Virginia Mason Memorial

BACKGROUND: Some copy-number variants are associated with genomic disorders with extreme phenotypic heterogeneity. The cause of this variation is unknown, which presents challenges in genetic diagnosis, counseling, and management. METHODS: We analyzed the genomes of 2312 children known to carry a copy-number variant associated with intellectual disability and congenital abnormalities, using array comparative genomic hybridization. RESULTS: Among the affected children, 10.1% carried a second large copy-number variant in addition to the primary genetic lesion. We identified seven genomic disorders, each defined by a specific copy-number variant, in which the affected children were more likely to carry multiple copy-number variants than were controls. We found that syndromic disorders could be distinguished from those with extreme phenotypic heterogeneity on the basis of the total number of copy-number variants and whether the variants are inherited or de novo. Children who carried two large copy-number variants of unknown clinical significance were eight times as likely to have developmental delay as were controls (odds ratio, 8.16; 95% confidence interval, 5.33 to 13.07; P=2.11×10(-38)). Among affected children, inherited copy-number variants tended to co-occur with a second-site large copy-number variant (Spearman correlation coefficient, 0.66; P<0.001). Boys were more likely than girls to have disorders of phenotypic heterogeneity (P<0.001), and mothers were more likely than fathers to transmit second-site copy-number variants to their offspring (P=0.02). CONCLUSIONS: Multiple, large copy-number variants, including those of unknown pathogenic significance, compound to result in a severe clinical presentation, and secondary copy-number variants are preferentially transmitted from maternal carriers. (Funded by the Simons Foundation Autism Research Initiative and the National Institutes of Health.).

Deletions at 2p16.3 involving exons of NRXN1 are associated with susceptibility for autism and schizophrenia, and similar deletions have been identified in individuals with developmental delay and dysmorphic features. We have identified 34 probands with exonic NRXN1 deletions following referral for clinical microarray-based comparative genomic hybridization. To more firmly establish the full phenotypic spectrum associated with exonic NRXN1 deletions, we report the clinical features of 27 individuals with NRXN1 deletions, who represent 23 of these 34 families. The frequency of exonic NRXN1 deletions among our postnatally diagnosed patients (0.11%) is significantly higher than the frequency among reported controls (0.02%; P = 6.08 × 10(-7) ), supporting a role for these deletions in the development of abnormal phenotypes. Generally, most individuals with NRXN1 exonic deletions have developmental delay (particularly speech), abnormal behaviors, and mild dysmorphic features. In our cohort, autism spectrum disorders were diagnosed in 43% (10/23), and 16% (4/25) had epilepsy. The presence of NRXN1 deletions in normal parents and siblings suggests reduced penetrance and/or variable expressivity, which may be influenced by genetic, environmental, and/or stochastic factors. The pathogenicity of these deletions may also be affected by the location of the deletion within the gene. Counseling should appropriately represent this spectrum of possibilities when discussing recurrence risks or expectations for a child found to have a deletion in NRXN1.

Abstract Introduction Chemoimmunotherapy with purine analogues and the anti-CD20 antibody rituximab is the standard of care as initial therapy in younger and physically fit patients with chronic lymphocytic leukemia (CLL). However, most CLL patients are elderly and/or have comorbidities, meaning that fludarabine-containing regimens are often inappropriate, carry greater toxicity, and treatment of these patients remains challenging. Most randomized studies in previously untreated CLL have been conducted in younger or fit patients and results cannot necessarily be extrapolated to older, less fit patients. While chlorambucil (CHL) remains a standard of care for this patient population, more effective but tolerable treatment choices are still needed. Ofatumumab (O) demonstrated superior preclinical activity, compared to rituximab, against cells with low CD20 density like CLL and showed clinical activity as monotherapy, with high overall response rates (ORR) in patients with refractory CLL. Therefore, the addition of O to CHL could provide superior clinical outcomes than CHL alone, while being tolerable, for patients who are elderly and/or have comorbidities and currently have limited treatment options. Methods Patients with CLL who required therapy (2008 NCI-WG guidelines) and were considered inappropriate for fludarabine-based therapy due to advanced age and/or co-morbidities were randomized (1:1) to receive either O+CHL or CHL. CHL was given orally (10mg/m2 at days 1-7 of each 28 day cycle) and O was administered as intravenous infusions (Cycle 1: 300mg day 1 and 1000mg day 8, subsequent cycles: 1000mg at day 1). O premedication included acetaminophen, antihistamine and glucocorticoid. Treatment duration was a minimum of 3 cycles, until best response up to a maximum of 12 cycles. The primary endpoint was progression-free survival (PFS) assessed by an Independent Review Committee (IRC) and secondary endpoints included overall response rate (ORR), overall survival (OS) and safety. Patients 447 patients from 16 countries were randomized. Baseline demographics and disease characteristics were well balanced between the 2 arms. Median age was 69 years with 82% ≥65 years and/or having ≥2 comorbidities. All modified Rai stages were represented (Low 8%, intermediate 51%, high 40%). 56% of patients had unmutated IgVH, 6% showed 17p deletions and 75% had β-2-microglobulin levels ≥3500μg/L. Results PFS as assessed by an IRC was significantly prolonged in the O+CHL arm (22.4 months) compared to CHL alone (13.1 months, p&lt;0.001). ORR was higher for O+CHL vs CHL (82% vs 69%, p=0.001), with a superior CR rate (12% vs 1%). 37% of O+CHL subjects with an IRC-assessed CR were MRD negative. With a median follow-up of 29 months, median OS was not reached for O+CHL or CHL. Median duration of treatment for both arms was 6 cycles and 82% of patients received 6 or more cycles of O+CHL. Grade ≥3 AEs that occurred from start of treatment until 60 days after the last dose were experienced by 50% of patients receiving O-CHL and 43% of patients on CHL with the most common being neutropenia (O+CHL: 26%, CHL: 14%). Grade ≥3 infusion-related AEs were reported in 10% of patients. No fatal infusion reactions were reported. Grade ≥3 infections were reported in 15% (O+CHL) and 14% (CHL) of patients, with the most common infection being pneumonia (O+CHL: 4%, CHL: 3%). Deaths during treatment occurred in 2% of subjects in both arms. Conclusion Ofatumumab added to chlorambucil (O+CHL) demonstrated clinically important improvements with a manageable side effect profile in patients with CLL who have not received prior therapy and who are considered inappropriate for fludarabine based therapy. Disclosures: Hillmen: Roche Pharmaceuticals: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Pharmacyclics: Research Funding; Celgene: Honoraria; GlaxoSmithKline: Honoraria, Research Funding. Off Label Use: The use of ofatumumab in combination with chlorambucil in previously untreated CLL. The reported trial will support the extension of the ofatumumab licence. Robak:GlaxoSmithKline: Honoraria, Research Funding. Janssens:GlaxoSmithKline: Speakers Bureau; Roche: Speakers Bureau; Mundipharma: Speakers Bureau; Amgen: Speakers Bureau. Mayer:Glaxo: Consultancy, Research Funding; Roche: Consultancy, Research Funding. Panagiotidis:Novartis: Consultancy, Honoraria; Roche: Consultancy, Honoraria; GSK: Consultancy, Honoraria. Kimby:Pharmacyclics: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Teva: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Mundipharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Emergent: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Schuh:GSK: Honoraria, Research Funding. Montillo:Janssen: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Mundipharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; GSK: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. McKeown:GSK: Employment. Carey:GlaxoSmithKline: Employment. Gupta:GSK: Employment. Chang:GSK: Employment. Lisby:Genmab: Employment, hold stock options Other. Offner:Lilly: Membership on an entity’s Board of Directors or advisory committees.

PURPOSE: To determine whether a low-fat diet high in vegetables, fruit, and fiber differentially affects prognosis in breast cancer survivors with hot flashes (HF) or without HF after treatment. PATIENTS AND METHODS: A secondary analysis was conducted on 2,967 breast cancer survivors, age 18 to 70 years, who were randomly assigned between 1995 and 2000 in a multicenter, controlled trial of a dietary intervention to prevent additional breast cancer events and observed through June 1, 2006. We compared the dietary intervention group with a group who received five-a-day dietary guidelines. RESULTS: Independent of HF status, a substantial between-group difference among those who did and did not receive dietary guidelines was achieved and maintained at 4 years in intake of vegetable/fruit servings per day (54% higher; 10 v 6.5 servings/d, respectively), fiber (31% higher; 25.5 v 19.4 g/d, respectively), and percent energy from fat (14% lower; 26.9% v 31.3%, respectively). Adjusting for tumor characteristics and antiestrogen treatment, HF-negative women assigned to the intervention had 31% fewer events than HF-negative women assigned to the comparison group (hazard ratio [HR] = 0.69; 95% CI, 0.51 to 0.93; P = .02). The intervention did not affect prognosis in the women with baseline HFs. Furthermore, compared with HF-negative women assigned to the comparison group, HF-positive women had significantly fewer events in both the intervention (HR = 0.77; 95% CI, 0.59 to 1.00; P = .05) and comparison groups (HR = 0.65; 95% CI, 0.49 to 0.85; P = .002). CONCLUSION: A diet with higher vegetable, fruit, and fiber and lower fat intakes than the five-a-day diet may reduce risk of additional events in HF-negative breast cancer survivors. This suggestive finding needs confirmation in a trial in which it is the primary hypothesis.

Purpose This first-in-human study evaluated SGN-CD70A, an antibody-drug conjugate (ADC) directed against the integral plasma membrane protein CD70 and linked to a pyrrolobenzodiazepine (PBD) dimer, in patients with relapsed or refractory (R/R) CD70-positive non-Hodgkin lymphoma (NHL) including diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL), and Grade 3b follicular lymphoma (FL3b). Methods SGN-CD70A was administered intravenously on Day 1 of 3-week cycles beginning at 8 mcg/kg with planned dose escalation to 200 mcg/kg. Due to observations of prolonged thrombocytopenia, the study was amended to dose every 6 weeks (q6wk). Results Twenty patients were enrolled and treated with SGN-CD70A. The maximum tolerated dose of SGN-CD70A was 30 mcg/kg q6wk. The most common adverse events (AEs) reported were thrombocytopenia (75%), nausea (55%), anemia (50%), and fatigue (50%). The onset for treatment-related thrombocytopenia typically occurred during Cycle 1. Most of the treatment-related events of thrombocytopenia were ≥ Grade 3. Antitumor activity in patients included 1 complete remission (CR) and 3 partial remissions (PRs), 2 of which were ongoing for at least 42.9 weeks. SGN-CD70A exposures were approximately dose proportional, with a mean terminal half-life of 3 to 5 days. Conclusions While modest single-agent activity was observed in heavily pretreated NHL patients, the applicability of SGN-CD70A is limited by the frequency and severity of thrombocytopenia, despite the long-term response with limited drug exposure.

This study evaluated the efficacy and safety of single-agent bortezomib in indolent B-cell lymphoma that had relapsed from or was refractory to rituximab. Sixty patients enrolled: 59 were treated with bortezomib 1.3 mg/m(2) on days 1, 4, 8, and 11 for up to eight 21-day cycles; responders could receive 4 additional cycles; maintenance was optional. Fifty-three evaluable patients completed more than 2 cycles. The median age was 70 years, 53% female, Ann Arbor stage III-IIIE (28%) and IV (65%); 43 patients (72%) had more than 2 prior regimens; and 6 patients went on to maintenance. Overall responses are as follows: 1 complete response (1.9%), 3 unconfirmed complete response (5.7%), 3 partial response (5.7%), 34 stable disease (64.2%), and 12 progressive disease (22.6%). Median time to response = 2.2 months (range, 1.2-5.3 months); duration of response = 7.9 months (2.8-21.3 months); 1-year survival was 73% and 2-year survival was 58%; median survival = 27.7 months (range, 1.4-30.9 months); median progression-free survival = 5.1 months (range, 0.2-27.7 months), median time to progression = 5.1 months (range, 0.2-27.7 months), and median event-free survival = 1.8 months (range, 0.2-27.7 months). Treatment-related grade 3 or 4 adverse events included: thrombocytopenia (20%), fatigue (10%), neutropenia (8.5%), and neuropathy and diarrhea (6.8% each). This study demonstrates that bortezomib has modest activity against marginal zone and follicular lymphoma; it has the potential for combination with other agents in low-grade lymphomas. Maintenance therapy should be explored further.

Multiple myeloma is a treatable, but currently incurable, hematological malignancy of plasma cells characterized by diverse and complex tumor genetics for which precision medicine approaches to treatment are lacking. The Multiple Myeloma Research Foundation’s Relating Clinical Outcomes in Multiple Myeloma to Personal Assessment of Genetic Profile study ( NCT01454297 ) is a longitudinal, observational clinical study of newly diagnosed patients with multiple myeloma (n = 1,143) where tumor samples are characterized using whole-genome sequencing, whole-exome sequencing and RNA sequencing at diagnosis and progression, and clinical data are collected every 3 months. Analyses of the baseline cohort identified genes that are the target of recurrent gain-of-function and loss-of-function events. Consensus clustering identified 8 and 12 unique copy number and expression subtypes of myeloma, respectively, identifying high-risk genetic subtypes and elucidating many of the molecular underpinnings of these unique biological groups. Analysis of serial samples showed that 25.5% of patients transition to a high-risk expression subtype at progression. We observed robust expression of immunotherapy targets in this subtype, suggesting a potential therapeutic option. Longitudinal genomic and transcriptomic profiling of 1,143 patients with multiple myeloma by the Relating Clinical Outcomes in Multiple Myeloma to Personal Assessment of Genetic Profile study yields an improved copy number and gene expression subtype scheme, most notably a high-risk proliferative subtype associated with complete loss of RB1 or MAX.

BACKGROUND: Substantial variability exists in the care of febrile, well-appearing infants. We aimed to assess the impact of a national quality initiative on appropriate hospitalization and length of stay (LOS) in this population. METHODS: The initiative, entitled Reducing Variability in the Infant Sepsis Evaluation (REVISE), was designed to standardize care for well-appearing infants ages 7 to 60 days evaluated for fever without an obvious source. Twelve months of baseline and 12 months of implementation data were collected from emergency departments and inpatient units. Ill-appearing infants and those with comorbid conditions were excluded. Participating sites received change tools, run charts, a mobile application, live webinars, coaching, and a LISTSERV. Analyses were performed via statistical process control charts and interrupted time series regression. The 2 outcome measures were the percentage of hospitalized infants who were evaluated and hospitalized appropriately and the percentage of hospitalized infants who were discharged with an appropriate LOS. RESULTS: In total, 124 hospitals from 38 states provided data on 20 570 infants. The median site improvement in percentages of infants who were evaluated and hospitalized appropriately and in those with appropriate LOS was 5.3% (interquartile range = -2.5% to 13.7%) and 15.5% (interquartile range = 2.9 to 31.3), respectively. Special cause variation toward the target was identified for both measures. There was no change in delayed treatment or missed bacterial infections (slope difference 0.1; 95% confidence interval, -8.3 to 9.1). CONCLUSIONS: Reducing Variability in the Infant Sepsis Evaluation noted improvement in key aspects of febrile infant management. Similar projects may be used to improve care in other clinical conditions.

BACKGROUND: Cluster of differentiation 70 (CD70) is frequently expressed in renal cell carcinoma (RCC) and has immunomodulatory properties. An antibody-drug conjugate targeting CD70, SGN-CD70A, was developed to treat patients with CD70-positive RCC. METHODS: The objective of this phase 1, open-label, dose-escalation, multicenter study was to evaluate the safety and tolerability of SGN-CD70A and establish its maximum tolerated dose in patients with CD70-positive, metastatic RCC (mRCC). All subtypes of RCC were permitted, and no limit was set on the number of prior therapies. Safety assessments consisted of monitoring and recording all adverse events (AEs) and dose-limiting toxicities (DLTs). Treatment response was assessed by radiographic tumor evaluation according to the Response Evaluation Criteria for Solid Tumors, version 1.1. A model-based, modified continual-reassessment method was used to estimate the probabilities of DLT and response. RESULTS: The maximum tolerated dose was determined to be 30 μg/kg, with thrombocytopenia as the DLT. The most common AEs were fatigue (67%), anemia (61%), and thrombocytopenia (56%). Of 18 enrolled patients, 1 achieved a partial response and 13 achieved stable disease, for a clinical benefit rate of 78%. Limitations of the study included the heavily pretreated nature of patients, receipt of a median of 4 prior lines of therapy (range, 1-8 prior lines of therapy), and diminishing response potential. CONCLUSIONS: The modest antitumor activity of SGN-CD70A does not support its development in mRCC. However, given the high disease control rate in a heavily pretreated population and the modest toxicity profile, CD70 remains of interest because of its immunomodulatory properties.

BACKGROUND: Cytotoxic therapy for relapsed and refractory germ cell tumors or metastatic sex cord stromal tumors is rarely effective and is often accompanied by high adverse event rates. Expression of CD30 has been observed in testicular cancers, and patients with CD30-expressing embryonal carcinomas have worse progression-free survival and overall survival than those with CD30-negative tumors. The objective of this study (NCT01461538) was to characterize the antitumor activity of brentuximab vedotin in patients with CD30-expressing nonlymphomatous malignancies. Enrolled patients included seven patients with relapsed or refractory germ cell tumors or metastatic sex cord stromal tumors described in this case series. MATERIALS AND METHODS: Forty patients with relapsed or refractory germ cell tumors, metastatic sex cord stromal tumors, or testicular tumors were screened for CD30 expression; 14 patients had tumors that expressed CD30. Seven patients with CD30-expressing testicular cancer were enrolled in the treatment study: five patients with germ cell tumors, one patient with a Leydig cell tumor, and one patient with a Sertoli cell tumor. Patients were treated with brentuximab vedotin at initial doses of 1.8 or 2.4 mg/kg every 3 weeks. Response assessments were performed at cycles 2 and 4 and every 4 cycles thereafter while the patient was receiving treatment. RESULTS: Two of seven patients achieved an objective response, including one durable complete response and one partial response at a single time point. Both responding patients had germ cell tumors. Treatment with brentuximab vedotin was generally well tolerated. CONCLUSION: Treatment of relapsed or refractory germ cell tumors with brentuximab vedotin can induce durable responses with a manageable toxicity profile. IMPLICATIONS FOR PRACTICE: This case series of seven patients with relapsed or refractory CD30-expressing germ cell tumors (GCTs) or sex cord stromal tumors demonstrates that brentuximab vedotin has activity against GCTs and is well tolerated in heavily pretreated patients with these aggressive tumor types. One patient achieved a complete response that has been durable for almost 4 years since the discontinuation of treatment with brentuximab vedotin. Therefore, brentuximab vedotin may be a valuable option for physicians who care for this difficult-to-treat patient population.

result in defects in synapse growth and synaptic transmission. Our study defines a new autism-related syndrome and highlights the functional role of CSDE1 in synapse development and synaptic transmission.

Abstract Abstract 191 Introduction: PI3Kdelta drives proliferation and survival in malignant B-cells. GS-1101 is an orally bioavailable, small-molecule inhibitor of PI3Kdelta that has shown considerable monotherapy activity when given at dose levels of 3100 mg BID in patients with heavily pretreated CLL. Methods and Patients: This Phase 1 combination study has evaluated repeated 28-day cycles of GS-1101 in combination with rituximab and/or bendamustine in patients with previously treated CLL. GS-1101 was administered starting on Day 1 of Cycle 1 with rituximab (R) (375 mg/m2 given weekly for 8 doses) (GS-1101/R regimen), with bendamustine (B) (90 mg/m2 given on Days 1 and 2 of each cycle for 6 cycles) (GS-1101/B regimen), or in combination with R (375 mg/m2, on Day 1 of each cycle for 6 cycles) and B (90 mg/m2 given on Days 1 and 2 of each cycle for 6 cycles) (GS-1101/BR regimen). Initial cohorts of patients received a GS-1101 dose of 100 mg/dose BID in the GR or GB regimens. Thereafter, all patients received a GS-1101 dose of 150 mg/dose BID. Tumor response was evaluated according to standard criteria (Hallek 2008). Chemokine/cytokine plasma levels were assessed at baseline and on Day 28 of therapy using multiplexed bead suspension arrays. Results: The study enrolled a total of 51 patients with CLL. Patient characteristics and safety and efficacy results are depicted in the table The majority of patients had bulky adenopathy and had undergone extensive prior therapy, with virtually all patients receiving prior rituximab and many receiving prior bendamustine. Grade 33 adverse events and lab abnormalities were generally consistent with those expected with each of the single agents. Lymph node shrinkage was rapid, and almost all evaluable patients had reductions in lymphadenopathy. As reported by investigators, the overall response rates (ORR) for the GS-1101/R, GS-1101/B, and GS-1101/BR regimens were 78%, 82% and 87%, respectively. With a minimum follow-up of 340 weeks for all regimens, 1-year progression-free survival (PFS) rates were 74%, 88% and 87% in the GS-1101/R, GS-1101/B, and GS-1101/BR treatment groups, respectively. Disease-associated chemokines/cytokines were commonly elevated at baseline and were significantly reduced by GS-1101-based combination treatment. Conclusions: A favorable safety profile and lack of overlapping toxicities allows the oral PI3Kdelta inhibitor, GS-1101, to be delivered at the full single-agent starting dose when coadministered with chemoimmunotherapies in heavily pretreated patients with CLL. GS-1101-based combination therapies with rituximab and/or bendamustine offer major and rapid reductions in lymphadenopathy and durable tumor control. Based on these results, Phase 3 trials evaluating the efficacy of GS-1101 in combination with R or BR have been initiated (NCT01539512 [GS-1101/placebo+R], NCT01569295 [GS-1101/placebo+BR]). Disclosures: Coutre: Gilead: Consultancy. Off Label Use: Phase 1 trial of GS-1101 (CAL-101)-based combination therapy. Leonard:Gileade: Consultancy. Barrientos:Gilead: Research Funding. de Vos:Gilead: Consultancy. Sharman:Gilead: Honoraria, Research Funding. Holes:Gilead: Employment. Lannutti:Gilead Sciences Inc: Employment. Johnson:Gilead Sciences: Employment. Miller:Gilead: Employment. Jahn:Gilead: Employment.

7017 Background: PI3K-delta signaling is critical for proliferation, survival, homing and tissue retention of malignant B cells. Idelalisib is a first-in-class, selective, oral inhibitor of PI3Kδ that has shown considerable monotherapy activity in pts with heavily pretreated CLL. Methods: This phase I study evaluated idelalisib continuously given at 150 mg BID in combination with rituximab (R, 375 mg/m 2 every wk x 8), bendamustine (B, 70 or 90 mg/m 2 x 2, every 4 wks x 6) or BR (every 4 wks x 6) for relapsed/refractory CLL. Pts still on treatment after 48 weeks were eligible to continue idelalisib on an extension study. Clinical response was evaluated according to published criteria (Hallek 2008; Cheson 2012). Results: 52 pts (23F/29M) with a median (range) age of 64 (41-87) years were enrolled. Adverse disease characteristics included bulky lymphadenopathy (62%), refractory disease (50%), multiple prior therapies (median 3, range: 1-14) with 96% receiving prior R and 44% receiving prior B. As of 14 Jan 2013, the median (range) treatment duration was 18 (1-33) months. 31/52 (60%) pts enrolled into the extension study; of those, 24/52 (46%) pts are continuing idelalisib treatment on the extension study. The ORR was 81%, with 1 CR, and a median (range) time to response of 1.9 (1.5-8.3) months. The 2-year PFS and OS were 62% and 85%, respectively. At 2 years follow up, 71% of responses were still enduring. There was no difference in outcomes for pts with &lt;3 prior treatments (n=21) vs ≥3 prior treatments (n=31). The most common TEAEs (any Grade/≥Gr 3, independent of causality) included pyrexia (44%/6%), diarrhea (40%/14%), cough (31%/2%), fatigue (29%/2%), nausea (29%/0%). Pneumonia (any Gr/≥Gr 3) occurred in 15%/12% and rash was seen in 15%/0%. 10% of patients experienced ≥Gr 3 ALT/AST elevation based on laboratory values. Conclusions: A lack of overlapping toxicities allowed idelalisib to be co-administered with R, B, or BR, and all 3 combination regimens were highly active, resulting in durable tumor control in pts with heavily pretreated relapsed/refractory CLL. Phase III trials evaluating the efficacy of idelalisib in combination with R or BR are ongoing. Clinical trial information: NCT01088048.

PURPOSE OF REVIEW: To provide an updated overview of prognostic models in advanced cancer and highlight the role of prognostic calculators. RECENT FINDINGS: In the advanced cancer setting, many important healthcare decisions are driven by a patient's prognosis. However, there is much uncertainty in formulating prognosis, particularly in the era of novel cancer therapeutics. Multiple prognostic models have been validated for patients seen by palliative care and have a life expectancy of a few months or less, such as the Palliative Performance Scale, Palliative Prognostic Score, Palliative Prognostic Index, Objective Prognostic Score, and Prognosis in Palliative Care Study Predictor. However, these models are seldom used in clinical practice because of challenges related to limited accuracy when applied individually and difficulties with model selection, computation, and interpretation. Online prognostic calculators emerge as tools to facilitate knowledge translation by overcoming the above challenges. For example, www.predictsurvival.com provides the output for seven prognostic indexes simultaneously based on 11 variables. SUMMARY: Prognostic models and prognostic websites are currently available to augment prognostication in the advanced cancer setting. Further studies are needed to examine their impact on prognostic accuracy, confidence, and clinical outcomes.

BACKGROUND: Using a self-service kiosk to measure blood pressure (BP) has the potential to increase patients' awareness of their BP control and free up medical assistant (MA) time. The objective of this study was to evaluate BP kiosk acceptability and usability, as well as its effects on the workflow of patient BP self-measurement in a primary care clinic. METHODS: We used qualitative and quantitative assessments of kiosk implementation via meetings with clinic leaders, focus groups with clinic providers and staff, observations of kiosk users, and surveys of kiosk users at 2 and 8 months. RESULTS: Most patients were comfortable using the kiosk (82% at 2 months, 87% at 8 months). Initial provider concerns included accuracy, but most gained confidence after comparing it with other monitors and reviewing the literature supporting its accuracy. Patients and providers saw many benefits: easier BP checks, increased patient engagement, and saved MA time for other tasks. The clinic addressed early concerns (eg, infection control, confusing instructions, perceived loss of personal touch). Most patients (86%) supported the clinic continuing to use the kiosks. CONCLUSIONS: Providers, staff, and patients adapted to the use of BP kiosks, providing value by engaging patients in their own care and saving MA time. The clinic decided to keep the self-service kiosk after the pilot period.

Abstract Introduction: The anti-apoptotic protein BCL2 is overexpressed in a number of hematological malignancies, including chronic lymphocytic leukemia (CLL). Venetoclax (VEN) is a selective, oral BCL2 inhibitor with demonstrated activity and an acceptable safety profile both as monotherapy and in combination regimens in relapsed/refractory (R/R) CLL patients (pts). VEN has demonstrated preclinical activity with bendamustine/rituximab (BR), a standard treatment in this population, as well as clinical efficacy with R. The anti-CD20 mAb obinutuzumab (G) has demonstrated improved efficacy in combination with chlorambucil compared with R. Here we present an interim analysis of an ongoing phase 1b study (GO28440) evaluating the maximum tolerated dose (MTD) of both VEN+BR and VEN+BG, plus safety, tolerability, efficacy and optimal order of administration in both R/R or 1L CLL pts (NCT01671904). Methods: Pts with ECOG PS ≤1, 0-3 prior chemotherapy lines, and adequate marrow, hepatic, renal and coagulation function are being enrolled in dose finding cohorts (VEN 100-400mg/day +BR or +BG in a 3+3 dose escalation design) and subsequent safety expansion cohorts (400mg). Dose finding occurs in one of two dosing schedules: Schedule A (VEN introduced before BR or BG) or Schedule B (BR or BG introduced before VEN), with one chosen for expansion per unique population/drug grouping. Both schedules include a gradual VEN dose ramp-up and other prophylactic measures based on risk stratification to reduce the risk of tumor lysis syndrome (TLS). Following completion of 6 months of combination therapy, pts continue single-agent VEN until unacceptable toxicity, disease progression, or (for 1L pts only) up to 1 year total VEN. Dose-limiting toxicity (DLT) data are reviewed after all pts in a cohort have completed 21 days of combination treatment at the target VEN dose and focus on TLS and cytopenias. Efficacy is assessed by iwCLL guidelines; Hallek et al. 2008. Results: At data cutoff (May 2, 2016), 55 pts (baseline characteristics and disposition in Table 1) have been treated; 47 pts received VEN+BR: 30 R/R (12 on Schedule A at doses 100-400mg, 18 on Schedule B all at 400mg) and 17 1L (all at 400mg: 6 on Schedule A, 11 on Schedule B). Eight pts received VEN+BG: all on Schedule B at 400mg. Safety is summarized for VEN+BR (R/R and 1L) and VEN+BG (1L) in Table 2. The most common AEs across all groups were neutropenia, thrombocytopenia, and nausea. Most G3-4 AEs across all groups were hematological toxicities; common non-hematological AEs included diarrhea and fatigue. Platelet transfusions occurred in 4 (13%) R/R VEN+BR and 1 (13%) 1L VEN+BG pts. There were serious AEs in 21 pts (43% R/R VEN+BR, 35% 1L VEN+BR, 25% 1L VEN+BG) including febrile neutropenia, nausea, vomiting, erythema, and infection. No deaths were reported. No TLS events (laboratory or clinical) were observed. Dose interruptions or modifications for VEN and/or BR/BG occurred in 35 (75%) of VEN+BR pts (22 R/R, 13 1L) and 7 (88%) VEN+BG pts, mainly due to neutropenia. Early VEN discontinuations for toxicity: 7 pts VEN+BR (R/R), 2 pts VEN+BR (1L), 1 pt VEN+BG. Early B and/or R/G discontinuations for toxicity: 10 pts VEN+BR (R/R), 4 pts VEN+BR (1L), 2 pts VEN+BG. Common reasons for discontinuations (≥1 pt) included neutropenia and thrombocytopenia. Across all pts, a median of 4 cycles of B were completed. Best overall response and minimal residual disease (MRD) status for evaluated pts are presented in Table 3. All but one R/R pt (off study early for disease transformation) responded across all groups. Conclusion: This study is the first to evaluate both VEN+BR and VEN+BG in pts with CLL. VEN 400mg daily can be combined with BR or BG in patients with either R/R or 1L CLL; neutropenia and thrombocytopenia are manageable with an otherwise acceptable safety profile. Administration schedules (VEN or BR first) appear to have similar toxicity profiles, with no DLT or lab/clinical TLS reported for either during dose finding. As expected, due to the known safety profile of VEN and B, hematologic toxicity was observed with VEN+BR; early VEN+BG safety data appears similar. Events appeared manageable, although early discontinuations contributed to a median of 4 completed cycles of B across all pts. Even with median of &lt;6 cycles of BR, all evaluated pts responded, with more than half showing CR and/or undetectable MRD. Responses may continue to deepen as more data is collected; the study is still enrolling. Disclosures Stilgenbauer: Pharmacyclics: Consultancy, Honoraria, Other: Travel grants , Research Funding; Genentech: Consultancy, Honoraria, Other: Travel grants , Research Funding; Sanofi: Consultancy, Honoraria, Other: Travel grants , Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel grants, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel grants, Research Funding; Boehringer Ingelheim: Consultancy, Honoraria, Other: Travel grants , Research Funding; Celgene: Consultancy, Honoraria, Other: Travel grants , Research Funding; Mundipharma: Consultancy, Honoraria, Other: Travel grants , Research Funding; GSK: Consultancy, Honoraria, Other: Travel grants , Research Funding; Hoffmann-La Roche: Consultancy, Honoraria, Other: Travel grants , Research Funding; Genzyme: Consultancy, Honoraria, Other: Travel grants , Research Funding; Janssen: Consultancy, Honoraria, Other: Travel grants , Research Funding; Novartis: Consultancy, Honoraria, Other: Travel grants , Research Funding; Gilead: Consultancy, Honoraria, Other: Travel grants , Research Funding. Morschhauser:Gilead Sciences: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Honoraria; Servier: Consultancy, Honoraria. Wendtner:Novartis: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Hoffmann-La Roche: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Servier: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Glaxo-SmithKline: Consultancy, Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding. Cartron:Roche: Consultancy, Honoraria; Celgene: Honoraria; Gilead: Honoraria; Jansen: Honoraria. Hallek:Gilead: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; F. Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau. Eichhorst:Gilead: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; GlaxoSmithKline: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding; AbbVie: Consultancy; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau. Kozloff:AbbVie: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Lozanski:Genentech: Research Funding; Boehringer Ingelheim: Research Funding; Beckman Coulter: Research Funding; Stemline Therapeutics Inc.: Research Funding. Punnoose:Genetech, Inc.: Employment. Wang:Genetech, Inc.: Employment. Hilger:Genetech, Inc.: Employment. Mobasher:Genentech, Inc.: Employment. Salles:Celgene: Consultancy, Honoraria; Janssen: Honoraria; Gilead: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Amgen: Consultancy.

6518^ Background: PI3Kδ is expressed in cells of hematopoietic origin where it regulates the survival and proliferation of malignant B-cells. GS-1101 is an orally bioavailable, small-molecule inhibitor that selectively targets PI3Kδ and is highly active in patients with hematologic malignancies. Methods: This Phase 1/2 study evaluated repeated 28-day cycles of GS‑1101 in combination with ofatumumab. GS-1101 (150mg BID) was co-administered with a total of 12 infusions of ofatumumab over 24 weeks (300mg initial dose either on Day 1 or Day 2 (relative to the first dose of GS-1101), followed 1 week later by 1,000mg weekly for 7 doses, followed 4 weeks later by 1,000mg every 4 weeks for 4 doses). Thereafter, each subjects received single-agent GS‑1101 as long as the subject was benefitting. Results: Accrual is complete with 21 subjects enrolled and 11 evaluable. Six subjects started ofatumumab treatment on Day 1 and 5 on Day 2. Median [range] age was 63 [54‑76] years. The majority (9/11; 82%) of patients had bulky adenopathy. The median [range] number of prior therapies was 3 [1‑6], including prior exposure to alkylating agents (10/11; 90%), rituximab (9/11; 82%), purine analogs (8/11; 72%), alemtuzumab (3/11; 28%) and/or ofatumumab (2/11;18%). At the data cutoff, the median [range] treatment duration was 5 [0‑7] cycles. Almost all subjects (9/11;82%) experienced marked and rapid reductions in lymphadenopathy within the first 2 cycles. The lymphocyte mobilization that is expected with PI3Kδ inhibition was significantly reduced in magnitude and duration and persisted past Cycle 1 in only 1 patient. Early follow up data support a favorable safety profile and confirm a lack of clinically significant myelosuppression. Elevated baseline levels of CCL3, CCL4, CXCL13, and TNFa were significantly reduced after 28 days of treatment. Conclusions: GS-1101/ofatumumab offers a well-tolerated noncytotoxic combination regimen with substantial activity in previously treated patient with bulky adenopathy. Data on the complete cohort of 21 subjects will be presented.

OBJECTIVE: To report a case of increased aripiprazole concentrations during coadministration with darunavir, ritonavir, and duloxetine. CASE SUMMARY: A 43-year-old HIV-positive Hispanic man received darunavir/ritonavir-based antiretroviral therapy (ART) in addition to aripiprazole and duloxetine for depression and anxiety. A month after the aripiprazole dosage was increased to 50 mg daily, the patient developed confusion and loss of coordination. Weeks later, he presented to the emergency department with fever, cough, headache, neck stiffness, back pain, and blurred vision and was admitted for possible meningitis. Because symptoms improved with pain control and intravenous fluids during hospitalization, he was discharged within a couple days after admission. One month later he was readmitted for worsening symptoms, and the resulting diagnostic workup showed unremarkable findings except for lymphadenopathy (LAD). This finding was attributed to discontinuing ARTs after his first admission. He was discharged on aripiprazole 50 mg daily, darunavir 800 mg daily, ritonavir 100 mg daily, and duloxetine 60 mg daily. A random steady-state concentration of aripiprazole was 1100 ng/mL (therapeutic concentration 100-200 ng/mL) obtained 49 days after discharge. DISCUSSION: The Horn Drug Interaction Probability Scale demonstrated a possible relationship between the increased aripiprazole concentration and coadministration of darunavir/ritonavir and duloxetine, which inhibit CYP3A4 and 2D6. Potential confounders to the increased concentration include duloxetine inhibition of CYP2D6 polymorphism, possible 2D6 polymorphism, and exceeding aripiprazole's maximum dose. The initial presentation of confusion and loss of coordination may have been early signs of aripiprazole toxicity, which relapsed as shown by his symptoms prior to admission. CONCLUSIONS: The interaction between aripiprazole and darunavir, ritonavir, and duloxetine may be significant. Clinicians should be cognizant of increased risk of aripiprazole toxicity in HIV-positive patients concurrently taking ritonavir-boosted ART and other cytochrome P450 inhibitors like duloxetine. Dose adjustments or monitoring parameters should be an area of research and discussion.

BACKGROUND: Mammalian target of rapamycin (mTOR) inhibitor-associated stomatitis (mIAS) is a frequent adverse event (AE) associated with mTOR inhibitor therapy and can impact treatment adherence. The objectives are to evaluate two steroid-based mouthrinses for preventing/ameliorating mIAS in patients with metastatic breast cancer (MBC) treated with everolimus. MATERIALS AND METHODS: This prospective, randomized phase II study enrolled 100 postmenopausal patients with hormone receptor-positive MBC within the US Oncology Network who were initiating therapy with an aromatase inhibitor + everolimus (AIE; 10 mg/day). Patients were randomized to prophylactic therapy with one of two oral rinses (Arm 1: Miracle Mouthwash [MMW] 480 mL recipe: 320 mL oral Benadryl [diphenhydramine; Johnson & Johnson, New Brunswick, NJ, USA], 2 g tetracycline, 80 mg hydrocortisone, 40 mL nystatin suspension, water; or Arm 2: prednisolone [P] 15 mg/5 mL oral solution, 1.8% alcohol). Patients were instructed to swish/expectorate 10 mL of the assigned rinse for 1-2 minutes four times daily starting with day 1 of AIE treatment, for the first 12 weeks. RESULTS: = 17/49) and 37% (19/51) in the MMW and P arms, respectively. The incidence of grade 2 oral AEs was 14% (7/49) and 12% (6/51) with MMW or P, respectively. There were two grade 3 oral AEs (MMW arm) and no grade 4 events. There was one everolimus dose reduction (MMW) and six dose delays (four MMW, two P) and one dose reduction + delay (MMW) during the first 12 weeks of treatment. No patients stopped steroid mouthwash therapy because of rinse-related toxicity. CONCLUSION: Prophylactic use of steroid-containing oral rinses can prevent/ameliorate mIAS in patients with MBC treated with AIE. MMW + hydrocortisone is an affordable option, as is dexamethasone oral rinse. IMPLICATIONS FOR PRACTICE: This prospective phase-II study showed that two steroid-containing mouthrinses substantially reduced incidences of all-grade and grade ≥2 stomatitis and related oral adverse events (AEs), and the number of everolimus dose-delays and/or dose-reduction in metastatic breast cancer (MBC) patients receiving everolimus treatment plus an aromatase inhibitor. Both oral rinses were well tolerated and demonstrated similar efficacy. Prophylactic use of steroid mouth rinse provides a cost-effective option that substantially decreases the incidence and severity of mammalian target of rapamycin (mTOR) inhibitor-associated stomatitis and related oral AEs as well as the need for dose modification in MBC patients undergoing treatment with an mTOR inhibitor.

Abstract Introduction PI3Kδ signaling is critical for the proliferation and survival as well as for homing and tissue retention of malignant B cells. Idelalisib is a first-in-class, targeted, highly selective, oral inhibitor of PI3Kδ that has shown considerable monotherapy activity in patients with heavily pretreated CLL. Methods This Phase 1 study evaluated idelalisib for relapsed/refractory CLL continuously given at 150 mg BID in combination with a total of 8 infusions of rituximab (R, 375 mg/m2 weekly x 8), or a total of 12 infusions of ofatumumab (O, 300mg initial dose either on Day 1 or Day 2 relative to the first dose of idelalisib, then 1,000 mg weekly x 7, then 1,000 mg every 4 wks x 4). Pts on treatment after 48 weeks were eligible to continue idelalisib on an extension study. Clinical response was evaluated according to published criteria (Hallek 2008; Cheson 2012). Results 40 pts (12F/28M) with a median (range) age of 66 (43-87) years and a WHO performance status of 0 (24, 60%) or 1 (16 40%) were enrolled. 19 pts received idelalisib in combination with R, 21 with O. Adverse disease characteristics (n, %) included Rai Stage III/IV (20, 50%), bulky lymphadenopathy (24, 60%), refractory disease (14, 35%), multiple prior therapies (median 2, range: 1-;9). Almost all patients (39, 98%) had at least 1 prior therapy containing R, and 3 of the 21 pts (14%) receiving idelalisib + O had received prior O. 63% of the pts receiving idelalisib + R, and 43% of the pts receiving idelalisib + O were refractory to R. Prior therapies also included alkylating agents (31, 78%, [bendamustine: 20, 50%]) and purine analogs (31, 78%, [fludarabine: 28, 70%]). Data available from 39 pts showed that 11 (28%) pts had evidence of del(17p) and/or TP53 mutations and 30 (75%) had unmutated IGHV. As of May 2013, the median (range) treatment duration was 18 (0-33) months. 23 (58%) pts have completed the primary study and enrolled into the extension study. A total of 14 pts (35%) were continuing idelalisib treatment on the extension study. The most common reasons for discontinuation either from the primary or extension study were disease progression (10, 25%) and adverse events (AEs) (9, 23%). There were 6 deaths reported on study; 3 pts experienced PD before death. Selected treatment-emergent AEs (any Grade/≥Gr 3, regardless of causality) included diarrhea (53%/10%), cough (40%/3%), pyrexia (40%/3%), dyspnea (30%/3%), fatigue (25%/0%) nausea (25%/0%), rash (20%/0%), pneumonia (18%/15%), colitis (10%/10%) and pneumonitis (10%/7.5%). Elevation of liver transaminases (TA, any Grade/≥Gr 3) was seen in 30%/10%. Of those, only 1 pt discontinued the study because of (recurrent) TA elevation. The ORR (N=40) was 83% (33/40), with 3 CRs (8%), and a median (range) time to response of 1.9 (1.7-21.8) months. Median progression-free survival (PFS) for all patients (N=40) and duration of response (n=33) were 20 and 19 months, respectively. Median overall survival (OS) has not been reached. For the 11 pts with del(17p) and/or TP53 mutations, the response rate was 73% (8/11) and the median PFS and DOR were 19 months. Conclusions Combinations of idelalisib with therapeutic anti-CD20 antibodies such as rituximab or ofatumumab represent non-cytotoxic regimens with acceptable safety profiles and high activity resulting in durable tumor control in pts with heavily pretreated relapsed/refractory CLL. Phase 3 trials evaluating the efficacy of idelalisib in combination with R or O are ongoing (NCT01539512, NCT01659021). Disclosures: Furman: Gilead Sciences: Research Funding. Off Label Use: Idelalisib is a PI3K-delta inhibitor currently in phase III trials for multiple hematologic malignancies. De Vos:Gilead Sciences: Research Funding. Leonard:Gilead Sciences: Research Funding. Barrientos:Gilead Sciences: Research Funding. Schreeder:Gilead Sciences: Research Funding. Flinn:Gilead Sciences: Research Funding. Sharman:Gilead Sciences: Research Funding. Boyd:Gilead Sciences: Research Funding. Fowler:Gilead Sciences: Research Funding. Rai:Gilead Sciences: Research Funding. Kim:Gilead Sciences: Employment. Holes:Gilead Sciences: Employment. Dansey:Gilead Sciences: Employment. Jahn:Gilead Sciences: Employment. Coutre:Gilead Sciences: Research Funding.