Publications
78 results found
Claudiani S, Chughtai F, Khan A, et al., 2024, Long-term outcomes after upfront second-generation tyrosine kinase inhibitors for chronic myeloid leukemia: managing intolerance and resistance., Leukemia, Vol: 38, Pages: 796-802
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.
Claudiani S, Chee L, Fernando F, et al., 2024, Treatment-free remission in CML patients with additional chromosome abnormalities in the Philadelphia-positive clone or variant Philadelphia translocations., Am J Hematol
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).
Ng HL, Robinson ME, May PC, et al., 2024, Promoter-centred chromatin interactions associated with EVI1 expression in EVI1+3q- myeloid leukaemia cells., Br J Haematol, Vol: 204, Pages: 945-958
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.
Rampotas A, Carter-Brzezinski L, Somervaille TCP, et al., 2024, Outcomes and characteristics of nonmelanoma skin cancers in patients with myeloproliferative neoplasms on ruxolitinib., Blood, Vol: 143, Pages: 178-182
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.
McLornan DP, Psaila B, Ewing J, et al., 2024, The management of myelofibrosis: A British Society for Haematology Guideline., Br J Haematol, Vol: 204, Pages: 136-150
McLornan DP, Godfrey AL, Green A, et al., 2024, Diagnosis and evaluation of prognosis of myelofibrosis: A British Society for Haematology Guideline., Br J Haematol, Vol: 204, Pages: 127-135
May P, Reid A, Robinson M, et al., 2023, FISH-negative BCR::ABL1-positive e19a2 chronic myeloid leukaemia: the most cryptic of insertions, BMC Medical Genomics, Vol: 16, Pages: 1-6, ISSN: 1755-8794
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 detectable 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
Fernando F, Innes AJ, Claudiani S, et al., 2023, The outcome of post-transplant asciminib in patients with chronic myeloid leukaemia, BONE MARROW TRANSPLANTATION, Vol: 58, Pages: 826-828, ISSN: 0268-3369
Simini G, Vinayagam S, Karawitage N, et al., 2023, Thrombocytosis and acquired bleeding disorders in patients with myeloproliferative neoplasms, 63rd Annual Scientific Meeting of the British-Society-for-Haematology, Publisher: WILEY, Pages: 53-54, ISSN: 0007-1048
Milojkovic D, Reynolds CJ, Sandoval DM, et al., 2023, COVID-19 vaccine boosted immunity against Omicron in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors, LEUKEMIA, Vol: 37, Pages: 244-247, ISSN: 0887-6924
Rampotas A, Carter-Brzezinski L, Somervaille TCP, et al., 2022, Disease Characteristics and Outcomes of Non-Melanoma Skin Cancers in Myeloproliferative Neoplasm (MPN) Patients Treated with Ruxolitinib, 64th Annual Meeting and Exposition of the American-Society-of-Hematology (ASH), Publisher: AMER SOC HEMATOLOGY, Pages: 9721-9723, ISSN: 0006-4971
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Hederih J, Charania A, Waldman A, et al., 2022, Total Body Irradiation Is Associated with Higher Prevalence of Cerebral Microbleeds in Haematopoietic Stem Cell Transplant Survivors, 64th Annual Meeting and Exposition of the American-Society-of-Hematology (ASH), Publisher: AMER SOC HEMATOLOGY, Pages: 12910-12912, ISSN: 0006-4971
Innes AJ, Hayden C, Orovboni V, et al., 2022, Real-World Experience of Asciminib: Factors Associated with Response, 64th Annual Meeting and Exposition of the American-Society-of-Hematology (ASH), Publisher: AMER SOC HEMATOLOGY, Pages: 6796-6797, ISSN: 0006-4971
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Cook L, O'dell G, Vourvou E, et al., 2022, Third primary SARS-CoV-2 mRNA vaccines enhance antibody responses in most patients with haematological malignancies, Nature Communications, Vol: 13, Pages: 1-6, ISSN: 2041-1723
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-strategyoffered 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 sub-optimal 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.
Innes A, McVinnie K, Nadal-Melsio E, et al., 2022, A case of chronic neutrophilic leukaemia and multiple myeloma showing the benefits of lenalidomide and cyclophosphamide therapy in treating both conditions, American Journal of Hematology, ISSN: 0361-8609
Guerrero A, Innes AJ, Roux P-F, et al., 2022, 3-Deazaadenosine alleviates senescence to promote cellular fitness and cell therapy efficiency in mice, Nature Aging, Vol: 2, Pages: 851-866, ISSN: 2662-8465
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 inhibitor, alleviates replicative and oncogene-induced senescence. 3DA-treated senescent cells showed reduced global histone H3 lysine 36 trimethylation, 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. Notably, 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 cells in immunocompromised mice. Together, our results identify 3DA as a promising drug enhancing the efficiency of cellular therapies by restraining senescence.
Mullish BH, 2022, National clinical expert consensus statement: Coronavirus monoclonal antibodies as a prophylactic therapy against COVID-19 for immunocompromised groups
- Novel long-acting coronavirus prophylactic monoclonal antibodytherapies have been shown to be effective in preventing COVID19 in immunocompromised individuals who are at increased riskfrom SARS-CoV-2.- Prophylactic antibody therapies should be made available in atimely manner to give an antibody immunity boost to vulnerablepatients.- Real world evaluations should be co-implemented to provideconfidence of ongoing effectiveness.- Successful delivery of a coronavirus prophylactic antibodytherapy programme would deliver significant benefits tohealthcare systems, communities and immunocompromisedindividuals.
Claudiani S, Parker EL, Milojkovic D, et al., 2022, Long-term persistence of natural anti-SARS-CoV-2 antibodies and mild impact of SARS-CoV-2 infection in CML patients: results from a seroprevalence study, LEUKEMIA & LYMPHOMA, Vol: 63, Pages: 1504-1507, ISSN: 1042-8194
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- Citations: 1
Claudiani S, Apperley JF, Parker EL, et al., 2022, Durable humoral responses after the second anti-SARS-CoV-2 vaccine dose in chronic myeloid leukaemia patients on tyrosine kinase inhibitors, BRITISH JOURNAL OF HAEMATOLOGY, Vol: 197, Pages: E1-E4, ISSN: 0007-1048
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- Citations: 11
Charania AS, Vergis N, Phillips R, et al., 2021, Multi-Arm Trial of Inflammatory Signal Inhibitors (MATIS) for hospitalised patients with mild or moderate Covid-19 pneumonia: a structured summary of a study protocol for a randomised controlled trial, 63rd ASH Annual Meeting and Exposition, Publisher: American Society of Hematology, Pages: 4200-4200, ISSN: 0006-4971
Booth S, Curley HM, Varnai C, et al., 2021, 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, British Journal of Haematology, Vol: 196, Pages: 892-901, ISSN: 0007-1048
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.
Innes AJ, Mullish BH, Ghani R, et al., 2021, Fecal microbiota transplant mitigates adverse outcomes in patients colonized with multidrug-resistant organisms undergoing allogeneic hematopoietic cell transplantation, Frontiers in Cellular and Infection Microbiology, Vol: 11, Pages: 1-8, ISSN: 2235-2988
The gut microbiome can be adversely affected by chemotherapy and antibiotics prior to hematopoietic cell transplantation (HCT).This affects graft success and increases susceptibility to multidrug-resistant organism (MDRO) colonization and infection. Weperformed an initial retrospective analysis of our use of fecal microbiota transplantation (FMT) from healthy donors as therapy forMDRO-colonized patients with hematological malignancy. FMT was performed on eight MDRO-colonized patients pre-HCT (FMT-MDROgroup), and outcomes compared with 11 MDRO colonized HCT patients from the same period. At 12 months, survival wassignificantly higher in the FMT-MDRO group (70% versus 36% p = 0.044). Post-HCT, fewer FMT-MDRO patients required intensivecare (0% versus 46%, P = 0.045) or experienced fever (0.29 versus 0.11 days, P = 0.027). Intestinal MDRO decolonization occurred in25% of FMT-MDRO patients versus 11% non-FMT MDRO patients. Despite the significant difference and statistically comparablepatient/transplant characteristics, as the sample size was small, a matched-pair analysis to non-MDRO colonized control cohorts(2:1 matching) was performed. At 12 months, the MDRO group who did not have an FMT had significantly lower survival (36.4%versus 61.9% respectively, p=0.012), and higher non relapse mortality (NRM; 60.2% versus 16.7% respectively, p=0.009) than theirpaired non-colonized cohort. There was no difference in survival (70% versus 43.4%, p=0.14) or NRM (12.5% versus 31.2%respectively, p=0.24) between the FMT-MDRO group and their paired cohort. Negative outcomes, including mortality associatedwith MDRO colonization, may be ameliorated by pre-HCT FMT, despite lack of intestinal decolonization. Further work is needed toexplore the observed benefit.
Mullish BH, Innes AJ, Ghani R, et al., 2021, FECAL MICROBIOTA TRANSPLANT PRIOR TO ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANT IN PATIENTS COLONIZED WITH MULTI-DRUG RESISTANT ORGANISMS IS ASSOCIATED WITH IMPROVED SURVIVAL, Society-for-Surgery-of-the-Alimentary-Tract Annual Meeting at Digestive Disease Week (DDW), Publisher: W B SAUNDERS CO-ELSEVIER INC, Pages: S168-S169, ISSN: 0016-5085
Ghani R, Mullish BH, McDonald JAK, et al., 2021, Disease prevention not decolonization – a model for fecal microbiota transplantation in patients colonized with multidrug-resistant organisms, Clinical Infectious Diseases, Vol: 72, Pages: 1444-1447, ISSN: 1058-4838
Fecal microbiota transplantation (FMT) yields variable intestinal decolonization results for multidrug-resistant organisms (MDROs). This study showed significant reductions in antibiotic duration, bacteremia and length of stay in 20 patients colonized/ infected with MDRO receiving FMT (compared to pre-FMT history, and a matched group not receiving FMT), despite modest decolonization rates.
Vergis N, Phillips R, Cornelius V, et al., 2021, Multi-arm Trial of Inflammatory Signal Inhibitors (MATIS) for hospitalised patients with mild or moderate COVID-19 pneumonia: a structured summary of a study protocol for a randomised controlled trial, Trials, Vol: 22, ISSN: 1745-6215
OBJECTIVES: The primary objective of MATIS is to determine the efficacy of ruxolitinib (RUX) or fostamatinib (FOS) compared to standard of care (SOC) with respect to reducing the proportion of hospitalised patients progressing from mild or moderate to severe COVID-19 pneumonia. Secondary objectives, at 14 and 28 days, are to: Determine the efficacy of RUX or FOS to reduce mortality Determine the efficacy of RUX or FOS to reduce the need for invasive ventilation or ECMO Determine the efficacy of RUX or FOS to reduce the need for non-invasive ventilation Determine the efficacy of RUX or FOS to reduce the proportion of participants suffering significant oxygen desaturation Determine the efficacy of RUX or FOS to reduce the need for renal replacement therapy Determine the efficacy of RUX and FOS to reduce the incidence of venous thromboembolism Determine the efficacy of RUX and FOS to reduce the severity of COVID-19 pneumonia [graded by a 9-point modified WHO Ordinal Scale* Determine the efficacy of RUX or FOS to reduce systemic inflammation Determine the efficacy of RUX or FOS to the incidence of renal impairment Determine the efficacy of RUX or FOS to reduce duration of hospital stay Evaluate the safety of RUX and FOS for treatment of COVID-19 pneumonia. TRIAL DESIGN: A multi-arm, multi-stage (3-arm parallel-group, 2-stage) randomised controlled trial that allocates participants 1:1:1 and tests for superiority in experimental arms versus standard of care. PARTICIPANTS: Patients will be recruited while inpatients during hospitalisation for COVID-19 in multiple centres throughout the UK including Imperial College Healthcare NHS Trust. INCLUSION: Patients age ≥ 18 years at screening Patients with mild or moderate COVID-19 pneumonia, defined as Grade 3 or 4 severity by the WHO COVID-19 Ordinal Scale Patients meeting criteria: Hospitalization AND SARS-CoV2 infection (clinically suspected or laboratory confirmed) AND Radiological change consistent with COVID-19 disease C
Maynard S, Ros-Soto J, Chaidos A, et al., 2021, The role of ibrutinib in COVID-19 hyperinflammation: a case report, International Journal of Infectious Diseases, Vol: 105, Pages: 274-276, ISSN: 1201-9712
Continuing ibrutinib in patients with COVID-19 may be advantageous given its immunomodulatory properties and withdrawal of ibrutinib therapy may be detrimental. Further evidence is required to explore the potential therapeutic impact of BTKis and other immunomodulatory agents on the clinical course of COVID-19 as is currently being carried out in a number of clinical trials.
Claudiani S, Apperley JF, Szydlo R, et al., 2021, TKI dose reduction can effectively maintain major molecular remission in patients with chronic myeloid leukaemia, BRITISH JOURNAL OF HAEMATOLOGY, Vol: 193, Pages: 346-355, ISSN: 0007-1048
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- Citations: 14
Ghani R, Mullish B, Innes A, et al., 2021, Faecal microbiota transplant (FMT) prior to allogeneic haematopoietic cell transplantation (HCT) in patients colonised with multidrug-resistant organisms (MDRO) results in improved survival, ECCMID
Innes A, Sun B, Wagner V, et al., 2021, XPO7 is a tumor suppressor regulating p21CIP1-dependent senescence, Genes and Development, Vol: 35, Pages: 379-391, ISSN: 0890-9369
Senescence is a key barrier to neoplastic transformation. To identify senescence regulators relevant to cancer, we screened a genome-wide shRNA library. Here, we describe exportin 7 (XPO7) as a novel regulator of senescence and validate its function in telomere-induced, replicative and oncogene-induced senescence (OIS). XPO7 is a bidirectional transporter that regulates the nuclear-cytoplasmic shuttling of a broad range of substrates. Depletion of XPO7 results in reduced levels of TCF3 and an impaired induction of the cyclin dependent kinase inhibitor p21CIP1 during OIS. Deletion of XPO7 correlates with poorer overall survival in several cancer types. Moreover, depletion of XPO7 alleviated OIS and increased tumor formation in a mouse model of liver cancer. Our results suggest that XPO7 is a novel tumor suppressor that regulates p21CIP1 expression to control senescence and tumorigenesis.
Salisbury RA, Curto-Garcia N, OSullivan J, et al., 2021, Results of a national UK physician reported survey of COVID-19 infection in patients with a myeloproliferative neoplasm, Leukemia, Vol: 35, Pages: 2424-2430, ISSN: 0887-6924
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