Prognostic value of postinduction medullary myeloid recovery by flow cytometry in acute myeloid leukemia.

Risk stratification and treatment response evaluation are key features in acute myeloid leukemia (AML) management. Immunophenotypic and molecular approaches all rely on the detection of persisting leukemic cells by measurable residual disease techniques. A new approach is proposed here by assessing medullary myeloid maturation by flow cytometry through a myeloid progenitor ratio (MPR). The normal MPR range was defined using reference normal bone marrows (n = 48). MPR was considered balanced if between 1 and 4 and unbalanced if < 1 or > 4. MPR was retrospectively assessed at baseline and post-induction for 206 newly diagnosed AML patients eligible for intensive treatment from two different French centers. All AML baseline MPR were unbalanced and thus significantly different from normal MPR (p < 0.0001). Patients with an unbalanced MPR after induction had worse 3-year overall survival (OS) (44.4% vs. 80.2%, HR, 2.96; 95% CI, 1.81-4.84, p < 0.0001) and 3-year relapse free survival (RFS) (38.7% vs. 64.4%, HR, 2.11; 95% CI, 1.39-3.18, p < 0.001). In multivariate analysis, postinduction unbalanced MPR was significantly associated with shorter OS and RFS regardless of the European LeukemiaNet 2010 risk stratification or NPM1/FLT3-ITD status. A balanced postinduction MPR conversely conferred favorable outcomes and reflects medullary myeloid recovery.

Lifetime occupational and recreational physical activity and risk of lymphoma subtypes. Results from the European Epilymph case-control study.

Physical activity is known to convey protection against several cancers. However, results on the risk of lymphoma overall and its subtypes have been inconsistent. The aim of this study was to investigate occupational and recreational physical activity in relation to risk of lymphoma subtypes adjusting for established occupational risk factors. We applied standardized tools to assess energy expenditure at work and in recreational physical activities to the questionnaire information on lifetime work and exercise history in 1117 lymphoma cases, including Hodgkin lymphoma, and B-cell (including chronic lymphocytic leukemia, and multiple myeloma) and T-cell non-Hodgkin's lymphoma (NHL) subtypes, and 1207 controls who took part in the multicentre European EpiLymph case-control study. We calculated the risk of lymphoma (all subtypes), B-cell NHL and its most represented subtypes, and Hodgkin's lymphoma (all subtypes) associated with weekly average Metabolic Equivalent of Task (MET-hours/week) and cumulative MET-hours of lifetime recreational, occupational, and total physical activity, with unconditional logistic regression and polytomous regression analysis adjusting by age, centre, sex, education, body mass index, history of farm work and solvent use. We observed an inverse association of occupational, and total physical activity with risk of lymphoma (all subtypes), and B-cell non-Hodgkin's lymphoma among women, and an upward trend in risk of Hodgkin's lymphoma with recreational and total physical activity among men, for which we cannot exclude chance or bias. Our results suggest no effect of overall physical activity on risk of lymphoma and its subtypes.

Lymphoma In Patients With Inflammatory Bowel Disease: A Multicenter Collaborative Study Between Getaid And Lysa.

BACKGROUND: IBD is associated with an increased risk of developing lymphoma. Although recent data clarifies lymphoma epidemiology in IBD patients, clinical and pathological characteristics of lymphoma occurring in IBD remain ill-known. METHODS: Patients with IBD and lymphoma were retrospectively identified in the framework of a national collaborative study including the Groupe d'Étude Thérapeutique des Affections Inflammatoires du Tube Digestif (GETAID) and the Lymphoma Study Association (LYSA). We characterized clinical and prognostic features for the 3 most frequent lymphoma subtypes occurring in IBD. We performed a multicentric case-control study. Controls (lymphoma de novo) were matched (5:1) to cases on gender, age at diagnosis, lymphoma subtype, year of diagnosis, IPI/FLIPI indexes. Overall survival (OS) and progression free survival were compared between cases and controls. RESULTS: 133 IBD patients with lymphoma were included (males = 62.4 %, median age at lymphoma diagnosis = 49 years in males ; 42 in females). Most had Crohn's disease (73.7 %) and were exposed to thiopurines (59.4 %). The most frequent lymphoma subtypes were diffuse large B cell lymphoma (DLBCL, 45.1 %), Hodgkin lymphoma (HL, 18.8 %), and follicular lymphoma (FL, 10.5 %). When matched with 365 controls, prognosis was improved in IBD patients with DLBCL compared to controls (p = 0.0064, hazard ratio = 0.36) or similar (HL and FL). CONCLUSION: Lymphomas occurring in IBD patients do not seem to have a worse outcome than in patients without IBD. Due to the scarcity of this situation, those patients should be managed in expert centers.

Factors Affecting Health-Related Quality of Life among Survivors of Non-Hodgkin Lymphoma: A Population-Based Study.

PURPOSE: To describe Health-Related Quality of Life (HRQoL) and to identify the association between sociodemographic, clinical and psychosocial factors, and self-reported HRQoL among NHL survivors. METHODS: The data of the cancer registry specialized in hematological malignancies in Côte d'Or (France) were used to identify all patients diagnosed with follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) from 2010 to 2017. Patients were invited to complete SF-12 and other questionnaires. RESULTS: The HRQoL of NHL survivors was poorer than that of the French general population (p < 0.05) in vitality (48 vs. 56), general health (56 vs. 63), role physical scores (60 vs. 70), role emotional scores (64 vs. 72) and the Mental Component Scale (45 vs. 49). The mean difference in physical functioning decreased per unit increase in age (ß = -1.1 (0.3); p < 0.001). Men had better vitality than women (ß = 12.4 (6.1); p = 0.04) and the high education level was associated with greater role emotional scores (ß = 14.1 (5.4); p = 0.01). Symptoms of anxiety and depression were associated with poorer HRQoL. The satisfaction of social support was associated with significantly greater scores on mental health (ß = 17.3 (5.1); p = 0.001) and social functioning (ß = 15.7 (7.8); p = 0.04). Socioeconomic deprivation was associated with poorer general health (ß = -12.8 (5.2); p = 0.01). CONCLUSIONS: From 3 to 11 years post-diagnosis, the main factors found to be associated with poor HRQoL of NHL survivors were age, sex, presence of anxiety, depression and economic problems. These findings suggest the need for supportive care to improve HRQOL and the consideration of these problems when developing care plans for NHL survivors.

Factors influencing access to specialised haematology units during acute myeloblastic leukaemia patient care: A population-based study in France.

BACKGROUND: The excess mortality observed in Acute Myeloblastic Leukaemia (AML) patients, partly attributed to unequal access to curative treatments, could be linked to care pathways. METHODS: We included 1039 AML incident cases diagnosed between 2012-2016 from the 3 French blood cancer registries (3,625,400 inhabitants). We describe patients according to age, the medical entry unit and access to the specialised haematology unit (SHU) during follow-up. Multivariate logistic regression model was done to determine the association between covariables and access to SHU. A total of 713 patients (69%) had access to SHU during care. RESULTS: The most common care pathway concerned referral from the general practitioner to SHU, n = 459(44%). The univariate analysis observed a downward trend for the most deprived patients. Patients who consulted in SHU were younger (66 years vs. 83, p < 0.001), and 92% had access to cytogenetic analysis (vs. 54%, p < 0.001). They also had less poor prognosis AML-subtypes (AML-MRC, t-AML/MDS and AML-NOS) (38% vs. 69%); 77% with de novo AML (vs. 67%, p < 0.003)], more favourable cytogenetic prognostic status (23% vs. 6%, p < 0.001), less comorbidities (no comorbidity = 55% vs. 34%, p < 0.001) and treatments proposed were curative 68% (vs. 5.3%, p < 0.001). Factors limiting access to SHU were age over 80 years (OR, 0.14; 95% CI, 0.04-0.38), severe comorbidities (OR, 0.39; 95% CI, 0.21-0.69), emergency unit referral (OR, 0.28; 95% CI, 0.18-0.44) and non-SHU referral (OR, 0.12; 95% CI, 0.07-0.18). Consultation in an academic hospital increased access to SHU by 8.87 times (95% CI, 5.64-14.2). CONCLUSION: The high proportion of access to cytogenetic testing and curative treatment among patients admitted to SHU, and the importance of early treatment in AML underlines the importance of access to SHU for both diagnosis and treatment.

Clear Improvement in Real-World Chronic Myeloid Leukemia Survival: A Comparison With Randomized Controlled Trials.

Tyrosine kinase inhibitors (TKIs) have been improving the prognosis of patients with chronic myeloid leukemia (CML), but there are still large differences in survival among European countries. This raises questions on the added value of results from population-based studies, which use real-world data, compared to results of randomized controlled trials (RCTs) involving patients with CML. There are also questions about the extent of the findings on RCTs effectiveness for patients in the general population. We compare survival data extracted from our previous systematic review and meta-analysis of CML RCTs with the latest updated population-based survival data of EUROCARE-6, the widest collaborative study on cancer survival in Europe. The EUROCARE-6 CML survival estimated in patients (15-64 years) diagnosed in 2000-2006 vs. 2007-2013 revealed that the prognostic improvement highlighted by RCTs was confirmed in real-world settings, too. The study shows, evaluating for the first time all European regions, that the optimal outcome figures obtained in controlled settings for CML are also achievable (and indeed achieved) in real-world settings with prompt introduction of TKIs in daily clinical practice. However, some differences still persist, particularly in Eastern European countries, where overall survival values are lower than elsewhere, probably due to a delayed introduction of TKIs. Our results suggest an insufficient adoption of adequate protocols in daily clinical practice in those countries where CML survival values remain lower in real life than the values obtained in RCTs. New high-resolution population-based studies may help to identify failures in the clinical pathways followed there.

Mortality and Major Cardiovascular Events among Patients with Multiple Myeloma: Analysis from a Nationwide French Medical Information Database.

BACKGROUND: No robust data assesses the risk of all-cause death and cardiovascular (CV) events in multiple myeloma (MM) patients. PATIENTS AND METHODS: From 1 January to 31 December 2013, 3,381,472 adults were hospitalised (for any reason) in French hospitals. We identified 15,774 patients diagnosed with known MM at baseline. The outcome analysis (all-cause death, CV death, myocardial infarction (MI), ischaemic stroke, or hospitalization for bleedings) was performed with follow-ups starting at the time of the last event. For each MM patient, a propensity score-matched patient without MM was selected. RESULTS: The mean follow-up in the propensity-score-matched population was 3.7 ± 2.3 years. Matched patients with MM had a higher risk of all-death (yearly rate 20.02 vs. 11.39%) than patients without MM. No difference was observed between the MM group and no-MM group for CV death (yearly rate 2.00 vs. 2.02%). The incidence rate of MI and stroke was lower in the MM group: 0.86 vs. 0.97%/y and 0.85 vs. 1.10%/y, respectively. In contrast, MM patients had a higher incidence rate of rehospitalization for major bleeding (3.61 vs. 2.24%/y) and intracranial bleeding (1.03 vs. 0.84%/y). CONCLUSIONS: From a large nationwide database, we demonstrated that MM patients do not have a higher risk of CV death or even a lower risk of both MI and ischaemic stroke. Conversely, MM patients had a higher risk of both major and intracranial bleedings, highlighting the key issue of thromboprophylaxis in these patients.

COVID-19 Lockdown in Patients with Chronic Diseases: A Cross-Sectional Study.

Background: We aimed to investigate the impact of the first COVID-19 lockdown on medication adherence, physician access, lifestyle behaviours, and mental health in patients with chronic conditions. Methods: A cross-sectional phone survey was conducted in 1274 housebound adults recruited from 8 regional chronic disease cohorts (CLEO CD study: NCT04390126). Results: Medication adherence was 97%; 305 (41%) patients declared that at least one scheduled visit with a physician was missed during the first lockdown. The main changes in lifestyle behaviours were deterioration in sleep time (duration and/or quality; 71%), increase in screen time (46%), and decrease in physical activity (46%). Nineteen percent experienced psychological distress (Kessler-6 score ≥ 5). An urban living place (OR, 1.76 vs. rural; 95% CI, 1.32−2.33; p = 10−4), worse self-reported mental health (OR, 1.62 vs. about the same or better; 95% CI, 1.17−2.25; p = 0.003), and a K6 score ≥ 5 (OR, 1.52 vs. <5; 95% CI, 1.05−2.21; p = 0.03) were independent factors associated with at least one unhealthy behaviour. Conclusions: Encouraging results were observed in terms of medication adherence. Caution is needed in chronic disease patients living in urban places as well as those presenting psychological distress and worse self-reported mental health to reduce unhealthy behaviours.

Prescription of Blood Lymphocyte Immunophenotyping in the Diagnosis of Lymphoid Neoplasms in Older Adults.

Lymphoid neoplasms are a heterogeneous group of lymphoid neoplastic diseases with multiple presentations, and varying prognoses. They are especially frequent in older patients (OPs) and the atypism of this frail elderly population can make the diagnostic process even more difficult. Blood lymphocyte immunophenotyping (BLI) is essential in rapid noninvasive diagnosis orientation and guides complementary investigations. To our knowledge, BLI prescription has never been evaluated in OPs. We hypothesized that, when there is a suspicion of lymphoid neoplasm in the geriatric population, a BLI is performed in view of various clinical or biological abnormalities. This study aimed to: (1) describe the characteristics of hospitalized OPs having undergone BLI for suspected lymphoid neoplasm, (2) identify the causes leading to BLI prescription, and (3) identify the most profitable criteria for BLI prescription. This was a descriptive retrospective study on 151 OPs aged ≥75 years who underwent BLI over a 2-year period. Regarding BLI prescriptions, eight had lymphocytosis, constituting the "lymphocytosis group" (LG+), while the 143 others had BLI prescribed for reasons other than lymphocytosis (LG-), mainly general weakness and anemia. In the LG-, we compared OPs with positive and negative BLI results. The criteria found to be profitable for BLI prescription were lymphadenopathy, splenomegaly, lymphocytosis, and thrombocytopenia. BLI identified circulating lymphoid neoplasms (positive BLI) in 21/151 OPs, mainly marginal zone lymphoma and chronic lymphocytic leukemia. In polymorbid OPs, as per our study population, the diagnostic and therapeutic complexity explained in part the sole use of indirect and minimally invasive diagnostic techniques such as BLI.

Impact of first COVID-19 lockdown on paediatric and adult haemophilia patients treated in a French Haemophilia Comprehensive Care Centre.

INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic has created an unprecedented global health crisis. AIM: To investigate the impact of the 1st COVID-19 lockdown on haemophilia patients in terms of symptoms, management, medication adherence, mental health and lifestyle behaviours. METHODS: A prospective cross-sectional phone survey using a two-part questionnaire was conducted in haemophilia patients (adults and children) followed-up in a French Haemophilia Comprehensive Care Centre between May 5, 2020 and June 2, 2020 (CLEO CD study: NCT04390126). RESULTS: Among 284 haemophilia A or B patients with FVIII or FIX < 40% contacted for the study, 239 (84%) including 183 adults and 56 children participated to the survey. In 81% of children and 78% of adults, bleeding episodes remained unchanged or decreased. Medication adherence was 82.0% in adults and 98.2% in children. Non-adherence concerned haemostatic agents in six patients and analgesics in three. Overall, 67% of adults and 71% of children felt as good as before lockdown. In both adults and children, the three major changes in lifestyle behaviours were: increase in screen time (49% and 57%), decrease in physical activity (43% and 48%), and weight gain (32% and 27%), respectively. CONCLUSIONS: Encouraging results were observed in terms of haemophilia symptoms, medication adherence, and mental health. Conversely, a negative impact was observed on lifestyle behaviours in a cohort of French haemophilia patients during the 1st lockdown.

B-Cell NHL Subtype Risk Associated with Autoimmune Conditions and PRS.

BACKGROUND: A previous International Lymphoma Epidemiology (InterLymph) Consortium evaluation of joint associations between five immune gene variants and autoimmune conditions reported interactions between B-cell response-mediated autoimmune conditions and the rs1800629 genotype on risk of B-cell non-Hodgkin lymphoma (NHL) subtypes. Here, we extend that evaluation using NHL subtype-specific polygenic risk scores (PRS) constructed from loci identified in genome-wide association studies of three common B-cell NHL subtypes. METHODS: In a pooled analysis of NHL cases and controls of Caucasian descent from 14 participating InterLymph studies, we evaluated joint associations between B-cell-mediated autoimmune conditions and tertile (T) of PRS for risk of diffuse large B-cell lymphoma (DLBCL; n = 1,914), follicular lymphoma (n = 1,733), and marginal zone lymphoma (MZL; n = 407), using unconditional logistic regression. RESULTS: We demonstrated a positive association of DLBCL PRS with DLBCL risk [T2 vs. T1: OR = 1.24; 95% confidence interval (CI), 1.08-1.43; T3 vs. T1: OR = 1.81; 95% CI, 1.59-2.07; P-trend (Ptrend) < 0.0001]. DLBCL risk also increased with increasing PRS tertile among those with an autoimmune condition, being highest for those with a B-cell-mediated autoimmune condition and a T3 PRS [OR = 6.46 vs. no autoimmune condition and a T1 PRS, Ptrend < 0.0001, P-interaction (Pinteraction) = 0.49]. Follicular lymphoma and MZL risk demonstrated no evidence of joint associations or significant Pinteraction. CONCLUSIONS: Our results suggest that PRS constructed from currently known subtype-specific loci may not necessarily capture biological pathways shared with autoimmune conditions. IMPACT: Targeted genetic (PRS) screening among population subsets with autoimmune conditions may offer opportunities for identifying those at highest risk for (and early detection from) DLBCL.

Genome-wide homozygosity and risk of four non-Hodgkin lymphoma subtypes.

AIM: Recessive genetic variation is thought to play a role in non-Hodgkin lymphoma (NHL) etiology. Runs of homozygosity (ROH), defined based on long, continuous segments of homozygous SNPs, can be used to estimate both measured and unmeasured recessive genetic variation. We sought to examine genome-wide homozygosity and NHL risk. METHODS: We used data from eight genome-wide association studies of four common NHL subtypes: 3061 chronic lymphocytic leukemia (CLL), 3814 diffuse large B-cell lymphoma (DLBCL), 2784 follicular lymphoma (FL), and 808 marginal zone lymphoma (MZL) cases, as well as 9374 controls. We examined the effect of homozygous variation on risk by: (1) estimating the fraction of the autosome containing runs of homozygosity (FROH); (2) calculating an inbreeding coefficient derived from the correlation among uniting gametes (F3); and (3) examining specific autosomal regions containing ROH. For each, we calculated beta coefficients and standard errors using logistic regression and combined estimates across studies using random-effects meta-analysis. RESULTS: We discovered positive associations between FROH and CLL (ß = 21.1, SE = 4.41, P = 1.6 × 10-6) and FL (ß = 11.4, SE = 5.82, P = 0.02) but not DLBCL (P = 1.0) or MZL (P = 0.91). For F3, we observed an association with CLL (ß = 27.5, SE = 6.51, P = 2.4 × 10-5). We did not find evidence of associations with specific ROH, suggesting that the associations observed with FROH and F3 for CLL and FL risk were not driven by a single region of homozygosity. CONCLUSION: Our findings support the role of recessive genetic variation in the etiology of CLL and FL; additional research is needed to identify the specific loci associated with NHL risk.

Second- or third-generation tyrosine kinase inhibitors in first-line treatment of chronic myeloid leukemia in general population: Is there a real benefit?

INTRODUCTION: Since 2009, multiple randomized trials have shown faster and deeper responses in CML patients treated with new-generation TKI (NG-TKI) compared to those treated with imatinib (IM). Are the same results observed in the general population? MATERIALS AND METHODS: Patients were identified from the three French hematological malignancies population-based registries. All CML patients (ICD-O-3: 9875/3) diagnosed between 2006 and 2016 and resided in registries areas were included. The TKI generation effect on achievement of MMR in first-line therapy was assessed through a multivariate competitive risk analysis. An alluvial plot described the pathways leading to death. RESULTS: In total, 507 CML patients received TKI in first-line treatment, 22% were enrolled in a clinical trial. After adjustment, NG-TKI patients were significantly more likely to achieve MMR during first-line therapy than IM patients (HR: 1.88 CI95% [1.35-2.61]). At the end of follow-up, 212 patients were still in first-line therapy (46 of them died), 203 switched to second-line (43 subsequently died), 26 were on TFR from first-line (4 subsequently died), and 20 stopped their treatment (16 subsequently died). DISCUSSION: In this comprehensive real-life setting, the results were consistent with clinical trials. The results are not sufficient to conclude that a NG-TKI treatment is superior with regard to these patients, despite indications regarding differences between the TKI generation effect on survival and tolerance.

Trends in endocrine therapy prescription and survival in patients with non-metastatic hormone receptor positive breast cancer treated with endocrine therapy: A population based-study.

PURPOSE: To identify prognostic factors of invasive-disease free survival (iDFS) in women with non-metastatic hormone receptor positive (HR+) breast cancer (BC) in daily routine practice. METHODS: We performed a retrospective study using data from the Côte d'Or breast and gynecological cancer registry in France. All women diagnosed with primary invasive non-metastatic HR + BC from 1998 to 2015 and treated by endocrine therapy (ET) were included. Women with bilateral tumors or who received ET for either metastasis or relapse were excluded. We performed adjusted survival analysis and Cox regression to identify prognostic factors of iDFS. RESULTS: A total of 3976 women were included. Age at diagnosis, ET class, SBR grade, treatment, stage and comorbidity were independently associated with iDFS. Women who had neither surgery nor radiotherapy had the highest risk of recurrence (HR = 3.75, 95%CI [2.65-5.32], p < 0.0001). Receiving aromatase inhibitors (AI) was associated with a lower risk of recurrence (HR = 0.70, 95%CI [0.54-0.90], p = 0.055) compared to tamoxifen. Compared to women with no comorbidities, women with 1 or 2 comorbidities were more likely to receive AI (OR = 1.63, 95%CI [1.22-2.17], p = 0.0009). CONCLUSIONS: Comorbidities, age at diagnosis and previous treatment were associated with iDFS in non-metastatic HR + BC patients. This study also showed that women who received tamoxifen for their cancer experienced worse iDFS compared to women treated with AI.

Heamatological malignancies in giant cell arteritis: a French population-based study.

OBJECTIVES: An increased risk of haematological malignancies (HM) has been reported in GCA patients. Our study aimed to investigate the incidence and the type of HM occurring in GCA. METHODS: All patients with GCA and HM living in Côte d'Or (France) were identified by crossing data from the RHEMCO (Registre des Hémopathies Malignes de Côte d'Or) and those having a positive temporal artery biopsy between 1 January 2001 and 31 December 2018. RESULTS: Among 276 biopsy-proven GCA patients, 14 HM were identified in 12 patients (4.3%). In comparison with the general population aged >50 y, the incidence of myeloid HM and myeloproliferative syndromes were increased in GCA patients [standardized incidence ratios (SIR) = 2.71 and 5.16, respectively], with a specific increase in men with GCA (SIR = 4.82 and 9.04, respectively) but not in women. In addition, the study of SIR depending on the chronology between GCA and HM diagnoses suggests that there was an increased risk of developing GCA in men but not in women, after a diagnosis of myeloid HM (SIR = 9.56), especially if it was a MPS (SIR = 17.56). CONCLUSIONS: Our study shows a particular epidemiology of HM in GCA patients, which is characterized by an increased incidence of myeloid HM, especially MPS, in male GCA patients. The chronology of the diagnoses of GCA and HM raises the hypothesis that clonal hematopoiesis may be implicated in some cases of GCA.

Flexible Modeling of Net Survival and Cure by AML Subtype and Age: A French Population-Based Study from FRANCIM.

With improvements in acute myeloid leukemia (AML) diagnosis and treatment, more patients are surviving for longer periods. A French population of 9453 AML patients aged ≥15 years diagnosed from 1995 to 2015 was studied to quantify the proportion cured (P), time to cure (TTC) and median survival of patients who are not cured (MedS). Net survival (NS) was estimated using a flexible model adjusted for age and sex in sixteen AML subtypes. When cure assumption was acceptable, the flexible cure model was used to estimate P, TTC and MedS for the uncured patients. The 5-year NS varied from 68% to 9% in men and from 77% to 11% in women in acute promyelocytic leukemia (AML-APL) and in therapy-related AML (t-AML), respectively. Major age-differenced survival was observed for patients with a diagnosis of AML with recurrent cytogenetic abnormalities. A poorer survival in younger patients was found in t-AML and AML with minimal differentiation. An atypical survival profile was found for acute myelomonocytic leukemia and AML without maturation in both sexes and for AML not otherwise specified (only for men) according to age, with a better prognosis for middle-aged compared to younger patients. Sex disparity regarding survival was observed in younger patients with t-AML diagnosed at 25 years of age (+28% at 5 years in men compared to women) and in AML with minimal differentiation (+23% at 5 years in women compared to men). All AML subtypes included an age group for which the assumption of cure was acceptable, although P varied from 90% in younger women with AML-APL to 3% in older men with acute monoblastic and monocytic leukemia. Increased P was associated with shorter TTC. A sizeable proportion of AML patients do not achieve cure, and MedS for these did not exceed 23 months. We identify AML subsets where cure assumption is negative, thus pointing to priority areas for future research efforts.

Identification of novel, clonally stable, somatic mutations targeting transcription factors PAX5 and NKX2-3, the epigenetic regulator LRIF1, and BRAF in a case of atypical B-cell chronic lymphocytic leukemia harboring a t(14;18)(q32;q21).

Diagnosis of B-cell chronic lymphocytic leukemia (B-CLL) is usually straightforward, involving clinical, immunophenotypic (Matutes score), and (immuno)genetic analyses (to refine patient prognosis for treatment). CLL cases with atypical presentation (e.g., Matutes ≤ 3) are also encountered, and for these diseases, biology and prognostic impact are less clear. Here we report the genomic characterization of a case of atypical B-CLL in a 70-yr-old male patient; B-CLL cells showed a Matutes score of 3, chromosomal translocation t(14;18)(q32;q21) (BCL2/IGH), mutated IGHV, deletion 17p, and mutations in BCL2, NOTCH1 (subclonal), and TP53 (subclonal). Quite strikingly, a novel PAX5 mutation that was predicted to be loss of function was also seen. Exome sequencing identified, in addition, a potentially actionable BRAF mutation, together with novel somatic mutations affecting the homeobox transcription factor NKX2-3, known to control B-lymphocyte development and homing, and the epigenetic regulator LRIF1, which is implicated in chromatin compaction and gene silencing. Neither NKX2-3 nor LRIF1 mutations, predicted to be loss of function, have previously been reported in B-CLL. Sequencing confirmed the presence of these mutations together with BCL2, NOTCH1, and BRAF mutations, with the t(14;18)(q32;q21) translocation, in the initial diagnostic sample obtained 12 yr prior. This is suggestive of a role for these novel mutations in B-CLL initiation and stable clonal evolution, including upon treatment withdrawal. This case extends the spectrum of atypical B-CLL with t(14;18)(q32;q21) and highlights the value of more global precision genomics for patient follow-up and treatment in these patients.

Occupational exposure to organic dust and risk of lymphoma subtypes in the EPILYMPH case-control study.

Objectives This study aimed to estimate the risk of lymphoma and its major subtypes in relation to occupational exposure to specific organic dusts. Methods We explored the association in 1853 cases and 1997 controls who participated in the EpiLymph case-control study, conducted in six European countries in 1998-2004. Based on expert assessment of lifetime occupational exposures, we calculated the risk of the major lymphoma subtypes associated with exposure to six specific organic dusts, namely, flour, hardwood, softwood, natural textile, synthetic textile, and leather, and two generic (any types) groups: wood and textile dusts. Risk was predicted with unconditional regression modeling, adjusted by age, gender, study center, and education. Results We observed a 2.1-fold increase in risk of follicular lymphoma associated with ever exposure to leather dust [95% confidence interval (CI) 1.01-4.20]. After excluding subjects who ever worked in a farm or had ever been exposed to solvents, risk of B-cell lymphoma was elevated in relation to ever exposure to leather dust [odd ratio (OR) 2.2, 95% CI 1.00-4.78], but it was not supported by increasing trends with the exposure metrics. Risk of Hodgkin lymphoma was elevated (OR 2.0, 95% CI 0.95-4.30) for exposure to textile dust, with consistent upward trends by cumulative exposure and three independent exposure metrics combined (P=0.023, and P=0.0068, respectively). Conclusions Future, larger studies might provide further insights into the nature of the association we observed between exposure to textile dust and risk of Hodgkin lymphoma.