Chronic Myeloid Leukemia: Modern therapies, current challenges and future directions

Abstract

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm caused by a reciprocal translocation [t(9;22)(q34;q11.2)] that leads to the fusion of ABL1 gene sequences (9q34) downstream of BCR gene sequences (22q11) and is cytogenetically visible as Philadelphia chromosome (Ph). The resulting BCR/ABL1 chimeric protein is a constitutively active tyrosine kinase that activates multiple signaling pathways, which collectively lead to malignant transformation. During the early (chronic) phase of CML (CP-CML), the myeloid cell compartment is expanded, but differentiation is maintained. Without effective therapy, CP-CML invariably progresses to blast phase (BP-CML), an acute leukemia of myeloid or lymphoid phenotype. The development of BCR-AB1 tyrosine kinase inhibitors (TKIs) revolutionized the treatment of CML and ignited the start of a new era in oncology. With three generations of BCR/ABL1 TKIs approved today, the majority of CML patients enjoy long term remissions and near normal life expectancy. However, only a minority of patients maintain remission after TKI discontinuation, a status termed treatment free remission (TFR). Unfortunately, 5-10% of patients fail TKIs due to resistance and are at risk of progression to BP-CML, which is curable only with hematopoietic stem cell transplantation. Overcoming TKI resistance, improving the prognosis of BP-CML and improving the rates of TFR are areas of active research in CML.

Keywords: BCR/ABL1; Chronic myeloid leukemia; Philadelphia chromosome; Treatment free remission; Tyrosine kinase inhibitor.

Figure 1.. Response to treatment and residual leukemia in chronic myeloid leukemia.

CHR –complete hematologic response; CCyR –complete cytogenetic response; MMR –major molecular response.

Fig. 2.

BCR-ABL1 kinase domain mutations confer resistance to first and second generation TKIs. The crystal structure of the ABL1 kinase domain in complex with the indicated TKI (indicated in green) is shown. The P-loop is shown in yellow and the activation loop in green. Mutations at the highlighted residues confer resistance to the indicated TKI in vitro, with orange (moderate) and red (high) spheres indicating the level of resistance. Compared with imatinib, the newer inhibitors have less vulnerability to kinase domain mutations. Imatinib has a broad range of resistance mutations and a switch to a 2G TKI is indicated at in imatinib resistant disease. From O’Hare et al. Nat Rev Cancer. 2012;12(8):513–26.

Fig. 3.

Only a small subset of patients with newly diagnosed CML will be able to achieve treatment free remission. Among 100 patients with newly diagnosed CML about 10 percent will have accelerated or blast phase at diagnosis and are not eligible for a trial of treatment free remission per current guidelines. Of the 90% who have chronic phase CML, two thirds will achieve sustained DMR. Half of the patients who qualify for a TKI discontinuation trial will experience recurrence necessitating reintroduction of TKIs.