Haematology

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Venetoclax + obinutuzumab for chronic lymphocytic leukaemia: Is stringent TLS monitoring proportional to risk?
(Wiley, 2024-04-25) Mayo, Thomas; Bond, Adam; Wheeler, Michele; Lush, Richard; McCulloch, Rory; Mayo, Thomas; Bond, Adam; Wheeler, Michele; Lush, Richard; McCulloch, Rory; Medical and Dental; Nursing and Midwifery Registered
Background: Venetoclax + obinutuzumab (VenO) has been available as a first line treatment option for CLL in England since 2021. Although well tolerated, stringent tumour lysis syndrome (TLS) monitoring during venetoclax dose escalation, and risk of obinutuzumab-associated infusion related reactions (IRRs) can make treatment initiation onerous. We aimed to review adverse events and TLS monitoring frequency during the first two cycles of VenO for patients treated at a single NHS site. Methods: In this retrospective study we collected data on consecutive patients treated with VenO at Gloucestershire Hospitals between May 2021 and October 2023. The primary outcome was the rate of venetoclax induced biochemical and clinical TLS. Secondary outcomes included the rate of obinutuzumab IRRS requiring unplanned hospital admission and/or treatment delay. Results: In total, 28 patients initiated VenO. At baseline, median age was 69 years (range 35–80), Eastern Cooperative Oncology Group (ECOG) performance status was ≥2 in 4 patients (14%), median lymphocyte count was 145 × 109/L (range 6–675), 10 patients (36%) had maximum lymph node diameter >5 cm and 21 patients (75%) had estimated glomerular filtration rates (eGFR) <80 mL/min. Post obinutuzumab pre-phase and pre-first dose venetoclax, median lymphocyte count dropped to 1.7 × 109/L (range 0.34–12.2). Seven patients (25%) commenced venetoclax as an inpatient for additional monitoring. All patients received allopurinol or rasburicase prophylaxis and had TLS monitoring bloods, as minimum, at 6 and 24 h post venetoclax 50 and 100 mg dose initiation. Twelve patients (43%) continued TLS monitoring for 200 mg, and 6 patients (21%) for 400 mg dose initiation. In total, there was one case of biochemical TLS following 50 mg dose initiation in a high-risk patient which resolved by 24 h following IV hydration. There were no episodes of clinical TLS. In 21 patients receiving first obinutuzumab as an outpatient, 4 (19%) required unplanned admission due to IRRs. Of seven electively admitted for their first dose, three experienced adverse effects that delayed subsequent therapy (IRR = 2; TLS = 1). Conclusion: The low frequency of venetoclax related TLS observed in this study illustrates the success of obinutuzumab loading and venetoclax dose escalation in mitigating against TLS. It suggests that current TLS monitoring recommendations are excessive relative to actual risk. Results suggest that first dose obinutuzumab poses a significantly higher risk to patients and encourages judicious elective admissions. A large scale, multi-site retrospective study is recommended to consolidate the findings of this study.
BSH24-PO43 A single-site audit of treatment-free remission identification and monitoring in chronic myeloid leukaemia patients
(Wiley, 2024-04-25) Evans, Sophie; Frewin, Rebecca; Frewin, Rebecca; Medical and Dental
Patients with chronic-phase chronic myeloid leukaemia (CML) with sustained deep molecular remission (DMR) may be eligible for de-escalation of their tyrosine kinase inhibitor (TKI). Approximately 40%–50% of patients stopping their TKI will maintain DMR, without medication side effects/interactions, increased cardiovascular risk (up to 8%)1 and reducing treatment cost. Strict monitoring of blood parameters during de-escalation/cessation of TKI therapy is crucial for early detection of disease recurrence.2 This single-site audit sought to assess identification of eligible patients and compliance with guidelines on monitoring of full blood count (FBC) and BCR-ABL during treatment de-escalation/treatment-free remission (TFR). Patients were identified from a local database. The eligibility guidelines were the European LeukemiaNet 2020 recommendations for CML management,3 and South West Regional Myeloproliferative Neoplasm Forum guidance on monitoring frequency during dose reduction. Of 33 eligible patients: 63% had started TFR, 12% had declined and 24% had never been approached. Analysis of monitoring compliance included 18 patients (3 excluded as TFR predated guideline). During 50% dose reduction, 83% of patients had a FBC and 61% had a BCR-ABL measured 2-monthly. After dose reduction 77.7% maintained their DMR and fully discontinued treatment, and although two of four that lost DMR had inconsistent BCR-ABL measurements, all maintained MR3. After treatment cessation 50% (of 12 patients) had both monitoring tests monthly for the first 6 months, 43% (of 7 patients) had both monitoring tests 2-monthly during months 7–12 and 66% (of 3 patients) had both monitoring tests 3-monthly at >12 months. A cost analysis found savings of up to £79 706 for the eight eligible patients not yet approached about TFR, and risk of adverse cardiac events would also be reduced. Actions: a robust system for timely identification of eligible patients is required, led by the local laboratory or a clinical or administrative team member. Patient empowerment to manage monitoring tests should be encouraged, and reducing clinic appointments to only reviewing abnormal results.
Investigation and management of thrombocytosis without JAK2, CALR or MPL mutations: A British Society for Haematology Guideline
(Wiley, 2025-12-04) Godfrey, Anna; Khan, Alesia; McGregor, Andrew; Innes, Andrew; Altohami, Mohammed; Cross, Nicholas; Frewin, Rebecca; Garg, Mamta; Green, Anna; Grinfeld, Jacob; McLornan, Donal; Wilson, Andrew; Harrison, Claire; Mead, Adam; Nangalia, Jyoti; Frewin, Rebecca; Medical and Dental
No abstract available
(PS1592) Myeloproliferative neoplasms with concomitant chronic myeloid leukaemia are associated with TKI resistance and poor outcomes: A review of 46 cases
(Wiley, 2025-06-13) Li Gagnon, Laura; Sobas, Marta; Virchis, Andres; Bentley, Helen; Godfrey, Anna; Shih, Lee-Yung; Chee, Ashlyn; Mead, Adam; Lewandowski, Krzysztof; Frewin, Rebecca; Frewin, Rebecca; Medical and Dental
No abstract available Article freely available on publisher's website. Click DOI below. Article is on PDF pages 2694-2695 (published pages 2669-2670)
(PF862) MyMPNvoice app: Remote longitudinal monitoring of patient-reported outcomes and biometrics in patients with myeloproliferative neoplasms
(Wiley, 2025-06-13) Harrington, Patrick; Summers, Kim; Preston, Andrea; Street, Debbie; Taylor, Mark; Sheikh, Amna; Yusuf, Muna; Frewin, Rebecca; Wallis, Louise; Loughran, Catherine; Woodley, Claire; Sriskandarajah, Priya; Khan, Alesia; Alimam, Sam; Duminuco, Andrea; Kordasti, Shahram; Agrippa, Orlando; Harrison, Claire; Frewin, Rebecca; Medical and Dental
No abstract available Full text freely available on publisher's website. Click DOI below. Article is on PDF pages 1156-1157 (published pages 1131-1132)
Impact of BCR::ABL1 single nucleotide variants on asciminib efficacy
(Springer Nature, 2024-09-17) Innes, Andrew; Hayden, Chloe; Orovboni, Victoria; Claudiani, Simone; Fernando, Fiona; Khan, Afzal; Rees, David; Byrne, Jennifer; Gallipoli, Paolo; Francis, Sebastian; Copland, Mhairi; Frewin, Rebecca; Frewin, Rebecca; Medical and Dental
Asciminib is a potent and selective inhibitor of BCR::ABL1, with potential to avoid toxicity resulting from off-target kinase inhibition. Forty-nine patients treated with asciminib under a managed access program in the UK were evaluated for toxicity and response. Intolerance, rather than resistance (65% vs. 35%), was the most common reason for cessation of the last-line of treatment but asciminib was well tolerated, with most patients (29, 59%) remaining on treatment at a median of 14 months follow-up, and only 6 (12%) stopping for intolerance. Of 44 patients assessable for response, 29 (66%) achieved a complete cytogenetic response (CCyR) or better, with poorer responses seen in those stopping their last-line of therapy for resistance. Fewer patients with a prior history of a non-T315I-BCR::ABL1 single nucleotide variant (BSNV), or a non-T315I-BSNV detectable at baseline achieved CCyR. Serial tracking of BSNV by next generation sequencing demonstrated clonal expansion of BSNV-harbouring populations, which in some settings was associated with resistance (E459K, F317L, F359I), while in others was seen in the context of ongoing response, often with intensified dosing (T315I, I502F). These data suggest that asciminib exerts selective pressure on some BSNV-harbouring populations in vivo, some of which may respond to intensified dosing.
BSH2020-EP-112 The use of urine Bence-Jones protein testing in the investigation of a new paraprotein – a DGH perspective
(Wiley, 2020-04-27) Aggarwal, Asha; Johny, Asha; Aggarwal, Asha; Johny, Asha; Medical and Dental
Current BCSH guidelines recommend that following the detection of a new paraprotein, an early morning urine sample is tested for the presence of a Bence-Jones protein (BJP). If this result is positive or testing is not possible, then it is recommended that serum-free light chains (SFLC) be tested. In our trust, when a new paraprotein is found, a flag or alert is placed on the result to the patient's GP or ward team requesting early morning urine be sent for testing to the laboratory. It was noted that many of these urine tests were never sent. It was felt that this guidance was difficult to enact and follow at our hospital trust, a large BCSH Level 3 DGH, and a project to assess this was devised. We retrospectively audited 51 new paraprotein results, detected over a period of 2 weeks from 24 June 2019 to 11 July 2019. Of these new paraproteins, 35 were on blood tests sent from general practice, 15 from the hospital wards and two from haematology. In all but two cases, a urine BJP test was suggested with the results. Of the 49 samples requested, 21 urine BJP tests were sent to the laboratory. Of these 21, none were positive for a paraprotein or light chains. Six patients had a SFLC sent, of which five were on haematology advice. Two patients of the 51 patients that we know of have a diagnosis of multiple myeloma. We felt it would be useful to know what proportion of urine BJP samples received were positive across a larger sample size. Data from the laboratory have shown that, on average, 300 urine BJP tests are processed per month. Of these, around 55 will lead to the process of immunofixation. This will be followed up in more detail. There are several reasons why the urine tests may not be sent. It involves hassle, particularly in the community, for the GP and the patient. In addition, some urine samples may be sent in the wrong container or for the wrong test and were therefore discarded. The best way of rectifying this is difficult, particularly in a DGH setting. It is not possible for laboratory staff to chase urine tests with the GPs or the wards, or indeed to specifically request SFLC on samples that are not followed up with the recommended urine BJP test. A more consistent approach would be to send every sample with a new paraprotein for a SFLC automatically. However, in our trust, SFLC is not done on site, and is £10 more expensive than a urine BJP test. In addition to the monetary cost, there is labour involved for the laboratory staff in packaging and sending away the SFLC to the regional centre and processing the results when they come back. The cost of sending every sample for SFLC rather than doing urine BJP tests will be more expensive, but reduces the risk of missing patients with a diagnosis of light chain myeloma. This is a currently a significant risk, given that 15% of patients with myeloma fall in to this group. In summary, we have followed the BSH guidelines for the investigation of a new paraprotein by requesting the appropriate tests. The testing of early morning urine for a Bence-Jones protein has a very low uptake. This may result in missing patients with light-chain myeloma. However, the alternatives to urine BJP testing are more expensive and labour-intensive. From our perspective, this is a challenge. We would be interested to know what other DGH's recommend in terms of deviations from the BSH guideline for the investigation of a new paraprotein.
Efficacy of R-BAC in relapsed, refractory mantle cell lymphoma post BTK inhibitor therapy
(Wiley, 2020-05) McCulloch, Rory; Visco, Carlo; Eyre, Toby; Frewin, Rebecca; Phillips, Neil; Tucker, David; Quaglia, Francesca; McMillan, Annabel; Lambert, Jonathan; Crosbie, Nicola; Rule, Simon; Frewin, Rebecca; Medical and Dental
Patients with mantle cell lymphoma progressing on Bruton's tyrosine kinase inhibitor (BTKi) have very poor prognosis and there is currently no standard of care. In this retrospective cohort study, patients progressing on BTKi received R-BAC (rituximab, bendamustine, cytarabine). Overall response rate was 83% (complete response 60%) and 31% were bridged to allogeneic stem cell transplant (alloSCT). Median progression-free survival was 10.1 months (95% confidence interval (CI) 6·9-13·3) and median overall survival was 12·5 months (95% CI 11·0-14·0). In those consolidated with alloSCT only one patient relapsed. R-BAC demonstrates a high response rate in the post-BTKi setting and in transplant eligible patients is an effective bridge to alloSCT.
Response to tyrosine kinase inhibitors in myeloid neoplasms associated with PCM1-JAK2, BCR-JAK2 and ETV6-ABL1 fusion genes
(Wiley, 2020-04-28) Schwaab, Juliana; Naumann, Nicole; Luebke, Johannes; Jawhar, Mohamad; Somervaille, Tim; Williams, Mark; Frewin, Rebecca; Jost, Philipp; Lichtenegger, Felix; La Rosée, Paul; Storch, Nicola; Haferlach, Torsten; Horny, Hans-Peter; Fabarius, Alice; Haferlach, Claudia; Burchert, Andreas; Hofmann, Wolf-Karsten; Cross, Nicholas; Hochhaus, Andreas; Reiter, Andreas; Metzgeroth, Georgia; Frewin, Rebecca; Medical and Dental
We report on 18 patients with myeloid neoplasms and associated tyrosine kinase (TK) fusion genes on treatment with the TK inhibitors (TKI) ruxolitinib (PCM1-JAK2, n = 8; BCR-JAK2, n = 1) and imatinib, nilotinib or dasatinib (ETV6-ABL1, n = 9). On ruxolitinib (median 24 months, range 2-36 months), a complete hematologic response (CHR) and complete cytogenetic response (CCR) was achieved by five of nine and two of nine patients, respectively. However, ruxolitinib was stopped in eight of nine patients because of primary resistance (n = 3), progression (n = 3) or planned allogeneic stem cell transplantation (allo SCT, n = 2). At a median of 36 months (range 4-78 months) from diagnosis, five of nine patients are alive: four of six patients after allo SCT and one patient who remains on ruxolitinib. In ETV6-ABL1 positive patients, a durable CHR was achieved by four of nine patients (imatinib with one of five, nilotinib with two of three, dasatinib with one of one). Because of inadequate efficacy (lack of hematological and/or cytogenetic/molecular response), six of nine patients (imatinib, n = 5; nilotinib, n = 1) were switched to nilotinib or dasatinib. At a median of 23 months (range 3-60 months) from diagnosis, five of nine patients are in CCR or complete molecular response (nilotinib, n = 2; dasatinib, n = 2; allo SCT, n = 1) while two of nine patients have died. We conclude that (a) responses on ruxolitinib may only be transient in the majority of JAK2 fusion gene positive patients with allo SCT being an important early treatment option, and (b) nilotinib or dasatinib may be more effective than imatinib to induce durable complete remissions in ETV6-ABL1 positive patients.
The UK NCRI study of chlorambucil, mitoxantrone and dexamethasone (CMD) versus fludarabine, mitoxantrone and dexamethasone (FMD) for untreated advanced stage follicular lymphoma: molecular response strongly predicts prolonged overall survival
(Wiley, 2020-03-09) Bishton, Mark; Rule, Simon; Wilson, William; Turner, Deborah; Patmore, Russell; Clifton-Hadley, Laura; McMillan, Andrew; Lush, Richard; Haynes, Andrew; Lush, Richard; Medical and Dental
We present a long-term follow-up of the UK chlorambucil, mitoxantrone and dexamethasone (CMD) versus fludarabine, mitoxantrone and dexamethasone (FMD) for untreated advanced, symptomatic follicular lymphoma (FL). This trial was the first to prospectively assess molecular response and the impact on outcomes for 400 patients. The median progression-free survival (PFS) and overall survival (OS) for CMD were 3·6 and 14·6 years vs. 3·0 and 15·7 years for FMD, respectively. Estimates for Restricted Mean Survival Time (RMST) suggested no difference in PFS or OS. For the whole cohort there was a highly significant difference in survival by POD24, with a median OS from a risk-defining event of 3·9 years compared to 13·7 years for all others (RMST P < 0·001). Molecular remission was achieved in 25/46 patients (54·3%) in the CMD arm and 20/41 (48·8%) in the FMD arm (P = 0·6). Molecular negativity resulted in median PFS of 5·6 years vs. 2·3 years for molecularly positive (log-rank P < 0·001) and median OS not reached versus 12·5 years (log-rank P < 0·01). No cases of progression occurred in minimal residual disease (MRD) negative patients after six years of follow-up. Although there was no difference in outcomes between arms, this is the first prospective study to report MRD negativity resulting in significantly improved OS.
30-Day Mortality Following Systemic Anti-Cancer Treatment (SACT) Review in Driving Quality of Care in Hematologic Malignancies in a Tertiary Care Hospital
(American Society of Hematology (ASH Publications), 2021-12-24) Zakout, Ghada; Khan, Nowrina; Naumann, Isobel; Zakout, Ghada; Khan, Nowrina; Naumann, Isobel; Medical and Dental
No abstract available
Results of a national UK physician reported survey of COVID-19 infection in patients with a myeloproliferative neoplasm
(Springer Nature, 2021-02-12) Salisbury, Richard; Curto-Garcia, Natalia; O'Sullivan, Jennifer; Chen, Frederick; Polzella, Paolo; Godfrey, Anna; Russell, James; Knapper, Steven; Willan, John; Frewin, Rebecca; Joshi, Shivani; Frewin, Rebecca; Medical and Dental
No abstract available
UK Guidelines on the Diagnosis and Treatment of Breast Implant-Associated Anaplastic Large Cell Lymphoma on behalf of the Medicines and Healthcare products Regulatory Agency Plastic, Reconstructive and Aesthetic Surgery Expert Advisory Group
(Wiley, 2020-11-22) Turton, Philp; El-Sharkawi, Dima; LYBURN, IAIN; Sharma, Bhupinder; Mahalingam, Preethika; Turner, Suzanne; MacNeill, Fiona; Johnson, Laura; Hamilton, Stephen; Burton, Cathy; Mercer, Nigel; Lyburn, Iain; Medical and Dental
Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is an uncommon T-cell non-Hodgkin Lymphoma (NHL) associated with breast implants. Raising awareness of the possibility of BIA-ALCL in anyone with breast implants and new breast symptoms is crucial to early diagnosis. The tumour begins on the inner aspect of the peri-implant capsule causing an effusion, or less commonly a tissue mass to form within the capsule, which may spread locally or to more distant sites in the body. Diagnosis is usually made by cytological, immunohistochemical and immunophenotypic evaluation of the aspirated peri-implant fluid: pleomorphic lymphocytes are characteristically anaplastic lymphoma kinase (ALK)-negative and strongly positive for CD30. BIA-ALCL is indolent in most patients but can progress rapidly. Surgical removal of the implant with the intact surrounding capsule (total en-bloc capsulectomy) is usually curative. Late diagnosis may require more radical surgery and systemic therapies and although these are usually successful, poor outcomes and deaths have been reported. By adopting a structured approach, as suggested in these guidelines, early diagnosis and successful treatment will minimise the need for systemic treatments, reduce morbidity and the risk of poor outcomes.
Copy number evolution and its relationship with patient outcome—an analysis of 178 matched presentation-relapse tumor pairs from the Myeloma XI trial
(Springer Nature, 2020-12-01) Croft, James; Ellis, Sidra; Sherborne, Amy; Sharp, Kim; Price, Amy; Jenner, Matthew; Drayson, Mark; Owen, Roger; Chown, Sally; Lindsay, Jindriska; Karunanithi, Kamaraj; Hunter, Hannah; Gregory, Walter; Davies, Faith; Morgan, Gareth; Cook, Gordon; Atanesyan, Lilit; Savola, Suvi; Cairns, David; Jackson, Graham; Houlston, Richard; Kaiser, Martin; Chown, Sally; Medical and Dental
Structural chromosomal changes including copy number aberrations (CNAs) are a major feature of multiple myeloma (MM), however their evolution in context of modern biological therapy is not well characterized. To investigate acquisition of CNAs and their prognostic relevance in context of first-line therapy, we profiled tumor diagnosis–relapse pairs from 178 NCRI Myeloma XI (ISRCTN49407852) trial patients using digital multiplex ligation-dependent probe amplification. CNA profiles acquired at relapse differed substantially between MM subtypes: hyperdiploid (HRD) tumors evolved predominantly in branching pattern vs. linear pattern in t(4;14) vs. stable pattern in t(11;14). CNA acquisition also differed between subtypes based on CCND expression, with a marked enrichment of acquired del(17p) in CCND2 over CCND1 tumors. Acquired CNAs were not influenced by high-dose melphalan or lenalidomide maintenance randomization. A branching evolution pattern was significantly associated with inferior overall survival (OS; hazard ratio (HR) 2.61, P = 0.0048). As an individual lesion, acquisition of gain(1q) at relapse was associated with shorter OS, independent of other risk markers or time of relapse (HR = 2.00; P = 0.021). There is an increasing need for rational therapy sequencing in MM. Our data supports the value of repeat molecular profiling to characterize disease evolution and inform management of MM relapse.
Ibrutinib for mantle cell lymphoma at first relapse: a United Kingdom real-world analysis of outcomes in 211 patients
(Wiley, 2021-02-23) McCulloch, Rory; Lewis, David; Crosbie, Nicola; Eyre, Toby; Bolam, Simon; Arasaretnam, Anita; Creasey, Thomas; Goradia, Harshita; McMillan, Annabel; Dawi, Safia; Harrison, Samuel; Miles, Oliver; Robinson, Andrew; Dutton, David; Wilson, Matthew; McKay, Pam; Follows, George; Phillips, Neil; Patmore, Russell; Lambert, Jonathan; Bishton, Mark; Osborne, Wendy; Johnston, Rosalynd; Kirkwood, Amy; Rule, Simon; Miles, Oliver; Medical and Dental
Ibrutinib is an established treatment for relapsed/refractory (R/R) mantle cell lymphoma (MCL) and clinical trial data supports use at second line compared to later relapse. We aimed to investigate outcomes and tolerability for ibrutinib when given second line in a real-world setting. Our multicentre retrospective analysis included 211 R/R MCL patients, median age 73 years, receiving ibrutinib second-line within the United Kingdom’s National Health Service. Overall response to ibrutinib was 69% (complete response 27%). The median progression-free survival (PFS) was 17·8 months (95% CI 13·1–22·2) and median overall survival (OS) 23·9 months (95% CI 15·0–32·8). Drug-related adverse event led to dose reduction in 10% of patients and discontinuation in 5%. In patients with progressive disease, accounting for 100 of 152 patients stopping ibrutinib, 43% received further systemic therapy. Post-ibrutinib rituximab, bendamustine and cytarabine (R-BAC) showed a trend toward improved survival compared to alternative systemic treatments (post-ibrutinib median OS 14·0 months, 95% CI 8·1–19·8, vs. 3·6 months, 95% CI 2·6–4·5, P = 0·06). Our study confirms the clinical benefit and good tolerability of ibrutinib at first relapse in a real-world population. Patients progressing on ibrutinib had limited survival but outcomes with R-BAC in select patients were promising.
Challenging the Concept of Triple-Negative Thrombocytosis: Real-World Evidence from a Single Institution Experience
(American Society of Hematology (ASH Publications), 2022-11-15) Mahdi, Ali; Bhagat, Sahil; Langford, Grace; Frewin, Rebecca; Mahdi, Eamon; Frewin, Rebecca; Medical and Dental
No abstract available
Real-World Experience of Asciminib: Factors Associated with Response
(American Society of Hematology (ASH Publications), 2022-11-15) Innes, Andrew; Hayden, Chloe; Orovboni, Victoria; Rees, David; Claudiani, Simone; Fernando, Fiona; Khan, Afzal; Byrne, Jennifer; Gallipoli, Paolo; Francis, Sebastian; Copland, Mhairi; Horne, Gillian; Raghavan, Manoj; Arnold, Claire; Collins, Angela; Cranfield, Tanya; Cunningham, Nicholas; Danga, Akila; Forsyth, Peter; Frewin, Rebecca; Garland, Paula; Hannah, Guy; Hassan, Sandra; Huntly, Brian; Husain, Jissan; Makkuni, Sudhakaran; Rothwell, Kate; Foroni, Letizia; Apperley, Jane; Milojkovic, Dragana; Frewin, Rebecca; Medical and Dental
Background - Asciminib is an allosteric BCR::ABL1 inhibitor with proven efficacy in multiply treated CML. Prior to licensing, the drug was available in the UK through a Novartis supported managed access program since 2017. Here we report our national real-world experience of asciminib, with a focus on identifying factors associated with response. Patient cohort - Fifty-three patients from 14 centres were included. The median age was 57 [23-88] years, and 29 (55%) were male. The median time from diagnosis to asciminib treatment was 69 [11-386] months, and the median number of prior tyrosine kinase inhibitors was 4 [2-5], with 33 (62%) of patients having received ponatinib. The reason for stopping the last TKI was intolerance in 33 (62%) and resistance in 20 (38%) patients. Baseline BCR:ABL1 PCRs were greater than 10% in 21 (40%) patients, 1-10% in 13 (25%), 0.1-0.999% in 8 (15%), less than 0.1% in 9 (17%) and unknown in 2 (4%). A history of tyrosine kinase domain mutations (TKDM) was present in 22 (42%) patients. T315I was most common (n=13, 25%) but non-T315I mutations were seen either alone (n=9, 17%) or in combination with a T315I mutation (n=2, 4%). Medical comorbidities were common in the group, with 30 (57%) patients having at least one cardiovascular or vascular disorder (hypertension n=18 (34%), peripheral vascular disease n=10 (19%), ischaemic heart disease n=8 (15%), atrial fibrillation n=6 (11%), stroke or transient ischaemic attack n=4 (8%)). Nine (17%) patients had chronic kidney disease and 4 (8%) had diabetes. Results - Thirty-four patients (64%) continued on treatment at the time of reporting, while 9 (17%) had stopped for resistance and 7 (13%) for intolerance. One patient had stopped for a treatment free remission attempt, one for pregnancy and one for poor compliance. The median treatment durations were 14.4 [3-51] months for those still on treatment, and 5 [1-24] and 2 [1-26] months for those stopping for resistance and intolerance, respectively. Cytogenetic response (CCyR; BCR::ABL1 PCR <1% IS) or better was achieved in 32 (58%) patients, and 29 (52%) achieved major molecular response (MMR; BCR::ABL1 PCR <0.1% IS) or better. Higher rates of MMR were seen in patients who has previously achieved a CCyR with any prior therapy (69% vs 25%, p<0.01), stopped their last TKI for intolerance rather than resistance (70% vs 30%, p<0.01), and in those with a baseline BCR::ABL1 PCR at the initiation of asciminib of less than 10% (84% vs 17%, p<0.01). While no difference was seen in the rate of MMR between those harboring a T315I mutation or not (54% vs 55%, p=0.68), a history of a non-T315I-TKDM was associated with a lower rate of MMR (27% vs 62%, p=0.014). No significant differences were seen between those who had previously received ponatinib or not (48% vs 65%, p=0.450), although those with ponatinib resistance, rather than intolerance, had a tendency toward a lower rate of MMR (33% vs 65%, p=0.11). While asciminib was generally well tolerated, haematological toxicity of any grade was seen in 18 (33%) patients, with grade 3-4 in 10 (18%). The commonest non-haematological toxicities were fatigue, fluid retention, rash, nausea, insomnia, bone pain and deranged liver function tests. One patient had recurrence of a pleural effusion thought to be related to treatment. One patient suffered a myocardial infarction, and one a recurrence of a DVT whilst on treatment but causative relationships to the drug were unclear. Discussion - Asciminib is a well-tolerated therapy for CML in a previously heavily treated group with multiple comorbidities. Prior responses to therapy appear an important predictor of response to asciminib, with those resistant to the last TKI, and those never achieving a CCyR on any prior therapy showing a lower rate of MMR. While the presence of T315I mutations does not appear to significantly impact on the response to asciminib, the presence of non-T315I mutations is associated with a lower rate of MMR. Importantly the standard dosing regimen in patients with T315I mutations is fivefold higher but whether this explains the discrepant responses to T315I and non-T315I mutations requires further investigation.
Addendum to British Society for Haematology Guideline for the management of mantle cell lymphoma, 2018 (Br. J. Haematol. 2018; 182: 46-62): Risk assessment of potential CAR T candidates receiving a covalent Bruton tyrosine kinase inhibitor for relapsed/refractory disease
(Wiley, 2022-07-27) O'Reilly, Maeve; Sanderson, Robin; Wilson, William; Iyengar, Sunil; Lambert, Jonathan; McCulloch, Rory; Eyre, Toby; McCulloch, Rory; Medical and Dental
No abstract available
Diagnosis and management of Waldenström macroglobulinaemia-A British Society for Haematology guideline
(Wiley, 2022-01-12) Pratt, Guy; El-Sharkawi, Dima; Kothari, Jaimal; D'Sa, Shirley; Auer, Rebecca; McCarthy, Helen; Krishna, Rajesh; Miles, Oliver; Kyriakou, Charalampia; Owen, Roger; Miles, Oliver; Medical and Dental
Scope: The objective of this guideline is to provide healthcare professionals with clear guidance on the management of patients with Waldenström macroglobulinaemia. In individual patients, circumstances may dictate an alternative approach. Methodology: This guideline was compiled according to the British Society for Haematology (BSH) process at http://www.b-s-h.org.uk/guidelines/proposing-and-writing-a-new-bsh-guideline/. Recommendations are based on a review of the literature using Medline, Pubmed, Embase, Central, Web of Science searches from beginning of 2013 (since the publication of the previous guidelines) up to November 2021. The following search terms were used: Waldenström('s) macroglobulin(a)emia OR lymphoplasmacytic lymphoma, IgM(-related) neuropathy OR cold h(a)emagglutinin disease OR cold agglutinin disease OR cryoglobulin(a)emia AND (for group a only) cytogenetic OR molecular OR mutation OR MYD88 OR CXCR4, management OR treatment OR transfusion OR supportive care OR plasma exchange OR plasmapheresis OR chemotherapy OR bendamustine OR bortezomib OR ibrutinib OR fludarabine OR dexamethasone OR cyclophosphamide OR rituximab OR everolimus, bone marrow transplantation OR stem cell transplantation. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) nomenclature was used to evaluate levels of evidence and to assess the strength of recommendations. The GRADE criteria can be found at http://www.gradeworkinggroup.org. Review of the manuscript was performed by the British Society for Haematology (BSH) Guidelines Committee Haemato-Oncology Task Force, the BSH Guidelines Committee and the Haemato-Oncology sounding board of BSH. It was also on the members section of the BSH website for comment. It has also been reviewed by UK Charity WMUK; these organisations do not necessarily approve or endorse the contents.
Safety and Efficacy of Busulphan Based on Dosing Patterns in the Real-World Management of Myeloproliferative Neoplasms
(Wiley, 2025-03-19) Mahdi, Ali; Rampotas, Alexandros; Roberts, Patrick; Stokes, Joanna; Mahdi, Eamon; Witherall, Ruth; Mannari, Deepak; Ibrahim, Naheed; Naylor, Georgina; Garg, Mamta; Manjra, Imran; Glancy, Paula; Katis, George; Bhagat, Sahil; Coppell, Jason; McGregor, Andrew; Frewin, Rebecca; Butt, Nauman; Stokes, Joanna; Frewin, Rebecca; Nursing and Midwifery Registered; Medical and Dental
Introduction Myeloproliferative neoplasms (MPNs), such as polycythaemia vera (PV), essential thrombocythemia (ET) and myelofibrosis (MF), are primarily treated by managing blood counts to reduce the thrombotic risk using cytoreductive agents. Busulphan, an oral alkylating agent, has been historically used for MPN management due to its myelosuppressive effects, but concerns about its risk of leukaemic transformation have limited its use. Methods This real-world retrospective study evaluated the safety and efficacy of busulphan in 115 MPN patients across 13 UK hospitals. Responses in patients with ET and PV only were assessed using European LeukemiaNet (ELN) criteria. Results With a median age of 78 years, the overall response rate was 78.1%, with 29% of PV and 18% of ET patients achieving complete responses. Dosing regimens were similarly distributed between repeated single doses of busulphan (31%), courses of treatment lasting 1–4 weeks (30%) and continuous therapy for more than 4 weeks (35%). No cases of disease progression to acute leukaemia or myelofibrosis were recorded during the median follow-up of 23 months. Adverse events were infrequent, with fatigue and cytopaenia being the most common (4% each). Conclusion Busulphan demonstrated a favourable safety profile and is a viable cytoreductive option, particularly for elderly patients who are intolerant to hydroxycarbamide. Trial Registration The authors have confirmed clinical trial registration is not needed for this submission

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