Editor’s Note: Acute myeloid leukemia (AML) is a common and aggressive hematological malignancy with poor prognosis. For patients with relapsed/refractory (R/R) AML, allogeneic hematopoietic stem cell transplantation (allo-SCT) is one of the important treatment options. However, patients with R/R AML often face primary or secondary drug resistance and limited treatment options due to complications and physical condition, resulting in low re-induction remission rates. Therefore, selecting the appropriate chemotherapy regimen before transplantation to achieve deeper remission and secure better timing for transplantation, thereby optimizing the outcome of allo-SCT and extending patient survival, is a critical clinical issue. From April 14 to 17, 2024, the 50th European Society for Blood and Marrow Transplantation (EBMT) Annual Meeting was held in Glasgow, UK, focusing on the latest advances in stem cell transplantation and cellular therapy, and pushing forward better clinical outcomes for patients with hematological diseases and malignancies. In this issue, we are pleased to have Professor Jie Jin share her insights on the latest research in pre-transplant chemotherapy for patients with relapsed/refractory AML.
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FLAG-IDA/VENETOCLAX versus VENETOCLAX/AZACITIDINE: Higher Remission Rates and Improved Post-Transplant Survival in Relapsed/Refractory AML Patients
Background
The remission rates for relapsed/refractory (R/R) AML patients are low, and the duration of remission is short. The combined use of BCL2 inhibition has been shown to synergize with both low-intensity and intensive chemotherapy to achieve high remission rates. In this single-center study, authors compared the post-transplant outcomes of R/R AML patients who received low-intensity (azacitidine [AZA]) or intensive (FLAG-Ida) regimens combined with venetoclax [VEN] as a “bridging” strategy before undergoing allo-SCT.
Methods
Between 2019 and 2023, 90 R/R AML patients (males, n=53; median age, 59 years [range, 19-75 years]) who underwent allo-SCT (sibling matched, n=58) at the University of Hamburg Medical Center were included in the study. Measurable residual disease (MRD) was assessed by flow cytometry. The primary endpoint was to compare the overall survival (OS) post-allo-SCT between patients receiving VEN combined with low-intensity or high-intensity chemotherapy. Secondary endpoints included differences in leukemia-free survival (LFS), relapse, and non-relapse mortality (NRM) post-allo-SCT.
Results
Most allografts were performed following myeloablative conditioning (n=57, 63%), with ATG used for GvHD prevention (n=65, 72%). Sixty-two patients underwent their first transplant, 26 (29%) underwent a second, and 2 underwent a third. At the time of allo-SCT, 62 patients (69%) were in complete remission (CR). Bridging treatments included AZA-VEN for 41 patients (one or two cycles) or FLAG-Ida-VEN for 49 patients. MRD data were available for 49 patients pre-transplant. The FLAG-Ida-VEN group showed higher rates of MRD-negative CR (16/27, 59% vs. 11/27, 41%) and MRD-positive CR (16/22, 73% vs. 6/22, 27%) compared to the AZA-VEN group. The rate of not achieving CR was higher in the AZA-VEN group (17/28, 61% vs. 11/28, 39%, P=0.055). During a median follow-up of 13 months (2-140 months), there were 34 deaths, 27 relapse events, and 13 NRM events. The 2-year OS (61%, 43-77% vs. 46%, 29-64%, P=0.089) and LFS (46%, 27-66% vs. 39%, 24-52%, P=0.045) were better in the FLAG-Ida-VEN group. The rates of relapse and NRM were similar between the groups. Univariate analysis showed significant effects of remission status and donor type. Multivariate analysis showed that CR at the time of allo-SCT had a significant independent effect on OS (HR 0.17, 0.08-0.35, P<0.0001), LFS (HR 0.18, 0.1-0.35, P<0.0001), and relapse (HR 0.19, 0.08-0.43, P<0.0001).
Furthermore, the authors specifically analyzed the prognostic impact of MRD status at remission (n=77). The 1-year OS for MRD-negative CR, MRD-positive CR, and non-CR patients were 93% (77-98%), 63% (40-81%), and 30% (16-49%, P<0.001) respectively. The 1-year LFS for MRD-negative CR, MRD-positive CR, and non-CR patients were 92% (76-98%), 59% (37-78%), and 21% (11-51%, P<0.001) respectively. The 1-year relapse rates for MRD-negative CR, MRD-positive CR, and non-CR patients were 9% (2-39%), 21% (8-44%), and 55% (36-72%, P<0.001) respectively. In multivariate analysis, MRD-positive CR and non-CR had adverse impacts on OS (HR 5.2, 1.1-24.4, P=0.035; HR 11.5, 2.7-49.9, P=0.001; Wald test, P=0.002), LFS (HR 2.9, 0.9-9.2, P=0.076; HR 8.6, 2.9-25, P<0.001; Wald test, P<0.001), and relapse (HR 2.6, 0.5-14.2, P=0.24; HR 10.1, 2.5-39.8, P<0.001; Wald test, P<0.001) compared to MRD-negative CR.
Conclusion
Compared to AZA-VEN, the intensified FLAG-Ida-VEN bridging regimen achieves a higher CR rate and better overall outcomes.
Expert Introduction:
Professor Jie Jin
Affiliated First Hospital of Zhejiang University School of Medicine
MD, Professor, PhD Supervisor
Recipient of the State Council Special Government Allowance and National Advanced Worker in the Health System
Honorary Director of the Hematology Department at the First Hospital affiliated with Zhejiang University School of Medicine
Director of the Key Laboratory for Hematologic Oncology (Diagnosis and Treatment) at Zhejiang University
Leader of the National Health Commission’s Clinical Key Discipline – Hematology at the First Hospital
Director of the Zhejiang Provincial Clinical Medical Research Center for Hematologic Diseases
Head of Malignant Hematological Diseases Basic and Clinical Research at Zhejiang University Cancer Research Institute
Leader of the Zhejiang Provincial Key Innovation Team in Leukemia Basic and Clinical Research
Chairperson of the Hematology Committee of the Chinese Women Physicians Association
Former Chairperson of the Hematologic Disease Translational Medicine Committee of the Anti-Cancer Association
Vice Chairperson of the Chinese CSCO Leukemia Alliance
Standing Committee Member of the Chinese Medical Association’s Hematology Society
Vice Chairperson of the Integrated Hematology Society of the Chinese Medical Association
Vice Chairperson of the CSCO Leukemia Alliance
Standing Committee Member of the CSCO Lymphoma Alliance
Standing Committee Member of the Cross-Strait Hematology Society
Standing Committee Member of the Chinese Health Promotion Association’s Hematology Society
Former Chairperson of the Hematology Branch of the Zhejiang Medical Association
President of the Hematology Branch of the Zhejiang Physicians Association
Author of over 300 academic papers published in SCI-indexed journals such as Lancet Oncology, Cell, Blood, Leukemia, JHO, and recipient of one national second-class award for scientific and technological advancement and two first-class awards for scientific and technological advancement in Zhejiang Province.
