UNASSIGNED: Discontinuation of tyrosine kinase inhibitor (TKI) treatment is emerging as the main therapy goal for Chronic Myeloid Leukemia (CML) patients. The DESTINY trial showed that TKI dose reduction prior to cessation can lead to an increased number of patients achieving sustained treatment free remission (TFR). However, there has been no systematic investigation to evaluate how dose reduction regimens can further improve the success of TKI stop trials.
UNASSIGNED: Here, we apply an established mathematical model of CML therapy to investigate different TKI dose reduction schemes prior to therapy cessation and evaluate them with respect to the total amount of drug used and the expected TFR success.
UNASSIGNED: Our systematic analysis confirms clinical findings that the overall time of TKI treatment is a major determinant of TFR success, while highlighting that lower dose TKI treatment for the same duration is equally sufficient for many patients. Our results further suggest that a stepwise dose reduction prior to TKI cessation can increase the success rate of TFR, while substantially reducing the amount of administered TKI.
UNASSIGNED: Our findings illustrate the potential of dose reduction schemes prior to treatment cessation and suggest corresponding and clinically testable strategies that are applicable to many CML patients.

Tyrosine kinase inhibitors (TKIs) targeting BCR::ABL1 have turned chronic myeloid leukaemia (CML) from a fatal disease into a manageable condition for most patients. Despite improved survival, targeting drug-resistant leukaemia stem cells (LSCs) remains a challenge for curative CML therapy. Aberrant lipid metabolism can have a large impact on membrane dynamics, cell survival and therapeutic responses in cancer. While ceramide and sphingolipid levels were previously correlated with TKI response in CML, the role of lipid metabolism in TKI resistance is not well understood. We have identified downregulation of a critical regulator of lipid metabolism, G0/G1 switch gene 2 (G0S2), in multiple scenarios of TKI resistance, including (1) BCR::ABL1 kinase-independent TKI resistance, (2) progression of CML from the chronic to the blast phase of the disease, and (3) in CML versus normal myeloid progenitors. Accordingly, CML patients with low G0S2 expression levels had a worse overall survival. G0S2 downregulation in CML was not a result of promoter hypermethylation or BCR::ABL1 kinase activity, but was rather due to transcriptional repression by MYC. Using CML cell lines, patient samples and G0s2 knockout (G0s2-/- ) mice, we demonstrate a tumour suppressor role for G0S2 in CML and TKI resistance. Our data suggest that reduced G0S2 protein expression in CML disrupts glycerophospholipid metabolism, correlating with a block of differentiation that renders CML cells resistant to therapy. Altogether, our data unravel a new role for G0S2 in regulating myeloid differentiation and TKI response in CML, and suggest that restoring G0S2 may have clinical utility.

BACKGROUND: Chronic myeloid leukaemia (CML) presenting with only ocular manifestations either at the initial stage of diagnosis or at relapse is uncommon. We report two cases of CML presenting with isolated visual symptoms.
METHODS: The first case is a 21-year-old healthy gentleman who presented with left eye painless loss of vision for a one-week duration. Visual acuity was 6/60 in the left eye and 6/6 in the right eye. There were scattered retinal haemorrhages in both eyes and a sub-macular bleed over the left eye. The full blood count revealed a high white cell count of 134.6 × 109/L. Peripheral blood smear showed hyper-leucocytosis with absolute eosinophilia and basophilia and the presence of blasts suggestive of CML thus chemotherapy was commenced. The second case is a 28-year-old in haematological, molecular, and cytogenic remission from CML for the past two years, presented with left eye painless vision loss for five days duration. Vision in the left eye was counting fingers. There was a large subretinal mass involving the left optic disc. Magnetic resonance imaging of the brain and orbit showed an elliptical orbital mass at the left globe posteriorly with diffuse thickening of the optic nerve. The patient was diagnosed as CML relapsed to the left optic nerve. He underwent intrathecal chemotherapy and orbital irradiation.
CONCLUSIONS: Both these cases are unique since the manifestation of CML was with only ocular features at the time of presentation as per in the first case during the initial diagnosis and in the second case during relapse. This highlights that it is evident that the knowledge of ocular involvement in leukaemia is crucial since the eye is the only organ where leukemic infiltration to nerves and blood vessels can be observed directly. Recognizing fundus changes in leukaemia allows earlier diagnosis and prompt treatment. These case reports highlight the importance of recognizing early fundus changes, which should allow earlier diagnosis and treatment.

Despite the advent of molecular assessment, banding cytogenetics and fluorescence in situ hybridization (FISH) still have a significant role in diagnostic and prognostic approaches to chronic myeloid leukaemia (CML). Area covered: At diagnosis and during treatment with tyrosine kinase inhibitors (TKIs), cytogenetics is used to detect the Philadelphia chromosome, with its typical translocation t(9;22)(q34;q11.2), and any additional or other chromosomal aberrations (ACAs and OCAs) that may arise in 5-10% of cases, the latter associated to transformation of the disease in blast phases. In this review, the potential role of banding cytogenetics and FISH is discussed through a review of published papers on the prognostic impact of these tools in CML treatment and monitoring. Expert commentary: Cytogenetic techniques, including banding cytogenetics and FISH, continue to maintain a crucial role in CML monitoring. At diagnosis and after 3 months of therapy, banding cytogenetics will continue to be an essential test to perform, but it will become redundant after the achievement of a major molecular response (MMR) assessed with molecular techniques. FISH analysis maintains its usefulness in monitoring the response to TKIs only in special situations.

Myeloid leukaemias share the common characteristics of being stem cell-derived clonal diseases, characterised by excessive proliferation of one or more myeloid lineage. Chronic myeloid leukaemia (CML) arises from a genetic alteration in a normal haemopoietic stem cell (HSC) giving rise to a leukaemic stem cell (LSC) within the bone marrow (BM) \'niche\'. CML is characterised by the presence of the oncogenic tyrosine kinase fusion protein breakpoint cluster region-abelson murine leukaemia viral oncogene homolog 1 (BCR-ABL), which is responsible for driving the disease through activation of downstream signal transduction pathways. Recent evidence from our group and others indicates that important regulatory networks involved in establishing primitive and definitive haemopoiesis during development are reactivated in myeloid leukaemia, giving rise to an LSC population with altered self-renewal and differentiation properties. In this review, we explore the role the bone morphogenic protein (BMP) signalling plays in stem cell pluripotency, developmental haemopoiesis, HSC maintenance and the implication of altered BMP signalling on LSC persistence in the BM niche. Overall, we emphasise how the BMP and Wnt pathways converge to alter the Cdx-Hox axis and the implications of this in the pathogenesis of myeloid malignancies.

Most patients now receiving a haematopoietic stem cell transplant (HSCT) for chronic myeloid leukaemia (CML) have been treated with first and second line TKIs pre-HSCT, raising concerns that these patients will have more resistant disease and accumulated greater toxicity from sequential lines of therapy, potentially compromising their outcome. We outline a series of 9 patients treated with imatinib then second generation TKIs for CML followed by HSCT and compare their outcomes with patients receiving imatinib-only pre-HSCT. Our case series demonstrates that second line and sequential tyrosine kinase inhibitors followed by HSCT is a safe and effective therapeutic approach for high risk CML.