Feasibility of Allogeneic Hematopoietic Cell Transplantation Among High-Risk AML Patients in First Complete Remission: Results of the Transplant Objective from the SWOG (S1203) Randomized Phase III Study of Induction Therapy Using Standard 7+3 Therapy or Idarubicin with High-Dose Cytarabine (IA) Versus IA Plus Vorinostat

Abstract

Background: Adult acute myeloid leukemia (AML) patients with high-risk cytogenetics have a significantly worse survival compared to similarly treated intermediate- or favorable-risk patients. Although prior studies suggest better outcome in high-risk AML patients in first complete remission (CR1) who undergo allogeneic hematopoietic cell transplantation (HCT) compared with consolidation chemotherapy, only 40% of patients proceed to HCT. The lack of a matched sibling donor (available in about 33%) should not be a barrier to HCT since alternative donors are available for the large majority of high-risk AMLpatients and recent data suggest outcomes after allogeneic HCT from fully matched unrelated donors are similar to those following matched related donor transplantation. We sought to determine if a prospective organized effort could rapidly identify alternative donors to improve the historical 40% allogeneic HCT rate in high-risk CR1 AML patients ≤ age 61. Secondly, we hypothesized that transplanting significantly more adults with high-risk AML in CR1 would lead to an improved outcome compared with the historical relapse-free survival (RFS) of 22%. Patients and Methods: Adult patients between ages 18 and 60 years with untreated AML were randomized to receive induction therapy with standard cytarabine plus daunorubicin (7+3; n=261), idarubicin with high-dose cytarabine (IA; n=261), or IA with vorinostat (IA+V; n=216). Conventional cytogenetics were obtained at time of enrollment and used to determine risk classification by standard criteria. All patients with high-risk cytogenetics underwent expedited HLA-typing. High-risk patientswere encouraged tobe referred for consultation with a transplant team with the goal of conducting an allogeneic HCT in CR1. Results: Of 738 eligible patients (median age, 49 years; range, 18-60), 159 (22%) had high-risk cytogenetics, of whom 60 (38%), 61 (38%), and 38 (24%) received induction with 7+3, IA, or IA+V, respectively. A total of 107 of the 159 high-risk patients achieved CR/CRi (67%). HCT was performed in 317 of all 738 patients (43%) and 68 (64%) of the high-risk patients received a transplant in CR1 (p Conclusions: In newly diagnosed adults with AML age 18-60, early cytogenetic testing with an organized effort to identify a suitable allogeneic HCT donorled to a CR1 transplant rate of 64% in the high-risk group, which in turn led to a significant improvement in RFS over historical controls. Better outcomes in poor prognosis AML patients may be achieved simply by rapidly finding unrelated donors and performing allogeneic HCT in CR1 as soon as possible. Clinical Trials Registry: NCT #0180233; Support: NIH/NCI grants: CA180888, CA180819, CA18020, CA180821, CA180863, CA077202; CCSRI #021039 Disclosures Othus:Glycomimetics: Consultancy; Celgene: Consultancy. Radich:Novartis: Consultancy, Other: laboratory contract; ARIAD: Consultancy; Pfizer: Consultancy; TwinStrand: Consultancy; Bristol-MyersSquibb: Consultancy. Strickland:Alexion Pharmaceuticals: Consultancy; Ambit: Consultancy; Baxalta: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding; CTI Biopharma: Consultancy; Daiichi Sankyo: Consultancy; Sunesis Pharmaceuticals: Consultancy, Research Funding; Abbvie: Research Funding; Astellas Pharma: Research Funding; Celator: Research Funding; Cyclacel: Research Funding; GlaxoSmithKline: Research Funding; Karyopharm Therapeutica: Research Funding; Sanofi: Research Funding. Savoie:AbbVie: Consultancy; Lundbeck: Consultancy; BMS: Consultancy, Honoraria; Velgene: Consultancy; Pfizer: Consultancy; Amgen: Consultancy; Novartis: Consultancy, Honoraria; Jazz: Consultancy. Sekeres:Millenium/Takeda: Membership on an entity9s Board of Directors or advisory committees; Celgene: Membership on an entity9s Board of Directors or advisory committees. Stone:Amgen: Consultancy; Celgene: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Xenetic Biosciences: Consultancy; Jansen: Consultancy; Pfizer: Consultancy; ONO: Consultancy; Juno Therapeutics: Consultancy; Merck: Consultancy; Roche: Consultancy; Seattle Genetics: Consultancy; Sunesis Pharmaceuticals: Consultancy; Abbvie: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Agios: Consultancy; Novartis: Consultancy; Celator: Consultancy; Karyopharm: Consultancy. Erba:Seattle Genetics: Consultancy, Research Funding; Pfizer: Consultancy; Jannsen: Consultancy, Research Funding; Juno: Research Funding; Celator: Research Funding; Ariad: Consultancy; Agios: Research Funding; Amgen: Consultancy, Research Funding; Novartis: Consultancy, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Gylcomimetics: Other: DSMB; Sunesis: Consultancy; Daiichi Sankyo: Consultancy; Astellas: Research Funding.