Search

Venetoclax has efficacy in patients relapsing after B-cell receptor pathway inhibitors (BCRis); however, because of the risk of tumor lysis syndrome (TLS), a 5-week dose ramp-up is required to attain the target dose. Patients relapsing after BCRis frequently have proliferative disease, requiring a faster time to target dose than this scheme allows. This limitation can potentially be overcome with rapid dose escalation (RDE). We analyzed 33 chronic lymphocytic leukemia patients who underwent venetoclax RDE after prior BTKi treatment. Median time to target dose was 9 days. Seventeen patients (52%) developed laboratory TLS, and 5 (15%) developed clinical TLS, all as a result of renal injury. TLS was seen in more patients with a higher initial tumor burden. TLS occurred at all dose levels, with most episodes occurring at the 50- and 100-mg doses. Most interestingly, a decrease in absolute lymphocyte count (ALC) from pre–venetoclax dose to 24 hours post–venetoclax dose of 10 × 103/μL was associated with an increased risk of TLS (hazard ratio, 1.32; P = .02), after controlling for venetoclax dose level. Venetoclax RDE with close in-hospital monitoring at experienced centers and in select patients is feasible. The rapidity with which ALC drops helps predict TLS and could help guide dose-escalation decisions.

Background B-cell receptor signaling inhibition (BCRi) is an effective treatment (trtmt) for patients (pts) with chronic lymphocytic leukemia (CLL), but resistance develops. Venetoclax selectively inhibits anti-apoptotic protein B-cell lymphoma 2 (BCL-2), and has demonstrated efficacy in relapsed/refractory CLL pts, particularly after BCRi. Venetoclax is started at 20 mg daily and escalated weekly over 5 weeks to the goal dose to avoid acute tumor lysis syndrome. However, we observed that many pts with relapsed/refractory CLL relapsing on BCRi progress more quickly than this schedule allows; they may progress while still taking BCRi or vigorously after its discontinuation. Given the need to promptly attain goal venetoclax dose in this population, we developed a rapid dose escalation scheme for venetoclax and reviewed our experience to understand the feasibility, safety, and efficacy of this approach in a properly equipped university setting. Methods We retrospectively evaluated adult pts with relapsed/refractory CLL presenting to The Ohio State University who were treated with a "rapid dose escalation" of venetoclax. Charts were reviewed for previous and concomitant CLL treatments, tumor burden, prognostic factors, performance status, and co-morbidities. Venetoclax dosing was planned for a shorter time period than the 5 weeks described in the label dosing. The dose was increased as quickly as tolerated following the customary doses (20mg, 50mg, 100mg, 200mg, then 400mg). We reviewed the evaluated safety and efficacy outcomes with this approach. Results We treated 34 pts with rapid venetoclax dose escalation. Median age at venetoclax start was 54 years old and were 73.5% men. Pts had a median of 5 previous CLL trtmts (range 2-18). The most recent trtmt was single-agent BCRi in 18 cases, which overlapped with venetoclax in the majority. Only 6 pts had high tumor burden and the majority had low or medium tumor burden. Cytogenetic abnormalities at venetoclax start included: 17 (50.0%) pts with 17p deletion, 5 (14.7%) with 13q deletion, 6 (17.6%) with 11q deletion, and 3 (8.8%) with trisomy 12. Fifty percent of pts had a complex karyotype, and 76.5% had unmutated IGVH status. 24 (80%, n=30 pts that had testing done) pts had confirmed BTK/PLCу2 mutations. The mean time to goal venetoclax dose was 9.6 days (range 4-31); all but 1 pt reached goal dose. Eighteen (52.9%) pts developed tumor lysis syndrome (TLS) by lab criteria at doses from 20-400 mg, 5 pts developed TLS by clinical criteria, and 1 pt experienced grade 3 severity TLS (per Cairo-Bishop definition). Only 4 pts had an elevated uric acid requiring rasburicase. Seventy-three percent of pts achieved at least a partial remission, and 4 pts each had stable or progressive disease. Three pts died within 30 days: 1 from uncontrolled bleeding and neutropenia, 1 due to neutropenic sepsis with invasive fungal infection and gastric perforation, and 1 due to neutropenic septic shock and respiratory failure. Time to best response was mean 50.7 days (range 2-428). Median time to subsequent trtmt was 279.5 days (range 73-430). 23 pts (67.6%) had not progressed at 1 year, and 26 (76.5%) were surviving at 1 year. Conclusion/summary Rapid dose escalation of venetoclax in this pt population is safe and feasible. Despite a high percentage of patients developing TLS (52.9%), all patients recovered without lasting complications and all but one were able to achieve the goal dose of venetoclax. This dosing scheme achieved disease control with 67.6% remaining progression-free at 1 year and the majority of pts surviving. It is reasonable to implement venetoclax rapid dose escalation in the proper hospital setting with ample ancillary support. This approach may be needed for CLL patients with rapidly progressive disease on BCRi. Disclosures Dotson: Abbvie: Consultancy. Bhat:Pharmacyclics: Consultancy; Janssen: Consultancy. Byrd:Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Genentech: Research Funding; Ohio State University: Patents & Royalties: OSU-2S; Acerta: Research Funding; BeiGene: Research Funding; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel Expenses, Speakers Bureau; Genentech: Research Funding; Acerta: Research Funding; BeiGene: Research Funding; Ohio State University: Patents & Royalties: OSU-2S; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel Expenses, Speakers Bureau. Woyach:Janssen: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Research Funding; Karyopharm: Research Funding; Loxo: Research Funding; Morphosys: Research Funding; Verastem: Research Funding. Awan:Genentech: Consultancy; Sunesis: Consultancy; Gilead: Consultancy; Abbvie: Consultancy, Speakers Bureau; Janssen: Consultancy; Pharmacyclics: Consultancy, Research Funding; AstraZeneca: Consultancy, Speakers Bureau. Rogers:AbbVie: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Acerta Pharma: Consultancy. OffLabel Disclosure: Venetoclax- we will be suggesting a faster increase from starting to maximum/goal dose than the dosing label recommends. This is in order to achieve faster disease control.

e15168 Background: 2-8% of all colorectal cancer (CRC) cases are in younger adults (YAs), patients (pts) less than age 50. However, current understanding of CRC in YAs is inadequate, especially that of sporadic onset. We conducted a study to describe the landscape of genomic alterations in YA CRC pts presenting to a large academic practice. Methods: Adult pts with CRC presenting to The Ohio State University Comprehensive Cancer Center oncology clinics were offered next generation sequencing (NGS) through a customized 22-gene Ion AmpliSeq Mutation Panel as part of clinical care. Commonly mutated areas of select genes (including AKT1, ALK, BRAF, EGFR, ERBB2/4, FBXW7, FGFR1/2/3, KRAS/NRAS, MET, NOTCH1, PIK3CA, PTEN, TP53) were sequenced from tumor sections. Institutional review board approval was obtained to retrospectively analyze this NGS testing between 1/2013-3/2016. Results: 258 CRC pts underwent genomic profiling. 57 pts (22.1%) were YAs at diagnosis (range 22-49 years); 20 pts (7.8%) were 40 years old or younger. 31 YA pts (54.4%) had metastatic disease. Of the YAs with CRC, 18 pts (31.6%) were diagnosed with R-sided colon, 16 pts (28.1%) with L-sided colon, and 22 pts (38.6%) with rectal cancer. 110 genomic alterations were found in YA pts, with a mean of 1.9 mutations per tumor (range 0-6); 35 (31.8%) of these in 32 (56.1%) YA pts were actionable. Of these 110 alterations, 41.8% were in TP53, 28.2% in KRAS/NRAS, 10.0% in PIK3CA, 3.6% in BRAF, 3.6% in FBXW7, and 2.73% in PTEN. 6 YA pts (10.5%) had microsatellite instability (MSI-H). Only 1 pt had concomitant MSI-H and a BRAF mutation; 4 pts with BRAF mutations were microsatellite stable. Comparing our YA pts to a separate cohort of pts age > 50 who had testing done, no significant difference was seen in mutation incidence in KRAS/NRAS (p = 1.0), TP53 (p = 0.3), PIK3CA (p = 0.128), or BRAF (p = 1.0). Conclusions: Genomic profiling through a targeted NGS panel is feasible as part of routine clinical practice. There is disagreement in the literature on genetic mutations in YA compared to older age CRC pts. Knowledge of the genomic landscape in YAs with CRC will lead to improved understanding of the underlying biology of CRC in YAs as it differs from CRC in older pts, and could impact future care of this cohort.

584 Background: Tumor genomic profiling has become critical in the identification of targeted therapeutic options for patients (pts) with advanced malignancies. Mutational frequencies and their therapeutic importance vary among tumor types. This analysis was undertaken to characterize the landscape of genomic alterations in gastrointestinal (GI) malignancies found in a large academic institutional practice, and to determine the frequency of alteration-specific targeted therapy selection based on genomic profiling. Methods: Adult pts with GI malignancies presenting to the Ohio State University Comprehensive Cancer Center oncology clinics were offered next generation sequencing through FoundationOne testing as part of routine clinical care. Institutional review board approval was obtained to retrospectively analyze results from FoundationOne testing performed between 2012 and 2015. Results: 265 pts with GI malignancies underwent successful genomic profiling. 1205 genomic alterations were found, with an average of 4.5 per tumor (range 0-20); 365 (30%) of these were potentially actionable and most often found in colorectal or gastroesophageal tumors. 14 pts (5.3%) had actionable alterations in MET, CDKN2A/B, FGFR2, KRAS, BRAF, or NF2 that led to enrollment in genotype-directed clinical trials or off label use of targeted therapies beyond standard of care. Pt performance status at the time of genomic alteration identification was a significant factor in precluding genotype-directed therapy. One variant of unknown significance involving FGFR2 identified at initial testing subsequently became actionable and led to pt enrollment on a clinical trial. One pt with rectal cancer was found to have a KRAS wild-type and BRAF mutant primary but KRAS mutant and BRAF wild-type liver metastasis. Conclusions: Genomic profiling of GI malignancies through next generation sequencing is feasible and can lead to genotype-directed therapy selection; however, it should be considered early in the pt’s course to optimize use of targeted therapies through clinical trials. Consideration should be given to serial tumor testing to identify emerging genomic alterations for optimal therapy selection.