Sequential therapy or patients with primary refractory acute myeloid leukemia: a historical prospective analysis of the German and Israeli experience

Primary refractory acute myeloid leukemia (AML) is associated with a dismal prognosis. The FLAMSA-reduced intensity conditioning protocol (total body irradiation or treosulfan-based) has been described as an effective approach in patients with refractory leukemia undergoing allogeneic hematopoietic cell transplantation. A modified protocol (without amsacrine) has also recently been used. We retrospectively analyzed the transplantation characteristics and outcomes of all consecutive patients between the years 2003 and 2017 (n=51) diagnosed with primary refractory AML who underwent transplantation at the University of Cologne and the Tel Aviv Medical Center. Median age was 54 years and median follow up was 37 months. Median time to neutrophil and platelet engraftment was 13 (range, 8-19) and 13 (range, 7-30) days, respectively. None of the patients had primary graft failure. Incidences of grade 2-4 and grade 3-4 acute graft-versus-host disease (GvHD), overall and moderate-severe chronic GvHD were 50% (95%CI: 41-67%), 12% (95%CI: 3-25%), 61% (95%CI: 47-72%), and 42% (95%CI: 34-51%), respectively. Anti-thymocyte globulin administration was associated with lower incidence of acute GvHD (FIR: 0.327; P=0.02). Non-relapse mortality at three months and three years were 6% and 16%, respectively. Relapse incidences were 6% and 29%, respectively. Overall survival rates at three months, three and five years were 90%, 61%, and 53%, respectively. Chronic GvHD disease was associated with a decreased mortality rate (HR 0.397; P=0.045). We conclude that sequential therapy in patients with primary refractory acute myeloid leukemia is safe and provides a remarkable anti-leukemic effect with durable survival and should be considered for every patient with primary refractory disease.