Fludarabine-treosulfan compared to thiotepa-busulfan-fludarabine or FLAMSA as conditioning regimen for patients with primary refractory or relapsed acute myeloid leukemia: a study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT)

Abstract

Background Limited data is available to guide the choice of the conditioning regimen for patients with acute myeloid leukemia (AML) undergoing transplant with persistent disease. Methods We retrospectively compared outcome of fludarabine-treosulfan (FT), thiotepa-busulfan-fludarabine (TBF), and sequential fludarabine, intermediate dose Ara-C, amsacrine, total body irradiation/busulfan, cyclophosphamide (FLAMSA) conditioning in patients with refractory or relapsed AML. Results Complete remission rates at day 100 were 92%, 80%, and 88% for FT, TBF, and FLAMSA, respectively ( p = 0.13). Non-relapse mortality, incidence of relapse, acute (a) and chronic (c) graft-versus-host disease (GVHD) rates did not differ between the three groups. Overall survival at 2 years was 37% for FT, 24% for TBF, and 34% for FLAMSA ( p = 0.10). Independent prognostic factors for survival were Karnofsky performance score and patient CMV serology ( p = 0.01; p = 0.02), while survival was not affected by age at transplant. The use of anti-thymocyte globulin (ATG) was associated with reduced risk of grade III–IV aGVHD ( p = 0.02) and cGVHD ( p = 0.006), with no influence on relapse. Conclusions In conclusion, FT, TBF, and FLAMSA regimens provided similar outcome in patients undergoing transplant with active AML. Survival was determined by patient characteristics as Karnofsky performance score and CMV serology, however was not affected by age at transplant. ATG appears able to reduce the incidence of acute and chronic GVHD without influencing relapse risk. Electronic supplementary material The online version of this article (10.1186/s13045-019-0727-4) contains supplementary material, which is available to authorized users.

Haploidentical versus HLA-matched sibling transplantation for refractory acute leukemia undergoing sequential intensified conditioning followed by DLI: an analysis from two prospective data

“…So far, allogeneic hematopoietic stem cell transplantation(allo-HSCT)remains the most effective way to cure refractory leukemia [1][2][3][4] and undergoing allo-HSCT promptly is essential for them. Recently, some studies showed that intensified conditioning followed by allo-HSCT could achieve acceptable outcomes for refractory leukemia [5][6][7][8][9]. In our transplant center, a strategy of sequential intensified conditioning followed by donor lymphocyte infusion (DLI) was implemented since 2009, and encouraging outcomes were reported previously [10].…”

FLAMSA-RIC for Stem Cell Transplantation in Patients with Acute Myeloid Leukemia and Myelodysplastic Syndromes: A Systematic Review and Meta-Analysis

“…A total of eighteen articles underwent full-text review and 9 of them were excluded because they did not report the primary outcomes of interest. Finally, 12 studies fulfilled the eligibility criteria and were included in the meta-analysis [3,6,7,8,9,10,11,12,13,14,15,16]. A manual review of the bibliography of the included studies, and some selected review articles, did not yield any additional eligible studies.…”

“…The pooled 1-, 2- and 3-year OS rates were 59.6% (95% CI, 47.9–70.2%; I 2 94%; Figure 2A) [6,7,8,14,15,16], 48.4% (95% CI, 37.3–59.6%; I 2 96%; Figure 2B [3,6,8,10,13,14,15,16], and 40.2% (95% CI, 28.0–53.7%; I 2 96%; Figure 2C) [6,7,11,12,14,15,16], respectively. The pooled 1-, 2- and 3-year LFS were 57.4% (95% CI, 38.6–74.2%; I 2 98%; Figure 2D) [6,14,15,16], 49.4% (95% CI, 38.1–60.8%; I 2 95%; Figure 2E [3,6,9,13,14,15,16], and 39.3% (95% CI, 26.4–53.9%; I 2 97%; Figure 2F) [6,7,12,14,15,16], respectively. The pooled 2- and 3-year RR were 31.3% (95% CI, 21.1–43.8%; I 2 96%; Figure 3A) [3,6,10,13,14,15,16] and 41.9% (95% CI, 30.9–53.8%; I 2 95%; Figure 3B) [6,7,11,12,14,15,16], respectively.…”

“…A total of 9 studies reported the rate of Grade 2–4 aGVHD. The pooled rate across those studies was 29.0% (95% CI, 25.5–32.7%; I 2 63%; Figure 4A) [3,9,10,11,12,13,14,15,16], whereas the pooled rate of cGVHD was 35.6% (95% CI, 30.0–41.6%; I 2 84%; Figure 4B), which was derived from 9 studies [3,7,9,10,12,13,14,15,16]. There was a slight increase in the rate of NRM for each year of follow-up with the pooled 1-year NRM rate of 17.9% (95% CI, 16.1–19.8%; I 2 0%; Figure 4C) [3,6,7,14,15,16], and the pooled 3-year NRM rate of 21.1% (95% CI, 18.8–23.7%; I 2 30%; Figure 4D) [6,7,9,11,12,14,15,16].…”

“…The combination of fludarabine, amsacrine, and cytarabine (FLAMSA)-polychemotherapy with RIC was initially adopted by Schmid et al for patients with high-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) [3,4,5] to combine high anti-leukemic activity with the advantages of RIC. Although several variations have been published [6,7,8,9,10,11,12,13,14,15,16], the ‘classic’ FLAMSA-RIC regimen consists of fludarabine, amsacrine, and cytarabine, followed by RIC with 4-Gy total body irradiation (TBI), high-dose cyclophosphamide (Cy), antithymocyte globulin (ATG), and prophylactic donor lymphocyte infusions (DLI) if indicated. Because of initially promising data, especially in poor prognosis AML patients, FLAMSA-RIC was adopted by many transplantation centers, and variations that included busulfan (Bu) or treosulfan were established.…”