bluuebunny/crossref_metadata_2025 huggingface dataset:
Increase in time to initiating cancer therapy and association with worsened survival in curative settings: A U.S. analysis of common solid tumors.
Authors: Khorana Alok A. , Tullio Katherine , Elson Paul , Pennell Nathan A. , Kalady Matthew F. , Raymond Daniel , Klein Eric A. , Abraham Jame , Grobmyer Stephen R. , Monteleone Emily Elizabeth , Bolwell Brian James
Published: September 2018

6557

Background: Increase in time to treatment initiation (TTI) for new cancer diagnoses causes patient distress and may adversely affect outcomes. We investigated trends in TTI for common solid tumors treated with curative intent, determinants of delayed TTI and impact on overall survival. Methods: We utilized population-based, prospective data from the National Cancer Database for newly diagnosed US patients with early-stage breast, prostate, lung, colorectal, renal and pancreas cancers from 2004-13. TTI was defined as days between diagnosis of cancer and first treatment (surgery, systemic or radiation therapy). Negative binomial regression and Cox proportional hazard models were used for analysis. Results: The study population of 3,672,561 patients included breast (N = 1,368,024), prostate (N = 944,246), colorectal (N = 662,094), non-small cell lung (NSCLC)(N = 363,863), renal(N = 262,915) and pancreas (N = 71,419) cancers. Median TTI increased from 21 days in 2004 to 29 days in 2013 (P < 0.0001). Aside from year, determinants of delays included care at academic centers and change in treating facility. Increased TTI was associated with worsened overall survival (OS) for stages I and II breast, lung, renal, and pancreas cancers, and stage II colorectal cancers, with hazard ratios per week of delay ranging from1.005 (1.002-1.008) to 1.030 (1.025-1.035), adjusting for comorbidities and other variables. Prolonged TTI ( > 6 wks) was associated with substantially worsened OS e.g., 5-yr OS for stage I NSCLC was 56% (±0.2) for TTI ≤ 6wks v 43% (±0.2) for TTI > 6 wks and for stage I pancreas was 38% (±0.6) v 29% (±1) respectively (P < 0.0001 for both). Conclusions: TTI has lengthened significantly over recent years, associated with multiple factors. Increase in TTI is associated with substantial increase in mortality ranging from 0.5-3.2% per week of delay in curative settings such as early-stage breast, lung and pancreas cancers. Simplifying access and navigation of complex health systems is essential to diminish this apparently iatrogenic impact on outcomes.
PROMs and PREMs in Dutch integrated head and neck cancer care.
Authors: Hermens Rosella , van Overveld Lydia Francisca Jacoba , Takes Robert P. , Braspenning Jozé C.C. , Smeele Ludi E , Merkx Matthias A.W.
Published: September 2018

6570

Background: Providing patient-centred care is an essential component of high quality integrated care. A method to get insight in patients perspectives about the quality of health care they received, is measuring Patient Reported Outcome Measures (PROMs) and Patient Reported Experience Measures (PREMs). We aimed to determine the outcomes of, and differences between PROs and PREs over time and between treatment groups for patients with head and neck cancer (HNC). Methods: Patientswere recruited from nine hospitals participating in the DHNA. Validated questionnaires were distributed at baseline, 3, 6 and 12 months follow-up. Included PROMs were EuroQol 5 Dimension 3 Level (EQ-5D-3L), EORTC QLQ-C30 and -H&N35. Included PREMs, Consumer Quality index for Oncologic care (CQO) and Radiotherapeutic care (CQR), have similar domains with different questions. With descriptive analysis, ANOVA and mixed model analysis, differences over time and between treatment groups were analyzed. Results: Questionnaires were filled in by 426 patients. Pain decreased significantly at 6 and 12 months follow-up (14 and 21 points on a scale of 0-100) and dry mouth increased significantly at 3, 6 and 12 months follow-up compared to baseline (35, 27 and 20 points). Sticky Salvia, problems with social eating and sense problems increased at 3 and 6 months follow-up, but were similar to the baseline score at 12 months follow-up. Pain and sticky saliva differed between radiotherapy and chemoradiotherapy or surgery and radiotherapy respectively (p≤0.05). Regarding the CQO domain scores, all treatment groups differed significantly from each other (p≤0.05), especially for the domain Personal input. There was no difference regarding the CQR domain scores. Recognizing the emotional side of HNC and guidance after the treatment scored low in patients. Conclusions: This study gives clues to improve healthcare according the experiences of the patient and we can predict more carefully the outcomes of the patients with different treatment types. PROMs according to the ICHOM criteria and PREMs are promising for measuring and improving quality and personalization of HNC care. However, recognizing the emotional side of HNC and intensifying guidance after the treatment period needs improvement.
CEASE: A novel patient directed electronic smoking cessation platform for cancer patients.
Authors: Jones Jennifer M. , Liu Geoffrey , Selby Peter , Eng Lawson , Goldstein David Paul , Giuliani Meredith Elana
Published: September 2018

6584

Background: Continued smoking in cancer patients receiving treatment results in decreased efficacy, reduced survival, amd increased risk of recurrence. Despite ASCO and AACR policy statements, routine tobacco use screening and provision of smoking cessation treatment has not been widely implemented in the cancer setting. A paper-based tobacco use screening and clinician-dependent referral program for new ambulatory cancer patients was initiated at Princess Margaret Cancer Centre in 2013 resulting in moderate screen rates but low referral rates. In response, we developed and implemented a tailored patient directed electronic smoking cessation platform (CEASE) which included three elements:1) tobacco use assessment tool; 2) patient education on benefits of cessation; 3) a patient directed automatic referral system to smoking cessation programs. Methods: Interrupted time series design to examine the impact of CEASE on process of care (screening rates, referrals offered and accepted) and patient reported (quit attempts, smoking status, uptake of cessation programs) outcomes. Included 20 monthly intervals: 6 pre implementation (Apr-Sept 2015) (PRE), 8 gradual implementation across all tumour sites (Oct 2015-May 2016), and 6 postb implementation (Jun 2016-Nov 2016) (POST). A time series segmented linear regression was conducted to evaluate changes in process of care outcomes (excluding the implementation period). Pre-post self-report patient outcome data was also compared. Results: We assessed data from n = 3785 (PRE) and n = 4726 (POST) new patients. Screening rates increased from 44% using the paper-based approach to 65% with CEASE (p = 0.0019). Referrals offered to smokers who were willing to quit increased from 24% to 100% (p < 0.0001). Accepted referrals decreased from 45% to 26%; though the overall referral rate increased from 11% to 26% (p = 0.0001). The proportion of those using tobacco or attempting to quit did not differ at 3-months. However, engagement with the referral source increased from 4% to 62.5% (p < 0.001). Conclusions: CEASE was successfully implemented across all clinics and resulted in improvements in overall screening and referral rates and engagement with referral services.
Validity and reliability of four value frameworks for cancer drugs.
Authors: Bentley Tanya GK , Cohen Joshua T. , Elkin Elena B. , Huynh Julie , Mukherjea Arnab , Neville Thanh H. , Mei Matthew Genyeh , Copher Ronda , Knoth Russell L. , Popescu Ioana , Lee Jackie , Zambrano Jenelle , Broder Michael
Published: September 2018

6603

Background: Little is known about the validity and reliability of value assessment frameworks. Methods: Eight panelists used the ASCO, ESMO, ICER, and NCCN frameworks to conduct value assessments of 15 drugs for advanced lung and breast cancers and castration refractory prostate cancer. Panelists received instructions and published clinical data to complete the assessments, assigning each drug a numeric or letter score. We used Kendall’s W coefficient to measure convergent validity by cancer type among frameworks and intraclass correlation coefficients (ICC) to measure framework inter-rater reliability across cancers. Panelists were surveyed on their experiences. Results: Kendall’s W for breast, lung, and prostate cancer drugs were 0.560 ( p= 0.010), 0.562 ( p= 0.010), and 0.920 ( p< 0.001), respectively. Pairwise and subdomain W are shown in the table. ICC (95% CI) for ASCO, ESMO, ICER, and NCCN were 0.800 (0.660-0.913), 0.818 (0.686-0.921), 0.652 (0.466-0.834), and 0.153 (0.045-0.371), respectively. Panelists generally agreed the frameworks were logically organized and easy to use. Conclusions: Convergent validity among the frameworks was fair to excellent, increasing with clinical benefit subdomain concordance and simplicity of drug trial data. Inter-rater reliability, highest for ASCO and ESMO, improved with clarity of instructions and specificity of score definitions. Continued use, analyses, and refinements of the frameworks will bring us closer to using value-based treatment decisions to improve patient care and outcomes. [Table: see text]
Impact of intravenous cancer drug wastage on economic evaluations.
Authors: Truong Judy , Cheung Matthew C. , Mai Helen , Letargo Jessa , Chambers Alexandra , Sabharwal Mona , Trudeau Maureen E. , Chan Kelvin K.
Published: September 2018

6607

Background: Intravenous drugs administered through body-surface area (BSA) or weight-based dosing may cause wastage due to large and/or limited fixed vial sizes, and vial sharing restrictions. Drug wastage leads to incremental costs without incremental value to patients. Bach et al. (2016) estimated 10% of revenue ($1.8 billion) from cancer drugs would result from wastage in 2016. The pan-Canadian Oncology Drug Review (pCODR) committee provides recommendations on which drugs to publicly reimburse by reviewing clinical and economic evidence. There is considerable potential that drug wastage could impact the economic evaluations. We sought to determine the impact of modeling cancer drug wastage on the results of economic evaluations. Methods: Economic evaluations submitted by drug manufacturers and reviewed by the pCODR Economic Guidance Panel (EGP) were assessed for frequency of wastage reporting and modeling. Cost-effectiveness analyses and budget impact analyses were conducted for scenarios in which “no wastage” and “wastage” of drugs occurred. Sensitivity analyses were performed to determine the effects of BSA and weight variation. Results: 12 drugs for use in 17 indications were analyzed. Wastage was reported in 71% and incorporated in 53% of manufacturer’s models, resulting in a mean incremental cost-effectiveness ratio (ICER) increase of 6.1% (range: 1.3% to 14.6%). EGP reported and incorporated wastage for 59% of models, resulting in a mean ICER increase of 15.0% (2.6% to 48.2%). When maximum wastage (i.e. the entire unused portion of each vial is discarded) was incorporated in our independent analysis, the mean ICER increased by 24.0% (0.0% to 97.2%) and the mean 3-year total incremental costs increased by 26.0% (0.0% to 83.1%). Over a 3-year period, wastage can increase the total incremental drug budget cost by CAD $102 million nationally. Changing the mean BSA or body weight caused 45% of the drugs to use a different vial size (if available) and/or quantity, resulting in further increased drug costs. Conclusions: Wastage can have an under-recognized and significant impact on economic evaluations of intravenous chemotherapy drugs. Guidelines are needed to promote uniform and optimal modeling of drug wastage in economic evaluations.
Cost-effectiveness of ovarian cancer screening: An analysis of the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) from a U.S. health system perspective.
Authors: Moss Haley , Myers Evan , Berchuck Andrew , Havrilesky Laura Jean
Published: September 2018

6608

Background: UKCTOCS is the largest randomized controlled trial to evaluate screening’s impact on ovarian cancer mortality, assigning women to multimodal screening (MMS) with serum CA125 interpreted with a risk algorithm; annual transvaginal ultrasound; or no screening (NS). There was a non-statistically significant 15% reduction in mortality over 11 years in MMS group. As most of the potential benefit of screening was seen after 7 years, follow-up is ongoing to determine if an observed stage shift translates into significant mortality reduction. The current study estimates the cost-effectiveness of an MMS screening program in the US. Methods: A modified Markov model was constructed using data from UKCTOCS to compare MMS to NS. Published estimates of the long term effect of MMS screening on ovarian cancer mortality were used to simulate mortality over 40 years from the start of screening. Base case costs included CA125, ultrasounds, clinical evaluations and false-positive surgeries, with an annual weighted cost of $35 in addition to an estimated risk algorithm cost of $100. The utility and costs of ovarian cancer treatment were incorporated into the model. Incremental cost-effectiveness ratios (ICERs) were calculated in 2016 U.S. dollars per quality-adjusted year of life saved (QALY). Additional sensitivity analyses were performed. Results: MMS is both more expensive and more effective in reducing ovarian cancer mortality over a lifetime than NS. Screening women from age 50 to 75 with MMS reduced mortality by 24% with an ICER of $98,062/QALY. If screening begins at age 60, MMS reduces mortality by 12%, with ICER below the willingness to pay threshold of $100,000/QALY only if the algorithm costs < $50. In probabilistic sensitivity analyses, the probability that screening from age 50-75 at an algorithm cost of $100 was less than $100,000/QALY was 41%. Conclusions: Ovarian cancer screening is potentially cost-effective in the US depending on final significance of mortality reduction and cost of the CA-125 risk algorithm. These results are limited by uncertainty around the effect of screening on ovarian cancer mortality beyond the 11 years of UKCTOCS.
Cost-effectiveness analysis of first-line treatments for early-stage, low-grade follicular lymphoma.
Authors: Yang Joanna C. , Elkin Elena B. , Parikh Rahul , Yahalom Joachim
Published: September 2018

6619

Background: Low-grade follicular lymphoma (FL) can present as localized stage I to II disease in up to one-third of patients. Upfront involved-site radiation therapy (RT) to 24-30Gy is the preferred first-line management strategy for these patients. However, the National LymphoCare Study found that less than one quarter of patients with early-stage, low-grade FL received upfront RT, while more than half received either chemoimmunotherapy or observation. Methods: We performed a cost-effectiveness analysis using a Markov state-transition model to simulate the progression of early-stage, low-grade FL in a cohort of 60-year-old men. The following first-line treatments were compared: RT, observation, rituximab induction (RI), rituximab and bendamustine (BR), and rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP). Patients who relapsed received second-line therapies that were dependent on their first-line treatment: RT for RI and observation, RCHOP for RT and BR, and BR for RCHOP. Disease-progression probabilities and other model inputs were from published trials. Results: First-line RT followed by RCHOP for relapses had a quality-adjusted life expectancy (QALE) of 11.4 years, superior to first-line observation, RI, BR, and RCHOP strategies. First-line RT strongly dominated observation, BR, and RCHOP. Compared with RI, first-line RT resulted in an incremental cost-effectiveness ratio of $2,740 per quality-adjusted life year. The probability of dying from other causes, the probability of a complete response to RT, and the probability of relapse had the greatest impact on both cost and effectiveness expected values. Conclusions: In contrast to current practice patterns, first-line RT is the most effective upfront treatment for patients with early-stage, low-grade FL. Further, first-line RT paired with RCHOP for relapses is a cost-effective treatment paradigm, relative to other strategies. [Table: see text]
Algorithmic matching of genomic profiles to precision cancer medicine clinical trials at DFCI.
Authors: Lindsay James , Del Vecchio Fitz Catherine , Zwiesler Zachary , Kumari Priti , Do Khanh Tu , Shapiro Geoffrey , Cerami Ethan
Published: September 2018

6620

Background: Genomic profiling and access to precision medicine clinical trials are now standard at leading cancer institutes and many community practices. Interpreting patient-specific genomic information and tracking the complex criteria for precision medicine trials requires specialized computational tools, especially for multi-institutional basket studies such as NCI-MATCH and TAPUR. Methods: To address this challenge we have developed an open source computational platform for patient-specific clinical trial matching at Dana-Farber Cancer Institute (DFCI) called MatchMiner, which aides in both patient recruitment to precision medicine trials, as well as decision support for oncologists. Trial matches are computed based on genomic criteria, including mutations, CNAs, and SVs, as well as clinical and demographic information, including cancer type, age, and gender. A formal standard called clinical trial markup language (CTML) to encode complex clinical trial eligibility criteria has also been created. Results: MatchMiner is now available at DFCI. Currently 123 precision medicine clinical trials have been transformed into CTML and 13,000 patient records are available, with over 88% of current patients having at least 1 match (average 2.6). A total of 103 genes are specified as criteria for at least 1 trial. KRAS, TP53, PTEN, PIK3CA and BRAF are the genes driving the most number of matches. General usage statistics and trial enrollment rates are currently being monitored to determine the system effectiveness. As this is an open source initiative, the software is also now publically available at https://github.com/dfci/matchminer. Conclusions: We have developed an open source computational platform that enables patient-specific matching and recruitment to precision medicine clinical trials at DFCI. We are actively seeking collaborators and plan to make CTML a multi-institution standard for encoding complex clinical trial eligibility in a computable form.
Enasidenib in mutant-IDH2 relapsed or refractory acute myeloid leukemia (R/R AML): Results of a phase I dose-escalation and expansion study.
Authors: Stein Eytan M. , Dinardo Courtney Denton , Pollyea Daniel Aaron , Fathi Amir Tahmasb , Roboz Gail J. , Altman Jessica K. , Stone Richard M. , Flinn Ian , Kantarjian Hagop M. , Collins Robert , Patel Manish R. , Stein Anthony Selwyn , Sekeres Mikkael A. , Swords Ronan T. , Medeiros Bruno C. , Knight Robert D. , Agresta Samuel V. , de Botton Stéphane , Tallman Martin S.
Published: September 2018

7004

Background: Recurrent mutations in isocitrate dehydrogenase 2 (m IDH2) occur in 8-15% of AML pts. mIDH2 proteins synthesize an oncometabolite, 2-hydroxyglutarate (2HG), causing DNA and histone hypermethylation and blocked myeloid differentiation. Enasidenib (AG-221) is an oral, selective, small-molecule inhibitor of mIDH2 protein. Methods: This phase 1/2 study assessed the maximum tolerated dose (MTD), pharmacokinetic and pharmacodynamic profiles, safety, and clinical activity of enasidenib in pts with m IDH2 myeloid malignancies. Safety for all pts and efficacy outcomes for R/R AML pts from the phase 1 dose-escalation and expansion phases are reported. Results: In all, 239 pts received enasidenib. In the dose-escalation (n=113), the MTD was not reached at doses up to 650 mg daily. Median 2HG reductions from baseline were 92%, 90%, and 93% for pts receiving <100 mg, 100 mg, and >100 mg daily, respectively. Enasidenib 100 mg QD was chosen for the expansion phase (n=126) based on PK/PD profiles and demonstrated efficacy. Median number of enasidenib cycles was 5 (range 1–25). Grade 3-4 drug-related investigator reported AEs included indirect hyperbilirubinemia (12%) and IDH-inhibitor-associated differentiation syndrome (ie, retinoic acid syndrome; 7%). For R/R AML pts, overall response rate (ORR) was 40.3%, including 34 (19.3%) complete remissions (CR; Table). Response was associated with cellular differentiation, typically with no evidence of aplasia. Median overall survival (OS) for R/R AML pts was 9.3 months (mos). For pts who attained CR, OS was 19.7 mos. Pts who had received ≥2 prior AML regimens (n=94; 53%) had median OS of 8.0 mos. Conclusions: Enasidenib was well tolerated, induced CRs, and was associated with OS of >9 mos in pts who had failed prior AML therapies. Differentiation of myeloblasts, not cytotoxicity, appears to drive the clinical efficacy of enasidenib. Clinical trial information: NCT01915498. [Table: see text]
Updated results of a phase I/II study of inotuzumab ozogamicin in combination with low-intensity chemotherapy (mini-hyper-CVD) as frontline therapy for older patients with acute lymphoblastic leukemia.
Authors: Short Nicholas James , Kantarjian Hagop M. , O'Brien Susan Mary , Ravandi Farhad , Thomas Deborah A. , Garcia-Manero Guillermo , Daver Naval Guastad , Borthakur Gautam , Jain Nitin , Konopleva Marina , Sasaki Koji , Pemmaraju Naveen , Alvarado Yesid , Jacob Jovitta , Garris Rebecca , Thompson Philip A. , Cortes Jorge E. , Jabbour Elias
Published: September 2018

7014

Background: Inotuzumab ozogamicin (InO) is an anti-CD22 antibody-toxin conjugate that is effective in patients (pts) with relapsed/refractory ALL. Given the poor tolerance of elderly pts to intensive chemotherapy, we evaluated the safety and efficacy of low-intensity chemotherapy (mini-hyper-CVD) plus InO as frontline treatment for older pts with newly diagnosed ALL. Methods: Pts ≥60 years of age with newly diagnosed Ph-negative pre-B ALL received mini-hyper-CVD (no anthracycline, dose reductions of cyclophosphamide, dexamethasone, MTX and Ara-C). Pts received InO 1.3-1.8 mg/m2 on day 3 of cycle 1 and 0.8-1.3 mg/m2 on day 3 of cycles 2-4. Rituximab (if CD20+) and prophylactic IT chemotherapy were given for the first 4 cycles. Responding pts received POMP maintenance for up to 3 years. Results: 47 pts have been treated, 4 of whom were in CR at enrollment. Median age was 68 years (range, 60-81) and median CD22 expression was 97% (range, 72-100%). Among 43 pts evaluable for response, 41 (95%) achieved CR or CRp (CR, n = 36, CRp, n = 5). 1 pt achieved CRi and 1 did not respond. MRD negativity by 6-color flow cytometry was achieved in 31/41 pts (76%) after 1 cycle and in 44/46 pts (96%) overall. Median times to platelet and ANC recovery in cycle 1 were 23 and 16 days, respectively, and for subsequent cycles were 22 and 17 days, respectively. Prolonged thrombocytopenia ( > 6 weeks) occurred in 37 pts (79%). 4 pts (9%) developed VOD, 1 after allogeneic stem cell transplant (ASCT) and 3 unrelated to ASCT. Only 1 pt developed severe VOD. Among 46 responders, 6 (13%) relapsed, 3 (7%) underwent ASCT in CR1, 27 (59%) remain on treatment or have completed maintenance, and 10 (22%) died in CR/CRp. With a median follow-up of 24 months, the 3-year continued remission and OS rates were 72% and 54%, respectively. Compared to a historical cohort of older pts treated with hyper-CVAD ± rituximab (n = 79), mini-hyper-CVD + InO resulted in significantly higher 3-year OS (54% vs 31%; P = 0.007). Conclusions: Mini-hyper-CVD plus InO is safe and effective in elderly pts with newly diagnosed ALL and appears to improve outcomes compared to hyper-CVAD in this population. Clinical trial information: NCT01371630.
Creating a synthetic control arm from previous clinical trials: Application to establishing early end points as indicators of overall survival in acute myeloid leukemia (AML).
Authors: Berry Donald A. , Elashoff Michael , Blotner Steven , Davi Ruthie , Beineke Philip , Chandler Mark , Lee David S. , Chen Lin Chi , Sarkar Somnath
Published: September 2018

7021

Background: Clinical trials of experimental drugs require controls. Concurrently randomized controls are the gold standard for judging drug effect. Historical controls are not ideal but are much more efficient and economical. Historical controls derived from a single clinical trial have the biases of that trial. Using many trials with comparable end points and eligibility minimizes such bias. Medidata’s archive contains >3000 trials with clinical data rights for deidentified aggregated analyses. We used this resource to develop a synthetic control arm (SCA) for a particular phase I/II single-arm trial in AML. We demonstrate the utility of this approach by addressing a different but equally important issue: establishing early end points as predictors of long term clinical outcomes. Methods: We built an SCA from 7 relapsed/refractory AML trials completed in last 5 yrs. They had similar eligibility criteria as a particular phase I/II trial for an investigational agent. We selected subjects for the SCA who had baseline covariates matching the subjects in the tri.al. Data cleaning and standardization ensured consistency of data fields. The primary outcomes were CR (complete remission) and CRi (CR without hematologic recovery) at 56 days, and overall survival (OS) subsequent to 56 days. Non-CR/non-CRi deaths before 56 days were set to OS=0. We used a landmark analysis to correlate CR and CRi with OS, calculating the hazard ratio (HR) of OS of CR and CRi vs its comparison group. Results: The SCA included 340 subjects (median age 63 yrs, 55% male, 77% White Non-Hispanic, 28% ECOG 0). Results are in this table. Conclusions: The Medidata trial archive is a resource for creating SCAs. The example SCA we created identified well-defined subjects for whom a CR or CRi is associated with longer OS. Investigations of SCAs for other drugs could aid in addressing the types of subjects and drug categories for which CR or CR/CRi predict longer OS. Such information can help build more efficient and more informative adaptive clinical trials. [Table: see text]
Efficacy of anti-CD19 chimeric antigen receptor modified T(CAR-T) cell therapy in Chinese patients with relapsed/refractory acute lymphocytic leukemia in a multicenter trial.
Authors: Xiao Lei , Huang He , Huang Xiaojun , Ke Xiaoyan , Hu Yu , Li Junmin , Zhang Qing , Hu Yongxian , Jiang Qian , Hu Jiong , Jing Hongmei , Zhang Xiaohong , Wu Zhao
Published: September 2018

7028

Background: r/r B-ALL was reported as the most-threatening disease because of the low disease free survival even treatment with allogeneic hematopoietic stem cell transplantation. For overcoming conventional therapies limitation, autologous CD19CAR-T was performed in our clinical trials to induce remission in patients with r/r disease. 30 patients (from 7 clinical centers, in China) as volunteers with r/r B-ALL were treated by autologous CD19 CAR-T. Methods: 5 juveniles and 25 adults with r/r ALL received autologous CD19 targeted CAR-T, the doses between 1.03 × 106 CAR-T cells/kg and 10.09 × 106CAR-T cells/kg. These 30 cases(from 7 clinical centers, in China) were treated with CAR-T cells from May. 8 2015 to January. 4 2017 (Table1). Patients were monitored for a response. Highly standardized CAR T cell preparation protocol and manageable CRS in most were kept for no significant difference in 7 clinical centers. Results: After treated with CAR-T, a total of 30 cases (5 juveniles and 25 adults coming from 7 clinical centers, in China) with r/r B-ALL were all detected the CAR-T cells proliferated in the blood and bone marrow. The results showed that complete remission (CR) is 26/30(86.67% ) between day7-14 after CD19 CART cell infusion, and 25/30(83.33%) cases arrived at MRD negative. There is about 1/3 of the total cases receiving a repeat infusions following initial ones since these patients have no safety concerns. Additionaly, the severe Cytokine release syndrome (CRS) was 8/30(26.67%) of cases and 24/30(80%) of cases was seen CRS. The anti-IL6R agent tocilizumab and Methylprednisolone were effective confrontation Severe CRS. Conclusions: This is the first multicentre report to our knowledge of successful treatment of r/r ALL with anti-CD19 CAR T cells in China. Even r/r B-ALL with high-burden leukemia patients also was effective and associated with a high remission rate after infused autologous CD19 CAR-T).(NCT 02813837).
Correlation between mutation clearance and clinical response in elderly patients with acute myeloid leukemia (AML) treated with azacitidine and pracinostat.
Authors: Takahashi Koichi , Abaza Yasmin , Atallah Ehab L. , Medeiros Bruno C. , Khal Sam , Arellano Martha Lucia , Patnaik Mrinal , Ghalie Richard , Garcia-Manero Guillermo
Published: September 2018

7034

Background: In a phase II study in 50 elderly patients (pts) with AML who were not eligible for intensive chemotherapy, treatment with pracinostat + azacitidine (AZA) was well tolerated, led to 42% complete remission (CR) rate and a median overall survival (OS) of 19.1 months (Blood 2016: 128;100). Here we investigate the impact of somatic mutations and their clearance on disease response and patient outcomes. Methods: 88 samples from 41 study pts were sequenced. All 41 pts were analyzed pre-treatment, and a median of 3 longitudinal samples were analyzed from 19 pts between Cycle 2 and 9. Mutations were assayed by SureSelect targeted capture exon sequencing (Agilent) of 295 genes that are recurrently mutated in hematologic malignancies. Longitudinal mutation clearance was analyzed by plotting variant allele frequency (VAF). Results: At baseline, 96 mutations in 28 genes were detected in 38 pts, with the most frequent being in SRSF2 (27%), DNMT3A (20%), IDH2 (17%), RUNX1 (17%), and TET2(17%). Mutations associated with CR rate and OS are indicated in the Table. A CR was achieved in 10/19 pts that had longitudinal sequencing analysis and at the time of CR, 9 (90%) had persistently detectable mutations in their bone marrow. In 7 of them, continued exposure to pracinostat + AZA lowered the VAF or cleared residual mutations. In 2 pts, relapsed samples showed re-expansion of the founder clone. Conclusions: Mutations in NPM1, and DNA methylation pathway were associated with a better response to pracinostat + AZA, while TP53 mutation was associated with a poor response. Persistent mutation at the time of CR suggests residual preleukemic clonal hematopoiesis in this elderly population. Benefit of prolonged exposure to pracinostat + AZA was also confirmed at molecular level where continued decline of mutation VAF was seen after achieving CR. Clinical trial information: NCT01912274. [Table: see text]
Efficacy by consolidation administration site: Subgroup analysis of a phase III study of CPX-351 versus 7+3 in older adults with newly diagnosed, high-risk acute myeloid leukemia (AML).
Authors: Kolitz Jonathan E. , Strickland Stephen Anthony , Cortes Jorge E. , Hogge Donna , Lancet Jeffrey E. , Goldberg Stuart L. , Chung Karen C , Ryan Robert , Chiarella Michael , Louie Arthur Chin , Stuart Robert K. , Medeiros Bruno C.
Published: September 2018

7036

Background: The CPX-351 liposomal formulation delivers a synergistic 5:1 molar ratio of cytarabine (C) and daunorubicin (D) preferentially to leukemia cells. CPX-351 has demonstrated significantly improved overall survival (OS) versus 7+3 in a randomized, open-label, phase III study in patients (pts) aged 60-75 years with newly diagnosed, high-risk AML. In contrast to 7+3, which includes C continuous infusion, CPX-351 is administered as a 90-minute infusion and has the potential to be given in the outpatient setting. The current analysis of the phase III trial assessed the setting of consolidation therapy. Methods: Pts were randomized 1:1 to 1-2 induction cycles of CPX-351 or 7+3; pts with complete remission (CR) or CR with incomplete platelet or neutrophil recovery (CRi) could receive up to 2 consolidation cycles (CPX-351: 65 u/m2 [C 65 mg/m2 + D 28.6 mg/m2] on Days 1 and 3; 7+3: C 100 mg/m2/day x 5 days + D 60 mg/m2 on Days 1 and 2). Site of administration was not protocol defined. Results: Few pts received induction as outpatient therapy (CPX-351 n = 3/153 and 7+3 n = 1/151 in each cycle). 49/153 CPX-351 pts and 32/151 7+3 pts received consolidation, with a substantial proportion of pts receiving CPX-351 as outpatients (consolidation 1: 51%; consolidation 2: 61%). CPX-351 consolidation was associated with substantial improvement in median OS versus 7+3 irrespective of inpatient/outpatient status (Table). Median OS was not diminished with CPX-351 administration in the outpatient versus inpatient setting (consolidation 1: 25.43 and 14.72, respectively; consolidation 2: 26.32 and not reached). Conclusions: Some pts can successfully receive CPX-351 consolidation as outpatients without diminished efficacy, potentially reducing hospitalizations associated with treatment administration. Clinical trial information: NCT01696084. [Table: see text]
Phase 2 study of ruxolitinib in combination with 5-azacitidine in patients with myelofibrosis.
Authors: Masarova Lucia , Cortes Jorge E. , Pemmaraju Naveen , Jabbour Elias , Bose Prithviraj , Ohanian Maro , Zhou Lingsha , Pierce Sherry , Gergis Romany , Borthakur Gautam , Estrov Zeev , Garcia-Manero Guillermo , Kantarjian Hagop M. , Verstovsek Srdan , Daver Naval Guastad
Published: September 2018

7063

Background: Ruxolitinib (RUX) is effective in controlling symptoms and organomegaly in patients with myelofibrosis (MF). Combination with azacitidine (AZA) may further improve its efficacy. Methods: RUX 15 or 20 mg orally twice daily was given continuously since cycle 1. AZA 25 to 75 mg/m2 on days 1-5 of each 28-day cycle was added starting cycle 4. Responses were assessed per International Working Group for Myelofibrosis Research and Treatment 2013 criteria (IWG-MRT). Results: Among 44 pts enrolled between 03/2013 and 06/2016, 39 patients (89%) were evaluable for response. After median (med) follow-up of 20.4+ months (range, 0.5-37+); 24 pts (54%) are on study with a med overall survival of 39+ months. Med age was 66 years (range, 48-87), 36 pts (82%) had int-2/high IPSS score, 29 (66%) had spleen ≥5cm, and 24 (55%) were JAK2 V617F positive. Twenty five pts (57%) were previously treated. Twenty eight (72%) pts had objective response regardless of previous therapy (Table). Med time to response was 1.0 months. 7 (25%) responses occurred after the addition of AZA with med time to response of 4.2 months. In total, 23 pts (79%) had palpable spleen reduction by > 50%, which occurred after AZA was added in 6 (28%) of them. JAK2V617Fallele reduction was noted in 13 (87%) evaluable pts, including > 50% reduction in 3 pts (13%). A reduction in bone marrow fibrosis grade was observed in 12 (31%) responders, including ≥2 and 1 grade reduction in 2 and 9 pts, respectively. Grade 3/4 non-hematological and hematological toxicities occurred in 4 and 16 pts, respectively. The most common reasons for therapy discontinuation (n=17) were stem cell transplantation (n=6), lack of response (n=3) and progression to AML (n=2). Conclusions: Concomitant RUX with AZA was feasible with overall IWG-MRT response rate of 72%, including >50% spleen reduction in 79% of patients, which compares favorably to single RUX. Clinical trial information: NCT01787487. [Table: see text]
Richter's syndrome (RS) in patients with chronic lymphocytic leukemia (CLL) on novel agent therapy.
Authors: Davids Matthew Steven , Huang Ying , Rogers Kerry Anne , Stern Robert , Brown Jennifer R. , Thompson Philip A. , Brander Danielle M. , Danilov Alexey Valeryevich , Ujjani Chaitra Shankar , Parikh Sameer Ashok , Barrientos Jacqueline Claudia , Tam Constantine , Woyach Jennifer Ann
Published: September 2018

7505

Background: Novel agents (NA) targeting B cell receptor kinases and Bcl-2 have substantially improved outcomes in CLL; however, the development of RS in CLL patients (pts) on NAs has been observed, and has not been systematically evaluated. Methods: We retrospectively reviewed pts at 9 academic centers diagnosed with pathologically-confirmed RS from 2011-16. Informed consent was provided through IRB-approved protocols. Descriptive statistics were utilized and overall survival (OS) was calculated from RS diagnosis (dx) to death or last follow-up by Kaplan-Meier. Results: 71 pts who developed RS on NAs for CLL were identified. Median age at CLL dx was 55 yrs (range 21-82), median of 3 therapies (range 0-12) prior to the NA. 68% pts were fludarabine-refractory, and 5 pts (7%) had relapsed post alloHCT. Median time from CLL dx to initiation of NA was 68.5 mo. (range 1.1-246.2). FISH at NA initiation: del(17p) 30/61 (49%), del(11q) 15/61 (25%), trisomy 12 15/61 (25%). Complex karyotype was present in 40/53 (75%). 46/52 (88%) were IGHV unmutated, VH1-69 10/43 (23%), VH4-39 4/43 (9%). 59 (83%) pts were on a BTK inhibitor, 6 (8%) PI3K inhibitor, 6 (8%) venetoclax. RS histology: DLBCL (87%), plasmablastic (6%), Hodgkin (4%), 3% other. RS Ki-67%: >90 (23%), 75-90 (25%), 50-75% (25%), <50% (28%). Median time from start of NA to RS dx was 9.1 mo (range 0.9-48.2), with 65% developing RS within 12 mo. of starting NA. In 56 pts, 19 different regimens were used as initial RS therapy, including: R-EPOCH (36%), R-CHOP (20%), checkpoint blockade (9%), OFAR (7%), or a different NA (7%). Of the 48 pts evaluable for response, ORR was 42% (15% CR, 27% PR). In 29 evaluable pts receiving R-EPOCH/CHOP, ORR was 48% (21% CR). With a median follow-up of 10.6 mo., median OS was only 3.3 mo. (95%CI 2.2-6.0), though none of the 7 pts who achieved CR has died. Conclusions: We report to our knowledge the largest series of CLL pts developing RS on NAs. Pts often had high risk CLL, particularly complex cytogenetics, and RS frequently developed within the first year of NA therapy. Substantial variation exists in treatment, and outcomes are poor for those who do not achieve CR. Identification of molecular drivers of RS and development of novel treatment strategies are urgently needed.
Long-term efficacy and safety with ibrutinib (ibr) in previously treated chronic lymphocytic leukemia (CLL): Up to four years follow-up of the RESONATE study.
Authors: Byrd John C. , Hillmen Peter , O'Brien Susan Mary , Barrientos Jacqueline Claudia , Reddy Nishitha M. , Coutre Steven , Tam Constantine S. , Mulligan Stephen P. , Jäger Ulrich , Barr Paul M. , Furman Richard R. , Kipps Thomas J. , Thornton Patrick , Pagel John M. , Burger Jan Andreas , Jones Jeffrey Alan , Dai Sandra , Vezan Remus N. , James Danelle Frances , Brown Jennifer R.
Published: September 2018

7510

Background: Ibr, a first-in-class, once-daily inhibitor of Bruton’s tyrosine kinase, is FDA-approved for all pts with CLL/SLL. We report updated safety and efficacy results with up to 4 y follow-up from the ph III RESONATE trial of ibr vs ofatumumab (ofa). Methods: Pts had ≥1 prior therapy. Pts received 420 mg ibr PO until PD or ofa up to 24 wks. At interim analysis (median 9 mo follow-up), the DMC declared superiority of ibr vs ofa for PFS and OS, and ibr access was recommended for all ofa pts. Long-term follow-up efficacy endpoints are per investigator assessment. Ofa pts were censored at crossover for OS. Results: 391 pts were randomized to receive ibr (n = 195) or ofa (n = 196). Median age was 67 y (40% ≥70 y); 57% had Rai stage III/IV. With median follow-up of 44 mo (53 mo max) for ibr arm, PFS was significantly longer for ibr vs ofa (median NR vs 8 mo, [HR 0.133; P< 0.0001]; 3-y PFS 59% vs 3%) with significant benefit across subgroups. PFS with ibr for del11q subgroup trended to have the most favorable outcome; however, PFS was not statistically different for pts with del17p or del11q or without these FISH abnormalities. At analysis, with the majority of pts (68%) randomized to ofa crossing over to ibr, OS was longer for ibr vs ofa (median OS NR for either arm). The OS rate for ibr at 3 y was 74%. ORR for ibr was 91% with CR/CRi rates (now 9%) increasing over time. Baseline cytopenias improved with extended ibr therapy for hemoglobin (85%), platelet (95%), and absolute neutrophil counts (95%). AE profile of ibr was consistent with previous reports. Major hemorrhage, Gr ≥3 atrial fibrillation, and Gr ≥3 hypertension occurred in 6%, 6%, and 8% of pts, respectively, over a follow-up of up to 4 y. Incidence of most Gr ≥3 AEs decreased from y 1 vs y 2-3: neutropenia- 18% vs 8%; pneumonia- 11% vs 4%; atrial fibrillation- 4% vs 2%, respectively. Discontinuations were most frequently PD (27%) and AE (12%). At analysis, 90 ibr pts (46%) continue ibr on study. Conclusions: Long-term treatment with ibr in this international ph III RESONATE study is tolerable and continues to show sustained PFS and OS regardless of high-risk cytogenetics. Ph III results in relapsed del17p and del11q pts compare favorably to prior ph II reports. Clinical trial information: NCT01578707.
MYC/BCL2/BCL6 triple hit lymphoma: A study of 33 patients who had an aggressive clinical course similar to patients with double hit lymphomas.
Authors: Li Shaoying , Huang Wenting , Oki Yasuhiro , Medeiros L Jeffrey
Published: September 2018

7559

Background: Large B cell lymphomas with MYC, BCL2, and BCL6 rearrangements, designated as triple hit lymphoma (THL), are uncommon. Large series studies of THL are scant and studies comparing THL to different types of double hit lymphoma (DHL) are lacking. Methods: We studied the clinicopathologic features and prognosis of 33 patients with THL and compared them to 83 patients with MYC/BCL2 DHL and 13 patients with MYC/BCL6DHL. Results: There were 21 men and 12 women, with a median age of 63 years (range, 34-85). Six patients had a history of low-grade B cell lymphoma and 27 had de novo lymphoma. These tumors were classified histologically as: 21 DLBCL, 10 high grade B-cell lymphoma, one concurrent DLBCL and follicular lymphoma (FL), and one concurrent DLBCL and mantle cell lymphoma. Immunohistochemical analysis showed that these tumors were positive for CD10 (94%), BCL6 (80%), BCL2 (93%), and MYC (69%, 40% as cutoff). 62% of tumors (8/13) with available data showed coexpression of MYC and BCL2. Using the Hans algorithm, 30 of 33 (91%) tumors had a germinal center B cell like (GCB) immunophenotype. All 7 cases tested by conventional cytogenetics showed a complex karyotype. Although BCL2 was always translocated with IGH, BCL6 translocated to MYC in 2of 7 cases of THL. Twenty-nine patients had treatment information available and all received immune-chemotherapy induction, including 11 with R-CHOP, 14 with R-EPOCH, 3 with R-HyperCVAD, and one with RICE (patient had a history of FL). The clinicopathological features of THL including induction chemotherapy were very similar to both the MYC/BCL2 DHL and MYC/BCL6 DHL (all P>0.05). There was no significant difference in median overall survival (OS) between patients with de novo lymphoma and those with a history of low-grade lymphoma (P=0.99). The OS in THL patients was 17.9 months, similar to the OS (17.2 months) of patients with MYC/BCL6 DHL and those with MYC/BCL2DHL (19.9 months) (P=0.60). Conclusions: MYC/BCL2/BCL6 THL is an aggressive B cell lymphoma and >90% of cases have a GCB immunophenotype. THL patients usually have an aggressive clinical course and a poor prognosis, similar to patients with double hit lymphomas.
The outcome of high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements or NOS compared to DLBCL patients from a single institution.
Authors: Romejko-Jarosinska Joanna , Rymkiewicz Grzegorz , Domanska-Czyz Katarzyna , Blachnio Katarzyna , Paszkiewicz-Kozik Ewa , Osowiecki Michal , Ostrowska Beata , Grygalewicz Beata , Woroniecka Renata , Druzd-Sitek Agnieszka , Dabrowska-Iwanicka Anna P. , Kotarska Martyna , Targonski Lukasz , Szymanski Marcin , Poplawska Lidia , Prochorec-Sobieszek Monika , Pienkowska-Grela Barbara , Walewski Jan Andrzej
Published: September 2018

7560

Background: 2016 update of the WHO 2008 classification of lymphoid neoplasms introduced new categories of highly aggressive B lymphomas (BCL): high grade B lymphoma (HGBL) with MYC and BCL2 and/or BCL6 rearrangements (HGBLR) and HGBL not otherwise specified (NOS). The prognosis for HGBL is generally considered poor, the optimal therapy is unknown. Here we evaluated outcome after first line treatment in patients with a diagnosis of HGBLR, HGBL, NOS, and DLBCL at our institution. Methods: Medical records of 591 consecutive patients with aggressive BCL were evaluated, archived pathology reports and samples were reviewed, diagnosis revised if necessary according to 2016 update of WHO classification. We identified 16 cases of HGBLR (3%), 26 cases of HGBL, NOS (4%), and 565 cases of DLBCL (93%). Response to first line therapy, progression free survival (PFS), and overall survival (OS) were calculated and compared between these three entities. Results: DLBCL patients were treated with RCHOP between 2005-2012, HGBL patients were treated between 2005-2016 with RDAEPOCH (n = 31, 5%), RCHOP or other regimens. For the first line treatment in patients with DLBCL, HGBLR and HGBL NOS, the overall response/complete response rate was 92%/75%, 81%/56%, 93%/65%, respectively (p = NS). After a median (range) follow up of 42(1-155) months, median PFS and OS for DLBCL was not reached. For both HGBLR and HGLB, NOS patients median PFS was 10 months, median OS was 16 months. The HR for risk of progression in patients with HGBLR vs DLBCL and HGBL NOS vs DLBCL was 2.4 (1.1-4.7), p = 0.01 and 2.0 (1.1-3.5), p = 0.01. The HR for risk of death, for HGBLR vs DLBCL and HGLB NOS vs DLBCL was 2.59(1.32-5.07), p < 0.01 and 1.8(0.9-3.3), p = 0.08. The risk of progression and the risk of death in HGBLR vs HGBL, NOS was similar, for PFS: 1.08 (0.46- 2.5), p = NS for OS: 1.2 (0.5 -3,1) p = NS. Conclusions: Our data confirms reports by others on poor prognosis for patients with a diagnosis of HGBL with MYC and BCL2 and/or BCL6 rearrangements as well as HGBL, NOS with an increased risk of death and risk of progression compared to DLBCL patients. There was no difference in outcome between HGBL-R and HGBL, NOS patients in our series.
Patterns of use of CNS prophylaxis in DLBCL in a large health system.
Authors: Thompson Michael A. , Yoder Sol Atienza , Robinson Lisa Ann , Aranda Renee
Published: September 2018

7562

Background: Diffuse large B-cell lymphoma (DLBCL) patients (pts) with risk factors based on the R-IPI (Sehn et al. 2007 http://ow.ly/k4Xu308hsBM) and CNS IPI (Schmitz et al. 2016 http://ow.ly/dZIb301YyQ4 ) may relapse in the central nervous system (CNS). NCCN Guidelines (v2.2016) rec lumbar puncture (LP) if 4-6 risk factors present or HIV, testicular, breast, or double expresser and notes optimal management is uncertain. We wished to evaluate the use of CNS px in a large community health system. Methods: The Aurora Health Care cancer registry was searched for DLBCL from 1/1/16 to 12/31/16. Pts with CNS px were selected for more detailed analysis for stage, Myc, R-IPI, CNS IPI and cost of px. CNS px was categorized as: 1) intravenous (IV) high dose methotrexate (HD MTX), 2) IT chemo via Ommaya, or 3) IT via LP. Outcomes were CNS px utilization, survival, and costs. Results: 146 DLBCL pts were treated (5 R-CHOP, 2 DA-R-EPOCH). CNS px was given in 7/146 (4.8%). Pts were 5 males, 2 females. Median age was 58, (range: 38-76). Median R-IPI was 2.4 (range: 0-5). Median CNS IPI was 2.7 (range: 0-5). HD MTX was used in 3 pts. IT was used in 4 pts, with 0 by Ommaya and 4 by LP. Except for one death, there was no CNS or other recurrences yet. Costs per cycle were (drug + administration): 1) HD MTX: $587+ 3166 (hospitalization and leucovorin) = $3753, 2) IT Ommaya: $20 + 921 = $941 (not including Ommaya surgery), 3) IT LP: $20 + 2460 (includes interventional radiology) = $2480. Conclusions: CNS px rate was low across a range of stages and risk scores, which potentially reflects lack of recognition of risk as well as uncertainly about the value including utility (risk reduction) vs cost ($ and pt toxicity). Evaluating for improved utility is necessary, such as lenalidomide (a small molecule with CNS penetration) in R2CHOP (Ayed et al. 2016 http://ow.ly/6s5d308G4I4 ). If that 6 fold risk reduction holds, the value may be high for lenalidomide added to high risk CNS IPI DLBCL pts therapy. [Table: see text]