Russell Patmore

Incidence of haematological malignancy by sub-type: a report from the Haematological Malignancy Research Network.

Background:Ascertainment of cases and disease classification is an acknowledged problem for epidemiological research into haematological malignancies.Methods:The Haematological Malignancy Research Network comprises an ongoing population-based patient cohort. All diagnoses (paediatric and adult) across two UK Cancer Networks (population 3.6 million, >2000 diagnoses annually, socio-demographically representative of the UK) are made by an integrated haematopathology laboratory. Diagnostics, prognostics, and treatment are recorded to clinical trial standards, and socio-demographic measures are routinely obtained.Results:A total of 10 729 haematological malignancies (myeloid=2706, lymphoid=8023) were diagnosed over the 5 years, that is, from 2004 to 2009. Descriptive data (age, sex, and deprivation), sex-specific age-standardised (European population) rates, and estimated UK frequencies are presented for 24 sub-types. The age of patients ranged from 4 weeks to 99 years (median 70.6 years), and the male rate was more than double the female rate for several myeloid and lymphoid sub-types, this difference being evident in both children and adults. No relationship with deprivation was detected.Conclusion:Accurate population-based data on haematological malignancies can be collected to the standard required to deliver reproducible results that can be extrapolated to national populations. Our analyses emphasise the importance of gender and age as disease determinants, and suggest that aetiological investigations that focus on socio-economic factors are unlikely to be rewarding.

The Haematological Malignancy Research Network (HMRN) : a new information strategy for population based epidemiology and health service research

The Haematological Malignancy Research Network (HMRN) was established in 2004 to provide robust generalizable data to inform clinical practice and research. It comprises an ongoing population‐based cohort of patients newly diagnosed by a single integrated haematopathology laboratory in two adjacent UK Cancer Networks (population 3·6 million). With an emphasis on primary‐source data, prognostic factors, sequential treatment/response history, and socio‐demographic details are recorded to clinical trial standards. Data on 8131 patients diagnosed over the 4 years 2004–08 are examined here using the latest World Health Organization classification. HMRN captures all diagnoses (adult and paediatric) and the diagnostic age ranged from 4 weeks to 99 years (median 70·4 years). In line with published estimates, first‐line clinical trial entry varied widely by disease subtype and age, falling from 59·5% in those aged <15 years to 1·9% in those aged over 75 years – underscoring the need for contextual population‐based treatment and response data of the type collected by HMRN. The critical importance of incorporating molecular and prognostic markers into comparative survival analyses is illustrated with reference to diffuse‐large B‐cell lymphoma, acute myeloid leukaemia and myeloma. With respect to aetiology, several descriptive factors are highlighted and discussed, including the unexplained male predominance evident for most subtypes across all ages.

Haematological malignancy: are patients appropriately referred for specialist palliative and hospice care? A systematic review and meta-analysis of published data

Haematological malignancies are complex diseases, affecting the entire age spectrum, and having marked differences in presentation, treatment, progression and outcome. Patients have a significant symptom burden and despite treatment improvements for some sub-types, many patients die from their disease. We carried out a systematic review and meta-analysis to examine the proportion of patients with haematological malignancies that received any form of specialist palliative or hospice care. Twenty-four studies were identified, nine of which were suitable for inclusion in the meta-analysis. Our review showed that patients with haematological malignancies were far less likely to receive care from specialist palliative or hospice services compared to other cancers (Risk Ratio 0.46, [95% confidence intervals 0.42–0.50]). There are several possible explanations for this finding, including: ongoing management by the haematology team and consequent strong bonds between staff and patients; uncertain transitions to a palliative approach to care; and sudden transitions, leaving little time for palliative input. Further research is needed to explore: transitions to palliative care; potential unmet patient needs; where patients want to be cared for and die; existing practices in the delivery of palliative and end-of-life care; and barriers to specialist palliative care and hospice referral and how these might be overcome.

Results of a Randomized Trial of Chlorambucil Versus Fludarabine for Patients With Untreated Waldenström Macroglobulinemia, Marginal Zone Lymphoma, or Lymphoplasmacytic Lymphoma

PURPOSE Treatment options for patients with Waldenström macroglobulinemia (WM) and closely related disorders include alkylating agents, purine analogs, and monoclonal antibodies. No large randomized studies have yet been reported comparing any of these approaches. PATIENTS AND METHODS The randomized WM1 study (Trial Comparing Chlorambucil to Fludarabine in Patients With Advanced Waldenström Macroglobulinemia) was undertaken in 101 centers in five countries enrolling 414 eligible patients (339 with WM, 37 with non-mucosa-associated lymphoid tissue marginal zone lymphoma, and 38 with lymphoplasmacytic lymphoma) who were randomly assigned to receive chlorambucil or fludarabine. The primary end point was the overall response rate (ORR). RESULTS On the basis of intent-to-treat analysis, the ORR was 47.8% (95% CI, 40.9% to 54.8%) in the fludarabine arm versus 38.6% (95% CI, 32.0% to 45.7%) in the chlorambucil arm (P = .07). With a median follow-up of 36 months (interquartile range, 18 to 58 months), median progression-free survival (PFS), and duration of response (DR) were significantly improved in the fludarabine arm compared with the chlorambucil arm: PFS, 36.3 versus 27.1 months (P = .012) and DR, 38.3 versus 19.9 months (P < .001). In patients with WM, median overall survival (OS) was not reached in the fludarabine arm versus 69.8 months in the chlorambucil arm (95% CI, 61.6 to 79.8 months; P = .014). Grade 3 to 4 neutropenia was significantly higher among patients treated with fludarabine (36%) compared with patients treated with chlorambucil (17.8%; P < .001). Second malignancies were significantly more frequent in the chlorambucil arm with 6-year cumulative incidence rate of 20.6% versus 3.7% in the fludarabine arm (P = .001). CONCLUSION In the complete intent-to-treat study population, fludarabine significantly improved PFS compared with chlorambucil, and in patients with WM, it improved OS.

Lymphoma incidence, survival and prevalence 2004–2014: sub-type analyses from the UK’s Haematological Malignancy Research Network

Background:Population-based information about cancer occurrence and survival are required to inform clinical practice and research; but for most lymphomas data are lacking.Methods:Set within a socio-demographically representative UK population of nearly 4 million, lymphoma data (N=5796) are from an established patient cohort.Results:Incidence, survival (overall and relative) and prevalence estimates for >20 subtypes are presented. With few exceptions, males tended to be diagnosed at younger ages and have significantly (P<0.05) higher incidence rates. Differences were greatest at younger ages: the <15 year male/female rate ratio for all subtypes combined being 2.2 (95% CI 1.3–3.4). These gender differences impacted on prevalence; most subtype estimates being significantly (P<0.05) higher in males than females. Outcome varied widely by subtype; survival of patients with nodular lymphocyte predominant Hodgkin lymphoma approached that of the general population, whereas less than a third of those with other B-cell (e.g., mantle cell) or T-cell (e.g., peripheral-T) lymphomas survived for ≥5 years. No males/female survival differences were detected.Conclusions:Major strengths of our study include completeness of ascertainment, world-class diagnostics and generalisability. The marked variations demonstrated confirm the requirement for ‘real-world’ data to inform aetiological hypotheses, health-care planning and the future monitoring of therapeutic changes.

Destined to die in hospital? Systematic review and meta-analysis of place of death in haematological malignancy

BackgroundHaematological malignancies are a common, heterogeneous and complex group of diseases that are often associated with poor outcomes despite intensive treatment. Research surrounding end-of-life issues, and particularly place of death, is therefore of paramount importance, yet place of death has not been formally reviewed in these patients.MethodsA systematic literature review and meta-analysis was undertaken using PubMed to identify all studies published between 1966 and 2010. Studies examining place of death in adult haematology patients, using routinely compiled morbidity and mortality data and providing results specific to this disease were included. 21 studies were identified with descriptive and/or risk-estimate data; 17 were included in a meta-analysis.ResultsCompared to other cancer deaths, haematology patients were more than twice as likely to die in hospital (Odds Ratio 2.25 [95% Confidence Intervals, 2.07-2.44]).ConclusionHome is generally considered the preferred place of death but haematology patients usually die in hospital. This has implications for patients who may not be dying where they wish, and also health commissioners who may be funding costly end-of-life care in inappropriate acute hospital settings. More research is needed about preferred place of care for haematology patients, reasons for hospital deaths, and how these can be avoided if home death is preferred.

Whole genome expression profiling based on paraffin embedded tissue can be used to classify diffuse large B‐cell lymphoma and predict clinical outcome

This study tested the validity of whole‐genome expression profiling (GEP) using RNA from formalin‐fixed, paraffin‐embedded (FFPE) tissue to sub‐classify Diffuse Large B‐cell Lymphoma (DLBCL), in a population based cohort of 172 patients. GEP was performed using Illumina Whole Genome cDNA‐mediated Annealing, Selection, extension & Ligation, and tumours were classified into germinal centre (GCB), activated B‐cell (ABC) and Type‐III subtypes. The method was highly reproducible and reliably classified cell lines of known phenotype. GCB and ABC subtypes were each characterized by unique gene expression signatures consistent with previously published data. A significant relationship between subtype and survival was observed, with ABC having the worst clinical outcome and in a multivariate survival model only age and GEP class remained significant. This effect was not seen when tumours were classified by immunohistochemistry. There was a significant association between age and subtype (mean ages ABC – 72·8 years, GC – 68·4 years, Type‐III – 64·5 years). Older patients with ABC subtype were also over‐represented in patients who died soon after diagnosis. The relationship between prognosis and subtype improved when only patients assigned to the three categories with the highest level of confidence were analysed. This study demonstrates that GEP‐based classification of DLBCL can be applied to RNA extracted from routine FFPE samples and has potential for use in stratified medicine trials and clinical practice.

Determinants of survival in patients with chronic myeloid leukaemia treated in the new era of oral therapy: findings from a UK population-based patient cohort

Objectives To examine contemporary survival patterns in the general population of patients diagnosed with chronic myeloid leukaemia (CML), and to identify patient groups with less than optimal outcomes. Design Prospective population-based cohort. Setting The UKs Haematological Malignancy Research Network (catchment population 3.6 million, with >2000 new haematological malignancies diagnosed annually). Participants All patients newly diagnosed with CML, from September 2004 to August 2011 and followed up to 31 March 2013. Main outcome measure Incidence and survival. Results With a median diagnostic age of 59 years, the CML age standardised (European) incidence was 0.9/100 000 (95% CIs 0.8 to 0.9), 5-year overall survival was 78.9% (72.3 to 84.0) and 5-year relative survival 88.6% (81.0 to 93.3). The efficacy of treatment across all ages was clearly demonstrated; the relative survival curves for those under 60 and over 60 years being closely aligned. Survival findings were similar for men and women, but varied with deprivation; the age and sex adjusted HR being 3.43 (1.89 to 6.22) for deprivation categories 4–5 (less affluent) versus 1–3 (more affluent). None of these differences were attributable to the biological features of the disease. Conclusions When therapy is freely provided, population-based survival for CML is similar to that reported in clinical trials, and age loses its prognostic significance. However, although most of the patients with CML now experience close to normal lifespans, those living in more deprived areas tend to have poorer outcomes, despite receiving the same clinical care. A significant improvement in overall population outcomes could be achieved if these socioeconomic differences, which may reflect the treatment compliance, could be eliminated.

Myeloid malignancies in the real-world: Occurrence, progression and survival in the UK’s population-based Haematological Malignancy Research Network 2004–15

Highlights • ICD-O3 analysis of “real-world” data revealed novel variations by sub-type, sex and age.• Males experience higher incidence and worse survival than females; the reasons for this are unknown.• Lack of concordance in the use of standard populations impacts markedly on the comparability of national incidence estimates.• Lack of concordance in recording progressions impacts on the comparability of national AML occurrence & survival estimates.

Variations in specialist palliative care referrals: findings from a population-based patient cohort of acute myeloid leukaemia, diffuse large B-cell lymphoma and myeloma

Objective To develop and implement a methodology for capturing complete haematological malignancy pathway data and use it to identify variations in specialist palliative care (SPC) referrals. Methods In our established UK population-based patient cohort, 323 patients were diagnosed with acute myeloid leukaemia, diffuse large B-cell lymphoma or myeloma between May 2005 and April 2008, and died before April 2010. A day-by-day calendar approach was devised to collect pathway data, including SPC referrals, to supplement routinely collected information on clinical presentation, diagnosis, treatment, response, and date and place of death. Results 155 (47.9%) of the 323 patients had at least one SPC referral. The likelihood of referral increased with survival (OR 6.58, 95% CIs 3.32 to 13.03 for patients surviving ≥1 year compared to ≤1 month from diagnosis), and varied with diagnosis (OR 1.96, CIs 1.15 to 3.35 for myeloma compared to acute myeloid leukaemia). Compared to patients dying in hospital, those who died at home or in a hospice were also more likely to have had an SPC referral (OR 3.07, CIs 1.59 to 5.93 and 4.74, CIs 1.51 to 14.81, respectively). No associations were found for age and sex. Conclusions Our novel approach efficiently captured pathway data and SPC referrals, revealing evidence of greater integration between haematology and SPC services than previously reported. The likelihood of referral was much higher among those dying outside hospital, and variations in practice were observed by diagnosis, emphasising the importance of examining diseases individually.