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.
Abstract
Introduction. CLL has a highly heterogeneous clinical course. In fact, while some patients experience a very aggressive disease, others may present with an indolent form, and eventually die ...of “other” causes. Here we report the findings of a prospective cohort study evaluating the comorbidities and causes of death in newly diagnosed patients with CLL.
Methods. Clinical information was collected from 1174 patients with newly diagnosed CLL (within 9 months of diagnosis), who consented to participate in a prospectively observational trial with standardized longitudinal follow-up between 01/2002 and 11/2014. All comorbidities were diagnosed before presentation.
Results. Baseline characteristics are shown in the Table. Co-existent health conditions included: cardiac (28% of patients), respiratory (18%), endocrinological (14%), rheumatologic (42%), gastrointestinal (33%), genitourinary (35%), and psychiatric diseases (17%), diabetes (10%), hyperlipidemia (41%), other cancers (20%), stroke (3%), hypertension (40%), venous thromboembolism (3%), substance abuse (5%), sexually-transmitted infections (3%), and obesity (32%). After a median follow up of 4 years, 197 patients died and the cause of death could be accurately determined in 135 patients. Among these, death was due to CLL progression in 69 (51%) patients, infections in absence of CLL progression in 7 (5%), other cancers in 29 (21%), and other comorbid health conditions in 30 (22%).
CLL patients (N = 1174)Number (%), median rangeAge (years)63 23-89Males791 (67)Females383 (33)Rai stage 0604 (51)I-II512 (44)III-IV54 (4)missing4 (1)B2M < 4 mg/dL717 (61)> 4 mg/dL97 (8)missing360 (31)CD49d negative638 (54)positive277 (24)missing259 (22)CD38 < 30%780 (66)> 30%332 (28)missing62 (6)ZAP70 negative650 (55)positive380 (32)missing135 (13)IGHV mutated506 (43)unmutated394 (34)missing274 (24)FISH del13q395 (34)negative173 (14)+12276 (23)del11q90 (8)del17p50 (4)other2 (1)missing188 (16)
Conclusions. Despite the advanced age at CLL diagnosis, the frequent presence of comorbidities, and the indolent nature of the disease, CLL progression is the ultimate cause of death in 51% of newly diagnosed CLL patients, with an additional 26% dying of causes potentially related to CLL, such as infections and second cancers. The influence of comorbidities and other clinical factors at diagnosis (e.g. smoking, Charlson Comorbidity Index) on survival and ultimate cause of death are being abstracted, and will be presented at the meeting.
Citation Format: Paolo Strati, Kari Chaffe, Sara Achenbach, Timothy Call, Neil Kay, James Cerhan, Susan Slager, Tait Shanafelt. Comorbidity and cause of death in patients with chronic lymphocytic leukemia (CLL). abstract. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5267. doi:10.1158/1538-7445.AM2015-5267
Abstract
Introduction: The aim of our study was to evaluate the prognostic significance of our previously developed EpCAM independent RT-qPCR assay for CK-19 mRNA (Stathopoulou et al, Int J Cancer ...2006) and validate its analytical and clinical performance in early breast cancer.
Methods: Quality control on analytical sensitivity and specificity, linearity, intra- and inter-assay reproducibility, and stability of the external standard used for the preparation of the calibration curves was performed. Reproducibility of the assay between our labs was evaluated by analyzing 26 cDNAs. The prognostic significance of the assay in respect to DFI and OS was evaluated by analysing peripheral blood of 179 patients with stage I/II breast cancer postoperatively, before the administration of adjuvant chemotherapy.
Results: The limit of detection (LOD) is 3 copies/reaction and limit of Quantitation (LOQ) 10 copies/reaction. The linear range of the calibration curve was 10-105copies/reaction and the intra- and inter-assay reproducibility are shown below:
CK19 transcriptsReproducibility of the assay (n = 3)copies/reactionIntra-assay RSD (%)Inter-assay RSD (%)101.973.151020.932.241030.450.861040.122.581050.11.52
The inter-lab reproducibility of the assay was evaluated by analyzing 26 cDNA samples in both labs and there was a 100% concordance. During the follow up period (8 years) 32/179 (17.9%) patients relapsed and 18/179 (10%) patients died from the disease. 45/179 (25.1%) samples were found positive for CK-19 and 134/179 (74.9%) negative. In the group of CK-19 positive patients 15/45(33.3%) relapsed and 9/45(20.0%) died while in the group of CK-19 negative patients 17(12.7%) patients relapsed and 9(6.7%) died. Kaplan-Meier analysis showed that CK-19 mRNA positivity was significantly associated with DFI (P = 0.014) and OS (P = 0.051).
Conclusions: This EpCAM independent assay can be used for a high-throughput detection of CTCs in peripheral blood and has prognostic significance in early breast cancer.
Citation Format: Areti Strati, Athina Markou, Aliki Stathopoulou, Stella Apostolaki, Dimitris Mavroudis, Vasilis Georgoulias, Evi S. Lianidou. Analytical and clinical validation of an EpCAM-independent assay for CTC detection in peripheral blood of early breast cancer patients based on Cytokeratin-19 (CK-19) RT-qPCR. abstract. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 373. doi:10.1158/1538-7445.AM2015-373
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e20013
Background: Nivolumab and Pembrolizumab are effective immune checkpoint inhibitor (ICI) therapies targeting PD-1/ PDL-1 immune axis. The drugs are currently approved for ...relapsed/ refractory classical Hodgkin lymphoma (cHL)based on phase I and II trial data. Methods: We conducted a retrospective study of patients (pts) with relapsed refractory cHL treated with ICI therapy at M.D. Anderson Cancer center from 4/2013 to 5/2019 to evaluate the efficacy of this treatment. The responses were assessed using revised response criteria according to the Lugano classification Results: Ninety-two pts treated with nivolumab (66) and pembrolizumab (26) were included. Fifty six pts (63%) were advanced stage at diagnosis, most treated initially with ABVD (88%) and BV-AVD (3%). Seventy percent pts had primary refractory disease or relapsed < 12 months after frontline therapy. At the time of ICI initiation, pts had the following characteristics: median age 35 (range 18-86), extranodal disease - 28 pts (37%), prior BV exposure in 81 pts (89%) with 66% considered BV refractory. Sixty one percent patients were refractory to the last prior line of salvage therapy. Median prior lines of therapy was of 3 (range 1-13) and 53 pts (58%) had a prior HSCT. At a median follow-up time of 20.2 months (range: 1.58 - 55.98 months), median progression free survival was 12.3 months and median overall survival was not reached. Among the 39 patients with no prior transplant, 11 patients who achieved CR with ICI were consolidated with HSCT (autologous - 7 and allogeneic - 4). Of this cohort, 2 pts (1 post auto, 1 post-allo) have relapsed. Five patients in our cohort were treated with an alternative ICI for subsequent relapse; of four patients with response assessment, 3 achieved CR and 1 experienced PD. Conclusions: In this cohort of cHL pts, ICI offered high response rates before and after HSCT supporting the possibility for using ICI earlier in the treatment course for refractory or early relapsed HL.
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8011
Background: Corticosteroids are commonly used for management of severe toxicities associated with chimeric antigen receptor (CAR) T-cell therapy. However, it remains unclear ...whether the dose, duration, and timing of corticosteroid therapy may impact clinical efficacy of CAR T-cell therapy. Methods: This is a retrospective analysis of patients with relapsed or refractory LBCL treated with standard of care axi-cel at MD Anderson Cancer Center, Houston, Texas between 01/2018 and 05/2019 (data cut-off 12/21/2019). Progression-free survival (PFS) was defined as time from axi-cel infusion to progression/death or last follow-up, and the Breslow test was used for comparisons between subgroups. Results: One hundred patients with relapsed or refractory LBCL were included in the study, and 60 (60%) received corticosteroids for management of toxicities after axi-cel infusion. There was no significant difference in baseline tumor burden, disease stage or international prognostic index between the 2 groups. The median cumulative dexamethasone-equivalent dose was 186 mg (range, 8-1803 mg) and the median duration of corticosteroid treatment was 9 days (range 1-30); 45 (45%) patients started corticosteroid treatment between day 0 and 7, and 15 (15%) beyond day 7. After a median follow-up of 10 months (95% CI 8-10 months), median PFS was 8 months (95% CI, 3-13 months), and use of corticosteroids (any dose) showed a trend for association with shorter PFS (6 vs 9 months, p = 0.13). Use of high-dose corticosteroids (Quartiles (Q) 3-4, 195-1803 mg) significantly associated with shorter PFS (2 vs 9 months, p = 0.005). A trend for shorter PFS was observed among patients receiving corticosteroids for a prolonged time (Q3-Q4, 10-30 days) (5 vs 8 months, p = 0.12) and among patients starting corticosteroids within the first 7 days after axi-cel infusion (6 vs 11 months, p = 0.07). At most recent follow-up, 36 patients died, 28 of progression. Median overall survival has not been reached, and was significantly shorter among patients who received corticosteroids (13 vs not reached, p = 0.006). Conclusions: Early and prolonged use of high-dose corticosteroids is associated with early progression and death in patients with LBCL treated with axi-cel. Additional evaluation is needed to understand the mechanism underlying this association.
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