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.

Temporal changes in survival among adult patients with acute myeloid leukaemia in the period 2000-2016: a Danish population-based study.

In the present study, we quantify the progress in overall survival (OS) during the period 2000-2016 among Danish patients with acute myeloid leukaemia (AML). This population-based study, including 3820 adult patients with AML, demonstrates a significantly improved OS over time with the 2-year age-standardised OS increasing from 22% in 2002 to 31% in 2016. The improvement in OS was exclusively seen in patients with AML aged ≥50 years, with absolute improvements in 2-year OS from 2002 to 2016 of ≥10% among patients aged 50-75 years and a small absolute increase in those aged >75 years.

Structural aberrations are associated with poor survival in patients with clonal cytopenia of undetermined significance.

Not available.

The prognostic effect of smoking status on intensively treated acute myeloid leukaemia - A Danish nationwide cohort study.

With rising life expectancy, the importance of patient-related prognostic factors and how to integrate such data into clinical decision-making becomes increasingly important. The aim of this study was to evaluate the prognostic impact of smoking status in patients with acute myeloid leukaemia (AML) treated with intensive chemotherapy. We conducted a nationwide cohort study based on data obtained from the Danish National Leukaemia Registry (DNLR). The study comprised Danish patients aged 18-75 years, diagnosed with AML between 1 January 2000 and 31 December 2012. Medical records were reviewed and data on smoking status were collected. A total of 1040 patients (median age 59 years) were included, and 602 patients (58·9%) were categorised as ever-smokers and the remaining as never-smokers. Kaplan-Meier survival estimates revealed that ever-smokers had a significant shorter median overall survival (OS) at 17·2 months [95% CI (14·9;19·1)] compared to never-smokers at 24·5 months (95% CI [19·2;30·7]). Multivariate analysis revealed smoking status as a significant prognostic factor for inferior OS with a hazard ratio (HR) of 1·22 [95% CI (1·04;1·44)]. In conclusion, smoking status was found to be associated with inferior OS in intensively treated AML patients.

Addressing the room for improvement in management of acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) is highly curable. To achieve high cure rates, targeted therapy with retinoic acid (ATRA) must be started promptly at time of suspected diagnosis. Early death rates (EDRs, ≤30 days from diagnosis) differ markedly in patients treated on clinical trials compared to the general population. OBJECTIVES AND METHODS: We used the comprehensive Danish National Acute Leukemia Registry (DNLR) to investigate the incidence, treatment, EDR, and long-term clinical outcome in APL between 2000 and 2014. RESULTS: Twenty-two of 41 deaths occurring in 122 APL patients were EDs which were primarily caused by intracranial hemorrhage, disseminated intravascular coagulation (DIC), sepsis, and multiorgan failure. The overall EDR was 18.0%, whereas clinical trial participants had an EDR of 6.7%. Fifteen patients recruited to the NCRI AML17 APL trial from 2010 to 2013 were younger and had decreased mortality (HR 0.18, CI 0.04-0.86, P = 0.02) compared to contemporarily treated patients (n = 15) not recruited to a clinical trial. Performance status, leukemia origin, and Sanz-score were independent prognostic variables. CONCLUSIONS: The very low EDR for on-trial patients is not observed in the general cohort of APL patients. Diagnostic awareness emerges as the greatest clinical challenge in management of APL.

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.

Autoimmune diseases, infections, use of antibiotics and the risk of acute myeloid leukaemia: a national population-based case-control study.

Previous studies reported increased risk of acute myeloid leukaemia (AML) in individuals with inflammatory conditions. However, it is unclear whether this association is explained by preceding cytotoxic therapy or haematological diseases. We conducted a nationwide case-control study that included 3053 AML patients, diagnosed in Denmark between 2000 and 2013, and 30 530 sex- and age-matched population controls. We retrieved information on autoimmune disease, infections, and use of antibiotics and computed odds ratios for AML (conditional logistic regression). Results were stratified by AML type, sex, and age. Autoimmune diseases were associated with an overall increased risk of AML {odds ratio [OR] 1·3 [95% confidence interval (CI) = 1·1-1·5]}. However, the risk was confined to patients with previous haematological disease or cytotoxic therapy exposure [secondary/therapy-related AML (sAML/tAML0) OR 2·0 (95% CI = 1·6-2·6)] and not de novo AML [OR 1·1 (95% CI = 0·9-1·3)]. Similarly, any prior infection requiring hospitalization was associated with a higher risk of AML [OR 1·3 (95% CI = 1·1-1·4)]. Again, this association was evident for sAML/tAML [OR 1·8 (95% CI = 1·5-2·2)], and not de novo AML [OR 1·1 (95% CI = 1·0-1·2)]. In conclusion, autoimmune diseases and infections were associated with an increased AML risk only in subjects with prior haematological disease and/or cytotoxic treatment. These observations suggest, that inflammation plays - if any - a minor role for the development of de novo 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.

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.

Eltrombopag for management of chronic immune thrombocytopenia (RAISE): a 6-month, randomised, phase 3 study.

BACKGROUND: Eltrombopag is an oral thrombopoietin receptor agonist for the treatment of thrombocytopenia. We aimed to compare the response to once daily eltrombopag versus placebo in patients with chronic immune thrombocytopenia during a 6-month period. METHODS: We undertook a phase 3, double-blind, placebo-controlled study in adults with previously treated immune thrombocytopenia of more than 6 months' duration who had baseline platelet counts lower than 30,000 per µL. Patients were randomly allocated (in a 2:1 ratio) treatment with local standard of care plus 50 mg eltrombopag or matching placebo once daily for 6 months. Randomisation was done centrally with a computer-generated randomisation schedule and was stratified by baseline platelet count (≤ 15,000 per µL), use of treatment for immune thrombocytopenia, and splenectomy status. Patients, investigators, and those assessing data were masked to allocation. Dose modifications were made on the basis of platelet response. Patients were assessed for response to treatment (defined as a platelet count of 50,000-400,000 per µL) weekly during the first 6 weeks and at least once every 4 weeks thereafter; the primary endpoint was the odds of response to eltrombopag versus placebo. Analysis was by intention to treat. This study is registered at ClinicalTrials.gov, number NCT00370331. FINDINGS: Between Nov 22, 2006, and July 31, 2007, 197 patients were randomly allocated to treatment groups and were included in the intention-to-treat analysis (135 eltrombopag, 62 placebo). 106 (79%) patients in the eltrombopag group responded to treatment at least once during the study, compared with 17 (28%) patients in the placebo group. The odds of responding were greater in patients in the eltrombopag group compared with those in the placebo group throughout the 6-month treatment period (odds ratio 8·2, 99% CI 3·59-18·73; p<0·0001). 37 (59%) patients receiving eltrombopag reduced concomitant treatment versus ten (32%) patients receiving placebo (p=0·016). 24 (18%) patients receiving eltrombopag needed rescue treatment compared with 25 (40%) patients receiving placebo (p=0·001). Three (2%) patients receiving eltrombopag had thromboembolic events compared with none in patients on placebo. Nine (7%) eltrombopag-treated patients and two (3%) in the placebo group had mild increases in alanine aminotransferase concentration, and five (4%) eltrombopag-treated patients (vs none allocated to placebo) had increases in total bilirubin. Four (7%) patients taking placebo had serious bleeding events, compared with one (<1%) patient treated with eltrombopag. INTERPRETATION: Eltrombopag is effective for management of chronic immune thrombocytopenia, and could be particularly beneficial for patients who have not responded to splenectomy or previous treatment. These benefits should be balanced with the potential risks associated with eltrombopag treatment. FUNDING: GlaxoSmithKline.

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.

A national Danish proof of concept on feasibility and safety of home -based intensive chemotherapy in patients with acute myeloid leukemia.

Technological advances have made it possible to offer home-based chemotherapy to patients without health care professionals being present. Prior studies on effects of home-based treatment lack inclusion of patients with hematologic malignancies. We present data from a multicenter single-arm feasibility and safety study of home-based intensive chemotherapy in patients with newly diagnosed acute myeloid leukemia and their quality of life and psychological wellbeing. This national study included patients from six sites in Denmark who received intensive chemotherapy on programmed CADD Solis infusion pumps through a central venous catheter and were also managed as outpatients during treatment-induced pancytopenia. Data are presented from 104 patients, receiving 272 treatments with 1.096 (mean 4.57, SD 3.0) home infusion days out of 1.644 treatment days (67 %). Sixty-two of 168 (36.9 %) reinduction and consolidation treatment cycles ensuing pancytopenia phases were solely handled in the outpatient clinic. Patients reported high satisfaction with home-based treatment, which had a positive influence on their ability to be involved in their treatment and be socially and physically active. No unexpected events occurred during the intervention. Overall, patients improved in all quality of life outcomes over time. Home-based intensive chemotherapy treatment was feasible and safe in this population. ClinicalTrials.gov identifier: NCT04904211.

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.

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.

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.

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.

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.