Morgane Mounier

Survival for haematological malignancies in Europe between 1997 and 2008 by region and age: results of EUROCARE-5, a population-based study

BACKGROUND More effective treatments have become available for haematological malignancies from the early 2000s, but few large-scale population-based studies have investigated their effect on survival. Using EUROCARE data, and HAEMACARE morphological groupings, we aimed to estimate time trends in population-based survival for 11 lymphoid and myeloid malignancies in 20 European countries, by region and age. METHODS In this retrospective observational study, we included patients (aged 15 years and older) diagnosed with haematological malignancies, diagnosed up to Dec 31, 2007, and followed up to Dec 31, 2008. We used data from the 30 cancer registries (across 20 countries) that provided continuous incidence and good quality data from 1992 to 2007. We used a hybrid approach to estimate age-standardised and age-specific 5-year relative survival, for each malignancy, overall and for five regions (UK, and northern, central, southern, and eastern Europe), and four 3-year periods (1997-99, 2000-02, 2003-05, 2006-08). For each malignancy, we also estimated the relative excess risk of death during the 5 years after diagnosis, by period, age, and region. FINDINGS We analysed 560 444 cases. From 1997-99 to 2006-08 survival increased for most malignancies: the largest increases were for diffuse large B-cell lymphoma (42·0% [95% CI 40·7-43·4] to 55·4% [54·6-56·2], p<0·0001), follicular lymphoma (58·9% [57·3-60·6] to 74·3% [72·9-75·5], p<0·0001), chronic myeloid leukaemia (32·3% [30·6-33·9] to 54·4% [52·5-56·2], p<0·0001), and acute promyelocytic leukaemia (50·1% [43·7-56·2] to 61·9% [57·0-66·4], p=0·0038, estimate not age-standardised). Other survival increases were seen for Hodgkins lymphoma (75·1% [74·1-76·0] to 79·3% [78·4-80·1], p<0·0001), chronic lymphocytic leukaemia/small lymphocytic lymphoma (66·1% [65·1-67·1] to 69·0% [68·1-69·8], p<0·0001), multiple myeloma/plasmacytoma (29·8% [29·0-30·6] to 39·6% [38·8-40·3], p<0·0001), precursor lymphoblastic leukaemia/lymphoma (29·8% [27·7-32·0] to 41·1% [39·0-43·1], p<0·0001), acute myeloid leukaemia (excluding acute promyelocytic leukaemia, 12·6% [11·9-13·3] to 14·8% [14·2-15·4], p<0·0001), and other myeloproliferative neoplasms (excluding chronic myeloid leukaemia, 70·3% [68·7-71·8] to 74·9% [73·8-75·9], p<0·0001). Survival increased slightly in southern Europe, more in the UK, and conspicuously in northern, central, and eastern Europe. However, eastern European survival was lower than that for other regions. Survival decreased with advancing age, and increased with time only slightly in patients aged 75 years or older, although a 10% increase in survival occurred in elderly patients with follicular lymphoma, diffuse large B-cell lymphoma, and chronic myeloid leukaemia. INTERPRETATION These trends are encouraging. Widespread use of new and more effective treatment probably explains much of the increased survival. However, the persistent differences in survival across Europe suggest variations in the quality of care and availability of the new treatments. High-resolution studies that collect data about stage at diagnosis and treatments for representative samples of cases could provide further evidence of treatment effectiveness and explain geographic variations in survival. FUNDING Compagnia di San Paolo, Fondazione Cariplo, European Commission, and Italian Ministry of Health.

Concordance of assays designed for the quantification of JAK2V617F: a multicenter study.

This study shows that different techniques, particularly following calibration to a reference standard, can guarantee accurate quantification of the JAK2 (V617) mutant allele burden. See related perspective article on page 7. Background Many different techniques have been designed for the quantification of JAK2V617F allelic burden, sometimes producing discrepant results. Design and Methods JAK2V617F quantification techniques were compared among 16 centers using 11 assays based on quantitative polymerase chain reaction (with mutation-specific primers or probes, or fluorescent resonance energy transfer/melting curve analysis), allele-specific polymerase chain reaction, conventional sequencing or pyrosequencing. Results A first series of blinded samples (granulocyte DNA, n=29) was analyzed. Seven assays (12 centers) reported values inside the mean±2SD; the mean coefficient of variation was 31%. Sequencing techniques lacked sensitivity, and strong discrepancies were observed with four techniques, which could be attributed to inadequate standards or to different modes of expression of results. Indeed, quantification of JAK2V617F in relation to another control gene produced higher than expected values, suggesting the possibility of more than two JAK2 copies/cell. After calibration of assays with common 1% to 100% JAK2V617F standards (dilutions of UKE-1 cells in normal leukocytes), 14 centers tested ten new samples. JAK2V617F allelic burdens greater or equal than 1% were then reliably quantified by five techniques – one allele specific-polymerase chain reaction and four TaqMan allele-specific quantitative polymerase chain reaction assays, including one previously giving results outside the mean±2SD – with a lower mean coefficient of variation (21%). Of these, only the two TaqMan allele-specific quantitative polymerase chain reaction assays with primer-based specificity could detect 0.2% JAK2V617F. Conclusions Techniques expressing the allelic burden as JAK2V617F/total JAK2 and using a common set of standards produced similar quantification results but with variable sensitivity. Calibration to a reference standard improved reproducibility.

Twenty-five years of epidemiological recording on myeloid malignancies: data from the specialized registry of hematologic malignancies of Côte d’Or (Burgundy, France)

Background Epidemiological data on myeloid malignancies are very rare in the literature due to a lack of registration by cancer registries until 2000. The Registry of Hematologic Malignancies of the Côte d’Or Department in France has, however, steadfastly registered data on cases occurring in the Department since 1980, resulting, to date, in a database of over 5,000 cases classified according to the ICD-O-3 classification, following the most recent World Health Organization classification criteria. Design and Methods Twenty-five years of data on myeloid malignancies, including acute myeloid leukemia, myeloproliferative neoplasms, myelodysplastic syndromes and myelodysplastic/myeloproliferative syndromes were analyzed. World population standardized incidence rates were calculated as were as observed and relative survival. Results Incidence rates per 100,000 inhabitants/year were 2.5 for acute myeloid leukemia, 1.3 for myelodysplastic syndromes, 3.2 for myeloproliferative neoplasms and 0.6 for myelodysplastic/myeloproliferative syndromes. It was found that the incidence rate of myelodysplastic syndromes increased significantly over the period. The median overall survival is 8.9 months for patients with acute myeloid leukemia, 33.8 months for patients with myelodysplastic syndromes, 91.7 months for those with myeloproliferative neoplasms and 26.6 months for patients with myelodysplastic/myeloproliferative syndromes. Observed and relative 20-year survival rates are, respectively, 12% and 13% in acute myeloid leukemia, 2% and 6% in myelodysplastic syndromes and 20% and 34% in myeloproliferative neoplasms. Conclusions These population-based data on myeloid malignancies are the first data collected over such a long period and provide interesting information for clinicians and public health authorities, particularly given the paucity of other long-term, population-based data from cancer registries.

Frequent reduction or absence of detection of the JAK2-mutated clone in JAK2V617F-positive patients within the first years of hydroxyurea therapy

In this study, hydroxyurea treatment reduced the percentage of JAK2V617F mutant alleles by >30% in 13/25 patients with essential thrombocythemia or polycythemia vera within the first year after diagnosis. We analyzed the effect of hydroxyurea on the JAK2V617F allelic ratio (%JAK2V617F), measured in purified blood granulocytes, of patients with polycythemia vera and essential thrombocythemia. Thirty-six patients were examined sequentially prior to and after start of hydroxy-urea therapy (8 polycythemia vera, 17 essential thrombocythemia), or while remaining untreated (2 polycythemia vera, 9 essential thrombocythemia). Hydroxyurea therapy (median duration: 15 months) reduced the %JAK2V617F by >30% in 13/25 patients (4 polycythemia vera, 9 essential thrombocythemia). For 3 patients, JAK2V617F remained undetectable for 3–27 months. In addition, a single time point study of two large cohorts of patients, examined either at the time of diagnosis (99 polycythemia vera, 178 essential thrombocythemia) or while receiving hydroxyurea (36 polycythemia vera, 98 essential thrombocythemia; median length of therapy: 32 months), confirmed reduction of %JAK2V617F in the hydroxyurea-treated group (24% vs. 33% JAK2V617F at diagnosis, p<0.01). Prospective studies are needed to determine the prognostic value of reduced JAK2V617F allele burden under cytoreductive therapy.

Increased Risk of Acute Myeloid Leukemias and Myelodysplastic Syndromes in Patients Who Received Thiopurine Treatment for Inflammatory Bowel Disease

BACKGROUND & AIMS Treatment with immunosuppressive thiopurines such as azathioprine is associated with an increased risk of leukemogenesis. We assessed the risk of myeloid disorders, such as acute myeloid leukemia and myelodysplastic syndromes, in a large cohort of patients with inflammatory bowel disease (IBD) in France. METHODS We performed a prospective observational study of 19,486 patients with IBD enrolled in the Cancers Et Surrisque Associé aux Maladies inflammatoires intestinales En France (CESAME) study from May 2004 through June 2005; patients were followed through December 31, 2007. The incidence of myeloid disorders in the general population, which was used for reference, was determined from the French Network of Cancer Registries. RESULTS During 49,736 patient-years of follow-up, 5 patients were diagnosed with incident myeloid disorders (2 with acute myeloid leukemia and 3 with myelodysplastic syndromes). Four of these patients had been exposed to thiopurines (1 with ongoing treatment and 3 with past exposure). The risk of myeloid disorders was not increased among the overall IBD population, compared with the general population; the standardized incidence ratio (SIR) was 1.80 (95% confidence interval [CI], 0.58-4.20). The risk of myeloid disorders was not increased among patients with IBD and ongoing thiopurine treatment (SIR, 1.54; 95% CI, 0.05-8.54), but patients with past exposures to thiopurines had an increased risk of myeloid disorders (SIR, 6.98; 95% CI, 1.44-20.36). CONCLUSIONS Past exposure to thiopurines increases the risk of myeloid disorders 7-fold among patients with IBD. This finding should be considered when initiating thiopurine therapy, so risks and benefits can be calculated.

Leucocytosis and thrombosis at diagnosis are associated with poor survival in polycythaemia vera: a population-based study of 327 patients

Three hundred and twenty‐seven patients from two population‐based cohorts with an established diagnosis of polycythaemia vera were studied for prognostic risk factors for survival and leukaemia in a long‐term survey. The relative survival (RS) was 72% and 46% at 10 and 20 years respectively, from the time of diagnosis. Multivariate analysis identified age >70 years, white blood cell count >13 × 109/l and thrombo‐embolism at diagnosis as independent risk factors. Patients with two or three of these factors had a 10 year RS of 26%, compared with 59% and 84% in patients with one and no risk factors, respectively. Age and leucocyte count are the main predicting factors for survival in polycythaemia vera.

Significant increase in the apparent incidence of essential thrombocythemia related to new WHO diagnostic criteria: a population-based study

The findings of this study confirm the relevance of the new WHO diagnostic criteria in allowing earlier diagnosis of essential thrombocythemia. To observe the effect of the new World Health Organization (WHO) criteria on the incidence of myeloproliferative neoplasms, we performed a retrospective study of a population-based registry in the Côte d’Or area, France, from 1980 to 2007. A total of 524 myeloproliferative neoplasms were registered for the 1980–2007 period, including 135 polycythemia vera, 308 essential thrombocythemia and 81 idiopathic myelofibroses. No change in the incidence of either polycythemia vera or idiopathic myelofibrosis was observed for the 2005–2007 period, compared to 1980–2004. On the contrary, a pronounced increase in the incidence of essential thrombocythemia was noted after 2005, mainly due to the use of JAK2 mutation screening and a lower threshold of platelet count. Our study confirms the relevance of the new WHO diagnostic criteria in allowing earlier diagnosis of essential thrombocythemia.

Clinical features and course of refractory anemia with ring sideroblasts associated with marked thrombocytosis

Background Refractory anemia with ring sideroblasts associated with marked thrombocytosis was proposed as a provisional entity in the 2001 World Health Organization classification of myeloid neoplasms and also in the 2008 version, but its existence as a single entity is contested. We wish to define the clinical features of this rare myelodysplastic/myeloproliferative neoplasm and to compare its clinical outcome with that of refractory anemia with ring sideroblasts and essential thrombocythemia. Design and Methods We conducted a collaborative retrospective study across Europe. Our database included 200 patients diagnosed with refractory anemia with ring sideroblasts and marked thrombocytosis. For each of these patients, each patient diagnosed with refractory anemia with ring sideroblasts was matched for age and sex. At the same time, a cohort of 454 patients with essential thrombocythemia was used to compare outcomes of the two diseases. Results In patients with refractory anemia with ring sideroblasts and marked thrombocytosis, depending on the Janus Kinase 2 V617F mutational status (positive or negative) or platelet threshold (over or below 600×109/L), no difference in survival was noted. However, these patients had shorter overall survival and leukemia-free survival with a lower risk of thrombotic complications than did patients with essential thrombocythemia (P<0.001) but better survival (P<0.001) and a higher risk of thrombosis (P=0.039) than patients with refractory anemia with ring sideroblasts. Conclusions The clinical course of refractory anemia with ring sideroblasts and marked thrombocytosis is better than that of refractory anemia with ring sideroblasts and worse than that of essential thrombocythemia. The higher risk of thrombotic events in this disorder suggests that anti-platelet therapy might be considered in this subset of patients. From a clinical point of view, it appears to be important to consider refractory anemia with ring sideroblasts and marked thrombocytosis as a distinct entity.

Risk assessment of second primary cancer according to histological subtype of non-Hodgkin lymphoma

Non-Hodgkin lymphoma (NHL) represents a heterogeneous group of diseases that are known to carry a considerable risk of second primary cancer (SPC). However, little attention has been paid to SPC risk assessment according to NHL subtypes. Data from 10 French population-based cancer registries were used to establish a cohort of 7546 patients with a first diagnosis of NHL (eight subtypes) between 1989 and 2004. Standardized incidence ratios (SIRs) of metachronous SPC were estimated. Among the 7546 patients diagnosed with a NHL, the overall SPC risk was 25% higher than that in the reference population (SIR = 1.25, 95% confidence interval 1.15–1.36). In univariate analysis, the SPC risk differed by lymphoma subtype. Interestingly, multivariate analysis showed that SPC risk did not differ significantly across NHL subtypes after adjustment for the other covariates (p = 0.786). Patients with NHL have an increased risk of SPC that is not influenced by the histological NHL subtype.

Trends in excess mortality in follicular lymphoma at a population level

Since the 1990s and since the development of humanised monoclonal antibodies in 1998, the treatment of non‐Hodgkin lymphoma has undergone profound changes. Follicular lymphoma (FL) was the first to benefit from this treatment, and several clinical trials have shown a significant improvement in overall survival, but little information is available at a population level.