Citations

Abstract Abstract 4527 Introduction: The prognosis for pts with intermediate or high risk AML remains dismal, with relapse rates typically in the 60–80% range after treatment with chemotherapy alone. While allo-SCT can decrease the risk of relapse to 10–20%, widespread use of this modality is limited by relatively high rates of non-relapse mortality (NRM), often due to severe acute and/or chronic GVHD. Attenuation of severe GVHD, without a concomitant increase in relapse or NRM, should improve outcomes and result in cure of a larger fraction of AML pts. We therefore investigated the use of in-vivo T-cell depletion with r-ATG in pts with intermediate- or high-risk AML but without active leukemia at the time of allo-SCT. Patients and Methods: Pts (n = 43) were included in this retrospective analysis if they were between 18 and 65 years of age and had no evidence of active AML at the time of allo-SCT (see Table). All pts had 1 or more high-risk features: 1) adverse or intermediate risk cytogenetics (without NPM1 mutation if cytogenetically normal); 2) therapy-related or secondary AML; 3) high WBC count at diagnosis; 4) failure to achieve CR after 1 cycle of induction; or 5) not in CR1 at allo-SCT. Among the 43 pts, 10 received grafts from related donors, 14 from 10/10 matched unrelated donors (URDs), and 19 from mismatched URDs (9/10, n = 11; 8/10, n = 8). All pts received r-ATG according to institutional standard operating policy, with doses ranging from 2.5 – 10 mg/kg depending on donor type and degree of mismatch. All transplants were performed using PBSC. Additional GVHD prophylaxis included tacrolimus plus either methotrexate or mycophenolate mofetil. Results: The median age was 47 (range 20 – 65), and median follow-up for surviving pts is 12 (range 1 – 66) months. As of 8/5/11, 39 pts were alive, and 4 had died from multiorgan failure (n = 1), relapse (n = 1), GVHD (n = 1), and veno-occlusive disease (n = 1). The 2-year estimate of PFS is 84.7% (Fig. 1). The 2-year cumulative incidence of relapse is 6.8% (2 pts, days 97 and 147), and of non-relapse mortality 9.4%. Three pts developed severe (grades III-IV) acute GVHD by day 100 (cumulative incidence 4.6% at day 100) with no additional cases of severe acute GVHD beyond day 100. To date, 4 pts have developed moderate/severe chronic GVHD (cumulative incidence 16.8% at 2 yrs), with one death at day 344 related to complications of acute and chronic GVHD. CMV reactivation occurred in 29 pts (56%), with no deaths related to CMV. Three pts have reactivated EBV, with one case of PTLD (all treated with Rituximab). Conclusions: In this retrospective analysis of single center data, the inclusion of r-ATG in the GVHD prophylactic strategy appeared to significantly attenuate the incidence and severity of both acute and chronic GVHD. Although follow-up is relatively early, the incidence of relapse and NRM does not appear to be increased compared to contemporaneous pts treated without ATG. Given that almost half of the pts received grafts from mismatched URDs, this abrogation in risk of GVHD is significant and clinically relevant. While randomized studies are needed, these data suggest that in-vivo T-cell depletion with r-ATG ameliorates severe GVHD, without increasing relapse or non-relapse mortality, in AML pts without overt leukemia at the time of allo-SCT. Using this strategy, cure rates of 70 – 80% may be realistic and attainable for younger (</= age 65) AML patients who achieve a leukemia-free state and who have a reasonably matched related or unrelated donor. Disclosures: Reeder: Celgene: Research Funding; Millennium Pharmaceuticals Inc.: Research Funding; Novartis: Research Funding.

Abstract 44 patients with relapsed or refractory CD20+ NHL were enrolled on a phase I trial of dose-escalated 90YZ followed by high-dose BEAM and autotransplant in which the 90YZ dose was patient-specific based on dosimetry. 90YZ doses were calculated to deliver cohort-defined radiation doses (100–1700 cGy) to critical organs (liver, lung or kidney) with 3–6 patients per cohort. On D-22, rituximab (R) 250 mg/m2 was infused followed by 111In Zevalin®. Imaging was performed immediately and at 4, 24, 72 and 144 hours; dosimetry was performed on D-15. On D-14, R was followed immediately by 90YZ at the cohort-prescribed dose. On D-6 through D-1, patients received high-dose BEAM. On D0, a minimum of 2.0 × 106 CD 34+ cells/kg was infused and G-CSF 5 μg/kg SQ daily begun. The median age was 54 (range: 25–73) years. NHL histologic subtypes were as follows: 16% mantle cell, 57% diffuse aggressive, 11% low-grade and 16% transformed. 43% had recieved 3 or more chemotherapy regimens, and 70% had received R either alone or in combination with chemotherapy. The toxicity profile was similar to that associated with high-dose BEAM. The most common grade III/IV toxicities were infection, fever, stomatitis, nausea, vomiting, diarrhea. One patient experienced transient veno-occlusive disease at the 700 cGy dose level. Two dose-limiting toxicities occurred at the 1700 cGy dose level: one patient with grade 4 stomatitis died of pneumonia and sepsis on D+10, and one patient experienced septic emboli to the lung on D+13. Engraftment occurred at a median of 10 days (range: 8–18 ) to granulocytes ≥ 500/μL, and 21 days (range: 11–40 days) to platelets ≥20,000/μL. One heavily pretreated patient developed MDS on D+291 and expired of sepsis on D+483. With a median follow-up of 21 months, the three year overall and progression-free survivals are 52% and 37%, respectively. 90YZ Zevalin ® Dosing for Cohorts 5–9 (median;range) Cohort (cGy) Total Dose (mCi) mCi/kg 900(n=3) 28(27–37) 0.3(0.3–0.4) 1100(n=5) 51(29–65) 0.6(0.5–0.8) 1300(n=5) 61(39–98) 0.6(0.5–1.1) 1500(n=6) 73(51–99) 0.9(0.5–1.4) 1700(n=3) 98(82–104) 1.2(1.1–1.2) For dosimetry-based trials, 1500 cGy to the critical organ (nearly always liver) is the recommended dose. Although patient-specific doses calculated to deliver a cohort-prescribed absorbed radiation dose to the critical organ were highly variable, the two dose-limiting toxicities ocurred at nearly identical doses (1.14, 1.20 mCi/kg) when calculated according to weight. Whereas eight other patients safely received at least twice the conventional 0.4 mCi/kg dose, 0.8 mCi/kg is the recommended dose for phase II studies, if dosing is to be based on weight and not dosimetry. Outcomes are encouraging given the high-risk patient population. A phase III trial will be required to establish whether or not the addition of 90YZ to high-dose BEAM improves outcomes in NHL patients undergoing autotransplant.

Preclinical and clinical evidence suggest a potential advantage for infusional therapy in lymphoma. Sixty-two analyzable patients with predominantly intermediate-grade non-Hodgkin lymphoma received cyclophosphamide (200 mg/m2 per day), doxorubicin (12.5 mg/m2 per day), and etoposide (60 mg/m2per day) (CDE) by continuous intravenous infusion for 4 days (96 hours) every 3 weeks for a maximum of 8 cycles. By the age-adjusted International Prognostic Index (IPI), 42% were at high risk and 58% were at high-intermediate risk. Complete response (CR) occurred in 30 (48%) patients (95% confidence interval [CI], 35%, 64%), and partial response occurred in 16 (26%) patients, yielding an overall response rate of 74% (95% CI, 62%, 84%). Failure-free survival (FFS) rates at 1 and 2 years were 55% (95% CI, 43%, 67%) and 50% (95% CI, 38%, 62%), respectively. When comparing the outcome for 62 patients receiving infusional CDE with historical data derived from 927 IPI-matched lymphoma patients using a Cox proportional hazards model, there was a nonsignificant trend favoring CDE in FFS (P = .12) and overall survival (P = .09). Severe or life-threatening toxicity included neutropenia (68%), anemia (57%), thrombocytopenia (44%), and infection (24%). Two patients (3%) died of treatment-related infectious complications. The primary end point of improving 1-year FFS from 55% to 70% was not achieved with infusional CDE given as initial therapy in patients with poor-risk intermediate-grade lymphoma. It is unlikely that infusional therapy as used in this study produces a 25% or greater relative improvement in FFS compared with standard therapy.

We showed in a phase I trial that the maximum tolerated dose of the ProMACE-CytaBOM regimen in patients with aggressive lymphoma was 200% (Gordon et al, J Clin Oncol 14:1275, 1996). Based on these observations, we initiated a phase II trial designed to determine response, toxicity, and dose intensity using this regimen. We analyzed 74 patients with advanced-stage (III or IV) or bulky stage II aggressive lymphoma. The overall complete response rate was 69% (72% in evaluable patients). With a median follow-up of 4.5 years, the median survival has not yet been reached. The 4-year survival rate is 73% (95% confidence interval [CI] 62, 83%) and no difference was observed among International Prognostic Index (IPI) groups. The 4-year disease-free survival was 71% (95% CI 58, 84%) with no statistical difference between patients with IPI 0 to 1 versus 2 to 4. The toxicity was acceptable, though the grade 4 hematologic toxicity rate for this regimen was 100%. Grade 4 nonhematologic toxicity was 36%. Three cases of either myelodysplastic syndrome or acute leukemia occurred at 7 months, 3.4 years, and 4.2 years after registration. Cytogenic analysis was available in two cases, showing inv(16) without French American British classification (FAB) M4 EO histology in one patient and a 5q-syndrome in the other. These data suggest that 200% ProMACE-CytaBOM with either granulocyte-macrophage colony-stimulating factor (GM-CSF) or G-CSF results in a high complete remission rate and a disease-free survival comparable to any prior risk-based analysis in aggressive lymphoma. Before using this regimen in general practice, phase III clinical trials should be conducted.

Abstract Background: We recently clarified the use of consolidative autologous stem cell transplantation (ASCT) as first remission consolidation therapy for high grade diffuse aggressive T and B non-Hodgkin's lymphoma (NHL)in patients with high-intermediate (HI) or High (H) age adjusted IPI disease (Stiff et al, NEJM 369:1681). After receiving CHOP or R-CHOP for 5 cycles responding patients were randomized to either 3 more induction cycles or 1 cycle followed by an ASCT using either a BCNU or TBI based preparative regimen. We found a PFS but not OS advantage for those randomized to transplant and no differential treatment effect for those with T-NHL patients as compared to B-NHL in the initial analysis of this study. In light of Phase II data suggesting a value of early ASCT for T-NHL, a lack of randomized ASCT trials for T-NHL and the inferior prognosis for T-NHL as compared to B cell disease, we further evaluated this sub group, since a post hoc analysis of the entire trial did find a survival advantage for those with H IPI disease. This then provided a unique opportunity to evaluate the role of ASCT consolidation for T-cell NHL in the setting of a prospective randomized trial. Method: Among the 370 eligible B-NHL and T-NHL patients with HI/H IPI disease treated on this trial, 40 had a T-NHL phenotype and were the subject of this analysis. Individual patient files were re-reviewed and those randomized after the first 5 cycles of CHOP were further analyzed for stage, IPI group, histology (centrally reviewed), and response to induction and consolidation and updated survival outcome. Results: Of the 40 T-NHL patients enrolled on study, 28 (70%) were randomized after induction therapy, a similar ratio to the entire trial (68%). Twelve were not randomized; 1 was ineligible for study, and of the eligible 11, 9 were HI IPI and 8 had peripheral T cell (PTCL-NOS). These 11 were not randomized due to patient choice in 2, and all of the remaining 9 pts progressed early: 2 after C1; 3 after C3, 1 after C4, and 3 after C5. For the 28 randomized, their median age was 50 and 19 were males. Of the group, 21/28 had B symptoms at diagnosis, 14 had stage IV disease, and 18 and 10 were in the HI and H IPI groups respectively. Histologies included 11 with PTCL-NOS, 7 angioimmunoblastic and 10 anaplastic large cell NHL. At randomization 13 were to continue CHOP and 15, ASCT. Of the 15 assigned to ASCT, 3 did not undergo transplant (2-refusals, 1- unable to mobilize); 7 received the BCNU-etoposide-cyclophosphamide and 5 the TBI-etoposide-cyclophosphamide preparative regimen. The 5 year estimates of PFS and OS for the randomized ASCT vs CHOP only groups (intent to treat) were 40% vs 38% (p=0.56) and 40% vs 45% (p=0.98) respectively. We found no difference in outcome based on IPI group, histology or stage of disease. Interestingly, only 1/7 patients who received BCV as the ASCT preparative regimen are long term survivors vs 4/5 receiving the TBI-based regimen. Conclusions: We did not observe a PFS/OS advantage for those with high-risk T-NHL in first remission randomized to ASCT following CHOP induction vs CHOP alone in this retrospective analysis. In addition, the 30% early drop out rate before randomization due primarily to early progression strongly suggests that more optimal induction regimens need to be developed for this disease. While the numbers are small the finding that TBI based preparative regimens might be associated with a higher PFS is of interest and deserves further study. Support: NIH/NCI grants CA180888 and CA180819; Bristol-Myers Squibb. Contributions of Dr. Raymond R Tubbs, deceased, are gratefully acknowledged. Figure 1 Figure 1. Disclosures Porcu: miRagen: Other: Investigator in a clinical trial; celgene: Other: Investigator in a clinical trial; Millenium: Other: investigator in a clinical trial; Innate Pharma: Other: Investigator in a clinical trial. Winter:Pharmacyclics: Research Funding; Medivation: Other: Provision of investigational agent for clinical trial; Seattle Genetics: Research Funding; GSK: Research Funding. Kahl:This study was coordinated by the ECOG-ACRIN Cancer Research Group (Robert L. Comis, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported by the National Cancer Institute of the National Institutes of Health under the following award number: Research Funding. Smith:Juno: Consultancy; TGTX: Consultancy; AbbVie: Consultancy; Celgene: Consultancy; Genentech: Consultancy, Other: on a DSMB for two trials ; Gilead: Consultancy; Portola: Consultancy; Amgen: Other: Educational lecture to sales force; Pharmacyclics: Consultancy. Rimsza:NCI/NIH: Patents & Royalties: L.M. Rimsza is a co-inventor on a provisional patent, owned by the NCI of the NIH, using Nanostring technology for determining cell of origin in DLBCL.. Fisher:Gilead: Consultancy; Seattle Genetics: Consultancy; Johnson and Johnson: Consultancy. Friedberg:Bayer: Honoraria, Other: Data Safety Monitoring Board.

Abstract Abstract 1954 Introduction: Vitamin D (VD) deficiency can cause osteomalacia, aching bone pain, muscle weakness, fatigue, increase risk of fracture and precipitate or exacerbate osteopenia/osteoporosis. Allogeneic hematopoietic stem cell transplant (HCT) patients are susceptible to low VD level secondary to poor oral intake, decreased exposure to sunlight and treatment related malabsorption. VD level has been correlated to cancer incidence and VD metabolites have been used in the treatment of myeloid leukemia. VD shows promising immunomodulatory properties and correction of low VD level may mitigate manifestations of graft versus host disease (GVHD). Reports have suggested that low VD level appears to increase the incidence of GVHD. We hypothesize that there is a relationship between low VD level and morbidity (specifically incidence of acute GVHD), mortality and relapse incidence after HCT. We therefore studied VD levels pre- and post-HCT to determine if VD level impacts these outcomes. Patients and Methods: 241 patients underwent myeloblative or non-myeloablative HCT between January 1, 2009 and January 31, 2011 at our institution. Baseline demographic data, disease characteristics, transplant variables and outcomes data were obtained from the transplant database. These data were supplemented by retrospective chart review for pre- and post-transplant VD level. Categories for VD level included normal (>30 ng/ml) or abnormal (<30 ng/ml). Results: 131 (54%) of patients who underwent myeloblative or non-myeloablative HCT had their VD level evaluated either pre-transplant, post-transplant or both. Pre-HCT 57 (56%) patients, 100 days post-HCT 55 (59%) patients and 365 days post-HCT 12 (32%) patients had a low VD level. 51 (38%) of patients had a reduced intensity HCT and 80 patients (62%) had an ablative conditioning regimen. 11 (8.4%) patients had acute GVHD. Comparison of VD level among those with acute GVHD did show a higher incidence of acute GVHD between those with a low or normal VD level (HR=3.14, 95% CI: 0.35–28.33) however this association was not statistically significant (p=0.3079). Survival analysis in those with a low VD level pre-HCT showed there was not a higher risk of mortality (HR=1.14, 95% CI: 0.18–7.38) after adjusting for post- VD level, and this association was not statistically significant (p=0.8921). Survival analysis in those with a low VD level post-HCT did show a higher risk of mortality (HR=2.59, 95% CI: 0.26–25) after adjusting for pre-HCT VD level, however, this association was not statistically significant (p=0.4155). The relationship between VD level and relapse at 1 year post-HCT was not able to be examined because the VD level for patients who relapsed was not available. Conclusions: Half of patients undergoing HCT had VD testing pre- or post- HCT. Just over half of the patients tested had a low VD level pre- and 100 days post-HCT. It is notable that 365 days post HCT the number of patients with low VD level had decreased. This could be attributable to less time in the hospital thus increasing sun exposure, increasing performance status allowing better ingestion and absorption of VD in the gastrointestinal tract or proper supplementation of a low level noted previously. There was no significant difference in incidence of acute GVHD by VD level though there was a trend for increased risk. Pre- and post-HCT VD level did not significantly impact mortality but there was a trend toward higher risk in those with a low VD level post-HCT. This is the first study, to our knowledge, to evaluate the impact of VD level on mortality post-HCT. Our study confirms that many patients have a low VD level pre-and post-HCT. These findings, especially the trend towards a higher mortality risk and higher incidence of acute GVHD in those who have a low VD level post-HCT, warrant further prospective investigation. VD supplementation may be a low cost, easy to implement addition to routine post HCT care that might reduce HCT associated mortality. Disclosures: Reeder: Celgene: Research Funding.

Objective: Much has been written about the patients’ perspective concerning weight management in health care. The purpose of this survey study was to assess perspectives of primary care providers (PCPs) and nurses toward patient weight management and identify possible areas of growth. Patients and Methods: We emailed a weight management–focused survey to 674 eligible participants (437 [64.8%] nurses and 237 [35.2%] PCPs) located in 5 outpatient primary care clinics. The survey focused on opportunities, practices, knowledge, confidence, attitudes, and beliefs. A total of 219 surveys were returned (137 [62.6%] from nurses and 82 [34.4%] from PCPs). Results: Among 219 responders, 85.8% were female and 93.6% were white non-Hispanic. In this study, PCPs and nurses believed obesity to be a major health problem. While PCPs felt more equipped than nurses to address weight management ( P < .001) and reported receiving more training than nurses (50.0% vs 17.6%, respectively), both felt the need for more training on obesity (73.8% and 79.4%, respectively). Although, PCPs also spent more patient contact time providing weight management services versus nurses ( P < .001), the opportunity/practices score was lower for PCPs than nurses (−0.35 ± 0.44 vs −0.17 ± 0.41, P < .001) with PCPs more likely to say they lacked the time to discuss weight and they worried it would cause a poor patient-PCP relationship. The knowledge/confidence score also differed significantly between the groups, with nurses feeling less equipped to deal with weight management issues than PCPs (−0.42 ± 0.43 vs −0.03 ± 0.55, P < .001). Neither group seemed very confident, with those in the PCP group only answering with an average score of neutral. Conclusion: By asking nurses and PCP general questions about experiences, attitudes, knowledge, and opinions concerning weight management in clinical care, this survey has identified areas for growth in obesity management. Both PCPs and nurses would benefit from additional educational training on weight management.

Abstract Background: I-SPY2 is a multicenter, Phase II trial using response-adaptive randomization within biomarker subtypes to evaluate novel agents as neoadjuvant therapy for high-risk at least T2N0 breast cancer. The primary endpoint is pathologic complete response (pCR) at surgery. The goal is to identify regimens that have ≥ 85% Bayesian predictive probability of success in a 300-patient phase 3 neoadjuvant trial defined by hormone-receptor (HR) and HER2 status, and MammaPrint (MP). Regimens may leave the trial for futility (&lt; 10% probability of success), maximum sample size accrual (with probability of success ≥ 10% and &lt; 85%), or as recommended by the independent DSMB. For HER2- subjects the control arm is weekly paclitaxel x12 then doxorubicin & cyclophosphamide (AC) q2-3 weeks x4. For this arm, paclitaxel was omitted and replaced with maximum tolerated dose PARPi talazoparib with synergy dosed irinotecan (25mg/m2). Paclitaxel could be given adjuvantly for these subjects and non-responding subjects could be taken off of experimental therapy. Methods: Women with tumors ≥ 2.5cm were eligible for screening. MP low/HR+ tumors were ineligible. MRI scans (baseline, 3 cycles after start of therapy, prior to AC, and prior to surgery) were used in a longitudinal statistical model to predict pCR for individual patients. Talazoparib was given at 1mg daily with 25mg/m2 irinotecan q2wks. Analysis was intention to treat. Subjects who switched to non-protocol therapy count as non-pCR. Subjects on experimental therapy at time of arm closure are non-evaluable. Talazoparib/irinotecan (TI) was open only to HER2- tumors and eligible for graduation in 3 of 10 pre-defined signatures: HER2-, HR+HER2- and HR-/HER2-. Results: TI did not meet criteria for graduation and was stopped at the recommendation of the DSMB based on expectations of limited activity beyond that seen with standard treatment. Maximum sample size had been reached at the time of this recommendation and subjects currently receiving TI were allowed to continue or change to standard therapy. Exploratory “as treated” analysis for response in gBRCA mutation carriers showed 6/10 gBRCA carriers attained a pCR in the TI arm. Except for 1 patient these gBRCA pCR subjects had &gt;90% tumor reduction by MRI after TI and prior to AC (range: 68-96%). In the TI arm pCR rates were also higher in subjects with a PARPi7-High/MP2 gene expression signature (0.344 vs 0.146). Expected differences in toxicity were seen between arms including g3/4 peripheral neuropathy on control therapy which included paclitaxel (2.6% vs none) and g3/4 neutropenia with TI (30.2% vs 8.2%). Notably gBRCA mutation carriers receiving TI had higher rates of g3/4 neutropenia (60% vs 25.9%). Conclusion: The I-SPY2 study finds the probability that investigational regimens will be successful in a Phase III neoadjuvant trial; TI did not reach the efficacy threshold of 85% probability of success in Phase III in any of the 3 signatures. However by adding talazoparib with synergy dosed irinotecan we were able to omit paclitaxel and observe similar estimated pCR rates. This informs current work to evolve the I-SPY2 trial design to reduce toxicity without compromising outcomes and develop successful combinations targeted to biology, including DNA repair deficiency. Citation Format: Richard Schwab, Amy S. Clark, Christina Yau, Nola Hylton, Wen Li, Denise Wolfe, A Jo Chien, Anne M. Wallace, Andres Forero-Torres, Erica Stringer-Reasor, Rita Nanda, Nora Jaskowiak, Judy Boughey, Tufia Haddad, Heather S. Han, Catherine Lee, Kathy Albain, Claudine Isaacs, Anthony D. Elias, Erin D. Ellis, Payal Shah, Julie E. Lang, Janice Lu, Debasish Tripathy, Kathleen Kemmer, Douglas Yee, Barbara Haley, Melanie Majure, Erin Roesch, Christos Vaklavas, Cheryl Ewing, Teresa Helsten, W Fraser Symmans, Jane Perlmutter, Hope S. Rugo, Michelle Melisko, Amy Wilson, Ruby Singhrao, Laura van 't Veer, Angela DeMichele, Smita Asare, Don Berry, Laura J. Esserman. Evaluation of talazoparib in combination with irinotecan in early stage, high-risk HER2 negative breast cancer: Results from the I-SPY 2 TRIAL [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT136.

Background In the discipline of rhinology and endoscopic skull base surgery (ESBS), 3-dimensional (3D) printing has found meaningful application in areas including preoperative surgical planning as well as in surgical education. However, its scope of use may be limited due to the perception among surgeons that there exists a prohibitively high initial investment in resources and time to acquire the requisite technical expertise. Nevertheless, given the ever decreasing cost of advancing technology coupled with the need to understand the complex spatial relationships of the paranasal sinuses and skull base, the use of 3D printing in rhinology and ESBS is poised to blossom. Objective Help the reader identify current or potential future uses of 3D printing technology relevant to their rhinologic clinical or educational practice. Methods A review of published literature relating to 3D printing in rhinology and ESBS was performed. Results Results were reviewed and organized into 5 overarching categories including an overview of the 3D printing process as well as applications of 3D printing including (1) surgical planning, (2) custom prosthetics and implants, (3) patient education, and (4) surgical teaching and assessment. Conclusion In the discipline of rhinology and ESBS, 3D printing finds use in the areas of presurgical planning, patient education, prosthesis creation, and trainee education. As this technology moves forward, these products will be more broadly available to providers in the clinical and educational setting. The possible applications are vast and have great potential to positively impact surgical training, patient satisfaction, and most importantly, patient outcomes.

Abstract Zanubrutinib is a potent and highly selective inhibitor of Bruton tyrosine kinase (BTK). In this first-in-human, open-label, multicenter, phase 1 study, patients in part 1 (3 + 3 dose escalation) had relapsed/refractory B-cell malignancies and received zanubrutinib 40, 80, 160, or 320 mg once daily or 160 mg twice daily. Part 2 (expansion) consisted of disease-specific cohorts, including treatment-naive or relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). The primary end points were safety and tolerability, and definition of the maximum tolerated dose (part 1). Additional end points included pharmacokinetics/pharmacodynamics and preliminary efficacy. Reported herein are results from 144 patients enrolled in the dose-finding and CLL/SLL cohorts. No dose-limiting toxicities occurred in dose escalation. Median BTK occupancy in peripheral blood mononuclear cells was &gt;95% at all doses. Sustained complete (&gt;95%) BTK occupancy in lymph node biopsy specimens was more frequent with 160 mg twice daily than 320 mg once daily (89% vs 50%; P = .0342). Consequently, 160 mg twice daily was selected for further investigation. With median follow-up of 13.7 months (range, 0.4-30.5 months), 89 CLL/SLL patients (94.7%) remain on study. Most toxicities were grade 1/2; neutropenia was the only grade 3/4 toxicity observed in &gt;2 patients. One patient experienced a grade 3 subcutaneous hemorrhage. Among 78 efficacy-evaluable CLL/SLL patients, the overall response rate was 96.2% (95% confidence interval, 89.2-99.2). Estimated progression-free survival at 12 months was 100%. Zanubrutinib demonstrated encouraging activity in CLL/SLL patients, with a low incidence of major toxicities. This trial was registered at www.clinicaltrials.gov as #NCT02343120.