Patterns of survival among patients with myeloproliferative neoplasms diagnosed in Sweden from 1973 to 2008: a population-based study.

To access publisher full text version of this article. Please click on the hyperlink in Additional Links field.Reported survival in patients with myeloproliferative neoplasms (MPNs) shows great variation. Patients with primary myelofibrosis (PMF) have substantially reduced life expectancy, whereas patients with polycythemia vera (PV) and essential thrombocythemia (ET) have moderately reduced survival in most, but not all, studies. We conducted a large population-based study to establish patterns of survival in more than 9,000 patients with MPNs. We identified 9,384 patients with MPNs (from the Swedish Cancer Register) diagnosed from 1973 to 2008 (divided into four calendar periods) with follow-up to 2009. Relative survival ratios (RSRs) and excess mortality rate ratios were computed as measures of survival. Patient survival was considerably lower in all MPN subtypes compared with expected survival in the general population, reflected in 10-year RSRs of 0.64 (95% CI, 0.62 to 0.67) in patients with PV, 0.68 (95% CI, 0.64 to 0.71) in those with ET, and 0.21 (95% CI, 0.18 to 0.25) in those with PMF. Excess mortality was observed in patients with any MPN subtype during all four calendar periods (P < .001). Survival improved significantly over time (P < .001); however, the improvement was less pronounced after the year 2000 and was confined to patients with PV and ET. We found patients with any MPN subtype to have significantly reduced life expectancy compared with the general population. The improvement over time is most likely explained by better overall clinical management of patients with MPN. The decreased life expectancy even in the most recent calendar period emphasizes the need for new treatment options for these patients.Swedish Cancer Society CAN 2009/1203 Stockholm County Council SLL 20090201 Karolinska Institutet SLL 20090201 Karolinska Institutet Foundations 2009Fobi0072 Shire Pharmaceuticals Adolf H. Lundin Charitable Foundatio

Improved Prognosis in Multiple Myeloma-a Population Based Study on 13,376 Patients Diagnosed in Sweden 1973–2001

Abstract Background: Over the last decades there have been advances in the treatment of patients with multiple myeloma (MM) and prognosis has improved with the introduction of new treatment strategies. However, few studies have addressed the issue which patients benefit most from these therapeutic changes over the years. Aims: To evaluate relative survival in all diagnosed MM patients in Sweden 1973–2001 and relate the changes to age, sex and type of hospital where diagnosis was made. Methods: All patients with MM notified to the Swedish Cancer Register in 1973–2001 were followed up by record linkage to the nationwide Cause of Death Register. Survival analyses were performed by obtaining relative survival (RS) defined as the ratio of observed versus expected survival. The study period was divided arbitrarily to four calendar periods: 1973–1979, 1980–1986, 1987–1993, and 1994–2002. Patients were grouped according to age at diagnosis (0–40, 41–50, 51–60, 61–70, 71–80, and 80+), sex, and hospital category. RS was estimated using SAS (Cary, NC, USA) and excess mortality modelled using Poisson regression. Results: A total of 13,376 patients (7,114 males and 6,262 females, mean age 69.8 years, and 32% diagnosed at a university hospital) were diagnosed with MM in Sweden between January 1st 1973 and December 31st 2001. The overall one-year RS estimates were 73%, 78%, 80%, and 81%, respectively, for the four calendar periods. The overall five-year RS was 31%, 32%, 34%, and 36% and the ten-year RS remained stable at 12%, 11% 13% in the first three periods; ten-year RS could not be calculated for the last calendar period. The increase in one-year RS was observed in all age categories over the four calendar periods, while the increase in five-year RS was restricted to patients <70 years. Younger age at onset was associated with a superior survival in all calendar periods. Differences in survival by age at diagnosis and calendar period were highly statistically significant (p<0.0001). Females had a superior 1- (p=0.002), 5- (p=0.024), and 10-year RS (p=0.019) compared to males, after adjusting for age and period. Patients diagnosed at university hospitals had superior 5- and 10-year RS (p=0.007) but not 1-year RS. Summary/conclusions: The present study shows an improved prognosis over time in a population-based study including > 13,000 MM patients diagnosed during a 29-year period. Of interest is that even one-year RS has improved in all age groups over the whole study period. Increase in five-year RS was only observed in patients aged <70 years. The ten-year RS did not improve over the first 20 years and could not be estimated for patients diagnosed in the last period. Younger age at diagnosis was associated with superior one-, five- and ten-year RS in all calendar periods. Females had a significantly better survival than males. A significant difference in survival was seen according to type of hospital, with patients diagnosed at a university hospital surviving longer. In conclusion, the results show that survival of MM patients has improved during the study period. However, long-term survival has not improved significantly. Males, elderly patients and patients diagnosed during early calendar periods experienced higher excess mortality

Prognosis in Acute Myeloid Leukemia: A Population-Based Study on 5,809 Patients Diagnosed in Sweden 1973–2001

Abstract Background AML is an aggressive disease, which is rapidly fatal without specific therapy. Such treatment was not available until the early 1970’s when combinations of anthracyclines and cytarabine were introduced. Since then major improvements have been made in chemotherapy, stem cell transplantation (SCT) and supportive care. The aim of this study was to define the impact of modern AML treatment strategies on outcome. Extrapolation of results from clinical trials may not be appropriate for estimation of outcome in the whole population because of a varying degree of patient selection. In this study relative survival rates (RSR) were estimated in relation to age, sex, calendar period and region of residence in a cohort of 5,809 AML patients. Methods Records on all patients with AML reported to the Swedish Cancer Register between 1973 and 2001 were linked to the nationwide Cause of Death Register. Information on the number of SCT in AML patients in Sweden during the study period was obtained from the EBMT register. Survival analysis were performed by computing relative survival rates (RSR), defined as the ratio of observed survival of the patients in the cohort versus the expected survival among individuals of the same age, sex, and calendar year of observation. Results 5809 AML patients diagnosed between January 1, 1973 and December 31, 2001 were identified. The cases were divided into six age groups; 0–18, 19–40, 41–60, 61–70, 71–80, and 80+ years. The study period was arbitrarily divided into 7-year intervals. Improvement was seen in all age groups but the eldest. However, patients < 60 years benefited most from new treatment strategies (table 1). There was a marked increase in SCT during the study period with allogeneic SCT dominating in the last period (fig 1). A comparison between regions (with different therapeutical traditions) was made. The regions of Stockholm, Uppsala and Örebro have cooperated since 1971 within the Leukemia Group of Middle Sweden (LGMS) and was therefore considered as one region and compared with the rest of the country. During the first calendar period the 5-year RSR of residents with AML in LGMS counties was significantly higher than that of patients in remaining regions. However, this difference has disappeared with time. Conclusion Improvement in overall survival of AML patients was mainly confined to young patients (<60 years). However, among patients 60–71 years at diagnosis, a slightly improved RSR was observed. For patients above the age of 70 years, the prognosis remains very poor stressing the fact that the decision to use aggressive chemotherapy for this group of patients should consider the risk of iatrogenic morbidity and mortality as well as projected benefit. The early creation of a cooperative clinical AML group probably explains the improved RSR rates during the first study period (1973–1979). Table 1. Five-year RSR (%) according to age group and calendar period calendar period/age group (years) 1973–1979 1980–1986 1987–1993 1994–2000 0–18 17 31 52 68 19–40 14 17 38 58 41–60 7 13 22 36 61–70 6 8 12 15 71–80 3 3 7 6 81+ 1 0 0 1 Fig. 1 Number of stem cell transplantation in Sweden 1973–2001 Fig. 1. Number of stem cell transplantation in Sweden 1973–200

Familial aggregation of acute myeloid leukemia and myelodysplastic syndromes.

To access publisher full text version of this article. Please click on the hyperlink in Additional Links field.Apart from rare pedigrees with multiple cases of acute myeloid leukemia (AML), there is limited data on familial aggregation of AML and myelodysplastic syndromes (MDSs) in the population. Swedish population-based registry data were used to evaluate risk of AML, MDS, and other malignancies among 24,573 first-degree relatives of 6,962 patients with AML and 1,388 patients with MDS compared with 106,224 first-degree relatives of matched controls. We used a marginal survival model to calculate familial aggregation. AML and/or MDS did not aggregate significantly in relatives of patients with AML. There was a modest risk ratio (RR, 1.3; 95% CI, 0.9 to 1.8) in myeloproliferative/myeloid malignancies combined. The risks for any hematologic or any solid tumor were modestly but significantly increased. Relatives of patients with MDS did not show an increased risk for any hematologic tumors. In contrast, we found a significantly increased risk (RR, 6.5; 95% CI, 1.1 to 38.0) of AML/MDS and of all myeloid malignancies combined (RR, 3.1; 95% CI, 1.0 to 9.8) among relatives of patients diagnosed at younger than age 21 years. We did not find evidence for familial aggregation of the severe end of the spectrum of myeloid malignancies (AML and MDS). The risks of myeloproliferative neoplasms were modestly increased with trends toward significance, suggesting a possible role of inheritance. In contrast, although limited in sample size, relatives of young patients with AML were at increased risk of AML/MDS, suggesting that germline genes may play a stronger role in these patients. The increased risk of all hematologic malignancies and of solid tumors among relatives of patients with AML suggests that genes for malignancy in general and/or other environmental factors may be shared.National Cancer Institute, National Institutes of Health Adolf H. Lundin Charitable Foundation, Swedish Cancer Society Stockholm County Council Karolinska Institute

Chronic Immune Stimulation Might Act As a Trigger for the Development of Acute Myeloid Leukemia or Myelodysplastic Syndromes

Purpose Patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) often present with infections, but there are little data to assess whether a personal history of selected infections may act as pathogenic triggers. To additionally expand our knowledge on the role of immune stimulation in the causation of AML and MDS, we have conducted a large, population-based study to evaluate the risk of AML and MDS associated with a prior history of a broad range of infections or autoimmune diseases. Patients and Methods By using population-based central registries in Sweden, we included 9,219 patients with AML, 1,662 patients with MDS, and 42,878 matched controls. We used logistic regression to calculate odds ratios (ORs) and 95% CIs for the association of AML or MDS with infectious and/or autoimmune diseases. Results Overall, a history of any infectious disease was associated with a significantly increased risk of both AML (OR, 1.3; 95% CI, 1.2 to 1.4) and MDS (OR, 1.3; 95% CI, 1.1 to 1.5). These associations were significant even when we limited infections to those occurring 3 or more years before AML/MDS. A previous history of any autoimmune disease was associated with a 1.7-fold (95% CI, 1.5 to 1.9) increased risk for AML and 2.1-fold (95% CI, 1.7 to 2.6) increased risk for MDS. A large range of conditions were each significantly associated with AML and MDS. Conclusion Our novel findings indicate that chronic immune stimulation acts as a trigger for AML/MDS development. The underlying mechanisms may also be due to a common genetic predisposition or an effect of treatment for infections/autoimmune conditions. J Clin Oncol 29:2897-2903. (C) 2011 by American Society of Clinical Oncolog

Age and acute myeloid leukemia: real world data on decision to treat and outcomes from the Swedish Acute Leukemia Registry

Acute myeloid leukemia (AML) is most common in the elderly, and most elderly are thought to be unfit for intensive treatment because of the risk of fatal toxicity. The Swedish Acute Leukemia Registry covers 98% of all patients with AML (non-acute promyelocytic leukemia) diagnosed in 1997 to 2005 (n = 2767), with a median follow-up of 5 years, and reports eligibility for intensive therapy, performance status (PS), complete remission rates, and survival. Outcomes were strongly age and PS dependent. Early death rates were always lower with intensive therapy than with palliation only. Long-term survivors were found among elderly given intensive treatment despite poor initial PS. Total survival of elderly AML patients was better in the geographic regions where most of them were given standard intensive therapy. This analysis provides unique real world data from a large, complete, and unselected AML population, both treated and untreated, and gives background to treatment decisions for the elderly. Standard intensive treatment improves early death rates and long-term survival compared with palliation. Most AML patients up to 80 years of age should be considered fit for intensive therapy, and new therapies must be compared with standard induction. (Blood. 2009; 113: 4179-4187

Improved patient survival for acute myeloid leukemia: a population-based study of 9729 patients diagnosed in Sweden between 1973 and 2005

We evaluated survival patterns for all registered acute myeloid leukemia (AML) patients diagnosed in Sweden in 1973 to 2005 (N = 9729; median age, 69 years). Patients were categorized into 6 age groups and 4 calendar periods (1973-1980, 1981-1988, 1989-1996, and 1997-2005). Relative survival ratios were computed as measures of patient survival. One-year survival improved over time in all age groups, whereas 5- and 10-year survival improved in all age groups, except for patients 80+ years. The 5-year relative survival ratios in the last calendar period were 0.65, 0.58, 0.36, 0.15, 0.05, and 0.01 for the age groups 0 to 18, 19 to 40, 41 to 60, 61 to 70, 71 to 80, and 80+ years, respectively. Intensified chemotherapy, a continuous improvement in supportive care, and allogeneic stem cell transplantation are probably the most important factors contributing to this finding. In contrast, there was no improvement in survival in AML patients with a prior diagnosis of a myelodysplastic syndrome during 1993 to 2005 (n = 219). In conclusion, AML survival has improved during the last decades. However, the majority of AML patients die of their disease and age remains an important predictor of prognosis. New effective agents with a more favorable toxicity profile are needed to improve survival, particularly in the elderly. (Blood. 2009; 113: 3666-3672

Risk of Arterial and Venous Thrombosis in 11,155 Patients with Myeloproliferative Neoplasms and 44,620 Matched Controls; A Population-Based Study

Abstract Background Patients with myeloproliferative neoplasms (MPNs) are reported to have a higher risk of thrombosis compared to the general population. However, the magnitude of the increase in risk in MPNs patients is not known since there is a lack of studies including control subjects. Therefore, we conducted a large population-based study to assess the risk of arterial and venous thrombosis in patients with MPNs in relation to matched controls. Patients and Methods All patients with MPNs reported to the Swedish Cancer Register and/or registered in the Inpatient Register from 1980 to 2009 were included. For each patient, four controls matched for age, sex, and county of residence, were randomly identified from the Register of Total Population. End of follow-up was December 31st 2010. Events of arterial and venous thrombosis, including deaths, were identified from the Inpatient and Outpatient Registers and the Cause of Death Register. Arterial thrombosis was defined as myocardial infarction, ischemic stroke, or peripheral arterial thrombus/embolus. Venous thrombosis was defined as pulmonary embolism, deep venous thrombosis (DVT), liver or splanchnic vein thrombosis, cerebral venous sinus thrombosis, or other venous thrombosis/embolus. Odd ratios (ORs) of arterial and venous thrombosis at diagnosis +/-30 days were calculated using logistic regression. Cox regression and flexible parametric models were used to estimate proportional and non-proportional hazard ratios (HRs) with 95% confidence intervals (CIs). Follow-up in all regression models started 30 days after diagnosis to avoid detection bias at time of diagnosis. Results A total of 11,155 patients and 44,620 matched controls were identified. Forty-six percent (n=5,161) were men and median age at MPN diagnosis was 69 years. The OR for arterial and venous thrombosis at time of MPN diagnosis +/- 30 days was 55.0 (95% CI 51.1-59.2 p<0.001) and 64.3 (42.2-98.1 p<0.001) respectively in MPN patients compared to controls. In MPN patients, the risk of arterial thrombosis was significantly 4.9-fold (4.8-5.0 p<0.001) increased compared to matched controls. The HR of myocardial infarction was 3.9 (3.7-4.1 p<0.001) and stroke 4.9 (4.8-5.0 p<0.001) in MPN patients. The HR of arterial thrombosis in MPN patients decreased shortly after diagnosis but thereafter increased with follow-up time in relation to controls (Figure 1a). There was a similar risk of arterial thrombosis in patients of different MPN subtypes compared to controls, the HR in patients with polycythemia vera (PV) was 5.0 (4.8-5.2), essential thrombocythemia (ET) 4.7 (4.6-5.0), primary myelofibrosis (PMF) 5.0 (4.7-5.3), and MPN-unclassifiable (MPN-U) 5.1 (4.8-5.5), respectively. The HR of venous thrombosis in MPN patients was 6.7 (6.2-7.2 p<0.001), where the HRs of pulmonary embolism was 7.5 (6.6-8.5 p<0.001) and DVT was 5.3 (4.8-5.9 p<0.001) compared to matched controls. MPN patients had a substantially increased risk of liver and splanchnic vein thrombosis, HR=41.4 (26.4-64.9 p<0.001). The risk of venous thrombosis in MPN patients decreased shortly after diagnosis and thereafter remained stable in relation to controls during follow-up time (Figure 1b). Compared to controls, patients with PV had a larger increase in risk of venous thrombosis than the other subtypes (HR=9.0; 8.0-10.1), while the HR of venous thrombosis in patients with ET was 5.4 (4.7-6.2), PMF 6.0 (4.9-7.5), and MPN-U 4.6 (3.7-5.7), respectively. Conclusions Patients with MPNs have an overall five- to sevenfold elevated risk of thrombosis compared to the general population. The highest HRs were seen for venous thrombosis, especially abdominal thrombosis. The odds of having a thrombosis at time of MPN diagnosis were high, indicating that thrombosis is an important first symptom of MPN. The elevated risk of arterial thrombosis increased while the elevated risk of venous thrombosis remained stable during follow-up time. This large population-based study is, to our knowledge, the first to quantify the excess risk of thrombosis in MPN patients compared to the general population. Our results indicate that we need to consider time after diagnosis in risk score models and rethink the strategies for thromboprophylaxis in patients with MPN in order to decrease the risk of thrombotic events. Figure 1A Risk of arterial (a) and venous (b) thrombosis in MPN patients compared to matched controls during follow-up time. Figure 1A. Risk of arterial (a) and venous (b) thrombosis in MPN patients compared to matched controls during follow-up time. Figure 1B Figure 1B. Disclosures No relevant conflicts of interest to declare