Obesity in adult acute myeloid leukemia is not associated with inferior response or survival even when dose capping anthracyclines: An ECOG-ACRIN analysis.

BACKGROUND: Obesity (body mass index [BMI] ≥30 kg/m2 ) is an important epidemiological risk factor for developing acute myeloid leukemia (AML). Therefore, the authors studied the association of obesity with clinical and genetic phenotype and its impact on outcome in adults with AML. METHODS: The authors analyzed BMI in 1088 adults who were receiving intensive remission induction and consolidation therapy in two prospective, randomized therapeutic clinical trials of the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network: E1900 (ClinicalTrials.gov identifier NCT00049517; patients younger than 60 years) and E3999 (ClinicalTrials.gov identifier NCT00046930; patients aged 60 years or older). RESULTS: Obesity was prevalent at diagnosis (33%) and, compared with nonobesity, was associated with intermediate-risk cytogenetics group (p = .008), poorer performance status (p = .01), and a trend toward older age (p = .06). Obesity was not associated with somatic mutations among a selected 18-gene panel that was tested in a subset of younger patients. Obesity was not associated with clinical outcome (including complete remission, early death, or overall survival), and the authors did not identify any patient subgroup that had inferior outcomes based on BMI. Obese patients were significantly more likely to receive <90% of the intended daunorubicin dose despite protocol specification, particularly in the E1900 high-dose (90 mg/m2 ) daunorubicin arm (p = .002); however, this did not correlate with inferior overall survival on multivariate analysis (hazard ratio, 1.39; 95% confidence interval, 0.90-2.13; p = .14). CONCLUSIONS: Obesity is associated with unique clinical and disease-related phenotypic features in AML and may influence physician treatment decisions regarding daunorubicin dosing. However, the current study demonstrates that obesity is not a factor in survival, and strict adherence to body surface area-based dosing is not necessary because dose adjustments do not affect outcomes.

We were in the fight together: The expectations of bereaved caregivers of patients with acute myeloid leukemia from diagnosis to death.

PURPOSE: Patients with hematologic malignancies are more optimistic than their oncologists and their expectations may be a barrier to timely hospice care. Patient expectations toward the end of life (EOL), however, have not been characterized. In this study, we analyzed interviews of bereaved caregivers to understand the expectations of patients diagnosed with acute myeloid leukemia and the factors that influenced those expectations, from diagnosis until death. METHODS: Bereaved caregivers (n = 19) participated in an in-depth interview that included open-ended and semi-structured prompts, within 18 months following patient death. Interviews were analyzed using a modified grounded theory qualitative approach and constant comparative methods. RESULTS: We identified three themes relevant to expectations: Taking Stock, Being Stuck, and Disruption. Caregivers described clear and optimistic early expectations that AML is treatable. It was understood that treatment was required to survive. Later, when treatment options were limited, patients and caregivers became stuck in a belief that the patient could continue to live indefinitely on supportive care or at least until new more effective treatments were available. Caregivers often realized that the patient was at the end of life only when faced with a disruption, an event or conversation that changed their expectations for indefinite patient survival. CONCLUSIONS: Caregivers described continued expectations for patient survival until presented with irrefutable evidence to the contrary. The study suggests patients and caregivers may make better EOL care decisions if their early optimism is deliberately moderated by ongoing conversations with clinicians that highlight the sentinel events that signal treatment failure and explain how expectations and goals are changing from living a longer life to dying a more comfortable death.

Goals of care communication and higher-value care for patients with advanced-stage cancer: A systematic review of the evidence.

CONTEXT: Goals-of-care communication (GOCC) is recommended to increase the value of cancer care near the end of life (EOL). OBJECTIVES: Conduct a systematic review of the evidence that GOCC is associated with higher-value care. METHODS: We searched PubMed, Scopus, Ovid MEDLINE, EMBASE, EMB Reviews, CINAHL, and PsycInfo from inception to July 2019. We analyzed the population,design, and results and the authors' definitions of GOCC. Risk of bias was assessed. RESULTS: Thirty-two articles were selected. Ten articles reported results from 8 interventions; 17 characterized participants' perspectives; and 5 were retrospective The topics, behaviors, timing, and anticipated outcomes of GOCC varied significantly and were indistinguishable from practices such as advance care planning. GOCC typically focused on treatment outcomes rather than patients' goals. Four of 5 interventions increased evidence of GOCC after clinician training. Only one reported improved patient outcomes. CONCLUSION: No consensus exists about what GOCC entails. There is limited evidence that GOCC increases the value of EOL care. PRACTICE IMPLICATIONS: Future studies should focus on how to engage patients in conversations about their personal goals and integrate their goals into care planning. Clinicians can encourage GOCC by explaining how patients' goals influence decisions especially as treatment options become limited.

Bereaved Informal Caregivers Rarely Recall a Relationship Between Transfusions and Hospice in Acute Myeloid Leukemia.

AIMS: The inability to prescribe blood transfusions is a potential barrier to timely hospice enrollment for patients with blood cancers. The benefits and harms of transfusions near the end of life (EOL), however, are poorly characterized and patients' preferences are unknown. We sought to characterize the recollections of bereaved caregivers about the relationships between transfusions and hospice enrollment decisions. METHODS: We recruited 18 bereaved caregivers of 15 decedents who died within 6-18 months of the interview. Interviews focused on caregivers' recollections of transfusion and hospice enrollment decisions. Transcripts were analyzed for themes. RESULTS: We identified 2 themes. First, caregivers described that transfusions were necessary and the decisions to receive transfusions or not were deferred to the clinicians. Second, only 1 caregiver recalled transfusions as relevant to hospice decisions. In that instance there was a delay. Caregivers identified difficulties recognizing death was imminent, hope for miracles, and the necessity of accepting life was ending as more relevant barriers. CONCLUSIONS: The results indicate clinicians' beliefs in transfusion at EOL may be a more relevant barrier to hospice enrollment than patients' preferences. Strategies to evaluate accurately and discuss the actual benefits and harms of transfusions at the EOL are necessary to advise patients and integrate their preferences into decisions.

CNS involvement in AML at diagnosis is rare and does not affect response or survival: data from 11 ECOG-ACRIN trials.

Central nervous system (CNS) involvement in patients with newly diagnosed acute myeloid leukemia (AML) is rare, and systematic data regarding outcome are scarce. This retrospective study summarized data from 11 consecutive Eastern Cooperative Oncology Group-American College of Radiology Imaging Network (ECOG-ACRIN) clinical trials for patients with newly diagnosed AML. In all, 3240 patients with AML were analyzed, and 36 (1.11%) were found to have CNS involvement at diagnosis. The incidence of CNS disease among the 5 studies with per protocol mandatory lumbar puncture (LP) was similar to the incidence among studies in which LP was performed at the discretion of the investigator (0.86% vs 1.41%; P = .18). There was no significant difference in the rate of complete remission (CR) among patients with CNS involvement and those with other extramedullary disease (EMD) sites or those with no EMD (52.8% vs 59.3%-60%). The median overall survival (OS) for patients who were CNS positive, who had other EMD, or who had no EMD was 11.4, 11.3, and 12.7 months, respectively. There was no difference in OS among patients with CNS involvement, those with other EMD (hazard ratio [HR], 0.96; adjusted P = .84), and those with no EMD (HR, 1.19; adjusted P = .44). In conclusion, the reported incidence of CNS involvement in patients with newly diagnosed AML is low (1.1%), irrespective of whether an LP is mandatory or not. The presence of CNS disease at diagnosis in and of itself does not seem to portend a poor prognosis for achieving an initial CR or for OS.

Prognostic effect of gender on outcome of treatment for adults with acute myeloid leukaemia.

There are conflicting reports in the literature suggesting that one gender or the other has a better survival with acute myeloid leukaemia (AML). The present study was done in an attempt to resolve the issue. The effect of gender was examined on 3546 newly diagnosed patients with AML, including 548 patients with acute promyelocytic leukaemia (APL) enrolled in 10 multi-institutional treatment studies from March 1984 to November 2008. Kaplan-Meier estimates were used to estimate event-time distributions for survival and multivariate models were used to examine the gender effect after adjusting for multiple risk factors. P values were based on two-sided tests. Non-APL female patients had a significantly better overall (OS) but not disease-free survival (DFS) than males, irrespective of age, initial white blood cell count, or dose of daunorubicin. No differences were observed for obese or FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD)-positive patients. Female patients with APL had a significantly better OS and DFS than male patients with APL, and differences in survival were greater for patients with t(15;17) + other cytogenetic abnormalities compared with those with t(15;17) only. Gender is an independent prognostic variable in patients with AML. Whether these survival differences are due to hormonal, genetic or pharmacokinetic differences between the sexes or differential toxin exposure such as smoking is unknown. However, the former seems less likely as patient age did not influence the survival advantage for female patients.

Targeted detection and quantitation of histone modifications from 1,000 cells.

Histone post-translational modifications (PTMs) create a powerful regulatory mechanism for maintaining chromosomal integrity in cells. Histone acetylation and methylation, the most widely studied histone PTMs, act in concert with chromatin-associated proteins to control access to genetic information during transcription. Alterations in cellular histone PTMs have been linked to disease states and have crucial biomarker and therapeutic potential. Traditional bottom-up mass spectrometry of histones requires large numbers of cells, typically one million or more. However, for some cell subtype-specific studies, it is difficult or impossible to obtain such large numbers of cells and quantification of rare histone PTMs is often unachievable. An established targeted LC-MS/MS method was used to quantify the abundance of histone PTMs from cell lines and primary human specimens. Sample preparation was modified by omitting nuclear isolation and reducing the rounds of histone derivatization to improve detection of histone peptides down to 1,000 cells. In the current study, we developed and validated a quantitative LC-MS/MS approach tailored for a targeted histone assay of 75 histone peptides with as few as 10,000 cells. Furthermore, we were able to detect and quantify 61 histone peptides from just 1,000 primary human stem cells. Detection of 37 histone peptides was possible from 1,000 acute myeloid leukemia patient cells. We anticipate that this revised method can be used in many applications where achieving large cell numbers is challenging, including rare human cell populations.

Allogeneic hematopoietic cell transplantation compared to chemotherapy consolidation in older acute myeloid leukemia (AML) patients 60-75 years in first complete remission (CR1): an alliance (A151509), SWOG, ECOG-ACRIN, and CIBMTR study.

The preferred post-remission therapy for older patients with acute myeloid leukemia (AML) in first complete remission (CR1) remains uncertain. In this retrospective, multicenter study, we compared the outcomes for older AML patients (age 60-77 years) receiving allogeneic hematopoietic cell transplantation (alloHCT) (n = 431) with those treated on prospective National Clinical Trials Network induction and nontransplantation chemotherapy (CT) consolidation trials (n = 211). AlloHCT patients were younger (median age: 64.2 versus 67.9 years, p < 0.001), but more frequently had high-risk AML (high WBC, secondary AML, and unfavorable cytogenetics). Overall survival (OS) was worse in alloHCT during the first 9 months after CR1 (HR = 1.52, p = 0.02), but was significantly better thereafter (HR = 0.53, p < 0.0001) relative to CT. Treatment-related mortality (TRM) following HCT was worse in the first 9 months (HR = 2.8, 95% CI: 1.5-5.2, p = 0.0009), while post-HCT relapse was significantly less frequent beyond 9 months (HR = 0.42, 95% CI: 0.29-0.61, p < 0.0001). Despite higher early TRM, alloHCT recipients had superior long-term OS [29% (24-34%) versus CT 13.8% (9-21%) at 5 years]. Although this is a retrospective analysis with potential biases, it indicates that alloHCT led to heightened early risks from TRM, yet reduced relapse and superior long-term survival relative to CT in older AML patients in CR1.

Evidence of a role for functional heterogeneity in multidrug resistance transporters in clinical trials of P-glycoprotein modulation in acute myeloid leukemia.

BACKGROUND: Multidrug resistance (MDR) transporter proteins such as P-glycoprotein (P-gp) efflux a variety of chemotherapeutic drugs from acute myeloid leukemia (AML) blasts leading to clinical drug resistance. METHODS: This study examined heterogeneity of MDR functional efflux by AML blasts using two flow cytometry bioassays. Bone marrow specimens (N = 50) from elderly patients with newly diagnosed AML were analyzed for CD34+ blasts with MDR efflux function. Efflux was measured with a fluorescent dye (DiOC2 ) as a surrogate for oncology drugs that are substrates for MDR efflux. P-gp-mediated efflux was differentiated from non-P-gp MDR activities using zosuquidar, a highly selective P-gp modulator. The bioassays included a zosuquidar-dependent DiOC2 accumulation bioassay that measured only P-gp. The second method, termed the efflux bioassay, could detect P-gp and other non-P-gp efflux depending on bioassay culture conditions. RESULTS: Sixty-two percent of the specimens were considered positive for blasts with P-gp function, and 26% of such P-gp-positive specimens also exhibited zosuquidar-resistant (i.e., non-P-gp) MDR efflux activity; 37% of P-gp-negative AML blast specimens displayed zosuquidar-resistant MDR function in the efflux bioassay. CONCLUSIONS: These results confirm the heterogeneous nature of MDR efflux pumps in AML blasts, and provide support for the hypothesis that non-P-gp MDR contributed to negative results with zosuquidar in AML trials like ECOG-ACRIN E3999. © 2018 International Clinical Cytometry Society.

Very poor long-term survival in past and more recent studies for relapsed AML patients: The ECOG-ACRIN experience.

This study examines the long-term OS of relapsed AML patients who were enrolled to 9 successive ECOG-ACRIN trials for newly diagnosed AML, during 1984-2008. The objectives were to examine whether there is a trend of improvement in the survival of relapsed AML patients in the more recent studies and to search for prognostic factors that are associated with long-term OS after relapse. A total of 3012 patients were enrolled, 1779 (59.1%) achieved CR1 and of these, 58.9% relapsed. The median follow-up was 9.7 years. The median OS from relapse was 0.5 years and the 5-year OS was 10 (±1)%. These results were similar even for the most recent studies. A multivariate model showed that age, cytogenetics at diagnosis, duration of CR1 and undergoing allogeneic transplantation were significantly associated with OS from relapse. Even among patients who relapsed with better prognostic factors; age < 40 and CR1 > 12 months, there was no significant OS difference between the studies. In conclusion, this large cohort appears to confirm that the survival of AML patients postrelapse continues to be dismal and has not improved during the past quarter of a century.

Ambulatory Advanced Cancer Patients' and Oncologists' Estimates of Life Expectancy Are Associated with Patient Psychological Characteristics But Not Chemotherapy Use.

BACKGROUND: Patients with advanced cancer often face distressing decisions about chemotherapy. There are conflicting data on the relationships among perceived prognosis, psychological characteristics, and chemotherapy use, which impair the refinement of decision support interventions. OBJECTIVE: Clarify the relationships among patient and oncologist estimates of life expectancy for 6 and 12 months, chemotherapy use, and patient psychological characteristics. DESIGN: Secondary analysis of data from two cross-sectional studies. SETTING/SUBJECTS: One hundred sixty-six patients with advanced stage cancer recruited from ambulatory cancer clinics. MEASUREMENTS: All data were obtained at study enrollment. Patients completed the Adult Hope Scale, Hospital Anxiety and Depression Scale, and Life Orientation Test-Revised. Patients and their oncologists provided estimates of surviving beyond 6 and 12 months. Chemotherapy use was determined by chart review. RESULTS: There were no significant associations between life-expectancy estimates and chemotherapy use nor patient anxiety, depression, hope, or optimism and chemotherapy use. Patients' life expectancy estimates for 12 months and oncologists' for 6 months were associated with higher patient anxiety and depression. Finally, both oncologist and patient estimates of life expectancy for 6 and 12 months were associated with increased levels of trait hope. CONCLUSION: Advanced cancer patients who provide less optimistic estimates of life expectancy have increased anxiety and depression, but do not use chemotherapy more often. Increased patient trait hope is associated with more favorable oncologist estimates. These findings highlight the need for interventions to support both patients and oncologists as they clarify prognostic expectations and patients cope with the psychological distress of a limited life expectancy.

Predicting symptoms of anxiety and depression in patients living with advanced cancer: the differential roles of hope and optimism.

PURPOSE: Psychological distress is related to poorer functioning and reduced quality of life in patients with advanced cancer and may have untoward influences on treatment decisions. Current research on factors associated with this distress is limited, making targeted interventions to reduce it suboptimal. We examined the relationships between two goal-related expectancies and two of the most common symptoms of psychological distress in patients living with advanced cancer: anxiety and depressive symptoms. METHODS: Patients with advanced gastrointestinal cancer, colorectal cancer, lung cancer, or melanoma (N = 84) completed measures of anxiety, depressive symptoms, optimism, hope, and prediction for 12-month survival. Oncologists provided prediction for patient 12-month survival and patient performance status. RESULTS: Hope, but not optimism, was associated with less severe depressive symptoms (ß = - 0.42). Conversely, optimism, but not hope, was associated with less severe anxiety symptoms (ß = - 0.36). CONCLUSIONS: Hope and optimism appear to be associated with different aspects of psychological distress in patients living with advanced cancer. This may be explained by different appraisals of the uncertainty and distress that are associated with living with advanced-stage cancer. Hope- or optimism-focused interventions can be tailored to help alleviate specific aspects of psychological distress among these patients.

Differences between Supportive Music and Imagery and Music Listening during Outpatient Chemotherapy and Potential Moderators of Treatment Effects.

BACKGROUND: Supportive music and imagery and music listening interventions have been effective in decreasing distress and improving mood in cancer patients receiving chemotherapy, but it is unclear whether the two interventions differ in their treatment benefits. Furthermore, previous studies have not examined moderators to determine which subgroup(s) of patients may benefit most from each intervention. OBJECTIVE: To examine the effects of supportive music and imagery compared with preferred music listening on responsiveness to music therapy, distress, anxiety and depression, and benefit finding. A secondary purpose was to explore sense of coherence and locus of control as potential moderators of intervention effectiveness. METHODS: A single-session, two-group comparative effectiveness randomized trial in two cancer centers. Patients were randomized to supportive music and imagery or preferred music listening during outpatient chemotherapy treatment. Data were collected at baseline and immediately after the 45-minute session. ANCOVA models were used to determine main effects of intervention as well as pairing potential moderators with group assignment to explore differences in intervention effects by moderator. RESULTS: There were differential effects between the two interventions with the supportive music and imagery group scoring higher in responsiveness to music therapy and benefit finding. The music listening group scores indicated lower distress. The exploratory moderating analyses suggested Health Locus of Control-Internal and Sense of Coherence influenced intervention effectiveness. CONCLUSIONS: Music and imagery and preferred music listening experiences may serve different therapeutic purposes, access and activate different patient resources, and may be helpful at different stages of treatment.

Consecutive epigenetically-active agent combinations act in ID1-RUNX3-TET2 and HOXA pathways for Flt3ITD+ve AML.

Co-occurrence of Flt3ITD and TET2 mutations provoke an animal model of AML by epigenetic repression of Wnt pathway antagonists, including RUNX3, and by hyperexpression of ID1, encoding Wnt agonist. These affect HOXA over-expression and treatment resistance. A comparable epigenetic phenotype was identified among adult AML patients needing novel intervention. We chose combinations of targeted agents acting on distinct effectors, at the levels of both signal transduction and chromatin remodeling, in relapsed/refractory AML's, including Flt3ITD+ve, described with a signature of repressed tumor suppressor genes, involving Wnt antagonist RUNX3, occurring along with ID1 and HOXA over-expressions. We tracked patient response to combination of Flt3/Raf inhibitor, Sorafenib, and Vorinostat, pan-histone deacetylase inhibitor, without or with added Bortezomib, in consecutive phase I trials. A striking association of rapid objective remissions (near-complete, complete responses) was noted to accompany induced early pharmacodynamic changes within patient blasts in situ, involving these effectors, significantly linking RUNX3/Wnt antagonist de-repression (80%) and ID1 downregulation (85%), to a response, also preceded by profound HOXA9 repression. Response occurred in context of concurrent TET2 mutation/hypomorphy and Flt3ITD+ve mutation (83% of complete responses). Addition of Bortezomib to the combination was vital to attainment of complete response in Flt3ITD+ve cases exhibiting such Wnt pathway dysregulation.

"My Future is Now": A Qualitative Study of Persons Living With Advanced Cancer.

OBJECTIVES: Advance care planning (ACP) enables individuals to deliberate about future preferences for care based upon their values and beliefs about what is important in life. For many patients with advanced cancer, however, these critical conversations do not occur. A growing body of literature has examined the end-of-life wishes of seriously ill patients. Few studies have explored what is important to persons as they live with advanced cancer. The aim of the current study was to address this gap and to understand how clinicians can support patients' efforts to live in the present and plan for the future. METHODS: Transcriptions of interviews conducted with 36 patients diagnosed with advanced cancer were analyzed using immersion-crystallization, a qualitative research technique. RESULTS: Four overarching themes were identified: (I) living in the face of death, (II) who I am, (III) my experience of cancer, and (IV) impact of my illness on others. Twelve subthemes are also reported. SIGNIFICANCE OF RESULTS: These findings have significant implications for clinicians as they partner with patients to plan for the future. Our data suggest that clinicians consider the following 4 prompts: (1) "What is important to you now, knowing that you will die sooner than you want or expected?" (2) "Tell me about yourself." (3) "Tell me in your own words about your experience with cancer care and treatment." (4) "What impact has your illness had on others?" In honoring patients' lived experiences, we may establish the mutual understanding necessary to providing high-quality care that supports patients' priorities for life.

Dying From Cancer: Communication, Empathy, and the Clinical Imagination.

Medical oncologists and patients with advanced cancer struggle to discuss prognosis, goals, options, and values in a timely fashion. As a consequence, many patients die receiving aggressive treatment potentially inconsistent with their fully informed preferences and experience increased symptom burden and distress. The goals of patient - oncologist communication include exchanging information, building relationship, and engaging in shared decisions. Empathy is perhaps especially essential to effective patient - oncologist communication when the end of life is approaching. We speculate that, in addition to being a skilled response to a patient's negative emotions, empathy is an emergent property of the relationship that allows the patient and oncologist to imagine what it will be like to navigate the transition from living with to dying from cancer; and to prepare for the transition. We propose that effective empathy: 1) requires an attentive, curious and imaginative physician; 2) acknowledges the complex and shifting goals as the end of life approaches; and 3) begins with a willingness of physicians to check in and find out what she may have misunderstood or misperceived. Empathy in end of life conversations cultivates the shared experiences necessary to co-create the new goals of care that underlie excellent end of life care.

Independent Prognostic Significance of Monosomy 17 and Impact of Karyotype Complexity in Monosomal Karyotype/Complex Karyotype Acute Myeloid Leukemia: Results from Four ECOG-ACRIN Prospective Therapeutic Trials.

The presence of a monosomal karyotype (MK+) and/or a complex karyotype (CK+) identifies subcategories of AML with poor prognosis. The prognostic significance of the most common monosomies (monosomy 5, monosomy 7, and monosomy 17) within MK+/CK+AML is not well defined. We analyzed data from 1,592 AML patients age 17-93 years enrolled on ECOG-ACRIN therapeutic trials. The majority of MK+ patients (182/195; 93%) were MK+/CK+ with 87% (158/182) having ≥5 clonal abnormalities (CK≥5). MK+ patients with karyotype complexity ≤4 had a median overall survival (OS) of 0.4y compared to 1.0y for MK- with complexity ≤4 (p<0.001), whereas no OS difference was seen in MK+vs. MK- patients with CK≥5 (p=0.82). Monosomy 5 (93%; 50/54) typically occurred within a highly complex karyotype and had no impact on OS (0.4y; p=0.95). Monosomy 7 demonstrated no impact on OS in patients with CK≥5 (p=0.39) or CK≤4 (p=0.44). Monosomy 17 appeared in 43% (68/158) of CK≥5 patients and demonstrated statistically significant worse OS (0.4y) compared to CK≥5 patients without monosomy 17 (0.5y; p=0.012). Our data suggest that the prognostic impact of MK+is limited to those with less complex karyotypes and that monosomy 17 may independently predict for worse survival in patients with AML.