Review Article The significance of major and stable molecular responses in chronic myeloid leukemia in the tyrosine kinase inhibitor era Ilana Zalcberg Renault1 Vanesa Scholl1 Rocio Hassan1 Paola Capelleti1 Marcos de Lima2 Jorge Cortes2 1Molecular Biology Laboratory, Bone Marrow Transplantation Center – CEMO, Instituto Nacional de Câncer – INCA, Rio de Janeiro, RJ, Brazil 2MD Anderson Cancer Center – MDACC, Houston, Texas, USA Conflict-of-interest disclosure: The authors declare no competing financial interest Submitted: 9/24/2011 Accepted: 9/29/2011 Corresponding author: Ilana Zalcberg Renault Molecular Biology Laboratory Bone Marrow Transplantation Center – CEMO Instituto Nacional de Câncer –INCA Praça Cruz Vermelha 23, 6º floor 20230-130 – Rio de Janeiro, RJ, Brazil Phone: 55 21 3207 1506 zalcberg@inca.gov.br www.rbhh.org or www.scielo.br/rbhh DOI: 10.5581/1516-8484.20110122 Tyrosine kinase inhibitors have changed the management and outcomes of chronic myeloid leukemia patients. Quantitative polymerase chain reaction is used to monitor molecular responses to tyrosine kinase inhibitors. Molecular monitoring represents the most sensitive tool to judge chronic myeloid leukemia disease course and allows early detection of relapse. Evidence of achieving molecular response is important for several reasons: 1. early molecular response is associated with major molecular response rates at 18-24 months; 2. patients achieving major molecular response are less likely to lose their complete cytogenetic response; 3. a durable, stable major molecular response is associated with increased progression-free survival. However, standardization of molecular techniques is still challenging. Keywords: Leukemia, myelogenous, chronic, BCR-ABL positive; Cytogenetic; Monitoring; Mutation; Polymerase chain reaction Introduction Chronic myeloid leukemia (CML) is most frequently diagnosed in the chronic phase (CP) and, if left untreated, the disease will progress to the accelerated phase (AP) and, eventually within 3-5 years, to the terminal blast phase (BP). CML is characterized by a reciprocal translocation between chromosomes 9 and 22, which creates the BCR-ABL fusion gene. Breakpoints in the ABL gene are often upstream of exon 2 (ABL a2 fusion type) and rarely downstream of exon 2 (ABL a3). Breakpoints in the BCR gene are more variable; the most frequent are downstream of either exon 13 or exon 14 (e13 and e14 previously referred to as exons b2 and b3), leading to e13a2 or e14a2 mRNA fusion subtypes, respectively. These isoforms are found in approximately 98% of CML patients and are referred to as the major BCR-ABL fusion subtype. Both BCR-ABL mRNA molecules encode a 210 KDa constitutively active kinase protein, which is essential for leukemic transformation in CML. Most BCR-ABL breakpoints in CML patients are accounted by a variety of fusions, which involve BCR exons 6, 8 or 19 (e6a2, e8a2 or e19a2) and ABL exon 3 (e13a3 or e14a3), which encodes the p210 KDa protein. Less than 1% of CML show a breakpoint downstream of BCR exon 1 (e1a2) resulting in an mRNA fusion encoding the p190 KDa oncoprotein.(1) International Randomized Study of Interferon and STI571 (IRIS) trial and European Leukemia Net criteria to monitor response in chronic myeloid leukemia CML treatment was revolutionized by the advent of imatinib mesylate (IM), a tyrosine kinase inhibitor (TKI).(2) IM has become the treatment of choice for newly diagnosed patients in CP-CML based on the results of the International Randomized Study of Interferon and STI571 (IRIS) trial and confirmed by the recent 8-year update.(3,4) However, whilst the vast majority of newly diagnosed CP-CML patients in the IRIS trial treated with IM have a sustained benefit at 8 years, many patients do not reach what is considered an optimal response. Approximately 35% of CML patients initially treated with IM fail due to refractoriness (primary resistance), loss of response after an initial response (secondary resistance), or intolerance.(5) In addition, 12-33% of patients meet criteria for suboptimal response at any given time.(6) Unless the disease can be controlled with further therapy, these individuals invariably progress to the blastic phase that is usually terminal. With the aim of improving the results of IM therapy, second-generation TKIs, Dasatinib and Nilotinib, have been introduced to treat patients with IM resistance Rev Bras Hematol Hemoter. 2011;33(6):455-60 455