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Abstract Introduction: Bruton tyrosine kinase inhibitors (BTKi) have revolutionized the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and certain B-cell neoplasms. However, resistance to BTKi develops primarily through mutations at the cysteine binding site (C481) or PLCγ2 mutations. MK-1026 (formerly ARQ-531) is a non-covalent, potent inhibitor of both wild type and C481- mutated BTK. In the phase 1/2 dose escalation and dose expansion study NCT03162536, the preliminary recommended phase 2 dose (RP2D) of MK-1026 was determined to be 65 mg once daily. The efficacy and safety of MK-1026 in participants with CLL/SLL and B-cell non-Hodgkin lymphoma (NHL) were also evaluated at a higher dose during the dose expansion phase. Methods: In this open-label, single-arm phase 2 study, 9 expansion cohorts were initiated following determination of preliminary MK-1026 RP2D. Approximately 10-25 eligible participants were enrolled into Cohort A (relapsed/refractory (r/r) CLL/SLL, with ≥2 prior therapies including covalent BTKi, with documented C481 mutation), Cohort B (r/r CLL/SLL progressed on/intolerant to a BTKi, with ≥2 prior therapies without C481 mutation), Cohort C (participants with Richter transformation [RT] with ≥1 prior therapy), Cohort D-H (participants with follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), high-grade B cell lymphoma (BCL) with known MYC, BCL-2 or BCL-6 translocations, and Waldenström macroglobulinemia (WM), respectively, who received ≥2 prior therapies), Cohort I (food effect cohort including participants with B-cell NHL, CLL/SLL, and WM). Treatment continued until unacceptable toxicity, clinical or radiological progression, participant/physician withdrawal. Primary endpoint was overall response rate (per iwCLL criteria, by investigator) for participants with CLL/SLL. Secondary endpoints included duration of response and safety and tolerability. The data cut-off date for this analysis was April 7, 2021. Results: Among 118 participants enrolled, 44 had B-cell NHL (including 6 with DLBCL, 11 with FL, 3 with high-grade BCL, 6 with MCL, 2 with MZL, 16 with RT), 68 CLL/SLL, and 4 WM. Of these, 94 (79.6%) were treated at the preliminary RP2D, including 51 (54.3%) participants with CLL/SLL. Participants with CLL/SLL had a median (range) number of prior therapies of 4 (1-18), 43 (84%) had prior BTKi therapy, 12 (23%) had del17p, 26 (51%) had IGHV unmutated status, and 32 (63%) had C481S BTK mutation. At data cut-off, median (range) follow-up was 4.56 months (0.1-26.7) for all treated participants. ORR was 57.9% (N = 22 of 38; 1 CR, 21 PR/PRL) per iwCLL criteria in the efficacy evaluable population of participants with CLL/SLL treated at preliminary RP2D. The median duration of response in these participants was not estimable [NE] (range, 8.3 months-NE). At data cut-off, the median duration of treatment exposure was 3.2 months (range, 0-35.9). Among all treated participants, 114 (97%) had a treatment-emergent adverse event (TEAE), with 78 (66%) having a drug-related TEAE, and 9 (8%) having a drug-related TEAE that led to discontinuation. Common TEAEs (≥ 20%) included fatigue (33%), constipation (31%), dysgeusia (28%), cough (25%), nausea (25%), pyrexia (25%), dizziness (23%), hypertension (23%), peripheral edema (22%), arthralgia (20%), and diarrhea (21%). Grade ≥3 TEAEs occurred in 80 (68%) participants. Grade 5 TEAEs occurred in 7 (6%) participants and included death following disease progression in 3 (3%), sepsis 1 (1%), dyspnea 1 (1%), and respiratory failure 2 (2%) participants. Common drug-related TEAEs (≥10%) included dysgeusia (15%), nausea (11%), fatigue (11%), and decreased neutrophil count (10%). Grade 3-4 drug-related TEAEs occurred in 31 (26%) participants. No drug-related TEAEs led to death. Conclusion: MK-1026 has promising antitumor activity with a manageable safety profile in participants with CLL/SLL exposed to multiple lines of therapy, including in those who had progression of disease on prior covalent BTKi. Further evaluation of MK-1026 in B-cell malignancies is ongoing. Disclosures Woyach: AbbVie Inc, ArQule Inc, Janssen Biotech Inc, AstraZeneca, Beigene: Other: Advisory Committee; AbbVie Inc, ArQule Inc, AstraZeneca Pharmaceuticals LP, Janssen Biotech Inc, Pharmacyclics LLC, an AbbVie Company,: Consultancy; AbbVie Inc, Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company: Research Funding; Gilead Sciences Inc: Other: Data & Safety. Flinn: Verastem: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Genentech: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; IGM Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Gilead Sciences: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Juno Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Constellation Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Loxo: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Kite, a Gilead Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Novartis: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AbbVie: Consultancy, Other: All Consultancy and Research Funding payments made to Sarah Cannon Research Institute, Research Funding; AstraZeneca: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Great Point Partners: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; BeiGene: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Forty Seven: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Calithera Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Roche: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Unum Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; MorphoSys: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Merck: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; TG Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Janssen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Teva: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Takeda: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Seagen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Karyopharm Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Celgene: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Incyte: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Infinity Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Agios: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Curis: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Acerta Pharma: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; ArQule: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Pfizer: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forma Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Portola Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Rhizen Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Trillium Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Triphase Research & Development Corp.: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Century Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Hutchison MediPharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Vincerx Pharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Sarah Cannon Research Institute: Current Employment; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Seagen: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Unum Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute, Research Funding; Johnson & Johnson: Current holder of individual stocks in a privately-held company; Seattle Genetics: Research Funding. Awan: Verastem: Consultancy; Incyte: Consultancy; Dava Oncology: Consultancy; MEI Pharma: Consultancy; Beigene: Consultancy; Celgene: Consultancy; Johnson and Johnson: Consultancy; Karyopharm: Consultancy; Kite pharma: Consultancy; Gilead sciences: Consultancy; Pharmacyclics: Consultancy; Janssen: Consultancy; BMS: Consultancy; Merck: Consultancy; Cardinal Health: Consultancy; ADCT therapeutics: Consultancy; Abbvie: Consultancy; Astrazeneca: Consultancy; Genentech: Consultancy. Eradat: AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Speakers Bureau; Juno: Research Funding; Kite: Research Funding; Genentech: Research Funding. Brander: Pfizer: Consultancy, Other: Biosimilars outcomes research panel; Juno Therapeutics/Celgene/Bristol Myers Squibb: Research Funding; ArQule: Research Funding; Ascentage: Research Funding; AstraZeneca: Research Funding; BeiGene: Research Funding; DTRM: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; MEI Pharma: Research Funding; TG Therapeutics: Consultancy, Research Funding; Novartis: Research Funding; LOXO: Research Funding; Verastem: Consultancy; ArQule/Merck: Consultancy; Genentech: Consultancy, Research Funding; NCCN: Other: panel member; AbbVie: Consultancy, Other: informCLL registry steering committee, Research Funding. Parikh: Pharmacyclics, MorphoSys, Janssen, AstraZeneca, TG Therapeutics, Bristol Myers Squibb, Merck, AbbVie, and Ascentage Pharma: Research Funding; Pharmacyclics, AstraZeneca, Genentech, Gilead, GlaxoSmithKline, Verastem Oncology, and AbbVie: Membership on an entity's Board of Directors or advisory committees. Phillips: BMS: Consultancy, Research Funding; AstraZeneca: Consultancy; Incyte: Consultancy, Other: received travel expenses from Incyte, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Research Funding; ADCT, BeiGene, Bristol Myers Squibb, Cardinal Health, Incyte, Karyopharm, Morphosys, Pharmacyclics, Seattle Genetics: Consultancy; Bayer: Consultancy, Research Funding. Reddy: Merck & Co., Inc.: Current Employment. Farooqui: Merck & Co., Inc.: Current Employment, Other: Current Stockholder. Byrd: Vincerx Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, Syndax: Consultancy, Honoraria; Newave: Membership on an entity's Board of Directors or advisory committees. Stephens: CSL Behring: Consultancy; Innate Pharma: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees; Arqule: Research Funding; Mingsight: Research Funding; JUNO: Research Funding; Novartis: Research Funding; Abbvie: Consultancy; AstraZeneca: Consultancy; Celgene: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Background There are limited studies regarding the impact of post-operative leak on perforated peptic ulcer disease (PPUD) and conflicting results regarding routine drain placement in operative repair of PPUD. This study aims to identify risk factors for gastrointestinal leak after operative repair of PPUD to better guide intra-operative decisions about drain placement. Methods We performed a retrospective cohort study at a tertiary care center from 2008 to 2019, identifying 175 patients who underwent operative repair of PPUD. Results Patients who developed a leak (17%) were compared to patients who did not. Both hypoalbuminemia (albumin < 3.5 g/dL) ( P = .03) and duodenal ulcers ( P < .01) were identified as significant risk factors for leak. No significant difference was found between leak and no leak groups for AAST disease severity grade, repair technique, or pre-operative use of tobacco, alcohol, or steroids. Post-operative leaks were associated with prolonged hospital stay (29 days compared to 10, P < .01), increased complication rates (77% compared to 48%, P < .01), and increased re-operation rates (73% compared to 26%, <0.01). No difference was identified in patient characteristics or operative leak rates between patients who had drains placed at the index operation and those that did not. Discussion Leak after operative PPUD repair is associated with significant post-operative morbidity. Hypoalbuminemia and duodenal perforations are significant risk factors for post-operative leaks.

In adult congenital heart disease, there are situations that require both the aortic and pulmonary roots to be replaced at the time of a reoperation. This commonly involves the replacement of a previously implanted right ventricle-pulmonary artery conduit in a patient with late aortic root dilation and/or neo-aortic valve dysfunction following the Ross procedure. Similar scenarios are encountered in patients having undergone previous repair of conotruncal anomalies such as truncus arteriosus and tetralogy of Fallot with pulmonary atresia. We describe our standardized technique for twin root replacement.

Background: Although valve-sparing repair remains ideal for patients with tetralogy of Fallot, the durability of valve-sparing repair and which patients may have been better served with a transannular patch remain unclear. Methods: Retrospective review was performed of tetralogy of Fallot operations at our institution from January 2008 to December 2018. Standard demographic data were collected, including echocardiographic parameters, operative details, and clinical outcomes. Statistical analysis was performed comparing the transannular patch and valve-sparing repair groups. Results: Sixty-seven patients underwent tetralogy of Fallot repair with a median age of 4.5 (3.2-6.0) months and weight of 5.8 (5.2, 6.7) kg. Seventeen (25%) patients underwent transannular patch repair and 50 (75%) patients underwent valve-sparing repair. There was no difference in age or weight between patients who underwent a transannular patch repair and those who underwent a valve-sparing repair. At last follow-up (median 42 months), there was a trend of a higher peak pulmonary valve/right ventricular outflow tract gradient ( P = .06) in the valve-sparing group, but no difference in the pulmonary valve annulus z-scores. Additionally, the pulmonary valve z-scores in the valve-sparing group decreased from −2.3 ± 1.0 on predischarge echocardiogram of to −1.2 ± 1.6 on last follow-up, with the peak gradient on predischarge 23 (0-37) mm Hg remaining stable on last follow-up at 18 (0-29) mm Hg. There was one reoperation: pulmonary valve replacement six years after a transannular patch. Conclusions: Obtaining a postrepair pulmonary valve z-score of −2 yields satisfactory, stable valve-sparing repair with pulmonary valve growth, acceptable gradients, minimal regurgitation, and high freedom from reintervention during follow-up.

Three-dimensional (3D) modeling has become an invaluable tool for operative planning in the continually evolving complex field of adult congenital heart surgery. We present a case of an intra-atrial conduit leak after multiple repairs of common atrium and criss-cross morphology. 3D modeling was critical in preoperative evaluation and operative planning for complicated intracardiac anatomy after an uncommon initial approach to preserve a biventricular circulation. In the setting of complex or rare congenital cardiac anomalies, advanced imaging and 3D modeling are helpful with preoperative planning.

OBJECTIVES: To report the epidemiology, treatments, and outcomes of adult patients admitted to the ICU after cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome. DESIGN: Retrospective cohort study SETTING: Nine centers across the U.S. part of the chimeric antigen receptor-ICU initiative. PATIENTS: Adult patients treated with chimeric antigen receptor T-cell therapy who required ICU admission between November 2017 and May 2019. INTERVENTIONS: Demographics, toxicities, specific interventions, and outcomes were collected. RESULTS: One-hundred five patients treated with axicabtagene ciloleucel required ICU admission for cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome during the study period. At the time of ICU admission, the majority of patients had grade 3–4 toxicities (66.7%); 15.2% had grade 3–4 cytokine release syndrome and 64% grade 3–4 immune effector cell-associated neurotoxicity syndrome. During ICU stay, cytokine release syndrome was observed in 77.1% patients and immune effector cell-associated neurotoxicity syndrome in 84.8% of patients; 61.9% patients experienced both toxicities. Seventy-nine percent of patients developed greater than or equal to grade 3 toxicities during ICU stay, however, need for vasopressors (18.1%), mechanical ventilation (10.5%), and dialysis (2.9%) was uncommon. Immune Effector Cell-Associated Encephalopathy score less than 3 (69.7%), seizures (20.2%), status epilepticus (5.7%), motor deficits (12.4%), and cerebral edema (7.9%) were more prevalent. ICU mortality was 8.6%, with only three deaths related to cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome. Median overall survival time was 10.4 months (95% CI, 6.64–not available mo). Toxicity grade or organ support had no impact on overall survival; higher cumulative corticosteroid doses were associated to decreased overall and progression-free survival. CONCLUSIONS: This is the first study to describe a multicenter cohort of patients requiring ICU admission with cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome after chimeric antigen receptor T-cell therapy. Despite severe toxicities, organ support and in-hospital mortality were low in this patient population.

Objective: To identify risk factors for pediatric mechanical mitral valve replacement (mMVR) to improve management in this challenging population. Methods: From 1993 to 2019, 93 children underwent 119 mMVR operations (median age, 8.8 years [interquartile range [IQR]: 2.1-13.3], 54.6% females) at our institution. Twenty-six (21.8%) patients underwent mMVR at ≤2 years and 93 (78.2%) patients underwent mMVR at >2 years. Median follow-up duration was 7.6 years [IQR: 3.2-12.4]. Results: Early mortality was 9.7%, but decreased with time and was 0% in the most recent era (13.9% from 1993 to 2000, 7.3% from 2001 to 2010, 0% from 2011 to 2019, P = .04). It was higher in patients ≤2 years compared to patients >2 years (26.9% vs 2.2%, P < .01). On multivariable analysis for mitral valve reoperation, valve size <23 mm was significant with a hazard ratio of 5.38 (4.87-19.47, P = .01);. Perioperative stroke occurred in 1% and permanent pacemaker was necessary in 12%. Freedom from mitral valve reoperation was higher in patients >2 years and those with a prosthesis ≥23 mm. Median time to reoperation was 7 years (IQR: 4.5-9.1) in patients >2 years and 3.5 years (IQR: 0.6-7.1) in patients ≤2 years ( P = .0511), but was similar between prosthesis sizes ( P = .6). During follow-up period (median 7.6 years [IQR: 3.2-12.4], stroke occurred in 10%, prosthetic valve thrombosis requiring reoperation in 4%, endocarditis in 3%, and bleeding in 1%. Conclusion: Early and late outcomes of mMVR in children are improved when performed at age >2 years and with prosthesis size ≥23 mm. These factors should be considered in the timing of mMVR.

The optimal training of the highly specialized congenital heart surgeon is a long and complex process, which is a significant challenge in most parts of the world. The World Society for Pediatric and Congenital Heart Surgery (WSPCHS) has established the Global Council on Education for Congenital Heart Surgery as a nonprofit organization with the goal of assessing current training and certification and ultimately establishing standardized criteria for the training, evaluation, and certification of congenital heart surgeons around the world. The Global Council and the WSPCHS have reviewed the present status of training and certification for congenital cardiac surgery around the world. There is currently lack of consensus and standardized criteria for training in congenital heart surgery, with significant disparity between continents and countries. This represents significant obstacles to international job mobility of competent congenital heart surgeons and to the efforts to improve the quality of care for patients with Congenital Heart Disease worldwide. The purpose of this article is to summarize and document the present state of training and certification in congenital heart surgery around the world.

Substantial improvements in techniques of tracheal surgery for children have occurred in the past 20 years. Precise preoperative imaging with computed tomography clearly defines the anatomy for surgical planning and is assisted by on-the-table needle localization. The use of cardiopulmonary bypass greatly facilitates creation of an airtight, widely patent trachea. The use of Ciprodex as a postoperative nebulizer has significantly decreased granulation tissue along the suture line. Most important has been the adoption of slide tracheoplasty as the procedure of choice.