Cardiovascular events in CML patients treated with Nilotinib: validation of the HFA-ICOS baseline risk score.

BACKGROUND: The therapeutic landscape of chronic myeloid leukaemia (CML) has been transformed by tyrosine kinase inhibitors (TKI). Nilotinib, showed higher rates of major molecular response than imatinib, however associated with higher cardiovascular (CV) toxicity. We sought to describe the CV events associated with nilotinib in a real-world population and assess the predictive value of the HFA-ICOS risk score. METHODS: The HFA-ICOS baseline risk was calculated for patients with CML treated with nilotinib beween 2006 and 2021. The primary end point was the incidence of all CV events. The secondary end point was the incidence of ischaemic events. Survival analysis evaluated the risk (hazard ratio [HR]) of events stratified by baseline risk category, whilst on nilotinib therapy. RESULTS: Two hundred and twenty-nine eligible patients were included. The incidence of CV events was 20.9% (95% CI: 15.7-26.2%) following a median duration of treatment of 34.4 months. The secondary end point occurred in 12.7% (95% CI: 8.4-16.9%) of the population. Patients with higher HFA-ICOS baseline score had higher rates of CV events (low: 11.2%, medium: 28.2% [HR: 2.51, 95% CI: 1.17-5.66], high/very high: 32.4% [HR: 3.57, 95% CI: 1.77-7.20]) and ischaemic events (low: 5.20%, medium: 17.9% [HR: 2.19, 95% CI: 0.97-4.96], high/very high: 21.6% [HR: 3.9, 95% CI: 1.91-7.89]). In patients who did not have a CV event, the median total dose at last follow up or cessation of nilotinib therapy was lower when compared to the total daily median dose of nilotinib in patients who had a CV event (450 mg vs. 600 mg, p = 0.0074). CONCLUSIONS: The HFA-ICOS risk stratification tool is an efficient discriminator at low, medium and high/very high risk of developing cardiovascular events, with an overall positive trend towards increasing cardiotoxicity rates with rising risk catergories. This study provides evidence to support the use of this predictive tool in nilotinib treated patients.

Effect of tyrosine kinase inhibitors on male fertility in patients with chronic phase chronic myeloid leukemia.

Advancements in the management of patients with chronic myeloid leukemia (CML) allowed them to achieve survival comparable with their healthy counterparts. Consequently, their care has widened with growing focus on quality of life, including parenting children. Although tyrosine kinase inhibitors (TKI) are contraindicated in pregnancy given their teratogenic effect, their effect on male fertility is less clear with contradictory results from animal studies and case reports/series. We compared the sperm analysis parameters, as the gold-standard assessment for male fertility, of 11 patients with CP- CML before and after TKI therapy. Median therapy duration was 5.1 years (range: 2.5-16.5). The sperm concentration, % progressive, and total motility before and after therapy were not significantly different (p = 0.376, 0.569, and 0.595, respectively). Our results suggest no impairment in fertility potential in male patients after TKI therapy. A larger sample size is crucial to support/refute our findings.

Treatment-free remission in CML patients with additional chromosome abnormalities in the Philadelphia-positive clone or variant Philadelphia translocations.

Probability of treatment-free remission (TFR) in CML patients with additional chromosomal abnormalities (ACA) in the Philadelphia-positive clone or variant Philadelphia translocations (ACA/Var-Ph group, blue panel), in those with no cytogenetic abnormality other than the classical Philadelphia translocation (c-Ph group, green panel) and in the subgroups of CML patients with high-risk ACA (HR-ACA, yellow panel) and Var-Ph (red panel).

Long-term outcomes after upfront second-generation tyrosine kinase inhibitors for chronic myeloid leukemia: managing intolerance and resistance.

Second-generation tyrosine kinase inhibitors (2GTKI) are more effective in inducing rapid molecular responses than imatinib when used first-line in patients with chronic myeloid leukemia in chronic phase (CML-CP). However, failure of first line-2GTKI (1L-2GTKI) still occurs and there is no consensus regarding subsequent management. We retrospectively analyzed the outcome of 106 CML-CP patients treated with 1L-2GTKI and with a median follow-up of 91 months. 45 patients (42.4%) switched to an alternative TKI, 28 for intolerance (26.4%) and 17 (16%) for resistance. Most patients who remained on 1L-2GTKI achieved deep molecular responses (DMR) and 15 (14.1%) are in treatment-free remission (TFR). Intolerant patients also obtained DMR, although most required multiple TKI changes and were slower to respond, particularly if treated with 2L-imatinib. Inferior outcomes were observed in resistant patients, who failed alternative 2L-2GTKI and required 3/4GTKI and/or allogeneic hematopoietic stem cell transplant (alloSCT). 7yr-OS was significantly lower for these individuals (66.1%) than for intolerant patients and those who remained on 1L-2GTKI (100% and 97.9%, respectively; p = 0.001). It is apparent that failure of 1L-2GTKI is a challenging problem in modern CML therapy. Intolerance can be effectively managed by switching to an alternative 2GTKI, but resistance requires early consideration of 3/4GTKI.

Promoter-centred chromatin interactions associated with EVI1 expression in EVI1+3q- myeloid leukaemia cells.

EVI1 expression is associated with poor prognosis in myeloid leukaemia, which can result from Chr.3q alterations that juxtapose enhancers to induce EVI1 expression via long-range chromatin interactions. More often, however, EVI1 expression occurs unrelated to 3q alterations, and it remained unclear if, in these cases, EVI1 expression is similarly caused by aberrant enhancer activation. Here, we report that, in EVI1+3q- myeloid leukaemia cells, the EVI1 promoter interacts via long-range chromatin interactions with promoters of distally located, active genes, rather than with enhancer elements. Unlike in 3q+ cells, EVI1 expression and long-range interactions appear to not depend on CTCF/cohesin, though EVI1+3q- cells utilise an EVI1 promoter-proximal site to enhance its expression that is also involved in CTCF-mediated looping in 3q+ cells. Long-range interactions in 3q- cells connect EVI1 to promoters of multiple genes, whose transcription correlates with EVI1 in EVI1+3q- cell lines, suggesting a shared mechanism of transcriptional regulation. In line with this, CRISPR interference-induced silencing of two of these sites minimally, but consistently reduced EVI1 expression. Together, we provide novel evidence of features associated with EVI1 expression in 3q- leukaemia and consolidate the view that EVI1 in 3q- leukaemia is largely promoter-driven, potentially involving long-distance promoter clustering.

Diagnosis and evaluation of prognosis of myelofibrosis: a British Society for Haematology guideline

This document represents an update of the British Society for Haematology (BSH) guideline on myelofibrosis (MF) first published in 2012 and updated in 2015.1 This guideline aims to provide healthcare professionals with clear guidance on the diagnosis and prognostic evaluation of primary my-elofibrosis (PMF), as well as post-polycythaemia vera myelo-fibrosis (post-PV MF) and post-essential thrombocythaemia myelofibrosis (post-ET MF). A section on prefibrotic MF is also included. A separate BSH Guideline covers the manage-ment of MF and is published alongside this guideline.

The management of myelofibrosis: a British Society for Haematology guideline

This document represents an update of the British Society for Haematology guideline on Myelofibrosis first published in 2012 and updated in 2015 These guidelines aim to pro-vide healthcare professionals with clear guidance on stratified management for primary myelofibrosis (PMF), as well as post-polycythaemia myelofibrosis (post-PV MF) and postessential thrombocythaemia myelofibrosis (post-ET MF). A separate BSH guideline covers the diagnosis and prognostic evaluation of myelofibrosis and is published alongside this guideline

Outcomes and characteristics of nonmelanoma skin cancers in patients with myeloproliferative neoplasms on ruxolitinib.

ABSTRACT: Nonmelanoma skin cancers (NMSCs) in ruxolitinib-treated patients with myeloproliferative neoplasms behave aggressively, with adverse features and high recurrence. In our cohort, mortality from metastatic NMSC exceeded that from myelofibrosis. Vigilant skin assessment, counseling on NMSC risks, and prospective ruxolitinib-NMSC studies are crucial.

FISH-negative BCR::ABL1-positive e19a2 chronic myeloid leukaemia: the most cryptic of insertions.

BACKGROUND: Chronic myeloid leukaemia (CML) is one of the most well characterised human malignancies. Most patients have a cytogenetically visible translocation between chromosomes 9 and 22 which generates the pathognomonic BCR::ABL1 fusion gene. The derivative chromosome 22 ('Philadelphia' or Ph chromosome) usually harbours the fusion gene encoding a constitutively active ABL1 kinase domain. A small subset of patients have no visible translocation. Historically, these 'Philadelphia chromosome negative' patients caused diagnostic confusion between CML and other myeloproliferative neoplasms; it is now well established that the BCR::ABL1 fusion gene can be generated via submicroscopic intrachromosomal insertion of ABL1 sequence into BCR, or, more rarely, of BCR into ABL1. The fusion genes arising from cryptic insertions are not detectable via G-banded chromosome analysis [karyotype] but can nevertheless always be detected using fluorescence in situ hybridisation (FISH) and/or qualitative reverse transcriptase PCR. CASE PRESENTATION: A 43-year-old female presented with suspected CML in 2007; however, contemporaneous gold standard laboratory investigations, G-banded chromosome analysis and FISH, were both negative. The reverse transcriptase quantitative PCR (RT-qPCR) assay available at the time, which was capable of detecting the common BCR::ABL1 transcripts (e13a2/e14a2), was also negative. Upon review in 2009, the newly recommended reverse transcriptase multiplex PCR (capable of detecting all BCR::ABL1 transcripts including the atypical ones) subsequently detected an e19a2 fusion. The patient then responded to tyrosine kinase inhibitor therapy. In contrast, FISH studies of both samples with three commercially available probes remained consistently negative. Retrospective whole genome sequencing, undertaken as part of the 100,000 Genomes Project, has now revealed that the patient's BCR::ABL1 fusion gene arose via a uniquely small insertion of 122 kb ABL1 sequences into BCR. CONCLUSIONS: We present a patient with suspected chronic myeloid leukaemia whose genetic investigations were originally negative at the time of diagnosis despite the use of contemporaneous gold standard methods. This is the first report of a FISH-negative, BCR::ABL1 positive CML which demonstrates that, even after sixty years of research into one of the most well understood human malignancies, whole genome sequencing can yield novel diagnostic findings in CML.

Third primary SARS-CoV-2 mRNA vaccines enhance antibody responses in most patients with haematological malignancies.

SARS-CoV-2 infection, and resulting disease, COVID-19, has a high mortality amongst patients with haematological malignancies. Global vaccine rollouts have reduced hospitalisations and deaths, but vaccine efficacy in patients with haematological malignancies is known to be reduced. The UK-strategy offered a third, mRNA-based, vaccine as an extension to the primary course in these patients. The MARCH database is a retrospective observational study of serological responses in patients with blood disorders. Here we present data on 381 patients with haematological malignancies. By comparison with healthy controls, we report suboptimal responses following two primary vaccines, with significantly enhanced responses following the third primary dose. These responses however are heterogeneous and determined by haematological malignancy sub-type and therapy. We identify a group of patients with continued suboptimal vaccine responses who may benefit from additional doses, prophylactic extended half-life neutralising monoclonal therapies (nMAB) or prompt nMAB treatment in the event of SARS-CoV-2 infection.

3-deazaadenosine (3DA) alleviates senescence to promote cellular fitness and cell therapy efficiency in mice.

Cellular senescence is a stable type of cell cycle arrest triggered by different stresses. As such, senescence drives age-related diseases and curbs cellular replicative potential. Here, we show that 3-deazaadenosine (3DA), an S-adenosyl homocysteinase (AHCY) inhibitor, alleviates replicative and oncogene-induced senescence. 3DA-treated senescent cells showed reduced global Histone H3 Lysine 36 trimethylation (H3K36me3), an epigenetic modification that marks the bodies of actively transcribed genes. By integrating transcriptome and epigenome data, we demonstrate that 3DA treatment affects key factors of the senescence transcriptional program. Remarkably, 3DA treatment alleviated senescence and increased the proliferative and regenerative potential of muscle stem cells from very old mice in vitro and in vivo. Moreover, ex vivo 3DA treatment was sufficient to enhance the engraftment of human umbilical cord blood (UCB) cells in immunocompromised mice. Together, our results identify 3DA as a promising drug enhancing the efficiency of cellular therapies by restraining senescence.

Key findings from the UKCCMP cohort of 877 patients with haematological malignancy and COVID-19: disease control as an important factor relative to recent chemotherapy or anti-CD20 therapy.

Patients with haematological malignancies have a high risk of severe infection and death from SARS-CoV-2. In this prospective observational study, we investigated the impact of cancer type, disease activity, and treatment in 877 unvaccinated UK patients with SARS-CoV-2 infection and active haematological cancer. The primary end-point was all-cause mortality. In a multivariate analysis adjusted for age, sex and comorbidities, the highest mortality was in patients with acute leukaemia [odds ratio (OR) = 1·73, 95% confidence interval (CI) 1·1-2·72, P = 0·017] and myeloma (OR 1·3, 95% CI 0·96-1·76, P = 0·08). Having uncontrolled cancer (newly diagnosed awaiting treatment as well as relapsed or progressive disease) was associated with increased mortality risk (OR = 2·45, 95% CI 1·09-5·5, P = 0·03), as was receiving second or beyond line of treatment (OR = 1·7, 95% CI 1·08-2·67, P = 0·023). We found no association between recent cytotoxic chemotherapy or anti-CD19/anti-CD20 treatment and increased risk of death within the limitations of the cohort size. Therefore, disease control is an important factor predicting mortality in the context of SARS-CoV-2 infection alongside the possible risks of therapies such as cytotoxic treatment or anti-CD19/anti-CD20 treatments.