The inherent genetic heterogeneity of acute myeloid leukemia (AML) has challenged the development of precise and effective therapies. The objective of this study was to elucidate the genomic basis of ...drug resistance or sensitivity, identify signatures for drug response prediction, and provide resources to the research community.
We performed targeted sequencing, high-throughput drug screening, and single-cell genomic profiling on leukemia cell samples derived from patients with AML. Statistical approaches and machine learning models were applied to identify signatures for drug response prediction. We also integrated large public datasets to understand the co-occurring mutation patterns and further investigated the mutation profiles in the single cells. The features revealed in the co-occurring or mutual exclusivity pattern were further subjected to machine learning models.
We detected genetic signatures associated with sensitivity or resistance to specific agents, and identified five co-occurring mutation groups. The application of single-cell genomic sequencing unveiled the co-occurrence of variants at the individual cell level, highlighting the presence of distinct subclones within patients with AML. Using the mutation pattern for drug response prediction demonstrates high accuracy in predicting sensitivity to some drug classes, such as MEK inhibitors for RAS-mutated leukemia.
Our study highlights the importance of considering the gene mutation patterns for the prediction of drug response in AML. It provides a framework for categorizing patients with AML by mutations that enable drug sensitivity prediction.
Highlights • CPOE with PGx-CDS can improve medication safety. • Usability can drive adoption; few evaluations have been completed. • We conducted a usability study with cardiologists and oncologists. ...• Results suggest design improvements could be made to the user interface. • Provision of PGx information is important; must be presented in intuitive ways.
Given age-related differences in drug metabolism and indications for hematopoietic stem cell transplantation (HSCT), personalized drug dosing of the conditioning regimen and post-transplant ...immunosuppression may reduce graft rejection, relapse rates, and toxicity in pediatric HSCT recipients. This manuscript summarizes the pharmacokinetic/dynamic data of HSCT conditioning and postgrafting immunosuppression, presented at the First Annual Pediatric Bone Marrow Transplant Consortium meeting in April 2013. Personalized dosing of BU to a target plasma exposure reduces graft rejection in children and improves relapse/toxicity rates in adults. Current weight-based dosing achieves the target BU exposure in only a minority (24.3%) of children. The initial BU dose should be based on the European Medicines Agency nomogram or population pharmacokinetic models to improve the numbers of children achieving the target exposure. There are limited pharmacokinetic data for treosulfan, cyclophosphamide, fludarabine, and alemtuzumab as HSCT conditioning in children. For postgrafting immunosuppression, mycophenolic acid (MPA) clearance may be increased in younger children (< 12 years). The preferred MPA pharmacokinetic monitoring parameters and target range are still evolving in HSCT recipients. Multi-institutional trials incorporating properly powered pharmacokinetic/dynamic studies are needed to assess the effect of variability in the plasma exposure of drugs/metabolites on clinical outcomes in pediatric HSCT recipients.
Acute myeloid leukemia (AML) has a median survival of 6-12 months, with no major improvement over the last two decades. AML is a disease of elderly patients. Less-intensive induction therapies ...increasingly used in older patients, presuming they are more effective/better tolerated than intensive therapies.
Compare survival, quality of life (QOL), and function between less-intensive versus intensive therapies.
We studied a retrospective cohort (n=1,295) treated from 2008-2012 at six institutions, followed by a prospective observational cohort (n=692) treated from 2013-2017 at thirteen institutions. Both cohorts were ages 18-80 years.
Survival estimates were obtained with the Kaplan-Meier method. We used an AML-composite model (AML-CM) assigning higher scores to increasing age, comorbidity burden, and adverse cytogenetics. Less- and more-intensive induction therapies were compared within distinct prognostic groups defined by AML-CM. We used a competing-risk Cox regression model to test the impact of allogeneic transplant (HCT). Prospective QOL and function were compared between less-intensive and intensive groups across time using logistic regression.
20% and 21% of patients received less-intensive therapies in the retrospective and prospective cohorts, respectively. In both cohorts, less-intensive therapies were used more often with increasing age, comorbidity burden, and cytogenetic/molecular risks, and also with Karnofsky Performance Status (KPS) ≤ 70%. Retrospective cohort patients with AML-CM scores of 4-6, 7-9, and ≥10, respectively, had significantly higher hazard ratios (HR) for death after less-intensive therapies, independent from receipt of HCT in HCT-adjusted models, AML-CM=4-6: HR=1.82 (95% CI=1.25-2.63); =7-9: HR=1.67 (95% CI=1.22-2.27); >10: HR=1.32 (95% CI=0.99-1.72). Patients aged 70-79 years had similar results HR=1.37 (95% CI=1.02-1.85), p=0.04. Higher mortality risks were also seen in the prospective cohort after less-intensive therapies. In models adjusted for age, physician-assigned KPS and physician perceptions of chances of cure, mortality risks were similar between less-intensive and intensive therapies; QOL and function were also similar.
We did not find that receiving less-intensive induction led to better survival, QOL, or function compared to intensive therapies, including in those aged 70-79 years or with high comorbidity burden. This challenges current practice and demonstrates the need for a randomized trial. This research was, in part, funded by a Patient-Centered Outcome Research Institute award (CE-1304-7451), in part, by a Research Scholar Grant from the American Cancer Society (RSG-13-084-01-CPHPS), and, in part, supported by an American Society for Hematology Bridge Award.
Background: Induction therapy for newly diagnosed AML pts can be classified as intensive or non-intensive. Non-intensive therapies are increasingly used in pts aged >65 years due to concerns about ...their ability to tolerate intensive chemotherapy. However, the relative benefit-risk ratios associated with intensive versus non-intensive therapies in AML pts is likely affected by age, comorbidities, and disease-related characteristics, such as cytogenetic and molecular features. Here, we examine these relationships.
Methods: Data from 1295 newly diagnosed AML patients, given induction therapy between 2008 and 2012 at six participating academic centers, were retrospectively collected. We used two previously validated models to define distinct prognostic groups, and within each, compared 2-year mortality rates according to whether pts received intensive or non-intensive therapy. Non-intensive therapy principally included azacitidine, decitabine, or low-dose cytarabine, while intensive therapies primarily included the standard 7+3 regimen or "high-dose" cytarabine combinations with anthracyclines or purine analogs. The first model (Blood 2015; 126:532) was a composite of the prognostic effects of age, comorbidity index, and cytogenetic/genetics risks per European Leukemia Net (ELN) classification. The second (JCO 2011; 29(33): 4417) was a treatment related mortality (TRM) index including 8 pt- and AML-specific risk factors.
Results: Age distribution of the pts were ≤49 (23%), 50-59 (20%), 60-69 (33%), and ≥70 (24%) years old. Median follow-up for currently alive pts was 41 (range, 0-99) months. Cytogenetic-molecular risks per ELN classification were favorable (18%), intermediate I and II (39%), or unfavorable (43%). Induction treatments were intensive in 77% and non-intensive in 23% of pts. The proportion of patients receiving non-intensive therapy increased with increasing age (Table 1).
Almost all pts (99%) with the lowest composite scores (1-3) received intensive therapies and were therefore omitted from the comparisons with either model. Per the composite model grouping, pts had better survival rates if they received intensive therapy, although the differences were not statistically significant in pts with composite scores ≥10 (Table 2). Pts with TRM scores of 0-4 and ≥5, with a score of 5 corresponding to the median score, statistically significantly benefitted from intensive therapies (Table 2). Among all pts aged 70-79 years old (n=242), 41% received intensive therapy, while 59% received non-intensive therapy. The intensively treated pts in this age range had statistically significantly higher survival rates at 2 years (26% versus 13%, HR: 0.73, 95% CI: 0.54-0.98, P=0.04, Figure).
Conclusion: After accounting for underlying prognosis using 2 validated models, we found pts with newly diagnosed AML generally had better survival if they received intensive therapy. This survival benefit was not statistically proven for pts with the highest composite scores (≥10). Early mortality was not increased in older pts given intensive versus non-intensive therapy (Figure), likely due to improvements in supportive care which allowed the greater anti AML effect of intensive therapy to become manifest over time. While we cannot exclude the effects of selection bias, absent a randomized trial our results suggest intensive therapy could be considered for most pts, up to the age of 80 years, regardless of their comorbidity burden. Although results seem better with intensive therapy, less than 50% of patients with composite scores >3 given such therapies were predicted to be alive at 2 years, suggesting the need for randomized clinical trials between novel intensive and non-intensive therapies to achieve better survival.
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Fathi:Bexalata: Other: Advisory Board participation; Celgene: Consultancy, Research Funding; Merck: Other: Advisory Board participation; Agios Pharmaceuticals: Other: Advisory Board participation; Seattle Genetics: Consultancy, Other: Advisory Board participation, Research Funding. Sekeres:Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Mukherjee:Novartis: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Wang:Incyte: Speakers Bureau; Immunogen: Research Funding. Shami:JSK Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding.
The hematopoietic cell transplantation comorbidity index (HCT-CI) was specifically developed to assign weighted scores to comorbidities existing prior to allogeneic HCT; thus stratifying post-HCT ...mortality risks. The utility of comorbidities assessed prior to treatment for AML is unknown. Here, we a) investigated the impact of each comorbidity on 1-year overall mortality of patients (pts) with newly diagnosed AML, b) designed and validated a new comorbidity score (AML-CI) comparing its performance to that of the HCT-CI, and c) identified other relevant risk factors for AML outcomes.
We retrospectively collected comorbidities and laboratorydata from 1079 pts with newly diagnosed AML who received therapy at 5 institutions from 2008- 2012. Pts were aged ≤49 (29%), 50-59 (25%), 60-69 (26%), and ≥70 (20%) years old. Cytogenetic-risks were favorable (21%), intermediate (36%), or unfavorable (43%). Regimen intensity was low in 18%, intermediate in 63%, and high in 19%. HCT-CI comorbidities were evaluated per HCT-CI standard comorbidity definitions with the exception that renal comorbidity was defined per serum creatinine and/or creatinine clearance. Newly evaluated comorbiditiesincluded including hyperlipidemia, hypertension, deep venous thrombosis, gastroesophageal reflux disease, hypothyroidism, hypoalbuminemia, thrombocytopenia, neutropenia, anemia, elevated lactate dehydrogenase (LDH), smoking, and alcohol intake. Pts were randomly divided into a training (n=710) and a testing set (n=369). In the training set, the unadjusted hazard ratios (HRs) for 1-year overall mortality were calculated for each comorbidity as well as all adjustment factors: gender, age, race, cytogenetic-risks, regimen intensity, WBC, blast count, and marrow blast percentages. Only factors that were associated with overall mortality at a significance level of P <.10 proceeded to the multivariate model. Each comorbidity that entered the multivariate model was then adjusted for the effect of other comorbidities as well as gender, age, cytogenetic-risks, and regimen intensity (Table 1). The adjusted HRs were employedas weights for individual comorbidities. In the validation set, the new AML-CI incorporating comorbidities had comparable power of prediction for 1-year overall mortality as the HCT-CI (c-statistic estimates of 0.6 for each). Augmenting the HCT-CI with the three new covariates: platelets, albumin, and LDH yielded c-statistic estimate of 0.61. Other than comorbidities, age (c-statistic of 0.65) and cytogenetic-risks (c-statistic of 0.62) independently predicted overall mortality (Table 2).
Comorbidities at diagnosis of AML heavily influenced the survival of pts over the year following diagnosis. The new AML-CI has similar predictive power as the HCT-CI suggesting appropriateness of using the HCT-CI at diagnosis of AML given its familiarity to physicians. The augmented HCT-CI, age, and cytogenetic-risks independently stratified for risks of 1-year mortality. In the future, studying physical, cognitive, and social health might further clarify the prognostic role of increasing age. Targeting health limitations with interventions alongside specific AML-therapy might improve survival of patients.
Table 1Components of a new AML-CI based on multivariate evaluation of impact of comorbidities on 1-year mortality after diagnosis of AMLComorbiditiesHRAssigned score for AML-CIArrhythmia*1.0─Coronary Artery*1.1─Valvular*1.31Cerebrovascular *1.31Hepatic*Mild1.2─Moderate/severe1.2─Renal*Mild1.1─Moderate/severe.8─Pulmonary*Mild.9─Moderate/severe1.1─Diabetes*1.31Tumor*1.71Peptic Ulcer*1.31Psychiatric*1.31Hyperlipidemia1.0─HTN1.2─Albumin<4 - 3.51.31<3.5 - 31.21<31.71Platelets<100 - 501.2─<50 - 201.41<101.71LDH>200 - 5001.51>500 - 10001.41>10002.22SmokingFormer1.2─Current1.1─*included comorbidities within HCT-CI
Table 2Probabilities of 1-year survival per 6 different models in the validation setAML-CIHCT-CIAugmented HCT-CI*Score%OSScore%OSScore%OS0-11869020720-22470228681-235613-42863330563-428575-73358≥42345≥51842≥81534AgeCytogenetic-risksAugmented HCTCI* + age + cytoGroup%OSGroup%OSScore%OS0-492781Favorable19872-4178650-695160Intermediate36635-7376770+2231Unfavorable45458-102754≥111928*included HCT-CI + albumin, platelet counts and LDH
Fathi:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Ariad: Consultancy; Exelexis: Research Funding; Takeda Pharmaceuticals International Co.: Research Funding. Sekeres:TetraLogic: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees. Lee:Kadmon: Consultancy; Bristol-Myers Squibb: Consultancy.
Busulfan systemic exposure correlates with regimen-related toxicity, engraftment and relapse in select patients receiving high-dose oral busulfan (HD-BU) (1 mg/kg dose or 40 mg/m dose every 6 h for ...16 doses) as part of a preparative regimen for bone marrow transplantation. Therapeutic drug monitoring is frequently conducted after the first HD-BU dose in order to determine necessary dose adjustments. Limitations with this method include the need for rapid determination of busulfan plasma concentration and difficulties with estimating apparent oral clearance in patients who exhibit delayed absorption of HD-BU. This pharmacokinetic study was conducted to evaluate the ability of the apparent oral clearance obtained after administering a lower (0.25 mg/kg) test dose and the traditional (1 mg/kg) first dose to predict the dose required to achieve a desired area under the concentration–time curve (AUC) at steady-state (13th dose). In addition, the pharmacokinetic parameters of test, first and 13th dose were compared to assess intrasubject variability. Twenty-nine patients received a test dose of oral busulfan (0.25 mg/kg) the day immediately prior to initiation of HD-BU. Busulfan serum concentrations were measured following the test, first and 13th doses using gas chromatography with electron capture detection. The AUC and apparent oral clearance were calculated using non-compartmental analysis. Therapeutic drug monitoring following the first dose of HD-BU was conducted for clinical purposes in six patients, and dose adjustment between the first and 13th dose occurred in only two patients. The dose-corrected test dose and first dose AUC and apparent oral clearance were not bioequivalent (two one-sided t-tests, ±20%). The first dose and 13th dose AUC and apparent oral clearance were also not bioequivalent. Six of the 29 patients receiving HD-BU dose based on weight (1 mg/kg) would have achieved a steady-state AUC of 3600–5400 ng·h/ml, a frequently used target AUC, as compared to eight and 13 patients if their dose was based on the apparent oral clearance following the test dose and first dose HD-BU, respectively. Monitoring busulfan concentrations after a test dose or a first dose provides a better estimate of the dose needed to achieve the target steady-state AUC as compared to traditional weight-based dosing. However, significant intraindividual variability exists in the apparent oral clearance of busulfan and follow-up therapeutic drug monitoring is recommended particularly if the desired target AUC range is narrow.
The purpose of this article is to assess the comparative antiemetic efficacy of prochlorperazine, ondansetron, and dexamethasone in the prevention of delayed chemotherapy-induced nausea and vomiting ...(CINV) after moderately high to highly emetogenic chemotherapy. Cancer patients (n = 232) receiving moderately high to highly emetogenic chemotherapy were randomized to 1 of 3 treatments: 15 mg prochlorperazine spansules twice daily; 8 mg ondansetron tablets twice daily; or 8 mg dexamethasone tablets twice daily on days 2 through 5. All patients received 24 mg ondansetron and 20 mg dexamethasone orally before chemotherapy. Daily assessment (days 1 through 5) included the number of episodes of retching and vomiting, severity of nausea, restlessness, difficulty concentrating and fatigue, treatment satisfaction, and overall quality of life (measured using a 10-cm VAS). The Functional Living Index-Emesis (FLIE) was completed on day 5. Other side effects attributed to antiemetic therapy were recorded daily. For acute CINV, total control, defined as no vomiting, retching, nausea <1 cm on a 10-cm visual analog scale, and no administration of rescue medications, was achieved in 78% in the overall group and was not significantly different in the patients randomized to the 3 treatment arms for delayed CINV. Delayed CINV was reported by 43% to 57% of patients, with the highest incidence reported on day 3. For delayed CINV, patients receiving prochlorperazine reported the lowest average nausea score on days 2 to 5, whereas patients receiving ondansetron reported the highest nausea score (P = 0.05). No statistically significant differences in CINV or side effects of antiemetic therapy were noted between treatment groups on days 2 to 5. For patients similar to those included in this study, there does not appear to be a clinically important difference in efficacy, adverse effects, or treatment satisfaction among dexamethasone, prochlorperazine, and ondansetron in the doses used in these delayed CINV regimens on days 2 to 5 in this study.
In a previous study comparing fluconazole and itraconazole administered as antifungal prophylaxis in hematopoietic cell transplant (HCT) recipients, we found that fluconazole administration ...concurrent with cyclophosphamide (CY)-based conditioning was associated with fewer early toxicities compared to itraconazole. Fluconazole inhibits cytochrome P450 2C9, which is involved with the activation of CY, and so might provide protection from CY-related toxicities.
To investigate this further, we compared CY and CY-metabolite data from patients who received fluconazole (n=56) concurrent with CY-containing conditioning in patients who did not (n=17). The fluconazole group had greater exposure to CY, and lower peak serum concentration of CY-metabolite 4-hydroxycyclophosphamide. In a separate cohort, we examined outcomes in patients randomized to receive either fluconazole (n=152) or placebo (n=147) concurrent with CY-containing conditioning in a prior randomized trial. Patients who received fluconazole experienced less hepatic and renal toxicity, and had lower mortality. No difference in relapsed malignancy was apparent. These data support the hypothesis that fluconazole, when co-administered with CY, decreases CY-related toxicities by inhibiting cytochrome P450 2C9 metabolism.
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