Venetoclax-based therapy for relapsed or refractory acute myeloid leukaemia following intensive induction chemotherapy.

BACKGROUND: The treatment of relapsed or refractory (R/R) acute myeloid leukaemia (AML) remains challenging and outcomes extremely poor. The introduction of venetoclax has transformed the treatment of AML and emerging data suggest that venetoclax-based therapy may enforce salvage treatment. MATERIALS AND METHODS: In this nationwide Danish retrospective study, we analysed treatment outcomes of venetoclax-based salvage treatment for R/R AML between 2019 and 2022. Only venetoclax-naive patients who had previously received treatment with intensive chemotherapy therapy were included. RESULTS: The cohort consisted of 43 R/R patients with a median age of 57 years. Nine (20.9%) were primary refractory and 34 (79.1%) patients had relapsed, including 21 after previous allogeneic stem cell transplantation. The overall response rate was 76.2% including 61.9% with composite complete remission (CRc: CR + CRi). Among CRc-responders with information on measurable residual disease (MRD), 8/13 (61.5%) obtained an MRD-negativity response. The overall survival was 9.3 months for all patients with an estimated 1-year overall survival of 34%. For CRc-responders the median overall survival was 13.3 months, and the median relapse-free survival was 12.8 months. CONCLUSION: Venetoclax-based salvage treatment for R/R AML produced high response rates; however, for most patients the response was of limited duration. This study is limited by an observational design and prone to selection bias.

Psychotropic Drug Use in Acute Myeloid Leukaemia (AML) and Myelodysplastic Syndrome (MDS): A Danish Nationwide Matched Cohort Study of 2404 AML and 1307 MDS Patients.

INTRODUCTION: The diagnosis of a life-threatening disease can lead to depression and anxiety resulting in pharmacological treatment. However, use of psychotropic drugs (antidepressants, anxiolytics, and antipsychotics) in acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) is undetermined. METHODS: Prescription of psychotropic drugs in Danish AML and MDS patients was compared to a cohort matched on age, sex, and country of origin from the Danish background population using national population-based registries. RESULTS: In total, 2404 AML patients (median age 69 years) and 1307 MDS patients (median age 75 years) were included and each matched to five comparators from the background population. Two-year cumulative incidences showed that AML (20.6%) and MDS (21.2%) patients had a high risk of redemption of a psychotropic drug prescription compared to the background population (7.0% and 7.9%). High age, low educational level, and Charlson Comorbidity Index score ≥1 was associated with a higher risk in AML and MDS patients. Furthermore, non-curative treatment intent and performance status in AML patients, and high risk MDS were associated with elevated risk of psychotropic drug prescription. CONCLUSION: In conclusion, diagnoses of AML and MDS were associated with a higher rate of psychotropic drugs prescription compared to the background population.

Malignant but not maleficent: acute leukaemia as a possible explanation of disease and death in vampire victims.

BACKGROUND: A considerable amount of research has been put into the explanation of the origin of the vampire myth by focussing on possible symptoms of the vampire; however, very little attention has been given to the victims. AIMS: To elucidate whether the myth of vampire victims follows the course of disease of acute leukaemia. METHOD: We studied three classical vampire novels published 1819-1897, focusing on 8 victims and their symptoms. The novels were chosen based on their iconic status in classic vampire literature, which defined the vampire genre and the symptoms of the victims for many years. The symptoms and course of disease following vampire attacks described in these novels were then compared with symptoms commonly seen in untreated acute leukaemia and other contemporary disorders. RESULTS: The earliest novel (1819) did not provide a sufficient description of any symptoms in detail; however, the later novels (1872 and 1897) both provided elaborate portrayals of symptoms and course of the disease. The patients studied were all factitious-explaining the variation in symptoms; however, they share common features. One case, a young woman named Lucy Westenra, described by Bram Stoker, 1897, mirrors a textbook example of an acute leukaemia patient-despite being described before the time of common acknowledgment of the diagnosis. CONCLUSION: Victims in the gothic vampire novels from the nineteenth century could very likely be inspired by real-life acute leukaemia patients.

Longer distance to specialized treatment centers does not adversely affect treatment intensity or outcomes in adult acute myeloid leukemia patients. A Danish national population-based cohort study.

BACKGROUND: Treatment of acute myeloid leukemia (AML) is widely centralized. Longer distances to a specialized treatment center may affect patients' access to curative-intended treatment. Especially during outpatient treatment, distance may also affect survival. METHODS AND PATIENTS: The authors conducted a national population-based cohort study including all AML patients diagnosed in Denmark between 2000 and 2014. We investigated effects of distance (<10 kilometers [km; reference], 10-25, 25-50, 50-100, >100) to the nearest specialized treatment facility on the probability of receiving intensive chemotherapy, HSCT, and achieving a complete remission (CR) using logistic regression analysis (odds ratios; ORs). For overall survival, we used Cox proportional hazards regression (hazard ratios [HRs]) and adjusted (a) for relevant baseline characteristics. RESULTS: Of 2,992 patients (median age=68.5 years), 53% received intensive chemotherapy and 12% received low-dose chemotherapy outpatient regimens. The median distance to a specialized treatment center was 40 km (interquartile range=10-77 km). No impact of distance to specialized treatment centers was seen on the probability of receiving intensive chemotherapy (10-25 km, aOR=1.1 (CI=0.7-1.7), 25-50 km, aOR=1.1 (CI=0.7-1.7), 50-100 km, aOR=1.3 (CI=0.9-1.9), and >100 km, aOR=1.4 [CI=0.9-2.2]). Overall survival in patients regardless of therapy (<10 km, aOR=1.0 vs >100 km, aOR=1.0 [CI=0.9-1.2]), in intensive therapy patients, or in patients' choice of post-remission was not affected by distance to specialized treatment center. Distance to a transplant center also did not affect the probability of HSCT or survival post-HSCT. CONCLUSION: In Denmark, distance to a specialized treatment facility offering remission-induction chemotherapy and HSCT does not negatively affect access to curative-indented therapy, treatment-response, or survival in AML patients.

Rehabilitation during intensive treatment of acute leukaemia including allogenic stem cell transplantation: a qualitative study of patient experiences.

OBJECTIVES: The diagnosis and treatment of acute leukaemia (AL) affect physical, psychosocial and existential functioning. Long-lasting treatment periods with impaired immune system, hygienic and social restrictions challenge patient well-being and rehabilitation as compared with other individuals with cancer. This study elucidates how AL patients, treated with curative intent in an outpatient setting, assess their physical, psychosocial and existential capability during and following treatment, and furthermore reports on the health initiatives offered to support their rehabilitation. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: We conducted qualitative, semi-structured individual interviews with 16 AL patients, 6 months after end of treatment in the patients' homes. This was the final interview, in a line of three, carried out as part of a larger qualitative study. RESULTS: The data were analysed thematically through an inductive ongoing process consisting of four steps. The final step, selective coding, resulted in the three categories: physical activity, mental well-being and social activity. None of the patients were satisfied with their physical capability at the time of interview and experienced substantial impairment of functional capabilities. All patients struggled with anxiety and expressed a need for continuous progress in treatment and well-being to feel safe. It took an unexpected large effort to regain a meaningful social life, and patients still had to prioritise activities. CONCLUSIONS: AL patients suffered physically, psychologically and existentially throughout their illness trajectory. Rehabilitation initiatives deriving from the healthcare system and municipalities held room for improvement. Future programmes should pay attention to the contextual changes of treatment of this patient group and individuals' changing needs and motivation of physical exercise.

Living with outpatient management as spouse to intensively treated acute leukemia patients.

BACKGROUND: Spouses have a key position in the treatment of patients with acute leukemia (AL) who are increasingly managed in an outpatient setting. Patients live at home but appear at the hospital every second day for follow-up visits. Patients must adhere to specific precautions due to an impaired immune system, which challenges and influence the life of the whole family. This qualitative study, based on individual and group interviews with spouses to AL patients in curative intended treatment, elucidates how the intense and substantial caregiver role affects the everyday lives of spouses to AL patients in curative intended treatment. METHODS: Qualitative semi-structured group interviews (n = 6) and individual interviews (n = 5) with spouses to AL patients were conducted at different time points during the whole course of treatment. Theories of everyday life served as the theoretical framework. RESULTS: The spouses described their life as a constant state of vigilance and attention as a consequence of the responsibility they felt arising from the treatment in the outpatient setting. These made them experience their role as a burden. The social life of the spouses and the families suffered substantially due to the precautions that were instated in the home. However, many experienced that relations in the family were developed positively. CONCLUSIONS: Close relatives experience additional psychosocial burdens instigated by the outpatient management regimens. This is important knowledge for the health care system to include in future development of AL outpatient settings, to prioritize and support offers to the relatives that recognize their sense of burden. This could apply not only to relatives of AL patients but to the relatives of other severely ill patients as well.

NSAID consumption and risk of acute myeloid leukemia: a national population-based case-control study.

BACKGROUND: Most cases of acute leukemia arise without identifiable risk factors. Studies investigating the impact of autoimmune diseases and infections on leukemogenesis have revealed conflicting results. If inflammation increases the risk of acute myeloid leukemia (AML), nonsteroidal anti-inflammatory drug (NSAID) use may decrease the risk of leukemia. METHODS: We conducted a case-control study of 3,053 patients with AML diagnosed between 2000 and 2013, who were registered in the Danish National Acute Leukemia Registry, and 30,530 population controls matched on sex and age. We identified prescriptions through the Danish National Health Service Prescription Database. We used conditional logistic regression analysis to compute ORs associating AML with NSAID use overall, in patients with inflammatory diseases, and for specific AML subtypes (de novo AML, AML related to previous hematological disease, ie, secondary AML [sAML], or therapy-related AML [tAML; exposed to previous cytotoxic therapy]). RESULTS: Overall, NSAID use was not associated with a lower risk of AML (OR 1.1, 95% CI=1.0-1.2), de novo AML (OR 1.0, 95% CI=0.9-1.1), and sAML/tAML (OR 1.3, 95% CI=1.1-1.5). In addition, in patients with known inflammatory diseases, NSAIDs did not affect AML risk (OR 0.9, 95% CI=0.5-1.6). Number of prescriptions, type of NSAID, age, or sex did not influence the results. CONCLUSION: In line with our recent findings that showed no association between autoimmune diseases and infections and de novo AML, NSAID use was not found to reduce the risk of AML.

Impact of Allogeneic Stem Cell Transplantation in First Complete Remission in Acute Myeloid Leukemia: A National Population-Based Cohort Study.

To examine the outcomes of allogeneic stem cell transplantation (HSCT) in first complete remission (CR1) compared with chemotherapy alone in a population-based setting, we identified a cohort of patients with acute myeloid leukemia (AML) aged 15 to 70 years diagnosed between 2000 and 2014 in Denmark. Using the Danish National Acute Leukemia Registry, we compared relapse risk, relapse-free survival (RFS), and overall survival (OS) between patients with unfavorable cytogenetic features receiving postremission therapy with conventional chemotherapy only versus those undergoing HSCT in CR1. To minimize immortal time bias, we performed Cox proportional hazards regression, included date of allogeneic HSCT as a time-dependent covariate, and stratified the results by age (<60 or ≥60 years) and cytogenetic risk group. Overall, 1031 patients achieved a CR1. Of these, 196 patients (19%) underwent HSCT. HSCT was associated with a lower relapse rate (24% versus 49%) despite a similar median time to relapse (287 days versus 265 days). In all subgroups, the risk of relapse was lower and both RFS and OS were superior in recipients of HSCT (OS, adjusted mortality ratios: all patients, .54 [95% confidence interval (CI), .42-.71]; patients age <60 years, .58 [95% CI, .42-.81]; patients age ≥60 years, .42 [95% CI, .26-.69]; patients with intermediate-risk cytogenetics, .63 [95% CI, .43-.87]; patients with adverse-risk cytogenetics, .40 [95% CI, .24-.67]). In conclusion, in this population-based nationwide cohort study, HSCT was associated with improved survival in both younger and older patients and in patients with both intermediate and adverse cytogenetic risk.

Effects of Education and Income on Treatment and Outcome in Patients With Acute Myeloid Leukemia in a Tax-Supported Health Care System: A National Population-Based Cohort Study.

Purpose Previous US studies have shown that socioeconomic status (SES) affects survival in acute myeloid leukemia (AML). However, no large study has investigated the association between education or income and clinical characteristics, treatment, and outcome in AML. Methods To investigate the effects of education and income in a tax-supported health care system, we conducted a population-based study using individual-level SES and clinical data on all Danish patients with AML (2000 to 2014). We compared treatment intensity, allogeneic transplantation, and response rates by education and income level using logistic regression (odds ratios). We used Cox regression (hazard ratios [HRs]) to compare survival, adjusting for age, sex, SES, and clinical prognostic markers. Results Of 2,992 patients, 1,588 (53.1%) received intensive chemotherapy. Compared with low-education patients, highly educated patients more often received allogeneic transplantation (16.3% v 8.7%). In intensively treated patients younger than 60 years of age, increased mortality was observed in those with lower and medium education (1-year survival, 66.7%; adjusted HR, 1.47; 95% CI, 1.11 to 1.93; and 1-year survival, 67.6%; adjusted HR, 1.55; CI, 1.21 to 1.98, respectively) compared with higher education (1-year survival, 76.9%). Over the study period, 5-year survival improvements were limited to high-education patients (from 39% to 58%), increasing the survival gap between groups. In older patients, low-education patients received less intensive therapy (30% v 48%; adjusted odds ratio, 0.65; CI, 0.44 to 0.98) compared with high-education patients; however, remission rates and survival were not affected in those intensively treated. Income was not associated with therapy intensity, likelihood of complete remission, or survival (high income: adjusted HR, 1.0; medium income: adjusted HR, 0.96; 95% CI, 0.82 to 1.12; low income: adjusted HR, 1.06; CI, .88 to 1.27). Conclusion In a universal health care system, education level, but not income, affects transplantation rates and survival in younger patients with AML. Importantly, recent survival improvement has exclusively benefitted highly educated patients.

Refractory primary immune thrombocytopenia with subsequent del(5q) MDS: complete remission of both after lenalidomide.

A patient with refractory primary immune thrombocytopenia (ITP) characterised by severe skin and mucosal bleedings was treated with several ITP-directed therapies including cyclophosphamide. He later developed therapy-related del(5q) myelodysplastic syndrome with no dysplastic morphological features in bone marrow. He remained severely thrombocytopenic, which suggests ongoing immune mediated platelet destruction. After two 3 week cycles of low-dose lenalidomide, complete cytogenetic remission and complete normalisation of platelet count were observed. This suggests that lenalidomide may be a viable treatment option for ITP in the presence of del(5q) not responding to standard treatments.

The Danish National Acute Leukemia Registry.

AIM OF DATABASE: The main aim of the Danish National Acute Leukemia Registry (DNLR) was to obtain information about the epidemiology of the hematologic cancers acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and myelodysplastic syndrome (MDS). STUDY POPULATION: The registry was established in January 2000 by the Danish Acute Leukemia Group and has been expanded over the years. It includes adult AML patients diagnosed in Denmark since 2000, ALL patients diagnosed since 2005, and MDS patients diagnosed since 2010. The coverage of leukemia patients exceeds 99%, and the coverage of MDS patients is currently 90%. MAIN VARIABLES AND DESCRIPTIVE DATA: Approximately, 250 AML patients, 25 ALL patients, and 230 MDS patients are registered in the DNLR every year. In January 2015, the registry included detailed patient characteristics, disease characteristics, treatment characteristics, and outcome data on more than 3,500 AML, 300 ALL, and 1,100 MDS patients. Many of the included prognostic variables have been found to be of high quality including positive predictive values and completeness exceeding 90%. These variables have been used in prognostic observational studies in the last few years. To ensure this high coverage, completeness, and quality of data, linkage to the Danish Civil Registration System and the Danish National Registry of Patients, and several programmed data entry checks are used. CONCLUSION: The completeness and positive predictive values of the leukemia data have been found to be high. In recent years, the DNLR has shown to be an important high-quality resource for clinical prognostic research.

Improved outcome in acute myeloid leukemia patients enrolled in clinical trials: A national population-based cohort study of Danish intensive chemotherapy patients.

Clinical trials are critical to improve AML treatment. It remains, however, unclear if clinical trial participation per se affects prognosis and to what extent the patients selected for trials differ from those of patients receiving intensive therapy off-trial.We conducted a population-based cohort study of newly diagnosed Danish AML patients treated with intensive chemotherapy between 2000-2013. We estimated accrual rates and compared characteristics, complete remission (CR) rates, and relative risks (RRs) of death at 90-day, 1-year, and 3-years in clinical trial patients to patients treated off-trial.Of 867 patients, 58.3% (n = 504) were included in a clinical trial. Accrual rates were similar across age groups (p = 0.55). Patients with poor performance status, comorbidity, therapy-related and secondary AML were less likely to be enrolled in trials. CR rates were 80.2% in trial-patients versus 68.6% in patients treated off- trial. Also, trial-patients had superior survival at 1-year; 72%, vs. 54% (adjusted RR of death 1.28(CI = 1.06-1.54)), and at 3 years; 45% vs. 29% (adjusted RR 1.14(CI = 1.03-1.26)) compared to patients treated off-trial.Despite high accrual rates, patients enrolled in clinical trials had a favorable prognostic profile and a better survival than patients treated off-trial. In conclusion, all trial results should be extrapolated with caution and population-based studies of "real world patients" have a prominent role in examining the prognosis of AML.

Outpatient management of intensively treated acute leukemia patients--the patients' perspective.

PURPOSE: In recent years, patients with acute leukemia (AL) have, to a greater extent, been managed in an outpatient setting where they live at home but appear every other day for follow-up visits at hospital. This qualitative article elucidates how patients with AL experience the different conditions of the inpatient and outpatient settings and how they reflect on these transitions in order to create meaning in and keep up everyday life. METHODS: Qualitative semi-structured individual interviews twice with each AL patient focusing on the outpatient setting, impact on everyday life, responsibility and the home were performed. Twenty-two patients were interviewed the first time, and 15 of these were interviewed the second time. The data were analyzed in an everyday life relational perspective. RESULTS: Outpatient management facilitates time to be administrated by the patients and thereby the possibility of maintaining everyday life, which was essential to the patients. The privacy ensured by the home was important to patients, and they accepted the necessary responsibility that came with it. However, time spent together with fellow patients and their relatives was an important and highly valued part of their social life. CONCLUSIONS: Approached from the patient perspective, outpatient management provided a motivation for patients as it ensured their presence at home and provided the possibility of taking part in everyday life of the family, despite severe illness and intensive treatment. This may suggest a potential for extending the outpatient management further and also for patient involvement in own care.

Epidemiology and Clinical Significance of Secondary and Therapy-Related Acute Myeloid Leukemia: A National Population-Based Cohort Study.

PURPOSE: Secondary and therapy-related acute myeloid leukemia (sAML and tAML, respectively) remain therapeutic challenges. Still, it is unclear whether their inferior outcome compared with de novo acute myeloid leukemia (AML) varies as a result of previous hematologic disease or can be explained by differences in karyotype and/or age. PATIENTS AND METHODS: In a Danish national population-based study of 3,055 unselected patients with AML diagnosed from 2000 to 2013, we compared the frequencies and characteristics of tAML, myelodysplastic syndrome (MDS) -sAML, and non-MDS-sAML (chronic myelomonocytic leukemia and myeloproliferative neoplasia) versus de novo AML. Limited to intensive therapy patients, we compared chance of complete remission by logistic regression analysis and used a pseudo-value approach to compare relative risk (RR) of death at 90 days, 1 year, and 3 years, overall and stratified by age and karyotype. Results were given crude and adjusted with 95% CIs. RESULTS: Overall, frequencies of sAML and tAML were 19.8% and 6.6%, respectively. sAML, but not tAML, was associated with low likelihood of receiving intensive treatment. Among intensive therapy patients (n = 1,567), antecedent myeloid disorder or prior cytotoxic exposure was associated with decreased complete remission rates and inferior survival (3-year adjusted RR for MDS-sAML, non-MDS-sAML, and tAML: RR, 1.14; 95% CI, 1.02 to 1.32; RR, 1.27; 95% CI, 1.16 to 1.34; and RR, 1.16; 95% CI, 1.03 to 1.32, respectively) compared with de novo AML. Among patients ≥ 60 years old and patients with adverse karyotype, previous MDS or tAML did not impact overall outcomes, whereas non-MDS-sAML was associated with inferior survival across age and cytogenetic risk groups (adverse risk cytogenetics: 1-year adjusted RR, 1.47; 95% CI, 1.23 to 1.76; patients ≥ 60 years old: 1-year adjusted RR, 1.31; 95% CI, 1.06 to 1.61). CONCLUSION: Our results support that de novo AML, sAML, and tAML are biologically and prognostically distinct subtypes of AML. Patients with non-MDS-sAML have dismal outcomes, independent of age and cytogenetics. Previous myeloid disorder, age, and cytogenetics are crucial determinants of outcomes and should be integrated in treatment recommendations for these patients.

Extramedullary disease in patients with acute myeloid leukemia assessed by 18F-FDG PET.

BACKGROUND: Prevalence of extramedullary disease (EMD) in acute myeloid leukemia (AML) at the time of diagnosis is unknown. Previous estimates range from 2.5% to 30.5% and are usually based on clinical examination. This may cause an under diagnosis of EMD as not all extramedullary manifestations are easily detectable. Few recent studies have used positron emission tomography (PET) scans for diagnosing EMD in patients AML. METHOD: During a 9-month period, newly diagnosed patients with AML who were candidates for intensive chemotherapy were 18F-Fluoro-deoxy-glucose (FDG) PET-scanned prior to induction treatment. We compared the prevalence of EMD diagnosed by PET scans and by clinical examination. Subsequent PET scans following induction chemotherapy were performed for response evaluation of EMD. RESULTS: Twenty-six patients were included in the study. 18-F-FDG PET scans revealed more than twice as many patients with EMD than found by clinical examination (65% vs. 31%). PET demonstrated 55 EMD lesions compared with 15 diagnosed by clinical examination. In general, the responses of EMD detected by PET scans were concordant with the bone marrow responses assessed by pathology examination. CONCLUSION: 18-F-FDG PET is a useful tool for diagnosing EMD in AML and for assessing treatment responses of EMD in AML.