FBEM Conditioning Yields High GVHD- and Relapse-Free Survival After HSCT in ALL

A novel intensified conditioning regimen combining fludarabine, busulfan, etoposide, and melphalan (FBEM) resulted in a 2-year overall survival (OS) of 92.1% and a 2-year cumulative incidence of relapse (CIR) of 14.3% in patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (alloHSCT), according to results from a prospective phase 2 study (NCT04897139) presented at the European Hematology Association (EHA) 2026 Congress in Stockholm, Sweden.¹

Mengmeng Pan, MD, PhD, of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China, presented data on 203 patients with a median follow-up of 25.2 months (range, 3.4-49.3 months) from the study. The 2-year molecular leukemia-free survival (mLFS) was 83.4%, and the 2-year graft-vs-host-disease (GVHD)–free, relapse-free survival (GRFS) was 47.9%.

“FBEM conditioning showed favorable efficacy and safety in ALL, and our modified GVHD prophylaxis maintained effective GVHD control,” Pan said in his presentation. “Pre-HSCT MRD [minimal residual disease] positivity remained the strongest adverse prognostic factor, while targeted bridging therapy was associated with improved OS.”

Rationale: Building on the FBM Backbone

The FBEM regimen was developed in response to the persistent challenge of relapse as the primary barrier to long-term survival in high-risk ALL undergoing alloHSCT. Standard conditioning regimens face a difficult trade-off between disease control and treatment-related toxicity. The FBEM approach addresses this by combining busulfan and melphalan as a dual-alkylator strategy, exploiting synergistic DNA-damaging mechanisms to deepen the pretransplant response and eliminate MRD.

FBEM was built on the investigators’ previously established FBM platform studied in 100 patients with myeloid malignancies, which achieved a 2-year OS of 80.3%, a 2-year CIR of 5.3%, and a 2-year nonrelapse mortality (NRM) rate of 12.3%.² Melphalan given at 100 mg/m² maintained low relapse without excess NRM even in older patients. Following these results, etoposide was incorporated into the FBM backbone at total doses of 400, 500, or 600 mg/m² to further intensify antileukemic activity in the lymphoid setting.¹

Study Design and Patient Characteristics

Four GVHD prophylaxis strategies were evaluated alongside the conditioning regimen: antithymocyte globulin (ATG) alone, ATG plus posttransplant cyclophosphamide (PTCy), PTCy plus postengraftment ATG, and PTCy plus postengraftment basiliximab (Simulect). In the 2 postengraftment strategies, PTCy was administered early after transplantation at double doses (40 or 50 mg/kg for 2 days), with ATG (2.5 mg/kg) or basiliximab (20 mg) added on day +3 after neutrophil engraftment.

Among the 200 patients enrolled, the median age was 39 years. Nearly half had Philadelphia chromosome–positive ALL, 39% received pre-HSCT blinatumomab (Blincyto), and approximately 30% remained MRD positive by flow cytometry at the time of transplantation. The majority (71%) received grafts from haploidentical donors, and 88.5% received a PTCy-containing GVHD prophylaxis regimen. The most common regimen was PTCy plus postengraftment basiliximab, used in 52% of patients. Median CD34+ cell dose was 7.94 × 10⁶/kg.

Efficacy: Favorable Survival With Low Relapse and NRM

The 2-year CIR was 14.3%. Notably, 100-day NRM was 0%, and 2-year NRM was 2.2%, reflecting a highly favorable balance between disease control and treatment-related mortality. The FBEM regimen achieved these outcomes despite the predominance of haploidentical donors and a high-risk patient population.

Outcomes were comparable across etoposide dose groups (400/500 mg/m² vs 600 mg/m²), with no statistically significant differences in OS, mLFS, GRFS, CIR, or NRM. Escalation to 600 mg/m² etoposide was feasible without compromising long-term outcomes or increasing GVHD risk.

GVHD: Manageable Burden Across Regimens

The 180-day cumulative incidence of grade 2 to 4 acute GVHD was 20.5%, while grade 3 to 4 acute GVHD occurred in only 5.0% of patients. The 2-year incidence of all-grade chronic GVHD was 29.9%, and moderate-to-severe chronic GVHD was 13.5%.

GVHD incidence and long-term outcomes were broadly comparable across the 4 prophylaxis regimens. In multivariable analysis, PTCy plus postengraftment ATG and PTCy plus postengraftment basiliximab were associated with 67% and 86% lower odds of severe infection, respectively, compared with ATG-based reference regimens. PTCy plus postengraftment basiliximab was also associated with 74% lower odds of severe mucositis.

Hematologic Recovery and Safety

Hematopoietic recovery was prompt with a median time to neutrophil engraftment of 14 days (IQR, 13-14), and median time to platelet recovery was 13 days (IQR, 12-18). All patients achieved neutrophil recovery by day 30, and 98.5% achieved platelet recovery by day 90.

Early toxicities were generally manageable. Severe infection within 100 days occurred in 36.5% of patients, and severe oral/gastrointestinal mucositis within 30 days in 23.5%. Severe hemorrhagic cystitis occurred in 5.5%, and veno-occlusive disease and transplant-associated microangiopathy were each rare at 1.5%. The 180-day cytomegalovirus and Epstein-Barr virus reactivation rates were 21.0% and 7.0%, respectively. Multivariable analysis confirmed that etoposide dose was not an independent predictor of either severe infection or severe mucositis; GVHD prophylaxis was the dominant factor associated with early toxicities.

Prognostic Drivers: MRD and Targeted Therapy

In multivariable Cox analysis, pre-HSCT MRD positivity was the strongest adverse prognostic factor for both mLFS (HR, 4.24; 95% CI, 1.99-9.04; P <.001) and OS (HR, 10.83; 95% CI, 2.93-40.00; P <.001). Pre-HSCT immunotherapy was independently associated with improved OS (HR, 0.25; 95% CI, 0.06-0.97; P =.046), underscoring the importance of achieving deeper disease control before transplantation.

The investigators concluded that FBEM represents a promising intensified conditioning platform for high-risk ALL, with the choice of GVHD prophylaxis playing a critical role in optimizing early posttransplant outcomes.

REFERENCES

1. Pan M, Jiang C, Jiang J, et al. FBEM (fludarabine, busulfan, etoposide, and melphalan) conditioning regimen for patients with acute lymphoblastic leukemia undergoing allo-hsct: a prospective phase II study.Presented at: the European Hematology Association 2026 Congress; June 11-14, 2026; Stockholm, Sweden. Abstract S267.

2. Jiang JL, Gao WH, Wang LN, Wan M, Wang L, Hu J. Low incidence of relapse with a moderate conditioning regimen of fludarabine, busulfan, and melphalan for patients with myeloid malignancies: a single-center analysis of 100 patients. Transplant Cell Ther. 2023;29(8):512.e1-512.e8. doi:10.1016/j.jtct.2023.05.017