bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of hospital type with prices, spending, and acute care utilization among privately insured patients undergoing cancer surgery.
Authors: Takvorian Samuel U , Yasaitis Laura , Liu Manqing , Lee Daniel J. , Werner Rachel M. , Bekelman Justin E.
Published: May 2020

e19376

Background: With annual cancer spending estimated to surpass $170 billion in 2020, national attention has focused on the prices and utilization of cancer care. This is particularly important for privately insured patients, for whom healthcare prices are negotiated between insurers and providers and price transparency is lacking. Among privately insured patients undergoing common cancer surgery, we examined the relation between hospital type and prices, spending, and utilization. Methods: We conducted a retrospective study using Health Care Cost Institute’s multipayer national commercial claims data. The study population included patients with breast, colon or lung cancer undergoing cancer surgery from 2011-2014. The exposure was hospital type at which surgery was performed: National Cancer Institute (NCI), academic, or community. Spending outcomes were surgery-specific prices paid and 90-day total episode spending. Utilization outcomes were length of stay (LOS), emergency department (ED) use, and hospital readmission within 90 days. We estimated mean risk-adjusted spending and utilization outcomes for each hospital type using generalized linear mixed-effects models, adjusting for patient, hospital and region characteristics. Results: We identified 66,878 patients with incident breast (53.5%), colon (32.0%), or lung (14.5%) cancer undergoing cancer surgery at 2,995 hospitals (8.3% at NCI; 16.3% academic; 75.4% community). Treatment at NCI cancer centers was associated with higher surgical prices paid ($18,310 at NCI v $14,703 at community hospitals; diff +$3,607; p < 0.001) and 90-day total episode spending ($46,462 v $41,274; diff +$5,188; p = 0.008). There were no significant differences in LOS, ED use or hospital readmission within 90 days. Conclusions: Among privately insured patients undergoing cancer surgery, NCI cancer centers had higher surgical prices and episode spending without differences in utilization, compared to community hospitals. A better understanding of the drivers of prices and spending at NCI cancer centers is needed. [Table: see text]
Estimating productivity losses for cancer patients and caregivers of cancer patients.
Authors: Chiu Kevin , MacEwan Joanna P. , Bognar Katalin , Peneva Desi , May Suepattra Grace , Zhao Lauren , Yong Candice , Amin Suvina , Bolinder Bjorn , Batt Katharine , Baumgardner James
Published: May 2020

e19381

Background: Although cancer is a leading cause of illness in the United States, its true impact on productivity is poorly understood. Traditional approaches to capturing health-related productivity loss—e.g., the human capital method—focus on patients’ foregone wages, overlooking fringe benefits and the impacts incurred by caregivers and co-workers. Thus, the value of lost productivity is often underestimated. We sought to comprehensively estimate productivity loss incurred by working-age cancer patients and unpaid caregivers in the United States. Methods: We conducted a cross-sectional survey study of (i) non-small cell lung cancer (NSCLC) and breast cancer (BC) patients, and (ii) unpaid caregivers. To measure loss associated with absenteeism and presenteeism, participants reported pre- and post-cancer diagnosis income, hours worked, and time to complete tasks. The “multiplier effect” method was used to measure productivity loss incurred by co-workers due to patient or caregiver absenteeism and/or presenteeism. Exploratory multivariable analyses controlled for cancer type, stage, age, time since diagnosis, oncogene mutation status, and industry sector. Results: A total of 404 participants (104 BC, 100 NSCLC patients; 100 BC, 100 NSCLC caregivers) completed the surveys. Of these, 319 participants (162 BC, 157 NSCLC) who worked ≥40 weeks in the year pre-diagnosis and who did not transition from part- to full-time work after diagnosis were included in the analysis. Over a third of the NSCLC (33%) and BC (43%) patients left the workforce after diagnosis. For patients, estimated mean annual productivity loss equaled $123,792 (144% of mean income pre-diagnosis) for NSCLC and $123,502 (209% of mean income pre-diagnosis) for BC. For caregivers, the estimated mean annual productivity loss was $90,421 (108% of mean income pre-diagnosis) for NSCLC and $143,839 (190% of mean income pre-diagnosis) for BC. Exploratory analyses also found that patient age and stage at diagnosis were positively correlated with a greater absenteeism effect. Conclusions: This study found that traditional approaches, such as the human capital method, significantly underestimate productivity loss in cancer patients and caregivers. Holistic approaches that include lost wages, fringe benefits, and teamwork effects, are better approaches to understanding the amplified impact cancer can have for patients, caregivers, and co-workers.
Early physician spillover responses to the oncology care model.
Authors: Walker Brigham
Published: May 2020

e19393

Background: As Medicare increasingly seeks to transform beneficiary care through provider reimbursement incentives, there is a possibility that non-beneficiary care will change too. There is limited information on how the Oncology Care Model (OCM) has affected care in this way. This study seeks to analyze the early utilization and cost effects of the OCM on the non-Medicare population. Methods: This was a retrospective analysis of a large physician network comprised of OCM participants and non-participants alike. The data spanned July 1st, 2015 to June 30th, 2017 – one year before and after the launch of the OCM. Several states are represented, and this population includes about 20% of the non-hospital-based community oncology footprint. A difference-in-differences approach was used to compare primary first-year effects on the Medicare population with first-year spillover effects on the Medicare Advantage (MA), private, and Medicaid populations. The utilization and costs of care under management of the practices were evaluated. Effects of the OCM for breast, lung, colon, and prostate cancer among Medicare, MA, private, and Medicaid populations at the physician-by-month level are estimated. Results: The OCM appears to have reduced office visits for Medicare breast cancer and colon cancer. These effects look to have spilled over to the Medicaid breast cancer population, but not elsewhere. The OCM also modestly decreased overall costs for each sub-type but these reductions were not observed in the non-Medicare populations. Conclusions: This research was not randomized, so un-observable differences between groups unrelated to the OCM could drive these results. It is also limited to practice-based care and does not include hospital or pharmacy care. Finally, these are first year effects and the literature suggests that effects can develop for a few years after program launch. That said, this paper suggests that care patterns appear to have changed under the OCM for both Medicare and non-Medicare lives, but not uniformly.
Establishing the six-month resource utilization and cost-of-care for the treatment of first-line metastatic BRAF (V600) melanoma with combination BRAF and MEK inhibitors.
Authors: Halloush Shiraz , Huber Stephen , Kim Hanna , Koeller Jim M.
Published: May 2020

e19396

Background: Comparative data on cancer therapy health care resource utilization (HCRU) and associated cost will be helpful as value-based healthcare moves forward. BRAF & MEK inhibitor combinations are considered first-line treatment for BRAF (V-600) metastatic melanoma (MM), although head-to-head trials are lacking. We aimed to establish the real-world HCRU and 6-month (mo) cost-of-care in V-600 MM treated with BRAF & MEK inhibitor therapy. Methods: A single data team in 2018 performed a multicenter, retrospective chart audit of adult patients with BRAF V-600 MM. Four institutions from across the US with patients who had received either dabrafenib + Trametinib (DT) or vemurafenib + cobimetinib (VC) were enrolled. In the most recent 12 mo period, data was captured from the start of therapy for 6 mo or until therapy was stopped. Dose change or stoppage was accessed for cause (toxicity, disease, death, other). Variables included hospitalization, emergency room (ER), all clinic visits (routine + extra), scans, labs, and treatment drug (AWP). Medicare reimbursed rates were applied for cost estimates. Utilization and costs were measured on per patient per month (PPPM) bases and the total cost over 6 mo for each combination. Results: Of the 42 patients included, 34 and 8 were initiated on DT and VC, respectively. Proportions of patients with extra clinic visits and hospital admissions were 79%, 15% and 75%, 13%, respectively for DT and VC. PPPM hospitalization was the lowest among the resources utilized 0.24 for DT and 0.17 for VC. A higher proportion of VC patients (75%) had a dose reduction due to drug toxicity compared with 29% of patients treated with DT (P < 0.05). Discontinuation rates were the same between both combinations (0.26). 32 patients had completed 6 mo of treatment (26 DT and 6 VC). For those DT, the mean total costs including drug and the mean monthly total costs were $157,253 and $26,209 compared to $107,240 and $17,873 for VC, respectively. The mean total costs for hospitalization were $10,562 for DT and $7,456 for VC. The mean total costs for the drug were $145,012 for DT and $97,924 for VC. Conclusions: The 6-month total cost-of-care for the treatment of first-line V-600 MM with DT was $157,253 and $107,240 for VC, mostly attributable to drug cost. In a value-based healthcare system, total 6-month cost-of-care may help distinguish between equally effective regimens.
Cost-effectiveness of various maintenance therapies based on mutation status following first-line treatment of primary epithelial ovarian cancer in the United States.
Authors: Penn Courtney , Wong Melissa , Walsh Christine S.
Published: May 2020

e19399

Background: The recent SOLO1, PRIMA, and PAOLA trials all reported positive efficacy results, making it difficult to determine optimal upfront maintenance therapy for patients with primary, advanced ovarian cancer. We evaluated the cost-effectiveness of the maintenance strategies outlined in these trials for BRCA-positive patients, homologous-recombination deficient patients without a BRCA mutation (HRD-positive), and homologous-recombination proficient (HRD-negative) patients. Methods: Three decision analysis models were developed, one for each mutation status. We evaluated olaparib (SOLO1), olaparib/bevacizumab (PAOLA), bevacizumab alone (PAOLA), and niraparib (PRIMA) maintenance strategies. Base case 1 assessed olaparib vs olaparib/bevacizumab vs bevacizumab vs niraparib vs no maintenance therapy in BRCA-positive patients. Base cases 2 and 3 assessed olaparib/bevacizumab vs bevacizumab vs niraparib vs no maintenance therapy in HRD-positive and HRD-negative patients, respectively. Time horizon was 24 months. Costs, measured in U.S. dollars, were estimated from Medicare claims, wholesale acquisition prices, and previously published sources. Incremental cost-effectiveness ratios (ICERs) were in dollars per progression-free life-year saved (PF-LYS). One-way sensitivity analyses were performed varying drug cost and progression-free survival. Results: Assuming a willingness-to-pay threshold of $100,000/PF-LYS, none of the drug maintenance strategies could be considered cost effective compared with observation. In BRCA-positive patients (base case 1), olaparib monotherapy was the most cost-effective strategy, yielding an ICER of $181,059/PF-LYS. The third-party payer cost per 28-day supply of olaparib would need to be reduced from approximately $17,000 to $9,200 to be considered cost effective compared with observation. In HRD-positive patients (base case 2) and HRD-negative patients (base case 3), bevacizumab monotherapy was the most cost-effective option, with ICERs of $326,491/PF-LYS and $253,937/PF-LYS respectively. Conclusions: At current costs, maintenance therapy for primary ovarian cancer is not cost effective, regardless of mutation status. In BRCA-positive women, lowering the cost of olaparib may make it cost effective compared with observation.
Pharmaco-economic assessment of subcutaneous compared to intravenous trastuzumab in HER2-positive breast cancer patients: A single institution experience.
Authors: Elsamany Shereef Ahmed , Jafal Mohamed , Hassanin Fayza
Published: May 2020

e19409

Background: Traditionally, trastuzumab is given through intravenous (IV) administration. Recently, subcutaneous (SC) trastuzumab formulation has been developed showing similar efficacy and safety with shorter administration time. This study aims to assess the pharmaco-economics of SC compared to IV trastuzumab in patients with HER2-positive breast cancer treated in a single institution in Saudi Arabia. Methods: We checked the average number of trastuzumab doses, both IV and SC, given per year in King Abdullah Medical City, Saudi Arabia. One-year pharmaco-economic analysis of either trastuzumab forms were performed separately. This analysis included direct medication price based on hospital purchasing in addition to costs of drug preparation kits, nursing administration utilities and staff working time, based on average duration of drug preparation/ administration in chemotherapy unit records. IV trastuzumab dose was calculated based on an average body weight of 80 kg. Results: On average, the total number of trastuzumab doses, both IV and SC, were 1000 doses per year. We calculated the overall cost of 1000 doses of IV compared to SC trastuzumab separately. The average costs of one dose of IV and SC trastuzumab were 2,099 and 1,619 USD, respectively. This is translated to 2,099,000 and 1,619,000 USD per year for IV and SC trastuzumab, respectively. Other costs of trastuzumab administration were 24,933 and 2,666 USD per year of IV and SC trastuzumab, respectively. IV and SC trastuzumab administration needed 2,000 and 83 working hours per year, respectively, resulting in 1,917 saving in nursing working hours per year. This is translated to 18,106 USD saving per year based on average nursing salary. IV and SC trastuzumab pharmacy preparation needed 333 and 33 working hours per year, respectively, corresponding to annual saving of 300 hours in pharmacist- working time and 10,106 USD of pharmacist salary. The overall cost of IV trastuzumab per year was 2,153,667 compared to 1,623,236 USD for SC trastuzumab which corresponds to 2,153 and 1,623 USD per dose for IV and SC trastuzumab, respectively. This is translated to 24.6% overall cost reduction with the SC formulation. Conclusions: SC trastuzumab is associated with favorable pharmaco-economic profile with considerable cost saving compared to the IV counterpart. This is coupled with significant reduction of administration time and improved convenience.
Bleeding and thrombosis outcomes in patients with acute leukemia.
Authors: Kelkar Amar Harry , Dhanarajan Asha R. , Kelkar Mona Arti , Wingard John R.
Published: May 2020

e19501

Background: Management of acute leukemia is often complicated by acute venous thromboembolism (VTE) and bleeding. However, it is unknown which risk factors contribute to these VTE and bleeding events, how they impact survival, or whether they warrant VTE prophylaxis. Methods: A retrospective study was conducted at the University of Florida Health Shands Hospital System. The study included patients aged 18 or older with acute leukemia who received induction chemotherapy between January 2000 and December 2011. Bleeding was defined as clinically significant non-major bleeding and major bleeding per the International Society on Thrombosis and Haemostasis guidelines. VTE was defined as pulmonary embolism, deep vein thrombosis of the upper or lower extremities, or visceral vein thrombosis. Results: Of the 250 patients with acute leukemia, 65 had VTE, 60 had bleeding, and 152 had no significant VTE or bleeding. There were 27 patients with both VTE and bleeding. There were no significant differences in demographics or disease types between these three groups. There was a total of 77 VTE events and 72 bleeding events. We performed a logistic regression analysis in a mixed model to identify risk factors for VTE and bleeding, considering leukemia type, presence of infection, chemotherapy, number of comorbidities, VTE prophylaxis, and transplant as covariates. Presence of infection and number of comorbidities were significantly associated with VTE (p = 0.0094 and 0.0009, respectively). We did not find any significant risk factor associated with bleeding. Kaplan-Meier survival analysis showed a non-significant difference in survival between the non-VTE, non-bleed group and the VTE group (Logrank test, p = 0.52). In contrast, survival in the non-VTE, non-bleed group was significantly higher than the bleed group (Logrank test, p = 0.0006). The table demonstrates higher two-year survival in the non-VTE, non-bleed group (68.7%) compared to the VTE and bleed groups (54.4% and 30.3%, respectively). Conclusions: Acute leukemia patients without VTE or bleeding had significantly higher duration of survival than patients with bleeding. Patients with acute leukemia and presence of infection or multiple comorbidities may warrant greater consideration of VTE prophylaxis. [Table: see text]
Burden of relapsed/refractory (RR) acute myeloid leukemia.
Authors: Panjabi Sumeet , Hines Dionne M. , McGuiness Catherine Balderston , Yucel Emre , Yea Steven , McIver Zachariah , Wade Rolin L
Published: May 2020

e19509

Background: To examine treatment patterns and health care costs of RRAML in the US. Methods: We identified adults with ≥ 2 outpatient or ≥ 1 inpatient claim with a diagnosis of AML from 1/1/2011 to 12/31/2017 (first AML claim = index date) using IQVIA’s fully-adjudicated Health Plan Claims Data. Continuous health plan enrolment for ≥ 12 months prior to the index date and ≥ 1-month post-index, a RRAML diagnosis on or prior to the index date, or with hematopoietic stem cell transplantation (HSCT) or chemotherapy pre-index were required. Patients were grouped by post-index treatment (high- or low-intensity chemotherapy [HIC, LIC] with and with no HSCT, HSCT only, best supportive care [BSC], or no treatment within 90 days of index [NoTx]). Costs were evaluated for 12 months following index. Results: The final sample of patients with RRAML (n = 804) were grouped by age:18-59 (n = 411; 51.2%), 60-74 (n = 318; 39.5%), and ≥75 years (n = 75; 9.3%). Treatment within the three age cohorts was: HIC (13%, 11%, 1%); LIC (27%, 38%, 52%); HIC+HSCT (14%, 7%, 0%); LIC+HSCT (2%, 3%, 0%); HSCT (9%, 9%, 0%); BSC (21%, 21%, 31%); NoTx (13%, 12%, 16%), respectively. Mean monthly costs were lowest for BSC and highest for HSCT or HIC containing treatments, irrespective of age (Table). Inpatient costs were 50 to 100% of total costs. Monthly costs across treatment/age groups were higher earlier in treatment [month 1 range: $28,627 (BSC) to $180,867 (HIC)] and declined over time [month 12 range: $2,853 (BSC) to $53,003 (HIC+HSCT)]. Conclusions: Nearly half of all patients age ≥75 years and 33% of patients < 75 years received BSC or NoTx, which highlights a significant unmet need for new treatment options. Average costs per patient, especially early in treatment are high and driven by hospital service utilization. [Table: see text]
Clearance of leukemic blasts by flow cytometry versus minimal residual disease as predictors of clinical outcome in elderly patients with acute myeloid leukemia.
Authors: Rossi Giovanni , Giambra Vincenzo , Minervini Maria Marta , de Waure Chiara , Giacchetta Irene , la Torre Antonella , Ciavarella Michele , Melillo Lorella M , Scalzulli Potito Rosario , Carella Angelo Michele , Cascavilla Nicola
Published: May 2020

e19514

Background: Lower-intensity regimens, such as hypomethylating agents (HMAs) are better tolerated and more effective than standard chemotherapy in elderly patients( > 65 years old) with acute myeloid leukemia (AML). Scoring systems to predict clinical outcome in these patients are mainly based on cytogenetic assays and morphological response to therapy. Minimal residual disease (MRD) represents a powerful risk- stratification in younger AML patients but it remains poorly investigated in older patients, particularly in those undergone HMAs. In this subset, the survival benefit is not limited to patients achieving morphologic complete remission (CR). The clearance of leukemic blasts was never be valued as a predictive parameter of outcome in older patients. Thus, in this study we evaluated the most effective and predictive factor of outcome at the optimal time-point among leukemic blasts clearance by flow cytometry (FC), MRD and morphological response in older patients treated with HMAs. Methods: From april 2015 to may 2019, 76 older patients ( > 60 years old) with newly diagnosed AML were treated con azacitidine and decitabine. Among them, 56 completed at least six cycles but 31were properly monitored by FC. Log Clearance was defined as logarithmic ratio between the percentage of blast cells at specific time point and that at the diagnosis. Results: A total of 31 elderly patients with a median age 72 (60-85) were evaluated after 4(T4) and 6(T6) cycles of HMAs. A Median of 10 cycles were administered, equally distributed between azacitidine and decitabine. A higher frequency of CR (73.3%vs 20%) and MRD negativity (16.6% vs 0) was found at T6 compared to T4, thus T6 was chosen for the analysis. Performance status (PS > 2),Hgb < 10 g/dl, MRD positivity and a Log-reduction lower than 2 log predicted a significantly shorter DFS at univariate analysis. However, Log-reduction and PS only confirmed to predict a short DFS also at multivariate analysis, together with CRi (CR with incomplete recovery) and partial remission (PR). When the OS was investigated, only PS represented a strong indicator of prognosis at both univariate and multivariate analysis. Conclusions: Our results suggest that patients achieving 2 Log at least of blasts-reduction by FC had a longer DFS. Dynamic monitoring of blast –reduction stratified better and more widely than the absolute value of MRD in older AML patients. Having a high PS and achieving a CRi instead of a CR showed an unfavorable outcome in terms of both DFS and OS
Pharmacokinetics/pharmacodynamics of liposomal cytarabine (VYXEOS) in AML patients: Influence of cytidine deaminase genetic polymorphisms.
Authors: Donnette Mélanie , Venton Geoffroy , Farnault Laure , Pourroy Bertrand , Costello Regis , Lacarelle Bruno , Ouafik L'Houcine , Ciccolini Joseph , Fanciullino Raphaëlle
Published: May 2020

e19517

Background: Vyxeos is a liposomal formulation of daunorubicin and cytarabine recently approved for treating adults with newly-diagnosed sAML subtypes therapy-related (t-AML) or AML with myelodysplasia-related changes (AML-MRC). The objective of this pilot study was to evaluate the influence of cytidine deaminase, the enzyme responsible for cytarabine detoxification step in the liver, on drug exposition and clinical outcome. Methods: In this proof-of-concept study, 9 adult patients were treated with Vyxeos. CDA status (i.e., determination of Poor Metabolizer or Extensive Metabolizer phenotypes) was evaluated before treatment by measuring residual CDA activity in serum. Pharmacokinetic sampling was performed 90min before infusion stops, then from T4H to T168H after the end of the infusion. Total cytarabine, encapsulated cytarabine and released cytarabine were discriminated and assayed using a validated LC-MS/MS method. Results: Nine Vyxeos patients (3M, 6F, 66 ±13 years) were included in this pilot study. Aplasia duration was significantly longer in AML-MRC patients than in AML-t (38 ±5.5 days VS. 28 ±3 days, respectively (p < 0.05)). All AML-t had complete response after induction phase (VS. 60% in AML-MRC, p > 0.05). Similar cytarabine exposure was measured in both population. Surprisingly, 8 out of 9 patients (i.e., 88%) were identified as CDA PM (CDA < 2UI/mg). Marked differences in pharmacokinetics were observed between PM and EM patients. Total, encapsulated and released cytarabine AUC’s were 2.77, 1.42, and1.46 mg/ml*h in PM patients. In EM patient, total, encapsulated and released cytarabine AUC’s were 0.97, 0.76 and 0.17 mg/ml*h. When available, microscopy analysis confirmed the presence of liposomes in patients bone marrow. Conclusions: Differences in clinical outcome between AML-t and AML-MRC patient are not supported by differences in exposure levels upon Vyxeos administration. Surprisingly, we found that CDA status has a strong impact on cytarabine pharmacokinetics since PM patients treated with Vyxeos present a +185% increase in cytarabine levels as compared with EM patient. This suggests that upfront CDA testing could help to predict clinical outcome.
Allogeneic stem cell transplantation in elderly lymphoma patients: Single-center experience.
Authors: Gulbas Zafer
Published: May 2020

e19519

Background: Autologous stem cell transplantation is used as consolidation therapy in relapsed lymphoma patients. However, outcome of lymphoma patients relapsing after autologous stem cell transplantation is poor and allogeneic stem cell transplantation which can be curative is used in the transplant eligible patients in this setting. Besides, allogeneic stem cell transplantation can be an option before autologous stem cell transplantation in some high risk patients. In this study, we aimed to analyze the results of lymphoma patients older than 60 years of age who had undergone allogeneic transplantation in our center. Methods: We collected the data of lymphoma patients older than 60 years of age who had undergone allogeneic transplantation in our center and analyzed the results. Results: There were 20 patients over the age of 60 who had undergone allogeneic stem cell trasplantation with the diagnosis of lmphoma between 2011 and 2019. 18 patients had Non-Hodgkin lymphoma and 2 patients had Hodgkin lymphoma. 12 patients (60%) had been transplanted from HLA-matched sibling, while 6 patients (30%) had been transplanted from unrelted donors and 2 patients (10%) had been transplanted from haploidentical donors. The median age of the patients was 62 (61-66) and 30% of the patients were female. During the follow-up time only 1 patient had relapsed. The 2 year progression free survival (PFS) rate was 32% and the 2 year overall survival (OS) rate was 32%. The OS curve is shown in Figure 1. 100 day mortality was 30% and 1 year non-relapse mortalty (NRM) was 50%. The characteristics and results of the patients are summarized in Table 1. Conclusions: In the present study, although the number of patients is low, we showed that lymphoma patients over 60 years of age have a 2 year overall survival rate of 32% and a relapse rate of 5% suggesting that allogeneic stem cell transplantation which has a curative potential may be employed in transplant eligible elderly lymphoma patients.
A population-based study of chronic neutrophilic leukemia in the United States: 2004 to 2015.
Authors: Ruan Gordon , Smith Caleb , Day Courtney N. , Harmsen William S. , Zblewski Darci , Alkhateeb Hassan , Al-Kali Aref , Litzow Mark Robert , Hogan William J. , Szuber Natasha , Gangat Naseema , Patnaik Mrinal , Pardanani Animesh Dev , Elliott Michelle A. , Tefferi Ayalew , Go Ronald S. , Shah Mithun Vinod
Published: May 2020

e19538

Background: Chronic neutrophilic leukemia (CNL) is a rare and aggressive myeloproliferative neoplasm with poor survival. No standard of care exists. Case reports describe allogeneic stem cell transplantation (ASCT) as the only curative therapy. Using the National Cancer Database (NCDB), we studied prognostic factors and survival outcomes of CNL. Methods: Patients diagnosed in 2004-2015 were included. 9963/3 was the ICD-O-3 code. Overall survival (OS) was analyzed using the Kaplan-Meier method. Hazard ratios (HR) with confidence intervals (CI) were calculated using Cox proportional hazards model. Variables significant in univariate analysis were included in a multivariate analysis. Data on incidence was obtained from the Surveillance, Epidemiology, and End Results Program (SEER) 21 Registries (2004-2015). The analysis was done with SEER*Stat software. Incidence was age-adjusted to the U.S. 2000 standard population. Results: A total of 121 CNL patients were in NCDB. The median age at diagnosis was 70 years (range 21-90); 74 (61%) were males and 107 (88%) were ≥ 50 years. The median follow up time was 5.8 years (interquartile range [IQR] 2.9-7.4). 32 (26%) had a Charlson Deyo score (CDS) > 1. 80 (70%) had government insurance, while 34 (30%) had private insurance. Median OS was 2.2 years (IQR 0.8-6.7). OS was 70% at 1 year, 29% at 5 years, and 11% at 10 years. The year of diagnosis was not associated with improved OS (HR: 0.95 (95% CI: 0.88-1.02), p =0.14). 71 (59%) patients received chemotherapy. The median time to chemotherapy from the day of diagnosis was 15 days (IQR 7-35). The OS of those who received chemotherapy was 71% at 1 year and 27% at 5 years versus 69% and 32% at 1- and 5- years for those who did not ( p= 0.38). 2 patients received ASCT (age 52 and 61 years) as initial therapy and both were alive at 5 years. Factors predicting inferior OS on univariate analysis were age ≥ 50 years at diagnosis ( p= 0.005), male ( p< 0.001), CDS > 1 ( p= 0.038), and government insurance ( p= 0.004). The table shows the multivariate (MV) analysis. The overall incidence of CNL was 0.1 cases/1,000,000 individuals and did not change significantly from 2004-2015. The incidences by male, female, White, Black, and American Indian/Alaska Native were also 0.1 cases/1,000,000 individuals. Conclusions: OS and incidence of CNL have not changed over the years. Age ≥ 50 years, male gender, and use of government insurance predicted inferior OS. [Table: see text]
A comparison of CD34+ mobilization effects of standard dose pegfilgrastim (Peg) versus low-dose peg combined with plinabulin (Plin).
Authors: Blayney Douglas W. , Huang Lan , Mohanlal Ramon W.
Published: May 2020

e20000

Background: Plin is a novel, small molecule immune-enhancing agent with in vitro anticancer activity currently in Phase (Ph) 3 clinical trials for NSCLC treatment and Chemotherapy (Chemo)-Induced Neutropenia (CIN). Single agent (SA) Plin is equally effective as Peg for the prevention of CIN, however does not cause bone pain and is given on the same day of Chemo by 30 min IV infusion, 30 min after Chemo (Blayney ASH 2018). SA Plin also mobilizes CD34+ cells to clinically relevant levels (Blayney ASH 2019). Plin has been administered to > 600 patients (pts) and has a favorable safety/tolerability profile. In clinical practice, Peg dose is often reduced to 3 mg in patients (pts) experiencing side effects with standard dose (6 mg) Peg, such as bone pain, myalgia and leucocytosis (Kim ASCO 2010; Goodman Oncology Times 2008; Lacovelli JHOP 2012; Lower Cancer Chemother Pharmacol 2018). We evaluated CD34+ cell counts and adverse events (AE) with low dose Peg combined with Plin vs full dose Peg. Methods: In a subset of Breast Cancer pts in the CIN Ph 2 trial BPI-2358-106 (NCT0329457) receiving TAC (taxotere (75), doxorubicin (50 ) and cyclophosphamide (500) mg/m2, pts also received either Peg 6mg (n = 7) or low dose peg ( n = 9, of which 7pts received 3mg and 2 pts 1.5 mg Peg) combined with Plin (20 mg/m2). CD34+ counts were obtained by central laboratory FACS analysis (Covance) at screening (SC), Day (D) 6,8 and 21 cycle 1 (see table below) and AE frequency was collected. Results: Clinical trial information: NCT0329457 . Frequency of bone pain, myalgia and leukocytosis was numerically lower with low dose Peg/Plin vs 6mg Peg. Conclusions: Under highly myelosuppressive TAC Chemo conditions, CD34+ counts increased significantly (p < 0.03) vs predose SC in cycle 1 in the low dose Peg/Plin goup. CD34+ counts were not different for full dose Peg vs low dose Peg/Plin in cycle 1. Adverse Events were fewer with the low dose Peg/Plin. The Peg/Plin combination is worthy of test in hematopoietic stem cell mobilization regimens. [Table: see text]
Clonal lineage analysis of CLL research samples by IGH chain sequencing to reveal novel CLL subgroups defined by ongoing class-switch recombination and somatic hypermutation.
Authors: Looney Timothy , Quest Graeme , Feilotter Harriet , Davis Zadie
Published: May 2020

e20001

Background: B cell somatic hypermutation (SHM) and class switch recombination (CSR) are mechanistically related but distinct processes requiring precisely targeted generation and repair of single and double strand DNA breaks. Within the context of chronic lymphocytic leukemia (CLL), the presence of ongoing SHM or CSR may reveal the functionality of DNA damage repair pathways, with potential relevance to therapeutic strategies involving the generation of DNA breaks or inhibition of DNA repair machinery. Here we apply clonal lineage analysis of IGH chain sequencing data to evaluate CSR and SHM in a cohort of CLL and splenic marginal zone lymphoma (SMZL) research samples. We present evidence of ongoing CSR and SHM in a significant subset of samples. Methods: Multiplex primers targeting the IGH framework 1 region and isotype region (Oncomine IGH-LR assay; detection of all nine isotypes) were used for IGH repertoire sequencing via the Ion Gene Studio S5 from 25ng peripheral blood total RNA derived from 63 individuals with CLL and 4 individuals with SMZL. Clonotyping and clonal lineage analysis was performed by Ion Reporter, whereby clonal lineages are defined as sets of unique rearrangements having a shared variable and joining gene, the same CDR3 length, and a minimum CDR3 nucleotide similarity of 85%. Ongoing CSR was defined as the presence of IgM/IgD and at least one switched isotype (IgG, IgA, or IgE), or a combination of switched isotypes, within the same lineage. Ongoing SHM was defined as the presence of subclones that differ within the VDJ region sequence compared to other clonal lineage members. Results: 11/68 cases showed evidence of ongoing CSR or SHM. Of the 57 cases showing no evidence of ongoing CSR or SHM, variable gene mutation analysis revealed the presence of three distinct subgroups having either no SHM, intermediate SHM (average 98% sequence identity) or high SHM < 94% identity). 3 of 4 SMZL cases showed evidence of ongoing CSR or SHM. Conclusions: These results reveal previously underappreciated heterogeneity within CLL and suggest the subdivision of CLL based on a combination of IGHV mutation level and presence of ongoing SHM or CSR. The described heterogeneity may serve as a valuable criterion for stratifying CLL patients in the future.
Retrospective cohort study of real-world treatment patterns and overall survival in patients with chronic lymphocytic leukemia (CLL) diagnosed between 2010 to 2017 in Ontario, Canada.
Authors: Hassan Shazia , Hurry Manjusha , Seung Soo Jin , Walton Ryan , Elnoursi Ashlie , Scheider Krystin , Edwin Jonathan , Wagner Dennis , Aw Andrew Ta Wei
Published: May 2020

e20003

Background: With recent advances in treatment of CLL, it is important to understand emerging treatment patterns and associated outcomes. A population-based study was undertaken to describe the management and survival of CLL patients in Ontario, Canada. Methods: Patients diagnosed with CLL between January 1, 2010 and December 31, 2017 were identified in the Ontario Cancer Registry and linked to provincial administrative databases. Treatment patterns by line of therapy were characterized, including analyses of time to initiation and between therapies. Overall survival was calculated. Results: 2,887 CLL patients were identified (median age 68yr; 67% male). The mean time from diagnosis to first line (1L) treatment was 651 days with 35% of patients receiving fludarabine-cyclophosphamide-rituximab (FCR) based treatment. During the study period, 71% of patients did not yet receive second line (2L) therapy and did not have subsequent follow up, while 19% received 2L ibrutinib. Median time to 2L initiation from 1L treatment discontinuation was 636 days. The table summarizes 1L and 2L therapies. Of the 827 patients on 2L therapy, 65% received ibrutinib. After the introduction of publicly funded novel agents in 2015, a shift in treatment patterns away from FCR and chlorambucil based regimens was observed. Overall mean survival for the cohort from diagnosis was 6.8yrs, and mean 5 year probability of survival was 72.4%. Conclusions: A shift in treatment patterns for CLL can be seen with the introduction of newer therapies, such as ibrutinib. The results can support healthcare decision-makers by characterizing the size of this patient population, real world treatment patterns and survival outcomes for patients with CLL. [Table: see text]
Neutropenia analysis of venetoclax monotherapy in patients with relapsed or refractory chronic lymphocytic leukemia: Pooled data from VENICE-I and -II Phase IIIb trials.
Authors: Anderson Mary Ann , Davids Matthew Steven , Kater Arnon P. , Cochrane Tara , Demirkan Fatih , Herishanu Yair , Leber Brian , Nikitin Eugene , Masud Abdullah A. , Rosenberg Tanya S. , Sharmokh Simon , Fort Stan , Forconi Francesco
Published: May 2020

e20011

Background: Neutropenia is a common hematologic Grade (Gr) 3+ adverse event (AE) recorded in patients with chronic lymphocytic leukemia (CLL) receiving venetoclax (VEN). In this analysis, we evaluated fixed duration VEN monotherapy given to patients with relapsed or refractory (R/R) CLL with and without pre-existing Gr3+ neutropenia. Methods: This post-hoc analysis pooled data from patients in the ongoing Phase 3b trials VENICE-I and VENICE-II with R/R CLL who had received ≥1 dose of VEN monotherapy (ramp-up to 400 mg QD). Gr4 hematologic AEs and Gr3+ neutropenia ( < 1000 cells/mm3) with infection or fever were managed using dose interruption/reduction. Granulocyte colony stimulating factor (G-CSF) was used in Gr3+ neutropenia. Results: At data cutoff (June 30, 2019), 44/468 (9%) patients had Gr3+ neutropenia at baseline (BL; Gr3+ neutropenia group), 80% of whom received G-CSF during the study vs 38% of those with < Gr3 neutropenia at BL ( < Gr3 neutropenia group). Median on-study duration for VEN was 20.2 months (range: 0.1–36.1). Median number of prior CLL therapies was 2 for both groups (range: 1–10). Serious infections were experienced by 10/44 (23%) and 69/424 (16%) of patients in the Gr3+ and < Gr3 neutropenia groups, respectively. The most common AEs leading to discontinuation overall were second primary malignancies (13/468; 3%). 5/468 (1%) patients in the total population discontinued due to neutropenia/febrile neutropenia. One case of Gr5 infection with concomitant Gr3 neutropenia was reported in the < Gr3 neutropenia group post-VEN discontinuation. See Table. Conclusions: In this large post-hoc analysis, discontinuation due to neutropenia was rare (1%) in the overall population and accounted for 3/11 AE discontinuations in the Gr3+ neutropenia group; 10 patients had a serious infection. Patients with pre-existing neutropenia can be managed on VEN, though concurrent use of G-CSF is likely to be required. Additional data to follow. Clinical trial information: NCT02756611; NCT02980731 . [Table: see text]
Survival analysis of CLL/SLL patients with Richter’s transformation to DLBCL: An analysis of the SEER database.
Authors: Elnair Radowan , Ellithi Moataz , Kallam Avyakta , Bleeker Jonathan , Bociek Gregory
Published: May 2020

e20024

Background: Richter's transformation (RT) from Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) to a Diffuse Large B-Cell Lymphoma (DLBCL) is a rare complication with an estimated incidence of less than 5% and a poor prognosis based on small retrospective studies. Large studies investigating the natural history and patient outcomes with this entity of DLBCL are lacking, and prospective data on the best treatment option are scarce and limited by rarity of this condition. Methods: We queried the US Surveillance, Epidemiology, and End Results (SEER) 18 database for patients sequentially diagnosed with CLL/SLL followed by DLBCL from January 2000 to December 2016 with a cutoff latency of 2 months. Data obtained included patient demographics, history of treatment for CLL/SLL, overall survival (OS) after DLBCL diagnosis and latency period between CLL/SLL and DLBCL diagnoses. For comparison, SEER data was obtained for patients with de novo DLBCL and for CLL/SLL patients without RT in the same date range. Survival was estimated by Kaplan Meier method and log rank test was used to compare outcomes. Results: 471 patients who developed RT to DLBCL and 98425 patients with de novo DLBCL were identified. The median time for developing RT to DLBCL was 54 months. Median OS was worse for DLBCL arising from RT compared to de novo DLBCL (64 months versus 10 months, p < 0.0001). In patients with RT to DLBCL, no statistically significant difference in median OS was seen in patients who received treatment for CLL/SLL versus those assigned as No/Unknown treatment status (p = 0.51). In patients with CLL/SLL in the specified time period; median OS was significantly lower for those who developed RT to DLBCL compared to those who did not (91 months versus 100 months, p = 0.0012). Conclusions: DLBCL arising from RT in CLL/SLL patients is not necessarily a late complication. Prognosis is dismal with a trend towards a poor OS in the subset of patients with pretreated CLL/SLL. This large population study correlates with prior reports and highlights the need for prospective data to inform prognosis and treatment decisions.
Incidence patterns and survival outcomes in primary small intestine B-cell lymphoma (PSIBCL) and the effect of Rituximab.
Authors: Jayarangaiah Apoorva , Wang Shuai , Viteri Malone Mariuxi Alexandra , Elrafei Tarek N. , Steinberg Lewis , Kumar Abhishek
Published: May 2020

e20025

Background: PSIBCL is a rare manifestation of primary extra-nodal B-cell Non-Hodgkin’s lymphoma and is underreported in literature. We assessed the incidence patterns, and clinicopathologic features and their impact on survival in this population. Methods: Using the SEER database, we identified patients with PSIBCL who were ≥ 18 years old from 1975-2016. Patients were identified using ICD-O-3 and histology codes. Age-adjusted incidence rates were calculated using SEER*Stat 8.36. Using SPSS 26, overall survival (OS) was analyzed using the Kaplan-Meier method and multivariate Cox proportional hazards model was used to determine the prognostic factors. Results: We identified 4810 patients with PSIBCL. PSIBCL accounts for 0.8% of all B-cell Non-Hodgkin’s lymphoma. Age adjusted incidence rose from 0.2 to 0.4 per 100,000 during the study period. Annual percentage change of age adjusted incidence was +2.0 (95% CI 1.4-2.6). Incidence was highest among males, age > 80 years, white & Asian race. The median age of diagnosis was 63 yrs (51-75). 83% presented with either Diffuse large B-cell lymphoma (54%) or Follicular lymphoma (29%). The site of disease was specified in 65%; of those, duodenum (24%), jejunum (15%) and ileum (23%). Staging was reported in 88%; early stage disease (stage I/II) was found in 67%. Median OS for the entire cohort was 27 years (95% CI 23-32) and 5-year OS was 72.6%. Although the incidence was lower in black patients, the 10 year OS was worse (61% black vs 67.4% white). Survival was improved after 1997 (10-year OS rate 71.3% vs 52.0%). These results may correlate to Rituximab approval in 1997. In the multivariate analysis, age > 65, male sex, black race, late stage (stage III/IV), DLBCL and Burkitt lymphoma subtypes were associated with unfavorable OS. Conclusions: Analysis of four decades of data show an upward trend in incidence. PSIBCL has a favorable outcome with a clear survival advantage in patients diagnosed after 1997; this is likely attributable to Rituximab approval.
Toxicity and tolerability of DA-EPOCH-R for aggressive lymphomas in the elderly: A retrospective cohort study.
Authors: Banaag Shanley , Singla Manish , Kwok Mary , Chen Dechang
Published: May 2020

e20030

Background: There remain concerns regarding appropriate patient selection for dose-adjusted EPOCH-R in the treatment of lymphoma, particularly diffuse large B-cell lymphoma, where efficacy is comparable to R-CHOP but significantly more toxic. As the average age at diagnosis of DLBCL is between 60-70 years old, ability of elderly patients to complete and tolerate therapy is critical in treatment decision. Our aim was to investigate the differences in tolerability and toxicity of DA-EPOCH-R among different age groups. Methods: We conducted a retrospective review of patients treated with DA-EPOCH-R at Walter Reed National Military Medical Center. The institutional pharmacy database was queried to identify adult patients diagnosed with lymphoma and treated with DA-EPOCH-R from July 2005 through March 2018. Chart reviews were performed and information on dose reductions, delays, and adverse treatment effects were recorded and stratified between patients aged < 45 years, 45-59, 60-74 and ≥75 years. Results: 70 patients were identified for review. Average age was 55.8 +/- 15.5 years; 49% of patients were ≥ 60 years, including 9 patients who were ≥ 75 years. Diagnoses included diffuse large B-cell lymphoma (n = 46), transformed lymphoma (n = 12), primary mediastinal B-cell lymphoma (n = 4), Burkitt lymphoma (n = 3), T-cell lymphoma (n = 3), and high-grade B-cell lymphoma, NOS (n = 2). There was no significant difference in the median number of cycles completed between the age groups ( p= 0.2540). However, there was a significant difference in the maximum dose level achieved ( p= 0.0003). The median dose level achieved was 3.4 for patients age < 45 (range 1-5), 2.5 for patients age 45-59 (range 1-5), 1.88 for patients age 60-74 (range 1-4), and 0.88 for patients age ≥75 (range -2 to 2). Patients greater than 60 years were more likely to have any dose delay ( p= 0.001), more total dose delays (p = 0.004), and to experience gastrointestinal (GI) toxicities ( p= 0.014). There were no significant differences seen in peripheral neuropathies ( p= 0.425) nor hospitalizations ( p= 0.242). One patient passed away due to toxicity. Conclusions: This study demonstrates the use of DA-EPOCH-R in a real-world setting for the treatment of aggressive lymphomas. Our data suggest that elderly patients can complete all planned courses of DA-EPOCH-R but do not reach the dose intensity achieved by younger patients. In addition, elderly patients are more likely to require dose delays and experience GI toxicities without significant differences in hospitalizations or peripheral neuropathy.