Positive outcomes associated with stem cell transplantation in pediatric/AYA patients who receive FLAG-IDA-venetoclax for high-risk AML Free

Background: BCL-2 inhibitors like venetoclax have demonstrated encouraging remission rates when combined with fludarabine, cytarabine, idarubicin, and G-CSF (FLAG-IDA), enabling more patients to proceed to stem cell transplantation (SCT). However, Venetoclax (Ven) use in frontline pediatric AML remains investigational, and its effects on post-transplant immune reconstitution, engraftment kinetics, and graft-versus-host disease (GVHD) risk are not well defined. Recent data from Raj et al. demonstrate that the combined upfront use of a regimen such as FLAG-IDA-Ven in pediatric and adolescents and young adults (AYAs) with AML is associated with rapid remission, allowing the regimen to serve as a bridge to stem cell transplantation (SCT). Here, we conducted a retrospective review of the same cohort to evaluate transplant-related outcomes in children and AYAs with high-risk AML who received FLAG-IDA-Ven prior to SCT, focusing on engraftment, GVHD incidence, and early post-transplant recovery.

Methods: A retrospective chart review was performed at the University of Texas MD Anderson Cancer Center to evaluate adverse events (AEs), engraftment, GVHD rates, and infectious complications in pediatric and AYA patients who received FLAG-IDA-Ven prior to SCT. Response was assessed using the revised International Working Group Response Criteria for AML, and measurable residual disease (MRD) was measured by multiparameter flow cytometry (sensitivity: 0.01%).

Results: Of the 12 pediatric/AYA patients who received FLAG-IDA-Ven at our institution, 6 underwent SCT (3 male, 3 female). Five out of six patients (83%) underwent a matched unrelated donor SCT while 1 patient underwent a matched sibling donor SCT. All patients received a busulfan/fludarabine-based conditioning regimen and received post-transplant cyclophosphamide and tacrolimus as GVHD prophylaxis. The median age of patients was 20 years old (range: 2-24 years old). Prior to SCT, 3 patients demonstrated MRD negativity, 1 patient had 0.08% MRD, and 2 patients demonstrated hypocellular bone marrow but no increase in blasts consistent with no active disease. The median time to last follow up since transplantation was 711 days (range: 330-1125 days). The median time to neutrophil engraftment was 16.5 days (range: 15-25 days), and median time to platelet engraftment was 26.5 days (range: 13-44 days). No patients suffered from graft failure, acute GVHD, or sinusoidal obstruction syndrome. Four patients had MRD evaluation at day 30 and all demonstrated negativity, including the patient with pre-SCT MRD positivity of 0.08%. Two patients relapsed following HSCT at a median time of 203 days (196-209 days), including the patient undergoing SCT with positive MRD and a patient with very high risk acute megakaryoblastic leukemia who relapsed following cessation of a folate receptor 1-targeted antibody drug conjugate (STRO-002) due to adverse effects. No other patients received post-SCT maintenance therapy. While in remission, no patients experienced mixed chimerism with donor T-cell engraftment ranging 92-100% and 100% myeloid cell engraftment. One patient experienced CMV reactivation 28 days after SCT with peak level of 338 IU/mL requiring IV foscarnet, 1 patient experienced MRSA bacteremia on day 10 following SCT treated with appropriate antibiotic coverage, and 1 patient experienced disseminated mycobacterium fortuitum with skin nodules 19 days after SCT treated with antibiotics and disseminated candida treated with caspofungin. Four patients had immune reconstitution data available (cells/microliter). The median level of CD3 was 435.5, CD8 level of 34, CD19 level of 222 and NK cell level of 69 at a median time of 264 days. One patient died 314 days after SCT due to relapsed disease.

Conclusion: We demonstrate that SCT following FLAG-IDA-Ven in patients with high-risk AML is effective in maintaining remission, associated with manageable toxicities, and does not significantly impact engraftment or GVHD. Although 2 patients experienced a bacterial infection and 1 patient experienced a viral reactivation, all patients recovered following appropriate antimicrobial therapy, underscoring the regimen's tolerability and lack of delayed engraftment. These encouraging outcomes highlight the potential of FLAG-IDA-Ven as a bridge to SCT and warrant further prospective evaluation in larger, multi-institutional cohorts.