CHFR and Paclitaxel Sensitivity of Ovarian Cancer

The poly(ADP-ribose) binding protein CHFR regulates cellular responses to mitotic stress. The deubiquitinase UBC13, which regulates CHFR levels, has been associated with better overall survival in paclitaxel-treated ovarian cancer. Despite the extensive use of taxanes in the treatment of ovarian cancer, little is known about expression of CHFR itself in this disease. In the present study, tissue microarrays containing ovarian carcinoma samples from 417 women who underwent initial surgical debulking were stained with anti-CHFR antibody and scored in a blinded fashion. CHFR levels, expressed as a modified H-score, were examined for association with histology, grade, time to progression (TTP) and overall survival (OS). In addition, patient-derived xenografts from 69 ovarian carcinoma patients were examined for CHFR expression and sensitivity to paclitaxel monotherapy. In clinical ovarian cancer specimens, CHFR expression was positively associated with serous histology (p = 0.0048), higher grade (p = 0.000014) and higher stage (p = 0.016). After correction for stage and debulking, there was no significant association between CHFR staining and overall survival (p = 0.62) or time to progression (p = 0.91) in patients with high grade serous cancers treated with platinum/taxane chemotherapy (N = 249). Likewise, no association between CHFR expression and paclitaxel sensitivity was observed in ovarian cancer PDXs treated with paclitaxel monotherapy. Accordingly, differences in CHFR expression are unlikely to play a major role in paclitaxel sensitivity of high grade serous ovarian cancer.

Population Dynamics of Hybrid State during Adaptive Therapy in Cancer

Drug resistance emerges due to drug-induced phenotypic switching of drug-sensitive to drug-resistant subpopulations in cancer during therapy. Existing models indicate the competitive advantage of sensitive over resistant population to regulate tumor and reducing the treatment cost with increased time to progression of tumor ultimately benefiting the patient in a clinical setting. Here, we present a Lotka Volterra (LV) based population dynamics (PD) model of the drug-sensitive, drug-resistant, and transient drug-hybrid state along with phenotypic switching during adaptive therapy based on a simple cancer biomarker (CB) to decide the adaptive therapy dosage to regulate cancer. We identified that the strength of intra-competition along with phenotypic switching parameters is crucial to mediate the effectiveness of adaptive therapy and also investigated the significance of the initial fraction of subpopulations on AT. We hypothesize and predict the dynamics of drug-induced transient hybrid state playing a key role in the cancer cells undergoing metastasis.

Treatment Regimens and Clinical Outcomes Among Follicular Lymphoma Patients Treated with Third-Line Therapy in the United States: A Real-World EHR Study

Objective: To determine treatment regimens used in clinical practice and the associated clinical outcomes among third line (3L) follicular lymphoma (FL) patients in the United States (US). Methods: This non-interventional, retrospective study used Optum electronic health records (EHR) database for FL patients in the US between 1 Jan 2007 and 31 Dec 2020. The start of this period was selected to align with the Morrison et al. 2019, with 5 years of additional data. The identification period was 1 Jan 2008 to 31 Dec 2019, to ensure at least 1 year of baseline before and 60 days of follow-up (unless death happens before) after the index date, defined as start date of 3L treatment. Adult patients (≥18 years) treated in integrated delivery networks with at least one of the 3L treatments of interest (rituximab, bendamustine and rituximab, phosphatidylinositol 3-kinase [PI3K] inhibitors [copanlisib, duvelisib, idelalisib], lenalidomide and rituximab [R2], tazemetostat, and stem cell transplant) were included. Patients with Diffuse Large B-cell Lymphoma (DLBCL) diagnosis or clinical trial enrollment on or before the index date or any other cancer diagnosis before the first FL diagnosis were excluded. All agents initiated within 90 days after the index diagnosis constituted the 1L treatment. A subsequent line of therapy (LOT) was defined as treatment initiated after ≥180 days following the runout date of all agents, or addition or substitution of a new agent in the prior LOT after 90 days. The primary endpoints were time to progression (DLBCL transformation, new LOT initiation, or supportive care), overall survival (OS) and progression-free survival (PFS), while time to next treatment (TTNT) and treatment patterns were the key secondary endpoints. The analyses were conducted for the overall cohort, patients with early progression within 24 months (POD24) after 1L treatment, patients with index date after and including year 2014, as well as for different 3L treatment regimens. The sub-group with 2014 as index date was selected based on idelalisib approval in 2014. Results: The final cohort of patients (used one of the 3L treatments of interest and met inclusion/exclusion criteria) consisted of 687 patients: mean age 62.9 years (range 18 - 86), female (46.9%), Caucasians (87.3%), non-Hispanics (92.1%), and median Charlson Comorbidity Index (CCI) 3 (range 1 - 18). Rituximab-based regimens (73.7%) were the most common 3L treatments (mono 38.4%, combo 35.2%). Obinutuzumab was used as combination 3L therapy by 6 (0.87%) patients. Bendamustine, PI3K and lenalidomide monotherapies were administered to 3.1%, 2.2% and 1.9% patients, respectively (Figure 1). Rituximab-based regimens were also the most frequently used 1L, 2L, and 4L treatment options (50.8% moved to 4L and 33.6% had rituximab-based regimens). The median time to progression, PFS, and TTNT for 3L in the overall cohort were 16.6 (95% CI 14.4, 18.1), 12.5 (95% CI 11.3, 14.4), and 18 (95% CI 15.8, 19.9) months, respectively. The 1-, 2-and 5-year OS were 83.1%, 74.8% and 61.4%, respectively. The outcomes of 3L among POD24 , non-POD24, as well as patients with index date after and including year 2014 were similar to that of the overall cohort. The median time to progression, PFS, and TTNT with rituximab treatment were 19.1 (95% CI 16.7, 21.7), 15.7 (95% CI 14.2, 17.5), and 18.8 (95% CI 17, 21.7) months respectively. The median OS with rituximab therapy was not reached while the 5-year OS was 67% (Table 1). Moreover, we did not observe statistically significant differences in time to progression, OS, PFS, and TTNT for the 3L treatment between POD24 and non-POD24 patients using a Cox regression model with adjustment for baseline characteristics (age, gender, region, and CCI). The median time to progression, PFS, and TTNT among POD24 vs. non-POD24 were 15.7 vs. 17.9, 11.6 vs. 15.2, and 18 vs. 17.9 months, respectively. Conclusion: Rituximab-based regimens were the most common 3L treatment options for FL patients. Bendamustine, PI3K, and lenalidomide monotherapies were used by a smaller proportion of patients. R2 was used by a small number of patients for 3L treatment, but it is becoming an important option for FL treatment since its approval in 2019. The majority of outcomes observed could be considered poor, newer agents undergoing clinical trials could provide additional treatment choices to physicians to balance treatment effectiveness with safety and patients' quality of life. Figure 1 Figure 1. Disclosures Dai: Novartis: Current Employment, Current equity holder in publicly-traded company. Heo: Genesis Research: Current Employment, Current equity holder in publicly-traded company. Rava: Genesis Research: Current Employment, Current equity holder in publicly-traded company. Jousseaume: Novartis: Current Employment, Current equity holder in publicly-traded company. Ramos: Novartis: Current Employment, Current equity holder in publicly-traded company. Bollu: Novartis: Current Employment, Current equity holder in publicly-traded company.

Prognostic Role of IL-6 in POEMS Syndrome

INTRODUCTION POEMS syndrome is a paraneoplastic disorder that results in multi-organ disease, and Vascular endothelial growth factor (VEGF) is associated with disease activity. There is evidence that the cytokine Interleukin- 6 (IL-6) stimulates VEGF production in several cancer cell lines. It has also been suggested that patients with POEMS syndrome experience symptoms improvement when IL-6 levels are low. Our study aims to understand the role of IL-6 and whether it is a contributor to disease activity in POEMS syndrome. METHODS We conducted a retrospective study of patients (pts) seen at Mayo Clinic within 1 year of diagnosis for POEMS syndrome with an IL-6 level within 3 months of diagnosis between 01/01/2011-05/31/2021 were included. Our database comprised 358 pts,7 were excluded because did not have official diagnosis of POEMS syndrome. Two hundred and ninety-nine pts did not have IL-6 testing within 90 days of diagnosis and were excluded. Clinical data was abstracted from our electronic medical record. Descriptive statistics were used for IL-6 levels. The majority of IL-6 laboratory testing for pts utilized the same reference range. A minority of pts had alternate reference ranges; thus, all IL-6 values and reference ranges were fold-corrected to have a unified reference to determine elevation in IL-6. High IL-6 was considered any value above the normal range, also analyzed pts in quartiles and deciles. Hematologic, VEGF and PET response criteria were utilized to group pts into responders or non-responders. Time to progression (TTP) and overall survival (OS) was calculated using the Kaplan Meier method. Differences between curves were by log rank. Statistical analysis was conducted via JMP software package (SAS, Cary, NC, USA). Univariate analysis was done to determine the prognostic value of IL-6. Statistical significance is considered with p-values <0.05. RESULTS 52 patients from among 352 met criteria and were included for analysis. Twenty-one patients (40%) had elevated IL-6 levels (IQR 5.67, 22.6) at the time of diagnosis. The fold elevation about normal was typically not very high, with a median of 3.1-fold elevation (IQR 1.3, 4.4; and range 1.0, 8.3). The percentage of males in the high IL-6 versus the normal Il-6 group were 90% versus 65%, p=0.03. Compared to normal IL-6, those with elevated IL-6 values had more instances of hepatomegaly (43% vs 16%, p=0.03), ascites (28% vs 6%, p=0 .04), abnormal DLCO (26% vs 3%, p=0.03), mixed bone lesions (57% vs 29%, p= 0.04), and lower serum albumin (range 2.3-3.5 vs 2.5-4.5 g/dL, p=0.0008).There was a trend for lower VEGF values among the high IL-6 group, but this did not meet statistical significance (median 250 vs 438 pg/mL). There was no significant difference in the time to progression between pts with high versus normal IL-6 levels (HR 1.36; p=0.456). Overall survival was significantly longer in pts with normal IL-6 compared to pts with high IL-6 levels (Median OS 67.4 vs 47.8 months, p=0.02). Forty-two pts were evaluated for VEGF response after treatment; there was a significant improvement in time to progression (85.5 vs 14.9 months, p=0.03) in pts who were VEGF responders. Among pts evaluable for a hematologic response (n=15), time to progression in pts with baseline high IL6 was longer in hematologic responders compared to non-responders (p=0.02). Conclusion Although OS was longer for pts with normal IL-6, elevated IL-6 at the time of diagnosis does not prevent pts from achieving disease remission. The study demonstrates that response to treatment rather than interleukin-6 levels in pts with POEMS syndrome is more prognostic. This study is an important initial step into understanding the utility of IL-6 in POEMS syndrome. Figure 1 Figure 1. Disclosures Gertz: Akcea Therapeutics, Alnylam Pharmaceuticals Inc, Prothena: Consultancy; Aurora Biopharma: Other: Stock option; Ionis Pharmaceuticals: Other: Advisory Board; AbbVie Inc, Celgene Corporation: Other: Data Safetly & Monitoring; Akcea Therapeutics, Ambry Genetics, Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Karyopharm Therapeutics, Pfizer Inc (to Institution), Sanofi Genzyme: Honoraria. Kumar: Oncopeptides: Consultancy; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Consultancy; Merck: Research Funding; Antengene: Consultancy, Honoraria; Tenebio: Research Funding; Novartis: Research Funding; Roche-Genentech: Consultancy, Research Funding; Carsgen: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Dingli: GSK: Consultancy; Novartis: Research Funding; Janssen: Consultancy; Sanofi: Consultancy; Apellis: Consultancy; Alexion: Consultancy. Lin: Janssen: Consultancy, Research Funding; Merck: Research Funding; Novartis: Consultancy; Legend: Consultancy; Juno: Consultancy; Bluebird Bio: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Vineti: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Sorrento: Consultancy; Gamida Cell: Consultancy; Takeda: Research Funding. Kapoor: Karyopharm: Consultancy; Cellectar: Consultancy; BeiGene: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Amgen: Research Funding; Ichnos Sciences: Research Funding; Regeneron Pharmaceuticals: Research Funding; Glaxo SmithKline: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; AbbVie: Research Funding. Dispenzieri: Pfizer: Research Funding; Sorrento Therapeutics: Consultancy; Oncopeptides: Consultancy; Alnylam: Research Funding; Takeda: Research Funding; Janssen: Consultancy, Research Funding.

Tolerability and Single Agent Anti-Neoplastic Activity of the CD3xCD123 Bispecific Antibody APVO436 in Patients with Relapsed/Refractory AML or MDS

APVO436 is a recombinant T-cell engaging humanized bispecific antibody designed to redirect host T-cell cytotoxicity in an MHC-independent manner to CD123-expressing blast cells from patients with hematologic malignancies and has exhibited single-agent anti-leukemia activity in murine xenograft models of acute myeloid leukemia (AML). This first in human clinical trial of APVO436 (NCT03647800) was designed as a multi-institutional, open-label, multiple-dose Phase 1B dose escalation study in patients with relapsed /refractory (R/R) AML and myelodysplastic syndrome (MDS). 58 R/R adult AML/MDS patients were screened; 12 patients were screen failures, and the remaining 46 eligible patients were enrolled in the study between 15/05/18 and 04/06/21. Thirty nine patients (84.8%) had R/R AML and 7 had R/R MDS. The median age was 68 years. Patients had failed 1-8 prior lines of therapy (Mean±SE: 3.2±0.3). A 3+3 design was used to guide the dose escalation. APVO436 was administered as weekly intravenous (IV) infusions at 10 different dose levels (Cohorts 1-10), ranging from a minimum anticipated biological effect level (MABEL) of 0.3 mcg to 60 mcg. In Cohorts 5-10, APVO436 was administered according to an intra-patient step-up strategy to reduce the risk for cytokine release syndrome (CRS). Response criteria of the International Working Group (IWG) were used for assessment of MDS patients. Standard European LeukemiaNet (ELN) 2017 criteria were used for response assessments in AML patients. The date of data cutoff was July 22, 2021. The primary endpoint of identifying a clinically active recommended phase 2 dose (RP2D) level for further clinical development of APVO436 was met. APVO436 exhibited a favorable safety profile with acceptable tolerability and manageable drug-related adverse events (AEs), and its maximum tolerated dose (MTD) was not reached at a weekly dose of 60 mcg. The most common APVO436-related AEs were infusion-related reactions (IRR) occurring in 13 (28.3%) patients and cytokine release syndrome (CRS) occurring in 10 (21.7%). No hematologic DLT was observed in any of the 10 dose cohorts. Ten patients experienced 12 episodes of Grade 3 febrile neutropenia and each one of these 12 episodes was reported as not related to APVO436. APVO436-related transient neurotoxicity occurred only in 5 of 46 patients (10.9%). It was mild with Grade 1 AEs including headache, tremor, dizziness, lethargy, insomnia, memory loss, and confusion. A single case of Grade 3 confusion was encountered on the first day of treatment and resolved within a day. The single dose RP2D level has been identified as 18 mcg flat dose (Cohort 6; ~0.2 mcg/kg based on the body weights of the patients enrolled). Stable disease (SD), partial remissions (PR) and complete remissions (CR) were observed in 8 R/R AML patients as best overall responses to APVO436 at the RP2D level. Seven of 8 had failed 2-4 prior lines of anti-AML therapy and one patient had relapsed after achieving a remission on frontline venetoclax plus decitabine therapy. The onset and duration of the SD, PR or CR in these 8 patients is illustrated by the Swimmer plot depicted in Figure 1. One patient had clearance of peripheral blasts with >50% decrease in the BM blast percentage. Two primary AML patients with >25% BM blasts and unfavorable cytogenetics and/or adverse risk group genomic mutations achieved a PR at 58 days and 75 days, respectively, that deepened to a CR with full hematologic recovery at 92 and 113 days, respectively. Time-to-progression ranged from 87 to 238 days (Median: 177 days). Notably, the median overall survival OS was >300 days for the 8 R/R AML patients with a favorable response (prolonged SD and PRs/CRs). Five of the 8 patients remain alive at 110, 124, 323, 352, and 395 days, respectively. By contrast, the median OS for the remaining 31 AML patients in the intent to treat patient population (including 5 who were not evaluable for response) was 100 days (95% CI: 49.8-150.2) and 24 of 31 (77.4%) died (Log Rank c 2 = 5.298, P=0.021) (Figure 2). There were too few MDS patients to accurately analyze the clinical activity of APVO436. The time to progression in 6 evaluable patients ranged from >78 days to 321 days. Three of these 6 patients had marrow CRs. In conclusion, the safety and preliminary evidence of efficacy of APVO436 in R/R AML and MDS patients warrant further investigation of its clinical impact potential. Figure 1 Figure 1. Disclosures Watts: Takeda: Consultancy, Research Funding; Genentech: Consultancy; Rafael Pharma: Consultancy; Celgene/BMS: Consultancy. Lin: AbbVie, Aptevo Therapeutics, Astellas Pharma, Bio-Path Holdings, Celgene, Celyad, Genentech-Roche, Gilead Sciences, Incyte, Jazz Pharmaceuticals, Novartis, Ono Pharmaceutical, Pfizer, Prescient Therapeutics, Seattle Genetics, Tolero, Trovagene: Research Funding. Mims: BMS: Consultancy; Syndax Pharmaceuticals: Consultancy; Abbvie: Consultancy; Genentech: Consultancy; Kura Oncology: Consultancy; Leukemia and Lymphoma Society: Consultancy; Aptevo: Research Funding; Jazz Pharmaceuticals: Consultancy; Glycomemetics: Research Funding; Xencor: Research Funding; Daiichi-Saynko: Consultancy. Patel: Aptevo Therapeutics: Research Funding; BMS-Celgene, Agios: Membership on an entity's Board of Directors or advisory committees; Peerview: Honoraria. Shami: Bastion Biologics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chimerix: Research Funding; Takeda: Consultancy; Gilead: Consultancy; BMS: Consultancy; Chimerix: Research Funding; Amgen: Research Funding; JSK Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Aptevo: Research Funding. Cull: Aptevo: Research Funding. Cogle: Celgene: Membership on an entity's Board of Directors or advisory committees; Aptevo therapeutics: Research Funding. Lee: Aptevo therapeutics: Consultancy; oncotelic therapeutics: Current equity holder in publicly-traded company. Uckun: Aptevo therapeutics: Consultancy; Reven Pharmaceuticals (Reven LLC): Consultancy, Membership on an entity's Board of Directors or advisory committees; oncotelic therapeutics: Current equity holder in publicly-traded company.

Utilizing Clinical Features of Progression to Predict Richter's Syndrome in Patients with CLL Progressing after Ibrutinib

Background: Aggressive lymphoma arising in the setting of chronic lymphocytic leukemia (CLL), known as Richter's syndrome (RS), is associated with poor outcomes with standard of care therapies. There is limited capacity for PET-CT to distinguish patients (pts) who develop RS after ibrutinib (Mato Haematologica 2019). Data on outcomes of pts with RS having previously received ibrutinib is limited. Here we sought to determine if clinical characteristics associated with iwCLL criteria for progression (Hallek Blood 2018) predict the risk of RS and overall survival (OS) in pts treated with ibrutinib. Methods: We conducted a retrospective analysis of pts with CLL treated with ibrutinib from 2010-2019 at The Ohio State University. We identified pts that progressed after ibrutinib and classified the progression by 2018 iwCLL criteria. We then identified who developed RS on or after progression. Risk of developing RS was assessed through Fine and Gray model treating death as the competing risk. OS was measured from time of progression and estimated using Cox model. Results: We analyzed 559 pts who had received ibrutinib for CLL, and identified 179 pts who progressed per iwCLL criteria. 94% of the pts who progressed were relapsed/refractory prior to ibrutinib. 116 pts progressed on ibrutinib, and the median time to progression from ibrutinib start was 40.8 months (mos) (range: 0.2-103.9). 63 pts progressed after stopping ibrutinib due to an adverse event or development of a resistance mutation, and the median time to progression from ibrutinib start for these pts was 28.5 mos (range: 0.7-92.9). Of the 179 pts who progressed, 54 developed RS. Of these 54 pts; 83% had enlarging lymphadenopathy, 9% had an enlarging liver or spleen, 17% had constitutional symptoms, 31% had increasing lymphocytosis, 15%, 15%, and 2% had worsening thrombocytopenia, anemia, or neutropenia respectively. No pts had worsening of CLL in the bone marrow (BM) and 2% had new appearance of other organ involvement. As lymphadenopathy and lymphocytosis were the most common clinical features identified we analyzed them jointly; 61% had lymphadenopathy without lymphocytosis, 9% had lymphocytosis without lymphadenopathy, 22% had both, and 7% had neither. Among pts with RS, median time from progression to RS was 0.4 mos (range: 0-49.3). Nine pts had biopsy confirmed RS on the date of progression. Median time from ibrutinib start to RS was 27.8 mos (range: 0.7-92.9). We performed a univariable analysis to determine whether clinical signs of relapse were associated with subsequent risk of RS, and found that presence of lymphadenopathy without lymphocytosis at progression was significantly associated with risk of RS (HR 3.58, 95% CI 1.44-8.88, p=0.006) (Table 1, Figure 1A). To determine if there was an association between clinical features of progression and OS we evaluated all 179 pts that progressed; 72% had enlarging lymphadenopathy, 10% had an enlarging liver or spleen, 15% had constitutional symptoms, 46% had increasing lymphocytosis, 15%, 17%, and 2% had worsening thrombocytopenia, anemia, or neutropenia respectively, only 2% had worsening of CLL in the BM, and 1% had new appearance of other organ involvement. When analyzed jointly; 45% had lymphadenopathy without lymphocytosis, 20% had lymphocytosis without lymphadenopathy, 26% had both, and 9% had neither. Median OS from progression was 24.4 mos (95% CI: 18.6-45.5), while median OS from RS diagnosis was 4.0 mos (95% CI: 2.1-7.1). Median OS from progression was 15.2 mos (95% CI: 7.8-24.6), and 49.9 mos (95% CI: 20.0-NR) for the lymphadenopathy without lymphocytosis and the lymphocytosis without lymphadenopathy groups respectively (Figure 1B). On univariable analysis lymphadenopathy without lymphocytosis was associated with a shorter OS (Table 1). These findings were maintained on multivariable analysis, with lymphadenopathy without lymphocytosis remaining an independent predictor of OS (HR 2.12, CI 1.17-3.87, p=0.01). Conclusions: Here we show that pts who have received prior ibrutinib for CLL who progress with lymphadenopathy have a higher likelihood of having RS than those pts who progress without lymphadenopathy. Furthermore, pts who progressed with lymphadenopathy without lymphocytosis have a shorter OS. Our data suggests that consideration should be given to perform a biopsy to rule out RS in any pts progressing with lymphadenopathy after receiving ibrutinib therapy for CLL. Figure 1 Figure 1. Disclosures Kittai: Abbvie: Consultancy; Janssen: Consultancy; Bristol-Meyers Squibb: Consultancy. Bhat: Beigene: Consultancy; Onclive: Honoraria; AstraZeneca: Consultancy; Aptitude Health: Honoraria. Bond: Kite/Gilead: Honoraria. Byrd: Pharmacyclics LLC: Research Funding; Acerta Pharma: Research Funding; Genentech, Inc.: Research Funding; Janssen Pharmaceuticals, Inc.: Research Funding. Rogers: Genentech: Consultancy, Research Funding; Janssen: Research Funding; Abbvie: Consultancy, Research Funding; Novartis: Research Funding. 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; Gilead Sciences Inc: Other: Data & Safety; AbbVie Inc, Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company: Research Funding.

Impact of germline polymorphisms in genes regulating glucose uptake on positron emission tomography findings and outcome in diffuse large B-cell lymphoma: results from the PETAL trial

Background [18F]Fluoro-deoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) is the standard imaging procedure in diffuse large B-cell lymphoma (DLBCL). Disease presentation, FDG-PET/CT performance, and outcome may be influenced by germline single nucleotide polymorphisms (SNP) in genes regulating glucose uptake. Methods Clinical variables, FDG-PET findings, and outcome were analysed in relation to SNPs in 342 DLBCL patients participating in the ‘Positron Emission Tomography-Guided Therapy of Aggressive Non-Hodgkin Lymphomas’ (PETAL) trial. Genes analysed included SLC2A1 (SNPs rs1385129, referred to as HaeIII; rs710218, HpyCH4V; rs841853, XbaI), VEGFA (rs3025039), HIF1A (rs11549465, P582S; rs11549467, A588T), and APEX1 (rs1130409, D148E). Statistical significance was assumed at p ≤ 0.05. Results The SLC2A1 HaeIII and HpyCH4V SNPs were tightly linked and statistically significantly associated with baseline maximum standardized uptake value (SUVmax) and Ann Arbor stage, with slightly lower SUVmax (HaeIII, median 18.9, interquartile range [IQR] 11.5–26.6, versus 21.6, IQR 14.4–29.7; p = 0.019) and more frequent stage IV disease (HaeIII, 44.5% versus 30.8%; p = 0.011) in minor allele carriers. As previously reported for lung cancer, the association was dependent upon the coexistent APEX1 D148E genotype. The HIF1A A588T SNP was associated with total metabolic tumour volume (TMTV) and time-to-progression, with significantly lower TMTV (median 16 cm3, IQR 7–210, versus 146 cm3, IQR 34–510; p = 0.034) and longer time-to-progression in minor allele carriers (log-rank p = 0.094). Time-to-progression was also associated with the SLC2A1 XbaI and APEX1 D148E SNPs, with shorter time-to-progression in homozygous and heterozygous SLC2A1 XbaI (HR 1.456; CI 0.930–2.280; p = 0.099) and homozygous APEX1 D148E minor allele carriers (HR 1.6; CI 1.005–2.545; p = 0.046). In multivariable analyses including SNPs, International Prognostic Index factors, sex, and B symptoms, HIF1A A588T, SLC2A1 XbaI, and APEX1 D148E retained statistical significance for time-to-progression, and SLC2A1 XbaI was also significantly associated with overall survival. Conclusions Common SNPs in genes regulating glucose uptake may impact SUVmax, tumour distribution, tumour volume, and outcome in DLBCL. The effects on SUVmax are of low magnitude and appear clinically negligible. The results are consistent with findings in other types of cancer. They need to be confirmed in an independent DLBCL population of sufficient size. Trial registration Trial registration: ClinicalTrials.gov NCT00554164; EudraCT 2006-001641-33. Registration date November 5, 2007, https://www.clinicaltrials.gov/ct2/show/NCT00554164

Treatment of Ewingʼs sarcoma in children and adolescents: new vision

Introduction. Over the past decades, a significantly greater understanding of the morphology and molecular biological characteristics of tumors of the Ewing sarcoma family (ESFT) has been achieved. More than 70 % of relapses occur within 2 years from the date of diagnosis. In about 2/3 of cases, relapse occurs in distant places; this type of relapse is especially common in patients who initially have metastases. On the contrary, isolated local metastasis most often (in 1/5 of cases) occurs in patients with a localized form of the disease. In half of the patients, a relapse of the disease was detected during a routine examination, was asymptomatic and was a chance find.Purpose of the study – to evaluate the effectiveness of anti-relapse treatment in patients with ESFT, to develop an algorithm for a personalized approach, to improve the results of overall and relapse-free survival in children and adolescents with ESFT.Materials and methods. Our study included patients with a confirmed diagnosis of Ewing sarcoma (ES), who received treatment from 2008 to 2019. The analysis of follow-up data was closed on 19.02.2021. The study included 274 patients aged 6 months to 18 years, the average age was 11.6 years. Up to 1 year in our study there were 2 children. Twelve (4.3 %) patients went out of follow-up within 2 to 9 months from the start of treatment; we did not include them in the subsequent analysis. Analyzed were 262 patients with ES who received treatment according to the protocols at the Research Institute of Pediatric Oncology and Hematology of the N.N. Blokhin National Medical Research Center of Oncology. A relapse of the disease was revealed in 48 (18.3 %) children out of 262 – the study group; 58 (22.1 %) patients showed disease progression during treatment. In 70.8 % (34/48) patients had an isolated relapse, in 14 (29.2 %) cases – a combined one. The defeat of only the lung tissue with a relapse of the disease occurred in 19/48 (39.6 %) cases, local relapse without metastasis – 7/48 (14.5 %) cases. In general metastatic lung disease occurred in 66.6 % of cases. The defeat of the brain and lymph nodes occurred in 4 %. Most of the patients were in the group from 11 to 17 years, inclusive – 38/48 patients, which amounted to 79 %. All 48 patients from the study group received anti-relapse therapy depending on the duration of the disease relapse. For late relapses the primary treatment regimen was used: alternating courses of chemotherapy with vincristine/doxorubicin/cyclophosphamide and etoposide/ifosfamide. In early relapses two regimens were most used: vincristine/topotecan/cyclophosphamide and vincristine/irinotecan/temozolomide (VIT). The positive response rate with the antirelapse VIT regimen was 60 %, and the time to progression was 7.6 months. With the topotecan regimen the response rate was 45 % and the time to progression – 7 months.Results. The overall survival (OS) rate of patients when a relapse was detected was significantly (p £ 0.05) higher when compared with the group of patients who had progression of the disease, which is associated with the effect of anti-relapse chemotherapy. When analyzing OS of patients with ES it should be noted that the 5-year survival rate of all patients (n = 262) was 66.3 ± 3.3 %, compared with the group of patients with confirmed relapse (n = 48) – 53 ± 8.1 %. The median in the group of patients with relapse was 39.3 months. The follow-up time in the group with recurrent ES disease averaged 52.2 ± 32.3 months (from 12.6 to 142 months). OS of patients was analyzed depending on the interval of disease recurrence. The Interval No. 1 was from the beginning of the main treatment to the first relapse, with a median of 37.2 months. Interval No. 2 – from the date of the first relapse to the date of the second relapse with a follow-up time of 58.8 ± 29.1 months (from 28.6 to 108 months), the median was not reached. The second relapse occurred significantly less frequently than the first relapse (p = 0.000001).Conclusion. The outcome for patients with recurrent ES remains poor, and a standard approach to their treatment has not yet been established. Standard first and second lines chemotherapy can be effective in most patients in terms of reducing symptoms and increasing the time to further progression, but complete remission remains hard to reach. Further multidisciplinary study of prognostic factors, effects of various treatment regimens and protocols, study of the inclusion of targeted drugs in the therapy program is required.

T2/FLAIR Abnormity Could Be the Early Sign of Glioblastoma Dissemination

PurposeNewly emerged or constantly enlarged contrast-enhancing (CE) instead of T2/FLAIR lesions were the necessary sign for the diagnosis of glioblastoma (GBM) progression. This study aimed to investigate whether the T2/FLAIR abnormal transformation could predict and assess progression for GBMs, especially for dissemination. MethodsA consecutive cohort of 246 de novo GBM with regular follow-up and sufficient radiological data were included in this study. The series of T2/FLAIR, T1CE images were retrospectively reviewed. The patients were separated into T2/FLAIR and T1CE discordant and accordant subgroups based on the initial progression images.ResultsA total of 170 qualified patients were finally analyzed. The incidence of discordant T2/FLAIR and T1CE images was 25.9% (44/170). The median time of T2/FLAIR indicated tumor progression was 119.5 days (ranging from 57 days-unreached) prior to T1CE. Nearly half of patients (20/44, 45.5%) in discordant subgroup suffered from tumor dissemination, substantially higher than accordant patients (23/126, 20.6%, P<0.001). The median time to progression (TTP), post-progression survival (PPS), and overall survival (OS) were not statistically different (all P>0.05) between discordant and accordant patients. Conclusions T2/FLAIR abnormity could be the early sign of GBM progression, especially for newly emerged lesions disseminated from the primary cavity. Physicians should cast more attention on the dynamic change of T2/FLAIR images for progression assessment and subsequent clinical decision-making.