title: Significance of deeper molecular responses in patients with chronic myeloid leukemia in early chronic phase treated with tyrosine kinase inhibitors.
abstract: Most patients with chronic myeloid leukemia (CML) in chronic phase (CP) treated with tyrosine kinase inhibitors (TKI) achieve complete cytogenetic response (CCyR). An increasing number of patients also achieve deep molecular responses (MR). We determined the frequency and significance of deep MR after TKI therapy for CML in CP. MR included: major molecular response (MMR), MR4, MR4.5, and undetectable transcripts (UND), i.e., BCR-ABL/ABL of ≤0.1, ≤0.01, ≤0.0032%, and undetectable transcripts, respectively. Four hundred eighty-three patients received imatinib 400 mg/day (IM400, 71, July 2000 to April 2001), imatinib 800 mg/day (IM800, 204, June 2001 to July 2005), nilotinib (106, July 2005 to date), or dasatinib (102, November 2005 to date). UND rates at 36 months were 18.1, 30.6, 29.2, and 28.6%, respectively. Patients achieving UND have superior transformation-free survival (TFS) and overall survival (OS) versus those obtaining ≤MMR, but not other MR levels. At the 18- and 24-month landmark analysis, patients achieving UND have no advantage in TFS and OS compared to those achieving a lesser degree of MR. Among patients achieving MR4.5, those who maintain it for ≥2 years (susMR4·5) have no additional benefit in TFS or OS. Most patients with early CP CML receiving TKI achieve MMR. BCR-ABL transcripts become undetectable in a significant fraction of them. Deeper MR at 18 or 24 months are not associated with a benefit in TFS or OS. Furthermore, achieving susMR4·5 does not appear to further reduce the risk of transformation or death.
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Falchi
authors.forename: Hagop M
authors.initials: HM
authors.lastname: Kantarjian
authors.forename: Xuemei
authors.initials: X
authors.lastname: Wang
authors.forename: Dushyant
authors.initials: D
authors.lastname: Verma
authors.forename: Alfonso
authors.initials: A
authors.lastname: Quintás-Cardama
authors.forename: Susan
authors.initials: S
authors.lastname: O'Brien
authors.forename: Elias J
authors.initials: EJ
authors.lastname: Jabbour
authors.forename: Farhad
authors.initials: F
authors.lastname: Ravandi-Kashani
authors.forename: Gautam
authors.initials: G
authors.lastname: Borthakur
authors.forename: Guillermo
authors.initials: G
authors.lastname: Garcia-Manero
authors.forename: Srdan
authors.initials: S
authors.lastname: Verstovsek
authors.forename: Jan A
authors.initials: JA
authors.lastname: Burger
authors.forename: Raja
authors.initials: R
authors.lastname: Luthra
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Cortes
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use; D014408:Biomarkers, Tumor; D000069439:Dasatinib; D018572:Disease-Free Survival; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000097:blood / Q000235:genetics; D006801:Humans; D000068877:Imatinib Mesylate; D015466:Leukemia, Myeloid, Chronic-Phase / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000097:blood / Q000235:genetics; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D012333:RNA, Messenger / Q000097:blood; D012334:RNA, Neoplasm / Q000097:blood; D060888:Real-Time Polymerase Chain Reaction; D016019:Survival Analysis; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; C581634:BCR-ABL1 fusion protein, human; D001549:Benzamides; D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D013844:Thiazoles; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; C498826:nilotinib; D000069439:Dasatinib
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