Autologous Blood Stem Cell Transplantation Results In Better Relapse-Free Survival Than Consolidation Chemotherapy: Results of a HOVON/SAKK Phase III Trial In 519 AML Patients In First Complete Remission
Authors: Vellenga Edo , van Putten Wim , Ossenkoppele Gert J. , Fey Martin , Kuball Jurgen , Theobald Matthias , Cornelissen Jan J. , Huijgens Peter , Maertens Johan , Gratwohl Alois , Schaafsma Martyn Ronald , Manz Markus G , Graux Carlos , Lowenberg Bob 
Published: October 2019

Abstract
Abstract 367
Autologous bone marrow transplantation as post remission treatment in patients with acute myeloid leukemia (AML) has been associated with reduced relapse rates as compared to postremission chemotherapy but this advantage was offset by delayed hematopoietic recovery, excess mortality, and frequent premature withdrawals from planned transplantation. Autologous stem cell transplantation (ASCT) following myeloablative chemotherapy has regained interest when peripheral blood stem cells became available because many of the disadvantages of marrow grafts could be circumvented by the use of peripheral blood transplants. However, the clinical benefit of ASCT in comparison to consolidation chemotherapy has not been critically assessed in large prospective cohorts of patients with long term follow up. To define the optimal postremission strategy, AML patients up to 60 yrs in complete remission after two cycles of intensive chemotherapy according to the HOVON 29 or HOVON 42 protocol (NEJM 2003;349:743) and not eligible for allogeneic SCT were randomly assigned to a third cycle of chemotherapy with etoposide (100 mg/m2 days 1–5) and mitoxantrone (10 mg/m2 days 1–5) vs. ASCT with busulfan (4 mg/kg days 1–4) and cyclofosfamide (60 mg/kg days 5–6) as conditioning regimen followed by reinfusion of G-CSF mobilized peripheral blood stem cells. 261 patients were assigned to the third course of consolidation chemotherapy and 258 patients were assigned to ASCT. At least 90% of the patients received the planned treatment arm. The two groups were evenly matched with respect to various factors, including age and cytogenetic risk (intermediate risk group: 82% of chemotherapy arm and 79% of ASCT-arm). Median follow up of patients alive is more than 8 years. A significantly faster recovery of peripheral blood granulocyte and platelet count was seen following ASCT (ANC >0.5 109/l at day +14 and +28 was demonstrated in 42% vs. 1% and 88% vs. 32% of patients in the ASCT vs. chemotherapy arm respectively (p= .000). Comparable results were obtained for platelet recovery. Non-relapse mortality was estimated 4% in the ASCT arm and 1% in the chemotherapy arm. The ASCT treatment arm showed a better relapse free survival (RFS) at five years than the chemotherapy arm (39% vs. 29%, p= 0.055, HR 0.82 (0.66-1.1). In the ASCT arm 151 patients had recurrence of AML, while 186 patients relapsed in the chemotherapy arm, corresponding with actuarial relapse rate of 57% and 70% respectively. Overall survival (OS) was not different between both arms (44% vs. 40% at 5 years, p=0.9) due to a greater number of patients of the chemotherapy arm receiving salvage therapy by allogeneic SCT (25% vs. 17% of relapsed patients in the ASCT arm) or salvage by ASCT (15% vs. 1%). The relapsed patients that were given SCT salvage reached a 5 year survival of 30% against only 3% for the patients without SCT salvage. It resulted in 5 year survival probabilities after relapse of 15% in the chemotherapy arm versus 7% in the ASCT arm. Collectively, the findings from this large and mature randomized study demonstrate an advantage of consolidation by ASCT as compared to chemotherapy for AML patients in first complete remission both in terms of RFS and hematopoietic regeneration. No difference in OS was observed, possibly due to better salvage options in case of relapse after chemotherapy.

Disclosures:
Ossenkoppele: Bristol-Myers Squibb: Honoraria, Participated in advisory boards; Novartis: Particpated in advisory boards, Research Funding.