Efficacy and safety of melphalan/TBI-based conditioning regimens (MCAC/TCAC) for autologous HSCT in adult acute lymphoblastic leukemia: A multicenter, prospective cohort study Free

Introduction

Autologous hematopoietic stem cell transplantation (auto-HSCT) is a primary consolidation option for adult acute lymphoblastic leukemia (ALL) patients with sustained minimal residual disease (MRD) negativity, valued for its safety and independence from donor availability. Although traditional TBI-based conditioning offers robust anti-leukemic efficacy, its clinical use is limited by poor accessibility and severe long-term toxicities (e.g., infertility, metabolic syndromes, secondary malignancies), mandating an urgent need for safer and effective alternatives. To address this, we initiated a prospective, multicenter clinical trial to evaluate the efficacy and safety of a novel melphalan-based modified conditioning regimen for adult ALL patients undergoing auto-HSCT.

Method

From Oct 2023 to Apr 2025, a total of 81 patients diagnosed with ALL were enrolled. The assignment was determined by the availability of TBI at each center and the patient's choice.

Key eligibility criteria required Philadelphia chromosome-positive (Ph+) ALL patients to achieve both a complete molecular response and MRD negativity within three cycles of chemotherapy and sustain that response, while Ph-negative (Ph-) B-ALL patients were required to attain and sustain MRD negativity within the same timeframe.

Patients were excluded if they had a history of central nervous system leukemia or extramedullary disease, or if diagnosed with ETP-ALL, Ph-like ALL, or T-ALL. The MCAC regimen consisted of melphalan 70 mg/m² on days -8 and -7, followed by cyclophosphamide (CY) 40 mg/kg on days -6 and -5, and a combination of cladribine 5 mg/m² with cytarabine (Ara-C) 2 g/m² on days -4, -3, and -2. The TCAC regimen consisted of fractionated TBI at 3.33 Gy per day on days -9, -8, and -7, followed by the same doses and schedule of CY, Cladribine, and Ara-C as the MCAC group.

The primary endpoint was relapse-free survival (RFS), defined as the time from transplantation to the first occurrence of hematologic or extramedullary relapse, or death from any cause. A key secondary endpoint was molecular RFS (mRFS), which additionally included molecular relapse as an event.

Results

A total of 81 adult ALL patients were enrolled, with 55 in the MCAC group and 26 in the TCAC group. The MCAC and TCAC groups were comparable at baseline, with no significant differences in age, sex, infused cell dose, disease type, or risk stratification. The median follow-up period was 16.8 months. Engraftment kinetics were comparable between the MCAC and TCAC arms, with a median time to neutrophil engraftment of 11.9 vs. 11.8 days (p=0.8) and platelet engraftment of 20.3 vs. 23.9 days (p=0.4), respectively.

At 18 months, survival outcomes were comparable between the MCAC and TCAC groups. The OS rate was 87% (95% CI, 79-97%) for MCAC versus 87% (95% CI, 71-100%) for TCAC (p=0.52). There were no significant differences in RFS at 83% (95% CI, 74-94%) vs. 77% (95% CI, 59-100%) (p=0.97), or mRFS at 76% (95% CI, 65-88%) vs. 75% (95% CI, 57-98%) (p=0.75). The CIR was also similar at 8% (95% CI, 3-19%) vs. 16% (95% CI, 4-37%) (p=0.70), as was mCIR at 19% (95% CI, 10-30%) vs. 25% (95% CI, 8-47%) (p=0.76). Non-relapse mortality (NRM) was 9% (95% CI, 3-19%) in the MCAC group and 0% in the TCAC group (p=0.10).

The incidence of Grade 3-4 toxicities during conditioning for MCAC versus TCAC group was: diarrhea (8 [14.5%] vs. 0), hepatic dysfunction (2 [3.6%] vs. 0), and oral mucositis (2 [3.6%] vs. 1 [3.8%]). Other adverse events in MCAC group, included engraftment syndrome (4 [7.3%]), cardiac dysfunction (3 [5.5%]), and cerebral hemorrhage (1 [1.8%]). In TCAC group, notable events included engraftment syndrome (3 [11.5%]) and gastrointestinal bleeding (2 [7.7%]). The incidence of severe bacterial infections was higher in the MCAC group compared to the TCAC group (19/55, 34.5% vs. 3/26, 11.5%). In contrast, the rates of fungal infections (3/55, 5.5% vs. 3/26, 11.5%) and viral infections (5/55, 9.1% vs. 3/26, 11.5%) were comparable between the two groups.

Conclusion

These preliminary findings suggest that the MCAC regimen appears to be a viable and safe alternative to TBI-based conditioning for auto-HSCT in adult ALL patients who achieve and sustain early MRD negativity (by both flow cytometry and molecular biology). However, as the follow-up duration for both groups remains short, long-term efficacy and safety require further investigation.