treosulfan
Regulatory sources consulted
Approved indications
- Conditioning before allogeneic hematopoietic stem-cell transplantation in adults and pediatric patients older than one month, in combination with fludarabine.
Contraindications
Absolute
- Hypersensitivity; uncontrolled active infection; concomitant severe renal, hepatic, pulmonary, and cardiac failure.
- Fanconi anemia or other DNA-repair disorders; pregnancy; live vaccines.
Clinical warnings
- Profound myelosuppression is expected and must be followed by HSCT, anti-infective prophylaxis, and hematologic support. — CIMA/AEMPS, ficha técnica 1181351003
- Monitor infections, seizures, skin exposure, extravasation, organ toxicity, and secondary malignancy. — CIMA/AEMPS, ficha técnica 1181351003
Drug interactions
- HighNarrow-therapeutic-index CYP3A4 or CYP2C19 substrates, including tacrolimus
Mechanism: Treosulfan may alter their exposure during conditioning.
Recommendation: Avoid them during treatment when possible or monitor concentrations and toxicity.
CIMA/AEMPS, ficha técnica 1181351003
Adverse events
Common (≥1%)
Myelosuppression, nausea, vomiting, mucositis, and fatigue
Pregnancy and lactation
Contraindicated during pregnancy. Use contraception in both sexes during treatment and for 6 months afterward; do not breastfeed during treatment.
Recent literature (PubMed)
Allogeneic hematopoietic stem-cell transplantation (HCT) remains the only potentially curative therapy for patients with myelodysplastic neoplasms (MDS) and myelofibrosis (MF) and is the standard care for eligible patients with higher-risk disease. Despite significant advancements, both diseases pose unique challenges due to their clinical and molecular heterogeneity, necessitating personalized approaches to patient selection, timing, and transplant management. For MDS, genomic profiling has revolutionized prognostic frameworks such as IPSS-M, enabling tailored therapeutic decisions. In MF, driver mutations (e.g., JAK2, CALR, MPL) and additional high-risk molecular markers provide critical insights into disease biology and transplant outcomes. Optimal timing of HCT is critical, and recent models might help personalize treatment approaches. Molecular measurable residual disease monitoring has demonstrated prognostic value in both diseases, guiding preemptive strategies to mitigate relapse risk. Harnessing molecular technologies, clinical expertise, patient-centered decision-making, and innovative pharmaceutical strategies offers an exciting opportunity to shape a transformative and curative treatment framework. Here, we provide a contemporary review on HCT for MDS and MF, highlighting up-to-date insights into disease biology, standard of care, and recommendations, as well as open avenues.
The phase III study was designed to compare event-free survival (EFS) after treosulfan-based conditioning with a widely applied reduced-intensity conditioning (RIC) busulfan regimen in older or comorbid patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) undergoing allogeneic hematopoietic cell transplantation (HCT). A previously reported confirmatory interim analysis of the randomized clinical study including 476 patients demonstrated statistically significant noninferiority for treosulfan with clinically meaningful improvement in EFS. Here, the final study results and pre-specified subgroup analyses of all 570 randomized patients with completed longer-term follow-up are presented. Patients presenting HCT-specific comorbidity index >2 or aged ≥50 years were randomly assigned (1:1) to intravenous (IV) fludarabine with either treosulfan (30 g/m2 IV) or busulfan (6.4 mg/kg IV) after stratification by disease risk group, donor type, and participating institution. The primary endpoint was EFS with disease recurrence, graft failure, or death from any cause as events. EFS of patients (median age 60 years) was superior after treosulfan compared to RIC busulfan: 36-months-EFS rate 59.5% (95% CI, 52.2-66.1) vs. 49.7% (95% CI, 43.3-55.7) with a hazard ratio (HR) of 0.64 (95% CI, 0.49-0.84), p = 0.0006. Likewise, overall survival (OS) with treosulfan was superior compared to busulfan: 36-month-OS rate 66.8% vs. 56.3%; HR 0.64 (95% CI, 0.48-0.87), p = 0.0037. Post hoc analyses revealed that these differences were consistent with the confirmatory interim analysis, and thereby the treosulfan regimen appears particularly suitable for older AML and MDS patients.
A randomized study (acronym: MC-FludT.14/L Trial II) demonstrated that fludarabine plus treosulfan (30 g/m²) was an effective and well tolerated conditioning regimen for allogeneic hematopoietic cell transplantation (allo-HCT) in older patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). To further evaluate this regimen, all 252 study patients aged 50 to 70 years were compared with similar patients, who underwent allo-HCT after fludarabine/melphalan (140 mg/m²) (FluMel) or busulfan (12.8 mg/kg)/cyclophosphamide (120 mg/kg) (BuCy) regimens and whose data was provided by the European Society for Blood and Marrow Transplantation registry. In 1:1 propensity-score matched-paired analysis (PSA) of AML patients, there was no difference in 2-year-relapse-incidence after FluTreo compared with either FluMel (n = 110, p = 0.28) or BuCy (n = 78, p = 0.98). However, 2-year-non-relapse-mortality (NRM) was lower compared with FluMel (p = 0.019) and BuCy (p < 0.001). Consequently, 2-year-overall-survival (OS) after FluTreo was higher compared with FluMel (p = 0.04) and BuCy (p < 0.001). For MDS patients, no endpoint differences between FluTreo and FluMel (n = 30) were evident, whereas 2-year-OS after FluTreo was higher compared with BuCy (n = 25, p = 0.01) due to lower 2-year-NRM. Multivariate sensitivity analysis confirmed all significant results of PSA. Consequently, FluTreo (30 g/m²) seems to retain efficacy compared with FluMel and BuCy, but is better tolerated by older patients.
Chronic myelomonocytic leukemia (CMML) is a rare hematologic malignancy at the intersection of myelodysplastic (MDS) and myeloproliferative neoplasms, predominantly affecting older adults. Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only curative option, yet its application is limited by the advanced age and comorbidities of most patients. Recent classification updates and refined prognostic tools, particularly molecularly integrated models like CPSS-Mol have enhanced patient stratification and informed transplant timing. The aim of this review is to highlight the evolving landscape of CMML management, with a focus on the role of allo-HCT. Novel studies patients demonstrated that individualized transplant timing significantly improved life expectancy. Optimizing transplant outcomes hinges on several factors:managing pretransplant splenomegaly, choosing appropriate debulking strategies, selecting optimal donors, and tailoring conditioning regimens. New data favor treosulfan-based and thiotepa-busulfan regimens for their favorable toxicity and relapse profiles. Post-transplant, strategies like post-transplant cyclophosphamide (PTCy) for GVHD prophylaxis and emerging approaches to minimal residual disease (MRD) monitoring offer additional refinements in patient management. While no MRD studies are CMML-specific, extrapolation from MDS supports its role in relapse prediction. Innovative therapies, including hypomethylating agent combinations, venetoclax, targeted inhibitors, and immunotherapies are under active investigation, with potential to improve pre- and post-transplant outcomes. Advancements in molecular classification, dynamic prognostic tools, and therapeutic strategies are reshaping the CMML treatment paradigm. Personalized approaches that integrate genetic risk, patient fitness, and disease characteristics are enabling more effective transplant strategies, with the ultimate goal of extending survival and improving quality of life in t