Treatment of blast phase chronic myeloid leukaemia: A rare and challenging entity

Abstract

Despite the success of BCR-ABL-specific tyrosine kinase inhibitors (TKIs) such as imatinib in chronic phase (CP) chronic myeloid leukaemia (CML), patients with blast phase (BP)-CML continue to have a dismal outcome with median survival of less than one year from diagnosis. Thus BP-CML remains a critical unmet clinical need in the management of CML. Our understanding of the biology of BP-CML continues to grow; genomic instability leads to acquisition of mutations which drive leukaemic progenitor cells to develop self-renewal properties, resulting in differentiation block and a poor-prognosis acute leukaemia which may be myeloid, lymphoid or bi-phenotypic. Similar advances in therapy are urgently needed to improve patient outcomes; however, this is challenging given the rarity and heterogeneity of BP-CML, leading to difficulty in designing and recruiting to prospective clinical trials. This review will explore the treatment of BP-CML, evaluating the data for TKI therapy alone, combinations with intensive chemotherapy, the role of allogeneic haemopoietic stem cell transplantation, the use of novel agents and clinical trials, as well as discussing the most appropriate methods for diagnosing BP and assessing response to therapy, and factors predicting outcome.

Keywords: allogeneic stem cell transplantation; blast phase chronic myeloid leukaemia; clinical trials; combination therapy; tyrosine kinase inhibitors.

FIGURE 1

Clonal evolution in CML. The schematic diagram proposes a model for clonal evolution in CML. Acquisition of BCR‐ABL1 within a stem/progenitor cell results in an increase in ROS, genomic instability and epigenetic reprogramming with convergence on PRC1 and PRC2 complexes., , AP‐CML may develop when additional mutations, e.g. T315I, occur and treatment resistance ensues. Further progression to BP occurs when leukaemic progenitor cells acquire self‐renewal potential, which is combined with worsening genomic instability leading to acquisition of further genetic abnormalities, e.g. TP53 mutation, trisomy 8 and differentiation block. AP, accelerated phase; BP, blast phase; CML, chronic myeloid leukaemia; CP, chronic phase; ROS, reactive oxygen species; TKI, tyrosine kinase inhibitor.

FIGURE 2

Current management of BP‐CML. The flow chart summarises the current approach(es) for management of BP‐CML. Although there are some similarities in management, de novo BP‐CML and progression to BP‐CML on therapy are considered separately. ALL, acute lymphoblastic leukaemia; alloHSCT, allogeneic haemopoietic stem cell transplantation; AML, acute myeloid leukaemia; BP, blast phase; CML, chronic myeloid leukaemia; CNS, central nervous system; CP, chronic phase; DLI, donor lymphocyte infusion; FLAG‐IDA, fludarabine, cytarabine, granulocyte‐colony stimulating factor, idarubicin chemotherapy; lBP, lymphoid blast phase; NGS, next‐generation sequencing; TKI, tyrosine kinase inhibitor.