bluuebunny/crossref_metadata_2025 huggingface dataset:
Socioeconomic disparities in MGMT promoter methylation testing for glioblastoma patients.
Authors: Iorgulescu Bryan , Lamba Nayan , Smith Timothy R. , Reardon David A.
Published: May 2020

7029

Background: MGMT promoter methylation holds important prognostic and predictive implications for glioblastoma (GBM) patients. Herein we evaluate whether any barriers faced MGMT testing. Methods: Adults with newly-diagnosed GBMs were identified from the U.S. National Cancer Database (2010-2016). Patient socioeconomic, tumor, and cancer program features were evaluated for association with MGMT testing by multivariable logistic regression. Results: Of 12,380 GBM patients, only 57% had MGMT testing–a rate that increased to 74% by 2016. Testing was independent of patients' sex or race/ethnicity (all p > 0.05); and was largely independent of GBM histology, size, and location. Older patients were less likely to receive testing (54% of ≥70-years-olds vs 62% of those in their 40s, p = 0.01). Insurance status was an independent predictor of testing: only 43% of uninsured patients had testing, vs 61% of privately-insured or 55% of Medicare patients (p≤0.01). The uninsured rate dropped from 3.6% in 2010 to 2.5% in 2016 and was associated with Medicaid expansion under the Affordable Care Act. Patients from non-expansion states had the lowest rates of testing (55%), vs patients from expansion states (58%, p < 0.001). Additionally, household incomes were independently associated with testing: only 50% of patients living in the poorest quartile of households had testing vs 61% in the richest quartile (p = 0.001). Diagnosing hospital type was also an independent predictor of testing: patients diagnosed at academic/NCI-designated cancer programs were most likely to have testing (65%), vs only 45% of community and 44% of comprehensive community cancer program patients were provided testing (all p < 0.001). By 2016, testing rates had improved in all program types–particularly at comprehensive community (67%) and academic (80%) programs, but lagged at community programs (56%, p < 0.001). Patients without MGMT testing received less chemotherapy (mOR = 0.66, p < 0.001) and were associated with worse overall survival (mHR = 1.08, p = 0.002). Conclusions: Newly-diagnosed GBM patients in the U.S. who were uninsured, from the poorest quartile of households, or diagnosed at community cancer programs faced significant barriers to receiving MGMT testing. Medicaid expansion under the ACA was associated with reduced uninsurance, increased Medicaid insurance, and improved rates of testing. Reduced testing rates were associated with less chemotherapy and worse OS. Together our results indicate that substantial socioeconomic and care setting disparities exist in MGMT testing for GBM patients.
Disparities by race, socioeconomic status, and insurance type in the receipt of NCCN guideline concordant care for select cancer types in California.
Authors: Clair Kiran , Chang Jenny , Ziogas Argyrios , Tanjasiri Sora Park , Kansal Kari Joanne , Gin Greg E , Zell Jason A. , Bristow Robert E.
Published: May 2020

7031

Background: There are a limited number of studies that have evaluated the association between National Comprehensive Cancer Network (NCCN) guideline adherence and survival across different cancers. We aim to assess the relationship between race/ethnicity, socioeconomic status (SES), insurance type and the receipt of NCCN guideline concordant cancer care and survival. Methods: This is a retrospective population-based cohort study of patients with 7 types of invasive cancer using the California Cancer Registry. Adherence with NCCN guidelines was defined by appropriate surgical, radiation, and chemo- or hormonal therapies. Multivariate logistic regression was used to evaluate the relationship between the patient, insurance type, tumor, and guideline adherence. Disease-specific survival analysis was performed using multivariate proportional hazards model. Results: A total of 543,198 patients were identified with invasive cancer between 2004-2017 (cases by disease type: breast 189,311, prostate 156,502, colon 80,102, liver 25,857, gastric 22,066, ovary 22,551, and cervix 16,691). The proportion of patients receiving NCCN guideline-concordant care varied by disease type. Non-concordant guideline treatment was associated with increased disease-specific mortality across all cancer types: breast (HR 1.28, 95%CI 1.23-1.33), prostate (HR 1.31, 95%CI 1.22-1.41), colon (HR 1.73, 95%CI 1.67-1.78), liver (HR 2.52, 95%CI 2.42-2.63), gastric (HR 2.38, 2.28-2.49), ovary (HR 1.32, 95%CI 1.26-1.38), and cervical cancer (HR 1.17, 95%CI 1.08-1.26). In multivariate models, compared to White, black patients were less likely to receive guideline concordant care for breast (OR 0.88, 95%CI 0.84-0.92), prostate (OR 0.90, 95%CI 0.86-0.93), colon (OR 0.85, 95%CI 0.79-0.92), and ovarian cancer (OR 0.71, 95%CI 0.62-0.82). Compared to Managed care insurance patients, Medicaid payer status was also associated with lower guideline concordant care for breast (OR 0.81, 95%CI 0.78-0.84), prostate (OR 0.91, 95%CI 0.86-0.97), colon (OR 0.70, 95%CI 0.65-0.75), gastric (OR 0.69, 95%CI 0.63-0.75), and liver cancer (OR 0.66, 95%CI 0.61-0.72). Conclusions: Less than half of cancer patients received NCCN guideline concordant care. There was an incremental relationship observed between SES and the likelihood of receiving guideline concordant care. Patients receiving non-guideline concordant care had worse disease-specific survival.
Feasibility of switching to S-1 after other fluoropyrimidine-related cardiotoxicity during chemotherapy for solid tumors.
Authors: Osterlund Pia J. , Kinos Sampsa , Halonen Päivi , Soveri Leena-Maija , Kwakman Johannes J , Salminen Tapio , McDermott Raymond S. , Pfeiffer Per , Heervä Eetu , Liposits Gabor , Röckert Rebecka , Ålgars Annika , Kallio Raija S. , Sorbye Halfdan , Flygare Petra , Hagman Helga , Shah Carl-Henrik A. , van Werkhoven Erik D. , Glimelius Bengt , Punt Cornelis J. A. ,   Cardioswitch Group
Published: May 2020

7037

Background: Fluoropyrimidines (FP) are the cornerstone of chemotherapy in many solid tumors and linked to cardiotoxicity (CarTx) in about 5% (Polk, Cancer Treat Rev 2013), often leading to FP discontinuation. CarTx may be less common with S-1 and successful switch from other FP has been reported (Kwakman, EJC 2017). Methods: This 6-country, 12-center, cohort study included patients with solid tumors (ICD10 C15-C21, C24-25, C50, C80) who experienced FP-related CarTx. Primary endpoint was recurrent (R) CarTx during S-1 therapy after switch from any other FP. Results: CarTx during capecitabine (n = 124), continuous (n = 13) or bolus 5-fluorouracil (n = 4) was reported for 141 patients who switched to S-1 therapy. CarTx was chest pain including vasospasm without cardiac findings (55%), acute coronary syndrome or myocardial infarction (32%), atrial fibrillation (4%), heart failure/cardiomyopathy (4%), tachy-/bradycardia (3%), and/or other (15%). CarTx was grade 3-4 in 55%, appeared on cycle 1-2 in 89%, and at median 4 days (range 0-466) from FP initiation (Table). Causality was judged related in 26%, probable in 60%, and possible in 14%. Action with FP causing CarTx was permanent discontinuation in 91%. Treatment intent was curative in 70%. Cumulative incidence of RCarTx with S-1 was 3.5% (CI95%, 1.2-8.4%) and median time to R-CarTx was 11 (range 6-195) days. Four (out of 141) had grade 1 and one grade 2 R-CarTx. Three were judged possibly related to S-1 and 2 not related. S-1 was discontinued in one patient and continued in 4 (for 63-252 days) without action (n = 2), with dose reduction (n = 1), or delay (n = 1). There were no differences in demographic or risk factors regarding R-CarTx on S-1 (Table). Conclusions: FP-related CarTx is often severe, occurs early, and leads to permanent FP discontinuation. Switching to S-1-based therapy is safe, with, at the most, grade 1-2 R-CarTx in only 3.5%, and rarely leads to treatment discontinuation (0.7%), allowing patients to continue on an FP-based regimen. Clinical trial information: NCT04260269 . [Table: see text]
Implementing routine patient-reported outcome collection in a large, academic health system.
Authors: Shah Nishant , Wojcieszynski Andrzej , Davis Erin , Braun Jennifer , Garrett Meg , Shulman Lawrence N. , Metz James M. , Gabriel Peter Edward
Published: May 2020

7053

Background: Patients' symptoms and side effects have traditionally been assessed by clinicians. There is increasing evidence that patient self-reported symptom severity often differs from clinician assessment, and that collecting patient-reported outcomes (PRO) can improve communication, symptom management, and even survival. However, the implementation of routine PRO collection across a large healthcare system poses operational and informatics challenges. Methods: Using native electronic health record (EHR) functionality, we implemented a standardized PRO questionnaire across a large academic cancer center and associated community-based practices. The questionnaire is based on the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) developed by the National Cancer Institute. It assesses eleven common side effects of cancer care and is available for completion from home via the EHR patient portal or in clinic via tablet PC. Implementation was stepwise, beginning with a disease-specific patient population in the main academic cancer center and expanding over two years to include all cancer types, three specialties (radiation oncology, hematology/oncology, gynecologic oncology), and multiple satellite practice locations. Results: PRO collection was initiated for patients with gastrointestinal malignancies in two clinic locations at the main cancer center in 12/2017. During the first 3 months of implementation (12/2017-2/2018), questionnaires were completed for 1838 (56.3%) of 3267 eligible patient visits. Work with practice managers and staff to refine operational workflows led to improvement to a 75.6% capture rate for the period 3/2018 – 5/2018. From 6/2018 through 6/2019, the program was expanded to all multidisciplinary clinics in the main cancer center, as well as eight satellite practices. Aggregate capture rates from 7/2018 through 12/2019 have shown sustained performance, with 101,082 (76.7%) of 131,720 eligible visits captured. Of twelve total clinics participating, eleven have sustained capture rates above 70%, and nine capture over 80% of eligible visits. Questionnaires were completed through the online patient portal 12.1% of the time, with the remainder completed in clinic via tablet PC. Conclusions: Routine PRO collection as standard-of-care is possible across a variety of practice environments in a large, complex health system, with sustained capture of approximately three-fourths of eligible visits. Most patients prefer to complete the questionnaire in clinic.
Effectiveness of adjuvant FOLFOX versus 5FU for colon cancer treatment in community oncology practice using a hybrid study approach.
Authors: Lund Jennifer Leigh , Webster-Clark Michael , Keil Alexander P , Westreich Daniel , Sturmer Til , Sanoff Hanna Kelly
Published: May 2020

7067

Background: Treatment effects may differ between trials and community settings, in part due to underrepresentation of certain patient subgroups in trials. We used a hybrid approach combining clinical trial and real-world data to compare the effectiveness of adjuvant FOLFOX vs 5FU for stage II-III colon cancer in community oncology practice. Methods: We used Multicenter International Study of Oxaliplatin/5FU-LV in the Adjuvant Treatment of Colon Cancer (MOSAIC) combined with patients who met trial eligibility criteria within US Oncology from 1/1/2008-5/31/2019. In the combined data, we used logistic regression to estimate the probability of trial enrollment as a function of age, sex, substage, body mass index (BMI), and performance status. We estimated inverse odds of sampling weights and weighted MOSAIC participants to reflect three US Oncology populations: 1) patients meeting trial eligibility, 2) stage III patients, and 3) stage III patients initiating FOLFOX. Within the weighted trial populations, we estimated mortality hazard ratios (HRs) and bootstrapped 95% confidence intervals (CIs) comparing FOLFOX with 5FU. Results: There were 2246 MOSAIC participants and 9335 US Oncology patients. MOSAIC participants were younger, had more stage II cancer, lower BMI, and worse performance status compared with US Oncology patients. After weighting MOSAIC participants to reflect the US Oncology populations, the HRs were attenuated (Table) compared with the original MOSAIC estimate (HR = 0.84; 0.71,1.00). Conclusions: When differences between trial and clinical populations exist and response to therapy varies across subgroups, treatment efficacy can differ from clinical effectiveness. Compared with trial results, we found that effectiveness of FOLFOX versus 5FU was attenuated in community oncology practice. [Table: see text]
Differences in real-world (RW) non-small cell lung cancer (NSCLC) treatment patterns among people living with HIV/AIDS (PLWHA) compared to those without HIV/AIDS (PWoHA).
Authors: Klink Andrew J. , Falkenstein Angelica , Gajra Ajeet
Published: May 2020

7070

Background: NSCLC is the most common non-AIDS-defining cancer in PLWHA with an estimated prevalence 2-5 times that of PWoHA. Guidelines now support treatment of NSCLC among PLWHA to follow those for PWoHA. However, PLWHA have been often excluded from cancer clinical trials that test novel agents including immunotherapy (IO). This study aimed to assess differences in systemic therapy patterns for advanced NSCLC among PLWHA and PWoHA in the RW. Methods: Adult patients with ≥2 claims for NSCLC between 1/1/13-12/31/18 (earliest claim = index date), ≥3 months data pre/post index date, and no evidence of clinical trial participation, pregnancy or other malignancy prior to index date were identified from Symphony Health longitudinal prescription and medical claims. Patient characteristics and treatment patterns were summarized by descriptive statistics and comparisons by HIV status made on univariate analyses. Times to discontinuation were estimated by Kaplan-Meier method and compared by log-rank tests. Results: There were 60,278 NSCLC PWoHA who received systemic therapy. Of 1,344 PLWHA with NSCLC, 239 (18%) received systemic therapy. PLWHA differed significantly from PWoHA: median age at diagnosis (58 v 68 years), male preponderance (66% v 47%), payer mix (Medicare 26% v 42%; Medicaid 21% v 7%), Charlson Comorbidity Score (median 6 v 1), depression (13% v 5%) and liver disease (8% v 2%), respectively (all P< 0.01). Differences in common systemic therapies among PLWHA v PWoHA include use of first line (1L) carboplatin + paclitaxel (28% v 19%; P< 0.01), 1L erlotinib (6% v 11%, P= 0.02) and 2L gemcitabine (10% v 4%, P< 0.01). IOs were used in 1L among 43 (18%) and 7,149 (12%) of PLWHA v PWoHA, respectively ( P< 0.01). RW surrogates for PFS: median duration of 1L therapy was shorter among PLWHA (1.8 v 2.3 months, P< 0.01); median times from 1L initiation to 2L were similar (5.4 v 4.9 months; P= 0.48). Similar proportion of patients continued onto 2L (32% and 30%) and 3L (10% and 9%) among PLWHA and PWoHA, respectively (all P> 0.05). Total time from diagnosis to last follow-up (RW surrogate for overall survival) was 12.8 v 15.5 months in PLWHA and PWoHA ( P= 0 .07). Conclusions: PLWHA are younger at diagnosis of NSCLC and have higher comorbidity. Important differences in regimen selection and IO utilization exist across PLWHA and PWoHA. PLWHA have shorter 1L than PWoHA. Given higher risk and younger age at diagnosis, additional research is needed to establish screening and treatment guidelines for NSCLC in PLWHA.
Hospitalization for complications due to systemic therapy in the United States.
Authors: Rubens Muni , Ramamoorthy Venkataraghavan , Saxena Anshul , Veledar Emir , McGranaghan Peter , Boulanger Belinda , Chuong Michael David , Hall Matthew David , Kotecha Rupesh , Mehta Minesh P.
Published: May 2020

7078

Background: Management of complications of systemic therapy for cancer involves significant healthcare burden for both patients and healthcare system. Aim of this study is to estimate trends as well as burden associated with these hospitalizations, using a nationally representative data. Methods: National Inpatient Sample data during 2005-2016 was used to identify complications of systemic therapy using ICD-9 and ICD-10 external cause of injury codes. Primary outcome was hospitalization rate while secondary outcomes were cost and in-hospital mortality related to these complications. Results: There were 443,222,223 hospitalizations recorded during the study period, of which 2,419,722 were due to complications of systemic therapy. The average annual percentage change of these hospitalizations was 8.1%, compared to -0.5% for general hospitalizations. The 3 most common causes for hospitalization were anemia (12.8%), neutropenia (10.8%), and sepsis (7.8%). During the study period, hospitalization rates had highest relative increases for sepsis (1.9 fold) and acute kidney injury (1.6 fold) and highest relative decrease for dehydration (0.21 fold) and fever of unknown origin (0.35 fold). Complications responsible for highest costs per hospitalization were sepsis ($16,834), acute kidney injury ($13,172), and pneumonia ($13,040). Leading causes of in-hospital mortality associated with systemic therapy were sepsis (15.8%), pneumonia (7.6%), and acute kidney injury (7.0%). Conclusions: During 2005-2016, hospitalization rates for systemic therapy complications increased by an annual rate of 8.1%, with anemia, neutropenia, and sepsis as the most common complications requiring hospitalization. Initiatives such as rule OP-35 by the Centers for Medicare and Medicaid Service, improving access and providing coordinated care, early identification and management of symptoms, and expanding urgent care access could decrease these hospitalizations and the burden on healthcare. [Table: see text]
A cost analysis of managing cancer-related pain among hospitalized US cancer patients.
Authors: Alese Olatunji B. , Zhang Chao , Zakka Katerina Mary , Kim Sungjin , Wu Christina , Shaib Walid , Akce Mehmet , Chen Zhengjia , Switchenko Jeffrey M. , El-Rayes Bassel F.
Published: May 2020

7079

Background: Pain is a common symptom of cancer, affecting patients' function and quality of life. It is also a common cause of hospitalization for cancer patients. The aim of this study was to evaluate the cost of in-hospital pain management among US cancer patients. Methods: A retrospective analysis of data from all US hospitals that contributed to the National Inpatient Sample for 2011-2015 was conducted. All cancer patients admitted for pain management were included in the analysis. Main outcomes were factors significantly associated with hospital length of stay, total charge per hospital stay, and in-hospital mortality. Weighted chi-square test was used for categorical covariates and univariate analysis was performed using a logistic model. Results: 122,776 patient discharges were identified. Mean age was 59.3 years and 52.3% were female. 65.9% stayed in the hospital for longer than 72 hours, with a median total hospital charge of $48,156. Conversely, the median total hospital charge for those spending less than 72 hours on admission was $15,966. Median total charge per hospital stay was similar among insured and uninsured/self-pay patients ($32,879 vs. $32,323; p=0.013), but higher in patients without metastatic disease ($33,315 vs. $29,369; p<0.001). It was also higher in those with the highest income quartile when compared with lowest income patients ($38,223 vs. $30,047; p<0.001). Co-morbid medical illnesses were more prevalent in those with longer hospital stay (15 vs. 12; p<0.001) and the overall in-hospital mortality rate was 8.2%. There was no significant difference in median total hospital charges between those who died in, or those discharged from the hospital ($33,746 vs. $32,795; p<0.001). On multivariate analyses, gender, race, insurance status, diagnosis of metastatic cancer, age, number of co-morbid medical illnesses, year of diagnosis, and median income were significant predictors of length of stay. Race, insurance payor, metastatic cancer, age, and number of co-morbid medical illnesses were significant predictors of total hospital charges, after adjusting for other covariates. Conclusions: In-patient pain management of cancer patients is associated with significant health care costs. Optimization of outpatient pain management strategies could significantly lower the cost of care for cancer.
Interim analysis (IA) of OPTIC: A dose-ranging study of three ponatinib (PON) starting doses.
Authors: Cortes Jorge E. , Lomaia Elza , Turkina Anna , Moiraghi Beatriz , Undurraga Sutton Maria , Pavlovsky Carolina , Rojas Christine , Chuah Charles , Arthur Christopher Kevin , Apperley Jane , Kim Dong-Wook , Hochhaus Andreas , Rousselot Philippe H. , Rosti Gianantonio , Mauro Michael J. , Lipton Jeffrey Howard , Naranjo Daniel , Liu Guohui , Srivastava Shouryadeep , Deininger Michael W.N.
Published: May 2020

7502

Background: In PACE (NCT01207440) heavily pretreated patients (pts) with chronic-phase CML (CP-CML) had deep, lasting responses to PON; long-term follow-up showed increasing rates of arterial occlusive events (AOEs). We present IA results from OPTIC (NCT02467270), evaluating the association between PON exposure, efficacy, and safety, and response-based dose reduction in pts with CP-CML. Methods: This ongoing, multicenter, randomized phase 2 trial enrolled pts with CP-CML resistant or intolerant to ≥2 TKIs or with a T315I mutation to receive PON at a starting dose of 45 mg (cohort A), 30 mg (B), and 15 mg (C) qd. Doses were reduced to 15 mg qd on achievement of ≤1% BCR-ABL1IS in A/B. Primary endpoint: 12 mo ≤1% BCR-ABL1IS; secondary endpoints include cytogenetic and molecular response and AOE, VTE, and TEAE rates. Results are descriptive at this IA and will be inferential by adjusting multiplicity across 3 cohorts at final analysis. Results: 283 pts were randomized (A/B/C: n = 94/95/94); median age 48 y (18‒81 y). 26% had hypertension history; 2/43/55% received 1/2/≥3 TKIs; 40% had ≥1 baseline (BL) mutations, with 23% T315I. At IA data cutoff (20 Jul 2019), 162 pts (57%; n = 57/51/54) remained on study treatment. Among 282 pts in the safety population, median duration of exposure was ≈1 y (A/B/C, 12.9/11.2/11.0 mo). At 12 mo, 39% (95% CI, 27.6, 50.6), 27% (17.6, 39.1), and 26% (16.5, 38.6) in A, B, and C, respectively, achieved ≤1% BCR-ABL1IS. Additional efficacy in Table. Dose reductions due to efficacy (A/B): 35/21%. Most common TEAEs (any grade/≥3): thrombocytopenia 39/27%, neutropenia 25/17%. AOEs/serious AOEs were reported by (A, B, C) 5%/2%, 4%/3%, and 1%/0%. Dose reductions due to TEAEs: (A/B/C): 44/31/28%; discontinuations due to TEAEs: 18/15/14%. There were 4 (1.4%) on-study deaths; A, sudden death, n = 2; C, pneumonia, n = 2; no deaths were due to AOEs. Clinical trial information: NCT01207440 . Conclusions: OPTIC IA shows a trend toward dose-dependent efficacy and safety and may provide a refined understanding of the PON benefit:risk profile and its relation to dose. Data from longer follow-up may support an alternate dosing regimen for pts with CP-CML. [Table: see text]
Updated results from phase I dose-escalation study of AMG 330, a bispecific T-cell engager molecule, in patients with relapsed/refractory acute myeloid leukemia (R/R AML).
Authors: Ravandi Farhad , Walter Roland B. , Subklewe Marion , Buecklein Veit , Jongen-Lavrencic Mojca , Paschka Peter , Ossenkoppele Gert J. , Kantarjian Hagop M. , Hindoyan Antreas , Agarwal Suresh K , Dai Tian , Khaldoyanidi Sophia , Stein Anthony Selwyn
Published: May 2020

7508

Background: In this open label phase 1 dose escalation study, safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary efficacy of AMG 330 were evaluated in patients (pts) with R/R AML (NCT#02520427). Methods: AMG 330 was evaluated as a continuous IV (cIV) infusion using a 3+3 design. Response was assessed per revised IWG criteria. Each cycle (2–4 weeks duration) was followed by an infusion-free interval. Eligible pts were ≥18 y/o with > 5% blasts in bone marrow and ≥1 line/s of prior therapy. Results: As of December 10, 2019, 55 pts (median age, 58.0 [18.0–80.0] years) were enrolled in 16 cohorts. AMG 330 was administered on 4 schedules (0–3 dose steps) prior to the target dose (TD, 0.5–720 µg/day). Dose steps were implemented in the dose schedule design based on the adverse event (AE) profile. Across all schedules, 55 (100%) pts reported treatment-emergent AEs (any grade). AMG 330–related AEs reported in 49/55 (89%) pts included cytokine release syndrome (CRS; 67%; ≥ grade 3 in 13%), (60%) and nausea (20%) as the most frequent AEs. CRS was reversible and occurred in a dose/schedule-dependent manner mostly within the first 24 hours of administration of triggering AMG 330 dose. The frequency and severity of CRS correlated with the dose level and leukemic burden at baseline. AMG 330 exhibited dose-dependent increase in steady state exposures over the studied dose range with clinical PK profile consistent with cIV administration. Eight of 42 evaluable pts responded: 3 complete remissions (CR; including 1 CR with negative measurable residual disease reported after data snapshot), 4 CR with incomplete hematologic recovery, and 1 morphologic leukemia free state. Seven responders who achieved CR/CRi received a TD equal or above the minimal efficacious dose of 120 μg/day. Among analyzed CR/CRi responders, 4/6 (67%) had adverse cytogenetic risk profile, 3/6 (50%) had ≥4 lines of prior therapy and all had relapsed disease. Responders had higher AMG 330 exposures and 3 responders treated with ≥600 μg/day TD remain in CR/CRi: 1 patient for > 5 months after cycle 1, 1 patient bridged to hematopoietic stem cell transplant after cycle 4 and 1 patient is in cycle 3. Preliminary response assessment showed a correlation with lower tumor burden at baseline with a trend towards higher CD8+ lymphocyte count and E:T ratio. Conclusions: AMG 330 dosed up to 720 μg/day provided early evidence of acceptable safety profile, drug tolerability and anti-leukemic activity, and supports further dose escalation. Clinical trial information: NCT02520427 .
Five-year final results of a phase III study of CPX-351 versus 7+3 in older adults with newly diagnosed high-risk/secondary AML.
Authors: Lancet Jeffrey E. , Uy Geoffrey L. , Newell Laura F. , Lin Tara L. , Ritchie Ellen K. , Stuart Robert K. , Strickland Stephen Anthony , Hogge Donna , Solomon Scott R. , Bixby Dale , Kolitz Jonathan E. , Schiller Gary J. , Wieduwilt Matthew Joseph , Ryan Daniel H. , Faderl Stefan , Chang Yu-Lin , Cortes Jorge
Published: May 2020

7510

Background: CPX-351 (Vyxeos; daunorubicin and cytarabine liposome for injection), a dual-drug liposomal encapsulation of cytarabine [C] and daunorubicin [D], is approved by the FDA and EMA for the treatment of adults with newly diagnosed therapy-related AML or AML with myelodysplasia-related changes. Primary analysis of the pivotal phase 3 study (NCT01696084) that formed the basis for these approvals evaluated patients (pts) aged 60-75 y with newly diagnosed high-risk/secondary AML and found that CPX-351 significantly improved median overall survival (OS) vs conventional 7+3, with a comparable safety profile. Here, we report the prospectively planned final 5-y follow-up results from this phase 3 study. Methods: Pts were randomized 1:1 to receive ≤2 induction cycles of CPX-351 (100 units/m2 [C 100 mg/m2 + D 44 mg/m2] as a 90-min infusion on Days 1, 3, 5 [2nd induction: Days 1, 3]) or 7+3 (C 100 mg/m2/d continuously for 7 d + D 60 mg/m2 on Days 1-3 [2nd induction: 5+2]). Pts achieving complete remission (CR) or CR with incomplete platelet or neutrophil recovery could receive up to 2 consolidation cycles. Pts could receive a hematopoietic cell transplant (HCT) at the physician’s discretion. Pts were followed until death or up to 5 y following randomization. Results: In total, 309 pts were randomized to CPX-351 (n = 153) or 7+3 (n = 156). The survival rate at 5 y was higher for CPX-351 vs 7+3 (18% vs 8%; Table). Among pts who died, the most common primary cause of death was progressive leukemia in both arms (CPX-351: 56%; 7+3: 53%). After a median follow-up of 60.65 mo, improved median OS with CPX-351 vs 7+3 was maintained: 9.33 vs 5.95 mo; Kaplan-Meier (KM) OS curves plateaued at ~30 mo. HCT was received by 53 (35%) vs 39 (25%) pts after CPX-351 vs 7+3; among these pts, the survival rate at 5 y was higher for CPX-351 vs 7+3 (52% vs 23%), and median OS landmarked from the HCT date was not reached for CPX-351 vs 10.25 mo for 7+3 (Table). Conclusions: After 5 y of follow-up, improved OS was maintained in this phase 3 study, supporting that CPX-351 has the ability to produce or contribute to long-term remission and survival in older pts with newly diagnosed high-risk/secondary AML. Clinical trial information: NCT01696084 . [Table: see text]
A phase III study of venetoclax plus low-dose cytarabine in previously untreated older patients with acute myeloid leukemia (VIALE-C): A six-month update.
Authors: Wei Andrew H. , Montesinos Pau , Ivanov Vladimir , Dinardo Courtney Denton , Novak Jan , Laribi Kamel , Kim Inho , Stevens Don A. , Fiedler Walter M. , Pagoni Maria , Samoilova Olga , Wang Jianxiang , Anagnostopoulos Achilles , Bergeron Julie , Hou Jing-Zhou , Yamauchi Takahiro , Jiang Qi , Mendes Wellington , Hayslip John W. , Panayiotidis Panayiotis
Published: May 2020

7511

Background: VIALE-C was designed to compare the safety and efficacy of the BCL-2 inhibitor venetoclax (VEN) or placebo (PBO) plus low-dose cytarabine (LDAC) in previously untreated patient (pts) with acute myeloid leukemia (AML; ≥75 yr or ≥18 yr with comorbidities precluding intensive chemotherapy). The primary overall survival (OS) analysis showed a clinically meaningful improvement with VEN+LDAC, although the primary endpoint was not met. Herein, we present a 6-mo update after primary analysis, with a focus on OS. Methods: This double-blind, PBO-controlled phase 3 study (NCT03069352) randomized pts 2:1 to VEN (600 mg orally QD, days [d]1–28) with 4-d ramp-up in first cycle or PBO in 28-d cycles, plus LDAC (20 mg/m2 subcutaneously QD, d1–10). The primary endpoint was OS; secondary endpoints included response, transfusion independence (TI; red blood cells [RBC] or platelets), and event-free survival (EFS). OS and EFS were analyzed by the Kaplan-Meier method and compared between arms using the log-rank test stratified by AML status (de novo vs secondary) and age (18 to < 74 vs ≥75). The planned sample size was 210 pts (n = 140, VEN; n = 70, PBO) to detect a hazard ratio (HR) of 0.545 in OS with 2-sided alpha of 5% and power of 90%. Results: As of 15 Aug 2019, 211 pts were randomized (n = 143, VEN; n = 68, PBO); median age: 76 yr in both arms (range: 36–93); secondary AML: 38% (88% post-MDS/CMML); prior hypomethylating agent: 20%. With a median follow-up of 17.5 mo (range: 0.1–23.5), median OS was 8.4 mo vs 4.1 mo in the VEN+LDAC and PBO+LDAC arms (HR 0.70; 95% CI 0.50–0.99; P= .04), representing a 30% reduction in the risk of death. Complete remission (CR)/CRi and CR/CRh (CR with partial hematologic recovery) rates were both 48% for the VEN+LDAC arm, and 13% and 15%, respectively, for PBO+LDAC. RBC/platelets TI rates were 43%/49% vs 19%/32% for VEN+LDAC and PBO+LDAC. Median EFS was 4.9 mo vs 2.1 mo in the VEN+LDAC and PBO+LDAC arms (HR 0.61; 95% CI 0.44–0.84; P= .003). Grade ≥3 adverse events (AEs [ > 30%]; VEN+LDAC/PBO+LDAC) included neutropenia (49%/18%), thrombocytopenia (45%/38%), and febrile neutropenia (32%/29%); serious AEs ( > 10%) were febrile neutropenia (17%/18%) and pneumonia (14%/10%); tumor lysis syndrome occurred in 5.6%/0%. Conclusions: VEN+LDAC demonstrates a clinically meaningful improvement in OS compared with PBO+LDAC, with a tolerable and manageable safety profile. These data support VEN+LDAC as a frontline treatment option for older pts with AML, as well as those considered unfit for intensive chemotherapy. Clinical trial information: NCT03069352 .
Ivosidenib (IVO) prior to hematopoietic cell transplant for patients with IDH1-mutant relapsed or refractory acute myeloid leukemia (R/R AML).
Authors: Dinardo Courtney Denton , Stein Eytan , Pigneux Arnaud , Altman Jessica K. , Collins Robert , Erba Harry Paul , Watts Justin M. , Uy Geoffrey L. , Kapsalis Stephanie M. , Liu Hua , Winkler Thomas , Roboz Gail J. , de Botton Stéphane
Published: May 2020

7521

Background: Allogeneic hematopoietic cell transplantation (HCT) provides a potentially curative option for patients (pts) with R/R AML. Disease status at the time of transplant is a major determinant of long-term prognosis, with pts typically receiving salvage chemotherapy prior to HCT to induce a remission. However, older and/or heavily pre-treated pts frequently cannot tolerate intensive chemotherapy (IC) or do not obtain adequate disease control to permit an HCT. IVO is an oral, potent, targeted inhibitor of mutant IDH1 (mIDH1) approved for the treatment of adults with newly diagnosed AML ≥75 y of age or ineligible for IC, and those with R/R AML. We assessed HCT outcomes in pts with m IDH1 R/R AML who proceeded to HCT after treatment with IVO in a phase I study (NCT02074839). Methods: Baseline characteristics, clinical response (including CR, CRi/CRp, MLFS), and overall survival (OS) for the subgroup of pts with m IDH1 R/R AML who received IVO 500 mg QD, responded to treatment and then underwent HCT are reported. m IDH1 variant allele frequency (VAF) from bone marrow mononuclear cells was assessed using BEAMing digital PCR (0.02–0.04% VAF detection limit). Results: Among 179 pts with R/R AML treated with IVO, 18 proceeded to HCT: median age, 61.5 y (range 36–68); 56% male; 16.7% had secondary AML; 27.8% had ≥3 prior regimens; 11.1% had a prior HCT. The median duration of IVO treatment prior to HCT was 3.9 mo (range 2.1–15.2). The last reported response prior to HCT was 50.0% CR. Six- and 12-mo post-HCT survival rates were 77.8% and 50.0%; median relapse-free survival post HCT was 7.3 mo (range 2.6–NE). Median OS from start of IVO was 16.8 mo (95% CI 9.2, NE) for HCT pts vs 9.0 mo (95% CI 7.1, 10.2) in the entire study cohort; median follow-up time, 33.2 mo (range 3.2–41.9). Eight HCT pts were censored for OS: 5 are in remission, 2 relapsed and are in survival follow-up, and 1 was lost to follow-up. Median OS was not estimable (95% CI 9.1, NE) for the 12 HCT pts who achieved CR after IVO therapy and was 20.5 mo (95% CI 16.4, NE) for the 31 CR pts who did not undergo HCT. m IDH1 was undetectable in 1/18 (6%) pts; 4/18 (22%) pts had reduction below 1% VAF in ≥1 at the last assessment prior to HCT. Conclusions: IVO monotherapy is a putative treatment option to induce remissions prior to HCT for m IDH1 R/R AML pts who are not considered candidates for intensive salvage therapy. Post-transplant survival rates are encouraging and warrant further investigation of IVO monotherapy or combination salvage therapies prior to HCT. Clinical trial information: NCT02074839 .
Clinicopathologic and molecular profile of Philadelphia like ALL in Hispanic population of Central Valley California.
Authors: Akabane Hugo , Ali Mir , Abdulhaq Haifaa , Bukari Mohammed SANI
Published: May 2020

7524

Background: Philadelphia-like Acute B-ALL(PHL) are Ph negative B-ALL(PHN) with molecular signatures that mirrors Ph + B ALL. Studies have shown worse prognosis in this subtype of leukemias, but few have reported outcomes with incorporation of novel agents. Our study seeks to describe clinical and molecular profile of a single center experience. Methods: This is a retrospective study of patients treated for PHL in community referral center in central valley of California from 1/2009 to 12/2019. Of the initial 71 patients, 34 met the inclusion and exclusion criteria. 16 of the 34 patients who had Next Generation Sequencing (NGS) by Foundation Medicine (14) or NeoGenomics (2). Data for 34 PHN and 8 with PHL patients were analyzed. Results: There are no differences in mean ages (36.7 x 36) and gender between the PHN and PHL subgroup. There is over representation of Hispanics in both groups (63% x 65%) with slightly male predominance in PHL group (62%). This ratio is slightly higher than reported by 2010 census of 46%. The BMI 38.4(27.5-48.4) vs. 29.1(26.6-39.1), mean WBC (71 vs. 58), bone marrow CD20+ by flow cytometry (90% vs. 63%) and abnormal cytogenetics (50% vs.15%) are all higher in PHL compared to PHN group. The prevalence rate of PHL signature in 16 tested patients is 8(50%). CRLF2 like subtype accounted for 6/8(75%), with 1 each of ABL-like and JAK-Stat subtype. All patients harbored multiple other mutational abnormalities in addition to those associated with Ph-like genetic signatures (Table). The median number of mutations was 4.55(3-7). The distribution of the 20 other mutation is as shown in table. 6 patients had morphological remission after induction chemotherapy of HyperCVAD (37%) and CALGB 10403 (25%) with measurable MRD in 5 of the patients. 7 patients were exposed to novel therapy; Blinatumomab; 2nd line (6 patients), Cart T cell; 3rd line (2 patients), Inotuzumab; 3rd line (3 patients) and ASCT; (3 Patients post second- or third-line remission). 2 patients died at the time of data cut off, 1 from infection and other from refractory leukemia. Conclusions: Our data shows high incidence of PHL signatures in the cohort. The mutational heterogeneity between and within patients, may represent sub-clonal population vs. passenger and hence poor clinical outcomes. [Table: see text]
STAG2-mutated AML patients: ASXL1 cohesin binding motif status and mutation landscape.
Authors: Scarpa Frank J , Paul Madhuri , Wolfson Wendy A , Weiss Lawrence M. , Funari Vincent Anthony , Blocker Forrest
Published: May 2020

7538

Background: ASXL1 and the cohesin complex ( STAG2, RAD21, SMC1A, and SMC3) are commonly mutated chromatin regulators with significant clinical implications in AML. The ASXL1-cohesin interactome regulates gene expression through chromatin accessibility via ASXL1’s cohesin binding motif (CBM). ASXL1 variants are most commonly located in the ASXM1 domain and onwards, and characteristically lead to loss of the PHD domain. Gain-of-functions in truncated ASXL1 are suggested to increase catalytic activity of BAP1, which binds the ASXH domain at AA 351, and to gain an interaction with BRD4, which binds somewhere between the ASXN and ASXH domains, to drive H3K4Me3 and H2AK119Ub. Methods: 2463 suspected AML patient bone marrow, peripheral blood, or FFPE tissue samples were evaluated using an all exon amplicon-based 27 gene NGS panel. Patients with a VAF <10% in ASXL1 were excluded to avoid reporting artifacts, particularly in variant c. 1934dup. Statistics were performed using Fisher’s exact test. Results: Mutations in STAG2-mutated patients were enriched for sAML, as evidenced by the higher number of mutations in ASXL1, SRSF2, and BCOR (associated with sAML) compared to NPM1, DNMT3A, and PTPN11 (pAML). STAG2 mutations were found in 173 samples representing 93.5% of cohesin mutations. Of all ASXL1 mutations (VAF 10.1– 54.5%; median 32.2%) 4.0% occurred in the CBM. While 23.5% of samples with mutations outside ASXL1 CBM had concomitant mutations in STAG2, none of the 18 samples with CBM mutations (VAF 11.3 – 51.7%; median 42.5%) had any cohesin gene mutation (P = 0.0174). The proportion of BCOR (27.8% vs 9.2%; P = 0.024) and CEBPA (27.8% vs 8.2%; p = 0.016) mutated patients in the CBM+ group was significantly higher than the CBM- group. JAK2 (16.7% vs 5.4%), KRAS (22.2% vs 13.6%), EZH2 (22.2% vs 13.6%), and RUNX1 (38.9% vs 27.7%) mutations were also higher though not significantly in this group. Mutations throughout all of ASXL1, the 13 amino acids after the CBM, and hotspot variants all had STAG2 mutations at a frequency of 20.9-44.4%, further suggesting mutual exclusivity. Conclusions: STAG2 mutations and mutations in the CBM were mutually exclusive events and harbored different co-mutation frequencies. In compromised ASXL1 CBM cases, BCOR and CEBPA transcriptional regulators are significantly more mutated, but in cases of ASXL1 mutation outside the CBM, cohesin mutations are preferred, suggesting alternative chromatin accessibility mechanisms driving leukemogenesis. This observation has not been previously reported in the literature to our knowledge.
Venetoclax (Ven) added to intensive chemo with cladribine, idarubicin, and AraC (CLIA) achieves high rates of durable complete remission with low rates of measurable residual disease (MRD) in pts with newly diagnosed acute myeloid leukemia (AML).
Authors: Kadia Tapan M. , Garcia-Manero Guillermo , Yilmaz Musa , Dinardo Courtney Denton , Konopleva Marina , Montalban-Bravo Guillermo , Borthakur Gautam , Jabbour Elias , Jain Nitin , Andreeff Michael , Short Nicholas James , Issa Ghayas C. , Ohanian Maro , Bose Prithviraj , Daver Naval Guastad , Wang Sa A , Tidwell Rebecca , Estrov Zeev , Ravandi Farhad , Kantarjian Hagop M.
Published: May 2020

7539

Background: Ven is a BCL2 inhibitor that is approved in combination with lower intensity therapy for pts with newly diagnosed AML who are ineligible for intensive chemo. We previously reported the safety and efficacy of cladribine and araC with idarubicin in young and fit pts with AML. Here, we studied the combination of ven with the intensive CLIA regimen in newly diagnosed AML. Methods: Pts < 65 yrs with newly diagnosed FLT3-wildtype AML were enrolled. Induction was cladribine 5 mg/m2 IV on D 1-5, followed by ara-C 1.5 g/m2 IV on D 1-5, idarubicin 10 mg/m2 IV D 1-3, and ven at an effective dose of 400mg PO on D2-8. There was no ramp up for ven and dose modifications for CYP3A4 inhibitors were made. Consolidation consisted of up to 5 more cycles of CLIA+Ven. All pts underwent baseline next generation sequencing and MRD testing by multiparameter flow cytometry at the time of response. Results: 18 pts are enrolled, with a median age of 50 yrs (range, 18-64). Baseline pt characteristics are in Table. 16 pts were evaluable for response and 2 are too early. 14 of 16 pts (88%) achieved a remission, including 10 (63%) complete remission (CR) and 4 (25%) CR with incomplete count recovery (CRi). The median time to response was 1 cycle and the median number of cycles given was 2 (1-5). 10 of the 14 responders (71%) had undetectable MRD at the time of remission. Both nonresponding pts had a complex karyotype and 1 had a TP53 mutation. With a median follow up of 4.5 months (0.2 – 11.2), none of the responding pts have relapsed. 8 of the 14 responders (57%) have received allogeneic stem cell transplant. The median survival has not been reached; the 6-month OS and RFS are 90% and 100%, respectively. Treatment was well tolerated, with 0% 4-week mortality. The median days to ANC ≥ 1 and Platelets ≥ 100 were 30 (19-49) and 26 (18-39), respectively. Tumor lysis syndrome was not seen. The most common adverse events were neutropenic fever, pneumonia, nausea, and liver transaminitis. Conclusions: The addition of ven to CLIA was safe and effective in newly diagnosed pts with AML. The combination was not associated with early mortality or prolonged myelosuppression, but did result in high rates of durable MRD negative remissions. Clinical trial information: NCT02115295 . [Table: see text]
Incidence of graft versus host disease in peri transplant hospitalization after clostridium difficile infection.
Authors: Murray Drew Carl Drennan , Kumar Rohit , Bhandari Shruti , Hegazi Mohamed M.
Published: May 2020

7542

Background: Hyperacute graft versus host disease (GVHD) after allogenic stem cell transplantation (SCT) has adverse outcomes with increased rates of chronic GVHD and relapse. GVHD risks include mismatched related or matched unrelated donors, myeloablative conditioning, heavy pretreatment, and donor-recipient sex mismatch. Clostridium difficile infection (CDI) is a leading cause of diarrhea in immunocompromised patients. Proposed microbiome effect on immunity and GVHD in allogenic SCT recipients prompts concern of microbiome modulation from CDI and antibiotics inciting GVDH. Methods: National Inpatient Sample database 2014 for hospitalizations with allogeneic SCT in patients ≥18yo. Characteristics (age, sex, race, insurance, graft source, hospital type, region, comorbidities) were compared for hospitalizations with and without CDI. Primary outcome was the difference in the incidence of GVHD during the transplant hospitalization between the 2 groups. Other outcomes were mortality, length of stay and hospital charges. Chi-square, t-test, and multivariate logistic regression utilized. Results: Of 6210 patients with allogenic SCT, 745 (12%) had CDI during the transplant hospitalization. In transplanted patients without CDI the average age was 55yo, 43.9% female, 69.5% Caucasian (C), 7.1% African American (AA), 8.6% Hispanic (H), 32.1% had Medicare/Medicaid, 61.8% private insurance, 5.7% uninsured, 44.7% had hypertension, 13.7% had diabetes, graft source was 84.3% PBSC (peripheral blood stem cells), 11.3% bone marrow, and 4.4% cord blood. CDI group the average age was 52.5yo, 45.3% female, 73% C, 4.7% AA, 8.1% H, 25.7% had Medicare/Medicaid, 66.2% private insurance, 8.1% uninsured, 41.9% had hypertension, 10.1% had diabetes, graft source was 83.8% PBSC, 10.8% bone marrow, and 5.4% cord blood. 25.7% of patients with CDI developed GVHD during that hospitalization while 14.2% of patients without CDI developed GVHD during the hospital stay (OR 2.1, p < 0.001 multivariate analysis). GVHD during the hospitalization had no difference in length of stay (p = 0.32), total cost of stay (p = 0.50) or same hospitalization mortality (p = 0.94). Conclusions: Allogeneic SCT patients with CDI develop GVHD on the same hospitalization at significantly higher rates than patients without CDI. This is true after controlling for age, sex, race, insurance, comorbidities, graft source, hospital location, and type of institution. Despite known associations of early evidence of GVHD on relapse, overall mortality was not different between the two groups.