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TPS8551 Background: Multiple myeloma (MM) remains an incurable disease, with estimated median survival of 8–9 months in patients with relapsed or refractory (R/R) disease (Kumar et al. 2014; Usmani et al. 2016). There is no uniform standard of care for R/R MM, and combinations used in later lines have diminishing responses, especially after re-exposure to previously received classes of therapy (Gandhi et al. 2019). New targets and treatment modalities are needed. Fragment crystallizable receptor-like 5 (FcRH5) is expressed on myeloma cells across lines of therapy, and is overexpressed by myeloma cells with 1q21 gain; expression in healthy tissue is restricted to the B-cell lineage, and is retained in plasma cells (Li et al. 2017). BFCR4350A is an IgG-based T-cell-dependent bispecific antibody that was specifically engineered to target the most membrane-proximal domain of FcRH5 on myeloma cells and cluster of differentiation 3 (CD3) on T cells, with dual binding resulting in efficient immune synapse formation and T-cell killing of myeloma cells. BFCR4350A demonstrates potent killing of plasma cells and patient-derived myeloma cells (including those with low levels of FcRH5 expression) in vitro, and complete depletion of bone marrow plasma cells in primates, without severe or prolonged cytokine release (Li et al. 2017). GO39775 (NCT03275103) is an open-label, multicenter Phase I dose-escalation and dose-expansion trial evaluating the safety, pharmacokinetics (PK), and activity of BFCR4350A monotherapy in patients with R/R MM. Methods: Patients must be aged ≥18 years and must have R/R MM for which no established therapies are available or appropriate, or be intolerant to those therapies. Patients with prior CAR-T therapy and/or prior BCMA-directed therapy are not excluded. BFCR4350A is administered by intravenous infusion, and q3w dosing with Cycle 1 single-step or multi-step dosing is being investigated in dose-escalation (Arms A and B, respectively). Enrolment into both arms is ongoing, with patients receiving up to 17 cycles of treatment until disease progression or unacceptable toxicity. Primary objectives are to evaluate safety (including the maximum tolerated dose and dose-limiting toxicities) and to identify a recommended Phase II dose. Secondary objectives include assessment of PK, activity, immunogenicity, and pharmacodynamic biomarkers. Clinical trial information: NCT03275103 .

8547 Background: Venetoclax (Ven) is a selective, potent BCL-2 inhibitor that has synergistic activity with bortezomib (B) and dexamethasone (d). In the Phase 3 BELLINI trial, addition of Ven to Bd significantly improved median progression-free survival (PFS) and response rates, including minimal residual disease (MRD) negativity, but resulted in increased mortality vs placebo (Pbo). Here, we determine whether MRD negativity was associated with longer PFS and OS in relapsed/refractory multiple myeloma (RRMM) patients treated with Ven+Bd in the BELLINI dataset. Methods: In BELLINI (NCT02755597), RRMM patients (pts) sensitive or naïve to proteasome inhibitors with 1-3 prior lines of therapy were randomized 2:1 to Ven (800 mg) or Pbo plus B (1.3 mg/m2) and d (20 mg). Next-gen sequencing MRD assessments were done on bone marrow aspirates at the time of suspected CR/sCR, and 6- and 12-months post confirmation of CR/sCR. Patients with a missing or indeterminate assessment were considered MRD positive. Evaluation of MRD in biomarker-defined subgroups (cytogenetics and BCL2 expression) was also performed and will be presented. Results: In total, 291 pts were randomized; 194 to Ven, 97 to Pbo. As of 13 Sep 2019, the median follow-up was 29 months. Ven + Bd demonstrated significantly higher MRD negativity rates ( < 10−5), including a higher proportion of pts achieving sustained MRD negativity (Table). In the Ven arm, the median (m)PFS was not reached for MRD negative pts vs 16.2 months for MRD positive pts (HR = 0.23, 95% CI: 0.10-0.54, p < 0.001). While the mOS was not reached in the Ven arm, OS was significantly longer for MRD negative vs MRD positive pts (HR = 0.25, 95% CI: 0.08-0.80, p = 0.0194). Conclusions: The addition of Ven to Bd resulted in deep and durable responses, including higher rates of MRD negativity. MRD negativity in the context of Ven was associated with prolonged survival in patients with RRMM, consistent with the broader MRD body of evidence with other therapies in MM. Clinical trial information: NCT02755597 . [Table: see text]

8509 Background: Venetoclax (Ven) is a selective, potent, oral BCL-2 inhibitor. In the Phase 3 BELLINI trial, addition of Ven to bortezomib (B) + dexamethasone (d) significantly improved response rates and progression-free survival (PFS) vs placebo (Pbo) and showed significant efficacy in patients (pts) with either t(11;14) or BCL2high gene expression. Here we present updated safety and efficacy data from the prespecified second interim overall survival (OS) analysis. Methods: In this multicenter, randomized, double-blind study (NCT02755597), pts with relapsed/refractory multiple myeloma (RRMM) with 1-3 prior lines of therapy were randomized 2:1 to Ven (800 mg) or Pbo in combination with B (1.3 mg/m2) and d (20 mg). The primary endpoint was PFS; key secondary endpoints included overall response and overall survival (OS). Results: 291 pts were randomized; 194 to Ven, 97 to Pbo. Pt characteristics were well balanced among arms. In the Ven arm, median age was 66, 17% had high-risk cytogenetics, 11% had t(11;14), and 34% had BCL2high gene expression. As of 13 Sept 2019, 59 pts were still on study, 45 (23%) Ven vs 14 (14%) Pbo. At a median follow-up of 28.6 months, there were 64 (33%) deaths in the Ven arm vs 24 (25%) in Pbo. At the initial data cutoff (26 Nov 2018), PFS HR was 0.63 (0.44,0.90) and OS HR was 2.03 (1.04,3.95). Table shows updated PFS and OS. Most common treatment-emergent adverse events (TEAEs) with Ven were diarrhea (59%), nausea (37%), and constipation (35%). Most common grade 3/4 AEs (Ven/Pbo) were neutropenia (21%/8%), thrombocytopenia (15%/30%), anemia (16%/15%), diarrhea (15%/12%), and pneumonia (18%/13%). Serious AEs occurred in 54% Ven and 52% Pbo pts. 24% discontinued Ven due to AEs vs 12% Pbo. There were 14 treatment-emergent deaths in the Ven arm and 1 in Pbo. Conclusions: The addition of Ven to Bd significantly improves PFS but resulted in increased mortality vs Pbo in the total population. Greatest PFS improvement with Ven was observed in pts with t(11;14) or BCL2high gene expression, where Ven shows a favorable benefit-risk profile. The study continues for final OS analysis. Clinical trial information: NCT02755597 . [Table: see text]

AbstractBackgroundPostmenopausal hormone therapy (HT) is associated with a decreased colorectal cancer (CRC) risk. As CRC is a heterogeneous disease, we evaluated whether the association of HT and CRC differs across etiologically relevant, molecularly defined tumor subtypes and tumor location.MethodsWe pooled data on tumor subtypes (microsatellite instability status, CpG island methylator phenotype status, BRAF and KRAS mutations, pathway: adenoma-carcinoma, alternate, serrated), tumor location (proximal colon, distal colon, rectum), and HT use among 8220 postmenopausal women (3898 CRC cases and 4322 controls) from 8 observational studies. We used multinomial logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CIs) for the association of ever vs never HT use with each tumor subtype compared with controls. Models were adjusted for study, age, body mass index, smoking status, and CRC family history. All statistical tests were 2-sided.ResultsAmong postmenopausal women, ever HT use was associated with a 38% reduction in overall CRC risk (OR =0.62, 95% CI = 0.56 to 0.69). This association was similar according to microsatellite instability, CpG island methylator phenotype and BRAF or KRAS status. However, the association was attenuated for tumors arising through the serrated pathway (OR = 0.81, 95% CI = 0.66 to 1.01) compared with the adenoma-carcinoma pathway (OR = 0.63, 95% CI = 0.55 to 0.73; Phet =.04) and alternate pathway (OR = 0.61, 95% CI = 0.51 to 0.72). Additionally, proximal colon tumors had a weaker association (OR = 0.71, 95% CI = 0.62 to 0.80) compared with rectal (OR = 0.54, 95% CI = 0.46 to 0.63) and distal colon (OR = 0.57, 95% CI = 0.49 to 0.66; Phet =.01) tumors.ConclusionsWe observed a strong inverse association between HT use and overall CRC risk, which may predominantly reflect a benefit of HT use for tumors arising through the adenoma-carcinoma and alternate pathways as well as distal colon and rectal tumors.

Abstract Background: Pre-treatment cytogenetics is a known predictor of outcome in haematological malignancies. However, its value in adult ALL is generally limited to the presence of the Philadelphia (Ph) translocation; mostly due to the low incidence of other recurrent chromosomal abnormalities. Methods: Since 1993, cytogenetic data from patients enrolled on a joint MRC/ECOG trial have been collated and reviewed centrally in the UK and US. Karyotype data from patients registered before the Imatinib amendment were pooled using standard cytogenetic definitions and classification criteria. Results: A successful cytogenetic result was achieved in 938/1235 (76%) cases; while 297 (24%) failed with &lt;20 normal metaphases analyzed. Patients were classified into the following mutually exclusive groups: t(9;22)(q34;q11) n=193(21%); t(4;11)(q21;q23) n=50(5%); other MLL translocations n=11(1%), t(8;14)(q24;q32) and variants n=14(1%); t(1;19)(q23;p13) n=23(2%); T cell receptor translocations n=35(4%); low hypodiploidy (30–39 chromosomes) /near triploidy n=23(2%); high hyperdiploidy n=83(9%); tetraploidy n=12(1%); complex karyotype (&gt;=5 aberrations) n=48(5%); other abnormal n=255(27%); normal n=191(20%). MRC and ECOG patients showed similar cytogenetic distributions, except for t(9;22), which was significantly more prevalent in the ECOG cohort (27% v 18%, p&lt;0.001). However, the incidence of t(9;22) increased with age and ECOG patients were significantly older. Overall, the 5 year event free survival (EFS) was 32% (95% CI 30%–35%) with a median follow-up time of 5.1 years and did not differ between the two cohorts. The EFS of t(9;22) patients [15% (11%–21%)] was significantly inferior compared with all other cases [36% (32%–39%)] (p&lt;0.001) and was independent of age and white cell count (WCC). Univariate logrank analyses identified t(4;11) and high hyperdiploidy as indicators of poor and good prognosis, respectively, compared with other Ph negative cases, but neither was independent of age and WCC. Three subgroups were shown to have a significantly worse EFS compared to other Ph negative cases by logrank analyses after adjusting for age and WCC: t(8;14) 14% (2%–37%) v 36% (32%–40%) (p=0.01); low hypodiploidy 22% (8%–40%) v 36% (32%–40%) (p=0.02); complex karyotype 21% (10%–33%) v 32% (29%–35%) (p=0.005). Neither of the latter two subgroups were associated with other poor risk features such as age, WCC or failure to achieve a remission within 4 weeks. Conclusions: This is the largest cytogenetic dataset of adult ALL reported to date and demonstrates the importance of combining cohorts to increase the number of cases available for analysis. The observation that low hypodiploidy and, for the first time, karyotype complexity confer a poor risk, demonstrates that cytogenetic subgroups other than the Ph translocation can and should be used to risk stratify adults with ALL to alternative treatments.

Cold‐water swimming is a recreational activity that may become a future Winter Olympic event. However, unintentional cold‐water exposure can lead to hypothermia or death. Changes in body temperature are known to diminish swimming performance in persons experiencing hypothermia, although thermal changes during recreational exposure are not well characterized. This study examined skin temperature responses to a one‐kilometer swim in normal and cold‐water. Competitive swimmers (2 male and 2 female; age 44±17 years; BMI 24±2) completed a one‐kilometer swim (22 laps × 75 foot lengths) under free‐living indoor (25.5°C water and 25.0°C air) and cold outdoor (10.9°C water and 6.5°C) conditions. Skin temperature was determined with a digital infrared camera on the center of right palm, cubital fossa of arm, lateral aspect of pectoral muscle, cheek, and average of the four locations at 8.7±1.7 minutes before the swim (pre), then 0.6±0.2 and 6.4±2.1 minutes after the swim. Data (mean±SD) was analyzed with repeated measures ANOVA with significance if P<0.05. Swimmers completed the indoor and outdoor swim events in 20.7±1.7 and 21.8±1.1 minutes respectively. Average indoor skin temperature at −8.7, +0.6 and +6.4 minutes was 94.0±1.7, 85.3±1.9, and 88.1±2.2°C. Average outdoor skin temperature at −8.7, +0.6 and +6.4 minutes was 83.0±3.6, 53.5±2.3, and 67.7±2.0°C. At all times average outdoor skin temperature was lower than indoor, with the lowest temperature 0.6 minutes post‐swim. Palm indoor temperature at −8.7, +0.6 and +6.4 minutes was 91.6±3.9, 83.1±0.5, and 87.3±5.0°C. Palm outdoor temperature at −8.7, +0.6 and +6.4 minutes was 75.1±7.9, 47.4±2.7, and 58.1±2.7°C. At all times outdoor palm temperature was lower than indoor, with the lowest temperature 0.6 minutes post‐swim. Similar thermal responses were observed in the cheek, cubital fossa and pectoral locations. While time to complete the indoor and outdoor one km swims were similar, swimming in cold water was associated with delayed rewarming in the palm and cheek relative to cubital fossa and pectoral muscle.

Cold‐water swimming is a recreational activity that may become a future Winter Olympic event. However, unintentional cold‐water exposure can lead to arrhythmias, changes in electrocardiogram (ECG) appearance, and death. This study sought to characterize cardiac responses to recreational one‐kilometer swims performed in normal and cold‐water. Competitive swimmers (2 male 2 female; age 44±17 years; BMI 24±2) completed a one‐kilometer swim (22 laps × 75‐foot lengths) under free‐living indoor (25.5°C water and 25.0°C air) and cold outdoor (10.9°C water and 6.5°C) conditions. Continuous ECGs were obtained with a waterproof recording system (Actiwave, CamNtech Inc., Boerne, TX). ECG PR‐, QT‐, and RR‐intervals (sec), ventricular diastole (sec), and heart rate (beats/minute) were measured 8.7±1.7 minutes before the swim, then 0.6±0.2, 3.0±0.0 and 6.4±2.1 minutes after the swim. Data (mean±SD) was analyzed with repeated measures ANOVA with significance if P<0.05. Swimmers completed the indoor and outdoor swim events in 20.7±1.7 and 21.8±1.1 minutes, respectively. For the indoor swim, PR‐interval (sec) at −8.7, +0.6, +3, and +6.4 minutes was 0.12±0.01, 0.12±0.01, 0.11±0.01, and 0.12±0.01, and PR‐interval for the outdoor swim at −8.7, +0.6, +3.0 and +6.4 minutes was 0.13±0.01, 0.13±0.01, 0.13±0.01, and 0.14±0.01 (sec). PR‐interval was significantly longer at +6.4 minutes post cold‐water swim. For the indoor swim, ventricular diastole (sec) at −8.7, +0.6, +3, and +6.4 minutes was 0.37±0.06, 0.22±0.04, 0.30±0.01, and 0.32±0.05 (sec), and for the outdoor swim at −8.7, +0.6, +3.0 and +6.4 minutes ventricular diastole was 0.35±0.08, 0.19±0.02, 0.30±0.04, and 0.24±0.06 (sec). Ventricular diastole was significantly shorter at +6.4 minutes post cold‐water swim. No significant changes were observed for QT‐interval, RR‐interval, and heart rate between swim conditions. These parameters were also assessed for the ECG recordings collected during the 20.7±1.7‐minute normal and 21.8±1.1‐minute cold‐water swims to characterize the physiological response during swim exercise. This study of normal and cold‐water one‐kilometer recreational swimmers determined that a waterproof ECG could generate a continuous record of changes in cardiac function. During cold‐water swim recovery (+6.4 minutes) PR interval was lengthened and ventricular diastole was shortened suggesting an influence of temperature on cardiac function.

Abstract Background: Myelofibrosis (MF) shortens survival but also compromises quality of life from disease associated splenomegaly and constitutional symptoms (fatigue, weight loss, night sweats, and bone pain). No current validated instrument of patient reported outcomes (PRO) captures the spectrum of MF associated symptoms. In an era of rapid development and testing of therapeutic agents which may impact the natural history and symptoms associated with MF (such as JAK2 inhibitors) a uniform and validated instrument for capturing the presence, severity (and potentially improvement) of MF symptoms is needed. We sought to develop and validate such an instrument, the myelofibrosis symptom assessment form (MFSAF). Methods: Based upon the results in our MF QOL survey (Cancer2007;109(1):68–76), we developed the MFSAF to assess fatigue (via the brief fatigue inventory (BFI-Cancer1999;85:1186)), additional symptoms were independently assessed for presence and severity on a scale from 0 (absent) to 10 (worst possible) for splenomegaly associated symptoms (early satiety, pain, inactivity, cough) night sweats, itching, bone pain, fever, unintentional weight loss as well as an estimate of overall quality of life. Additionally, patients provided feedback on the quality and nature of the MFSAF, and also completed for comparison validated instruments including the Memorial Symptom Assessment Scale (MSAS), the Insomnia Severity Index (ISI), and the Brief Pain Index. Physician input was included including their assessment of patient’s fatigue, spleen symptoms, and quality of life (blinded to patient’s responses) as well as clinical history, lab and exam findings. Results: MFSAF Results 34 MPD patients were enrolled (24 MF, 10 in the comparison group (4 polycythemia vera (PV), 6 essential thrombocythemia (ET)). the MFSAF was rated by patients as easy to understand (median score 1, range 0–6), and “addressed most of my symptoms” (median score 1, range 0–6) both on a scale of 0 (as good as possible to 10 as bad as possible). When asked if a symptom was not addressed (open ended response) no single symptom was named more than once. As we have previously reported fatigue was common with BFI scores (median 3.6 (0–10) for MF and 2.5 (range 0.2–3.8) for the ET/PV group (increasing BFI score associated with worsening fatigue) worse than median score of published “healthy” controls 2.2. Additional MF associated symptoms were captured well by the MFSAF with splenic, constitutional symptoms, and QOL (median 3 (range 0–7) MF, median 2 (0–3) ET/PV) documented easily and worse than ET/PV controls. Physicians estimation of QOL was excellent (median 3 (0–8) for MF, median 2 (0–4) for ET/PV). MFSAF Comparison to other Instruments: The MSAS demonstrated more adverse values for MF (than ET/PV) in the PSYCH (psychologic stress; mean-1.27 (STD DEV 0.80), PHYS (physical symptoms; mean 0.90 (STD DEV 0.53)), GDI (Global Distress Index mean-1.29 (STD DEV 0.77)) and a total MSAS symptom score (mean 0.85 (std dev (0.49)) comparable with advanced renal disease (PSYCH 0.99, PHYS 0.99, GDI 1.27, and MSAS of 0.81; J of Pall Med2007;10(6):1266), as well as advanced lung disease, AIDS, and various advanced malignancies. Individual, previously validated MSAS questions were all highly correlated (all p&lt;0.01) with MFSAF (in italic) counterparts including lack of energy (fatigue), cough (same), pain (both abdominal pain and bone pain), sweats (night sweats), itching (same), and weight loss (same). Further validation of pain measurements in the MFSAF came from comparison to the BPI where both individually the presence, and intensity of pain (both abdominal and bone) were highly correlated (all p&lt;0.01). Insomnia, not yet included in the MFSAF, was present in 68% and 63% of patients (MSAS and ISI, respectively). Additionally, problems with sexual interest, or activity, was noted in 35% of patients to the MSAS. Conclusions: Currently available instruments of PRO and symptoms are lengthy, and individually incomplete for assessing the presence and severity of the diverse nature of symptoms associated with MF. The proposed MFSAF, was comprehensive and well understood by patients and the results for the individual symptoms assessed were highly correlated with previously validated instruments for other conditions as well as with physicians perceptions of fatigue and QOL. The MFSAF, with the addition of questions regarding insomnia and sexuality, should be utilized in all trials of therapeutic agents in MF patients in which symptomatic improvements are an endpoint.

Assessments of electrocardiographic (ECG) responses during swimming activities are impossible without mobile waterproof recording units and rarely completed. This preliminary study characterized changes in the ventricular diastolic, PR‐, QT‐, and RR‐intervals that occurred during a 1 km indoor swim in 78°F water with a waterproof Actiwave ECG recording system (CamNtech Inc., Boerne, TX) and the .epf data files were analyzed with software from ADInstruments Inc. (Colorado Springs CO). Values within times expressed as mean ± SE with significance evaluated using ANOVA and repeated measures. Competitive club swimmers (3 male, 1 female) with an age, height, and weight of 51 ± 3 years, 175 ± 4 cm, and 83 ± 8 kg, with a BMI of 27 ± 2 completed the 1 km swim (44 laps × 75 foot laps) using a standard crawl in 17.9 ± 1.3 minutes using 10.5 ± 0.50 arm cycles/second. A continuous ECG with waveform was obtained and measurements were performed 120 and 30 seconds before swim, during the swim (at end of lap‐1, ‐22 and ‐43), and at 30 and 300 seconds post‐completion. Heart rate (from RR‐interval) −120, and −30 seconds prior to the swim, at end of swim lap 1, 22 and 43, and during recovery 30 and 300 seconds post swim was 68 ± 5, 73 ± 6, 107 ± 3, 142 ± 4, 147 ± 5, 132 ± 8 and 89 ± 3 beats/minute (P<0.0001). Respective QT‐intervals were 392 ± 14, 374 ± 13, 307 ± 38, 259 ± 15, 254 ± 2, 255 ± 14, and 338 ± 6 msec (n = 2 at lap‐1, and n = 3 at lap‐22) (P<0.0001). Respective ventricular diastole time was 509 ± 61, 468 ± 61, 253 ± 45, 166 ± 10, 166 ± 7, 204 ± 25 and 339 ± 26 msec (P<0.0001). Respective PR‐Intervals were 130 ± 12, 127 ± 12, 111 ± 18, 111 ± 2, 105 ± 14, 107 ± 15 and 125 ± 18 msec (P<0.094). Heart rate increased and duration of ventricular diastole decreased between lap 1 and 22, and was relatively stable between lap 22 and the end of lap 43. This study determined that with appropriate waterproof equipment a continuous ECG record can be collected from swimming athletes and used to provide an accurate assessment swim‐associated changes in cardiac function. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .