Decitabine before Low-Dose Cytarabine-Based Chemotherapy Combined with Unrelated Umbilical Cord Blood Stem Cell Microtransplantation and IL-2 Treatment in Elderly Patients with Newly Diagnosed Acute Myeloid Leukemia

Introduction: The optimal treatment of acute myeloid leukemia (AML) in elderly patients remains a significant challenge, underscoring the urgent need for more feasible and safer treatment strategies. Microtransplantation (MST) has emerged as a novel therapeutic approach, involving the infusion of HLA-mismatched donor hematopoietic stem cells (HSC) to establish microchimerism, which has been shown to improve clinical outcomes. Umbilical cord blood (UCB) serves as a readily available source of allogeneic HSC, possessing intrinsic anti-tumor effects, immune modulation capabilities, and providing hematopoietic support. Furthermore, previous studies have indicated that interleukin-2 (IL-2) can bolster the proliferation and cytotoxic activity of both T cells and natural killer (NK) cells, potentially enhancing the immune response against AML.

In light of these findings, we conducted an investigator-initiated, prospective study (ChiCTR-OPC-1900024089) to evaluate the efficacy and toxicity of a regimen combining decitabine, granulocyte colony-stimulating factor (G-CSF) priming, low-dose aclarubicin, and cytarabine (DCAG) chemotherapy followed by unrelated HLA-mismatched UCB microtransplantation (UCB-MST) and interleukin-2(IL-2) in elderly AML patients.

Methods: A total of 100 patients with a median age of 68-years-old (60~85 years) who received DCAG combined with UCB-MST and IL-2 (MST, n=50) or DCAG regimen alone (non-MST, n=50) as induction and consolidation therapy were enrolled in the study. The patients in MST group received a DCAG regimen followed by an intravenous infusion of HLA-mismatched UCB after 24 to 72 hours without graft-versus-host-diseases (GVHD) prophylaxis. Additionally, subcutaneous injections of IL-2 at a dose of 1 million IU were administered every other day for 6 to 12 months after UCB infusion. Importantly, none of the patients received allogeneic or autolougous hematopoietic stem cell transplantation. Following UCB infusion, we performed real-time quantitative polymerase chain reaction (RQ-PCR) to assess microchimerism in the peripheral blood of 22 patients, with samples collected between 21 to 35 days post-transfusion. The immune cell populations and phenotypic characteristics of peripheral blood were analyzed in 13 patients (7 from the MST arm and 6 from non-MST arm) using single-cell mass cytometry, both before and after the first induction treatment.

Results:

Our data revealed that the patients in the MST group had significantly better complete remission (CR) rate (84% vs.66%, P=0.0377) and median overall survival (OS) (26 vs. 13.5months, P=0.0116) compared to those in non-MST group after one cycle of induction, with a median follow-up of 42 months. Notably, the CR rate after one induction cycle was significantly higher in the intermediate- and adverse-risk patients of the MST group compared to the non-MST group (77.8% vs. 52.9%, P=0.0287).

Among the MST group, 2 patients experienced severe infusion-related adverse reactions, which were effectively managed. Both groups exhibited grade III to IV hematological toxicities, including neutropenia and thrombocytopenia. Importantly, no early deaths (defined as deaths occurring within 8 weeks post-treatment) were reported in the MST group, whereas 2 patients in the non-MST group succumbed to early mortality due to severe infections resulting from disease progression.

Among the 22 patients who underwent microchimerism assessment, 17 displayed microchimerism, with values ranging from 0.002% to 0.034%. No definitive cases of acute or chronic GVHD were observed in all the patients. Additionally, single-cell mass cytometry analysis indicated that patients achieving CR in the MST group demonstrated significantly increased proliferation of naive T cells (TN), central memory T cells (Tcm), effector memory T cells (Tem), and natural killer (NK) cells in peripheral blood 21 to 28 days post-treatment, compared to CR patients in the non-MST group.

Conclusions: Our clinical study demonstrates that DCAG combined with UCB MST and IL-2 treatment might enhance the patients' immune function and serve as a promising therapeutic option for elderly patients with newly diagnosed AML.