Background: The F (fludarabine) LAG (cytarabine+granulocyte colony-stimulating factor, G-CSF) and C (cladribine) LAG regimens have been confirmed to be effective salvage therapies for relapsed/refractory (r/r) malignant hematologic diseases. We applied these regimens in the conditioning for allogeneic (allo-) hematopoietic stem cell transplantation (HSCT) as a replacement for cyclophosphamide (CTX) in the treatment of r/r malignant hematologic diseases, achieving excellent outcomes.

Aims: To evaluate the efficacy and safety of FLAG/CLAG regimens as a substitute for CTX in the conditioning for allo-HSCT patients with r/r malignant hematologic diseases.

Methods: Between Jan 2023 and Dec 2024, 132 consecutive patients with r/r malignant hematologic diseases who underwent allo-HSCT in our department were enrolled. The median age was 29.5 years (range, 2-64 years) and the female-to-male ratio was 69:63. Follow-up was conducted until June 2025. The diagnoses were as follows: 64 cases of acute lymphoblastic leukemia, 59 cases of acute myeloid leukemia, 4 cases of myelodysplastic syndrome, 3 cases of chronic myeloid leukemia in blastic phase and 2 cases of lymphoma. Among them, 65 patients received a second allo-HSCT, and 49 patients underwent salvage allo-HSCT. In the FLAG and CLAG groups, 18/64 (28.1%) and 31/68 (45.6%) patients underwent salvage allo-HSCT, respectively. Regarding donor types, 47 patients underwent unrelated donor allo-HSCT, 83 received haplo-identical allo-HSCT, and 2 underwent sibling-matched allo-HSCT. The conditioning regimens consisted of: total body irradiation (TBI, total 8-10 Gy) or busulfan (3.2mg/kg, once daily for 3 days), G-CSF (5ug/kg once daily for 5 days), fludarabine (30 mg/m² once daily for 5 days) or cladribine (5mg/m2 once daily for 5 days), cytarabine (1 g/m² once daily for 5 days), optional etoposide (200 mg/m² once daily for 3 days) and antithymocyte globulin (ATG). Cyclosporine, mycophenolate mofetil and short-term methotrexate were employed for graft-versus-host disease (GVHD) prophylaxis.

Results: All patients achieved durable engraftment. the median follow-up time was 9.72 (1-30) months, with a 2-year leukemia-free survival (LFS) rate of 47.3% and overall survival (OS) rate of 62.5%. The FLAG group showed relatively higher 2-year LFS and OS rates (54.3% and 66.8%) compared with the CLAG group (39.0% and 57.3%). However, the differences in LFS and OS between the two groups were not statistically significant. In the FLAG and CLAG groups, the relapse rates (RR) were 17.1% (11/64) and 26.5% (18/68), and the non-relapse mortality (NRM) rates were 15.6% (10/64) and 22.1% (15/68). The incidence of acute (a) GVHD was 28.1% (18/64) in the FLAG group and 30.9% (21/68) in the CLAG group, with grades III–IV aGVHD occurring in 21.9% (14/64) and 19.1% (13/68) of patients, respectively. For chronic (c) GVHD, the overall incidence was 37.5% (24/64) in the FLAG group and 35.3% (24/68) in the CLAG group, while the rate of extensive cGVHD was 20.3% (13/64) and 10.3% (7/68), respectively. No statistically significant differences were observed between the two groups in terms of RR, NRM, aGVHD, grades III–IV aGVHD, cGVHD, or extensive cGVHD. EB virus reactivation and infection rates were 12.5% (8/64) in the FLAG group and 19.1% (13/68) in the CLAG group. The reactivation and infection rates of CMV were 17.2% (11/64) and 19.2% (13/68) in the two groups, respectively. Additionally, there were no significant differences between the FLAG and CLAG groups in the incidence of hemorrhagic cystitis or severe bacterial and fungal infections.

Conclusion: Our cohort comprised heavily pretreated patients, among whom a substantial proportion had undergone second or salvage transplantation. Notably, the 2-year LFS and OS still reached to 47.3% and 62.5%, respectively, accompanied by a relatively low NRM. These findings thus suggest that substituting CTX with FLAG/CLAG regimens in the conditioning therapy for allo-HSCT is both effective and safe for patients with r/r malignant hematologic diseases. Additionally, no significant differences in efficacy and safety were observed between FLAG and CLAG regimens. Although the FLAG group showed numerically better LFS and OS compared with CLAG group, the difference did not reach statistical significance, and furthermore, a higher proportion of patients in the CLAG group underwent salvage transplantation, which might have influenced the outcomes.

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2025
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