Journal articles on the topic 'Brookmeyer'

As the populations of the developed world continue to age, the number of people who develop Alzheimer's disease (AD) or other forms of dementia is set to rise. In the United States, for example, the prevalence of AD is projected to quadruple over the next 50 years (Brookmeyer & Gray, 2000). The search for factors that might help to prevent or treat these conditions has therefore assumed a particular relevance.

There is increasing interest in finding markers of Alzheimer's disease (AD) that are discriminative even at an early, pre-dementia stage. This interest is driven partly by a desire to improve clinical diagnosis in more mildly affected individuals, and also by the recent paradigm shift in thinking about clinical trials for AD. This shift is a result of concern that the recent failures of high-profile clinical trials conducted in patients with mild to moderate AD may have been because therapy was “too little, too late.” The implication being that if only treatments had been trialled earlier they would have had a greater chance of success. Certainly, lessons from other aspects of medicine have shown that treatments may be most, or in some cases only, effective if given early in disease. If we did have therapies that could slow disease progression at a very early stage that would increase the interest in early markers of disease. Ideally, such therapies would be given when the minimum of functional decline and irreversible neuronal loss had already occurred. From economic and public health standpoints, delaying symptom onset would be very important: a delay of five years has been estimated to reduce projections for prevalence of symptomatic AD by about 50% (Brookmeyer et al., 1998).

4078 Background: In REFLECT, lenvatinib was noninferior to sorafenib based on overall survival in pts with uHCC (median 13.6 vs 12.3 mos; hazard ratio [HR] 0.92, 95% CI 0.79–1.06). The objective response rate (ORR) with lenvatinib was 18.8% by blinded independent imaging review (IIR) per RECIST v1.1; ORR was 40.6% by blinded IIR per mRECIST. Here we further characterize the tumor responses in pts with uHCC who were treated with lenvatinib in REFLECT. Methods: Assessments of ORR included all pts randomly assigned to lenvatinib treatment (12 mg/day for bodyweight ≥60 kg or 8 mg/day for bodyweight <60 kg). Time to first objective response (TTR) and duration of response (DOR) were calculated among pts who achieved a partial or complete tumor response. Tumors were assessed by IIR per RECIST v1.1 or mRECIST. Median DOR was estimated with the Kaplan-Meier product-limit method; 95% CI was estimated with a generalized Brookmeyer and Crowley method. Results: 478 Pts were randomly assigned to receive lenvatinib. Among the 90 pts (18.8%) who achieved an objective response by IIR per RECIST v1.1, median TTR was 2.8 mos (range 1–29) and median DOR was 7.4 mos (95% CI 5.6–9.2). Of the 194 pts who had an objective response by IIR per mRECIST, median TTR was 1.9 mos (range 1–15) and median DOR was 7.3 mos (95% CI 5.6–7.4). ORRs by selected baseline characteristics are reported in the Table. Notably, among responders by IIR per RECIST v1.1 (n=90), median overall survival (by Simon-Makuch method) was 23.4 mos (95% CI 17.6–26.3), median duration of treatment was 10.3 mos, and 65.6% of pts experienced grade ≥3 treatment-related adverse events. Conclusions: Pts with uHCC treated with lenvatinib achieved objective responses with a similar frequency to those seen with single-agent immune checkpoint inhibitors. These responses occurred irrespective of baseline characteristics. Tumor responses occurred early and were durable. Clinical trial information: NCT01761266. [Table: see text]

TPS685 Background: First-line treatment landscape of metastatic renal cell carcinoma (mRCC) is evolving with strong evidence in favour of PD-1/PD-L1 combinations over tyrosine kinase inhibitors (TKIs). No prospective data about efficacy of TKIs post immune-checkpoint inhibitor (CPI) combinations are available. Among TKIs, cabozantinib has demonstrated progression-free survival (PFS) and overall survival (OS) benefit over everolimus in pre-treated mRCC patients (pts). Methods: Overall 49 mRCC pts who received a previous CPI (anti PD-1/PD-L1) will be treated with cabozantinib. Pts will be stratified according to Heng prognostic group, duration of first-line and type of previous therapy received (CPI+CPI or CPI+TKI or CPI+anti-VEGF or CPI monotherapy). Key inclusion criteria include: one previous treatment with a PD-1/PD-L1 inhibitor in first-line and histological diagnosis of clear-cell RCC. The primary endpoint is to assess the efficacy of cabozantinib based on PFS. Secondary endpoints include evaluation of OS, objective response rate and safety profile of the drug. Exploratory endpoints include evaluation of PD-L1 levels by immunohistochemistry in tumor samples; the analysis of the immunological signature/profile of tumor cells; the state of circulating immune cells, as well as the modulating activity of cabozantinib on systemic tumor immunity; the evaluation of bone formation and reabsorption markers in pts with or without bone involvement. Cabozantinib will be administered orally at a dose of 60 mg/day continuously until evidence of disease progression or onset of unacceptable toxicity. Statistical design: By the methodology of Brookmeyer and Crowley, assuming an accrual period of 18 months and a minimum follow-up of 10 months (mos), 49 pts are necessary to detect an increment of the median PFS time from 3.8 mos to 7.4 mos with a power of 90% and one-sided alpha of 5%. The large sample critical value detecting the increment of the PFS median survival time will be 5.54 mos. To date, 2 pts have been enrolled. Clinical trial information: NCT03463681.

4542 Background: Sunitinib achieves robust OR and improved progression-free survival (PFS) in mRCC patients (N Engl J Med 2007;356:115). A retrospective analysis was performed to characterize the OR rate with sunitinib treatment (Tx) and OR-associated patient features and survival. Methods: Data from six phase II and III trials were pooled from 1,059 patients who received sunitinib on the approved 50 mg/d 4-week-on/2-week-off schedule (n=689; 65%) or at 37.5 mg continuous once-daily dosing (n=370; 35%), in both the 1st- (n=783; 74%) and 2nd-line (n=276; 26%) Tx settings. Median PFS and overall survival (OS) were estimated by the Brookmeyer and Crowley method, and compared between responders and nonresponders, and early and late responders (response ≤ and >12 weeks, respectively), by a log-rank test. Baseline characteristics were compared by Fisher-exact Test, T-Test, or Wilcoxon Rank-sum Test. Results: Of 1,059 patients, 398 (38%) had a confirmed investigator-assessed OR by RECIST (including 12 with a complete response), of whom 105 (26%), 243 (61%), 314 (79%), and 342 (86%) had a response by 6, 12, 18, and 24 weeks, respectively. Median (range) time to tumor response (TTR) in all patients was 10.6 (2.7–94.4) weeks, which was similar in the 1st- and 2nd-line Tx settings. Responders had better baseline ECOG scores, more favorable risk factor classification based on published MSKCC data, a longer interval since initial diagnosis, more prior nephrectomy, and less presence of baseline bone metastases (all p<0.05). Early responders had more lung metastases (p<0.01). Median PFS (16.3 vs. 5.3 months) and OS (40.1 vs. 14.5 months) were significantly longer in responders vs. nonresponders (both p<0.001), with similar results regardless of 1st- or 2nd-line Tx setting. Median OS did not differ between early and late responders (p=0.1438). Conclusions: OR was achieved in 38% of 1,059 mRCC patients treated with sunitinib and was predicted by favorable pretreatment prognostic factors. Patients with OR had longer PFS and OS. Median TTR was 10.6 weeks, and characteristics and outcome of early and late responders were similar, except for higher frequency of lung metastases among early responders.

e14541 Background: Anti-VEGF antibody Bevacizumab (Avastin: Roche Pharma AG) is the recommended drug for recurrent glioma. Multiple low-cost bio-similars of this drug are now available however their clinical efficacy has never been compared against the original molecule. The aim of the current analysis is to compare the overall survival (OS) between recurrent glioma patients with bio-similar and innovator molecule. Methods: Adult recurrent glioma patients treated with bevacizumab from 1st July 2015 to 30th July 2019 were identified from the Neuro-Medical Oncology database. These patients were either offered Avastin or Bevacizumab biosimilar (BevaciRel: Reliance Life sciences or Bryta: Zydus Oncosciences) depending upon the financial affordability. The primary endpoint of the study was OS. It was defined as the time in months from the start of bevacizumab to death. Progression-free survival (PFS) was defined as the time in months from the start of bevacizumab to progression or death. The time to event variables was estimated using Kaplan Meier method. The median with its 95% confidence interval (CI) was calculated using Brookmeyer and Crowley method. The estimates were compared between the original and bio-similar bevacizumab cohort using the log-rank test. The hazard ratio was calculated using COX regression analysis. Results: There were 82 patients, out of which 57 received innovator and 25 received bio-similar bevacizumab. At median follow up of 26 months, 76 patients had an event for progression. The median PFS was 3.66 (95% CI 2.08 to 5.25) and 3.3 months (95% CI 2.38 to 4.21) in innovator and bio-similar arm respectively (Log-rank test P-value = 0.072). The hazard ratio for progression was 0.61 (95% CI 0.35 to 1.05; P-value = 0.075). At the time of data cutoff, there were 69 deaths. The median OS was 5.53 (95% CI, 5.07 to 5.99) vs 7.33 months (95% CI, 5.63 to 9.03) in innovator and bio-similar arm respectively (Log-rank test P-value = 0.51). The hazard ratio for death was 1.21 (95% CI, 0.67 to 2.17; p-value = 0.51). Conclusions: In the brain tumor patients, both innovator and bio-similar bevacizumab seem to have similar clinical efficacy.

e22086 Background: Individualized care in MBC requires predictors of survival for tailored treatment. Although HD-ASCT has not resulted in improved overall survival (OS), retrospective analyses may identify patients who benefited. We reviewed records of all patients (n=96) in the bone marrow transplant registry at UCSD treated with HD-ASCT for MBC between 1989 and 2000. Methods: Age, race, stage at diagnosis, histology, estrogen receptor (ER) and menopausal status, body mass index (BMI) in kg/m2, time to transplant and death, sites of metastasis, disease status prior to and after transplant, and days in hospital were extracted. Brookmeyer & Crowley's 95% confidence intervals, Cox models for predictors of a time-to-event variable and Schoenfeld tests for proportional hazard assumptions were applied. Results: Median OS was 5.6 ys (CI 4.1–7.4) after initial diagnosis and 1.7 ys (CI 1.36–2.07) after transplant. OS after HD-ASCT at 12 ys was 8.2% and, although not statistically significant, 18.5% in ER- and 2.6% in ER+ patients, respectively. Stratified by ER status, stage at diagnosis was an independent predictor of OS. Patients with stage I at diagnosis were at lowest risk of death when compared to stage II-IV patients with HRs of 2.7 (II vs I CI 1.4–5.2), 4.6 (III vs I CI 2.1–10) and 17 (IV vs I CI 6.1- 47.8). Death risk was increased with BMI ≥ 30 (HR 3.1; CI 1.8–5.4), infiltrating lobular carcinoma (HR 2.5; CI 1.1–5.38) and visceral metastasis (HR 2.3; CI 1.3–4.1). Conclusions: The study highlights that ∼10% of patients experience ≥10 ys survival with HD- ASCT. Obesity, late stage at diagnosis, lobular infiltrating histology and visceral metastasis were independent negative predictors of OS. Surprisingly, ER- patients tended to live longer. Although survival was influenced by various disease characteristics, obesity was the only significant patient derived factor. How obesity negatively affects outcomes - whether affecting cancer growth or through associated morbidity - needs further study. These data may be useful stratification tools for future trials employing HD-ASCT as treatment modality in MBC. No significant financial relationships to disclose.

1093 Background: The treatment of patients with brain only metastatic breast cancer (BO-MBC) remains very challenging. There is also very limited literature informing on appropriate treatment or natural history of this entity. Systemic chemotherapy in addition to targeted therapy and/or anti-estrogen treatment is often used, but little is known if it adds to the overall or disease free survival. In this retrospective study, we examine this, as well as other factors which may be associated with increased risk of CNS or systemic recurrence in these patients. Methods: A database search at a single institution identified 178 patients with brain metastases (BM) from breast cancer out of which 45 patients had BO-MBC between 2007-2020. We collected demographic, clinical, radiographic and other treatment data. Leptomeningeal disease (LMD) was diagnosed by cerebrospinal fluid (CSF) cytology, neuroimaging, or both. We used the Brookmeyer and Crowley method. Results: The patients were followed for a median of 17.9 months; 36 out of 45 patients (80%) received local treatment for BM (surgery/radiation/both) and HER2 directed antibodies or tyrosine kinase inhibitors and/or anti-estrogen treatment, whereas 9 out of 45 patients (20%) received systemic chemotherapy in addition. There were 22 out of 45 (49%) HER2 +, 5 out of 45 (11%) HR + and 18 out of 45 (40%) triple negative breast cancer (TNBC) patients. There were 17 out of 45 patients (38%) who were deemed to have low burden of BM (defined as one to three BM and largest being ≤3 cm) whereas there were 24 out of 45 patients (53%) who had high burden of BM (defined as four or more BM or largest being > 3 cm). Conclusions: Patients with BO-MBC represent a distinct entity. Despite having better survival than patients with BM and extra CNS disease these patients have a high risk of developing LMD, CNS and systemic recurrences. The addition of chemotherapy to targeted therapy and/or anti-estrogens does not decrease the rates of systemic or CNS recurrence. The ER+ subset have a lower rate of development of systemic disease, as expected due to their relatively indolent biology. The CNS and systemic recurrence seem to be higher in patients with HER2+ cancers and counterintuitively even in those with low burden of BM; albeit these were statistically insignificant.[Table: see text]

4002 Background: Data on first-line treatment efficacy in elderly patients are limited. Many analyses adopt a questionable cut-off of 65 years and specific evidence with anti-EGFRs is low. FOLFOX-panitumumab (pan) is an option for RAS wild-type (wt) untreated mCRC patients. Guidelines recommend considering fluoropyrimidine monotherapy as an option for elderly patients, but no randomized studies have ever explored the role of the combination with an anti-EGFR. Methods: This is a prospective, open-label, multicenter phase II randomized trial. Unresectable and previously untreated RAS- BRAF wt mCRC patients aged ≥70 were randomized to receive FOLFOX-pan (arm A), or 5FU/LV-pan (arm B) for up to 12 cycles followed by pan maintenance until PD. The primary EP was PFS in both arms. Stratification criteria were age (≤75 vs > 75 years), ECOG PS (0–1 vs 2) and geriatric assessment with G8 Score (≤14 vs > 14). In each treatment arm, the null hypothesis for median PFS was set at ≤6 months. Assuming an expected median PFS time ≥9.5 months with both experimental regimens, a sample size of 90 patients in each arm granted to the study a power of 90%, with a type I error rate equal to 5% (1-sided Brookmeyer-Crowley test) for rejecting the null hypothesis. No formal comparison between the two arms was planned. Results: From Jul 2016 to Apr 2019 a total of 394 patients were screened, 211 were deemed eligible for inclusion and 185 were randomized (92 arm A and 93 arm B). Main pts’ characteristics were (arm A/B): males 66%/61%; median age 77/77y; PS≥1 49%/55%; right colon 23%/21%; G8 > 14 31%/30%. At a median follow up of 20.5 mos, 135 (arm A/B: 64/71) PD events were collected. Median PFS was 9.6 (95% CI 8.8-10.9) in arm A with FOLFOX-pan and 9.1 (95% CI 7.7-9.9) in arm B with 5FU/LV-pan. Response rates were (arm A/B): 65%/57%. Grade 3-4 toxicities were (arm A/B): neutropenia 9.8%/1.1%; diarrhea 16.3%/1.1%; stomatitis 9.8%/4.4%; neurotoxicity 3.3%/0%; fatigue 6.5%/4.4%; skin rash 25%/24.2%, hypomagnesemia 3.3%/7.7%. Conclusions: Large prospective randomized studies in molecularly selected elderly mCRC are feasible with multicenter collaborative efforts. Primary EP was met in both treatment arms. 5FU/LV plus panitumumab for up to 12 cycles followed by panitumumab maintenance until PD might be a reasonable option in elderly mCRC patients with RAS/BRAF wt tumors deserving further investigations in phase III trials. Clinical trial information: NCT02904031 .

14 Background: Our phase II randomized study was conducted in patients with previously untreated unresectable mCRC not eligible to receive standard oxaliplatin- or irinotecan- based chemotherapy regimens. The results of the primary study analysis were reported earlier and demonstrated a promising efficacy in terms of progression-free survival (PFS) and an acceptable safety profile for the combination of trifluridine/tipiracil + bevacizumab (E. Van Cutsem et al. Ann. Oncol. 2020). Here we present the final end-of-study analysis on the overall survival (OS). Methods: Eligible patients were randomized in 1:1 ratio to receive either trifluridine/tipiracil administered orally at 35 mg/m²/dose bid from days 1-5 and days 8-12, and bevacizumab at 5 mg/kg on days 1 and 15 of a 28-day treatment cycle (TT-B), or capecitabine administered orally at 1250 or 1000 mg/m²/dose bid (according to the patient’s status) from days 1-14 and bevacizumab at 7.5 mg/kg on day 1 of a 21-day treatment cycle (C-B). Cycles were repeated until documented disease progression, unacceptable toxicity, or investigator’s/patient’s decision. Following the treatment discontinuation, all patients were followed for OS until the end-of-study, which was defined as the date of the withdrawal visit for the last patient. In the absence of death confirmation or for patients alive as of the end-of-study date, survival time was censored at the date of their last study follow-up. For the OS analysis the HR and the corresponding 2-sided 80% and 2-sided 95% CIs for TT-B versus C-B were estimated using a Cox proportional hazard model adjusting for the stratification factors based on IWRS data. OS was summarized using Kaplan-Meier curves and further characterized in terms of the median and survival probabilities at 6, 12, 18, and 24 months along with the corresponding 2-sided 80% and 2-sided 95% CI (Brookmeyer and Crowley CI for median and Kalbfleisch and Prentice CI for survival probabilities). Results: From April 2016 to March 2017, 153 patients were randomized and followed until end-of-study on September 1, 2020. Twenty-one patients, 11 from TT-B and 10 from C-B, were alive and censored for the analysis. Median OS was 22.31 months in TT-B and 17.67 months in C-B with HR 0.78 (95% CI, 0.55, 1.10). Survival probability at 18 months in TT-B was 0.62 (95% CI, 0.50, 0.72), and 0.47 (95% CI, 0.35, 0.57) in C-B. Conclusions: Our study demonstrated earlier a median PFS of 9.2 months for TT-B and 7.8 months for C-B when administered to patients with previously untreated unresectable mCRC ineligible for standard combination chemotherapy. The final study analysis performed on OS, the main secondary endpoint, provided further evidence for TT-B as a noteworthy valuable regimen in this population settings. Clinical trial information: NCT02743221.

4569 Background: For many years, vascular endothelial growth factor (VEGF)-targeted therapy (tp) has been a milestone for metastatic renal cell carcinoma (mRCC). Recently, first line tp based on anti-PD-1/PD-L1 immune-checkpoint inhibitors (ICIs) plus tyrosine-kinase-inhibitors (IO-TKI) and anti-PD-1 plus anti-CTLA-4 combos (IO-IO) significantly improved survival of mRCC patients (pts). Prospective data are lacking to determine the efficacy of anti-VEGF tp after IO-IO or IO-TKI. Cabozantinib (Cabo) showed to prolong survival in mRCC pts pre-treated with TKIs and to target kinases involved in immune-escape. So, it may represent an ideal agent to be used sequentially after ICIs. Methods: This is an open label, single arm, multicenter, phase II study evaluating efficacy and safety of Cabo in mRCC pts who received an anti-PD-1/PD-L1-based adjuvant (adj) or first line tp. Cabo 60 mg/daily was administered until progressive disease (PD) or unacceptable toxicity. Primary endpoint was progression free survival (PFS) by Brookmeyer-Crowley test, secondary endpoints were overall survival (OS), objective response rate (ORR) and safety. Exploratory endopoints were to investigate tissue PD-L1 expression, to assess the modulating activity of Cabo on local and systemic tumor immunity and to explore bone formation and reabsorption markers. Results: From July 2018, 49 pts were enrolled and 48 were included in the analysis. Median age was 62.5 years (range: 30-78), 63% of pts were male. At baseline, 26% of pts had a good Heng risk score, 47% intermediate and 28% a poor risk, while in 2% of pts the class of risk was undetermined. 74% of pts received an IO-IO combo as first line tp, 17% IO-TKI, 9% pts an adj IO monotherapy. Pts received a median of 10 cycles of Cabo (range 5-17 cycles). 25 pts (53%) are still on tp, 1 patient discontinued Cabo for AEs, 13 pts for radiological PD, 6 pts discontinued for clinical PD or death, while 2 pts for reasons other than AEs or PD. Among evaluable cases, 17 pts (43%) achieved a partial response and 15 pts (37%) stable disease. Complete responses were not observed. At a median (m) follow-up of 8.0 months (mo) (4.4-13.5 mo), 71% of pts were alive and mPFS was 9.3 mo (95% CI 7.1-29.0 mo). Grade (G) 3-4 adverse events (AEs) occurred in 34% of pts, including more frequently serum bilirubin increase, hypertension, calcium and sodium serum levels alterations and oral mucositis. G1-2 were observed in 61% of pts, including in most of cases diarrhoea, nausea, oral mucositis, disgeusia, hand-foot syndrome, fatigue and hypothyroidism. Due to AEs, transitory withholding of Cabo was observed in 53.5% of pts and for 23 pts (48%) dose reductions were needed. Conclusions: So far, Cabo tp after IO-IO or IO-TKI showed promising results and was well tolerated. Longer follow-up is needed for final OS and exploratory endpoints results. Clinical trial information: NCT03463681.

Abstract Despite the introduction of modern therapeutics, overall survival (OS) in metastatic breast cancer (MBC) has not changed in 20 ys. In the 1990s a major effort was made to improve the situation through the use of high dose chemotherapy with autologous stem cell transplantation (HD-ASCT). Although OS was not affected in randomized trials, which led to near abandonment of this therapy, some studies suggested that progression-free survival (PFS) can be improved with HD-ASCT. To identify distinct transplant-, disease- and patient-related characteristics predictive of survival in patients with MBC who received HD-ASCT, we reviewed records of all patients in the bone marrow transplant registry at UCSD treated with HD-ASCT for MBC between 1989 and 2000. METHODS: Age, race, stage at diagnosis, histology, estrogen receptor (ER) and menopausal status, body mass index (BMI) in kg/m2, time to transplant and death, site of metastasis, disease status prior to and after transplant, and days in hospital were extracted from medical records. Brookmeyer & Crowley’s 95% confidence intervals were used for median survival times, Cox models for predictors of a time-to-event variable and Schoenfeld tests for proportional hazard assumptions, respectively. RESULTS: Of 96 patients with MBC 21, 43, 23, 8 and 1 had stage I, II, III, IV or unknown disease at diagnosis, respectively. Histologies were: infiltrating ductal, lobular, inflammatory or unknown in 79, 10, 6 and 1 of the cases, respectively. ER status was positive in 59.4% of patients and 29.2% of patients were post-menopausal. 84.4%, 4.2% and 11.5 % of patients were of caucasian, black or other ethnicity, respectively. Mean ages at diagnosis and at transplant were 43.7 ys (SD 8.6) and 47.4 ys (SD 8.7), respectively, with a median time to transplant of 29 months (range 3.8–180.8). When progression of disease (PD) was diagnosed, primary sites were visceral (39.6%), bone (29.2%), local (16.7%) or nodal (14.6%). Mean BMI at transplant was 26 (SD 5.9); 24% of patients were obese (BMI ≥ 30). Mean length of hospitalization after transplant was 17 days (SD 9.5 days); 33% of patients were hospitalized ≥ 18 days. Pre-transplant, 30.2% of patients were in complete remission; after HD-ASCT, this percentage increased to 41.7%. Median PFS and OS were 3.9 ys (CI 2.9–5.4) and 5.6 ys (CI 4.1–7.4) after initial diagnosis and 0.6 ys (CI 0.5–0.8) and 1.7 ys (CI 1.36–2.07) after transplant, respectively. As opposed to ER+ patients the rate of death events in ER− patients slowed down substantially after 5 ys from diagnosis. Although not statistically significant, at 12 ys, survival after HD-ASCT was 18.5% in ER− patients and 2.6% in ER+ patients. Stratified by ER status, stage at diagnosis was an independent predictor of length of PFS and OS. At diagnosis, stage I patients were at lowest risk of death when compared to stage II–IV patients with HRs of 2.7 (II vs I CI 1.4–5.2), 4.6 (III vs I CI 2.1–10) and 17 (IV vs I CI 6.1–47.8) disease; lower risk of death persisted for patients with initial stage I after PD was diagnosed with HRs of 2.4 (II vs I CI 1.3–4.6), 2.8 (III vs I CI 1.3–5.7) and 3.9 (IV vs I CI 1.6–9.9). Death risks were increased with infiltrating lobular carcinoma when compared with infiltrating ductal carcinoma (HR 2.5; CI 1.1–5.38) or when BMI was ≥ 30 (HR 3.1; CI 1.8–5.4); PFS in patients with a BMI ≥ 30 was significantly shorter after PD was diagnosed (death HR 3.1 [CI 1.8–5.5] when compared to BMI &lt; 30). Visceral when compared to bone metastasis was a negative predictor of OS (HR 2.3; CI 1.3–4.1). Hospitalization ≥ 18 days after HD-ASCT was the strongest predictor of time to death after transplant (HR 2.2; CI 1.4–3.6). DISCUSSION: The survival rate at 12 ys after HD-ASCT was 8.2% for patients with MBC. Survival was higher for ER- compared to ER+ patients. Negative prognostic factors for OS and PFS were higher stages of disease at initial diagnosis, but also once PD was diagnosed, infiltrating lobular histology and obesity. Since all transplants were carried out prior to routine assessment of Her-2 neu receptor status, this information was not part of our analysis. At PD, visceral metastasis translated into poorer OS and after HD-ASCT, length of hospitalization became the most important outcome predictor. Although HD-ASCT in MBC has lost favor because of no improvement in global OS, our analysis may provide a rationale for selection criteria to determine which patients could benefit from future trials of HD-ASCT.

Background: Aggressive B-cell lymphomas that secondarily involve the CNS (sCNSL) have a grave prognosis and no standard of care. Treatment includes chemotherapy that penetrates the CNS, such as high-dose methotrexate, but are relatively ineffective for extracranial disease. Diffuse large B-cell lymphomas with secondary CNS involvement are enriched for chronic active B-cell receptor signaling, and are responsive to BTK inhibitors. Ibrutinib is also active in other B-cell malignancies that spread to the CNS including MCL and transformed lymphomas. Ibrutinib achieves CNS penetrance and has a high overall response rate in CNS lymphomas, but duration of response is short and curative potential is limited (Grommes et al. 2017). Further, toxicities associated with ibrutinib can compromise outcomes when added to chemotherapy. Precise understanding of molecular determinants of response could enhance patient selection strategies. We developed a novel regimen that combines ibrutinib with temozolomide, etoposide, doxil, dexamethasone, and rituximab (TEDDi-R) for relapsed and refractory PCNSL. TEDDi-R achieved durable remissions in chemotherapy-refractory PCNSL (Roschewski et al. ASH 2018), but has been associated with opportunistic infections, including Aspergillus. Development of TEDDi-R continues with isavuconazole prophylaxis that inhibits clearance of ibrutinib. We opened a novel response-adapted clinical trial designed to study the safety and efficacy of TEDDi-R in sCNSL and elucidate molecular correlates of response to ibrutinib. Study Design and Methods: Phase II study of 29 evaluable patients with recurrent sCNSL [NCT03964090] Patients with untreated aggressive B-cell lymphomas are eligible if CNS lesions involve brain parenchyma Patients are first treated with a 14-day "window" of ibrutinib 560mg monotherapy with concomitant isavuconazole Response adapted: Patients with at least a 20% reduction in bidimensional masses following the 14-day ibrutinib window will receive ibrutinib with chemotherapy (TEDDi-R) for 4 cycles. Patients with less than a 20% reduction during the ibrutinib window will receive TEDD-R (without ibrutinib) for 4 cycles Primary endpoint: progression free survival (PFS) Secondary endpoints: Safety of TEDDi-R and TEDD-R Clinical activity after 14 days of ibrutinib monotherapy Best overall response rate of 4 cycles of TEDDi-R/TEDD-R Duration of response PKs and safety of ibrutinib and TEDDi-R with concomitant isovuconazole prophylaxis Overall survival Translational endpoints: Comprehensive molecular analysis of tumors using gene expression profiling, whole exome sequencing, and RNAseq analysis correlated with outcomeGenotype cell-free DNA in plasma and CSF correlated with clinical response Eligibility: Included Age ≥ 18Prior BTK inhibitors permitted, but patients known refractory to BTK will proceed directly with TEDD-RPatients with CLL or FL that have progressed in the CNS are considered to have transformed to an aggressive B-cell lymphoma and eligibleECOG performance status ≤2Adequate organ functionWilling to take appropriate contraception Excluded HIVInability to take isavuconazoleStatistical methods: Expected median PFS would be less than 4 months based on historical data. The goal is to improve to a median 10 months PFS. With 29 evaluable patients, there would be 90% power to determine a difference between a 4-month median PFS probability and an improved 10-month median PFS, with a one sided 0.05 alpha level test, using the method of Brookmeyer and Crowley. Confidence intervals and PFS probabilities will be reported, but no formal hypothesis test will be undertaken. Summary: This is a phase 2 study of TEDDi-R in aggressive B-cell lymphomas with secondary involvement of CNS that employs a novel response-adapted design for ibrutinib. The aim is to enhance selection of patients likely to benefit from ibrutinib and to investigate the molecular determinants of response to BTK inhibition. The study is open and the first patient has been enrolled. All patients will be treated at the NCI, but the development of TEDDi-R is supported by a consortium of regional academic centers who provide academic input, patient referrals, and data analysis. Current participating centers include Johns Hopkins University, George Washington University, University of Pennsylvania, University of Virginia, University of Pittsburgh and Penn State University. Figure Disclosures Dunleavy: Pharmacyclics: Membership on an entity's Board of Directors or advisory committees. Swinnen:Pharmacyclics: Consultancy; AbbVie: Consultancy. Portell:Kite: Consultancy, Research Funding; Infinity: Research Funding; Roche/Genentech: Research Funding; Acerta/AstraZeneca: Research Funding; TG Therapeutics: Research Funding; Xencor: Research Funding; AbbVie: Research Funding; Pharmacyclics: Consultancy; Janssen: Consultancy; Genentech: Consultancy, Research Funding; Amgen: Consultancy; Bayer: Consultancy; BeiGene: Consultancy, Research Funding. Svoboda:Pharmacyclics: Consultancy, Research Funding; AstraZeneca: Consultancy; Seattle Genetics: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Merck: Research Funding; Incyte: Research Funding; Celgene: Research Funding; Kite: Consultancy; Kyowa: Consultancy. Staudt:Nanostring: Patents & Royalties. OffLabel Disclosure: Ibrutinib used off-label for CNS lymphomas

Introduction: Myelodysplastic syndromes (MDS) is thought to develop and progress as a result of accumulation of genetic mutations. This multicenter, open-label, phase II study examined impact of gene mutations on the effect of darbepoetin alfa (DA) for anemia. Death within 1 year and progression to acute myeloid leukemia (AML) were also examined. Methods: DA ≤240 μg was administered once weekly for 16 weeks to DA-naive, low-risk MDS (low or Intermediate-1 [Int-1] risk defined by the International Prognostic Scoring System [IPSS] risk classification) patients with anemia. DNA was extracted from the peripheral blood of patients, and presence of previously reported high-frequency gene mutations in MDS (SF3B1, TET2, SFRS2, ASXL1, DNMT3A, etc.) was analyzed by next-generation sequencing. Primary endpoint was association between frequently observed mutated genes and therapeutic effect of DA (IWG criteria 2006 (HIE)) at 16 weeks. A secondary endpoint was survival analysis results for death and progression to AML within one year after 16 weeks of treatment, with the date of first treatment as the starting date. For AML, progression to AML and subsequent death were stated as events, and the patients without confirmed progression to AML were censored at the date of last known survival. For overall survival, death from any cause was considered an event, and for the survival cases, the study was terminated at the date of last known survival. For the primary endpoint, relative risk and 95% confidence intervals (CI) were calculated using Wilson's score method; statistical significance was assessed using Pearson's chi-square test. Multivariate analysis was performed by adding baseline erythropoietin (EPO) levels (low: &lt;91.8, high: 91.8+ [mIU/mL]) to the explanatory variables, and odds ratio was calculated using logistic regression model. Survival curve was estimated using Kaplan-Meier method and median survival time (MST) was calculated using Brookmeyer and Crowley method. Results: Of the 85 patients enrolled between August 2016 and May 2019, 4 patients who were judged ineligible and 2 patients who discontinued the study prior to the start of treatment were excluded, and 79 subjects were included in the analysis (full analysis set). Of 79 subjects, 52 (65.8%) were male (median age 77.0 [29-90] years). IPSS risk was low in 27 (36.7%) and Int-1 in 50 (63.3%) subjects. The frequently mutated genes (³10%) were SF3B1 (24, 30.4%), TET2 (20, 25.3%), SRSF2 (10 cases, 12.7%), ASXL1 (9, 11.4%), and DNMT3A (8, 10.1%). Overall response rate was 70.9%. Univariate logistic regression analaysis did not show any significant association between these mutations and therapeutic efficacy of DA. The same results were obtained when the analysis was limited to red blood cell transfusion-dependent subjects (n=15). After adjusting against baseline EPO values, mutations of ASXL1 gene were associated with significantly worse response (odds ratio 0.180 [0.035-0.928], p = 0.040). Six (7.6%) confirmed cases of AML and 17 (21.5%) deaths (death before confirmed AML) were observed. Overall, 21 deaths were observed including 4 deaths after progression to AML. The median survival time (95% confidence interval) from the start of treatment to confirmed AML or death was 41.3 months (30.6 months - Not reached). Conclusions: The results of this exploratory study suggest that the presence of ASXL1 gene mutations may result in poor response to the anemic treatment with DA in low-risk MDS. The current analysis of progression to AML and death included subjects whose observation period did not reach the prespecified number of days. For such cases, the outcome research will be conducted around October 2020 and updated results will be presented at the ASH 2020 conference. Disclosures Ichikawa: Novartis, Takeda: Honoraria. Shibayama:Taiho: Research Funding; Shionogi: Research Funding; Ono: Honoraria, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Research Funding; Takeda: Honoraria, Research Funding; Merck Sharp & Dohme: Research Funding; Sumitomo Dainippon: Honoraria, Research Funding; Nippon Shinyaku: Honoraria, Research Funding; Daiichi Sankyo: Honoraria; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Chugai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa Kirin: Honoraria; Otsuka: Honoraria; Bristol-Myers Squibb: Honoraria; Pfizer: Honoraria; Fujimoto: Honoraria; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Teijin: Research Funding; Mundi Pharma: Honoraria. Maeda:Kyowa Kirin Co.Ltd.: Honoraria, Research Funding. Kawabata:Celgene Corporation: Consultancy; Celgene Corporation: Honoraria; Sanofi K. K: Honoraria; Novartis Pharma K. K.: Honoraria; Chugai Pharmaceutical Co., Ltd: Honoraria. Matsumura:Shionogi & Co., Ltd.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Kyowa Kirin Co., Ltd.: Research Funding; ONO PHARMACEUTICAL CO., LTD.: Research Funding; Eisai Co., Ltd.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Janssen Pharmaceutical K.K: Speakers Bureau; Amgen K.K.: Speakers Bureau; Otsuka Pharmaceutical Co., Ltd.: Speakers Bureau; Astellas Pharma Inc.: Speakers Bureau; DAIICHI SANKYO COMPANY, LIMITED.: Speakers Bureau; Pfizer Japan Inc.: Speakers Bureau; Novartis Pharma KK: Speakers Bureau; Bristol-Myers Squibb Company: Speakers Bureau. Ogawa:Eisai Co., Ltd.: Research Funding; KAN Research Institute, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Chordia Therapeutics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Asahi Genomics Co., Ltd.: Current equity holder in private company; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding. Mitani:CHUGAI: Research Funding; Takeda: Research Funding; KYOWA KIRIN: Consultancy, Research Funding.

Introduction: Tyrosine kinase inhibitors (TKIs) have dramatically improved the standard of care for patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP). In the 5-year follow-up of the phase 3 DASISION study (NCT00481247), dasatinib was associated with faster and deeper molecular responses than imatinib as first-line therapy for CML-CP (Cortes J et al. J Clin Oncol 2016). The NCCN guidelines recommend that multiple factors independent of risk score should be considered when selecting TKI therapy, including the presence of comorbidities. More than 50% of pts with CML-CP have at least one comorbidity at diagnosis (Hoffmann et al. Leukemia 2015); as such, comorbidities may influence first-line treatment choice for most pts. In this exploratory post hoc analysis of DASISION at 5-years' follow-up, we investigated the effect of comorbidities on response outcomes with dasatinib vs imatinib. Methods: DASISION was a multinational, open-label, phase 3 trial assessing dasatinib vs imatinib for newly diagnosed CML-CP. Pts were randomized to receive 100 mg dasatinib (n = 259) or 400 mg imatinib (n = 260) once daily. Charlson Comorbidity Index (CCI) was retrospectively calculated for each pt at diagnosis. Efficacy and safety data were retrospectively stratified based on CCI score categories 2-4, 5-6, and ≥ 7 (higher scores indicate a higher comorbidity burden). Rates of major molecular response (MMR) and molecular response with a 4.5-log reduction (MR4.5) were compared between treatment groups using unstratified Cochran-Mantel-Haenszel tests. Time to MMR and MR4.5 were evaluated using Kaplan-Meier methodology with hazard ratios (HRs) based on Cox proportional hazards models and P values from unstratified log-rank tests. Confidence intervals (CI) for median time to response were calculated using the Brookmeyer and Crowley method. P values are descriptive and unadjusted for multiple comparisons. Results: In total, 14 (3%) pts had CCI 2-4 (dasatinib 7, imatinib 7), 260 (50%) had CCI 5-6 (dasatinib 132, imatinib 128), and 245 (47%) had CCI ≥ 7 (dasatinib 120, imatinib 125). Baseline characteristics and drug exposure data are shown in the Table. Dose reductions of dasatinib and imatinib occurred in 14% vs 29% (CCI 2-4 group), 23% vs 12% (CCI 5-6 group) and 54% vs 22% (CCI ≥ 7 group) of pts, respectively. In the CCI 2-4 group, the MMR rate was 85.7% with dasatinib and 57.1% with imatinib (P = 0.2542) and the MR4.5 rates were 71.4% and 14.3% (P = 0.0374), respectively. In the CCI 5-6 group, the MMR rate was significantly higher with dasatinib vs imatinib (81.1% vs 64.8%, P = 0.0033), as was the MR4.5 rate (42.4% vs 29.7%, P = 0.0329). Median time to MMR in the CCI 5-6 group was significantly shorter with dasatinib than imatinib (15.0 vs 24.0 months; HR, 1.64; 95% CI, 1.23-2.19; P = 0.0006). In the CCI ≥ 7 group, response rates were numerically higher with dasatinib than imatinib: MMR rates were 70.8% vs 64.0% (P = 0.2552) and MR4.5 rates were 45.0% vs 39.2% (P = 0.3589), respectively. Median time to MMR was significantly shorter in the CCI ≥ 7 group with dasatinib than imatinib (12.0 vs 21.4 months; HR, 1.41; 95% CI, 1.04-1.91; P = 0.0279; Figure). Grade 3-4 treatment-related adverse events (TRAEs) were reported in 0% vs 14% (dasatinib vs imatinib) of pts with CCI 2-4, 8% vs 9% of pts with CCI 5-6, and 24% vs 13% of pts with CCI ≥ 7. Grade 3-4 TRAEs leading to discontinuation did not occur in the CCI 2-4 group, and were reported with similar frequency with dasatinib and imatinib in both CCI 5-6 (1% vs 1%) and CCI ≥ 7 groups (8% vs 7%). No deaths occurred in the CCI 2-4 group; a similar percentage of pts treated with dasatinib and imatinib died in the CCI 5-6 group (8% vs 9%) and CCI ≥ 7 group (13% vs 11%). Conclusions: In this exploratory post hoc analysis, dasatinib was effective across all CCI groups, consistent with previous findings suggesting that comorbidities do not negatively affect TKI activity. Molecular response rates were significantly higher with dasatinib than imatinib in pts with CCI 5-6, and comparable between treatments in pts with CCI ≥ 7. Furthermore, time to response was significantly faster with dasatinib than imatinib in both the CCI 5-6 and CCI ≥ 7 groups, while the frequency of grade 3-4 TRAEs leading to discontinuation was similar between treatments. These findings highlight the benefit of first-line treatment with dasatinib in pts with CML-CP and a high comorbidity burden. Study support: BMS. Figure Disclosures Breccia: Bristol-Myers Squibb/Celgene: Consultancy, Honoraria; Abbvie: Consultancy; Pfizer: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Mauro:Sun Pharma/SPARC: Research Funding; Pfizer: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Takeda: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding. Jabbour:BMS: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding. Saglio:Pfizer: Research Funding; Bristol-Myers Squibb: Research Funding; Incyte: Research Funding; Roche: Research Funding; Ariad: Research Funding; Novartis: Research Funding. le Coutre:Pfizer: Honoraria; Novartis: Honoraria; Incyte: Honoraria. DeGutis:Bristol-Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Khan:Bristol-Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Sy:Bristol-Myers Squibb: Current Employment. Swanink:Bristol-Myers Squibb: Current Employment. Cortes:Amphivena Therapeutics: Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Immunogen: Research Funding; Merus: Research Funding; Bristol-Myers Squibb: Research Funding; Arog: Research Funding; BiolineRx: Consultancy, Research Funding; BioPath Holdings: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Research Funding; Telios: Research Funding; Sun Pharma: Research Funding.

Background High-grade B-cell lymphoma (HGBL) with MYC and BCL2 and/or BCL6 rearrangements (double- and triple-hit lymphoma), as well as diffuse large B-cell lymphoma (DLBCL), NOS with increased expression of MYC and BCL2 protein (double-expressor lymphoma) are associated with a poor prognosis after front-line treatment with standard immunochemotherapy. As such, therapies targeting MYC and BCL2 alterations are urgently needed. Currently, there are no approved therapies that target MYC. Fimepinostat is an investigational small molecule dual inhibitor of phosphotidyl-inositol-3-kinases (PI3Ks) and Class I and II histone deacetylases (HDACs). Both of fimepinostat's dual mechanisms of action lead to decreased MYC protein: PI3K inhibition leads to enhanced ubiquitin-mediated MYC protein degradation, and HDAC inhibition leads to repression of MYC gene expression. PI3K and HDAC were also inhibited by fimepinostat in peripheral blood mononuclear cells collected from patients (pts) receiving fimepinostat therapy. When dosed in combination with venetoclax in non-clinical studies, fimepinostat demonstrated striking synergistic anti-tumor effects in vitro and in vivo with nearly 100% tumor growth inhibition in a double-hit lymphoma mouse xenograft model (Landsburg 2018a). In clinical studies, fimepinostat +/- rituximab was well tolerated with a favorable safety profile in pts with R/R lymphoma, and resulted in robust and durable objective response rates (ORR) in pts with R/R MYC-altered DLBCL with an ORR of 23% and a median duration of response (DOR) of 13.6 months (Landsburg 2018b). Study Design and Methods CUDC-907-101 is a Phase 1/2, multi-center, dose-finding study that was recently amended to evaluate fimepinostat in combination with other anti-cancer therapies, including venetoclax. Cohorts of patients will receive increasing dose levels of fimepinostat administered on a 5-days-on-2-days-off (5/2) schedule in combination with venetoclax in 21-day cycles (Table 1). The primary objectives are to determine the maximum tolerated dose, PK, safety and tolerability, and to assess preliminary efficacy, as measured by the ORR and DOR. Eligible pts must have a histologically-confirmed diagnosis of DLBCL or HGBL with or without MYC and/or BCL2 alterations, which is refractory to, or relapsed after, ≥1 prior lines of therapy. Patients must also have an ECOG performance status of 0 or 1, a life expectancy of ≥3 months, measurable disease per Lugano criteria, and have archived or fresh tumor tissue available. Approximately 12 pts in the Ph 1 dose escalation (3+3 design) and 30 pts in the Ph 2 expansion will be enrolled to receive fimepinostat + venetoclax treatment. Patients will be treated until progression or unacceptable toxicity. The Ph 2 expansion will be an estimation study for detecting an efficacy signal. Patients who receive ≥1 dose and have ≥1 post-baseline response evaluation will be included in the efficacy analysis set. Investigator-assessed ORR based on Lugano criteria will be summarized as the proportion of pts who achieve a best response of CR or PR for each combination, and the corresponding two-sided 95% confidence interval (CI, Clopper-Pearson) will be calculated. DOR will be summarized for pts who achieve response using the Kaplan-Meier (KM) product-limit method. The median DOR along with the two-sided 95% CI using the Brookmeyer and Crowley method will be calculated. PFS and OS will be estimated in pts using the KM product-limit method, along with the median and two-sided 95% CI. The first patient in this study was treated in July 2019, and enrollment is on-going. This new study represents the first clinical trial of the novel-novel combination of fimepinostat with venetoclax in pts with non-Hodgkin lymphoma harboring alterations of both MYC and BCL2. Clinical trial: NCT01742988. References a. Landsburg, D. J. et al., Durable Responses Achieved in Patients with MYC-altered Relapsed/Refractory Diffuse Large B-cell Lymphoma Treated with Fimepinostat (CUDC-907): Combined Results from a Phase 1 and Phase 2 Study. Poster presented at: Society of Hematologic Oncology annual meeting. September 12-15, 2018. b. Landsburg, D. J. et al., (2018). A Pooled Analysis of Relapsed/Refractory Diffuse Large B-Cell Lymphoma Patients Treated with the Dual PI3K and HDAC Inhibitor Fimepinostat (CUDC-907), Including Patients with MYC-Altered Disease. Blood,132(Suppl 1), 4184. Disclosures Younes: Epizyme: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; AstraZeneca: Research Funding; Genentech: Research Funding; Biopath: Consultancy; Xynomics: Consultancy; Syndax: Research Funding; Curis: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Abbvie: Honoraria; Celgene: Consultancy, Honoraria; HCM: Consultancy; BMS: Research Funding; Pharmacyclics: Research Funding; Takeda: Honoraria. Batlevi:Juno Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Cohen:Takeda Pharmaceuticals North America, Inc.: Research Funding; Genentech, Inc.: Consultancy, Research Funding; Bristol-Meyers Squibb Company: Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding; Gilead/Kite: Consultancy; LAM Therapeutics: Research Funding; UNUM: Research Funding; Hutchison: Research Funding; Astra Zeneca: Research Funding; Lymphoma Research Foundation: Research Funding; Janssen Pharmaceuticals: Consultancy; ASH: Research Funding. de Vos:Verastem: Consultancy; Portola Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy. Landsburg:Triphase: Research Funding; Seattle Genetics: Speakers Bureau; Takeda: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Speakers Bureau; Triphase: Research Funding; Takeda: Research Funding. Patel:Sunesis: Consultancy; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Pharmacyclics/Janssen: Consultancy, Speakers Bureau. Phillips:Celgene: Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding; Pharmacyclics: Consultancy, Research Funding; Genentech: Consultancy; Incyte: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy; Seattle Genetics: Consultancy; Bayer: Consultancy. Smith:Portola Pharmaceuticals: Research Funding. Westin:Novartis: Other: Advisory Board, Research Funding; 47 Inc: Research Funding; MorphoSys: Other: Advisory Board; Kite: Other: Advisory Board, Research Funding; Genentech: Other: Advisory Board, Research Funding; Curis: Other: Advisory Board, Research Funding; Juno: Other: Advisory Board; Unum: Research Funding; Celgene: Other: Advisory Board, Research Funding; Janssen: Other: Advisory Board, Research Funding. Ma:Curis, Inc.: Employment. Grayson:Curis, Inc.: Employment. von Roemeling:Curis, Inc.: Employment. Barta:Takeda: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Mundipharma: Honoraria; Seattle Genetics: Honoraria, Research Funding; Bayer: Consultancy, Research Funding; Mundipharma: Honoraria; Merck: Research Funding; Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees.

The present article involves a qualitative study of the framing of dementia in ‘Alzheimer’s and Dementia’, the Journal of the Alzheimer’s Association, published in 2016. The aim of this study is to elucidate how dementia is framed qualitatively in the corpus consisting of scientific articles involving dementia published in ‘Alzheimer’s and Dementia’. The results of the qualitative analysis indicate that dementia is represented in ‘Alzheimer’s and Dementia’ in 2016 as the frames associated with gender, age, costs, caregiver and care-recipients, disability and death, health policy, spatial orientation, medical condition, and ethnic groups. These findings are further discussed in the article. References Andrews, J. (2011). We need to talk about dementia. Journal of Research in Nursing, 16(5),397–399. Aronowitz, R. (2008). Framing Disease: An Underappreciated Mechanism for the SocialPatterning Health. Social Science & Medicine, 67, 1–9. Bayles, K. A. (1982). 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AbstractTo report the status of switch rates and time-to-switch of antiretroviral therapy (ART) regimens by evaluating anchor drug classes and common switching patterns in Japanese people living with human immunodeficiency virus (HIV, PLWH). This cross-sectional cohort study extracted data of 28,089 PLWH from the National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB), which contains data representing the entire population of Japan. PLWH with first prescription records of ART administered between January 2011 and March 2019 were identified (n = 16,069). The median time-to-switch and switch rates of anchor drug classes were estimated by Kaplan–Meier analysis. Brookmeyer–Crowley and Greenwood methods were used to estimate 95% confidence intervals for switch rates and median days, respectively. Switch rates were compared between anchor drug classes by year using log-rank tests. A total of 3108 (19.3%) PLWH switched anchor drug classes from first to second regimens. Switch rates increased continuously over 8 years for non-nucleoside reverse transcriptase inhibitors (NNRTIs) (14.9–65.5%) and protease inhibitors (PIs) (13.2–67.7%), with median time-to-switch of 1826 and 1583 days, respectively. Integrase strand transfer inhibitors (INSTIs) maintained a low switch rate (3.0–7.6%), precluding median-days calculation. Overall, the majority of patients treated initially with NNRTIs and PIs switched to INSTIs regardless of switching times (< 1 year: 67.3% and 85.9%, respectively; ≥ 1 year: 95.5% and 93.6%, respectively). The foremost switching strategies for first-to-second ART regimens are from NNRTIs or PIs to INSTIs regimens that maintain low switch rates long term. There was no observable difference in trend between sex, age and status of AIDS disease at first ART regimen. INSTIs HIV agents may be the most durable anchor drug class for PLWH receiving ART.