Is there an impact of measurable residual disease as assessed by multiparameter flow cytometry on survival of AML patients treated in clinical practice? A population-based study.

The Swedish national guidelines for treatment of acute myeloid leukemia (AML) recommend analysis of measurable residual disease (MRD) by multiparameter flow cytometry (MFC) in bone marrow in the routine clinical setting. The Swedish AML registry contains such MRD data in AML patients diagnosed 2011-2019. Of 327 patients with AML (non-APL) with MRD-results reported in complete remission after two courses of intensive chemotherapy 229 were MRD-negative (70%), as defined by <0.1% cells with leukemia-associated immunophenotype in the bone marrow. MRD-results were reported to clinicians in real time. Multivariate statistical analysis adjusted for known established risk factors did not indicate an association between MFC-MRD and overall survival (HR: 1.00 [95% CI 0.61, 1.63]) with a median follow-up of 2.7 years. Knowledge of the importance of MRD status by clinicians and individualized decisions could have ameliorated the effects of MRD as an independent prognostic factor of overall survival.

Clinical and genomic characterization of patients diagnosed with the provisional entity acute myeloid leukemia with BCR-ABL1, a Swedish population-based study.

Acute myeloid leukemia (AML) with t(9;22)(q34;q11), also known as AML with BCR-ABL1, is a rare, provisional entity in the WHO 2016 classification and is considered a high-risk disease according to the European LeukemiaNet 2017 risk stratification. We here present a retrospective, population-based study of this disease entity from the Swedish Acute Leukemia Registry. By strict clinical inclusion criteria we aimed to identify genetic markers further distinguishing AML with t(9;22) as a separate entity. Twenty-five patients were identified and next-generation sequencing using a 54-gene panel was performed in 21 cases. Interestingly, no mutations were found in NPM1, FLT3, or DNMT3A, three frequently mutated genes in AML. Instead, RUNX1 was the most commonly mutated gene, with aberrations present in 38% of the cases compared to around 10% in de novo AML. Additional mutations were identified in genes involved in RNA splicing (SRSF2, SF3B1) and chromatin regulation (ASXL1, STAG2, BCOR, BCORL1). Less frequently, mutations were found in IDH2, NRAS, TET2, and TP53. The mutational landscape exhibited a similar pattern as recently described in patients with chronic myeloid leukemia (CML) in myeloid blast crisis (BC). Despite the concomitant presence of BCR-ABL1 and RUNX1 mutations in our cohort, both features of high-risk AML, the RUNX1-mutated cases showed a superior overall survival compared to RUNX1 wildtype cases. Our results suggest that the molecular characteristics of AML with t(9;22)/BCR-ABL1 and CML in myeloid BC are similar and do not support a distinction of the two disease entities based on their underlying molecular alterations.

Socioeconomic cost of AML in Sweden-A population-based study using multiple nation-wide registers.

Acute myeloid leukemia (AML) is associated with a high economic and clinical burden. Recently novel therapies have been added to standard treatment regimens. Here, we evaluated the economic impact of AML up until the introduction of these novel therapies. Individual data on 2954 adult patients diagnosed from 2007 to 2015 from five Swedish national population-based registers were used, enabling analyses from diagnosis to either death or 5-year follow-up for survival, inpatient and outpatient costs, costs of prescribed drugs, sick leave, and early retirement. Costs per patient were stratified by age group, treatment options, and FLT3-ITD status. The expected 5-year costs per patient differed substantially between age groups. Patients aged 18-59 years had an expected mean cost per patient of €170,748, while age groups 60-69 years, 70-79 years, and >80 years incurred an expected mean cost of €92,252, €48,344, and €24,118, respectively, over 5 years. Patients <60 years undergoing stem cell transplantation had the highest costs (€228,525 over 5 years). About 60% of costs for these patients were from hospitalizations and 20% from sick leave and early retirement; cost per day was highest from the first admission to complete remission. This study provides a baseline for socioeconomic evaluations of novel therapies in AML in Sweden.

Risk for Arterial and Venous Thrombosis in Patients With Myeloproliferative Neoplasms: A Population-Based Cohort Study.

Background: Patients with myeloproliferative neoplasms (MPNs) are reported to be at increased risk for thrombotic events. However, no population-based study has estimated this excess risk compared with matched control participants. Objective: To assess risk for arterial and venous thrombosis in patients with MPNs compared with matched control participants. Design: Matched cohort study. Setting: Population-based setting in Sweden from 1987 to 2009, with follow-up to 2010. Patients: 9429 patients with MPNs and 35 820 matched control participants. Measurements: The primary outcomes were rates of arterial and venous thrombosis. Flexible parametric models were used to calculate hazard ratios (HRs) and cumulative incidence with 95% CIs. Results: The HRs for arterial thrombosis among patients with MPNs compared with control participants at 3 months, 1 year, and 5 years were 3.0 (95% CI, 2.7 to 3.4), 2.0 (CI, 1.8 to 2.2), and 1.5 (CI, 1.4 to 1.6), respectively. The corresponding HRs for venous thrombosis were 9.7 (CI, 7.8 to 12.0), 4.7 (CI, 4.0 to 5.4), and 3.2 (CI, 2.9 to 3.6). The rate was significantly elevated across all age groups and was similar among MPN subtypes. The 5-year cumulative incidence of thrombosis in patients with MPNs showed an initial rapid increase followed by gentler increases during follow-up. The HR for venous thrombosis decreased during more recent calendar periods. Limitation: No information on individual laboratory results or treatment. Conclusion: Patients with MPNs across all age groups have a significantly increased rate of arterial and venous thrombosis compared with matched control participants, with the highest rates at and shortly after diagnosis. Decreases in the rate of venous thrombosis over time likely reflect advances in clinical management. Primary Funding Source: The Cancer Research Foundations of Radiumhemmet, Blodcancerfonden, the Swedish Research Council, the regional agreement on medical training and clinical research between Stockholm County Council and Karolinska Institutet, the Adolf H. Lundin Charitable Foundation, and Memorial Sloan Kettering Cancer Center.

Incidence and prognostic significance of isolated trisomies in adult acute myeloid leukemia: A population-based study from the Swedish AML registry.

OBJECTIVES AND METHODS: To ascertain the incidence/clinical implications of isolated autosomal trisomies in adult acute myeloid leukemia (AML), all such cases were retrieved from the Swedish AML Registry. RESULTS: Of the 3179 cytogenetically informative AMLs diagnosed January 1997-May 2015, 246 (7.7%) had isolated trisomies. The frequency increased by age (2.4% at age 18-60 years vs. 23% at >60 years; P<.0001); the median age was 69 years. The five most common were +8 (4.0%), +13 (0.9%), +11 (0.8%), +21 (0.7%), and +4 (0.5%). Age and gender, types of AML and treatment, and complete remission and early death rates did not differ between the single trisomy and the intermediate risk (IR) groups or among cases with isolated gains of chromosomes 4, 8, 11, 13, or 21. The overall survival (OS) was similar in the single trisomy (median 1.6 years) and IR groups (1.7 years; P=.251). The OS differed among the most frequent isolated trisomies; the median OS was 2.5 years for +4, 1.9 years for +21, 1.5 years for +8, 1.1 years for +11, and 0.8 years for +13 (P=.013). CONCLUSION: AML with single trisomies, with the exception of +13, should be grouped as IR.

Prognostic significance of high hyperdiploid and triploid/tetraploid adult acute myeloid leukemia.

To ascertain the clinical implications of high hyperdiploid (HH; 49-65 chromosomes) and triploid/tetraploid (TT; >65 chromosomes) adult acute myeloid leukemia (AML), all such cases were retrieved from the Swedish AML Registry. Of the 3,654 cytogenetically informative cases diagnosed between January 1997 and May 2014, 68 (1.9%) were HH (n = 50)/TT (n = 18). Patients with HH/TT were older than those with intermediate risk (IR) AML (median 71 years vs. 67 years; P = 0.042) and less often had de novo AML (63% vs. 79%; P = 0.004); no such differences were observed between HH/TT and complex karyotype (CK) AML. The overall survival (OS) was similar between patients with HH/TT and CK AML (median 0.9 years vs. 0.6 years; P = 0.082), whereas OS was significantly longer (median 1.6 years; P = 0.028) for IR AML. The OS was shorter for cases with HH than with TT (median 0.6 years vs. 1.4 years; P = 0.032) and for HH/TT AMLs with adverse abnormalities (median 0.8 years vs. 1.1 years; P = 0.044). In conclusion, HH/TT AML is associated with a poor outcome, but chromosome numbers >65 and absence of adverse aberrations seem to translate into a more favorable prognosis. Thus, HH/TT AMLs are clinically heterogeneous and should not automatically be grouped as high risk.

Risk and Cause of Death in Patients Diagnosed With Myeloproliferative Neoplasms in Sweden Between 1973 and 2005: A Population-Based Study.

PURPOSE: Myeloproliferative neoplasms (MPNs) are associated with a shortened life expectancy. We assessed causes of death in patients with MPN and matched controls using both relative risks and absolute probabilities in the presence of competing risks. PATIENTS AND METHODS: From Swedish registries, we identified 9,285 patients with MPN and 35,769 matched controls. A flexible parametric model was used to estimate cause-specific hazard ratios (HRs) of death and cumulative incidence functions, each with 95% CIs. RESULTS: In patients with MPN, the HRs of death from hematologic malignancies and infections were 92.8 (95% CI, 70.0 to 123.1) and 2.7 (95% CI, 2.4 to 3.1), respectively. In patients age 70 to 79 years at diagnosis (the largest patient group), the HRs of death from cardiovascular and cerebrovascular disease were 1.5 (95% CI, 1.4 to 1.7) and 1.5 (95% CI, 1.3 to 1.8), respectively; all were statistically significantly elevated compared with those of controls. In the same age group, no difference was observed in the 10-year probability of death resulting from cardiovascular disease in patients with MPN versus controls (16.8% v 15.2%) or cerebrovascular disease (5.6% v 5.2%). In patients age 50 to 59 years at diagnosis, the 10-year probability of death resulting from cardiovascular and cerebrovascular disease was elevated, 4.2% versus 2.1% and 1.9% versus 0.4%, respectively. Survival in patients with MPN increased over time, mainly because of decreased probabilities of dying as a result of hematologic malignancies, infections, and, in young patients, cardiovascular disease. CONCLUSION: Patients with MPN had an overall higher mortality rate than that of matched controls, primarily because of hematologic malignancy, infections, and vascular events in younger patients. Evidently, there is still a need for effective disease-modifying agents to improve patient outcomes.

Characterization and prognostic features of secondary acute myeloid leukemia in a population-based setting: a report from the Swedish Acute Leukemia Registry.

Patients with secondary acute myeloid leukemia (AML) often escape inclusion in clinical trials and thus, population-based studies are crucial for its accurate characterization. In this first large population-based study on secondary AML, we studied AML with an antecedent hematological disease (AHD-AML) or therapy-related AML (t-AML) in the population-based Swedish Acute Leukemia Registry. The study included 3,363 adult patients of which 2,474 (73.6%) had de novo AML, 630 (18.7%) AHD-AML, and 259 (7.7%) t-AML. Secondary AML differed significantly compared to de novo AML with respect to age, gender, and cytogenetic risk. Complete remission (CR) rates were significantly lower but early death rates similar in secondary AML. In a multivariable analysis, AHD-AML (HR 1.51; 95% CI 1.26-1.79) and t-AML (1.72; 1.38-2.15) were independent risk factors for poor survival. The negative impact of AHD-AML and t-AML on survival was highly age dependent with a considerable impact in younger patients, but without independent prognostic value in the elderly. Although patients with secondary leukemia did poorly with intensive treatment, early death rates and survival were significantly worse with palliative treatment. We conclude that secondary AML in a population-based setting has a striking impact on survival in younger AML patients, whereas it lacks prognostic value among the elderly patients.

Incidence and risk factors for suicide and attempted suicide following a diagnosis of hematological malignancy.

Solid tumors are associated with an increased risk of suicide, however, there is limited detailed information on the risk of suicide in patients with hematological malignancies. Therefore, we conducted a population-based study including 47,220 patients with hematological malignancies (diagnosed 1992-2006) and their 235,868 matched controls to define the incidence and risk factors for suicide and suicide attempt. Information on suicides, suicide attempts, and preexisting psychiatric disorders was obtained from Swedish registers and individual medical records. There was a twofold increased (hazard ratio [HR] = 1.9, 95% confidence interval 1.5-2.3, P < 0.0001) risk of suicide/suicide attempt during the first 3 years after diagnosis in patients with hematological malignancies compared to matched controls. Of all hematological malignancies, multiple myeloma was associated with the highest risk (HR = 3.4; 2.3-5.0, P < 0.0001). Patients with a preexisting psychiatric disorder were at a very high risk of suicide and suicide attempt (HR = 23.3; 16.6-32.6, P < 0.0001), regardless of type of hematological malignancy. Among patients who committed suicide, 19% were in a palliative phase and 44% were in remission with no active treatment. In conclusion, the risk of suicide and suicide attempt is elevated in patients with hematological malignancies. Certain high-risk patients may benefit from early detection and preventive measures.

Failure matters: unsuccessful cytogenetics and unperformed cytogenetics are associated with a poor prognosis in a population-based series of acute myeloid leukaemia.

Unsuccessful cytogenetics (UC) in patients with acute myeloid leukaemia (AML) treated on different SWOG trials was recently reported to be associated with increased age and dismal outcome. To ascertain whether this holds true also in unselected patients with AML, we retrieved all cytogenetic reports in cases from the population-based Swedish AML Registry. Between 1997 and 2006, 1737 patients below 80 yr of age without myelosarcoma or acute promyelocytic leukaemia received intensive treatment. The frequencies of UC and unperformed cytogenetics (UPC) were 2.1% and 20%, respectively. The early death rates differed between the cytogenetic subgroups (P = 0.006) with the highest rates in patients with UC (14%) and UPC (12%) followed by high-risk (HR) AML, intermediate risk (IR) and standard risk (SR) cases successfully karyotyped (8.6%, 5.9%, and 5.8%, respectively). The complete remission rate was lower in UC and UPC and HR compared with the other risk groups (P < 0.001). The overall five-year survival rates were 25% for UC and 22% for UPC, whereas the corresponding frequencies for SR, IR and HR AML patients without UC and UPC were 64%, 31% and 15%, respectively. In conclusion, lack of cytogenetic data translates into a poor prognosis.

Leukemic transformation in myeloproliferative neoplasms: therapy-related or unrelated?

Polycythemia vera, essential thrombocythemia, and primary myleofibrosis are chronic myeloproliferative neoplasms (MPNs) associated with an increased morbidity and mortality. MPNs are also associated with progression to acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS). The "true" rate of transformation is not known mainly due to selection bias in clinical trials and underreporting in population-based studies. The outcome after transformation is dismal. The underlying mechanisms of transformation are incompletely understood and in part remain an area of controversy. There is an intrinsic propensity in MPNs to progress to AML/MDS, the magnitude of which is not fully known, supporting a role for nontreatment-related factors. High doses of alkylating agents, P(32) and combined cytoreductive treatments undoubtedly increase the risk of transformation. The potential leukemogenic role of hydroxyurea has been a matter of debate due to difficulties in performing large prospective randomized trials addressing this issue. The main focus of this review is to elucidate therapy-related leukemic transformation in MPNs with a special focus on the role of hydroxyurea.

Self-reported fertility in long-term survivors of acute myeloid leukemia.

Acute myeloid leukemia (AML) survival rates in younger patients have improved considerably since the 1970s. In order to evaluate the impact of AML and its treatment on fertility and family situation in adult long-term survivors, we used the Swedish population-based registries to identify 161 adult patients diagnosed with AML within the Leukemia Group of Middle Sweden (LGMS) 1973-2003, who survived for more than 5 years and were alive in 2010. Ninety-eight patients (61 %) completed a questionnaire including items on reproductive concerns, family situation, and infertility-related distress. After excluding women >45 years and/or postmenopausal women and men >55 years, 22 women and 38 men were included in the final analysis. Nine of the women (41 %) tried to conceive after treatment, but only three succeeded. Five (83 %) of the unwillingly childless women reported "a moderate" or "a lot" of distress caused by this. Among men in the same age group, all six who wanted children after treatment succeeded. None of the men 46-55 years old cryopreserved their sperm or tried to father a child. Among patients who wanted children after AML treatment, 46 % of the women and 40 % of the younger men reported that they were not, or not fully, informed about fertility-related issues. In contrast, among men 46-55 years, none reported they would have wanted more information. Infertility among young female AML survivors thus remains an important clinical issue, and there is a need for improved clinical counseling and education in this area.

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

PURPOSE: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Familial aggregation of acute myeloid leukemia and myelodysplastic syndromes.

PURPOSE: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.

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.

Treatment-related risk factors for transformation to acute myeloid leukemia and myelodysplastic syndromes in myeloproliferative neoplasms.

PURPOSE: Patients with myeloproliferative neoplasms (MPNs), including polycythemia vera, essential thrombocythemia, and primary myelofibrosis, have a propensity to develop acute myeloid leukemia (AML) and myelodysplastic syndromes (MDSs). Using population-based data from Sweden, we assessed the role of MPN treatment and subsequent AML/MDS risk with special focus on the leukemogenic potential of hydroxyurea (HU). METHODS: On the basis of a nationwide MPN cohort (N = 11,039), we conducted a nested case-control study, including 162 patients (153 and nine with subsequent AML and MDS diagnosis, respectively) and 242 matched controls. We obtained clinical and MPN treatment data for all patients. Using logistic regression, we calculated odds ratios (ORs) as measures of AML/MDS risk. RESULTS: Forty-one (25%) of 162 patients with MPNs with AML/MDS development were never exposed to alkylating agents, radioactive phosphorous (P(32)), or HU. Compared with patients with who were not exposed to HU, the ORs for 1 to 499 g, 500 to 999 g, more than 1,000 g of HU were 1.5 (95% CI, 0.6 to 2.4), 1.4 (95% CI, 0.6 to 3.4), and 1.3 (95% CI, 0.5 to 3.3), respectively, for AML/MDS development (not significant). Patients with MPNs who received P(32) greater than 1,000 MBq and alkylators greater than 1 g had a 4.6-fold (95% CI, 2.1 to 9.8; P = .002) and 3.4-fold (95% CI, 1.1 to 10.6; P = .015) increased risk of AML/MDS, respectively. Patients receiving two or more cytoreductive treatments had a 2.9-fold (95% CI, 1.4 to 5.9) increased risk of transformation. CONCLUSION: The risk of AML/MDS development after MPN diagnosis was significantly associated with high exposures of P(32) and alkylators but not with HU treatment. Twenty-five percent of patients with MPNs who developed AML/MDS were not exposed to cytotoxic therapy, supporting a major role for nontreatment-related factors.