Andrew Hantel

TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes

BACKGROUND The molecular determinants of clinical responses to decitabine therapy in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) are unclear. METHODS We enrolled 84 adult patients with AML or MDS in a single-institution trial of decitabine to identify somatic mutations and their relationships to clinical responses. Decitabine was administered at a dose of 20 mg per square meter of body-surface area per day for 10 consecutive days in monthly cycles. We performed enhanced exome or gene-panel sequencing in 67 of these patients and serial sequencing at multiple time points to evaluate patterns of mutation clearance in 54 patients. An extension cohort included 32 additional patients who received decitabine in different protocols. RESULTS Of the 116 patients, 53 (46%) had bone marrow blast clearance (<5% blasts). Response rates were higher among patients with an unfavorable-risk cytogenetic profile than among patients with an intermediate-risk or favorable-risk cytogenetic profile (29 of 43 patients [67%] vs. 24 of 71 patients [34%], P<0.001) and among patients with TP53 mutations than among patients with wild-type TP53 (21 of 21 [100%] vs. 32 of 78 [41%], P<0.001). Previous studies have consistently shown that patients with an unfavorable-risk cytogenetic profile and TP53 mutations who receive conventional chemotherapy have poor outcomes. However, in this study of 10-day courses of decitabine, neither of these risk factors was associated with a lower rate of overall survival than the rate of survival among study patients with intermediate-risk cytogenetic profiles. CONCLUSIONS Patients with AML and MDS who had cytogenetic abnormalities associated with unfavorable risk, TP53 mutations, or both had favorable clinical responses and robust (but incomplete) mutation clearance after receiving serial 10-day courses of decitabine. Although these responses were not durable, they resulted in rates of overall survival that were similar to those among patients with AML who had an intermediate-risk cytogenetic profile and who also received serial 10-day courses of decitabine. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT01687400 .).

A new family with a germline ANKRD26 mutation and predisposition to myeloid malignancies

Recently a mother-daughter pair with life-long thrombocytopenia presented for consultation regarding their presumed diagnoses of autoimmune-based idiopathic thrombocytopenic purpura (ITP) and their extended family history of bleeding and myeloid malignancies (Figure 1A). The proband/mother (III:4) had been diagnosed with myelodysplastic syndrome (MDS), and the daughter (IV:3) was 32 weeks pregnant. A family history revealed 10 of 28 family members with thrombocytopenia, 4 of whom also had MDS/acute myeloid leukemia (AML). Consideration was given to known alleles associated with congenital thrombocytopenia with predisposition to MDS/AML. Among RUNX1, GATA2, and CEPBA, three genes in which germline mutations predispose to myeloid malignancies, only familial platelet disorder (FPD)/germline RUNX1 mutation is associated with thrombocytopenia and platelet dysfunction.1 Recently, however, mutations within the 5′ untranslated region (UTR) of ANKRD26 on chromosome 10p12 have been associated with Thrombocytopenia 2 (THC2), an autosomal-dominant congenital thrombocytopenia, and in one series a 30-fold increase in the frequency of MDS/AML. 2–5

No Exit: Identifying Avoidable Terminal Oncology Intensive Care Unit Hospitalizations

PURPOSE Terminal oncology intensive care unit (ICU) hospitalizations are associated with high costs and inferior quality of care. This study identifies and characterizes potentially avoidable terminal admissions of oncology patients to ICUs. METHODS This was a retrospective case series of patients cared for in an academic medical centers ambulatory oncology practice who died in an ICU during July 1, 2012 to June 30, 2013. An oncologist, intensivist, and hospitalist reviewed each patients electronic health record from 3 months preceding terminal hospitalization until death. The primary outcome was the proportion of terminal ICU hospitalizations identified as potentially avoidable by two or more reviewers. Univariate and multivariate analysis were performed to identify characteristics associated with avoidable terminal ICU hospitalizations. RESULTS Seventy-two patients met inclusion criteria. The majority had solid tumor malignancies (71%), poor performance status (51%), and multiple encounters with the health care system. Despite high-intensity health care utilization, only 25% had documented advance directives. During a 4-day median ICU length of stay, 81% were intubated and 39% had cardiopulmonary resuscitation. Forty-seven percent of these hospitalizations were identified as potentially avoidable. Avoidable hospitalizations were associated with factors including: worse performance status before admission (median 2 v 1; P = .01), worse Charlson comorbidity score (median 8.5 v 7.0, P = .04), reason for hospitalization (P = .006), and number of prior hospitalizations (median 2 v 1; P = .05). CONCLUSION Given the high frequency of avoidable terminal ICU hospitalizations, health care leaders should develop strategies to prospectively identify patients at high risk and formulate interventions to improve end-of-life care.

Efficacy of single-agent decitabine in relapsed and refractory acute myeloid leukemia

Abstract Improving therapy for relapsed/refractory AML remains a challenge. We performed a retrospective analysis of outcomes following decitabine treatment in 34 patients with relapsed/refractory AML (median age, 62; median Charlson comorbidity score, 6). Decitabine, 20 mg/m2 daily, was given in 5- (25%) or 10-day (75%) cycles. Overall response rate (OR) was 30% with 21% complete remission and 9% partial remission rate. Patients with therapy-related myeloid neoplasm (t-MN) and secondary AML had a significantly higher OR compared to those with de novo AML (70 vs. 30%; p = .02). Median overall survival of all patients was 8.5 months. Median survival in patients with t-MN or secondary AML was 12.4 months compared to 8 months in those with de novo AML (p = .20). Fifteen (44%) patients proceeded to hematopoietic stem cell transplant. These data support using 10-day treatment cycles of decitabine in patients with relapsed/refractory AML, particularly for those with secondary or therapy-related AML.

Molecular Minimal Residual Disease Testing in Acute Myeloid Leukemia: A Review for the Practicing Clinician

Abstract Minimal residual disease (MRD) testing in acute myeloid leukemia is increasingly being used to assess treatment response and stratify the risk of relapse for individual patients. Molecular methods for MRD testing began with PCR‐based assays for individual recurrent mutations. To date, there is robust evidence for testing NPM1, CBFB‐MYH11, and RUNX1/RUNXT1 mutations using this approach, though the best timing and threshold level for each mutation varies. More recent approaches have been with PCR‐based multigene panels, occasionally combined with flow cytometric techniques, and next‐generation sequencing techniques. This review outlines the various techniques used in molecular approaches to MRD, the evidence behind individual mutation testing, and the novel approaches for evaluating multigene MRD so that clinicians can understand and incorporate these evaluations into their practice.

Identifying avoidable terminal oncology ICU hospitalizations.

56 Background: Eight percent of cancer patients expire in the ICU. There is no association between spending on aggressive end of life (EOL) care and survival outcomes. This aggressive care is also associated with reduced quality of life for patients and families. The National Quality Forum endorses the number of patients admitted to the ICU in the last 30 days of life as a quality of care measure. Our hypothesis is that a significant number of oncology patients suffer avoidable terminal ICU hospitalizations. METHODS Using data from the University of Chicago (UCM) Cancer Registry, we identified patients who died in UCM adult ICUs in FY2013. Of the 1,388 oncology deaths, 115 were in the ICU. Of those, 72 were established patients having had at least one visit with a UCM oncologist. A physician from oncology, critical care, and hospital medicine directly reviewed the electronic medical record of each patient from 3 months prior to index hospitalization until death. Using a standardized assessment tool, these physicians then determined whether the terminal hospitalization was clinically avoidable through different medical management. The primary outcome was the proportion of terminal oncology ICU hospitalizations identified as potentially avoidable by two or more reviewers. RESULTS Seventy-one percent of this patient population had a solid malignancy and 53% of those had metastatic disease. The ECOG performance status was ≥ 2 prior to admission in 51% of patients. Eighty-two percent had at least one prior hospitalization. During the index hospitalization, 81% were intubated, 39% had resuscitation, and 22% had hemodialysis. Two or more physician reviewers identified 34 (47%) of terminal oncology ICU hospitalizations as clinically avoidable. All three specialty physicians agreed about the avoidability 43% of the time. CONCLUSIONS A review of terminal oncology ICU hospitalizations demonstrates that most of these patients had an advanced malignancy and poor clinical status and underwent aggressive EOL interventions. A significant number of these hospitalizations were identified as clinically avoidable by two or more physician reviewers. By identifying avoidable terminal oncology ICU hospitalizations, we can design interventions to prevent them.

Characterizing terminal oncology ICU hospitalizations.

167 Background: Twenty-five percent of Medicare cancer beneficiaries use the ICU in the last month of life, and 8% of cancer patients expire there. Cancer patients who die in the ICU have worse quality of life compared with those who die at home. Terminal ICU hospitalizations also come at high financial cost, accounting for 80.2% of all terminal hospitalization costs. Our hypothesis is that a significant number of oncology patients suffer avoidable terminal ICU hospitalizations. By better characterizing these hospitalizations, we will provide the knowledge backbone for future interventions. METHODS Using data from the University of Chicago (UC) cancer registry, we identified patients who died in UC adult ICUs in FY2013. Of the 1,388 oncology deaths, 115 were in the ICU. Of those, 73 were established patients having had at least one visit with a UC oncologist. We performed a chart abstraction to identify patient, clinical, and hospitalization characteristics. RESULTS The average age of this patient population was 64 years and 71% were men. Solid and hematologic malignancies comprised 71% and 29%, respectively. Of the solid malignancy patients, 54% had metastatic disease. The average duration of the patient-oncologist relationship was 693 days, and 77% had their last oncology appointment within 2 months of index hospitalization. The ECOG performance status was ≥ 2 prior to admission in 51% of patients. These patients had an average of 3 hospitalizations and 15 outpatient visits in the year prior to death. Eighty-one percent did not have advance directives and 86% did not have an outpatient palliative care consult. The average duration in the ICU was 8 days, during which 95% did not have an inpatient palliative care consult, 79% were intubated, and 38% had resuscitation attempted. CONCLUSIONS Most cancer patients who died in the ICU had an advanced stage malignancy and/or poor clinical status prior to admission. In addition, a significant number received intubation and resuscitation. Despite evidence of adequate interaction with the healthcare system, most patients had not had a palliative care consult or advance directives. This study will allow for further exploration of the avoidability of terminal oncology ICU hospitalizations to inform future interventions.