Conditioning with treosulfan and fludarabine followed by allogeneic hematopoietic cell transplantation for high-risk hematologic malignancies

Abstract

In this prospective study 60 patients of median age 46 (range: 5-60 years), with acute myelogenous leukemia (AML; n = 44), acute lymphoblastic leukemia (ALL; n = 3), or myelodysplastic syndrome (MDS; n = 13) were conditioned for allogeneic hematopoietic cell transplantation with a treosulfan/fludarabine (Flu) combination. Most patients were considered at high risk for relapse or nonrelapse mortality (NRM). Patients received intravenous treosulfan, 12 g/m(2)/day (n = 5) or 14 g/m(2)/day (n = 55) on days -6 to -4, and Flu (30 mg/m(2)/day) on days -6 to -2, followed by infusion of marrow (n = 7) or peripheral blood stem cells (n = 53) from HLA-identical siblings (n = 30) or unrelated donors (n = 30). All patients engrafted. NRM was 5% at day 100, and 8% at 2 years. With a median follow-up of 22 months, the 2-year relapse-free survival (RFS) for all patients was 58% and 88% for patients without high-risk cytogenetics. The 2-year cumulative incidence of relapse was 33% (15% for patients with MDS, 34% for AML in first remission, 50% for AML or ALL beyond first remission and 63% for AML in refractory relapse). Thus, a treosulfan/Flu regimen was well tolerated and yielded encouraging survival and disease control with minimal NRM. Further trials are warranted to compare treosulfan/Flu to other widely used regimens, and to study the impact of using this regimen in more narrowly defined groups of patients.

Figure 1. Non-relapse mortality

Estimates (solid line) and 95% confidence intervals (dotted lines) are shown.

Figure 2. Overall and relapse-free survival

Estimates of overall survival (left) and relapse-free survival (right) and 95% confidence intervals (dotted lines) for all patients.

Figure 3. Relapse-free survival by disease risk (A) and cytogenetic risk (B)

(A) Disease risk was classified using CIBMTR criteria. Low risk: ALL or AML in first remission or MDS-RA; standard risk: AML or ALL in second or greater remission; High risk: relapsed or primary refractory ALL or AML, RAEB and RAEBT. (B) Cytogenetic abnormalities were classified as favorable if t(8;21), t(15;17) or inversion 16 for AML or hyperdiploidy for ALL were present; high risk included 11q23 abnormalities, monosomy 7, monosomy 5, deletion 5q or abnormalities of 3q, t(9;22), extreme hypodiploid for ALL or complex abnormalities (≥ 3 chromosomes); intermediate risk included all other abnormalities.

Figure 4. Cumulative incidence of relapse by diagnosis and disease status at transplantation