"Randomized phase II study of azacitidine +/- lenalidomide in higher-risk myelodysplastic syndromes and acute myeloid leukemia with a karyotype including Del(5q)"

Non peer reviewe

Some lifestyle-related factors and risk of chronic renal failure : A population-based approach

Some renal diseases, i.e. rapidly progressive glomerulonephritis, are sufficient causes of a rapid, permanent total loss of renal function. However, the majority of renal diseases progress slowly over decades, initially often without symptoms, sometimes making it difficult to define the aetiologies. There is growing evidence that a multitude of lifestyle-related and environmental factors influence the risk and the progression rate of chronic renal failure (CRF), although genetic factors also appear to be of importance. Prevention is important since the prognosis of end-stage renal disease treated with dialysis is poor, but mortality is substantially increased also in patients with mild CRF. To identify risk factors for CRF, we performed a population-based nation-wide casecontrol study. The study base was the entire Swedish population born in Sweden and aged 1874 years. Eligible as cases were subjects who had a serum creatinine that for the first time and permanently exceeded 300 µmol/l (men) or 250 µmol/l (women) during the two-year study period, 1996-1998. The final study population included 926 cases and 998 randomly selected controls from the study base. A face-to-face interview and a self-administered questionnaire provided information about various exposures. Despite an overall non-significant association, high daily smoking dose, long duration of the smoking habit, and a high cumulative dose were associated with a significant excess risk of CRF. In smokers with a cumulative dose of >30 pack-years, the risk was increased by 52 % compared to non-smokers. A more than two-fold increased risk among heavy smokers was observed for CRF classified as nephrosclerosis, but significant positive associations were also noted with glomerulonephritis, and among women - also with diabetic nephropathy. Other tobacco use than smoking was unrelated to risk of CRF. A high protein intake was strongly and positively related to an increased risk of diabetic nephropathy. We cannot rule out that this association might be the result of reverse causality and recall bias, however, in an analysis confined to diabetic cases and controls, an almost 3fold risk gradient with protein intake remained, albeit imprecise due to small numbers. Protein intake was not associated with other types of renal disease. We could not confirm our hypothesis that a high intake of antioxidants reduces risk of CRF, with the possible exception that a high intake of vitamin E was linked to a low risk in individuals with hypertension. Being overweight in early adulthood and obese at anytime in life was associated with an increased risk of CRF. A body mass index exceeding 30 kg/m2 in men and 35 kg/m2 in women anytime during lifetime was linked to 3-to 4-fold increases in risk. Although much of the excess risk was driven by the higher prevalence of hypertension and diabetes among obese, an additional pathway may exist. Birth weight was unrelated to risk of CRF, while a short stature was associated with CRF, at least in men. Isolated regular use of either paracetamol or aspirin was associated with a 2.5-fold increased risk of CRF overall, with a positive dose-response. The elevations in risk were observed for most types of underlying renal diseases, albeit not always statistically significant. To avoid bias due to analgesic use triggered by CRF symptoms, we disregarded more recent use, but the risks became only slightly attenuated. Our results are consistent with an exacerbating effect of paracetamol and aspirin, but, we cannot exclude that predisposing conditions of CRF may have prompted analgesic use

Income, education and their impact on treatments and survival in patients with myelodysplastic syndromes

Objectives To assess whether socioeconomic indices such as income and educational level can explain part of the variation in survival among patients with myelodysplastic syndromes, and further to assess whether these factors influence care and treatment decisions. Methods Population-based cohort study on 2945 Swedish patients diagnosed between 2009 and 2018 and included in the Swedish MDS Register. Relative mortality was assessed by Cox regression, whereas treatment differences were assessed by Poisson regression. Regarding mortality, patients were also compared to a matched comparison group from the general population. Results Mortality was 50% higher among patients in the lowest income category compared to the highest and 40% higher in patients with mandatory school education only compared to those with college or university education. Treatment with hypomethylating agents and allogeneic stem cell transplantation, as well as investigation with cytogenetic diagnostics were also linked to income and education. The findings were not explained by differences in risk class or comorbidity at the time of diagnosis. Conclusions Income and education are linked to survival among patients with myelodysplastic syndromes. Socioeconomic status also seems to influence treatment intensity as patients with less income and education to a lesser degree receive hypomethylating agents and transplants

Therapy-related MDS dissected based on primary disease and treatment-a nationwide perspective

In this population-based study, we aimed to characterize and compare subgroups of therapy-related Myelodysplastic syndromes (t-MDS) and define the implications of type of previous treatment and primary disease. We combined data from MDS patients, diagnosed between 2009 and 2017 (n = 2705), in the nationwide Swedish MDS register, with several health registers. Furthermore, using matched population controls, we investigated the prevalence of antecedent malignancies in MDS patients in comparison with the general population. This first ever nationwide study on t-MDS confirms a shorter median survival for t-MDS compared to de novo MDS (15.8 months vs 31.1 months, p < 0.001). T-MDS patients previously treated with radiation only had disease characteristics with a striking resemblance to de novo-MDS, in sharp contrast to patients treated with chemotherapy who had a significantly higher risk profile. IPSS-R and the WHO classification differentiated t-MDS into different risk groups. As compared with controls, MDS patients had a six-fold increased prevalence of a previous hematological malignancy but only a 34% increased prevalence of a previous solid tumor. T-MDS patients with a previous hematological malignancy had a dismal prognosis, due both to mortality related to their primary disease and to high-risk MDS

Prognostic scoring systems and comorbidities in chronic myelomonocytic leukaemia : a nationwide population-based study

Outcomes in chronic myelomonocytic leukaemia (CMML) are highly variable and may be affected by comorbidity. Therefore, prognostic models and comorbidity indices are important tools to estimate survival and to guide clinicians in individualising treatment. In this nationwide population-based study, we assess comorbidities and for the first time validate comorbidity indices in CMML. We also compare the prognostic power of: the revised International Prognostic Scoring System (IPSS-R), CMML-specific prognostic scoring system (CPSS), MD Anderson Prognostic Scoring System (MDAPS) and Mayo score. In this cohort of 337 patients with CMML, diagnosed between 2009 and 2015, the median overall survival was 21 center dot 3 months. Autoimmune conditions were present in 25% of the patients, with polymyalgia rheumatica and Hashimoto's thyroiditis being most common. Of the tested comorbidity indices: the Charlson Comorbidity Index (CCI), Haematopoietic cell transplantation-specific Comorbidity Index (HCT-CI) and Myelodysplastic Syndrome-Specific Comorbidity Index (MDS-CI), CCI had the highest C-index (0 center dot 62) and was the only comorbidity index independently associated with survival in multivariable analyses. When comparing the prognostic power of the scoring systems, the CPSS had the highest C-index (0 center dot 69). In conclusion, using 'real-world' data we found that the CCI and CPSS have the best prognostic power and that autoimmune conditions are overrepresented in CMML

Clinical effect of increasing doses of lenalidomide in high-risk myelodysplastic syndrome and acute myeloid leukemia with chromosome 5 abnormalities

Background Patients with chromosome 5 abnormalities and high-risk myelodysplastic syndromes or acute myeloid leukemia have a poor outcome. We hypothesized that increasing doses of lenalidomide may benefit this group of patients by inhibiting the tumor clone, as assessed by fluorescence in situ hybridization for del(5q31). Design and Methods Twenty-eight patients at diagnosis or with relapsed disease and not eligible for standard therapy (16 with acute myeloid leukemia, 12 with intermediate-risk 2 or high-risk myelodysplastic syndrome) were enrolled in this prospective phase II multicenter trial and treated with lenalidomide up to 30 mg daily for 16 weeks. Three patients had isolated del(5q), six had del(5q) plus one additional aberration, 14 had del(5q) and a complex karyotype, four had monosomy 5, and one had del(5q) identified by fluorescence in situ hybridization only. Results Major and minor cytogenetic responses, assessed by fluorescence in situ hybridization, were achieved in 5/26 (19%) and 2/26 (8%) patients, respectively, who received one or more dose of lenalidomide, while two patients achieved only a bone marrow response. Nine of all 26 patients (35%) and nine of the ten who completed the 16 weeks of trial responded to treatment. Using the International Working Group criteria for acute myeloid leukemia and myelodysplastic syndrome the overall response rate in treated patients with acute myeloid leukemia was 20% (3/15), while that for patients with myelodysplastic syndrome was 36% (4/11). Seven patients stopped therapy due to progressive disease and nine because of complications, most of which were disease-related. Response rates were similar in patients with isolated del(5q) and in those with additional aberrations. Interestingly, patients with TP53 mutations responded less well than those without mutations (2/13 versus 5/9, respectively; P = 0.047). No responses were observed among 11 cases with deleterious TP53 mutations. Conclusions Our data support a role for higher doses of lenalidomide in poor prognosis patients with myelodysplastic syndrome and acute myeloid leukemia with deletion 5q. (Clinicaltrials.gov identifier NCT00761449)