A 66-year-old woman with follicular lymphoma on lenalidomide and rituximab presented with chest pain. High-sensitivity troponin T peaked at 7,566 ng/l. Cardiac biopsy revealed extensive inflammation ...consistent with medication-induced myocarditis. Lenalidomide was stopped with improvement in troponins and patient was initiated on high-dose corticosteroid therapy. (Level of Difficulty: Intermediate.)
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Summary
CD49d is a surface integrin that is expressed on chronic lymphocytic leukaemia (CLL) cells, and strongly correlates with more aggressive disease. Given its association with cell‐cell adhesion ...and leucocyte trafficking, we hypothesized that patients with high CD49d expression would experience a clinical course dominated by lymphadenopathy. CD49d expression was measured by flow cytometry and considered positive if expressed by ≥30% of CLL cells. The study included 797 newly diagnosed CLL/small lymphocytic leukaemia patients; 279 (35%) were CD49d positive. CD49d‐positive patients were more likely to present with lymphadenopathy (P < 0·001); a finding that persisted after adjusting for fluorescence in situ hybridisation (FISH) and IGHV mutation status odds ratio (OR) 2·51; 95% confidence interval (CI) 1·64–3·83; P < 0·001. Among CLL Rai 0 patients, CD49d positivity was associated with shorter time to development of lymphadenopathy (3·2 years vs not reached, P < 0·01). This association was maintained after adjusting for either FISH hazard ratio (HR) 2·18; 95% CI 1·25–3·81; P = 0·006) or IGHV status (HR 2·02; 95% CI 1·11–3·69; P = 0·02) individually, but was attenuated when adjusting by both (HR 1·72; 95% CI 0·88–3·38; P = 0·11).These data demonstrate that CD49d‐positive CLL patients experience a disease course dominated by lymphadenopathy. These findings could have implications for therapy selection and disease monitoring.
Clock synchronization procedures are mandatory in most physical experiments where event fragments are readout by spatially dislocated sensors and must be glued together to reconstruct key parameters ...(e.g., energy and interaction vertex) of the process under investigation. These distributed data readout topologies rely on an accurate time information available at the front end, where the raw data are acquired and tagged with a precise timestamp prior to data buffering and central data collecting. This makes the network complexity and latency, between front-end and backend electronics, negligible within upper bounds imposed by the front-end data buffer capability where the raw data are stored waiting for the trigger validation. The proposed research work describes a field-programmable gate array (FPGA) implementation of IEEE 1588 Precision Time Protocol (PTP) that exploits the European Organization for Nuclear Research (CERN) timing, trigger, and control (TTC) system as a multicast messaging physical and data link layer. The hardware implementation extends the clock synchronization to the nanoseconds range, overcoming the typical accuracy limitations inferred by computers Ethernet-based local area network (LAN). Establishing a reliable communication between master and timing receiver nodes is essential in a message-based synchronization system. In the backend electronics, the serial data streams synchronization with the global clock domain is guaranteed by a hardware-based finite state machine that scans the bit period using a variable delay chain and finds the optimal sampling point. The validity of the proposed timing system has been proven in point-to-point data links as well as in star topology configurations over standard CAT-5e cables. The results achieved together with weaknesses and possible improvements are hereby detailed.
The goal of this study was to characterize pigments used in the murals of two Byzantine churches, from Kastoria, northern Greece. The identification of the iconographer was also investigated by ...comparing the pigments applied in the wall paintings of the churches. Pigment microsamples of various colors were collected and analyzed by environmental scanning electron microscopy coupled with an energy dispersive system to characterize the elemental composition. Raman spectroscopy was employed to collect molecular spectra for characterization of mineralogical phases. Hematite, cinnabar, and minium were identified in red surfaces. Brown and yellow colors were assigned to mixtures of iron oxides, iron hydroxides, and calcite. Mixtures of iron, lead, and mercury compounds were used to produce different hues in the murals. Black tones were prepared primarily using charcoal and bone black. Grey colors were produced by a mixture of black carbon with calcite; blue hues, by a mixture of iron oxides, calcite, and black carbon. The minerals used were similar for both churches. However, the green color was prepared either by green earth or mixtures of iron oxides and calcite. A modern pigment, lithopone, was also determined, demonstrating restoration or overpainting and thus complicating possible correlations. Based on these preliminary results, the wall paintings could not be ascribed to a specific iconographer.
Abstract
AIMS: DNA methylation is an epigenetic alteration which plays a decisive role in the regulation of signal translation processes. In our lab, we have demonstrated for the first time the ...epigenetic silencing of tumor and metastasis suppressor genes in CTCs through their promoter methylation. Estrogen receptor (ER) is an important prognostic biomarker and is predictive of response to endocrine therapy in breast cancer. In this study, we evaluated for the first time ESR1 methylation in CTCs of breast cancer patients.
METHODS: We developed and validated a novel highly sensitive and specific qMSP assay for ESR1 methylation using commercially available DNA methylation controls and the MDA-MB-231 cell line. We further examined its performance in EpCAM-positive immune-magnetically isolated CTC fractions, followed by DNA isolation and sodium bisulfite (SB) treatment from: a) 74 operable, b) 48 metastasis- verified breast cancer patients and c) 30 healthy donors (control group).
RESULTS: The developed assay is highly specific and sensitive since it can detect 0.1% methylated ESR1 sequences in the presence of 99.9% un-methylated. ESR1 was found to be methylated in 16/74 (21.6%) operable breast cancer patients, in 10/48 (20.8%) patients with verified metastasis, but only in 1/30 (3.3%) healthy donors (EpCAM-positive CTC fraction).
CONCLUSIONS: The EpCAM-positive CTC fraction was found to be methylated for ESR1 in about 20% of patients with breast cancer. We will further evaluate these findings in respect to the clinical outcome of these patients, since the epigenetic silencing of ESR1 could be of important clinical significance especially for its impact on the efficacy of treatment.
Citation Format: Sofia Mastoraki, Areti Strati, Maria Chimonidou, Nikos S. Malamos, Vasilis Georgoulias, Evi S. Lianidou. ESR1 methylation in circulating tumor cells of patients with breast cancer. abstract. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 499.
Introduction
Patients (pts) with CLL who achieve blood or bone marrow (BM) undetectable minimal residual disease (U-MRD), assessed with a sensitivity of at least 10-4 (MRD4), have long PFS after ...1st-line treatment with FCR. A proportion of pts with mutated immunoglobulin heavy chain variable gene (M-IGHV) may be cured of CLL, given the reported PFS beyond 10 yrs. In contrast, most pts with unmutated (UM)-IGHV relapse, despite achieving BM U-MRD4. The likelihood of relapse and relapse kinetics relate to CLL biology, including depth of remission and proliferation rate. MRD testing using next generation sequencing (NGS) can achieve sensitivity up to 10-6 (MRD6) and can also be used to test for circulating tumor DNA in plasma, which may reflect residual tumor in the tissue (eg. lymph nodes), not detectable in the cellular fraction of blood or BM.
To better assess the depth of remission following first-line FCR treatment for CLL, we performed NGS MRD6 testing in BM, peripheral blood mononuclear cells (PBMC) and plasma of pts enrolled in a single center, prospective, phase II study. All pts had BM U-MRD4 by 4-color flow cytometry (FLC) at the end of treatment (EOT).
Methods
The following EOT samples from 62 pts were analyzed for MRD6: 57 BM, 29 PBMC and 32 plasma. Adaptive Biotechnologies' NGS MRD assay uses multiplex PCR and NGS to amplify rearrangements within the B cell receptor CDR3 and identify disease associated clonotypes. Specifically, the assay utilizes multiplexed primers complementing V-J rearrangements (IGH, IGK/L) and D-J (IGH) rearrangements. Pre-treatment samples were sequenced to determine the malignant clonotype, which was then quantitated in the EOT samples, within the polyclonal background.
Results
Regardless of assay sensitivity, U-MRD rates by HTS according to sample type were: 14/57 (25%) in BM; 16/29 (55%) in PBMC; 24/32 (75.0%) in plasma. All pts with MRD+ in plasma simultaneously had detectable disease in either BM or PBMC. Of 16 pts who had U-MRD in PBMC, 7/12 with simultaneous BM samples were MRD+ in BM. In all patients, there was a trend toward increased likelihood of U-MRD in pts with M-IGHV 12/30 (40%) vs 4/24 (17%), OR 3.3 (0.9-12.2), p = 0.06.
Assay sensitivity varies according to amount of DNA in the sample and with malignant clonotype. Sensitivity of at least 10-6 was achieved in 74% and 62% of samples in BM and PBMC, respectively. Among patients with U-MRD by NGS: 4/14 BM (1.06-3.2 x 10-6, median 1.96 x 10-6) and 8/16 PBMC (1.001 x 10-6 to 3.56 x 10-6, median 1.54 x 10-6) samples did not have sensitivity of 10-6. Notably, 3 pts also had detectable disease at a level <10-6 in BM, 2 of whom relapsed (Figure C).
Median follow-up was 82 months (mo) (range: 28-112.4). Fifty-six of 62 (90.3%) pts are alive; 28 are progression-free. Median PFS for the whole cohort was 89 mo. When PFS was analyzed according to whether MRD was detected or not (regardless of sensitivity), pts with U-MRD at the EOT had superior PFS vs pts with MRD+, whether the sample type used was BM (p=0.02, median NR vs 67 mo) or PBMC (p=0.02, median NR vs 74 mo), Figure A, B. When analyzed according to whether MRD was <10-6vs >/=10-6 (MRD6), 40/53 (75%) in BM and 13/21 (62%) in PBMC were MRD6+. For this analysis, pts were excluded if they had U-MRD but assay sensitivity did not reach at least 10-6. Despite smaller n, there were trends toward shorter PFS for pts with MRD6+ vs U-MRD6 (Figure C, D).
Discussion
The majority of pts with BM U-MRD4 after first-line FCR were MRD6+ and these patients had shorter PFS; MRD analysis with a more sensitive assay may therefore more accurately assign prognosis. Not accounting for sensitivity, a higher proportion of BM than PBMC samples were MRD+. Plasma analysis was uninformative as all pts MRD+ in plasma were MRD+ in simultaneous BM or PBMC samples.
Defining prognostically-relevant thresholds for MRD using more sensitive methodology is important, particularly if U-MRD is used a surrogate for PFS in clinical trials or as an endpoint for treatment cessation. MRD6 may become increasingly relevant if venetoclax-based regimens and the addition of novel agents to chemoimmunotherapy achieve U-MRD6 in more patients than FCR. In this retrospective study, a number of samples did not achieve 10-6 sensitivity; optimization of sample collection is important to achieve 10-6 sensitivity in most pts. Finally, additional studies will be required to determine the risk for and kinetics of relapse in patients with low-level MRD6+.
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Thompson:AbbVie: Honoraria, Research Funding; Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees. Srivastava:Adaptive Biotechnologies: Employment. Hether:Adaptive Biotechnologies: Employment. O'Brien:Acerta: Research Funding; Sunesis: Consultancy, Research Funding; Regeneron: Research Funding; GlaxoSmithKline: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Pharmacyclics: Consultancy, Research Funding; Vaniam Group LLC: Consultancy; Abbvie: Consultancy; Aptose Biosciences Inc.: Consultancy; Pfizer: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Janssen: Consultancy; Astellas: Consultancy; Alexion: Consultancy; Kite Pharma: Research Funding; Gilead: Consultancy, Research Funding. Jain:ADC Therapeutics: Research Funding; Celgene: Research Funding; Abbvie: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; Incyte: Research Funding; Genentech: Research Funding; Infinity: Research Funding; Astra Zeneca: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Servier: Research Funding; ADC Therapeutics: Research Funding; Verastem: Research Funding; Seattle Genetics: Research Funding; Cellectis: Research Funding; Incyte: Research Funding; Celgene: Research Funding; Adaptive Biotechnologioes: Research Funding; Astra Zeneca: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Research Funding; Verastem: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectis: Research Funding; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologioes: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wierda:Genentech: Research Funding; AbbVie, Inc: Research Funding.
Introduction. The combination of lenalidomide and rituximab induces response in patients (pts) with both treatment-naïve (TN) and relapsed (R) chronic lymphocytic leukemia (CLL). In order to identify ...the pts who benefit from this treatment, we conducted a phase II study to prospectively evaluate how clinical characteristics, prognostic factors and gene mutations correlated with response and survival in pts with TN and R CLL treated with this combination.
Methods. Treatment with lenalidomide started on day 9 of cycle 1 at 10 mg orally and administered daily. Rituximab, 375 mg/m2, was administered intravenously every 28 days for a total of 12 cycles. All pts had clinical staging, laboratory and pathological characteristics determined prior to treatment initiation. A SureSelect custom panel of 295 genes was performed in pretreatment bone marrow samples. The primary endpoint was overall response rate (ORR) and responses were assessed according to IW-CLL 2008 criteria at month 3, 6 and every 6 months thereafter. The secondary endpoints were treatment safety and association of baseline characteristics and gene mutations with response.
Results. One-hundred and twenty pts were enrolled in this study, 61 with TN and 59 with R CLL. Baseline characteristics are summarized in the Table. Twenty-one out of 54 (39%) TN pts and 18 out of 53 (34%) R pts had more than 1 mutation. Among TN pts, NOTCH1 mutations significantly associated with BCOR mutations (p=0.02) and SPEN mutations (p=0.02); among R pts NOTCH1 mutations significantly associated with XPO mutations (p=0.01) and MGA mutations (p=0.001), and TP53 mutations significantly associated with advanced Rai stage (p=0.01) and beta-2-microglobulin (B2M) > 4 mg/L (p=0.02). The frequency of single gene mutations did not significantly differ between the 2 groups.
ORR was 73% for TN pts and 64% for R pts; complete remission was achieved in 35% of TN pts and 28% of R pts, with MRD eradication in 16% and 2% of pts, respectively.
The association among all baseline characteristics, gene mutations and ORR was evaluated. Among TN pts, B2M < 4 mg/L was associated with higher ORR on univariate analysis (85% vs 55%, p=0.03). Among R pts, age < 65 years (78% vs 50%, p=0.05), Rai stage 0-II (79% vs 48%, p=0.03), B2M < 4 mg/L (84% vs 46%) and estimated glomerular filtration rate ≥ 60 mL/min (76% vs 38%, p=0.01) were associated with higher ORR on univariate analysis; on multivariate analysis (MVA), only B2M maintained its association with ORR (odds ratio 0.2; 95% confidence interval CI 0.1-0.9; p=0.03)
After a median follow-up of 41 months (range 1-62), 45 (74%) TN pts and 52 (88%) R pts interrupted treatment, and median PFS was 50 months (95% CI 31-69 months) and 28 months (95% CI, 17-39 months), respectively (Figure). On MVA, age ≥ 65 years (hazard ratio HR 5; 95% CI 1.4-21; p=0.02), KRAS mutation (HR 40; 95% CI 1.2-1000; p=0.04), SPEN mutation (HR 20; 95% CI 1.5-250; p=0.02) and ASXL1 mutation (HR 13; 95% CI 1.2-125; p=0.03) associated with shorter PFS among TN pts. SPEN mutation (HR 21; 95% CI 2.1-200; p=0.01) and FBXW7 mutation (HR 12; 95% CI 1.2-125; p=0.03) associated with shorter PFS among R pts.
At most recent follow-up, 4 TN pts (2 on study) and 16 R pts (5 on study) have died, and median OS has not been reached (Figure). Two TN and 5 R patients died while on study. Causes of death among TN pts included infection in 1 pt and 2nd primary neoplasm (SPN) in 1 pt. Among R pts, they included infection in 3 pts, SPN in 1, and sudden death of unknown etiology 1 pt. On MVA analysis TP53 mutation was associated with shorter OS in TN pts, and FISH positive for del17p/del11q was associated with a trend for shorter OS in R pts.
Grade 3-4 neutropenia was the most common toxicity, observed in 5% of cycles in TN pts and 17% in R pts, median duration of neutropenia was 7 days (range, 7-14 days) among TN pts, and 10 days (range, 7-14 days) among R pts.
Discussion. The combination of lenalidomide and rituximab is an effective and safe regimen for the treatment of pts with TN and/or R CLL. B2M is the only predictive factor of response to this regimen in both in TN and R pts. Gene mutations inducing increased NOTCH1 signaling, such as SPEN and FBXW7 mutations, predicted shorter PFS after treatment with lenalidomide and rituximab.
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Thompson:Adaptive Biotechnologies: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees. Daver:Incyte: Research Funding; Pfizer: Research Funding; Alexion: Consultancy; BMS: Research Funding; Karyopharm: Research Funding; Karyopharm: Consultancy; Incyte: Consultancy; Otsuka: Consultancy; ImmunoGen: Consultancy; Daiichi-Sankyo: Research Funding; Novartis: Research Funding; Pfizer: Consultancy; Sunesis: Research Funding; Novartis: Consultancy; Sunesis: Consultancy; ARIAD: Research Funding; Kiromic: Research Funding. Jain:Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Research Funding; Seattle Genetics: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Infinity: Research Funding; Genentech: Research Funding; Astra Zeneca: Research Funding; Abbvie: Research Funding; Verastem: Research Funding; ADC Therapeutics: Research Funding; Pharmacyclics: Research Funding; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; BMS: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Research Funding; ADC Therapeutics: Research Funding; Celgene: Research Funding; Pfizer: Research Funding; Astra Zeneca: Research Funding; Abbvie: Research Funding; Pfizer: Research Funding; Servier: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologioes: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Genentech: Research Funding; Cellectis: Research Funding; Cellectis: Research Funding; Incyte: Research Funding; Pharmacyclics: Research Funding; Infinity: Research Funding; Seattle Genetics: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologioes: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. O'Brien:Celgene: Consultancy; Gilead: Consultancy, Research Funding; Acerta: Research Funding; Pfizer: Consultancy, Research Funding; Astellas: Consultancy; Janssen: Consultancy; GlaxoSmithKline: Consultancy; Sunesis: Consultancy, Research Funding; Regeneron: Research Funding; Pharmacyclics: Consultancy, Research Funding; Vaniam Group LLC: Consultancy; TG Therapeutics: Consultancy, Research Funding; Kite Pharma: Research Funding; Amgen: Consultancy; Alexion: Consultancy; Aptose Biosciences Inc.: Consultancy; Abbvie: Consultancy. Wierda:Genentech: Research Funding; AbbVie, Inc: Research Funding.
Introduction. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are common adverse effects of chimeric antigen receptor (CAR) T-cell therapy. Elevated ...biomarkers, such as ferritin and LDH, have been shown to correlate with more severe toxicity. The endothelial activation and stress index (EASIX) is a surrogate of endothelial activation, and correlates to other biomarkers of endothelial dysfunction. In allogeneic hematopoietic cell transplantation (HCT), it is predictive of toxicity such as fluid overload, which is correlative with endothelial dysfunction, as well as sinusoidal obstruction syndrome, non relapse mortality and overall survival (Luft et al, BMT 2019, Varma et al, BBMT, 2020, Jiang et al, Haematologica, 2020). In this study we describe the correlation of EASIX to CAR T cell related CRS and ICANS.
Methods. Retrospective data from consecutive patients treated with standard of care axi-cel for non-Hodgkin’s lymphoma at MD Anderson Cancer Center between January 2018 and April 2020 were included in the study. CRS and ICANS were graded according to CARTOX criteria (Neelapu et al, Nat Rev Clin Oncol, 2018), and after 5/2019, according to the ASTCT criteria (Lee et al, BBMT, 2019). EASIX parameters were recorded prior to lymphodepletion (the latest value on days -12 to -6) and were available for all 171 patients. The score was defined as lactate dehydrogenase (U/L) × creatinine (mg/dL)/ thrombocytes (10^9 cells per L), with LDH adjusted to the upper limit of normal. Predictors of toxicity were evaluated using Fine and Grey regression analysis considering death before grade 2-4 toxicity as a competing risk.
Results. 171 consecutive patients treated with commercial axi-cel for diffuse large B cell lymphoma (n=133), transformed follicular lymphoma (n=28) and primary mediastinal lymphoma (n=10) were included in the study. Median age was 59 years (range, 18-85), and 120 (70%) were male. 151 patients had an ECOG performance status ≤1, 45 patients (26%) had a previous autologous HCT, and 3 (1.8%) had a previous allogeneic HCT. Prior to lymphodepletion, 96 (56%) patients had a high IPI score (≥3) and 134 (78%) were refractory to the previous line of treatment.
With a median follow-up of 259 days (range: 25-800) since infusion, ICANS of any grade was noted in 109 (64%) patients, with 84 (49%) having grades 2-4. CRS of any grade was observed in 160 (93%) patients, with 81 (47%) having grades 2-4 CRS. A total of 56 (33%) patients were diagnosed with grade 2-4 ICANS and CRS.
The median EASIX score for the entire cohort was 2.1 (range: 0.3-283; inter-quartiles: 1.1 and 4.6). On univariate analysis, EASIX levels above the median were associated with higher cumulative incidence (CI) of grade 2-4 ICANS (% CI: 61 vs 31%; HR=2.4, p<0.001); and levels above the upper quartile were associated with grade 2-4 CRS (% CI: 71 vs 38%; HR=2.2, p=0.02), (Figure 1,2). Additional predictors of grade 2-4 toxicity included IPI score ≥3 (HR=1.6, p=0.03) and female gender (HR=1.7, p=0.05) for ICANS; and IPI score ≥ 3 (HR=1.6, p=0.04) and lack of prior autologous transplant (HR=2, p=0.02) for CRS.
Multivariate analysis showed EASIX score to be an independent predictor of grade 2-4 ICANS (HR=2.3, p=0.001) or CRS (HR=2.3, p=0.001); female gender of ICANS (HR=1.7, p=0.03) and lack of prior autologous transplant of CRS (HR=1.9, p=0.02). The impact of IPI did not reach statistical significance for either ICANS (HR=1.3, p=0.3) or CRS (HR=1.2, p=0.4).
Further multivariate analysis for other biomarkers and their incorporation into a revised biomarker score will be presented at the meeting.
Conclusions. Our results suggest that the EASIX score prior to lymphodepletion predicts higher grade CRS and ICANS in patients receiving axi-cel. These results of routinely available clinical variables require further prospective studies for validation, however our study shows that this score may better stratify patient risk of toxicity, and possibly inform clinical decisions and prevention strategies for patients at higher risk.
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Nieto:Secura Bio: Other: Grant Support; Novartis: Other: Grant Support; Astra Zeneca: Other: Grant Support; Affimed: Consultancy, Other: Grant Support. Hosing:NKARTA Inc.: Consultancy. Westin:47: Research Funding; Amgen: Consultancy; Morphosys: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Curis: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Astra Zeneca: Consultancy, Research Funding; Genentech: Consultancy, Research Funding. Lee:Celgene: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Guidepoint Blogal: Consultancy; Aptitude Health: Speakers Bureau; Oncternal Therapeutics: Research Funding; Seattle Genetics: Research Funding; Takeda: Research Funding. Nastoupil:Celgene: Honoraria, Research Funding; Karus Therapeutics: Research Funding; Bayer: Honoraria; Genentech, Inc.: Honoraria, Research Funding; Gamida Cell: Honoraria; Gilead/KITE: Honoraria; Novartis: Honoraria, Research Funding; Merck: Research Funding; TG Therapeutics: Honoraria, Research Funding; LAM Therapeutics: Research Funding; Janssen: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. Parmar:Cellenkos Inc.: Current equity holder in private company, Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties, Research Funding. Wang:Guidepoint Global: Consultancy; Dava Oncology: Honoraria; Verastem: Research Funding; Molecular Templates: Research Funding; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding; OMI: Honoraria, Other: Travel, accommodation, expenses; Nobel Insights: Consultancy; Lu Daopei Medical Group: Honoraria; Beijing Medical Award Foundation: Honoraria; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; MoreHealth: Consultancy; AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Oncternal: Consultancy, Research Funding; OncLive: Honoraria; InnoCare: Consultancy; Targeted Oncology: Honoraria; Loxo Oncology: Consultancy, Research Funding; Pulse Biosciences: Consultancy; Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; Juno: Consultancy, Research Funding; BioInvent: Research Funding; VelosBio: Research Funding; Acerta Pharma: Research Funding. Flowers:AbbVie: Consultancy, Research Funding; Kite: Research Funding; Leukemia and Lymphoma Society: Membership on an entity’s Board of Directors or advisory committees; V Foundation: Research Funding; Cancer Prevention and Research Institute of Texas: Research Funding; Bayer: Consultancy; National Cancer Institute: Research Funding; Eastern Cooperative Oncology Group: Research Funding; Burroughs Wellcome Fund: Research Funding; TG Therapeutics: Research Funding; Millennium/Takeda: Consultancy, Research Funding; Acerta: Research Funding; Spectrum: Consultancy; Pharmacyclics/Janssen: Consultancy; Karyopharm: Consultancy; OptumRx: Consultancy; Gilead: Consultancy, Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Denovo Biopharma: Consultancy; Celgene: Consultancy, Research Funding; BeiGene: Consultancy. Hawkins:Kite: Membership on an entity’s Board of Directors or advisory committees. Rezvani:GemoAb: Membership on an entity’s Board of Directors or advisory committees; Affimed: Other: Educational grant; Adicet Bio: Membership on an entity’s Board of Directors or advisory committees; Pharmacyclics: Other: Educational grant; Virogen: Membership on an entity’s Board of Directors or advisory committees; Takeda: Other: Licensing agreement; Formula Pharma: Membership on an entity’s Board of Directors or advisory committees. Champlin:Takeda: Patents & Royalties; DKMS America: Membership on an entity’s Board of Directors or advisory committees; Genzyme: Speakers Bureau; Actinium: Consultancy; Johnson and Johnson: Consultancy; Omeros: Consultancy; Cytonus: Consultancy. Shpall:Magenta: Membership on an entity’s Board of Directors or advisory committees; Takeda: Other: Licensing Agreement; Novartis: Membership on an entity’s Board of Directors or advisory committees; Celgene: Membership on an entity’s Board of Directors or advisory committees; Zelluna: Membership on an entity’s Board of Directors or advisory committees; Adaptimmune: Membership on an entity’s Board of Directors or advisory committees. Neelapu:Novartis: Other: personal fees; Bristol-Myers Squibb: Other: personal fees, Research Funding; Merck: Other: personal fees, Research Funding; Kite, a Gilead Company: Other: personal fees, Research Funding; Celgene: Other: personal fees, Research Funding; Pfizer: Other: personal fees; Allogene Therapeutics: Other: personal fees, Research Funding; Cell Medica/Kuur: Other: personal fees; Incyte: Other: personal fees; Precision Biosciences: Other: personal fees, Research Funding; Legend Biotech: Other; Adicet Bio: Other; Calibr: Other; Unum Therapeutics: Other, Research Funding; Poseida: Research Funding; Cellectis: Research Funding; Karus Therapeutics: Research Funding; Acerta: Research Funding; Takeda Pharmaceuticals: Patents & Royalties; N/A: Other. Kebriaei:Jazz: Consultancy; Novartis: Other: Served on advisory board; Kite: Other: Served on advisory board; Ziopharm: Other: Research Support; Pfizer: Other: Served on advisory board; Amgen: Other: Research Support.
Background: Compared to other peripheral T cell lymphomas (PTCLs), patients with AITL have an aggressive clinical course and poor outcomes with conventional chemotherapies. Previous studies reported ...overall survival (OS) of <40% at 5 years. Furthermore, the prognostic factors of AITL are not well established, particularly because they are derived from the composite of all types of PTCL. In order to elucidate clinical characteristics and biomarkers with prognostic significance in patients with AITL, we conducted a single institution, retrospective study.
Methods: We performed a retrospective chart review for newly diagnosed AITL at our institution between February 1998 to August 2019. Patients with available clinical data were included in the analysis. Endpoints were progression-free survival (PFS) and OS. Other endpoints were to identify prognostic factors associated with survival. Univariate (UVA) and multivariate (MVA) Cox proportional hazards models were fitted to the data to assess the significance of variables at diagnosis on OS. A landmark analysis was conducted using only patients who achieved a complete remission (CR).
Results: A total of 109 patients with a median age of 66 (range, 28-83) years and female predominance (56%) were identified. Patient and disease characteristics are outlined in Table 1. With a median follow up of 42 (range, 1-232) months, the median PFS and OS for all study patients were 16 and 49 months, respectively, with respective 4-year PFS and OS estimates of 26% and 52%. Fifty-nine (54%) of patients died during the study period. All variables listed in Table 1 were assessed in UVA. Among those factors, age<65, achieving CR to frontline therapy, and receipt of upfront stem cell transplantation (SCT) were associated with improved PFS and OS. The respective 4-year PFS for age <65 vs ≥65 for achieving CR to frontline therapy were 39% and 13% (p=0.0165), vs no CR were 34% and 6% (p<0.0001); the PFS for receipt of upfront SCT vs no SCT vs SCT for relapsed AITL were 57%, 19%, and 0% (p<0.0001) (Figure 1A-C). The respective 4-year OS for age <65 vs ≥65 were of 68% and 38% (p=0.0011), for achieving CR to frontline therapy vs no CR were 61% and 37% (p<0.0001), and for receipt of upfront SCT vs no SCT were 85% and 41% (p=0.0137). A subgroup analysis was performed for 73 patients with available data on CD30 staining. We found a trend for improved OS for patients with positive CD30 (4-year OS 60% vs 30% for negative CD30; p=0.07 (Figure 1D). In MVA we included variables with p<0.15 significance in UVA and excluded Stage I-II disease and CD30 status given small number and missing values, respectively. In MVA, age ≥65 (HR 2.563, 95% CI: 1.419-4.628; p=0.0018), not achieving CR (HR 6.113, 95% CI: 3.048-12.258; p<0.0001), not receiving upfront SCT (HR 2.204, 95% CI: 1.125-4.317; p=0.0212) were associated with worse PFS. Similarly, age ≥65 (HR 2.339, 95% CI: 1.214-4.509; p=0.0111), not achieving CR (HR 2.533, 95% CI: 1.24-5.174; p=0.0107), and not receiving upfront SCT (HR 2.395, 95% CI: 1.009-5.688; p=0.0477) were associated with inferior OS in MVA.
Conclusions: Age <65 years, achieving CR to induction treatment, and upfront autologous SCT are strong predictors for improved PFS and OS. Further, we identified the potential prognostic role for CD30 status, for better OS. Upfront consolidation with SCT improves survival, however as majority of patients with AITL may not be transplant-eligible, it is imperative that novel therapies that disrupt the distinct biology be explored. Additional studies exploring additional prognostic markers will be provided at the annual meeting.
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Parmar:Cellenkos Inc.: Current equity holder in private company, Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties, Research Funding. Nastoupil:Pfizer: Honoraria, Research Funding; Karus Therapeutics: Research Funding; Celgene: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding; Bayer: Honoraria; LAM Therapeutics: Research Funding; Janssen: Honoraria, Research Funding; Gamida Cell: Honoraria; Merck: Research Funding; Novartis: Honoraria, Research Funding; TG Therapeutics: Honoraria, Research Funding; Gilead/KITE: Honoraria. Nieto:Affimed: Consultancy, Other: Grant Support; Novartis: Other: Grant Support; Astra Zeneca: Other: Grant Support; Secura Bio: Other: Grant Support. Hosing:NKARTA Inc.: Consultancy. Lee:Takeda: Research Funding; Oncternal Therapeutics: Research Funding; Seattle Genetics: Research Funding; Celgene: Research Funding; Guidepoint Blogal: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Aptitude Health: Speakers Bureau. Westin:Novartis: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Amgen: Consultancy; Janssen: Consultancy, Research Funding; Morphosys: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Astra Zeneca: Consultancy, Research Funding; Curis: Consultancy, Research Funding; 47: Research Funding; Genentech: Consultancy, Research Funding. Champlin:Actinium: Consultancy; Takeda: Patents & Royalties; Johnson and Johnson: Consultancy; Genzyme: Speakers Bureau; Omeros: Consultancy; DKMS America: Membership on an entity’s Board of Directors or advisory committees; Cytonus: Consultancy. Khouri:Bristol Myers Squibb: Research Funding; Pfizer: Research Funding. Wang:Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Nobel Insights: Consultancy; Dava Oncology: Honoraria; Pulse Biosciences: Consultancy; Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; MoreHealth: Consultancy; Loxo Oncology: Consultancy, Research Funding; Targeted Oncology: Honoraria; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Guidepoint Global: Consultancy; AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Juno: Consultancy, Research Funding; BioInvent: Research Funding; VelosBio: Research Funding; Acerta Pharma: Research Funding; InnoCare: Consultancy; Oncternal: Consultancy, Research Funding; Verastem: Research Funding; Molecular Templates: Research Funding; OncLive: Honoraria; Beijing Medical Award Foundation: Honoraria; Lu Daopei Medical Group: Honoraria; OMI: Honoraria, Other: Travel, accommodation, expenses; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding. Vega:NCI: Research Funding. Neelapu:Celgene: Other: personal fees, Research Funding; Novartis: Other: personal fees; Pfizer: Other: personal fees; Bristol-Myers Squibb: Other: personal fees, Research Funding; Legend Biotech: Other; Precision Biosciences: Other: personal fees, Research Funding; Adicet Bio: Other; Calibr: Other; Cell Medica/Kuur: Other: personal fees; Cellectis: Research Funding; Karus Therapeutics: Research Funding; Acerta: Research Funding; Kite, a Gilead Company: Other: personal fees, Research Funding; Merck: Other: personal fees, Research Funding; N/A: Other; Unum Therapeutics: Other, Research Funding; Poseida: Research Funding; Takeda Pharmaceuticals: Patents & Royalties; Allogene Therapeutics: Other: personal fees, Research Funding; Incyte: Other: personal fees. Flowers:National Cancer Institute: Research Funding; Kite: Research Funding; Leukemia and Lymphoma Society: Membership on an entity’s Board of Directors or advisory committees; Eastern Cooperative Oncology Group: Research Funding; Cancer Prevention and Research Institute of Texas: Research Funding; AbbVie: Consultancy, Research Funding; Bayer: Consultancy; Burroughs Wellcome Fund: Research Funding; TG Therapeutics: Research Funding; Millennium/Takeda: Consultancy, Research Funding; Acerta: Research Funding; Spectrum: Consultancy; Pharmacyclics/Janssen: Consultancy; Karyopharm: Consultancy; OptumRx: Consultancy; Gilead: Consultancy, Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Denovo Biopharma: Consultancy; Celgene: Consultancy, Research Funding; BeiGene: Consultancy; V Foundation: Research Funding. Iyer:Spectrum: Research Funding; Merck: Research Funding; Target Oncology: Honoraria; Afffimed: Research Funding; Seattle Genetics, Inc.: Research Funding; Rhizen: Research Funding; CRISPR: Research Funding; Trillium: Research Funding; Daiichi Sankyo: Consultancy; Curio Biosciences: Honoraria; Legend Biotech: Consultancy.
Micro-Abstract Patients with trisomy 12 (+12) have unique features, but large series better defining this group are lacking. When compared to 516 previously untreated patients with negative ...cytogenetic findings, they showed a higher incidence of thrombocytopenia, other than of Richter transformations and other second cancers, which were their main cause of death. These patients may benefit from increased surveillance for second cancers.
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