bluuebunny/crossref_metadata_2025 huggingface dataset:
A survival-based cost-effectiveness analysis of 5 years of letrozole versus tamoxifen as adjuvant therapy in postmenopausal women with early breast cancer: 76-month update of BIG-1–98
Authors: Karnon J. , Kaura S.
Published: August 2020

6566

Background: The latest update of the BIG 1–98 study reports a hazard ratio for overall survival (OS) of 0.81 (95% CI 0.69 = 0.94) (censoring TAM patients who crossed over to LET). Previous economic analyses of the aromatase inhibitors extrapolated observed differences in time to recurrence. This study uses observed differences in OS to estimate the incremental cost per life year (LY), and per quality adjusted LY (QALY) gained of 5 years LET versus 5 years TAM in ER+ postmenopausal women, from a UK NHS perspective. Methods: Annual survival probabilities over the first 7 years post-surgery were extracted from updated BIG 1–98 results. Survival was extrapolated to 20 years using data reported by the Early Breast Cancer Trialists’ Group for women receiving 5 years TAM. Equivalent annual survival probabilities were assumed for the LET and TAM groups post-7 years (likely to be a conservative assumption given diverging OS between 5 and 7 years). Costs included those of the interventions and and a wide range of adverse events (AEs). Published five year costs for locoregional recurrence (LR) and metastases (METS) were applied to reported recurrence rates over 9 years. A Markov model applied published utility weights for DFS with AEs, LR, and METS. All costs and health benefits were discounted at 3.5% annually. Results: The reference case results show that over a 20 year period, the discounted additional treatment costs of LET'are £4,427, and AEs incur an additional £88 per patient, while the reduced frequency decreases the cost difference by £807. The total cost difference between LET and TAM is £3,707. The discounted gain in LYs is 0.286. The incremental cost per LY gained for LET over TAM is £12,970. The Markov model estimated a difference in discounted QALYs of 0.297, with an incremental cost per QALY gained of £12,500. Conclusions: The economic analysis of 5 years LET compared to 5 years TAM based on observed differences in OS produces similar results to earlier modelled extrapolations based on differences in time to recurrence. However, the 20 year time horizon used in this analysis is shorter than previous analyses, and so the results may be considered conservative, i.e. LET may be more cost-effective than previously estimated.

[Table: see text]
Logical inconsistency in comorbid health state preference assessment for prostate cancer
Authors: Dale W. , Bilir S. P. , Hemmerich J. , Basu A. , Meltzer D. O.
Published: August 2020

6568

Background: With increasing need for efficient resource allocation, attention is turning to evidence-based decision making and cost-effectiveness analysis (CEA). Policy decisions depend on quality-adjusted outcomes from such analyses. Even small variations in the health state utilities used to quality adjust can have considerable effects, yet measuring utilities accurately is difficult. A particular challenge in the aging population with high cancer risk is maintaining logical consistency when evaluating comorbid utilities. We define this as ensuring that a single health state (SS) is rated no worse than a health state that adds another SS to that first one to make a comorbid health state (CS). Determining why or by whom this condition fails could improve elicitation practices and CEA for cancer and comorbid diseases. Methods: Men were surveyed at the time of prostate biopsy. SS and CS utility values were elicited via the time-trade off method. Demographic information, current health, and scores on anxiety subscales (HADS and MAX-PC) were collected also. The most prevalent health states associated with prostate cancer in the SEER database were chosen for assessment. CS were combinations of the SS “impotence” with each of incontinence, asymptomatic localized disease, and post-prostatectomy. Regression analysis showed the association of other survey elements to utility inconsistency. Mann-Whitney U-tests determined whether utility values differed by consistency. Results: 68% of respondents rated inconsistently at least once. Marriage and anxiety were correlated with rating inconsistently in univariate logistic analysis (p < 0.01, p < 0.05, respectively). Higher education was independently associated with more consistent answers (p < 0.05). Inconsistent raters had significantly lower utility values for all SS, but not for CS (p < 0.01). Conclusions: Over two thirds of men gave at least one logically inconsistent response across the three CS conditions. Being married, feeling anxious, and having less education were correlated with giving fewer consistent responses. Correcting these inconsistencies may change the results of quality-adjusted analyses. Strategies for eliciting more consistent responses are needed to accurately quality-adjust comorbid health states.

No significant financial relationships to disclose.
Seasonal mortality in terminally ill cancer patients
Authors: Policzer J. , Kinzbrunner B. , Tanis D.
Published: August 2020

6575

Background: There is ample evidence that the death rate in elderly patients increases in winter months. The increase in deaths may be amplified in terminally ill patients where place of care home, hospital, or long-term care facility might play a significant role in seasonal mortality. In this paper, we compare seasonal variation in death rates for terminally ill cancer patients to terminally ill patients who are “frail,” i.e., those with neurodegenerative disease, general debility, or chronic heart failure. Methods: We reviewed monthly deaths for Medicare patients age 65 or older with terminal cancer or “frail” patients who were admitted to one of 45 hospice programs and died on service between January 2004 and November 2008. The 72,066 records were analyzed using a three-way analysis of variance (season, place of care, diagnosis) with Bonferroni correction for post-hoc comparisons. Results: Compared to frail patients who died during June, July, and August, the number of deaths of frail patients increased an average of 20% in January, February, and March. This near-sinusoidal pattern was remarkably consistent over a five year period. The effect was most pronounced in patients in nursing facilities, followed by those in hospital, and then by patients receiving home care (all p < 0.005). For cancer patients, this seasonal variation was not observed in any place of care (all p > 0.05). Conclusions: Although frail patients generally have a longer length of stay in hospice than cancer patients hence allowing more opportunity for exposure to infection a number of other factors may serve to insulate cancer patients from seasonal effects. These include a smaller “symptom burden” than frail patients, who frequently have comorbid disease(s) and who are often unable to make their needs known; less compromised immune systems; more aggressive medical treatment; better nutrition; a strong support system (particularly from family and caregivers); and increased sensitivity to factors that may prolong survival, e.g., timely immunizations and even the avoidance of crowds in winter months.

No significant financial relationships to disclose.
Patient out-of-pocket and insurer payment decisions for bevacizumab for metastatic colorectal cancer: A Canadian analysis
Authors: Yunger S. , Douglas P. , Anglin P. , Crump M. , Lepage S. , Shum D. , Phillips L. , Milliken D.
Published: August 2020

6576

Background: Like many health care services in Canada, intravenous (IV) cancer therapies are typically funded publicly through hospitals and provincial cancer agencies. Delays may be encountered between regulatory approval and public funding of new drugs. IV drugs are not routinely covered through private insurance (PRI) plans, requiring patients to appeal for special consideration, including employer exceptions or pay cash. Uncertainty of drug funding may create challenges for physicians and patients when discussing treatment options. The Roche Patient Assistance Program (RPAP) provides reimbursement navigation, copay/financial assistance and access to infusion clinics. This observational study examines patient access to bevacizumab (B) in the absence of public funding. Methods: An analysis of the RPAP database for the period of July 2006 to August 2008 was conducted assessing patients enrolled, insurance status, approval rates, and access to B. Receipt of treatment with B was evaluated according to insurance coverage. Results: A total of 877 patients accessed the RPAP for treatment with B. 647 (74%) had PRI and 230 (26%) were uninsured. Of PRI patients, 310 (48%) were approved coverage and 337 (52%) were denied. 204 patients (65%) with approved PRI coverage received B therapy. Of patients with PRI but denied coverage for B, 135 (40%) elected to pay for B. Of patients with no PRI, 120 (52%) paid for B. Of all patients with no coverage for B (no PRI or denied PRI), 255 patients (45%) elected to pay for B. Conclusions: In a public healthcare environment, when B was not publicly funded, approximately half of patients without any PRI coverage who accessed the RPAP were willing to pay for B. Although private insurers state IV drugs are not plan benefits, almost half of patients were able to obtain B coverage. A conventional analysis of willingness-to-pay should be conducted to better understand reasons behind patient and private insurer decisions observed in this study. Further research should also be conducted to determine whether results can be generalized to other unfunded anticancer agents within the Canadian health care system.

[Table: see text]
Integration between primary care providers and the cancer system: Gaps and opportunities
Authors: Sussman J. , Evans W. , Whelan T. , Bainbridge D. , Schiff S. , Hasler A.
Published: August 2020

6584

Background: A number of reports suggest that family physicians (FPs) are poorly integrated with the cancer care system. The specific gaps in care integration are poorly understood. In this study we examine specific processes of care associated with integration between FPs and regional cancer programs. Methods: Cross sectional survey of all identified primary care providers within a representative health region in Ontario, Canada. The survey instrument was created specifically for this study with items generated from published literature and expert input and pilot tested in a representative sample. A modified dilman method was used. Results: 500 physicians responded (response rate 60%). Overall 90% of respondants reported confidence in the workup of a new cancer case for the major disease sites but only half (54%) knew the process of referring to the regional cancer program. Only 57% felt investigations necessary could be done in a timely manner and 44% indicated that coordination of care needs to be improved. Most indicated preferance for an active navigation structure for newly diagnosed patients. Despite over 80% of respondents indicating use of the internet only 10% reported accessing cancer program web portals for information on the regional cancer program (such as waiting times). The majority of respondants (75%) indicated ongoing involvement in care during the active treatment phase, mostly for non cancer related medical issues but 20% indicated that they were not properly infomed of patients’ health status by the oncology program and only 57% indicated that they felt their role was valued by the cancer program during this phase in the care trajectory. In the follow up phase, 35% were unclear of their role specific to monitoring and surveillance. 60% felt their current compensation model was inadequate to support care of cancer patients. This did not vary by compensation model reported. Factors associated with better integration included attendance at educational sessions and years in practice. Conclusions: Cancer systems need to be more responsive to the needs of FPs to better integrate them and support optimal quality of care for cancer patients. Policies to clarify and support roles and responsibilites are necessary to ensure that FPs are integrated team members.

No significant financial relationships to disclose.
Costs and outcomes associated with hospitalizations for venous thromboembolic disease in patients with malignant neoplasm
Authors: Weidner S. , Schilling M. B. , Parks C.
Published: August 2020

6590

Background: Venous thromboembolic disease (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE) is a common occurrence in oncology, as patients with cancer have a greatly increased risk of VTE. Costs of VTE treatment are significant, including direct costs (expenditures for procedures, tests, medications, and services), indirect morbidity costs (lost income from work due to the condition or disability), and indirect mortality costs (lost income due to early mortality). Costs associated with VTE contribute to the overall cost of cancer care, however studies that examine the cost of care for oncology patients that develop VTEs are limited. Methods: A retrospective cohort study identified patients with cancer hospitalized during January 2006 through May 2008 using a large US healthcare database (>342 inpatient facilities across all US regions, ∼ 11 million patients and > 300 million charge- detail records). Patients with an ICD-9-CM code for malignant neoplasm (140.xx-208.xx) in combination with DVT or PE (415.11,415.19, 453.4,453.41,453.42) were included. Using Aspen's charge cost model, the hospital's clinical, utilization and billing, and cost accounting records healthcare cost, LOS, and mortality rates associated with these hospitalizations were calculated. Results: Data from 74 facilities with a mean bed size of 349 was utilized. A total of 77% of these facilities were not classified as teaching hospitals. Overall 1136 inpatients were identified with a diagnosis of malignant neoplasm and either DVT or PE. Table 1 shows the results. Conclusions: DVT/PE contributes to the cost of cancer treatment and is a considerable cost driver. Additionally, human costs are high. Aggressive practices to prevent these complications can result in a lower healthcare burden. In an era of restricted resources and value based purchasing, these data can be used to prioritize resource utilization.

[Table: see text]

[Table: see text]
Direct and indirect economic evaluation of upfront and sequential adjuvant treatment in postmenopausal women with breast cancer based on the BIG 1–98 trial
Authors: Skedgel C. , Rayson D. , Younis T.
Published: August 2020

6594

Background: The monotherapy arms of the BIG 1–98 trial established the clinical superiority of upfront letrozole (LET) relative to tamoxifen alone (TAM) but direct comparison of sequential TAM-LET, LET-TAM and upfront LET did not establish a clinically superior strategy. We undertook an economic evaluation to identify an economically preferred strategy based on the relative cost-effectiveness (CE) of TAM, LET, TAM-LET, and LET-TAM in terms of cost per quality-adjusted life year gained (QALYG). Methods: A state-transition model was developed to calculate cumulative costs and QALYs over a 25yr horizon for hypothetical cohorts of postmenopausal women with HR+ breast cancer undergoing adjuvant hormonal treatment. As the sequential arms were not directly compared to TAM alone, it was not possible to directly compare all strategies. As such, the analysis conducted direct within-arm comparisons and an indirect between-arm comparison. DFS endpoints and relative DFS benefit were derived from the monotherapy and sequential arms of BIG 1–98. Adverse events were not included as these have not yet been reported. Sensitivity analyses were conducted for the key parameters and assumptions, including the baseline recurrence risk and the duration of carry-over benefit. Costs and utility weights were derived from the literature. The analysis took a Canadian direct payer perspective and drug costs were based on 2008 Canadian average wholesale prices. Costs and outcomes were discounted at 3%. Results: In the monotherapy arms LET had a CE of $16,650 relative to TAM. In the sequential arms LET-TAM had superior QALYGs and cost savings relative to LET and TAM-LET. In economic terms, LET-TAM dominated LET and TAM-LET. In the indirect comparison, LET-TAM dominated LET and TAM-LET and had superior QALYGs at increased cost relative to TAM for a CE of $178. Conclusions: Direct comparisons confirm the economic favourability of LET relative to TAM and establish the dominance of LET-TAM over LET and TAM-LET. These indirect comparisons support the strong economic favourability of LET-TAM relative to TAM in the indirect comparison. In the absence of superior clinical outcomes, economic evaluation is a useful in suggesting a preferred strategy.

No significant financial relationships to disclose.
Randomized phase II trials (RP2T): Selection design or poor man's phase III?
Authors: Riechelmann R. , Sasse E. , Borghesi G. , Miranda V. , Fede A. , Saad L. , Oliveira V. , Barros E. , Campos M. P. , Del Giglio A. , Saad E. D.
Published: August 2020

6595

Background: With the increasing number of new anticancer agents, RP2Ts have been used more often, aiming to select active agents to be tested further. RP2Ts are typically underpowered for statistical comparisons of endpoints between treatment arms. We sought to investigate how frequently formal statistical testing (as opposed to “picking the winner”) has been used in RP2Ts. Methods: We systematically searched PubMed for RP2Ts on systemic cancer therapy, using the medical subject headings “drug therapy” and “neoplasms,” and limiting the search to years 1995/1996 and 2005/2006, and to publication type “randomized controlled trials.” For each study, relevant data that were collected independently by two investigators included reporting of P values and confidence intervals (CIs) for primary (PE) and other endpoint(s) results. Results: 288 articles were retrieved and 107 were eligible: 22 were published in 1995/96 and 85 in 2005/06. Median number of arms and patients per RP2Ts were 2 and 94, respectively. PE was response rate in 71 (66.4%), a control arm was present in 55 (51.4%) and 48 (45%) were partially or entirely sponsored by for-profit organizations. For the PE, P values were reported in 50 (47%), and CIs in 69 (65%) RP2Ts. Either P values or CIs for the PE were reported in 85 (79.4%; 95% CI: 70.8% - 86.1%) cases. No temporal trend was identified in such practice (17 of 22 RP2Ts from 1995/1996 and 68 of 85 RP2Ts from 2005/2006). Likewise, source of funding and use of a control group were not associated with reporting P values/CIs for PE. Conclusions: Our study suggests that formal statistical comparisons are frequently performed between arms of RP2Ts. Further studies are needed in order to identify factors that are associated with such practice.

[Table: see text]
First evaluation of the French cancer clinical research projects funding program (PHRC)
Authors: Pauporte I. , Brain E. G. , Hennequin C. , Auleley G. R. , Reiffers J.
Published: August 2020

6601

Background: Data on success and failure rates of clinical studies are cruelly missing, especially for public funded programs. The French Cancer Plan 2003–2007 has launched such program as a specific extension of the wider ‘Programme Hospitalier de Recherche Clinique‘ (PHRC). Grant applications are submitted yearly. Funding is competitively based, projects being selected by a national committee supported by independent experts. A substantial financial support for the recruitment of clinical research associates (CRA) was launched simultaneously.We performed a preliminary analysis of the projects’ outcome 5 years after their funding. Methods: We carried out a survey of the projects funded in 2003 and 2004. A questionnaire was sent to the principal investigator. Data on project status, number of patients recruited per project, reasons for delay or failure, and publication results were collected. Projects were classified as failure (not started or closed for lack of inclusions) or success (ongoing or completed). Results: Of 257 projects submitted, 85 (33%) were selected. Of them, 24 failed (28%). Higher failure rates were observed for breast (5/11, 45%), gastrointestinal tract (6/16, 38%), genitourinary tract (4/11, 36%), and immune or cell therapy (8/15, 53%) projects. In contrast, haematological malignancies projects showed a low failure rate (3/20, 15%) as well as studies associated with translational research (6/34, 18%) or led by cooperative groups. The main reason for trials delay or failure was recruitment difficulties, due to overestimation of recruitment potential or restrictive inclusion criteria. Very few (< 5%) mentioned difficulty raised by the evolution of the scientific question or competing studies. No financial issue was reported. With 4-year of follow-up, 25% and 52% of projects have been respectively published in a peer-reviewed journal or presented at scientific meetings. Conclusions: In this first set of trials funded by the French Cancer Plan 2003–2007, more than a quarter failed despite apparent adequate funding. Main cause was a discrepancy between inclusion potential announced and real accrual. Application processes should evaluate more carefully this issue in order to improve the effectiveness of public health funding interventions in the future.

No significant financial relationships to disclose.
Non-breast cancer mortality after a breast cancer diagnosis: A retrospective population-based study
Authors: Beadle G. F. , McCarthy N. J. , Baade P. D.
Published: August 2020

6619

Background: Survivorship research after a breast cancer (BC) diagnosis has identified psychosocial, functional and comorbidity outcomes that adversely influence daily life. Little is known, however, about non-breast cancer (NBC) mortality after a BC diagnosis. Methods: This retrospective cohort study included Australian women aged 30–79 years diagnosed with BC between January 1982 and December 2004, with mortality examined from January 1993 to December 2005. The age-standardized mortality ratio (SMR) was used to compare NBC causes of death in the BC cohort and the age-matched Australian female population between January 1993 and December 2005. Results: The median follow-up time for the cohort of 159,550 Australian women diagnosed with BC was 7.04 years (range 0–24.7 years). During the follow-up period, 30,819 (19.3%) died of BC, 5,403 (3.4%) died of other cancers (OC), 18,349 (11.5%) died of non-cancer (NC) causes, while 104,979 (65.8%) were still alive at the end of the follow-up period. Excluding the first year after diagnosis, women with a prior BC diagnosis had a higher risk of mortality (SMR = 328.6.95% CI = 324.8–332.3, p < 0.001) than the age matched female population. NBC mortality risk was elevated for OC (SMR = 103.7, CI = 100.1–107.5, p = 0.022) but reduced for NC causes (SMR = 94.9, CI = 92.3–97.5, p < 0.001). For the age groupings 30–49 years (n = 46,736), 50–69 years (n = 82,967), and 70–79 years (n = 29,847), SMR's for NC causes were 168.2 (CI = 144.1–195.1, p < 0.001), 100.9 (CI = 95.9–106.1, p = 0.355), and 90.5 (CI = 87.5–93.5, p < 0.001) respectively. Following the first year of diagnosis, the SMR for OC was non-significantly elevated with time after diagnosis. In comparison, the SMR for NC causes reduced with time after diagnosis; SMR = 96.4 (CI = 92.1–100.8, p = 0.055) at 2–5 years after diagnosis, 98.2 (CI = 93.7–102.8, p = 0.222) at 6–10 years, 92.8 (CI = 87.2–98.7, p = 0.008) at 11–15 years and 82.2 (CI = 74.8–90.2, p < 0.001) at more than 15 years. Conclusions: BC survivors have a higher risk of mortality from OC compared to the aged-matched Australian female population, but a reduced risk from NC causes. Although NC mortality is lower in older women and as time from BC diagnosis increases, women less than 50 years have a higher risk of NC mortality.

No significant financial relationships to disclose.
Characterization of published errors in high-impact oncology journals
Authors: Molckovsky A. , Vickers M. M. , Tang P. A.
Published: August 2020

6627

Background: Knowledge within oncology is disseminated primarily via peer-reviewed journals. The potential for dissemination of erroneous data exists, an issue that has not been explored in oncology. We evaluated errata from the Journal of Clinical Oncology and the Journal of the National Cancer Institute published between 2004–2007. Methods: Two authors independently abstracted data regarding errata and classified them as trivial (eg typographical error) or serious (eg change in outcome). For serious errors, the frequency of citation and error propagation was determined using the Science Citation Index in Web of Science. For publications cited > 150 times, a random sample of 10% were evaluated for error propagation. Canadian oncologists were surveyed regarding attitudes towards published errata. Results: There were 190 published errors, out of a total of 5118 papers, for an error rate of 4 ± 1% (SD) per year. 26/190 errors were identified as serious (14%). The median time from publication of the original article to publication of the erratum was 3.5 mo for trivial errors compared to 8.3 mo for serious errors (p = 0.03). A median of 1 error per article was reported for papers with trivial errors compared to a median of 2 errors per article with serious errors (p < 0.01). The 26 articles with serious errors were cited 256 times before publication of the error and 1056 times afterwards; of these, 96 and 527, respectively, were evaluated for propagation. Error propagation occurred in 14.6% of the citations published before error publication, and in 3.4% of citations published afterwards (p < 0.001). Survey results indicate that 30% of oncologists do not read the erratum section of journals, and that 45% of oncologists have only read the abstract of an article before citing it in a publication. Although 58% of oncologists have noticed errors in cancer publications, only 15% of these errors were reported. Conclusions: Error rates in high impact oncology journals average 4% per year, but this is likely an underestimate since errors noticed by readers are not consistently reported to the journal. The accuracy of articles submitted for publication is of utmost importance; while error propagation decreases after erratum publication, serious errors continue to be propagated in the literature.

No significant financial relationships to disclose.
The impact of midlevel providers on productivity in outpatient oncology clinics at National Comprehensive Cancer Network (NCCN) institutions
Authors: Hinkel J. M. , Vandergrift J. L. , Perkel S. J. , Waldinger MHSA M. B. , Levy PA-C W. , Stewart F. M.
Published: August 2020

6628

Background: An ASCO workforce study has predicted an oncologist shortage by 2020. Increased reliance on mid-level providers (PA/NPs) has been proposed to ameliorate the physician shortage. However, no methods currently exist to assess the impact of PA/NPs as physician extenders in an oncology setting. Obtaining productivity data is challenging due to variations in PA/NP utilization and billing. NCCN developed a survey to evaluate the use of PA/NPs in cancer centers and to pilot test PA/NP productivity metrics in outpatient oncology clinics. Methods: An online survey instrument was developed in consultation with oncologists, executive administrators, and PA/NP leaders at NCCN institutions. It included questions on work characteristics, allocation of time and labor, and productivity. PA/NP outpatient clinic productivity was measured as the average number of new and follow-up patients seen per half-day clinic (patients per clinic, PPC). A convenience sample was obtained through 15 NCCN institutions that distributed the survey through their own internal PA/NP e-mail lists. Results: A total of 206 PA/NPs completed the survey. A greater proportion of respondents were NPs (54%) than PAs (46%). Most responding PA/NPs listed their primary specialty as medical oncology (MO, 34%), followed by hematologic malignancies/BMT (HM/BMT, 28%) and surgical oncology (SO, 23%). The highest reported productivity was observed for SO specialists (mean = 8.7 PPC, SD = 3.5), followed by MO (mean = 7.6, SD = 4.3), and HM/BMT (mean = 6.1, SD = 2.8). Within the SO and HM/BMT specialties, little difference was observed between NP and PA productivity. Among MO specialists, NPs reported seeing more follow-up patients per clinic (mean = 7.2, SD = 4.3) than PAs (mean = 5.5, SD = 2.7, p = 0.04). In most cases, productivity was unrelated to seniority. However, more experienced HM/BMT NPs were more productive with new patients (rs = 0.46, p = 0.03). Conclusions: Mid-level providers have a measurable impact on productivity in outpatient oncology clinics. Refining productivity metrics for PAs/NPs will help inform workforce projections and staffing decisions for oncology practices/specialists and cancer centers, especially in the face of future physician shortages.

No significant financial relationships to disclose.
NPM1 mutations as an independent prognosticator for older cytogenetically normal acute myeloid leukemia (CN AML)
Authors: Becker H. , Marcucci G. , Maharry K. , Margeson D. , Radmacher M. D. , Whitman S. P. , Mrózek K. , Baer M. R. , Larson R. A. , Bloomfield C. D.
Published: August 2020

7000

Background: In younger CN AML without FLT3-ITD, NPM1 mutations predict favorable outcome. Their prognostic impact in older [≥60 years (y)] patients (pts) requires further evaluation. Methods: Pretreatment marrow was studied in 189 older CN AML pts [median age 69 y (60 - 83 y); 162 de novo & 27 secondary (s; prior hematologic disorders) cases] enrolled on CALGB 9720 (n=106) & 10201 (n=83). Both protocols had standard-dose (100 mg/m2/d) cytarabine (AraC)/daunorubicin (DN)-based induction; consolidation was based on standard-dose AraC/DN/etoposide (1 cycle) in 9720 & intermediate-dose (2 g/m2/d) AraC (2 cycles) in 10201. Pts transplanted in 1st complete remission (CR) were excluded. Median follow-up was 3.3 y for pts alive. Analyses of NPM1 exon 12 by direct sequencing, gene & microRNA (miR) expression profiling by Affymetrix U133 plus 2.0 & OSU CCC v4.0 arrays, & other markers (FLT3-ITD, FLT3-TKD, WT1mut) were performed centrally. Results: In de novo CN AML, NPM1 mutated (NPM1mut) pts (54%) had more CRs (85% v 45%, P<.0001) & longer relapse-free (RFS) (P=.02; 3 y rates 23% v 10%) & overall survival (OS) (P<.0001; 3 y 34% v 7%) than NPM1 wild-type (NPM1wt) pts. In multivariable models, NPM1 mutations independently predicted favorable outcome (Table) - NPM1mut pts had 10-fold higher odds of CR & 64% reduction in relapse risk. In genome-wide analyses, miR-10 & miR-16 were upregulated in NPM1mut pts, accompanied by highly expressed HOX genes & downregulated BCL2, respectively. NPM1mut were rare in sAML pts (15%), precluding study of their impact. Conclusions: NPM1 mutations independently predict better outcome in older CN AML. Upregulation of proapoptotic microRNAs & downregulation of antiapoptotic microRNA targets may explain the impact of NPM1 mutations.

[Table: see text]

No significant financial relationships to disclose.
Improving the molecular risk classification for younger (<60 years) de novo cytogenetically normal acute myeloid leukemia (CN AML) patients (pts)
Authors: Marcucci G. , Maharry K. , Whitman S. P. , Paschka P. , Baldus C. D. , Langer C. , Mrózek K. , Kolitz J. E. , Larson R. A. , Bloomfield C. D.
Published: August 2020

7002

Background: CN AML pts are currently stratified into Low-risk [FLT3-ITD negative (neg)/NPM1 mutated (mut)] and High-risk [FLT3-ITD positive (pos) or NPM1 wild type (wt)] groups (FLT3-ITD/NPM1-only classification). We recently showed that low ERG expression and CEBPAmut identify pts with better outcome within, respectively, the Low- and High-risk groups, and that WT1mut confers poor outcome regardless of FLT3-ITD/NPM1 status. Here, we assess if adding CEBPA and WT1 mutation and ERG expression testing improves the currently used CN AML molecular risk classification. Methods: FLT3, NPM1, CEBPA and WT1 mutations and ERG and BAALC expression were tested at diagnosis in 143 CN AML adults enrolled on CALGB treatment protocols 9621 and 19808. Pts were divided into two molecular risk groups: i) CALGB Group I that included Low-risk pts with low ERG & High-risk pts with CEBPAmut and ii) CALGB Group II that included WT1mut pts & Low-risk pts with high ERG & High- risk pts with CEBPAwt. Results: CALGB Group I (n=56) v Group II (n=87) had more complete remissions (CRs) (P=.005; 96% v 79%), and longer disease-free (DFS; P<.0001; 5 year (y) 69% v 21%) and overall (OS; P<.0001; 5 y 70% v 31%) survival [median follow-up for pts alive 6 y]. In multivariable (MV) analyses, Group I predicted higher rate of CR (P=.02), and longer DFS (P<.0001) and OS (P=.0002), after correcting for other variables (Table). In contrast, for the same cohort of pts grouped by the FLT3-ITD/NPM1-only classification, CRs were 94% v 82% and 5 y DFS 59% v 32% and OS 67% v 36% in the Low- v High-risk groups. Based on the Akaike Information Criterion, MV models for DFS and OS using the CALGB risk Groups were better than those using the FLT3-ITD/NPM1-only risk groups. Conclusions: Prognostic classification of younger de novo CN AML pts is improved by adding CEBPA and WT1 mutation and ERG expression testing. While mutational analyses are ready for use in clinical trials, quantification of ERG expression is yet to be standardized.

[Table: see text]

No significant financial relationships to disclose.
Phase Ib/II pharmacokinetic/pharmacodynamic (PK/PD) study of combination voreloxin and cytarabine in relapsed or refractory AML patients
Authors: Lancet J. E. , Karp J. , Cripe L. , Roboz G. , Wollman M. , Berman C. , Conroy A. , Hawtin R. , Fox J. , Michelson G.
Published: August 2020

7005

Background: Voreloxin is a naphthyridine analog that intercalates DNA and inhibits topoisomerase II, inducing apoptosis. Clinical activity is observed in ovarian cancer and AML. Voreloxin combined with cytarabine (Ara-C) show supra-additive activity preclinically. Interim results from a phase Ib/II study in relapsed or refractory AML are reported. Methods: Dose-escalation in relapsed/refractory AML patients (pts) with ≤ 3 prior induction regimens; phase II expansion in first-relapse pts (CR1 ≥ 3 months) at MTD. Voreloxin given d1 and d4, combined with: A) continuous infusion 400 mg/m2/d x 5d Ara-C (CIV), or B) bolus 1 g/m2/d IV x 5d Ara-C. Voreloxin starting dose: A) 10 mg/m2/dose; B) 70 mg/m2/dose. Treatment: induction, reinduction if needed, and up to 2 courses for consolidation. DLT, PK, and PD were assessed in cycle 1. Pts’ PBMC were evaluated for induction of DNA damage response markers. Ex vivo sensitivity of pt BMA to voreloxin and Ara-C were evaluated by CellTiter-Glo proliferation assay. Results: 52 pts treated to date (A: 41 pts, dose-escalation; 5 pts Phase 2; B: 6 pts dose-escalation). A) MTD is 80 mg/m2/dose voreloxin. Infections are the most common G3 or higher toxicity. Voreloxin PK were dose proportional to 50 mg/m2, then plateaued. Evaluation of PBMC pre- and posttreatment suggests modulation of pDNA-PKcs and pChk2 may reflect response. Ex vivo BMA assay results suggest that voreloxin is the primary contributor to the majority of CRs observed. Phase Ib: 9 CRs + CRp were observed in multiply relapsed or 1° refractory pts. B) 70 mg/m2/dose voreloxin, no DLT; too early to evaluate activity. Conclusions: Voreloxin in combination with CIV Ara-C is generally well-tolerated, with CR in relapsed/refractory pts. Enrollment continues: A) phase II; B) phase Ib. Ex vivo activity assay results suggest that voreloxin is the primary contributor to the majority of CR. Induction of pDNA-PKcs and pChk2 in PBMCs from treated pts may reflect response.

[Table: see text]
Clinical experience with different dosing schedules of decitabine in patients with myelodysplastic syndromes (MDS)
Authors: Steensma D. , Kantarjian H. , Wijermans P.
Published: August 2020

7011

Background: Decitabine, a potent DNA hypomethylating agent, has demonstrated efficacy in MDS patients using two dosing regimens: 15 mg/m2 intravenous (IV) over 3 hours (hrs) every (q) 8 hrs for 3 days q 6 weeks (wks) and 20 mg/m2 IV over 1 hr once daily for 5 consecutive days q 4 wks. Methods: Results were reviewed from two randomized phase 3 studies comparing the 3-day dosing schedule of decitabine with supportive care, D-0007 and EORTC-06011, and two phase 2 studies with the 5-day dosing schedule, DACO-020 and ID03–0180. Data from each clinical trial supporting overall improvement, duration of improvement, time to AML or death, progression-free survival (PFS), and transfusion independence was assessed. Results: Patients had IPSS classification scores of intermediate-2 or high-risk (D-0007, 70%; EORTC-06011, 93%; ID03–0180, 66%; DACO-020, 46%) and de novo MDS (D-0007, 87%; EORTC-06011, 88%; ID03–0180, 70%; DACO-020, 89%). Comparable overall improvement (complete response [CR] + partial response [PR] + hematologic improvement [HI]), time to AML or death, and PFS was observed across all trials (Table). The duration of improvement ranged between 9.2 and 11.3 months. A trend was observed for improved outcomes with an increased number of decitabine treatment cycles. Conclusions: Overall improvement rates by IWG criteria exceeded 30% in all 4 studies. Higher overall improvement rates corresponded to increased median number of treatment cycles. Increasing the number of decitabine treatment cycles administered may provide additional benefit to MDS patients.

[Table: see text]

[Table: see text]
Age-specific differences in oncogenic pathway deregulation and chemosensitivity in patients with acute myeloid leukemia: Strategies to maximize response to induction chemotherapy
Authors: Rao A. V. , Valk P. , Metzeler K. H. , Acharya C. , Rizzieri D. A. , Delwel R. , Bohlander S. H. , Buske C. , Potti A. , Lowenberg B.
Published: August 2020

7013

Background: Despite all the advances made in understanding the poor prognosis of acute myeloid leukemia (AML) in the elderly, the underlying biology at a molecular signaling pathway level has yet to be defined. Methods: Clinically annotated, microarray data from 425 patients with newly diagnosed AML from two publicly available datasets GSE1159 and GSE12417 were analyzed. Age-specific cohorts (young ≤45 years; n = 175 and elderly ≥55 years; n = 144) were prospectively identified. Gene expression analysis was conducted by applying previously defined and tested signature profiles reflecting deregulation of oncogenic signaling pathways, altered tumor environment, and signatures of chemotherapy sensitivity. Standard Kaplan-Meier survival curves were generated using the two-sided log-rank test and individual differences in the probability of oncogenic pathway deregulation between young vs. elderly were analyzed via the non-parametric Mann-Whitney U test and a one-sided p-value ≤ 0.05 was considered statistically significant. Results: Elderly AML patients had worse OS (median 8.8 months vs. 24.1 months in younger patients; p = 0.001) and EFS (median 7.1 months vs. 15.3 months in younger patients; p < 0.0001). Analysis of oncogenic pathways revealed that older patients had higher probability of Ras, Src, and TNF pathway activation, p < 0.0001. Older patients were also less sensitive to anthracycline compared to younger AML patients, p < 0.0001. Unsupervised hierarchical clustering of younger AML patients revealed two clusters and clinically better survival for cluster 1 compared to cluster 2 (high Ras, Src, TNF pathway activation) and the latter were in turn less sensitive to adriamycin. However, in elderly patients those in cluster 2 also had high Ras, Src, TNF but this did not translate into differences in survival or chemotherapy sensitivity. Conclusions: AML arising in the elderly represents a distinct biologic entity characterized by unique patterns of deregulated signaling pathways that contributes to poor survival and resistance to adriamycin. We hope these findings will enable clinically meaningful adjustments of treatment strategies in the older patient population.

No significant financial relationships to disclose.
Use of SNP-array-based karyotyping for cytogenetic prognostication in unclassified cases of myelodysplasia and associated overlap disorders
Authors: Bhatnagar B. , Tiu R. V. , Gondek L. P. , O'Keefe C. , Huh J. , Advani A. S. , Sekeres M. A. , Maciejewski J. P.
Published: August 2020

7016

Background: Myeloproliferative disorders (MPD) and myelodysplastic syndromes (MDS) often have overlapping features resulting in unclassifiable cases (MDS-U and MDS/MPD-U). Chromosomal abnormalities impact prognosis, but 50% of cases show normal karyotype by metaphase cytogenetics (MC). Single nucleotide polymorphism arrays (SNP-A) are novel karyotyping tools with superior resolution and ability to detect copy neutral loss of heterozygosity, a defect not detected by MC. Methods: MDS-U (N = 17) and MDS/MPD-U (N = 61) patients were selected from an MDS database (N = 720, median age = 76, median follow-up = 42 mos). SNP-A was performed on 67 patients and 751 controls. An algorithm for identification of somatic lesions was designed: 1) Lesions detected by MC and SNP-A required no further analysis; 2) Micro-duplications/ deletions overlapping with copy number variants (CNV) were excluded. Lesions not in CNV databases were confirmed by CD3 lymphocytes; 3) UPD <25 Mb were unlikely somatic and excluded. Telomeric and interstitial (≥ 25 Mb) UPD were considered somatic. International Prognostic Scoring System (IPSS) was used to assess routine risk. Fisher's exact test was used for categorical variables. Overall (OS) and event-free (EFS) survival defined by the MDS working group criteria were analyzed by Kaplan Meier analysis (log-rank or Wilcoxon and 2-sided significance). Results: SNP-A yielded superior detection rate for chromosomal defects compared to MC (71% vs 47%, p = 0.008). UPD was seen in 17 patients and frequently involved chromosomes 1, 3, 6, 8, 11, 17. MDS/MPD-U and MDS-U patients had similar OS and EFS (OS = 42 vs. 45 mos, p = 0.13; EFS = 42 vs. 45 mos p = 0.63). SNP-A revealed a more complex karyotype in patients with advanced MDS. Furthermore, SNP-A karyotyping resulted in prognostic refinement of previously assigned IPSS: Unclassified cases = 6% versus 0%, int-1 = 45% versus 53%, int-2 = 6% versus 19%, high = 5% versus 8%. Overall, patients with new SNP-A lesions had worse OS and EFS (OS = 41 mos vs NR, p = 0.07; EFS = 32 vs 112 mos, p = 0.07). Conclusions: SNP-A karyotyping complements MC in detecting chromosomal defects in MDS-U and MDS/MPD-U. This technology will be helpful in refining diagnosis based on characteristic recurrent chromosomal lesions including UPD.

No significant financial relationships to disclose.
Combined tumor necrosis factor-α (TNF–α) and interleukin-2 (IL-2) blockade in acute steroid refractory graft-versus-host disease (SR-GVHD) following allogeneic hematopoietic stem cell transplantation (HCT)
Authors: Ramanathan M. , Srinivasan R. , Geller N. , Donohue T. , Goodwin R. , Cook L. , Ramos C. , Barrett J. , Childs R.
Published: August 2020

7023

Background: SR-GVHD is a frequent and often fatal complication of HCT. A variety of inflammatory cytokines have been implicated in the pathogenesis of GVHD; single agent therapy against targets such as the IL-2 receptor α chain (daclizumab) or TNF-α (infliximab) has modest activity in SR-GVHD. We hypothesized that concomitant blockade of both TNF-α and IL-2 pathways would be more effective in controlling SR-GVHD than inhibition of either cytokine alone. Methods: The incidence of and outcome following SR-GVHD in 141 pts undergoing nonmyeloablative HCT from an HLA-matched family donor at our institution between February 2001 and November 2008 were analyzed. All SR-GVHD pts were treated with a combination of daclizumab (1 mg/kg, days1, 4, 8, 15, 22) and infliximab (10 mg/kg, days1, 8, 15, 22); in addition, aspergillus prophylaxis, empiric broad-spectrum antibiotics, and a rapid reduction in the dose of corticosteroids was initiated in order to minimize the risk of opportunistic infections associated with immunosuppression. Results: Twenty-three pts (23/141, 16%) developed SR-GVHD (median age 35 y, range 17–65 y); involved organs included the GI tract (n = 23), liver (n = 3), and skin (n = 8). We observed a remarkably high response rate following therapy, with 20/23 (87%) pts experiencing complete resolution of GVHD. Responses were usually delayed (median onset 2 weeks) but durable. The most notable complication associated with therapy was the development of opportunistic infections (invasive fungal infections in 3 pts); in 2/3 of these cases, prophylactic antifungal therapy had been discontinued prematurely due to drug toxicity. The median survival for the SR-GVHD cohort was 255 days (range 67–2,148 days), with 10/23 pts surviving at the time of this analysis. Causes of death included underlying cancer (5 pts), CMV disease (2 pts), and infectious complications (5 pts). Conclusions: These data suggest combined TNF-α /IL-2 blockade is a highly effective therapeutic option for pts with SR-GVHD and highlight the need for aggressive antimicrobial prophylaxis in the management of this condition.

No significant financial relationships to disclose.
Nilotinib in chronic myeloid leukemia patients in chronic phase (CML-CP) with imatinib (IM) resistance or intolerance: Longer follow-up results of a phase II study
Authors: Kantarjian H. , Giles F. , Bhalla K. , Pinilla J. , Larson R. A. , Gattermann N. , Ottmann O. G. , Gallagher N. J. , Baccarani M. , leCoutre P.
Published: August 2020

7029

Background: Nilotinib is a potent and highly selective BCR-ABL inhibitor approved for the treatment of Ph+ CML patients (pts) in CP or accelerated phase who are resistant or intolerant to prior therapy including IM. This study evaluated the efficacy and safety of nilotinib (400 mg bid) in CML-CP pts resistant or intolerant to IM. Methods: Primary endpoint was major cytogenetic response (MCyR). Secondary endpoints included complete cytogenetic response (CCyR), complete hematological response (CHR), MCyR duration, overall survival (OS), and safety. Results: CML-CP pts (n = 321, 70% IM-resistant, 30% IM-intolerant with resistance) with a minimum follow-up of 19 months (mos) were evaluated; 72% were treated with ≥600 mg/day IM prior to enrollment. Median duration of prior IM treatment was 32 (<1–94) mos. Median dose intensity of nilotinib (790 mg/day; range 151–1,110 mg/day) closely approximated the planned dose. Nilotinib led to rapid and durable CHR and MCyR. CHR was observed in 94% of pts. 59% achieved an MCyR (2.8 mos median time to MCyR; 56% in IM-resistant, and 65% in IM-intolerant pts), including 73% of pts with a baseline CHR and 44% achieved a CCyR (41% in IM-resistant; 51% in IM-intolerant pts). Responses were durable, with 78% pts maintaining MCyR at 24 mos. Estimated OS rate was 88% at 24 mos. Safety profile did not change with longer follow-up. Most frequent grade (gr) 3/4 biochemical laboratory abnormalities were elevated lipase (17%), hypophosphataemia (16%), hyperglycemia (12%), and total bilirubin (8%) which were transient and clinically asymptomatic. Gr 3/4 non-hematologic AEs were infrequent: rash, headache, and diarrhea occurred in 2% of pts. Most common gr 3/4 hematological laboratory abnormalities were neutropenia (31%), thrombocytopenia (31%), and anemia (10%). Brief dose interruptions were successful in management of most AEs. Pleural or pericardial effusions (gr 3/4) were uncommon (< 1%). Conclusions: These results demonstrate that nilotinib was highly effective, with rapid and durable responses in CML-CP pts failing prior therapy due to resistance or intolerance. Nilotinib was well tolerated with favorable risk/benefit.

[Table: see text]