Acute Myeloid Leukemia Survivors Research Articles

Overexpression of REC8 induces aberrant gamete meiotic division and contributes to AML pathogenesis - a multiplexed microarray analysis and mendelian randomization study.

Acute myeloid leukemia (AML) is a notably lethal disease, characterized by malignant clonal proliferation of hematopoietic stem cells in the bone marrow. This study seeks to unveil potential therapeutic targets for AML, using a combined approach of microarray analysis and Mendelian randomization (MR). We collected data samples from the Gene Expression Omnibus (GEO) database and extracted pQTL data from genome-wide association studies (GWAS) to identify overlapping genes between the DEGs and GWAS data. Gene enrichment and pathway annotation analyses were performed on these genes. Furthermore, we validated gene expression levels and assessed their clinical relevance. By taking the intersection of these gene sets, we obtained a list of co-expressed genes, including four upregulated genes (REC8, TPM2, ZMIZ1, CD82) and two downregulated genes (IFNAR1, TMCO3). MR analysis demonstrated that genetically predicted protein levels of CD82, REC8, ZMIZ1, and TPM2 were significantly associated with increased odds of AML, while IFNAR1 and TMCO3 showed a protective effect. Gene ontology and KEGG pathway analyses revealed significant enrichment in functions related to female gamete generation, meiosis, p53 signaling pathway, and cardiac muscle contraction. Differences in immune cell profiles were observed between AML survivors and those with poor prognosis, including lower levels of neutrophils and higher levels of follicular helper T cells in the latter group. This study identifies a causal relationship between gene expression and AML and highlights the potential role of REC8 in leukemogenesis, possibly through its impact on gametocyte meiotic abnormalities. The findings provide new insights into the prevention and treatment of leukemia.

Shorter long-term post-transplant life expectancy may be due to prior chemotherapy for the underlying disease: analysis of 3012 patients with acute myeloid leukemia enrolled on 9 consecutive ECOG-ACRIN trials

Several studies reported that patients with acute myeloid leukemia (AML) who remain in long-term remission after allogeneic or autologous transplant have a shorter life expectancy, compared to the general population. However, little is known about the life expectancy of adult long-term survivors of AML who were treated with chemotherapy alone without a transplant and there have been no comparisons with survival among the general population. The current study indicates that the life expectancy of AML patients who achieved and maintained CR for at least 3 years is shorter than expected for age in the US population. This was observed also in patients who did not undergo a transplant including those who have not relapsed during the entire long follow-up period. Thus, late relapse does not explain why patients without transplants have a shortened life expectancy. Taken together, these data strongly suggest that prior chemotherapy for the underlying AML is at least a major contributing factor for the known shortened life expectancy post-transplant.

Late Adverse Effects after Treatment for Childhood Acute Leukemia.

The aim of this review is to raise awareness and knowledge among healthcare professionals and policymakers about late adverse effects in survivors of childhood leukemia. With contemporary treatment, over 90% of children with acute lymphoblastic leukemia (ALL) and over 60% with acute myeloid leukemia (AML) are cured. Large cohort studies demonstrate that 20% of ALL and most AML survivors have at least one chronic health condition by 20-25 years after diagnosis. These are life-changing or threatening in some survivors and contribute to increased premature mortality. We describe the frequency, causes, clinical features, and natural history of the most frequent and severe late adverse effects in childhood leukemia survivors, including subsequent malignant neoplasms, metabolic toxicity, gonadotoxicity and impaired fertility, endocrinopathy and growth disturbances, bone toxicity, central and peripheral neurotoxicity, cardiotoxicity, psychosocial late effects, accelerated ageing and late mortality. The wide range of late effects in survivors of haemopoietic stem cell transplant is highlighted. Recent developments informing the approach to long-term survivorship care are discussed, including electronic personalized patient-specific treatment summaries and care plans such as the Survivor Passport (SurPass), surveillance guidelines and models of care. The importance of ongoing vigilance is stressed given the increasing use of novel targeted drugs with limited experience of long-term outcomes. CONCLUSION: It is vital to raise awareness of the existence and severity of late effects of childhood leukemia therapy among parents, patients, health professionals, and policymakers. Structured long-term surveillance recommendations are necessary to standardize follow-up care.

Longitudinal changes in cognitive and physical function and health-related quality of life in older adults with acute myeloid leukemia

IntroductionMany older adults with acute myeloid leukemia (AML) do not receive chemotherapy because of physicians' and patients' concern for toxicities and functional decline. This highlights the critical and urgent need to generate knowledge of functional changes following new treatments. Materials and MethodsAs a part of a pragmatic single-center trial, 59 older adults ≥60 years with AML completed geriatric assessment and health-related quality of life measures before treatment and at one month and three months after chemotherapy initiation. Changes in scores of various geriatric assessment measures were computed by subtracting the baseline score from the one-month and three-month scores for each patient. Established cut-offs were used to determine a clinically meaningful change (improvement or worsening). This study provides results of descriptive exploratory analyses. ResultsPatients experienced significant comorbidity burden and a high prevalence of functional impairments before treatment, with 56% of patients having ≥2 comorbid conditions, 69% having abnormal cognitive function (using Montreal Cognitive Assessment), 69% having impaired objective physical function (using Short Physical Performance Battery), and 64% having a positive depression screen (Patient Health Questionnaire-9). Patients (n = 53) received treatment with predominantly low-intensity chemotherapy; six patients received intensive chemotherapy. Among those who completed some or all of the three-month evaluation (N = 43), from baseline before treatment to three months later, cognitive function improved (38.7%) or remained stable (38.7%), objective physical function improved (51.6%) or remained stable (22.6%), and depression scores improved (9.4%) or remained stable (53.1%). Global health status score and role functioning moderately improved by a score of >16. DiscussionAn exploratory analysis of our phase 2 trial demonstrated improvement or stabilization of cognitive and physical function and depression score at three months in a high proportion of older survivors of AML, despite a high prevalence of frailty and significant comorbidity burden at baseline. These results demonstrate success of treatment in improving cognitive and physical function and depression score, and, if confirmed in larger studies, should encourage oncologists to offer chemotherapy to older adults with AML.Clinical Trial Registration: The study is registered in the ClinicalTrials.gov ID: NCT03226418.

Lifestyle Behaviors and Health-Related Quality of Life in Long-Term Survivors of Acute Myeloid Leukemia: An International Survivorship Study By the Gimema, EORTC Quality of Life and Leukemia Groups

Background Major advances have been made in the treatment of acute myeloid leukemia (AML), and the number of survivors is expected to rise over the coming years. Therefore, a better understanding of the relationships between lifestyle behaviors and health-related quality of life (HRQoL) is important to better inform survivorship care programs. Although valuable evidence exists in this area of research for survivors of solid tumors, little data is available on patients with AML. Objective We aimed to investigate the prevalence of lifestyle behaviors of long-term AML survivors and to identify associations with HRQoL profile. A secondary objective was to describe the prevalence of clinically important functional problems and symptoms by level of physical activity (PA). Methods: In this international AML survivorship study, patients were eligible if they were diagnosed at least 5 years before and were disease-free at study entry. Patients were invited to participate by their treating hematologist and all consenting patients were requested to complete a survey booklet. Clinical data were retrieved via hospital medical records. The following lifestyle behaviors were assessed: PA, maintaining a healthy weight, eating pattern, smoking status, and alcohol consumption. PA was assessed by the Godin Leisure-Time Exercise questionnaire. Using only moderate and strenuous scores, those with a leisure score index≥24 were classified as active and those with a score≤23 were classified as insufficiently active. Maintaining a healthy weight was evaluated by the BMI and patients were categorized into: non-overweight/obese (BMI <25) and overweight/obese (BMI ≥25). HRQoL profile was assessed by the EORTC QLQ-C30 questionnaire. Univariable and multivariable linear regression analyses were used to investigate the associations of lifestyle behaviors and HRQoL. The summary score of the EORTC QLQ-C30 was used as outcome variable in regression analyses and the following covariates were considered: sex, age at study entry, time since AML diagnosis, ECOG performance status at diagnosis, education, living arrangements, hematopoietic stem cell transplantation history, being treated within a randomized controlled trial (RCT), and current comorbidity. Prevalence of clinically important problems and symptoms, by PA, was assessed based on recently developed thresholds for the EORTC QLQ-C30. Results Overall, 225 AML survivors with a median time from diagnosis to study entry of 8.8 years (IQR 6.4-11.9) were enrolled across 24 centers in 6 countries (Italy, France, Turkey, North Macedonia, Belgium, Slovenia). Median age at study entry was 58.0 years (IQR 47.3-66.9) and 119 (52.9%) were women. Overall, there were 165 (73.7%) patients who received at least one stem cell hematopoietic transplantation, and 70 (31.1%) patients treated in the setting of a RCT as first line therapy. One hundred ninety-five survivors (88.6%) reported at least one comorbidity and 103 (46.8%) reported four or more comorbidities. Overall, 74 (33.8%) patients were considered physically active, 121 (55.3%) were considered as overweight/obese, and 43 (19.8%) reported healthy eating habits. The majority of patients were non-smoker (n=184, 83.6%) and reported low alcohol consumption (n=209, 95.9%). In univariable analyses, no comorbidity (p=.046), no smoking habits (p=.035), higher level of education (p=.017), and being physically active (p<.001) were associated with a higher EORTC QLQ-C30 summary score. However, in multivariable analysis, only being physically active (p=.005) remained independently associated with a higher EORTC QLQ-C30 summary score. Marked differences were observed in the prevalence of clinically important functional problems and symptoms between the two groups. For example, the prevalence of patients reporting clinically important fatigue and dyspnea in patients who were physically active versus those who were not, was: 8.1% vs. 23.6% and 23% vs 43.1%, respectively. Likewise, patients who were physically active tended to report a lower prevalence of clinically important functional problems (Figure 1). Conclusion: We found an independent association between being physically active and reporting a better HRQoL profile in long-term survivors of AML. Our findings suggest that interventions aimed to increase PA in survivors of AML may be critical to improve their functional outcomes and reduce symptom burden.

Evaluation of cardiac failure and recovery in acute myelogenous leukemia.

7038 Background: Cardiac failure causes significant comorbidity and death in acute myeloid leukemia (AML) patients, with incidence estimated at 10-15% (Neuendorff N Blood Adv. 2020). We sought to describe the post-treatment cardiac experience in AML survivors including factors associated with onset, persistence, and outcome of cardiac dysfunction during and following treatment. Methods: 86 patients with AML or other high-grade myeloid neoplasms treated with induction chemotherapy with or without allogeneic hematopoietic cell transplant were identified at the University of Washington/Fred Hutchinson Cancer Center from 1/2000-1/2022. All patients sustained cardiac dysfunction, defined as left ventricular ejection function (LVEF) decline of 10% with absolute LVEF below 50% during chemotherapy. A multivariable analysis was performed to compare those who recovered (LVEF recovery) and those who did not (LVEF non-recovery), examining baseline health factors, disease risk (ELN 2017), time to dysfunction and recovery, most probable cause of cardiac dysfunction based on cardiologist evaluation, and goal-directed medical therapy (GDMT) use and dosage. Results: 48% (41 out of 86) failed to recover following LVEF decline. This cohort tended to be older, male, and had more ASCVD risk factors ( p < 0.05). Neither the choice of chemotherapy regimen ( p= 0.43) nor the cumulative anthracycline dose ( p= 0.44) was significantly different between the LVEF recovery and non-recovery groups. Onset of cardiac dysfunction tended to occur later in the LVEF recovery cohort (median 72 vs. 48.5 days, p= 0.660). In subjects who recovered, the median time to recovery was 87 days (range 2-268 days). When chemotherapy was identified as the probable cause, it was associated with greater likelihood of eventual recovery ( p= 0.014), whereas ischemic coronary etiology was associated with non-recovery ( p= 0.005). Failing to recover from cardiac dysfunction correlated with shorter survival (median 229 vs 650 days, p = 0.005). Multivariable analysis is shown in the Table below. Importantly, the use of GDMT with higher doses of renin-angiotensin inhibitor medications (RAASi) were associated with higher probability of recovery (not shown, p < 0.05). Conclusions: The present study demonstrates recovery occurring in over half of AML patients who experienced cardiac dysfunction during their chemotherapy. Recovery was more common in patients whose cardiac dysfunction is precipitated by chemotherapy and in patients who received GDMT with aggressive use of RAASi. Since cardiac recovery was associated with improved survival, next steps include establishing a cardiac monitoring algorithm to initiate early and aggressive GDMT. [Table: see text]

At What Point Are Long-Term (>5 Years) Survivors of APL Safe? A Study from the SEER Database.

Acute promyelocytic leukemia (APL) is a highly curable cancer, but it is not clear whether it is also necessary to monitor long-term toxicity in "cured" patients who survive for more than five years, which is critical to ensuring maximum survival in APL patients. A total of 1952 APL 5-year survivors and 5973 non-APL acute myeloid leukemia (AML) 5-year survivors were included from the Surveillance, Epidemiology, and End Results (SEER) database. The standardized mortality ratio (SMR) was calculated to measure the risk of death. Cumulative mortality is calculated as the incidence of specific causes of death under competing risk events. The SMR of all causes of death in >5-year survivors of APL was higher than that of the general population only at 60-119 months (SMR, 1.41). This was mainly because a significant increase in mortality from AML (SMR, 87.67) and second malignant neoplasms (SMNs) (SMR, 1.56) was found only at 60-119 months. However, there was no higher risk of death from non-cancer-related disease in >5-year survivors of APL than that of the general population (SMR, 0.89). The SMR of all-cause deaths in >5-year survivors of non-APL AML decreased year by year and was no higher than that of the general population until after 216 months. The cumulative incidence of AML-related death, SMN-related death, and non-cancer-related death was significantly lower in APL patients than in non-APL AML patients throughout the follow-up period. Compared with the general population, the risk of death of patients with APL was higher within 5 to 10 years but not higher over 10 years. Therefore, we believe that long-term survivors of APL are safe after 10 years.

Bone Marrow WT1 mRNA Upregulation in Acute Myeloid Leukemia (AML) in Complete Molecular Remission (mCR): Understanding the Limitations and Advantages of WT1 As a Measurable Residual Disease (MRD) Target

Introduction WT1 mRNA levels assessed by q-PCR have been employed as a marker of remission in AML patients undergoing intensive chemotherapy (Nomdedeu J. et al. Leukemia 2013;27:2157) and hematopoietic cell transplantation (HCT) (Nomdedeu J et al. Biol Blood Marrow Transplant 2018;24:55). Patients with adjusted bone marrow WT1 mRNA levels greater than 100 copies showed a high probability of relapse. Despite the usefulness of WT1 quantification in this and other settings, this marker is scarcely employed as an MRD target because levels greater than >100 copies can also be observed in normal bone marrows. Furthermore, 10-20% of AML at diagnosis and most chronic myelomonocytic leukemia (CMML) cases lack WT1 upregulation. The high levels of bone marrow WT1 copy numbers observed in most AML, decline in responding patients, although the utility, if any, of WT1 levels in long-term survivors of AML is currently unknown. We investigated the frequency and biological findings of mCR AML samples showing WT1 upregulation(>100 copies) compared to that mCR AML with concordant low WT1 levels. Patients and methods The study included 717 bone marrow samples from 80 AML patients (23 patients with RUNX1-RUNX1T1, 18 pts with CBFb-MYH11, four pts with NPM1 mutations, and 35 pts with PML-RARa). Samples were obtained at diagnosis (58 samples) and the follow-up (659 samples, all in mCR and without relapses) from one month to 219 months after diagnosis. Chimeric transcripts and WT1 levels were investigated by standardized real-time methods (ELN). Hemoglobin and leukocyte counts were also recorded. Flow cytometry immunophenotyping was also performed using four-color flow cytometry. We analyzed the percentage of CD34+, CD117+, CD123+ cells, and the Myeloid/Lymphoid CD34 ratio. nCounter Stem cell panel (Nanostring) was used to investigate the differences between that AML in mCR, showing high (>100) and low (<100) WT1 levels. In an additional cohort (11 samples: 4 with WT1>100 and 7 with WT1 <100), we performed bulk RNAseq (Novogene) to investigate enriched genes in samples with high WT1 levels. Results Thirty-five patients had at least one sample with WT1 levels greater than 100 copies (44%) despite being in mCR. Twelve samples had WT1 levels greater than 300 copies. In one case, this level reached 770 copies. These WT1 "peak" samples were distributed as follows: 49/306 PML-RARa, 25/161 RUNX1-RUNX1T1, 10/174 CBFb-MYH11, and 1/18 NPM1. Patients showing WT1 peaks were older than those without elevations (47 years vs. 36 years, p:0.003) For PML-RARa samples, "peaking" was associated with low levels of hemoglobin (133 g/L for <100 copies vs. 125 g/L >100 copies, p:0.009). For RUNX1-RUNX1T1, "peaking" was linked to less platelets (132x109 vs. 197x109 p:0.05) , higher CD34 (1.5% vs. 1% p:0.05) and also higher CD117+ cells (1.6 vs.1%, p:0.01). Lastly, CBFb-MYH11+ samples with WT1 peaks had higher leukocyte counts that those showing low WT1 levels (4.5x109 vs. 2.9x109, p:0.006). Nanostring comparisons between mCR WT1 high vs. low samples showed upregulation of TOR1A, PIK3CB, PTPN6, and PGM1 with downregulation of HMGA1, HOXB2 and CDC6. RNA seq analysis detected an enrichment of SUZ12 targets in those samples with high WT1 levels. Conclusions Bone marrow mRNA WT1 levels commonly exceed the clinical relevant value of 100 copies in AML samples in mCR (13%). Peak samples were related to peripheral blood values and/or raised numbers of immature bone marrow cells (CD34, CD117). Bone marrow WT1 although unable to accurately predict relapses in long-term survivors of AML may be a non-invasive sensor of a yet undefined myeloid state.

Secondary Neoplasms in AML Long-Term Survivors: Even More Cancer to Come?

Introduction: As outcomes of patients with acute myeloid leukemia (AML) have improved, the fraction of patients surviving long-term is increasing. Information on somatic and psycho-social health consequences of AML and its treatment is sparse. The aim of our study was to perform a multi- dimensional analysis of health outcomes in AML long-term survivors (AML-LTS). This report focuses on secondary neoplasms (SN) after AML. Data on psychosocial outcomes and clonal hematopoiesis are presented by Telzerow et al., Görlich et al. and Krauss et al. Methods: We conducted a cross-sectional study including AML survivors who had been enrolled in clinical trials or the patient registry of the AML-CG study group, and were alive ≥5 years after initial diagnosis. Data concerning somatic health status were collected through patient questionnaires, assessments by the patients' physicians, and medical and laboratory reports. (DRKS00023991) Results: Data on somatic health status is available for 355 AML-LTS, 58% female, aged 28 to 93 years [y] (median 60y), 5 to 19y after initial diagnosis (median, 11.6y). Sixteen percent were initially diagnosed with secondary AML (sAML) or therapy-related AML (tAML) and 38% were treated with chemotherapy only while 62% had undergone allogeneic stem cell transplantation (alloHSCT). Fifty-five AML-LTS (15.5%) had developed SN after AML, that manifested 3 months to 18y after initial diagnosis (median, 12.4y), at age 31 to 83y (median 59y). Forty-two percent of AML-LTS with SN were female, 66% had undergone alloHSCT and 24% were initially diagnosed with sAML or tAML. At the time of study participation, 96% percent of all AML-LTS and 90 % of those diagnosed with SN fulfilled CR criteria (neutrophils >1G/L and thrombocytes >100G/L). Most common tumor types were non-melanoma skin cancers (30%), breast cancer (11%, all female, 25% of female AML-LTS with SN), head and neck cancers (7%) and, in 5% each, cancers of the esophagus, lung, bladder and prostate (9.4% of male AML-LTS with SN). Kaplan-Meier-Analyses show a 20%-risk of AML-LTS to develop SN 15 years after initial diagnosis, with no significant difference between patients treated by alloHSCT or chemotherapy only (log-rank p=.26; Fig. 1). However, 10y-risk was 5.6% and 15y-risk was 18.5% for AML-LTS treated with chemotherapy only, whereas for AML-LTS treated with alloHSCT 10y-risk was 12% and 15y-risk was 21%. AML-LTS >60y at the time of AML diagnosis had a significantly higher risk to develop secondary cancer, with a 10y-risk of 17.7% compared to 7.9% for AML-LTS aged 30-60y and 6.6% aged <30y at initial diagnosis (Fig. 2). Using Cox regression models, we analyzed the influence of age at AML diagnosis, sex, smoking status, sAML/tAML vs. de novo-AML, AML relapse (as time-dependent covariable) and treatment with alloHSCT vs. chemotherapy only on the risk of developing secondary malignancies after AML. Only older age at initial diagnosis (OR=1.03 per year, 95% CI: 1.01 - 1.05, p=.01) and male sex (OR=1.93, 95%-CI: 1.12 - 3.37, p=.02), but none of the diagnosis- and treatment-related factors significantly associated with higher risks for secondary malignancies. However, AML-LTS diagnosed with sAML/tAML tended to develop SN earlier after initial diagnosis than those diagnosed with de novo AML. Ten-years-risk was 9% and 15y-risk was 20% for AML-LTS diagnosed with de-novo-AML, whereas for AML-LTS diagnosed with sAML/tAML 10y-risk was 14% and 15y-risk was 23% (log-rank p=.08). Conclusion: Our study includes a large cohort of AML-LTS representing a wide age range, a long follow-up period of 5 to nearly 20 years, and heterogeneous therapy regimens (chemotherapy + autoHSCT vs. alloHSCT), close to real-life clinical settings. We found that the 15y-risk to develop a SN after AML is ~20%, with men having a 2-fold higher risk, and older age at the time of diagnosis being a negative predictor. We did not identify diagnosis- or treatment-related factors associated with increased risks for SN, although SN tended to occur earlier in patients who received alloHSCT compared to those treated with chemo only. We hope that our results may guide future recommendations for risk-adapted follow-up of AML-LTS. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Evaluating a patient-centered discrete choice experiment to quantify individual treatment preferences of newly diagnosed older adults with acute myeloid leukemia: A mixed methods study.

256 Background: Numerous studies have demonstrated that physician perceptions of patient priorities and patients’ stated preferences differ substantially. Use of preference clarification using discrete choice experiments (DCEs) has been shown to improve preference-concordance for patients with solid tumors. Previously, we developed a DCE to describe preferences of survivors of acute myeloid leukemia (AML). We sought to evaluate this DCE among newly diagnosed patients with AML to inform shared decision-making. Methods: We used a sequential explanatory (quantitative to qualitative) mixed methods design to assess acceptability, feasibility, and content validity of the DCE to elicit individual preferences. Newly diagnosed older (≥ 60 years) adults with AML completed the DCE at the time of treatment decision. Patients and caregivers then completed semi-structured interviews to expand on quantitative findings. Based on initial results, healthy volunteers completed think-aloud sessions while completing the DCE and semi-structured interviews to further evaluate comprehensibility. Results: 47 participants were enrolled (18 patients [8 female, 10 male; aged 60-87], 16 caregivers, 15 healthy volunteers). Patients received best supportive care (n = 1), hypomethylating agents (n = 9), and high-intensity chemotherapy (n = 8). Feasibility/Acceptability: All patients completed the DCE (100% feasibility), and all reported that they answered according to their preferences (100% acceptability). Content Validity: 1) Relevance: 17/18 (94%) felt the DCE was relevant. 2) Comprehensiveness: In addition to the attributes in the DCE, provider recommendations and family considerations were noted to be critical in treatment decision-making. 3) Comprehensibility: Only 13/18 (72%) felt the DCE was easy to understand, and 14/18 (78%) felt it was easy to answer. Explanatory Interviews: Patients reported being in “shock,” “devastated” from receiving the diagnosis, feeling overwhelmed (“I was floored”) and not being able to reliably concentrate on the DCE due to these factors. Caregivers corroborated patients’ reports. Healthy volunteers also reported “information overload” and that the DCE was “technical” and the included outcome levels were “confusing.”. Conclusions: This DCE designed for older adults with AML was relevant, feasible, and acceptable. However, nearly 30% of patients reported difficulty understanding the DCE. Some reported not being able to attend to the complex tasks in the DCE, thereby compromising content validity of the measure. We suspect this was due to the distress caused by the diagnosis. This study demonstrates the challenge of developing valid preference elicitation instruments for newly diagnosed patients and highlights the need for extensive evaluation prior to clinical implementation.

Chronic conditions, late mortality, and health status after childhood AML: a Childhood Cancer Survivor Study report

AbstractFive-year survival following childhood acute myeloid leukemia (AML) has increased following improvements in treatment and supportive care. Long-term health outcomes are unknown. To address this, cumulative incidence of late mortality and grades 3 to 5 chronic health condition (CHC) were estimated among 5-year AML survivors diagnosed between 1970 and 1999. Survivors were compared by treatment group (hematopoietic cell transplantation [HCT], chemotherapy with cranial radiation [chemo + CRT], chemotherapy only [chemo-only]), and diagnosis decade. Self-reported health status was compared across treatments, diagnosis decade, and with siblings. Among 856 survivors (median diagnosis age, 7.1 years; median age at last follow-up, 29.4 years), 20-year late mortality cumulative incidence was highest after HCT (13.9%; 95% confidence interval [CI], 10.0%-17.8%; chemo + CRT, 7.6%; 95% CI, 2.2%-13.1%; chemo-only, 5.1%; 95% CI, 2.8%-7.4%). Cumulative incidence of mortality for HCT survivors diagnosed in the 1990s (8.5%; 95% CI, 4.1%-12.8%) was lower vs those diagnosed in the 1970s (38.9%; 95% CI, 16.4%-61.4%). Most survivors did not experience any grade 3 to 5 CHC after 20 years (HCT, 45.8%; chemo + CRT, 23.7%; chemo-only, 27.0%). Furthermore, a temporal reduction in CHC cumulative incidence was seen after HCT (1970s, 76.1%; 1990s, 38.3%; P = .02), mirroring reduced use of total body irradiation. Self-reported health status was good to excellent for 88.2% of survivors; however, this was lower than that for siblings (94.8%; P < .0001). Although HCT is associated with greater long-term morbidity and mortality than chemotherapy-based treatment, gaps have narrowed, and all treatment groups report favorable health status.

P558: GERMAN AMLCG-SURVIVORSHIP STUDY – SOMATIC LONG-TERM CONSEQUENCE OF AML AND ITS THERAPY: FROM HEART TO KIDNEY.

Background: As outcomes of patients with acute myeloid leukemia (AML) have improved, the fraction of patients surviving long-term are increasing. Information on somatic and psycho-social health consequences of AML and its treatment is sparse. Aims: Our aim was to perform a multi-dimensional analysis of health outcomes in AML long-term survivors (AML-LTS). This report focuses on somatic morbidity; overall and health-related quality of life are reported separately (Telzerow et al.). Methods: We conducted a cross-sectional study including AML survivors who had been enrolled in clinical trials or the patient registry of the AML-CG study group and were alive ≥5 years after initial diagnosis. Data concerning somatic health status were collected through patient questionnaires, assessment by the patients’ physicians, and medical and laboratory reports. An age- and sex-matched control cohort was derived from German population-based health surveys (Robert Koch Institute, DEGS1 survey; n=6013). Results: Data on somatic health status was available for 355 survivors, aged 28-93 years, who participated 5 to 19 years after their AML diagnosis. Thirty-eight percent of survivors were treated with chemotherapy with or without an autologous transplant, whereas 62% had undergone allogeneic transplantation (alloSCT). We compared the prevalence of somatic diseases between AML-LTS and the general German population (DEGS1 sample), focusing on cardiovascular diseases and risk factors due to their relevance for overall morbidity and mortality, and their known association with survivorship in other cancers. Using age- and sex-adjusted multivariate models (Figure A), we found that AML survivors had a 2-fold higher risk of type 1/2 diabetes (DM 1/2), and a 3.5-fold increased risk of congestive heart failure (CHF) compared to the general population. Prevalence of hypertension, coronary artery disease (CAD) and myocardial infarction were similar between the groups. To identify factors associated with development of CHF among AML-LTS, we constructed multivariate models incorporating patient- and treatment-related covariables. We found an increased risk of CHF for AML-LTS who have had AML relapse (OR, 3.16; 95% CI: 1.46 – 6.83; P=0.004) and, in trend, for patients with sAML or tAML (OR 2.19; 95%CI: 0.92 – 5.22, P=0.076). Disease- or treatment-related factors did not significantly associate with any of the other comorbidities we studied. Furthermore, AML-LTS had significantly impaired kidney function, as assessed by the glomerular filtration rate (eGFR) estimated using the CKD-EPI-formula. Figure B displays the median eGFR according to age groups for AML-LTS and DEGS1. For each age group AML-LTS had significantly lower eGFR in comparison to DEGS1. We did not find an association between kidney function and time since diagnosis (p=.5) and no differences between AML-LTS treated by chemotherapy or alloSCT (p=.5), survived a relapse (p=.9) or were diagnosed with de novo-AML vs. sAML/tAML (P=.6). Image:Summary/Conclusion: Compared to the German general population, AML-LTS had increased risks of CHF and diabetes, but not hypertension or CAD. We identified AML relapse as a risk factor for developing of CHF, suggesting that cumulative chemotherapy exposure might be causally involved. Notably, AML-LTS who had undergone alloSCT did not have increased risks of CHF, CAD, hypertension or diabetes, compared to survivors treated with chemotherapy only. In addition, AML-LTS had a higher prevalence of impaired renal function. We did not identify treatment- or disease-related factors that might cause the lower kidney function in AML-LTS.

Burden of Long-Term Morbidity Borne by Survivors of Acute Myeloid Leukemia Treated With Blood or Marrow Transplantation: The Results of the BMT Survivor Study.

PURPOSEBlood or marrow transplantation (BMT) is an integral part of consolidation and/or salvage therapy for patients with acute myeloid leukemia (AML). With the growing population of AML survivors, there is a need to understand the quality of their survival.MATERIALS AND METHODSThis multisite study included 1,369 2-year survivors who underwent BMT for AML between 1974 and 2014 at age ≥ 21 years and 1,310 siblings. Using Common Terminology Criteria for Adverse Events, severe/life-threatening and fatal chronic health conditions were identified. Multivariable regression analysis was used to compare the risk of severe/life-threatening conditions and health status between survivors and siblings, and to identify risk factors for health conditions among BMT survivors.RESULTSThe prevalence of severe/life-threatening conditions was 54.9% in BMT survivors compared with 28.5% in siblings (P < .001), yielding 3.8-fold higher odds of severe/life-threatening conditions (95% CI, 3.1 to 4.7) among the BMT survivors. The most prevalent conditions included subsequent neoplasms, diabetes, cataracts, venous thromboembolism, and joint replacement. Survivors were more likely to report poor general health (odds ratio [OR], 3.8; 95% CI, 2.8 to 5.1), activity limitation (OR, 3.7; 95% CI, 3.0 to 4.5), and functional impairment (OR, 2.9; 95% CI, 2.3 to 3.6). Among BMT recipients, the 20-year cumulative incidence of severe/life-threatening/fatal conditions was 68%. History of chronic graft-versus-host disease was associated with a higher risk of pulmonary disease (hazard ratio [HR], 3.1; 95% CI, 1.0 to 9.3), cataract (HR, 2.6; 95% CI, 1.4 to 3.8), and venous thromboembolism (HR, 2.3; 95% CI, 1.3 to 4.7). Relapse-related mortality (RRM) plateaued at 30%, whereas non-RRM increased to 50% at 30 years.CONCLUSIONThe burden of severe/life-threatening conditions is substantially higher in BMT recipients when compared with an unaffected comparison group, contributing to an increasing incidence of non-RRM over time. Chronic graft-versus-host disease was an important risk factor for severe/life-threatening/fatal conditions among BMT recipients, informing the need for close monitoring to anticipate and manage morbidity.

Neurocognitive deficits in survivors of childhood acute myeloid leukemia

BackgroundAlthough treatment of acute myeloid leukemia (AML) contains neurotoxic agents, studies investigating neurocognitive outcomes in children with AML are sparse. We evaluated late cognitive effects in children treated with a high-dose cytarabine based regimen, focusing on general intellectual ability and specific neurocognitive domains.MethodsWe evaluated 12 survivors of childhood AML who were treated between 2006 and 2016 and completed the Wechsler Intelligence Scales. One-sample t-tests were used to compare full-scale intelligence quotient (FSIQ) and primary index scores to norms. The overall effect of index scores and subtests was examined with one-way ANOVA. Univariate analyses and multiple regression models examined demographic and clinical characteristics associated with FSIQ.ResultsParticipants who underwent the Wechsler Intelligence Scale for Children demonstrated impairment on working memory index and participants who underwent the Wechsler Adult Intelligence Scale showed low score in the subtests that reflect working memory, whereas they exhibited no statistical differences versus the population means for FSIQ. There were no significant differences in the overall effect of index scores and subtests. On univariate analysis, FSIQ were related to time since diagnosis and age at assessment, and both were significant predictors of FSIQ on multiple linear regression.ConclusionsSurvivors of childhood AML exhibited impairment of working memory, even if their FSIQ was within the normal range. Difficulties in specific cognitive domains are associated with reduced quality of life. It is important to identify survivors who are at risk and provide tailored interventions.

Tailoring a physical activity intervention to older adults receiving intensive chemotherapy for acute myeloid leukemia (AML): One size does not fit all

Older adults are at risk for functional decline during acute myeloid leukemia (AML) therapy [ [1] Klepin H.D. Tooze J.A. Pardee T.S. et al. Effect of intensive chemotherapy on physical, cognitive, and emotional health of older adults with acute myeloid leukemia. J Am Geriatr Soc. 2016; 64: 1988-1995 Crossref PubMed Scopus (55) Google Scholar ]. While some survivors demonstrate resilience [ [2] Mohamedali H. Breunis H. Timilshina N. et al. Older age is associated with similar quality of life and physical function compared to younger age during intensive chemotherapy for acute myeloid leukemia. Leuk Res. 2012; 36: 1241-1248 Crossref PubMed Scopus (38) Google Scholar , [3] Timilshina N. Breunis H. Tomlinson G.A. et al. Long-term recovery of quality of life and physical function over three years in adult survivors of acute myeloid leukemia after intensive chemotherapy. Leukemia. 2019; 33: 15-25 Crossref Scopus (13) Google Scholar ], short-term declines in physical function can be dramatic during an induction hospitalization [ [1] Klepin H.D. Tooze J.A. Pardee T.S. et al. Effect of intensive chemotherapy on physical, cognitive, and emotional health of older adults with acute myeloid leukemia. J Am Geriatr Soc. 2016; 64: 1988-1995 Crossref PubMed Scopus (55) Google Scholar ]. Physical performance (measured by the Short Physical Performance Battery [SPPB]) is predictive of survival at the time of diagnosis [ [4] Klepin H.D. Geiger A.M. Tooze J.A. et al. Geriatric assessment predicts survival for older adults receiving induction chemotherapy for acute myelogenous leukemia. Blood. 2013; 121: 4287-4294 Crossref PubMed Scopus (254) Google Scholar ], declines during induction therapy [ [1] Klepin H.D. Tooze J.A. Pardee T.S. et al. Effect of intensive chemotherapy on physical, cognitive, and emotional health of older adults with acute myeloid leukemia. J Am Geriatr Soc. 2016; 64: 1988-1995 Crossref PubMed Scopus (55) Google Scholar ], and is associated with shorter survival when measured at the time of remission [ [5] Saad M. Loh K.P. Tooze J.A. et al. Geriatric assessment and survival among older adults receiving post-remission therapy for acute myeloid leukemia. Blood. 2020; 136: 2715-2719 Crossref PubMed Google Scholar ]. Interventions designed to maintain physical performance may enhance the quality of survivorship, eligibility for subsequent therapies, and could potentially improve survival [ 6 Alibhai S.M. Durbano S. Breunis H. et al. A phase II exercise randomized controlled trial for patients with acute myeloid leukemia undergoing induction chemotherapy. Leuk Res. 2015; (S0145-2126(15)30365-9) Crossref Scopus (39) Google Scholar , 7 Alibhai S.M. O’Neill S. Fisher-Schlombs K. et al. A pilot phase II RCT of a home-based exercise intervention for survivors of AML. Support Care Cancer. 2014; 22: 881-889 Crossref PubMed Scopus (33) Google Scholar , 8 Klepin H.D. Danhauer S.C. Tooze J.A. et al. Exercise for older adult inpatients with acute myelogenous leukemia: a pilot study. J Geriatr Oncol. 2011; 2: 11-17 Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar , 9 Thomas R. Kenfield S.A. Yanagisawa Y. et al. Why exercise has a crucial role in cancer prevention, risk reduction and improved outcomes. Br Med Bull. 2021; 139: 100-119 Crossref Scopus (3) Google Scholar , 10 Ezzatvar Y. Ramírez-Vélez R. Sáez de Asteasu M.L. et al. Physical function and all-cause mortality in older adults diagnosed with cancer: a systematic review and meta-analysis. J Gerontol A Biol Sci Med Sci. 2021; 76: 1447-1453 Crossref Scopus (13) Google Scholar ].

Impact of aerobic versus resistive training on functional capacity in acute myeloid leukemia survivors: a comparative study

Background. Cancer-related fatigue is a persistent symptom in acute myeloid leukemia survivors, with associated decreased functional capacity, which further deteriorates their quality of life. The current study aimed to compare between the impact of aerobic training and resistive training on functional capacity in acute myeloid leukemia (AML) survivors. Fifty nine patients with AML from both sexes aged between 35 and 45 years,were selected from hematology department in (BLINDED FOR PEER REVIEW), where the study was conducted. Patients were randomly assigned into two groups; Group (A) underwent aerobic training in the form of cycling within 50-60% of maximum heart rate. Group (B) underwent resistive training conducted in the form of a series of exercises using free weights, and dumbbells. Sessions were carried out three times per week, for a total of eight weeks period. Six minute walk test (6MWT), 10 repetitions maximum test (10 RM). Ventilatory functions test, fatigue severity assessment (FAS) and quality of life (QoL) scales were measured in both groups before and after the study period. Results. Significant improvement in 6MWT, maximum oxygen consumption (VO2 max) and vital capacity in group (A), significant improvement in fatigue and QoL in both groups and significant improvement in 10 RM test in group (B). Conclusion. Both aerobic and resistive training significantly improved functional capacity in acute myeloid leukemia survivors with a more significant improvement due to aerobic training.

High Prevalence of CHF and Diabetes in AML Long-Term Survivors - a Patient Forever?

Introduction: As outcomes of patients with acute myeloid leukemia (AML) have improved over the past decades, the fraction of patients surviving long-term is increasing. Information on long-term somatic and psycho-social health consequences of AML and its treatment is sparse. Previous studies suggested a higher prevalence of cardiovascular diseases in AML survivors, especially those treated with allogeneic stem cell transplantation (alloHSCT). The aim of our study was to perform a multi-dimensional analysis of health outcomes in AML long-term survivors (AML-LTS). This report focuses on somatic, especially cardiovascular, morbidity in AML-LTS. Overall and health-related quality of life are reported separately (Telzerow et al.).Methods: We conducted a cross-sectional study including AML survivors who had been enrolled in clinical trials or the patient registry of the AML-CG study group and were alive ≥5 years after initial diagnosis. Data concerning somatic health status were collected through patient questionnaires, assessment by the patients' physicians, and medical and laboratory reports. An age- and sex-matched control cohort was derived from German population-based health surveys (Robert Koch Institute, DEGS1 survey; n=6013; persons diagnosed with leukemia [n=11] were excluded).Results: 427 AML-LTS, aged 28 to 93 years, participated in this study. Data on somatic health status is available for 355 survivors, 5 to 19 years after their AML diagnosis. Thirty-eight percent of survivors were treated with chemotherapy with or without an autologous transplant (autoHSCT), whereas 62% had undergone alloHSCT. Focusing on cardiovascular diseases and risk factors, we found that that 49% of AML-LTS had hypertension, 33% had hypercholesterolemia, 15% had type 1/2 diabetes, 10% had congestive heart failure (CHF), and 9% had coronary artery disease (Figure A). The mean body-mass index (BMI) of AML-LTS was 26.7, similar to the DEGS1 cohort (mean BMI, 26.8).Next, we compared the prevalence of cardiovascular diseases and risk factors between AML-LTS and the general German population (represented by the DEGS1 sample), using multivariate models adjusting for age and sex (Table B). Compared to persons not diagnosed with leukemia, AML survivors had similar risks of hypertension, coronary heart disease and myocardial infarction. Prevalence of diagnosed hypercholesterolemia was higher in AML-LTS compared to non-AML controls. In addition, AML-LTS had a 2-fold higher risk of having type 1/2 diabetes, and a 3.5-fold increased risk of CHF compared to the general population.To identify factors associated with the increased risks of diabetes and CHF among AML-LTS, we constructed multivariate models incorporating patient- and treatment related covariables (age, sex, BMI, smoking, prior AML relapse, treatment [chemotherapy + autoHSCT vs. alloHSCT], and type of leukemia [de novo versus secondary / therapy-related]). We found an increased risk of CHF for AML-LTS who had had a relapse (OR, 3.16; 95% CI: 1.46 - 6.83; P=0.004) and, in trend, for patients with sAML or tAML (OR 2.19; 95%CI: 0.92 - 5.22, P=0.076). In addition, we found an increased risk of type 1/2 diabetes for AML-LTS who are smokers (OR: 3.43; 95% CI: 1.43 - 8.21; p: 0.006). Disease- or treatment-related factors did not significantly associate with any of the other comorbidities we studied.Conclusion: To the best of our knowledge, this is the largest analysis of somatic health outcomes in AML-LTS. Strengths of our study include the relatively large cohort representing a wide age range, the long follow-up period of 5 to nearly 20 years, and the heterogeneity regarding therapy regimens (chemotherapy + autoHSCT vs. alloHSCT). We found that, compared to the general population, AML-LTS have increased risks for CHF and diabetes, but not for hypertension or coronary artery disease. We identified AML relapse as a risk factor for the development of CHF, suggesting that cumulative chemotherapy exposure might be causally involved. On the other hand, we found no treatment- and disease-related risk factors that might explain the higher prevalence of diabetes in AML-LTS. Notably, AML-LTS who had undergone alloHSCT did not have increased risks of CHF, cardiovascular disease, hypertension or diabetes, compared to survivors treated with chemotherapy only. Our results may guide future recommendations for follow-up and inform personalized treatment decisions. [Display omitted] DisclosuresBerdel: Philogen S.p.A.: Consultancy, Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees. Hiddemann: Janssen: Research Funding; F. Hoffmann-La Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Metzeler: Jazz Pharmaceuticals: Consultancy; Novartis: Consultancy; AbbVie: Honoraria; Celgene/BMS: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Honoraria; Pfizer: Consultancy; Astellas: Honoraria.

Discovery of Donor Genotype Associated with Long-Term Survival of Patients with Hematopoietic Stem Cell Transplantation in Refractory Acute Myeloid Leukemia

Introduction: Hematopoietic stem cell transplantation (HSCT) has been only option for treatment of acute myeloid leukemia (AML) refractory to induction chemotherapy. However, only less than 10% of patients can achieve long-term survival by HSCT in refractory AML. We hypothesized that certain donor genotype may confer leukemia clearing effects after HSCT in long-term survivors of refractory AML. This genotype may also associate with favorable clinical outcome of HSCT in AML with complete remission.Methods: From 1985 to 2015, we retrospectively reviewed AML patients with HSCT from sibling donor at refractory status after induction and salvage chemotherapy in Seoul National University Hospital (SNUH). Only long-term survivors (> 30 months after HSCT) were included in training cohort. Whole-exome sequencing (WES) to discover specific donor germline genotype compared to corresponding patients' included in the training cohort. Considering cure rate of AML by HSCT, we focused on shared genotypes of donors in the training cohort, as high-effect, common variants. To validate the shared, specific donor genotype, called leukemia-clearing genotype (LCG), survival analysis of AML patients with HSCT in their complete remission status (SNUH validation cohort) were performed according to donor's LCG. Survival analysis according to germline LCG in The Cancer Genome Atlas (TCGA) was also validated for biologic significance of LCG.Results: Twelve pairs of germline DNAs of donor and refractory patient were initially analyzed, among them, 5 sibling pairs were enrolled in the training cohort and finally analyzed. Gerrmline WES analysis of 5 donors resulted in 45,493 donor specific variants. Filtering out low allele carrier, variants in 1000 Genomes database, and poor quality reads, only 2 variants were remained and significant for known interaction, which were EGFR c.2982C>T and CDH11 c.945G>A, as LCGs. In SNUH validation cohort, among a total of 96 pairs of donor-patient, 22 (22.2%) donors had both LCGs in their germline DNA. Interestingly, overall survival of patients who received HSCT from donors with germline LCGs were significantly prolonged compared to others (hazard ratio [HR] 0.47, 95% confidence interval [CI] 0.24-0.94, log rank P= 0.033). In TCGA cohort, patients who had germline LCGs had favorable prognosis in both pan-cancer analysis (HR 0.83, 95% CI 0.69-0.99, log rank P= 0.048) and especially stomach adenocarcinoma (HR 0.44, 95% CI 0.21-0.95, log rank P= 0.037).Conclusions: Germline variants of EGFR c.2982C>T and CDH11 c.945G>A, or LCGs, have phenotypically cancer-clearing effects when transplants to AML patients, and TCGA analysis showed patients with both LCGs are related to favorable prognosis. Prospective evaluation if donor with germline LCGs are related to favorable clinical outcome of HSCT should be warranted. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Burden of Long-Term Morbidity Borne by Survivors of Acute Myeloid Leukemia (AML) Treated with Blood or Marrow Transplantation (BMT) – Results of the BMT Survivor Study (BMTSS)

Background: Blood or marrow transplantation (BMT) is an integral part of consolidation and/or salvage therapy for patients with acute myeloid leukemia (AML). With the growing population of AML survivors, there is a need to understand the quality of their survival. Methods: This multi-site study included 1,369 2y survivors who underwent BMT for AML between 1974 and 2014 at age ≥21y and 1,310 siblings. Using Common Terminology Criteria for Adverse Events, severe/life-threatening and fatal chronic health conditions were identified. Multivariable regression analysis was used to compare the risk of severe/life-threatening conditions and health status between survivors and siblings, and to identify risk factors for grades 3-5 chronic health conditions among BMT survivors. Findings: The cumulative incidence of severe/life-threatening conditions by age 70 was 74.7% in BMT survivors compared to 48.7% in siblings (p<0.001), yielding 3.8-fold higher odds of severe/life-threatening conditions (95%CI=3.1-4.6) among the BMT survivors. The most prevalent conditions included subsequent neoplasms, diabetes, cataracts, venous thromboembolism, and joint replacement. Survivors were more likely to report poor general health (OR=3.8, 95%CI=2.8-5.1), activity limitation (OR=3.7, 95%CI=3.0-4.5), and functional impairment (OR=2.9, 95%CI=2.3-3.6). Among BMT recipients, the 20y cumulative incidence of severe/life-threatening/fatal conditions was 68%. History of chronic graft versus host disease was associated with a higher risk of pulmonary disease (HR=3.1, 95%CI=1.0-9.3), cataract (HR=2.6, 95%CI=1.3-3.8), and venous thromboembolism (HR=2.3, 95%CI=1.2-4.6). Relapse-related mortality plateaued at 30%, while non-relapse-related mortality continued to increase, approaching 50% at 30 years. Interpretation: The burden of severe/life-threatening conditions is substantially higher in BMT recipients when compared with an unaffected comparison group, informing the need for close monitoring to anticipate and manage morbidity. Funding: This study was supported in part by grants from the National Cancer Institute (R01 CA078938, U01 CA213140), and the Leukemia Lymphoma Society (R6502-16) Declaration of Interest: None to declare. Ethical Approval: UAB serves as the single Institutional Review Board of record; participants provided informed consent

Young Survivors of Acute Myeloid Leukemia Have Long-Term Complications

Young Survivors of Acute Myeloid Leukemia Have Long-Term Complications