Sequential Induction Chemotherapy, and Early Intensified Conditioning for Allogeneic Hematopoietic Stem Cell Transplantation in Patients with High-Risk Myeloid Leukemia.

PURPOSE: To improve the outcome of allogeneic stem-cell transplantation by sequential use of an intensive induction chemotherapy, and early intensified conditioning in refractory and high-risk acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and blast transformation of a myeloproliferative disorder (MPD).

PATIENTS AND METHODS: In this prospective study 38 patients with AML/MDS and 12 patients with blast transformation of a MPD were included between June 2003 and February 2006. There were 35 male and 15 female patients with a median age of 49.8 years (range: 16.6–64.8). High risk was defined by progressive (7) or refractory (18) disease, early relapse (14), or high risk karyotype (11). Among all patients an unfavorable karyotype was found in 58% of informative patients. The mean marrow blast count at the start of induction chemotherapy was 21.5% (range: 0%–96%). Patients received a 4 day regimen of fludarabine (30mg/m2/d) and high-dose cytarabine (2g/m2/d), which was combined with amsacrine (100mg/m2/d) in 42 cases (84%). After 3 days of ATG (10–20mg/kg/d), high-dose melphalan (100–150mg/m2) with (68%) or without (30%) thiotepa (10mg/m2) was used for conditioning. In one case of a lymphatic blast crisis of a CML, 12 Gy TBI were given instead of Mel/Thio. All patients received tacrolimus and MMF for GvHD prophylaxis. Following transplantation of a median of 7,1×10E6 CD34+ cells/kg (range 0.85–17.2) from related (13) or unrelated (37) donors, the median time to a wbc >1000/μl and plt >20000/μl was 15 days (range 8–24) and 15 days (range 7–30), respectively.

RESULTS: With a medium follow up of 335 days (range: 130–1292), 22 patients (44%) are alive. At day +30, two patients had died in aplasia, 45 patients were in CR, and 3 had persisting leukemia. One of them achieved a CR after immediate discontinuation of immunosuppression. One-year overall and leukemia-free survival were 50% and 43%, respectively. Among this very high risk patients the outcome of patients with refractory disease or with complex cytogenetic aberrations was identical to that of better prognostic subgroups. Survival was best in patients who developed grade I–II acute GvHD (p< .0001). The 1-year relapse rate and treatment related mortality were 29% and 35%, respectively. Acute and chronic GvHD were associated with a lower RR. In all, 18 patients (36%) died due to TRM, conspicuously 17 of them had received the combination of melphalan and thiotepa. The 1-year TRM was 47% in the Mel/Thio group and 7% in the Mel-only group (p = .007). The exclusive use of high dose melphalan conditioning resulted in a 1-year OS of 67%.

CONCLUSION: The combination of intensive induction chemotherapy and early high dose conditionig during aplasia is feasible and represents a promising approach to the treatment of high-risk myeloid leukemia. The addition of HD-Thiotepa to HD-Melphalan resulted in increased TRM and should be avoided.