a prospective multi-center study to investigate efficacy and safety of the third generation tyrosine kinase inhibitors (TKIs) combined with azacitidine and B-cell lymphoma-2 (Bcl-2) inhibitor in patients with myeloid blast phase chronic myeloid leukemia (CML-MBP).

Study Overview

• Status: Not yet recruiting
• Conditions: Chronic Myeloid Leukemia
• Intervention / Treatment: Drug: Ponatinib; Drug: Azacitidine; Drug: Venetoclax; Drug: Olverembatinib

Detailed Description

CML-MBP has dismal outcome. Currently, there is no standardized induction treatment approach in CML-MBP. The European LeukemiaNet (ELN) recommendations and NCCN guideline recommended the combination of TKI and chemotherapy in CML-MBP. The previous study revealed that TKI combined with hypomethylating agents had promising efficacy. However, imatinib and second generation TKI are the most widely applied in combination treatment, there is limited data in third generation TKI.

Currently, venetoclax in combination with hypomethylating agents such as azacitidine is standard treatment for patients with AML unsuitable for intensive induction chemotherapy. Maiti et al. reported that TKI combined with venetoclax and detectable had promising efficacy in CML-MBP. Therefore, the investigator conducted a study to explore the efficacy and safety of a third generation TKI in combination with azacitidine and Bcl-2 inhibitor in CML-MBP and multi-omics exploratory analysis was performed to identify potential biomarkers correlated with the outcome.

• Study Type: Observational
• Enrollment (Estimated): 30

Contacts and Locations

• Study Contact: Name: Qian Jiang, MD; Phone Number: +861088326006; Email: jiangqian@medmail.com.cn

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China, 100044
      • Peking University People's Hospital
      • Principal Investigator: Qian Jiang, MD
      • Contact: Cuicui Cong Peking university people's hospital; Phone Number: +861088324516; Email: rmyyllwyh@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: N/A

• Sampling Method: Non-Probability Sample

Study Population

Peking universuty people's hospital Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Henan Cancer Hospital The First Affiliated Hospital, Zhejiang University School of Medicine Chinese Academy of Medical Sciences & Peking Union Medical College Hospital Nanfang Hospital, Southern Medical University Chuiyangliu hospital affiliated to tsinghua university

Description

Inclusion Criteria:

1. age ≥ 18 years old;
2. philadelphia chromosome (Ph)-positive or BCR::ABL-positive;
3. serum creatinine ≤ 1.5 × upper limit of normal (ULN) or 24h creatinine clearance ≥ 50 mL/min when serum creatinine was > 1.5 × ULN;
4. serum total bilirubin ≤ 1.5 × ULN;
5. aspartate aminotransferase and alanine aminotransferase ≤ 2.5 × ULN;
6. amylase ≤ 1.5 × ULN; (7) lipase ≤ 1.5 × ULN;
7. ejection fraction > 50%; corrected QT interval on electrocardiographic evaluation was ≤ 450 ms in men or ≤ 470 ms in women.

Exclusion Criteria:

1. concurrent diseases requiring treatment(s) with potential to interact with 3G-TKI;
2. diagnosis of other primary malignancies;
3. history of allogeneic HSCT;
4. extramedullary disease only.

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

3G-TKI + AZA + Ven group; Adult CML-MBP

Drug: Ponatinib; CML-MBP receive ponatinib or olverembatinib daily combined with venetoclax ( 2 weeks) and azacitidine (D1-D7) in 28-day cycles. Subjects receive allogeneic HSCT after returning to chronic phase if applicable, whereas continuing the regimen until loss of response.; Drug: Azacitidine; CML-MBP receive ponatinib or olverembatinib daily combined with venetoclax ( 2 weeks) and azacitidine (D1-D7) in 28-day cycles. Subjects receive allogeneic HSCT after returning to chronic phase if applicable, whereas continuing the regimen until loss of response.; Drug: Venetoclax; CML-MBP receive ponatinib or olverembatinib daily combined with venetoclax ( 2 weeks) and azacitidine (D1-D7) in 28-day cycles. Subjects receive allogeneic HSCT after returning to chronic phase if applicable, whereas continuing the regimen until loss of response.; Drug: Olverembatinib; CML-MBP receive ponatinib or olverembatinib daily combined with venetoclax ( 2 weeks) and azacitidine (D1-D7) in 28-day cycles. Subjects receive allogeneic HSCT after returning to chronic phase if applicable, whereas continuing the regimen until loss of response.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Major hematologic response (MaHR)	either a complete hematologic response (CHR) or no evidence of leukemia (NEL).	At the end of Cycle 2 (each cycle is 28 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Return to chronic phase	< 10% blasts in blood and bone marrow with no extra-medullary leukemia and last for ≥ 4 weeks	At the end of Cycle 2 (each cycle is 28 days)
Major cytogenetic response (MCyR)	Ph-positive cells ≤ 35%	Up to 3 years
Complete cytogenetic response (CCyR)	no Ph-positive cell	Up to 3 years
Major molecular response (MMR)	BCR::ABL1IS ≤ 0.1%	Up to 3 years
Event-free survival (EFS)	interval from therapy start to lacking RCP after 1 cycle, MaHR after 2 cycles, loss of hematologic response, progression to blast phase again, or death from any causes	Up to 3 years
CML-related survival	interval from therapy start to death from blast phase, or censored at the last follow-up	Up to 3 years
Survival	interval from therapy start to death from any cause or censored at the last follow-up	Up to 3 years
Incidence of adverse events	Adverse effects (AEs) were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. and assessed continuously.	Up to 3 years

Collaborators and Investigators

• Sponsor: Peking University People's Hospital
• Collaborators: Henan Cancer Hospital; Wuhan Union Hospital, China; Zhejiang University; Peking Union Medical College; Beijing Chuiyangliu Hospital; Nanfang Hospital, Southern Medical University
• Investigators: Principal Investigator: Qian Jiang, MD, Peking University People's Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2024
• Primary Completion (Estimated): December 1, 2025
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: April 18, 2024
• First Submitted That Met QC Criteria: April 28, 2024
• First Posted (Actual): April 30, 2024

Study Record Updates

• Last Update Posted (Actual): May 1, 2024
• Last Update Submitted That Met QC Criteria: April 29, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Disease Attributes; Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Chronic Disease; Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Protein Kinase Inhibitors; Tyrosine Kinase Inhibitors; Venetoclax; Azacitidine; Ponatinib
• Other Study ID Numbers: 2023PHB323-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No