title: Nilotinib combined with multiagent chemotherapy for newly diagnosed Philadelphia-positive acute lymphoblastic leukemia.
abstract: We investigated the effects of nilotinib plus multiagent chemotherapy, followed by consolidation/maintenance or allogeneic hematopoietic cell transplantation (allo-HCT) for adult patients with newly diagnosed Philadelphia-positive (Ph-pos) acute lymphoblastic leukemia (ALL). Study subjects received induction treatment that comprised concurrent vincristine, daunorubicin, prednisolone, and nilotinib. After achieving complete hematologic remission (HCR), subjects received either 5 courses of consolidation, followed by 2-year maintenance with nilotinib, or allo-HCT. Minimal residual disease (MRD) was assessed at HCR, and every 3 months thereafter. The molecular responses (MRs) were defined as MR3 for BCR-ABL1/G6PDH ratios ≤10(-3) and MR5 for ratios <10(-5). Ninety evaluable subjects, ages 17 to 71 years, were enrolled in 17 centers. The HCR rate was 91%; 57 subjects received allo-HCT. The cumulative MR5 rate was 94%; the 2-year hematologic relapse-free survival (HRFS) rate was 72% for 82 subjects that achieved HCR, and the 2-year overall survival rate was 72%. Subjects that failed to achieve MR3 or MR5 were 9.1 times (P = .004) or 6.3 times (P = .001) more prone to hematologic relapse, respectively, than those that achieved MR3 or MR5. MRD statuses just before allo-HCT and at 3 months after allo-HCT were predictive of 2-year HRFS. Adverse events occurred mainly during induction, and most were reversible with dose reduction or transient interruption of nilotinib. The combination of nilotinib with high-dose cytotoxic drugs was feasible, and it effectively achieved high cumulative complete molecular remission and HRFS rates. The MRD status at early postremission time was predictive of the HRFS. This trial was registered at www.clinicaltrials.gov as #NCT00844298.
authors.affiliation: Department of Hematology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea;
authors.forename: Dae-Young
authors.identifier: http://orcid.org/0000-0002-2894-0462
authors.initials: DY
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Haeundae Paik Hospital, College of Medicine Inje University, Busan, Korea;
authors.forename: Young-Don
authors.initials: YD
authors.lastname: Joo
authors.affiliation: Department of Internal Medicine, Haeundae Paik Hospital, College of Medicine Inje University, Busan, Korea;
authors.forename: Sung-Nam
authors.initials: SN
authors.lastname: Lim
authors.affiliation: Department of Hematology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea;
authors.forename: Sung-Doo
authors.initials: SD
authors.lastname: Kim
authors.affiliation: Department of Hematology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea;
authors.forename: Jung-Hee
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Hematology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea;
authors.forename: Je-Hwan
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea;
authors.forename: Dong Hwan Dennis
authors.initials: DH
authors.lastname: Kim
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea;
authors.forename: Kihyun
authors.initials: K
authors.lastname: Kim
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea;
authors.forename: Chul Won
authors.initials: CW
authors.lastname: Jung
authors.affiliation: Division of Hematology-Medical Oncology, Department of Internal Medicine, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea;
authors.forename: Inho
authors.initials: I
authors.lastname: Kim
authors.affiliation: Division of Hematology-Medical Oncology, Department of Internal Medicine, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea;
authors.forename: Sung-Soo
authors.initials: SS
authors.lastname: Yoon
authors.affiliation: Division of Hematology-Medical Oncology, Department of Internal Medicine, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea;
authors.forename: Seonyang
authors.initials: S
authors.lastname: Park
authors.affiliation: Department of Hematology and Oncology, Chonnam National University Hwasun Hospital, Jeollanam-do, Korea;
authors.forename: Jae-Sook
authors.initials: JS
authors.lastname: Ahn
authors.affiliation: Department of Hematology and Oncology, Chonnam National University Hwasun Hospital, Jeollanam-do, Korea;
authors.forename: Deok-Hwan
authors.initials: DH
authors.lastname: Yang
authors.affiliation: Department of Hematology and Oncology, Chonnam National University Hwasun Hospital, Jeollanam-do, Korea;
authors.forename: Je-Jung
authors.initials: JJ
authors.lastname: Lee
authors.affiliation: Division of Hematology/Oncology, Department of Internal Medicine, Kosin University College of Medicine, Kosin University Gospel Hospital, Busan, Korea;
authors.forename: Ho-Sup
authors.initials: HS
authors.lastname: Lee
authors.affiliation: Division of Hematology/Oncology, Department of Internal Medicine, Kosin University College of Medicine, Kosin University Gospel Hospital, Busan, Korea;
authors.forename: Yang Soo
authors.initials: YS
authors.lastname: Kim
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, Ewha Womans University School of Medicine, Seoul, Korea;
authors.forename: Yeung-Chul
authors.initials: YC
authors.lastname: Mun
authors.affiliation: Division of Hematology and Cellular Therapy, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea;
authors.forename: Hawk
authors.initials: H
authors.lastname: Kim
authors.affiliation: Division of Hematology and Cellular Therapy, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea;
authors.forename: Jae Hoo
authors.initials: JH
authors.lastname: Park
authors.affiliation: Department of Hematology/Oncology, Kyungpook National University Hospital, Daegu, Korea;
authors.forename: Joon Ho
authors.initials: JH
authors.lastname: Moon
authors.affiliation: Department of Hematology/Oncology, Kyungpook National University Hospital, Daegu, Korea;
authors.forename: Sang Kyun
authors.initials: SK
authors.lastname: Sohn
authors.affiliation: Department of Hemato-Oncology, Inje University Busan Paik Hospital, Busan, Korea;
authors.forename: Sang Min
authors.initials: SM
authors.lastname: Lee
authors.affiliation: Department of Hemato-Oncology, Inje University Busan Paik Hospital, Busan, Korea;
authors.forename: Won Sik
authors.initials: WS
authors.lastname: Lee
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, Soonchunhyang University Hospital, Soonchunhyang University College of Medicine, Seoul, Korea;
authors.forename: Kyoung Ha
authors.initials: KH
authors.lastname: Kim
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, Soonchunhyang University Hospital, Soonchunhyang University College of Medicine, Seoul, Korea;
authors.forename: Jong-Ho
authors.initials: JH
authors.lastname: Won
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea;
authors.forename: Myung Soo
authors.initials: MS
authors.lastname: Hyun
authors.affiliation: Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Korea;
authors.forename: Jinny
authors.initials: J
authors.lastname: Park
authors.affiliation: Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Korea;
authors.forename: Jae Hoon
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Hematology-Oncology, School of Medicine, Pusan National University Hospital Medical Research Institute, Busan, Korea;
authors.forename: Ho-Jin
authors.initials: HJ
authors.lastname: Shin
authors.affiliation: Department of Hematology-Oncology, School of Medicine, Pusan National University Hospital Medical Research Institute, Busan, Korea;
authors.forename: Joo-Seop
authors.initials: JS
authors.lastname: Chung
authors.affiliation: Hematologic Oncology Clinic, Center for Specific Organs Center, National Cancer Center, Goyang, Korea;
authors.forename: Hyewon
authors.initials: H
authors.lastname: Lee
authors.affiliation: Hematologic Oncology Clinic, Center for Specific Organs Center, National Cancer Center, Goyang, Korea;
authors.forename: Hyeon-Seok
authors.initials: HS
authors.lastname: Eom
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, Gyeongsang National University Hospital, Gyeongsang National University School of Medicine, Jinju, Korea; and.
authors.forename: Gyeong Won
authors.initials: GW
authors.lastname: Lee
authors.affiliation: Department of Laboratory Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Young-Uk
authors.initials: YU
authors.lastname: Cho
authors.affiliation: Department of Laboratory Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Seongsoo
authors.initials: S
authors.lastname: Jang
authors.affiliation: Department of Laboratory Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Chan-Jeoung
authors.initials: CJ
authors.lastname: Park
authors.affiliation: Department of Laboratory Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Hyun-Sook
authors.initials: HS
authors.lastname: Chi
authors.affiliation: Department of Hematology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea;
authors.forename: Kyoo-Hyung
authors.initials: KH
authors.lastname: Lee
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D003630:Daunorubicin / Q000008:administration & dosage; D004334:Drug Administration Schedule; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D018365:Neoplasm, Residual; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D011239:Prednisolone / Q000008:administration & dosage; D011446:Prospective Studies; D011743:Pyrimidines / Q000008:administration & dosage*; D012008:Recurrence; D012074:Remission Induction; D016019:Survival Analysis; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D014750:Vincristine / Q000008:administration & dosage
chemical_list: D011743:Pyrimidines; D014750:Vincristine; D011239:Prednisolone; C498826:nilotinib; D003630:Daunorubicin