Citations

Abstract Overexpression of B-cell leukemia/lymphoma 2 (BCL2) renders acute myeloid leukemia (AML) cells resistant to chemotherapy and has been associated with unfavorable outcomes. Oblimersen (G3139) is a phosphorothioate 18-mer antisense oligonucleotide directed against the first 6 BCL2 codons. In a phase 1 study of AML patients treated with G3139, cytarabine, and daunorubicin induction with cytarabine consolidation, no antisense-related toxicity was reported, and BCL2 downregulation occurred in patients achieving complete remission. In this phase 3 trial, untreated older AML patients were randomized to cytarabine (100 mg/m2 per day on days 4-10) and daunorubicin (60 mg/m2 per day on days 4-6) followed by cytarabine consolidation (2000 mg/m2 per day on days 4-8) with (arm A) or without (arm B) G3139 (7 mg/m2 per day on days 1-10 [induction] or days 1-8 [consolidation]). A total of 506 patients were enrolled. No differences in toxicity were observed between arms. Estimated overall survival (OS) at 1 year was 43% for arm A and 40% for arm B (1-sided log rank P = .13), with no differences in disease-free (DFS; P = .26) or event-free survival (P = .80). Subgroup analyses showed patients age <70 years in arm A had improved OS by 1 month vs those in arm B (P = .04), and patients with secondary AML in arm A had better DFS vs those in arm B (P = .04). We conclude that addition of G3139 to chemotherapy failed to improve outcomes of older AML patients. However, more effective means of inhibiting BCL2 are showing promising results in combination with chemotherapy in AML. This trial was registered at www.clinicaltrials.gov as #NCT00085124.

Abstract Background: Conventional prognostic factors for LBCL were not associated with outcomes in the pivotal ZUMA-1 study of axi-cel in relapsed LBCL (Neelapu et al. NEJM. 2017); however, other attributes like chimeric antigen receptor (CAR) T-cell fitness and composition (CCR7+CD45RA+ T cells), reduced preTx tumor burden, and immune tumor microenvironment (TME) with presence of activated CD8+PD-1+LAG-3+/-TIM-3- T cells were associated with efficacy (Locke et al. Blood Adv. 2020; Galon et al. ASCO 2020. #3022). Here, we evaluated preTx immune cell phenotypes in premanufacturing apheresis (premfg aph) material, comprising peripheral blood mononuclear cells, to determine associations with product attributes, immune TME features, and clinical efficacy in ZUMA-1. Methods: Evaluable samples from patients (pts) in Phase (Ph) 1 and Ph2 Cohorts (C) 1-3 were analyzed (NCT02348216; Ph1 and Ph2 C1+2, ≥2-y follow-up; C3, ≥6-mo follow-up). Memory T, myeloid, NK, NKT, and B cells in premfg aph material (n=101, excluding C3) were characterized by flow cytometry (FC). PreTx immune TME was analyzed by multiplex IHC (n=18) and gene expression analysis (n=30) as previously described (Rossi et al. AACR 2018. #LB-016; Galon et al. ASCO 2020. #3022). CAR T-cell fitness was analyzed by doubling time, viability during manufacturing, and product T-cell phenotypes by FC (n=145). Associations between these covariates, and with routine hematology tests, were performed by Spearman rank correlation or Wilcoxon tests. Effects on survival were assessed by Kaplan-Meier with optimized cutpoint selection. Results: The percentage (%) of naive (CCR7+CD45RA+) T helper (Th; CD4+CD127+CD25low) cells coexpressing CD27 and CD28 (median, 1%; range, 0.01%-15.8%; IQR, 0.3%-3.8%) in aph associated positively with axi-cel efficacy. The % of intermediate monocytes (IMs; CD14+CD16+; median, 1.8%; range, 0.003%-16.7%; IQR, 1%-3%) in aph associated negatively with efficacy. The % of circulating CD27+CD28+ naive Th cells associated positively with an enriched preTx immune TME T-cell signature, % CCR7+CD45RA+ product T cells, objective response rate, PFS, and OS. An increased % of IMs associated directly with negative predictive markers (preTx serum levels of LDH, IL-6, and CRP) and inversely with TME T-cell signature, PFS, and OS. The premfg ratio of CD27+CD28+ naive Th cells/IMs associated directly with CAR T-cell expansion and efficacy. Conclusions: This work points to a link between the pre-existing state of the immune system, reflected in premfg aph, and immune TME, as well as product attributes influencing axi-cel efficacy in LBCL. These data bear practical implications towards the development of predictive biomarkers for axi-cel efficacy. [JB and JC contributed equally.] Citation Format: Justin Budka, Justin Chou, Vicki Plaks, Francesca Milletti, Zixing Wang, Frederick L. Locke, Sattva S. Neelapu, David B. Miklos, Caron A. Jacobson, Lazaros J. Lekakis, Yi Lin, Armin Ghobadi, Zahid Bashir, Nathalie Scholler, Jérôme Galon, John M. Rossi, Adrian Bot. Pretreatment (PreTx) immune cell phenotypes in peripheral blood associated with the tumor immune contexture, product attributes, and durable clinical efficacy in patients with large B-cell lymphoma (LBCL) treated with axicabtagene ciloleucel (axi-cel) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT166.

Objectives Sex as a biological variable affects response to opioids. However, few reports describe the prevalence of specific adverse reactions to commonly prescribed opioids in men and women separately. A large cohort was used to investigate sex differences in type and occurrence of adverse reactions associated with use of codeine, tramadol, oxycodone and hydrocodone. Design Retrospective cohort study. Setting Participants in the Right Drug, Right Dose, Right Time (RIGHT) Study. Participants The medical records of 8457 participants in the RIGHT Study who received an opioid prescription between 1 January 2004 and 31 December 2017 were reviewed 61% women, 94% white, median age (Q1–Q3)=58 (47–66). Primary and secondary outcome measures Adverse reactions including gastrointestinal, skin, psychiatric and nervous system issues were collected from the allergy section of each patient’s medical record. Sex differences in the risk of adverse reactions due to prescribed opioids were modelled using logistic regression adjusted for age, body mass index, race and ethnicity. Results From 8457 participants (of which 449 (5.3%) reported adverse reactions), more women (6.5%) than men (3.4%) reported adverse reactions to at least one opioid (OR (95% CI)=2.3 (1.8 to 2.8), p<0.001). Women were more likely to report adverse reactions to tramadol (OR (95% CI)=2.8 (1.8 to 4.4), p<0.001) and oxycodone (OR (95% CI)=2.2 (1.7 to 2.9), p<0.001). Women were more likely to report gastrointestinal (OR (95% CI)=3.1 (2.3 to 4.3), p<0.001), skin (OR (95% CI)=2.1 (1.4 to 3.3), p=0.001) and nervous system issues (OR (95% CI)=2.3 (1.3 to 4.2), p=0.004). Conclusions These findings support the importance of sex as a biological variable to be factored into pain management studies.

Mono‐and polyunsaturated fats in nuts, such as pistachios (PI), may improve lipoprotein and glycemic status. Overweight persons trend for dyslipidemia and high diabetes risk. The lower limits of PI consumption required for health benefits are unknown. This study determined if PI at bedtime promotes beneficial changes in metabolic status in overweight persons. Overweight subjects (n=22; 55 ± 2 yrs; 90 ± 3.6 kg; BMI 31 ± 1) were randomized to 35.4 g PI self‐administered at bedtime or control (CO; no PI) for 6 weeks. There was no difference in physical activity level between subjects receiving PI and CO. Body weight was not different in PI and CO at wk 0, 1, 2, 4, and 6. HDL cholesterol at wk 0 and 6 in PI was 49.2 ± 3.5 to 50.3 ± 3.0, and CO was 60.8 ± 3.8 and 58.0 ± 2.7 mg/dL, at wk 6 PI had improved slightly relative to CO (P= 0.12). Plasma glucose at wk 0 and 6 in PI was 104.6 ± 2.8 and 99.6 ± 2.6 mg/dL, and CO was 102.0 ± 2.8 and 101.1 ± 2.6 mg/dL, at wk 6 PI had improved slightly relative to CO (P= 0.16). Plasma insulin at wk 0 and 6 in PI was 8.5 ± 1.0 and 8.4 ± 0.9, and CO was 7.2 ± 0.7 to 8.8 ± 0.7 μU/mL, at wk 6 PI had improved slightly relative to CO (P = 0.21). Beneficial changes in HDL, glucose, and insulin probably requires slightly more than 35.4 g/d PI for 6 wks. To increase the probability of metabolic health benefits, nutritionists may wish to encourage levels of daily PI consumption higher than those administered in this study.

Background: Closed-loop control (CLC) has been shown to improve glucose time in range and other glucose metrics; however, randomized trials >3 months comparing CLC with sensor-augmented pump (SAP) therapy are limited. We recently reported glucose control outcomes from the 6-month international Diabetes Closed-Loop (iDCL) trial; we now report patient-reported outcomes (PROs) in this iDCL trial. Methods: Participants were randomized 2:1 to CLC ( N = 112) versus SAP ( N = 56) and completed questionnaires, including Hypoglycemia Fear Survey, Diabetes Distress Scale (DDS), Hypoglycemia Awareness, Hypoglycemia Confidence, Hyperglycemia Avoidance, and Positive Expectancies of CLC (INSPIRE) at baseline, 3, and 6 months. CLC participants also completed Diabetes Technology Expectations and Acceptance and System Usability Scale (SUS). Results: The Hypoglycemia Fear Survey Behavior subscale improved significantly after 6 months of CLC compared with SAP. DDS did not differ except for powerless subscale scores, which worsened at 3 months in SAP. Whereas Hypoglycemia Awareness and Hyperglycemia Avoidance did not differ between groups, CLC participants showed a tendency toward improved confidence in managing hypoglycemia. The INSPIRE questionnaire showed favorable scores in the CLC group for teens and parents, with a similar trend for adults. At baseline and 6 months, CLC participants had high positive expectations for the device with Diabetes Technology Acceptance and SUS showing high benefit and low burden scores. Conclusion: CLC improved some PROs compared with SAP. Participants reported high benefit and low burden with CLC. Clinical Trial Identifier: NCT03563313.

7552 Background: Axi-cel is approved in the US for the treatment of adult patients with relapsed or refractory LBCL after 2 or more lines of systemic therapy. Post-market long term follow up study of commercial Axi-cel recipients using the Center for International Blood and Marrow Transplant Research was recently completed. Methods: From October 2017 to August 2020, 1,500 Axi-cel recipients from 79 centers were enrolled. Of these, 1001 patients with at least 6 months of follow-up were included in this analysis. Outcomes include complete and overall responses rates (CR and ORR), duration of response (DOR), progression-free and overall survival (PFS and OS), cytokine release syndrome (CRS) (Lee D 2014 and American Society for Transplantation and Cellular Therapy [ASTCT]), immune effector cell associated neurotoxicity syndrome (ICANS), hematologic recovery and subsequent neoplasm (SN). Subgroup analysis by sensitivity to therapy, defined as responsive to the last line of therapy prior to Axi-cel. Median follow-up was 12 months (range, 6-28 months). Results: The median age overall was 62 years, 37% were ≥ 65 years, 83% with Eastern Cooperative Oncology Group (ECOG) performance score 0-1, 28% with transformed lymphoma, 14% with high grade lymphoma, 29% with prior autologous transplant, and 66% with chemotherapy-resistant disease prior to Axi-cel. The median time from diagnosis to Axi-cel infusion was 15 months. Best ORR was 70% (CR 53%). Landmark analysis of patients in CR at 6 months post Axi-cel demonstrates a low number of subsequent progression/death events. With respect to outcomes for chemotherapy-sensitive disease versus resistant disease, the ORR, CR, 12-month PFS and OS were 78% vs. 66%, 60% vs. 48%, 55% (95% CI, 48-62%) vs. 40% (95% CI, 37-44%), and 70% (95% CI, 63-76%) vs. 54% (95% CI, 50-58%), respectively. CRS of any grade was reported in 83% of patients. Incidence of Grades ≥ 3 CRS was 10% according to Lee et al 2014, and 13% according to ASTCT Consensus Grading. Median time to any grade CRS was 4 days (range, 1-28 days), and 93% of CRS cases resolved with a median duration of 7 days (range, 1-121 days). ICANS were reported in 576 (57%) patients, grade >3 was 26%. The median time to onset of ICANS was 7 days (range, 1-82 days), and 86% resolved with a median duration of 9 days (range, 1 to 115 days). Twenty-nine patients (2.9%) reported SN: hematologic (N = 17), solid tumors (N = 12). Conclusions: This is the largest report on Axi-cel in the real-world setting and demonstrates consistent efficacy outcomes and further characterizes safety outcomes. Patients in CR at 6 months have sustained disease control with low number of relapse events. Although patients with therapy-sensitive disease experience better outcomes than patients with therapy-resistant, the overall outcomes on both groups of patients are favorable.

3591 Background: Adiponectin is a peptide hormone exclusively secreted by adipocytes that plays a role in immune regulation and in the host inflammatory response to cancer. We examined postsurgical adiponectin levels in relationship to tumor infiltrating lymphocytes (TILs), clinicopathological features, vitamin D status, and patient survival in participants in a phase 3 trial of adjuvant chemotherapy. Methods: Plasma adiponectin and 25-hydroxyvitamin D [25(OH)D] were analyzed by radioimmunoassay in 600 patients with stage III colon carcinoma who received adjuvant FOLFOX +/- cetuximab. TIL densities were determined at light microscopy in routine histopathological sections. The associations between adiponectin and 25(OH)D, TILs, other factors were evaluated by Fisher’s Exact, Chi-squared, t-test, and Kruskal-Wallis tests where appropriate. The association between adiponectin or 25(OH)D with disease-free survival (DFS), time to recurrence (TTR) and overall survival (OS) were evaluated by multivariable Cox regression, adjusting for body mass index (BMI), race, T, N stage, performance status, tumor location, TILs, BRAF/KRAS, and mismatch repair status. Results: A statistically significant and inverse association between adiponectin level and BMI was observed with lower levels found with obesity (BMI > 30 kg/m2) [p < 0.001]. The level of adiponectin was significantly lower in men vs women (p < 0.001), in blacks vs whites or Asians (p < 0.032), and in patients with fewer regional lymph node metastases (N1 vs N2 stage, p = 0.011). A significantly lower level of adiponectin was found in patients whose tumors had high vs low TIL densities (p = 0.040), but was unrelated to 25(OH)D. Insufficiency of 25(OH)D ( < 30 ng/ml) was detected in 291 (49%) of patients and was not associated with TILs. By multivariable analysis, adiponectin was not associated significantly with patient DFS (HRadj= 0.98, 95% CI 0.74-1.29, padj= 0.88) nor with OS nor time-to-recurrence (TTR). TIL densities were significantly prognostic, but 25(OH)D was not (DFS: HRadj= 1.12, 95% CI 0.85-1.47, padj= 0.44). No significant interaction was observed for adiponectin with TILs for the association with DFS. Conclusions: Lower adiponectin levels were associated with significantly increased TIL densities in colon cancers, indicating an enhanced anti-tumor immune response. In contrast to TILs, adiponectin was not independently associated with patient outcome. Nearly one-half of stage III patients were vitamin D insufficient, although 25(OH)D was not prognostic.

3030 Background: Diarrhea, HFS, and hypertension are common toxicities of sorafenib. No markers are validated to predict patients at risk of these toxicities. This study aimed to identify genetic predictors of sorafenib-induced toxicities. Methods: A two-step, discovery-validation approach was used. The discovery set included 140 renal cell carcinoma patients from the TARGET study treated with sorafenib (400 mg twice daily) and genotyped for 1040 single-nucleotide polymorphisms (SNPs) in 56 genes. The three most statistically significant SNPs associated with grade ≥2 composite toxicity (either hypertension, diarrhea, HFS, or other skin toxicities, CTCAE v.3.0) were tested for association with grade 3 composite toxicity (either hypertension, diarrhea, or HFS, CTCAE v.4.0) in a validation set of 240 hepatocellular carcinoma patients from Alliance/CALGB 80802 treated with sorafenib (400 mg twice daily) alone or with doxorubicin. Associations between SNPs and composite toxicity was performed by logistic regression, with adjusting covariates (age, gender, race, and treatment arm, the latter two covariates for the validation set only). A meta-analysis odds ratio (OR) of each SNP-grade 3 toxicity association between the discovery and validation sets was obtained by inverse variance to point toward effects specific to a type of toxicity. Results: In the discovery set, the top three SNPs associated with grade ≥2 composite toxicity were rs12366035 (C>T, minor allele frequency, MAF 0.34) in VEGFB (p 0.0007), rs4035887 (G>A, MAF 0.49) in EPAS1 (p 0.0021), and rs4864950 (T>A, MAF 0.23) in KDR (p 0.0058). These SNPs were genotyped in the validation set and only rs4864950 in KDR was replicated. No grade 4 toxicities were reported. Similar to the discovery set (OR 2.41, 95% CI 1.29-4.51), the A allele of rs4864950 increased the risk of grade 3 composite toxicity (p 0.032, OR 2.12, 95% CI 1.70-4.27) in the validation set. Grade 3 toxicity prevalence in the discovery and validation sets were 3.6% and 7.4% diarrhea, 8.6% and 12.3% HFS, 3.6% and 8.8% hypertension, respectively. The meta-analysis of the two datasets showed that the A allele of rs4864950 increased the risk of grade 3 diarrhea (p 0.045, OR 3.09, 95% CI 1.03-9.29), grade 3 HFS (p 0.012, OR 2.57, 95% CI 1.24-5.37), but not grade 3 hypertension (p 0.207, OR 0.51, 95% CI 0.18-1.45). Conclusions: We provide the first evidence of clinical validity of a marker of sorafenib-induced diarrhea and HFS. Sorafenib inhibits VEGFR2 (coded by KDR), leading to epithelial hypoxia and causing diarrhea and HFS. Variant rs4864950 might affect the function VEGFR2, which, during VEGFR2 inhibition, increases the risk of diarrhea and HFS. This SNP is common and can be genotyped in patients before receiving sorafenib for a better risk assessment. Support: U10CA180821, U10CA180882, U24CA196171; https://acknowledgments.alliancefound.org ClinicalTrials.gov Id: NCT01015833.