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17-11-2015 | Hematologic cancers | Article

Allogeneic transplantation for CML in the TKI era: striking the right balance

Authors: Andrew J. Innes, Dragana Milojkovic, Jane F. Apperley

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Abstract

The management of chronic myeloid leukaemia (CML) has changed extensively over the past 15 years. Prior to the development of targeted therapies and in the absence of allogeneic haematopoetic stem-cell transplantation (HSCT), the median survival was 5–7 years. HSCT was quickly established as the standard of care for eligible patients through the 1980s and 1990s, when considerable advances were made in the optimization of conditioning regimens and supportive care. Exploiting a deeper understanding of the molecular basis of CML, the development of tyrosine kinase inhibitors (TKIs) in the late 1990s revolutionized the management of the disease. TKIs offer the prospect of long-term disease control with a simple oral therapy, and are the first-line treatment in the 21st century. The majority of patients treated with TKIs achieve excellent responses with sustained treatment, and some even continue to have undetectable or exceptionally low level disease upon TKI withdrawal; however, for an almost equal number of patients, an adequate response cannot be achieved with any of the currently available TKIs. For those patients who fail to respond adequately to TKIs, HSCT offers the best prospect of long-term survival.

Nat Rev Clin Oncol 2016; 13: 79û91. doi:10.1038/nrclinonc.2015.193

Subject terms: Chemotherapy • Chronic myeloid leukaemia • Targeted therapies • Transplantation

Chronic myeloid leukaemia (CML) is a clonal haematopoetic stem-cell disorder that is characterized by the presence of the oncogenic BCR–ABL1 gene fusion. The reciprocal translocation of the long arms of chromosome 9 and chromosome 22 was named the 'Philadelphia chromosome' following its place of discovery in the early 1960s1. The translocation positions ABL1 next to the breakpoint cluster region (BCR) gene and, depending on the exact breakpoint location, the fused BCR–ABL1 oncogene is translated into a protein of 185–210 kDa; there are three clinically important variants of this protein, p190, p210 and p230, with the p210 variant being typical of CML2, 3. The mutant Bcr–Abl1 protein is a dysregulated non-receptor tyrosine kinase that phosphorylates a variety of substrate proteins, resulting in loss of cell-cycle control with consequential increased proliferation, loss of stromal adhesion and resistance to apoptosis.

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