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AbstractIntroductionRelapsed or refractory (r/r) acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL) remains a therapeutic challenge. Preclinical data in both B‐ and T‐ALL suggests synergy of venetoclax (VEN) with vincristine (VCR). We designed a phase I/II trial (EA9152) of the combination of L‐VCR and VEN for patients with r/r B‐or T‐cell ALL or LL. Here, we report the safety and efficacy outcomes of the phase I portion of this trial (NCT03504644).MethodsIn a 3+3 dose escalation design, r/r ALL subjects were given single‐agent VEN doses reaching 400, 600, or 800 mg for the three respective dose levels. Weekly L‐VCR at 2.25 mg/m2 IV was started on D15 of cycle 1. The primary phase I objective was to determine the maximum tolerated dose (MTD) of the combination.ResultsAmong the 18 patients in phase I, grade ≥ 3 treatment‐related adverse events were reported in 89% of treated patients. Two patients (two of three) at dose level 3 experienced dose‐limiting toxicities. Therefore, the MTD of the combination was determined to be dose level 2 (VEN 600 mg). Twenty‐two percent of evaluable patients (N = 4) achieved a complete response, with two of them showing no evidence of measurable residual disease (MRD).ConclusionThe combination of VEN and L‐VCR was found to be safe for patients with r/r ALL and encouraging preliminary efficacy, including MRD negative responses. With the removal of L‐VCR from the US market, the phase 2 portion of this trial is actively enrolling with vincristine sulfate.

Chronic lymphocytic leukemia (CLL) is characterized by multiple copy number alterations (CNAs) and somatic mutations that are central to disease prognosis, risk stratification, and mechanisms of therapy resistance. Fluorescence in situ hybridization (FISH) panels are widely used in clinical applications as the gold standard for screening prognostic chromosomal abnormalities in CLL. DNA sequencing is an alternative approach to identifying CNAs but is not an established method for clinical CNA screening. We sequenced DNA from 509 individuals with CLL or monoclonal B-cell lymphocytosis (MBL), the precursor to CLL, using a targeted sequencing panel of 59 recurrently mutated genes in CLL and additional amplicons across regions affected by clinically relevant CNAs [i.e., del(17p), del(11q), del(13q), and trisomy 12]. We used the PatternCNV algorithm to call CNA and compared the concordance of calling clinically relevant CNAs by targeted sequencing to that of FISH. We found a high accuracy of calling CNAs via sequencing compared to FISH. With FISH as the gold standard, the specificity of targeted sequencing was >95%, sensitivity was >86%, positive predictive value was >90%, and negative predictive value was >84% across the clinically relevant CNAs. Using targeted sequencing, we were also able to identify other common CLL-associated CNAs, including del(6q), del(14q), and gain 8q, as well as complex karyotype, defined as the presence of 3 or more chromosomal abnormalities, in 26 patients. In a single and cost-effective assay that can be performed on stored DNA samples, targeted sequencing can simultaneously detect CNAs, somatic mutations, and complex karyotypes, which are all important prognostic features in CLL.

ImportanceIntraocular pressure (IOP) elevations of clinical relevance have been observed after the commonly used 0.05-mL volume for intravitreous injections. However, more recently approved intravitreous agents involve volumes from 0.07 to 0.1 mL. It is not well established whether repeated 0.1-mL intravitreous injections may result in IOP-related complications.ObjectiveTo investigate the effect of 1 year of repeated 0.1-mL intravitreous injections on IOP outcomes.Design, Setting, and ParticipantsThis study was a post hoc analysis of 2 clinical trials investigating the IOP safety of intravitreous lampalizumab on geographic atrophy secondary to age-related macular degeneration. Both trials were conducted between 2014 and 2018 and recruited participants who were 50 years or older and had bilateral geographic atrophy. This post hoc analysis was performed between 2018 and 2022.InterventionsIntravitreous lampalizumab, 0.1 mL, every 4 weeks; lampalizumab, 0.1 mL, every 6 weeks; or sham procedure every 4 weeks or 6 weeks for 48 weeks.Main Outcomes and MeasuresIOP changes in the 4-week-frequency study arms and ocular adverse events to week 48 in all arms. The hypothesis for this analysis was formulated after data collection.ResultsAmong a total of 1851 participants, there was no change in mean pre-injection IOP values through 48 weeks in either arm. The adverse events glaucoma and ocular hypertension were reported for 1.8% of participants treated with lampalizumab and 1.6% of those in the sham arm.Conclusions and RelevanceOver 1 year, IOP increases were rare and did not affect treated participants more frequently than sham arm participants. These findings support the low risk of persistent IOP increases, on average, of intravitreous 0.1-mL injection volumes administered for 1 year in a manner similar to that performed in these clinical trials. These results may be valuable in the design of future therapeutic trials considering this volume for injections particularly as more recently approved agents use volumes of 0.07 to 0.1 mL.Trial RegistrationClinicalTrials.gov Identifiers: NCT02247479 and NCT02247531

6009 Background: E3311 is a phase II trial of TOS by credentialed surgeons with pathology-driven deintensified post-operative management in HPV+ OPC. Intermediate risk patients were randomized between standard and reduced dose radiation. We present mature outcome data, at median follow up of 52.4 months (m). Methods: Patients were eligible who had resectable cT1-2 stage III/IV AJCC7 p16+ OPC without matted neck nodes. Those with clear margins, 0-1 + nodes (LN), and no extranodal extension (ENE) were observed (Arm A, N=38); those with clear margins, 2-4 + LN, or ENE ≤1mm were randomized to 50Gy (Arm B, N=100) or 60Gy (Arm C, N=108); those with involved margins, >4 + LN, or >1mm ENE received weekly cisplatin 40 mg/m2 and 60-66Gy (Arm D, N=113). Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method and compared using a log-rank test, stratified by arm for comparisons of primary site and smoking history. Results: Among 359 evaluable patients, 54-m PFS and OS were 90.6% (90% CI: 87.2%, 93.1%) and 95.3% (90% CI: 93.0%, 96.9%). 54-m PFS by arm was: A 93.2% (90% CI: 79.6%, 97.8%); B 94.9% (90% CI: 89.7%, 97.5%); C 90.2% (90% CI: 82.7%, 94.6%) and D 85.5% (90% CI: 77.5%, 90.8%). 54-m OS by arm was: A 97.1% (90% CI: 85.7%, 99.4%); B 97.9% (90% CI: 93.5%, 99.3%), C 95.1% (90% CI: 90.1%, 97.6%) and D 92.5% (90% CI: 86.9%, 95.7%). Among patients in Arm A, 11 had N0 and 27 N1 stage. Median Arm A lymph node yield (LNY) was 29 (11 to 91 LN) and did not differ for patients with/without recurrence (p=0.83). All Arm A recurrences were in N1 patients: 1 at 18 m and 3 at > 40 m. No significant difference in PFS or OS was observed by prescribed radiation dose for intermediate risk patients (Arm B vs. C). Outcome did not differ by primary site of tonsil vs. other OPC (oOPC): 54-m PFS Tonsil 89.3% (90% CI: 84.9%, 92.5%) vs. oOPC 92.9% (90% CI: 87.0%, 96.2%), p=0.28, and 54-m OS Tonsil 94.6% (90% CI: 91.5%, 96.6%) vs oOPC 96.6% (90% CI: 92.4%, 98.5%), p=0.35. Smoking history also did not impact outcome. 54-m PFS was 89.9% (90% CI: 85.9%, 92.9%) for those with ≤10 pack-years (PY) tobacco exposure and 91.7% (90% CI: 83.9%, 95.9%) for those with >10 PY. Conclusions: TOS, neck dissection with deintensified risk-based post-operative management results in outstanding 54-m PFS and OS across all subsites of T1-2 p16+ OPC, irrespective of smoking history. Late recurrence is not increased when post-operative radiation is reduced from 60 to 50Gy for intermediate risk patients. Pathologic >1mm ENE (N=87), involved margin (N=12) or >4 involved LN (N=30) accurately identify patients at increased recurrence risk and outcomes were favorable among such patients. Among patients with favorable pathologic characteristics, a subset with N1 disease are at risk for late recurrence and further characterization of these patients is warranted. Clinical trial information: NCT01898494 .

7050 Background: The management of Richter transformation (RT) of CLL represents an unmet clinical need. We previously reported modest efficacy of pembrolizumab monotherapy in an initial cohort of patients with RT (Ding, et al, Blood 2017). Here we report updated results of this trial, including an expansion cohort and a combination therapy cohort. Methods: Patients with biopsy proven RT to diffuse large B-cell lymphoma were enrolled and treated with single agent pembrolizumab (200 mg IV Q3W). Patients with progressive disease (PD) or stable disease (SD) after 3 months of pembrolizumab monotherapy were allowed to add a B-cell receptor (BCR) kinase inhibitor. The primary end point was overall response rate (ORR). Results: A total of 26 patients with RT were enrolled (9 in initial cohort and 17 in expansion cohort). The median age was 68.5 years. Ten (38%) patients had del(17p) or TP53 mutation. The median number of prior lines of therapy was 3 (range 1-10). Fifteen (58%) patients had received ibrutinib previously (14 of whom had PD on ibrutinib). With pembrolizumab monotherapy (n=26), the ORR was 23.1%, with 2 (7.7%) complete response (CR), 4 (15.4%) partial response (PR), and 7 (26.9%) SD. Of the 6 patients with confirmed CR or PR, responses occurred after a median of 2 cycles of monotherapy. The median duration of response (DOR) was 3.2 months (95% CI 2.8-NA). The median progression-free survival (PFS) was 2.6 months (95% CI 1.6-3.6). Sixteen patients went on to receive a BCR kinase inhibitor (ibrutinib [n=15], idelalisib [n=1]) in combination with pembrolizumab, after SD or PD on pembrolizumab monotherapy. The ORR to combination therapy was 62.5%, with 4 (25.0%) CR and 6 (37.5%) PR. Of the 10 patients with confirmed CR or PR to combination therapy, responses occurred after a median of 4 cycles of therapy. The median DOR was 4.5 months (95% CI 1.6-NA). The median PFS was 7.6 months (95% CI 2.3-13.3). After a median follow-up of 50.4 (95% CI 34.0-56.0) months, the median overall survival (OS) for all 26 patients with RT was 11.6 months (95% CI 7.5-20.1), and the 2-year OS rate was 27%. Treatment-related adverse events (TRAEs) of any grade occurred in 24 (92%) patients, including anemia (54%), thrombocytopenia (58%), neutropenia (54%), leukopenia (35%), lymphopenia (23%), dyspnea (23%), diarrhea (19%), and nausea (23%). Treatment-related grade 3 or above AEs occurred in 21 (81%) patients, including neutropenia (38%), leukopenia (31%), thrombocytopenia (27%), anemia (15%), febrile neutropenia (12%), and lung infection (12%). Conclusions: This expanded analysis confirmed that pembrolizumab has modest single agent activity in RT. Combination therapy with pembrolizumab and a BCR kinase inhibitor is associated with increased efficacy (ORR >60%), similar to other reports. These results support further investigation of immune checkpoint inhibitor-based combination therapy in RT. Clinical trial information: NCT02332980 .

ABSTRACT Background The aim of this study was to determine the long-term effect of increasing water intake in patients with autosomal dominant polycystic kidney disease (ADPKD) on longitudinal changes in health-related quality of life (HRQoL) in the setting of a clinical trial. Methods Self-completed HRQoL (using the KDQoL-SF, v.1.3 questionnaire) was assessed annually in participants of a 3-year randomized controlled clinical trial (n = 187), allocated (1:1) either to increase water intake to reduce urine osmolality to ≤270 mosmol/kg (implemented by dietetic coaching, self-monitoring tools, text messaging) or continue usual water intake. Results Overall, 96% and 81.8% of participants (n = 187) completed the questionnaire at the baseline and final study visits, respectively. At baseline, the physical component summary score (PCS) and mental component summary score (MCS) were similar in the two groups (P > 0.05) and the five dimensions with the lowest scores in both groups were: energy and fatigue; general and overall health; sleep; emotional well-being; and pain. Within each group, there were no longitudinal changes over time. At the final visit, the PCS was higher in the increased water intake group (51.3 ± 7.6, mean ± standard deviation) compared to the usual water intake group 48.8 ± 9.3; P = 0.037) whereas the MCS was numerically similar. The improvement in the PCS was due to higher sub-scale values for physical functioning and pain (both P < 0.05). By multivariate analysis, only baseline PCS and height-corrected total kidney volume were associated with the final PCS (P < 0.05). Conclusion HRQoL scores remained stable over a 3 year period, and were not adversely affected by the intervention to increase water intake. Future studies should evaluate the clinical significance of the higher PCS in the increased water intake group.

5074 Background: PC commonly expresses PSMA and has dose-responsive radiosensitivity. 177Lu-based radioligands usually use an empiric dosing regimen. This 1st dose-escalation study of 177Lu-PSMA-617 employed a dose-dense fractionation schedule intended to allow delivery of higher total doses to overcome radioresistance due to repopulation. Here, we report mature results of the study. Methods: Progressive mCRPC following > 1 potent ARPI (e.g., abi/enza) and chemo (or unfit/refuse taxane) without limit of # prior therapies provided adequate organ function and ECOG PS 0-2. Treatment: single cycle of fractionated dose 177Lu-PSMA-617 on D1 and D15. In Ph I dose-escalation, patients (pts) received one cycle of 7.4 - 22 GBq followed by Simon 2-stage Ph II at 22.2 GBq. PSMA expression was not required for treatment, but pre- and post-treatment 68Ga-PSMA11 PET/CT and/or 177Lu-PSMA-617 SPECT done. Primary efficacy by PSA changes with 2ndary outcomes with CT/bone scans, PSMA PET, circulating tumor cell (CTC; CellSearch) counts, plasma DNA (PCF_SELECT), and survival. Results: Between 1/2017 – 2/2021, 50 pts treated with median PSA 164.3, 35 (70%) CALGB (Halabi) poor risk. 47 (94%) bone, 38 (76%) nodal, 12 (24%) lung, 5 (10%) liver mets (4 additional pts with PSMA PET+ liver mets not apparent on CT). 29 (58%) with prior >2 ARPI, 29 (58%) with >1 chemo, 14 (28%) with Ra-223, 2 (4%) with 177Lu-J591. 27 (54%) treated at 22 GBq. No dose-limiting toxicity during Ph I. 38 (76%) with any PSA decline, 27 (54%) with >50% PSA. Median rPFS 8.3 mo [5.6-16.7], and OS 15.7 mo [10.9-20.6]. Of 17 RECIST measurable, 6 (35.3%) responded, 7 (41.2%) stable, 4 (23.5%) progressed. Of 31 with paired CTC counts, 16 (52%) decreased, 5 (16%) were stable; 10 (32.3%) converted to favorable/undetectable. Plasma DNA with high allele-specific ploidy and ARcopy number gain associated with OS (univariate). Treatment emergent adverse events (TEAE): 32 (64%) dry mouth, 22 (44%) pain flare, 22 (44%) fatigue, 19 (38%) nausea, 15 (30%) anemia, 15 (28%) thrombocytopenia (plts), 9 (18%) neutropenia (ANC). All TEAEs restricted to grade (Gr) 1-2 except 6 (12%) with Gr 3 anemia, 2 (4%) Gr 3/4 plts, 1 (2%) Gr 3 ANC. TEAE incidence and Gr were not related to dose. On multivariable analysis, 177Lu dose administered (p=0.09), CALGB risk (p=0.04), prior chemo (p=0.009), associated with OS; dose (p=0.1), CALGB risk (p=0.2), and AR copy number (p=0.2) associated with PSA50 decline. Baseline PSMA imaging (by imaging score or SUVmax) was not associated with OS or response. Conclusions: A single-cycle of fractionated-dose 177Lu-PSMA-617 is safe. Despite no pre-selection for PSMA expression, most had PSA decline with favorable PFS and OS compared to historical controls and similar to PSMA-selected targeted radionuclide studies administering multiple cycles in a less dose-intense approach. Clinical trial information: NCT03042468 .

Regular, long-term aspirin use may act synergistically with genetic variants, particularly those in mechanistically relevant pathways, to confer a protective effect on colorectal cancer (CRC) risk. We leveraged pooled data from 52 clinical trial, cohort, and case-control studies that included 30,806 CRC cases and 41,861 controls of European ancestry to conduct a genome-wide interaction scan between regular aspirin/nonsteroidal anti-inflammatory drug (NSAID) use and imputed genetic variants. After adjusting for multiple comparisons, we identified statistically significant interactions between regular aspirin/NSAID use and variants in 6q24.1 (top hit rs72833769 ), which has evidence of influencing expression of TBC1D7 (a subunit of the TSC1-TSC2 complex, a key regulator of MTOR activity), and variants in 5p13.1 (top hit rs350047 ), which is associated with expression of PTGER4 (codes a cell surface receptor directly involved in the mode of action of aspirin). Genetic variants with functional impact may modulate the chemopreventive effect of regular aspirin use, and our study identifies putative previously unidentified targets for additional mechanistic interrogation.