Relapsed/Refractory AML1::ETO Acute Myeloid Leukemia Was Successfully Treated By Allogeneic Hematopoietic Stem Cell Transplantation with Modifyed Myeloablative Preconditioning Contains Olaparib

Background:

Acute myeloid leukemia with the t(8;21) (q22;q22) is generally associated with a favorable outcome, but AML with AML1::ETO+ has been shown clinical heterogeneity and relapse occurs in about 30% of patients. Despite undergoing allogeneic hematopoietic stem cell transplantation in CR1, the relapse rate among this cohort of patients remained at 22.1%-38.4%. In the initial three months post allo-HSCT, an inadequate AML1::ETO transcript levels decline indicates a heightened risk of disease recurrence. Adequate pre-conditioning regimen administered prior to transplantation are crucial for eliminating leukemia cells and achieving optimal gene decline levels. Notably, the AML1::ETO has been identified to sensitize cells to poly ADP-ribose polymerase inhibitors (PARPi), this effect is attributed to the suppression of crucial genes involved in homologous recombination repair mediated by AML1::ETO. Our prior investigation revealed that the combination of PARPi-olaparib and chemotherapy exhibited favorable efficacy and safety profiles in relapsed AML1::ETO+ patient, vitro studies have revealed a promising synergistic effect between PARPi and busulfan. Therefore, incorporating olaparib into the pre-conditioning regimen for relapsed/refractory AML1::ETO+ AML has the potential to augment the effectiveness of transplantation.

Methods:

AML patients with AML1::ETO+ were enrolled at Beijing Lu Daopei Hospital and Hebei Yanda Lu Daopei Hospital between June 2022 and Octerber 2023. The following inclusion criteria were applied: (1) 14 to 60 years old; (2)≥CR2 or active disease; (3) no contraindications to allo-HSCT; (4) first allo-HSCT; (5) patients sign informed consent forms. AML1::ETO+ AML with systemic mastocytosis was excluded.The pre-conditioning regimen used in the patients consisted of olaparib, FLAG, busulfan and cyclophosphamide.The detailed process is as follows: olaparib,150mg bid, from days -15 to -4; G-CSF, 5μg/kg/d, from days -14 to -10; fludarabine, 30mg/m²/d,from days -14 to -10; cytarabine 2g/m²/d from days -14 to -10; busulfan,3.2 mg/kg/d, from days -9 to -6; cyclophosphamide,1.0g/m²/d,from days -5 to -4.Tacrolimus, mycophenolate mofetil, intravenous methotrexate were used for the prophylaxis of GVHD for matched-related allo-HSCT, this protocols combined with rATG (1.875 mg/kg/d, Genzyme, from days -5 to -2) were used for the prophylaxis of GVHD for haploidentical allo-HSCT and matched-unrelated allo-HSCT.

Results:

Six relapsed/refractory AML1::ETO+ AML patients were enrolled. Of the six patients, four presented with extramedullary lesions, one of whom concurrently exhibited of the central nervous system leukemia. All six patients presented with one or more gene mutations, primarily KIT and FLT3. Among the six patients, two achieved CR following one cycle chemotherapy, whereas the remaining four attained CR after two cycles, all six patients experienced relapse after CR. Three attained re-remission, whereas the remaining three exhibit an active disease. All six patients tolerated the pre-conditioning regimen well. No unexpected toxicity reactions or deaths attributed to toxicity were observed. The median infused mononuclear cell (MNC) count was 10.625 × 10⁸/kg (range: 8.07-13.57), while the median infused CD34+ cell count was 5.985 × 10⁶/kg (range: 5-7.37).All patients successfully underwent hematopoietic reconstitution, with a median neutrophil engraftment time of 15 days (range: 11-17) and a median platelet engraftment time of 15 days (range: 11-21). Among the six patients, four exhibited aGVHD of varying severity. All six patients displayed manifestations of cGVHD.All six patients exhibited complete molecular remission (CMR) within three months following transplantation.PET-CT assessment demonstrated that patients with extramedullary lesions achieved remission. By July 1, 2024, all patients exhibited disease-free status, demonstrating a median OS and DFS of 16 months (range: 10-24).

Conclusion:

Our preliminary study revealed that AML1::ETO+ AML patients undergoing allo-HSCT with a preconditioning regimen incorporating olaparib achieved early CMR post-transplantation, accompanied by tolerable adverse effects.Nonetheless, further validation of the efficacy and safety of this approach in larger clinical trials is necessary.

No relevant conflicts of interest to declare.

olaparib-a poly ADP-ribose polymerase inhibitor,AML1::ETO has been identified to sensitize cells to poly ADP-ribose polymerase inhibitor, this effect is attributed to the suppression of crucial genes involved in homologous recombination repair mediated by AML1::ETO.