A Regimen of Treosulfan and Fludarabine Followed by Allogeneic Hematopoietic Cell Transplantation (HCT) for High-Risk Hematologic Malignancies Is Associated with Low Treatment-Related Mortality

Allogeneic HCT has the potential of curing high-risk hematologic malignancies, but intensive preparative regimens are associated with a significant risk of regimen-related toxicity and transplant-related mortality (TRM). Treosulfan is an alklyating agent with predictable inter- and intra-patient pharmacokinetics after IV administration. We conducted a dose optimization study of treosulfan in combination with fludarabine as conditioning regimen for allogeneic HCT in patients with acute myeloid (AML) or lymphoblastic leukemia (ALL) or myelodysplastic syndrome (MDS). The optimal treosulfan dose was determined by the incidence of severe/fatal regimen-related toxicity, graft failure and TRM. Sixty patients, 5–60 (median 46) years of age, with AML in first remission (n=26), AML in second remission (n=9), AML in relapse (n=9), ALL in second remission (n=3) or advanced MDS (n=13) were treated. Disease classification by CIBMTR risk categories was standard (n=26), intermediate (n=12) and advanced (n=22), with 63% of patients considered at high risk for relapse due to disease beyond first remission, treatment-induced malignancies or history of previous HCT. The majority of patients were considered at high risk for TRM with conventional transplant regimens for several reasons including: secondary (treatment-related) malignancy (n=12), previous HCT (n=8) or comorbid conditions. Comorbidity index (HCT-CI) was 0–7 (median 2); 50% of patients in first remission and 44% of patients in second remission or with more advanced disease had scores of 3 or higher. Patients received treosulfan at a dose of 12 g/m2/day (first 5 patients) or 14 g/m2/day (n=55) on days −6 to −4, and fludarabine (30 mg/kg/day) on days −6 to −2. Graft-versus-host disease (GVHD) prophylaxis was with tacrolimus (n=58) or cyclosporine (n=2) combined with methotrexate. Stem cell source was either from an HLA-matched sibling (n=30) or matched unrelated donor (n=30), and included bone marrow (n=7) or filgrastim-mobilized peripheral blood stem cells (n=53) on day 0. All evaluable patients engrafted, with a neutrophil count ≥500 reached by 5–30 (median 18) days. Acute GVHD occurred in 34 of 55 evaluable patients (CIBMTR grade A in 9 patients, grade B in 22, and grade C in 3 patients). Chronic GVHD occurred in 22 of 54 patients surviving beyond day 80 (limited in 12 and extensive in 10 patients). Dose limiting toxicity was observed in 2 patients (mucositis requiring intubation and acute renal failure, respectively). Forty-three patients are alive, with a follow-up of 2–32 (median 13) months. Day–100 mortality was 10%. Estimated one-year overall and disease-free survival, relapse and TRM were 69%, 61%, 34% and 8%, respectively. Event-free survival for patients considered at high risk for relapse was significantly lower than for the remaining patients (44% vs. 81%; HR= 0.27, 95% CI 0.15–0.78, p=0.01). There was no significant difference in TRM across groups defined by disease category. The following table summarizes outcomes by CIBMTR disease risk categories and comorbidity index:

In summary, treosulfan plus fludarabine is a well-tolerated regimen with promising disease control and low rates of toxicity and TRM in high-risk patients with acute leukemia and MDS. Further studies of this regimen in more homogeneous cohorts of patients are warranted.