Survival Advantage and Comparable Toxicity in Reduced-Toxicity Treosulfan-Based versus Reduced-Intensity Busulfan-Based Conditioning Regimen in Myelodysplastic Syndrome and Acute Myeloid Leukemia Patients after Allogeneic Hematopoietic Cell Transplantation

Abstract

Treosulfan has been incorporated in conditioning regimens for sustained remission without substantial toxicity and treatment-related mortality (TRM). We aimed to analyze the safety and efficacy of a fludarabine 150 mg/m and treosulfan 42 g/m (FluTreo) conditioning regimen in medically infirm patients. Outcomes were compared with those of a similar historical group treated with fludarabine 150 mg/m to 180 mg/m, busulfan 6.4 mg/kg, and antithymocyte globulin (ATG) 5 mg/kg to 7.5 mg/kg (FluBuATG). Thirty-one consecutive patients with acute myeloid leukemia (AML; n = 21), myelodysplastic syndrome (MDS; n = 6), or treatment-related AML (n = 4) received FluTreo conditioning. The historical group consisted of 26 consecutive patients treated with FluBuATG. In the FluTreo group, engraftment was prompt in all patients and 74% achieved >99% donor chimerism by day +30. No grades III or IV organ toxicities were noted. One-year cumulative incidences (CI) of acute and chronic graft-versus-host disease (GVHD) were 19.4% and 58.4%. The groups were similar for age, disease risk, lines of treatment, hematopoietic cell transplantation-specific comorbidity index, and acute or chronic GVHD incidence, except that there were more matched unrelated donor recipients in the FluTreo group (P < .001). With 20 (range, 2 to 36) months follow-up for FluTreo and 14 (range, 2 to 136) for FluBuATG, the 1-year cumulative overall survival (OS) probability was 76% versus 57%, respectively (P = .026); 1-year disease-free survival (DFS) was 79% versus 38% (P < .001). In multivariate analysis, the only significantly favorable factor for OS and DFS was FluTreo (P = .010 and P = .012). The CI of relapse mortality was markedly decreased in FluTreo versus FluBuATG (7.4% versus 42.3%, P < .001). In conclusion, the treosulfan-based regimen resulted in favorable OS and DFS with acceptable toxicity and low relapse rates compared with busulfan-based conditioning.

Allogeneic Hematopoietic Cell Transplantation Using Treosulfan-Based Conditioning for Treatment of Marrow Failure Disorders

“…Although HCT using nonmyeloablative conditioning was effective at correcting the underlying hematologic, immunologic and clinical manifestations of GATA2 deficiency, the authors stated that they are currently investigating a more intensive conditioning regimen consisting of busulfan and fludarabine with the goal of decreasing the risk of rejection and relapse. Our results as well as other published studies using treosulfan-based conditioning for patients with MDS/AML support that treosulfan-based conditioning may be another viable option for patients with GATA2 deficiency [43–45]. …”

Transplant Conditioning with Treosulfan/Fludarabine with or without Total Body Irradiation: A Randomized Phase II Trial in Patients with Myelodysplastic Syndrome and Acute Myeloid Leukemia

“…Ruutu et al [33] showed a 17% incidence of NRM and a 71% OS at 2 years in MDS patients conditioned with treosulfan. Casper et al [14] observed an NRM of 11% and an OS of 61% in a mixed cohort of patients, and Sakellari et al [34] showed, in a retrospective analysis, a survival advantage for patients with AML or MDS conditioned with a fludarabine (150 to 180 mg/m 2 )/ treosulfan (42 g/m 2 ) regimen in comparison with patients conditioned with fludarabine (150 to 180 mg/m 2 )/busulfan (6.4 mg/kg i.v.) (OS 76% versus 57%; PFS 70% versus 38%, respectively [P < .001]) without an increase in toxicity.…”

Pharmacokinetics and Pharmacodynamics of Treosulfan in Patients With Thalassemia Major Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

“…A Treo‐based conditioning regimen for hematological malignant and nonmalignant diseases has proven to be beneficial in patients undergoing allogeneic HSCT, especially as an attractive alternative to a busulfan‐based regimen. Although the dose‐limiting toxicity and maximum tolerated dose of Treo have been documented, the PK and PD of Treo have not been extensively reported in the HSCT setting.…”