The treatment of young patients with R/R acute myeloid leukemia (AML) poses a challenge for clinicians. Chemotherapy regimens, such as high doses of cytarabine, fludarabine, and other salvage reduction therapies, are often recommended. However, these therapies seldom achieve complete remission and often render patients ineligible for their second allogeneic hematopoietic stem cell transplant (SCT). Note that allogeneic hematopoietic stem cells, unlike autologous stem cells obtained from the patient, are received from a donor.
Due to these challenges, a study was conducted, including 31 young patients diagnosed with R/R AML and treated in the Hematology Department at Xi’an Jiaotong University from April 2021 through May 2023.
The criteria for inclusion were:
- R/R diagnosis
- Between 18 and 60 years of age
- Minimum of one VEN cycle + HMAs
- Minimum of one bone marrow follow-up
Complications may arise from treatment, including organ toxicity and an increased risk of severe infection. Additionally, the collective effect of prior treatment negatively impacts the bone marrow’s ability to recover, prolonging bone marrow suppression.
A further complication has been the worldwide shortage of blood donors, which began during the pandemic. Patients undergoing intensive chemotherapy depend on blood products for successful stem cell transplants.
Venetoclax and B-cell Lymphoma 2
Recent advances in AML therapy are attributed to the combination of VEN, a B-cell lymphoma 2 (Bcl-2) inhibitor, plus hypomethylating agents (HMAs).
VEN is a BCL-2 inhibitor that improves outcomes for patients with relapsed and refractory AML. The agent blocks an anti-apoptotic BCL2 gene, responsible for protecting cells from inadequate blood supply-induced apoptosis. If apoptosis is blocked, it can lead to prolific cell division and new tumor growth.
Studies have shown that hypomethylating agents (HMAs) may increase tumor cells’ sensitivity to VEN when administered to newly diagnosed AML patients. This finding is supported by several previously conducted clinical trials.
In addition, VEN + HMA has demonstrated encouraging remission rates in R/R patients. The combination therapy is well-tolerated, with low toxicity and low mortality (treatment-related), making it suitable for elderly or frail patients.
The combination of low-intensity therapy, VEN + HMA, may reduce the need for blood transfusions due to therapy-related neutropenia, which increases the risk of fungal and bacterial infections.
About the Study
The median age of the subgroup was 53 years, with a range of 18 to 60 years. The group consisted of 54.8% males. Twenty-six patients were newly diagnosed with AML, while five had therapy-related or secondary AML.
Seventeen out of a total of 31 patients had their dosage decreased due to bone marrow suppression. All participants reported adverse events during the first cycle, with Grade 3 neutropenia occurring in every patient.
Patients in the study received oral VEN therapy plus AZA. They received VEN initially at 100 mg per day, gradually increasing to 400 mg. Regular monitoring, including kidney and liver function tests, standard blood tests, and blood transfusions if necessary, was conducted.
Fifteen patients achieved complete remission but incomplete count recovery, and six patients achieved partial remission. The overall response rate was 67.7% (21 out of 31), with early mortality during the first eight weeks at 2 deaths out of 31 patients.
All patients showing a satisfactory clinical response continued treatment with VEN + AZA unless their condition changed to life-threatening reactions, disease progression, or allo-HSCT.
About the Results
Regimens including VEN (Venclexta) improved response rates for patients who had discontinued Bruton tyrosine kinase inhibitors, even if the study was their second or third intervention. These patients were diagnosed with either chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).
Dr. Nilanjan Ghosh, the presenting author, commented that the VEN-based study found venetoclax effective, generating impressive response rates following BTK discontinuance.
Data from a CORE study presented at the Annual ASH Meeting indicated that B-cell leukemia and lymphomas use B-cell receptor signaling for survival and growth.
The VEN + AZA combination appeared to be a well-tolerated and highly effective salvage regimen for young R/R AML patients.
Currently, only one active clinical trial (NCT03573024) is evaluating the combination with newly diagnosed young adults with AML. Future studies with a higher number of participants are recommended to confirm the combination’s advantages for these young patients.
