bluuebunny/crossref_metadata_2025 huggingface dataset:
Real-world progression-free survival among patients with newly diagnosed advanced ovarian cancer: Does maintenance therapy work?
Authors: Liu Jinan , Chan John , Sah Janvi , Maiese Eric M. , Bee Oscar , Hurteau Jean , Thaker Premal H.
Published: June 2021

e18707

Background: Options for first-line (1L) maintenance therapy in ovarian cancer (OC) have evolved in the US in recent years, particularly with FDA approvals of poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors (PARPi). Olaparib was approved in 2018 for 1L maintenance treatment of patients (pts) with advanced OC with BRCA mutation and in 2020 as combination therapy with bevacizumab for 1L maintenance treatment of pts with homologous recombination deficient (HRd)–positive tumors. Additionally, the FDA approved niraparib in 2020 for maintenance treatment of pts with advanced OC regardless of tumor biomarker status. This study aimed to describe use and outcomes of 1L maintenance vs. active surveillance (AS) among PARPi-eligible pts with OC in a real-world setting prior to the most recent 2020 FDA approvals. Methods: This retrospective cohort study included pts with newly diagnosed stage III/IV OC who received 6–9 cycles of 1L platinum-based chemotherapy (PBC) and either primary debulking surgery or interval debulking surgery following neoadjuvant chemotherapy between January 1, 2016, and February 29, 2020, regardless of biomarker status, from the Flatiron Health database, a longitudinal electronic health record-derived database consisting of de-identified patient-level data that are curated via technology-enabled abstraction. The end of the last cycle of 1L PBC was defined as the index date. Pts who started second-line (2L) treatment within 2 months of the index date were excluded. Primary endpoint was time to initiation of 2L systemic therapy (as a surrogate for progression) or death. Inverse probability of treatment weighting and Cox proportional hazard model were used to adjust for baseline differences among pts on maintenance therapy and pts on AS. Results: A total of 463 pts were included in the study, 87.7% from community practices and 12.3% from academic institutions. Of the pts included, 21.0% received maintenance therapy, while 79.0% did not. Of those who received maintenance therapy, 48.5% received bevacizumab, 40.2% received PARPi (olaparib, rucaparib), and 11.3% received paclitaxel. Median progression-free survival (PFS) for pts who received 1L maintenance therapy was 16.1 months, compared with 12.2 months in pts who did not receive 1L maintenance therapy. After adjusting for baseline differences in characteristics and demographics, including age, race, stage of cancer, and BRCA status, pts on maintenance therapy had a statistically significant, 29% lower risk of progression or death than those receiving AS (hazard ratio: 0.71; 95% CI, 0.52–0.99; P= 0.04). Conclusions: In this real-world analysis, the majority of pts did not receive maintenance therapy; however, a PFS benefit was found in those receiving maintenance therapy. Further studies are needed to understand how biomarker status drives practice patterns.
Head-to-head comparison of first-line FOLFIRINOX versus gemcitabine plus nabpaclitaxel (GN) in advanced pancreatic cancer (APC): A target trial emulation using Canadian real-world data.
Authors: Boyne Devon J. , Brenner Darren , Gupta Alind , Mackay Eric , Arora Paul , Wasiak Radek , Cheung Winson Y. , Hernan Miguel
Published: June 2021

e18713

Background: When randomized trials are not available, observational real-world data can be used to emulate a (hypothetical) target trial. The procedure starts with the specification of the protocol of the target trial, whose components are then explicitly emulated using observational data. This approach prevents biases that are common when using more conventional methods for real-world data. Advanced pancreatic cancer represents an opportunity for trial emulation since two main frontline therapies, FOLFIRINOX and GN, have never been directly compared in a randomized fashion. The choice between the two regimens is largely based on physician discretion and patient preference rather than direct comparison of effectiveness. Methods: We emulated a target trial using linked data from the provincial cancer registry, electronic health records and various administrative databases from Alberta, Canada. Eligible individuals had locally advanced or metastatic pancreatic cancer diagnosed between Jan. 2015- Dec. 2018, no prior treatment, and adequate hematologic and serum creatinine values. They were followed from diagnosis until March 2020, death, or date of last known contact with the healthcare system. We estimated the effect of initiating FOLFIRINOX vs. GN within 8 weeks of diagnosis on overall survival. Cloning, artificial censoring, and inverse probability weighting were used to address unknown treatment assignment at baseline, non-adherence, and confounding. Adjusted Kaplan-Meier survival curves and hazard ratios were estimated. Results: Of 298 eligible individuals, 70 adhered to the FOLFIRINOX strategy and 147 to the GN strategy. The mean age was 65 years, 173 (58%) were male, and 247 (83%) had metastatic disease. The adjusted median survival, 1-year survival, and 2-year survival for FOLFIRNOX was 8.2 months (95% CI: 5.3 to 9.4), 36.9% (22.2 to 55.8), and 14.1% (4.8 to 32.2), respectively; and for GN was 4.8 months (3.3 to 5.3), 22.2% (13.6 to 35.9), and 4.7% (1.7 to 13.0), respectively. The adjusted difference in median survival was 3.4 months (0.6 to 11.1) and the adjusted hazard ratio was 0.79 (0.56 to 1.05). Conclusions: Target trial emulations can help to inform medical decision making in situations where head-to-head randomized trial data are unavailable or unfeasible. Findings from this real-world trial emulation suggest improved overall survival with FOLFIRINOX over GN.
Characterizing safety and efficacy in ovarian cancer patients with thromboembolism treated with rivaroxaban.
Authors: Kohn Christine G. , Caranfa Jonathan T. , Brewer Molly , Singh Meghana , Coleman Craig I. , Costa Olivia S.
Published: June 2021

e18720

Background: There is a paucity of real-world data regarding rates of recurrent venous thromboembolism (VTE), major bleeding and all-cause mortality among ovarian cancer patients with thrombosis treated with direct oral anticoagulants (DOACs) currently available. We sought to evaluate the effectiveness and safety of rivaroxaban versus low molecular-weight heparin (LMWH) for cancer-associated thrombosis (CAT) treatment in patients with ovarian cancer. Methods: We utilized US Surveillance, Epidemiology and End Results-Medicare–linked data from 2013-2016 to identify adults with active ovarian cancer, undergoing hospitalization/emergency department admission for CAT and prescribed rivaroxaban or LMWH for outpatient anticoagulation. Rivaroxaban and LMWH cohorts were balanced using propensity score overlap weighting . Outcomes included the composite of recurrent thrombosis or major bleeding, each outcome separately and mortality at six-months using an intention-to-treat approach. On-treatment analysis after 12-months was also performed. Hazard ratios (HRs) with 95% confidence intervals using overlap weighted cox regression were reported. Results: We included 33 rivaroxaban and 92 LMWH-managed CAT patients. In each cohort, mean age was 73, 79.5% of patients were white, 46.9% had a history of ≥ stage 3 chronic kidney disease (CKD), two-thirds had metastatic disease at the time of VTE, and 32.6% had a prior VTE. Patients were diagnosed with ovarian cancer an average of 1.40 years prior to the index VTE event and 45.8% had a pulmonary embolism (with or without DVT) as the index event. Our analysis did not detect a significant difference in outcomes with rivaroxaban versus LMWH at six-months (Table). On-treatment analysis at 12-months showed similar results. Conclusions: Rivaroxaban may be a reasonable alternative to LMWH for CAT patients with ovarian cancer. Large observational studies are needed to confirm these results.[Table: see text]
Analyzing inmuno-related adverse event: A real-world DATA study.
Authors: Cantos Blanca , Sanchez Juan Cristobal , Nuñez García Beatriz , Mendez Miriam , Gonzalez del Alba Aranzazu , Sanchez Antonio , Cubedo Ricardo , Hernandez Lopez Roberto , Calvo Virginia , Provencio Mariano
Published: June 2021

e18751

Background: In the last years, Immunotherapy (IT) has emerged as a standard treatment in an increasing number of tumors. This type of treatment has a specific toxicity profile which is clearly different from chemotherapy, known as an Immuno-related Adverse Event (AEir). We know the data from clinical trials, but little about the incidence and impact of this EAir in our clinical practice. Methods: A retrospective observational study was carried out including all patients from our institution (HUPHM in Madrid) who had received IT, either in monotherapy or in combination between January 2014 and December 2019. A total of 279 patients were included and data were collected between January and July 2020, guaranteeing a minimum 6-month follow-up after receiving the first dose of immunotherapy. The toxicities found were classified into four categories: pulmonary, digestive, endocrine and others, and have been graded according to CTCEA v.5 (Common Terminology Criteria for Adverse Event) published in November 2017 and analyzed according to drug and tumor. Results: The most frequent diagnoses in our patients were: 60% lung carcinoma, 15% melanoma, 8% kidney carcinoma, and 6% bladder carcinoma. 76% of the patients received IT as first or second line in a metastatic context, 6% in the initial stage (clinical trials) and the rest in more advanced lines of treatment (3 or more). 67% received anti-PD1 drug, 6% anti-PDL1, 4% anti-CTL4 monotherapy, 10% a combination of several IT drugs, and 14% an IT combination and chemotherapy. 45% of the total presented EAir (16% grade I, 14% grade II, 11% grade III and 4% grade IV). 1/5 of the patients had manifestations in more than one organ. The incidence of the different toxicities in our population was listed in the table below. These patients reported 8% dermatological toxicities, 6% had renal toxicity (most of them grade III or IV), only 2% had arthralgia or myalgia, and 3% asthenia. Combined IT treatment had significantly higher rates of pneumonitis, colitis, and endocrine toxicities. These differences were not observed between the monotherapy treatment and the combination of immunotherapy plus chemotherapy. Conclusions: Immunotherapy has represented an important advance in oncology, achieving long survivals in a growing group of tumors. Immunotherapy has a unique toxicity profile that is very different from chemotherapy and with which we must become familiar. Most of the adverse events are mild and if they are diagnosed early and with the appropriate treatment, maintenance of IT is possible. Severe toxicity (III-IV) means in most cases the suspension of treatment, compromising its efficacy. Therefore, we must learn to recognize these toxicities early and apply the recommended treatments as soon as possible.[Table: see text]
Lung cancer health services utilization and associated cost for the Colombian health system: A propensity score analysis of a national cohort of prevalent patients.
Authors: Buitrago Giancarlo , Amaya-Nieto Javier , Torres Gabriel Fernando
Published: June 2021

e18784

Background: There is need for high quality data about the economic burden of disease in low- and middle-income countries. We aimed to determine the annual incremental cost of health care services utilized by lung cancer patients in the Colombian health system. Methods: We conducted a national cohort study of prevalent patients with lung cancer in Jan-2017 and followed-up until Dec-2017. We used two electronic algorithms to identify all lung cancer prevalent patients in the Contributory regime, using national health claims databases ( Base de datos de suficiencia de la Unidad de Pago por Capitación and Base de Datos Única de Afiliados), based on identification of ICD-10 codes for 4 months or more during the previous 3 years (sensitive algorithm) and adding the presence of at least one oncological procedure (specific algorithm). We identified all health services cost from the health system perspective (2017 USD). We performed a propensity score analysis to estimate the annual incremental cost of care of patients with lung cancer compared to those without the disease. Standardized differences lower than 0.1 were used to measure the balance of baseline variables. We used generalized linear models as a sensitivity analysis. Results: We identified 4,827 and 3,238 lung cancer prevalent patient using the sensitive and specific algorithm, respectively. Each cohort was matched 1:1 with a no-exposed cohort of 14,968,202 individuals without a diagnosis of lung cancer using a caliper of 0.0001. Matched samples showed good balance on baseline characteristics. Annual incremental cost for patients diagnosed with lung cancer in Colombia ranged between USD $ 3,146.92 and USD $ 4,156.23. We also estimated incremental cost for outpatient and inpatient healthcare services as shown in table. Conclusions: In 2017, each patient with lung cancer represented an incremental cost to the Colombian health system between 49.35% and 65.19% of GDP per capita. This information is paramount to understand lung cancer spending in Colombia and for other low- and middle-income countries. [Table: see text]
Stage migration in breast cancer: Better detection or semantics in staging?
Authors: Elson Leah , Bilani Nadeem , Liang Hong , Elimimian Elizabeth Blessing , Saravia Diana , Nahleh Zeina A.
Published: June 2021

e18800

Background: As oncology treatment has evolved to become more individualized, prognostic rationale has also undergone important changes. In breast cancer, disease staging was historically based upon anatomic features of the primary tumor, in combination with involvement of adjacent/distant tissues. However, as the understanding of molecular/genomic involvement became more advanced, staging definitions were redefined to incorporate receptors, histologic grade, and genetic expression. In this analysis, we use autoregressive integrated moving average (ARIMA) forecasting to understand how AJCC updates to prognostic definitions have contributed to stage migration, and to comment on whether better detection, or definitional changes, may be responsible for the increasing incidence in early stage breast cancer. Methods: In this time series forecast, ARIMA models, per stage (early: stage I/II vs. late: stage III/IV) were constructed based on 2004-2016 historic breast cancer incidence rates, as reported by the NCDB. Multiple models were generated, using differing autoregressive parameters; the most predictive model was chosen using the lowest Bayesian Information Criteria (BIC), and mean absolute percentage error (MAPE) to ensure best fit. Similar methodology has already been published to predict prostate cancer incidence. The best fit models were applied to forecast annual incidence, in the NCDB, in 2017. These data were compared to the real-world data captured in 2017. Statistics were performed using modeling systems in SPSS, version 27. Results: n=1,661,971 cases were included for these models, and 12 years of pre-AJCC updated NCDB breast cancer data were used. Using ARIMA modeling, best fit, stationary averages were identified, with autoregressive and difference terms which contributed to the lowest BIC, and MAPE < 5%, for both models. The best fit models forecasted 2017 incidence, by stage, without AJCC updates to staging criteria, and this data is compared to actual 2017 incidence with current updated AJCC 8th staging criteria (Table). Conclusions: During 2017, the first year of AJCC staging updates, there was an observed decrease in late stage diagnoses, and increase in early stage diagnoses, when compared with incidence rates that were forecasted using the old, anatomic AJCC criteria. Therefore, part of the stage migration noted may be a product of staging semantics, using updated definitions. Confirming appropriate improvement in long-term outcomes, based on new staging would be helpful. It is also important for clinicians and public health officials to bear this in-mind when interpreting epidemiologic data, for allocating resources, as shifts in staging may be a product of guideline changes, and not necessarily screening efficacy or early detection only.[Table: see text]
Propping up the parents: An environmental scan of childcare programs available to cancer patients in North America.
Authors: Preston Katherine , MacDonald Mackenzie , Giuliani Meredith Elana , Melosky Barbara L. , Leung Bonnie , Ingledew Paris-Ann
Published: June 2021

e18805

Background: Approximately 20% of newly diagnosed cancer patients are between the ages of 20 and 54, and many of these patients are also the primary caregivers of children. Qualitative studies focusing on this demographic indicate that patients who are parents struggle to balance their own care needs with those of their children. Further, a lack of childcare support during cancer treatments can negatively impact compliance and increase existing psychological stress for patients. In the efforts to establish a child-minding program at a major Canadian cancer centre, we carried out an environmental scan to evaluate the current state of childcare support for cancer patients. Methods: Firstly, a literature scan was conducted in order to assess current knowledge about childcare and cancer patients, which included the use of search engines, directed internet searches, a review of oncology conference proceedings and websites of oncology associations. Literature was selected based on pre-determined criteria. Secondly, 12 representatives from major Canadian cancer centres (CCC) completed a questionnaire assessing current childcare strategies at their respective institutions. Finally, a broad scan of the grey literature was conducted by investigating 161 Canadian and American hospitals for on-site childcare services, using lay-accessible searching techniques (hand-searching hospital websites, phone and email correspondences). Results: The literature scan identified seventeen primary articles, which focused largely on exploring the role strain faced by patients who are also parents. A single study explored the instrumental challenges of being a parent with cancer, and formally assessed the childcare needs of these patients. The questionnaire results indicated that only two of the twelve investigated CCCs had established an approach to child-minding for patients. The grey literature scan identified twenty-six on-site, patient-accessible child-minding centres at hospitals in Canada and the US based on pre-determined inclusion criteria. Of these, 76.9% of centres were associated with pediatric hospitals, and 69.2% were located in the United States. Most centres (76.9%) were open for over 30 hours per week, and 88.5% of centres were free of charge to users. Conclusions: These findings generally indicate that a minority of Canadian and American hospitals and cancer centres have formal childcare services in place to support patients who are also parents. As cancer patients are at increased risk for financial toxicity, they may be particularly in need of this kind of instrumental support. This highlights the importance of carrying out a targeted needs assessment in order to fully elucidate the need for patient-accessible childcare services at CCCs.
Impact of COVID-19 on initial treatment of breast and colorectal cancers in one integrated healthcare system.
Authors: Sundaram Jayasree P. , Liang Su-Ying , Colocci Natalia , De Bruin Monique A.
Published: June 2021

e18806

Background: There has been a significant decline in office visits and cancer screening interventions such as mammograms and colonoscopies during the COVID-19 pandemic. The aim of this study is to analyze treatment patterns and to identify if there was also a delay in time to treatment for breast and colorectal cancers diagnosed during the pandemic. Methods: We utilized a dataset linking the institutional tumor registry and electronic health records from a large ambulatory group practice in Northern California. We analyzed data from 1,047 patients with newly diagnosed breast and colorectal cancers between 1/2019 and 8/2020 who received care at Sutter Health-Palo Alto Medical Foundation until 12/2020. We performed a T-test to examine whether patterns of treatment status (surgery vs chemotherapy vs neither) and time-to-treatment are different in pre-COVID vs pandemic eras. Results: The proportion of patients who did not receive surgery or chemotherapy during the pandemic was significantly higher, compared to the pre-COVID era (34.5% vs. 13.0%, p < 0.01). Among the breast and colorectal cancer patients who received care, the time to initial treatment did not significantly vary in the pre-COVID (median 34 days, mean 36.8 days) era as compared to during the pandemic (median 30 days, mean 32.2 days) (p = 0.15). There was no difference when accounting for surgery (p = 0.15) vs chemotherapy (p = 0.52) as the initial treatment modality. A statistically significant difference was seen amongst the 888 breast cancer cases identified during the study period, but the mean time to treatment during the pandemic (31 days) was actually shorter than the mean time to treatment identified prior to the pandemic (38 days). This difference in breast cancer time to treatment was mainly driven by a statistically shorter time to surgery (p = 0.04) in the pandemic era with no statistically significant difference in time to chemotherapy following a breast cancer diagnosis in the pandemic era as compared to the pre-COVID era (p = 0.99). Conclusions: There was a significant difference in the number of patients who did not receive surgery or chemotherapy during the pandemic for newly diagnosed breast and colorectal cancers. However, amongst those patients who did receive treatment, there were no significant delays observed in time to initial treatment, regardless of treatment modality.[Table: see text]
U.S. budget impactanalysis of body surface area (BSA)dosing for a rituximab biosimilar vsflat-fixed-dosing for subcutaneous rituximab in non-Hodgkin lymphoma (NHL)and chronic lymphocytic leukemia (CLL).
Authors: Thompson Stephen , Trautman Holly , McBride Ali , Choudhry Azhar , James Elizabeth
Published: June 2021

e18822

Background: The first rituximab biosimilar approved in the US, rituximab-abbs, is a CD20-directed monoclonal antibody that is expected to significantly reduce drug acquisition costs. This economic analysis evaluated budgetary impact of BSA-based rituximab-abbs (IV-R-BIOSIM) vs flat-fixed rituximab/hyaluronidase human subcutaneous injection (SC-R) dosing in NHL (diffuse large B-cell lymphoma [DLBCL], follicular lymphoma [FL]) and CLL. The objective was to project incremental cost differences per patient between IV-R-BIOSIM and SC-R from a US healthcare insured (Medicare) population. Methods: An illustrative BIM estimated 1-year costs for IV-R-BIOSIM and SC-R. The model assumed equal efficacy and safety between products. Values for epidemiology, market share distribution, drug dosing, administration, and costs were derived from scientific literature, product labels, and publicly available cost resources. Costs for the first infused rituximab (IV-R) dose were excluded for appropriate comparison. IV-R-BIOSIM doses used BSAs of 1.6 m2, 1.8 m2, infusion duration was 3 hours. Annual dose counts of IV-R-BIOSIM or SC-R were: 9 untreated FL with maintenance; 7 untreated FL (without maintenance), relapsed/refractory FL, or untreated DLBCL; 5 CLL. Drug acquisition and administration costs were from 2020 Average Sales Price pricing file and Centers for Medicare and Medicaid Services Physician Fee Schedule. Patient cost share was 2020 Medicare Part B 20% cost-share for office visits and drugs. A scenario analysis was also performed to estimate FL maintenance costs for 2-year dosing. Results: Estimated 1-year savings with IV-R-BIOSIM for 1.8 m2 BSA dosing were $1,067–$6,893 with variability between indications (Table). For 1.6 m2 BSA dosing, estimated 1-year savings with IV-R-BIOSIM were $3,819–$10,856. Estimated 2-year savings with IV-R-BIOSIM for FL maintenance dosing were $9,191 for 1.8 m2 BSA dosing and $14,475 for 1.6 m2 BSA dosing. Savings of up to $1,900 were seen for higher-than-average BSA dosing, regardless of regimen. Conclusions: These findings demonstrate the potential economic benefits of replacing a proportion of SC-R use with BSA-based IV-R-BIOSIM from a US payer perspective, especially when lower BSA dosing is used. Savings are driven by drug costs and may increase with IV-R-BIOSIM as patient BSA decreases due to static costs with SC-R doses. These data also suggest that drug wastage may occur with SC-R in lower BSA patients.[Table: see text]
Cost-effectiveness of subcutaneous pertuzumab, trastuzumab, and hyaluronidase-zzxf for the treatment of high-risk HER2+ early breast cancer.
Authors: Sussell Jesse , Roth Joshua A. , Hansen Svenn , Meyer Craig S. , Fung Anita M.
Published: June 2021

e18846

Background: Standard therapy for high-risk HER2+ early breast cancer (EBC) begins with neoadjuvant dual targeted therapy with pertuzumab (P) + trastuzumab (T) + chemotherapy (CTX). After surgery, patients who achieve pathological complete response (pCR) should complete one year of dual targeted therapy, while patients with residual disease should receive ado-trastuzumab emtansine (T-DM1). Recently, a subcutaneously administered formulation of P, T, and hyaluronidase-zzxf (Phesgo) was approved for use in the U.S. This study assesses the value of this new formulation in EBC patients vs. a strategy in which patients initiate standard therapy, but discontinue P following ascertainment of pCR. Methods: We developed a six-state Markov model to assess EBC costs and quality-adjusted life years (QALYs) from a healthcare sector perspective over a lifetime time horizon. Two strategies were modeled: 1) Neoadjuvant therapy with subcutaneous P, T, and hyaluronidase-zzxf + CTX with adjuvant continuation if pCR is achieved, and T-DM1 if not (“intervention”), and 2) neoadjuvant therapy with infused P, T + CTX with adjuvant infused T if pCR is achieved, and T-DM1 if not (“comparator”). Event-free and invasive-disease free survival were derived from the PEONY and KATHERINE/APHINITY trials, respectively. Utility values, drug prices, and procedure costs were derived from KATHERINE EQ-5D data, Wholesale Acquisition Costs, and claims analyses, respectively. We assessed comparator costs using both biosimilar and branded T pricing. The primary outcome was the incremental cost-effectiveness ratio (ICER). Outcomes were discounted at 3%/year and costs are presented in 2020 U.S. dollars. Uncertainty in outcomes was assessed through Monte Carlo simulation (1,000 replicates). Results: The table shows key results. The intervention resulted in a gain of 0.092 QALYs. With biosimilar T pricing in the comparator (base case), the intervention increased costs by $7,575 (ICER = $81,793). With branded T pricing in the comparator (scenario analysis), the intervention increased costs by $982 (ICER = $10,602). In probabilistic analyses, the intervention was favored in 52% and 81% of simulations at a willingness-to-pay of $100,000/QALY with biosimilar and branded T pricing, respectively. Conclusions: This study provides additional evidence to support adjuvant continuation of P+T among patients achieving pCR. Neoadjuvant P, T, and hyaluronidase-zzxf + CTX (with adjuvant continuation of dual targeted therapy) is expected to be cost-effective ( < $100,000/QALY) vs. neoadjuvant P and T + CTX (with adjuvant T continuation) for patients with high-risk HER2+ EBC irrespective of whether the comparator uses biosimilar or branded T.[Table: see text]
Cost-effectiveness of adjuvant chemotherapy for stage III colon cancer in the South African public healthcare setting.
Authors: Pumpalova Yoanna S , Rogers Alexandra M. , Tan Sarah Xinhui , Herbst Candice-Lee , Ruff Paul , Neugut Alfred I. , Hur Chin
Published: June 2021

e18849

Background: Colon cancer incidence and mortality rates are increasing in low- and middle-income countries, such as South Africa (SA). Adjuvant chemotherapy after curative resection for stage III colon cancer prolongs overall survival, but it is unclear which regimen is most cost-effective in resource-constrained settings, such as the SA public healthcare system. Methods: A decision-analytic Markov model was developed to compare lifetime costs and health outcomes for 60-year-old stage III colon cancer patients treated with six adjuvant chemotherapy regimens in a public hospital in SA: fluorouracil, leucovorin, and oxaliplatin (FOLFOX) for 3 and 6 months, capecitabine and oxaliplatin (CAPOX) for 3 and 6 months, capecitabine for 6 months, and fluorouracil/leucovorin (5-FU/LV; Mayo regimen) for 6 months. Transition probabilities were derived from clinical trials to estimate risks of toxicity, disease recurrence, and survival. Costs from a SA societal perspective and utility estimates were obtained from literature and local expert opinion. The primary outcome was the incremental cost-effectiveness ratio (ICER) in international dollars (I$) per disability-adjusted life year (DALY) averted, with a willingness-to-pay (WTP) threshold of one times the 2020 GDP per capita of SA (I$13,006.57; ZAR89,225). Results: Our model found CAPOX for 3 months to be the most cost-effective strategy, at a lifetime cost below the local WTP threshold (I$5,380.82; ZAR36,912.44) and 5.74 DALYs averted, compared to no chemotherapy. FOLFOX for 6 months was also on the efficiency frontier, with a higher total cost (I$22,747.47; ZAR156,047.64) and 0.18 additional DALYs averted (ICER = I$99,021.35/DALY averted). All other strategies were absolutely dominated. One-way sensitivity analyses found that FOLFOX for 6 months is optimal when the administration cost (i.e.: port and pump) falls to 20% of the base case price. Conclusions: In the SA public healthcare system, CAPOX for 3 months is the most cost-effective adjuvant treatment for stage III colon cancer. FOLFOX for 6 months, with a greater effectiveness, may be cost-effective if the administration cost decreases significantly. The optimal strategy in other settings may vary according to the local WTP threshold.[Table: see text]
MRD assessment using NGS in patients with acute myeloid leukemia undergoing hematopoietic stem cell transplantation: Meta-analysis.
Authors: Mosalem Osama , Abdelsamia Mahmoud , Abdelhakim Haitham
Published: June 2021

e19002

Background: The presence of measurable residual disease (MRD) preceding hematopoietic stem cell transplantation (HSCT) in acute myeloid leukemia (AML) is increasingly recognized as a risk factor for leukemic relapse and decreased survival. Over many years, attempts have been looking at developing tools to detect MRD; this includes multiparametric flow cytometry, quantitative polymerase chain reaction, and most recently, next-generation sequencing (NGS). NGS offers higher sensitivity and detection rate of disease-related gene mutations, thereby potentially improving disease outcomes. Our study sought to review the scientific literature that included NGS‐detected molecular MRD in patients with AML who underwent bone marrow transplantation. Methods: We performed a systematic search using PubMed, Google Scholar, EMBASE, and SCOPUS up until October 2020. Inclusion criteria included articles that reported the association between pre-HSCT MRD detected by NGS and post HSCT outcome in patients with AML. We extracted hazard ratios for the cumulative incidence of relapse (CIR), overall survival (OS) and leukemia free survival (LFS). A random-effect model was utilized to calculate the hazard ratio (HR) with a 95% confidence interval (CI). Results: Six studies met our inclusion criteria. Our meta-analysis showed that the detection of pre-transplant MRD by NGS was associated with increased risk of cumulative incidence of relapse (hazard ratio=2.5, CI= 1.6-3.9, with p-value <0.001) and decreased overall survival (hazard ratio=1.6, CI= 1.6-2.3, p-value 0.005). LFS was significantly higher in those who had negative MRD detection by NGS before transplantation (HR=1.9, CI= 1.3-2.8 with p-value 0.001). These results were independent of the cytogenetic risk of conditioning intensity. There was heterogeneity between our studies (I2 = 53%, 52%, and 59% for CIR, OS, and LFS, respectively). Conclusions: The application of NGS to detect MRD is a strong predictor of outcome in patients with AML who are undergoing hematopoietic stem cell transplantation. NGS-detected MRD positive status prior to HSCT is indicative of a higher risk of relapse and decreased overall survival in this meta-analysis. Despite the limitations in our study, it demonstrates the value of MRD detection by NGS in HSCT recipients.
Treatment outcomes of cohesin complex-mutant myelodysplastic syndrome and acute myeloid leukemia.
Authors: Sadagopan Narayanan , Simin Karl , Shi Qiming , Cerny Jan , Gerber Jonathan Michael , Patel Shyam Ajay
Published: June 2021

e19007

Background: Mutations in the genes STAG1, STAG2, SMC1A, SMC3, and RAD21 which are part of the cohesin complex are recurrent in myelodysplastic syndrome and acute myeloid leukemia. The cohesin complex is involved in sister chromatid attachment during cell division and in DNA loop formation bringing enhancers and genes together. Prognosis and treatment efficacy for this subgroup has not been well studied in MDS or AML. We evaluated the treatment outcomes of a subgroup with cohesin mutations from a database of MDS and AML patients at the University of Massachusetts. Methods: We performed a retrospective analysis of adult patients with a new diagnosis of AML and/or MDS from 2015-2019 in the University of Massachusetts Leukemia Registry. Fisher’s exact test was used to compare initial response to treatment via induction chemotherapy or hypomethylating agents. Kaplan-Meier curves for overall survival were compared using the log-rank test. We considered < 5% blasts by morphology to be complete remission (regardless of hematologic recovery). Four patients who did not undergo treatment were excluded from treatment and survival analysis. Results: A total of 19 patients had mutations in a cohesin complex gene with one patient having mutations in both STAG2 and SMC1A. The cohesin complex mutation frequency was 9.95% (19 out of 191 patients) with STAG2 representing 70% of the mutations. First-line induction chemotherapy resulted in an improved rate of complete remission 83.3% compared to hypomethylating agents 0% (p = 0.002). For AML patients alone, there was improvement in complete response rate for induction chemotherapy vs. hypomethylating agents (p = 0.048). There was no overall survival benefit for induction chemotherapy compared to hypomethylating agents (44.4% vs 41.7% probability of survival at 2 years) with p = 0.87. Excluding the MDS patients, there was still no difference in overall survival with p = 0.63. Conclusions: In this retrospective analysis of cohesin complex-mutant MDS and AML, induction chemotherapy resulted in significantly improved complete remission rates compared to hypomethylating agents. There was no overall survival benefit. We also found one patient with simultaneous mutations in two cohesin genes while cohesin mutations were previously reported to be mutually exclusive. Further work looking at additional samples may be able to show induction chemotherapy is the treatment of choice for cohesin mutant AML.[Table: see text]
Association of acute graft versus host disease clinical outcomes and the Ann Arbor Biomarker Risk Probability Using the Commercial Assay.
Authors: Mountjoy Luke , McNally Hannah , Buras Matthew , McCallen Margaret , Rogers Jaime , Sproat Lisa Ostrosky , Slack James L. , Palmer Jeanne , Leis Jose Francisco , Khera Nandita
Published: June 2021

e19023

Background: Acute GVHD (aGVHD) is a major cause of mortality and morbidity following stem cell transplantation (HCT). In effort to prognostic patients with aGVHD, the Mount Sinai Acute GVHD International Consortium (MAGIC) combined two biomarkers, ST2 and REG3α to generate an algorithm known as the Ann Arbor (AA) biomarker risk. This is now available as a commercial test to help predict risk for severe acute GVHD and non-relapse mortality when done at the onset of symptomatic aGVHD. Our institution began utilizing these lab values and here we report our “real world” experience. The primary aim was to correlate AA risk probabilities with recently defined endpoints including day 28 overall response rate (ORR) and 6 month freedom from treatment failure (6mFFTF) and overall survival (OS). Methods: 58 HCT patients who underwent HCT between October 2018 and November 2019 and had the biomarker assay at the onset of aGVHD were identified from the institutional database and clinical information about disease, transplant and outcomes was obtained from the medical records. Clinical staging of aGVHD was documented per standardized published guidelines. Day 28 ORR was defined as complete response by day 28. 6mFFTF was defined as a patient being alive, without relapse of underlying disease or addition of new systemic therapy for aGVHD, and prior to the development of cGVHD. Results: When comparing low (n = 39), intermediate (n = 11), and high (n = 8) AA risk, there was no difference in age ( p =0.254), primary disease ( p =0.10), DRI ( p =0.994), donor source ( p =0.193), conditioning regimen intent ( p =0.537), GVHD prophylaxis ( p =0.351) ATG use ( p =0.06). Low AA risk was associated with lower grades of aGVHD at onset (grade I = 15%, grade II = 80%, grade III = 5%, grade IV = 0%), whereas high AA risk was associated with higher grades of aGVHD at onset (grade I = 0%, grade II = 50%, grade III = 25%, grade IV = 25%) ( p =0.009). For low, intermediate, and high AA risk the day 28 ORR was 69%, 45% and 29% ( p = 0.083); the 6mFFTF was 82%, 82%, and 25% ( p = 0.0001); 6 month OS was 92%, 100%, and 50% ( p = 0.0006) respectively. Conclusions: Our study shows a high correlation between AA risk and outcomes. High risk AA risk was associated with inferior outcomes This study was limited by the retrospective single institutional experience with relatively small numbers. However, our findings using the commercial assay mirror that seen with the MAGIC studies. Our “real world data” can serve as a foundation and continued validation for institutional implementation of AA risk stratification for aGVHD.
Clinicopathological characteristics of CML in children and young adults.
Authors: Yaqub Sobia , Zafar Amjad , Latif M Ahmed , Ahmad Zain , Bano Kausar , Khokhar Muhammad Abbas
Published: June 2021

e19029

Background: CML, although a disease of middle age, is not uncommon in younger age groups in developing countries like Pakistan. Methods: In this single center, cross sectional study, all patients diagnosed with CML below 30 years of age were enrolled. After collection, data was analyzed using Spss version 23.Quantitative variable were presented as mean and percentages. Chi-square was used for correlation between variables with p<0.05 considered significant. Results: Total 101 patients, with age range 7-30 years (mean 21.99±6.3), including 18(17.8%) below 15 years, were enrolled. Fever was most common presenting symptoms seen in 61(60.4%) followed by fatigue, abdominal distension in 40(39.6%) and 33(32.7%).Mean presenting TLC was 158.9±136.95. Of these, 97(96.03%) patients were in chronic phase, 3(2.97%) had accelerated and 1(1%) in blast phase. As per SOKAL score, 27 (26.73%), 51(50.49%) and 23(22.77%) had low, intermediate and high risk disease respectively. Imatinib was started in 80.19% while Nilotinib in 19.80% as 1st line TKI. Among these, 88.1% achieved CHR by end of 3rd month. After 1st year, 60.8% achieved a molecular response (MR≥3). 1(1%) transformed from chronic to blast phase.2nd line TKI was started in 13.8% due to lack of response. Grade ¾ thrombocytopenia and grade ½ per-orbital edema were main toxicities seen in 10.7% and 9.6% respectively. Co-relation of increasing age with high TLC (p=0.039) and better response to TKI (p=0.014) was statistically significant. Conclusions: Distinct clinical behavior of CML in children and young adults necessitates further studies to ensure better disease management.[Table: see text]
Increased mortality among smokers with myelodysplastic syndrome (MDS).
Authors: Zavras Phaedon D. , Pophali Prateek , Shastri Aditi , Bachier-Rodriguez Lizamarie , Sica Alejandro R. , Goldfinger Mendel , Kornblum Noah , Braunschweig Ira , Verma Amit K. , Mantzaris Ioannis
Published: June 2021

e19036

Background: Recent studies have shown smoking to be an independent risk factor for MDS. We aimed to assess whether smoking is associated with worse outcomes among patients (pts) with MDS at Montefiore Medical Center, Bronx, NY. Methods: Pts with MDS and chronic myelomonocytic leukemia (CMML) diagnosed between June 16, 2000 and November 13, 2020 were analyzed. Those without available tissue diagnosis or smoking history data were excluded. Descriptive statistics compared ever-smokers to non-smokers. Cox PH regression was used to analyze the risk of transformation to acute myeloid leukemia (AML) and mortality in the 2 groups and multivariable analysis (MVA) adjusted for age, sex, de novo disease and R-IPSS. Results: A total of 147 pts were identified, 109 (74.1%) had a diagnosis of de novo MDS, 89 (60.5%) had history of active or former smoking and 58 (39.5%) were non-smokers. Smokers were predominantly males (66.3%) in contrast to non-smokers (37.9%) (p=0.001). Smokers were diagnosed more frequently with high or very high risk MDS, although the difference was not statistically significant (38.1% vs 28.6%, respectively; p=0.28). TP53 mutations were numerically more frequent among smokers (24.4%), compared to non-smokers (12.8%) (p=0.16). Median follow-up time for smokers and non-smokers was 19.4 and 31.4 months, respectively. In MVA, there was a trend for increased risk of AML transformation in smokers vs non-smokers (HR 2.03, 95% CI 0.99 – 4.15; p=0.052). Smokers with MDS were found to have significantly greater mortality compared to non-smokers (HR 2.08, 95% CI, 1.22 – 3.54; p=0.007). Conclusions: Smoking was associated with worse survival among MDS pts in our cohort. Although not significantly different, the prevalence of TP53 mutations was higher among smokers. Larger studies are warranted to confirm our findings.
Acquired hypolipoproteinemia and hemophagocytic lymphohistiocytosis: A previously unexplored association?
Authors: Reap Leo Edward , Ma Vincent T , Takiar Radhika , Forman Adam Matthew
Published: June 2021

e19041

Background: Hemophagocytic lymphohistiocytosis (HLH) is a rare disease that is the result of macrophage hyperactivation, leading to disordered cellular phagocytosis that is highly fatal if left untreated. The precise precipitating factor that leads to HLH is presently unknown. Secondary HLH is more common in adults and has numerous causes, including several autoimmune diseases, rheumatological disorders, cancers, and infections. These predisposing conditions are similar in that they are characterized by increased rates of cellular replication and often accompanied by significant oxidative stress. Lipoprotein changes in HLH have not been previously described. Methods: Between August 2018 and June 2020, three cases of secondary HLH were discovered to have profound hypolipoproteinemia with severely reduced total cholesterol, undetectable LDL-C, and extremely depressed HDL-C levels. As a result, a retrospective review of the University of Michigan HLH registry was performed, identifying cases of HLH where full lipid panels were performed as part of their diagnosis and/or treatment between 2012 and 2020. 18 total patients were identified with a confirmed diagnosis of HLH and who had a full lipid panel performed as a part of their diagnostic evaluation. Results: 100% of patients were found to have HDL-C less than 30 mg/dL, consistent with severe HDL-C deficiency, and 84% had HDL-C less than 20 mg/dL. Similarly, 74% of patients were found to have LDL-C < 100 mg/dL, 47% with LDL-C < 50 mg/dL, and 33% had undetectable LDL-C levels. Median total cholesterol was 124 mg/dL, median LDL-C was 35 mg/dL, and median HDL-C was 7 mg/dL. Notably, these reductions were not explained by the observed variability in hypertriglyceridemia, and marked hypertriglyceridemia > 500 mg/dL was not seen in 88% of patients, with a median triglyceride value of 279. Interestingly, one patient displayed an opposite phenotype with extreme hyperlipidemia, with total cholesterol of 727 mg/dL and LDL-C of 658 md/dL. Conclusions: Severe derangements in circulating lipoproteins appear to be a common finding within sHLH.These findings have not been previously described within the context of the disease. Herein, we provide a framework for hypothesizing why HLH may potentially occur in the setting of hypolipidemia. Furthermore, we provide an additional hypothesis that serves to justify why these changes may occur in an evolutionary context.
A systematic review of post-transplant lymphoproliferative disorder after lung transplant.
Authors: Haider Mobeen Zaka , Zamani Zarlakhta , Kiran Fnu , Mirza Hasan Mehmood , Taqi Muhammad , Shahid Hafsa , Kumar Deepak , Neupane Karun , Khalid Yousra , Mughal Mohsin Sheraz , Faisal Muhammad Salman , Mushtaq Muhammad Umair , Anwer Faiz
Published: June 2021

e19046

Background: Post-transplant lymphoproliferative disorder (PTLD) is a serious complication after solid organ transplantation. This study aims to explore the association of PTLD diagnosed after lung transplant with infectious agents and immunosuppression regimen, explore types of PTLD, and their outcome. Methods: Following the PRISMA guideline, we searched the literature on PubMed, Cochrane, Embase, and clinicaltrials.gov. 1741 articles were screened and included five studies. Results: We analyzed data from five studies, n=13,643 transplant recipients with n=287 (2.10%) developed PTLD. Four studies showed that 32/63 (51%) PTLD patients were male and 31 (49%) were female. Three studies reported 53/55 (96.4%) patients were EBV positive at PTLD diagnosis. Courtwright. et al, reported that 217/224 (97%) PTLD was associated with either EBV positive donor or recipient. Four studies showed that the monomorphic B cell type 48/63 (76%) was the most common histological type of PTLD diagnosed with DLBCL the most common subtype 31/48 (64.6%). Data from 3 studies showed that the onset of PTLD following lung transplant varies with a median duration of 18.3 months (45 days to 20.2 years). Three studies showed that 26/55 (47.3%) patients had early-onset (≤ 1 yr of Tx) and 29/55 (52.7%) patients had late-onset PTLD (> 1 yr of Tx). Management of PTLD included a reduction in immunosuppression including corticosteroids, CNI, purine synthesis inhibitors, Rituximab, and chemotherapeutic agents. Three studies showed a mortality rate of 30/45 (66.7%) and 13/30 (43.3%) deaths were PTLD related. Conclusions: Our review concludes that PTLD is a serious complication, only 2% of lung transplant recipients developed PTLD. EBV seropositivity is the most factor associated with PTLD diagnosis. Monomorphic PTLD was reported as the most common type in the adult population and no association between gender and PTLD was found. The analysis shows that there is a slightly lower incidence of early (≤ 1 yr of Tx) than late-onset (> 1 yr of Tx) PTLD. Table 1 PTLD after a Lung transplant in adults - a review. [Table: see text]