Amin, Muhammad Kashif

The therapeutic landscape of adults with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is undergoing a paradigm shift, driven by the development of immunotherapy-based “chemo-free” and “chemo-light’ regimens. These strategies aim to achieve high efficacy with reduced toxicity, particularly in older adults who may not tolerate intensive chemotherapy. In Philadelphia chromosome-positive (Ph+) BCP-ALL, the incorporation of ABL tyrosine kinase inhibitors (TKIs) with blinatumomab (CD3/CD19 bispecific T-cell engager) has shown remarkable efficacy, with some studies reporting molecular response rates in the range of 90–100% and long-term survival exceeding 80% without the need for intensive chemotherapy or allogeneic hematopoietic cell transplantation (allo-HCT). In Philadelphia-negative (Ph−) BCP- ALL, an immunotherapy-based combination of blinatumomab and inotuzumab ozogamicin (anti-CD22 antibody-drug conjugate) has demonstrated high rates of complete remission and measurable residual disease (MRD) negativity, with manageable toxicity. While chimeric antigen receptor (CAR) T-cell therapy remains a transformative option for relapsed/refractory B-ALL, its integration into frontline treatment is still under investigation. Ongoing trials are evaluating the optimal sequencing and combinations of these agents and their potential to obviate the need for chemotherapy and/or allo-HCT in selected patients. As evidence continues to accumulate, chemo-free and chemo-light regimens, incorporating minimal chemotherapy with targeted agents to balance efficacy and reduced toxicity, are poised to redefine the standard of care for adults BCP-ALL, offering the possibility of durable remissions with reduced treatment-related morbidity.

e18503 Background: Acute Myeloid Leukemia (AML) with FLT3-ITD mutations has poor prognosis and high relapse rates after allogeneic hematopoietic stem cell transplantation (allo-HCT). Post-transplant FLT3 inhibitor (FLT3i) maintenance therapy aims to prevent relapse and improve survival. However, randomized trials vary in FLT3i potency, its use during induction, maintenance duration, and measurable residual disease (MRD) assessment, which contribute to conflicting impacts on relapse-free survival (RFS) and overall survival (OS). This systematic review and meta-analysis assessed the efficacy and safety of FLT3i maintenance versus standard-of-care (SOC) in FLT3-ITD-positive AML post-allo-HCT. Methods: A systematic review was conducted following PRISMA guidelines, focusing on randomized controlled trials (RCTs) assessing FLT3i maintenance after allo-HCT. Comprehensive searches in PUBMED, EMBASE, CENTRAL, and ClinicalTrials.gov identified eligible studies. Statistical analyses were performed in R software (version 4.4.0) using the “meta” package. Results: Four RCTs involving 701 patients were included, with 351 patients in the intervention group and 350 in the control group. Patients’ ages ranged from 18 to 78 years, with 51.4% male and 48.6% female. Cytogenetic risk in the intervention group was 4.7% favorable, 74.4% intermediate, and 4.7% adverse; in the control group, these rates were 2.5%, 65.9%, and 4.7%, respectively. FLT3i maintenance significantly reduced pooled relapse risk (HR 0.50, 95% CI: 0.34–0.74) and pooled mortality (HR 0.63, 95% CI: 0.44–0.91) at a median follow up of 24 months from allo-HCT. Hematologic toxicity was higher in the FLT3i group (RR 2.12, 95% CI: 1.67–2.70), as was chronic GVHD (RR 1.18, 95% CI: 1.00–1.41). Acute GVHD (RR 1.05, 95% CI: 0.78–1.41) and hepatotoxicity (RR 1.09, 95% CI: 0.72–1.66) rates were similar, while skin toxicity was less frequent in the FLT3i group (RR 0.36, 95% CI: 0.16–0.84). Conclusions: Our analysis suggests that FLT3i maintenance post-allo-HCT improves RFS and OS in FLT3-ITD-mutated AML patients compared to SOC but is associated with increased hematologic toxicity and chronic GVHD. Future clinical trials should evaluate the benefit of FLT3i maintenance post alloHCT based on MRD status assessed by next generation sequencing (NGS) based assays. Outcomes reported by the included studies. Type of FLT3-i Relapse free survival at 24 months Overall Survival at 24 months HR (95% CI) P-value HR (95% CI) P-value Levis et al. Giltetrinib 0.679(0.459-1.005) 0.52 0.846(0.554-1.293) 0.44 Burchert et al. Sorafenib 0.39(0.18-0.85) 0.01 0.516(0.239-1.112) 0.85 Maziarz et al. Midostaurin 0.60(0.17-2.14) 0.42 0.58(0.19-1.79) 0.34 Xuan et al. Sorafenib 0.37(0.22-0.63) <0.0001 0.48(0.27-0.86) 0.01 Pooled Hazard Ratio (95% CI) 0.50 (0.34-0.74) 0.63 (0.44-0.91)